Caffeineornlreport PDF

ADVERSE HEALTH EFFECTS OF CAFFEINE:
REVIEW AND ANALYSIS OF RECENT HUMAN AND ANIMAL

RESEARCH
Final Report
October 27, 2011
Prepared for
Office of Nutrition, Labeling and Dietary Supplements

Office of Food Additive Safety (Task 2008-39)
Center for Food Safety and Applied Nutrition
U.S. Food and Drug Administration
College Park, MD 20740-3835
Prepared by
Sylvia Milanez, Ph.D., D.A.B.T.

Toxicology and Hazard Assessment Group
Environmental Sciences Division
Oak Ridge National Laboratory
Oak Ridge, TN 37831
TABLE OF CONTENTS
LIST OF TABLES....................................................................................................................................................4
PREFACE .......................................................................................................................................................6
SUMMARY .......................................................................................................................................................7
CHAPTER 1. METABOLISM AND DISPOSITION OF CAFFEINE ................................................................11

1A. Caffeine Metabolism and Disposition in Humans.....................................................................11
1B. Effect of Co-Exposure with Other Chemicals on Caffeine Metabolism and Disposition
in Humans..................................................................................................................................18
1C. Metabolism and Disposition of Caffeine in Animals ................................................................27
CHAPTER 2. EFFECTS OF CAFFEINE ON COGNITIVE AND PSYCHOMOTOR FUNCTION ..................31

2A. Effects on Cognitive and Psychomotor Function in Humans....................................................31
2B. CNS Effects of Caffeine in Animals .........................................................................................68
CHAPTER 3. EFFECTS OF CAFFEINE ON SLEEP AND ON SLEEP-DEPRIVED HUMANS......................77
CHAPTER 4. INTERACTION OF CAFFEINE WITH OTHER CHEMICALS..................................................92

4A. Interaction of Caffeine and Ethanol – Human Studies ..............................................................92
4B. CNS Effects of Interaction of Caffeine and Ethanol – Animal Studies.....................................99
4C. Interaction of Caffeine with Common Drugs – Animal and In vitro Studies..........................102
CHAPTER 5. CARDIOVASCULAR EFFECTS OF CAFFEINE......................................................................126

5A. Cardiovascular Effects of Caffeine – Human Studies .............................................................126
5B. Cardiovascular Effects of Caffeine – Animal Studies .............................................................157
CHAPTER 6. EFFECTS OF CAFFEINE ON EXERCISE−RELATED PARAMETERS .................................160

CHAPTER 7. EFFECTS OF CAFFEINE ON BODY WEIGHT, GLUCOSE, LIPIDS, AND ENERGY
USE ..............................................................................................................................................177
7A. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Humans ..............177
7B. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Animals ..............192
CHAPTER 8. DEVELOPMENTAL EFFECTS OF CAFFEINE........................................................................197

8A. Developmental Effects of Caffeine in Humans .........................................................................197
8B. Developmental Effects of Caffeine in Animals .........................................................................214
CHAPTER 9. REPRODUCTIVE EFFECTS OF CAFFEINE ............................................................................220

9A. Reproductive Effects of Caffeine in Humans ..........................................................................220
9B. Reproductive Effects of Caffeine in Animals..........................................................................228
CHAPTER 10. EFFECTS OF CAFFEINE ON BONES AND TEETH .............................................................230

10A. Bone and Dental Effects of Caffeine in Humans.....................................................................230
10B. Bone and Dental Effects of Caffeine in Animals (post-natal exposure)..................................241
CHAPTER 11. EFFECT OF CAFFEINE ON THE KIDNEY, URINARY BLADDER, AND

ELECTROLYTE BALANCE ......................................................................................................244
11A. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance in Humans ......244
11B. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance in Animals ......249
CHAPTER 12. IMMUNOLOGICAL, GI, OCULAR, AND MAMMARY (NON-CANCER) EFFECTS
OF CAFFEINE.............................................................................................................................252
12A. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects in Humans.......................252
12B. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects in Animals ......................259
CHAPTER 13. THE IMPACT OF HUMAN GENOTYPE ON CAFFEINE EFFECTS ....................................262
CHAPTER 14. CAFFEINE GENOTOXICITY ..................................................................................................272
CHAPTER 15. CAFFEINE AND CANCER ......................................................................................................275

15A. Caffeine and Cancer in Humans ..............................................................................................275
15B. Caffeine and Cancer in Animals..............................................................................................290
FUTURE RESEARCH NEEDS ...........................................................................................................................291
REFERENCES ...................................................................................................................................................292
APPENDIX I : FDA WORK ASSIGNMENT # 2008-39 ...................................................................................377
APPENDIX II: FDA REVIEW COMMENTS ON THE DRAFT #1 CAFFEINE REPORT .............................383
APPENDIX III: FDA REVIEW COMMENTS ON THE DRAFT #2 CAFFEINE REPORT............................388

LIST OF TABLES
TABLE 1-1. Caffeine Metabolism and Disposition in Humans ................................................................ 12

TABLE 1-2. Caffeine Metabolism – Summaries of Reviews.................................................................... 17
TABLE 1-3. Metabolic Effects in Humans of Caffeine Co-Exposure with Other Agents ........................ 19
TABLE 1-4. Caffeine Metabolism – Interaction with Other Agents – Summaries of Reviews................ 26
TABLE 1-5. Caffeine Metabolism and Disposition in Animals................................................................ 28
TABLE 2-1. Cognitive and Psychomotor Effects of Caffeine and Caffeine Withdrawal in Humans –
Experimental Studies ........................................................................................................... 35
TABLE 2-2. Cognitive and Psychomotor Effects of Caffeine and Caffeine Withdrawal – Case Reports 56
TABLE 2-3. Cognitive and Psychomotor Effects of Caffeine and Caffeine Withdrawal – Summaries of
Reviews................................................................................................................................ 64
TABLE 2-4. CNS Effects of Caffeine in Animals..................................................................................... 69
TABLE 3-1. Effects of Caffeine on Sleep and on Sleep-Deprived Humans ............................................. 79
TABLE 3-2. Effects of Caffeine on Sleep – Summaries of Reviews ........................................................ 91
TABLE 4-1. Interaction of Caffeine and Ethanol – Human Studies ......................................................... 94
TABLE 4-2. CNS Effects of Co-Exposure of Caffeine with Ethanol – Summary of Reviews................. 98
TABLE 4-3. CNS Effects of Interaction of Caffeine and Ethanol – Animal Studies.............................. 100
TABLE 4-4. Interaction of Caffeine with Common Drugs – Animal and In vitro Studies ..................... 103
TABLE 4-5. Interaction of Caffeine with Receptor Ligands – Animal Studies ...................................... 116
TABLE 5-1. Cardiovascular Effects of Caffeine in Humans – Experimental Studies ............................ 130
TABLE 5-2. Cardiovascular Effects of Caffeine in Humans – Case Reports and Epidemiological
Studies................................................................................................................................ 141
TABLE 5-3. Cardiovascular Effects of Caffeine – Summaries of Reviews ............................................ 152
TABLE 5-4. Cardiovascular Effects of Caffeine – Animal Studies ........................................................ 158
TABLE 6-1. Impact of Caffeine on Exercise−Related Parameters ......................................................... 161

TABLE 6-2. Impact of Caffeine on Exercise−Related Parameters – Summaries of Reviews ................ 175
TABLE 7-1. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Humans.......... 180
TABLE 7-2. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Humans –
Summaries of Reviews....................................................................................................... 191
TABLE 7-3. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Animals ......... 193
TABLE 8-1. Developmental Effects of Caffeine – Human Studies ........................................................ 200

TABLE 8-2. Developmental Effects of Caffeine – Summaries of Reviews............................................ 211
TABLE 8-3. Developmental Effects of Caffeine – Animal Studies ........................................................ 216
TABLE 9-1. Reproductive Effects of Caffeine – Human Studies ........................................................... 223

TABLE 9-2. Reproductive Effects of Caffeine – Summaries of Reviews............................................... 227
TABLE 9-3. Reproductive Effects of Caffeine – Animal Studies........................................................... 229
TABLE 10-1. Effects of Caffeine on Bones and Teeth – Human Studies............................................... 233
TABLE 10-2. Bone and Dental Effects of Caffeine – Summaries of Reviews ....................................... 240
TABLE 10-3. Effects of Caffeine on Bones and Teeth – Animal Studies (Post-Natal Exposure) .......... 242
TABLE 11-1. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Human
Studies .............................................................................................................................. 245
TABLE 11-2. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Summaries
of Reviews ........................................................................................................................ 248
TABLE 11-3. Effects of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Animal
Studies .............................................................................................................................. 250
TABLE 12-1. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Human
Studies .............................................................................................................................. 254
TABLE 12-2. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Summaries
of Reviews ........................................................................................................................ 258
TABLE 12-3. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Animal
Studies .............................................................................................................................. 260
TABLE 13- 1. The Impact of Human Genotype on Caffeine Effects...................................................... 263

TABLE 13- 2. The Impact of Human Genotype on Caffeine Effects – Summaries of Reviews............. 271
TABLE 14- 1. Caffeine Genotoxicity Studies ......................................................................................... 273

TABLE 14- 2. Caffeine Genotoxicity – Summaries of Reviews............................................................. 274
TABLE 15- 1. Caffeine and Cancer – Human Studies ............................................................................ 278

TABLE 15- 2. Caffeine and Cancer – Summaries of Reviews................................................................ 288
TABLE 15- 3. Caffeine and Cancer – Animal Studies........................................................................... 290
PREFACE
The following Report is an evaluation of the toxic effects of caffeine, intended to satisfy
FDA Work Assignment (WA) 2008-39 (see Appendix I). In addition to writing the Report, a
major effort of the WA was developing a Word Access database to capture the published infor-
mation on caffeine. In the database, each study is described in one record, which consists of
fields that can be queried. The fields include subject area, test material(s), effects, species, age,
sex, number of subjects, country of study (human studies), exposure duration, and dose. The da-
tabase was indispensible for managing the large number of published studies, and was used to
generate the tables in this Report.
The studies included in this Report were published in 1994 or later, per the WA, and were
located by searching PubMed and TOXLINE. The search query initially used was: “(methylxan-
thine OR caffeine) AND (dose OR intake) AND (performance OR metabolism OR mood OR
calcium OR bone OR "blood pressure" OR cancer OR smoking OR teen OR adolescent OR im-
mune OR diabetes OR depression OR energy OR vascular OR supplement OR developmental
OR child OR pregnant OR lactating OR genetic OR polymorphism OR disease OR alcohol OR
interact) NOT hyperthermia. This search yielded ~3400 results in PubMed, which were scanned
by title to identify ones that appeared relevant, and these in turn were evaluated by reading the
abstract. In the final tally, ~1600 original studies were included in one Word Access database,
and ~300 reviews were included in a second Word Access database. Publications were consid-
ered in scope if they addressed one or more of the areas listed in WA 2008-39. Studies that were
omitted include the following:
 Studies in which caffeine was not the test material (e.g. studies testing caffeine me-
tabolites and other related materials)
 Studies that were published in a foreign language (unless sufficient information was
present in an English abstract)
 Mechanistic studies that evaluated sub-cellular effects of caffeine
 Studies that primarily addressed beneficial effects of caffeine (such as lowering the
risk of Parkinson’s disease or diabetes)
 Studies in which caffeine was being used therapeutically (e.g. to treat premature in-
fants with apnea; as an adjuvant for anti-cancer therapy or pain relief)
The 1572 original studies and 310 reviews on caffeine that are contained in the two Ac-
cess databases are listed in the “References” section of the document, where the publications that
were cited in the Report are preceded by an asterisk. Some of the studies that had appeared to be
relevant based on the abstract were found to be inappropriate after evaluating the whole publica-
tion.
This Final Report was preceded by two Draft Caffeine Reports. Draft 1 was sent to FDA
on January 26, 2010. ORNL received FDA comments on it July, 2010 (Appendix II). Draft 2
was sent to FDA on May 13, 2011, and FDA comments were received by ORNL on October 7,
2011 (Appendix III).
Final Report date: October 27, 2011

SUMMARY
Caffeine is one of the most widely consumed substances in the world, and scientists from
many countries have investigated its effects. For almost all parameters examined, there was
some inconsistency in the results found among investigators, which is likely due at least in part
to polymorphisms in the CYP1A2 and NAT2 genes, which code for two enzymes critical for caf-
feine metabolism, and differences in adenosine and dopamine receptors, which are involved in
caffeine’s mode of action.
Studies of caffeine pharmacokinetics showed a linear dose-response for up to at least 5

mg/kg/day in healthy adults. Data were conflicting regarding a possible difference between
adults and children, but age did not generally have an impact after 2 years. A number of com-
mon medications and health conditions impair caffeine metabolism and/or disposition, including
oral contraceptives (OC), ibuprofen, ethanol, several quinoline antibiotics, liver disease, preg-
nancy, and malaria. The most common agent that enhances caffeine metabolism is cigarette
smoking, by increasing the activity of the key caffeine-metabolizing enzyme CYP1A2. Caffeine
inhibits the metabolism and/or disposition of substances including several antibiotics and seda-
tives.
Caffeine’s impact on cognitive and psychomotor function was evaluated in many studies,
and intakes as low as 0.4-0.6 mg/kg, as either pure caffeine or in coffee, tea, or energy drinks
(ED), increased alertness and improved mood and psychomotor performance. However, slightly
higher doses (0.7-1.4 mg/kg) were in some studies associated with anxiety, decrements in psy-
chomotor performance, and/or decreased hand steadiness, and anxiety was often reported with
intakes of 2-3 mg/kg (~150-200 mg caffeine). Consumption of 250-500 mg (~4-7 mg/kg) caf-
feine caused more severe effects, including jitteriness, irritability, nausea, poor motor steadiness,
palpitations, and panic attacks in individuals with psychological disorders, in addition to height-
ened anxiety. Individuals who were not caffeine-habituated tended to have more adverse subjec-
tive effects than regular coffee consumers at a given caffeine challenge dose. Case reports of
adults with single day intakes of ~7-17 mg/kg caffeine as coffee, cola, or ED noted effects in-
cluding seizures, metabolic acidosis, tachycardia, and rhabdomyolysis. Based on the consistent
finding of increased anxiety from an intake of ≥2 mg/kg caffeine (~150 mg), 2.0 mg/kg is con-
sidered the LOAEL for psychomotor disturbance from a single dose of caffeine. The corre-
sponding NOAEL is half this amount, or 1.0 mg/kg, based on the infrequent observation of ad-
verse psychomotor effects at this dose. Epidemiological studies were inadequate to determine
effect levels for chronic exposure.
Caffeine had a detrimental effect on sleep quality and/or quantity in children and adults,
and was often intentionally ingested to counter sleepiness and fatigue after prolonged wakeful-
ness, with successful results. Abstinence from caffeine in caffeine-habituated children and adults
resulted in withdrawal symptoms including headache, drowsiness, dysphoric mood, decreased
alertness, fatigue, and a flu-like feeling. The available data were inadequate and/or inappropriate
for derivation of LOAEL or NOAEL values for sleep disturbance or withdrawal symptoms.
A number of studies evaluated the interaction of caffeine with ethanol on cognitive and
psychomotor performance. Most studies found that caffeine partially counteracted some aspects
of ethanol-induced physical or psychological decrements. Caffeine reduced subjects' perception
of headache, weakness, dry mouth, and impairment of motor coordination, but did not signifi-
cantly reduce alcohol-induced deficits in objective motor coordination and visual reaction time,
or alter the breath alcohol concentration. Several cohort prospective and cross-sectional studies
with young adults found that frequent users of EDs consumed more alcohol and were at greater
risk for adverse alcohol-related consequences.
Human studies were not available regarding the interaction of caffeine with commonly
ingested drugs other than ethanol on CNS-related parameters, although numerous animal studies
examined the effects of co-ingesting various drugs with caffeine. Caffeine potentiated the stimu-
lation of locomotor activity of amphetamine, increased self-administration of cocaine and rein-
stated extinguished cocaine-seeking, and potentiated MDMA-induced tachycardia, locomotor
activity, and hyperthermia. Caffeine did not affect the behavioral effects of alprazolam or most
anticonvulsants or anti-depressants, but partially reversed the effects of several diazobenzopines
and sedatives. Mechanistic studies in which caffeine was co-administered with adenosine recep-
tor agonists (adenosine analogs) and adenosine receptor antagonists (caffeine-related com-
pounds) showed that the motor-activating effects of caffeine are mediated by the blockade of
adenosine A1 and A2 receptors, and are inhibited by adenosine and its analogs. Caffeine was
also shown to increase extracellular levels of dopamine and glutamate in the shell of the brain
nucleus accumbens, which may be contribute to caffeine’s psychostimulant effects.
Experimental studies that investigated the cardiovascular effects of caffeine found an in-
crease in systolic and/or diastolic blood pressure (BP) and decreased heart rate (HR) at doses as
low as 1 mg/kg in children and 1.4 mg/kg in adults. In some studies caffeine caused increased
HR at ≥1.8 mg/kg. The dichotomous HR response occurs because caffeine elicits a vagally me-
diated bradycardia by baroreflex activation, but also has a direct cardioacceleratory effect and
can increase HR, especially in people with compromised cardiac function. Stress increased the
effect of caffeine on BP and HR. Caffeine intakes of ≥1.4 mg/kg increased aortic stiffness, in-
creased vascular resistance, decreased cerebral blood flow, and increased plasma epinephrine,
lipids, and renin activity. The effects were typically greater in low users and in older subjects
than in habitual caffeine consumers, and were exacerbated by concurrent hypertension. Caffeine
increased plasma homocysteine levels in most experimental and population studies where it was
evaluated. Epidemiological studies provided inconsistent association of caffeine with BP in
children. All but one of the 14 case-control studies with adults found a positive association of
caffeine intake with increased risk of cardiotoxicity, including myocardial infarction (MI) and
sudden cardiac death. The cohort prospective studies, however, provided conflicting results,
some finding an elevated risk of MI, increased BP, or coronary death from consumption of 6-19
mg/kg/day, but other studies finding no association or an inverse association. Due to the hetero-
geneity of the data, a LOAEL and NOAL cannot be reliably determined for the effect of caffeine
on cardiovascular parameters.
Evaluation of the ergogenic potential of caffeine found that an intake of ≥100 mg (~1.4
mg/kg) slightly improved physical performance with a concomitant increase in BP and HR,
plasma epinephrine and/or norepinephrine, cortisol, glycerol, lipids, and lactic acid. The effects
were seen in both habitual coffee drinkers and non-drinkers, although in some cases a greater
response was seen in non-habituated subjects. Some studies reported adverse effects from a dose
of ≥6 mg/kg, including anxiety, sleep disturbance, tremors, nervousness, agitation, nausea, and
hypokalemia. Thus 6 mg/kg can be considered a LOAEL for these effects in exercising indi-
viduals, and 5 mg/kg a NOAEL. However, adverse effects occurred at lower caffeine intakes in
studies in which exercise was not involved, as discussed elsewhere.
The effects of caffeine on plasma lipids, glucose, and insulin were evaluated due to its
potential effect on heart disease and weight loss; in the latter case caffeine was sometimes given
together with tea catechins. An increased thermogenic response was seen from ingesting as little
as 50 mg pure caffeine (0.7 mg/kg), and increased plasma levels of glucose, insulin, free fatty
acids, and epinephrine, and increased oxygen consumption and energy expenditure were seen
from intakes of ≥2 mg/kg as pure caffeine (e.g., a capsule or dissolved in a liquid), coffee, or an
ED. Epidemiological studies did not show a consistent association between caffeine intake and
blood lipids. Some found an association of caffeine intake with increased plasma triglycerides
and total cholesterol or LDL cholesterol levels for an intake of 1-9 cups coffee/day (~1.5-13 mg
caffeine/kg/day), whereas others found no effect, or only an effect if the coffee was boiled and
not filtered. The decreased insulin sensitivity seen in most studies was not correlated with ad-
verse health effects, in fact, drinking coffee was generally associated with a decreased risk for
type 2 diabetes. The available data were inadequate for derivation of LOAEL or NOAEL values
for caffeine effects on blood lipid levels.
A number of human studies examined the effect of maternal caffeine intake on the fetus.
Coffee was the major source of caffeine in most studies, with minor contributions from tea, so-
das, and chocolate beverages. In South American countries, yerba mate was a major source of
caffeine, as was tea in Japan. There was no evidence of caffeine teratogenicity, but conflicting
results were obtained regarding an increased risk for spontaneous abortion, decreased fetal
growth or birth weight, premature birth, SIDS, decreased placental weight, and childhood behav-
ior problems, with the majority of the studies finding a positive association. Because the overall
human evidence indicates that caffeine intake of >2 cups/day (~3 mg/kg/d) during pregnancy
may be detrimental to the fetus, the LOAEL for fetal toxicity is 3 mg/kg/day, which is about 2
cups of coffee per day, and the NOAEL is 1.5 mg/kg/day (~1 cup of coffee per day). Several
published reviews have recommended maximum daily intakes of 150-300 mg (~2.5-5.0
mg/kg/day) to preclude an increased risk of embryotoxicity.
Caffeine intake has been associated with reproductive toxicity in several epidemiological
studies. Adverse effects included delayed conception or decreased fecundability in non-smoking
men and women and in smoking women, an increased incidence of endometriosis and decreased
menses and cycle length in women consuming ≥5 mg/kg/day, dystocia from an intake of 3-5
mg/kg/day, and altered sex hormone levels from an intake of 1-3 mg/kg/day. Effects in males
included sperm aneuploidy for the X and Y chromosomes, sperm morphology alterations, and
reduced sperm count from an intake of ~1.3-3 mg/kg/day. Conversely, some studies found no
relationship of caffeine intake with various reproductive parameters. Based on an increased risk
for delayed conception, decreased fecundability, endometriosis, sperm DNA double-strand
breaks, and dystocia seen from intakes of 200-300 mg/day, the LOAEL for reproductive effects
for men and women is 4 mg/day (240-280 mg/kg/day), and the NOAEL is 2 mg/kg/day (120-140
mg/day) which was not associated with adverse reproductive effects. Published reviews have
recommended that reproductive-aged women should consume ≤300 mg caffeine/day.
Caffeine increased calcium excretion in men and women from a single intake of 1.5-6 mg
caffeine/kg, and decreased calcium absorption efficiency among all ages, which could be offset
by modest calcium intake. Several cross-sectional studies with children and/or adolescents
showed that intake of ~1-6 mg/kg/day was a risk factor for reduced bone mineral density. De-
creased bone mineral content and/or density was also observed in middle-aged and older women
with an intake of ~2-8 mg/kg/day, and in elderly men who consumed ~3-6 mg/kg/day, reported
as either coffee intake or total caffeine intake. An increased risk of osteoporotic fracture was
seen in middle aged and older men and women with an intake of ~3-6 mg/kg/day, in some cases
only if accompanied by low calcium intake (<700 mg/day). Although some epidemiological
studies found no association of caffeine intake with bone-related parameters, the weight of evi-
dence indicates that caffeine can have an adverse effect on bone integrity. Based on findings of
decreased bone mineral content or density and increased risk of osteoporotic fracture in men and
women who consumed ≥200 mg caffeine/day, 3 mg/kg/day is considered the LOAEL for adverse
effects on bone integrity. The corresponding NOAEL is 1.5 mg/kg/day (100 mg/day or ~ 1 cup
of coffee/day). The data is insufficient to determine whether these values are applicable to
young children.
Increased urination resulted from a single caffeine intake of 3.4-6 mg/kg, although the
diuretic response was diminished by the third day of treatment, and there was no overall effect
on electrolyte balance. Increased caffeine consumption was associated with detrusor instability
in women in a case-control study, and increased frequency of urination of smaller voided vol-
umes and urinary incontinence in pregnant women. Coffee intake increased the voided volume
but did not change the peak flow rate of men. A cross-sectional study with 5-12 year old chil-
dren found that intake of 2-3.6 mg/kg caffeine was not significantly correlated with enuresis, but
did reduce sleep.
Reliable estimates of LOAEL or NOAEL values could not be determined for several
endpoints due to inadequate data. A cross-sectional study of 18-44 year old women found no
association of mastalgia with consumption of caffeinated beverages. An increase in intraocular
pressure was observed after an intake of ~200 mg caffeine/day in subjects with glaucoma or ocu-
lar hypertension, and in a healthy Nigerian population from an intake of 30-50 mg caffeine as
coffee. A cohort study with a 2-year follow-up found an increased risk for primary open-angle
glaucoma with consumption of ≥5 cups/d coffee. Ingestion of caffeinated coffee (3.0 mg caf-
feine/kg), but not decaf (0.2 mg caffeine/kg) aggravated existing gastroesophageal reflux, but
caffeine intake was not associated with an increased risk of duodenal ulcer in men or women, or
of symptomatic diverticular disease in men.
Negative or conflicting results were found regarding the association caffeine intake and
the risk of cancer of the breast, ovaries, kidneys, endometrium, uterus, prostate, stomach, oral
cavity, pharynx, esophagus, pancreas, colon, rectum, lungs, and blood. The only organ for which
a positive association with cancer was consistently seen was the urinary bladder. An increased
risk for cancer was seen in men who consumed ≥1, 4, or 5 cups coffee/day, depending on their
smoking status. Limited human studies found that coffee and/or tea caused genotoxic effects,
and animal studies showed genotoxic effects at much greater doses than ingested by humans.
CHAPTER 1. METABOLISM AND DISPOSITION OF CAFFEINE
1A. Caffeine Metabolism and Disposition in Humans
Topics presented in this section include caffeine pharmacokinetics, the activities of caf-
feine-metabolizing enzymes in various ethnic populations, and the impact of age and gender on
caffeine metabolism and disposition. The metabolic effects resulting from interaction of caffeine
with co-administered chemicals or concurrent medical conditions (e.g. cystic fibrosis; liver dis-
ease, pregnancy, use of OC) are discussed in Section 12B. In general, studies that were con-
ducted only to establish the biotransformation pathway of caffeine are excluded from this sec-
tion.
Many studies examined the effect of caffeine on the key caffeine-metabolizing enzymes
cytochrome P450 1A2 (CYP1A2), arylamine N-acetyltransferase (NAT2 gene), and xanthine
oxidase (XO) among populations. The acetylator phenotype was distributed bimodally (fast or
slow type) in Caucasian populations, but was relatively unimodal in Asian and Arabic popula-
tions. The activity of CYP1A2 was inconsistently higher in males than females, but the activities
of XO and N-acetyltransferase were comparable between the sexes. The age of the subjects did
not generally impact the enzyme activities after age 2, before which, all children were slow N-
acetylators.
Caffeine metabolism and/or clearance were linear up to a dose of at least 5 mg/kg/day in

healthy subjects. Several studies found that the pharmacokinetics were linear up to 11
mg/kg/day, whereas others saw a decline at ≥7 mg/kg/day. It was unclear whether there was a
difference between adults and children in caffeine clearance, as two studies found that clearance
was more rapid in children, whereas one study found it was slightly more rapid in healthy adults.
Studies of which a major focus was the evaluation of some aspect of caffeine metabolism
or disposition in humans are summarized in Table 1-1. Brief summaries of reviews on this topic
are presented in Table 1-2.
TABLE 1-1. Caffeine Metabolism and Disposition in Humans
Study type; Subject age; Test material
Caffeine dose Effects; Comments Reference
country number; sex [condition]
STUDIES WITH CHILDREN
1-d experiment 8-9 yr pure caffeine 100 mg The pattern of recovered urinary metabolites suggested that N3-demethylation is the prin- Akinyinka et
(Nigeria) n=13 (9 M) [2.5 mg/kg] cipal pathway of caffeine metabolism in healthy African children; small amounts of un- al., 2001
changed caffeine, as well as 3,7-dimethyluric acid, 3-methyluric acid and 1,3,7-
dimethyluric acid were recovered. [Assumed BW 40 kg for dose estimate]
1-d experiment n=200 virtual sub- theoretical caf- theoretical In neonates 70% (7/10) of predicted median clearance values were within 2-fold of the Johnson et
(UK) jects M+F feine intake observed values. Corresponding results for infants, children and adolescents were 100% al., 2006
(9/9), 89% (17/19) and 94% (17/18), respectively. Predicted variability (95% CI) was
within 2-fold of the observed values in 70% (7/10), 67% (6/9), 63% (12/19) and 55%
(10/18) of cases, respectively. Accuracy of the physiologically based model incorporated
in the Simcyp software was superior to that of simple allometry, especially in children.
STUDIES WITH ADULTS
1-d experiment 19-39 yr pure caffeine 200 mg Frequency distribution analysis of the metabolic ratios AFMU/1X revealed two distinct Asprodini et
(Greece) n=83 (34 M) [2.9 mg/kg] groups with 66.3% slow acetylators and 33.7% rapid acetylators. No statistical difference al., 1998
was found between slow and fast acetylators in terms of gender, smoking habits and caf-
feine-intake habits.
1-d experiment Adult pure caffeine (100-300 mg) In the three main racial/ethnic groups living in Tunisia (Arabs, Berbers and Numides), the Attitallah et
(Tunisia) n=?? M+F [1.4-4.3 mg/kg] frequency of slow acetylators appeared identical and NAT-2 activity as a whole was low- al., 2000
er in Tunisians than in Caucasians.
1-d experiment Adult pure caffeine 100 mg CYP1A2 activity was low for G-3113A polymorphism and haplotype pairs 5, 8, 9, 12, Chen et al.,
(China) n=27 M+F [1.4 mg/kg] and 15, but was high for haplotype pairs 10 and 13 in Chinese subjects. 2005
1-d experiment Adult pure caffeine; 100 mg In the quercetin-treated group, CYP1A2 activity was decreased by 10.4%, whereas in- Chen et al.,
(China) n=12 M quercetin [1.4 mg/kg] creases were observed in CYP2A6 (by 25.3%), NAT2 (by 88.7%) and XO activity (by 2009
15.0%). Plasma C(max) and the AUC(0-24 h) of 1,7-dimethylxanthine were decreased by
17.2% and 16.2%, respectively. The urinary excretion of 1,7-dimethylxanthine and 1-
methylxanthine was significantly decreased by 32.4% and 156.1%, respectively. The uri-
nary excretion of 1,7-dimethylurate and 1-methylurate was increased by 82.9% and
97.8%, respectively. No changes were observed in the urinary excretion of caffeine and 5-
acetylamino-6-formylamino-3-methyluracil. These results indicate that quercetin inhibits
CYP1A2 function, but enhances CYP2A6, NAT2 and XO activity.
1-d experiment 22-46 yr pure caffeine 150-200 mg The urinary NAT2 ratios before and after caffeine intake correlated well in 65 volunteers; Jetter et al.,
(Germany) n=77 (60 M) [2.1-2.9 mg/kg] NAT2 genotyping, done in 41 volunteers using four SNPs, corroborated the phenotyping 2004
results.
1-d experiment Adult pure caffeine [49 2.1, 4.3, 8.6 A significant (p< 0.05) and disproportional increase occurred in the dose-normalized caf- Kamimori et
(USA) n=37 M hr sleep depriva- mg/kg feine AUC and a decrease in its clearance was associated with increasing dose. The par- al., 1995
tion] axanthine to caffeine ratio decreased with an increase in dose, indicating that the rate of
caffeine metabolism decreased.
1-d experiment 18-35 yr caffeine in chew- 50, 100, 200 mg The rate of caffeine absorption from the chewing gum formulation was significantly faster Kamimori et
(USA) n=84 M ing gum [0.7, 1.4, 2.9 than the capsule. al., 2002
mg/kg]
1-d experiment 20-46 yr pure caffeine 250, 500 mg Pleasant subjective effects at 250 mg and unpleasant at 500 mg (anxiety, irritability, nau- Kaplan et al.,
(USA) n=12 (5 M) [3.6, 7.1 mg/kg] sea, palpitations); enhanced performance on digit symbol substitution test and tapping 1997
speed test at 250 mg was greater than at 500 mg; EEG changes at both doses; metabolism
impaired at 500 mg.
1-d experiment 43 ± 8 yr pure caffeine; 400 mg Capsule (pure caffeine) was absorbed somewhat slower and its peak concentration was Liguori et al.,
(USA) n=13 M+F coffee; cola [5.7 mg/kg] lower, than from coffee or cola. 1997a
1-d experiment 28-46 yr pure caffeine; 144 mg in cap- Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min Mumford et
(USA) n=7 (3 M) chocolate; cola sules (split following both capsule treatments. Relative to capsules, caffeine absorption from cola and al., 1996
dose); 72 mg in chocolate was delayed and produced lower maximum caffeine plasma concentrations
cola, 72 mg in which peaked 1.5-2.0 hr after treatment. [The chocolate also contained 370 mg theobro-
chocolate [1.0, mine]
2.1 mg/kg]
1-d experiment Mean ~34 yr coffee 2 tb instant cof- The putative low risk phenotype for transitional cell carcinoma of the urinary bladder Muscat et al.,
(USA) n1=165 (82 M); fee (150 mg) (slow CYP1A2/rapid NAT2) was more common in blacks than in whites (25% vs. 15%); 2008
n2=183 (89 M) [2.1 mg/kg] no significant racial differences in slow and rapid CYP1A2 phenotypes, or in the slow
NAT2/rapid CYP1A2 phenotype. [No info on caffeine content; estimated 75 mg caffeine
per tb instant coffee]
1-d experiment 18-66 yr pure caffeine; 114 mg Human CYP1A2 gene point mutation in 5'-flanking region caused decreased CYP1A2 Nakajima et
(Japan) n1=50 smokers; instant coffee; [1.6 mg/kg] activity in Japanese smokers; mutant allele frequency was 0.23. al., 1999
n2=66 non- smoking [CYP
smokers M+F 1A2 mutation]
1-d experiment 17-90 yr pure caffeine 1 cup tea or cof- Five metabolic ratios claiming to reflect CYP1A2 activity were determined to be symmet- Notarianni et
(UK) n=237 M+F fee [0.6, 1.4 rically distributed, but did not correlate with each other [No info on caffeine per cup; al., 1995
mg/kg] assumed 100 mg/cup coffee; 40 mg/cup tea]
1-d experiment 18-23 yr pure caffeine 300 mg A 16-fold variation of CYP1A2 activity was found; coefficient of variation was 62.9%. Ou-Yang et
(China) n=229 (120 M) [4.3 mg/kg] Non-normal distribution of CYP1A2 activity showed 5.24% were poor CYP1A2 metabo- al., 2000
lizers; overall, men had higher CYP1A2 activity than women.
1-d experiment 49.0 ± 10.7 yr no caffeine -- no caffeine - CYP1A2 F21L and F186L polymorphisms [formerly CYP1A2(*)2 and (*)11 alleles] Pucci et al.,
(Italy) n=500 M+F DNA sequencing DNA sequenc- were absent in 500 Italian healthy subjects. 2007
ing
1-d experiment 19-85 yr pure caffeine 100 mg FMO3 (flavin monooxygenase 3) amino acid variants K158, G308, and M257 were found Sachse et al.,
(Germany) n=204; c=192 [FMO3 polymor- [1.4 mg/kg] and linkage analysis revealed 7 different alleles; subjects with these variants did not differ 1999b
M+F phism; schizo- in clozapine N-oxidation or caffeine oxidation compared with the wild-type.
phrenia]
1-d experiment 18-65 yr cola 46 mg Found 92.2% slow and 7.8% rapid acetylators in 51 urine samples from 61 Hmnong sub- Straka et al.,
(Minnesota n=51 (27 M) [0.7 mg/kg] jects living in Minnesota; a urinary caffeine metabolic ratio AFMU/1X (<0.6) was used to 2006
Hmong) classify subjects as slow acetylators.
1-d experiment 18-35 yr caffeine in chew- 150, 300, 600 (in Dose normalized C(max) and AUC(0-tau) values across doses were not significantly dif- Syed et al.,
(USA) n=48 (28 M) ing gum 3 doses) [2.1, ferent, suggesting linearity after multiple doses of the Stay Alert chewing gum. There 2005
4.3, 8.6 mg/kg] were no group-related differences in elimination.
1-d experiment mean 39 yr coffee 0.46 ± 0.38 L/d CYP1A2 activity was lower in OC users and residents of Bulgaria and Slovakia (than Tantcheva-
(Bulgaria; Slo- n=786 (371 M) (204 mg ± 169 Germany), and was higher in cigarette smokers. Poor et al.,
vak Republic; mg/d caffeine) 1999
Germany) [2-4 mg/kg]
1-d experiment Adult coffee; tea 1 cup Single locus control of N-acetyltransferase activity, with recessive allele for the homozy- Vincent-Viry
(France) n=281 M+F [1.4 mg/kg] gous slow phenotype; slow allelic frequencies were 0.739, 0.753, and 0.724, respectively, et al., 1994
phenotypic concordance was 90 to 92% with the AFMU/1X ratio. [No info on caffeine
per cup; assumed 100 mg/cup]
1-d experiment 18-50 yr pure caffeine 2 cups (~200 CYP1A2 did not show functionally significant polymorphism; the wide interindividual Welfare et
(UK) n=92 (43 M) mg) [2.9 mg/kg] variation in activity may be due to environmental factors. al., 1999
2- d experiment 59.2 ± 11.5 yr pure caffeine; tea, daily: 6 g green The mean excretion of urinary hippuric acid during black tea and green tea consumption Mulder et al.,
(The Nether- n=17 M black; tea, green tea solids, 6 g was 3.75 ± 0.28 mmol/24 hr and 4.22 ± 0.28 mmol/24 hr, respectively. The hippuric acid 2005
lands) black tea solids, excretion during the pure caffeine control treatment was much lower (1.89 ± 0.28
360 mg caffeine mmol/24 hr).
2-d experiment 20-70 yr pure caffeine; tea, 360 mg caffeine; Green and black tea ingestion resulted in similar increases in urinary excretion of hippuric Van Dorsten
(The Nether- n=17 M black; tea, green 6 x 1g tea sol- acid and 1,3-dihydroxyphenyl-2-O-sulfate; several unidentified aromatic metabolites were et al., 2006
lands) ids/d detected in urine after green tea intake; green tea increased urinary excretion of several
[5.1 mg/kg/d] citric acid cycle intermediates (6 x 1g tea solids/d =12 cups tea/d or 360 mg caffeine)
12-d experiment 21-35 yr pure caffeine 100 mg Human hepatic CYP1A2 activity may be assayed as the caffeine metabolic ratio (CMR) Kall et al.,
(Denmark) n=16 (14 M) [1.4 mg/kg/d] value. Broccoli increased CYP1A2 activity, as the mean CMR value increased by 19% (P 1996
< 0.0005) after 12 d on the broccoli diet. The average increase in the CMR, however,
covered a 0-82% inter-individual range of induction.
Cross-sectional 18-86 yr pure caffeine; 100 mg Gender had no effect on CYP1A2, CYP2C19, or CYP2E1 activity; CYP2C19 activity Bebia et al.,
(USA) N=161 (79 M) age; sex decreased with age; and CYP2E1 activity increased with age and developed earlier in life 2004
in M than F.
Cross-sectional 20-91 yr pure caffeine; 1 cup coffee or Arylamine N-acetyltransferase (NAT2) slow acetylation (58.9%) in German unrelated Cascorbi et
(Germany) n=844 M+F geno- coffee 100 mg tablet population; 6.7% of the cases deviated in genotype and phenotype; all mutant alleles al., 1995
typed; subset of [1.4 mg/kg] showed low in vivo acetylation capacities [1 cup assumed = 100 mg]
563 phenotyped
Cross-sectional ~57 ± 11 yr caffeine, all 200-400,>400 The adenosine A2A receptor (ADORA2A) genotype, but not the CYP1A2 genotype, was Cornelis et
(Costa Rica) n=2735 (~80% M) sources mg/d [2.9 to associated with the amount of habitual caffeine intake, particularly among current smok- al., 2007
[ADORA2A, >5.7 mg/kg/d] ers; those with the ADORA2A genotype TT were more likely to consume less caffeine
CYP-1A2 geno- than carriers of the C allele.
type]
Cross-sectional Adult Coffee; sex; 1 cup Smoking had the strongest impact on CYP1A2 activity, while gender (higher in men) and Gunes et al.,
(Turkey) n=146 M+F smoking [1.4 mg/kg] CYP1A2 haplotype H4 (higher activity) showed marginal effects [No info on caffeine 2009
content of cup of coffee; assume 100 mg/cup]
Cross-sectional 45 yr (n=146 F) caffeine, all 132-213, 93-193 In pre-menopausal F (not post-menopausal), CYP1A2 activity was positively related to Hong et al.,
(Canada) pre-menopausal; sources mg/d in pre- and insulin levels, caffeine intake, age, and plasma triglyceride levels, and negatively related 2004
56 yr (n=149 F) post-menopausal with total cholesterol levels and body mass index.
post-menopausal [1.5-3.6
mg/kg/d]
Cross-sectional Adult caffeine, all ≤0.8, 0.8-2.5, The weighted kappa coefficient between strata of caffeine intake and quartiles of serum Klebanoff et
(USA) n=239 F sources; smoking 2.5-5.0, >5 paraxanthine was 0.58 among smokers and 0.53 among nonsmokers, versus 0.44 and al., 1998
mg/kg/d 0.51, respectively, for quartiles of serum caffeine. The Pearson correlation coefficient
between intake and paraxanthine was 0.50 for smokers and 0.53 for nonsmokers, and 0.37
and 0.51, respectively, for serum caffeine. These values are comparable to the correlation
between reported smoking and serum cotinine in pregnancy.
Cross-sectional Adult pure caffeine; 150 mg Found that 11.0% of subjects were slow acetylators; 11.0% of subjects were poor XO Saruwatari et
(Japan) n=182 (108 M) smoking metabolizers; CYP1A2 was not polymorphic, but its mean ratio was greater in smokers. al., 2002
AUC=area under the curve; CMR= caffeine metabolic ratio; EEG=electroencephalograph; NAT2=N-acetyltransferase; OC=oral contraceptive; XO=xanthine oxidase
TABLE 1-2. Caffeine Metabolism – Summaries of Reviews Reference
The major enzyme involved in the biotransformation of caffeine and its metabolites is CYP1A2, a cytochrome P450. Since the contribution of CYP1A2 to Tang and Ka-
systemic caffeine clearance is estimated to be more than 95% of the total, clearance is the "gold standard" for an index of CYP1A2 activity for most subjects. low, 1996
Other enzymes with contributions to caffeine metabolism are CYP2E1 (the ethanol-inducible cytochrome P450), the polymorphic N-acetyltransferase, xan-
thine oxidase, and, to a minor extent, CYP3A4 and CYP2A6.
CYP1A2 becomes active in the fourth to fifth postfetal months in humans. Oesterheld,
1998
Enzyme activity is low immediately after birth, increases, then peaks at the young/mature adult level and, finally, decreases in old age (drugs catalyzed by Tanaka, 1998
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A3/4).
A 24-hr urine collection after a caffeine dose allows quantification of the metabolites excreted; the ratios of selected metabolites can be used to classify the Crews et al.,
volunteers into fast, intermediate or slow caffeine metabolizers by CYP1A2 phenotype. 2001
When ingested orally, caffeine is rapidly absorbed, distributes throughout total body water (including the fetus), and reaches a peak plasma level in 30-75 Mandel, 2002
minutes. In the human, slightly more than 80% of administered caffeine is metabolized by demethylation to paraxanthine via liver cytochrome P-450 1A2,
and about 16% is converted to theobromine and theophylline. Clearance is ~ 1-3 mg/kg/min in both men and women after low-dose caffeine intake. With
higher caffeine doses, clearance is diminished, largely because of saturable metabolism of paraxanthine and its decreased clearance. Earlier it was believed
that the action of caffeine was related to the inhibition of phosphodiesterase, leading to increased concentrations of cyclic AMP. However, this inhibition
requires caffeine dosages much higher than those consumed through beverages or foods. A more likely mechanism, following the intake of low doses of
caffeine, involves antagonism of adenosine receptors which are present in brain, blood vessels, kidneys, heart, the GI tract and the respiratory tree.
There is wide inter-individual variation in caffeine metabolism, primarily due to variations in CYP1A2 enzyme activity. Some variability in CYP1A2 activ- Lawson and
ity is due to genetic polymorphisms in the CYP1A2 gene. Considerable evidence exists that maternal caffeine metabolism is influenced by a variety of en- LeMasters,
dogenous and exogenous factors and studying the genetic polymorphisms may improve understanding of the potential effects of caffeine and its metabolites 2005
on perinatal outcomes.
Caffeine and theobromine are two important constituents of kola nuts. Although limited biological data are available for kola nut extract specifically, the Burdock et
published data of the major constituents of kola nuts suggest the pharmacological/ toxicological properties of kola nut extract parallel those of a roughly al., 2009
equivalent dose of caffeine. Frank developmental/reproductive effects have not been reported and changes in offspring cannot be extrapolated to humans. A
NOEL/NOAEL cannot be defined for repeated oral exposure to kola nut extract from available data.
Phenotyping using caffeine as a probe substrate may still provide useful assessment of CYP1A2, NAT2, XO and CYP2A6 activities in epidemiologic and Kh Hankooz,
drug-drug interaction studies despite the limitations that are associated with its use. 2009
1B. Effect of Co-Exposure with Other Chemicals on Caffeine Metabolism and Disposition
in Humans
In healthy adults, caffeine pharmacokinetics was not significantly affected by treatment

with a number of agents [bromocriptine (dopamine agonist), dextromethorphan (anesthetic), cre-
atine, grapefruit juice, ofloxacin and rufloxacin (quinolone antibiotics), polychlorinated biphen-
yls (PCBs)]. A number of concurrent conditions had no apparent impact on caffeine metabolism
or disposition (menstrual cycle, diabetes, Down’s syndrome, obesity). The effect of exercise was
not consistent among studies, one finding that it reduced the caffeine half-life, but another report-
ing a slowing in caffeine catabolism.
A number of commonly taken medications were found to impair caffeine metabolism

and/or disposition, due to decreased metabolic enzyme activity, increased caffeine area under the
curve (AUC) or half-life, and/or reduced clearance. These included OC and the quinoline antibi-
otics ciprofloxacin, enoxacin, fleroxacin, ibuprofen, norfloxacin, ofloxacin, remafloxacin, and
pipemidic acid. Others were allopurinol (XO inhibitor), cimetidine (histamine receptor antago-
nist), disulfiram (prevents dopamine breakdown), ethanol, estrogen, fluvoxamine (antidepres-
sant), furafylline (CYP1A2 ligand), methoxsalen (psoriasis treatment), and propafenone (anti-
arrhythmic). Medical conditions that impaired caffeine metabolism were liver disease (e.g., cir-
rhosis), pregnancy, heat dehydration, malaria, obesity, and sleep deprivation.
The most commonly used agent that enhances caffeine pharmacokinetics is cigarette
smoking. Smoking increased the activity of the key caffeine-metabolizing enzyme CYP1A2,
reduced the caffeine plasma half-life and volume of distribution, and enhanced its clearance.
Caffeine metabolism and/or disposition were also increased by ingesting Brassica vegetables
(e.g. cabbage), inhaling automobile exhaust (containing PAHs), and treatment with phenytoin
(anti-epileptic) and rifampin (antibiotic). Antipyrine (analgesic) enhanced caffeine metabolism
in one study, but had no effects in another.
Caffeine itself is capable of disrupting the metabolism and/or disposition of a number of

substances. These include the quinoline antibiotics ciprofloxacin and fleroxacin (which them-
selves inhibit caffeine metabolism), sulfamethazine (antibiotic), clozapine (anti-psychotic), di-
azepam (anxiolytic), fluvoxamine (anti-depressant), halofantrine (anti-malarial), melatonin, mex-
iletine (anti-arrhythmic), phenylpropanolamine (CNS stimulant), and zolpidem (hypnotic).
Studies that evaluated the metabolic effects of co-administration of caffeine with another
agent are summarized in Table 1-3. Brief summaries of reviews on this topic are presented in
Table 1-4.
TABLE 1-3. Metabolic Effects in Humans of Caffeine Co-Exposure with Other Agents
Study type; Co-exposure var-
country iable
1-d experiment cystic fibrosis 35 mg Mild cystic fibrosis did not alter the activities of CYP1A2, NAT2, XO, or CYP2D6 in children, by Kennedy et al.,
(USA) [1.2-2.3 mg/kg] use of standard caffeine and dextromethorphan (0.5 mg/kg) phenotyping methods [Assumed BW 15- 2004a
30 kg for dose estimates]
1-d experiment liver disease 3 mg/kg Caffeine metabolism was impaired in children with liver disease. Baker et al.,
(UK) 1995
1-d experiment liver disease 2 mg/kg Liver disease in pediatric subjects significantly reduced the salivary clearance of caffeine and the ac- el-Yazigi et al.,
(Saudi Arabia) tivity of cytochrome P4501A2, but had no impact on the activities of NAT2 and XO. 1999
1-d experiment malaria 300 mg Caffeine metabolism was impaired in children with malaria. [Assumed BW 50-70 kg for dose esti- Akinyinka et al.,
(Nigeria) [4.3-6.0 mg/kg] mates] 2000b
1-d experiment malaria, kwashi- 3.3-6.5 mg/kg The elimination half-life of caffeine was significantly longer in children with malaria (9.2 ± 3.5 hr) Akinyinka et al.,
(Nigeria) orkor (p< 0.01) and kwashiorkor (13.1 ± 7.9 hr) (P < 0.05) than in the healthy controls (3.7 ± 1.8 hr). 2000a
[Group intakes and doses: 40 mg (3.6-5.6 mg/kg) kwashiorkor; 100 mg (3.3-6.2 mg/kg) malaria; 100
mg controls (3.4-6.5 mg/kg)]
1-d experiment overweight 11 mg (4 oz Coca- XO activity was elevated in pediatric obese volunteers compared to non-obese pediatric volunteers Chine et al.,
(USA) Cola) (p<0.001). NAT2 activity was 5-fold higher in the obese as compared to non-obese children (p<0.05). 2011
[0.2 mg/kg] However, no difference was observed in CYP1A2 activity between the groups (p>0.05)
1-d experiment overweight 2.5 mg/kg XO activity was elevated in pediatric obese volunteers compared to non-obese pediatric volunteers Zielinska et al.,
(Poland) (p< 0.001). NAT2 activity was 5-fold higher in the obese vs. non-obese children (p< 0.05). No differ- 1999
ence was observed in CYP1A2 activity between the groups.
STUDIES WITH ADULTS
1-d experiment alcoholic cirrho- 200 mg Caffeine metabolism was reduced by half in patients with alcoholic cirrhosis, mainly due to decreased Bechtel et al.,
(France) sis [2.9 mg/kg] CYP1A2 activity. 2000a
1-d experiment alcoholism; liver 3.25 mg/kg Caffeine clearance was lower in subjects with abnormal liver function tests; NAT2 genotype status Kukongviriya-
(Thailand) disease did not apparently affect the PX/CA ratio. pan et al., 2004
1-d experiment antipyrine (100-200 mg) Caffeine metabolism was enhanced by 1000 mg antipyrine. Soto and Alsar,
(Spain) 1997
country iable
1-d experiment artemisinin (and 136.5 mg Thiabendazole and artemisinin inhibited 92 and 66%, respectively, of the CYP1A2 enzyme activity in Bapiro et al.,
(Tanzania) thiabendazole) vivo; caffeine had increases in AUC(0-24) of 1.6-fold (P < 0.01) and 1.3-fold in the presence of thia- 2005
bendazole and artemisinin, respectively.
1-d experiment automobile exhaust 180 mg Caffeine metabolism enhanced by automobile exhaust (containing polycyclic aromatic hydrocarbons) Wittayalertpanya
(PAH) et al., 2003
1-d experiment Brassica and api- 200 mg Brassica vegetables increased and apiaceous vegetables decreased cytochrome P450 1A2 activity. Lampe et al.,
(USA) aceous vegetables [2.9 mg/kg] 2000
1-d experiment carbamazepine; 3 mg/kg Carbamazepine (200-600 mg/d) increased the % labeled caffeine exhaled as carbon dioxide. Parker et al.,
(UK) epilepsy 1998
1-d experiment cimetidine 300 mg Caffeine metabolism impaired by cimetidine (1 g/d). Soto et al., 1995
(Spain)
3-d experiment ciprofloxacin 100 mg 3x/d Caffeine inhibited metabolism of ciprofloxacin (500 mg 2x/d for 3 d); ciprofloxacin inhibited caffeine Kim et al., 2003
(USA) metabolism; differences between the sexes disappeared when AUC and C(max) were normalized to
BW.
1-d experiment clozapine 400-1000 mg/d Clozapine (12.5 mg) metabolism was impaired by caffeine in non-smokers. Hägg et al., 2000
(Norway)
1-d experiment clozapine ad libitum Clozapine metabolism was impaired by caffeine. Raaska et al.,
(Finland) 2004
1-d experiment cystic fibrosis 46 mg CYP1A2, N-acetyltransferase, and 8-hydroxylation were similar in patients and controls, but patients Hamelin et al.,
(Canada) [1.2-2.3 mg/kg] had higher xanthine oxidase activity. [Assumed BW 20-40 kg for dose estimates] 1994
1-d experiment cystic fibrosis 3 mg/kg The cumulative percentage of labeled caffeine exhaled as carbon dioxide measured over two hours Parker et al.,
(UK) was significantly higher in the patients with cystic fibrosis than in controls. 1997
1-d experiment estrogen; post- 200 mg After 8 weeks of estrogen replacement therapy, caffeine metabolic ratios were reduced 29.2±25.0% Pollock et al.,
(USA) menopausal (or -38.2±14.2% if exclude 2 subjects who had exogenous caffeine) 1999
1-d experiment ethanol 400 mg The AUC for caffeine was significantly higher when administered with alcohol. Azcona et al.,
(Spain) 1995
3-d experiment fleroxacin 100 mg 3x/d Caffeine inhibited metabolism of fleroxacin (400 mg/d for 3 d); fleroxacin inhibited caffeine metabo- Kim et al., 2003
(USA) lism; differences were seen between the sexes that disappeared when AUC and C(max) were normal-
ized to BW.
country iable
1-d experiment fluvoxamine 250 mg Caffeine metabolism impaired by fluvoxamine (100 mg 4x/d over 2 d); CNS changes Culm-Merdek et
(USA) al., 2005
2-14 d experiment fluvoxamine 300 mg/d Fluvoxamine (50 mg) metabolism was impaired by caffeine. Fukasawa et al.,
(Japan) 2006
1-d experiment fluvoxamine 200 mg Caffeine metabolism was impaired by fluvoxamine (50 mg per day for 4 d and 100 mg/d for 8 d) Jeppesen et al.,
(Denmark) 1996
1-d experiment FMO3 polymor- 100 mg FMO3 (flavin monooxygenase 3) amino acid variants K158, G308, and M257 were found and linkage Sachse et al.,
(Germany) phism; schizo- [1.4 mg/kg] analysis revealed 7 different alleles; subjects with these variants did not differ in clozapine N- 1999b
phrenia oxidation or caffeine oxidation compared with the wild-type.
1-d experiment grapefruit juice 3.3 mg/kg Grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamics; BP increase. Maish et al.,
(USA) 1996
1-d experiment halofantrine 12.5 g kola nut Halofantrine HCl (500 mg) metabolism was impaired by caffeine. Kolade et al.,
(Nigeria) 2008
1-d experiment heat dehydration 4.9+/-0.1 mg/kg Caffeine metabolism was impaired. Chambaz et al.,
(Switzerland) 2001
1-d experiment ibuprofen 200 mg Ibuprofen (800 mg) inhibited the renal excretion of caffeine metabolites, creating the appearance of Vrtic et al., 2003
(Switzerland) increased N-acetyltransferase activity
1-d experiment liver disease 280 mg Patients with liver cirrhosis had significantly lower paraxanthine/caffeine ratio which correlated with Perlík et al.,
(Czech Republic) [4.0 mg/kg] lowered elimination of caffeine. 2001
1-d experiment liver disease 200 mg During the recovery period, in viral but not drug-induced hepatitis, caffeine metabolism and bio- Bechtel et al.,
(France) [2.9 mg/kg/d] chemical tests returned to the normal values. 2000b
1-d experiment liver disease 200 mg Caffeine metabolism was impaired in persons with liver disease, but improved after a liver transplant. Bechtel et al.,
(France) [2.9 mg/kg] 2001
1-d experiment liver disease (100-200 mg) Liver patients had 3-fold greater caffeine t1/2; caffeine metabolism impaired. Calatayud et al.,
(Spain) 1995
1-d experiment liver disease 300 mg Elimination of caffeine was decreased in cirrhotics compared to healthy volunteers: clearance, elimi- Jodynis-Liebert
(Poland) [4.3 mg/kg] nation coefficient, and half-life and serum metabolite/caffeine ratios were reduced by >80%, TB/CA et al., 2004
by 50% to 70%, and TP/CA by 40% to 70%. The reduction of the ratios in chronic hepatitis patients
was lower and did not occur at all time points.
country iable
1-d experiment liver disease 178.0 ± 84.3 mg/d Caffeine metabolism was impaired. Mizuno et al.,
(Japan) 1996
1-d experiment liver disease; 2 mg/kg Caffeine metabolism was impaired by liver disease (noncirrhotic chronic hepatitis B or C; cirrhosis) Park et al., 2003
(Australia) smoking but enhanced by cigarette smoking.
1-d experiment liver disease (100-300 mg) Caffeine metabolism was impaired in persons with liver disease, compared to healthy subjects. Tangkijvanich et
(Thailand) [1.4-4.3 mg/kg] al., 1999
1-d experiment liver disease ~200 mg Total overnight salivary caffeine in cirrhotic patients was higher than in controls and could differenti- Tarantino et al.,
(Italy) [2.9 mg/kg] ate the type of cirrhosis; rapid caffeine metabolizers more frequently had had cirrhosis of metabolic 2006
origin.
1-d experiment liver disease 3.5 mg/kg Caffeine clearance and elimination in decompensated cirrhotic patients were significantly lower than Wittayalert-
(Thailand) those in compensated cirrhotic patients and much lower than in normal subjects (p<0.01). Caffeine panya et al.,
clearance in chronic hepatitis patients was also significantly lower than in normal subjects. The vol- 1996
ume of distribution of caffeine in compensated and decompensated cirrhotic patients and normal sub-
jects were significantly different. There was also a significant difference between normal subjects and
the chronic hepatitis group.
1-d experiment Liver disease 200 mg CYP1A2 activity was decreased but XO and mainly CYP2A6 activities were increased in primary Lelouet et al.,
(France) [2.9 mg/kg] biliary cirrhosis patients; clear-cut bimodal distribution in NAT-2 index, most patients being fast ace- 2001
tylators.
1-d experiment liver disease; 150 mg Caffeine clearance and elimination were slower in liver patients; smoking increased both parameters. Shyu et al., 1996
(Taiwan) smoking
1-d experiment malaria-induced 3.5 mg/kg Hepatic microsomal metabolism of caffeine is apparently slow in severe falciparum malaria but re- Wilairatana et
(Thailand) liver impairment verts to normal in convalescence. Liver metabolic function does not appear to be significantly af- al., 1994
fected in uncomplicated malaria.
1-d experiment melatonin 200 mg Melatonin (6 mg) metabolism was impaired; CYP1A2*1A allele homozygotes had greater effect than Härtter et al.,
(Finland) those with *1F/*1F or *1F/*1A genotypes. 2006
1-d experiment melatonin; smok- 3 x 200 mg Melatonin (6 mg) metabolism was impaired by caffeine; inhibitory effect of caffeine was greater in Härtter et al.,
(Finland) ing nonsmokers and those with the *1F/*1F CYP1A2 genotype. 2003
1-d experiment menstrual cycle 300 mg The menstrual cycle phase did not significantly alter caffeine pharmacokinetics in women. Kamimori et al.,
(USA) phase [4.3 mg/kg] 1999
Cross-sectional menstrual cycle 2 mg/kg Median coefficients of variation for CYP1A2, NAT2 extensive and poor metabolizers, and XO ratios Kashuba et al.,
(USA) phase were 16.8% (4.5-49.3%), 2.9% (2.2-4.7%), 13.4% (7.5-27.2%), and 4.5% (2.3-13.0%). 1998
country iable
30 d-experiment menstrual cycle mean 149 mg/d CYP1A2 activity did not differ between menstrual cycle phases; there was long-term fluctuation of Zaigler et al.,
(Germany) phase [2.1 mg/kg/d] CYP1A2 activity in most individuals. 2000
1-d experiment menthol 200 mg Menthol (100 mg) delayed caffeine absorption and blunted the heart-rate slowing effect of caffeine, Gelal et al., 2003
(Turkey) but did not affect caffeine metabolism.
1-d experiment mexiletine 100 mg 4x/d Mexiletine HCl (200 mg) metabolism was impaired by caffeine. Labbé et al.,
(Canada) 1999
1-d experiment OC 200 mg Caffeine metabolism was decreased in non-smoking women using OC. Petersen et al.,
(Denmark) 2006
1-d experiment OC (100-200 mg) Caffeine metabolism impaired; acetylator fast/slow identified. Tang et al., 1994
(Canada)
1-d experiment OC 200 mg Compared with pretreatment values, the clearance of caffeine was reduced by about 54% and 55% Balogh et al.,
(Germany) [2.9 mg/kg] after one treatment cycle with gestodene-containing and the levonorgestrel-containing OC, respec- 1995
tively; caffeine tmax and Cmax, were not affected. Clearance values returned to pretreatment values 1
month after the last dose of the OC.
1-d experiment OC; smoking 200 mg CYP1A2 ratio was higher in M and in smokers, but lower in F using OC; these effects were not seen Rasmussen and
(Denmark) for the N-acetyltransferase or XO ratio. Brøsen, 1996
1-d experiment OC; smoking; eth- (100-200 mg) CYP1A2 activity was lower in OC users and residents of Bulgaria and Slovakia, and was higher in Tantcheva-Poór
(Germany, etc.) nicity smokers. et al., 1999
1-d experiment pregnancy 100 mg During pregnancy maternal CYP1A2 activity decreased (33-65%), [these were not found using caf- Tracy et al.,
(USA) [1.4 mg/kg] feine as a substrate: CYP2D6 activity increased (26-48%), and CYP3A activity increased (35%- 2005
38%)]
1-d experiment propafenone 300 mg Caffeine metabolism was impaired by propafenone (300 mg). Michaud et al.,
(Canada) 2006
1-d experiment quercetin 100 mg In the quercetin-treated group, CYP1A2 activity was decreased by 10.4%, whereas increases were Chen et al.,
(China) [1.4 mg/kg] observed in CYP2A6 (by 25.3%), NAT2 (by 88.7%) and XO (by 15.0%) activities. Plasma C(max) 2009
and the AUC(0-24 h) of 1,7-dimethylxanthine were decreased by 17.2% and 16.2%, respectively. The
urinary excretion of 1,7-dimethylxanthine and 1-methylxanthine was decreased by 32.4% and
156.1%, respectively. The urinary excretion of 1,7-dimethylurate and 1-methylurate was increased by
82.9% and 97.8%, respectively. No changes in urinary excretion of caffeine and 5-acetylamino-6-
formylamino-3-methyluracil. Thus quercetin appears to inhibit CYP1A2 function, but enhance
CYP2A6, NAT2 and XO activities.
country iable
1-d experiment rifampin 300 mg Caffeine metabolism was enhanced by treatment with rifampin (600 mg/d for 21d). Soto et al., 1996
(Spain)
1-d experiment smoking 148 mg Caffeine metabolism was enhanced. Faber and Fuhr,
(Germany) 2004
Cross-sectional smoking ≤0.8, 0.8-2.5, 2.5- The weighted kappa coefficient between strata of caffeine intake and quartiles of serum paraxanthine Klebanoff et al.,
(USA) 5.0, >5 mg/kg/d was 0.58 among smokers and 0.53 among nonsmokers, versus 0.44 and 0.51, respectively, for quar- 1998
tiles of serum caffeine. The Pearson correlation coefficient between intake and paraxanthine was 0.50
for smokers and 0.53 for nonsmokers, and 0.37 and 0.51, respectively, for serum caffeine. These val-
ues are comparable to the correlation between reported smoking and serum cotinine in pregnancy.
1-d experiment smoking 200 mg Caffeine metabolism was increased in all smokers. Petersen et al.,
(Denmark) 2006
3-d experiment smoking 60, 120 mg/d CYP1A2 activity was increased (194 and 203% by the two sodas), compared to 179% by smoking. Ryu and Chung,
(Korea) 2003
Cross-sectional smoking 150 mg Found that 11.0% of subjects were slow acetylators; 11.0% of subjects were poor XO metabolizers; Saruwatari et
(Japan) CYP1A2 was not polymorphic, but its mean ratio was greater in smokers. al., 2002
1-d experiment smoking 3, 5 mg/kg Caffeine metabolism enhanced; the data fit a one-compartmental model with first-order absorption Seng et al., 2009
(Singapore) and elimination.
1-d experiment Smoking; 114 mg Human CYP1A2 gene point mutation in 5'-flanking region decreased CYP1A2 activity in Japanese Nakajima et al.,
(Japan) CYP1A2 mutation [1.6 mg/kg] smokers; mutant allele frequency was 0.23. 1999
1-d experiment smoking; ethanol 3 mg/kg Caffeine metabolism enhanced; ethanol (≤0.3 L/d) and smoking effect on metabolism were not evalu- Terziivanov et
(Bulgaria) ated separately. al., 2003
1-d experiment smoking; OC 200 mg CYP1A2 activity was higher in men, in smokers, and in women not taking OC; comparison of twins Rasmussen et
(Denmark) yielded heritability estimate of 0.725. al., 2002
1-d experiment Smoking; P450 100 mg Overall 46% were homozygous for variant A, 44% were heterozygous, and 10% were homozygous Sachse et al.,
(Germany) CYP1A2 gene [1.4 mg/kg] for variant C. The 5 hr plasma 17X/caffeine ratios in non-smokers did not differ between the three 1999a
mutation CYP1A2 genotypes. In the smokers, there were significant differences in the 5 hr plasma
17X/caffeine ratios between the genotypes. The mean ratio was 1.37 in carriers of the A/A genotype,
0.88 in heterozygotes and 0.82 in carriers of C/C. The mean difference between A/A and C/A groups
was 0.48 (0.15-0.81; p=0.01).
1-d experiment smoking; pregnant 100 mg Caffeine metabolism was enhanced by smoking in pregnant women. Nordmark et al.,
(Sweden) 1999
country iable
1-d experiment Smoking; race; sex 100 mg The 4-hr plasma 17X/137X ratio (CYP1A2 activity) was higher in Swedes (1.5x) than Koreans, and Ghotbi et al.,
(Korea; Sweden) [1.4 mg/kg] in smokers, and was lower in OC users; no gender effect. 2007
Cross-sectional Smoking; sex; 1 cup Smoking had the strongest impact on CYP1A2 activity, while gender (higher in men) and CYP1A2 Gunes et al.,
(Turkey) [1.4 mg/kg] haplotype H4 (higher activity) showed marginal effects [No info on caffeine content of cup of coffee; 2009
assume 100 mg/cup]
1-d experiment zolpidem 250, 500 mg Zolpidem (7.5 mg) metabolism was impaired by caffeine in non-smokers; caffeine clearance was in- Cysneiros et al.,
(USA) dependent of dose and unaffected by zolpidem; caffeine partially reversed zolpidem sedating effects. 2007
AUC=area under the curve; BP=blood pressure; BW=body weight; NAT2=N-acetyltransferase; OC=oral contraceptive; XO=xanthine oxidase
TABLE 1-4. Caffeine Metabolism – Interaction with Other Agents – Summaries of Reviews Reference
Decreased clearance in women using OC and during pregnancy; obesity, exercise, diseases, smoking, drug interactions affect elimination by stimulation or Arnaud, 2011
inhibition of CYP1A2; metabolic pathways differ in animals and man; diet (broccoli, herbal tea, alcohol) modifies caffeine pharmacokinetics.
Caffeine is metabolized by the CYP1A2 enzyme and can interact with a wide range of psychiatric medications, including antidepressant agents, antipsy- Broderick et al.,
chotic agents, antimanic agents, antianxiety agents, and sedative agents. These interactions may lead to caffeine-related or medication-related side effects 2005
that may complicate psychiatric treatment.
PBPK models for caffeine and theophylline simulated the large differences in half-life and clearance between neonates and adults, and reproduced the faster Ginsberg et al.,
metabolic clearance of theophylline relative to caffeine in neonates (due primarily to an extra metabolic pathway available to theophylline, back-methylation 2004a
to caffeine).
Age-related changes have been observed for caffeine and theophylline metabolism. Studies with caffeine and antipyrine indicate that this change in drug Lane and Connor,
disposition occurs over a short period of time, is seen earlier in girls than in boys, and is related to pubertal (Tanner) stage and the "growth spurt". 1994
In human volunteers, hyperbaric or hyperoxic or both conditions together did not affect the disposition of caffeine. Rump et al., 1999
1C. Metabolism and Disposition of Caffeine in Animals
Studies with animals examined various aspects of caffeine metabolism and disposition, as
well as the impact of co-treatment of caffeine with other substances of interest. Caffeine me-
tabolism was non-linear (i.e., affected by dose) in rats fed ad libitum, but was linear in food-
limited rats up to a dose of 20 mg/kg i.v., 40 mg/kg i.p., and 38 mg/kg in the drinking water
(Smith et al., 1999a; Lau et al., 1995). Caffeine induced a number of metabolic enzymes, includ-
ing CYP1A1/1A2 (Goasduff et al., 1996; Berthou et al., 1995; Ayalogu et al., 1995; Bu-Abbas et
al., 1998; Kokwaro et al., 1996), adenosine deaminase (Bandyopadhyay and Poddar, 1994),
CYP1A2-dependent O-methoxyresorufin demethylase (Chen et al., 1996), glutathione S-
transferase, arginase (Ofluoglu et al., 2009), acetylcholinesterase (da Silva et al., 2008), and
UDP-glucuronosyl transferase (Bu-Abbas et al., 1998).
Caffeine metabolism and/or disposition were inhibited by treatment with alprazolam

(Lau et al., 1997a; Lau and Wang, 1996), oxamniquine (Kokwaro and Indalo, 1996), the antide-
pressants imipramine and amitriptyline (Kot et al., 2007), and the anti-psychotic perazine (Wo-
jcikowski and Daniel, 2009). However, several compounds enhanced caffeine metabolism, in-
cluding the antidepressants fluoxetine, nefazodone, sertraline, and mirtazapine (Kot et al., 2007),
as well as the organic compounds phenobarbital, β-naphthoflavone; pregnenolone carbonitrile,
and ethanol (Kot and Daniel, 2007). Caffeine increased metabolism of pyrazinamide (Meh-
medagic et al., 2002), but had no effect on fluoride metabolism in rats (Chen and Whitford.,
1994).
Animal studies of which the major focus was the evaluation of some aspect of caffeine
metabolism or disposition are summarized in Table 1-5.
TABLE 1-5. Caffeine Metabolism and Disposition in Animals
Species; Exposure Test material; Caffeine
Effects; Comments Reference
condition time route dose(s)
Rat 28 d black tea; black 2.5. 5.0, Glutathione S-transferase and UDP-glucuronosyl transferase activities were increased but hepatic cata- Bu-Abbas et
tea decaffeinated; 7.5% lase activity was inhibited. al., 1998
green tea (DW)
Rat, lactat- 7, 14, 21 d pure caffeine 1 g/L Caffeine was not able to change the age-dependent increase of acetylcholinesterase activity or the age- da Silva et al.,
ing (PND 0-7, (DW) dependent decrease of acetylcholinesterase expression. However, caffeine promoted an increase of 2008
0-14, 0-21) acetylcholinesterase activity (42%) without modifications of the level of acetylcholinesterase mRNA
transcripts in 21-day-old rats.
Rat 1 day pure caffeine (ga- 30, 100 Brain tissue and/or serum arginase activity and malondialdehyde levels decreased and serum nitric Ofluoglu et al.,
vage) mg/kg oxide levels increased at both doses. 2009
Rat 3d pure caffeine (ga- 150 Data suggest that caffeine increased its own metabolism through P4501A induction. Berthou et al.,
vage) mg/kg/d 1995
(split dose)
Rat 3d pure caffeine (ga- 50, 150 Caffeine increased its own metabolism in a dose-dependent manner and induced CYP1A1/1A2 expres- Goasduff et al.,
vage) mg/kg/d sion through either transcriptional activation or mRNA stabilization. 1996
Rat 1 day pure caffeine (i.p.) 10, 50 At 10 mg/kg, there was a nearly 2-fold difference between brain cortex and striatum caffeine concen- Carey and De-
mg/kg trations (smaller difference at 50 mg/kg). Palma, 1994
Rat, chron- 1 day; 11 d pure caffeine (i.p.; 10-40 Food-limited rats given 10-40 mg/kg i.p. had serum caffeine, but not its metabolites, proportional to Lau et al., 1995
ic food- DW) mg/kg i.p.; dose. Steady state for all was reached after 11 days at 20 mg/kg; non-linear kinetics seen with ad lib
limitation 9-38 intake in DW.
mg/kg DW
Rat, food- 1 day pure caffeine (i.v.) 1- 20 In food-limited rats, caffeine pharmacokinetic parameters were dose independent following iv doses of Smith et al.,
limited mg/kg 1-20 mg/kg; the caffeine AUC increased linearly as a function of dose. The mean fraction of caffeine 1999a
converted to paraxanthine, theobromine, and theophylline was 16%, 16%, and 7%, respectively.
Rat 1 day pure caffeine 10, 20 Adenosine deaminase activity was increased in spleen and thymus, not liver; dose-response seen. Bandyop-
(oral) mg/kg/d adhyay and
Poddar, 1994
Rat 14 d pure caffeine 0.1, 0.2, Increased hepatic CYP1A2, and at the highest dose only, CYP2B apoprotein; no effect on erythromy- Ayalogu et al.,
(oral?) 0.3% cin N-demethylase, p-nitrophenol hydroxylase and lauric acid hydroxylase activities, or total cyto- 1995
chrome P450 content.
Rat 7d pure caffeine (s.c.) 25 mg/kg Increased plasma clearance and volume of distribution from evening dosing; disrupted daily rhythmic- Pelissier-Alicot
ity for locomotion, body temperature, and HR. et al., 2002
Rat 1, 3, 7 d; pure caffeine; 100 mg/kg Green tea (2%) or black tea (2%) given for 21 d in the DW caused a 2.4- or 2.7-fold induction, respec- Chen et al.,
21 d black tea; green green tea; tively, of CYP1A2-dependent O-methoxyresorufin demethylase (MROD) activity in liver microsomes. 1996
tea; green tea de- 2%; black Treatment with caffeine (0.04%) also resulted in a 1.9-fold increase in the MROD activity, but decaf-
caffeinated (DW; tea; 2%; feinated green tea (0.8%) did not cause such an induction. Rats treated with green tea (2%) or caffeine
gavage) caffeine (0.055%) in the DW for 1, 3, and 7 d, or with 100 mg/kg by gavage had a 1.7- to 2.1-fold induction of
MROD activity. The induced MROD activity corresponded to the increase in liver microsomal
CYP1A2 protein. Close correlation of the increase in the MROD activity was observed only with the
plasma caffeine level, not with the combined tea polyphenol level. This study establishes caffeine as an
inducer of CYP1A2 and demonstrates that caffeine, not tea polyphenols, is the component in tea re-
sponsible for the induction of this enzyme.
Rat 1 day pure caffeine; al- 5, 10, 20 Alprazolam pharmacokinetics was not altered by caffeine, but alprazolam slowed caffeine absorption Lau et al.,
prazolam (gavage) (+A), 30 and decreased methylxanthine levels. Alprazolam was more potent than caffeine in decreasing rein- 1997a
(+A) 40, forcement rate.
80, 120
mg/kg
Rat 1 day pure caffeine; al- 5, 10 (+ No acute tolerance was observed for either drug or their combinations; they did not interact in the be- Lau and Wang,
prazolam (i.p.) A), 20 havior-time profiles (DRL 45-s); pharmacokinetics of alprazolam was not altered by caffeine, but those 1996
(+A) 40, of caffeine were affected by alprazolam.
80, 120
mg/kg
Rat 1 day pure caffeine; cof- 3.0 mg/kg Decaffeinated coffee and caffeine had no effect on fluoride metabolism; caffeinated coffee appeared to Chen and
fee; fluoride (ga- increase the initial absorption rate but not the 4-hour bioavailability. Whitford, 1994
vage)
Mouse 1 day pure caffeine; flu- 10 mg/kg Fluvoxamine inhibited the activity of CYP1A2 as indicated by a 40% reduction in the clearance of a 10 Thomsen et al.,
voxamine (i.p.?) mg/kg dose of caffeine. 1995
Mouse 1 day pure caffeine; 5.1 µg Oxamniquine inhibited the metabolism of caffeine, catalyzed by cytochrome P450 1A2(CYP1A2). Kokwaro and
oxamniquine (i.p.) Indalo, 1996
Mammal- 1 day pure caffeine; mM Perazine at its therapeutic concentrations was a potent inhibitor of human CYP1A2 and caffeine me- Wojcikowski
ian cell perazine (in vitro) tabolism. and Daniel,
culture 2009
29
Rat liver 1 day pure caffeine; 100, 800 β-naphthoflavone (CYP1A inducer) potently accelerated the metabolism of caffeine, whereas pregne- Kot and Dan-
micro- phenobarbital; β- µM nolone-16alpha-carbonitrile, phenobarbital, and ethanol were modest inducers. iel, 2007
somes naphthoflavone;
ethanol (i.p.)
Rat 1 day pure caffeine; py- 50, 100, Administration of 100 mg/kg caffeine + 50 mg/kg pyrazinamide increased excretion of the metabolite Mehmedagic et
razinamide (oral) 150 mg/kg 5-hydroxypyrazinoic acid (5-OH-PA). This effect was more pronounced at 100 mg/kg pyrazinamide. al., 2002
Rat 1 day Pure caffeine; imi- 800 μM The antidepressants imipramine and amitriptyline decreased caffeine metabolism, while fluoxetine, Kot et al., 2007
pramine; amitrip- nefazodone, sertraline and mirtazapine enhanced caffeine metabolism in liver microsomes of treated
tyline; fluoxetine; rats.
nefazodone; ser-
traline; mirtaza-
pine (i.p.)
30
CHAPTER 2. EFFECTS OF CAFFEINE ON COGNITIVE AND
PSYCHOMOTOR FUNCTION
2A. Effects on Cognitive and Psychomotor Function in Humans
The effect of caffeine on cognitive and psychomotor function was evaluated in numerous
studies, perhaps more so than any other parameter. This is not surprising, since the caffeine psy-
chostimulant effects are the primary reason why most humans consume caffeinated beverages.
The majority of the human studies were experimental, and evaluated the effect of a single dose
of pure caffeine (i.e., given as a capsule or as caffeine dissolved in a liquid). A few one or two-
week experimental studies were also conducted, primarily to examine caffeine dependence
and/or withdrawal effects. A number of case reports and epidemiological studies were also
available. The latter consisted primarily of cross-sectional studies, in which caffeine was typi-
cally ingested in coffee, tea, and carbonated drinks [“cola” or “energy drink” (ED)]. A few stud-
ies evaluated the effects of caffeine ingested as guarana or cocoa powder.
In the single-dose experimental studies, the lowest dose of caffeine that could be dis-
criminated from a placebo was 1.8 mg (Mumford et al., 1994). An intake as low as 12.5 mg pure
caffeine (~0.2 mg/kg) improved mood and cognitive performance (Smit and Rogers, 2000), and
intakes of 30-40 mg (0.4-0.6 mg/kg) as either pure caffeine or in coffe, tea, or EDs, increased
alertness and improved mood and psychomotor performance (Quinlan et al., 2000; Smit et al.,
2006; Mucignat-Caretta et al., 1998; Smith, 2009b). However, consumption of as little as 50-
100 mg (0.7-1.4 mg/kg) caffeine was associated with increased anxiety, decrements in psycho-
motor performance, and/or decreased hand steadiness in some subjects compared to placebo (Bo-
tella and Parra, 2003; Rogers et al., 2003; Lesk et al., 2009; Richardson et al., 1995; Urso-
Baiarda et al., 2007). Anxiety was often reported to result from intakes of 2-3 mg/kg (~150-200
mg caffeine) (Flaten and Blumenthal, 1999; Smith et al., 2006; Alsene et al., 2003; Brice and
Smith, 2002), with a report of visual disturbances (Coren, 2002), increased hand tremor (Huma-
yun et al., 1997), and impaired motor learning (Mednick et al., 2008). In many other studies,
however, adverse psychomotor effects were not seen from similar intakes (e.g., Smit and Rogers,
2000; Quinlan et al., 2000; Own et al., 2008; Howard and Marczinski, 2010; Warburton, 1995).
This discrepancy is not surprising since some people are known to be more sensitive to the ef-
fects of caffeine than others. This is likely due to polymorphisms in the genes coding for the
adenosine and dopamine receptors, which mediate the effects of caffeine (Childs et al., 2008), as
well as the CYP1A2 and NAT2 genes, which code for two enzymes important for caffeine me-
tabolism.
Intakes of 250-500 mg (~4-7 mg/kg) caused more severe effects, including jitteriness, ir-
ritability, nausea, poor motor steadiness, palpitations, and panic attacks in individuals with psy-
chological disorders, in addition to heightened anxiety (Rogers et al., 2008; Kaplan et al., 1997;
Bovim et al., 1995; Scott et al., 2002; Masdrakis et al., 2009; Nardi et al., 2007a, 2007b, 2008).
Based on the consistent finding of increased anxiety from an intake of ≥2 mg/kg caffeine (~150
mg), this dose is considered the LOAEL for psychomotor disturbance from a single dose of caf-
feine. The NOAEL is considered to be half this amount, or 70 mg/kg, based on the infrequent
observation of adverse psychomotor effects at this dose. The data used to determine the NOAEL
and LOAEL are plotted below, with the study authors shown along the top X-axis.
ENDPOINT: Anxiety (single-dose human studies with caffeine)
Al ith al. 200 att , 1 94

,1 4
4
9
Sm h e a l . n d a t t , 1 7
se et , 2 2 ig 99
99
00
a s t a B ig 0
t , B ig 9
N sh e atz nd att 20
19 4
M lds t a , 20 it, 2 06
06
C s a W , 2 06
Yo tl a t a l 2 0 0 9 8 , 2
C ds nd ar , 2 03
C ilds nd Par , 2 03
C ds d W , 2 03
C ilds nd e Wit, 2 03
., 00
98
Ar tt e et a ., 1 97 2
0
ille e l., 08 0
hi e d i 0
o e , 9 e
te an P , 19 4
ra 4
a f r a B n,
hi a P r a 0
ra 0
hi a d r a 0
0
o s l 9 0
og e l. , 5
al , 2
M er al. , 1 be
Bo l l a d a r 9
Bo ella and al. 199
C ella and Par , 2
Sc er t a , 1 20
R lan et a ith 99
N en atz nd so
N iero and 200 08

Ar ero l. , 2 7
Ka lan d S al., 3
et a n
Pe ler e al. 20 8
H l i n al . 19 9 8
te h 9
t
ag t l . s
Ka e a d e . , 2 0 6
ci t a l. 99
p n t 0
as g , 5
a fr d 5
un nd ., 1 9
as fr a w
., 2
m 1
2
il t l., 0
e t , 0
gs D i 9 9
D i e t a O rm
, 0
ic r l 0
H e n an 19 9
Pr ne al 00
t ,
dt m
M re a 0
H sen atz Da
Bo lla e l.
Br cha et a 20
2
te ein t a
e
e
h a d
s
hi e l .
Bo nst in e
e
t
t
h a
r e
Be nst
d
p
l
l
l
ar
r
c
it
Be
1.0E+02 Study author(s) No Effect
Non-SS increase in
anxiety
Dose (mg caffeine/kg BW)
1.0E+01 Significant increase

in anxiety
LOAEL for anxiety LOAEL
1.0E+00 NOAEL for anxiety NOAEL
1.0E-01
1.0E-02
IL ;
ad D ;
a d t;
a d lt;
a d lt;
t;
a d lt;
a d lt;
a d lt;
a d t;
a d lt;
a d t;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
a d lt;
ad ;
a d lt;
a d t;
a d lt;
a d lt;
ad ;
a d t;
a d lt;
a d t;
CHILD
u lt
u lt
ul
ul
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ul
ul
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u
u
CH
Case reports of adults with single day intakes of ~7-17 mg/kg caffeine as coffee, cola, or
ED noted effects including seizures, metabolic acidosis, tachycardia, and rhabdomyolysis (Tra-
bulo et al., 2011; Iyadurai and Chung, 2007; Mortelmans et al., 2008). One individual who in-
gested >10 g caffeine tablets (~143 mg/kg) had convulsions, cardiac arrest, and died, despite
medical treatment (Shum et al., 1997), whereas another who ingested a similar amount had nau-
sea, vomiting, cardiovascular collapse, but survived with medical treatment (Kapur and Smith,
2009). A number of case reports concerned individuals with psychological disorders, whose
condition deteriorated after caffeine intake of ~2.4-14 mg/kg/day caffeine for one or more days,
with effects such as manic episodes, insomnia, aggression, delusions, paranoia, and seizures
(Kaufman and Sachedo, 2003, Machado-Vieira et al., 2001; Chelben et al., 2008; Caykoylu et
al., 2008; Boniha and Li, 2004).
Epidemiological studies showed an increased frequency of headaches, premenstrual anx-

iety, and mood changes in women from chronic intake of ~4 mg/kg/day (Scher et al., 2004; Gold
et al., 2007) and in men and women from an intake of 4 or 7 mg/kg/day (Hagen et al., 2009;
Boardman et al., 2006). Chronic caffeine intake was associated with greater cognitive ability in
older adults, or with smaller cognitive decline over time in some studies, whereas others found
no significant effect (Hameleers et al., 2000; Kyle et al., 2010; Ritchie et al., 2010; Laitala et al.,
2009; van Boxtel et al., 2003).
32
Individuals who were not caffeine-habituated tended to have more adverse subjective ef-
fects than regular coffee consumers at a given caffeine challenge dose. Objective measures
(cognitive performance, BP) were similar in the two groups in some studies, but others found
that habituated subjects performed better on cognitive assays, especially at the beginning of the
test. A few investigators asserted that caffeine beneficial effects were merely a reversal of caf-
feine withdrawal (headache, drowsiness, dysphoric mood, decreased alertness, fatigue, and flu-
like feeling) (James, 1995; James and Gregg, 2004a). This theory, however, was shown to be
invalid, as caffeine induced similar, albeit in some cases of lower magnitude, cognitive and psy-
chomotor (and other) changes in habituated and non-habituated subjects (e.g., Smith et al., 2005;
2006).
The effect of caffeine in naïve children was examined in two experimental studies. Barry
et el. (2009) found that 80 mg caffeine (~1.6-2.7 mg/kg) increased skin conductance and altered
EEG activity in 8-13 year old children. Bernstein et al. (1994) found that 2.5 and 5.0 mg/kg caf-
feine improved some measures of cognitive performance in 8-12 year old children, but also
caused feelings of anxiety. Other experimental studies with children examined the effect of caf-
feine on children habituated to caffeine. These studies found that a daily intake of ≥1 serving (≥
0.6 mg/kg/d) was associated with increased fatigue during the day and poor sleep (Orbeta et al.,
2006), as well as caffeine dependence. The latter was manifested as fatigue, dysphoric symp-
toms, and poorer performance on cognitive tests in the absence of caffeine (Hale et al., 1995;
Heatherly et al., 2006; Bernstein et al., 1998; Goldstein and Wallace, 1997).
An abstract describing nine cases (age 13-46 years) of individuals who consumed 250-
500 mg caffeine (~4-11 mg/kg) as an ED containing vinpocetin and yohimbine, reported effects
including nausea, vomiting, tachycardia, jitteriness, anxiety, tremors, dizziness, chest pain, bilat-
eral numbness, and increased BP (Walsh et al., 2006). A serving of caffeine (not quantified;
likely 1-2 mg/kg/d) caused an increase in tics in two related boys aged 11 and 13 years (Davis
and Osorio, 1998) and in a group of Tourette syndrome patients aged 5-72 years (Muller-Vahl et
al., 2008). Epidemiological studies with children showed that chronic daily intake of one or
more servings per day (≥1 mg/kg/day) was associated with anxiety, fatigue, sleep problems, rest-
lessness, headaches, and depressive symptoms (Whalen et al., 2008; Oberstar et al, 2002; Bern-
stein et al., 2002; Hering-Hanit and Gadoth, 2003; Luebbe and Bell, 2009; Fulkerson et al., 2004;
Ghandour et al., 2004; James et al., 2010; Milde-Busch et al., 2010). The findings of one study
suggested that younger children are more sensitive to CNS stimulation by caffeine, as 10-12-year
olds ingesting ~ 2-3 mg/kg/day caffeine (as colas) had more psychological and stimulating ef-
fects than 15-17-year olds (Luebbe and Bell, 2009). The available data do not, however, allow a
definitive conclusion regarding the sensitivity to caffeine adverse effects of children vs. adults.
A number of experimental studies examined the effect of caffeine on brain activity.

Techniques used included electroencephalography (EEG), in which event-related potentials are
evaluated, and functional magnetic resonance imaging (fMRI), in which fluctuations in the blood
oxygenation level dependent (BOLD) signal are used to assess functional connectivity between
different brain regions. Caffeine treatment resulted in changes consistent with increased arousal,
from an intake as low as 40 mg (~0.6 mg/kg), and the response was dose-related for doses up to
33
~8 mg/kg, for both habitual and non-habitual caffeine users (e.g., Rao et al., 2005; Specterman et
al., 2005; Chen and Parrish, 2009a; Seidl et al., 2000; Watters et al., 1998).
Experimental studies of which the primary focus was investigating the cognitive and psy-
chomotor effects of caffeine are summarized in Table 2-1, and the respective case reports and
epidemiological studies are presented in Table 2-2. Brief summaries of conclusions drawn by
authors of reviews concerning the cognitive and psychomotor effects of caffeine are presented in
Table 2-3. Hughes and Hale (1998) concluded that >3 mg/kg caffeine can cause effects includ-
ing nervousness, jitteriness, stomachaches, and nausea in children, but that it also slightly im-
proves vigilance performance in those who habitually consume little caffeine. Similar effects in
children were described by Pennington et al. (2010). The increased sensitivity to caffeine-
induced anxiety and/or psychotic symptoms of individuals with psychological disorders was not-
ed by several authors (Smith, 2002; Broderick and Benjamin, 2004; Winston et al., 2005; Lara,
2010; Boison, 2011; Seifert et al., 2011). The involvement of adenosine receptors in caffeine’s
mode of action was discussed (Fisone et al., 2004; Bastia and Schwarzschild, 2003; Ferre, 2010;
Rossi et al., 2010). Juliano and Griffiths (2004) concluded that caffeine withdrawal should be
considered as a disorder, as it consists of specific identifiable effects. Meltzer et al. (2008) de-
termined NOEL and LOEL values of 0.3 and 1.0-1.3 mg/kg body weight, respectively, for toler-
ance development, and a LOAEL of 2.5 mg/kg bw for anxiety and jitteriness for children and
adolescents in Nordic countries.
34
TABLE 2-1. Cognitive and Psychomotor Effects of Caffeine in Humans – Experimental Studies
Caffeine dose(s) Effects; Comments (sorted by exposure duration, then dose) Reference
1-d experiment 11-15 yr caffeinated 33 mg Across-subjects ratings of depression, drowsiness, and fatigue were increased on non- Hale et al.,
(USA) n=18 M+F drink, carbon- [0.5-0.8 mg/kg] caffeinated compared with caffeinated soda sampling days. Results are similar to research in 1995
ated adults showing that 31–36% of coffee drinkers reliably self-administer caffeine and experience
adverse effects from abstinence. [Assumed BW 40-60 kg for dose estimates]
1-d experiment 9-11 yr caffeine, all 50 mg After overnight fast, 50 mg caffeine improved high consumers (109 mg/d) accuracy on a cogni- Heatherley
(UK) n=26 (13 M) sources [1.0-1.6 mg/kg] tive test, decreased headaches, increased alertness; no significant effect in non/low-consumers et al., 2006
(<12 mg/d). [Assumed 30-50 kg BW for dose calculation]
1-d experiment 8-13 yr pure caffeine 80 mg Caffeine was associated with increased skin conductance, and a global reduction in EEG power Barry et al.,
(Australia) n=30 (19 M) [1.6-2.7 mg/kg] in the theta and alpha bands, as well as topographically-focused reductions in delta and beta 2009
power, and a focal increase in alpha frequency. Only global alpha level demonstrated the ex-
pected inverse relationship with skin conductance level in both placebo and caffeine conditions.
[Assumed 30-50 kg BW for dose estimates]
1-d experiment 8-12 yr pure caffeine 2.5, 5.0 mg/kg Caffeine improved performance on two of four measures of the Test of Variables of Attention Bernstein et
(USA) n=21 (12 M) and on a test of manual dexterity in the dominant hand. There was a trend toward increased cur- al., 1994
rent level of self-reported anxiety after caffeine on a visual analogue measure of anxiety. Chil-
dren reported feeling significantly less "sluggish" after caffeine than after placebo ingestion.
7-d experiment 12-17 yr caffeinated M: 72 ± 63 mg/d; There was no difference in reinforcing value of noncaffeinated or caffeinated soda as a function Temple et
(USA) n=49 (26 M) drink, carbon- F: 63 ± 47 mg/d of usual caffeine consumption. However, males found the caffeinated soda significantly more al., 2009
ated [~1 mg/kg/d] reinforcing than did females after the exposure period.
13-d experiment 8-12 yr cola 120-145 mg/d 24 hr after habituated children discontinued caffeine, there was a decrease in performance on Bernstein et
(USA) n=30 (17 M) [2.4-4.1 mg/kg/d] reaction time of a task requiring sustained attention. [Assume BW 35-50 kg for dose estimates] al., 1998
Cohort prospec- 13-17 yr caffeinated mean 259 mg/d Caffeine-dependent adolescents had a tendency to more anxiety and depression. [Assumed BW Oberstar et
tive (1-yr fol- n=21 M+F drinks [3.7-5.2 mg/kg/d] 50-70 kg for dose estimates] al., 2002
low-up) (USA)
Cross-sectional 13-17 yr coffee; cola; mean 244 mg/d Caffeine tolerance/addiction; similar intake for those with or without caffeine dependence; high- Bernstein et
(USA) n=36 (21 M) tea [3.5-4.9 mg/kg/d] er anxiety and depression scores in dependent users; those with other drug abuse ingested more al., 2002
caffeine; caffeine dependence not associated with increased comorbid diagnoses, use of alcohol
or street drugs in the prior year, or severity of substance abuse. [Assumed BW 50-70 kg for
dose estimates]
35
Cross-sectional 11-12 yr caffeine, all ≤10 mg, 10-50, Caffeine tolerance/addiction; high-consumption group (≥1.8 mg/kg/d) reported more stimulation Goldstein
(USA) n=289 M+F sources ≥50 mg/d [~0.3 and more dysphoric symptoms during abstinence. and Wallace,
to >1.8 mg/kg/d] 1997
Cross-sectional 11-17 yr caffeine, all 0, <1/wk, 1/d, Feeling tired in the morning and having difficulty sleeping was experienced more commonly in Orbeta et al.,
(USA) n=15,606 sources >1/d [<0.1 to >1 adolescents with a moderate or high intake of caffeine (≥1 serving/d). [No info on caffeine con- 2006
M+F mg/kg/d] tent; assumed 40 mg/serving and BW 40-70 kg for dose estimates]
STUDIES WITH ADULTS
1-d experiment 28-46 yr pure caffeine 1.8 to 178 mg The lowest caffeine dose discriminated was 1.8-178 mg; alertness increased; mood improved. Mumford et
(USA) n=7 (3 M) [0.03-2.5 mg/kg] al., 1994
1-d experiment 18-31 yr pure caffeine 3, 75, 150, 300 No sex differences in the pharmacokinetics of caffeine; sex differences in estimation of time Botella et al.,
(Spain) n=99 (39 M) mg [0.04-4.3 intervals and in reaction time were removed by moderate but not high doses of caffeine. 2001
mg/kg]
1-d experiment 18-31 yr coffee 3, 75, 150, 300 Caffeine increased state anxiety, in a dose-dependent manner, in males but not in females. In- Botella and
(Spain) n=99 (39 M) mg [0.04-4.3 crease compared to placebo (decaf) was non-significant at 75 mg, but significant at 150 and 300 Parra, 2003
mg/kg] mg.
1-d experiment mean 21.38 guarana 37.5, 75, 150, Improved secondary memory performance and increased alert and content mood ratings, more Haskell et
(UK) yr 300 mg extract so at the two lower doses. [Assumed guarana contains 4-8% caffeine, using 6% w/w yields ~5- al., 2007
n=26 (8 M) [0.07-0.5 mg/kg] 36 mg caffeine ingested]
1-d experiment 18-24 yr guarana; gin- 75 mg guarana Guarana improved 'attention' tasks (but with some evidence of reduced accuracy) and a sentence Kennedy et
(UK) n=28 M+F seng (~9 mg caffeine) verification task; guarana + ginseng (panax G115); improved serial subtraction task perform- al., 2004b
[0.13 mg/kg] ance.
1-d experiment 18-56 yr pure caffeine 0, 12.5, 25, 50, After overnight abstinence, all doses improved mood and cognitive performance (simple reac- Smit and
(UK) n=23 (11 M) 100 mg tion time task and rapid visual information processing task) without a dose-response, but effects Rogers, 2000
[0.2-1.4 mg/kg] were greater with a higher level of habitual intake; thirst was increased only in low consumers.
1-d experiment 18-70 yr pure caffeine; 19 mg caffeine Identical improvements on "energetic arousal" and cognitive function were found for cocoa Smit et al.,
(UK) n=42 (14 M) cocoa powder; [0.27 mg/kg]; powder and the caffeine + theobromine (250 mg) combination vs. placebo. 2004a
theobromine 11.6 g cocoa
powder
36
1-d experiment 21-51 yr pure caffeine; Experiment 1: In study 1, tea and coffee produced mild autonomic stimulation and an elevation in mood. There Quinlan et
(UK) n1=17; coffee; tea 37.5, 75 mg in were no effects of tea vs. coffee or caffeine dose, despite a fourfold variation in the latter. In- al., 2000
n2=15 M+F tea; 75, 150 mg creasing beverage strength was associated with greater increases in DBP and energetic arousal.
in coffee; Ex- In study 2, caffeinated beverages increased SBP, DBP, and skin conductance and lowered HR
periment 2: 25, and skin temperature compared to water. Significant dose-response relationships to caffeine
50, 100, 200 mg were seen only for SBP, HR, and skin temperature. There were significant effects of caffeine on
+ decaf tea energetic arousal but no consistent dose-response effects.
[0.4-2.9 mg/kg]
1-d experiment 18-40 yr ED 30 mg Both the familiar drink and its placebo improved alertness, mental energy and mental perform- Smit et al.,
(UK) n=76 (33 M) [0.4 mg/kg] ance compared to baseline and to the novel placebo drink. After repeated exposure (gaining fa- 2006
miliarity) with the novel drinks, only the caffeine + CHO containing drinks showed sustained
beneficial effects compared to placebo and baseline. [ED=Lucozade]
1-d experiment mean 22.0- ED 32 mg Improved performance of F in the go-no-go task but not in the simple reaction times task; no Mucignat-
(Italy) 22.5 yr; n=12 [0.5 mg/kg] caffeine effect in M, who responded faster at baseline. Caretta,
(6 M) 1998
1-d experiment 32-57 yr coffee; cola 33 mg/serving Caffeine reinforcement did not differ as a function of vehicle or serving dose, and no vehicle- Liguori and
(USA) n=11 M+F (cola); 100 dose interactions were found. With both cola and coffee at the commonly used doses, self- Hughes,
mg/serving (cof- reported motivation to work was greater and drowsiness and laziness smaller with caffeinated 1997
fee) than noncaffeinated beverages.
[0.5-1.4 mg/kg]
1-d experiment 18-34 yr pure caffeine; 40 mg Improved accuracy during task switching and self-reported alertness (both p< 0.01) and reduced Giesbrecht et
(The Nether- n=44 (16 M) theanine [0.6 mg/kg] self-reported tiredness (P < 0.05); no significant effects on other cognitive tasks, such as visual al., 2010
lands) search, choice reaction times, or mental rotation; increased systolic and diastolic BP.
1-d experiment 18-30 yr ED 40 mg Enhanced accuracy and speed of psychomotor reactions; event-related potentials had enhanced Rao et al.,
(UK) n=40 (14 M) [0.6 mg/kg] components Cl/P1 (early visual cortical processing) and N1, N2 and P3 (later decision-making 2005
and responses).
1-d experiment 18-40 yr ED 0.6, 1.2, 1.7 ED decreased reaction times on the behavioral control task, increased subjective ratings of stim- Howard and
(USA) n=80 (34 M) mg/kg ulation, and decreased ratings of mental fatigue; improvements greatest at lowest dose and di- Marczinski,
minished as dose increased. [Ed=Red Bull] 2010
1-d experiment Adult caffeine in 40 mg More positive mood and better performance on tasks requiring sustained attention (speed of en- Smith,
(UK) n=118 (59 chewing gum [0.6 mg/kg] coding of new information). 2009b
M)
37
1-d experiment 21-50 yr ED; carbon- 46 mg Mean fasting blood glucose and mean areas of motor-evoked potentials (MEPs) rose after Lu- Specterman
(UK) n=10 (5 M) ated water ± [0.7 mg/kg] cozade intake and were elevated for 90 min. Similar rises in MEP areas were seen from carbon- et al., 2005
glucose or ated water + caffeine or glucose, but not from carbonated water alone. Thus Lucozade can affect
caffeine the size of MEPs to activation of the motor cortex with fixed-intensity transcranial magnetic
stimulation. [ED=Lucozade; contains 68 g glucose and 46 mg caffeine]
1-d experiment 28.3 ± 5.34 pure caffeine; 50 mg Caffeine improved subjective alertness at 60 min and accuracy on the attention-switching task at Owen et al.,
(UK) yr L-theanine [0.7 mg/kg] 90 min; L-theanine + caffeine improved both speed and accuracy of performance of the atten- 2008
n=27 (14 M) tion-switching task at 60 min, and reduced susceptibility to distracting information in the mem-
ory task at 60 and 90 min.
1-d experiment Adult pure caffeine; 50, 100 mg Caffeine decreased scores on negative mood scales, especially on the anxiety/sadness scale. The Huppe and
(Germany) n=96 M aspirin [0.7, 1.4 mg/kg] combination of aspirin and caffeine failed to increase any score on scales measuring positive Janke, 2001
moods. The results do not support the suggestion that caffeine increases the potential for abuse
of aspirin.
1-d experiment 19-25 yr caffeinated 50, 100 mg Increased alertness in consumers and non-consumers; significant reinforcing, mood and psy- Rogers et al.,
(UK) n=20 (6 M) drinks [0.7, 1.4 mg/kg] chomotor performance effects in consumers only; some non-consumers had a worsening of per- 2003
formance after intake.
1-d experiment 18-35 yr pure caffeine 0, 50, 150, 450 Caffeine significantly increased BP, produced feelings of arousal, positive mood, increased the Childs and
(USA) n=102 (51 mg number of hits and decreased reaction times in a vigilance task, increased systolic and diastolic de Wit, 2006
M) [0.7, 2.1, 6.4 BP and slightly decreased HR at 150 or 450 mg; 450 mg impaired performance on a memory
mg/kg] task and caused anxiety feelings (50 and 150 mg caused slight increase in anxiety).
1-d experiment 18-35 yr pure caffeine 0, 50, 150, 450 An intake of ≥150 mg caused anxiety in light caffeine users, which was associated with gene Childs et al.,
(USA) n=102 (51 [Adenosine mg variants ADORA2A rs5751876 (1976C/T), rs2298383 (intron 1a) and rs4822492 (3'-flank), and 2008
M) and dopamine [0.7-6.4 mg/kg] DRD2 rs1110976 (intron 6), as well as two-locus interactions of selected ADORA2A and DRD2
receptor geno- polymorphism.
type]
1-d experiment Adult pure caffeine; 60 mg Caffeine reduced the effect of a distracter on reaction time in the key-press test, and reduced Durlach et
(USA) n=?? M+F tea [0.9 mg/kg] reaction time in the touch-screen task; occurred within minutes of consumption. al., 2002
1-d experiment mean=38.1 pure caffeine; 60 mg Speeding of reaction time in pattern recognition, delayed match to sample and match to sample Durlach,
(UK) yr tea [0.9 mg/kg] visual search; effect within minutes of consumption. 1998
n=8 M
38
1-d experiment 19-28 yr pure caffeine 70 mg Caffeine had no significant effects on drink preference or mood in subjects with habitually low Rogers et al.,
(UK) n=49 (20 M) [caffeine- [1.0 mg/kg] intakes of caffeine. In contrast, moderate users developed a relative dislike for the drink lacking 1995
deprived] caffeine and showed somewhat lowered mood following overnight abstinence (e.g., less lively,
clearheaded and cheerful), which was improved by caffeine.
1-d experiment 67-95 yr caffeine, all + or - (mean 70.3 In some neuropsychological tests (episodic memory, Stroop interference and color, speed of Lesk et al.,
(UK) n=89 (34 M) sources mg 4 hr before pattern and letter comparison), those with recent intake of caffeine-containing foodstuffs showed 2009
test) [1.0 mg/kg] a linear decrease in performance with increasing age.
1-d experiment mean ~22.8 pure caffeine 1, 2 mg/kg After overnight fast, caffeine improved alertness and vigilance, more so with increasing dose; no Hewlett and
(UK) yr difference in users and non-users on mood or performance. Smith, 2007
n=120 M+F
1-d experiment mean 21-23 pure caffeine 0, 1, 2 mg/kg; Caffeine reliably improved performance on a sustained attention task, and increased rated men- Yeomans et
(UK) yr then 0, 1 mg/kg tal alertness, in moderate caffeine consumers who were tested when caffeine-deprived. al., 2002
n=30 (11 M)
1-d experiment 17-40 yr pure caffeine 1, 2.5, 5 mg/kg The cerebral blood flow signal dropped by 22%, 25% and 32% for caffeine doses of 1, 2.5, and Chen and
(USA) n=27 (8 M) 5 mg/kg, respectively. The BOLD baseline was unchanged for the lowest caffeine dose (1 mg), Parrish,
but dropped by ~1.9% and 2.2% for the 2.5 and 5 mg/kg doses. 2009a
1-d experiment 19-24 yr pure caffeine 1, 2, 3, 4 mg/kg Caffeine facilitated performance (decreased error in perceptual judgment) in high impulsives but Gupta et al.,
(India) n=160 M [personality] had no significant influence on the performance of low impulsives. 1994
1-d experiment Adult pure caffeine 1, 3 mg/kg Caffeine increased energy level and improved mood at 3 mg/kg independent of time of day; self- Miller et al.,
(USA) n=188 M reported anxiety was not affected; performance on multiple forceband discrimination task was 1995
affected by time of day, caffeine dose, and their interaction.
1-d experiment Adult pure caffeine 1, 3 mg/kg Increased whole-arm physiological tremor at 3 but not 1 mg/kg; no effect of time of day. Miller et al.,
(USA) n=188 M 1998
1-d experiment 18-23 yr pure caffeine 70, 250 mg Acute caffeine intake affected withdrawn consumers, nonwithdrawn consumers, and noncon- Richardson
(UK) n1=49; [caffeine- [1.0, 3.6 mg/kg] sumers similarly (increased jitteriness and decreased tiredness and headache); hand steadiness et al., 1995
n2=18 M+F deprived] decreased as dose increased; 70 mg, but not 250 mg, enhanced performance on a simple reaction
time task.
1-d experiment 18.7 ± 0.8 yr pure caffeine; 1, 3, 5 mg/kg Caffeine enhanced the initial learning of a proprioceptive motor task but did not improve per- Miller and
(USA) n=93 (35 M) smoking formance beyond that of normal practice; two higher dose groups initially outperformed low Miller, 1996
dose group.
39
1-d experiment 19-28 yr pure caffeine 75 mg Caffeine decreased cerebral blood flow non-significantly in habitual consumers and greatly in Kennedy and
(UK) n=20 (10 M) [1.1 mg/kg] non-habitual consumers. Haskell,
2011
1-d experiment 18-55 yr ED; carbona- 75 mg Caffeine was the ED constituent responsible for the effects found: improved and/or maintained Smit et al.,
(UK) n=271 (134 tion [1.1 mg/kg] mood and performance during fatiguing and cognitively demanding tasks relative to placebo; 2004b
M) carbonation may have slowed the absorption of caffeine. [ED not identified; contained 75 mg
caffeine, 1 g taurine, 37.5 g CHO in 250 mL]
1-d experiment 18-32 yr pure caffeine; 75 mg Improved "secondary memory" and "speed of attention" only seen from ED, not glucose or caf- Scholey and
(UK) n=20 M+F ED [1.1 mg/kg] feine by itself. [ED was simulated, containing 37.5 g glucose and 75 mg caffeine and ginkgo Kennedy,
biloba at flavouring levels in 250 mL] 2004
1-d experiment 18-46 yr pure caffeine 75, 150 mg At 75 and/or 150 mg, users and non-users had improved alertness, simple and digit vigilance Haskell et
(UK) n1=24; [1.1, 1.4 mg/kg] reaction time, working memory reaction time, sentence verification accuracy; users performed al., 2005
n2=24 M+F better in rapid visual information processing and spatial memory tasks.
1-d experiment 20-28 yr pure caffeine; 80 mg caffeine At end of experiment (midnight), placebo group had greater P300 latency (component of event- Seidl et al.,
(Austria) n=10 M+F taurine [1.1 mg/kg] + 1 g related potential waveforms) and motor reaction time and lower well-being scores, which were 2000
taurine + 0.6 g unchanged in the caffeine group; effects seen in habitual users and non-users.
glucuronolactone
1-d experiment 19-56 yr ED 75 mg (± guara- Intake was ‘alerting’, ‘revitalizing’, ‘awakening’ and provided mental energy [two different uni- Smit and
(UK) n=23 (10 M) na) dentified EDs were tested; one contained guarana]. Rogers, 2002
[≥1.1 mg/kg]
1-d experiment 18-55 yr ED; carbona- 75 mg Caffeine was the ED constituent responsible for the effects found: improved and/or maintained Smit et al.,
(UK) n=271 (134 tion [1.1 mg/kg] mood and performance during fatiguing and cognitively demanding tasks relative to placebo; 2004b
M) carbonation may have slowed the absorption of caffeine (and possibly carbohydrates) [ED not
identified but contained 75 mg caffeine, 1000 mg taurine, 37.5 g CHO in 250 mL]
1-d experiment 18-29 yr pure caffeine; 1.1 mg/kg Enhanced performance on vigilance task; task-induced stress was unaffected. Temple et
(USA) n=64 (32 M) stress al., 2000
1-d experiment 18-30 yr decaf ± caf- 75, 150 mg After 1 hr deprivation, caffeine improved attention, problem solving and delayed recall, but not Warburton,
(UK) n=18 M feine [1.1, 1.4 mg/kg] immediate recall or working memory; increased clearheadedness, happiness and calmness; de- 1995
creased tenseness.
1-d experiment 20-23 ± 2 yr pure caffeine 1, 2 mg/kg Caffeine reinforced changes in flavor pleasantness in acutely withdrawn habitual consumers but Tinley et al.,
(UK) n=50 not in nonconsumers or nondependent low-caffeine consumers. 2004
40
1-d experiment 18-24 yr ED 80 mg In 1-hr deprived and non-deprived subjects: improved attention and verbal reasoning (mean Warburton et
(UK) n=42 (sex [1.1 mg/kg] number correct and reaction times); reduced variability of attentional performance between par- al., 2001
NS) ticipants; no effects on memory; no effect of glucose [ED not identified but is likely Red Bull,
based on the stated ingredients]
1-d experiment mean=21 yr pure caffeine; 90, 250 mg Non-coffee drinkers needed a low dose of caffeine for their optimal multi-task (cognitive) per- Kourtidou-
(Greece) n=16 M+F smoking [1.3, 3.6 mg/kg] formance while a higher dose significantly increased their BP. Coffee drinkers and smokers Papadeli et
needed a higher dose of caffeine for optimal performance, which increased very quickly, but did al., 2002
not last and increased their BP non-significantly. HR was decreased and respiration rate in-
creased significantly.
1-d experiment ~30 ± 10 yr tea, black 90-100 mg Black tea improved attention and self-reported alertness. In addition to caffeine, it also con- De Bruin et
(The Nether- n=58 (23 M) [1.3-1.4 mg/kg] tained 36-46 mg theanine. al., 2011
lands)
1-d experiment 19-30 yr pure caffeine; 100 mg Caffeine administration induced arousing effects (lesser somnolence and greater activation) in Adan et al.,
(Spain) n=688 (238 decaf [1.4 mg/kg] all sleepy subjects, while the effects of decaf drink were only apparent at 10 min. Caffeine ef- 2008
M) fects were greater in men, and the decaf beverage produced greater effects in women. Circadian
typology only showed effects for time of day (morning/afternoon).
1-d experiment Adult pure caffeine 100 mg Students perceived themselves to be significantly more awake, clear minded, energetic, alert, Peeling and
(Australia) n=10 (sex [1.4 mg/kg] anxious, and could concentrate better. Dawson,
NR) 2007
1-d experiment ~18.5-19.5 yr coffee; decaf 100 mg Caffeinated coffee increased the amplitude and duration of reflex blinks, which occurred at a Schicatano,
(USA) n=6 M+F [1.4 mg/kg] shorter latency than reflex blinks following ingestion of decaf. 2005
1-d experiment 46-60 yr pure caffeine 100 mg No effect on short-term memory span or speed, long-term memory retrieval functions, or fo- Schmitt et
(The Nether- (n=16) ; 60- [1.4 mg/kg] cused attention. al., 2003
lands) 74 yr (n=14)
M+F
1-d experiment 18-20 yr pure caffeine 100, 200 mg With increasing caffeine dose the level of reported visual disturbances increased. The increased Coren, 2002
(Canada) n=20 (10 M) [1.4, 2.8 mg/kg] cortical arousal associated with caffeine intake may interact with the structural properties of the
visual cortex to increase the perceptual instability associated with viewing grid patterns.
1-d experiment Adult pure caffeine 100, 200 mg Intake of 200 mg caffeine improved mood and cognitive performance. Maridakis et
(USA) n=18 M [1.4, 2.8 mg/kg] al., 2009b
41
1-d experiment 19-22 yr pure caffeine 100, 200 mg Participants detected more targets under high intake of caffeine than low intake, which was Tiwari et al.,
(India) n=30 (12 M) [1.4, 2.8 mg/kg] greater than placebo. Participants took significantly more time to detect signal in placebo than 2009
caffeine intake conditions across blocks.
1-d experiment Adult pure caffeine 100, 200, 300, Dose-response relationship between caffeine and EEG D2 (correlation dimension). Watters et
(Australia) n=10 (sex 400, 500, 600 mg al., 1998
NS) [1.4-8.6 mg/kg]
1-d experiment mean=19.08 pure caffeine 100, 200, 400 mg Caffeine improved alerting and executive control function in a dose-response manner, asymptot- Brunye et
(USA) yr [1.4, 2.9, 5.7 ing at 200 mg. al., 2010a
n=36 (16 M) mg/kg]
1-d experiment mean=19.08 pure caffeine 100, 200, 400 mg Caffeine enhanced both vigilance and the executive control of visual attention, but only at 400 Brunye et
(USA) yr [1.4, 2.9, 5.7 mg for heavy caffeine users (mean 592.3 mg/d). al., 2010b
n=36 (16 M) mg/kg]
1-d experiment 28-39 yr pure caffeine; 1.4, 2.9, 5.7 Increased ratings of unusual smell and/or taste (all doses, dose-related); 1.4 mg/kg had no other Garrett and
(USA) n=9 M+F nicotine [prior mg/kg effect; 2.9 mg/kg decreased HR and skin temperature, increased diastolic BP; 2.9 and 5.7 mg/kg Griffiths,
use of to- increased ratings of drug effect, good effect, like drug, high, stimulated, and bad effect (dose- 2001
bacco, co- related).
caine]
1-d experiment mean 25 ± pure caffeine 100, 200, 400 mg Reduced P50 auditory sensory gating from ≥200 mg (non-significant from 100 mg) independent Ghisolfi et
(Brazil) 1.7 yr [1.4, 2.9, 5.7 of gender and habitual caffeine intake; high users had lower S(2) amplitudes at baseline than low al., 2006
n=24 (12 M) mg/kg] users.
1-d experiment Adult caffeine, all 100-120 mg Caffeine had a detrimental effect on microsurgical ability (motor steadiness impaired). Urso-
(UK) n=20 (sex sources [1.4-1.7 mg/kg] Baiarda et
NS) al., 2007
1-d experiment 18-30 yr coffee; decaf 1.5 mg/kg Increased alertness and psychomotor performance of the subjects with colds to level of healthy Smith et al.,
(UK) n=100 (53 [have a cold] group; decaf also led to improvement. 1997
M)
1-d experiment 18-44 yr pure caffeine 1.5 mg/kg 1, 2x Caffeine led to a more positive mood and improved performance on a number of tasks; effects Smith et al.,
(UK) n=60 (18 M) depended on the person's level of arousal; linear effects with caffeine dose; this is evidence 2005
against the argument that behavioral changes due to caffeine are merely the reversal of negative
effects of caffeine abstinence.
42
1-d experiment Adult pure caffeine 1.5, 3 mg/kg Improvement (usually dose-related) in task performance (focused attention, 5-choice, simple Brice and
(UK) n=144 (72 reaction time, repeated digits); saliva caffeine levels not related to performance or influenced by Smith, 2001a
M) time of day, habitual use, psychosocial factors, or health-related behavior.
1-d experiment 23.2 ± 4.6 yr pure caffeine 1.5, 3 mg/kg Caffeine (both doses) speeded responses in visual selective attention tasks, but these effects did Kenemans
(The Nether- n=24 (sex not differ across conditions within-task. Thus, there was no indication that they were due to spe- and Ver-
lands) NS) cific effect(s) on one or more of the attentional sub-functions. baten, 1998
1-d experiment 23-44 yr pure caffeine 1.5, 3, 6 mg/kg Dose-related increase for alpha- and beta-EEG frequencies, anxiety (p=0.082 at 6 mg/kg), wake- Hasenfratz
(Switzerland) n=20 F fulness, and some coffee ratings; negative dose-effect for rapid information processing rate and and Battig,
BP; no dose-effect for reaction time and motor activity. 1994
1-d experiment 20-35 yr pure caffeine 1.5, 3.0, 4.5 At 4.5 mg/kg, skilled writers had more fluent handwriting movements and increased maximum Tucha et al.,
(Germany) n=20 (10 M) mg/kg velocity and maximum positive and negative accelerations. 2006
1-d experiment 60-82 yr pure caffeine 116, 231 mg Significant improvement on the continuous attention task was seen at 116 mg, while at 231 mg Bryant et al.,
(UK) n=10 (3 M) [1.7-3.3 mg/kg] there was a non-significant trend towards placebo scores. There was little effect on the subjec- 1998
tive effects measured by visual analogue scales.
1-d experiment 18-23 yr pure caffeine 125, 250 mg No effect on performance of either the classic color-word version or numerical version of the Edwards et
(UK) n=20 (10 M) [1.8, 3.6 mg/kg] Stroop task. al., 1996
1-d experiment Adult pure caffeine 125, 325 mg Decreased hand steadiness, reaction time, and fatigue, and increased BP, HR, and tension- Nash et al.,
(USA) n=52 M+F [1.8, 4.6 mg/kg] anxiety not influenced by dosing instructions; only those uninformed of the placebo condition 2002
had BP and vigor increases at 125 mg and impaired hand steadiness at 325 mg.
1-d experiment 20.4 ± 0.70 ED 134 mg During 2nd and 3rd hr of 3-hr test, ED increased VO2 and energy expenditure; mean systolic BP Rashti et al.,
(USA) yr [1.9 mg/kg] was higher with ED; no differences were seen in HR, diastolic BP, or profile of mood states at 2009
n=10 F any time point. [ED=Meltdown RTD]
1-d experiment 18-65 yr pure caffeine 2 mg/kg (split Improved vigilance, simple reaction time, semantic memory, and verbal reasoning in users and Hewlett and
(UK) n=176 M+F dose) non-users; decreased choice reaction time in users but increased in non-users; no effect on epi- Smith, 2006
sodic memory; little effect of caffeine withdrawal.
1-d experiment 21-40 yr pure caffeine 2 mg/kg Caffeinated coffee increased the accuracy and speed of response in a Posner letter-recognition Barraclough
(UK) n=10 (2 M) task. In the noncaffeine condition, pattern-matching was faster by the right hemisphere and pho- and Beech,
nologic matching was faster by the left hemisphere. However, under caffeine, a previously unre- 1995
ported reversal in the balance of hemispheric processing efficiency was found.
43
1-d experiment 20-62 yr pure caffeine 2 mg/kg Mood and performance on a number of cognitive measures were improved in regular caffeine Christopher
(UK) n=68 (25 M) consumers who had their normal amount of caffeine prior to the experiment. This study provides et al., 2005
evidence against the argument that behavioral changes due to caffeine are merely the reversal of
negative withdrawal effects.
1-d experiment 18-35 yr pure caffeine 2 mg/kg Increased alertness, arousal, BP, skin conductance level and response, startle reflex magnitude, Flaten and
(Norway) n=21 (13 M) and feeling of stress; expectation increased the arousal induced by caffeine. Blumenthal,
1999
1-d experiment 20-43 yr pure caffeine 2 mg/kg Caffeine-associated stimuli increased arousal and improved mood; information about the drink Mikalsen et
(Norway) N=69 M+F content modulated arousal in the direction indicated by the information. al., 2001
1-d experiment 18-62 yr pure caffeine; 2 mg/kg BP increased, more so for the false information group; nonsignificant subjective well-being Schneider et
(Germany) N=90 M+F decaf (alertness, calmness) changes were found for correctly informed participants. al., 2006
1-d experiment 18-28 yr pure caffeine 2 mg/kg Improved mood and cognitive performance (re: caffeine content of drink) in overnight- Smith et al.,
(UK) n1=25 (13 withdrawn users and in non-users; non-users had fewer lapses of attention and higher ratings of 2006
M); n2=25 (6 alertness and anxiety; no negative withdrawal effects. [n1=consumers; n2=non-consumers]
M)
1-d experiment Adult pure caffeine 140 mg There was a significant potentiating effect of caffeine on vigilance in both introverts and extra- Amir et al.,
(United Arab n1=47 F; [personality] [2.0 mg/kg] verts. 2001
Emirates) n2=43 F
1-d experiment 19-47 yr coffee; decaf 143 mg Expectation of a beneficial effect improved signal detection but not memory scanning or delayed Oei and
(Australia) n1=16; [2.0 mg/kg] recall; reaction time under caffeine was shorter. [Decaf contained 27 mg caffeine, 0.4 mg/kg] Hartley,
n2=16 M+F 2005
1-d experiment 20-35 yr pure caffeine 2, 4 mg/kg Caffeine increased the indexes of arousal. There were, however, no significant main effects of Flaten and
(Norway) n1=24; caffeine on acoustic startle eyeblink reflex. Elden, 1999
n2=18 M+F
1-d experiment Adult pure caffeine 2, 4 mg/kg Caffeine effects on mood and task performance did not significantly interact with extraversion, Liguori et
(USA) n1=17; [personality] except for NS trends for caffeine to increase happiness and vigor more among extraverts than al., 1999
n2=19 M+F introverts. No 3-way interactions of group, time, and dose were found.
1-d experiment 22-35 yr pure caffeine 2, 4 mg/kg Small increases in arousal may be detrimental to learning, and larger increases in arousal may Flaten, 1998
(Norway) n1=48; reverse this effect; BP increase; skin conductance increase.
n2=45 M+F
44
1-d experiment ~21 ± 3.5 yr pure caffeine 150 mg Found a significant association between self-reported anxiety after caffeine administration and Alsene et al.,
(USA) n=94 (51 M) [anxiety pre- [2.1 mg/kg] two linked polymorphisms on the A2a receptor gene, the 1976C>T and 2592C>Tins polymor- 2003
disposition] phisms. Individuals with the 1976T/T and the 2592Tins/Tins genotypes reported greater in-
creases in anxiety after caffeine administration than the other genotypic groups.
1-d experiment 18-34 yr pure caffeine; 150 mg Improved digit vigilance reaction time, simple reaction time, numeric working memory reaction Haskell et
(UK) n=24 (9 M) theanine [2.1 mg/kg] time, sentence verification accuracy, and rapid visual information processing accuracy; fewer al., 2008
'headache' and 'tired' ratings and more 'alert' ratings; L-theanine further improved delayed word
recognition reaction time.
1-d experiment 18-24 yr coffee; decaf 150 mg BP increase; mood improved; effects caused only by caffeinated coffee. [Decaf contained 9 mg Tse et al.,
(China) n=77 (35 M) [2.1 mg/kg] caffeine, 0.13 mg/kg] 2009
1-d experiment 18-32 yr ED 160 mg No significant effect, either with eyes open or eyes closed, on movement of the body's center of Enriquez et
(USA) n=23 (13 M) [2.3 mg/kg] pressure (postural stability). [ED= Red Bull] al., 2009
1-d experiment 23-30 yr ED 160 mg Drinking an ED prior to a driving task had a significant, positive effect in counteracting fatigue, Gershon et
(Israel) n=20 M+F [2.3 mg/kg] though it may have long-term negative rebound effects. [ED not identified but is likely Red al., 2009
Bull]
1-d experiment 18-34 yr pure caffeine 2.4 mg/kg (split Psychostimulant action of caffeine was seen after 8 hr but not 3-6 hr of abstinence; hand steadi- Heatherley
(UK) n=49 (22 M) dose) ness was decreased and perception of task demand was increased by caffeine after 4 h, but not et al., 2005
after 6- and 8-hr abstinence; BP increase.
1-d experiment Adult pure caffeine; 2.5 mg/kg Caffeine produced an increase in self-reported muscular tension and tended to increase anxiety Pritchard et
(USA) n=?? M+F smoking and delta magnitude. Smoking and caffeine did not interact for any measure, suggesting that the al., 1995
epidemiological link between smoking and coffee drinking may have a non-pharmacological
basis.
1-d experiment 21-50 yr pure caffeine 180 mg Had greater average number of answers and number of correct answers on the Uchida-Kraepelin Higashi et
(Japan) n=14 M+F [2.6 mg/kg] psychodiagnostic tests; cerebral blood flow decrease. al., 2004
1-d experiment mean= 21.0 decaf ± 100 200 mg (split No effect on initial mood or working memory; improved encoding of new information and Smith et al.,
(UK) yr mg caffeine dose) counteracted fatigue that developed over the test session; increased BP and pulse rate; no inter- 1999b
n=144 (72 [breakfast] [2.9 mg/kg] action with breakfast.
M)
1-d experiment Adult pure caffeine 200 mg Caffeine appeared to intensify the strength of connections among list words and critical lures, Capek and
(USA) n=?? M+F [2.9 mg/kg] thereby enhancing both true and false memory. Guenther,
2009
45
1-d experiment 19-28 yr pure caffeine 200 mg Increased number of correct responses and decreased response times; low habitual consumers Fine et al.,
(USA) n=24 M [2.9 mg/kg] (<100 mg/d) and non-smokers had more correct responses than did high habitual caffeine con- 1994
sumers (>100 mg/d) and smokers, but only in the placebo condition. Caffeine improved certain
aspects of mood.
1-d experiment 18-81 yr pure caffeine 200 mg Caffeine reduced duration estimates in the prospective condition but not in the retrospective Gruber and
(USA) n=106 (25 [2.9 mg/kg] condition; no effect on very long duration comparisons (the past year compared with a year at Block, 2003
M) one-half and one-quarter of one's age); the most parsimonious explanation is that caffeine in-
creased arousal level, which led to a narrowing of the focus of attention to the most salient task.
1-d experiment 21-41 yr pure caffeine 200 mg No effect on BP, HR, respiratory rate, or verbal memory performance; cerebral blood flow de- Haase et al.,
(Germany) n=18 M [2.9 mg/kg] crease. 2005
1-d experiment Adult pure caffeine 200 mg Caffeine non-significantly increased hand tremor; increased systolic BP (p<0.001, F-test) and Humayun et
(USA) n=17 (14 M) [2.9 mg/kg] diastolic BP (p=0.002, F-test) and pulse rate (p=0.002, F-test). al., 1997
1-d experiment 24 ± 0.3 yr pure caffeine 200 mg Caffeine produced a positive effect when subjects were primed with phonologically related Lesk and
(Italy) n=64 M+F [2.9 mg/kg] words. When primed with unrelated words, caffeine produced a significant increase in the num- Womble,
ber of tip-of-the-tongue states (suggests that positive priming was not a result of caffeine's alert- 2004
ness effects).
1-d experiment 18-39 yr pure caffeine 200 mg Caffeine improved perceptual learning but significantly impaired motor learning compared to Mednick et
(USA) n=61 M+F [2.9 mg/kg] placebo and 60-90 min naps. al., 2008
1-d experiment Adult pure caffeine 200 mg On the vigilance task, caffeine increased the number of stimuli detected (P < 0.02) and de- Olson et al.,
(USA) n=57 M+F [2.9 mg/kg] creased the reaction time (P = 0.001). Caffeine increased self-reported vigor and reduced fatigue 2010
and total mood disturbance scores compared with placebo.
1-d experiment 21-37 yr pure caffeine 200 mg Caffeine caused a further increase in P100 latency in subjects sensitive to the effects of hypogly- Owen et al.,
(UK) n=16 (8 M) [hypoglyce- [2.9 mg/kg] caemia, which was associated with poorer performance in tests of visual information processing. 2001
mia] [hypoglycemia was induced by a hyperinsulinemic clamp]
1-d experiment 23-41 yr pure caffeine 200 mg Significantly reduced resting-state BOLD connectivity in the motor cortex and baseline cerebral Rack-Gomer
(USA) n=9 (5 M) [2.9 mg/kg] blood flow, and spectral energy in the low-frequency BOLD fluctuations. et al., 2009
1-d experiment 18-40 yr pure caffeine 200 mg Improved working memory, but only for extraverted participants. Smillie and
(UK) n=59 (20 M) [personality] [2.9 mg/kg] Gokcen,
2010
1-d experiment mean=20.5 coffee; decaf 200 mg No easily interpretable effects on mood; pharmacological effects of caffeine acted synergisti- Elliman et
(UK) yr [2.9 mg/kg] cally with expectancy. al., 2010
n=25 (4 M)
46
8-d experiment 36.5 ± 5.2 yr pure caffeine 200 mg During the tasks, performance of the caffeine group was better than of the placebo group. After Ataka et al.,
(Japan) n=17 (8 M) [2.9 mg/kg] fatigue-inducing tasks, although subjective perception of fatigue, motivation, or sleepiness was 2008
not significantly different, plasma branched-chain amino acid levels in the caffeine group were
lower than those of the placebo group.
1-d experiment 20-31 yr pure caffeine 200 mg (~3.3 The cortical silent period (CSP) was reduced in fatigued muscles after caffeine consumption, de Carvalho
(Portugal) n=13 (3 M) mg/kg) when stimulating the motor cortex with intensities slightly above threshold; authors conclude et al., 2010
that CSP can be considered a surrogate marker of the effect of caffeine in the brain, in particular
of its central ergogenic effect.
1-d experiment 19-23 yr pure caffeine 4 x 65 mg over 5 In both dosing regimens, caffeine led to increased alertness and anxiety and improved perform- Brice and
(UK) n=24 M hr; 200 mg ance on simple and choice reactive tasks, a cognitive vigilance task, a task requiring sustained Smith, 2002
[2.9; 3.7 mg/kg] response, and a dual task involving tracking and target detection.
1-d experiment 23-45 yr pure caffeine 200, 400 mg Caffeine elicited a consistent decrease of the cortical silent period after magnetic stimulation, Cerqueira et
(Portugal) N=24 M+F [2.9, 5.7 mg/kg] suggesting that caffeine increases cortical neuronal excitability. al., 2006
1-d experiment 19-45 yr pure caffeine 200, 400 mg Increased alertness, contentedness, arousal, stress, startle eyeblink and skin conductance re- Flaten et al.,
(Norway) n=20 (10 M) [2.9, 5.7 mg/kg] sponses, and BP; dose-response seen. 2003
1-d experiment 18-30 yr pure caffeine; 200, 400 mg Salivary alpha-amylase activity increased in response to stress and caffeine (i.e., 200 and 400 Klein et al.,
(USA) n=45 M stress [2.9, 5.7 mg/kg] mg groups) but not to stress alone. 2010
1-d experiment 24.3 ± 0.9 yr pure caffeine 200, 400 mg Reduced reaction times (no dose-response) but no effect on time perception or timing tasks (tap- Terry et al.,
(UK) n=36 (8 M) [2.9, 5.7 mg/kg] ping, picking up object). 2009
1-d experiment 21-76 yr coffee 3 cups/d mean Moderate ingestion of coffee was not shown to interfere in the results of the vestibular test. Felipe et al.,
(Brazil) n=19 F [~3 mg/kg/d] [One cup of Brazilian coffee (60 mL) normally has 50.4 mg caffeine, and may vary from 85 mg 2005
to 125 mg.]
1-d experiment 19-34 yr pure caffeine 3 mg/kg Improved steering accuracy in a 1 hr simulated drive. Measures of mood and performance on a Brice and
(UK) n=24 (12 M) sustained attention task also showed the benefits of caffeine; alertness increased. Smith,
2001b
1-d experiment Adult pure caffeine 3 mg/kg There was a non-significant decrease in latency of event related potentials N1, P2, N2 and P3 Dixit et al.,
(India) n=40 M and a significant decrease in reaction time after caffeine consumption. The amplitude of P3 2006a
showed a significant increase after intake of caffeine. The results of this study indicate that caf-
feine leads to facilitation of information processing and motor output response of the brain.
1-d experiment Adult pure caffeine 3 mg/kg Decreased latency of evoked potential waves of auditory brainstem, mid-latency response, and Dixit et al.,
(India) n=40 M slow vertex response (improved transmission in peripheral and central brain auditory pathways). 2006b
47
1-d experiment Adult pure caffeine 3 mg/kg A composite measure of developmental instability (minor physical anomalies and fluctuating Jung et al.,
(USA) n=100 M+F [developmen- asymmetry) predicted the magnitude of caffeine-induced verbal memory decrement. 2000
tal instability]
1-d experiment 19-29 yr pure caffeine 3 mg/kg Caffeine resulted in lower slow-alpha power (EEG); subjects made faster responses to target Kenemans
(The Nether- n=16 (8 M) conjunctions and more hits, whereas the false-alarm rate was unaffected; an early differential and Lorist,
lands) positivity was found indicative of increased selectivity; no effect on sensory discrimination; re- 1995
sponse-related lateralization above the motor cortex were not affected, suggesting that the short-
er reaction times were due to faster central or peripheral motor processes.
1-d experiment 18-29 yr pure caffeine 3 mg/kg After overnight abstinence, caffeine decreased the time to localize the target and the response Lorist and
(The Nether- n=16 (8 M) (put in decaf) preparation started earlier in a visual selective attention task. Snel, 1997
lands)
1-d experiment 19-29 yr pure caffeine 3 mg/kg After overnight abstinence, caffeine decreased the reaction time; the P3b peak latency was de- Lorist et al.,
(The Nether- n=16 (8 M) creased in the low display load condition and in the focused attention condition; the search proc- 1996
lands) esses were not affected.
1-d experiment 19-47 yr pure caffeine 3 mg/kg Cerebral perfusion decrease similar in low and high consumers; activation of brain regions Nehlig et al.,
(France) n=26 (10 M) mainly involved in the control of vigilance, anxiety, and cardiovascular regulation, but not in 2010
reinforcing and reward.
1-d experiment 24-38 yr pure caffeine; 3 mg/kg Caffeine in a concentration similar to that in a strong cup of coffee did not have a major effect Orth et al.,
(UK) n=11 (7 M) decaf on transcranial magnetic stimulation measures of motor cortex excitability. 2005
1-d experiment Adult pure caffeine 3 mg/kg Caffeine improved alertness and performance on sustained attention tasks; interactions between Smith et al.,
(UK) n=48 (24 M) caffeine conditions and levels of impulsivity of the subjects were also found in memory tasks. 1994b
1-d experiment 21.1 ± 3.0 yr pure caffeine 3 mg/kg Results of the AX-continuous performance test, the flanker task, and the stop task indicated that Tieges et al.,
(The Nether- n=15 (9 M) neither active nor reactive inhibition were significantly modulated by caffeine. 2009
lands)
1-d experiment 24 ± 6 yr pure caffeine; 3 mg/kg Decreased reaction times but not accuracy in single and dual tasks; increase in reaction time in van Duinen
(The Nether- n=23 (11 M) fatigue dual task due to fatigue was partly prevented by caffeine; no effect on absolute force, endurance et al., 2005
lands) time or electromyographic amplitude.
1-d experiment 18-26 yr pure caffeine 3, 5 mg/kg Both doses enlarged the error-related negativity, which reflects the monitoring of ongoing cogni- Tieges et al.,
(The Nether- n=15 (8 M) tive processes for signs of erroneous outcomes. 2004
lands)
48
1-d experiment 18-30 yr pure caffeine 3, 5 mg/kg Event-related brain potentials revealed a negative deflection developing within the preparatory Tieges et al.,
(The Nether- n=18 (8 M) interval, which was larger for switch than for repeat trials - both doses increased this switch- 2006
lands) related difference.
1-d experiment 18-31 yr pure caffeine 3, 5 mg/kg Caffeine improved task-switching performance by increasing general effects on task switching, Tieges et al.,
(The Nether- n=18 (9 M) related to task-nonspecific (rather than task-specific) anticipatory processes. 2007
lands)
1-d experiment 25.1 ± 5.29 pure caffeine 3, 5, 7 mg/kg, i.v. Olfactory hallucinations immediately after the 30-45 second iv caffeine infusion (all subjects Nickell and
(USA) yr hallucinated during at least one caffeine infusion, 6/10 with each infusion); dose-related in- Uhde, 1994-
n=10 (9 M) creases in ratings of anxiety and blood levels of cortisol and lactate. One subject experienced a 1995
DSM-III-R panic attack.
6-11 d experi- 22 ± 3 yr caffeine, all 3 mg/kg/d, then Few cognitive and psychomotor differences existed after 5 d of controlled caffeine ingestion Judelson et
ment n=20 M sources 0, 3, or 6 between subjects consuming 0, 3, or 6 mg/kg/d caffeine, suggesting that chronic caffeine intake al., 2005
(USA) mg/kg/d has few perceptible effects on cognitive and psychomotor well-being, and may lead to a toler-
ance to some aspects of caffeine's acute effects.
1-d experiment 72.2 ± 4.1 yr coffee; decaf 220-270 mg Decline in memory performance from morning to afternoon test session unless ingested caffein- Ryan et al.,
(USA) n=40 M+F [3.1-3.9 mg/kg] ated coffee. (220-270 mg was about 2 cups coffee) 2002
1-d experiment 18-40 yr coffee; decaf 222 mg Caffeine intake resulted in a significant decrease in cerebral perfusion. However, both the con- Bendlin et
(USA) n=21 (7 M) [3.2 mg/kg] trol and caffeine groups showed an increase in BOLD signal amplitude across two sets of novel al., 2007
word stems. Additionally, the control group showed a 50% reduction in the extent of BOLD
activation, while the caffeine group showed no change in activation extent. Neither group
showed changes in BOLD baseline signal over time, which had been suggested to mediate caf-
feine-related BOLD signal changes. The results suggest that caffeine may attenuate general task
practice effects.
1-d experiment 18-62 yr pure caffeine 250 (split dose) Greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake in the Rogers et al.,
(UK) n=416 (198 [3.6 mg/kg] rs5751876 TT genotype group, and a reduced anxiety response in med/hi vs. low consumers 2010
M) irrespective of genotype.
1-d experiment 18-57 yr pure caffeine 3.6 mg/kg (in 3 Increased energetic mood and improved psychomotor performance (1-min tapping task, and Robelin and
(UK) n=64 (20 M) doses) long-duration simple reaction time task) relative to placebo; effect was same after one, two or Rogers, 1998
three spaced doses; dose-response not seen.
1-d experiment 30 ± 8 yr pure caffeine 250 mg Caffeine had a greater effect on mood and choice reaction time in the abstained state than in the Addicott and
(USA) n=17 (8 M) [3.6 mg/kg] normal caffeinated state, but caffeine improved selective attention and memory in both states. Laurienti,
2009
49
1-d experiment mean=21 yr pure caffeine 250 mg Caffeine was associated with increased skin conductance level, a global reduction in EEG power Barry et al.,
(Australia) n=18 (5 M) [3.6 mg/kg] in the alpha band, and a global increase in alpha frequency. There were no cardiovascular effects 2005
(HR, systolic and diastolic BP).
1-d experiment 17-46 yr pure caffeine 250 mg Auditory changes: the major ERP effects of caffeine were focal rather than global increases in Barry et al.,
(Australia) n=24 (8 M) [3.6 mg/kg] P1, P2 and P3b amplitudes to Go stimuli, with no changes in latency. There were no effects on 2007
N1 or N2 to Go stimuli, and no effects on any components in response to NoGo stimuli.
1-d experiment 17-36 yr pure caffeine 250 mg Caffeine was associated with increased skin conductance, increased respiratory rate, and a glob- Barry et al.,
(Australia) n=24 (7 M) [3.6 mg/kg] al reduction in EEG alpha power. There were no significant cardiovascular effects of caffeine- 2008
induced arousal.
1-d experiment 21.8 ± 2.8 yr pure caffeine 250 mg Reduced interference at the level of error rates in the number-digit task and at the level of reac- Kenemans et
(The Nether- n=16 F [3.6 mg/kg] tion times in the color-word task. al., 1999
lands)
1-d experiment 18-55 yr pure caffeine 250 mg Those low in anxiety sensitivity had caffeine-related hypoalgesia; BP increase; mood improved; Keogh and
(UK) n=36 F [anxiety sensi- [3.6 mg/kg] pain tolerance increased. Chaloner,
tivity] 2002
1-d experiment 24-64 yr pure caffeine 250 mg BOLD response altered; change was greater in high users than in low users, and its magnitude Laurienti et
(USA) n=20 (16 M) [3.6 mg/kg] was correlated with caffeine consumption al., 2002
1-d experiment 18-23 yr pure caffeine 250 mg After abstaining for ≥ 12 hr, caffeine improved performance on a visual selective search task Lorist et al.,
(The Nether- (n=30, 8 M); [3.6 mg/kg] followed by a controlled memory search, and increased the amplitude of the N1, N2b, and P3b 1995
lands) 60-72 yr (event-related potentials) in both young and old subjects.
(n=15, 4 M)
1-d experiment 26-52 yr pure caffeine 250 mg Caffeine deprivation for 4 hr was associated with decreased vigor and increased fatigue and with Phillips-Bute
(USA) n=31 (13 M) [3.6 mg/kg] symptoms including sleepiness and yawning. BP was lower by 5-6 mm Hg. No changes in psy- and Lane,
chomotor performance were observed. 1998
1-d experiment 20-25, 50-65 caffeine, all 250 mg Improved psychomotor performance and cognitive functioning in both groups (20-25 and 50-65 Rees et al.,
(UK) yr; n=48 sources [3.6 mg/kg] yr), particularly in offsetting declining performance over time in the older subjects; alertness 1999
M+F increased.
1-d experiment 18-28 yr pure caffeine; 250 mg Caffeine increased self-rated alertness and jitteriness (but not subjective anxiety) and BP. Rogers et al.,
(UK) n=48 M+F theanine [3.6 mg/kg] Theanine antagonized the effect of caffeine on BP but did not significantly affect jitteriness, 2008
alertness, or other aspects of mood. Theanine slowed overall reaction time on the visual probe
task.
50
1-d experiment 20-25 yr pure caffeine 250 mg ERP data revealed more positive frontal P2 and parietal P3 components, but a combination of Ruijter et al.,
(The Nether- n=12 (4 M) [3.6 mg/kg] different indices of the behavioral data did not show any effects of caffeine intake. 2000a
lands)
1-d experiment Adult pure caffeine 250 mg ERP changes indicating a higher overall arousal level, more profound processing of both at- Ruijter et al.,
(The Nether- n=11 M+F [3.6 mg/kg] tended and unattended information, and an acceleration of motor processes. 2000b
lands)
1-d experiment 20-25 yr pure caffeine 250 mg ERP changes suggesting that caffeine has no specific influence on spatial-selective attention, but Ruijter et al.,
(The Nether- n=11 (4 M) [3.6 mg/kg] has a more general facilitating effect on perceptual processing and possibly on focusing attention 2000c
lands) and increasing selectivity.
1-d experiment Adult pure caffeine 250 mg Caffeine effects on psychomotor performance occurred after some time delay relative to changes Seng et al.,
(Singapore) n=20 M [3.6 mg/kg] in plasma caffeine concentration. 2010
1-d experiment 20-46 yr pure caffeine 250, 500 mg Pleasant subjective effects at 250 mg and unpleasant at 500 mg (anxiety, irritability, nausea, Kaplan et al.,
(USA) n=12 (5 M) [3.6, 7.1 mg/kg] palpitations); enhanced performance on digit symbol substitution test and tapping speed test at 1997
250 mg greater than at 500 mg; EEG changes at both doses; metabolism impaired at 500 mg.
1-2 d experi- mean 25-28 pure caffeine 4 mg/kg Improved sustained attention and delayed free recall but not memory prediction; there was some Kelemen and
ment (USA) yr evidence that expectancies about caffeine were related to cognitive performance. Creeley,
n=142 M+F 2001
1-2 d experi- ~23 ± 7 yr pure caffeine 4 mg/kg Participants who drank the same beverage on both days (either caffeine or a placebo) recalled Kelemen and
ment (USA) n=83 (29 M) more word pairs than did those who drank different beverages (caffeine on 1 day and a placebo Creeley,
on the other day). 2003
1-d experiment mean 22.6 yr pure caffeine 280 mg Caffeine improved vigilance (reaction time and accuracy on the rapid visual information proc- Harrell and
(USA) n=60 (19 M) [4.0 mg/kg] essing task; affected by expectation) and improved psychomotor performance (finger tapping Juliano,
task; unaffected by expectation). Impair instructions produced greater negative somatic effects 2009
than enhance instructions, but only when caffeine was administered.
1-d experiment Adult pure caffeine 4 mg/kg Increased mental alertness; improved performance on tasks of sustained attention, semantic Smith et al.,
(UK) n1=48 (24 [breakfast] memory, logical reasoning, free recall and recognition memory; increased BP; no interaction 1994a
M); n2=48 with breakfast.
(24 M)
1-d experiment 23-38 yr pure caffeine 300 mg A significantly poorer motor steadiness performance was found after ingestion of caffeine vs. a Bovim et al.,
(Norway) n=24 F [4.3 mg/kg] placebo (decaffeinated coffee). Both error time and error count were increased after caffeine 1995
consumption. Caffeine also tended to reduce maze coordination test performance.
51
1-d experiment 28 ± 9 yr pure caffeine 300 mg No effect on any evaluated marksmanship measure (engagement time, friend-foe discrimination, Gillingham
(Canada) n=13 M [mild cold [4.3 mg/kg] accuracy, and precision), but caffeine did alleviate cold stress and fatigue. et al., 2003
stress]
1-d experiment Adult pure caffeine 300 mg (in 3 Caffeine abstinence selectively influenced subjective effects without altering social behavior or Comer et al.,
(USA) n=12 (10 M) doses) performance on tasks assessing memory, vigilance, and psychomotor skills in habituated sub- 1997
[4.3 mg/kg] jects.
1-d experiment 19-31 yr pure caffeine; 300 mg (split Decreased EEG power across almost all conditions; enhanced vigilance performance; level of Gilbert et al.,
(USA) n=12 M smoking dose) depressive mood depended on an interaction of caffeine and nicotine. 2000
[4.3 mg/kg]
1-d treatment; 4 18-48 yr caffeine, all ≥300 mg/d Significant increases in alpha and theta absolute power accompany the caffeine withdrawal pro- Reeves et al.,
d withdrawal n=13 M+F sources [≥4.3 mg/kg] cess with return to the pre-abstinent EEG levels when caffeine usage is resumed. 1995
(USA)
1-d treatment; 4 18-48 yr caffeine, all ≥300 mg/d Quantitative EEG changes; most of these changes returned to pre-abstinence baseline levels rap- Reeves et al.,
d withdrawal n=13 M+F sources [caf- [≥4.3 mg/kg] idly after resuming caffeine consumption. 2002
(USA) feine-
deprived]
1-d experiment 26-50 yr pure caffeine mean 333 mg/d Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and Jones et al.,
(USA) n=10 (4 M) [caffeine- [4.8 mg/kg/d] quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of 2000
deprived] headache, drowsiness and decreased alertness.
1-d experiment mean 21.47 pure caffeine 5 mg/kg Alertness increased; felt more vigorous and less fatigued; no effects on memory or on feelings of Herz, 1999
(USA) yr n=48 (24 pleasure.
M)
1-d experiment Adult pure caffeine; 5 mg/kg Caffeine improved performance on the hand-eye coordination test but not on basic mathematics, Scott et al.,
(USA) n=31 M+F exercise simple response, logical reasoning, or spatial and assembly skills; significant rise in anxiety after 2002
caffeine consumption, persisting at post-test.
1-d experiment 19-26 yr; 65- pure caffeine 5 mg/kg lean Systolic and diastolic BP increased in old but not young men; tension-anxiety and anger de- Arciero et
(USA) 80 yr mass creased in old men, while anger increased in young men; norepinephrine increased in old men al., 1998
n1=n2=10 M only.
1-d experiment 18-22 yr pure caffeine 5 mg/kg fat-free Systolic and diastolic BP increased in the older F, but only diastolic BP increased in younger F; Arciero and
(USA) (n=10 F); 50- [age] mass HR decreased in both groups; feelings of tension-anxiety and vigor increased and feelings of Ormsbee,
67 yr (n=10 fatigue decreased (p < 0.05) in younger F, but depression decreased in older F; the level of phys- 2009
F) ical activity was inversely related to change in diastolic BP in younger F.
52
1-d experiment 21-56 yr pure caffeine 360 mg/d On withdrawal, 27 subjects reported tiredness and 18 developed headache. EEG, skin conduc- Lader et al.,
(UK) n=40 (19 M) [5.1 mg/kg/d] tance and BP changes were apparent. Sleep improved on withdrawal but subjects reported feel- 1996
ing less alert and more tired. The higher the usual caffeine intake (mean was 360 mg/d), the
greater the unpleasant feelings on withdrawal and the more marked the reversal of feelings on
resumption. The faster the metabolism of caffeine (assayed using 500 mg caffeine), the less the
drop in anxiety during withdrawal and the less its return on resumption. These correlations were,
however, rather weak and sporadic.
1-d experiment 18-41 yr caffeine, all 400 mg High consumers, but not moderate consumers, demonstrated significantly faster simple and Attwood et
(UK) n=49 (18 M) sources [5.7 mg/kg] choice reaction times after caffeine relative to placebo. These effects were not attributable to al., 2007
obvious group differences in withdrawal or tolerance because there were no group differences in
baseline mood or in reports of negative affect after caffeine.
1-d experiment 21-38 yr pure caffeine 400 mg Altered EEG visual evoked potential (P300); improved cognitive performance (non-significant Deslandes et
(Brazil) n=15 (6 M) [5.7 mg/kg] decrease in reaction time and Stroop execution time, and increased Stroop raw score). al., 2004;
2005
1-d experiment 19-40 yr pure caffeine 400 mg Increased startle blink reflexes and skin conductance responses; alertness increased; BP in- Flaten et al.,
(Norway) n=94 (29 M) [5.7 mg/kg] crease; skin conductance increase. 2004
1-d experiment 20-47 yr pure caffeine 400 mg Patients panicking after caffeine administration (14/40, 4 M) had reduced post-challenge breath- Masdrakis et
(Greece) n=40 (12 M) [psych disor- [5.7 mg/kg] holding duration, which was not related to higher anxiety levels-as reflected in the State-Trait al., 2009
der] Anxiety Inventory-State Form scores, independently of the occurrence of a panic attack. Panick-
ers had significantly lower baseline breath-holding duration, compared to non-panickers.
1-d experiment 26.5 ± 2.0 yr pure caffeine 6 mg/kg Increased occurrence of self-sustained firing in tibialis anterior motor unit. Walton et
(Canada) n=7 M al., 2002
1-d experiment 26.5 ± 2.0 yr pure caffeine 6 mg/kg Increased spinal excitability. Walton et
(Canada) n=7 M al., 2003
1-d experiment ~34-44±14 pure caffeine 480 mg There was an association between panic attacks in patients with panic disorder and patients with Nardi et al.,
(Brazil) yr n=109 (27 [psych disor- [6.9 mg/kg] major depression, and hyper-reactivity to an oral caffeine challenge test. 2007a
M) der]
1-d experiment ~38 ± 14 yr pure caffeine 480 mg A panic attack was induced in 45.8% of patients during the caffeine test. All patients who had a Nardi et al.,
(Brazil) n=70 (45 M) [psych disor- [6.9 mg/kg] panic attack during the caffeine test also had a panic attack during the CO2 test. The responsive 2007b
der] subjects had respiratory panic disorder (PD) subtype more often, the disorder started earlier, a
higher familial prevalence of PD, less previous alcohol abuse, and more previous depressive
episodes.
53
1-d experiment ~33.9 ± 13 yr pure caffeine 480 mg Panic disorder patients and their first-degree relatives were more sensitive than healthy volun- Nardi et al.,
(Brazil) n=74 (21 M) [predisposi- [6.9 mg/kg] teers to the panic attack symptoms from caffeine intake, but less sensitive to headache, increase 2008
tion to panic] in BP, and insomnia.
1-d experiment ~38 ± 10 yr pure caffeine 480 mg The panic disorder and performance social anxiety disorder patients had more panic attacks, Nardi et al.,
(Brazil) n=98 F [psych disor- [6.9 mg/kg] some specific anxiety symptoms, and a more severe anxiety response than generalized social 2009
der] anxiety disorder patients and normal volunteers.
1-d experiment Intolerant: pure caffeine 10 mg/kg The caffeine-intolerant individuals, but not the regular caffeine users, experienced psychological Dager et al.,
(USA) 31.3 ± 6.4 yr [caffeine in- and physiological distress in response to caffeine ingestion (8/9 intolerant individuals had severe 1999
(n=9); users: tolerant] anxiety; 1/9 tolerant had mild anxiety). Significant increases in global and regionally specific
39.6 ± 11.6 brain lactate were observed only among the caffeine-intolerant subjects. Re-exposure of the reg-
yr (n=9) ular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical re-
M+F action but significant rises in brain lactate similar to the caffeine-intolerant group.
1-d experiment 21.4 ± 2.3 yr pure caffeine; 10 mg/kg Caffeine consumption did not influence the amplitude of the soleus H-reflex, but it did increase Motl and
(USA) n=16 M exercise state anxiety; acute exercise reduced the soleus H-reflex after either caffeine or placebo, but Dishman,
reduced state anxiety only after caffeine; there was no relationship between changes in the so- 2004
leus H-reflex and state anxiety.
1-d experiment 25.1 ± 3.8 yr pure caffeine; 800 mg State anxiety was elevated by caffeine, which was reduced by exercise. Youngstedt
(USA) n=11 M exercise [11 mg/kg] et al., 1998
1-d experiment mean=38 yr pure caffeine 400 mg + (400- Caffeine facilitated speed of response to incoming information but decreased utilization of op- Streufert et
(USA) n=24 (22 M) 1000) mg/d portunity; no effect on managerial effectiveness (activity, breadth, strategy, and emergency real., 1997
[11-20 mg/kg] sponse).
7-d experiment 18-52 yr pure caffeine 5.25 mg/kg/d (in No evidence that caffeine improved performance, either from acute or habitual use; subjects James, 1998
(Australia) n=36 (18 M) [caffeine- 3 doses) were more alert and less tired from acute exposure but less alert from chronic exposure; with-
deprived] drawal was associated with headache and sleeping longer and more soundly.
7-d experiment Adult pure caffeine 5.25 mg/kg/d (in Caffeine had no significant net enhancing effects for either performance or mood when partici- James et al.,
(Ireland) n=96 M+F [caffeine- 3 doses) pants were rested, and produced no net restorative effects when performance and mood were 2005
deprived; degraded by sleep restriction.
sleep depri-
ved]
54
7-d experiment Adult pure caffeine 5.25 mg/kg/d (in Caffeine challenge and acute caffeine withdrawal caused few effects in EEG theta and alpha Keane et al.,
(Ireland) n=22 M+F [caffeine- 3 doses) bandwidths, which casts doubt on whether caffeine has direct stimulant effects. Results could 2007
deprived] suggest that change in drug state, whether from acute caffeine withdrawal or challenge, may be
disruptive to electrophysiological activity in the brain.
7-d experiment 23-38 yr pure caffeine 400 mg/d (split In caffeine-habituated and naïve subjects, caffeine decreased cerebral artery blood velocity Watson et
(UK) n=12 (6 M) dose) for 7 d, (more for caffeine-naïve); increased systolic BP similar in two groups but more sustained over al., 2002
then 200 mg time in naïve subjects; cognitive performance was unaffected; chronic consumers (400 mg/d,
[5.7 mg/kg/d] split dose) were more tense at baseline. The results suggest that tolerance is incomplete with
respect to both peripheral and central effects of caffeine.
14-d experiment ~29 ± 1.5 yr pure caffeine 100, 300, 600 Caffeine withdrawal symptoms were similar when 300 mg was consumed as 1 or 3 doses; symp- Evans and
(USA) n1=15; mg; 3 x 100 mg toms increased with maintenance dose (100, 300, and 600 mg/d); those on 300 mg caffeine/d Griffiths,
n2=17; [1.4-8.6 mg/kg/d] had withdrawal from ≤100 mg/d but not 200 mg/d; withdrawal of those on 300 mg/d occurred 1999
n3=19; after ≥3 d exposure (not 1 d), with greater severity after 7 or 14 d exposure.
n4=25 M+F
≥14-d experi- 24–54 yr pure caffeine 400 mg/d Acute caffeine abstinence (evaluated 24 hr after placebo substitution) increased cerebral blood Sigmon et
ment n=16 (4 M) [caffeine- [5.7 mg/kg/d] flow, altered the EEG, and increased measures of tired, fatigue, sluggish, and weary and deal., 2009
(USA) deprived] creased ratings of energetic, friendly, lively, and vigor. Tolerance and "complete" tolerance were
observed on subjective but not physiological measures. Chronic caffeine effects were demon-
strated only on the measure of EEG beta 2 power.
BOLD=blood-oxygenation-level-dependent; BP=blood pressure; CHO=carbohydrate; DBP=diastolic blood pressure; ED=energy drink; EEG=electroencephalograph;
ERP=event-related potential(s); HR=heart rate; SBP=systolic blood pressure
55
TABLE 2-2. Cognitive and Psychomotor Effects of Caffeine – Case Reports and Epidemiological Studies
Study type; Subject age; Test material Caffeine
country number; sex [condition] dose(s)
Case report 11 yr; 13 yr caffeine, all 3-7 serv- Appearance and disappearance of tics were correlated with ingestion (few days) and elimination Davis and
(USA) n=2 M sources ings/wk [0.5- of caffeine in the diet behavior change [No info on caffeine per serving; assume BW 35-50 kg, Osorio, 1998
1.1 mg/kg/d] 40 mg caffeine per serving (cola)]
Case report 13-46 yr ED 250-500 mg Nausea, vomiting, tachycardia, jittery, anxious, tremors, dizziness, chest pain, bilateral numb- Walsh et al.,
(USA) n=9 (8 M) [4-11 mg/kg] ness; BP increase. [ED=Redline; concentrate=250 mg/5cc (1 tsp); ready to drink (RTD) =250 2006
mg/8 oz; the ED contains vinpocetin and yohimbine, which likely potentiate the effects of caf-
feine] [Assumed BW of 45-70 kg for dose estimates]
Case-control 7-17 yr caffeinated mean 5.3 serv- Youth with major depressive disorder reported more caffeine use and sleep problems than Whalen et al.,
(USA) cases=30; drinks [major ings/d [~3-10 healthy youth, and more anxiety on days they consumed caffeine; when caffeine use decreased 2008
controls=23 depressive mg/kg/d] across treatment, sleep complaints remained elevated. [No info on caffeine per serving; assumed
(36% M) disorder] 40 mg/serving cola and BW of 20-65 kg for dose estimates]
Cohort prospec- 13-17 yr caffeinated mean 259 mg/d Caffeine-dependent adolescents had a tendency to more anxiety and depression. [assume BW of Oberstar et
tive (USA) n=21 M+F drinks [4.3 mg/kg/d] 60 kg] al., 2002
Cross-sectional 13-17 yr coffee; cola; mean 244 mg/d Similar intake for those with or without caffeine dependence; higher anxiety and depression Bernstein et
(USA) n=36 (21 M) tea [4 mg/kg] scores in dependent users; those with other drug abuse ingested more caffeine; caffeine depend- al., 2002
ence not associated with increased comorbid diagnoses, use of alcohol or street drugs in the prior
year, or severity of substance abuse. [Assumed BW of 60 kg for dose estimate]
Cross-sectional M=14.9± 1.7 caffeine, all M:44.2, 51.9, Total caffeine consumption was positively associated with depressive symptoms among both M Fulkerson et
(USA) yr; F=14.7± sources 64.1 mg/d; F: and F. Coffee use was significantly associated with depressive symptoms in M, with reports of al., 2004
1.7 yr 38.6, 42.8, daily servings of coffee highest in the high-depressive symptom group, who reported a higher
n=4734 (50% 53.6 mg/d [0.6- mean number of daily servings of soft drinks than M in the low- or moderate- depressive symp-
M) 1.2 mg/kg/d] tom groups (38.6, 42.8, 53.6 mg/d, respectively). Consumption of diet soft drinks was not associ-
ated with depressive symptoms. [Assumed BW of 45-65 kg for dose estimates]
56
Cross-sectional 10-16 yr caffeinated none; "high" Somatic complaints of headache, stomachache, backache, and morning fatigue are common Ghandour et
(USA) n=8250 F drinks among U.S. adolescent girls and co-occur often. Heavy alcohol use, high caffeine intake, and al., 2004
smoking cigarettes every day were strongly associated with all symptoms. A dose-response was
observed between the prevalence of frequent symptoms and the increasing levels caffeine con-
sumption. For example, the proportion of frequent headache sufferers increased 30 percentage
points between low- and high-caffeine consumers (data not provided). [No further info on caf-
feine intake]
Cross-sectional 6-18 yr Cola mean 193 mg/d Withdrawal from cola drinks led to complete cessation of all headaches in 33/36 subjects. [As- Hering-Hanit
(Israel) n=36 (19 M) [3-10 mg/kg] sumed BWs ranging from 20-70 kg for dose estimate] and Gadoth,
2003
Cross-sectional 14-16 yr (9th caffeinated 0, 1, 2, 3, 4, 5, Caffeine use was very strongly related to licit substance use (alcohol, nicotine) (beta =0.44), James et al.,
(Iceland) &10th grade) drinks ≥6 servings/d moderately related to sleepiness (beta=0.18), and strongly inversely related to academic 2010
n=7377 [0.7 to ≥4.0 achievement (beta= -0.27). [No info on caffeine per serving; assume 40 mg/serving from cola
(49.8% M) mg/kg/d] and BW of 60 kg for dose estimate]
Cross-sectional 10-12 yr caffeinated ~2.1 mg/kg/d Fifth graders had more psychological and stimulating effects than 10th graders; depression was Luebbe and
(USA) (n=135, 60 drink, carbon- positively related to caffeine use for both cohorts, though mediated by caffeine withdrawal ef- Bell, 2009
M); 15-17 yr ated fects.
(n=78, 39 M)
Cross-sectional 14 ± 2 yr caffeinated 0-1, 2-3, ≥4 High users (≥4 drinks/d [2.6 mg/kg]) had more aggressive behavior, attention deficit, social prob- Martin et al.,
(USA) n=132 M+F drinks [psych drinks/d lems, unspecified somatic complaints, and cigarette smoking. [No info on caffeine per drink; 2008
disorder] [0.7-2.7 assume 40 mg/drink cola, assume BW of 60 kg for dose estimate]
mg/kg]
Cross-sectional 14-20 yr coffee <1 cup/wk, <1 High (≥ 1 cup/d [1.5 mg/kg/d]) consumption of coffee (OR=2.4; 1.3-4.7) (also cocktails, smok- Milde-Busch
(Germany) n=1260 (47% cup/d, ≥ 1 ing, and lack of physical activity) were associated with migraine and tension-type headache epi- et al., 2010
M) cup/d [up to sodes [No info on caffeine per cup; assumed 100 mg/cup; assumed BW of 65 kg for dose esti-
>1.5 mg/kg/d] mate]
Cross-sectional 5-72 yr caffeinated + or – Of 887 Germans in a Tourette outpatient clinic, 34% and 47% assessed that coffee and coke, re- Muller-Vahl
(Germany) n=224 (76% drinks [Tou- [~1.5 mg/kg/d] spectively, deteriorate tics [No info on caffeine intake; assume 1 serving per episode of 1 cup et al., 2008
M) rette syn- coffee for adults (100 mg), or 1 can soda for children (40 mg); child BW assumed 25 kg]
drome]
57
Cross-sectional 11 yr; 13 yr; coffee 0, 1, 2-4 Drinking coffee was not correlated with fatigue. [No info on caffeine per cup; assume 100 Tynjala et al.,
(Finland) 15 yr; cup/wk, 1, >1 mg/cup; assume BW of 35-65 kg for dose estimate] 1997
n = 4187 cup/d
(49.6% M) [1.5-3 mg/kg]
STUDIES WITH ADULTS
Case report 24 yr caffeinated ~900 mg/d Muscular weakness, paralysis, increased serum CPK, AST, urinary sodium, potassium, magne- Appel and
(USA) n=1 F drink, carbon- [13 mg/kg] sium, and protein; hypokalemia; seen after “several months” of high caffeine intake. Subject was Myles, 2001
ated a pregnant malnourished asthmatic.
Case report 40 yr Coffee up to 10 cups/d Case of a man with a partial symptomatic epilepsy whose daily habit "lately" of heavy coffee Boniha and
(Brazil) n=1 M [epilepsy] [≤14 mg/kg/d] drinking was associated with an increased seizure frequency. He had a dramatic decrease in the Li, 2004
frequency of seizures after stopping coffee ingestion. [No info on caffeine per cup coffee; as-
sume 100 mg/cup.]
Case report 46 yr cola; smoking 460-575 mg/d Man who was taking anti-psychotic drugs (haloperidol, biperiden, lithium carbonate) with high Caykoylu et
(Turkey) n=1 M [psych disor- [6.6-8.2 amount of caffeinated cola (duration not specified) developed delusions, auditory hallucinations, al., 2008
der] mg/kg] grandiosity, aggressive behaviors, psychomotor agitation, excitation, logorrhea, irritable mood,
and decreased need for sleep. The symptoms reduced after caffeine intake was stopped.
Case report 43 yr ED; haloperi- 1.3-1.6 g caf- Excessive caffeine intake for 8 wk resulted in paranoia and delusions; symptoms improved after Cerimele et
(USA) n=1 M dol [alcoholic feine/day (~20 discontinuing use of ED; patient managed schizophrenia with haloperidol. [ED was not identi- al., 2010
in remission; mg/kg/d) fied but contained 160 mg caffeine/16 oz can]
schizophre-
nia]
Case report 41 yr; 38 yr; ED 400-800 mg/d Case hospitalizations were associated with deterioration of mental state, manifested by hypervigi- Chelben et al.,
(Israel) 25 yr [psych disor- [5.7-11 mg/kg] lance, psychomotor unease, and intensified affected responses; anxiety; BP increase; HR in- 2008
n=3 (1 M) der] crease; hyperthermia. [ED were taurine-containing but were not identified]
Case report 47 yr Coffee 36 cups/d High coffee intake resulted in delusions and paranoia (at presentation, he was taking paroxetine, Hedges et al.,
(USA) n=1 M [psych disor- [51 mg/kg] alprazolam, clonazepam, and propranolol); symptoms resolved within 7 weeks after lowering 2009
der] caffeine intake. [No info on caffeine per cup; assume 100 mg/cup]
58
Case report 19-28 yr ED 480 mg ± "diet Four patients had discrete seizures, BP increase, headache, and also in some cases tachycardia on Iyadurai and
(USA) n=4 M+F pills" multiple occasions, following heavy consumption of EDs. Abstinence from the ED eliminated the Chung, 2007
[>7 mg/kg/d] seizures. [Intake EDs were (1) two bottles of the 24-oz ED Rockstar on an empty stomach (2)
ED unknown (‘‘couple of 24-oz cans’’); (3) Monster ED + caffeinated diet pills; (4) ≥2 cans
Monster ]
Case report 36 yr tea, oolong ≤ 3 g/d Excessive tea intake for ~8 d resulted in delirium, acute renal failure, markedly elevated CPK Kamijo et al.,
(Japan) n=1 M [schizophre- [50 mg/kg] (rhabdomyolysis), and hyponatremia. [Assume BW of 60 kg] 1999
nia]
Case report 18 yr pure caffeine 10 g Cardiovascular collapse; sweating; anxiety/irritability; nausea or vomiting survived after treat- Kapur and
(USA) n=1 M [140 mg/kg/d] ment with lidocaine and phenylephrine and hemodialysis. Smith, 2009
Case report 49 yr Tea [epilepsy] 168 mg/d Increase in myoclonic and atonic seizures after excessive tea consumption for ~2 months; pa- Kaufman and
(USA) n=1 M [2.4 mg/kg] tient’s seizure frequency returned to baseline upon cessation of intake (patient was taking pheny- Sachdeo,
toin and primidone). [tea= Peach Diet Snapple Iced Tea] 2003
Case report 36 yr ED [bipolar I 240 mg Intake of 3 cans ED caused a manic episode; hyperactive, insomnia, increased libido, irritability Machado-
(Brazil) n=1 M disorder] [3.4 mg/kg] [ED=Red Bull] Vieira et al.,
2001
Case report 54 yr cola 1179 mg Excessive intake on one occasion caused seizures; plasma creatine kinase increased (rhabdo- Mortelmans et
(Belgium) n=1 F [17 mg/kg] myolysis); hyponatremia. [cola=diet Coke] al., 2008
Case report 40 yr; 59 yr pure caffeine; >1 g/d; 1.4 g/d Excessive caffeine intake over a 1-2 month period led to caffeine tolerance/addiction; anxiety, Ogawa and
(Japan) n=2 (1 M); ED [20 mg/kg] hyperactivity, impulsiveness, psychological decrement, and sleep disturbance. [ED was unspeci- Ueki, 2007
fied Japanese drink]
Case report 15 yr; 32 yr pure caffeine >10 g Cardiac arrest; sinus tachycardia; anxiety/irritability; seizures or convulsions nausea or vomiting; Shum et al.,
(USA) n=2 F [>140 mg/kg] premature death. 1997
Case report 52 yr caffeinated 20-25 cups/d Psychotic relapse characterized by predominant delusions of persecution; his sleep was disturbed Tibrewal and
(Australia) n=1 M drinks [schiz- [29-36 mg/kg] and he was noted to be markedly agitated on admission; symptoms resolved upon caffeine re- Dhillon, 2010
ophrenia] striction (treated with risperidone, olanzapine). [No info on caffeine per cup; assume 100
mg/cup]
Case report 28 yr ED + coffee ~480 mg +cof- Sudden onset of tonic-clonic seizures and metabolic acidosis after drinking several cans of a caf- Trabulo et al.,
(Portugal) n=1 M fee [7 mg/kg] feinated ED. [ED=Red Bull; no info on caffeine from coffee intake] 2011
59
Case-control 20-76 yr coffee; tea median: 2300 No significant correlation between caffeine intake and disease duration or total tremor score in Prakash et al.,
(Singapore) cases=79; [essential mg-years vs. essential tremor patients. 2006
controls=100 tremor] 1500 for con-
M+F trols
Case-control 18-65 yr caffeine, all mean ~300 Association of caffeine intake with headache seen only for younger (age <40) women and those Scher et al.,
(USA) cases=206; sources mg/d with chronic episodic headaches, without physician consultation and of recent (<2 years) onset. 2004
controls=507 [4.3 mg/kg/d]
M+F
Cross-sectional Adult coffee; smok- 0 or 3.0 ± 2.0 Coffee drinking was significantly and independently associated with suicidal acts [OR = 2.42; CI Baethge et al.,
(Sardinia; Italy) n=352 M+F ing [bipolar cups/d [mean 1.15-5.09]. Risk increased with greater coffee consumption (cups/day; r(s) = 0.312; p = 0.008). 2009
disorder] 4.3 mg/kg/d] Intake was not related to yearly rates of all episodes, depressions, or manias. [No info on caf-
feine per cup coffee; assumed 100 mg/cup]
Case-control 18-65 yr caffeine, all 630±549 vs. Patients suffering from eating disorders reported higher current caffeine intake than those with Ciapparelli et
(Italy) cases=369; sources 504±344 mg/d anxiety or mood disorders. The prevalence of dependence and intoxication was significantly al., 2010
controls=104 [psych disor- lifetime [7.1-9 higher in patients than in healthy subjects, without inter-group differences. Healthy subjects
M+F der] mg/kg/d] showed a trend towards a higher prevalence of withdrawal.
Cross-sectional 45.8 ± 2.69 caffeine, all ≤80, 81-160, Caffeine dietary intake was positively associated with premenstrual anxiety and mood changes, Gold et al.,
(USA) yr sources 161-240, 241- but not in a monotonic dose-response (significant for 241-320 mg/d only [4.0-5.3 mg/kg/d]). 2007
n=3302 F 320, ≥321 [Assumed BW of 60 kg for dose estimates]
mg/d [1.3 to
≥5.3 mg/kg/d]
Cross-sectional ≥20 yr caffeinated 0-240, 241- Intake of >500 mg/d caffeine [7.1 mg/kg/d] was associated with greater prevalence of infrequent Hagen et al.,
(Norway) n=50,483 drinks, medi- 400, 401-540, headache. 2009
(40% M) cation >540 mg/d
[<4.6 to >7.7
mg/kg/d]
Cross-sectional 24-81 yr coffee; tea 0, 0-2, 3-5, 6- Habitual caffeine consumption was related to better long-term memory performance and faster Hameleers et
(The Nether- n=1875 M+F 9, >9 cups/d locomotor speed, but not to short-term memory, information processing, planning, and attention al., 2000
lands) [1.9 to >13 as measured with the Stroop Test. No difference was found in sensitivity to caffeine intake be-
mg/kg/d] tween different age groups, suggesting that caffeine intake did not counteract age-related cogni-
tive decline. [No info on caffeine per cup; assume 100 mg/cup]
60
Cross-sectional ~36 ± 8 yr caffeine, all heavy use was The resemblance in twin pairs for total caffeine consumption, caffeine use, caffeine intoxication, Kendler and
(USA) n=1934 F sources [geno- ≥625 mg/d caffeine tolerance, and caffeine withdrawal were greater in monozygotic than in dizygotic twin Prescott, 1999
type] [10 mg/kg/d] pairs; model fitting suggested broad heritabilities of between 35% and 77% [Assumed estimates
of caffeine content: brewed coffee, 125 mg/cup; instant coffee, 90 mg/cup; tea, 60 mg/cup; caf-
feinated soft drinks, 40 mg/can]
Cross-sectional 37.9 ± 8.9 yr caffeinated <, ≥625 mg/d Maximal caffeine use, heavy caffeine use, and caffeine-related toxicity and dependence were Kendler et al.,
(USA) n=3600 (48% drinks [geno- [8.9 mg/kg/d] significantly and positively associated with psychiatric and substance use disorders. However, 2006
M) type] within monozygotic twin pairs, controlling for genetic and family environmental factors, these
associations, while positive, were all non-significant. ['heavy use' = consume caffeine at least
several days per week at ≥ 625 mg/d (=5 cups of ground coffee)]
Cross-sectional ~64 ± 1 yr caffeine, all 226-504, 505- Higher quartiles of caffeine intake were associated with slower digit symbol speed (F =3.38, p< Kyle et al.,
(UK) n=351 (176 sources 634, 635-751, 0.02) but this finding was removed after allowing for socioeconomic status. No evidence was 2010
M) 743-1134 mg/d found in support of cognitive enhancing effects of caffeine.
[3.2-16
mg/kg/d]
Cross-sectional 20-29 yr caffeine, all <100, 100-200, The 14 withdrawal symptoms were grouped into three factors termed "fatigue and headache", Ozsungur et
(Canada) n=495 (126 sources >200 mg/d "dysphoric mood", and "flu-like somatic". The likelihood of reporting the fatigue and headache al., 2009
M) [<1.4 to >2.9 and dysphoric mood factors, but not flu-like symptoms, increased with higher levels of habitual
mg/kg/d] caffeine consumption.
Cross-sectional M=74.2 ± caffeine, all ≤1, 2-3, >3 Caffeine consumption was associated with lower cognitive change over time for F only; it was Ritchie et al.,
(France) 5.6y; F=74.4 sources units/d dose-dependent and temporarily related. White matter lesion/cranial volume ratios were lower in 2010
± 5.6 yr [≤1.4 to >4.3 F consuming >3 units of caffeine/d after adjustment for age than in F consuming 3 units or less.
n=641 (317 mg/kg/d] [1 unit = 100 mg caffeine]
M)
Cross-sectional 20-69 yr caffeine, all 100 mg/d Total daily caffeine intake of 100 mg inclusive of green tea, black tea, coffee and other caffeine- Shimbo et al.,
(Japan) n=380 (46- sources; tea, [1.4 mg/kg/d] containing beverages was associated with a higher risk of mental ill-health among F; brewed 2005
49% M) green green tea was not associated with decreased mental ill-health among either M or F.
Cross-sectional 18-65 yr caffeine, all mean 4.7 Neither in those with a high consumption of coffee: ≥10 cups a day (n = 134), nor in those with a Sjaastad and
(Denmark) n=1741 M+F sources cups/d considerable variation in consumption: ≥10 cups/day (n = 31) did there seem to be a definite in- Bakketeig,
[6.7 mg/kg/d] crease in headache resembling caffeine-withdrawal headache, for instance during weekends. 2004
[Cited 75-99 mg/cup; 1 cup=150 mL; used 100 mg/cup for dose estimate]
61
Cross-sectional 18-61 yr caffeine, all < or >220 Higher consumers had greater alertness over the working day and less slowing of reaction time; Smith, 2005
(UK) (n1=110, sources mg/d median secondary data analysis study (n2=41 yr (1253, 55% M); n3=40 yr (1555, 60% M)) showed that
46% M) [3.1 mg/kg/d] higher caffeine consumption was associated with about half the risk of frequent/very frequent
cognitive failures and a similar reduction in risk for accidents at work.
Cross-sectional 17-92 yr coffee; tea 0, 1-140, 141- All caffeine groups had similarly fewer cognitive failures (errors of memory, attention, or ac- Smith, 2009a
(UK) n=3223 (43% 260, >260 tion); dose-related reduced risk of angina and depression.
M) mg/d [≤2.0 to
>3.7 mg/kg/d]
Cross-sectional 21-50 yr caffeine, all mean 357 mg/d In the double-blind caffeine-withdrawal evaluation portion of the study, 9/11 subjects showed Strain et al.,
(USA) n=11 (2 M) sources [5.1 mg/kg] objective evidence of withdrawal, including 8/11 with functional impairment. 1994
Cohort prospec- 30-55 yr at caffeinated Median quin- Use of estrogen replacement hormones was associated with a reduced risk of Parkinson's disease Ascherio et
tive (18 yr fol- baseline drinks; estro- tiles: 68, 189, among F with low caffeine consumption (RR 0.39, 95% CI 0.13 to 1.17), and with increased risk al., 2003
low-up) n=77,713 F gen [post- 321, 421, 688 with high caffeine consumption (RR 2.44, 95% CI 0.75 to 7.86; p for interaction = 0.01). Among
(USA) menopausal] mg/d [1.1 to 11 hormone users, an intake of ≥6 cups/d [10 mg/kg/d] had a 4-fold higher risk of PD (RR 3.92,
mg/kg/d] 95% CI 1.49 to 10.34; p = 0.006) than F who never drink coffee. [Coffee intake categories were
1-6 cups/wk; 1-3, 4-5, ≥6 cups/d, and ≥4 cups/d; for total caffeine intake used 137 mg/cup coffee;
47 mg/cup tea, 46 mg/can cola, 7 mg/serving chocolate candy]
Cohort prospec- 18-90 yr Coffee 0, 1-2, 3-5, ≥6 Caffeine consumption predicted the onset of new headache (dose-response; risk greatest for ≥3 Boardman et
tive (1 yr fol- n=1859 (44% cups/d cups/d [5.7 mg/kg/d]) and recovery from headache (no dose-response), but was not associated al., 2006
low-up) (UK) M) [1.4 to ≥8.6 with changes in headache disability over 1 year; sleep deprivation reversed. [No info on caffeine
mg/kg/d] per cup; assume 100 mg/cup]
Cohort prospec- 25-42 yr caffeine, all <200, 200-399; Long-term caffeine intake and moderate alcohol intake were not associated with seizure or epi- Dworetzky et
tive (follow-up at baseline sources ≥400 mg/d lepsy. The reference group was <200 mg caffeine/day intake. al., 2010
16 yr) (USA) n=95,316 F [<2.9 to ≥5.7
mg/kg/d]
Cohort prospec- ≥ 65 yr at coffee 0-3, 3.5-8, >8 No consistent differences in coffee consumption and cognitive score were observed within dis- Laitala et al.,
tive (28 yr fol- interview; cups/d cordant twin pairs; coffee drinking did not affect the risk of mild cognitive impairment or demen- 2009
low-up) (Fin- n=2606 (52% [≤4.3 to >11 tia. [1 cup = 237 mL, but no info on caffeine per cup; assumed 100 mg/cup]
land) M) mg/kg/d]
62
Cohort prospec- 42, 48, 54, or caffeine, all 0, <375, 375- Heavy caffeine drinkers (>813 mL/d [12 mg/kg/d) had a decreased risk for depression compared Ruusunen et
tive (follow-up 60 yr sources; cof- 813, >813 with non-drinkers, after adjustment for age and examination years; no associations were observed al., 2010
17-22 yr) at baseline fee; tea mL/d between depression and intake of tea or caffeine. Authors assumed 100 mL of coffee and tea
(Finland) n=2232 M [<5.3, 5.3-12, contain 100 mg and 40 mg of caffeine, respectively.
>12 mg/kg/d]
Cohort prospec- 24-81 yr at coffee; tea 0, 1-3, 4-6, 7- Small but significant association between overall caffeine intake at baseline and the 6-year van Boxtel et
tive (6-yr fol- baseline 10, >10 cups/d change in complex motor speed (motor choice reaction time); previously found association be- al., 2003
low-up) (The n=1376 [1.2 to >12 tween caffeine intake and verbal memory performance was not seen. [cups of coffee equiva-
Netherlands) (~50% M) mg/kg/d] lents/d based on 1 cup coffee = 85 mg, 1 cup tea = 30 mg]
ED=energy drink; EEG=electroencephalogram; ERP=event-related potential; RR=relative risk
63
TABLE 2-3. Cognitive and Psychomotor Effects of Caffeine and Caffeine Withdrawal – Summaries of Reviews Reference
Human A1 and A2A subtypes of adenosine receptors are significantly blocked at concentrations of caffeine achieved with single servings of our most Bastia and
favored dietary vehicles, including brewed coffee (~100 mg), tea (~50 mg), cola soda (~45 mg), and even dark chocolate (~40 mg). Beyond the sugges- Schwarzschild,
tion that cAMP serves as a classical second messenger regulated by caffeine, we know little of caffeine’s downstream intracellular targets. A recent report 2003
by Lindskog et al., has now identified DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kD) as an attractive candidate mediator of caf-
feine’s sustained psychomotor effects.
Caffeine-containing over-the-counter products increased risk of migraine progression to chronic migraine. Bigal and Lipton,
2009
Receptor antagonists such as methylxanthines generally exacerbate seizures. The impact of the methylxanthines caffeine and theophylline on seizures and Boison, 2011
excitotoxicity depends on timing, dose, and acute versus chronic use.
Caffeine can cause anxiety symptoms in normal individuals, especially in vulnerable patients, like those with pre-existing anxiety disorders. Caffeine use Broderick and
is also associated with symptoms of depression due to either a self-medication theory, or a theory that caffeine itself causes changes in mood. Psychosis Benjamin, 2004
can be induced in normal individuals ingesting caffeine at toxic doses, and psychotic symptoms can also be worsened in schizophrenic patients using caf-
feine. Sleep and symptoms of ADHD may be altered by caffeine as well.
The main mechanism of action of caffeine occurs via the blockade of adenosine A1 and A2A receptors. Adenosine is a modulator of CNS neurotransmis- Cauli and Morelli,
sion and its modulation of dopamine transmission through A2A receptors has been implicated in the effects of caffeine. The review focuses on the effects 2005
of caffeine mediated by adenosine A2A receptors and on the influence that pre-exposure to caffeine may exert on the effects of classical drugs of abuse.
Genetic knockout animal models have provided insight into (1) the molecular basis for caffeine's effects on psychomotor activity; (2) the involvement of Chen et al., 2010b
adenosine receptors in caffeine-mediated arousal and cognitive effects; and (3) a novel approach using knockout animals coupled with microarray profil-
ing to validate multiple molecular targets of caffeine in striatal gene expression.
The amounts of guarana, taurine, and ginseng found in popular EDs are far below the amounts expected to deliver either therapeutic benefits or adverse Clauson et al.,
events. However, caffeine and sugar are present in amounts known to cause a variety of adverse health effects (insomnia, nervousness, headache, tachy- 2008
cardia, seizures, and death).
Caffeine has weak reinforcing properties, but with little or no evidence for upward dose adjustment, possibly because of the adverse effects of higher Daly and Fred-
doses. Withdrawal symptoms, although relatively limited with respect to severity, do occur, and may contribute to maintenance of caffeine consumption. holm, 1998
Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms (irritability, sleepiness, dysphoria, delirium, nau- Dews et al., 2002
sea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face), but some of these have also been reported
from excess intake of caffeine. It is suggested that non pharmacological factors related to knowledge and expectation are the prime determinants of symp-
toms and their reported prevalence on caffeine withdrawal.
64
Motor and reinforcing effects depend on the ability of caffeine to release pre- and post-synaptic brakes that adenosine imposes on the ascending dopa- Ferre, 2010
minergic system. By targeting A1-A2A receptor heteromers in striatal glutaminergic terminals and A1 receptors in striatal dopaminergic terminals (pre-
synaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potenti-
ated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A-D2 and A1-D1 receptor heteromers. Arousing effects
of caffeine depend on the blockade of multiple inhibitory mechanisms that adenosine, as an endogenous sleep-promoting substance, exerts on the multiply
interconnected ascending arousal systems. Those mechanisms include a direct A1-receptor mediated modulation of the corticopetal basal forebrain system
and an indirect A2A-receptor mediated modulation of the hypothalamic histaminergic and orexinergic systems.
The psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving Fisone et al., 2004
area of the basal ganglia. These cells express high levels of adenosine A2A receptors, which are involved in various intracellular processes, including the
expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDA phosphoprotein DARPP-32.
Caffeine is not a typical drug of dependence. Its weak reinforcing properties are due to a unique and atypical mechanism of action. The drug is self- Fredholm et al.,
limiting and subjects do not gradually increase the dose, because tolerance development to both the reinforcing and aversive effects is limited. Caffeine 1999
interacts with dopaminergic transmission, but the mechanism is very different from that of other drugs such as cocaine and amphetamine.
Caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Survey data sug- Griffiths and
gest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria. Chausmer, 2000
Early studies suggest caffeine self-administration and withdrawal can occur in some adolescent soda drinkers. High doses (>3 mg/kg) of caffeine in chil- Hughes and Hale,
dren who consume little caffeine produce negative subjective effects such as nervousness, jitteriness, stomachaches, and nausea. Caffeine appears to 1998
slightly improve vigilance performance and decrease reaction time in healthy children who habitually consume caffeine but does not consistently improve
performance in children with attention deficit-hyperactivity disorder.
The available evidence shows unequivocally that psychomotor performance is degraded by abrupt cessation of caffeine intake. The interpretation by James, 1994a2
Smith et al., (1993) that caffeine enhances performance is not warranted.
The caffeine-withdrawal syndrome has been well characterized and there is sufficient empirical evidence to consider caffeine withdrawal as a disorder Juliano and Grif-
(valid symptom categories: headache, fatigue, decreased energy/activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, fiths, 2004
difficulty concentrating, irritability, and foggy/not clearheaded; also likely valid categories: flu-like symptoms, nausea/vomiting, and muscle
pain/stiffness).
Moderate caffeine intake (< 6 cups/d) has been associated with less depressive symptoms, fewer cognitive failures, and lower risk of suicide. Conversely, Lara, 2010
in rare cases high doses of caffeine can induce psychotic and manic symptoms, and more commonly, anxiety. Patients with panic disorder and perform-
ance social anxiety disorder seem to be particularly sensitive to the anxiogenic effects of caffeine.
Behavioral measurements indicate a general improvement in the efficiency of information processing after caffeine, while the EEG data support the gen- Lorist and Tops,
eral belief that caffeine acts as a stimulant. Studies using ERP measures indicate that caffeine has an effect on attention, which is independent of specific 2003
stimulus characteristics. Behavioral effects on response related processes turned out to be mainly related to more peripheral motor processes.
Because of its documented ability to enhance cognitive and physical performance during both rested and sleep-deprived states, caffeine (100-600 mg in McLellan et al.,
chewing gum) can be of use during military operations. The use of caffeine has minimal side effects and its use as a drug (as defined in Canada) is well 2003-2004
tolerated and accepted within the military community.
65
In children and adolescents in Nordic countries, low level caffeine exposure caused tolerance development, withdrawal symptoms and anxiety and jitteri- Meltzer et al.,
ness. For tolerance development NOEL- and LOEL-values of 0.3 and 1.0–1.3 mg/kg bw respectively, were established, whereas a LOAEL for anxiety 2008
and jitteriness was identified as 2.5 mg/kg bw.
For healthy adults, caffeine intake up to 400 mg/d (6 mg/kg BW in a 65-kg person) is not associated with general toxicity, cardiovascular effects, effects Nawrot et al.,
on bone status and calcium balance (with consumption of adequate calcium), changes in adult behavior, incidence of cancer, or effects on male fertility. 2003
Lower consumption is recommended for two 'at risk' subgroups: reproductive-aged women should consume ≤300 mg caffeine/d (4.6 mg/kg BW for a 65-
kg person) and children should consume ≤2.5 mg/kg BW.
Although caffeine fulfills some of the criteria for drug dependence and shares with amphetamines and cocaine a certain specificity of action on the cere- Nehlig, 1999
bral dopaminergic system, the methylxanthine does not act on the dopaminergic structures related to reward, motivation and addiction.
Both animal and human studies have indicated that acute caffeine exposure leads to constriction of cerebral vessels and reduced cerebral blood flow, as Pelligrino et al.,
well as diminished neurovascular coupling. Those effects likely arise from inhibitory actions on A1, A2A, and A2B receptors distributed among the neu- 2010
rons, astrocytes and vascular smooth muscle. The principal site of acute caffeine influence on A1 receptors is likely presynaptic nerve endings.
Effects that have been reported from ED use by adolescents include jitteriness, nervousness, dizziness, the inability to focus, difficulty concentrating, GI Pennington et al.,
upset, and insomnia. Health care providers have seen dehydration, accelerated Hr, anxiety, seizures, acute mania, and strokes. 2010
In children and adolescents who are not habitual caffeine users, vulnerability to caffeine intoxication may be markedly increased due to an absence of Reissig et al., 2009
pharmacological tolerance. Genetic factors may also contribute to an individual's vulnerability to caffeine-related disorders including caffeine intoxica-
tion, dependence, and withdrawal. The combined use of caffeine and alcohol may increase the rate of alcohol-related injury. Several studies suggest that
EDs may serve as a gateway to other forms of drug dependence.
Low doses of caffeine may enhance cognitive function, although most studies on caffeine and cognition, as with studies on glucose and cognition, have Riedel and Joris-
not been carried out in elderly individuals. sen, 1998
Under conditions of habitual sleep the evidence indicates that caffeine, rather than enhancing performance, is merely restoring performance degraded by Roehrs and Roth,
sleepiness. Studies have shown that caffeine dependence develops at relatively low daily doses and after short periods of regular daily use. Children and 2008
adolescents, while reporting lower daily, weight-corrected caffeine intake, similarly experience sleep disturbance and daytime sleepiness associated with
their caffeine use.
No age-related differences in the effects of caffeine on psychomotor performance were found. Overall there is little unequivocal evidence to show that Rogers and Der-
regular caffeine use is likely to substantially benefit mood or performance. One of the significant factors motivating caffeine consumption appears to be noncourt, 1998
"withdrawal relief."
Current evidence points to true performance-enhancing effects of caffeine, although the extent of these and the conditions under which caffeine is most Rogers et al., 1995
effective have yet to be fully determined. At the same time, the existence of significant detrimental effects of caffeine deprivation on psychomotor per-
formance has not been ruled out.
66
Chronic caffeine consumption enhances the sensitivity of striatal GABAergic synapses to the stimulation of cannabinoid CB1 receptors. The endocan- Rossi et al., 2010
nabinoid system is involved in the psychoactive effects of many compounds, and adenosine A2A receptors (the main receptor target of caffeine) elicit a
permissive effect towards CB1 receptors, thus suggesting that A2A-CB1 receptor interaction plays a major role in the generation and maintenance of caf-
feine reinforcing behavior.
The common-sense use of the term addiction is that regular consumption is irresistible and that it creates problems. Caffeine use does not fit this profile. Satel, 2006
Its intake does no harm to the individual or to society and its users are not compelled to consume it.
EDs have been reported in association with serious adverse effects, especially in children, adolescents, and young adults with seizures, diabetes, cardiac Seifert et al., 2011
abnormalities, or mood and behavioral disorders or those who take certain medications. Of the 5448 U.S. caffeine overdoses reported in 2007, 46% oc-
curred in those younger than 19 years.
Chronic repetitive exposures to caffeine increase the risks for development of analgesic-overuse headache, chronic daily headache, and physical depend- Shapiro, 2007;
ency. The complex effects of caffeine on headache disorders suggest important roles for adenosine in these disorders and in the induction of caffeine de- 2008
pendency.
Caffeine consumed by most people has largely positive effects on behavior. Negative effects have occurred when very large amounts were given or in Smith, 2002
sensitive groups (e.g. patients with anxiety disorders): increased anxiety and impaired sleep. There is also some evidence that fine motor control may be
impaired as a function of the increase in anxiety.
Analysis of 9 controlled studies did not indicate that caffeine intake resulted in significant deleterious effects on cognition or behavior. There was a small, Stein et al., 1996
positive effect on parental reports of externalizing behavior.
Children can develop tolerance to caffeine. It is not known whether caffeine paired with sweeteners conditions a taste preference for sugar sweetened Temple, 2009
foods and beverages in children, as occurs in adults. The reinforcing value of caffeinated beverages in children is not well understood, but data from
adults and the rising consumption patterns of caffeine in children support the hypothesis that caffeine added to beverages enhances their reinforcing value.
Research in animal models suggests it is possible that habitual caffeine use may lead to cross-sensitization of the neural reward substrate to illicit drugs.
Most of the effects of ED on cognitive performance are related to the presence of caffeine. Further investigation is needed into the effects of the lesser van den Eynde et
known ingredients of ED (taurine, glucuronolactone) if we are to have a better understanding of the possible interactions. al., 2008
Caffeine is implicated in the exacerbation of anxiety and sleep disorders, and people with eating disorders often misuse it. It antagonizes adenosine recep- Winston et al.,
tors, which may potentiate dopaminergic activity and exacerbate psychosis. In psychiatric in-patients, caffeine has been found to increase anxiety, hostil- 2005
ity and psychotic symptoms.
Twin studies find the heritability of caffeine-related traits to range between 0.36 and 0.58. Analysis of polysubstance use shows that predisposition to caf- Yang et al., 2010
feine use is highly specific to caffeine itself and shares little common disposition to use of other substances. Genome association studies link variations in
adenosine and dopamine receptors to caffeine-induced anxiety and sleep disturbances. Polymorphism in the metabolic enzyme cytochrome P-450 is asso-
ciated with risk of myocardial infarction in caffeine users.
67
2B. CNS Effects of Caffeine in Animals
Studies with monkeys (rhesus, squirrel, and pigtail) showed that a caffeine dose of ≥1
mg/kg increased the response rate in various psychomotor tests. However, performance on cog-
nitive tasks worsened at doses ranging from 2-30 mg/kg.
Adverse CNS effects occurred in rodents that were treated as neonates (≤21 days old)
with 1-20 mg/kg caffeine (i.p. or s.c.), or that suckled mother’s milk containing caffeine (dams
were given 10-40 mg/kg/day caffeine in the diet). The pups grew more slowly, were hypoactive,
and had motor impairment, earlier onset of auditory startle and air righting reflexes, and impaired
learning as adults. Physical changes were noted in the pups’ brains, such as reduced glial fibril-
lary acidic protein and s100beta protein expression during the first 2 postnatal weeks. Also seen
were lower brain zinc contents and alkaline phosphatase activity, decreased brain weight and
DNA and RNA content, altered content of fatty acids and cholesterol, and increased dendritic
length of the cortical pyramidal neurons.
Single-exposure studies with adult rats and mice consistently showed an inverse U-
shaped locomotor activity response. Activity was unaffected at low doses (<2 mg/kg), was
maximally increased at 10-20 mg/kg, and was inhibited at high doses (>50 mg/kg). Similarly,
low doses of caffeine improved performance (0.3-10 mg/kg, i.p.) on various psychomotor tasks,
whereas treatment with ≥20 mg/kg disrupted learning and retention of information. Administra-
tion of 1-10 mg/kg caffeine to spontaneously hypertensive rats (a model for ADHD in humans)
improved their learning ability, but had no effect on normal (Wistar) rats. Caffeine also in-
creased acetylcholine release in the hippocampus (3-30 mg/kg, gavage), decreased caudate do-
pamine release (49-97 mg/kg, i.p.), increased cerebral contents of pregnenolone, progesterone,
and allopregnalone (25-100 mg/kg i.p.), and altered mRNA levels of c-fos, c-jun, and junB in the
striatum and nucleus accumbens (25-100 mg/kg i.p.).
Multiple-exposure studies showed a similar locomotor activity and cognitive ability dose-
response as did the single-exposure studies. They also showed an attenuation of locomotor
stimulation (i.e. tolerance) after as few as 2-4 days of treatment. Several studies examined the
levels of tryptophan, 5-hydroxytryptamine (serotonin), and 5-hydroxyindoleacetic acid (sero-
tonin metabolite) in various parts of the brain after 1-28 days of treatment, but consistent results
were not obtained.
Studies that evaluated the CNS effects of caffeine in animals treated with only caffeine
are summarized in Table 2-4.
68
TABLE 2-4. CNS Effects of Caffeine in Animals
Species; Exposure Test material Caffeine
condition time (route) dose(s)
Rat 1 day pure caffeine; 0.25, 0.5, 0.7, Caffeine did not engender stable patterns of self-injection. Briscoe et al.,
(i.v.) 1 mg/kg 1998
Gerbil 1 day pure caffeine 0.5, 5, 15, 30 The stimulant effects of caffeine were evident at the lower doses in the male gerbils, while the higher Bradley et al.,
(i.p.) mg/kg doses were anxiogenic. Females were more sensitive to the anxiogenic effects at lower doses. 2011
hamster, 1 day pure caffeine 10-20 mg/kg Caffeine worsened the dystonia in dt(sz) hamsters (model of paroxysmal dystonia). Richter and
paroxysmal (i.p.) Hamann,
dystonia 2001
Mammalian 1 day pure caffeine mM Caffeine inhibited TREK-1 channels and consequent membrane depolarization, which may contribute to Harinath and
cell culture in vitro the convulsive seizures induced by toxic levels of these compounds. Sikdar, 2005
Mammalian 1 day pure caffeine 50 mg/kg, Neuronal death in various brain areas 24 hr after dosing; nuclear chromatin in TUNEL (dUTP-biotin nick Kang et al.,
cell culture; (PND 7) (i.p.) 3x/d end label)-positive cells was condensed and marginated, suggestive of apoptotic cell death. 2002
Rat
Mouse 1 day pure caffeine 1, 3, 10, 30 Mice given inhibitory avoidance and habituation training had impaired retention from 10-30 mg/kg given Angelucci et
(gavage) mg/kg 30 min before training; improved inhibitory avoidance (but not habituation) when 1-30 mg/kg given right al., 1999
after training or 3-10 mg/kg given 30 min before testing.
Mouse 1 day pure caffeine 10-30 mg/kg Caffeine did not selectively affect inhibitory avoidance acquisition, but 30 mg/kg did impair escape laten- Carvalho-
(i.p.) cies. Netto and de
Souza, 2004
Mouse 1 day pure caffeine 25, 50, 100 Depending on the dose, the blockade of A(2A)-R or A(1) receptors by caffeine is preferentially revealed Dassesse et
(i.p.) mg/kg leading to highly differential alterations in striatal gene expression. al., 2001
Mouse 1 day pure caffeine 50-300 mg/kg In the absence of auditory stimulation, caffeine increased the incidence of both clonic and tonic seizures in De Sarro et
(i.p.) DBA/2 mice, ED50 values for caffeine= 207.5 mg/kg. Following a subconvulsant audiogenic stimulus of al., 1999
83 db, ED50=0.04 mg/kg.
Mouse 1 day pure caffeine 6.25, 25, 100 The stimulant effect of low doses of caffeine is mediated by A(2A) receptor blockade while the depressant El Yacoubi et
(i.p.) mg/kg effect seen at higher doses under some conditions is explained by A(1) receptor blockade. al., 2000b
Mouse 1 day pure caffeine 30-100 mg/kg Prepulse inhibition of the startle reflex in DBA/2 mice increased at 100 mg/kg in DBA/2 mice. Flood et al.,
(i.p.) 2010
Mouse 1 day pure caffeine 0.1, 0.3, 1.0, Caffeine facilitated retention of information when given immediately but not 180 minutes after training, Kopf et al.,
(i.p.) 3.0 mg/kg only in mice foot-shocked during training; dose response was a bell-shaped curve. 1999
69
Mouse 1 day pure caffeine; 3, 15, 30 C57BL mice had higher basal activity; both strains had dose-dependent increase in rearing, motility and Kuzmin et al.,
cocaine (i.p.) mg/kg locomotion; effect on rearing was greater in C57 than in 129 mice, but motility and locomotion were simi- 2000a
lar in the two strains (maximal at 15 mg/kg).
Mouse 1 day pure caffeine 15, 30, 60 Locomotor activity increased; effect at all test doses. Shimada et
(i.p.) mg/kg al., 1995
Mouse 1 day pure caffeine 10, 50 mg/kg Caffeine (10 mg/kg) elicited a distinct profile of striatal gene expression in wild type mice compared with Yu et al.,
(i.p.) that by A(2A)R gene deletion or by administering caffeine into A(2A)R KO mice; adipocyte differentia- 2009
tion/insulin signaling is highly enriched in the striatal gene sets elicited by both doses of caffeine.
Mouse 1 day pure caffeine 10, 30, 100 Caffeine increased the traveled distance at lower doses (maximum at 10 mg/kg) but decreased it at higher Zhang et al.,
(i.p.) mg/kg doses (30 and 100 mg/kg) during the initial 1 hr after dosing 2011
Mouse, ± 1 day pure caffeine 3.75, 7.5, 15, Locomotor activity increased at 30 mg/kg but decreased at 100 mg/kg for all A1R genotypes; peak activity Halldner et
A1A, A2A (i.p.) 30, 100 mg/kg for A1R knockout (KO) mice was at 7.5 mg/kg vs. 30 mg/kg for WT and heterozygous (HET) mice; mice al., 2004
receptor with A2R KO were not stimulated by caffeine but HET-A2R mice were.
Primate 1 day pure caffeine 1, 5, 20, 50 Mean of 17 mg/kg (≥5 mg/kg) reversed distractor-induced decrements in the delayed matching task (19% Bain et al.,
(oral) mg/kg improvement) and decreased sample (but not choice) latencies. 2003
Rat 1 day pure caffeine 0.3 - 30 mg/kg In Morris water maze task 0.3-10 mg/kg, but not 30 mg/kg, given post-training improved memory reten- Angelucci et
(i.p.) tion, and when given pre-test, slightly improved memory retrieval; dosing pre-training was ineffective al., 2002
(memory acquisition).
Rat 1 day pure caffeine 5, 10, 20, 40 Caffeine increased general locomotor activity; stimulant effects were eliminated at higher doses. Caffeine Antoniou et
(i.p.) mg/kg produced bell-shaped dose-response curves, and did not induce stereotypy. al., 1998
Rat 1 day pure caffeine 0.3, 1, 3, 10 Caffeine reduced impulsive choice behavior only in the medium (not low or high) basal level of impulsiv- Barbelivien et
(i.p.) mg/kg ity (BLI) sub-population. Dopamine utilization was similar in the three sub-populations, but serotonin al., 2008
utilization was lower in the prefrontal cortex of the medium and very high BLI sub-populations as com-
pared to the low BLI population.
Rat 1 day pure caffeine 1, 5, 10, 30, The locomotor-enhancing effects of low doses of caffeine did not appear to be associated with significant Bennett and
(i.p.) 75 mg/kg Fos expression in the rat brain. Semba, 1998
Rat 1 day pure caffeine 2.5-20 mg/kg At low dose rats only had decreased omission errors, but not improved performance, after training to ob- Bizarro et al.,
(oral) tain food reinforcers. 2004
Rat 1 day pure caffeine 3, 10 mg/kg Rats treated either with 3.0-mg/kg or 10.0-mg/kg doses of caffeine showed reduced sensitivity in response Borre et al.,
(i.p.??) distributions to differences in reinforcement schedule ratios. 2007
70
Rat 1 day pure caffeine 10, 20 mg/kg Performance-enhancing effects of caffeine in a modified forced swim task and a dominance task. Boyer et al.,
(i.p.) 2003
Rat 1 day pure caffeine 100 mg/kg Decreased time spent in open zones in elevated plus and zero mazes (behavior related to anxiety). Braun et al.,
(s.c.) 2011
Rat 1 day pure caffeine 3-30 mg/kg Enhanced acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 Carter et al.,
(gavage) receptors 1995
Rat 1 day pure caffeine 10, 20, 30 20 or 30 mg/kg given 15 min before tone-shock conditioning disrupted context conditioning (hippocam- Corodimas et
(i.p.) mg/kg pal-dependent) but only slightly decreased tone conditioning (hippocampal-independent); not due to the al., 2000
fact that context conditioning is a weaker form of learning than tone conditioning.
Rat 1 day pure caffeine 10, 30, 75 10 and 30 mg/kg, but not 75 mg/kg, increased motor activities, including locomotion, and caused distinct Deurveilher et
(i.p.) mg/kg dose-related patterns of c-Fos immunoreactivity in several arousal-promoting areas. al., 2006
Rat 1 day pure caffeine; caffeine 15 Both the extract (400 and 800 mg/kg) and caffeine (15 mg/kg) caused significant increases in the number Ettarh et al.,
kola nut ex- mg/kg; kola of entries, but reduced the frequency of rearing. The extract did not significantly reduce the number of 2000
tract (oral) nut 400, 800 entries after 24 h. It is suggested that kola nut stimulates exploratory locomotor activity due to its caffeine
mg/kg content, but does not enhance habituation.
Rat 1 day pure caffeine 10, 17 and 30 Caffeine did not significantly change inhibitory avoidance or one-way escape (inhibitory avoidance in the Graeff et al.,
(i.p.) mg/kg elevated T-maze may be related to generalized anxiety disorder, while one-way escape may be associated 1998
with panic disorder).
Rat 1 day pure caffeine 3, 10 mg/kg Caffeine reversed the vigilance performance decrement: increased % correct responses, reduced correct Grottick and
(i.p.) latency and omissions, and increased premature and perseverative responses; no significant changes in Higgins, 2002
accuracy over time.
Rat 1 day pure caffeine 2 or 4 wk old Locomotor activity increased; CNS effects were qualitatively similar, but quantitatively different in neo- Himmel, 2008
(gavage) 20 mg/kg; 8-9 natal, juvenile and adult rats.
wk old 10, 20,
100 mg/kg
Rat 1 day pure caffeine 3.0, 10.0, 30.0 Caffeine (30 mg/kg) increased animals' propensity to escape from the maze, i.e. it had a clear anxiogenic Jones et al.,
(i.p.) mg/kg effect. 2002
Rat 1 day pure caffeine 140, 185 140 and 185 mg/kg/day (but not lower unspecified doses) caused mild self-injurious behavior (skin dam- Kies and De-
(s.c.) mg/kg/d age on tail or paws) in 33% of the rats, first seen after 4-7 d; had increased locomotor activity, weight loss vine, 2004
throughout study, increased plasma ACTH and corticosterone, increased adrenal weight, decreased thy-
mus weight, and chromodacryorrhea.
71
Rat 1 day pure caffeine 3-24 mg/kg Dose-dependent excitation-related effects; the two automated activity-detection systems exhibited similar Lynch et al.,
(gavage) sensitivities in determining changes in locomotor activity, but with the LABORAS being more sensitive 2011
than the Actimeter in detecting caffeine-induced increases in vertical activity (rearing behavior).
Rat 1 day pure caffeine 10, 30, 75 Increased locomotion at 10 and 30 mg/kg, but not at 75 mg/kg; all doses increased the number of cells Murphy et al.,
(i.p.) mg/kg immunoreactive for both orexin and c-Fos; orexin neurons were preferentially activated, esp. in the peri- 2003
fornical region where orexin neurons are most concentrated.
Rat 1 day pure caffeine 10, 30 mg/kg Either dose of caffeine functioned as a Pavlovian cue as a positive drug feature and weakly as a condi- Murray et al.,
(i.p.) tional stimulus. 2007
Rat 1 day pure caffeine 5.0, 10.0, Caffeine produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec Randall et al.,
(i.p.) 20.0, or 40.0 schedule but decreasing responding on the FR20 schedule. A(1) antagonists failed to increase the lever 2011
mg/kg pressing rate.
Rat 1 day pure caffeine 10, 50 mg/kg Caffeine significantly increased c-Fos expression in cholinergic neurons of the horizontal limb of the di- Reznikov et
(i.p.?) agonal band of Broca but no other basal forebrain regions. al., 2009
Rat 1 day pure caffeine 3, 10, 30, 50 Modified maximum peak frequency and bandwidth of the 50-khz range ultrasonic vocalizations, but not in Simola et al.,
(i.p.) mg/kg their occurrence 2009
Rat 1 day pure caffeine 3, 10, 30, 50 Caffeine modified the maximum peak frequency and bandwidth of the 50-khz range ultrasonic vocaliza- Simola et al.,
(i.p.) mg/kg tions (index of changes involving emotional state), but not an elevation in the number of 50-khz usvs. 2010
Rat 1 day pure caffeine 50 mg/kg Stress (social isolation) attenuated the activating and anxiogenic effects of caffeine. Sudakov et
(i.p.); stress al., 2003a
Rat 1 day pure caffeine 75 mg/kg C-fos was induced in rat striatum following administration of caffeine. Svenningsson
(i.p.) et al., 1995a
Rat 1 day pure caffeine 25, 50, 100 mRNA increased for c-fos, c-jun, and junB but not junD in striatum and nucleus accumbens; induced acti- Svenningsson
(i.p.) mg/kg vator protein 1 in striatum for 2-4 hr; induced preproenkephalin mRNA in lateral and caudal striatum up to et al., 1995b
8 hr.
Rat 1 day pure caffeine 7.5, 15, 30 Endogenous adenosine, via adenosine A2A receptors, causes a tonic activation of striatopallidal neurons. Svenningsson
(i.p.) mg/kg By blocking this adenosine effect, caffeine causes behavioral activation. et al., 1997
Rat 1 day pure caffeine 5, 10, 20, 40, In a reinforcement of low rate schedule (DRL 45-s) study, both i.p. and oral dosing similarly decreased the Wang and
(gavage; i.p.) 80, 120 mg/kg reinforcement rate and increased the nonreinforced response rate (dose-related) with plateau at >40 mg/kg; Lau, 1998
serum caffeine similar at a given dose for the two routes.
Rat 1 day pure caffeine 2.5, 5, 10, 20, Aggressive behavior (against an intruder) was most elevated at 5-20 mg/kg, less elevated at 2.5 mg/kg or Wilson et al.,
(i.p.?) 30, 40 mg/kg 30 mg/kg, and reduced above 40 mg/kg and below 2.5 mg/kg. 2000
72
Rat, hyper- 1 day pure caffeine 3.0, 10.0 Caffeine reversed the social memory impairment in spontaneously hypertensive rats, but did not alter the Prediger et al.,
tensive (i.p.) mg/kg hypertension state. 2005a
Rat, ova- 1 day pure caffeine 7.5, 15, 30 An intake by a female of15 mg/kg shortened the latency to return to a male following an ejaculation and Guarraci and
riectomized, (i.p.) mg/kg increased locomotor activity; 7.5 and 15 mg/kg (not 30 mg/kg) shortened the latency to return to a male Benson, 2005
given estro- following an ejaculation; 15 mg/kg did not disrupt preference for a sexual partner. These results suggest
gen + pro- that caffeine increased both sexual motivation and locomotor activity in females.
gesterone
Rat, hyper- 1 day pure caffeine 1-10 mg/kg Pre-training dosing (1-10 mg/kg) improved spatial learning by SHR but not by Wistar rats; post-training Prediger et al.,
tensive (i.p.) dosing (3 mg/kg i.p.) did not alter SHR performance but increased memory retention in Wistar rats; no 2005b
effect on BP in either strain.
Rat, hyper- 1 day pure caffeine 1-10 mg/kg Pre-training caffeine treatment improved the performance of spontaneously hypertensive rats (ADHD Pires et al.,
tensive (i.p.) model) in an object-recognition task. 2009
Rat 1 day; 2 d pure caffeine 100 mg/kg One dose decreased mRNA levels of neuropeptide S (NPS) in the brainstem; 1 or 2 doses increased levels Lage et al.,
(i.p.) of NPS receptor in both the hypothalamus and brainstem. 2006
Rat 1 day; 5 d pure caffeine 20, 40, 80 20 and 40 mg/kg increased but 80 mg/kg decreased open field locomotion; 80 mg/kg given 5 d increased Haleem et al.,
(i.p.) mg/kg for 1 d; activity in home cages the most after 1st day, less later; at 80 mg/kg hepatic T-pyrrolase activity was in- 1994
80 mg/kg 5 d creased after 1 d , more after 5 d.
Rat 1 day; 5 d pure caffeine 1 d: 20, 40, 80 Single dose of 20-80 mg/kg increased brain levels of tryptophan, 5-hydroxytryptamine (5-HT) and 5- Haleem et al.,
(i.p.) mg/kg; 5 d: hydroxyindole acetic acid (5-HIAA); 80 mg/kg/d given for 5 d decreased brain levels of 5-HT and 5- 1995
80 mg/kg HIAA but brain and plasma tryptophan were unaffected.
Mouse, 1 or 7 d pure caffeine 1 d: 50, 100 Adaptive mechanisms following mutation in A(2A) receptors or their long-term blockade after chronic El Yacoubi et
A(2A) re- i.p.; 8 d (i.p.; DW) mg/kg; 7 d: 50 ingestion of caffeine may be responsible for increase proneness to anxiety. However, the short-term anxi- al., 2000a
ceptor or 60 d mg/kg 2x/d; ety-like effect of caffeine in mice might not be related solely to the blockade of adenosine A(2A) recep-
knockout DW 0.3 g/L tors, since it is not shared by A(2A) selective antagonists.
Rat 1 day; 14 pure caffeine 7.5 mg/kg i.p.; Caffeine (7.5 mg/kg i.p.) increased locomotion and NGFI-A mRNA in the hippocampal area CA1, but Svenningsson
d (i.p.; DW) 0.3 g/mL DW decreased NGFI-A mRNA in rostral striatum and nucleus accumbens; intake of 0.3 g/L in DW for 14 d et al., 1999
caused tolerance to a challenge with caffeine (7.5 mg/kg) and a smaller decrease of NGFI-A mRNA.
Rat 1 day; 15- pure caffeine acute: 10, 17, High acute doses increased larger-delayed-reinforcer choice; repeated exposure decreased the larger- Diller et al.,
23 d (i.p.) 30 mg/kg; delayed choice, which was still greater than baseline; caffeine withdrawal returned choice to baseline lev- 2008
repeated: 30 els; reintroduction of caffeine increased the larger-delayed choice to near acute levels.
mg/kg
73
Rat 1 day; 21 pure caffeine 0.1% DW Effect of short-term and chronic intake depended on both genetically determined sensitivity and environ- Sudakov et
d (DW); stress (123 mg/kg/d) mental factors (social isolation); chronic dosing did not induce persistent emotional changes because al., 2001
withdrawal did not affect animal anxiety.
Rat 1 day; 40 pure caffeine; 10 mg/kg caf- Acute or chronic administration of crude extract (3-60 mg/kg) did not affect the plus maze test. In the Otobone et
d guarana crude feine; guarana forced swimming test, chronic treatment with 30.0 mg/kg crude extract and 4.0 mg/kg purified extract A al., 2007
or purified 3.0, 30.0, 60.0 (not B) decreased the immobility time. Locomotor activity in the open field test was not increased by the
extract mg/kg crude, extracts. Caffeine reduced immobility time in the swimming test and increased locomotor activity in the
(gavage) 10 mg/kg pure open field test.
Mouse 4d pure caffeine 10 mg/kg 15 min after training, caffeine-treated mice recognized more efficiently familiar and novel objects; 90 min Costa et al.,
(i.p.) and 24 hr after training, time spent in the familiar object was unchanged but the object recognition index 2008
was increased; hippocampus had increased neurotrophic factor and receptor content.
Rat 5 d (PND pure caffeine 15-20 mg/kg/d Neonatal caffeine exposure significantly improved retention in females (P < 0.01) and significantly de- Fisher and
2-6) (gavage) creased retention in males (P < 0.05). Guillet, 1997
Rat 5 d (PND pure caffeine 15-20 mg/kg/d Juveniles had hyperalgesia in hot-plate test, less anxiety in the elevated plus-maze and dark-light transi- Pan and Chen,
2-6) (gavage) tion, impairment in the step-through avoidance learning test. 2007
Rat 5 d (PND pure caffeine 10 mg/kg, 20 15, 18, and 21-d-old pups treated at PND 7-11 had motor impairment and were hyperactive in an open Tchekalarova
7-11, 13- (s.c.) mg/kg field; pups treated during PND 13-17 had worse performance in the bar holding test at PND 18 and de- et al., 2005
17) creased motor activity at PND 25 and 32.
Rat 7d pure caffeine 25 mg/kg Increased plasma clearance and volume of distribution from evening dosing; disrupted daily rhythmicity Pelissier-
(s.c.) for locomotion, body temperature, HR. Alicot et al.,
2002
Rat every pure caffeine 15 mg/kg 126% increase in striatal dopamine D2(High) receptors was found in caffeine-sensitized rats. Simola et al.,
other day (i.p.) 2008
for 14 d
Rat 9d pure caffeine 20, 40 or 80 Increased opioid neuropeptide mRNA expression in the striatum and the nucleus accumbens of the rat Datta et al.,
(i.p.) mg/kg 2x/d brain by a dopamine-independent mechanism. 1997
Mouse 8 d (PND pure caffeine 10 mg/kg on Dose-dependent transient reduction of glial fibrillary acidic protein and S100beta protein expression in Desfrere et
3-10) (i.p.) PND 3, then various brain areas during the first 2 postnatal weeks; reduced glial proliferation; effect was blocked by al., 2007
2.5 mg/kg/d co-injection of an agonist (CPA; CGS 21680).
on PND 4-10
74
Rat 10 d pure caffeine 15 mg/kg/d Males had a 37% increase in the level of A(2A) receptor and a 17% decrease in tyrosine hydroxylase in Bairam et al.,
(PND 3- (gavage) the carotid body of caffeine vs. water-treated rats. In the nucleus tractus solitarius, there was a 13% and 2009
12) 19% decrease in A(1) receptor expression in water and caffeine-treated rats vs. naive rats. In the superior
cervical ganglion, there was no change. In female rats, the only changes observed were decreases of 12%
and 15% in A(1) receptor levels in the nucleus tractus solitarius of water and caffeine-treated rats vs. naive
rats. Thus, caffeine induces long-term changes in the adenosine receptor system.
Rat 10 d pure caffeine 15, 30 mg/kg Increased emotional reactivity in caffeine-treated animals (changes in rearing and emergence latencies, Anderson and
(i.p.) ambulation, defecation and corner and center squares occupancy). Hughes, 2008
Rat 10 d pure caffeine 2 g/L 3 d, then Decreased brain arginase, diamine oxidase, and lipid peroxidation. Nikolic et al.,
(DW) 4 g/L 7 d 2003
Rat 14 d pure caffeine 0.3, 1 g/L in Caffeine administered in DW at 0.3 g/L or 1 g/L for 14 days failed to affect nucleotide hydrolysis, but da Silva et al.,
(DW; i.p.) DW; 30 acute dose 30 mg/kg (i.p.) enhanced ATP (50%) and ADP (32%) hydrolysis in synaptosomes of the hip- 2003
mg/kg (i.p.) pocampus and striatum, respectively.
Rat 14 d pure caffeine 0.1% solution 12 hr after caffeine pre-treatment, there was no caffeine-associated change in the threshold for the induc- Hoexter et al.,
(DW) [~100 mg/kg] tion of seizures by a subconvulsant dose of pilocarpine (i.p.) or kainic acid (i.p.). 2005
Mouse 14 d pure caffeine 0.1, 0.3, 1 g/L At 1 g/L animals had increased A1 agonist binding without change in A1 mRNA or in A1 antagonist bind- Johansson et
(DW) (35, 80, 240 ing; increased number of A2A receptors in the striatum. al., 1997
mg/kg/d)
Mouse 15 d pure caffeine 3 mg/kg Chronic administration of caffeine led to an A(1)-mediated enhancement of the CB(1)-dependent acute Sousa et al.,
(i.p.) disruptive effects of Δ(9)-tetrahydrocannabinol (THC, a CB(1) receptor agonist) on a short-term spatial 2011
memory task, despite inducing a reduction in cortical and hippocampal CB(1) receptor number and an
attenuation of CB(1) coupling with G protein. A(1) receptor levels were increased.
Primate 21 d + pure caffeine 10-15, 25-30 Dose-related increase in the number of infant deaths at parturition. At PND 30-44 the high-dose group Gilbert and
(prior to (DW) mg/kg/d infants had longer pause times and longer inter-response times than the controls group; the treated infants Rice, 1994
+ preg- spent more time feeding than controls (infants were separated from mothers at birth).
nancy)
Mouse, 28 d pure caffeine 4 mg/d Decreased body fat in obese mice with unchanged food intake; increased levels of brain norepinephrine Chen et al.,
overweight (DW) and epinephrine in lean and obese mice, more so in the latter (which had baseline lower levels than lean 1994
controls); brain levels of serotonin, tryptophan, and 5-hydroxyindoleacetic unaffected.
Rat 28 d pure caffeine 0.3 g/L (~75 Caffeine intake slowed hippocampus-dependent learning and impaired long-term memory; reduced hippo- Han et al.,
(DW) mg/kg/d) campal neurogenesis. 2007
75
Rat 28 d tea (DW) 2 tbsp Decreased brain tryptophan (TRP) and serotonin (5-HT) levels, but no change in plasma TRP or brain 5- Haider et al.,
leaves/L water hydroxyindole acetic acid; increased home cage but not open field activity. 1998
Mouse 40 d pure caffeine 0.01%, 0.05% High-dose M had increased activity which peaked on d 5 of dosing; both F groups had increased activity Nagasawa et
(DW); heat in DW that peaked at 30 d; no effect on food intake; increased plasma ALT, AST, cholesterol and glucose in al., 2001
high-dose M and F.
Rat 90 d cola (oral) 30-60 mg/kg/d A light-dark box showed increased locomotor activity and anxiety in all groups with cola intake. A subtle Celec and
anti-depressive effect was seen in the forced swim test. Chronic cola intake increased both estradiol and Behuliak,
testosterone levels suggesting an additional mechanism of action beyond the adenosine receptors. 2010
DW=drinking water; PND=postnatal day
76
CHAPTER 3. EFFECTS OF CAFFEINE ON SLEEP AND ON SLEEP-
DEPRIVED HUMANS
A number of one-day experimental studies evaluated the effect of caffeine intake on sleep
quantity and/or quality in adults. Doses tested ranged from 100-1200 mg/day (~1.4-17
mg/kg/day). Sleep was adversely affected at all tested doses. Effects found included delayed
sleep onset, sleep disruption, shorter sleep duration, enhanced nighttime body temperature, mela-
tonin suppression, and altered EEG activity. Caffeine decreased the quality and quantity of the
recovery sleep following prolonged sleep deprivation. Chronic insomnia and the presence of
bright light exacerbated caffeine-induced sleep disruption. No difference in sleep effects were
seen between a group aged 20-30 years and a group aged 40-65 years. The sedatives zolpidem
and trazodone both counteracted the caffeine-induced delay in sleep latency, each compound af-
fecting somewhat different sleep parameters. Smoking, which enhances caffeine clearance, also
reduced sleep latency. Short-term (2-7 days) exposure caused similar sleep disruption as seen in
the one-day studies, and a 7-day experiment showed that some degree of adaptation occurred to
the sleep effects. Heavy coffee drinkers had an increased risk of grinding their teeth during sleep
(≥6 cups/day; ~8.6 mg/kg/d) and reduced time in bed per night (≥8 cups/day or 680 mg, or ~9.7
mg/kg/d).
One case-control and several cross-sectional studies with children from age 3-18 years
showed that caffeine decreased sleep duration, and increased sleep disturbance/insomnia, para-
somnia, bruxism and feelings of fatigue the next day. The data were insufficient to determine a
clear dose-response relationship. Effects were typically seen in those consuming “higher” vs.
“lower” levels of caffeine, or in children who consumed one or more caffeinated drinks per day,
which would be ≥1 mg/kg/day (e.g. 35 mg caffeine in a can of cola ingested by a 35-kg child).
A surprisingly large number of studies examined the effect of caffeine on adults who
were seriously sleep-deprived, i.e., for 24-77 hours, during which time they were periodically
administered caffeine. This topic has important safety implications, as caffeine is used to stay
awake for prolonged periods while performing physically dangerous jobs, such as driving a vehi-
cle, and in military situations. The majority of the one-day studies found that intakes of 80 to
600 mg caffeine over 24 hours of sleep deprivation (~1.1-8.6 mg/kg) improved mood, increased
alertness, enhanced performance on various psychomotor tests, and altered the subjects’ EEG
profiles. A few studies, however, found no caffeine effect. For example, 200 mg caffeine (~2.9
mg/kg) given to sleep-deprived military pilot students did not improve simulated flight perform-
ance, contrary to their belief (Lohi et al., 2007). Ingestion of 250 mg caffeine (~3.6 mg/kg) did
not improve single-target and divided-attention responses in different parts of the visual field
(Mills et al., 2001). Ingestion of 200 mg caffeine four times over 8 hours (~11 mg/kg/day) dur-
ing 77 hours of sleep deprivation did not improve performance on the Iowa Gambling Task
(Killgore et al., 2007). The utility of studies with such long sleep deprivation is questionable, as
is the ability to detect consistent and reproducible responses for one subject, or for a group of
individuals, under such extreme conditions.
77
The available data were inadequate and/or inappropriate for derivation of LOAEL or
NOAEL values for any of the discussed endpoints. It is unclear that these endpoints are adverse
for overall human health.
Studies that evaluated the effects of caffeine on the quality and quantity of sleep, and on
reversing the effect of fatigue in sleep-deprived humans, are summarized in Table 3-1. Brief
summaries of conclusions drawn by authors of reviews regarding the effects of caffeine on sleep
and on reversing the effects of sleep deprivation are presented in Table 3-2. A recent review
(Porkka-Heiskanen, 2011) noted that the main effects of caffeine on sleep are decreased sleep
latency, shortened total sleep time, decrease in power in the delta range, sleep fragmentation, and
possibly a decreased accumulation of sleep propensity during waking. They also pointed out that
the great variability in the sensitivity for caffeine among individuals may be at least in part ex-
plained by genetic variations in genes related to adenosine metabolism. The sleep-disrupting ef-
fect of caffeine in children and adolescents was discussed by Roehrs and Roth (2008), who con-
cluded that under conditions of habitual sleep, caffeine merely restores performance degraded by
sleepiness, and does not actually enhance it. Bonnet et al. (2005) considered use of caffeine as a
stimulant to be warranted, under medical supervision, when public health and safety personnel
are responding to a disaster or when military personnel must engage in prolonged operations.
78
TABLE 3-1. Effects of Caffeine on Sleep and on Sleep-Deprived Humans
Case-control 7-17 yr caffeinated mean 5.3 serv- Youth with major depressive disorder (MDD) reported more caffeine use and sleep problems Whalen et al.,
(USA) Cases=30; drinks [major ings/d than healthy youth, and more anxiety on days they consumed caffeine; when caffeine use 2008
controls=23 depressive dis- [2-10 mg/kg/d] decreased, sleep complaints remained elevated. [No info on caffeine per serving; assumed
(36% M) order] 40 mg from cola; assumed that children <20 kg were limited to 1 serving/day; assumed BW
15-70 kg for dose estimates]
Cross-sectional 12-18 yr caffeinated 23-1458 mg/d Caffeine consumption tended to be lower in those with 8-10 hr sleep/night (p p<0.067); caf- Calamaro et
(USA) n=100 (42 M) drinks; ED [0.3, 21 mg/kg] feine consumption tended to be 76% higher by those who fell asleep during school. al., 2009
Cross-sectional 10-16 yr caffeinated none; "high" Somatic complaints of headache, stomachache, backache, and morning fatigue are common Ghandour et
(USA) n=8250 F drinks among U.S. adolescent girls and co-occur often. Heavy alcohol use, high caffeine intake, and al., 2004
smoking cigarettes every day were strongly associated with all symptoms, while parent and
teacher support served as protective factors. A dose-response was observed between the
prevalence of frequent symptoms and the increasing levels caffeine consumption. For ex-
ample, the proportion of frequent headache sufferers increased 30 percentage points between
low- and high-caffeine consumers (data not provided). [No further info on caffeine intake]
Cross-sectional 11-14 yr caffeinated 3.3 ± 4.1 Boys consumed more caffeinated beverages than girls, but this did not correlate with self- Lee et al.,
(USA) n=144 M+F drinks colas/wk reports of waking after sleep onset. The amount of caffeine consumed, and the consumption 1999
[2.2-3.3 mg/kg] of hot chocolate alone, were related to sleepwalking, bruxism, and head banging. [No info
on caffeine content; assume 40 mg/serving and 40-60 kg BW for dose estimates]
Cross-sectional 13-19 yr caffeine, all 1-2, 3-9, ≥10 Most (95%) participants reported recent caffeine use-most often soda-where typical first use Ludden and
(USA) n=197 (96 M) sources servings per 2 of the day was in the evening. In contrast with high soda users, mixed users (undefined) Wolfson,
wk [<0.05 to drank more coffee, expected more dependence symptoms and energy enhancement from 2010
≥1.3 mg/kg/d] caffeine, and were more likely to report getting up early, daytime sleepiness, and using caf-
feine to get through the day. [No info on caffeine per serving; assume 40 mg from cola; as-
sumed BW of 60 kg for dose estimates, and a daily intake of ≤2 servings/d]
Cross-sectional 3-10 yr caffeinated 0, ≥1 servings/d Preschoolers and older children who had at least one caffeinated beverage per day slept less Mindell et al.,
(USA) n=1473 M+F drinks [1-2.7 mg/kg/d] than non-consumers. [No info on caffeine per serving; assumed 40 mg from cola; assumed 2009
BW 15-40 kg for dose estimates]
Cross-sectional 11-17 yr soda; coffee 0, <1 serv- Feeling tired in the morning and having difficulty sleeping was experienced more commonly Orbeta et al.,
(USA) n=15,606 ing/wk; 1, >1 in adolescents with a moderate or high intake of caffeine (≥1 serving/d) [No info on caffeine 2006
M+F serving/d [0.5 to content of the soda or coffee; assumed 40 mg/serving cola and at least 0.5 servings/d; as-
>1 mg/kg/d] sumed BW 40-70 kg for dose estimates]
79
Cross-sectional 12-15 yr caffeine, all mean 63 mg/d Higher intake was associated with shorter nocturnal sleep duration, increased wake time after Pollak and
(USA) n=191 M+F sources up to 380 mg/d sleep onset, and increased daytime sleep; dose-response seen. [Assumed BW 45-65 kg for Bright, 2003
[1-8.4 mg/kg/d] dose estimate]
Cross-sectional 11, 13, 15 yr coffee 0, 1, 2-4 Drinking coffee was not correlated with fatigue, but was correlated with cigarette smoking. Tynjala et al.,
(Finland) n = 4187 cup/wk, 1, >1 [No info on caffeine per cup; assumed 100 mg/cup, and that a daily intake was 0.5-2 cups; 1997
(49.6% M) cup/d assumed BW of 40, 50, and 60 kg for ages 11, 13, and 15, respectively, for the dose esti-
[1-5 mg/kg/d] mates]
STUDIES WITH ADULTS
1-d experiment 22.4 ± 14.4 yr ED [sleep dep- 30 mg High-sugar ED did not counteract sleepiness, and led to slower reaction times and more Anderson and
(Denmark) n=10 M+F rivation] [0.4 mg/kg/d] lapses 80 min after consumption. [ED not identified; 250 mL contained 42 g sugars and 30 Horne, 2006
mg caffeine and was lightly carbonated)]
1-d experiment poor sleepers pure caffeine 2.5 mg/kg Prior to caffeine administration, poor sleepers compared to normal sleepers had faster Hr, Tiffin et al.,
(UK) 37.3 ± 11.2 yr [sleep disorder] lower ratings for concentration and relaxation, poorer performance on the Digit Symbol Sub- 1995
(n=10); nor- stitution Test, and EEG changes. These differences persisted after caffeine ingestion and
mal sleepers overall differences between the groups on these measures were significant (p< 0.01-.001).
34.4 ± 12.6 yr Post-dose, but not pre-dose, scores for vigilance and TR were significantly lower overall in
(n=10) M+F poor compared with normal sleepers. Despite the baseline differences between poor and
normal sleepers, the changes following caffeine administration were similar in direction and
magnitude in both groups.
1-d experiment Adult pure caffeine; 200 mg Choice Reaction Time (RT) recorded during the four post-treatment sessions were shorter Babkoff et al.,
(USA) n=11 M+F light; [sleep [2.9 mg/kg] for the Bright or Dim Light + Caffeine conditions than for the Dim Light-Placebo condition. 2002
deprivation] The shortest RT was recorded for the Bright Light + Caffeine treatment, which also had the
largest number of trials without false alarms per session for the working memory task (letter
cancellation). Caffeine reduced melatonin levels, although to a lesser degree than 1 hr expo-
sure to 3000 lx.
1-d experiment 29-48 yr pure caffeine; 140 mg Following caffeine intake, caffeine-intolerant subjects had increased vigilance levels with Bchir et al.,
(Tunisia) n1=4; n2=4 M smoking [sleep [2.0 mg/kg] faster peak alpha, beta frequency and lower delta and theta power when compared to tolerant 2006
disorder] subjects. Pharmacokinetic parameters and EEG data showed significant differences between
sleep-sensitive and control subjects. These variations may be, in part, explained by cigarette
smoking and the higher caffeine intake observed in the subjects of the control groups.
80
1-d experiment 19-27 yr pure caffeine 600 mg slow- Multiple sleep latency tests showed that caffeinated subjects were more vigilant from the Beaumont et
(France) n=16 M [64 hr sleep release (in 3 onset to the end of sleep deprivation. Some cognitive functions were improved until the 33rd al., 2001
deprivation] doses) hr of sleep deprivation; others were ameliorated throughout the deprivation period; alertness
[8.6 mg/kg] was better from the 13th hr of sleep deprivation, as shown by Stroop's test.
1-d experiment Adult pure caffeine 600 mg slow- During a 42-hour recovery period following a 64-hour wakefulness (caffeine given twice Beaumont et
(France) n=16 M [sleep depriva- release (in 3 during the first 48 h), caffeine and placebo-treated subjects had recovery sleep with almost al., 2005
tion] doses) the same sleep architecture. Wakefulness level and cognitive functions were similarly im-
[8.6 mg/kg] paired in both groups on the first day of recovery and partially returned to baseline on the
second day.
1-d experiment 18-30 yr pure caffeine 400 mg slow Comparing nap + caffeine to naps only, with caffeine subjects had increased objective and Bonnet and
(USA) n=12 M [sleep depriva- release (split subjective alertness, increased oral temperature, and increased performance on complex Arand, 1994
tion; nap] dose) tasks like logical reasoning and correct additions.
[5.7 mg/kg]
1-d experiment 18-30 yr pure caffeine 400 mg Caffeine increased metabolic rate during a nap which had an increase in stage 1 and a de- Bonnet and
(USA) n=12 M [sleep depriva- [5.7 mg/kg] crease in stage 4 sleep; after caffeine + nap performance on addition and vigilance tasks was Arand, 1996
tion] decreased but was unaffected on the multiple sleep latency tests, and subjective vigor was
increased.
1-d experiment 18-39 yr pure caffeine 400 mg There was a significant caffeine by sleep stage interaction for electrocardiogram LF/HF ra- Bonnet et al.,
(USA) n=15 M+F [asleep] [5.7 mg/kg] tios, which were higher during REM following caffeine dosing. There was also a significant 2005b
caffeine by sleep stage interaction for QTvi (QT variability normalized), which was also
higher during REM following caffeine administration. These effects during REM are most
likely due to the sympathetic effects of caffeine, and indicate that excessive caffeine intake
may result in adverse cardiovascular events in vulnerable subjects.
1-d experiment mean ~23-40 pure caffeine 200 mg (split Caffeine lengthened sleep latency, increased stage 1 and reduced stage 2 and slow-wave Carrier et al.,
(Canada) yr [sleep depriva- dose) [2.9 sleep; effect was greater for those who were sleep deprived for one night and recovery sleep 2007
n=34 M+F tion] mg/kg] started in the morning than those sleeping at night.
1-d experiment 20-30 yr; 45- pure caffeine 200 mg Caffeine decreased sleep efficiency, sleep duration, slow-wave sleep and REM sleep during Carrier et al.,
(Canada) 60 yr [sleep depriva- [2.9 mg/kg] daytime recovery sleep similarly in both age groups (20-30; 45-60 yr), and reduced N-REM 2009
n1=12 (6 M); tion; age] sleep EEG synchronization during daytime recovery sleep
n2=12 (5 M)
81
1-d experiment Adult pure caffeine 200 mg After partial sleep deprivation (3:30 am) heavier caffeine consumers exhibited the greatest Childs and de
(USA) n=35 (16 M) [sleep depriva- [2.9 mg/kg] decreases in Profile of Mood States (POMS) Vigor. CAF produced stimulant-like effects and Wit, 2008
tion] significantly improved mood and reaction times upon the tasks. These effects did not vary
with level of habitual caffeine consumption.
1-d experiment Adult pure caffeine 200 mg Caffeine maintained cognitive performance (flight simulation task) during sustained wake- Dagan and
(Israel) n=?? M [sleep depriva- [2.9 mg/kg] fulness equally as effectively as modafinil; both drugs abolished the nocturnal drop in cog- Doljansky,
tion] nitive performance, as well as of oral temperature and BP 2006
1-d experiment 20-25 yr pure caffeine 300 mg slow- Caffeine intake gave rise to a decrease in lane drifting and after PSD it led to a smaller speed De Valck and
Belgium n=12 (7 M) [sleep depriva- release deviation and accident liability in sleep-deprived drivers. Cluydts, 2001
tion] [4.3 mg/kg]
1-d experiment Adult pure caffeine 300 mg slow- A 30-min. nap and 300 mg of slow-release caffeine both were successful in counteracting De Valck et
Belgium n=12 M+F [sleep depriva- release drivers' sleepiness. The remedial effect of slow-release caffeine lasted longer than that of the al., 2003
tion] [4.3 mg/kg] nap, that is, it was also effective in the afternoon session.
1-d experiment Adult pure caffeine 400 mg No cognitive or behavioral changes; decrease in EEG relative alpha and theta in the caffeine Deslandes et
(Brazil) n=10 M+F [sleep depriva- [5.7 mg/kg] group after sleep deprivation. al., 2006
tion]
1-d experiment 26-45 yr caffeine, all 400 mg (split Significant (p < 0.05) improvements in performance were present in all five cognitive tasks Doan et al.,
(USA) n=12 M sources [sleep dose) either as main effects, interactions, or absence of significant degradation in the caffeine 2006
deprivation] [5.7 mg/kg] treatment condition compared with the placebo condition; most sleep deprivation-induced
performance decrements were attenuated by 200 mg of caffeine in tube food consumed every
4 h, and in some cases, performance was improved beyond baseline levels.
1-d experiment mean 33-34 yr pure caffeine 3 mg/kg Normal sleepers with an identified vulnerability to stress-induced sleep disturbance exhibited Drake et al.,
(USA) n1=11; n2=10 greater objectively verifiable sleep-reactivity in response to a caffeine challenge compared to 2006
M+F non-vulnerable individuals.
1-d experiment 20-30 yr; 40- pure caffeine 200 mg Compared with placebo, evening ingestion of caffeine lengthened sleep latency, reduced Drapeau et al.,
(Canada) 60 yr [2.9 mg/kg] sleep efficiency, and decreased sleep duration and amount of stage 2 sleep in both age 2006
n=24 M+F groups. Caffeine also altered EEG parameters in both groups, with some similarities.
1-d experiment 23-30 yr pure caffeine 400 mg (split Caffeine ameliorated the decrease in the number of responses but did not mitigate other defi- Gottselig et
(Switzerland) n=21 M [sleep depriva- dose) cits in random number generation that arose during sleep deprivation (rule violations, real., 2006
tion] [5.7 mg/kg] sponse redundancy, stereotypy of adjacent response pairs).
82
1-d experiment 18-34 yr pure caffeine 350 mg Caffeine reduced subjective sleepiness in sleep deprived + caffeine (SDc). Recognition was Harrison and
(UK) n=40 (20 M) [sleep depriva- [5.0 mg/kg] unaffected by sleep deprivation, whereas for recency, sleep deprivation groups scored sig- Horne, 2000
tion] nificantly lower than controls. There was no significant improvement of recency with caf-
feine in the SDc group. Both sleep deprivation groups had poorer insight into their perform-
ance with recency. Self-ordered pointing remained unchanged.
1-d experiment 19-36 yr coffee; tea 150, 300 mg as Both beverages maintained aspects of cognitive and psychomotor performance throughout Hindmarch et
(UK) n=30 (15 M) tea; 300, 600 mg the day and evening given repeatedly; day-long tea consumption produced similar alerting al., 2000
as coffee (in 4 effects to coffee, despite lower caffeine levels, but was less likely to disrupt sleep.
doses)
1-d experiment 24 ± 2 yr ED [sleep dep- 160 mg The ED significantly improved lane drifting and a secondary task (reaction time), particu- Horne and
(UK) n=11 (6 M) rivation] [2.3 mg/kg] larly for the first hr of the 2-hr task. [ED=Red Bull] Reyner, 2001
1-d experiment Adult pure caffeine 600 mg After sleep deprivation, for simple affective faces, neither sleep loss nor caffeine affected the Huck et al.,
(USA) n=54 M+F [47 hr sleep [8.6 mg/kg] accuracy of judgments. For complex emotion blends, caffeine improved the ability to dis- 2008
deprivation] criminate subtle aspects of emotion correctly relative to placebo.
1-d experiment 22 ± 2 yr ED [24.5 hr 160 mg (split After an extended wakefulness (0700-0730 h-24.5 h) followed by an 8-hr daytime 'recovery' Jay et al.,
(Australia) n=15 (8 M) sleep depriva- dose) sleep (0730-1530 h), sleep onset latency remained unchanged as did stage 2 and slow wave 2006
tion] sleep, but total sleep time was 29.1 min shorter (p<.05) after ED and sleep efficiency was
also reduced; subsequent performance was unaffected. [ED not identified but appeared to be
Red Bull based on contents]
1-d experiment Adult pure caffeine 2.1, 4.3, 8.6 There was a significant (p < 0.05) and disproportional increase in the dose normalized caf- Kamimori et
(USA) n=37 M [49 hr sleep mg/kg feine AUC and a decrease in its clearance associated with increasing dose. In addition, the al., 1995
deprivation + 12 paraxanthine to caffeine ratio decreased with an increase in dose, indicating that the rate of
hr after caffeine] caffeine metabolism decreased.
1-d experiment 18-32 yr pure caffeine 2.1, 4.3, 8.6 Caffeine had no effect on noradrenaline, but adrenaline was increased 1-4 hr post-dosing in Kamimori et
(USA) n=50 M [sleep depriva- mg/kg the high dose group. Responses to sleep latency, sleepiness scores, and reaction time scores al., 2000
tion] showed dose-related changes with significant correlation coefficients.
1-d experiment 18-35 yr caffeine in 150, 300, 600 Caffeine reduced the number of lapses in a dose-related manner; and performance was main- Kamimori et
(USA) n=48 (28 M) chewing gum mg (as 3 doses) tained at baseline levels for the entire sleep loss period with multiple doses of 200 mg caf- al., 2005
[sleep depriva- [2.1, 4.3, 8.6 feine. There was a significant main effect for session on the SSS, the score increasing over
tion] mg/kg] time, but no significant differences between groups.
83
1-d experiment 18-36 yr pure caffeine 600 mg Caffeine had no effect on the appreciation of verbal humor during sleep loss, but improved Killgore et al.,
(USA) n=54 (29 M) [49.5 hr sleep [8.6 mg/kg] psychomotor response speed and ratings of subjective sleepiness. 2006
deprivation]
1-d experiment 18-36 yr pure caffeine 600 mg Caffeine restored psychomotor vigilance test speed and reduced lapses but caused nervous- Killgore et al.,
(USA) n=53 (29 M) [61 hr sleep [8.6 mg/kg] ness, excitation, happiness, abdominal pain, and jitteriness. Subsequent recovery sleep was 2008
deprivation] not affected and there was no effect on post-recovery performance. [Caffeine was given
after 44 hr of wakefulness; after 61 h, participants got 12 hr of recovery sleep]
1-d experiment 18-36 yr pure caffeine 600 mg Subjects receiving caffeine completed the computerized versions of the 5-Ring Tower of Killgore et al.,
(USA) n=54 (29 M) [44 hr sleep [8.6 mg/kg] Hanoi in fewer moves, although the speed of completion was not influenced. 2009
deprivation]
1-d experiment 18-36 yr pure caffeine 200 mg Chewing gum did not reverse sleep deprivation but caffeine did; no effect on HR or ECG. Kohler et al.,
(Australia) n=14 (7 M) [sleep depriva- [2.9 mg/kg] 2006
tion]
1-d experiment 21-56 yr pure caffeine 360 mg/d On withdrawal, 27 subjects reported tiredness and 18 developed headache. EEG, skin con- Lader et al.,
(UK) n=40 (19 M) [5.1 mg/kg/d] ductance and BP changes were apparent. Sleep improved on withdrawal but subjects re- 1996
ported feeling less alert and more tired. The higher the usual caffeine intake (mean was 360
mg/d), the greater the unpleasant feelings on withdrawal and the more marked the reversal of
feelings on resumption. The faster the metabolism of caffeine (assayed using 500 mg caf-
feine), the less the drop in anxiety during withdrawal and the less its return on resumption.
These correlations were, however, rather weak and sporadic.
1-d experiment Adult pure caffeine 150, 300, 600 The 300 and 600 mg doses improved vigilance and performance when subjects became tired, Lagarde et al.,
(France) n=24 (12 M) [32-hour sleep mg slow-release the effect lasting 13 hr after treatment. The optimal dose for both men and women was 300 2000
deprivation] [2.1, 4.3, 8.6 mg (side effects seen at 600 mg). Globally, there was no difference between placebo and
mg/kg] caffeine during the recovery night period.
1-d experiment 18-35 yr pure caffeine 300, 900 mg (in Caffeine exerted mild deleterious dose-response effects on recovery sleep following total LaJambe et
(USA) n=9 M+F [sleep depriva- 3 doses) sleep deprivation, primarily early in the sleep period. al., 2005
tion] [4.3, 13 mg/kg]
1-d experiment 21-25 yr pure caffeine 200 mg Compared to placebo, sleep efficiency and total sleep time were significantly reduced that Landolt et al.,
(Switzerland) n=9 M [2.9 mg/kg] evening; EEG changes. [administered caffeine at 07.10 h] 1995
1-d experiment 21-25 yr pure caffeine 100 mg In the night following caffeine administration, stage 4 sleep had reverted to the baseline Landolt et al.,
(Switzerland) n=9 M [1.4 mg/kg] level, but sleep latency was still increased, and stage 2 sleep, as well as SWA in the first 1995
NREMS episode, were reduced.
84
1-d experiment 20-30 yr pure caffeine 400 mg (split Reduced sleepiness and EEG theta activity during wakefulness; compared with baseline Landolt et al.,
(Switzerland) n=12 M [40 hr sleep dose) sleep, sleep after deprivation (recovery sleep) had altered EEG activity. 2004
deprivation] [5.7 mg/kg]
1-d experiment 23.0 ± 3.0 yr pure caffeine; 100, 200, 300 Caffeine (200 and 300 mg) improved mood, visual vigilance, choice reaction time, repeated Lieberman et
(USA) n=68 M stress [72 hr mg acquisition, self-reported fatigue and sleepiness with the greatest effects on tests of vigilance, al., 2002
sleep depriva- [1.4, 2.9, 4.3 reaction time, and alertness (dose-related). Marksmanship was not affected by caffeine. The
tion] mg/kg] greatest effects were 1 hr post-administration, but effects persisted for 8 h. Some (~15%)
also reported nervousness, blurry vision, dizziness, nausea, clammy mouth, and weak mus-
cles.
1-d experiment 23-24 yr pure caffeine 200 mg Intake of caffeine was associated with higher axillary temperatures, but it did not affect sub- Lohi et al.,
(Finland) n=13 M [sleep depriva- [2.9 mg/kg] jectively assessed sleepiness. Flight performance was similar ± caffeine during the four 2007
tion] rounds flown under sleep deprivation, but subjective evaluation of overall flight performance
in the caffeine group tended to be too optimistic, indicating a potential flight safety problem.
1-d experiment Adult pure caffeine 200 mg, then 50 Caffeine shortened reaction time; event-related potentials (ERPs) results supported the view Lorist et al.,
(The Nether- n1=15; n2=15 [sleep depriva- mg that caffeine increases cortical arousal and perceptual sensitivity. Fatigued subjects showed 1994a
lands) M+F tion] [3.6 mg/kg] larger improvements in performance after caffeine than well-rested subjects. 6/30 subjects
did not show arousing effects of caffeine.
1-d experiment Adult pure caffeine; 200 mg, then 50 Subjects reacted faster with caffeine condition; selection of relevant information was im- Lorist et al.,
(The Nether- n1=15; n2=15 decaf [sleep mg proved. Search negativity was not affected. Caffeine effects on the P3 elicited by target let- 1994b
lands) M+F deprivation] [3.6 mg/kg] ters were more pronounced in the fatigued than in the well-rested subjects.
1-d experiment Adult pure caffeine 4.3 mg/kg Following sleep deprivation, caffeine improved running memory, logical reasoning, mathe- Magill et al.,
(USA) n=?? M [overnight sleep matical processing, tracking and visual vigilance. 2003
deprivation]
1-d experiment Adult Caffeinated 0, ≥1 cup (the Carriers of the A allele (adenosine deaminase polymorphism) who consumed caffeine in the Mazzotti et
(Brazil) n=958 M+F drinks previous day) day prior to polysomnography had higher sleep efficiency and REM sleep percentage, after al., 2011
[≥1.4 mg/kg/d] adjustment for confounders. No effect was observed in the absence of caffeine. [Caffeine
content per cup not specified; assumed 100 mg/cup]
1-d experiment 29.8 ± 5.4 yr pure caffeine; 600 mg (split in Caffeine maintained vigilance and improved running performance during an overnight field McLellan et
(Canada) n=16 M; c=15 exercise [sleep 3 doses) operation, but did not improve marksmanship. al., 2005
M deprivation] [8.6 mg/kg]
85
1-d experiment 22.8 ± 1.4 yr ED 80 mg In a 4-hr driving task, the ED had no effect during the first 2 hr, but improved driving per- Mets et al.,
(The Nether- n=21 (9 M) [1.1 mg/kg] formance during the 3rd and 4th hr (reduced sleepiness, weaving, speed deviations and men- 2010
lands) tal effort to perform the test, and improved subjective driving quality). [ED=Red Bull]
1-d experiment 18-29 yr pure caffeine 200 mg Caffeine significantly reduced Johns Drowsiness Scale scores and reaction times, for 3-4 hr. Michael et al.,
(Australia) n=12 (5 M) [sleep depriva- [2.9 mg/kg] Self-reports of sleepiness were not as sensitive, with Karolinska Sleepiness Scale scores only 2008
tion] being significantly lower in the caffeine vs. placebo condition at 30 min post-dosing.
1-d experiment 19-37 yr pure caffeine 250 mg Under fatigue or no fatigue, caffeine had no performance-enhancing effect; participants rated Mills et al.,
(USA) n1=18; n2=32 [sleep depriva- [3.6 mg/kg] effects more stimulating and less sedating while fatigued. 2001
M+F tion]
1-d experiment 21.2 ± 4.1 yr pure caffeine 300 mg Caffeine caused an increase in nocturnal worry and sleeplessness. Omvik et al.,
(Norway) n=96 F [4.3 mg/kg] 2007
1-d experiment Adult pure caffeine 600 mg slow Caffeine significantly antagonized the detrimental effects of sleep deprivation on vigilance Patat et al.,
(France) n=12 M [sleep depriva- release [8.6 (increase in EEG beta waves, speed of reaction, sustained attention and reduction in subjec- 1999
tion] mg/kg] tive sedation).
1-d experiment 19-27 yr pure caffeine 600 mg slow The slow-release caffeine formulation reversed the deleterious effect of 36 hr sleep depriva- Patat et al.,
(France) n=12 M [36 hr sleep release [8.6 tion for at least 24 h; alertness increased; cognitive/psychomotor improvement; EEG 2000
deprivation] mg/kg] changes.
1-d experiment 21-34 yr pure caffeine; 150 mg Caffeine prolonged objective sleep onset latency; the effect was sensitive to zolpidem and Paterson et
(UK) n=12 M zolpide; tra- [2.1 mg/kg] trazodone, both of which attenuated the caffeine-induced increase in latency. al., 2007
zodone
1-d experiment Adult pure caffeine 150 mg Caffeine delayed sleep onset, decreased total sleep time, sleep efficiency, and stage 2 sleep Paterson et
(UK) n=12 M zolpidem; tra- [2.1 mg/kg] without altering wake after sleep onset or the number of awakenings; effects were differen- al., 2009b
zodone tially attenuated by Zolpidem and/or Trazodone.
1-d experiment Adult exercise; pure 6 mg/kg Caffeine improved repeated sprint ability, including next day performance, but had little ef- Pontifex et al.,
(Australia) n=10 M caffeine fect on reactive agility time or sleep quality. 2010
1-d experiment 23 ± 2 yr pure caffeine 200 mg Caffeine significantly reduced incidents and subjective sleepiness throughout the 2-hr drive, Reyner and
(UK) n1=8; n2=8 [sleep depriva- [2.9 mg/kg] and EEG power for the second 30-min period. Horne, 2000
M+F tion]
1-d experiment 24 ± 2 yr ED 80 mg Compared with the control, the ED significantly reduced sleep-related driving incidents and Reyner and
(UK) n=12 (7 M) [sleep depriva- [1.2 mg/kg] subjective sleepiness for the first 90 min of the drive. There was a trend for the EEG to re- Horne, 2002
tion] flect less sleepiness during this period. [ED=Red Bull]
86
1-d experiment ~26-36 ± 9 yr; pure caffeine 200 mg Insomniacs had significantly longer sleep latency and less total sleep time in the multiple Salín-Pascual
(Mexico) n=12 (8 M) [sleep depriva- [2.9 mg/kg] sleep latency test compared to normal volunteers. et al., 2006
tion; sleep dis-
order]
1-d experiment 24-63 yr pure caffeine 450 mg (as 3 Those who consumed caffeine presented the same level of energy before and after sleep dep- Schwartz-
(Brazil) n=20 (5 M) [depression; 24 doses) rivation (lethargic-energetic item of the Bond-Lader scale), while the patients in the placebo haupt et al.,
hr sleep depriva- [6.4 mg/kg/d] group had a reduced level of energy after sleep deprivation (p=0.0045). There was no differ- 2009
tion] ence between the caffeine and placebo groups in the other items of the Bond-Lader scale.
1-d experiment 32 ± 12 yr coffee; decaf 728 mg/24 h Drinking regular caffeinated coffee, compared to decaffeinated coffee, decreased the total Shilo et al.,
(Israel) n=6 (3 M) [10 mg/kg] amount of sleep and quality of sleep, and increased the length of time of sleep induction. 2002
Caffeinated coffee caused a decrease in 6-sulphoxymelatonin excretion the following night.
[130 mg caffeine per cup coffee]
1-d experiment 18-26 yr pure caffeine; 600 mg slow Increased sleep latency; decreased calmness; no differences for alertness, contentedness and Sicard et al.,
(France) n=100 M; OC; smoking release caffeine sleep quality; effects related to plasma caffeine levels, which were only influenced by to- 1996
c=20 M [8.6 mg/kg] bacco consumption.
1-d experiment 24 ± 0.3 yr pure caffeine 100, 200, 300 Sighting time was significantly faster in sleep deprived individuals after taking 200 or 300 Tharion et al.,
(USA) n=62 M [73 hr sleep mg [1.4. 2.9, mg of caffeine compared with placebo or 100 mg of caffeine. No differences in accuracy 2003
deprivation] 4.3 mg/kg] measures between caffeine treatment groups were evident at any test period.
1-d experiment ~36±12 yr; pure caffeine 2.5 mg/kg Despite caffeine intake, poor sleepers had greater variability in caffeine Cmax and clearance Tiffin et al.,
(UK) n=20 (10 M) [sleep disorder] half-life than normal sleepers, and had lower scores for vigilance and tapping rate; BP in- 1995
crease; EEG changes.
1-d experiment 26.7 ± 7.2 yr pure caffeine 200 (split dose), The cognitive component of the shooting task (i.e., target detection, number of shots fired) Tikuisis et al.,
(Canada) n=20 M [22 hr sleep then 400 mg benefited from caffeine whereas the psychomotor component (marksmanship) did not. 2004
deprivation] [2.9, 5.7 mg/kg]
1-d experiment 21-47 yr pure caffeine 0.3 mg/kg/hr for In the placebo condition, sleep inertia was manifested as significantly impaired psychomotor Van Dongen
(USA) n=28 M [sleep depriva- 66 hr vigilance upon awakening from the naps. This impairment was absent in the caffeine condi- et al., 2001
tion] tion. Caffeine had only modest effects on nap sleep.
1-d experiment 18-35 yr pure caffeine 300 mg/70 kg Caffeine decreased sleep drive during sleep deprivation. Waters et al.,
(USA) n=76 M [40.5 hr sleep [4.3 mg/kg] 2003
deprivation]
87
1-d experiment 18-30 yr pure caffeine 600 mg Performance and alertness were significantly improved by caffeine during the early morning Wesensten et
(USA) n=50 (37 M) [41.5 hr sleep hours, when the combined effects of sleep loss and the circadian trough of performance and al., 2002
deprivation] alertness trough were manifest.
1-d experiment 18-30 yr pure caffeine 600 mg Time-on-task effects contributed to the performance degradation seen during sleep depriva- Wesensten et
(USA) n=50 (37 M) [sleep deprivation; effects which were reversed by caffeine. al., 2004
tion]
1-d experiment Adult pure caffeine; 400 mg (split Enhanced night-time performance; caffeine + all-night bright light (Bright Light-Caffeine) Wright et al.,
(USA) n=46 M [sleep depriva- dose) enhanced performance to a larger degree than either the Dim Light-Caffeine or the Bright 1997a
tion] [5.7 mg/kg] Light-Placebo condition. Beneficial effects were largest during the early morning hours (e.g.
after 02.00 hours) when performance in the Dim Light-Placebo group was at its worst. The
Bright Light-Caffeine condition was able to overcome the circadian drop in performance for
most tasks measured. Both caffeine conditions improved objective alertness.
1-d experiment 18-28 yr pure caffeine; 400 mg (in 4 Enhanced nighttime body temperature; reduced the onset of melatonin levels (non- Wright et al.,
(USA) n1=30 F; OC doses) contraceptive users). 2000
n2=32 F [5.7 mg/kg]
1-d experiment 24.5 ± 4.3 yr pure caffeine; 1200 (split in 3 In general, the effects of exercise on sleep were not greater following caffeine compared to Youngstedt et
(USA) n=8 M exercise doses) placebo; increases in slow-wave sleep after exercise were approximately 1/3 smaller follow- al., 2000
ing caffeine treatment compared to placebo.
1, 7-d experi- 18-50 yr pure caffeine 400 mg; 1200 1-d experiment: sleep latency and mood measures were similar after nap ± 400 mg caffeine; Bonnett and
ment n=9 (7 M); [sleep depriva- mg (in 3 doses) 3-d experiment: poor sleep, increased latency on the Multiple Sleep Latency Test, increasing Arand, 2003
(USA) c=9 (7 M) tion] [5.7; 17 mg/kg] fatigue, and increased anxiety.
2-d experiment 18-25 yr pure caffeine 400 mg (split Combining caffeine ingestion with bright light exposure (≥ 2000 lux) suppressed melatonin Wright et al.,
(USA) n=40 M [sleep depriva- dose) and attenuated the normal nighttime drop in temperature to a larger degree than either condi- 1997b
tion] [5.7 mg/kg] tion alone.
2-d experiment 18-30 yr pure caffeine 1x 400 mg; 150, For countering sleep deprivation over 48 hr naps were superior to caffeine; small repetitive Bonnet et al.,
(USA) n=140 M [sleep depriva- 300 mg every 6 doses of caffeine maintained performance, mood, and alertness better than no naps or large 1995
tion 2 days and hr [5.7 to ~10 single doses of caffeine; neither naps nor caffeine were better than placebo beyond 24 hours.
nights] mg/kg] Caffeine had peak effectiveness and loss of effect in 6 hours.
88
3-d experiment 25.8 ± 4.3 yr pure caffeine 600 mg/d (in 3 Statistical analysis of results of psychomotor vigilance test conducted during the wakefulness Benitez et al.,
(USA) n=18 (14 M) [77 hr sleep doses) period suggests (1) the presence of a performance inhibitor that increases and saturates over 2009
deprivation] [8.6 mg/kg] the period of continuous wakefulness, (2) competitive inhibition of this inhibitor by caffeine,
(3) the persistence of an internally driven circadian rhythm of alertness, and (4) a multiplica-
tive relationship between circadian rhythm and performance inhibition.
3-d experiment 20-35 yr pure caffeine 800 mg (in 4 The severity of performance impairment did not increase significantly from 51 to 75 hr of Killgore et al.,
(USA) n=26 (21 M) [51, 75 hr sleep doses/ 8 hr) wakefulness, and caffeine had no significant effects on Iowa Gambling Task performance 2007a
deprivation] [11 mg/kg] during sleep deprivation.
3-d experiment Adult caffeine in 800 mg (200 mg No effect after 51 hr; after 75 hr of sleep deprivation had significant increase in behavioral Killgore et al.,
(USA) n=25 (21 M) chewing gum every 2 hr)/night risk-taking but not self-reported perception of risk-propensity; overnight caffeine prevented 2010
[75 hr sleep [11 mg/kg] this increase in risky behavior.
deprivation]
3-d experiment Adult pure caffeine 4 mg/kg (split Caffeine decreased physiological sleep tendency on the night shift compared with placebo; Muehlbach
(USA) n=30 M+F dose) however, the two groups performed at equivalent levels on a performance task. and Walsh,
1995
4-d experiment 28.6 ± 4.7 yr pure caffeine; 200 mg/d for 2 Caffeine maintained both vigilance and physical performance during sustained overnight McLellan et
(Canada) n=10 M; c=10 exercise [sleep d, then 3x/d for operations. al., 2007
M deprivation] 3 d [2.9, 8.6
mg/kg]
4-d experiment 19-62 yr pure caffeine 4 mg/kg Napping, caffeine, and their combination all improved alertness and performance as meas- Schweitzer et
(USA) n=68 (31 M); [sleep depriva- ured by Maintenance of Wakefulness Test and Psychomotor Vigilance Task, but the combi- al., 2006
n2=53 tion] nation of napping and caffeine was best in improving alertness.
7-d experiment 17-52 yr pure caffeine 5.25 mg/kg (as 3 No net enhancing effect on mood when participants were rested, and no net restorative ef- James and
(Ireland) n=48 (18 M) [sleep depriva- doses) fects when mood was degraded by sleep restriction; caffeine-induced decrements in mood Gregg, 2004a
tion] were observed during both conditions of rest and sleep restriction.
7-d experiment Adult pure caffeine 5.25 mg/kg (as 3 No significant enhancement of performance or mood when participants were rested or sleep- James et al.,
(Ireland) n=96 M+F [sleep depriva- doses) deprived. 2005
tion]
7-d experiment 18-52 yr pure caffeine 5.25 mg/kg (as 3 No evidence that caffeine improved performance, either from acute or habitual use; subjects James, 1998
(Australia) n=36 (18 M) [sleep depriva- doses) were more alert and less tired from acute exposure by but less alert from chronic exposure;
tion] withdrawal was associated with headache and sleeping longer and more soundly.
89
7-d experiment 17-19 yr pure caffeine 5.25 mg/kg (as 3 Effects on EEG activity were few, weak and inconsistent, and there was no net restorative Keane and
(Ireland) n=15 (4 M) [sleep depriva- doses) effect on cognitive function. James, 2008
tion]
29-d experiment 18-30 yr pure caffeine 0.3 mg/kg/hr Rising caffeine levels markedly attenuated wake-dependent deterioration of cognitive per- Wyatt et al.,
(USA) n=16 M [28.57-hr sleep formance, particularly at the circadian performance nadir. Caffeine enhanced the ability of 2004
deprivation] subjects to remain consistently awake for extended periods, holding subjects back from
completing the full transition to sleep, but at the expense of increasing subjective sleepiness.
30-d experi- 19-64 yr caffeine, all mean 476 mg/d Sleep improved by 35% in HIV subjects (~1 SD from pre-PSQI scores) who reduced their Dreher, 2003
ment (Brazil; n=88 (71 M) sources [HIV] [6.8 mg/kg/d] caffeine intake by 90% or greater from baseline for 30 d. [HIV= Human Immunodeficiency
Canada; USA) Virus]
Case-control 18-50 yr caffeinated + or - Attempted to assess whether alcohol and caffeinated drinks are associated with narcolepsy Ton et al.,
(USA) Cases=67; drink, carbon- among those with human leukocyte antigen (HLA) DQB1*0602. The results do not support 2010
controls=95 ated; coffee; tea etiologic roles for coffee, alcohol, or tea in narcolepsy; cases avoided alcohol and self-
M+F HLA DQB1- medicated with coffee as a result of symptoms or treatments. [No info on caffeine intake]
0602 carrier
Cross-sectional 30-60 yr pure caffeine 103 mg/d; 295 Patients with obstructive sleep apnea (OSA) (N=27) reported significantly greater caffeine Bardwell et
(USA) n=61 (38 M) [obstructive mg/d consumption than those without OSA (N=34) (295 vs. 103 mg, P=0.010), but caffeine was al., 2000
sleep apnea; [1.5, 4.2 not significantly correlated with their ambulatory BP. In contrast, urinary norepinephrine
hypertension] mg/kg/d] (NE) excretion correlated with caffeine consumption, apnea severity and BP. Significant
OSA-NE and BP-NE relationships remained even after controlling for caffeine consumption.
Cross-sectional 15-100 yr coffee 0, 1-2, 3-5, ≥6 Heavy coffee drinkers (≥6 cups/d [8.6 mg/kg/d]) were at greater risk of sleep tooth grinding Ohayon et al.,
(Germany; Italy; n=13,057 cups/d (bruxism); more common in younger subjects. [No info on caffeine per cup; assumed 100 2001
UK) (48% M) [1.4 to ≥ 8.6 mg/cup]
mg/kg/d]
Cross-sectional ≥ 60 yr caffeinated 0-8 cups/d Insomnia subjects, but not good sleepers, showed increased concentrations of IL-6 associated Okun et al.,
(USA) n = 222 M+F drinks [≤11 mg/kg/d] with caffeine use. [No info on caffeine per cup; assumed 100 mg/cup] 2011
Cross-sectional 44-58 yr caffeine, all 1-20 cups/d Total sleep time was reduced from caffeine intake of ≥ 8 cups/d coffee; time in bed was re- Sanchez-
(France) n=1498 F sources [1.2-24 duced as caffeine intake increased; higher caffeine intake was not related to a higher daytime Ortuno et al.,
mg/kg/d] somnolence. [1 cup of coffee = 85 mg, 1 cup of tea = 30 mg, 1 can of cola = 36 mg; as- 2005
sumed coffee was the primary caffeine source for dose estimates]
EEG=electroencephalograph; ED=energy drink; HR=heart rate
90
TABLE 3-2. Effects of Caffeine on Sleep – Summaries of Reviews Reference
In those for whom sleep loss is inevitable (e.g., in emergencies, when public health and safety personnel are responding to a disaster or when military per- Bonnet et al.,
sonnel must engage in prolonged operations), judicious voluntary use of a stimulant under appropriate medical supervision may be warranted. 2005
The amounts of guarana, taurine, and ginseng found in popular EDs are far below the amounts expected to deliver either therapeutic benefits or adverse Clauson et al.,
events. However, caffeine and sugar are present in amounts known to cause a variety of adverse health effects (insomnia, nervousness, headache, tachycar- 2008
dia, seizures, death).
The main effects of caffeine on sleep are decreased sleep latency, shortened total sleep time, decrease in power in the delta range, and sleep fragmentation. Porkka-
Caffeine may also decrease the accumulation of sleep propensity during waking, thus inducing long-term harmful effects on sleep quality. The sensitivity Heiskanen, 2011
for caffeine varies markedly among individuals. Recently, genetic variations in genes related to adenosine metabolism have provided at least a partial ex-
planation for this variability.
Children and adolescents, while reporting lower daily, weight-corrected caffeine intake, similarly experience sleep disturbance and daytime sleepiness as- Roehrs and
sociated with their caffeine use. Under conditions of habitual sleep the evidence indicates that caffeine, rather than enhancing performance, is merely restor- Roth, 2008
ing performance degraded by sleepiness. Studies have shown that caffeine dependence develops at relatively low daily doses and after short periods of regu-
lar daily use.
Caffeine abstinence was associated with significant lengthening of sleep duration, better sleep quality, and less difficulty falling asleep. Sin et al., 2009
Caffeine consumed by most people has largely positive effects on behavior. Negative effects have occurred when very large amounts were given or in sen- Smith, 2002
sitive groups (e.g. increased anxiety and impaired sleep in patients with anxiety disorders). There is also some evidence that fine motor control may be im-
paired as a function of the increase in anxiety.
91
CHAPTER 4. INTERACTION OF CAFFEINE WITH OTHER
CHEMICALS
4A. Interaction of Caffeine and Ethanol – Human Studies
The interaction of caffeine with ethanol has been evaluated in a number of experimental
and epidemiological studies, perhaps more so than any other co-ingredient. One of the central
questions in the experimental studies has been whether, and to what extent, caffeine can reverse
alcohol-induced physical and psychological impairment. Subjects were given 69-400 mg caf-
feine (~1-6 mg/kg) with 0.4-1.5 g/kg ethanol. The epidemiological studies examined the effect
of caffeine and ethanol co-exposure on parameters such as fertility and child birth weight, and
the propensity to consume greater amounts of alcohol with the co-ingestion of caffeine. The
human studies are summarized in Table 4-1.
Most studies found that caffeine partially counteracted some aspects of ethanol-induced
physical or psychological decrements. Compared to ingestion of 0.6 or 1.0 g/kg alcohol only,
alcohol plus 1.1 mg/kg caffeine as an ED (Red Bull) reduced subjects' perception of headache,
weakness, dry mouth, and impairment of motor coordination, but did not significantly reduce
alcohol-induced deficits in objective motor coordination and visual reaction time, or alter the
breath alcohol concentration (Ferreira et al., 2006). An intake of 100-120 mg caffeine signifi-
cantly antagonized an ethanol-induced increase in mismatch negativity peak latency (Hirvonen et
al., 2000), weakly antagonized the increase in errors made in psychomotor tests, and signifi-
cantly increased psychomotor speed (Mackay et al., 2002). A caffeine intake of 140-400 mg (2-
6 mg/kg) partially antagonized alcohol’s detrimental effects on response execution on various
psychomotor parameters (a cued go/no-go task, dual-task interference test, Stroop test, critical
fusion performance task, stop light task, simple or choice reaction time). It also decreased sleep
latency on a multiple sleep latency test, increased (car) braking latency, and decreased the per-
ception of alcohol intoxication. However, there was no effect on visual analog rating of dizzi-
ness, inhibitory control, the degree of errors in the dual-task interference test, or body sway
(Marczinski and Fillmore, 2003; 2006; Fillmore and Vogel-Sprott, 1999; Roehrs et al., 2004;
Drake et al., 2003; Liguori and Robinson, 2001; Azcona et al., 1995; Martin and Garfield, 2006).
A history of combined alcohol and caffeine administration increased alcohol tolerance (i.e., less
debilitated performance on psychomotor tests) compared with an exposure history to either drug
alone (Fillmore, 2003). One study found that individuals expecting counteracting effects of caf-
feine on ethanol displayed greater impairment than those led to expect no effect (Fillmore et al.,
2002).
In contrast, some studies found no significant interactions between caffeine and ethanol.
Marsden and Leach (2000) obtained similar results for a visual search task when subjects were
given 100 mg caffeine (~1.4 mg/kg) with or without 30 g alcohol (~0.4 g/kg). Ferreira et al.
(2004a) saw no significant difference in maximal effort (physical) test performance between sub-
jects who ingested alcohol (1.0 g/kg) or alcohol + an ED (1.1 mg/kg caffeine), although there
were differences in several respiratory and hormonal parameters. The impairment in driving
ability caused by drinking one 12-oz beer (4.8% alcohol) was not countered by an intake of 69
mg caffeine (~1 mg/kg) (Howland et al., 2011).
92
Most of the epidemiological studies were conducted relatively recently, and examined the
impact of caffeine, primarily in the form of EDs, and ethanol co-ingestion on alcohol drinking
behavior. The study authors expressed a concern for the health and safety of consumers of EDs
with caffeine, as caffeine masks the self-awareness of intoxication, leading to risk-taking and
dangerous behavior. The caffeine doses of the subjects were not readily quantifiable due to the
nature of the studies. Cohort prospective studies by Arria et al. (2010; 2011) found that frequent
users of EDs had heavier alcohol consumption patterns, were at greater risk for alcohol depend-
ence, and were more likely to have used other drugs. Similar findings were obtained by a num-
ber of cross-sectional studies. Study participants reported drinking significantly more alcohol
when it was co-administered with EDs (Price et al., 2010). Consumption of alcohol mixed with
EDs was associated with increased heavy episodic drinking and twice as many episodes of
weekly drunkenness (O’Brien et al., 2008) or jolt and crash episodes (Malinauskas et al., 2007).
Bar patrons who consumed alcohol with EDs had a 3-fold greater risk of leaving the bar intoxi-
cated and intending to drive later (Thombs et al., 2010a). A multivariate regression analysis in-
dicated that caffeinated alcoholic beverage consumption was significantly associated with bar
patron intoxication, and there was no significant difference between the intoxication levels
whether the caffeine was in the form of an ED or a cola (Thombs et al., 2010b). Amit et al.
(2004) found an association between drinking alcohol and caffeinated beverages regardless of a
family history of alcoholism.
Cohort prospective studies found that maternal intake of ≥1 cup/day of coffee did not
significantly affect the probability of conception, but may have enhanced ethanol’s negative ef-
fect (Hakim et al., 1998).
NOAEL values for any of the discussed endpoints.
Brief summaries of conclusions drawn by authors of reviews addressing the interaction of

caffeine and ethanol are presented in Table 4-2. Bigard (2010) asserted that the consumption of
ED may increase the risk for caffeine overdose and toxicity in children and teenagers, and in-
crease the risk of serious injury, sexual assault, drunk driving, and death. Even after adjusting for
alcohol consumption, students who consumed alcohol + ED had markedly higher rates of serious
alcohol-related consequences. Reissig et al. (2009) expressed a concern that ED may serve as a
gateway to other forms of drug dependence. In children and adolescents who are not habitual
caffeine users, vulnerability to caffeine intoxication may be markedly increased due to an ab-
sence of pharmacological tolerance. Weldy (2010) pointed out that adding ED to alcohol tends to
increase its rate of absorption by carbonation and dilution of the alcohol, and keep a person
awake longer, allowing ingestion of a greater volume of alcohol. At low blood alcohol levels,
caffeine appears to decrease some of the impairment from the alcohol, but at higher blood alco-
hol levels, caffeine does not appear to modify either the physical or mental impairment induced
by alcohol.
93
TABLE 4-1. Interaction of Caffeine and Ethanol – Human Studies
1-d experiment 21-30 yr pure caffeine; 69 mg Drinking a beer (12 oz, 4.8% alcohol) significantly impaired driving ability and sustained Howland et
(USA) n=127 M+F ethanol [1.0 mg/kg] attention/reaction time; the addition of caffeine did not enhance driving performance or sus- al., 2011
tained attention/reaction time performance relative to alcohol alone.
1-d experiment 24 ± 3 yr ED; ethanol 1.14 mg/kg No significant differences between alcohol (1.0 g/kg) and alcohol + ED in maximal effort Ferreira et
(Brazil) n=14 M test performance. Compared to the placebo or ED-only, the alcohol and alcohol + ED trials al., 2004a
showed higher HR at the ventilatory threshold, smaller RER, higher blood lactate and
noradrenaline levels. No significant differences among trials in blood alcohol concentration,
BP, glucose, insulin, dopamine, adrenaline, ACTH, or cortisol levels. [ED=Red Bull]
1-d experiment 23 ± 3 yr ED; ethanol 1.14 mg/kg Compared to ingestion of alcohol alone (0.6 or 1.0 g/kg), alcohol + ED reduced subjects' Ferreira et
(Brazil) n=26 M perception of headache, weakness, dry mouth, and impairment of motor coordination. How- al., 2006
ever, the ED did not significantly reduce the deficits caused by alcohol on objective motor
coordination and visual reaction time, or alter the breath alcohol concentration. [3.57
mL/kg =1.14 mg caffeine/kg)] [ED=Red Bull]
1-d experiment 19-34 yr pure caffeine; 100 mg The increase in mismatch negativity peak latency due to ethanol (0.55 g/kg) ingestion was Hirvonen et
(Finland) n=12 (7 M) ethanol [1.4 mg/kg] significantly antagonized by caffeine. al., 2000
1-d experiment 25-52 yr coffee; ethanol 100 mg Caffeine enhanced performance on a visual search. Combining alcohol (30 g) and caffeine Marsden and
(UK) n=12 M [1.4 mg/kg] did not produce any significant differences in performance on any of the tasks. [Caffeine Leach, 2000
was supplied in the form of 250 mg black coffee without sugar; assumed this means 250 mL
coffee containing ~100 mg caffeine]
1-d experiment mean 21.3 yr pure caffeine; 110-120 mg Subjects given alcohol (0.66 g/kg) made more errors during both fixed and random four Mackay et
(UK) n=64 (22 M) ethanol [1.6-1.7 mg/kg] choice reaction time task sequences, and there was evidence of weak antagonism of these al., 2002
effects by caffeine on the latter measure. On test of psychomotor speed, alcohol was associ-
ated with a significant slowing; the caffeine group was significantly faster and there was
clear antagonism of the effects of alcohol by caffeine.
1-d experiment 21-30 yr pure caffeine; 2.0, 4.0 mg/kg Alcohol (0.65 g/kg) impaired both inhibitory and activational aspects of behavioral control. Marczinski
(USA) n=12 (6 M) ethanol Caffeine (4.0 mg/kg) antagonized alcohol effects on response execution on a cued go/no-go and Fill-
task, but had no effect on inhibitory control. more, 2003
1-d experiment 21-28 yr pure caffeine; 2.0, 4.0 mg/kg Alcohol (0.65 g/kg) impaired task performance by increasing dual-task interference and Marczinski
(USA) n=12 (6 M) ethanol increasing errors; coadministration of caffeine counteracted the effects of alcohol on inter- and Fill-
ference but had no effect on the degree to which alcohol increased errors. Coadministration more, 2006
of caffeine with alcohol reduced participants' perceptions of alcohol intoxication compared
with administration of alcohol alone.
94
1-d experiment 21-35 yr pure caffeine; 150, 300 mg Ethanol (0.5 g/kg) reduced mean latency on the multiple sleep latency test, which was re- Drake et al.,
(USA) n=13 (6 M) ethanol [2.1, 4.3 mg/kg] versed by 150 mg caffeine, and 300 mg increased mean latency (greater alertness) signifi- 2003
[sleep depriva- cantly beyond placebo levels. Ethanol impaired psychomotor performance and memory, but
tion] 300 mg caffeine restored performance and memory measures to placebo levels. Visual ana-
log ratings of dizziness were increased by ethanol, but were not diminished by either caf-
feine dose.
1-d experiment 21-35 yr pure caffeine; 150, 300 mg Under conditions where risk-taking depends on responding rapidly (like the Stop Light Roehrs et al.,
(USA) n=13 M+F ethanol [2.1, 4.3 mg/kg] Task), ethanol (0.5 g/kg) may impair responding and caffeine may attenuate this effect. 2004
1-d experiment 21.59 ± 1.55 yr ED + ethanol; 160 mg ED + ethanol (~1 g) caused lower post-test performance on visuo-spatial/constructional and Curry and
(USA) n=27 F ethanol [2.3 mg/kg] language tests; ED alone caused slightly improved attention. Stasio, 2009
1-d experiment 18-43 yr pure caffeine; 200 mg Caffeine shortened decision time in the choice reaction time (RT) task, shortened N200 la- Martin and
(Australia) n=16 F ethanol [2.9 mg/kg] tency at right hemisphere sites and in the choice RT task in combination with alcohol (0.7 Garfield,
mL/kg) compared to alcohol alone. Caffeine also increased P300 amplitude in the choice 2006
RT task and reduced the integral of the N500 difference wave at most sites when combined
with alcohol. It was concluded that whereas alcohol slows attention allocation and impairs
working memory, caffeine accelerated response-related decisions and enhanced cortical
arousal.
1-d experiment 21-45 yr pure caffeine; 200, 400 mg Caffeine alone increased ratings of 'alert' and 'jittery', but did not significantly affect body Liguori and
(USA) n=15 (6 M) ethanol [2.9, 5.7 mg/kg] sway or psychomotor performance. Both caffeine doses comparably counteracted alcohol Robinson,
(0.6 g/kg) impairment of brake latency but not choice reaction time or body sway. Brake 2001
latency with either alcohol-caffeine combination remained significantly longer than that
with placebo. Stroop and critical flicker fusion performance were unaffected by any drug
condition. The results suggest that caffeine may increase alertness and improve reaction
time after alcohol use but will not completely counteract alcohol impairment in a driver.
1-d experiment 21-32 yr pure caffeine; 4.0 mg/kg Those groups led to expect counteracting effects of caffeine on ethanol (0.65 g/kg) dis- Fillmore et
(USA) n=42 (23 M) ethanol played greater impairment than those led to expect no counteraction. al., 2002
1-d experiment 21-31 yr pure caffeine; 4.0 mg/kg A history of combined alcohol (0.65 g/kg) and caffeine administrations increased alcohol Fillmore,
(USA) n=21 (13 M) ethanol tolerance (i.e. less debilitated performance on psychomotor tests) compared with an expo- 2003
sure history to either drug alone.
1-d experiment 19-30 yr ED; ethanol; 240 mg Following exercise, final HR was higher for ED+ethanol (0.4 g/kg) and ED than without; Wiklund et
(Sweden) n=10 (5 M) exercise [4.3 mg/kg] post-exercise recovery in HR and HR variability were slower if consuming ED and alcohol al., 2009
before exercise; no severe cardiac arrhythmia but one subject had frequent premature atrial
contractions starting ~10 min after ED intake and lasting 40 min. [ED=Red Bull]
95
1-d experiment 19-24 yr pure caffeine; 4.4 mg/kg Alcohol (0.62 g/kg) impaired inhibitory control in a go-stop task, and all three treatments Fillmore and
(Canada) n=7 M ethanol (behavioral reinforcement, caffeine, or both) counteracted the impairment. Vogel-
Sprott, 1999
1-d experiment 23-27 yr pure caffeine; 400 mg Results with caffeine in the psychomotor (objective) measures showed a decrease in simple Azcona et
(Spain) n=8 M ethanol [5.7 mg/kg] reaction time and an increase in the amplitude of the evoked potentials; the subjects' self- al., 1995
ratings showed a tendency to be more active. Alcohol (0.8 g/kg) increased simple reaction
time and decreased amplitude of the evoked potentials, although the subjects rated them-
selves as being active. Alcohol + caffeine showed no significant difference from placebo in
the objective tests; nevertheless, the subjective feeling of drunkenness remained. The AUC
for caffeine was significantly higher when administered with alcohol. Only those objective
tests which were affected by caffeine were subject to counteracting with ethanol.
EPIDEMIOLOGICAL STUDIES
Cohort prospec- 23-41 yr caffeinated 0-25, 26-100, Intake of ≥1 cup coffee/d [1.7 mg/kg/d] did not significantly affect the probability of con- Hakim et al.,
tive (100 mo n=124 F) drinks; ethanol 101-300, >300 ception but possibly enhanced alcohol's negative effect. [Converted coffee, tea, and caf- 1998
follow-up) mg/d [0.4 to feinated soft drinks into 100, 50, and 40 mg of caffeine/drink, respectively]
(USA) >5.0 mg/kg/d]
Cohort prospec- 20-23 yr at ED; ethanol low- or high- Compared to the low-frequency ED group, high-frequency ED users drank alcohol more Arria et al.,
tive (4 yr follow- baseline frequency users; frequently and in higher quantities, and were at significantly greater risk for alcohol de- 2011
up) n=1097 M+F consumption var- pendence relative to both nonusers and low-frequency ED users (the latter did not differ on
(USA) ied widely their risk for alcohol dependence). ["low-frequency" and "high-frequency" ED users (drank
ED 1-51 d, and ≥52 d, respectively, in the past year; a daily dose could not be reliably esti-
mated due to variable unknown consumption]
Cohort prospec- Adult ED; caffeinated 7.7 ± 0.4 drinks ED users had heavier alcohol consumption patterns, and were more likely to have used Arria et al.,
tive (4-yr fol- n=1060 65% drinks; ethanol /wk in ED users; other drugs; year 2 ED use was associated with Year 3 nonmedical use of prescription 2010
low-up) M ED users; 6.7 ± 0.3 caff stimulants and prescription analgesics. [No info on mg caffeine/can for this study. Unre-
(USA) 39% M ED drinks/wk in non lated survey showed 75-174 mg/can for 8 top-selling ED brands, 50-500 for others]
non-users ED-users
96
Cross-sectional ~25-65 yr caffeine, all 8.8±0.7 units/d Relationships were observed between alcohol and caffeinated beverage intake and between Amit et al.,
(Israel) n=105 (91% sources; coffee; (0-30/d) caffeine use and smoking in subjects with or without a family history of alcoholism. How- 2004
M) ethanol [mean 13 ever, coffee intake and tobacco use were not related. [a standard unit of caffeine: cup of
mg/kg/d] coffee containing 1 spoon (5 cm3) of instant coffee, cup of Turkish coffee containing 1
spoon of coffee, glass of tea with 1 teabag, and a glass (200 mL) of a cola beverage; caf-
feine content was not provided; assumed 100 mg/unit]
Cross-sectional 21.5 ± 3.7 yr ED; ethanol 1, 2, ≥3 drinks/d The majority of users consumed one ED for insufficient sleep or to increase energy; using Malinauskas
(USA) n=253 M+F [1.4 to ≥4.3 three or more was a common practice to drink with alcohol while partying (49%). Weekly et al., 2007
mg/kg/d] jolt and crash episodes were experienced by 29% of users, 22% reported ever having head-
aches, and 19% heart palpitations from consuming EDs. There was a significant dose effect
only for jolt and crash episodes. [Specific EDs ingested or the caffeine content were not
identified; assumed 100 mg caffeine/drink for dose estimates]
Cross-sectional mean=20 yr ED; ethanol M: 2.49 Sport-related identity, masculinity, and risk taking are components of "toxic jock identity," Miller,
(USA) n=795 (52% drinks/mo; F: which may signal an elevated risk for health-compromising behaviors. [No info on caf- 2008a
M) 1.22 drinks/mo) feine/drink]
Cross-sectional 17-30 yr ED; ethanol ≥1 drink over last Consumption of AmED (alcohol mixed with EDs) was associated with increased heavy O'Brien et
(USA) n=4271 (39% 30 d episodic drinking and twice as many episodes of weekly drunkenness, a higher prevalence al., 2008
M) of being taken advantage of sexually, taking advantage of another sexually, riding with an
intoxicated driver, being physically hurt or injured, and requiring medical treatment. The
effect of consuming AmED on driving while intoxicated depended on a student's reported
typical alcohol consumption. [The ED identity or its caffeine content were not provided]
Cross-sectional Adult ED; ethanol ~ 13 mg/kg on Participants reported drinking significantly more alcohol when it was co-administered with Price et al.,
(Canada) n=72 M+F ED + ethanol EDs: 9.4 vs. 5.3 drinks reported by 8 participants). [No info on caffeine per drink; assumed 2010
drinking days 100 mg/drink for dose estimate]
Cross-sectional mean ~23 yr ED; ethanol mean 7-9 ED Patrons who consumed alcohol mixed with ED had a 3-fold increased risk of leaving a bar Thombs et
(USA) n=802 (60- +alcoholic drinks highly intoxicated (breath alcohol ≥0.08g/210L), and 4-fold increased risk of intending to al., 2010a
82% M in 3 drive upon leaving the bar district, compared to drinkers who did not consume alcoholic
subgroups) beverages mixed with ED. [ED not identified]
Cross-sectional Adult cola; ED; etha- 3-10 drinks con- A multivariate regression model indicated that the quantity of caffeinated alcoholic bever- Thombs et
(USA) n=328 (61.2% nol taining ED or age consumption had a significant, positive association with bar patron intoxication after al., 2010b
M) cola adjusting for potential confounders; there was no significant difference between the intoxi-
cation level of the alcohol + ED group and the cola-caffeinated group.
AmED=alcohol mixed with ED; AUC=area under the curve; ED=energy drink; HR=heart rate; RER=respiratory exchange ratio; RT=reaction time
97
TABLE 4-2. CNS Effects of Co-Exposure of Caffeine with Ethanol – Summary of Reviews Reference
Regular (nonalcoholic) EDs may pose just as great a threat to individual and public health and safety as “premixed” alcoholic EDs. Arria and
O’Brien, 2011
Premixed caffeine-alcohol combinations - especially popular with college students and other young people - should soon be gone from U.S. store shelves in Benac, 2011
response to warning letters that the U.S. Food and Drug Administration sent to four manufacturers on Nov. 17, 2010, advising them that the drinks were un-
safe and could be subject to seizure.
The consumption of ED may increase the risk for caffeine overdose and toxicity in children and teenagers. Consumption of ED + alcohol during heavy epi- Bigard, 2010
sodic drinking increases the risk of serious injury, sexual assault, drunk driving, and death. Even after adjusting for alcohol consumption, students who con-
sumed alcohol + ED had dramatically higher rates of serious alcohol-related consequences. It has been reported that subjective perceptions of some symptoms
of alcohol intoxication are less intense after the ingestion of alcohol + ED, but these effects are not detected in objective measures of motor coordination and
visual reaction time.
The consumption of EDs does not seem to carry adverse effects that are any different from drinking similar amounts of other caffeinated beverages. However, Kaminer, 2010
frequent consumption of EDs may serve as a useful screening indicator to identify students at risk for substance use and other problem behaviors.
The combined use of caffeine and alcohol may increase the rate of alcohol-related injury. Several studies suggest that EDs may serve as a gateway to other Reissig et al.,
forms of drug dependence. In children and adolescents who are not habitual caffeine users, vulnerability to caffeine intoxication may be markedly increased 2009
due to an absence of pharmacological tolerance. Genetic factors may also contribute to an individual's vulnerability to caffeine-related disorders including
caffeine intoxication, dependence, and withdrawal.
The alcohol industry markets alcoholic-ED with messages that fail to alert users to the potential for misjudging one’s intoxication and, instead, suggest that Simon and
the beverages will enhance alertness and energy. The industry promotes their use precisely in circumstances that may lead to alcohol-related harm: in social Mosher, 2005
situations that may involve driving, as an enhancement to sexual encounters, and in late-night partying environments that may result in violence.
Adding ED to alcohol tends to increase the rate of absorption through its carbonation and dilution of the alcohol, and keep a person awake longer allowing Weldy, 2010
ingestion of a greater volume of alcohol. At low blood alcohol levels, caffeine appears to decrease some of the impairment from the alcohol, but at higher
blood alcohol levels, caffeine does not appear to modify either the physical or mental impairment induced by alcohol.
98
4B. CNS Effects of Interaction of Caffeine and Ethanol – Animal Studies
Studies with rats and mice, like human studies, showed an antagonistic relationship of the
two compounds, with the most commonly examined endpoints being locomotor activity and
anxiety. The interactions were largely dependent on the dose of ethanol and caffeine involved.
Ethanol blocked the anxiogenic effect of caffeine in mice (Gulick and Gould, 2009; Prediger et
al., 2004). Caffeine attenuated the deficit in accelerod performance and motor activity due to
ethanol in rats and mice (Connole et al., 2004; Ferreira et al., 2004b) and delayed the onset time
of the loss of righting reflex due to ethanol (Koo, 1999). In some studies, however, ethanol in-
creased motor activity, which was enhanced by caffeine (Sudakov et al., 2003). Caffeine dimin-
ished the hypnotic effects of ethanol in mice (El Yacoubi et al., 2003). Caffeine did not alter
blood ethanol levels in rats (Kunin et al., 2001). Low doses of caffeine enhanced ethanol drink-
ing in rats (Kunin et al., 2000a).
Animal studies that evaluated the effect of co-ingestion of caffeine and ethanol on CNS-
related parameters are summarized in Table 4-3.
99
TABLE 4-3. CNS Effects of Interaction of Caffeine and Ethanol – Animal Studies
Exposure Test material; Caffeine
Species Effects; Comments Reference
time route dose(s)
Rat 1 day pure caffeine; 2.5, 10 Caffeine (both doses) promoted an ethanol-induced conditioned taste aversion at a low ethanol dose (1.0 g/kg) Kunin et al.,
ethanol (i.p.) mg/kg but had no effect at 1.5 g/kg ethanol; caffeine had no effect in altering blood ethanol levels at the doses tested. 2001
Mouse 1 day pure caffeine; 3.0 - 30.0 Repeated dosing with 2.25 g/kg ethanol reduced motor impairment on day 2 (i.e. rapid tolerance), which was Batista et
ethanol (i.p.) mg/kg blocked by caffeine. al., 2005
Mouse 1 day ED; ethanol 3.57, 10.71, The administration of 3.57, 10.71 or 17.86 ml/kg of ED alone increased the locomotor activity of the animals in Ferreira et
(oral) 17.86 mL/kg relation to a control group. Low doses of ethanol (0.5, 1.0 and 1.5 g/kg) alone or in combination with 10.71 al., 2004b
of ED =1.1, ml/kg of ED did not affect their locomotor activity. However, the reduction of activity observed after 2.5 g/kg of
3.6, 5.7 mg ethanol was antagonized by 10.71 ml/kg of ED.
caffeine/kg
Rat 1 day pure caffeine; 5 mg/kg Caffeine given 1 hr after 3 g/kg ethanol, or 20 min prior to habituation to a novel odor, negated ethanol-induced Spinetta et
ethanol (i.p.) impairment of memory for the novel odor. al., 2008
Mouse 1 day pure caffeine; 5, 10, 20, 40 Caffeine dose-dependently increased anxiety and decreased locomotion and learning. Caffeine failed to reverse Gulick and
ethanol (i.p.) mg/kg ethanol-induced (1.0-1.4 g/kg) learning deficits. However, 1.4 g/kg ethanol blocked the anxiogenic effect of 40 Gould,
mg/kg caffeine. 2009
Rat 1 day pure caffeine; 5, 20 mg/kg Ethanol (2.5 g/kg, orally) decreased motor performance on the accelerod, but caffeine (5, 20 mg/kg) dose- Connole et
ethanol (ga- dependently attenuated this deficit; caffeine (20 mg/kg) alone did not affect test performance. al., 2004
vage)
Mouse 1 day pure caffeine; 10, 30 mg/kg 30.0 mg/kg caffeine produced an anxiogenic-like effect; prior administration of "non-anxiogenic" doses of caf- Prediger et
ethanol (i.p.) feine (10.0 mg/kg) reduced the anxiolytic-like effect of ethanol (1.2 g/kg, i.p.). al., 2004
Mouse 1 day pure caffeine; 20 mg/kg The onset time of loss of righting reflex (LR) in mice pre-treated with coffee or caffeine 10 min before ethanol Koo, 1999
coffee; ethanol caffeine; 600 (24 mg/kg) was delayed but the duration of sleep was not affected; dosing 10 min after ethanol was ineffective in
(gavage) mg/kg in- counteracting the LR effect of ethanol.
stant coffee
Mouse 1 day pure caffeine; 25 mg/kg Caffeine reduced hypnotic effects induced by ethanol (3.5 or 4 g/kg). El Yacoubi
ethanol (i.p.) et al., 2003
Mouse 1 day pure caffeine; 50, 300 A crude green tea extract and the tea components as (-)-epigallocatechin gallate (EGCg), (-)-epigallocatechin Kakuda et
EGCG; ethanol mg/kg pure (EGC), and caffeine were administered 1 hr before 2g/kg ethanol. Dosing with 500 mg/kg GTE decreased levels al., 1996
(gavage) caffeine; 500 of ethanol and acetaldehyde, and increased the levels of acetate and acetone in the blood and liver. Administra-
mg/kg green tion of 75 and 225 mg/kg EGCG decreased acetate and acetone concentrations in the blood and liver. The mice
tea extract given caffeine at the same dose as that in the tea extract had almost the same effects as the tea extract group. This
suggests that EGCG and caffeine both affected ethanol metabolism.
100
TABLE 4-3. CNS Effects of Interaction of Caffeine and Ethanol – Animal Studies
Species Effects; Comments Reference
time route dose(s)
Mouse 1 day; 7 d pure caffeine; 1 g/L (7 d) The locomotor stimulant effects of ethanol (2.5 g/kg) were slightly decreased after chronic ethanol intake, but Daly et al.,
ethanol (DW) 10, 25, 35 were markedly reduced in mice after chronic caffeine ingestion. 1994
mg/kg
Rat, 6d pure caffeine; 2.5, 5, 10 Caffeine produced a dose-related facilitation in ethanol drinking (2-10% v/v) whereby the lower caffeine dose Kunin et al.,
ethanol ethanol (i.p.) mg/kg enhanced ethanol drinking. In rats acclimatized to ethanol + caffeine, only 5 mg/kg enhanced ethanol drinking 2000a
habi- that persisted throughout the post-treatment period; another experiment showed that caffeine did not alter levels
tutated of blood ethanol during the ethanol drinking session.
Rat 11 d pure caffeine; ~24-27 At PND 120, caffeine potentiated the ethanol-induced (~1.2 g/kg/d ethanol) lower levels of adult anxiety in Hughes,
(PND 45- ethanol (DW) mg/kg/d males, but caused higher anxiety levels in females. 2010
55)
Rat 21 d pure caffeine; 50 mg/kg Kolanut and caffeine independently produced an increase in Na+-K+-ATPase activity, while there was a signifi- Obochi et
kola nut; ethanol kola nut, cant (P<0.05) decrease in the Na+-K+-ATPase values of the alcohol (~0.3 g), alcohol-kolanut and alcohol- al., 2007b
(gavage) caffeine caffeine treated groups. This resulted in a decrease in Na(+)-K(+)ATPase activity, ATP production, ion transport
and action potential, leading to loss of neuronal activities.
Rat 30 d pure caffeine 0.1% in DW Caffeine counteracted morphine-induced decrease of locomotion, and enhanced increased locomotion due to Sudakov et
(DW); ethanol, (100 mg/kg) ethanol (1.5 g/kg i.p.) and nicotine. al., 2003b
morphine (i.p.);
nicotine (s.c.)
ED=energy drink; GD=gestation day; PND=postnatal day
101
4C. Interaction of Caffeine with Common Drugs – Animal and In vitro Studies
Although experimental studies in which humans were simultaneously treated with caf-
feine and common drugs (other than ethanol) were not located, numerous animal and mammalian
culture in vitro studies evaluated these interactions, as summarized in Table 4-4. The few studies
that evaluated the metabolic interactions of caffeine with other substances are also presented in
Chapter 1 (Table 1-6). Mechanistic-type animal studies in which caffeine was co-administered
with various ligands of the adenosine or dopamine receptors are presented in Table 4-5 (Section
4D).
Co-exposure of caffeine with acetominophen reduced the incidence of caffeine-induced

convulsions, but co-exposure with toluene or theophylline reduced the caffeine seizure threshold.
Aspirin prolonged caffeine-induced hyperactivity. Inconsistent results were found regarding the
interaction of caffeine and alprozalam on CNS/behavioral effects. Caffeine potentiated the
stimulation of locomotor activity by amphetamine, cocaine, and ketamine, and reduced the anti-
convulsant effect of phenobarbital, phenytoin, carbamazepine, and valproate. It increased the
anti-catalepsy effect of trihexyphenidyl and the intensity and duration of tremors caused by the
CNS stimulant harmaline. Diazepam, haloperidol, theanine, and pentobarbital antagonized caf-
feine’s stimulation of locomotion. Moderate doses of caffeine (3-30 mg/kg, i.p.) counteracted
ethanol-induced hypnotic and anxiolytic effects and deficits in cognitive and motor performance,
and enhanced ethanol-induced locomotion. Higher caffeine doses (≥48 mg/kg i.p.), however, ex-
acerbated ethanol-induced motor incoordination and decreased locomotor activity.
Caffeine increased the hyperthermic response of MDMA (“Ecstasy”) and MDA

(“Love”), the drug combination reducing serotonin and 5-hydroxyindole acetic acid levels in
various brain regions and increasing lethality. Morphine potentiated caffeine-induced cell death
in the thalamus. Caffeine counteracted the morphine-induce decrease in locomotion, and de-
creased morphine self-administration in WAG/G but not F-344 rats. Caffeine enhanced in-
creased locomotion due to nicotine (had no effect in one study) and speeded the acquisition of
nicotine discrimination in rats. Stress decreased the stumbling frequency of a high dose of caf-
feine (120 mg/kg) and blocked the caffeine-induced activity of some brain antioxidant enzymes
Studies that evaluated the interaction of caffeine with common drugs in animals are
summarized in Table 4-4.
102
TABLE 4-4. Interaction of Caffeine with Common Drugs – Animal and In vitro Studies
Species Effects; Comments (sorted by test material) Reference
time route dose(s)
Rat 1 day pure caffeine; 5, 10 (±A), 20 No acute tolerance was observed for either drug or their combinations; they did not interact in the behavior- Lau and
alprazolam (A) (±A), 40, 80, time profiles (DRL 45-s); pharmacokinetics of alprazolam were not altered by caffeine, but those of caf- Wang, 1996
(i.p.) 120 mg/kg feine were affected by alprazolam.
Rat 1 d; 65-76 pure caffeine; 5, 10, 20, 40, Both drugs decreased the reinforcement rate and increased the shorter-response rate (dose-related); com- Lau et al.,
d alprazolam 80, 120 plete tolerance to caffeine was observed on day 2; independent interaction of alprazolam and caffeine and 1997b
(DW; i.p.) mg/kg; no cross-tolerance behavior change.
chronic 40
mg/kg/d
Rat 1 day pure caffeine; 5, 10, 20 Alprazolam pharmacokinetics (PK) not altered by caffeine, but alprazolam slowed caffeine absorption and Lau et al.,
alprazolam (A) (±A), 30 (±A) decreased methylxanthine levels; interaction was PK linked and independent. Alprazolam was more potent 1997a
(gavage) 40, 80, 120 than caffeine in decreasing reinforcement rate behavior change.
mg/kg
Rat 1 day pure caffeine; 1 mg/kg at 1, Caffeine prevented the increase of immobility times in both groups, the methylxanthine abolished the effect Enríquez-
amitriptyline 20 and 23 hr of amitriptyline in high immobility-rats (165±23 s vs. 165±46 s, n=9), leaving the antidepressant action Castillo et
(i.p.) after the first unaffected in low immobility-rats (87±23 s vs. 96±58 s, n=9). These results suggest that the anti- al., 2008
swimming immobility effect of amitriptyline in high immobility-rats is mediated in part by endogenous adenosine.
session
Rat 1 day pure caffeine; 1, 7, 14, 30 Caffeine completely reversed escape deficits in shocked rats when injected just before shuttle-escape test- Minor et al.,
amphetamine mg/kg ing, but not if injected before shock pretreatment; caffeine reversed an amphetamine-induced escape deficit 1994
(i.p.) in restrained (no-shock) controls.
Rat 1 day pure caffeine; 3.0-56.0 Caffeine (10-56.0 mg/kg) produced ~50% methamphetamine-like responding (mimic the discriminative- Munzar et
amphetamine mg/kg stimulus effects of dopamine releaser methamphetamine); caffeine (30.0 mg/kg) shifted the methampheta- al., 2002
(i.p.) mine dose-response curve to the left; effect of caffeine + amphetamine was more than additive.
Rat 1 day pure caffeine; 10, 20 mg/kg 20 mg/kg caffeine slightly attenuated the acquisition of amphetamine-induced conditioned place preference Poleszak and
amphetamine (CPP) (p < 0.05). However, caffeine at 10 mg/kg (p < 0.001) increased the time spent by rats in drug- Malec, 2003
(i.p.) associated compartment.
Rat 1 day pure caffeine; 15 mg/kg Sensitization to caffeine and cross-sensitization to amphetamine are associated with post-synaptic neuro- Tronci et al.,
amphetamine adaptive changes in selective neuronal populations of the striatum. 2006
(i.p.)
Rat, le- every pure caffeine; 15 mg/kg Caffeine increased motor and turning behavior, and potentiated the motor effects of amphetamine in both Simola et al.,
sioned other d amphetamine intact and 6-hydroxydopamine-lesioned rats. 2006b
over 14 d (i.p.)
103
time route dose(s)
Mouse 1 day; 5 d pure caffeine; 1, 3, 10, 30 Dose-dependent increase in ambulation from caffeine or methamphetamine (MAP), greater effect when Kuribara,
amphetamine mg/kg given together; repeated dosing (5 times every 3 to 4 d) with caffeine did not sensitize mice to caffeine or 1994c
(s.c.) MAP, which did occur with MAP (1 mg/kg) + CAF (30 mg/kg).
Mouse 1 day pure caffeine; 1, 3, 10 mg/kg Caffeine potentiated the locomotor stimulating effect of methamphetamine and cocaine; caffeine also en- Kuribara,
amphetamine; hanced cocaine but not methamphetamine sensitization. 1994b
cocaine (s.c.)
Rat 30 d pure caffeine; 10, 30 Caffeine pre-exposure enhanced the acute and chronic locomotor effects of amphetamine but not nicotine; Palmatier et
amphetamine; mg/kg/d caffeine pre-exposure did not affect expression of conditioned hyperactivity. al., 2003
nicotine (i.p.)
Mouse 1 day pure caffeine; ≤46.2 mg/kg Caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed Chrościńska-
anticonvulsants by electroconvulsions in mice. Chronic caffeine (4 mg/kg) administration was associated with an increase Krawczyk et
(i.p.) in tiagabine concentration. al., 2009
Rat, 3d coffee; atorvas- coffee: Caffeinated coffee blunted the myocardial protective effects of the statin atorvastatin against ischemia- Ye et al.,
ischemic tatin (DW) 338±49 reperfusion injury. [The caffeine plasma levels were average 5.99±0.11 μg/mL for rats receiving coffee and 2008
injury μg/mL; decaf: 1.73±0.01 μg/mL for rats receiving decaf.]
25±2.3 μg/mL
Rat 1 day pure caffeine; 10, 25 mg/kg Rats receiving dopamine D(2) agonist bromocriptine (5 mg/kg i.p.) were sensitized to its motor stimulating Fenu et al.,
bromocriptine s.c.; 10 mg/kg effects and showed cross-sensitization to 10 mg/kg but 25 mg/kg caffeine. In contrast, caffeine (10 mg/kg 2000
(i.p.; s.c.) i.p. i.p.) failed to show an increased locomotor and stereotyped response in rats given bromocriptine but not
sensitized.
Rat 1 day pure caffeine; 56 mg/kg Caffeine (56 mg/kg) blocked the discriminative stimulus properties of the training dose of chlordiazepoxide Gauvin et al.,
chlordiazepox- and shifted the chlordiazepoxide discriminative dose-response function to the right. 1994
ide (i.p.)
Mouse 1 day pure caffeine; 20 mg/kg During training, chlordiazepoxide increased and caffeine decreased % time spent in the open arms (PTO) Silva and
chlordiaze- (suggests anxiolytic and anxiogenic effect, resp.); during testing, both agents increased % time spent in Frussa-Filho,
poxide (i.p.) aversive enclosed arm (suggests amnestic effects); co-dosing did not alter PTO and eliminated the amnesic 2000
effect.
Mouse 1 day; 10 d pure caffeine; 3 mg/kg i.p.; Caffeine injection increased the amount of cocaine self-administered whereas caffeine drinking reduced it. Kuzmin et
cocaine 150 mg/kg/d al., 2000b
(DW; i.p.) in DW
104
time route dose(s)
Primate 1 day pure caffeine; 0, 100, 200 Caffeine pretreatment produced small, but significant increases in smoked cocaine self-administration. Comer and
cocaine (cap- mg Carroll, 1996
sule)
Rat 1 day pure caffeine; 0.32, 1.0, 3.2, Several doses of cocaine and caffeine were found to condition place preference and stimulate locomotor Bedingfield
cocaine (i.p.) 5.6, 10.0 activity. A combination of low doses (0.32 mg/kg) of each drug appeared to be additive. et al., 1998
mg/kg
Mouse 1 day pure caffeine; 3 mg/kg Caffeine prevented the extinction of cocaine-seeking behavior by acting on adenosine A(1) receptors. Kuzmin et
cocaine (i.p.) al., 1999
Rat 1 day pure caffeine; 5, 10, 20.0 Reinstatement of cocaine seeking was produced by experimenter-administered injections caffeine. Schenk and
cocaine (i.p.) mg/kg Partridge,
1999
Rat 1 day pure caffeine; 20 mg/kg Caffeine was an effective cue for reinstatement of extinguished cocaine taking; effect was reduced when Schenk et al.,
cocaine (i.p.) every 4 d repeated exposures occurred; when 4 drug-free days were interspersed between self-administration and 1996
reinstatement testing, the caffeine effect was greater than when testing was conducted 1 day following the
last self-administration session.
Rat 1 day pure caffeine; 20 mg/kg Caffeine markedly decreased the expression of conditioned place preference induced by cocaine, and caf- Poleszak and
cocaine (i.p.) feine (20 mg/kg) decreased also the acquisition of this reaction. Malec, 2002
Dog 1 day pure caffeine; 5 mg/kg Cocaine + caffeine attenuated cocaine excitatory effects; caffeine+cocaine synergistically increased cocaine Mehta et al.,
cocaine (i.v.) excitatory effects on the cardiovascular system; both agents decreased coronary flow reserve. 2004
Primate 1 day pure caffeine; 0.1-1.8 mg/kg Caffeine dose-dependently increased cocaine-seeking but not food-seeking. Weerts and
cocaine (i.v.) Griffiths,
2003
Rat 1 day pure caffeine; 5.0, 10.0, Both cocaine and caffeine induced a dose-dependent increase in the number of responses made on the pre- Worley et
cocaine (i.v.) 20.0, 40.0 viously cocaine-associated lever by rats with extinguished cocaine-taking behavior. al., 1994
mg/kg
Rat 1 day pure caffeine 0.2% w/w Dietary caffeine accelerated acquisition of cocaine self-administration (i.v.) in rats. Carroll and
(diet); cocaine food Lac, 1998
(i.v.)
Rat 1 day pure caffeine; 20 mg/kg i.p.; Both i.p. and i.v. administration of caffeine increased the intake of all doses of cocaine (p < 0.01). Schenk et al.,
cocaine infu- 0.25mg/kg i.v. 1994
sion (i.p.; i.v.)
105
time route dose(s)
Mouse 1 day pure caffeine; 0.25, 0.5, 1 Caffeine (0.25-1 mg/kg) enhanced the memory consolidation of mice. The D2 dopamine receptor antago- Cestari and
cocaine; (-)- mg/kg nist, (-)-sulpiride, antagonized the enhancing effect of caffeine on memory. A clear interaction between Castellano,
sulpiride (i.p.) caffeine and cocaine was evident. 1996
Rat 1 day pure caffeine; 1.25-20 mg/kg Caffeine reinstated extinguished cocaine-taking behavior; pretreatment with SCH 23390 (dopaminergic Green and
cocaine; SCH D1-like antagonist) or eticlopride (D2-like antagonist) produced a dose-dependent attenuation of caffeine- Schenk,
23390; eticlo- produced reinstatement at doses that did not decrease cocaine self-administration. These findings suggest 2002
pride (i.p.) that dopaminergic mechanisms underlie the ability of caffeine to reinstate extinguished cocaine-taking be-
havior.
Mouse 18 d pure caffeine; 0.5 g/L Caffeine slightly reduced diazepam-induced immobility and increased the frequency of crossings in active Sansone et
diazepam periods. al., 1995
(DW)
Rat 1 day pure caffeine; 10 mg/kg Diazepam altered caffeine-induced effects on beta-endorphin in specific rat brain regions. Khalil and
diazepam (i.p.) Soliman,
1997
Mouse 1 day pure caffeine; 20 mg/kg sin- One caffeine dose (not four) increased the number of hole-dips (into hole-board), indicating an anxiolytic- Rao et al.,
diazepam (oral) gle or 2x/d for like effect (like diazepam at 0.375 and 0.75 mg/kg), and right-shifted the diazepam dose-response curve 1999
4d (esp. at 1.5 mg/kg); repeated caffeine dosing impaired diazepam effect behavior change.
Mouse 1 day; 21 d pure caffeine; 2.0, 4.0, 6.0 Caffeine alone produced dose- and duration-dependent clastogenicity at doses of 2.0, 4.0 and 6.0 mg/kg Sen et al.,
fenfluramine mg/kg when given by gavage. Using caffeine post-treatment (4.0 and 6.0 mg/kg) 2 hr after fenfluramine applica- 1994
(gavage) tion, a strong synergism could be seen in the late treatment period as shown by the dose-response curves
and by statistical analysis.
Rat 1 day pure caffeine; 3.0 mg/kg Decaffeinated coffee and caffeine had no effect on fluoride metabolism; caffeinated coffee appeared to Chen and
coffee; fluoride increase the initial absorption rate but not the 4-hour bioavailability. Whitford,
(gavage) 1994
Rat liver 1 day Pure caffeine; 800 μM The antidepressants imipramine and amitriptyline decreased caffeine metabolism, while fluoxetine, nefa- Kot et al.,
micro- antidepressants zodone, sertraline and mirtazapine enhanced caffeine metabolism. 2007
somes (i.p.)
Mouse 1 day pure caffeine; 10 mg/kg Fluvoxamine inhibited the activity of CYP1A2 as indicated by a 40% reduction in the clearance of a 10 Thomsen et
fluvoxamine mg/kg dose of caffeine. al., 1995
(i.p.?)
106
time route dose(s)
Rat 1 day pure caffeine; 12.5-100 Caffeine produced a dose-related antinociception the hot plate (HP) (50-100 mg/kg) and formalin tests Sawynok et
formalin; na- mg/kg (12.5-75 mg/kg). During the formalin test, caffeine stimulated locomotor activity between 12.5 and 50 al., 1995
loxone; phento- mg/kg, while 75 mg/kg depressed activity. Caffeine did not produce an anti-inflammatory effect. Peripheral
lamine; prazo- co-administration of caffeine and formalin did not produce antinociception. Naloxone did not reduce the
sin; idazoxan; antinociceptive or locomotor stimulant effects of caffeine, but phentolamine, prazosin, idazoxan, enhanced
6-OHDA antinociception by caffeine but inhibited locomotor stimulation. Microinjection of 6-hydroxydopamine (6-
(i.p.?) OHDA) into various brain regions, which depleted noradrenaline (NA), inhibited the action of caffeine in
the HP test. These results suggest an involvement of noradrenergic mechanisms in the antinociceptive ac-
tion of caffeine in the HP and formalin tests and in locomotor stimulation.
Mouse 1 day pure caffeine; 10 mg/kg At doses higher than 0.5 g/kg, Ginkgo bilboa extract (GBE) not only inhibited motor activity but also sup- Kuribara et
Ginkgo extract; pressed active avoidance behavior, reduced caffeine-induced stimulation, and enhanced pentobarbital- al., 2003
ginkgolide-A induced sleep, while ginkgolide-A (up to 20 mg/kg) did not exhibit these effects.
(gavage)
Rat 1 day pure caffeine; 5.0-20.0 Caffeine reversed the effects of the dopamine D(2) antagonist haloperidol (reduced lever pressing and sub- Salamone et
haloperidol mg/kg stantially increased chow intake). al., 2009
(i.p.)
Rat 1 day pure caffeine; 1-3 mg/kg; 1 Pretreatment with 1-3 mg/kg caffeine dose dependently reduced the intensity and increased the onset la- Moo-Puc et
haloperidol; mg/kg 3x/d tency of catalepsy induced by haloperidol; caffeine (1 mg/kg) potentiated the anti-catalepsy effect of trial., 2003
trihexypheni- for 7 d hexyphenidyl and atropine.
dyl; atropine
(i.p.)
Rat 1 day; 14 d pure caffeine; ~136 mg/kg/d Caffeine-induced locomotor activity (10, 30 mg/kg) was blocked by haloperidol, enhanced by GBR 12909, Powell et al.,
haloperidol; oral; 10, 30 and unaffected by nisoxetine and fluoxetine. Haloperidol infused during 14-d caffeine intake did not block 2001
GBR 12909; mg/kg i.p. development of caffeine tolerance but impaired recovery from tolerance. Caffeine-treated rat D SCH
nisoxetine; 23390 (DA D(1)) dopamine binding sites were down-regulated in the nucleus accumbens and striatum and
fluoxetine; upregulated in the prefrontal cortex of, but their affinity for SCH 23390 was unchanged. Changes in DA
(DW) (i.p.) D(1) receptors could be one component of the mechanism underlying caffeine-induced tolerance.
Rat 1 day pure caffeine; 0, 50, 100, Caffeine increased the intensity, duration, and electromyographic amplitude of tremors induced by harma- Al-Deeb et
harmaline (i.p.) 150 mg/kg line. al., 2002
Mouse 1 day pure caffeine; 5, 10, 20 Caffeine enhanced ketamine-induced locomotor hyperactivity, disruption of rotarod performance, and mor- Hsu et al.,
ketamine (i.p.) mg/kg tality, but prepulse inhibition deficits and anesthesia remained unaffected. 2009a
107
time route dose(s)
Mouse 1 day pure caffeine; 4-16 mg/kg Caffeine increased locomotor activity of the mice, which was blocked by Hypericum perforatum (HPE) (6- Uzbay et al.,
L-arginine; 24 mg/kg); pretreatment of l-arginine reversed the inhibitory effect of HPE (l-arginine had no effect on 2007
HPE; (i.p.) locomotor activity given alone).
Rat 1 day pure caffeine; 16 mg/kg Acute caffeine administration decreased NOS and Bcl2 expression in rat skeletal muscles. Caffeine in- Corsetti et
L-arginine; L- creased mean arterial pressure temporarily, while caffeine + L-NAME increased it for a longer period. The al., 2007
NAME (i.v.) L-arginine administration reversed these caffeine and L-NAME effects.
Mouse 1 day pure caffeine; 2-10 mg/kg Locomotor activity induced by 2 mg/kg caffeine was enhanced by co-administration of 600 mg/kg L- Kimura et
L-arginine; arginine or 400 mg/kg taurine. The enhancement was inhibited by pretreatment with 40 mg/kg N-nitro-L- al., 2009
taurine; L- arginine methyl ester (L-NAME).
NAME (i.p.?)
Rat 1 day; 21 d pure caffeine; 10, 25 and 50 Caffeine produced dose-related behavioral changes indicating an anxiogenic effect: reduced ambulation Bhattacharya
at 50 lorazepam mg/kg and rears, increased immobility and defecation in the open-field test, decreased entries and time spent on et al., 1997
mg/kg (i.p.) the open arms of the elevated-plus maze, reduced social interaction in paired rats, and increased feeding
latency in an unfamiliar environment. Lorazepam, a benzodiazepine anxiolytic agent, attenuated the anxio-
genic effects of caffeine. Subchronic caffeine dosing for 21 days (50 mg/kg, i.p.; different animals), in-
duced tolerance in the maze test (p<0.05 after 14 and 21 d). When caffeine (50 mg/kg, i.p.) was withdrawn
after 21 days dosing (separate group of rats), withdrawal anxiety was observed 48 hr later as noted in the
elevated plus-maze test.
Rat 1 day pure caffeine; 10 mg/kg Co-administration of caffeine with MDMA induced a profound tachycardic response compared to either McNamara
MDMA (s.c.) drug alone; neither caffeine (30 microM) nor MDMA (1-30 microM), alone or in combination, affected the et al., 2007
electrocardiogram of the isolated heart.
Mouse 1 day pure caffeine; 10 mg/kg Caffeine potentiated the increase in CD11b and GFAP (markers of microglia and astroglia activation) in the Khairnar et
MDMA (i.p.?) striatum but not in the substantia nigra pars-compacta in mice treated with MDMA (3,4- al., 2010
methylenedioxymethamphetamine).
Rat 1 day pure caffeine; 1, 5, 10 mg/kg MDMA + caffeine did not show any synergistic interaction on antinociception; when caffeine was adminis- Camarasa et
MDMA (s.c.) tered prior to MDMA, locomotor activity was potentiated. Caffeine alone failed to alter body temperature, al., 2006
but potentiated MDMA-induced hyperthermia. Caffeine also significantly increased MDMA lethality (from
22% to 34%). MDMA caused a persistent decrease in the number of serotonin transporter sites in the cor-
tex, striatum and hippocampus, which was potentiated by caffeine co-treatment. A transient down-
regulation of 5-HT(2) receptors occurred in the cortex of MDMA-treated rats, whose recovery was slowed
by co-treatment with caffeine.
108
time route dose(s)
Rat 1 day; 4 d pure caffeine; 10 mg/kg Caffeine enhanced hyperthermic response of MDMA and MDA and increased lethality; single and/or re- McNamara
MDMA; MDA once; 10 peated administration of caffeine with MDA and MDMA reduced serotonin and 5-hydroxyindole acetic et al., 2006
(i.p.; s.c.) mg/kg 2x/d acid concentrations in various brain regions (not by MDMA and MDA alone).
for 4 d
Rat 1 day pure caffeine; 10 mg/kg Co-administration of caffeine with MDMA provoked a switch from MDMA-induced hypothermia and bra- Vanattou-
SCH 23390; dycardia to hyperthermia and tachycardia without influencing MDMA-induced hyperlocomotion. Pre- Saïfoudine et
sulpiride; treatment with a specific dopamine D(1/5) antagonist SCH 23390 enhanced MDMA-induced hypothermia al., 2010
MDMA (s.c.) and blocked the ability of caffeine to provoke a switch from MDMA-induced hypothermia to hyperthermia.
Furthermore, SCH 23390 blocked MDMA-induced hyperactivity and the ability of caffeine to promote a
tachycardic response to MDMA. By contrast, pre-treatment with the selective D(2) antagonist, sulpiride
blocked MDMA-induced hypothermia, failed to influence the ability of caffeine to promote tachycardia
whilst enhancing MDMA-induced hyperactivity. The results suggest that the ability of caffeine to provoke
MDMA-induced toxicity is associated with the promotion of dopamine D(1) over D(2) receptor-related
responses.
Mammal- 1 day pure caffeine; 100 μM Caffeine (100μM) induced dopamine release in the striatum and hypothalamus, albeit to a much lesser ex- Vanattou-
ian cell MDMA; tent than MDMA. When striatal tissue slices were superfused with MDMA (30μM) + caffeine (30μM), Saifoudine,
culture DPCPX; caffeine enhanced MDMA-induced dopamine release, provoking a greater response than that obtained fol- et al., 2011
CCPA; rolip- lowing either caffeine or MDMA applications alone. Cyclopentyl-1,3-dipropylxanthine (DPCPX), a spe-
ram; SCH cific A(1) antagonist, like caffeine, enhanced MDMA-induced dopamine release from striatal slices while
58261 (in vi- 1μM 2,chloro-N(6)-cyclopentyladenosine (CCPA), a selective adenosine A(1) receptor agonist, attenuated
tro) this. Treatment with either SCH 58261, a selective A(2A) receptor antagonist, or rolipram, a selective PDE-
4 inhibitor, failed to reproduce a caffeine-like effect on MDMA-induced dopamine release. The results
suggest that caffeine regulates MDMA-induced dopamine release in striatal tissue slices via inhibition of
adenosine A(1) receptors.
Mouse 8d pure caffeine; 40-100 mg/kg 24 hr after last caffeine dose mice had increased duration and frequency of defensive behavior and de- Sukhotina et
memantine; 2x/d, then 1 creased locomotor activity (faded in 72 hr); treatment with memantine or neramexane 24 hr after the last al., 2004
neramexane mg/kg caffeine dose reduced defensive behavior and increased motor activity behavior change.
(i.p.)
Rat 1 day; 30 d pure caffeine; 0.1% DW Acute and chronic caffeine intake decreased morphine self-administration in WAG/G but not F-344 rats, Sudakov et
morphine (0.05 mg/kg which attested to increased sensitivity of these rats to reinforcing effects of morphine. al., 2002
(DW; i.p.) (50?)
Mouse 1 day pure caffeine; 5, 10, 20 Caffeine (10 and 20 mg/kg) attenuated the development of sensitization during co-administration with Weisberg
morphine (i.p.) mg/kg morphine and also following morphine-only challenge. and Kaplan,
1999
109
time route dose(s)
Rat, 1 day pure caffeine; 50 mg/kg Caffeine induced withdrawal signs (head shakes, tooth chattering, ejaculation, chewing, and irritability) in Khalili et al.,
morphine- morphine morphine-dependent rats, and enhanced activity of paragigantocellularis neurons in both control and mor- 2001
dependent (PGC injection; phine-dependent rats. [PGC= paragigantocellularis]
i.p.)
Rat 1 day pure caffeine; 100 mg/kg In 3-d old rats, at 12 and 24 hr post-injection, caffeine increased cell death in the cortex, caudate, nucleus Black et al.,
morphine (s.c.) accumbens, hypothalamus, hippocampus and superior colliculus; no effect of morphine alone, but it poten- 2008
tiated caffeine-induced cell death in the thalamus.
Mouse 1 day pure caffeine; 2.5, 5, 10 Caffeine had no effect on shuttle-box avoidance learning at 2.5 and 5 mg/kg but 10 mg/kg impaired learn- Sansone et
nicotine (i.p.?) mg/kg ing; caffeine + nicotine did not interact in avoidance learning; in a locomotor activity test caffeine + nico- al., 1994
tine increased locomotor activity at doses ineffective by themselves.
Dog 1 day pure caffeine; 5 mg/kg Caffeine or nicotine caused nonsignificant and significant increases in hemodynamics, respectively. Caf- Jain et al.,
nicotine (i.v.) feine + nicotine produced synergistic excitatory effects, but nicotine + caffeine caused attenuation by caf- 1997
feine of the excitatory effects produced by nicotine.
Rat 1 day pure caffeine; 0.25, 1.0 Caffeine (23 mg/kg/d) potentiated stimulation of nicotine, amphetamine, and cocaine on ambulatory activ- Gasior et al.,
nicotine (DW) mg/mL (23, ity but did not produce tolerance to caffeine acute stimulatory effects; 82 mg/kg/d did not alter the stimu- 2000
82 mg/kg) lants' effects but resulted in complete tolerance to caffeine; 23 mg/kg/d caffeine speeded acquisition of
nicotine discrimination.
Rat 7d pure caffeine; 150-180 Rats treated with caffeine in the DW for 7 d prior to the beginning and throughout behavioral testing ac- Shoaib et al.,
nicotine (DW) mg/kg/d quired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. 1999
Exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine
to the DW of control rats increased responding maintained by nicotine over 90%.
Mouse 1 day pure caffeine; 2.5-20 mg/kg; Locomotor activity increased at ≥5 mg/kg caffeine, but was increased more in mice (given 5 mg/kg caf- Celik et al.,
nicotine (i.p.) 5 mg/kg + feine) that were sensitized with 1 or 2 mg/kg nicotine (not 0.5 mg/kg). 2006
nicotine
Rat 1 day pure caffeine; 32 mg/kg There was no cross-tolerance to 32 mg/kg of caffeine citrate in previously sensitized animals tolerant to the Domino,
nicotine (i.p.) stimulant effects of nicotine. 2001
Mouse 1 day pure caffeine; 70 mg/kg Caffeine (70 mg/kg) had an anxiogenic effect in the elevated plus-maze (EPM) test but no effect on loco- Kayir and
nicotine (i.p.) motor activity; nicotine (0.25 mg/kg) pretreatment blocked the caffeine-induced anxiety; nicotine (0.05- Uzbay, 2006
0.25 mg/kg) alone had no effect in the EPM test or on locomotor activity.
Rat 1 day; 14 d pure caffeine; 2.5 mg/kg 1 d; Acute but not repeated dose of caffeine inhibited nicotinic acid-induced vasodilation (no change in skin Turenne et
nicotine (i.p.) 5 mg/kg/d 14 temperature). al., 2001
d
110
time route dose(s)
Rat 10, 30 d pure caffeine; 10, 30 mg/kg Nicotine-CTA (conditioned taste avoidance) was found for rats pre-exposed to 30 mg/kg, but not 10 mg/kg, Palmatier
nicotine (i.p.) caffeine for 10 d. The anorexic effects of caffeine were evident after exposure to 30 mg/kg for 10 d. and Bevins,
2001
Primate 1 day pure caffeine; 1.0 - 30.0 Caffeine markedly increased ventilation during normocapnia and hypercapnia, but nicotine had less pro- Howell,
nicotine (s.c.); mg/kg nounced effects. The effect of caffeine + nicotine on ventilation generally did not differ from those of caf- 1995
hypoxia feine alone. Chronic administration of nicotine (1.0 mg/kg/d) for 4 wk via osmotic pumps significantly
decreased the half-life of caffeine but had little effect on ventilation or on sensitivity to the respiratory-
stimulant effects of caffeine.
Mouse 1 day pure caffeine; 10 mg/kg Caffeine co-treatment with oseltamivir (Tamiflu) increased time spent in the open area in the light-dark Uchiyama et
oseltamivir; preference test and increased ambulation, which was not inhibited by a benzodiazepine receptor antagonist, al., 2010
flumazenil; flumazenil; this enhancement was inhibited by a dopamine D(2) receptor antagonist, haloperidol. These
haloperidol findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems.
(i.p.)
Mouse 1 day pure caffeine; 10 mg/kg Oxcarbazepine (anticonvulsant drug that has been explored as a novel therapeutic agent to treat neuropathic Sawynok et
oxcarbazepine pain in humans) produced dose-related suppression of formalin-evoked flinching responses in wild-type al., 2010
(i.p.) mice following both systemic and intraplantar administration; this action was reversed by systemic and
intraplantar administration of caffeine, respectively.
Mouse 1 day pure caffeine; 5.1 µg Oxamniquine inhibited the metabolism of caffeine, catalyzed by cytochrome P450 1A2(CYP1A2). Kokwaro and
oxamniquine Indalo, 1996
(i.p.)
Mammal- 1 day pure caffeine; mM Perazine at its therapeutic concentrations was a potent inhibitor of human CYP1A2 and caffeine metabo- Wojcikowski
ian cell perazine (in lism. and Daniel,
culture vitro) 2009
Rat liver 1 day pure caffeine; 100, 800 µM β-naphthoflavone (CYP1A inducer) potently accelerated the metabolism of caffeine, whereas pregne- Kot and
micro- phenobarbital; nolone-16alpha-carbonitrile, phenobarbital, and ethanol were modest inducers. Daniel, 2007
somes β-naphtho-
flavone; etha-
nol (i.p.)
Dog, fas- 1 day pure caffeine; 6 mg/kg Pretreatment with either prazosin or propranolol (alpha and beta adrenergic receptor blockers) reduced caf- Salahdeen
ted; anes- prazosin; pro- feine-induced hyperglycemia, glucose extraction and hindlimb glucose uptake at rest but not during con- and Alada,
thetized pranolol (i.v.) traction. 2009a
111
time route dose(s)
Rabbit 1 day pure caffeine; 0.3 or 1.0 Caffeine induced ventricular tachyarrhythmia (VT) at 1.0 mg/kg per min, but not at 0.3 mg/kg per min; this Ishida et al.,
propranolol; mg/kg/min was suppressed by iv bolus injections of verapamil, propranolol and adenosine, suggesting that catechola- 1996
adenosine ; mine-associated triggered activity may be responsible for caffeine-induced VT.
verapamil (i.v.)
Rat 1 day pure caffeine; 50, 100, 150 Administration of 100 mg/kg caffeine + 50 mg/kg pyrazinamide increased excretion the metabolite 5- Mehmedagic
pyrazinamide mg/kg hydroxypyrazinoic acid (5-OH-PA). This effect was more pronounced when 100 mg/kg pyrazinamide was et al., 2002
(oral) given.
Rat 1 day pure caffeine; 25, 50, 100 100 mg/kg decreased locomotor activity and increased NGFI-A and NGFI-B mRNA in entire striatum; 50 Svennings-
raclopride (i.p.) mg/kg mg/kg weakly enhanced both messages in the lateral caudate-putamen and increased horizontal, but not son et al.,
vertical, activity; 25 mg/kg decreased mRNA for NGFI-A, NGFI-B, and jun B and increased horizontal and 1995c
vertical locomotor activity; caffeine could significantly decrease the expression seen following treatment
with the D2 antagonist raclopride. (NGF=nerve growth factor)
Rat 1 day; 14 d pure caffeine; 50 mg/kg A significant induction of c-fos mRNA, but not of any of the other immediate early genes (fos B, c-jun, jun Svennings-
raclopride; B, NGFI-A and NGFI-B), was found 2-8 hr after injection of 50 mg/kg caffeine. Following repeated injec- son and
quinpirole (i.p.) tions of caffeine for 2 weeks a single challenge with caffeine did not induce the expression of any of the Fredholm,
studied genes. c-fos mRNA expression was also induced by the dopamine D2/3 receptor agonist quinpirole 1997
but not the dopamine D2/3 receptor antagonist raclopride. Caffeine and quinpirole did not have synergistic
effects when given together. The caffeine-induced c-fos mRNA expression was not counteracted by con-
comitant treatment with raclopride. Thus caffeine reduces the activity of the striatopallidal neuron, and
since this neuron is inhibitory, the result is an increased activity in globus pallidus.
Dog 1 day pure caffeine; 1, 2, 4, 10 Caffeine (1-10 mg/kg) decreased the duration of the 2-fold increase in coronary blood flow (dose-related) Zhao et al.,
regadenoson mg/kg caused by the A2A receptor agonist regadenoson; 4 and 10 mg/kg caffeine attenuated the effects of re- 2007
(i.v.) gadenoson on mean arterial pressure and HR.
Mouse 4d pure caffeine; 10 mg/kg In the novel object recognition task, pre-treatment with caffeine prevented the disruption of short- and Botton et al.,
scopolamine long-term memory by scopolamine. In the inhibitory avoidance task, caffeine prevented short- but not long- 2010
(i.p.) term memory disruption by pre training administration of scopolamine. Caffeine prevented short- and long-
term memory disruption by post training administration of scopolamine. Both treatments did not affect lo-
comotor activity of the animals.
Mouse 1 day; pure caffeine; guarana 0.3, Only 0.3 mg/mL guarana increased physical capacity in a stressful situation such as forced swimming after Espinola et
100-200 d; scopolamine; 3.0, 30 100 and 200 d treatment. Guarana, both after a single (3.0 and 30 mg/kg) or chronic dosing (0.3 mg/mL), al., 1997
23 mo exercise; gua- mg/mL; caf- partially reversed the amnesic effect of scopolamine as measured through a passive avoidance test in mice
rana (DW) feine 0.1 and rats, but not an active avoidance task in rats.
mg/mL
112
time route dose(s)
Rat 1 day pure caffeine; 33 mg/kg cof- Pretreatment with 33 mg/kg coffee or 1.7 mg/kg caffeine reduced the second restraint-induced increase in Yamato et
stress; coffee fee or 1.7 dopamine and serotonin levels (the restraint stress was for 100 min, the first was followed by a 100 minute al., 2002
(brain microdi- mg/kg caf- recovery before the second restraint).
alysis) feine
Rat 40 d pure caffeine 0.3, 1.0 g/L Chronic administration of caffeine led, in some cases, to increased activity of antioxidant enzymes (high Noschang et
(DW); stress ~40, ~108 dose). However, these effects were not observed in the stressed (repeated restraint) animals. al., 2009a
mg/kg/d
Rat 50+ d pure caffeine 0.3 or 1 g/L Caffeine consumption and chronic stress increased anxiety-like behavior (no interaction when given to- Noschang et
(DW); stress ~40, ~108 gether) as well as DNA breaks in the hippocampus (less than additive effect when given together) of male al., 2009b
mg/kg/d rats, but there were no effects in females.
Mouse 1 day pure caffeine 30, 60, 120 In unstressed mice, caffeine decreased the investigatory behavior and behavioral disinhibition appeared at Meyer and
(i.p.); stress mg/kg low but not high doses; in stressed mice, the dose-dependent action of caffeine was almost abolished and Caston, 2004
there was a slight increase of the investigatory behavior and a strong behavioral disinhibition.
Mouse 1 day pure caffeine 30, 60, 120 In unstressed mice, caffeine induced a linear dose-dependent increase of stumbling frequency in the hole Meyer and
(i.p.); stress mg/kg board test; stress alone impaired motor coordination, but decreased the stumbling frequency induced by the Caston, 2005
highest dose of caffeine.
Rat 1 day pure caffeine 2, 20, 40, 100 In the open field (OF) test, caffeine dose-dependently increased motor activity; caffeine reversed the oppo- Pechlivanova
(i.p.); stress mg/kg site effect due to chronic stress; 40 mg/kg increased the motor activity in plus maze (PM) test and de- et al., 2010
creased the immobility in the forced swimming test; 2 (PM test), 20 and 40 mg/kg caffeine after stress di-
minished its depressive effect on these tests; caffeine increased or decreased body temperature depending
on dose and stress state of the animals.
Rat 1 day pure caffeine 2, 10, 30 Loud noise with 2 mg/kg caffeine increased plasma corticosterone and ACTH levels 30 min after injec- Patz et al.,
(i.p.); stress; mg/kg tions, but levels returned to baseline after 60 min; loud noise with ≥30 mg/kg caffeine (not 2 or 20 mg/kg) 2006
noise elevated plasma hormone levels for at least 2 hr.
Mouse 1 day pure caffeine 3, 10 mg/kg Caffeine (both doses) reduced an impairment of the avoidance acquisition induced by pairs of tone signal Kuribara,
(i.p.); tone + and shock. 1994a
shock
113
time route dose(s)
Rat, over- 9 wk pure caffeine; 0.1% in DW Caffeine reduced BW and glycosuria, improved glucose tolerance, increased plasma cholesterol, proteinu- Tofovic et
weight, tempol (DW) [~100 mg/kg] ria, renal vascular resistance and HR, augmented the influx of glomerular and interstitial macrophages al., 2007
kidney (ED1+ cells), glomerular and tubular proliferative response, and glomerular collagen IV content. Caffeine
disease, had no effect on elevated plasma triglycerides, plasma cholesterol, and BP. Tempol attenuated caffeine-
diabetes induced increase in HR and RVR, and renal inflammation, proliferation, and fibrosis. [Prolonged admini-
stration of 0.1% caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that are seen in hu-
mans after an intake of 2-3 cups coffee]
Rat 1 day pure caffeine; 0.194, 0.388, Theanine (≥5 µmol/kg) inhibited caffeine's stimulatory action (per EEG brain wave analysis) at an almost Kakuda et
theanine (i.v.) 0.970, 1.940 equivalent molar concentration. However, the excitatory effects were shown in the rat i.v. dosed with 1 or 2 al., 2000
mg/kg µmol/kg of theanine alone.
Rat 1 day pure caffeine; 50, 100 mg/kg Caffeine (50 or 100 mg/kg, i.p.) produced anxiogenic-like activity that was reversed by pretreatment with Jain et al.,
THP; diaze- the neurosteroid THP (3-alpha-hydroxy-5-alpha-pregnane-20-one), or progesterone, the GABA(A) agonist 2005
pam; Bicu- muscimol, or the benzodiazepine receptor agonist diazepam. However, caffeine produced higher anxiety in
culline; animals previously treated with the GABA(A) receptor antagonist, bicuculline or the neurosteroid biosyn-
trilostane; fi- thesis enzyme inhibitors trilostane, finasteride or indomethacin. Pretreatment with dehydroepiandrosterone
nasteride; in- sulphate (DHEAS), a neurosteroid that negatively modulates GABA(A) receptors, also enhanced the caf-
domethacin; feine-induced anxiety. Adrenalectomy potentiated the anxiogenic-like response of caffeine, indicating the
DHEAS (i.p.) contributory role of peripheral steroidogenesis. Thus, THP may counter caffeine-induced anxiety through
positive modulation of GABA(A) receptor activity.
Mouse 1 day pure caffeine; ~60-170 Animals pre-treated with toluene 1 hr, but not 1 d, before caffeine dosing had lower caffeine-induced sei- Chan and
toluene (i.v.) mg/kg zure thresholds and lethal dose. Chen, 2003
Rat 1 day pure caffeine; 10 mg/kg Caffeine disrupted sleep: it increased awake time, decreased non-REM sleep time, bout duration (but not Paterson et
zolpidem; tra- bout number), and delta activity in non-REM sleep. It increased locomotor activity and body temperature. al., 2009a
zodone (ga- When given alone, zolpidem suppressed REM while trazodone increased non-REM sleep time at the ex-
vage) pense of awake time, increased non-REM bout duration and EEG delta activity in non-REM sleep, and
reduced body temperature. In combination, zolpidem attenuated caffeine's effects on wake time, while tra-
zodone attenuated its effects on non-REM sleep, bout duration, and delta activity, body temperature and
locomotor activity. Caffeine is a potential model of sleep disruption in the rat.
DRL45-s=low rate schedule; DW=drinking water; EEG=electroencephalograph; HR=heart rate; PK=pharmacokinetic(ally); REM=rapid eye movement; RVR= renal vascular
resistance
114
4D. Interaction of Caffeine with Receptor Ligands – Animal Studies
Animal studies in which caffeine was administered together with another compound were
conducted to elucidate the mechanism of caffeine action at the level of CNS receptor binding, as
caffeine is an antagonist of the adenosine receptor. Thus, caffeine was administered either to-
gether with, shortly before, or after dosing with adesonine receptor agonists (adenosine, 2-
chloroadenosine, N6-cyclohexyladenosine, cyclopentyl adenosine, CGS-21680, NECA, and
PIA) or with adenosine receptor antagonists (cyclopentyl theophylline, DPX, DPCPX, KW-
6002, MSX-3, SCH 58261, SCH 412348). A few studies examined the interaction of caffeine
with dopamine and glutamine agonists and antagonists, and the effect of caffeine on brain gluta-
mate and dopamine levels.
Studies with the adenosine receptor agonists (adenosine analogs) and adenosine receptor
antagonists (caffeine-related compounds) showed that the motor-activating effects of caffeine are
mediated by the blockade of adenosine A1 and A2 receptors, and are inhibited by adenosine and
its analogs. Caffeine was also shown to increase extracellular levels of dopamine and glutamate
in the shell of the brain nucleus accumbens, which may be contribute to caffeine’s psychostimu-
lant effects. Consistent with this, caffeine enhancement of locomotor activity was potentiated by
a GABA antagonist and dopamine agonists, but was inhibited by a GABA agonist and a dopa-
minergic antagonist.
Studies that evaluated the effects of caffeine in animals treated with caffeine plus a recep-
tor ligand are summarized in Table 4-5.
115
TABLE 4-5. Interaction of Caffeine with Receptor Ligands – Animal Studies
Rat 1 day pure caffeine; 0, 50, 100, Caffeine increased the intensity, duration, and electromyographic amplitude of tremors induced by harma- Al-Deeb et
harmaline (i.p.) 150 mg/kg line. al., 2002
Rat 1 day pure caffeine; 3, 10, 30 Behavior induced by caffeine was mimicked by the A(1) antagonist 8-cyclopentyl-1,3-dimethylxanthine, Antoniou et
CPA; CGS mg/kg and was inhibited the A(1) agonist N (6)-cyclopentyladenosine (CPA). al., 2005
21680 (i.p.)
Rat 1 day pure caffeine 3-30 mg/kg Enhanced acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 Carter et al.,
(gavage) receptors. 1995
Rat 1 day pure caffeine; 5.0, 10.0, Caffeine (5.0-20.0 mg/kg IP) reversed the suppression of locomotion induced by the D(2) antagonist eti- Collins et al.,
D(1) and D(2) 20.0 mg/kg clopride, but not the attenuation induced by the D(1) antagonist SCH 39166. 2010
antagonists (i.p.)
Mouse 1 day pure caffeine; cumulative 3, Caffeine-induced locomotion was unaltered by the dopamine D2/3 antagonists eticlopride and nafadotride, Cook and
D2/3 agonists; 10, 30, 100 and the partial D2/3 agonist BP897, but was attenuated by the dopamine D2/3 agonists quinelorane and Beardsley,
D2/3 antagonists mg/kg quinpirole. 2003
(i.p.)
Rat 1 day pure caffeine; L- 16 mg/kg Acute caffeine administration decreased NOS and Bcl2 expression in rat skeletal muscles. Caffeine in- Corsetti et al.,
NAME, L-arg creased mean arterial pressure temporarily, while caffeine + L-NAME increased it for a longer period. The 2007
(i.v.) L-arginine administration reversed these caffeine and L-NAME effects.
Rat 1 day pure caffeine; 0.2 mg Intracerebroventricular caffeine increased spontaneous activity and increased run time to fatigue; caffeine Davis et al.,
adenosine re- did not block the reduction in spontaneous activity induced by the adenosine A(1)/A(2) receptor agonist 2003
ceptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA); pretreatment with caffeine blocked the decrease in run time
(i.c.v..; i.p.) by NECA. No differences were found with i.p. dosing.
Mouse 1 day pure caffeine; 6.25, 25, 100 The stimulant effect of low doses of caffeine is mediated by A(2A) receptor blockade while the depressant El Yacoubi et
A(2A) or A(1) mg/kg effect seen at higher doses under some conditions is explained by A(1) receptor blockade. al., 2000b
receptor ago-
nists, antago-
nists (i.p.)
Rat 1 day pure caffeine; 1 mg/kg at 1, Caffeine prevented the increase of immobility times in both groups, the methylxanthine abolished the ef- Enríquez-
amitriptyline 20 and 23 hr fect of amitriptyline in high immobility-rats (165±23 s vs. 165±46 s, n=9), leaving the antidepressant ac- Castillo et al.,
(i.p.) after the first tion unaffected in low immobility-rats (87±23 s vs. 96±58 s, n=9). These results suggest that the anti- 2008
swimming immobility effect of amitriptyline in high immobility-rats is mediated in part by endogenous adenosine.
session
116
Rat 1 day pure caffeine; 20 mg/kg Caffeine induced increase in the locomotor activity was significantly blocked by the Ca2+ channel blocker Eroglu et al.,
nifedipine; Bay nifedipine and the channel activator Bay K 8644 (0.5 mg kg-1), possibly due to the inhibitory effects of 1996
K 8644 (i.p.) nifedipine and Bay K 8644 on the uptake of adenosine by rat brain.
Rat 1 day pure caffeine; 10, 25 mg/kg Rats receiving dopamine D(2) agonist bromocriptine (5 mg/kg i.p.) were sensitized to its motor stimulat- Fenu et al.,
bromocriptine (s.c.); 10 ing effects and showed cross-sensitization to 10 mg/kg but 25 mg/kg caffeine. In contrast, caffeine (10 2000
(s.c.; i.p.) mg/kg (i.p.) mg/kg i.p.) Administered to rats which had received bromocriptine but were not sensitized failed to show
an increased locomotor response.
Rat 1 day pure caffeine; 3.0-100 Caffeine dose dependently increased locomotor activity. This was blocked by the D1 dopamine antagonist Garrett and
D1 and D2 do- mg/kg SCH23390, and the D2 dopamine antagonists sulpiride and eticlopride. These results suggest that the lo- Holtzman,
pamine an- comotor stimulant effect of caffeine is mediated through dopaminergic systems and both D1 and D2 re- 1994a
tagonists (i.p.) ceptors appear to be involved.
Mouse; Rat 1 day pure caffeine; 1-5 mg/kg Caffeine produced significant antinociception in the hot-plate, abdominal constriction tests in mice and the Ghelardini et
pirenzepine; s.c. in mice; tail flick and paw-pressure tests in rats. This was prevented by atropine, pirenzepine, hemicholinium-3 al., 1997
hemicholinium- 2.5-5 mg/kg and N6-cyclopentyladenosine (CPA), but not by naloxone, CGP 35348, alpha-methyl p-tyrosine (AMPT)
3, CPA; atro- i.p. in rats or reserpine. This suggests that the caffeine antinociceptive effect is mediated by central amplification of
pine, naloxone, cholinergic transmission.
CGP 35348,
reserpine,
AMPT
Mouse: ± 1 day pure caffeine 3.75, 7.5, 15, Locomotor activity increased at 30 mg/kg but decreased at 100 mg/kg for all A1R genotypes; peak activ- Halldner et
A1A and/or (i.p.) 30, 100 ity for A1R knockout (KO) mice was at 7.5 mg/kg vs. 30 mg/kg for WT and heterozygous (HET) mice; al., 2004
A2A recep- mg/kg mice with A2R KO were not stimulated by caffeine but HET-A2R mice were.
tor
Rat 1 day pure caffeine; 3-10 mg/kg Caffeine increased reaction speed in both rat strains, with no effect on accuracy, as did A(2A) antagonists Higgins et al.,
SCH 412348; SCH 412348 (0.1-1 mg/kg PO) and KW-6002 (1-3 mg/kg PO), but not the A(1) antagonist DPCPX (3-30 2007
KW-6002; mg/kg PO); the A(2A) agonist CGS-21680 (0.03-0. 3mg/kg IP) slowed reaction speed and increased
CGS-21680; omissions.
DPCPX (i.p.)
Mouse 1 day pure caffeine; 10 mg/kg Low doses of caffeine and a selective adenosine A(2A) antagonist SCH58261 elicited locomotor sensitiza- Hsu et al.,
SCH58261 tion and cross-sensitization, which were associated with elevated dopamine concentration and TH phos- 2010
(i.p.) phorylation at Ser31 in the striatum.
117
Rabbit 1 day pure caffeine; 0.3 or 1.0 Caffeine induced ventricular tachyarrhythmia (VT) at 1.0 mg/kg per min, but not at 0.3 mg/kg per min; Ishida et al.,
propranolol; mg/kg/min this was suppressed by iv bolus injections of verapamil, propranolol and adenosine, suggesting that cate- 1996
adenosine; vera- cholamine-associated triggered activity may be responsible for caffeine-induced VT.
pamil (i.v.)
Mouse 1 day pure caffeine; 30 mg/kg Caffeine had anxiogenic-like activity at 30 mg/kg, which was prevented by the selective A1 receptor ago- Jain et al.,
CPA (i.p.) nist N6-cyclopentyladenosine (CPA) at 50 µg/kg. 1995
Rat 1 day pure caffeine; 50, 100 Caffeine (50 or 100mg/kg, i.p.) produced anxiogenic-like activity that was reversed by pretreatment with Jain et al.,
THP; diazepam; mg/kg the neurosteroid THP (3-alpha-hydroxy-5-alpha-pregnane-20-one), or progesterone, the GABA(A) agonist 2005
Bicuculline; muscimol, or the benzodiazepine receptor agonist diazepam. However, caffeine produced higher anxiety
trilostane; finas- in animals previously treated with the GABA(A) receptor antagonist, bicuculline or the neurosteroid bio-
teride; indo- synthesis enzyme inhibitors trilostane, finasteride or indomethacin. Pretreatment with dehydroepiandros-
methacin; terone sulphate (DHEAS), a neurosteroid that negatively modulates GABA(A) receptors, also enhanced
DHEAS (i.p.) the caffeine-induced anxiety. Adrenalectomy potentiated the anxiogenic-like response of caffeine, indicat-
ing the contributory role of peripheral steroidogenesis. Thus, THP may counter caffeine-induced anxiety
through positive modulation of GABA(A) receptor activity.
Rat 1 day pure caffeine; 1, 3.2, 10, 32 Caffeine (10 and/or 32 mg/kg) enhanced aversion induced by neurosurgical stimulation of the dorsal Jenck et al.,
dPAG stimula- mg/kg periaqueductal gray matter (dPAG stimulation); effects seen as dose-dependent decreases in the frequency 1995
tion (i.p.) threshold and the latency for self-interruption behavior in rats (e.g., increased aversion).
Rat 1 day pure caffeine; 5 mg/kg Caffeine caused 1.6-fold increase in the AUC of phenylpropanolamine in the brain. Kaddoumi et
phenylpropa- al., 2004
nolamine (i.p.)
Rat 1 day pure caffeine; 0.194, 0.388, Theanine (≥5 µmol/kg) inhibited caffeine's stimulatory action (per EEG brain wave analysis) at an almost Kakuda et al.,
theanine (i.v.) 0.970, 1.940 equivalent molar concentration. However, the excitatory effects were shown in the rat i.v. dosed with 1 2000
mg/kg and 2 µmol /kg of theanine alone.
Rat 1 day pure caffeine; acute: 3, 10, Motor activation at 10, 30, 50 mg/kg; 14 d DW intake of 121 mg/kg resulted in tolerance to acute caffeine Karcz-
adenosine ago- 30, 50, 100 dose (10 mg/kg); interaction studies with A(1) receptor agonist CPA, the A(2A) receptor agonist CGS Kubicha et al.,
nists and an- mg/kg; chro- 21680, the selective A(1) receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 indicated 2003
tagonists (DW) nic: 0.25, 1.0 that the motor-activating effects of caffeine involved the blockade of A(1) and A(2A) receptors.
mg/mL (33,
121 mg/kg/d)
Mouse 1 day pure caffeine; 70 mg/kg Caffeine (70 mg/kg) had an anxiogenic effect in the elevated plus-maze (EPM) test but no effect on loco- Kayir and
nicotine (i.p.) motor activity; nicotine (0.25 mg/kg) pretreatment blocked the caffeine-induced anxiety; nicotine (0.05- Uzbay, 2006
0.25 mg/kg) alone had no effect in the EPM test or on locomotor activity.
118
Rat, mor- 1 day pure caffeine 50 mg/kg Caffeine induced withdrawal signs (head shakes, tooth chattering, ejaculation, chewing, and irritability) in Khalili et al.,
phine- (paragiganto- morphine-dependent rats, and enhanced activity of paragigantocellularis neurons in both control and mor- 2001
dependent cellularis injec- phine-dependent rats.
tion; i.p.)
Mouse 1 day pure caffeine; L- 2-10 mg/kg Locomotor activity induced by 2 mg/kg caffeine was enhanced by co-administration of 600 mg/kg L- Kimura et al.,
NAME, L-arg- arginine or 400 mg/kg taurine. The enhancement was inhibited by pretreatment with 40 mg/kg N-nitro-L- 2009
inine; taurine; arginine methyl ester (L-NAME).
(i.p.?)
Mouse 1 day pure caffeine; 8, 15, 30, 60 Caffeine had psychostimulatory action at lower doses and anxiogenic effect at higher doses; pretreatment Kulkarni et
adenosine (i.p.) mg/kg with caffeine reversed the anxiolytic effect of adenosine. al., 2007
Mouse 1 day pure caffeine 3, 10 mg/kg Caffeine (both doses) reduced an impairment of the avoidance acquisition induced by pairs of tone signal Kuribara,
(i.p.); tone + and shock. 1994a
shock
Mouse 1 day pure caffeine; 3-30 mg/kg All caffeine doses increased motility and locomotion (dose-dependent); rearing tended to increase at 30 Kuzmin et al.,
SCH58261; mg/kg; NGFI-A mRNA was increased at 15 mg/kg in the piriform cortex 4 hr after injection, which was 2006
DPCPX (i.p.) reproduced by dosing with A(1) + A(2A) receptor antagonists (DPCPX and SCH 58261, resp.).
Rat 1 day pure caffeine; 1-3 mg/kg; 1 Pretreatment with 1-3 mg/kg caffeine dose dependently reduced the intensity and increased the onset la- Moo-Puc et
haloperidol; mg/kg 3x/d tency of catalepsy induced by haloperidol; caffeine (1 mg/kg) potentiated the anti-catalepsy effect of trial., 2003
atropine; tri- for 7 d hexyphenidyl and atropine.
hexyphenidyl
(i.p.)
Rat 1 day pure caffeine; 10-40 mg/kg Caffeine enhanced locomotor activity, which was potentiated by a GABA antagonist (bicuculline) and the Muk-
GABA and do- dopamine agonists L-Dopa + carbidopa; caffeine effect was inhibited by a GABA agonist (muscimol), a hopadhyay
pamine agonist dopaminergic antagonist (haloperidol), a muscarinic receptor blocker (atropine), an inhibitor of acetylcho- and Poddar,
and antagonists line esterase (physostigmine), and a nicotinic receptor agonist (nicotine). Results suggest that caffeine 1995
(gavage) potentiates locomotor activity by antagonism of the adenosine receptor and activation of the dopaminergic
system which, in turn, reduces GABAergic activity through the reduction of the cholinergic system.
Rat 1 day pure caffeine; 10, 56 mg/kg The results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of Powell et al.,
dopamine recep- caffeine, are dependent on, but not limited to, DA D1 and D2 dopamine receptor mechanisms. 1999
tor agonists and
antagonists (i.p.)
119
Rat 1 day pure caffeine; 10.0, 30.0 Caffeine (10.0-30.0 mg/kg) improved short-term social memory; 10.0 mg/kg prevented disruption of so- Prediger and
adenosine (i.p.) mg/kg cial memory by 5.0 mg/kg adenosine. Takahashi,
2005
Rat 1 day pure caffeine; 5.0, 10.0, Caffeine produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec Randall et al.,
A(1) antagonists 20.0, or 40.0 schedule but decreasing responding on the FR20 schedule. A(1) antagonists failed to increase the lever 2011
(i.p.) mg/kg pressing rate.
Hamster, 1 day pure caffeine; 10-20 mg/kg Caffeine worsened the dystonia in dt(sz) hamsters (model of paroxysmal dystonia); seizures or convul- Richter and
paroxysmal adenosine sions Hamann,
dystonia (i.p.) 2001
Dog, fas- 1 day pure caffeine; 6 mg/kg Pretreatment with either prazosin or propranolol (alpha and beta adrenergic receptor blockers) reduced Salahdeen and
ted; anesthe- prazosin; pro- caffeine-induced hyperglycemia, glucose extraction and hindlimb glucose uptake at rest but not during Alada, 2009a
tized pranolol (i.v.) contraction.
Rat 1 day pure caffeine; 5.0-20.0 Caffeine reversed the effects of the dopamine D(2) antagonist haloperidol (reduced lever pressing and Salamone et
haloperidol (i.p.) mg/kg substantially increased chow intake). al., 2009
Rat 1 day pure caffeine; 12.5-100 Caffeine produced a dose-related antinociception the hot plate (HP) (50-100 mg/kg) and formalin tests Sawynok et
formalin; na- mg/kg (12.5-75 mg/kg). During the formalin test, caffeine stimulated locomotor activity between 12.5 and 50 al., 1995
loxone; phento- mg/kg, while 75 mg/kg depressed activity. Caffeine did not produce an anti-inflammatory effect. Periph-
lamine; prazo- eral co-administration of caffeine and formalin did not produce antinociception. Naloxone did not reduce
sin; idazoxan; 6- the antinociceptive or locomotor stimulant effects of caffeine, but phentolamine, prazosin, idazoxan, en-
hydroxydopa- hanced antinociception by caffeine but inhibited locomotor stimulation. Microinjection of 6-
mine (i.p.?) hydroxydopamine (6-OHDA) into various brain regions, which depleted noradrenaline (NA), inhibited the
action of caffeine in the HP test. These results suggest an involvement of noradrenergic mechanisms in the
antinociceptive action of caffeine in the HP and formalin tests and in locomotor stimulation.
Mouse 1 day pure caffeine; 10 mg/kg Oxcarbazepine (anticonvulsant drug that has been explored as a novel therapeutic agent to treat neuro- Sawynok et
oxcarbazepine pathic pain in humans) produced dose-related suppression of formalin-evoked flinching responses in wild- al., 2010
(i.p.) type mice following both systemic and intraplantar administration; this action was reversed by systemic
and intraplantar administration of caffeine, respectively
Mouse 1 day pure caffeine; 20 mg/kg During training, chlordiazepoxide increased and caffeine decreased % time spent in the open arms (PTO) Silva and
chlordiaze- (suggests anxiolytic and anxiogenic effect, resp.); during testing, both agents increased % time spent in Frussa-Filho,
poxide (i.p.) aversive enclosed arm (suggests amnestic effects); co-dosing did not alter PTO and eliminated the amne- 2000
sic effect.
120
Rat 1 day pure caffeine; 30 mg/kg Results indicate that adenosine A1 receptor blockade is involved in the discriminative-stimulus effects of Solinas et al.,
DMPX; CPT; behaviorally relevant doses of caffeine; A 2A receptor blockade does not play a central role in caffeine's 2005
CGS21680; discriminative effects and counteracts the A1 receptor-mediated discriminative-stimulus effects of caf-
MSX-3 (i.p.) feine.
Mouse; 1 day pure caffeine; 50 mg/kg Caffeine stimulates transcription of the dopamine 2 receptor (D2R) gene in PC-12 cells and primary stri- Stonehouse et
Mammalian CGS 21680 atal cultures and increases D2R protein expression in the striatum. Simultaneous treatment with CGS al., 2003
cell culture (i.p.) 21680 (specific adenosine 2A receptor agonist), eliminated this effect. In primary striatal cultures, caffeine
increased spontaneous firing of neurons between 12 and 80 min after treatment, whereas it increased D2R
mRNA expression after only 4 h. In vivo, female mice treated with 50 mg/kg caffeine had a ~2-fold in-
creases in D2R mRNA and protein expression, but males had a 31% decrease in D2R mRNA expression
and no changes in D2R protein expression. These results demonstrate for the first time that caffeine alters
D2R expression in neurons.
Mouse, 1 day pure caffeine 0.01, 0.1, 1, Results indicate that adenosine A1 and A2A receptors are not upstream of caffeine's dopamine D2 recep- rgess et al.,
C57Bl/6; (i.p.) 3, 10, 15, 30, tor-dependent aversive effects and dopamine-independent rewarding effects. Although the adenosine 2010
A(2A) re- 100 mg⁄kg A(2A) receptor is important for caffeine's physiological effects, this receptor seems only to modulate the
ceptor appetitive and aversive effects of caffeine.
knockout
Rat 1 day pure caffeine; 25, 50, 100 100 mg/kg decreased locomotor activity and increased NGFI-A and NGFI-B mRNA in entire striatum; 50 Svenningsson
raclopride (i.p.) mg/kg mg/kg weakly enhanced both messages in the lateral caudate-putamen and increased horizontal, but not et al., 1995c
vertical, activity; 25 mg/kg decreased mRNA for NGFI-A, NGFI-B, and jun B and increased horizontal
and vertical locomotor activity; caffeine could significantly decrease the expression seen following treat-
ment with the D2 antagonist raclopride (NGF=nerve growth factor).
Rat 1 day pure caffeine; c- 100 mg/kg Caffeine induction of striatal preprotachykinin A mRNA and neurotensin/neuromedin N mRNA, but not Svenningsson
fos antisense of preproenkephalin mRNA or prodynorphin mRNA, may at least in part be mediated by a pathway in- et al., 1997b
oligonucleotides volving Fos protein.
(i.p.)
Mouse 1 day pure caffeine; 10 mg/kg Caffeine co-treatment with oseltamivir (Tamiflu) increased time spent in the open area in the light-dark Uchiyama et
oseltamivir; preference test and increased ambulation, which was not inhibited by a benzodiazepine receptor antago- al., 2010
flumazenil; nist, flumazenil; this enhancement was inhibited by a dopamine D(2) receptor antagonist, haloperidol.
haloperidol (i.p.) These findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems.
Mouse 1 day pure caffeine; 4-16 mg/kg Caffeine increased locomotor activity of the mice, which was blocked by Hypericum perforatum (HPE) Uzbay et al.,
HPE; l-arginine (6-24 mg/kg); pretreatment of l-arginine reversed the inhibitory effect of HPE (l-arginine had no effect on 2007
(i.p.) locomotor activity given alone).
121
Rat 1 day pure caffeine; 10 mg/kg Co-administration of caffeine with MDMA provoked a switch from MDMA-induced hypothermia and Vanattou-
SCH 23390; bradycardia to hyperthermia and tachycardia without influencing MDMA-induced hyperlocomotion. Pre- Saïfoudine et
sulpiride; treatment with a specific dopamine D(1/5) antagonist SCH 23390 enhanced MDMA-induced hypothermia al., 2010
MDMA (s.c.) and blocked the ability of caffeine to provoke a switch from MDMA-induced hypothermia to hyperther-
mia. Furthermore, SCH 23390 blocked MDMA-induced hyperactivity and the ability of caffeine to pro-
mote a tachycardic response to MDMA. By contrast, pre-treatment with the selective D(2) antagonist,
sulpiride blocked MDMA-induced hypothermia, failed to influence the ability of caffeine to promote
tachycardia whilst enhancing MDMA-induced hyperactivity. The results suggest that the ability of caf-
feine to provoke MDMA-induced toxicity is associated with the promotion of dopamine D(1) over D(2)
receptor-related responses.
Mammalian 1 day pure caffeine; 100 μM Caffeine (100μM) induced dopamine release in the striatum and hypothalamus, albeit to a much lesser Vanattou-
cell culture MDMA; extent than MDMA. When striatal tissue slices were superfused with MDMA (30μM) + caffeine (30μM), Saifoudine, et
DPCPX; CCPA; caffeine enhanced MDMA-induced dopamine release, provoking a greater response than that obtained al., 2011
rolipram; SCH following either caffeine or MDMA applications alone. Cyclopentyl-1,3-dipropylxanthine (DPCPX), a
58261 (in vitro) specific A(1) antagonist, like caffeine, enhanced MDMA-induced dopamine release from striatal slices
while 1μM 2,chloro-N(6)-cyclopentyladenosine (CCPA), a selective adenosine A(1) receptor agonist, at-
tenuated this. Treatment with either SCH 58261, a selective A(2A) receptor antagonist, or rolipram, a se-
lective PDE-4 inhibitor, failed to reproduce a caffeine-like effect on MDMA-induced dopamine release.
The results suggest that caffeine regulates MDMA-induced dopamine release in striatal tissue slices via
inhibition of adenosine A(1) receptors.
Dog 1 day pure caffeine; 1, 2, 4, 10 Caffeine (1-10 mg/kg) decreased the duration of the 2-fold increase in coronary blood flow (dose-related) Zhao et al.,
regadenoson mg/kg caused by the A2A receptor agonist regadenoson; 4 and 10 mg/kg caffeine attenuated the effects of re- 2007
(i.v.) gadenoson on mean arterial pressure and HR.
Mouse; 1 day; 50 pure caffeine 50, 100 Adaptive mechanisms after mutation in A(2A) receptors or their long-term blockade after chronic inges- El Yacoubi et
A(2A) re- mg/kg (i.p.) mg/kg tion of caffeine may be responsible for increase proneness to anxiety. However, the short-term anxiety- al, 2000a
ceptor 2x/d x 7 d like effect of caffeine in mice might not be related solely to the blockade of adenosine A(2A) receptors,
knockout since it is not shared by A(2A) selective antagonists.
Mouse 1 day; 7 d pure caffeine; 1 mg/mL 7 d Caffeine 7-d treatment caused habituation and substantial tolerance to acute caffeine (30 mg/kg, i.p.) lo- Dall'Igna et
MK-801 (DW; DW, then 30 comotor effects; MK-801 (0.25 mg/kg, i.p.) caused hyperlocomotion, which was abolished in caffeine- al., 2003
i.p.) mg/kg, i.p. drinking mice.
122
Rat 1 day; 7 d pure caffeine; 86 mg/kg/d Rats treated chronically with oral caffeine were tolerant to the motor stimulant effects of caffeine (3.0-100 Garrett and
SKF-77434; (7 d, DW); mg/kg, i.p.). Caffeine-treated rats were cross-tolerant to the locomotor stimulant effect of the partial do- Holtzman,
quinpirole; NPA acute 3, 10, pamine D1 receptor agonist SKF-77434 and the dopamine D2 receptor agonists quinpirole and R(-)-pro- 1994b
(DW; i.p.) 30, 100 pylnorapomorphine (NPA).
mg/kg
Rat 1 day; pure caffeine; 15 mg/kg; 5 Caffeine sensitized the motor stimulant effects of dopamine D(1) and D(2) receptor agonists. Cauli and
every SKF77434, mg/kg Morelli, 2002
other day quinpirole
(gavage)
Mouse 1 day; 14 pure caffeine; 5, 10, 20, 30 Caffeine (≥ 5 mg/kg) and SCH58261 but not DPCPX induced CPP and locomotor sensitization in Hsu et al.,
d SCH58261; mg/kg acute; C57BL/6 mice; the sensitization after chronic treatment with 20 mg/kg was associated with increased 2009b
DPCPX 20 mg/kg DARPP-32 phosphorylation at Thr75 in the striatum.
(i.p.) chronic
Rat 1 day; 14 pure caffeine; ~136 Caffeine-induced locomotor activity (10, 30 mg/kg) was blocked by haloperidol, enhanced by GBR Powell et al.,
d haloperidol; mg/kg/d oral; 12909, and unaffected by nisoxetine and fluoxetine. Haloperidol infused during 14-d caffeine intake did 2001
GBR 12909; 10, 30 mg/kg not block development of caffeine tolerance but impaired recovery from tolerance. Caffeine-treated rat D
nisoxetine; SCH 23390 (DA D(1)) dopamine binding sites were down-regulated in the nucleus accumbens and stria-
fluoxetine; tum and upregulated in the prefrontal cortex of, but their affinity for SCH 23390 was unchanged. Changes
(DW) (i.p.) in DA D(1) receptors could be one component of the mechanism underlying caffeine-induced tolerance.
Rat 1 day; 14 pure caffeine; 50 mg/kg A significant induction of c-fos mRNA, but not of any of the other immediate early genes (fos B, c-jun, Svenningsson
d quinpirole; ra- jun B, NGFI-A and NGFI-B), was found 2-8 hr after injection. Following injections for 2 weeks a chal- and Fredholm,
clopride (i.p.) lenge with caffeine did not induce the expression of any of the studied genes. c-fos mRNA expression was 1997
also induced by the dopamine D2/3 receptor agonist quinpirole but not the dopamine D2/3 receptor an-
tagonist raclopride. Caffeine and quinpirole did not have synergistic effects when given together. The caf-
feine-induced c-fos mRNA expression was not counteracted by concomitant treatment with raclopride.
Thus caffeine reduces the activity of the striatopallidal neuron, and since this neuron is inhibitory, the re-
sult is an increased activity in globus pallidus.
Mouse 1 day; 1, pure caffeine; acute: 30 Exposure to caffeine for only 24 hr did not produce measurable changes of the sensitivity of cannabinoid Rossi et al.,
10, 20, 30 cannabinoid mg/kg i.p.; CB1 receptors (tested CNQX, 3,5-DHPG, AM251, baclofen, HU210, MK-80, tetrodotoxin, and bicu- 2009
or 45 d CD1 agonists repeated: 1 culline), but it was able to contrast the down-regulation of CB1 receptor-mediated responses after social
and antagonists; mg/mL DW defeat stress.
stress (210
(i.p., DW) mg/kg/d)
123
Mouse 1 day; pure caffeine; guarana 0.3, Only 0.3 mg/mL guarana increased physical capacity in a stressful situation such as forced swimming Espinola et
100-200 scopolamine; 3.0, 30 after 100 and 200 d treatment. Guarana, both after a single (3.0 and 30 mg/kg) or chronic dosing (0.3 al., 1997
d; 23 mo exercise; guara- mg/mL; caf- mg/mL), partially reversed the amnesic effect of scopolamine as measured through a passive avoidance
na (DW) feine 0.1 test in mice and rats, but not an active avoidance task in rats.
mg/mL
Mouse 4d pure caffeine; 0.2, 0.5, 1 Chronic caffeine ingestion markedly affects levels of cortical A1-adenosine, muscarinic, and nicotinic Shi et al.,
forskolin; do- g/L receptors, but not on dopamine receptors, dopamine uptake systems, or dopamine-stimulated adenylate 1994
pamine; NECA (~40, 80, 100 cyclase. There are subtle changes in behavioral responses to adenosine analogs in the presents of agents
(DW) mg/kg/d) that affect dopaminergic function such as amphetamine and cocaine, and marked changes in responses to
nicotine either alone or in combination with caffeine.
Mouse 4d pure caffeine; 10 mg/kg In the novel object recognition task, pretreatment with caffeine prevented the disruption of short- and Botton et al.,
scopolamine long-term memory by scopolamine. In the inhibitory avoidance task, caffeine prevented short- but not 2010
(i.p.) long-term memory disruption by pre training administration of scopolamine. Caffeine prevented short-
and long-term memory disruption by post training administration of scopolamine. Both treatments did not
affect locomotor activity of the animals.
Mouse 6 d; 20 d pure caffeine; 49 mg/kg Treatment for 20 days (but not 6 d) shifted the A1 low affinity receptors into an agonist-specific high af- Traversa et
CHA (i.p.) finity state, and decreased the affinity of 3H-CHA to A1 receptors in the high affinity state; the A2A stri- al., 1994
atal receptors were dose- and time-dependently up-regulated.
Mouse 8d pure caffeine; 40-100 24 hr after last caffeine dose mice had increased duration and frequency of defensive behavior and de- Sukhotina et
memantine; mg/kg 2x/d, creased locomotor activity (faded in 72 hr); treatment with memantine or neramexane 24 hr after the last al., 2004
neramexane then 1 mg/kg caffeine dose reduced defensive behavior and increased motor activity behavior change.
(i.p.)
Rat 9d pure caffeine; 20, 40, 80 Increased TH mRNA levels in the SNc (up to 64%) and the VTA (33%). The increases at 80 mg/kg caf- Datta et al.,
MK-801 (i.p.) mg/kg 2x/d feine were prevented by co-administration of the non-competitive N-methyl-D-aspartate (NMDA) recep- 1996
tor antagonist MK-801.
Mouse 14 d pure caffeine; 0.1, 0.3, 1 At 1 g/L (not 0.1 or 0.3 g/L), caffeine increased binding of the A1 agonist [3H]cyclohexyladenosine Johansson et
A1 agonist, an- g/L (35, 80, (CHA) without change in A1 mRNA or in binding of A1 antagonist [3H]1,3-dipropyl-8-cyclopentyl xan- al., 1997
tagonist (DW) 240 mg/kg/d) thine (DPCPX); increased levels of A2A receptors in the striatum.
Mouse 15 d pure caffeine; 3 mg/kg Chronic administration of caffeine led to an A(1)-mediated enhancement of the CB(1)-dependent acute Sousa et al.,
THC disruptive effects of Δ(9)-tetrahydrocannabinol (THC, a CB(1) receptor agonist) on a short-term spatial 2011
(i.p.) memory task, despite inducing a reduction in cortical and hippocampal CB(1) receptor number and an
attenuation of CB(1) coupling with G protein. A(1) receptor levels were increased.
124
Rat, over- 9 wk pure caffeine; 0.1% in DW Caffeine reduced BW and glycosuria, improved glucose tolerance, increased plasma cholesterol, proteinu- Tofovic et al.,
weight, kid- tempol (DW) [~100 mg/kg] ria, renal vascular resistance and HR, augmented the influx of glomerular and interstitial macrophages 2007
ney disease, (ED1+ cells), glomerular and tubular proliferative response, and glomerular collagen IV content. Caffeine
diabetes had no effect on elevated plasma triglycerides, plasma cholesterol, and BP. Tempol attenuated caffeine-
induced increase in HR and RVR, and renal inflammation, proliferation, and fibrosis. [Prolonged admini-
stration of 0.1% caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that are seen in hu-
mans after an intake of 2-3 cups coffee]
AMPT = alpha-methyl-para-tyrosine (inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis)
CGS-21680 = specific adenosine A2 receptor agonist
CHA = N6-cyclohexyladenosine (adenosine A1 receptor ligand/agonist)
CPA = cyclopentyl adenosine (adenosine receptor agonist)
CPT = cyclopentyl theophylline (adenosine A1 receptor antagonist)
DPCPX = 1,3-dipropyl-8-cyclopentylxanthine; 8-cyclopentyl-1,3-dimethylxanthine (adenosine A1 receptor antagonist)
DPX = 3H-diethylphenylxanthine (adenosine A1 receptor antagonist)
DW=drinking water
HR=heart rate
KW-6002 = Istradefylline (adenosine A2 receptor antagonist)
MK-801 = Dizocilpine (non-competitive antagonist of the N-methyl-d-aspartate (NMDA) brain glutamate receptor
MSX-3 = 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine (adenosine A2 receptor antagonist)
NECA = N-ethyl carboxamidoadenosine, 5'-N-ethylcarboxamide adenosine (adenosine A2 receptor agonist)
L-NAME = N-omega-Nitro- l-arginine methyl ester (nitric oxide synthase (NOS) inhibitor)
PIA = N6-(phenylisopropyl)-adenosine (adenosine analog)
PND = post-natal day
RVR=renal vascular resistance
SCH 58261 = selective adenosine A2 receptor antagonist
SCH 412348 = selective adenosine A2 receptor antagonist
125
CHAPTER 5. CARDIOVASCULAR EFFECTS OF CAFFEINE
5A. Cardiovascular Effects of Caffeine – Human Studies
The cardiovascular effects of caffeine were assessed in many single-exposure experimen-

tal studies, a few short-term (5-42 days) experimental studies, and numerous case reports and
epidemiological studies. The experimental studies tested doses of 1-5 mg/kg in children (one
study administed two 5 mg/kg doses), and from 0.7-7.1 mg/kg in adults. The vast majority of the
adult subjects were age 18-45, the exceptions being studies that specifically evaluated the effects
of caffeine in older people, or people with various pre-existing conditions such as hypertension.
In the single-dose experimental studies, caffeine intake caused an increase in systolic and/or dia-
stolic BP and decreased HR at caffeine doses of as low as 1 mg/kg in children and 1.4 mg/kg in
adults. In some studies caffeine caused increased HR at ≥1.8 mg/kg. The dichotomous HR re-
sponse is seen because caffeine elicits a vagally mediated bradycardia by baroreflex activation,
but also has a direct cardioacceleratory effect and can increase HR, especially in people with
compromised cardiac function. Stress increased the effect of caffeine on BP and HR. Caffeine
intakes of ≥1.4 mg/kg increased aortic stiffness, increased vascular resistance, decreased cerebral
blood flow (and changes in blood oxygenation levels), and increased plasma epinephrine, lipids,
and renin activity. The effects were typically greater in low users than in habitual caffeine con-
sumers and in older subjects, and were exacerbated by concurrent hypertension, but caffeine had
inconsistent effects on subjects with ventricular arrhythmia. One single-exposure study and sev-
eral one to 6-week studies examined the effect of caffeine on plasma homocysteine levels, and
all found that caffeine and/or coffee caused a slight increase (4-19%) (Hodgson et al., 2007;
Strandhagen et al., 2004a; Verhoef et a., 2002; Grubben et al., 2000; Urgert et al., 2000; Chris-
tensen et al., 2001). The repeat-exposure experimental studies showed that partial habituation
occurs to the pressor response to caffeine.
Case reports of 15-17 year old children who ingested on one occasion >30 mg/kg pure
caffeine or a caffeine-containing supplement experienced effects including sinus and ventricular
tachycardia, nausea, vomiting and in one case, death (Kromhout et al., 2008; Shum et al., 1997;
Fujiyoshi et al., 2008). A 16-year old girl who ingested 320-400 mg/day caffeine as an ED for 7
days (5-7 mg/kg/day) had dizziness, tachycardia, and a transient loss of consciousness (Terlizzi
et al., 2008). Case reports of adults who ingested 305 mg caffeine on one occasion as an ED, or
0.6 to 50 g caffeine as an ED or pure caffeine noted palpitations, chest tightness, cardiac arrest,
and atrial fibrillation, and one individual who ingested 10 g died (Nagajothi et al., 2008; Artin et
al., 2010; Berger and Alford, 2009; Rudolph and Knudsen, 2010; Kapur and Smith, 2009). Ef-
fects noted in case reports of repeated caffeine intake included a ruptured arterial aneurysm, se-
vere heart palpitations, anxiety, hypertensive retinopathy, malignant hypertension, aortic dissec-
tion, and atrioventricular block (Argano et al., 2011; Baghkhani and Jafari, 2002; Willis et al.,
2006; Ahmed, 2009; Aizaki et al., 1999).
Epidemiological studies provided conflicting findings regarding the effects of caffeine on

BP in children. In an 8-year follow up study of 9-10 year old children, higher calorie and caf-
feine intake were associated with higher hypertension incidence (Obarzanek et al., 2010). Cross-
sectional studies by Savoca et al. (2004; 2005) found a positive association of caffeine intake
126
with BP in 15-19 year old adolescents, which was higher in African-Americans. Conversely,
Reddy et al. (2008) and Suguyama et al. (2007) found no relationship between caffeine intake
and BP in 8-10 year old African-American girls, and in 12-19 year old American males and fe-
males, respectively.
All but one of the 14 case-control studies with adults found a positive association of caf-
feine intake with increased risk of cardiotoxicity. A non-significantly increased risk for acute
myocardial infarction (MI) was seen in men with a family history of acute MI from an intake of
<2 to >4 cups espresso coffee/day (Azvedo and Barros, 2006). An increased risk of MI from an
intake of ≥2 cups coffee/day (2.9 mg/kg) or ≥303 mg caffeine/day (4.3 mg/kg/day) was observed
by several investigators, in some cases only in subjects who were carriers of the slow *1F allele
for CYP1A2 (Cornelis et al., 2006; El-Sohemy et al., 2007; Kabagambe et al., 2007). An intake
of ~8-10 mg/kg/day caffeine was associated with an increased risk of first MI (Hammar et al.,
2003; Tavani et al., 2001a; Weinmann et al. (1997). Consumption of >10 cups coffee/day (14
mg/kg/day) was a risk factor for sudden cardiac death in a Dutch population (de Vreede-
Swagemakers et al., 1999). A short-term increase in the risk of death from coronary heart dis-
ease and ischemic stroke was observed for an intake of ≥3 and ≥5 cups/day in an Italian popula-
tion (Marchioli et al., 1996). Feldmann et al. (2005) found an increased risk of intracerebral
hemorrhage from intake of ≥5 cups/day coffee. Conversely, Sesso et al. (1999) found no asso-
ciation of coffee intake with risk of MI, and tea was associated with a lower risk.
Unlike the case-control studies, the cohort prospective studies did not portray a consistent
relationship between caffeine intake and adverse cardiovascular effects. Consumption of ≥814
mL/day coffee (9.3 mg/kg/day) was associated with increased risk of acute MI or coronary death,
and an intake of 938 mL/day (13 mg/kg/day) was associated with an increased risk for acute
coronary events in drinkers with low activity polymorphism of the catechol-O-methyltransferase
gene (Happonen et al., 2004; 2006). An intake of ≥4 cups/day coffee (5.7 mg/kg/day) was asso-
ciated with a higher risk of MI or coronary artery disease in current and ex-smokers (Klatsky et
al., 2008). An intake of ≥5 cups/day (7.1 mg/kg/day) was associated with increased risk of heart
failure, future hospitalization for fibrillation, hypertension, and/or mortality from coronary heart
disease (Wilhelmsen et al., 2001; 2001b; Klag et al., 2002; Stensvold et al., 1996). Klag et al.
(1994) observed an increase in coronary heart disease risk for all caffeine intake categories (low-
est was 1-2 cups/day), although most of the risk was attributed to drinking prior to 1975, and the
diagnosis of hypertension was associated with a subsequent reduction in coffee consumption.
Palatini et al. (2009) found that carriers of the slow *1F allele of CYP1A2 had an increased risk
of hypertension, from drinking 1-3 cups or more per day (1.4-4.3 mg/kg/day), whereas carriers of
the fast allele had reduced risk. Several cohort studies found non-linear relationships between
caffeine intake and heart disease, where moderate caffeine intakes increased risk whereas low
and/or high intakes decreased risk, for endpoints of hypertension (Hu et al., 2007; Winkelmayer
et al., 2005; Uiterwaal et al., 2007), cardiovascular disease (de Koning Gans et al., 2010) cardio-
vascular disease mortality (Paganini-Hill, 2011), and all-cause mortality (Kleemola et al., 2000).
Conversely, a number of cohort studies found no association or an inverse association be-

tween habitual caffeine intake via coffee, tea, and/or total caffeine and adverse cardiovascular
effects. The examined endpoints included hypertension (Chen et al., 2010a), MI (Rosner et al.,
2007), coronary and carotid atherosclerosis (Reis et al., 2010); heart failure hospitalization (Ah-
127
med, 2009), atrial fibrillation (Conen et al., 2010; Frost and Vestergaard, 2005; Shen et al, 2011),
cardiovascular disease and/or death (Lopez-Garcia et al., 2006; 2008; Mineharu et al., 2010; Sil-
letta et al., 2007; Sugiyama et al., 2010; Willett et al., 1996; Woodward and Tunstall-Pedoe,
1999), cardiovascular disease and/or death in diabetic men and women (Zhang et al., 2009a;
2009b), stroke (Garcia-Lopez et al., 2009; Silletta et al., 2007), heart failure (Wang et al., 2011),
and ischemic heart disease mortality (Mukamal et al., 2004; Silletta et al., 2007; Leurs et al.,
2010).
Cross-sectional chronic exposure studies most commonly evaluated the effect of caffeine
intake on plasma total homocysteine concentration, as high levels have been linked with an in-
creased risk for cardiovascular disease. All studies found a significant dose-related positive as-
sociation with a significant trend. Intakes identified as increasing homocysteine levels were all
caffeine intake categories >0 (Panagiotakos et al., 2004), ≥1 cup coffee or ≥2 sodas per day
(Jacques et al., 2001), ≥3, ≥4, or ≥5 cups coffee/day (Stolzenberg-Solomon et al., 1999; Ulvik et
al., 2008; Nygard et al., 1998). Some studies did not identify specific intakes that were statisti-
cally different from the controls (Nygard et al., 1997; Carlsen et al., 2005).
Several cross-sectional studies evaluated the effect of caffeine on BP. A trend to higher
systolic BP during the first and third trimester was seen in pregnant women consuming ~ 3
mg/kg/day caffeine as coffee (Bakker et al., 2011). Giggey et al. (2010) found a positive asso-
ciation between intake of >6 cups/day coffee and increased systolic BP and pulse pressure.
However, Wakabayashi et al. (1998) and Palatini et al. (1996) found no consistent relationship or
an inverse association between caffeine intake and BP. Vlachopoulos et al. (2005; 2007) ob-
served a dose-related increase in the carotid-femoral pulse augmentation index, but not the pulse
wave velocity (aortic stiffness). Two studies concluded that coffee may be a trigger for MI or
ischemic stroke during the hour after ingestion, the risk being the greatest for occasional drinkers
(Baylin et al., 2006; Selb Semerl and Selb, 2004; Mostofsky et al., 2010).
Due to the heterogeneity of the data, a LOAEL and NOAL cannot be reliably determined
for the effect of caffeine on cardiovascular parameters.
Experimental studies that evaluated the cardiovascular effects of caffeine in humans

treated with caffeine are summarized in Table 5-1, and the case reports and epidemiological
studies are summarized in Table 5-2. Summaries of conclusions drawn in reviews of the cardio-
vascular effects of caffeine are summarized in Table 4-3. Most of the reviews concluded that the
available evidence does not support an association between caffeine intake and cardiovascular
disease, based on the negative results in cohort studies (Chou and Benowitz, 1994; Gensini and
Conti, 2004; Sudano et al., 2005; Hamer, 2006; Kim, 2006; Sofi et al., 2007; Geleijnse, 2008;
IFIC, 2008; van Dam, 2008a; Wu et al., 2009; Beaudoin and Graham, 2011). Riksen et al.
(2009) postulated that coffee may trigger acute coronary events and increase infarct size in se-
lected populations, rather than promoting atherosclerosis in the general population. Riksen et al.
(2011) recognized the lack of caffeine effect in cohort studies, but did not exclude the possibility
that caffeine may adversely impact select vulnerable groups of people based on their genetic pro-
file or medication use. Kawachi et al. (1994) hypothesized that the difference in response in the
case-control and cohort studies may be due to the chosen endpoints, period of study, or to con-
founding by smoking or gender. A number of reviews confirm the pressor effect of caffeine seen
128
in the cross-sectional and experimental studies, in some cases noting that the response was
strongest in hypertensive subjects and blunted but not eliminated in habitual consumers of caf-
feine (Jee et al., 1999; Nurminen et al., 1999; Hartley et al., 2001; James, 2004; Cohen and
Townsend, 2006; Flammer et al., 2006; Higdon and Frei, 2006; Mort and Kruse, 2008). Several
authors bring up the difference in response between pure caffeine and caffeine in coffee, noting
that the latter elicits a much weaker effect on BP (Noordzij et al., 2005; Geleijnse, 2006). Rodri-
guez and Klein (2006) note the lack of data regarding the effect of caffeine or coffee on C-
reactive protein, which is an indicator of CVD risk. In their review, O’Connor and Irwin (2010)
note that moderate to high intake of non-filtered coffee, but not filtered coffee, was related to in-
creases in C-reactive protein and homocysteine in epidemiological studies.
129
TABLE 5-1. Cardiovascular Effects of Caffeine in Humans – Experimental Studies
Caffeine dose Effects; Comments (sorted by caffeine dose) Reference
1-d experi- 12-17 yr pure caffeine 50, 100, 200 mg HR decreased and diastolic BP increased with increasing caffeine dose; there were significant Temple et al.,
ment (USA) n=54 (28 M) [~1, 2, 4 mg/kg] interactions among gender, caffeine use, and time on DBP. 2010
1-d experi- 7-9 yr pure caffeine; 1, 3, 5 mg/kg Low, mild, and moderate (1, 3, and 5 mg/kg) doses of caffeine had no effect on substrate use as Turley et al.,
ment (USA) n=40 (20 M) exercise reflected by the respiratory exchange ratio; caffeine increased BP and decreased HR at pre- 2008
exercise and slightly decreased HR at 3 and 5 mg/kg during exercise.
1-d experi- 7-9 yr (n=26 pure caffeine; 5 mg/kg BP was not significantly affected by caffeine, but on average it was always higher in boys for dia- Turley et al.,
ment (USA) M); 18-29 yr exercise stolic BP (3 mm Hg) and systolic BP (3-4 mm Hg) and men for diastolic BP (2-3 mm Hg) and 2007
(n=26 M) systolic BP (1-6 mm Hg) both at rest and during exercise. HR was significantly (p < .05) lower at
rest, 25W and 50W in caffeine versus PL in boys, with no change in adults. During exercise, VO2
and respiratory exchange ratio were not different in caffeine versus placebo in either group.
1-d experi- 7-9 yr pure caffeine; 10 mg/kg (split BP increase; HR decreased; no effect on metabolism (VO2 or RER) in young children at low- Turley and
ment (USA) n=52 (26 M) exercise dose) moderate intensities of exercise. Gerst, 2006
STUDIES WITH ADULTS
1-d experi- 25-30 yr coffee; decaf <18 mg; 75 mg In the supine but not seated position, coffee but not decaf increased high frequencies of HR vari- Monda et al.,
ment n=20 (10 M) [<0.3, 1.1 ability power spectral analysis; no modification of low frequencies. [1 cup espresso: <18 mg in 2009
(Italy) mg/kg] decaf; 75 mg in caffeinated]
1-d experi- 18-35 yr pure caffeine 0, 50, 150, 450 Increased systolic and diastolic BP and slightly (NS) decreased HR at 150 or 450 mg; produced Childs and de
ment (USA) n=102 (51 mg feelings of arousal, positive mood, increased the number of hits and decreased reaction times in a Wit, 2006
M) [0.7, 2.1, 6.4 vigilance task; 450 mg impaired performance on a memory task and caused anxiety feelings (50
mg/kg] and 150 mg caused slight increase in anxiety).
1-d experi- 19-28 yr pure caffeine 75 mg Caffeine decreased cerebral blood flow non-significantly in habitual consumers and greatly in Kennedy and
ment (UK) n=20 (10 M) [1.1 mg/kg] non-habitual consumers. Haskell, 2011
1-d experi- 22-40 yr cola ± candy 76 mg (cola + Cola intake decreased middle cerebral artery velocity and increased feelings of pleasure and en- Watson et al.,
ment n=11 F bar candy); 10 mg ergy but 4-choice reaction time was unaffected; systolic BP increased (up to 15± 2 mm Hg with 2000a
(UK) (candy) [1.1, caffeine and +l2 ± 2 mm Hg with caffeine-free beverage); alertness increased
0.14 mg/kg]
1-d experi- 22±2 yr sugar-free ED 80 mg ED consumption increased platelet aggregation; decreased endothelial function (by peripheral Worthley et
ment n=50 (34 M) [1.1 mg/kg] arterial tonometry); increased mean arterial pressure; HR was unaffected. [ED not identified but al., 2010
(Australia) may be Red Bull: 250-mL can contained 80 mg caffeine, 1000 mg taurine, and 600 mg glucuro-
nolactone]
130
1-d experi- 26 ± 4 yr ED; exercise 80 mg Stroke volume was influenced only in the "Red Bull group", mainly due to a reduced endsystolic Baum and
ment n=13 M [1.1 mg/kg] diameter and volume; in this group the peak late diastolic inflow in the regeneration period was Weiss, 2001
(Germany) higher compared with pre-exercise levels; this was also seen in the caffeine group but without
effect on ventricular function.
1-d experi- 29 ± 3.2 yr coffee; decaf 80 mg Regular coffee, but not decaf, increased central systolic and diastolic BP from 96.2±9.9 to Karatzis et al.,
ment n=16 (8 M) [1.1 mg/kg] 101.1±10.1 mmHg, and from 72.6±9.4 to 76.5±9.0 mmHg, respectively; peripheral systolic BP 2005
(Greece) did not change significantly after either coffee; the augmentation index increased after regular
coffee consumption.
1-d experi- 28.9 ± 3.0 yr coffee; decaf 80 mg Decreased endothelium-dependent flow-mediated dilatation of the brachial artery from caffeinated Papamichael
ment n=17 (9 M) [1.1 mg/kg] coffee; no effect of decaf. et al., 2005
(Greece)
1-d experi- 19.8 ± 1.6 yr ED [cold pres- 80 mg M had increased diastolic BP immediately after submersion of the hand in the 5 degrees C water, Ragsdale et
ment (USA) n1=68; sor test] [1.1 mg/kg] which was negated by the ED; no BP changes in F with or without ED; M and F had increased al., 2010
n2=21 M+F pain tolerance. [ED=Red Bull]
1-d experi- 25 ± 2 yr caffeine, all 100 mg No changes in ventricular function in habituated non-smokers after caffeine intake; caffeine po- Giacomin et
ment n=45 (60% sources; [1.4 mg/kg] tentiated the negative effect of cigarette smoking by impairing both left and right ventrivilar dia- al., 2008
(Italy) M) smoking stolic function.
1-d experi- 42 ± 13 yr pure caffeine 100 mg Caffeine increased BP, early systolic wave intensity and wave speed, but late-systolic wave inten- Swampillai et
ment n=17; c=10 [1.4 mg/kg] sity and mid-systolic reflections were unchanged; in 11 smokers studied before and after smoking al., 2006
(UK) M+F one cigarette, BP and arterial stiffness increased but wave intensity was unchanged; no changes in
controls.
1-d experi- 37 ± 7 yr pure caffeine; 100, 500 mg Mean workday BP and HR were higher when 500 mg caffeine was consumed; dose-related differ- Lane et al.,
ment (USA) n=21 M+F stress [1.4, 7.1] ences were 4 mm Hg for systolic BP and 3 mm Hg for diastolic BP, and were 3 bpm for HR. 1998
1-d experi- 23-32 yr pure caffeine 100, 200 mg Increased BP and decreased HR variability without change in HR. Sondermeijer
ment n=10 (6 M) [1.4, 2.9 mg/kg] et al., 2002
(Australia)
1-d experi- 25 ± 3 yr pure caffeine 100, 200 mg No differences in HR variability parameters up to 90 min after caffeine ingestion in young and Rauh et al.,
ment n=30 M [1.4, 2.9 mg/kg] healthy habitual caffeine consumers. 2006
(Germany)
1-d experi- Adult coffee; cola 45 mg (cola); Intake of 45 mg caffeine had no significant effect on global VMCA (velocity in the middle cere- Perod et al.,
ment (USA) n=?? 117 mg (coffee) bral artery), but 117 mg suppressed VMCA by 5.8%. 2000
[0.6, 1.7 mg/kg]
131
1-d experi- 25-49 yr decaf espresso 1, 2 cups [0.07, In the hour after ingestion of 2 cups, brachial artery flow-mediated dilation (indicator of endothe- Buscemi et al.,
ment n=15 (8 M) 0.14 mg/kg] lial function) increased compared to intake of 1 cup; BP did not differ between groups, and basal 2009
(Italy) HR was lower in the 2-cup group at baseline and 60 min. [Italian espresso 5 mg caffeine per 25
mL cup]
1-d experi- Adult pure caffeine 125, 325 mg Decreased hand steadiness, reaction time, and fatigue, and increased BP, HR, and tension not in- Nash et al.,
ment (USA) n=52 M+F [1.8, 4.6 mg/kg] fluenced by dosing instructions; only those uninformed of the placebo condition had BP and vigor 2002
increases at 125 mg and impaired hand steadiness at 325 mg.
1-d experi- 21-49 yr coffee; decaf 1 cup (130 or 5 Systolic and diastolic BP were higher in the hour after coffee ingestion; HR increased 30 min after Buscemi et al.,
ment n=40 (19 M) mg) [1.9, 0.07 ingestion; increase of QT duration was seen one hour after decaf but not coffee ingestion; QT in- 2011
(Italy) mg/kg] terval corrected for HR did not change following coffee or decaf ingestion. [Italian espresso caf-
feine per 25 mL cup: 5 mg in decaf; 130 mg in caffeinated]
1-d experi- 25-49 yr coffee; decaf 1 cup caffeinated Caffeinated espresso, but not decaf, caused progressive decrease in endothelial function (meas- Buscemi et al.,
ment 20 (10 M) or decaf espresso ured by brachial artery flow-mediated dilation), increased both systolic and diastolic BP, and de- 2010a
(Italy) [1.9, 0.07 creased blood insulin and C-peptide; blood glucose was unaffected. [Italian espresso caffeine per
mg/kg] 25 mL cup: 5 mg in decaf; 130 mg in caffeinated]
1-d experi- 20.4 ± 0.70 ED 134 mg During 2nd and 3rd hr of 3-hr test, ED increased VO2 and energy expenditure; mean systolic BP Rashti et al.,
ment (USA) yr [1.9 mg/kg] was higher with ED; no differences were seen in HR, diastolic BP, or profile of mood states at any 2009
n=10 F time point.
1-d experi- 19-49 yr pure caffeine 2, 4 mg/kg Increased diastolic BP, plasma epinephrine levels, and free fatty acids; response at both doses. Benowitz et
ment (USA) n=12 (6 M) al., 1995
1-d experi- 20-39 yr Coffee [hyper- 1 cup (148-314 Arabian, Turkish, American, and instant coffee all had the potential to cause a BP lowering effect. Awaad et al.,
ment (Saudi n=400 (200 tension] mg) [Caffeine in one 250 mL cup of coffee 314 mg in Arabian, 296 mg in Turkish and 148 mg in 2010
Arabia) M) [2.1-4.5 mg/kg] American coffee]
1-d experi- 18-62, 20-62 pure caffeine; 2 mg/kg BP increased, more so for the false information (re caffeine content) group; correctly informed Schneider et
ment yr decaf participants had nonsignificant subjective well-being changes (alertness, calmness). al., 2006
(Germany) n=90 M+F
1-d experi- n1=23 ± 5.0 coffee; stress 140 mg Systolic BP only increased in caffeine-naïve participants; diastolic BP decreased from caffeine + Kennedy et
ment yr, 10 F; [2.0 mg/kg] stress; alertness increased; HR increase. al., 2008
(UK) n2=25 ± 6 yr
10 F
1-d experi- 26 ± 2.6 yr coffee; decaf 150 mg Carotid femoral pulse wave velocity and arterial wave reflection increased (arterial stiffness). Mahmud and
ment n=7 (3 M) [2.1 mg/kg] Feely, 2001
(Ireland)
132
1-d experi- 45-70 yr tea, black; 3 cups (~150 Endothelium-dependent dilatation was increased by the meal with tea but by tea alone; systolic BP Hodgson et
ment n=20 (sex high-fat meal mg) was increased by tea alone, meal with water, and meal with tea; eating a meal negated the acute al., 2005
(Australia) NR) [CVD] [2.1 mg/kg] increase in systolic BP from tea while fasting. [2.2 g of black tea leaves in 250 mL of water, ~50
mg caffeine/cup]
1-d experi- 45-70 yr tea, black 3 cups (~150 Drinking black tea caused a small acute increase in total plasma homocysteine that was not en- Hodgson et
ment n=20 (17 M) mg) hanced in the non-fasting state. [each cup of tea had ~50 mg caffeine and 300 mg polyphenols] al., 2007
(Australia) [2.1 mg/kg]
1-d experi- 18-24 yr coffee; decaf 150 mg; 9 mg BP increase; mood improved; effects caused only by caffeinated coffee. Tse et al.,
ment (China) n=77 (35 M) [2.1 mg/kg] 2009
1-d experi- 27±10 yr pure caffeine 2.5 mg/kg i.v. Cerebral blood flow decrease. Chen and Par-
ment (USA) n=14 (4 M) rish, 2009b
1-d; 7-d ex- 25-73 yr pure caffeine; 1 d: 180 mg; 7 d: Tea caused greater BP increase than pure caffeine; difference was significant for 1-d exposure Hodgson et
periment n=20 M tea, black; tea, 5 x 50 mg/d after 30 min but not 60 min (green tea +5.5/3.1 mmHg systolic/diastolic; black tea +10.7/5.1 al., 1999
(Australia) green [hyper- [2.6, 3.6 mg/kg] mmHg), and not for 24-hr BP after 7 d (green tea +1.7/0.9 mmHg; black tea +0.7/-0.7 mmHg).
tension]
1-d experi- ~25 ± 3 yr caffeine, all 200 mg Cerebral blood flow decrease; caffeine non-users had slightly greater effect than habitual users. Sedlacik et al.,
ment n=27 (14 M) sources [2.9 mg/kg] 2008
(Germany)
1-d experi- Adult pure caffeine 200 mg Increased systolic, diastolic and mean BP; decreased arterial compliance, but HR, peripheral resis- Schutte et al.,
ment (South n=38 M [2.9 mg/kg] tance, stroke volume and cardiac output did not change. 2003
Africa)
1-d experi- 61 ± 9 yr pure caffeine; 200 mg Resting myocardial blood flow (MBF) was not affected by caffeine; exercise-induced MBF re- Namdar et al.,
ment (Swit- n=15; c=15 exercise [2.9 mg/kg] sponse decreased after caffeine in controls, remote and in stenotic segments; caffeine decreased 2009
zerland) M+F [CVD] myocardial perfusion reserve (MPR) by 14% in controls; in coronary arterial disease patients
MPR decreased by 18%.
1-d experi- 33 ± 7 yr pure caffeine 200 mg Cerebral blood flow decrease. Perthen et al.,
ment (USA) n=10 (5 M) [2.9 mg/kg] 2008
1-d experi- Adult pure caffeine 200 mg Caffeine non-significantly increased hand tremor; increased systolic BP (p< 0.001, F- test) and Humayun et
ment (USA) n=17 (14 M) [2.9 mg/kg] diastolic BP (=0.002, F-test) and pulse rate (p=0.002, F-test). al., 1997
1-d experi- 23-41 yr pure caffeine 200 mg Cerebral blood flow decrease; BOLD response altered. Rack-Gomer
ment (USA) n=9 (5 M) [2.9 mg/kg] et al., 2009
133
1-d, 7-d ex- 20-39 yr ED 200 mg/d Although no significant ECG changes were observed, HR increased 5-7 beats/min and systolic BP Steinke et al.,
periment n=15 (7 M) [2.9 mg/kg] increased 10 mm Hg after ED consumption. [ED not identified, but its contents were, per 250 mL 2009
(USA) can: 1000 mg of taurine, 100 mg of caffeine, sugars and vitamins/nutritional supplements]
1-d experi- 18-40 yr coffee; decaf 222 mg Cerebral blood flow decrease; cognitive/psychomotor improvement. Bendlin et al.,
ment (USA) n=21 (7 M) [3.2 mg/kg] 2007
1-d experi- n1=24 ± 0.6 pure caffeine; 3.3 mg/kg BP increased with caffeine or stress in subjects at low and high risk for hypertension (caffeine: + Shepard et al.,
ment (USA) yr, 20 M; stress [familial 5/4 vs. + 3/3 mm Hg; Stress: + 4/1 vs. + 7/3 mm Hg); stress + caffeine caused additive increases 2000
n2=24 ± 0.5 hypertension] in BP (Low Risk + 9/5 mm Hg, High Risk + 10/6 mm Hg); plasma cortisol or corticosterone in-
yr, 11 M creased.
1-d experi- 30-45 yr pure caffeine; 3.3 mg/kg Increased systolic and diastolic BP and peripheral vascular resistance, decreased HR, and greater Sung et al.,
ment (USA) n=20 M; exercise [hy- exercise-induced increase in HR and systolic BP. 1995
c=12 M pertension]
1-d experi- 30-45 yr pure caffeine 3.3 mg/kg Hypertensive group had persistent elevation in diastolic BP for 3 h, whereas the increment of dia- Sung et al.,
ment (USA) n=18 M; [hypertension] stolic BP became smaller in the normotensive group after 90 min. 1994
c=12 M
1-d experi- M=27±0.8 pure caffeine; 3.3 mg/kg Increased systolic and diastolic BP in F (4.5, 3.3 mm Hg) and M (4.1, 3.8 mm Hg); M had in- Hartley et al.,
ment (USA) yr; F=29±1 stress creased vascular resistance with no difference in cardiac output; F had increased stroke volume 2004
yr and cardiac output; the effect of caffeine on BP was similar at rest and during stress.
n=37; c=40
1-d experi- mean 26-39 pure caffeine 3.3 mg/kg Caffeine raised systolic and diastolic BP; strongest response was among men diagnosed with hy- Hartley et al.,
ment (USA) yr [hypertension] pertension, who had a pre-to-post-caffeine BP change >1.5x greater than the optimal group. 2000
n=182 M
1-d experi- 20-39 yr pure caffeine; 3.3 mg/kg Borderline hypertensive men had modestly larger BP increases to the task and a greater combined Lovallo et al.,
ment (USA) n=24 M stress [hyper- effect of caffeine plus the task (+15/+11 mmHg) than controls. 1996a
tension]
1-d experi- 20-35 yr pure caffeine 3.3 mg/kg Caffeine-induced changes in diastolic BP were 2-3x larger in borderline hypertensives than in Pincomb et al.,
ment (USA) n=24 M; [hypertension] controls (+8.4 vs. +3.8 mm Hg), and were due to increased systemic vascular resistance; BP 1996
c=24 M change seen in 96% of hypertensives; 33% of borderline subjects achieved hypertensive BP levels
after caffeine ingestion.
1-d experi- 29.2 ± 1.4 yr pure caffeine 240 mg BP increase; approximate entropy measurements showed that caffeine induced greater "random- Papaioannou
ment n=14 M [3.4 mg/kg] ness" in BP fluctuations et al., 2006
(Greece)
134
1-d experi- 19-30 yr ED; 240 mg Following exercise, final HR was higher for ED+ethanol and ED than without; post-exercise re- Wiklund et al.,
ment (Swe- n=10 (5 M) ED+ethanol [3.4 mg/kg] covery in HR and HR variability were slower if consuming ED+alcohol before exercise; no severe 2009
den) 0.4 g/kg; exer- cardiac arrhythmia but one subject had frequent premature atrial contractions starting ~10 min
cise after ED intake and lasting 40 min. [ED=Red Bull]
1-d experi- 21-25 yr pure caffeine 2 mg/kg; 240 mg Power spectral analysis of heartbeat R-R intervals showed transient increase in values of high Hibino et al.,
ment n=10 (9 M) [3.4 mg/kg] frequency power, suggesting an increase in vagal autonomic nerve activity; BP, surface body 1997
(Japan) temperature and HR were not significantly affected.
1-d experi- 20-35 coffee 3.5 mg/kg HR fell slightly after water but increased after caffeine (+ 16 beats/min, group x time interaction Stubbs and
ment n=8 (4 M) analysis of variance, p < 0.03), with peak responses at 40-60 min and a return to baseline by 120 Macdonald,
(UK) min. Calf blood flow fell slightly after caffeine. 1995
1-d experi- 20-70 yr pure caffeine 250 mg Increased aortic stiffness; enhanced wave reflection and velocity; BP increase; HR increase. Vlachopoulos
ment n=20 (17 M) [3.6 mg/kg] et al., 2003b
(Australia)
1-d experi- mean=21 yr pure caffeine 250 mg No cardiovascular effects (HR, systolic and diastolic BP); alertness increased; EEG changes; skin Barry et al.,
ment n=18 (5 M) [3.6 mg/kg] conductance increase. 2005
(Australia)
1-d experi- 21-72 yr pure caffeine 250 mg Older hypertensive subjects (58 ± 10.4 yr) had increased systolic and diastolic BP; non-responders Rachima-
ment n=23 (17 M) [hypertension] [3.6 mg/kg] were younger (44.5 ± 15.8 years); for 60 min after intake both groups had decreased HR, diuresis, Maoz et al.,
(Israel) and natriuresis. 1998
1-d experi- n=48-86 yr; pure caffeine 250 mg Significant fall in cerebral blood flow and middle cerebral artery blood velocity compared to pla- Ragab et al.,
ment c=52-85 yr [stroke his- [3.6 mg/kg] cebo. 2004
(UK) n=19 (11 M); tory]
c=10 (6 M)
1-d experi- 48-86 yr pure caffeine 250 mg Reduced middle cerebral artery diameter; effects similar in patients and controls; cerebral blood Lunt et al.,
ment n=19; c=10 [stroke his- [3.6 mg/kg] flow decrease. 2004
(UK) (sex NS) tory]
1-d experi- 60 ± 3 yr pure caffeine 250 mg BP increase; HR increase; caffeine increased aortic stiffness in hypertensive patients. Vlachopoulos
ment n=12 (7 M) [treated hyper- [3.6 mg/kg] et al., 2003a
(Greece) tension]
1-d, 6-d ex- 21-28 yr pure caffeine 250 mg Acute caffeine ingestion and orthostasis were both associated with a reduction in middle cerebral Debrah et al.,
periment n=9 (4 M) [3.6 mg/kg] artery velocity (Vmca) and a rise in mean arterial pressure and adrenaline levels; the effects on 1995
(UK) mean arterial pressure and adrenaline but not on Vmca were lost with sustained caffeine intake.
135
1-d experi- 24-64 yr pure caffeine 250 mg Caffeine reduced cerebral blood flow (CBF) by 18-23% in all subjects; withdrawal CBF in high Field et al.,
ment (USA) n=20 (16 M) [3.6 mg/kg] users exceeded that in low users; mean post-caffeine CBF reduction in anterior gray matter was 2003
26% in high users versus 19% in low users.
1-d experi- 18-50 yr pure caffeine 250 mg Cerebral blood flow decrease; high users (950 mg/day habitual) had less effect than low or mod- Addicott et al.,
ment (USA) n=45 (20 M) [3.6 mg/kg] erate (45, 405 mg/d habitual) chronic users. 2009a
1-d experi- 34-35 ± 6.1 pure caffeine; 250 mg as triple In non-users, a triple espresso (but not i.v. caffeine) further increased systolic BP (9±6.3 mm Hg; Sudano et al.,
ment (Swit- yr coffee; stress espresso or i.v. P=0.003) during mental stress; in users, the stress-induced BP increase was blunted (+4±3.9 mm 2005
zerland) n=15 (9 M) [3.6 mg/kg] Hg; P=NS); cold pressor test was not influenced by coffee drinking in either group.
1-d experi- 38-73 yr pure caffeine; 4 mg/kg i.v. Heart failure patients had increased exercise time, peak minute ventilation, and resting and peak Notarius et al.,
ment n=10 M+F exercise BP; peak oxygen consumption was unaffected. 2006b
(Canada) [CVD]
1-d experi- 51.1 ± 3.2 yr pure caffeine; 4 mg/kg i.v. Systolic and mean BP, 10 min after exercise, were higher on the caffeine than on the vehicle day Notarius et al.,
ment n=14 (13 M) exercise (by 9 ± 3 and 6 ± 2 mm Hg, respectively; p<0.05), as was HR (100 ± 5 vs. 93 ± 4 beats/min; 2006a
(Canada) p<0.05).
1-d experi- 21-55 yr caffeine, in 280 mg The resting metabolic rate and systolic BP AUCs increased significantly in the herbal supplement Roberts et al.,
ment (USA) n=16 (7 M) supplement [4.0 mg/kg] group vs. placebo: the AUC and average rise in systolic BP over 2 hr were 10.3±14 mm Hg/hr and 2005
mix; guarana 3.7±4.4 mm Hg, respectively.
1-d experi- 18-45 yr pure caffeine 300 mg Caffeine increased central systolic and diastolic BP by 7 ± 3 (P <.01) and 3 ± 2 mm Hg (P <.05), Waring et al.,
ment n=20 (8 M) [4.3 mg/kg] respectively at 45 min, but had no effect on peripheral BP; caffeine caused augmentation index to 2003
(UK) increase by 7 ± 2 and 0 ± 1%, respectively (P <.05), and pressure amplification to decrease by 1.0
± 0.1 v 0.2 ± 0.2 (P <.001) placebo at 45 min; this suggests that the effects of caffeine on BP may
be significantly underestimated by measurement of BP at the brachial artery.
1-d experi- 25-59 yr pure caffeine 300 mg Cerebral blood flow decrease. Blaha et al.,
ment (USA) n=17 (7 M) [4.3 mg/kg] 2007
1-d experi- Adult caffeine, all 4.5 mg/kg fat- Caffeine increased systolic BP and diastolic BP at rest and during exercise: systolic BP during Kaminsky et
ment (USA) n1=8 M; sources; exer- free mass exercise 7-8 mmHg at all exercise intensities, diastolic BP 4 mmHg at highest exercise intensity. al., 1998
n2=8 M; cise There was a wide range in the resting BP response (combined SBP and DBP was 10-39 mmHg).
habituated No differences in effect between regular consumers and non-consumers.
light user
1-d experi- 26.9 ± 1.4 yr pure caffeine; 5 mg/kg Increased O2 uptake, energy expenditure, systolic, diastolic, and mean arterial BP (p < 0.05); ef- Engels et al.,
ment (USA) n=8 (7 M) exercise fects were similar during constant-load, light intensity cycling and at rest; respiratory exchange 1999
ratio, cardiac output, HR, stroke volume, and systemic vascular resistance were not significantly
affected.
136
1-d experi- 21-26 yr pure caffeine 5 mg/kg Electrocardiogram QRS duration prolonged in 9 of 11 subjects at 90 min and in 8 of 9 after 3 hr; Donnerstein et
ment (USA) n=12 (6 M) no significant change in P-wave duration or HR. al., 1998
1-d experi- 18-43 yr Caffeine + 5 mg/kg Pre-exercise caffeine was associated with a significant increase of HR variability, especially in the Yeragani et
ment (USA) n=11 (6 M) caffeine-free high-frequency range (0.15-0.5 Hz), and also approximate entropy (APEN), which is usually atal., 2005
diet cola; tributed to cardiac vagal function; during progressive exercise, caffeine intake resulted in a greater
exercise decrease of HF power as well as HR APEN; caffeine also was associated with significantly higher
LF power during exercise compared to the placebo condition.
1-d experi- 21-28 yr pure caffeine 5 mg/kg F had significant echo changes in (echocardiogram) mitral leaflet morphology and auscultation Friedman-
ment (USA) n=12 (6 M) suggestive of mitral valve prolapse; F and M had increased afterload and contractility. Kelly et al.,
1998
1-d; 7-d ex- 22 ± 4.8 yr pure caffeine 5 mg/kg Both acute and chronic consumption of caffeine led to impaired cardiovascular function (de- Berry et al.,
periment n=16 M+F creased resting HR and an inability to maintain mean arterial pressure) after exposure to an or- 2003
(Australia) thostatic challenge (+75 degree head-up tilt); HR increase after head tilt.
1-d experi- 18-22 yr; 50- pure caffeine 5 mg/kg fat-free Systolic and diastolic BP increased significantly in the older F, but only diastolic BP increased in Arciero and
ment (USA) 67 yr mass younger F; HR decreased significantly in both groups; feelings of tension and vigor increased and Ormsbee,
n1=10 F; feelings of fatigue decreased (p< 0.05) in younger F, but depression decreased in older F; the level 2009
n2=10 F of physical activity was inversely related to change in DBP following caffeine ingestion in
younger F.
1-d experi- 19-26 yr; 65- pure caffeine 5 mg/kg lean Systolic and diastolic BP increased in old but not young men; tension and anger decreased in old Arciero et al.,
ment (USA) 80 yr mass men, while anger increased in young men; norepinephrine increased in old men only. 1998
n1=10 M;
n2=10 M
1-d experi- 22-29 yr pure caffeine 400 mg BP increase; caffeine-naive subjects had persistent elevations in systolic and diastolic BP 3 hr Ammar et al.,
ment (USA) n=10 (5 M) [5.7 mg/kg] after caffeine ingestion; no significant changes in ECG variables . 2001
1-d experi- 18-39 yr pure caffeine 400 mg There was a significant caffeine by sleep stage interaction for electrocardiogram LF/HF ratios, Bonnet et al.,
ment n=15 M+F [asleep] [5.7 mg/kg] which were higher during REM following caffeine dosing. There was also a significant caffeine 2005b
(USA) by sleep stage interaction for QTvi (QT variability normalized), which was also higher during
REM following caffeine administration. These effects during REM are most likely due to the
sympathetic effects of caffeine, and indicate that excessive caffeine intake may result in adverse
cardiovascular events in vulnerable subjects.
1-d experi- 23.4 ± 3.6 yr pure caffeine; 6 mg/kg Increased HR (+10 beats/min), systolic BP (+ 8-10 mmHg), and rate-pressure product with caf- Astorino et al.,
ment (USA) n=22 M exercise feine ingestion versus placebo, but no change in diastolic BP across time or treatment after resis- 2007
tance training.
137
1-d experi- 30 ± 0.3 yr pure caffeine; 6 mg/kg Before exercise, caffeine increased both systolic BP (17%) and mean arterial pressure (11%) Daniels et al.,
ment (USA) n=10 (3 M) exercise without affecting forearm blood flow (FBF) or forearm vascular conductance (FVC). During dy- 1998
namic exercise, caffeine attenuated the increase in FBF (53%) and FVC (50%) and accentuated
exercise-induced increases in angiotensin II (44%).
1-d experi- Adult pure caffeine 400 mg (6.1 No effect on ECG P-wave variables. Caron et al.,
ment (USA) n=10 M+F mg/kg mean) 2001
1-d experi- 20.9 ± 1.7 yr caffeine, in 450 mg 7/10 subjects were responders to JF (had a higher AUC for VO2); mean systolic BP was higher (p Hoffman et
ment (USA) n=10 (8 M) supplement [6.4 mg/kg] < 0.05) in JF (118 ± 7 mmHg) than Placebo (115 ± 8 mmHg) in both the total sample and the sub- al., 2006
mix group of responders; no differences in average HR or diastolic BP in the total sample or the re-
sponders. [JavaFittrade mark (JF) coffee, containing 450 mg of caffeine, 1200 mg of garcinia
cambogia, 360 mg of citrus aurantium extract, and 225 μg of chromium polynicotinate]
1-d experi- 22-45 yr pure caffeine; 500 mg Caffeine raised average ambulatory BP during the workday and evening by 4/3 mm Hg and re- Lane et al.,
ment (USA) n=47 (27 M) stress [7.1 mg/kg] duced average HR by 2 bpm; increased by 32% epinephrine excreted during the workday and the 2002
evening; amplified the increases in BP and HR associated with higher levels of self-reported stress
during the day; effects were undiminished through the evening until bedtime.
1-d, 6-7 d 18-52 yr pure caffeine 5.25 mg/kg (in 3 BP increased immediately after caffeine ingestion; during abstinence BP decrease was smaller in James, 1994c
experiment n=36 M+F doses) those with 6-d intake (6.0/5.2 mmHg) than with 1-d intake (7.7/6.8 mmHg).
(Australia)
5-d experi- n1=65.3± instant coffee; 4.7± 1.1 cups/d In the regular coffee (not the decaf group) group, parasympathetic activity increased by up to 96% Richardson et
ment 12.1 yr; coffee; decaf coffee (352.5± (P = 0.04) after 5 d; no detrimental effect of regular coffee on cardiac rhythm post-STEMI (post al., 2009
(UK) n2=65.6± [ST-segment 90 mg); 4.5± 1.3 ST-segment elevation MI).
10.6 yr elevation MI] cups/d decaf
n=103 M+F [5.0 mg/kg/d]
5 + 1 d ex- 28± 1 yr pure caffeine 300 or 600 for 5 Habitual caffeine consumers (low and high tolerance groups) had BP responses to caffeine con- Farag et al.,
periment n=85 (47 M) d, then 750 mg sumed after a week of placebo; the low tolerance group showed increases from 300 mg/d in sys- 2005a
(USA) (each in 3 doses) tolic/diastolic BP during the waking hours (2.8± 1.1, p=0.01; 2.2± 0.9, p=0.02) and in systolic BP
[4.3, 11 mg/kg] during sleep (2.3± 1, p=0.03).
5 d + 1 d ex- 28 ± 0.6 yr pure caffeine 300, 600 mg/d Systolic/diastolic BP increases as a result of 250 mg of caffeine remained significant at all levels Lovallo et al.,
periment n=97 (49 M) (in 3 doses); of previous daily consumption (0, 300, 600 mg). Although half the subjects had complete loss of 2004
(USA) then 500 mg systolic and diastolic BP responses to the 250 mg challenge doses, the other half showed no loss
(split dose) [4.3- in BP response, even after using 600 mg of caffeine per day for the previous 5 days. The sexes did
8.6 mg/kg/d] not differ in degree of tolerance formation.
138
6-d experi- 21-35 yr pure caffeine; 300, 600 mg/d, Caffeine ingestion before stress caused both M and F to have enhanced hemodynamic responses Farag et al.,
ment n=47 (25 M) stress then 500 mg to the stressor; associated with an increase in cardiac index and a drop in the peripheral resistance 2006
(USA) (split dose) [4.3, index.
11 mg/kg/d]
6-d experi- 21-35 yr pure caffeine 300, 600 mg/d, BP increase (≤3.5± 3 mm Hg systolic; 2.8± 2.4 mm Hg diastolic); half of the subjects developed Farag et al.,
ment n=43 (21 M) then 500 mg tolerance to the pressor effect of caffeine, but for others peripheral resistance increased as caffeine 2005b
(USA) (split dose) [4.3, dose increased.
11 mg/kg/d]
6 + 1 d ex- 18-52 yr pure caffeine; 5.25 mg/kg/d (in BP increase was additive for caffeine + stress; following habitual caffeine consumption of caf- James, 1994b
periment n=36 (18 M) stress 3 doses) feine, BP effects were diminished (indicative of tolerance) but not eliminated; HR increase.
(Australia)
7-d experi- 17-52 yr pure caffeine 5.25 mg/kg/d (in Finapres measurements of BP, cardiac output, and total peripheral resistance showed that caffeine James and
ment (mean=19 3 doses) produced persistent BP increases with a vascular hemodynamic profile. Gregg, 2004b
(Ireland) yr)
n=96 (42 M)
7-d experi- 21-27 yr pure caffeine 750 mg (in 3 Diastolic BP increased 24 hr after the first intake, but not on subsequent days; platelet aggregation Cavalcante et
ment n=13 M+F doses) for 7 d tests did not reveal significant alterations at any time during the study. al., 2000
(Brazil) [11 mg/kg/d]
7-d experi- 29-65 yr coffee; folic 600 mL/d (~4 The homocysteine increasing effect of coffee was particularly seen in individuals with the homo- Strandhagen et
ment n=120 (26 acid cups/d) zygous 677TT genotype, but the A1298C polymorphism had no effect. Intake of 200 µg folic al., 2004a
(Sweden) M) [5.7 mg/kg/d] acid/d decreases the homocysteine effect. [No info on caffeine per cup; assume 100 mg/cup]
7-d experi- 35-49 yr; 50- pure caffeine; 250 mg; 240 mg Caffeine resulted in an increase in BP in healthy, normotensive, young M and F and older F (sys- Farag et al.,
ment 64 yr OC (in 3 doses) [3.4, tolic 4± 0.6; diastolic 3± 0.4); non-significant increase in older M (2± 1.0, p=0.1). 2010
(USA) n=165 M+F 3.6 mg/kg/d]
8-d experi- 23-38 yr pure caffeine 400 mg/d (split In caffeine-habituated and naïve subjects, caffeine decreased cerebral artery blood velocity (more Watson et al.,
ment n=12 (6 M) dose) for 7 d, for caffeine-naïve); systolic BP was increased similarly in two groups but more sustained over 2002
(UK) then 200 mg time in naïve subjects; cognitive performance unaffected; chronic consumers were more tense at
[5.7 mg/kg/d] baseline.
14-d experi- 54-89 yr Coffee 300 mg/d Hypertensive group mean 24-hr systolic/diastolic BP was greater by 4.8/3.0 mm Hg in coffee Rakic et al.,
ment n=26; c=22 [hypertension] [4.3 mg/kg/d] drinkers than in abstainers; no differences between abstainers and coffee drinkers in the nor- 1999
(Australia) M+F motensive group.
139
14-d experi- 19-65 yr pure caffeine; 870 mg/d (as 6 19% increase in plasma homocysteine 4 hr after consumption of 0.45 L coffee vs. placebo; pure Verhoef et al.,
ment n=48 (21 M) coffee doses) in coffee caffeine had a much weaker acute effect on homocysteine (4%; P = 0.09). Effects of caffeine were 2002
(The Nether- or capsules stronger in F than in M, but the effects of coffee did not differ significantly between M and F.
lands) [12 mg/kg/d]
14-d experi- 43± 11 yr coffee, unfil- 1 L/d (~0.7-1 g Consumption of 1 L/d unfiltered coffee for 2 wk significantly raised fasting plasma homocysteine Grubben et al.,
ment (The n=64 (31 M) tered caffeine/d) concentrations (10%). 2000
Netherlands) [10-14 mg/kg/d]
28-d experi- 18-53 yr coffee 1 L/d (~1 g/d) Increased homocysteine concentrations in 24 of 26 individuals (1.5 μmol/L, 18%); circulating Urgert et al.,
ment (The n=26 (10 M) [14 mg/kg/d] concentrations of vitamin B-6, vitamin B-12, and folate were unaffected. 2000
Netherlands)
28-d experi- 29.7± 1.2 yr caffeinated 288 mg (as 4
Habitual coffee consumption was related to baseline systolic BP and increased HR and von Wille- Hamer et al.,
ment n=85 M drinks; pure doses)brand factor antigen (inflammation marker) responses to mental stress; after 4 weeks of substitut- 2006
(UK) caffeine [4.1 mg/kg/d]
ing caffeine for coffee these effects persisted but baseline systolic BP had decreased.
42-d experi- 24-69 yr coffee 0, 1-3, ≥4 cups/d
Abstention from coffee for 6 wk in participants who had been drinking ~4 cups/d of filtered coffee Christensen et
ment n=191 M+F [5.7 mg/kg/d]
for the past year was associated with a decrease in the total homocysteine concentration and a al., 2001
(Norway) decrease in the total cholesterol concentration (97% of participants consumed filtered coffee).
[No info on caffeine per cup coffee; assume 100 mg/cup]
42-d experi- 47.77± 3.46 coffee; decaf 1-11 cups/d Decreased caffeine intake for 6 wk had no effect on palpitation scores or ventricular premature Newby et al.,
ment yr [arrhythmia] [1.4-14 mg/kg/d] beat frequencies [arrhythmia consisted of idiopathic ventricular premature beats] [No info on 1996
(UK) n=13 (1 M) caffeine per cup coffee; assume 100 mg/cup]
AUC=area under the curve; BP=blood pressure; CVD=cardiovascular disease; ECG=electrocardiogram; EEG=electroencephalogram; ED=energy drink; HR=heart rate;
RER=respiratory exchange ratio
140
TABLE 5-2. Cardiovascular Effects of Caffeine in Humans – Case Reports and Epidemiological Studies
Case report (The 15 yr; 17 yr caffeine, in ~2.1 g; 3.5 g Sinus tachycardia; GI irritation or pain; hypokalemia; nausea or vomiting; plasma glucose
Kromhout et
Netherlands) n=2 M supplement [30, 50 mg/kg] increase. [Supplement='herbal energy capsules' containing 200 mg each] al., 2008
Case report 15 yr; 32 yr pure caffeine >10 g Cardiac arrest; sinus tachycardia; anxiety/irritability; nausea or vomiting; premature death;
Shum et al.,
(USA) n=2 F [140 mg/kg] seizures or convulsions. 1997
Case report 17 yrpure caffeine 68 g Sinus and ventricular tachycardia from intake of 340 tablets of 200 mg caffeine. Fujiyoshi et
(Japan) n=1 F [970 mg/kg] al., 2008
Case report 16 yr ED 320-400 mg/d
Intake for 7 days resulted in nausea, dizziness, transient loss of consciousness, blurred vi- Terlizzi et al.,
(Italy) n=1 F [5.3-6.7 mg/kg]
sion, sleep deprivation; postural tachycardia syndrome; HR increase [ED=Red Bull] 2008
Cohort prospec- 9-10 yr at
caffeine, all 9.2± 0.3, 11.9±
Higher calorie and caffeine intake were associated with hypertension incidence: mean intake Obarzanek et
tive (8 yr follow- baseline sources 1.7 mg/1000 kcal
(mg/1000 kcal) was 11.9± 1.7 for those who developed hypertension vs. 9.2± 0.3 (p=0.095) al., 2010
up) (USA) n=2368 F for those who did not.
Cross-sectional 8-10 yr caffeine, all 0, ≤10, 20, 30, 40, Caffeine intake was not associated with BP in pre-adolescent African American girls. [As- Reddy et al.,
(USA) n=303 F sources 50, 100, >100 sumed a BW of 35 kg for dose estimates.] 2008
mg/d
[0.3 to >3 mg/kg]
Cross-sectional 15-19 yr caffeine, all 0-50, >50-100, The positive association between systolic BP and caffeine category varied by race, being Savoca et al.,
(USA) n=159 M+F sources >100 mg/d [0.8 to higher in African Americans consuming >100 mg/d of caffeine. [Assumed a BW of 65 kg 2004
>1.5 mg/kg/d] for dose estimates.]
Cross-sectional 15-19 yr caffeine, all 0-50, >50-100, The level of dietary caffeine was positively associated with daytime systolic and diastolic Savoca et al.,
(USA) n=82 M+F sources >100 mg/d [0.8 to BP; effect on systolic BP was most pronounced for African-American subjects. [Assumed a 2005
>1.5 mg/kg/d] BW of 65 kg for dose estimates.]
Cross-sectional 12-19 yr caffeine, all 71.5± 4.3 mg/d Caffeine intake was not associated with systolic BP in U.S. adolescents. [A BW of 40-70 kg Sugiyama et
(USA) n=4508 (50.9% sources [1.0-1.8 mg/kg/d] was assumed for 12-19 year old subjects to estimate a daily dose; no info on caffeine con- al., 2007
M) tent of food or drinks.]
STUDIES WITH ADULTS
Case report 23 yr ED; soda 305 mg Palpitations, chest tightness, increased BP and HR, supraventricular tachycardia. [ED=GNC Nagajothi et
(USA) n=1 F [4.4 mg/kg] Speed Shot; soda=Mountain Dew] al., 2008
Case report 25 yr ED [mitral 540 mg Intractable ventricular fibrillation; premature death. Cannon et al.,
(USA) n=1 F valve prolapse] [7.7 mg/kg] 2001
141
Case report 27 yr coffee 6 cups Palpitations; tachycardia with irregular rhythm; atrial fibrillation which spontaneously re- Artin et al.,
(USA) n=1 M [~ 8.6 mg/kg] verted to normal sinus rhythm. [No info on caffeine per cup; assume 100 mg] 2010
Case report 28 yr ED; exercise 640 mg Cardiac arrest; survived with medical intervention. [ED not identified; is likely Red Bull Berger and
(UK) n=1 M [9.1 mg/kg] based on the stated caffeine content] Alford, 2009
Case report 21 yr pure caffeine 10 g Hypokalemia, cardiac arrest, myoclonus, acidosis; premature death. Rudolph and
(Sweden) n=1 F [140 mg/kg] Knudsen,
2010
Case report 18 yr pure caffeine 10 g Cardiovascular collapse; sweating; survived after treatment with lidocaine and Kapur and
(USA) n=1 M [140 mg/kg] phenylephrine and hemodialysis; anxiety/irritability; nausea or vomiting. Smith, 2009
Case report 41 yr pure caffeine 50 g Multisystem organ failure; BP decrease; patient survived and made a complete recovery Holstege et al.,
(USA) n=1 F [710 mg/kg] after medical intervention. 2003
Case report 38 yr ED 400 mg/d Intake for 4 days caused headache, nausea, vomiting, hypertension, ruptured aneurysm of Argano et al.,
(Italy) n=1 M [5.7 mg/kg] the anterior communicating artery. [ED=Red Bull] 2011
Case report 51 yr Caffeine, in ~400-1000 mg/d Excessive caffeine intake for over a month resulted in severe heart palpitations, anxiety, Baghkhani
(USA) n=1 F supplement; [5.7-14 mg/kg/d] irritability; symptoms started after two days and worsened with time; resolved 7-10 d after and Jafari,
coffee; cola; discontinuing intake of herbal supplements. [ingredients (not brand name) of two supple- 2002
smoking ments taken were provided and both included caffeine, guarana, and kola nut]
Case report 42 yr caffeine, in 600 mg/d Excessive caffeine intake for over two months resulted in hypertensive retinopathy; BP in- Willis et al.,
(USA) n=1 M supplement [8.6 mg/kg] crease. [supplement=Hydroxycut, a caffeine-based ephedra-free weight loss supplement] 2006
Case report 36 yr caffeine, in 1.1-2 g/d Excessive caffeine intake for over two months resulted in malignant hypertension and aortic Ahmed, 2009
(Sweden) n=1 F supplement; [15-29 mg/kg/d] dissection. [supplement=Xenadrine EFX, a caffeine-based weight-loss supplement contain-
smoking ing a small amount of synephrine]
Case report 61 yr tea, oolong 2 to 3 L/d (28-42 Habitual excessive drinking of oolong tea resulted in atrioventricular block; ventricular Aizaki et al.,
(Japan) n=1 F [hypoalbu- mg/kg/d) tachycardia with syncope; hypokalemia. 1999
minemia]
Case-control 40-91 yr Espresso; cof- 0, ≤2, >2-4, >4 Coffee drinking was non-significantly associated with an increased risk of first acute MI Azevedo and
(Portugal) cases= 290; fee [family cups/d [≤0.5, 0.5- (AMI) in M with a family history of AMI, but there was a significant inverse association Barros, 2006
controls = 364 history of AMI] 1.2 mg/kg/d] with the occurrence of MI among M with no family history of AMI. [Caffeine intake =
M ≤34.3, 34.4-83.4, >83.5 mg per day]
Case-control ~57± 11 yr Coffee <1, 1, 2-3, ≥4 55% of cases (n = 1114) and 54% of controls (n = 1082) were carriers of the slow *1F allele Cornelis et al.,
(Costa Rica) cases=controls [CYP1A2 cups/d [<1.4-5.7 for CYP1A2, for whom the intake of ≥2 cups/d coffee [2.9 mg/kg/d] was associated with an 2006
= 2014 (74% genotype] mg/kg/d] increased risk of nonfatal MI. [No info on caffeine per cup coffee; assume 100 mg/cup]
M)
142
Case-control ~ 64± 8 yr; Coffee 0, 1-3, 4-6, 7-10, Previous MI, hypertension, heavy coffee consumption (>10 cups/d [14 mg/kg/d]; OR 55.7, de Vreede-
(The Nether- cases= 117 [CAD] >10 cups/d 95% CI 6.4-483), and a left ventricular ejection fraction <40% were independent risk indica- Swagemakers
lands) (84% M); con- [1.4 to >14 tors for sudden cardiac arrest in patients with CAD. [No info on caffeine per cup coffee; et al., 1999
trols = 144 mg/kg/d] assume 100 mg/cup]
(83% M)
Case-control Adult coffee <1, 1, 2–3, ≥4 Risk of MI was increased in slow metabolizers with intake of ≥2 cups/d [2.9 mg/kg/d], and El-Sohemy et
(Canada) cases= con- cups/d was greater in those <50 yr old; protective effect but no linear dose-response was seen in al., 2007
trols= 2014 [<1.4 to ≥5.7 fast metabolizers <50 yr old. [No info on caffeine per cup coffee; assume 100 mg/cup]
M+F mg/kg/d]
Case-control 20-49 yr caffeinated ≥5 cups/d (others Intake of ≥5 cups/d coffee and caffeinated medications increased risk for intracerebral hem- Feldmann et
(USA) cases= 217; drinks; caffein- NR); caffeine in orrhage. [No info on caffeine per cup coffee; assume 100 mg/cup] al., 2005
controls = 419 ated medication drugs NR
M+F [7.1 mg/kg/d]
Case-control 45-70 yr filtered or ≤2, 2.7-4, 4.7-6,
Increased incidence of first MI in M who consumed coffee; intake of ≥ 10 dL/d [6.7 cups or Hammar et al.,
(Sweden) cases= 1643 boiled coffee >6 cups/d ~10 mg/kg/d] had RR=1.93 (1.42-2.63) for filtered and 2.20 (1.17-4.15) for boiled coffee; 2003
controls = 2667 [<2.9 to >8.6
boiled coffee tended increase MI incidence in F; MI incidence was greater for boiled than
(~70% M) mg/kg/d] filtered coffee for M (RR=1.41; 1.07-1.80) and F (RR=1.63; 1.04-2.56). [150 mL/cup; no
info on caffeine per cup coffee; assume 100 mg/cup]
Case-control 55± 11 yr caffeine, all ≤151, 152-302, MI risk was increased for intake of ≥303 mg/d caffeine. Kabagambe et
(Costa Rica) cases= 889; sources 303-454, >454 al., 2007
controls = 1167 mg/d
M+F [2.1-6.5 mg/kg/d]
Case-control Adult coffee 0, 1, 2, 3, 4, ≥5 The results support the existence of a short term effect of coffee intake on increased death Marchioli et
(Italy) cases= 750; cups/d from CHD (≥3 cups /d for MI [4.3 mg/kg/d]; ≥ 5 cups/d [9.1 mg/kg/d] for ischemic stroke). al., 1996
controls = 750 [1.4 to ≥7.1 [No info on caffeine per cup coffee; assume 100 mg/cup]
M+F mg/kg/d]
Case-control cases= 57.7± coffee; decaf; Coffee: l-3 or >4 Coffee had no effect, but tea was associated with a lower risk of MI (OR for drinking 0 vs. ≥ Sesso et al.,
(USA) 9.6 yr (n=340); tea cups/d [1.4-5.7 1 cup/d was 0.56 (95% CI 0.35-0.90). [No info on caffeine per cup; assume 100 mg/cup as 1999
controls = mg/kg/d] coffee, 40 mg/cup tea; tea intake categories were 0, 1-3 cups/mo, 1-6 cups/wk, ≥1 cup/d]
57.7± 9.7 yr
(n=340) M+F
143
Case-control 25-79 yr coffee; decaf; ≤1, 1-2, >2-3, >3- The OR for acute MI risk for coffee intake (espresso and mocha) was ~1 up to 3 cups/d, but Tavani et al.,
(Italy) cases= 507 ethanol; smok- 5, ≥6 cups/d rose to 1.9 (95% CI: 1.1-3.3) for ≥ 6 cups/d. Moderate decaffeinated coffee and tea intake 2001a
(378 M); con- ing; tea [≤1.4 to ≥ 8.6 was not associated with AMI risk. Compared to non-smokers drinking ≤ 3 cups coffee/d,
trols = 478 mg/kg/d] OR=1.6 among non-smokers drinking >3 cups of coffee/d and 3.3 (95% CI: 2.1-5.0) among
(297 M) current smokers drinking ≤ 3 cups coffee/d. Compared to alcohol drinkers with a coffee
intake of ≤ 3 cups/d, alcohol non-drinkers with higher coffee intake had OR of 2.2, and
compared to non-smokers alcohol drinkers, the OR=3.3 in current smokers alcohol non-
drinkers. [No info on caffeine per cup coffee; assume 100 mg/cup]
Case-control 25-74 yr caffeinated 0-20, 20-275, High usual caffeine consumption (≥ 687 mg/d [9.8 mg/kg/d]) was associated with a mod- Weinmann et
(USA) cases= 362; drinks; smok- 275-687, 687- estly elevated risk of primary cardiac arrest [OR=1.44; 95% CI = 0.82-2.53]. The elevated al., 1997
controls = 581 ing 4120 mg/d risk appeared to be restricted to never-smokers (for ≥ 687 mg/d OR= 3.2; 95% CI = 1.3-8.1).
M+F [0.3-59 mg/kg/d]
Cohort prospec- 45-79 yr at coffee ≤ 1, 2, 3, 4, ≥5 Coffee consumption was not associated with increased rates of heart failure hospitalization Ahmed et al.,
tive (9 yr follow- baseline cups/d [≤1.4 to ≥ or mortality. [No info on caffeine per cup coffee; assume 100 mg/cup] 2009
up) (Sweden) n=37,315 M 7.1 mg/kg/d]
Cohort prospec- 25-79 yr caffeine, all per 100 mg/d Decreased caffeine consumption had no effect on BP. Chen et al.,
tive (18 mo fol-n=810 (~40% sources [per 1.4 mg/kg/d] 2010a
low-up) (USA) M)
Cohort prospec- 45 yr at caffeine, all median quintiles Higher caffeine consumption was not associated with an increased risk of incident atrial Conen et al.,
tive (13.8-14.8 baseline sources 22, 135, 285, 402, fibrillation. 2010
yr follow-up) n=33,638 F and 656 mg/d
(USA) [0.3-9.4 mg/kg/d]
Cohort prospec- 20-69 yr at coffee; tea <1.0, 1.0-2.0, 2.1- U-shaped association between coffee and CVD and tea and CVD; tea was inversely associ- de Koning
tive (13 yr fol- baseline 3.0, 3.1-4.0, 4.1- ated with CVD; no associations between tea or coffee and stroke and all-cause mortality; Gans et al.,
low-up) n=37,514 M+F 6.0, >6.0 cups/d coffee slightly reduced the risk for CVD mortality (hazard ratio 0.64; 95% CI, 0.37 to 1.11). 2010
(The Nether- [<1.4 to ≥8.6
lands) mg/kg/d]
Cohort prospec- 50-64 yr caffeine, all quintiles mean No association was found between the amount of caffeine consumed per day and the risk of Frost and
tive (5.7 yr fol- n=47,949 M+F sources 248, 475, 584, atrial fibrillation or flutter; adjusted Hr (95% CIs) in quintiles 2, 3, 4, and 5 were 1.12 (0.87, Vestergaard,
low-up) 769, 997 mg/d 1.44), 0.85 (0.65, 1.12), 0.92 (0.71, 1.20), and 0.91 (0.70, 1.19), respectively. 2005
(Denmark) [3.6-14 mg/kg/d]
144
Cohort prospec- 42-60 yr at boiled or fil- 0, 1-375, 376-For daily nondrinkers and light (≤375 mL [4.3 mg/kg/d]), moderate (reference level [4.3-9.3 Happonen et
tive (14 yr mean baseline tered coffee 813, ≥814 mL/d mg/kg/d]), and heavy (≥814 mL [>9.3 mg/kg/d]) drinkers, RR=0.84 (0.41-1.72), 1.22 (0.90- al., 2004
follow-up) n=1971 M [≤4.3, 4.3-9.3,
1.64), 1.00, and 1.43 (1.06-1.94) for acute MI or coronary death. During the first 5 yr, the
(Finland) >9.3 mg/kg/d] respective RR=0.42 (0.06-3.10), 2.00 (1.16-3.44), 1.00, and 2.07 (1.17-3.65). Neither the
brewing method (boiling vs. filtering) nor the serum LDL cholesterol had any impact on the
RR. [1 cup = 125 mL; no info on caffeine per cup coffee; assume 100 mg/cup]
Cohort prospec- 42-60 yr at Coffee median mL/d: OR (90% CI)=3.2 (1.2-8.4) for acute coronary events when comparing heavy coffee drink- Happonen et
tive (13 yr mean baseline [polymorphism 269, 579, 938 ers (13 mg/kg/d) with the low activity COMT (catechol-O-methyltransferase) genotype vs. al., 2006
follow-up) n=773 M of COMT gene] [3.8, 8.3, 13 high activity or heterozygotic genotypes; urinary adrenaline excretion increased with in-
(Finland) mg/kg/d] creasing coffee intake, being over two-fold in heavy drinkers vs. nondrinkers. [If estimate
coffee=0.5-1 mg caffeine/mL, then caffeine= 135-269 mg, 290-579 mg, 469-938 mg for
light, moderate, and heavy consumption, respectively]
Cohort prospec- 25-64 yr at coffee 0-1, 2-3, 4-5, 6-7, Coffee drinking seemed to increase the risk of antihypertensive drug treatment, and this risk Hu et al., 2007
tive (13.2 yr baseline or ≥8 cups/d was higher in subjects with low-to-moderate coffee intakes [2.9-10 mg/kg/d]; however,
mean follow-up) n=24710 (47% [0-1.4; 2.9-4.3; there was no significantly increased trend in drinkers of approximately 1 cup (100 mL)/d or
(Finland) M) 5.7-7.1; 8.6-10; >or=8 cups/d (for 0-1, 2-3, 4-5, 6-7, or >or=8 cups/d coffee multivariate-adjusted HR=1.00,
≥11 mg/kg/d] 1.29 (1.09, 1.54), 1.26 (1.06, 1.49), 1.24 (1.04, 1.48), and 1.14 (0.94, 1.37) (P for trend =
0.024, but p=0.077 after adjustment for baseline systolic B). [No info on caffeine per cup
coffee; assume 100 mg/cup]
Cohort prospec- 26.3± 2.4 yr at coffee; decaf 0, 1-2, 3-4, ≥5 CHD risk increased with coffee intake (RR increased for all >0 intake) in smokers and non- Klag et al.,
tive (28-44 yr baseline cups/d smokers and was stronger for MI; most of the excess risk was associated with coffee drink- 1994
follow-up) n=1040 M [1.4 to ≥7.1 ing prior to 1975 (the diagnosis of hypertension was associated with a subsequent reduction
(USA) mg/kg/d] in coffee intake; intake questionnaire did not distinguish between caffeinated and decaffein-
ated coffee). [no info on caffeine per cup coffee; assume 100 mg/cup]
Cohort prospec- mean 26 yr at coffee 0, 1-2, 3-4, ≥5 Drinking 1 cup/d coffee raised systolic BP by 0.19 mm Hg (0.02-0.35) and diastolic BP by Klag et al.,
tive (33 yr me- baseline cups/d 0.27 mm Hg (0.15-0.39) after adjustment for parental incidence of hypertension and time- 2002
dian follow-up) n=1017 M [1.4 to ≥7.1 dependent body mass index, cigarette smoking, alcohol drinking, and physical activity.
(USA) mg/kg/d] Compared with nondrinkers at baseline, coffee drinkers had a greater incidence of hyperten-
sion during follow-up (18.8% vs. 28.3%; P =.03). RR of hypertension associated with drink-
ing ≥5 cups/d was 1.35 (0.87-2.08) for baseline intake and 1.60 (1.06-2.40) for intake over
follow-up. After adjustment for variables, these associations were not significant. [No info
on caffeine per cup coffee; assume 100 mg/cup]
145
Cohort prospec- mean=40.7 yr coffee; smok- ~0, <1, 1-3, 4-6, Coffee drinking was unrelated to CAD risk in never smokers, but in ex-smokers and current Klatsky et al.,
tive (20 yr fol- n=127,212 ing ≥4, ≥6 cups/d baseline smokers, daily coffee intake was associated with higher CAD risk; increased CAD 2008
low-up) (44% M) [<1.4 to ≥8.6 risk for heavier coffee drinkers among smokers was slightly stronger in F (e.g. for ever
(USA) mg/kg/d] smokers reporting ≥4 cups of coffee/d, RR=1.3 (95% CI 1.1-1.6). [No info on caffeine per
cup coffee; assume 100 mg/cup]
Cohort prospec- 30-59 yr at coffee <1, 1-3, 4-7, >7 Risk of nonfatal MI was not associated with coffee drinking in M: the age-adjusted associa- Kleemola et
tive (10 yr fol- baseline cups/d tion of coffee drinking was J shaped with CHD mortality and U shaped with all-cause mor- al., 2000
low-up) n=20,179 (50% [<1.4 to >10 tality. The highest CHD mortality was in coffee abstainers. In F, all-cause mortality de-
(Finland) M) mg/kg/d] creased by increasing coffee drinking. The prevalence of smoking and mean serum choles-
terol increased with increasing coffee drinking. [Assumed 1 cup= 110 mL, containing 100
mg caffeine]
Cohort prospec- 55-69 yr at coffee; tea Coffee: 0-2, >2-4, Positive association between coffee consumption (increment 270 mL/d) and ischemic heart Leurs et al.,
tive (10 -yr fol- baseline >3-6, >6 cups/d disease mortality in M (HR= 1.09 [1.00, 1.18]), but an inverse relationship in F (Hazard 2010
low-up) n=120,852 [2.9 to >8.6 Ratio=0.88 [0.78, 1.00]). For tea consumption (increment of 253 mL/d) M had inverse rela-
(The Nether- M+F mg/kg/d]; tionship with IHD mortality (Hazard ratio= 0.91 [0.83, 1.00]). In categorical analysis, asso-
lands) Tea: 0-1, >1-2, ciation between coffee consumption and IHD mortality was not significant for M; for tea, all
>2-3, >3 cups/d categories were inversely related to IHD mortality in M; and F association between tea con-
[0.6 to >1.7 sumption and IHD mortality was not significant. [1 cup=125 mL; no info on caffeine per
mg/kg/d] cup; assume 100 mg/cup for coffee, 40 mg/cup for tea]
Cohort prospec- M=52-53 yr, coffee <1 cup/mo, ¼ -4, The data did not provide any evidence that coffee consumption increased the risk of CHD in Lopez-Garcia
tive (follow-up F=45-46 yr 5-7 cups/wk, 2-3, M or F. [Estimated: 137 mg/cup of coffee, 47 mg/cup of tea, 46 mg per can or 12-oz bottle et al., 2006
14 yr for M, 20 mean at base- 4-5, ≥6 cups/d of soft drink, 7 mg per 1-oz serving of chocolate candy.]
yr for F) (USA) line n=128,493 [<1.4 to ≥8.6
(34.2% M) mg/kg/d]
Cohort prospec- M=52-53 yr, coffee; decaf <1 cup/mo; ≤4, 5- Coffee consumption was not associated with risk for cancer or CVD death, or with an in- Lopez-Garcia
tive (18 yr fol- F=45-46 yr 7 cups/wk, 2-3, 4- creased overall mortality rate in either M or F; decaf consumption was associated with a et al., 2008
low-up in M, 24 mean at base- 5, ≥6 cups/d small reduction in all-cause and CVD mortality. [Estimated: 137 mg/cup of coffee, 47
yr in F) (USA) line [<1.4 to ≥8.6 mg/cup of tea, 46 mg per can or 12-oz bottle of soft drink, 7 mg per 1-oz serving of choco-
n=127,950 mg/kg/d] late candy.]
(32.6% M)
Cohort prospec- mean 45-46 yr coffee <1 cup/mo, 1/4-4, Long-term coffee consumption was not associated with an increased risk of stroke in F; data Lopez-Garcia
tive (24 yr fol- at baseline 5-7 cups/wk, 2-3, suggested that coffee consumption may modestly reduce risk of stroke. [Estimated: 137 et al., 2009
low-up) n=83,076 F ≥4 cups/d [<1.4 to mg/cup of coffee, 47 mg/cup of tea, 46 mg per can or 12-oz bottle of soft drink, 7 mg per 1-
(USA) ≥5.7 mg/kg/d] oz serving of chocolate candy.]
146
Cohort prospec- 40-79 yr coffee; black 1-6 cups/wk; 1-2 Consumption of coffee, green tea, and oolong tea, as well as total caffeine intake were asso- Mineharu et
tive (13.1 yr n=76,979 tea; green tea; cups/d; ≥ 3 cups/d ciated with a reduced risk of mortality from CVD in Japanese people. [Mean caffeine intake al., 2010
follow-up) (Ja- (~42% M) oolong tea [mean intake 4.1 287 mg/d for men, 254 mg/d for women]
pan) mg/kg/d]
Cohort prospec- mean ~56-65± Coffee coffee 0, ≤7, >7- Coffee consumption was not associated with an overall change in long-term post-infarction Mukamal et
tive (3.8 yr fol- 12 yr [post-MI] 14, >14 cups/wk; mortality rate; apparent inverse association in the first 90 d after infarction; no evidence of al., 2004
low-up) n=1902 M+F cola: 0, ≤2, >2-7, an association of cola intake and total mortality rate or cardiovascular mortality rate. [No
(USA) >7 cups/wk [cof- info on caffeine intake; assume 100 mg/cup coffee; 35 mg/can cola]
fee ≤10, 10-20,
>20 mg/kg/d; cola
≤1.0, 1.0-3.5,
>3.5 mg/kg/d]
Cohort prospec- 44-101 yr at caffeine, all <50, 50-100, 100- Caffeine intake showed no consistent effect: a shallow U-shaped association of caffeine Paganini-Hill,
tive (13.5 yr baseline sources 199, 200-399, intake with CVD mortality was observed in both sexes (no statistical significance). 2011
median follow- n=13,296 ≥400 mg/d
up) (36.5% M) [0.7 to ≥5.7
(USA) mg/kg/d]
Cohort prospec- 18-45 yr at Coffee 0, 1-3, ≥4 cups/d For carriers of the slow *1F allele (59%), hazard ratios of hypertension from multivariable Palatini et al.,
tive (8.2 yr fol- baseline [CYP1A2 [1.4-4.3, ≥5.7 Cox analysis were 1.00 in abstainers (reference), 1.72 (95%CI, 1.21-2.44) in moderate cof- 2009
low-up) (Italy) n=553 M+F genotype] mg/kg/d] fee drinkers (P = 0.03), and 3.00 (1.53-5.90) in heavy drinkers (P = 0.001). In contrast, haz-
ard ratios for coffee drinkers with the rapid *1A/*1A genotype were 0.80 (0.52-1.23, P =
0.29) for moderate drinkers and 0.36 (0.14-0.89, P = 0.026) for heavy drinkers. In a two-
way ANCOVA, a gene x coffee interactive effect was found on follow-up changes in sys-
tolic (P = 0.000) and diastolic (P = 0.007) BP. Urinary epinephrine was higher in coffee
drinkers than abstainers but only among individuals with slow *1F allele (P = 0.001).
Cohort prospec- 18-30 yr at caffeine, all 0,<1, 1-2, 3-4, ≥4 No substantial association between coffee or caffeine intake and coronary and carotid Reis et al.,
tive (2-20 yr baseline sources; coffee; cups/d atherosclerosis; possible inverse association between tea and coronary artery calcified 2010
follow-up) n=5115 M+F decaf; tea [total caffeine: plaque but not carotid atherosclerosis. [mean total caffeine (sum of all caffeinated foods and
(USA) 0.8, 1.7, 4.1, 7.7, beverages: 58.5, 116.2, 290.2, 542.3, 1244.0 mg/d; caffeine content of beverages and foods
18 mg/kg/d] not provided, but assumed 1 cup=8 oz=237 mL]
Cohort prospec- 40-74 yr coffee 0-4, 5-7 cups/wk; Coffee consumption of ≥5 cups/wk [1.0 mg/kg/d] was nonsignificantly inversely associated Rosner et al.,
tive (5 yr follow- n=32,650 F 2-3, 4-5, ≥6 with MI risk among older Swedish F. [No info on caffeine per cup coffee; assume 100 2007
up) (Sweden) cups/d [0.8- ≥8.6 mg/cup]
mg/kg/d]
147
Cohort prospec- Adult caffeine, all Quartiles: 23, No significant associations between caffeine intake and atrial fibrillation risk; HR for in- Shen et al.,
tive (4 -yr fol- n=4526 (44% sources 142, 347, 452 creasing quartiles for caffeine, 0.84 (95% CI: 0.62, 1.15), 0.87 (0.64, 1.2), and 0.98 (0.7, 2011
low-up) (USA) M) mg/d [0.3, 2.0, 1.39). [No info on caffeine content of drinks and food]
5.0, 6.5 mg/kg/d]
Cohort prospec- mean 52-63± Coffee never/almost Coffee consumption did not change the risk of CHD events, stroke, or sudden death in post- Silletta et al.,
tive (3.5 yr fol- 10 yr; [recent (≤3 mo) never, 4 cups/d MI patients; coffee consumption was strongly associated with younger age. [No info on 2007
low-up) (Italy) n=11,231 MI] [5.7 mg/kg/d] caffeine per cup coffee; assume 100 mg/cup]
(9584 M)
Cohort prospec- 35-36 yr at coffee <1, 1-2, 3-4, 5-6, Association between coffee consumption and mortality from CHD was seen after first 6 yr Stensvold et
tive (12 yr fol- baseline 7-8, ≥9 cups/d [compared to <1 cup/d RR=1.8, 1.8, 2.2, 3.0, 3.3 for consecutively higher intake groups] but al., 1996
low-up) n=38,564 [<1.4 to ≥13 not during the second 6 yr; overall for 1-12 yr, compared to <1 cup d, RR=1.0, 1.1, 1.4, 1.4,
(Norway) (50.3% M) mg/kg/d] 1.7; RR values were all lower when the cholesterol concentration was adjusted for. [No info
on caffeine per cup coffee; assume 100 mg/cup]
Cohort prospec- 40-64 yr coffee never, occasion- Inverse association between coffee consumption and mortality due to CHD in F but not M; Sugiyama et
tive (10.3 yr n=37742 (48% ally, 1-2, ≥3 death due to cancer was associated with coffee consumption for colorectal cancer in F. [No al., 2010
follow-up) M) cups/d info on caffeine per cup coffee; assume 100 mg/cup]
(Japan) [1.4-2.9; ≥4.3
mg/kg/d]
Cohort prospec- Adult coffee 0, >0-3, >3-6, >6 Coffee abstinence was associated with a lower hypertension risk than is low coffee con- Uiterwaal et
tive (6 and 11 yr M=2985; cups/d sumption; F had an inverse U-shaped relation between coffee intake and risk of hyperten- al., 2007
follow-up) (The F=3383 [≤4.3 to >8.6 sion. [No info on caffeine per cup coffee; assume 100 mg/cup]
Netherlands) mg/kg/d]
Cohort prospec- 25-74 yr coffee 0, 1-2, 3-4, 5-6, 7- No increase the risk of heart failure in Finnish M and F; F had an inverse association with Wang et al.,
tive (19.2 yr n=59,490 M+F 9, ≥10 cups/d risk for intakes of 1-2, 3-4, and 5-6 cups/d. [No info on caffeine per cup coffee; assume 100 2011
mean follow-up) [1.4 to ≥14 mg/cup]
(Finland) mg/kg/d]
Cohort prospec- 47-55 yr at coffee 0, 1-4, ≥5 cups/d Consumption of ≥ 5 cups/d coffee was independently associated with an increased risk for Wilhelmsen et
tive (27 yr fol- baseline [1.4-5.7, ≥7.1 heart failure (OR=1.17, 1.05-1.30, p< 0.005). [No info on caffeine per cup coffee; assume al., 2001a
low-up) n=7495 M mg/kg/d] 100 mg/cup]
(Sweden)
Cohort prospec- 47-55 yr at coffee 0, 1-4, ≥5 cups/d In bivariate analysis adjusted for age, coffee consumption was weakly associated with future Wilhelmsen et
tive (27 yr fol- baseline [1.4-5.7, ≥7.1 hospitalization for fibrillation (OR=1.24 [1.00-1.54] for 1-4 cups/d; OR=1.09 [0.87-1.38] for al., 2001b
low-up) n=7495 M mg/kg/d] ≥ 5 cups/d).
(Sweden)
148
Cohort prospec- 34-59 yr at coffee 0, 0.03-0.6, 0.7-1, No evidence for an association between coffee consumption and risk of subsequent CHD. Willett et al.,
tive (10 yr fol- baseline 2-3, 4-5, ≥6 For F drinking 0 vs. ≥6 cups of coffee/d in 1980, RR=0.95 (95% CI, 0.73 to 1.26). There 1996
low-up) (USA) n=85,747 F cups/d [0.06 to was no association with caffeine intake from all sources combined or with decaffeinated
≥8.6 mg/kg/d] coffee consumption. [Assumed 137 mg caffeine per cup coffee]
Cohort prospec- 35-37 yr at caffeine, all Coffee or tea: <1, An inverse U-shaped association was seen between total caffeine consumption (quintiles: Winkelmayer
tive (12 yr fol- baseline sources 1, 2-3, 4-5, ≥6 <45, 45-144, 144-297, 297-417, 417-1788 mg/d) and incident hypertension (greatest in- et al., 2005
low-up) n=155,594 F cups/d; cola: <1, crease at ~200 mg/d); drinking ≥1 cola beverages/d (± sugar), but not coffee or tea, was as-
(USA) 1, 2-3, ≥4 cans/d sociated with an increased risk of hypertension. [assumed caffeine=137 mg/cup coffee, 47
[quintiles: 0.6-25 mg/cup tea, 46 mg/can or bottle cola, and 7 mg/serving of chocolate]
mg/kg/d]
Cohort prospec- 40-59 at base- coffee; tea 0, 1-2, 3-4, ≥5 Increased coffee consumption was associated with beneficial effects for mortality and coro- Woodward
tive (7.7 yr fol- line cups/d nary morbidity, whereas tea showed the opposite; adjustment for other risk factors removed and Tunstall-
low-up) n=~11,500 [1.4 to ≥ 7.1 the associations for tea and most of those for coffee although there was a residual benefit of Pedoe, 1999
(UK) (49% M) mg/kg/d] coffee consumption in avoiding heart disease among men. [No info on caffeine per cup
coffee; assume 100 mg/cup]
Cohort prospec- 34-59 yr at caffeine, all mean =101.7, Habitual coffee consumption was not associated with increased risk of CVD or premature Zhang et al.,
tive (24 yr fol- baseline sources 139.3, 269.2, mortality among diabetic F. Intake categories were: coffee: <1/mo; 1/mo-4/wk; 5-7/wk; 2- 2009a
low-up) (USA) n=7170 F [diabetes, type467.1, 775.8 mg/d 3, ≥4 cups/d; decaf: <1/mo; 1/mo-4/wk; 5-7/wk, ≥2 cups/d. [No info on caffeine content of
II] [2.0-11 mg/kg/d] drinks or food]
Cohort prospec- 40-75 yr at Coffee <1 cup/mo, ¼ -4, Caffeinated coffee consumption was not associated with increased risk for cardiovascular Zhang et al.,
tive (18 yr fol- baseline [diabetes, type5-7 cups/wk, 2-3, diseases or mortality in diabetic M. [No info on caffeine per cup coffee; assume 100 2009b
low-up) (USA) n=3497 M II] ≥4 cups/d mg/cup]
[<1.4 to ≥5.7
mg/kg/d]
Cross-sectional Adult coffee; decaf; <2, 2–3.9, 4–5.9, Higher caffeine intake (≥2 units/d [2.6 mg/kg/d]) tended to be associated with higher sys- Bakker et al.,
(The Nether- n=7890 F tea ≥6 units/d tolic BP in the 1st and 3rd trimester (trend p<0.05), but not in 2nd trimester; no consistent as- 2011
lands) [pregnant] [<2.6 to ≥7.7 sociation with diastolic BP, or the risk of pregnancy-induced hypertension. [a serving (125
mg/kg/d] mL) of coffee, decaf, and tea contain ~90, 3 and 45 mg caffeine (1, 0, 0.5 units, respec-
tively)]
Cross-sectional 50-67 yr coffee ≤1, 2-3, ≥4 cups/d The findings indicated that coffee intake may trigger MI. The RR of MI in the hour after Baylin et al.,
(Costa Rica) n=503 M+F (none; occasional; coffee intake for occasional, moderate, and heavy drinkers was 4.14 (2.03-8.42), 1.60 (1.16- 2006
moderate; heavy) 2.21), and 1.06 (0.69-1.63; P = 0.006, test of homogeneity). Those with sedentary lifestyle
[≤1.4, 2.9-4.3, or with ≥3 risk factors for CHD had additional risk. [No info on caffeine per cup coffee;
≥5.7 mg/kg/d] assume 100 mg/cup]
149
Cross-sectional Adult caffeine, all mean ~180 mg/d In smokers, homocysteine levels were associated with caffeine consumption at gestational Carlsen et al.,
(Norway; Swe- n=92 F sources; smok- non-smokers, weeks 17 and 33; in non-smokers, caffeine consumption was not associated with homocys- 2005
den) ing [pregnant] 250-290 mg/d teine levels.
smokers
[2.6; 3.9 mg/kg/d]
Cross-sectional 18-97 yr at coffee 0, 1-3, 4-6, >6 M, but not F, had significant three-way interaction among coffee intake (nonlinear), baseline Giggey et al.,
(USA) baseline cups/d age, and length of follow-up for systolic BP and pulse pressure; most notable from ≥ 6 2010
n=2442 (64.6% [1.4-4.3, 5.7-8.6, cups/d [8.6 mg/kg/d] and at 70 yr and in overweight to obese M; no effect in F. [No info on
M) >8.6 mg/kg/d] caffeine per cup coffee; assume 100 mg/cup]
Cross-sectional 28-82 yr coffee; cola; tea ≤88, 89-182, 183- Consumption of ≥1 cup/d coffee or ≥2 cans/d soda was associated with higher total plasma Jacques et al.,
(USA) n=1960 M+F 355, 356-419, homocysteine concentration; there was a weak inverse association with tea intake (coffee: 2001
≥420 mg/d [≤1.3 <1, 1-3/mo; 1-6/wk; 1, 2-3, ≥4 cups/d; decaf, cola, tea: <1, 1-3/mo, 1-6/wk, 1, ≥2 cups/d).
to ≥6 mg/kg] [No info on caffeine per cup; assume 100 mg/cup coffee; 40 mg/cup tea; 35 mg/can cola]
Cross-sectional hypertensive: Coffee; caf- 0, 1, 2-3, >3 Normotensive non-habitual coffee consumers were more likely to convert arrhythmia within Mattioli et al.,
(Italy) 54± 10 yr feine, all cups/d coffee; 48 hr from the onset of symptoms. Hypertensive patients showed a U-shaped relationship 2010
(n=247, 135 sources total caffeine 90, between coffee consumption and spontaneous conversion of atrial fibrillation, moderate
M) normoten- [hypertension] 90-180, 180-360, coffee consumers were less likely to show spontaneous conversion of arrhythmia. Patients
sive: 61± 10 yr >360 mg/d with left ventricular hypertrophy showed a reduced rate of spontaneous conversion of ar-
(n=353, 246 [1.3, 1.3-2.6, 2.6- rhythmia. [caffeine mg/cup: espresso=90, cappuccino=110, American coffee=160, 1 can of
M) 5.1, >5.1 cola=42, 1 chocolate snack=6; coffee consumption categories were none, low, medium, and
mg/kg/d] heavy for 0, 1, 2-3, >3 cups/d ]
Cross-sectional ~68-70± 14 yr Coffee <1, 1-3, >3 cups/d RR of ischemic stroke in the hour after consuming coffee was 2.0 (95% CI, 1.4-2.8; p < Mostofsky et
(USA) n=309 (209 M) [0-14 d after [<1.4, 1.4-4.3, 0.001); no similar risk for caffeinated tea or cola; effect only seen among those consuming al., 2010
stroke] >4.3 mg/kg/d] ≤1cup/d. [No info on caffeine per cup; assume 100 mg/cup]
Cross-sectional 40-67 yr coffee; smok- 0, <1, 1-4, 5-8, ≥ Dose-response increase of coffee consumption and plasma total homocysteine, which was Nygard et al,
(Norway) n=7589 M, ing 9 cups/d stronger than the relation between coffee and total serum cholesterol; cigarette smoking + 1997
8585 F [<1.4 to ≥13 high coffee intake was associated with particularly high homocysteine. [No info on caffeine
mg/kg/d] per cup coffee; assume 100 mg/cup]
Cross-sectional 40-67 yr coffee; smok- 0, <1, 1-4, 5-8, ≥9 In multivariate analysis, sex, age, folate intake, smoking status, and coffee consumption (≥5 Nygard et al.,
(Norway) n=11,941 M+F ing cups/d cups/d [7.1 mg/kg/d]) were the strongest determinants of homocysteine concentration; the 1998
[<1.4 to ≥13 combined effect of the three modifiable factors was larger than the effect from each factor
mg/kg/d] alone. [No info on caffeine per cup coffee; assume 100 mg/cup]
150
Cross-sectional 18-45 yr Coffee 0, 1-3, >3 cups/d BP, HR, and urinary catecholamines did not differ according to coffee intake; chronic coffee Palatini et al.,
(Italy) n=351 M; [hypertension] [1.4-4.3, >4.3 intake and physical training showed an inverse relationship with plasma renin activity in 1996
mg/kg/d] mild hypertensive M. [The caffeine content per cup of 'espresso' Italian coffee averages 100
mg]
Cross-sectional M=46± 13 yr; caffeine, all 0, <100, 200-400, A dose-response relationship of homocysteine levels with coffee consumption was observed Panagiotakos
(Greece) F=45± 13 yr sources >500 mL/day (r = 0.10, P = 0.034), increased levels seen at all intake levels >0. [All reported types of et al., 2004
n=514 M, 1528 [<2.6 to >13 coffee were adjusted for one cup (150 mL) of coffee and concentration of 27.5% caffeine]
F mg/kg/d]
Cross-sectional mean age at Coffee 1-5 cups/d The relative risk of dying due to sudden cardiac death during 1 hour after coffee consump- Selb Semerl
(Slovenia) death M=57 yr; [2.8 risk factors [1.4-7.1 mg/kg/d] tion was 1.73 (95% CI=1.13-2.65). [No info on caffeine per cup coffee; assume 100 and Selb, 2004
F=58 yr; n=309 for CVD] mg/cup]
(253 M)
Cross-sectional 60-69 yr coffee 0, 1, 2, 3-9 cups/d Significant positive dose-response relation between coffee consumption and fasting serum Stolzenberg-
(USA) n=260 (109 M) [1.4, 2.9, 4.3-13 total homocysteine; significant for ≥3 cups/d. [No info on caffeine per cup coffee; assume Solomon et
mg/kg/d] 100 mg/cup] al., 1999
Cross-sectional 50-64 yr coffee 0, 1-3, ≥4 cups/d Dose-dependently lower plasma B-vitamin concentration (for 0 vs. ≥4 cups/d p<0.001), and Ulvik et al.,
(Norway) n=10,601 M+F [1.4-4.3, ≥5.7 increased mean total homocysteine concentration (for 0 vs. ≥4 cups/d 6.8%; P < 0.001); 2008
mg/kg/d] effect progressively greater at higher B-vitamin levels. [No info on caffeine per cup coffee;
assume 100 mg/cup]
Cross-sectional 41± 9 yr caffeine, all 0, <200, 200-450, A linear relation between coffee consumption and carotid-femoral pulse wave velocity Vlachopoulos
(Greece) n=228 (141 M) sources >450 mL/d (PWV), augmentation index (AIx), and augmented pressure (AP) of the aortic pressure et al., 2005
[<1.1, 1.1-3.4, waveform was observed (some effect seen in every category). [All coffee types were ad-
>3.4 mg/kg/d] justed for 1 cup = 150 mL of coffee and 80 mg caffeine; consumption classification was low
(<200 mL/d), moderate (200-450 mL/d), and high (>450 mL/d).]
Cross-sectional 50± 12 yr Coffee 0, <200, 200-450, Dose-related increase in carotid-femoral pulse augmentation index (wave reflection), but not
Vlachopoulos
(Greece) n=259 (165 M) [hypertension] >450 mg/d [<2.9 pulse wave velocity (aortic stiffness); 35% increase for every cup of coffee (80 mg/150 mL
et al., 2007
to >6.4 mg/kg/d] cup, or 0, 240 mg/d).
Cross-sectional 48-56 yr coffee; tea, Coffee: 0, 1-2, 3- A significant inverse relation between habitual coffee consumption and BP was found with
Wakabayashi
(Japan) n=3336 M; green 4, ≥5 cups/d [1.4 and without adjustment for alcohol use, cigarette smoking, body mass index, glucose toler-
et al., 1998
to ≥7.1 mg/kg/d]; ance, and green tea intake (per cup per day -0.6 mmHg (-0.9 to -0.3) in systolic BP and -0.4
Tea: 0-2, 3-4, 5-6, mmHg (-0.5 to -0.2) in diastolic BP. Green tea intake was unrelated to BP. [No info on caf-
≥7 cups/d [1.1 to feine per cup coffee; assume 100 mg/cup coffee; 40 mg/cup tea]
≥4.0 mg/kg/d]
BP=blood pressure; CI=confidence interval; CAD=coronary artery disease; HR=heart rate; MI=myocardial infarction; NS=not specified; OR=odds ratio; RR=relative risk
151
TABLE 5-3. Cardiovascular Effects of Caffeine – Summaries of Reviews Reference
(sorted by publication year)
Initial investigations, showing an association between coffee and CHD, suffer from confounding variables and have been difficult to replicate. Recent studies, Chou and Be-
showing a significant effect over long follow-up periods and with high coffee intake, have again raised the question of a role for coffee and/or caffeine con- nowitz, 1994
sumption in the pathogenesis of atherosclerotic heart disease. Contrary to common belief, the published literature provides little evidence that coffee and/or
caffeine in typical dosages increases the risk of infarction, sudden death or arrhythmia.
The 8 pooled case-control OR for CHD for 0 vs. 5 cups/d coffee =1.63 (95% CI=1.50 to 1.78) and the 15 pooled cohort study RR=1.05 (95% CI 0.99 to 1.12). Kawachi et al.,
The discrepancy could not be attributed to differences in the end points chosen, period of study, or to confounding by smoking status or sex. 1994
No association exists between coffee consumption and plasma homocysteine levels. Nieto et al.,
1997
In the 11 controlled clinical trials (duration 14 to 79 d; median 5 cups/d coffee), systolic and diastolic BP increased by 2.4 (1.0 to 3.7) mm Hg and 1.2 (0.4 to Jee et al., 1999
2.1) mm Hg, respectively, compared with control. There was an independent, positive relationship between cups of coffee consumed and change in systolic
BP, independent of subject age and study design; the effect was greater in trials with younger participants.
Acute intake of coffee and caffeine increases BP. The pressor response is strongest in hypertensive subjects. Some studies with repeated administration of caf- Nurminen et
feine showed a persistent pressor effect, whereas in others chronic caffeine ingestion did not increase BP. Epidemiologic studies have contradictory findings al., 1999
regarding the association between BP and coffee consumption. During regular use, tolerance to the cardiovascular responses develops in some people, thus no
systematic elevation of BP in long-term and in population studies can be shown.
Caffeine raises BP by elevating vascular resistance, and the effect is larger and more prolonged in hypertensive than in normotensive patients. The pressor re- Hartley et al.,
sponse to caffeine occurs equally in persons at rest and under stress. The elevated baseline BP of the hypertensive patient is therefore increased by both caf- 2001
feine and stress, potentially leading to undesirably high pressures. These effects are not abolished by pharmacologic tolerance to caffeine, as tolerance may not
be complete with daily intake.
Cannot reach definitive conclusions on the possible health hazards (hypertensive potential) of coffee by analyzing the cardiovascular effect of caffeine only. Corti et al.,
All potentially vasoactive substances in coffee have not been characterized. The interaction between the different components could result in additive or inhibi- 2003
tory effects and may explain the different results between studies looking at the effect of caffeine and of coffee.
For healthy adults, caffeine intake up to 400 mg/d (6 mg/kg BW in a 65-kg person) is not associated with general toxicity, cardiovascular effects, effects on Nawrot et al.,
bone status and calcium balance (with consumption of adequate calcium), changes in adult behavior, incidence of cancer, or effects on male fertility. Lower 2003
consumption is recommended for two 'at risk' subgroups: reproductive-aged women should consume ≤300 mg caffeine/d (4.6 mg/kg BW for a 65-kg person)
and children should consume ≤2.5 mg/kg BW.
BP tracking patterns in childhood confirm that persistent BP elevation in youth may be related to hypertension in adulthood. The presence of hypertension in Couch and
childhood has been linked with left ventricular hypertrophy and atherosclerotic fibrous plaque formation prior to the third decade of life. (most info is from Daniels, 2004
pre-1994 sources)
Large prospective studies do not support the hypothesis that moderate (<5 cups of coffee a day) caffeine consumption significantly increases the risk of CHD. Gensini and
Data on higher coffee consumption are scanty and do not allow conclusions, even if they suggest a statistically significant trend in coronary risk with increas- Conti, 2004
ing dose.
152
Experimental and epidemiologic studies show that BP remains reactive to the pressor effects of caffeine in habitual users. Overall, the impact of dietary caf- James, 2004
feine on population BP levels is likely to be modest, probably in the region of 4/2 mm Hg. At these levels, however, caffeine use could account for premature
deaths in the region of 14% for CHD and 20% for stroke.
It is still not certain if caffeine increases BP only under ideal laboratory conditions or if it causes a clinically important pressor response with regular use during Myers, 2004
usual daily activities.
Caffeine by itself has not been associated with serious cardiotoxicity, but ED consumption has been associated with four deaths. Dhar et al.,
2005
Regular caffeine intake increased BP. When ingested through coffee, however, the BP effect of caffeine was small. A rise of 2.04 mm Hg [95% CI, 1.10-2.99] Noordzij et al.,
in systolic BP and 0.73 mmHg [95% CI, 0.14-1.31] in diastolic BP was found after pooling of coffee and caffeine trials. When coffee trials (n=18, median in- 2005
take: 725 ml/day) and caffeine trials (n=7, median dose: 410 mg/day) were analyzed separately, BP elevations appeared to be larger for caffeine [systolic: 4.16
mmHg (2.13-6.20); diastolic: 2.41 mmHg (0.98-3.84)] than for coffee [systolic: 1.22 mmHg (0.52-1.92) and diastolic: 0.49 mmHg (-0.06-1.04)]. Effects on
HR were negligible.
Acute intake of coffee or beverages containing caffeine can increase BP, heart minute volumes, and cardiac index, as well as activate the sympathetic nervous Sudano et al.,
system in nonhabitual coffee drinkers, but is not observed in habitual coffee drinkers. No clear association between coffee and the risk of hypertension, MI, or 2005
other CVD has been demonstrated. In contrast to early studies, recent research indicates that habitual moderate coffee intake does not represent a health hazard
and may even be associated with beneficial effects on cardiovascular health.
Caffeine causes a pressor response due to increased sympathetic activity and antagonism of endogenous adenosine. Caffeine can acutely raise BP by as much Cohen and
as 10 mm Hg in patients who are infrequently exposed, although the average response is an increase of about 4–5/3 mm Hg when evaluated with ambulatory Townsend,
BP monitoring. The effects of caffeine appear to be more pronounced in persons who are at risk for hypertension, such as individuals with a family history of 2006
hypertension or obesity. Although there is often less or no effect of caffeine on BP in habitual coffee drinkers, this is not always true; some people do not de-
velop a tolerance to the BP effects of caffeine.
We found that while coffee increased BP in nonhabitual drinkers, the effect was blunted in habitual drinkers, despite the same sympathetic activation. Caffeine Flammer et al.,
infusion similarly increased sympathetic nervous activity and BP in habitual and nonhabitual coffee drinkers. The lack of BP response after coffee in habitual 2006
drinkers may explain why, in the study of Baylin et al., heavy drinkers were less likely to develop MI. Moreover, we were able to demonstrate that coffee
blunts cardiovascular response to mental stress in habitual coffee drinkers, whereas nonhabitual drinkers showed a stress-induced response of systolic BP.
When caffeine trials (n=7) and coffee trials (n=18) were analyzed separately, BP elevations appeared to be 4 times greater for caffeine given as tablets (4.2 mm Geleijnse,
Hg systolic and 2.4 mm Hg diastolic) than for caffeinated coffee (1.2 and 0.5 mm Hg, respectively). Bioavailability of caffeine, however, may differ between 2006
coffee and tablets, and coffee is a rich source of polyphenols, potassium, magnesium, and other plant-derived substances, which could reduce BP and possibly
counterbalance harmful effects of caffeine.
There is no clear evidence for a causal relationship between coffee and hypertension. Coffee was associated with a small increase (2-3 mm Hg) in BP in short- Hamer, 2006
term intervention trials, which may reduce with habitual intake.
Coffee consumption is associated with increases in BP and plasma homocysteine; there is little evidence that coffee consumption increases the risk of cancer. Higdon and
Adults consuming moderate amounts of coffee (3-4 cups/d providing 300-400 mg/d of caffeine), have little health risk, but some groups may be more vulner- Frei, 2006
able (people with hypertension, children, adolescents, and the elderly). It may be prudent for pregnant women to limit coffee consumption to 3 cups/d (≤300
mg/d caffeine) to exclude any increased probability of spontaneous abortion or impaired fetal growth.
153
Coffee consumption was not associated with an increased risk of hypertension, but consumption of sugared or diet cola was associated with it. Kim, 2006
There is a significant interaction between smoking and coffee use on ambulatory BP. Palatini, 2006
The literature indicates a strong relationship between boiled, unfiltered coffee consumption and elevated cholesterol levels; however, there is a critical gap in Rodrigues and
the literature regarding the effects of coffee or caffeine consumption on fibrinogen or C-reactive protein, which is an independent predictor of CVD risk. Klein, 2006
The potential bioactives in coffee are caffeine, the diterpenes cafestol and kahweol found in the oil, and the polyphenols, most notably chlorogenic acid. It is Bonita et al.,
concluded that only heavy consumption (>6 cups/d) of boiled unfiltered coffee is harmful to the heart as a result of the dose-related plasma cholesterol and 2007
LDL increase due to the diterpene oils.
Diterpenes present in unfiltered coffee and caffeine each appear to increase risk of CHD. A lower risk of CHD among moderate coffee drinkers might be due Cornelis and
to antioxidants found in coffee. El-Sohemy,
2007
External triggers, such as heavy physical activity, emotional stress, eating, cold or heat exposure, coffee or alcohol consumption, cocaine or marijuana use and Culic, 2007b
sexual intercourse are recognized as most important acute risk factors for myocardial infarction.
A significant association was found between coffee intake and CHD for 13 case-control studies (9483 cases; 27,747 controls) for the highest 2 intake groups Sofi et al.,
(3-4 and >4 cups/d OR=1.33 (1.04-1.71) and 1.83 (1.49-2.24)). No association with CHD was found for the 10 cohort studies (n=403,631; follow-up 3-44 yr): 2007
RR=1.16 (0.95-1.41) for the highest intake category.
Although the precise nature of the relation between coffee and BP is still unclear, most evidence suggests that regular intake of caffeinated coffee does not in- Geleijnse,
crease the risk of hypertension. 2008
Most prospective cohort studies found that caffeine consumption does not significantly increase the risk of CHD, stroke, cancer or many women’s health is- IFIC, 2008
sues. However, sensitive sub-populations, including pregnant women, children and older individuals, and those with a history of heart disease, may experience
effects at lower levels of caffeine and should limit their consumption to 3 cups of coffee/d or ≤300 mg/day to avoid adverse effects. For healthy adults, 300
mg/day caffeine is safe and can even have beneficial health implications.
Reviews of caffeine's acute effect on BP indicate changes of 3-15 mm Hg systolic and 4-13 mm Hg diastolic. Typically, BP changes occur within 30 minutes, Mort and
peak in 1-2 hr, and may persist for more than 4 hr. Caffeine tolerance diminishes the acute effect of caffeine on BP, and hypertensive individuals are more sus- Kruse, 2008
ceptible to BP changes.
The association between chronic coffee consumption and CVD is still controversial. The findings from the study by Ye et al. demonstrating that coffee intake Riksen et al.,
can blunt statin-induced cardioprotection provides yet another experimental basis to study the acute effects of caffeine (i.e. the plasma caffeine concentration at 2008
the moment of ischemia) on the outcome after a cardiac ischemic event in selected patients with preinfarction ischemia or in patients treated with statins.
Several early studies suggested that coffee consumption could result in a marked increase in risk of CHD and several types of cancer. However, more recent van Dam,
prospective cohort studies that are less prone to selection and information bias have not confirmed these findings. High consumption of unfiltered types of cof- 2008b
fee, such as French press and boiled coffee, has been shown to increase low-density-lipoprotein-cholesterol concentrations.
Explanation for “coffee paradox”: (1) acute effects of coffee consumption may differ from chronic effects, (2) effects of coffee can depend on the type of cof- van Dam,
fee consumed and may not be the same as for caffeine in isolation, (3) coffee may have compensatory beneficial effects on other aspects of development of 2008a
CHD, (4) risk markers (e.g. homocysteine) may not causally affect the development of CHD, or their effects may be too modest to translate into a substantial
increase in disease risk.
154
The risk of CVD may be increased in individuals who are slow metabolizers of caffeine and drink two or more cups of coffee per day. The ingestion of large Celik et al.,
quantities of caffeine might be associated with arrhythmic and cardiovascular events, especially in patients with underlying heart disease. 2009
Most prospective studies have not shown a positive association of coffee intake and CHD, whereas case-control studies in general have reported such an asso- Riksen et al.,
ciation. This discrepancy could be explained by an acute adverse effect of coffee, rather than a long-term adverse effect. We postulate that coffee drinking may 2009
have an acute detrimental effect in triggering coronary events and increasing infarct size in selected patient groups, rather than promoting the development of
atherosclerosis in the general population.
Meta-analysis does not support the hypothesis that coffee consumption increases the long-term risk of coronary heart disease. Effects were pooled from 21 Wu et al., 2009
independent prospective cohort studies that tested CHD risk by coffee consumption (15,599 cases from 407,806 participants). Compared to light consumption
(<1 cup/d in U.S. or <or=2 cups/d in Europe), the RRs (95% CI) were 0.96 (0.87-1.06), 1.04 (0.92-1.17) and 1.07 (0.87-1.32) for moderate (1-3 or 3-4 cups/d),
heavy (4-5 or 5-6 cups/d) and very heavy (>or=6 or >or=7 cups/d) consumption (all p>0.05). Moderate consumers followed <=10 years had decreased RR (F:
0.82; 0.73-0.92; M: 0.87, 0.80-0.86) (p=0.001).
ED + alcohol are gaining popularity in young adults, which poses significant concerns about health risks; ED-related health concerns include case reports of Duchan et al.,
seizures and cardiac arrest following ED consumption and dental enamel erosion resulting from the acidity of ED. 2010
In endothelial cells, caffeine increases intracellular calcium stimulating the production of nitric oxide through the expression of the endothelial nitric oxide Echeverri et
synthase enzyme. Nitric oxide is diffused to the vascular smooth muscle cell to produce vasodilation. In vascular smooth muscle cells its effect is predomi- al., 2010
nantly a competitive inhibition of phosphodiesterase, producing an accumulation of cAMP and vasodilation. It also blocks the adenosine receptors present in
the vascular tissue to produce vasoconstriction.
High coffee intake was not clearly associated with an increased risk of atrial fibrillation, and a potential U-shaped association (lower risk in moderate drinkers) Gronroos and
could exist. Alonso, 2010
One can of an ED during one training session is safe for most healthy individuals. However, excess consumption and consumption with other caffeine- Higgins et al.,
containing beverages or alcohol may lead to adverse effects and possibly death. Patients with clinically relevant underlying medical conditions, including heart 2010
disease and hypertension, should consult with their physician before drinking EDs.
In epidemiologic studies, non-filtered coffee consumed at moderate to high doses has been found to be related to increases in C-reactive protein, TNF-a, IL-6, O'Connor and
and homocysteine. In contrast, filtered coffee drinking appears to have minimal impact on markers of inflammation. Irwin, 2010
Effects that have been reported from ED use by adolescents include jitteriness, nervousness, dizziness, the inability to focus, difficulty concentrating, GI upset, Pennington et
and insomnia. Health care providers have seen dehydration, accelerated HR, anxiety, seizures, acute mania, and strokes. al., 2010
Twin studies find the heritability of caffeine-related traits to range between 0.36 and 0.58. Analysis of polysubstance use shows that predisposition to caffeine Yang et al.,
use is highly specific to caffeine itself and shares little common disposition to use of other substances. Genome association studies link variations in adenosine 2010
and dopamine receptors to caffeine-induced anxiety and sleep disturbances. Polymorphism in the metabolic enzyme cytochrome P-450 is associated with risk
of myocardial infarction in caffeine users.
Caffeine reduces insulin sensitivity in skeletal muscle. This may be due to a combination of direct antagonism of A(1) receptors and indirect β-adrenergic Beaudoin and
stimulation as a result of increased sympathetic activity. Caffeine may also induce reduced hepatic glucose output. With the exception of bone mineral density, Graham, 2011
there is little evidence that caffeine impacts negatively on other health issues. Coffee does not increase the risk of CVD or cancers.
155
Limited but consistent evidence suggested that caffeine intake acutely increases arterial stiffness (Cohen's d = 0.34-0.51). Pase et al.,
2011
For concentrations normally achieved in humans, the cardiovascular effects of methylxanthines are primarily due to antagonism of adenosine A(1) and A(2) Riksen et al.,
receptors. Inhibition of phosphodiesterases or mobilization of intracellular calcium requires much higher concentrations. In conscious humans, acute exposure 2011
to caffeine results in an increase in BP by an increased total peripheral resistance, and a slight decrease in HR. Although most prospective studies have not as-
sociated CHD with coffee consumption, they do not exclude that coffee consumption could have an adverse effect in selected patient groups who are more
vulnerable for these effects, based on their genetic profile or medication use.
ED have been associated with serious adverse effects, especially in children, adolescents, and young adults with seizures, diabetes, cardiac abnormalities, or Seifert et al.,
mood and behavioral disorders, or those who take certain medications. Of the 5448 U.S. caffeine overdoses reported in 2007, 46% occurred in those younger 2011
than 19 years.
BP=blood pressure; CHD= coronary heart disease; CVD=cardiovascular disease; ED=energy drink(s); HR=heart rate; MI= myocardial infarction
156
5B. Cardiovascular Effects of Caffeine – Animal Studies
A modest number of animal studies were located of which a primary goal was to evaluate
cardiovascular parameters. Studies were excluded from this section if a caffeine-only group was
not included in the experiment, or if exposure was via mother’s milk. The studies showed that
caffeine increased BP and HR, but decreased cerebral blood flow. Caffeine enhanced the tachy-
cardia caused by MDMA, and the slow BP increase of chronic low-dose infusion of angiotensin
II. Caffeine attenuated the effects of an adenosine A2A receptor agonist (regadenoson) on mean
arterial pressure and HR, and the inhibitory effect of adenosine on renin activity and BP (after
one but not 6 weeks of dosing). Acute but not repeated dosing inhibited vasodilation induced by
nicotinic acid. Caffeine did not interact with the asthma drugs (beta-agonists) isoproterenol hy-
drochloride, fenoterol hydrobromide, or terbutaline hemisulfate.
The studies that evaluated the effect of caffeine on cardiovascular parameters in animals
157
TABLE 5-4. Cardiovascular Effects of Caffeine – Animal Studies
Species; Test Test material Caffeine
condition time (route) dose
Dog 1 day pure caffeine 1, 2, 4, 10 Caffeine at 1, 2, 4, and 10 mg/kg decreased the duration of the 2-fold increase in coronary blood flow Zhao et al., 2007
(i.v.) mg/kg (dose-related) caused by the A2A receptor agonist regadenoson; 4 and 10 mg/kg caffeine attenuated the
effects of regadenoson on mean arterial pressure and HR.
Dog; anes- 1 day pure caffeine 1, 2.5, 5 1, 2.5, and 5 mg/kg generated dose-related sinus bradycardia, arrhythmia, arrest, atrial ectopics, wandering Mehta et al.,
thetized (i.v.) mg/kg of pacemaker, and ventricular premature contractions compared with control ECGs. Atrial flutter and fib- 1997
rillation were observed in two experiments only.
Dog 1 day pure caffeine; 5 mg/kg Caffeine did not significantly alter cardiovascular parameters; caffeine + alcohol (400 mg/kg) had synergis- Jain et al., 1999
ethanol (i.v.) tic effects (increased HR, BP), but when the order of drug dosing was reversed (i.e., alcohol was followed
by caffeine), the effect was antagonistic alcohol effects antagonized.
Dog 1 day pure caffeine; 5 mg/kg Caffeine or nicotine caused nonsignificant and significant increases in hemodynamics, respectively. Caf- Jain et al., 1997
nicotine 50 feine + nicotine produced synergistic excitatory effects, but nicotine + caffeine caused attenuation by caf-
µg/kg (i.v.) feine of the excitatory effects produced by nicotine.
Dog 1 day pure caffeine; 5 mg/kg Cocaine + caffeine attenuated cocaine excitatory effects; caffeine+cocaine synergistically increased co- Mehta et al.,
cocaine (i.v.) caine excitatory effects on the cardiovascular system; both agents decreased coronary flow reserve; BP in- 2004
crease.
Mammal- 1 day pure caffeine 3.16x10(-9) to The vasodilator response to caffeine in human internal mammary artery was independent of endothelial Montes et al.,
ian cell (in vitro) 10(-4) mol/ function and was not mediated by potassium channels. 2009
culture
Mouse; 1 day pure caffeine 20 mg/kg Maternal exposure to one dose of caffeine inhibited cardiac ventricular development by 53% in hypoxia Wendler et al.,
pregnant (i.p.); hypoxia and 37% in room air; caffeine exposure inhibited hypoxia-induced HIF1alpha protein expression in em- 2009
bryos by 40%; adult offspring from dams treated with a single dose of caffeine had a 38% decrease in car-
diac function by echocardiography; males exposed to caffeine in utero had a 20% increase in body fat.
Rat 1 day; pure caffeine; 2.5 mg/kg (1 Acute but not repeated dose inhibited nicotinic acid-induced vasodilation (no change in skin temperature). Turenne et al.,
14 d nicotinic acid d); 5 mg/kg/d 2001
(i.p.) (14 d)
Rat 1 day pure caffeine 5, 15, 45 No arrhythmias or visual changes in the ECG complex. The increase in systolic BP at 15 mg/kg remained Ilback et al.,
(gavage) mg/kg for 20 hr; 45 mg/kg induced a biphasic response, with an early increase in body temperature, spontaneous 2007
physical activity, systolic and diastolic BP that later decreased, except for the systolic BP.
Rat 1 day pure caffeine; 10 mg/kg Administration of caffeine + MDMA induced a profound tachycardic response compared to either drug McNamara et al.,
MDMA (s.c.) alone; neither caffeine (30 µM) nor MDMA (1-30 µM), alone or in combination, affected the electrocar- 2007
diogram of the isolated heart.
158
TABLE 5-4. Cardiovascular Effects of Caffeine – Animal Studies
Species; Test Test material Caffeine
condition time (route) dose
Rat; heart 1 day; pure caffeine 10 mg/kg Caffeine infusion increased HR, systolic pressure, and workload in hypertensive but not normotensive rats Tofovic et al.,
failure; 10 d (DW; i.v.) +150 µg/min without affecting cardiac contractility; caffeine increased plasma renin activity, norepinephrine, and epi- 1999
hyperten- over 40 min; nephrine levels, the most in hypertensive rats; 10-day DW treatment only changed (increased) renal renin
sion 0.1% in DW secretion. [Prolonged administration of 0.1% caffeine in the DW results in plasma levels of caffeine (5-10
[~100 mg/kg] µg/mL) that are seen in humans after an intake of 2-3 cups coffee]
Rat 1 day pure caffeine 10, 100 mg/kg Early focal myocardial lesions were histopathologically observed in 7/10 rats 4 hr after i.v. injection with Kemi et al., 1996
(i.v.) 100 mg/kg (not 10 mg/kg) caffeine. The lesions consisted of homogeneously intensely eosinophilic stain-
ing, contraction band formation and fragmentation of cardiac muscle fibers, and were interspersed in the
inner left ventricular walls including the papillary muscles.
Rat 1 day pure caffeine; 16 mg/kg Acute caffeine administration decreased NOS and Bcl2 expression in rat skeletal muscles. Caffeine in- Corsetti et al.,
L-NAME; L- creased mean arterial pressure temporarily, while caffeine + L-NAME increased it for a longer period. The 2007
arg (i.v.) L-arg administration reversed these caffeine and L-NAME effects.
Rat; heavy 1 day pure caffeine 40 mg/kg Caffeine caused myocardial lesions but not death. Whitehurst et al.,
rat model (s.c.) 1994
Rat; 3d coffee; decaf mean 338.0± Caffeinated coffee blunted the myocardial protective effects of statins against ischemia-reperfusion injury. Ye et al., 2008
ischemia- (DW); ator- 48.7 μg/mL in [The caffeine plasma levels were average 5.99±0.11 μg/mL for rats receiving coffee and average 1.73±0.01
reperfusion vastatin (ga- coffee, 24.9± μg/mL for rats receiving decaf]
injury vage) 2.3 μg/mL in
decaf
Rat 7d pure caffeine 25 mg/kg Caffeine did not suppress the circadian rhythmicity of HR, body temperature, or motor activity but in- Pelissier et al.,
(s.c.) creased mesors and decreased amplitudes of the three rhythms and advanced acrophases of temperature 1999
and activity.
Rat; mal- PND 1- pure caffeine 40 mg/kg Decrease in the copper levels of dams' plasma and milk and in pups' plasma and heart tissue; disruption in Asadifar et al.,
nourished 10 (diet) the pups' heart mitochondria; malnutrition caused decreased heart wt. 2005
Rat 140 d Coffee (diet) ~11-22, 25-50 Slightly increased total serum homocysteine and cholesterol; urinary 8-hydroxy-2-deoxyguanosine was Sakamoto et al.,
mg/kg/d significantly increased; no effect on production of IL-6 and TNF-alpha or on serum level of 15-isoprostane 2005
F(2t); serum glutathione peroxidase (GPx) activity tended to decrease.
Rat; kid- 5 mo pure caffeine 0.1, 0.2, 0.32 BP was greater in rats with polycystic kidney disease (PKD) than normal rats and was increased more by Tanner and Tan-
ney disease (DW) mg/mL caffeine; no effect on kidney GFR or cyst development in rats with PKD. ner, 2001
BP=blood pressure; ECG=electrocardiogram; GD=gestational day; HR=heart rate; PND=postnatal day
159
CHAPTER 6. EFFECTS OF CAFFEINE ON EXERCISE−RELATED
PARAMETERS
There is a long-standing interest in the ability of caffeine to enhance performance in

sports (ergogenic aid), prompting human studies in countries all over the world. The vast major-
ity of the studies used a single-day treatment, although a few were repeat-exposure. The studies
tested doses ranging from approximately 1-11 mg/kg. In addition to evaluating its ergogentic
potential, these studies often also determined caffeine’s effect on cardiovascular and respiratory
parameters, energy use, plasma lipids and catecholamines, and the perception of pain or physical
exertion from exercise. Studies in which the primary focus was to evaluate the effect of caffeine
on exercise-related parameters are summarized in Table 6-1.
Most studies showed that caffeine slightly improved physical performance compared to
placebo groups, effects being seen from an intake of ≥100 mg (~1.4 mg/kg). There was a con-
comitant increase in BP and HR, as well as increased levels of plasma epinephrine and/or nore-
pinephrine, cortisol, glycerol, lipids, and lactic acid. The respiratory exchange ratio was often
decreased. Caffeine lowered the perception of physical pain or exertion from intense exercise.
These effects were seen in both habitual coffee drinkers and non-drinkers, although in some
cases a greater response was seen in subjects who were not habitual coffee drinkers. A similar
response was seen whether pure caffeine was ingested (as a solution or capsule), or as a caffeine-
containing beverage such as coffee or an ED. There was insufficient information to determine
which caffeine medium was most potent. Some studies found adverse effects from a dose of ≥6
mg/kg, including anxiety, sleep disturbance, tremors, nervousness, agitation, nausea, and hypo-
kalemia. Thus 6 mg/kg can be considered a LOAEL for these effects in exercising individuals,
and 5 mg/kg a NOAEL. However, some of these adverse effects occurred at lower caffeine in-
takes in studies in which exercise was not involved, as discussed in Chapter 2.
Only a few studies tested children (ages 1-17). These found similar effects as in adults,
but insufficient data were available to determine whether children were more sensitive than
adults to the ergogenic or toxic effects of caffeine.
Reviews of published studies that evaluated the effects of caffeine on exercise-related pa-
rameters are summarized in Table 6-2. The review authors concluded that caffeine taken before
(3-6 mg/kg) or during (1-2 mg/kg) endurance exercise enhances performance, through CNS and
direct muscle effects, whereas higher doses can be toxic and appear to be ergolytic (Tarnopolsky,
2010). Caffeine improves performance and endurance during prolonged, exhaustive exercise
and to a lesser degree short-term, high-intensity athletic performance, and habitual intake does
not diminish caffeine's ergogenic properties. It does not cause significant dehydration or electro-
lyte imbalance during exercise (Paluska, 2003), and has no effect on maximal VO2 or related pa-
rameters (Graham, 2001b). The performance-enhancing effects of caffeine are most probably
related to effects on the CNS rather than to effects on fat oxidation and glycogen sparing (Brouns
and van der Vusse, 1998). Adenosine receptor blockade is the favored mode of explaining caf-
feine ergogenic action. Proposed alternative modes of action involving proteins such as DARPP-
32 (dopamine and cAMP-regulated phosphoprotein) are helping to rationalize the molecular de-
tails of stimulant action in the CNS (Jones, 2008).
160
TABLE 6-1. Impact of Caffeine on Exercise−Related Parameters
Study type; Subject age; Test mate- Caffeine Effects; Comments (sorted by caffeine dose) Reference
country number; sex rial(s) dose(s)
1-d experiment 7-9 yr pure caffeine; 1, 3, 5 mg/kg Low, mild, and moderate (1, 3, and 5 mg/kg) doses of caffeine had no effect on substrate use as re- Turley et al.,
(USA) n=40 (20 M) exercise flected by the respiratory exchange ratio; caffeine increased BP and decreased HR at pre-exercise 2008
and slightly decreased HR at 3 and 5 mg/kg during exercise.
1-d experiment 18.3± 3.0 yr pure caffeine; 3 mg/kg Caffeine increased serve velocity in the final set of the match (P = .014) compared with placebo and Hornery et al.,
(Australia) n=12 M exercise; heat CHO conditions. CHO and cooling afforded physiological advantage (increased blood glucose and 2007
reduced pre-exercise thermal sensation, P < 0.01), but did not affect performance relative to placebo.
1-d experiment 7-9 yr (n=26 pure caffeine; 5 mg/kg BP was not significantly affected by caffeine, but on average it was higher in boys for diastolic BP Turley et al.,
(USA) M); 18-29 yr exercise (3 mm Hg) and systolic BP (3-4 mm Hg) and men for diastolic BP (2-3 mm Hg) and systolic BP (1- 2007
(n=26 M) 6 mm Hg) both at rest and during exercise. HR was significantly (p <0.05) lower at rest, 25W and
50W in caffeine versus placebo in boys, with no change in adults. During exercise, VO2 and respira-
tory exchange ratio were not different in caffeine versus placebo in either group.
1-d experiment 7-9 yr pure caffeine; 10 mg/kg No effect on metabolism (VO2 or respiratory exchange ratio) in young children at low-moderate Turley and
(USA) n=52 (26 M) exercise (split dose) intensities of exercise; BP increased; HR decreased. Gerst, 2006
STUDIES WITH ADULTS
1-d and 28-d ~21± 1 yr caffeine, in 60 mg/d Acute ingestion of CRAM can maintain reaction time, and subjective feelings of focus and alertness Hoffman et
experiment n=19 (17 M) supplement; [0.86 to both visual and auditory stimuli in following exhaustive exercise. However, some habituation may al., 2010
(USA) exercise mg/kg/d] occur following 4 weeks of supplementation. [Supplement= CRAM, containing α-glycerophospho-
choline, choline bitartrate, phosphatidylserine, vitamins B3, B6, and B12, folic acid, L-tyrosine, an-
hydrous caffeine, acetyl-L-carnitine, and naringin]
1-d experiment 41± 8 yr pure caffeine; 4 x 150 mL Caffeine had no effect on GI complaints or performance (no difference from sports drink effects) van Nieuwen-
(The Nether- n=98 (90 M) exercise (90 mg) during an 18-km run. [150 mg caffeine per liter] hoven et al.,
lands) [1.3 mg/kg] 2005
1-d experiment 18-35 yr ED; exercise 80 mg Alertness increased; cognitive/psychomotor improvement; interaction-synergistic or additive; physi- Alford et al.,
(UK) n=36 M+F [1.4 mg/kg] cal performance improved [ED=Red Bull] 2001
1-d experiment Adult pure caffeine; 100 mg Caffeine significantly improved endurance performance and complex cognitive ability during and Hogervorst et
(UK) n=24 M exercise [1.4 mg/kg] after exercise. al., 2008
1-d experiment 29.4± 4.5 yr pure caffeine; 1.5, 3 mg/kg No significant time trial performance improvements; no significant increase in maximal exogenous Desbrow et
(Australia) n=9 M exercise CHO oxidation. al., 2009
1-d experiment 19-25 yr pure caffeine; 1.5, 3.0 Both doses lowered (p < 0.05) HR during submaximal exercise but not at rest or maximal exercise. McClaran and
(USA) n=9 M exercise mg/kg BP was higher (p < 0.05) at rest and after the 3 mg/kg caffeine vs. placebo (116± 13 vs. 123± 10 mm Wetter, 2007
Hg). Neither dose affected BP during submaximal exercise, or had any effect on minute ventilation,
tidal volume, VO2, perceived exertion, maximal power output, or time to exhaustion.
161
1-d experiment 27.1± 1.3 yr pure caffeine; 1.5, 6 mg/kg 6 mg/kg caffeine enhanced time trial performance independent of timing of intake; replacing sports Cox et al.,
(Australia) n1=12 M; cola; exercise drink with Coca-Cola during the latter stages of exercise was equally effective in enhancing endur- 2002
n2=8 M ance performance, primarily due to the intake of caffeine (~1.5 mg/kg).
1-d experiment 23± 4 yr caffeinated 1.6 mg/kg An isotonic CHO sports drink containing caffeine prior to and during a round of golf improved put- Stevenson et
(UK) n=20 M drinks; exer- (split in 3 ting performance and increased feelings of alertness. al., 2009
cise doses)
1-d experiment 20.3± 1.6 yr caffeine, in 110 mg Number of repetitions and training volume tended (p = 0.08) to be higher with the supplement com- Hoffman et
(USA) n=8 M supplement; [1.6 mg/kg] pared to placebo. Serum growth hormone and insulin concentrations were higher at 15 minutes post- al., 2008
exercise and immediately post-exercise, respectively, in the supplement-treated group. [Supplement: combi-
nation of branched chain amino acids, creatine, taurine, caffeine, and glucuronolactone]
1-d experiment 20.5± 1.6 yr ED; exercise 110 mg For fatigue rate, supplement was significantly lower than baseline. Total testosterone and growth Ratamess et
(USA) n=8 M [1.6 mg/kg] hormone responses did not differ between supplement and placebo. [ED=Amino Shooter, consisting al., 2007
of amino acids, creatine monohydrate, taurine, glucuronolactone, and 110 mg of caffeine in 500 mL]
1-d experiment 21.1± 1.3 yr ED; exercise 125 mg Significant increase in reaction performance, with no effect on anaerobic power performance; im- Hoffman et
(USA) n=12 M [1.8 mg/kg] proved subjective feelings of focus and energy. al., 2009
1-d experiment 27.3± 1.7 yr ED; exercise 160 mg Performance improved with ED compared to placebo, but there was no difference in rating of per- Ivy et al.,
(USA) n=12 (6 M) [2.3 mg/kg] ceived exertion between treatments. β-Endorphin levels increased during exercise, with the increase 2009
for ED approaching significance (p = 0.10). Substrate utilization, as measured by open-circuit spi-
rometry, did not differ between treatments. [ED=Red Bull]
1-d experiment 21± 4 yr ED; exercise 2 mg/kg No effect on run time-to-exhaustion, perceived exertion, or blood lactate. [ED= sugar-free Red Bull] Candow et al.,
(Canada) n=17 (9 M) 2009
1-d experiment 21± 5 yr ED; exercise 2 mg/kg Significantly increased upper body muscle endurance but no effect on anaerobic peak or average Forbes et al.,
(Canada) n=15 (11 M) power during repeated Wingate cycling tests in young healthy adults. [ED=Red Bull] 2007
1-d experiment Adult pure caffeine; 2, 4 mg/kg No performance benefits (shooting accuracy, reaction time or target tracking times) to elite perform- Share et al.,
(Australia) n=7 M exercise ers of clay target shooting from ≤ 4 mg/kg caffeine. 2009
1-d experiment 20.6± 1.4 yr pure caffeine; 2, 4, 6 mg/kg Time trial performance was unaffected by caffeine but post-exercise plasma glucose and lactate con- Skinner et al.,
(Australia) n=10 M exercise centrations were increased; there was considerable interindividual variation in plasma caffeine con- 2010
centrations in response to the various caffeine doses.
1-d experiment mean=26± 4 pure caffeine; 2, 5 mg/kg Physical performance improved. Astorino et
(USA) yr; n=15 M exercise al., 2010
162
1-d experiment 26.4± 3.9 yr pure caffeine; 2, 5 mg/kg Across all treatments, pain perception was significantly increased (p < .05) during exercise, as well Astorino et
(USA) n=15 M exercise as from Bout 1 to 2, yet there was no effect (p >.05) of caffeine on pain perception or rating of per- al., 2011
ceived exertion (RPE). Various measures of muscle function were improved (p < .05) with a 5-
mg/kg caffeine dose vs. the other treatments. In the 5-mg/kg trial, it is plausible that subjects were
able to perform better with similar levels of pain perception and exertion.
1-d experiment mean 23.3 yr caffeine, in 2.1, 3.2, 4.5 Before exercise, long term memory was improved by CHO electrolyte solutions (CES) plus low dose Hogervorst et
(The Nether- n=15 M supplement; mg/kg (split caffeine compared to both placebos. Immediately after exercise, all cognitive functions were imal., 1999
lands) exercise dose) proved by CES plus low- and medium-dose caffeine compared to placebo. [Supplement=CES, con-
taining caffeine, vitamins, minerals, amino acids, taurine, myoinositol, and choline]
1-d experiment Adult pure caffeine; 2.5, 5.0 Re-dosing with caffeine after exhaustive exercise in the AM was not necessary to maintain the er- Bell and
(Canada) n=9 M exercise mg/kg 1x or gogenic effect of the drug during subsequent exercise 6 hr later; dose-response not seen. McLellan,
2x/d 2003
1-d experiment 21.5± 1.4 yr caffeine, in 200 mg The active supplement did not alter muscular strength or cycling endurance when compared to a Walter et al.,
(USA) n=20 M supplement; [2.9 mg/kg] placebo trial. The lack of increases in BP and leg press strength and cycle ergometry endurance elic- 2009
exercise ited by this supplement may have been related to the relatively small dose of caffeine, the high inten-
sity of exercise, the untrained status of the participants, and/or the potential for caffeine and capsai-
cin to increase CHO oxidation. [Supplement contained caffeine, capsaicin, bioperine, and niacin]
8-wk experi- 22.4± 2.9 yr caffeine, in 201 mg Caffeine had no ergogenic effects (VO2 peak, time to running exhaustion) or effect on BW, % body Malek et al.,
ment (USA) n=36 (14 M) supplement; [2.9 mg/kg] fat, fat weight, or fat-free weight. [Supplement contained yerba mate, guarana, black tea extract, and 2006
exercise vitamins, with a total of 201 mg caffeine per dose]
1-d experiment Adult pure caffeine; 200, 400, Testosterone concentration increased 15% during exercise; caffeine raised this in a dose-dependent Beaven et al.,
(New Zealand) n=24 M exercise 800 mg manner by 21% (± 24%) at the highest dose, which also increased cortisol by 52% (± 44%), for a 2008
[2.9, 5.7, 11 decrease in the testosterone:cortisol ratio (14%± 21%).
mg/kg]
1-d experiment 24± 7 yr caffeine in 240 mg Caffeine attenuated fatigue during repeated, high-intensity sprint exercise in competitive cyclists; it Paton et al.,
(New Zealand) n=9 M chewing gum; [3.4 mg/kg] was associated with elevated testosterone concentrations and decreased cortisol. 2010
exercise
1-d experiment Adult pure caffeine; 250 mg Caffeine did not enhance short-term performance in non-specific trained subjects despite increased Collomp et
(France) n=8 M exercise [3.6 mg/kg] blood lactate and plasma insulin. al., 2002
1-d experiment Adult pure caffeine; 3 mg/kg Physical performance improved; plasma lactate increase. Bridge and
(UK) n=8 M exercise Jones, 2006
7-d experiment Adult pure caffeine; 3 mg/kg Caffeine, but not green tea, benefited cycling performance; physiological responses after caffeine Dean et al.,
(New Zealand) n=8 M EGCG; exer- ingestion included an increase in HR, glucose at the 40-min exercise time point, and resting plasma 2009
cise free fatty acids; no change in the amount of CHO and fat being oxidized.
163
12-d experi- 21.6± 0.4 yr pure caffeine; 3 mg/kg, There were no between-group differences (p >0.05) in plasma, urinary, thermoregulatory, cardiovas- Roti et al.,
ment (6 or 12 d n=59 M heat; exercise then 0, 3, 6 cular, and perceptual variables across time pre- vs. post-exercise in an exercise heat tolerance test, 2006
treatment) mg/kg although some of these variables increased significantly over time (p < 0.05). The test time was sig-
(USA) nificantly greater at 3 mg/kg vs. 0 mg/kg caffeine.
1-d experiment 19-28 yr pure caffeine; 3, 6 mg/kg 6 mg/kg increased VO2, rate of energy expenditure, and %VO2R; no effect on perceived exertion, Ahrens et al.,
(USA) n=20 F exercise HR, or respiratory exchange ratio. 2007b
1-d experiment 19-28 yr pure caffeine; 3, 6 mg/kg No effect on VO2, VCO2, minute ventilation, respiratory-exchange ratio, rate of energy expenditure, Ahrens et al.,
(USA) n=20 F exercise HR, or perceived exertion. 2007a
1-d experiment 19-34 yr pure caffeine; 3, 6, 9 mg/kg Endurance was enhanced with both 3 and 6 mg/kg but not at 9 mg/kg of caffeine; plasma epineph- Graham and
(Canada) n=8 M exercise rine was increased with 6 and 9 mg/kg; increases in glycerol and free fatty acids at 9 mg/kg. These Spriet, 1995
results are not compatible with the theory that caffeine mediates its ergogenic effect via enhanced
catecholamines.
1-d experiment Adult pure caffeine; 3.0 mg/kg Caffeine significantly improved exercise performance in habitual caffeine users irrespective of Irwin et al.,
(Australia) n=12 M exercise (split dose) whether a 4-day withdrawal period was imposed; HR increase. 2011
1-d experiment 21.3± 3 yr pure caffeine; 3.7 mg/kg The addition of caffeine to the CHO-electrolyte solution improved sprinting performance, counter- Gant et al.,
(New Zealand) n=15 M exercise; movement jumping, and the subjective experiences of players. There were no significant differences 2010
CHO in passing skill, rating of perceived exertion, blood lactate concentration, or body-mass losses be-
tween trials. HR was increased throughout the trials.
1-d experiment 25.5± 0.8 yr pure caffeine; 300 mg No significant effects on HR or systolic BP; spectrum integrated values of the low frequency power Nishijima et
(Japan) n=8 M exercise [4.3 mg/kg] and total power components in the caffeine trial were significantly greater than placebo during exer- al., 2002
cise. Caffeine enhanced lipid oxidation, shown by lower respiratory gas exchange ratio and increased
diastolic BP during exercise.
1-d experiment Adult pure caffeine; 300 mg No effect on muscle strength, muscle endurance, or peak anaerobic power; alertness increased; mood Williams et
(Australia) n=9 M exercise [4.3 mg/kg] improved. al., 2008
1-d experiment 19-42 yr caffeine, in 239 mg Compared with placebo, Xenadrine EFX but not Advantra Z increased systolic and diastolic BP with Haller et al.,
(USA) n=10 (5 M); supplement [3.4 mg/kg] peak changes from baseline at 2 hr of 9.6 ± 6.2 mm Hg systolic (P = 0.047), and 9.1 ± 7.8 mm Hg 2005b
mix [over- diastolic (P = 0.002). HR was increased from baseline at 6 hr compared with placebo (16.7 beats/min
weight] with Xenadrine EFX, P = 0.011; 11.4 beats/min with Advantra Z, P = 0.031)
1-d experiment 18-45 yr caffeine, in 304 mg Synephrine and caffeine pharmacokinetics were unaffected by exercise. Post-exercise diastolic BP Haller et al.,
(USA) n=10 (7 M) supplement; [4.3 mg/kg] was higher after the supplement (peak mean 71.7± 8.7 mm Hg) than placebo (63.0± 4.9 mm Hg). No 2008
exercise differences in post-exercise HR, systolic BP, or temperature. Postprandial plasma glucose increased
with the supplement and exercise vs. placebo and exercise. No effects on exercise-related oxygen
consumption, serum lactate, or insulin; exercise was rated less difficult with DS than placebo. [Sup-
plement= Ripped Fuel Extreme Cut(R) with 21 mg synephrine and 304 mg caffeine by analysis]
164
1-d experiment Adult pure caffeine; 4 mg/kg Caffeine increased the epinephrine and norepinephrine response associated with exercise and also Bell et al.,
(Canada) n=12 M+F exercise increased blood lactate, glucose, and glycerol levels. Run time was decreased compared to placebo. 2002
VO(2) and rating of perceived exertion were not affected.
1-d experiment 17-24 yr pure caffeine; 4 mg/kg Physical performance improved; effect seen only at high altitude. Fulco et al.,
(USA) n=8 M exercise; high 1994
altitude
1-d experiment 21-25 ± 1 yr pure caffeine; 4 mg/kg Caffeine impaired protection of ischemia-reperfusion injury in the thenar muscle by ischemic pre- Riksen et al.,
(The Nether- n=42 M; exercise conditioning (dependent on adenosine receptor stimulation) in humans. 2006
lands)
1-d experiment 22.0± 3.5 yr pure caffeine; 4 mg/kg For CHO + caffeine, 15-m sprints were faster than for placebo (P=0.05) and the motor skills test was Roberts et al.,
(UK) n=8 M CHO; exer- performed faster in the CHO + caffeine trial than the CHO and placebo trials (P < 0.05), while the 2010
cise rating of perceived exertion was lower in the CHO + caffeine trial than the CHO and placebo trials
(P < 0.05).
1-d experiment 51.1± 3.2 yr pure caffeine; 4 mg/kg Caffeine attenuated early post-exercise hypotension: significant reductions in mean and diastolic BP Notarius et
(Canada) n=14 (13 M) exercise (i.v.) (BP) were elicited by prior exercise on the vehicle day (from 93± 2 to 85± 2 mm Hg v from 79± 2 to al., 2006a
73± 3 mm Hg, respectively; both P < .05), but not after caffeine infusion. Systolic and mean BP, 10
min after exercise, were higher on the caffeine than on the vehicle day (by 9± 3 and 6± 2 mm Hg,
respectively; P < .05), as was HR (HR) (100± 5 v 93± 4 beats/min; P < .05).
1-d experiment Adult pure caffeine; F: 260 mg During match play blood glucose did not differ between CAF and PLA. Immediately after the rest- Ferrauti et al.,
(Germany) n=16 (8 M) exercise [4.3 mg/kg] ing period GLU temporary declined in CHO and PLA, while no significant changes occurred in 1997
M: 364 mg CAF. Post-exercise urine concentration of epinephrine was higher in CAF. Perception ratings and
[5.2 mg/kg]; hitting accuracy were not affected by treatment.
1-d experiment 21-47 yr pure caffeine; 4.45 mg/kg Plasma epinephrine was increased by Caffeine ingestion, but the increase was greater with caffeine Graham et al.,
(Canada) n=9 (8 M) coffee; decaf; capsules than with Coffee. Endurance was only increased in the caffeine capsule trial; there were no 1998
exercise differences among the other four tests. One cannot extrapolate the effects of caffeine to coffee; there
must be a component(s) of coffee that moderates the actions of caffeine.
1-d experiment Adult pure caffeine; 4.5 mg/kg Caffeine did not augment markers of muscle damage (CK, LDH, ALT, AST) or leukocyte levels Machado et
(Brazil) n=15 M exercise following exercise. al., 2010
1-d experiment Adult caffeine, all 4.5 mg/kg Caffeine increased systolic BP and diastolic BP at rest and during exercise: systolic BP during exer- Kaminsky et
(USA) n=16 M sources; exer- fat-free mass cise 7-8 mm Hg at all exercise intensities, diastolic BP 4 mm Hg at highest exercise intensity. There al., 1998
cise was a wide range in the resting BP response (combined SBP and DBP was 10-39 mm Hg). No dif-
ferences in effect between regular consumers and non-consumers.
1-d experiment 23.0± 2.6 yr caffeine, in 400 mg The supplement had no effect on 1 repetition maximum (1RM) bench press strength, 1RM leg exten- Hendrix et al.,
(USA) n=21 M supplement; [5.7 mg/kg] sion strength, or time to exhaustion at 80% VO2 peak. [Supplement not identified, but contained 2010
exercise 400 mg of caffeine, 66.7 mg of capsicum extract, 10 mg of bioperine, and 40 mg of niacin]
165
1-d experiment 19-40 yr pure caffeine; 5 mg/kg Lymphocyte count increase, possibly caused by greater muscle cell injury; MCV increase, thrombo- Bassini-
(Brazil) n=22 M exercise cytosis increase; plasma alanine transaminase increase. Cameron et
al., 2007
1-d experiment 32± 7 yr pure caffeine; 5 mg/kg Physical performance improved; effect was greater in caffeine non-habituated users. Bell and Mc-
(Canada) n=21 M+F exercise Lellan, 2002
1-d experiment 31± 5 yr pure caffeine; 5 mg/kg Oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE) and the Bellet al.,
(Canada) n=8 M exercise respiratory exchange ratio were similar during exercise for all trials. HR during exercise was signifi- 1998
cantly increased. Lactate, free fatty acid levels, glycerol levels, and glucose levels were increased.
No significantly changed time to exhaustion. The improved performance was attributed to increased
central nervous system stimulation.
1-d experiment Adult pure caffeine; 5 mg/kg Caffeine increased time to exhaustion and O2 deficit during the cycling to exhaustion, increased Bell et al.,
(Canada) n=24 M exercise blood lactate, glucose, and catecholamine levels. 2001
1-d experiment 19.4± 0.36 yr pure caffeine; 5 mg/kg Ergogenic effects of carnitine coingested with caffeine may be greater than those of carnitine alone. Cha et al.,
(Korea) n=5 M exercise; car- 2001
nitine
1-d experiment 20.4± 2.3 yr pure caffeine; 5 mg/kg No differences in free fatty acids or lactate levels between CAF and placebo during and immediately Denadai and
(Brazil) n=8 M exercise after exercise; glucose increased in the CAF trial; perceived exertion was lower and time to exhaus- Denadi, 1998
tion was significantly higher during exercise below, but not above, the anaerobic threshold. Subjects
were not caffeine-habituated.
1-d experiment 22.7± 6.0 yr pure caffeine; 5 mg/kg Physical performance improved; perceived exertion was unaffected by caffeine; HR increase; mood Duncan and
(UK) n=13 M exercise improved. Oxford, 2011
1-d experiment 26.9± 1.4 yr pure caffeine; 5 mg/kg Increased oxygen uptake, energy expenditure, systolic, diastolic, and mean arterial BP (p < 0.05); Engels et al.,
(USA) n=8 (7 M) exercise effects were similar during constant-load, light intensity cycling and at rest. Respiratory exchange 1999
ratio, cardiac output, HR, stroke volume, and systemic vascular resistance were not significantly
affected.
1-d experiment Adult pure caffeine; 5 mg/kg HR increase; physical performance improved; plasma lactate increase. Glaister et al.,
(UK) n=21 M exercise 2008
1-d experiment 23.4± 3.9 yr pure caffeine; 5 mg/kg Caffeine resulted in a large reduction in leg muscle pain intensity ratings compared with placebo, Gliottoni and
(USA) n=16 F exercise and the reduction in leg muscle pain intensity ratings was larger in those with lower anxiety- Motl, 2008
sensitivity scores than those with higher anxiety-sensitivity scores.
1-d experiment Adult pure caffeine; 5 mg/kg Caffeine ingestion resulted in a statistically significant and moderate reduction in quadriceps muscle- Gliottoni et
(USA) n1=12 M; exercise pain-intensity ratings during the 30-min bout of high-intensity cycle ergometry compared with pla- al., 2009
n2=13 M cebo ingestion in both low (d = -0.42) and high (d = -0.55) caffeine consumers.
166
1-d experiment 21.5± 1.8 yr pure caffeine; 5 mg/kg Caffeine did not impact power output during a 30 s high-intensity cycling bout, and did not impact Greer et al.,
(Canada) n=18 M exercise the neuromuscular drive (similar IEMG scores between treatments) or the frequency content of the 2006
surface EMG signal, and thus the nature of recruited motor units before and after the expression of
fatigue.
1-d experiment 19.7± 2.6 yr coffee; exer- 5 mg/kg During exercise at 22°C, the multiple choice reaction time (RT) was significantly shorter in caffeine Kruk et al.,
(Poland) n=9 M cise than in the placebo test. Cold exposure did not affect RT either at rest or during exercise. Neither 2001
caffeine nor cold exposure influenced the maximal VO2, the maximal HR and blood lactate thresh-
old.
1-d experiment Adult pure caffeine; 5 mg/kg Caffeine trial resulted in 1.1% (90% CI 0.4-1.6) and 1.0% (0.2-2%) faster times for the well-trained O'Rourke et
(Australia) n=30 M+F exercise and recreational runners. al., 2008
1-d experiment 21.3± 0.6 yr pure caffeine; 5 mg/kg Significant subjective and cardiovascular effects of nicotine nasal spray and caffeine individually Perkins et al.,
(USA) n=19 (9 M) exercise; nico- whether resting or engaged in casual physical activity; the combination of nicotine and caffeine gen- 1994a
tine erally produced additive or greater than additive effects for each measure. No differences between
males and females.
1-d experiment ~21± 0.8 yr coffee; decaf; 5 mg/kg Thermogenic effects of nicotine nasal spray and caffeine individually, with the combination produc- Perkins et al.,
(USA) n=20 (10 M) exercise; nico- ing additive effects; expenditure attributable to nicotine, caffeine, or their combination was signifi- 1994b
tine cantly enhanced during activity compared with rest, but only for males.
1-d experiment 25.4± 6.9 yr pure caffeine; 5 mg/kg Running time to exhaustion was significantly (P <0.05) higher in the caffeine trial, but there were no Ping et al.,
(Malaysia) n=9 M exercise differences in (the increase in) HR, core body temperature, oxygen uptake and rate of perceived ex- 2010
ertion from the placebo group.
1-d experiment Adult pure caffeine; 5 mg/kg Endurance time to exhaustion was significantly increased and the respiratory exchange ratio was Ryu et al.,
(Korea) n=?? M exercise significantly lower of the caffeine trial of the placebo trial (p <0.05). Blood free fatty acid and lactate 2001
levels were increased by caffeine ingestion during exercise (p<0.05).
1-d experiment 21± 1 yr pure caffeine; 5 mg/kg The mean values of delta VO(2) were significantly lower in caffeinated than in placebo groups. Santalla et al.,
(Spain) n=9 (8 M) exercise 2001
1-d experiment 26± 2 yr pure caffeine; 5 mg/kg Increased time to exhaustion (14.8%) and accumulated O(2) deficit (6.5%) but no changes in accu- Simmonds,
(Australia) n=6 M exercise mulated O(2) deficit at isotime, VO2 kinetics, blood lactate at exhaustion or peak K(+) following 2010
caffeine ingestion. However, K(+) was significantly reduced (13.4%) during warm-up cycling.
1-d experiment 26± 2 yr pure caffeine; 5 mg/kg During a 100-min euglycemic-hyperinsulinemic (100 microU/ml) clamp, whole-body glucose dis- Thong et al.,
(Denmark) n=7 M exercise posal was reduced (P < 0.05) in caffeine vs. placebo; the AUC over 100 min for insulin-stimulated 2002
glucose uptake in caffeine was reduced ~50% in rested and exercised muscle. Caffeine also reduced
glycogen synthase activity before and during insulin infusion in both legs. Exercise increased insulin
sensitivity of leg glucose uptake in both caffeine and placebo. Caffeine did not alter insulin signal-
ing in either leg. Plasma epinephrine and muscle cAMP concentrations were increased in caffeine.
167
1-d experiment Adult pure caffeine; 5 mg/kg Caffeine-treated had longer time to exhaustion, higher serum free fatty acid levels, smaller decline in Trice and
(USA) n=8 M exercise blood glucose levels than placebo. No effect on serum glycerol or blood lactate, perceived exertion, Haymes, 1995
HR, or O2 cost.
1-d experiment 24.8± 5.6 yr pure caffeine; 5 mg/kg Although there was a clear tendency for improved performance in the Propranolol (Pr) + Caff trial Van Baak and
(The Nether- n=15 M propranolol; compared to the Pr trial, it was not associated with increased plasma FFA concentration and/or re- Saris, 2000
lands) exercise duced plasma potassium concentration. These results do not support the hypothesis that caffeine im-
proves endurance performance by stimulating lipolysis or lowering plasma potassium concentration.
1-d experiment Adult ED ± caf- 5 mg/kg Relaxed G tolerance was 13% higher with caffeinated ED; hip adductor muscle strength was 37% Walker et al.,
(USA) n=10 (8 M) feine; exercise higher from caffeinated or uncaffeinated ED; simulated air combat maneuver duration was unaf- 2010
fected. [ED= Full Throttle®, containing 9.0 mg caffeine per 1 oz fluid]
1-d experiment 32± 6 yr pure caffeine; 5 mg/kg Caffeine ingestion resulted in improved performance time, mean speed, mean power, and peak Wiles et al.,
(UK) n=8 M exercise power compared with the placebo and/or control condition. 2006
1-d experiment 24.1± 5.8 yr pure caffeine; 5 mg/kg During the caffeine trial, more total weight was lifted with the chest press, and a greater peak power Woolf et al.,
(USA) n=18 M exercise was obtained during the Wingate test. No effects on leg press and average power, minimum power, 2008
and power drop (Wingate test). Postexercise systolic BP, glucose, insulin, and cortisol higher con-
centrations were found in the caffeine trial. No effect on serum free-fatty-acid concentrations,
plasma lactate concentrations, serum cortisol concentrations, HR, or rating of perceived exertion.
1-d experiment 20± 2 yr pure caffeine; 5 mg/kg No significant differences were found between treatments for the exercise tests. However, 59% of Woolf et al.,
(USA) n=17 M exercise the participants improved in performance with the caffeine during the bench press and the 40-yard 2009
dash. No differences were found between treatments for rating of perceived exertion, HR, and BP.
1-d experiment 18-43 yr caffeine + 5 mg/kg Pre-exercise caffeine condition was associated with a significant increase of HR variability, espe- Yeragani et
(USA) n=11 (6 M) caffeine-free cially in the high-frequency range (0.15-0.5 Hz), and also approximate entropy (APEN), which is al., 2005
diet cola; usually attributed to cardiac vagal function. But during progressive exercise, caffeine intake resulted
exercise in a greater decrease of HF power as well as HR APEN. Caffeine also was associated with signifi-
cantly higher LF power during exercise compared to the placebo condition.
1-d experiment 21-26 yr pure caffeine; 5 mg/kg A 100-mg dose of caffeine enhanced swimming performance in training and competition by ap- Vandenbogae-
(New Zealand) n= 10 (6 M) exercise proximately 1.3%. There were substantial but unclear individual responses to training and caffeine rde and Hop-
(SD of 0.3% and 0.8%, respectively). kins, 2010
1-d experiment Adult pure caffeine; 5 mg/kg caf- Prior consumption of coffee did not decrease the ergogenic effect of the subsequent ingestion of an- McLellan and
(Canada) n=13 M+F coffee; decaf; feine; 1.1 hydrous caffeine. Bell, 2004
exercise mg/kg in
coffee
3-d experiment 21-24 yr pure caffeine; 5 mg/kg/d x Caffeine intake (3 days) prolonged muscle relaxation time, which overrode the shortening of relaxa- Hespel et al.,
(Belgium) n=10 (9 M) creatine; exer- 1 d or 3 d tion time due to creatine. 2002
cise
168
2-d experiment 29.8 ± 5.8 yr pure caffeine; 5 mg/kg 1-5x Relative to the caffeinated state, 48-hr caffeine withdrawal resulted in no significant differences in Hetzler et al.,
(USA) n=6 M exercise [caf- over 48 hr absolute O2 uptake, O2 uptake relative to maximal O2 uptake, respiratory exchange ratios, or free 1994
feine- [2.5-12.5 fatty acid concentrations. Glycerol levels were significantly attenuated in the withdrawal condition.
deprived] mg/kg/d]
1-d experiment 27± 2 yr pure caffeine; 5 mg/kg/hr x Average exogenous CHO oxidation over the 90- to 120-min period was 26% higher (P < 0.05) in Yeo et al.,
(UK) n=8 M 48 g glu- 2 hr Glu+Caf compared with Glu. Total CHO oxidation rates were higher (P < 0.05) in the CHO inges- 2005
cose/hr x 2 hr; tion trials compared with water, but they were highest when Glu+Caf was ingested. There was also a
exercise trend (P = 0.082) toward an increased endogenous CHO oxidation with Glu+Caf.
1-d experiment 23-51 yr pure caffeine; 5, 9 mg/kg No ergogenic benefit in endurance races during high heat stress; no effects on blood levels of Na+, Cohen et al.,
(USA) n=7 (5 M) exercise; heat K+, glucose, lactate, or hematocrit. 1996
1-d experiment Adult pure caffeine; 5, 10 mg/kg Perception of pain/physical exertion lowered; dose-response not seen. Motl et al.,
(USA) n=11 F exercise 2006
1-d experiment 22.2± 2.7 yr pure caffeine; 5, 10 mg/kg Caffeine increased resting systolic BP (dose-dependent) that was not maintained during exercise. O'Connor et
(USA) n=12 M exercise Caffeine had a significant linear inverse effect on leg muscle pain ratings. The reduction of leg mus- al., 2004
cle pain during cycling exercise was unrelated to BP.
1-d experiment 22.1± 2.8 yr pure caffeine; 5, 9, 13 A significant increase in endurance performance was found for all caffeine tests compared to pla- Pasman et al.,
(The Nether- n=9 M exercise mg/kg cebo, with no dose-response; increased free fatty acid and glycerol concentration in blood (no dose- 1995
lands) response).
1-d experiment M=26.8± 6 pure caffeine; 5, then 2.5 Caffeine ingestion improved target detection and engagement speed during vigilance situations, but Gillingham et
(Canada) yr; F=26.3 ± exercise mg/kg was not effective during more complex operations requiring higher levels of cognitive processing al., 2004
6 yr (n=12, 9 and fine motor control and coordination.
M)
1-d experiment Adult pure caffeine; 5.3 mg/kg Peak exogenous CHO oxidation rates were not different between glucose (GLU) and GLU + caf- Hulston and
(UK) n=10 M glucose solu- feine trials. Rates of appearance and disappearance of glucose were higher with GLU ingestion than Jeukendrup,
tion; exercise placebo (P < 0.01) but were similar for GLU and GLU + caffeine trials. 2008
1-d experiment 27.5± 7.0 yr ED; exercise; 5.7 mg/kg HR increase; hyperthermia; sweat rate, urine output, and serum electrolytes accumulation were not Millard-
(USA) n=16 M heat (1.2+3.5) affected. [ED=PowerAde, containing vitamins B3, B6, and B12; carnitine, taurine, and 195 mg/L Stafford et al.,
caffeine] 2007
1-d experiment 25± 6 yr pure caffeine; 6 mg/kg Increased ambient temperature had a detrimental effect on cycling performance in both the caffeine Ganio, 2010a
(USA) n=11 M exercise; heat (split dose) and placebo; caffeine improved performance independent of environmental temperature (12 and
33°C).
1-d experiment 25± 6 yr pure caffeine; 6 mg/kg Although exercise in the heat increased muscle pain compared to a cooler environment (12°C vs. Ganio et al.,
(USA) n=11 M exercise (split dose) 33°C), caffeine reduced this pain. 2011
169
1-d experiment 25.5± 5 yr pure caffeine; 6 mg/kg as Dividing a caffeine dose provided no ergogenic effect over a bolus dose but reduced postexercise Conway et al.,
(Australia) n=9 M exercise one or two urinary concentration; nervousness, agitation; nausea or vomiting. 2003
doses
1-d experiment 23.4± 3.6 yr pure caffeine; 6 mg/kg Significant (P < 0.05) increases in HR (+10 beats/min), systolic BP (+8-10 mm Hg), and rate- Astorino et
(USA) n=22 M exercise pressure product with caffeine ingestion versus placebo, but no change in diastolic BP across time or al., 2007
treatment after resistance training.
1-d experiment 18-29 yr pure caffeine; 6 mg/kg Non-significant increase in muscular strength or endurance; anxiety/irritability; BP increase; energy Astorino et
(USA) n=22 M exercise expenditure/thermal increase; HR increase; sleep disturbance or insomnia; tremors. al., 2008
1-d experiment 23.1± 1.1 yr pure caffeine; 6 mg/kg Small but significant increase (p < 0.05) on repetitions completed for the leg press but not for upper- Astorino et
(USA) n=14 M exercise body exercise. Total weight lifted across sets was similar, yet there were 9 'responders' to caffeine, al., 2011b
represented by a meaningful increase in total weight lifted with caffeine vs. placebo.
1-d experiment Adult pure caffeine; 6 mg/kg Plasma lactate increased; physical performance improved. Carr et al.,
(Australia) n=10 M exercise 2008
1-d experiment Adult pure caffeine; 6 mg/kg Hypokalemia; physical performance worse; plasma lactate increase. Crowe et al.,
(Australia) n=17 (12 M) exercise 2006
1-d experiment 30± 0.3 yr pure caffeine; 6 mg/kg Before exercise, caffeine increased both systolic BP (17%) and mean arterial pressure (11%) without Daniels et al.,
(USA) n=10 (3 M) exercise affecting forearm blood flow (FBF) or forearm vascular conductance (FVC). During dynamic exer- 1998
cise, caffeine attenuated the increase in FBF (53%) and FVC (50%) and accentuated exercise-
induced increases in angiotensin II (44%). Subjects were not caffeine-habituated.
1-d experiment Adult pure caffeine; 6 mg/kg During prolonged exercise in the heat, caffeine ingestion maintained maximal cycling power despite Del Coso et
(Spain) n=7 M exercise; heat dehydration and hyperthermia. When combined with water and CHO, caffeine ingestion increased al., 2008
maximal leg force by increasing voluntary activation (i.e., reducing central fatigue).
1-d experiment Adult pure caffeine; 6 mg/kg Sweat loss of sodium, chloride, and potassium increased; diuresis; hyperthermia. Del Coso et
(Spain) n=7 M exercise; heat al., 2009
1-d experiment Adult coffee; decaf; 6 mg/kg No effect on oxygen uptake, respiratory exchange ratio, HR, or plasma lactate; perception of Demura et al.,
(Japan) n=10 M exercise pain/physical exertion lowered. 2007
1-d experiment Adult pure caffeine 6 mg/kg Caffeine ingestion resulted in consistently faster total time (2.3%), reactive agility time (3.9%), Duvnjak-
(Australia) n=10 M movement time (2.7%) decision time (9.3%), and decision making accuracy (3.8%) compared to Zaknich et al.,
placebo. 2011
1-d experiment 23± 3 yr pure caffeine; 6 mg/kg No effect of prior caffeine ingestion on neuromuscular recovery after maximal fatiguing contrac- Fimland et al.,
(Norway) n=13 M exercise tions. 2010
1-d experiment 23.8 ± 4.5 yr pure caffeine; 6 mg/kg Caffeine ingestion before simulated soccer activity improved players' passing accuracy and jump Foskett et al.,
(New Zealand) n=12 M exercise performance without any detrimental effects on other performance parameters. 2009
170
1-d experiment 18-45 yr pure caffeine; 6 mg/kg Greater bench press maximum with caffeine (p ≤ 0.05) with no significant differences between con- Goldstein et
(USA) n=15 F exercise ditions in 60% 1RM repetitions (p = 0.81). Systolic BP was significantly greater post-exercise, with al., 2010b
caffeine (p < 0.05) (116.8± 5.3 mm Hg vs. 112.9± 4.9 mm Hg).
1-d experiment Adult pure caffeine; 6 mg/kg In bench press, no significant differences (Caff vs. Placebo) were observed (reps, ratings of per- Green et al.,
(USA) n=17 M+F exercise ceived exertion (RPE) or peak HR. During set 3 of leg press training, caffeine was associated with 2007
significantly higher reps and peak HR (158.5± 11.9 vs. 151.8± 13.2). No RPE differences were
found during leg press.
1-d experiment 29.1± 2.7 yr pure caffeine; 6 mg/kg No ergogenic effect of caffeine on power output during repeated bouts of short-term, intense exer- Greer et al.,
(Canada) n=9 M exercise cise; no increase in anaerobic metabolism (blood lactate, O2 consumption, or aerobic contribution) 1998
after caffeine ingestion except for an increase in NH3 concentration. Plasma epinephrine concentra-
tion was significantly increased 60 min after caffeine ingestion, but the increase disappeared once
exercise began.
1-d experiment Adult pure caffeine; 6 mg/kg Caffeine resulted in greater (p < 0.05) HR for leg extensions (LE) and arm curls (AC), total repeti- Hudson et al.,
(USA) n=15 M exercise tions (for LE), and repetitions in set 1 (for LE and AC) compared with aspirin and placebo. 2008
1-d experiment 23.5± 2.0 yr pure caffeine; 6 mg/kg Increase in endurance and in plasma epinephrine but not norepinephrine; blood lactate not affected Jackman et
(Canada) n=14 (11 M) exercise but during the exercise bouts muscle lactate concentration was increased. The net decrease in muscle al., 1996
glycogen was not different between treatments.
1-d experiment 22.3± 2.4 yr pure caffeine; 6 mg/kg Voluntary activation at maximal voluntary contraction increased but there was no change in H-reflex Kalmar and
(Canada) n=11 M muscle con- amplitude. Neither the force-EMG relationship nor motor unit firing rates were altered. Time to fa- Cafarelli,
traction tigue increased, and was associated with an attenuated decline in twitch amplitude. 1999
1-d experiment Adult pure caffeine; 6 mg/kg End-exercise GI temperature, ventilation and tidal volume were higher in CAFF compared to PLA; Kellawan et
(Canada) n=10 M exercise perceived exertion was decreased and the physiological strain index was increased in the caffeine al., 2009
condition.
1-d experiment 26± 1 yr pure caffeine; 6 mg/kg Muscle glycogen content was increased; after cycling 2 h, caffeine-treated had greater increase in Laurent et al.,
(USA) n=20 M exercise plasma lactate, epinephrine, and cortisol levels. Plasma free fatty acid increase and muscle glycogen 2000
decrease were similar in both groups. Plasma beta-endorphin almost doubled in the caffeine-treated
group vs. no change in the placebo group.
1-d experiment Adult pure caffeine; 6 mg/kg No significant change was observed in the proagility run after caffeine ingestion compared with pla- Lorino et al.,
(USA) n=16 M+F exercise cebo. No significant change was observed in peak power, mean power, or percent power decrease. 2006
1-d experiment 30.7± 12 yr pure caffeine; 6 mg/kg The cyclists rode significantly further in the caffeine trial but no differences were seen in HR or in McNaughton
(UK) n=6 M exercise the amount of blood lactate increase. et al., 2008a
1-d experiment 30.2±10.1 yr pure caffeine; 6 mg/kg The cyclists rode significantly further in the caffeine trial and had a lower respiratory exchange ratio. McNaughton
(UK) n=8 M exercise The free fatty acid concentrations were significantly higher in the caffeine trials both post ingestion et al., 2008b
(P < 0.005) and post exercise (P < 0.0001) than control or placebo trials.
171
1-d experiment 23.5± 4.7 yr pure caffeine; 6 mg/kg Increased limit of endurance. The amplitude of the evoked twitch and its maximal instantaneous rate Meyers and
(Canada) n=10 M exercise of relaxation did not decline to the same degree in the caffeine trial of the responders. Cafarelli,
2005
1-d experiment 74.7± 5.5 yr pure caffeine; 6 mg/kg Perception of pain/physical exertion lowered; physical performance improved; motor steadiness im- Norager et al.,
(Denmark) n=30 (15 M) exercise paired. 2005
1-d experiment Adult pure caffeine; 6 mg/kg Negligible effect on mean sprint performance and fatigue. Paton et al.,
(New Zealand) n=16 M exercise 2001
1-d experiment 22.6± 0.6 yr pure caffeine; 6 mg/kg Perception of pain/physical exertion lowered; physical performance improved. Plaskett and
(Canada) n=15 M exercise Cafarelli,
2001
1-d experiment Adult pure caffeine; 6 mg/kg Caffeine improved repeated sprint ability, including next day performance, but had little effect on Pontifex et al.,
(Australia) n=10 M exercise reactive agility time or sleep quality. 2010
1-d experiment Adult pure caffeine; 6 mg/kg No effect on plasma glucose kinetics or energy substrate oxidation during prolonged exercise in Roy et al.,
(Canada) n=12 (7 M) exercise trained endurance athletes; plasma lactate increase. 2001
1-d experiment 20± 3 yr pure caffeine; 6 mg/kg The total amount of sprint work performed during the caffeine trial was 8.5% greater than during the Schneiker et
(Australia) n=10 M exercise placebo trial in the first half, and was 7.6% greater in the second half. The mean peak power during al., 2006
sprints in the caffeine trial was 7.0% greater than during the placebo trial in the first half, and was
6.6% greater in the second half.
1-d experiment Adult pure caffeine; 6 mg/kg Increased cutaneous blood flow during exercise in the heat was not reduced by caffeine; BP increase; Stebbins et
(USA) n=11 M exercise; heat HR increase; plasma lactate increase. al., 2001
1-d experiment Adult pure caffeine; 6 mg/kg Caffeine improved mean performance: sprint speeds, first-drive power, second-drive power, and Stuart et al.,
(New Zealand) n=9 M exercise passing accuracy. The enhancements were mediated partly through a reduction of fatigue and partly 2005
by enhanced performance for some measures from the first circuit. Caffeine increased the mean epi-
nephrine concentration; correlations between individual changes in epinephrine concentration and
changes in performance were mostly unclear, but there were some strong positive correlations with
sprint speeds and a strong negative correlation with passing accuracy.
1-d experiment n1=29± 7 yr pure caffeine; 6 mg/kg Caffeine potentiated the force of contraction during the final minute of the 20-Hz stimulation (P Tarnopolsky
(Canada) (6 M) exercise <0.05) with no effect of habituation. There was no effect of caffeine on 40-Hz stimulation strength, and Cupido,
n2=26± 4 yr maximal voluntary contraction, or peak twitch torque. 2000
(6 M)
1-d experiment 36.7± 4.2 pure caffeine; 6 mg/kg Subjects responded to caffeine with increases in plasma epinephrine (P < 0.05) at exhaustion and Van Soeren
(Canada) n=6 M exercise prolonged exercise time in all caffeine trials vs. placebo, regardless of caffeine withdrawal. and Graham,
1998
172
1-d experiment Adult pure caffeine; 6 mg/kg Caffeine ingestion had no effect on the PMA-stimulated oxidative burst response to prolonged cy- Walker et al.,
(UK) n=19 M exercise cling, yet it attenuated the exercise-induced decline in f-MLP stimulated response that occurred with 2006
placebo. Caffeine ingestion significantly increased serum caffeine concentration, plasma adrenaline
concentration, and lymphocyte count following exercise, but there was no effect on neutrophil num-
ber. [PMA=phorbol 12-myristate 13-acetate; f-MLP= N-formyl-methionyl-phenyl-alanine]
1-d experiment Adult pure caffeine; 6 mg/kg Ingestion of CAF+CHO (CHO=6% carbohydrate drink) attenuated epinephrine and IL-6 responses Walker et al.,
(UK) n=12 M exercise; that occurred after ingestion of CAF alone and the transient alterations in circulating leukocyte and 2007
CHO neutrophil counts. Perceived exertion during exercise was significantly lower on CAF/CHO than the
other three trials (P<0.05).
1-d experiment Adult pure caffeine; 6 mg/kg Time-trial performance was 4% faster in the caffeine than placebo trial (P = 0.043). Caffeine was Walker et al.,
(UK) n=9 M exercise associated with an increased plasma adrenaline concentration after 90 min of exercise (P = 0.046) 2008
and immediately after the time-trial (P = 0.02). However, the f-MLP-stimulated neutrophil oxidative
burst response fell after exercise (P = 0.002). There was no effect of caffeine on circulating leuko-
cyte or neutrophil counts, but the lymphocyte count was significantly lower on caffeine (20%) after
the time-trial. [f-MLP= N-formyl-methionyl-phenyl-alanine]
1-d experiment 21± 1 yr pure caffeine; 6 mg/kg Caffeine and exercise were associated with a greater heat shock protein ehsp72 response than exer- Whitman et
(UK) n=10 M exercise cise alone. The increased ehsp72 was associated with a greater epinephrine response to exercise with al., 2006
caffeine. There was an increase in norepinephrine and cortisol, with no intertrial differences.
4-d experiment Adult pure caffeine; 6 mg/kg Caffeine enhanced maximal voluntary strength and activation in uninjured but not injured muscle. Park et al.,
(USA) n=13 (4 M) exercise 2008
1-d experiment 23.5± 6.7 yr pure caffeine; 6 mg/kg, Caffeine increased mean HR during both high intensity epochs (HIE), but had no effect on HIE av- Hunter et al.,
(South Africa) n=8 M exercise then 0.33 erage power, time to completion, 100-km time to completion, EMG amplitude or mean power fre- 2002
mg/kg quency spectrum.
1-d experiment Adult pure caffeine; 6 mg/kg Increased time to exhaustion; increased plasma epinephrine, blood glycerol, and muscle camps at 15 Greer et al.,
(Canada) n=15 M exercise min; no effect on muscle glycogen use. 2000
1-d experiment Adult pure caffeine; 6, 9 mg/kg Physical performance improved; plasma lipids increase. Bruce et al.,
(New Zealand) n=8 M exercise 2000
1-d experiment 22± 3 yr pure caffeine; 6, 9 mg/kg Plasma free fatty acid concentrations before exercise were higher with caffeine than for 6 and 9 Anderson et
(Australia) n=8 F exercise mg/kg caffeine and placebo, respectively; p <.05). Performance time improved 0.7% (CI: 0 to 1.5%) al., 2000
with 6 mg/kg caffeine and 1. 3% (CI 0.5 to 2.0%) with 9 mg/kg caffeine.
1-d experiment ~28±4 yr; ED; coffee; 450 mg The ED significantly increased VO2 at 3 minutes post-exercise when compared to baseline (p = Roberts et al.,
(USA) n=10 (5 M) decaf; exer- [6.4 mg/kg] 0.04) and decaf (p = 0.02) values in regular coffee drinkers (mean 223.9 ± 62.7 mg/d). [ED= 2007
cise JavaFittrade mark Energy Extreme (JEE), containing 450 mg caffeine, 1200 mg garcinia cambogia,
360 mg citrus aurantium extract, and 225 mcg of chromium polynicotinate]
173
1-d experiment Adult pure caffeine; 7 mg/kg Lung function improved; perception of pain/physical exertion lowered; physical performance im- Birnbaum and
(USA) n=10 (5 M) exercise proved. Herbst, 2004
1-d experiment 26.9± 5.6 yr pure caffeine; 8 mg/kg In trained subjects coingestion of caffeine with CHO (4 g/kg) had an additive effect on rates of post- Pedersen et
(Australia) n=7 M CHO; exer- exercise muscle glycogen accumulation compared with consumption of CHO alone. al., 2008
cise
1-d experiment 18-37 yr pure caffeine; 9 mg/kg Caffeine did not enhance endurance exercise performance during compensable heat stress. Cheuvront et
(USA) n=10 M exercise; heat al., 2009
1-d experiment 23.9± 0.9 yr pure caffeine; 9 mg/kg Muscle glycogen use decreased by 28% after caffeine in 6 of 12 subjects; in both groups, caffeine Chesley et al.,
(Canada) n=12 M exercise increased resting free fatty acid concentration, increased epinephrine concentration twofold during 1998
exercise, and increased the muscle glycogen phosphorylase a mole fraction at 3 min of exercise
compared with placebo, although NS. Caffeine improved the energy status of the muscle during ex-
ercise in the glycogen sparers group: muscle phosphocreatine degradation was significantly reduced
and the accumulations of free ADP and free AMP were significantly reduced. Caffeine had no effect
on these measurements in the glycogen nonsparers group. [Glycogen "sparing" was defined as a
≥10% reduction in muscle glycogen use during exercise compared with placebo]
1-d experiment 21.4± 2.3 yr pure caffeine; 10 mg/kg Exercise reduced caffeine-induced anxiety. Motl and Dis-
(USA) n=16 M exercise hman, 2004
1-d experiment 21.4± 2.3 yr pure caffeine; 10 mg/kg Perception of pain/physical exertion lowered. Motl et al.,
(USA) n=16 M exercise 2003
1-d experiment M=27± 0.8 pure caffeine; 750 mg (split The cortisol response to mental stress was smaller in F than M. Caffeine + mental stress further in- Lovallo et al.,
(USA) yr; F= 30± stress; exer- in 3 doses) creased cortisol levels, similarly in M and F. Exercise alone did not increase cortisol, but caffeine 2006
0.9 yr cise [11 mg/kg] taken before exercise elevated cortisol in M and F. After a postexercise meal, F had a larger cortisol
n=96 M+F response than M, which was increased after caffeine. Repeated caffeine dosing increased cortisol
levels across the test day without regard to the sex of the subject or type of stressor.
1-d experiment 25.1± 3.8 yr pure caffeine; 800 mg State anxiety was elevated by caffeine, which was reduced by exercise; BP increase. Youngstedt et
(USA) n=11 M exercise [11 mg/kg] al., 1998
174
TABLE 6-2. Impact of Caffeine on Exercise−Related Parameters – Summaries of Reviews Reference
Caffeine consumption (3-9 mg/kg BW) before exercise delays fatigue and increases the performance of individuals engaging in prolonged moderate exercise, Adler, 2000
and possibly also in intense short-term exercise.
Unrestrained consumption of dietary supplements (including caffeine) should be avoided by adolescents, since, besides the lack of evidence that such practice Alves and Lima,
will lead to improvement of performance, it exposes adolescents to several adverse effects. 2009
Many (11/17) studies revealed significant improvements in team sports exercise and power-based sports with caffeine ingestion, yet these effects were more Astorino and
common in elite athletes who do not regularly ingest caffeine; 6/11 studies showed significant benefits of caffeine for resistance training. Some studies showed Roberson, 2010
decreased performance with caffeine ingestion when repeated bouts are completed.
There is good evidence that caffeine can improve single-sprint performance, while caffeine, creatine and sodium bicarbonate ingestion have all been demon- Bishop, 2010
strated to improve multiple-sprint performance; anecdotal reports suggest that team-sport athletes often ingest more than one dietary supplement and very little is
known about the potential adverse effects of ingesting multiple supplements.
The performance-enhancing effects of caffeine are most probably related to effects on the CNS rather than to effects on fat oxidation and glycogen sparing. Brouns and van
der Vusse, 1998
The literature suggests that performance benefits can be seen with moderate amounts (~3 mg/kg body mass) of caffeine, and these benefits are likely to occur Burke, 2008
across a range of sports, including endurance events, stop-and-go events, and sports involving sustained high-intensity activity lasting from 1-60 min. The direct
effects on single events involving strength and power, such as lifts, throws, and sprints, are unclear.
Caffeine acts antagonistically on adenosine receptors, thereby inhibiting the negative effects adenosine induces on neurotransmission, arousal, and pain percep- Davis and
tion. The hypoalgesic effects of caffeine have resulted in dampened pain perception and blunted perceived exertion during exercise. This could potentially have Green, 2009
favorable effects on negating decreased firing rates of motor units and possibly produce a more sustainable and forceful muscle contraction.
Caffeine improved test outcome by 12.3% (95 % CI, 9.1 to 15.4); time-to-exhaustion (Tlim) protocols had a significantly greater effect than either the graded or Doherty and
the non-Tlim protocol(s). Smith, 2004
International society of sports nutrition position stand on caffeine and performance: 1.) Caffeine is effective for enhancing sport performance in trained athletes Goldstein et al.,
when consumed in low-to-moderate dosages (~3-6 mg/kg) and overall does not result in further enhancement in performance when consumed in higher dosages 2010a
(≥ 9 mg/kg). 2.) Caffeine exerts a greater ergogenic effect when consumed in an anhydrous state as compared to coffee. 3.) It has been shown that caffeine can
enhance vigilance during bouts of extended exhaustive exercise, as well as periods of sustained sleep deprivation. 4.) Caffeine is ergogenic for sustained maxi-
mal endurance exercise, and has been shown to be highly effective for time-trial performance. 5.) Caffeine supplementation is beneficial for high-intensity exer-
cise, including team sports such as soccer and rugby, both of which are categorized by intermittent activity within a period of prolonged duration. 6.) The litera-
ture is equivocal when considering the effects of caffeine supplementation on strength-power performance, and additional research in this area is warranted. 7.)
The scientific literature does not support caffeine-induced diuresis during exercise, or any harmful change in fluid balance that would negatively affect perform-
ance.
Caffeine does not improve maximal oxygen capacity directly, but could permit the athlete to train at a greater power output and/or to train longer. It has also Graham, 2001a
been shown to increase speed and/or power output in simulated race conditions. Intake does not cause dehydration, ion imbalance, or any other adverse effect.
Caffeine as coffee appears to be ineffective compared to pure caffeine. Male and female athletes have similar caffeine pharmacokinetics.
175
TABLE 6-2. Impact of Caffeine on Exercise−Related Parameters – Summaries of Reviews Reference
It is clear that caffeine, in moderate amounts, can be used orally as an ergogenic aid in aerobic activity lasting for more than 1 min. It increases endurance and Graham, 2001b
speed, but not maximal VO2 and related parameters. While there are fewer well-controlled studies for resistance exercise, the literature would suggest similar
improvements: increased endurance at submaximal tension and power generated in repeated contractions and no change in maximal ability to produce force. It
appears unlikely that increased fat oxidation and glycogen sparing is the prime ergogenic mechanism.
Caffeine may significantly improve selected volitional anaerobic performances while inhibiting others. Primarily dependent on dose and tolerance, caffeine in- Jacobson, 1998
gestion may influence voluntary strength of large muscle groups, reaction time and movement time following a visual stimulus, reflex time, and selected visu-
ally dependent tasks.
Adenosine receptor blockade is the favored mode of explaining caffeine ergogenic action. Proposed alternative modes of action involving proteins such as Jones, 2008
DARPP-32 (dopamine and cAMP-regulated phosphoprotein) are helping to rationalize the molecular details of stimulant action in the CNS.
Caffeine and carbohydrate loading have the most evidence-based support of being both ergogenic and safe. Juhn, 2002
Some supplements do offer the prospect of improved performance; these include creatine, caffeine, bicarbonate and, perhaps, a few others. Maughan et al.,
2004
Caffeine can improve performance, in part by a stimulation of fatty acid mobilization and sparing of the body's limited carbohydrate stores, but also via direct Maughan, 1999
effects on muscle and possibly by CNS effects on the perception of effort and fatigue.
Caffeine improves performance and endurance during prolonged, exhaustive exercise and to a lesser degree short-term, high-intensity athletic performance. Caf- Paluska, 2003
feine improves concentration, reduces fatigue, and enhances alertness. Habitual intake does not diminish caffeine's ergogenic properties. It has no known nega-
tive performance effects, nor does it cause significant dehydration or electrolyte imbalance during exercise.
Lower doses can be as effective as higher doses during exercise performance without any negative coincidence; after a period of cessation, restarting caffeine Sokmen et al.,
intake at a low amount before performance can provide the same ergogenic effects as acute intake; caffeine can be taken gradually at low doses to avoid toler- 2008
ance during the course of 3 or 4 days, just before intense training to sustain exercise intensity; and, caffeine can improve cognitive aspects of performance, such
as concentration, when an athlete has not slept well.
Caffeine ingestion (3-9 mg/kg BW) prior to exercise increases performance during prolonged endurance exercise and short-term intense exercise lasting ~5 Spriet, 1995
minutes in the laboratory. Caffeine does not appear to enhance performance during incremental exercise tests lasting 8-20 min or during sprinting lasting less
than 90 seconds.
Caffeine at doses of ~ 6 mg/kg is not of ergogenic benefit to high intensity exercise performance, but similar doses are ergogenic in endurance exercise perform- Tarnopolsky,
ance. 1994
Caffeine taken before (3-6 mg/kg) or during (1-2 mg/kg) endurance exercise enhances performance, through CNS and direct muscle effects. Higher doses of Tarnopolsky,
caffeine can be toxic and appear to be ergolytic. 2010
Analysis of 34 studies conducted between 1939 and 2008 (27 on maximal voluntary contraction strength and 23 on muscular endurance) indicated that caffeine Warren et al.,
ingestion improves maximal voluntary contraction strength exclusively in the knee extensors, and improves muscular endurance only with open end point tests. 2010
176
CHAPTER 7. EFFECTS OF CAFFEINE ON BODY WEIGHT, GLUCOSE,
LIPIDS, AND ENERGY USE
7A. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Humans
A number of experimental and epidemiological studies examined the effect of caffeine on

plasma lipids, glucose, and insulin, as they related to heart disease (via increased blood lipids),
diabetes (via increased blood glucose and decreased insulin sensitivity), and weight loss (via in-
creased fat oxidation and resting energy expenditure (REE)). For weight loss, caffeine was often
ingested together with tea catechins. The major catechin is epigallocatechin gallate (EGCG),
which represents ~50% of the catechins in green tea. A number of studies found a positive asso-
ciation between caffeine intake and a reduced risk for type 2 diabetes (Pimentel et al., 2009;
Huxley et al., 2009); these studies will not be discussed because beneficial effects of caffeine are
out of the scope of the present review. However, studies that evaluated the effect of caffeine on
blood glucose and insulin levels will be presented, as these effects could impact other aspects of
human health.
Studies with children included two case reports in which 15-17 year old adolescents con-
sumed excessive caffeine (32-120 mg/kg) as pure caffeine (e.g., in capsules or as tablets), or in a
caffeine-containing supplement. Effects included elevated blood glucose as well as sinus tachy-
cardia, hypokalemia, and respiratory alkalosis (Kromhout et al., 2008). A cohort prospective
study with a 1-year follow-up found no evidence that drinking coffee promotes weight gain in
14-21 year old females (Berkey et al., 2008).
One-day experimental studies with adults found an association between caffeine intake
and increased REE, thermogenic response; decreased insulin sensitivity, and increased levels of
plasma lipids, glucose, insulin (also proinsulin and C-peptide), and epinephrine; and urinary or
plasma norepinephrine. Insulin sensitivity was typically evaluated using an oral glucose toler-
ance test (OGGT) with 75 g glucose, but in some cases with a hyperinsulinemic-euglycemic glu-
cose clamp. An increased thermogenic response was seen from ingesting as little as 50 mg pure
caffeine (0.7 mg/kg) (Belza et al., 2009; Jessen et al., 2003). The lowest caffeine intakes that
increased plasma levels of glucose, insulin, free fatty acids, and epinephrine, and increased oxy-
gen consumption and energy expenditure were ~134-150 mg (~2 mg/kg) as pure caffeine, coffee,
or an ED (Benowitz et al., 1995; Rashti et al., 2009; Johnston et al., 2003). Rush (2006), how-
ever, found that intake of an ED (containing 28 g sucrose and 81 mg caffeine per 250 mL) in-
creased carbohydrate oxidation and reduced lipid oxidation, raising the concern that EDs are
contributing to the obesity epidemic in children. An intake of 200 mg pure caffeine (2.9 mg/kg)
similarly increased REE in smokers and non-smokers; smoking had an additive effect (Collins et
al., 1994). Decreased insulin sensitivity was observed following an intake of 200 mg pure caf-
feine (~3 mg/kg) in men and women (Pizziol et al., 1998; Keijzers et al., 2002), and in pregnant
women with gestational diabetes, who also had increased plasma free fatty acids and epinephrine
and norepinephrine levels (Robinson et al., 2009).
The increase in REE induced by 4 mg/kg pure caffeine was affected by the genotype of
the Arg allele of the β-adrenergic receptor gene (a marker for obesity-related traits), with sub-
177
jects carrying the Arg/Arg genotype having lower REE than those with the Trp/Trp or Trp/Arg
genotype (Hamada et al., 2010). The metabolic rate and thermogenic responses were similar in
obese and lean groups of Japanese women, although the response in the obese group varied
widely (Yoshida et al., 1994). The increase in plasma glucose and insulin from ingestion of 4.45
mg caffeine/kg was greater for pure caffeine than for coffee or decaf (Battram et al., 2006). Age
had no effect on the increase in plasma caffeine levels or energy expenditure after ingestion of 5
mg/kg pure caffeine, as similar changes were seen in young (19-26 years) and older (65-80
years) men, although the younger men had a faster rate of appearance of fatty acids (Arciero et
al., 1995). Plasma caffeine and fatty acids were similarly increased in younger (21-31 years) and
older (50-67 years) women after an intake of 5 mg/kg, but the younger women had a greater en-
ergy use and thermogenic response (Arciero et al., 2000).
Repeat-exposure experimental studies found similar effect as the single-day studies.

Kempf et al. (2010) observed that consumption of 4 cups/day coffee for 30 days (~6-7 mg/kg)
followed by 8 cups/day coffee for 30 days (~11-13 mg/kg/day) by men and women changed se-
rum levels of interleukin-18, 8-isoprostane, and adiponectin (medians: -8%, -16%, and +6%, re-
spectively, for 8 vs. 0 cups/d); increased levels of total cholesterol, HDL cholesterol, and apoli-
poprotein A-I (12%, 7%, and 4%, respectively), and the ratios of LDL to HDL cholesterol and of
apolipoprotein B to apolipoprotein A-I decreased 8% and 9%, respectively (8 vs. 0 cups/d). An
intake of 600 mL coffee (~6 mg/kg) for 4 weeks increased total serum cholesterol by 0.15-0.25
mmol/L, whereas abstention for 3 weeks lowered it by 0.22-0.36 mmol/L (Strandgahed and
Thelle, 2003). In free-living patients with type I diabetes, ingestion of 200 mg/day caffeine for
90 days did not affect glycemic control or the lipid profile, but did increase the number of symp-
tomatic episodes (Watson et al., 2000b). However, a case report of a 33-year old male with type
I diabetes who ingested ~8 cups instant coffee (~8.6 mg/kg) developed marked hyperglycemia
(Kerr and Everett, 2005).
The epidemiological studies with adults, which were less plentiful than the shorter stud-
ies, did not paint a consistent picture of the association between caffeine intake and blood lipids
and glucose. Two case-control studies in which caffeine intake was not provided determined
that plasma caffeine concentrations were related to plasma triglycerides and were weakly corre-
lated to serum glucose levels in caffeine users, but not in non-users, with no association with to-
tal cholesterol or LDL cholesterol (Du et al., 2005; 2007). Cohort prospective studies found that
an intake of ≥2 cups coffe/day (~3 mg/kg) was associated with lower LDL (Balk et al., 2009).
Total serum cholesterol was significantly increased from chronic intake of ≥1 cup coffee/day
(1.4 mg/kg/day) (Wei et al., 1995) or ≥2 cups boiled coffee/day (2.9 mg/kg/day) (Jensen et al.,
1995).
Most of the cross-sectional studies examined the relationship between caffeine intake and
plasma lipid concentrations. Increased LDL cholesterol levels and/or a higher ratio of total to
HDL cholesterol was associated with a mean daily intake of 3.2 servings of caffeinated drinks
(~4.6 mg/kg) (Lane et al., 1994), or with consumption of 1-3 and ≥4 cups coffee/day (1.4 to ≥5.7
mg/kg/day) only in subjects with the longevity-associated mitochondrial DNA 5178 C/A poly-
morphism (Mt5178 C/A) (Kokaze et al., 2010). Total coffee consumption (filtered + boiled un-
filtered) was associated with increased total cholesterol in Norwegian and Finnish men and
women, but the association for only boiled coffee was significant for only Norwegian men who
178
ingested ≥9 cups/day [13 mg/kg/d] (Nystad et al., 2010). Chronic consumption of ≥5 cups/day
boiled coffee (7.1 mg/kg/day) resulted in higher serum levels of lipoprotein(a) than of filter cof-
fee, but an intake of ≥9 cups/d non-significantly increased lipoprotein(a) levels in both coffee
groups (Urgert et al., 1996). Carson et al. (1993) and Lewis et al. (1993) found no relationship
between caffeinated drink intake and cholesterol or triglycerides, but noted a positive association
between consumption of cola and levels of apolipoprotein A-1. Plasma caffeine concentrations
in the upper two quartiles (caffeine intake not provided) in a group of women were associated
with higher insulin resistance (Laughon et al., 2011). Plasma caffeine concentrations in the up-
per two quartiles (caffeine intake not provided) in a group of women were associated with higher
insulin resistance (Laughon et al., 2011). Caffeinated and decaffeinated coffee and total caffeine
were inversely associated with C-peptide concentration in a large group of middle-aged women
(Wu et al., 2005), contrary to findings of increased C-peptide levels in most of the experimental
studies.
NOAEL values for any of the discussed endpoints. It is unclear that these endpoints are adverse
for overall human health.
Studies that evaluated the effect of caffeine on body weight, glucose, lipids, and energy
use are summarized in Table 7-1. Reviews that evaluated the results of published studies regard-
ing the effects of caffeine on these parameters are summarized in Table 7-2. A positive associa-
tion between intake of boiled, unfiltered coffee consumption and elevated cholesterol levels was
noted in several reviews, and filtered coffee had much milder effects (Rodrigues and Klein,
2006; Jee et al., 2001; van Dam, 2008b; Urgert and Katan, 1997). It is thought that the com-
pounds in coffee responsible for increased cholesterol are the diterpene lipids cafestol and kah-
weol, which are extracted by hot water but are retained by a paper filter (Urgert and Katan,
1997). Caffeine-catechol mixtures, such as are found in green tea, were noted as being useful for
body weight loss and weight maintenance by increasing energy expenditure and fat oxidation;
the effects were dependent on the presence of caffeine (Hursel and Westerterp-Plantenga, 2010;
Phung et al., 2010; Hursel et al., 2011). The caffeine-induced reduction in insulin sensitivity in
skeletal muscle was hypothesized to be due to a combination of direct antagonism of A(1) recep-
tors and indirect β-adrenergic stimulation as a result of increased sympathetic activity, and possi-
bly reduced hepatic glucose output (Beaudoin and Graham, 2011).
179
TABLE 7-1. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Humans
Study type; Subject age; Test material; Caffeine
country number; sex condition dose(s)
Case report 15 yr; 17 yr caffeine, in sup- ~2.1 g; 3.5 g Sinus tachycardia; GI irritation or pain; hypokalemia; nausea or vomiting; plasma glucose Kromhout et
(The Nether- n=2 M plement [32-54 mg/kg] increase. [Supplement='herbal energy capsules' each containing 200 mg caffeine; as- al., 2008
lands) sumed BW of 65 kg for dose estimates]
Cohort prospec- 14-21 yr Coffee 1-3 cups/mo; 1, No evidence that drinking coffee promotes weight gain in older adolescent females. [No Berkey et al.,
tive (1-yr fol- n ≥ 5000 F 2-4, ≥5 cups/wk info on caffeine per cup; assume 100 mg/cup; assumed BW of 60 kg for dose estimate.] 2008
low-up) (USA) [<0.01 to 1.1
mg/kg/d]
SINGLE-EXPOSURE EXPERIMENTAL STUDIES WITH ADULTS (sorted by caffeine dose)
1-d experiment 25 ± 1 yr Pure caffeine; 50 mg Green tea extract increased 24-hr energy expenditure and urinary norepinephrine, and Dulloo et al.,
(France) n=10 M tea, green ex- [0.7 mg/kg] decreased the respiratory quotient without change in urinary nitrogen; pure caffeine 1999
tract alone had no effect. [green tea extract contained 50 mg caffeine+90 mg EGCG]
1-d experiment 23.7 ± 2.6 yr pure caffeine; 50 mg caffeine; Green tea extract had no thermogenic effect; only caffeine was thermogenic in the given Belza et al.,
(Denmark) n=12 M tea, green ex- 500 mg green dose and caused no hemodynamic side effects; appetite decrease. 2009
tract tea extract
[0.7 mg/kg/d]
1-d experiment 18-45 yr caffeine in 50, 100 mg Adding caffeine to 1 and 2 mg nicotine significantly enhanced the thermogenic response, Jessen et al.,
(Denmark) n=12 M chewing gum; [0.7, 1.4 mg/kg] but changing the caffeine dose (from 50 to 100 mg) did not change the thermogenic ef- 2003
nicotine in fect. None of the combinations changed the respiratory quotient compared with placebo.
chewing gum
1-d experiment 24.3 ± 3.1 yr caffeine in 50, 100 mg Caffeine appeared to amplify the effects of nicotine on hunger and fullness as a caffeine x Jessen et al.,
(Denmark) n=12 M chewing gum; [0.7, 1.4 mg/kg] nicotine x time interaction was observed in these scores (p < 0.05). The 2-mg dose of 2005
nicotine in nicotine in combination with the 100-mg dose of caffeine caused nausea in four of the
chewing gum non-smokers.
1-d experiment 35.5 ± 1.5 yr pure caffeine; 1.0, 3.0 g tea; 52 3.0 g tea drink caused GI symptoms; plasma glucose concentrations <60 min in response Bryans et al.,
(UK) n=16 (4 M) CHO; instant mg pure caf- to the drinks were similar, but were reduced at 120min (P<0.01) with the 1.0 g tea drink 2007
black tea feine [0.7 relative to the control and caffeine drinks. Tea consumption resulted in elevated insulin
mg/kg] concentrations compared with the control and caffeine drinks at 90min (P<0.01) and
compared with caffeine drink alone at 150 min (P<0.01).
180
1-d experiment 20±1 yr tea, green; tea, 77 mg; 161 mg The cumulative increases of energy expenditure (EE) for 120 min were increased 10% Komatsu et
(Japan) n=11 F oolong [1.1, 2.3 mg/kg] and 4% after the consumption of oolong tea and green tea, respectively. In comparison al., 2003
with green tea, oolong tea contained half the caffeine and EGCG, while polymerized
polyphenols were double, suggesting that oolong tea increases EE by its polymerized
polyphenols. [77 mg caff + 78 mg EGCG in oolong tea; 161 mg caff + 94 mg EGCG in
green tea; assumed BW of 60 kg for dose estimates]
1-d experiment 18-22 yr ED; CHO 1.3 mg/kg Increased carbohydrate oxidation and reduced lipid oxidation (oxygen consumption and Rush et al.,
(New Zealand) n=10 F carbon dioxide production were measured). [ED= New Zealand's "V" ED containing 28g 2006
sucrose and 81 mg caffeine per 250-mL can]
1-d experiment 25-49 yr Coffee; decaf 1 cup Caffeinated espresso, but not decaf, caused progressive decrease in endothelial function Buscemi et
(Italy) 20 (10 M) [1.9 mg/kg] (measured by brachial artery flow-mediated dilation), increased both systolic and dia- al., 2010a
stolic BP, and decreased blood insulin and C-peptide; blood glucose concentrations were
unaffected (caffeinated = 130 mg/cup, decaf = 5 mg/cup, 1 cup = 25 mL)
1-d experiment 19-49 yr pure caffeine 2, 4 mg/kg Significantly increased diastolic BP, plasma epinephrine levels, and free fatty acids. Benowitz et
(USA) n=12 (6 M) al., 1995
1-d experiment 26 ± 3.2 yr coffee ~150 mg Glucose and insulin concentrations increased for 30 min after intake; glucose-dependent Johnston et
(UK) n=9 M+F [2.1 mg/kg/d] insulinotropic polypeptide secretion was decreased. al., 2003
1-d experiment 23.6 ± 2.7 yr pure caffeine; 150 mg No significant effect on energy expenditure (EE) or respiratory quotient. EGCG + caf- Gregersen et
(Denmark) n=15 M EGCG [seden- [2.1 mg/kg] feine insignificantly raised EE and fat oxidation vs. caffeine-only and placebo. Cate- al., 2009
tary] chin/caffeine combinations at these dosages and mode of application had non-significant
acute effects on EE and fat oxidation. [50 mg caffeine ± green tea catechin mixture (600
mg)]
1-d experiment 20-35 yr coffee; decaf; 150 mg Coffee caused a 28% increase in postprandial glycemia; coffee + sucrose decreased gly- Louie et al.,
(Australia) n=8 (5 M) tea, black; CHO [2.1 mg/kg] cemia compared to coffee or control groups without effect on insulin; decaf, tea, and su- 2008
crose had no significant effects on postprandial responses. [Instant coffee (~ 150 mg
caffeine/250 mL cup), decaf (no info), tea (no info)]
1-d experiment 20.4 ± 0.70 yr ED 134 mg During 2nd and 3rd hr of 3-hr test, ED increased VO2 and energy expenditure; mean sys- Rashti et al.,
(USA) n=10 F [2.2 mg/kg] tolic BP was higher with ED; no differences were seen in HR, diastolic BP, or profile of 2009
mood states at any time point. [ED= Meltdown RTD]
1-d experiment 18-32 yr pure caffeine; 200 mg Caffeine or naringin did not alter VO(2) or VO(2) area under the curve; resting energy Ballard et al.,
(USA) n=10 (5 M) naringin [2.9 mg/kg] expenditure [REE] was 10% higher with caffeine versus naringin; co-consumption did 2006
not affect respiratory exchange ratio, VO(2), and prevented an increase of REE.
1-d experiment Adult pure caffeine 200 mg Caffeine similarly increased REE in non-smokers and smoking smokers (smoking had Collins et al.,
(USA) n=10 M smoking [2.9 mg/kg] additive effect with caffeine). 1994
181
1-d experiment 26-32 yr pure caffeine; 200 mg Caffeine intake induced a rise in blood glucose levels that appeared to be insulin inde- Pizziol et al.,
(Italy) n=30 (12 M) CHO [2.9 mg/kg/d] pendent in a glucose tolerance test (75 g CHO). 1998
1-d experiment M=26 ± 2.1 yr; ED; coffee 400 mg (ED); Resting energy expenditure increased more from ED than coffee. [ED= JavaFittrade Taylor et al.,
(USA) F=28.8 ± 5.3 yr 200 mg (coffee) mark Energy Extreme (JF)] 2007
n=10 (5 M) [2.9; 5.7 mg/kg]
1-d experiment 21-39 yr Coffee; decaf 3 mg/kg (cof- The appetite-related ratings, the appetite plasma hormonal responses as well as the Gavrieli et
(Greece) n=16 M fee); decaf caf- plasma glucose, serum insulin, and plasma and serum inflammatory marker responses, al., 2011
feine NR and ad libitum energy intake did not differ among the 3 interventions. However, cortisol
concentrations were significantly higher following the caffeinated coffee intervention,
compared to control, at 60 min and thereafter.
1-d experiment n=33.4 ± 1.2 yr; pure caffeine; 3 mg/kg pre- In controls, caffeine did not affect blood glucose, insulin, or C-peptide; gestational diabe- Robinson et
(Canada) c=30.1 ± 1.2 yr CHO [gestatio- pregnancy BW tes group had increased glucose and C-peptide AUC, and 18% lower insulin sensitivity al., 2009
n=8; c=19 nal diabetes] index after caffeine than after placebo.
1-d experiment 22.6 ± 2.0 yr pure caffeine 3 mg/kg, then Caffeine decreased insulin sensitivity by 15% and increased plasma free fatty acids (P < Keijzers et
(The Nether- n1=12; n2=10 0.6 mg/kg/hr i.v. 0.05). Insulin sensitivity was determined using a hyperinsulinemic-euglycemic glucose al., 2002
lands) M+F clamp. Plasma epinephrine increased fivefold; smaller increases in plasma norepineph-
rine (P < 0.02) and BP (P < 0.001).
1-d experiment Adult pure caffeine 250 mg Mean plasma glucose AUC at 2 hr was 28% larger and the mean plasma insulin AUC at 2 Lane et al.,
(USA) n=20 (9 M) [diabetes, type [3.6 mg/kg] hr was 19% larger after administration of caffeine than after administration of placebo. 2007
II]
1-d experiment 32.7 ± 0.9 yr pure caffeine 250 mg Caffeine enhanced adrenaline responses to hypoglycaemia and restored brain activation Rosenthal et
(UK) n=6 M [hypoglycemia] [3.6 mg/kg] response to the non-cued four-choice reaction time. al., 2007
1-d experiment 38-52 yr pure caffeine 4 mg/kg Caffeine ingestion did not increase epinephrine concentration or impair glucose tolerance Battram et
(Canada) n=14 M [tetraplegia] in persons with tetraplegia (do not exhibit an increased epinephrine response following al., 2007a
caffeine ingestion).
1-d experiment 21 ± 1 yr pure caffeine; 4 mg/kg At the baseline, subjects with the Arg/Arg genotype had a significantly lower energy ex- Hamada et
(Japan) n=44 F beta(3)-AR penditure (EE) level than those with the Trp/Trp or Trp/Arg genotype. There were similar al., 2010
genotype caffeine-induced increases in EE in all genotypes. [Arg allele in the beta(3)-adrenergic
receptor gene (beta(3)-AR), a marker for obesity-related traits]
1-d experiment 25.3 ± 3.3 yr coffee 4 mg/kg A significant correlation was found between the total thermogenic responses (net re- Tagliabue et
(Italy) n=12 (5 M) sponses) and the temperature changes between 90 and 120 min from the coffee intake. al., 1994
1-d experiment M=24 ± 4 yr; ED ~200-300 mg Ingestion of ED resulted in an increase in catecholamine secretion, lipolysis, and meta- Bloomer et
(USA) F=22 ± 2 yr [4 mg/kg] bolic rate, with a similar response for both sexes. [ED= Meltdown; caffeine content not al., 2009
n=20 (10 M) given precisely]
182
1-d experiment Adult pure caffeine 4 mg/kg ideal Metabolic rate and thermogenic responses were similar in obese and lean groups, but Yoshida et
(Japan) n=136 F; c=10 F [overweight] BW varied widely in obese subjects; the response to caffeine was correlated with subsequent al., 1994
weight loss in a low-calorie/exercise program.
1-d experiment 23.2 ± 0.6 yr pure caffeine; 4.45 mg/kg The AUC for glucose and insulin were higher (P≤0.05) after caffeine capsules than pla- Battram et
(Canada) n=11 M coffee; CHO cebo or decaf [OGGT 1 hr after dosing]. A similar but less pronounced effect was seen al., 2006
after coffee intake. Decaf intake resulted in a 50% lower glucose response (P≤0.05) than
placebo. These findings suggest that the effects of pure caffeine and coffee are not identi-
cal and may provide a partial explanation of why acute pure caffeine ingestion impairs
glucose tolerance while chronic coffee ingestion protects against type 2 diabetes.
1-d experiment 19-26 yr (n=10 pure caffeine 5 mg/kg Young (19-26 yr) and older (65-80 yr) men had similar increases in plasma caffeine lev- Arciero et
(USA) M); 65-80 yr [age] els and energy expenditure; younger men had increased rate of appearance of fatty acids; al., 1995
(n=10 M rates of fat oxidation and norepinephrine appearance and clearance were unaffected.
1-d experiment 23 ± 1 yr pure caffeine; 5 mg/kg Caffeine increased adrenaline levels without effect on endogenous glucose production in Battram et
(Denmark) n=26, c=12 M adrenaline (i.v.) subjects who completed three isoglycaemic-hyperinsulinaemic clamps (with 3- al., 2005
[(3)H]glucose infusion) 30 min after dosing.
1-d experiment 25 ± 2 yr pure caffeine; 5 mg/kg Caffeine or adrenaline each decreased insulin-mediated glucose disposal, the combination Battram et
(Denmark) n=8 M adrenaline (i.v.) had a greater effect, although it was not fully additive. al., 2007b
1-d experiment Adult pure caffeine; 5 mg/kg Caffeine ingestion resulted in an increase (P ≤ 0.05) in serum fatty acids, glycerol, and Graham et
(Canada) n=18 M CHO plasma epinephrine prior to the OGTT. During the OGTT, these parameters decreased to al., 2001
placebo levels. With caffeine the serum insulin and C peptide concentrations were in-
creased (P ≤0.001) for the last 90 min of the OGTT and AUC were 60 and 37% greater (P
≤0.001), respectively. The prolonged increase in insulin did not decrease blood glucose;
in fact, the AUC for blood glucose was 24% greater (P = 0.20) in the caffeine group.
Thus caffeine ingestion may have resulted in insulin resistance.
1-d experiment 25 ± 0.5 yr pure caffeine 5 mg/kg Significant decrease (24%, p<0.05) in glucose disposal after caffeine ingestion; carbohy- Greer et al.,
(Canada) n=9 M [sedentary] drate storage was 35% lower (P<0.05) in the caffeine trial than in the placebo trial. 2001
1-d experiment Adult coffee; decaf; 5 mg/kg Co-ingestion of caffeinated coffee with one meal (high glycemic index cereal) resulted in Moisey et
(Canada) n=10 M food insulin insensitivity during the postprandial phase of a second meal in the absence of fur- al., 2010
ther coffee ingestion.
1-d experiment 23.3±1.1 yr Coffee; food; 5 mg/kg Caffeinated coffee taken with either a high or low-glycemic index meal increased the Moisey et
(Canada) n=10 M CHO AUC for glucose, insulin, and C-peptide. al., 2008
183
1-d experiment 23-34 yr pure caffeine; 5 mg/kg Caffeine caused a greater (P≤ 0.05) OGTT insulin response and a lower (P< = 0.05) insu- Petrie et al.,
(Canada) n=9 M CHO [over- lin sensitivity index both before and after weight loss. The proinsulin-insulin ratio indi- 2004
weight] cated that neither weight loss nor caffeine affected the nature of the beta cell secretion of
insulin. Thus, a nutrition and exercise intervention improved, whereas caffeine ingestion
impaired, insulin-glucose homeostasis in obese men.
1-d experiment 49 ± 2 yr pure caffeine; 5 mg/kg Caffeine increased (P < 0.05) serum insulin, proinsulin, and C-peptide during the OGTT Robinson et
(Canada) n=12 M glucose [over- (75 g CHO) relative to placebo. Insulin AUC was 25% greater (P < 0.05) after caffeine al., 2004b
weight] than placebo. Despite this, blood glucose was also increased (P < 0.01) in the caffeine
trial. After caffeine ingestion, blood glucose remained elevated (P < 0.01) at 3 hr post-
glucose load (8.9 ± 0.7 mmol/L) vs. baseline (6.7 ± 0.4 mmol/L). The insulin sensitivity
index was lower (14%, P = 0.02) after caffeine than after placebo ingestion.
1-d experiment 24 ± 1 yr pure caffeine; 5 mg/kg Plasma epinephrine was elevated from caffeine or caffeine + propranolol; the insulin and Thong and
(Canada) n=7 M propranolol; C-peptide AUC were ~40% greater from caffeine than placebo, propranolol, or caffeine + Graham,
CHO propranolol. 2002
1-d experiment 26 ± 2 yr pure caffeine; 5 mg/kg During a 100-min euglycemic-hyperinsulinemic (100 microU/mL) clamp, whole-body Thong et al.,
(Denmark) n=7 M exercise glucose disposal was reduced (P < 0.05) in caffeine vs. placebo; the AUC over 100 min 2002
for insulin-stimulated glucose uptake in caffeine was reduced ~50% in rested and exer-
cised muscle. Caffeine also reduced glycogen synthase activity before and during insulin
infusion in both legs. Exercise increased insulin sensitivity of leg glucose uptake in both
caffeine and placebo. Caffeine did not alter insulin signaling in either leg. Plasma epi-
nephrine and muscle cAMP concentrations were increased with caffeine.
1-d experiment Adult coffee; decaf; 1 5 mg/kg Caffeinated coffee produced the highest glucose concentrations (P < 0.05). Glucagon-like Beaudoin et
(Canada) n=10 M g lipid/kg BW at peptide-1 active (GLP-1a) and glucose-dependent insulinotropic polypeptide (GIP) were al., 2011
time zero both increased for up to 6 hr in all OFTT (oral fat tolerance test) trials (P < 0.05). Com-
(OFTT) pared to all other treatments, caffeinated and decaffeinated coffee produced higher GLP-
1a response at 6.25 hr (P < 0.05), whereas only caffeinated coffee increased GIP secre-
tion (P < 0.05).
1-d experiment 21-31 yr (10 F); pure caffeine 5 mg/kg fat-free Plasma caffeine and fatty acids increased similarly in younger (21-31 yr) and older (50- Arciero et
(USA) 50-67 yr (10 F) [age] mass 67 yr) women; plasma insulin and glucose were unchanged; energy use increased in both al., 2000
groups (younger, 15.4%, older, 7.8%); older women had a blunted thermic response.
1-d experiment 61 ± 9 yr Pure caffeine; 375 mg (split Caffeine increased glucose and insulin during the mixed-meal tolerance test (MMTT); no Lane et al.,
(USA) n=14 (11 M) CHO [diabetes, dose) effect on the fasting levels of plasma, glucose, or insulin compared to placebo; the 2 hr 2004
type II] [5.4 mg/kg] AUC values showed significant caffeine effects for both plasma glucose (P<0.04) and
plasma insulin (P<0.01) responses to the MMTT.
184
1-d experiment 23.5 ± 5.7 yr pure caffeine; 6 mg/kg Within the first hour of the glucose (75 g) test, glucose and insulin were higher for decaf Greenberg et
(USA) n=11 M coffee; decaf; than for placebo (P < 0.05); decaf yielded higher insulin than placebo and lower glucose al., 2010
CHO and a higher insulin sensitivity index than caffeine.
1-d experiment Adult pure caffeine 6 mg/kg Caffeine treatment increased epinephrine, norepinephrine, fatty acids, and lactate at dif- Norager et
(Denmark) n=30 M+F ferent times and led to insulin resistance (homeostasis model assessment-IR). al., 2006
1-d experiment 20.9 ± 1.7 yr ED 450 mg Found 7/10 subjects were responders to JF (had a higher AUC for VO2 during JF vs. Hoffman et
(USA) n=10 (8 M) [6.4 mg/kg/d] placebo). Average systolic BP was higher (p < 0.05) in JF (118 ± 7 mmHg) than placebo al., 2006
(115 ± 8 mmHg) in both the total sample and the subgroup of responders. No differences
in average HR and average diastolic BP in the total sample or the responders.
[ED=JavaFittrade mark (JF) coffee (450 mg of caffeine, 1200 mg of garcinia cambogia,
360 mg of citrus aurantium extract, and 225 mcg of chromium polynicotinate]
1-d experiment 44.3 ± 9.2 yr pure caffeine 500 mg (split Caffeine was associated with reduction in nocturnal hypoglycemia due to a decline in the Richardson
(UK) n=19 (9 M) [diabetes, type I] dose) number of episodes of moderate hypoglycemia at the expense of mild hypoglycemic epi- et al., 2005
[7.1 mg/kg] sodes.
1-d experiment 20-50 yr pure caffeine; 600 mg (split in 24-hr energy expenditure increased with all EGCG-caffeine mixtures compared with pla- Berube-
(Canada) n=14 M EGCG; tea, 3 doses) cebo, similar with all doses of EGCG. No effect of the EGCG-caffeine for lipid oxida- Parent et al.,
green [8.6 mg/kg] tion. Systolic and diastolic BP increased by about 7 and 5 mmHg, respectively, with the 2005
EGCG-caffeine mixtures vs. placebo (significant only for 24 hr diastolic BP).
1-d experiment 23.1 ± 2.6 yr pure caffeine; 10 mg/kg Lipid turnover increased 2-fold (P < 0.005), and the mean thermic effect was 13.3 ±2.2% Acheson et
(Switzerland) n=8 M propranolol (P < 0.001), both of which were greater than after ingestion of placebo or caffeine during al., 2004
beta-adrenoceptor blockade with propranolol. After ingestion of caffeine, oxidative free
fatty acid (FFA) disposal increased 44%, but nonoxidative FFA disposal increased 2.3-
fold (P < 0.01). In post-absorptive conditions, 34% of lipids were oxidized and 66% were
recycled. Caffeine ingestion increased energy expenditure 13% and doubled the turnover
of lipids, of which 24% were oxidized and 76% were recycled. beta-Adrenoceptor block-
ade decreased, but did not inhibit, these variables.
1-d experiment 25 ±2.9 yr pure caffeine; 800 mg (as 4 Red pepper and caffeine consumption significantly reduced the cumulative ad libitum Yoshioka et
(Canada) n=8 M red pepper doses) energy intake and increased energy expenditure. The power spectral analysis of HR sug- al., 2001
[11 mg/kg/d] gested that this effect of red pepper was associated with an increase in sympathetic: para-
sympathetic nervous system activity ratio.
185
REPEAT-EXPOSURE EXPERIMENTAL STUDIES WITH ADULTS
1, 10, 45 d; 12 Adult caffeine, in sup- 3 capsules/d The herbal preparation significantly delayed gastric emptying, reduced the time to per- Andersen
mo experiment n=51; c=47 plement [over- [13-24 mg caf- ceived gastric fullness and induced significant weight loss over 10 and 45 days in over- and Fogh,
(Denmark) M+F weight] feine] weight patients, and maintained the loss for 12 mo. [Supplement= herbal preparation 2001
[0.3 mg/kg/d] 'YGD'; each capsule contained 112 mg Yerbe Mate (3-6% caffeine), 95 mg Guarana (1-
1.5% caffeine) and 36 mg Damiana extract.]
2-d experiment 63 ± 13 yr pure caffeine 500 mg/d, split Increased average daytime glucose interstitial levels compared to placebo (8.0 vs. 7.4 Lane et al.,
(USA) n=10 (5 M) [diabetes, type [7.1 mg/kg/d] mmol/L), and 3 hr post-prandially (8.7 vs. 8.0; 7.8 vs. 6.8; 8.6 vs. 6.8 mmol/L after 2008
II] breakfast, lunch, and dinner, respectively).
3-d experiment 18-35 yr caffeine, in sup- 100 mg 24 hr energy expenditure (EE) and 24-hr fat oxidation were lower in women than in men. Rudelle et
(Switzerland) n=31 (15 M) plement [1.4 mg/kg/d] Although there were no treatment or treatment/gender effects on substrate oxidation, al., 2007
treatment increased 24-hour EE by 106 ± 31 kcal/24 hours (p = 0.002). No significant
differences were observed in hemodynamic parameters. [Supplement= beverage contain-
ing green tea catechins, caffeine, and calcium]
3-d experiment 25-60 yr pure caffeine tea: 135, 270 Relative to the water treatment, EE was significantly increased 2.9 and 3.4% for the full- Rumpler et
(USA) n=12 M tea, oolong mg; caffeine strength tea and caffeinated water treatments, respectively. Fat oxidation was signifi- al., 2001
270 mg [1.9, cantly higher (12%) when subjects consumed the full-strength tea rather than water.
3.9 mg/kg/d]
3-d experiment 23-40 yr pure caffeine; 200 mg Low EGCG (300 mg), high EGCG (600 mg), caffeine, and caffeine + 300 mg EGCG Thielecke et
(Germany) n=10 M EGCG [2.9 mg/kg] treatments increased fat oxidation during first 2 hr after overnight fast. al., 2010
7-d experiment 18-22 yr pure caffeine 400 mg (split Insulin levels were higher after caffeine intake than placebo, and the homeostasis model MacKenzie
(USA) n=16 (8 M) dose) assessment index of insulin sensitivity was reduced by 35% (95% CI, 7%-62%). No dif- et al., 2007
[5.7 mg/kg/d] ferences in glucose, dehydroepiandrosterone, androstenedione, and melatonin between
treatment periods. This study provides evidence that daily caffeine intake reduces insulin
sensitivity.
14-d experiment 21.9 ± 0.02 yr pure caffeine; 5 mg/kg/d Serum insulin and blood glucose AUC were significantly elevated vs. placebo on day 0 Dekker et al.,
(Canada) n=12 M CHO (36 and 103%, respectively) but not on day 7. On day 14, insulin AUC was 29% greater 2007
than PLA, and glucose was greater during the first hour, although the 50% elevation in
glucose AUC was not different from PLA. Before the OGTT, caffeine increased serum
non-esterified fatty acids (NEFA) and plasma adrenaline on all three days, but both
NEFA and adrenaline were decreased on day 14 v. day 0. Thus, although 14 d of caf-
feine consumption by previously caffeine-naive subjects reduced its impact on glucose
homeostasis, carbohydrate metabolism remained disrupted.
186
21-d experiment 18-60 yr caffeine, all 104 mg Weight maintenance after 7.5% body-weight loss was not affected by subsequent intake Kovacs et
(The Nether- n=104 M+F sources; tea, [1.5 mg/kg/d] of green tea; habitual high caffeine consumption (mean 511 mg/d) (in addition to that al., 2004
lands) green [over- from tea extract) was associated with a higher weight regain than habitual low caffeine
weight] intake (mean 149 mg/d). [Green tea contained caffeine (104 mg) and catechins (573 mg,
of which 323 mg was EGCG)]
21-d, 28-d ex- 26-69 yr Coffee, filter 600 mL/d (~4 Coffee abstention for 3 wk decreased total serum cholesterol by 0.22-0.36 mmol/l. A vol- Strandhagen
periments n=121 (22% M) brewed cups/d) ume of 600 ml (~4 cups) of filtered coffee/day during 4 weeks raised total serum choles- and Thelle,
(Sweden) [5.7 mg/kg/d] terol by 0.15-0.25 mmol/L. [No info on caffeine per cup; assumed 100 mg/cup] 2003
28-d experiment 29-65 yr Coffee [APOE 600 mL/d (~4 Individuals positive for APOE epsilon2 polymorphism (apolipoprotein E (APOE) epsi- Strandhagen
(Sweden) n=121 (22% M) polymorphism] cups/d) lon2/epsilon3/epsilon4) had significantly lower total cholesterol concentration at baseline et al., 2004b
[5.7 mg/kg/d] (4.68 mmol/L and 5.28 mmol/L, respectively, p = 0.01), but the cholesterol-raising effect
of coffee was not influenced significantly by APOE allele carrier status. [No info on caf-
feine per cup; assumed 100 mg/cup]
60-d experiment 54.0 ± 9.0 yr Coffee; CHO 0, 4, 8 cups/d Coffee consumption changed serum levels of interleukin-18, 8-isoprostane, and adi- Kempf et al.,
(30 d low, then n=47 (11 M) [5.7, 11 ponectin (medians: -8%, -16%, and +6%, respectively, for 8 vs. 0 cups/d); increased lev- 2010
30 d high in- mg/kg/d] els of total cholesterol, HDL cholesterol, and apolipoprotein A-I (12%, 7%, 4%, respec-
take) tively); the ratios of LDL to HDL cholesterol and of apolipoprotein B to apolipoprotein
(Germany) A-I decreased 8% and 9%, respectively (8 vs. 0 cups/d). No changes for markers of glu-
cose in an OGTT. [1 cup coffee=150 mL; caffeine content NR; assumed 100 mg/cup]
84-d experiment 47-49 ± 1.3 yr caffeine, in sup- 39 mg Trend (P = 0.079) toward greater loss of BW in the catechin group compared to caffeine- Maki et al.,
(USA) n=107 M+F plement [over- [0.6 mg/kg/d] only group; similar changes in fat mass, but changes in total abdominal fat area, subcuta- 2009
weight] neous abdominal fat area, and fasting serum triglycerides were greater in catechin group.
[Supplement= beverage containing ~625 mg of green tea catechins with 39 mg caffeine]
87-d experiment 19-57 yr coffee; GTE 300 mg/d (in 3 Reductions in weight, BMI, waist:hip ratio, fat mass and fat-free mass were not statisti- Diepvens et
(The Nether- n=46 F [overweight] doses) cally affected by green tea treatment in women on a low-calorie diet. [GTE=Green tea al., 2005
lands) [5.0 mg/kg/d] extract, which contained 75 mg caffeine +1125 mg tea catechins; other daily caffeine
intake was 225 mg. for a total of 300 mg/d]
90-d experiment 44 ± 2 yr caffeine, in sup- 150 mg/d Decreased BW; increased REE and fat-free mass, and decreased respiratory quotient; the Hursel and
(The Nether- n=80 M+F plement [over- [2.1 mg/kg/d] green tea-caffeine mixture was only effective with an adequate protein (not a high- Westerterp-
lands) weight] protein) diet. [Supplement= green tea-caffeine mixture containing 270 mg EGCG + 150 Plantenga,
mg caffeine] 2009
187
90-d experiment 38 ± 2 yr pure caffeine 200 mg In free-living patients with type 1 diabetes, no caffeine-induced changes were seen in Watson et
(UK) n=34 (22 M) [diabetes, type I] [2.9 mg/kg/d] glycemic control or lipid profile. The number of symptomatic episodes was greater with al., 2000b
caffeine (1.3 vs. 0.9 episodes/week; P < 0.03) and was associated with more intense
warning symptoms. For women, caffeine ingestion caused a modest pressor response
(115 vs. 110 mm Hg; P < 0.01). Four-choice reaction time improved slightly with caf-
feine intake (P < 0.05).
120-d experi- 18-60 yr caffeine, in sup- 150 mg/d + During the 4-wk low-energy period, habitual high caffeine consumers (>300 mg/d) had Westerterp-
ment 4-wk low- n=76 (23 M) plement [over- <300 or >300 greater reduced weight, fat mass, and waist circumference, and REE was reduced less and Plantenga et
energy diet, then weight] mg/d habitual respiratory quotient was reduced more than in low caffeine consumers. During the 3-mo al., 2005
3 mo weight [2.1 to >6.4 weight maintenance period (WM), in low caffeine consumers green tea still reduced BW,
maintenance mg/kg/d] waist circumference, respiratory quotient and body fat, whereas REE was increased com-
with caffeine pared with a restoration of these variables with placebo (p < 0.01). In the high caffeine
(The Nether- consumers, no effects of the green tea-caffeine mixture were observed during WM.
lands) [Supplement=green tea-caffeine mixture with 45 mg EGCG + 25 mg caffeine per cap-
sule; took 2 before each meal (6/day)]
CASE REPORTS AND EPIDEMIOLOGICAL STUDIES WITH ADULTS
Case report 33 yr Coffee [diabe- ~8 cups instant Coffee ingestion was associated with marked hyperglycemia. [No info on caffeine per Kerr and
(UK) n=1 M tes, type I] coffee [8.6 cup; assumed 75 mg/cup] Everett, 2005
mg/kg]
Case-control ~45 ±12 yr M+F caffeine, all caff blood concs Plasma caffeine concentrations were related to triglycerides in caffeine users and to Du et al.,
(Germany) Cases=814; sources given only HDL-C in female nonusers; no association with total cholesterol or LDL-C. 2005
Controls=623
Case-control users 45.1± 12.4 caffeinated + or - Caffeine concentrations were weakly correlated to serum glucose levels in caffeine users, Du et al.,
(Germany) yr; non-users medication particularly in women. Serum glucose levels were higher but the magnesium level was 2007
43.2 ± 12.3 yr lower in caffeine users than in non-users. No associations of caffeine concentrations with
Cases=814; con- serum glucose levels were found in any groups of non-users. [No info on caffeine intake
trols=623 M+F amounts].
Cohort prospec- 13 yr at base- coffee ≤2, >2 and ≤4, Moderate and high (>2 cups/day [>2.9 mg/kg/d]) coffee consumption was associated with Balk et al.,
tive (15 yr fol- line; evaluated >4 and ≤6, >6 lower HDL and slightly lower mean arterial pressure in F; consumption was not associ- 2009
low-up) (The at 27, 29, 32, 36, cups/d ated with any of the components of the metabolic syndrome for M. [‘metabolic syn-
Netherlands) and 42 yr; [≤2.9 to >8.6 drome’ consists of (1) elevated BP, (2) low HDL cholesterol levels, (3) high triglyceride
n=344 at 42 yr mg/kg/d] levels, (4) high fasting glucose levels and (5) abdominal obesity. When 3/5 or more of the
M+F components are present, metabolic syndrome is diagnosed. [No info on caffeine per cup;
assume 100 mg/cup]
188
Cohort prospec- 25-65 yr coffee 0, 1-7, 8-14, 15- 2-3 mg/dL total cholesterol increase was associated with an increase of 1 cup/d of regular Wei et al.,
tive (16.7-mo n=2109 (1776 21, 22-28, >28 coffee; dose-response seen; opposite effect with decreased intake; no effect of decaf, tea, 1995
mean follow-up) M) cups/wk [<1.4 or cola [No info on caffeine per cup; assumed 100 mg/cup]
(USA) to >5.7 mg/kg/d]
Cross-sectional 65-84 yr coffee (boiled) 0, 1, 2 cups/d Serum total cholesterol levels were 8.2% higher (P < 0.05) in men consuming 2 small Jansen et al.,
(Serbia) n=319 M+F [1.4, 2.9 cups of Turkish (boiled) coffee/d compared with abstainers, even after adjustment for 1995
mg/kg/d] cigarette smoking, age, body mass index, cohort, and alcohol consumption. [No info on
caffeine per cup; assume 100 mg/cup]
Cross-sectional 53.9 ± 7.8 yr Coffee [Mt5178 <1, 1-3, ≥4 Among subjects who consumed <1 cup of coffee/d, OR for hyper-LDL cholesterolemia Kokaze et
(Japan) n=397 M C/A polymor- cups/d was lower in those with the longevity-associated mitochondrial DNA 5178 C/A poly- al., 2010
phism] [<1.4 to ≥5.7 morphism (Mt5178 C/A) than with the Mt5178C allele; coffee consumption was posi-
mg/kg/d] tively associated with serum LDL cholesterol only in subjects with Mt5178A (for 1-3 and
≥4 cups/d). [No info on caffeine per cup; assumed 100 mg/cup]
Cross-sectional 44-46 yr caffeinated mean 3.2 serv- Higher caffeinated beverage intake was associated with higher LDL cholesterol levels Lane et al.,
(USA) n=763 M+F drinks ings/d and a higher ratio of total to HDL cholesterol; the effect of caffeine on hostility was am- 1994
[4.6 mg/kg] biguous, although there tended to be stronger effects on LDL and on total cholesterol in
people with less hostility. [A "'serving" was defined as an average-sized cup, glass, or
bottle; no info on caffeine per serving; assumed 100 mg/serving]
Cross-sectional Adult caffeine, all Plasma caffeine Plasma caffeine concentrations in the upper two quartiles (>266 ng/mL) were associated Laughon et
(USA) n=251 F sources [mean quartiles: 0-93, with 3-fold higher odds of having higher insulin resistance estimated by log homeostasis al., 2011
gestational age 94-266, 267- model assessment (HOMA) ≥ 75th percentile (third quartile odds ratio [OR], 3.02; 95%
of 20.3 ± 2.0 wk 555, >555 CI: 1.21-7.54 and fourth quartile OR, 2.95; 95% CI: 1.19 to 7.31). Slow versus fast
pregnant] ng/mL (CYP1A2) metabolism did not make an important difference.
Cross-sectional 36-79 yr coffee boiled, <5, 5-9, ≥9 Total coffee consumption was associated with increased total cholesterol for M and F; for Nystad et al.,
(Finland; Nor- n=11,994 (47% unfiltered cups/d [<7.1 to those who drank only unfiltered coffee, a significant association was found only in Nor- 2010
way) M) >13 mg/kg/d] wegian men, adjusted for physical activity, BMI and smoking habits. For <5 vs. ≥9
cups/d [13 mg/kg/d], mean total cholesterol increased by 0.29 mmol/L in Norwegian
men. [No info on caffeine per cup; assume 100 mg/cup]
Cross-sectional 40-42 yr Coffee, boiled; 5-8, ≥9 cups/d Chronic consumers of unfiltered, boiled coffee had higher serum levels of lipoprotein(a) Urgert et al.,
(Norway) n1=150 (boiled); coffee, filtered [7.1-11, ≥13 than filter coffee drinkers (25.8 ± 2.4 vs. 19.6 ± 2.0 mg dL-1, respectively). Subjects 1996
n2=159 mg/kg/d] consuming ≥9 cups/d coffee had non-significantly higher lipoprotein(a) levels than those
(filtered) M+F drinking 5-8 cups/d in both coffee groups. [No info on caffeine/cup; assumed 100 mg]
189
Cross-sectional 43-69 yr caffeine, all 0, <1, 1, 2-3, ≥4 Caffeinated and decaffeinated coffee and total caffeine were inversely associated with C- Wu et al.,
(USA) 24.1 ± 5.8 yr sources; coffee; cups/d peptide concentration (for every 100 mg increase intake, C-peptide decreased 0.03 2005
n=2112 F decaf [over- [<1.4 to ≥5.7 ng/mL); effect was greater in obese and overweight F (27%, 20% reduction) than in nor-
weight] mg/kg/d] mal weight F (11% reduction). [Estimated caffeine content was 137 mg/cup for coffee,
47 mg/cup for tea, and 46 mg/12 oz bottle or can for cola beverages]
AUC=area under the curve; BMI=body mass index; CHO=carbohydrate; CI=confidence interval; EGCG= epigallocatechin gallate; HDL-C=HDL-cholesterol; LDL-C=LCL
cholesterol; OR=odds ratio; REE=resting energy expenditure
190
TABLE 7- 2. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Humans – Summaries of Reviews Reference
Some coffee brewing techniques raise the serum concentration of total and low-density-lipoprotein cholesterol in humans, whereas others do not. The re- Urgert and Katan,
sponsible factors are the diterpene lipids cafestol and kahweol, which make up about 1% (wt:wt) of coffee beans. Diterpenes are extracted by hot water but 1997
are retained by a paper filter.
A dose-response relation between coffee consumption and both total cholesterol and LDL cholesterol was identified (p < 0.01). Increases in serum lipids Jee et al., 2001
were greater in studies of patients with hyperlipidemia and in trials of filtered or boiled coffee. Trials using filtered coffee demonstrated very little increase in
serum cholesterol.
The literature indicates a strong relationship between boiled, unfiltered coffee consumption and elevated cholesterol levels; however, there is a critical gap in Rodrigues and
the literature regarding the effects of coffee or caffeine consumption on fibrinogen or C-reactive protein, which is an independent predictor of CVD risk. Klein, 2006
High consumption of unfiltered types of coffee, such as French press and boiled coffee, has been shown to increase low-density-lipoprotein-cholesterol con- van Dam, 2008b
centrations. Several early studies suggested that coffee consumption could result in a marked increase in risk of coronary heart disease and several types of
cancer. However, more recent prospective cohort studies that are less prone to selection and information bias have not confirmed these findings.
There is conflicting evidence regarding the impact of ED on weight loss, although some data suggest that combining ED use with exercise may enhance Ballard et al.,
body fat reduction. Observed ergogenic benefits of ED are likely attributable to caffeine and glucose content. ED are associated with adverse effects and 2010
combining ED with alcohol exacerbates safety concerns and is an increasingly common practice contributing to toxic jock identity among college-aged male
athletes.
Consumption of caffeine, capsaicin and different teas such as green, white and oolong tea, have been proposed as strategies for weight loss and weight main- Hursel and
tenance, as they may increase energy expenditure (4-5%), fat oxidation (10-16%) and have been proposed to counteract the decrease in metabolic rate that is Westerterp-
present during weight loss. Plantenga, 2010
The administration of green tea catechins (GTCs) with caffeine in 15 randomized controlled trials (n = 1243) was associated with small but significant reduc- Phung et al.,
tions in body mass index, BW, and waist circumference; GTCs alone did not cause these changes. 2010
Positive effects on body-weight management have been shown using green tea mixtures. Green tea, by containing both tea catechins and caffeine, may act Westerterp-
through inhibition of catechol O-methyl-transferase, and inhibition of phosphodiesterase. Here the mechanisms may also operate synergistically. A green Plantenga, 2010
tea-caffeine mixture improves weight maintenance, through thermogenesis, fat oxidation, and sparing fat free mass.
Caffeine reduces insulin sensitivity in skeletal muscle and this may be due to a combination of direct antagonism of A(1) receptors and indirect β-adrenergic Beaudoin and
stimulation as a result of increased sympathetic activity. Caffeine may also induce reduced hepatic glucose output. With the exception of bone mineral, there Graham, 2011
is little evidence that caffeine impacts negatively on other health issues.
Catechin-caffeine mixtures or a caffeine-only supplementation stimulates daily energy expenditure dose-dependently by 0.4-0.5 kJ/mg administered. Com- Hursel et al.,
pared with placebo, daily fat-oxidation was only significantly increased after ingestion of catechin-caffeine mixtures. 2011
191
7B. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Animals
Short-term studies (21-210 days) with rats and mice found that caffeine intake decreased
food intake and body weight gain, and decreased body fat. Plasma lipids were elevated in some
studies, whereas others found a decrease. However, these studies tested doses not relevant to
human consumption, e.g., 0.1% of the drinking water (~100 mg/kg/day) or 50 mg/kg i.p. Tea
extracts, which contain caffeine as well as several catechins, were also effective in reducing
weight gain. Again, effects were seen at high intake levels, such as 3-5% of the diet. A recent
study concluded that catechins and caffeine were synergistic in their anti-obesity effects (Zhang
et al., 2004). Thus, the animal studies qualitatively support the findings in human studies regard-
ing the effect of caffeine on body weight.
Animal studies of which the primary focus was the effect of caffeine on body weight or
lipids are summarized in Table 7-3.
192
TABLE 7-3. Effects of Caffeine on Body Weight, Glucose, Lipids, and Energy Use in Animals
Dog; anes- 1 day pure caffeine; 6 mg/kg (caf- Caffeine and ethanolic extract of kolanut significantly increased hindlimb glucose uptake due to the in- Salahdeen
thetized kolanut (i.v.) feine); 5 mg/ creases in glucose extraction. and Alada,
kg (kolanut) 2009b
Dog; fasted; 1 day pure caffeine; 6 mg/kg Pretreatment with either prazosin or propranolol (alpha and beta adrenergic receptor blockers) reduced caf- Salahdeen
anesthetized prazosin; pro- feine-induced hyperglycemia, glucose extraction and hindlimb glucose uptake at rest but not during contrac- and Alada,
pranolol (i.v.) tion. 2009a
Dog; mild 1 day pure caffeine; 25 mg/kg In dogs infused with caffeine, net hepatic glucose uptake was significantly higher than in controls. Caffeine Pencek et
hyper- carbohydrate increased net hepatic lactate output compared with controls. Arterial insulin, glucagon, norepinephrine, and al., 2004
insulinemia (i.v.) glucose did not differ between groups. [Dogs were given infusions of somatostatin, glucose, glucagon, and
insulin to establish mild hyperinsulinemia prior to caffeine treatment.]
Mouse 1 day pure caffeine 60 mg/kg Caffeine upregulated the expression of uncoupling protein UCP-1, UCP-2 and UCP-3 in brown adipose Kogure et
(s.c.) tissue and UCP-2 and UCP-3 in skeletal muscles, which may contribute to thermogenesis in obese mice. al., 2002
Plasma free fatty acids and adrenaline levels were significantly elevated.
Mouse 1 day pure caffeine 10, 50 mg/kg Caffeine (10 mg/kg) elicited a distinct profile of striatal gene expression in wild type mice compared with Yu et al.,
(i.p.) that by A(2A)R gene deletion or by administering caffeine into A(2A)R KO mice; adipocyte differentia- 2009
tion/insulin signaling is highly enriched in the striatal gene sets elicited by both low and high doses of caf-
feine.
Rat 1 day pure caffeine 50 mg/kg Spontaneous food intake was significantly lower in caffeine than in saline-treated rats. In food-deprived rats, Racotta et
(i.p.); α- the anorectic effect of caffeine was biphasic (significant at 0.5, 1, and 6 hr after dosing). In both the sponta- al., 1994
helical CRF neously fed and food-deprived rats, caffeine reduced the rate of weight gain 12 or a 24 hr after caffeine in-
(i.c.v.) jection. The effects of caffeine on food intake and BW gain were largely prevented by a corticotropin-
releasing factor (CRF) antagonist.
Rat; ova- 1 day pure caffeine; ~100 mg/kg The lymphatic total 14C-cholesterol and esterified cholesterol were lowered by EGCG, caffeine, and EGCG Wang et al.,
riectomized EGCG (in- + caffeine vs. Control. EGCG and caffeine lowered the absorption of alpha-tocopherol. The lymphatic out- 2006
traduodenal) puts of oleic acid and other fatty acids were not affected by EGCG but were lowered by caffeine + EGCG.
Caffeine (±EGCG) lowered the lymph flow and lipid absorption vs. EGCG alone or controls. [Rats were
infused intraduodenally with a lipid emulsion containing 14C-labeled cholesterol, alpha-tocopherol, triolein,
and sodium taurocholate, without (control) or with EGCG, caffeine, or EGCG plus caffeine, in PBS, pH 6.5]
Rat muscle 1 day pure caffeine mM Caffeine and theophylline blocked insulin-stimulated glucose uptake independently of Ca2+ release, and Kolnes,
strips (in vitro) reduced contraction-stimulated glucose uptake, which occurs independently of PI3-kinase/PKB. 2010
Mammalian 1 day pure caffeine mM Inhibited insulin-induced glucose uptake and suppressed insulin-induced GLUT4 translocation into cells. Akiba et al.,
cell culture (in vitro) 2004
Mammalian 1 day green tea ex- mM Thermogenesis was increased to an extent which greater than can be attributed to its caffeine content alone. Dulloo et al.,
cell culture tract (in vitro) 2000
193
Mammalian 1 day pure caffeine 10 mM Glucose transport was impaired in cultured cells with Glut1DS (Glucose transporter type 1 deficiency syn- Ho et al.,
cell culture, (in vitro) drome). 2001
Glut1DS
Rat; high-fat 1 day; 21 pure caffeine 1 d: 5 mg/kg Caffeine dietary intake for 21 d progressively reduced the body fat mass and body fat percentage in rats fed Kobayashi-
diet d (gavage, diet) gavage; 21 d: on a high-fat diet with dose-response. Caffeine also increased the serum concentrations of catecholamines Hattori et
0.025, 0.05, and free fatty acids in rats gavaged with CF (5 mg/kg). al., 2005
0.1% diet
Mouse; dia- 3d pure caffeine; 250, 375 Arginine or caffeine suppressed an increase in hepatic lipid contents in fasted-refed KK mice, and reduced Muroyama
betes, type TACC mg/kg diet adipose tissue weight in KK mice fed a high-calorie diet; adipose tissue weight decrease was greater with et al., 2003
II (diet) [13, 19 arg+caff, and much greater with TACC (mixture of thiamine, arginine, caffeine, and citric acid); plasma
mg/kg/d est.] insulin was lower from TACC body fat or plasma lipids decrease
Rat 14 d caffeine in G1=0.130 Muscle oleate incorporation and CPT I mRNA expression in the gastrocnemius were lower in rats receiving Lima et al.,
supplement; g/kg; decaffeinated than caffeinated guarana in relation to G1 and G2; caffeinated, but not decaf extract reduced 2005
decaf guara- G2=0.325 plasma lactate (G1 and G2), higher muscle glycogen (G1). [0.065 g/kg of guarana, corresponding to 0.010
na; guarana; g/kg g/kg of caffeine, had no significant effect]
(diet)
Mouse 14 d pure caffeine 20, 40 mg/kg In mice loaded with olive oil (5 ml/kg), caffeine reduced serum triglyceride level but had no effect on he- Shimoda et
(diet) caffeine patic carnitine palmitoyltransferase (CPT) activity. al., 2006
Rat 14 d pure caffeine; 0.125 mg/g Rats consumed more caffeinated than noncaffeinated solutions when they were maintained on a low-fat Swithers et
carbohydrate chow diet (Experiment 1) or a sweet, high-fat, high calorie chow diet (Experiment 2). Consumption of sac- al., 2010
(DW) charin resulted in higher BW gain in both experiments. Caffeine reversed this effect in Experiment 1.
Rat, high- 2-12 wk pure caffeine; 0.05% w/v Caffeine exacerbated the effect of ethanol to deplete liver glycogen, decrease epididymal fat pad weight, and Martin et al.,
fat, high- ethanol in ~130-170 lower serum leptin; no caffeine-only group; locomotor activity increased. 2004
CHO diet liquid diet mg/kg/d
Mouse; 28 d pure caffeine 4 mg/d Decreased body fat in obese mice with unchanged food intake; increased levels of brain norepinephrine and Chen et al.,
overweight (DW) epinephrine in lean and obese mice, more so in the latter (which had baseline lower levels than lean con- 1994
trols); brain levels of serotonin, tryptophan, and 5-hydroxyindoleacetic unaffected.
Rat 28 d green tea 0, 500, 1000, The clinical condition of the animals, functional observational battery, motor activity, clinical pathology Chengelis et
catechins 2000 mg/kg/d evaluations, organ weights, and gross necropsy findings were unaffected by any of the green tea catechin al., 2008
(GTC) (ga- GTC (3.7% (GTC) preparations. GTC-HDC (decaffeinated) or GTC-UH (non-heat-sterilized) dosing had no effects on
vage) caffeine), de- BWs or microscopic findings, whereas lower BWs and food consumption were observed in the 1000 and
caf GTC, 2000 mg/kg/day GTC-hr (heat-sterilized) group males. The NOAEL for localized gastric effects for GTC-hr
2000 mg/kg/d was 1000 mg/kg/day. No other target organs were identified. Thus, the NOAEL for systemic toxicity fol-
lowing oral dosing was 2000 mg/kg/day for GTC-H, GTC HDC, and GTC-UH.
194
Rat 28 d coffee (diet); 1.2 g/kg/d Triglyceride levels were significantly higher in coffee than in control group; triglyceride level of after- Choi et al.,
exercise freeze dried exercise (AE) group was significantly higher than that of before-exercise (BE) group; exercise and coffee- 2010
instant coffee exercise interaction effects were significant in total cholesterol; AE and BE of coffee intake group showed
higher superoxide dismutase levels than the other 4 groups; catalase activities were significantly higher in
coffee intake group than control group.
Rat; diet 28 d tea extract; 3% extracts Decreased BW, fat tissue mass and plasma leptin level, increased lipid excreted to feces and total 24-h- Sogawa et
restriction; green tea ex- energy consumption; no difference in effects between Awa tea and green tea. al., 2009
overweight tract (oral)
Mouse 28 d pure caffeine; caffeine Chronic consumption of kola nut and caffeine diets caused decrease in food intake and BW; the caffeine- Umoren et
kola nut (diet) 0.66% w/w; diet also decreased water intake and locomotor activity. The effect of kola nut-diets on water intake and al., 2009
kola nut 25% locomotor activity was not significant.
w/w
Mouse 40 d pure caffeine 0.01%, 0.05% High-dose M had increased activity which peaked on d 5 of dosing; both F groups had increased activity Nagasawa et
(DW); heat in DW that peaked at 30 d; no effect on food intake; increased plasma ALT, AST, cholesterol and glucose in high- al., 2001
dose M and F metabolic enzyme increase.
Rat, diabe- 8 wk pure caffeine 0.1% in DW Caffeine treatment reduced BW, food, and fluid consumption and improved insulin sensitivity. After 8 wk, Tofovic et
tes, hyper- (DW) [~100 mg/kg] animals were less glycosuric as compared with controls. AUC-glucose in oral glucose tolerance test was al., 2001
tension, unaffected, but caffeine decreased AUC-insulin. Caffeine increased cholesterol levels, decreased creatinine
overweight clearance, and increased plasma norepinephrine after 4 and/or 8 weeks. No effect on plasma triglycerides,
glycerol, or renin activity, BP, renal blood flow, or renal vascular resistance. [Prolonged administration of
0.1% caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that are seen in humans after an
intake of 2-3 cups coffee]
Rat, diabe- 9 wk pure caffeine; 0.1% in DW Caffeine reduced BW and glycosuria, improved glucose tolerance, increased plasma cholesterol, proteinuria, Tofovic et
tes, kidney tempol (DW) [~100 mg/kg] renal vascular resistance and HR, augmented the influx of glomerular and interstitial macrophages (ED1+ al., 2007
disease; cells), glomerular and tubular proliferative response, and glomerular collagen IV content. Caffeine had no
overweight effect on elevated plasma triglycerides, plasma cholesterol, and BP. Tempol attenuated caffeine-induced
increase in HR and RVR, and renal inflammation, proliferation, and fibrosis. [Prolonged administration of
0.1% caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that are seen in humans after an
intake of 2-3 cups coffee]
Mammalian 10 wk tea, oolong 5% tea pow- Oolong tea prevented the obesity and fatty liver induced by a high-fat diet, due to the caffeine; enhanced Han et al.,
cell culture; (diet) der noradrenaline-induced lipolysis in fat cells and accelerated the hormone-induced lipolysis in a cell-free sys- 1999
Mouse, tem.
overweight
195
Rat 12 wk pure caffeine 0.01% solu- Reduced BW, fats, and insulin resistance, without a change in food intake, regardless of an 11% sucrose Park et al.,
(DW) tion (7.6 ± 0.9 supplement. Caffeine enhanced glucose-stimulated first- and second-phase insulin secretion and beta-cell 2007
mg/d caffeine) hyperplasia. Sucrose supplementation deteriorated insulin sensitivity and attenuated insulin/IGF-1 signaling
in islets, which reduced the number of beta cells.
Mouse 15 wk pure caffeine; 0.4 mg/mL Dermal muscle layer thickness increased; decreased weight of parametrial fat pad and decreased thickness Michna et
green tea ± caffeine; 6 mg of the dermal fat layer body fat or plasma lipids decrease; locomotor activity increased. (0.047 mg/mL decaf al., 2003
caffeine (DW) /mL tea solids green tea)
Mouse 16 wk green tea 2% green tea The BW increase and weight of intraperitoneal adipose tissues (IPAT) were reduced by dietary green tea, Zheng et al.,
catechins; powder; 0.3% theanine, and caffeine ± catechins and theanine. Serum concentrations of triglycerides (TG) and non- 2004
green tea ex- green tea esterified fatty acids (NEFA) were decreased by green tea, catechins and theanine. Serum NEFA was de-
tract; theanine catechins creased by caffeine ± catechins and theanine. The liver TG level was reduced by catechins and catechins +
(diet) 0.03% theanine vs. Control. Catechins and caffeine were synergistic in anti-obesity activities. [diets contained 2%
theanine green tea powder or 0.3% catechins, 0.05% caffeine and 0.03% theanine, which is their content in 2% green
tea powder]
Rat 140 d coffee (diet) 0.62%, 1.36% Urinary 8-hydroxy-2-deoxyguanosine was significantly increased; slightly increased total serum homocys- Sakamoto et
w/w (~11-22, teine and cholesterol; no effect on production of IL-6 and TNF-alpha or on serum level of 15-isoprostane al., 2005
25-50 F(2t); serum glutathione peroxidase activity tended to decrease.
mg/kg/d)
Rat; 30 wk pure caffeine 0.1% in DW Caffeine reduced BW, glycosuria, fasting glucose and insulin levels, improved glucose tolerance, slightly Tofovic et
diabetes, (DW) [~100 mg/kg] increased mean arterial BP and HR, increased proteinuria, reduced creatinine clearance, increased plasma al., 2002
type I; cholesterol, renal vascular resistance and decreased inulin clearance, and potentiated severe tubulointerstitial
overweight changes and focal glomerulosclerosis. Thus, despite improving insulin sensitivity, caffeine exacerbated re-
nal failure in obese, diabetic rats. [Prolonged administration of 0.1% caffeine in the DW results in plasma
levels of caffeine (5-10 µg/mL) that are seen in humans after an intake of 2-3 cups coffee]
Mouse, 10 mo pure caffeine; caffeine Hypersecretion of insulin and obesity from a high-fat diet and brain atrophy were suppressed by intake of Unno et al.,
brain with green tea 0.05% of diet; green tea catechin + caffeine; working memory was improved. A strong correlation was found between 2009
aging catechin catechin 0.3% working memory and insulin release in these mice.
(diet) of diet
ALT=alanine aminotransferase; AST=aspartate aminotransferase; AUC=area under the curve; BP=blood pressure; DW=drinking water; EGCG= Epigallocatechin gallate;
HR=heart rate; IVC=intracerebroventricular; RVR= renal vascular resistance
196
CHAPTER 8. DEVELOPMENTAL EFFECTS OF CAFFEINE
8A. Developmental Effects of Caffeine in Humans
The potential of maternal intake of caffeine prior to, during, and after pregnancy to cause
adverse fetal effects is of great public health importance, since most women consume caffeine.
A number of human studies have examined the effect of maternal caffeine intake on the fetus.
Endpoints evaluated include spontaneous abortion, low birth weight, premature birth (shortened
gestation period), intrauterine growth retardation, developmental toxicity, and chromosomal ab-
normalities. A few studies examined the association of prenatal caffeine exposure with sudden
infant death syndrome (SIDS), behavior during childhood, and endometriosis in adult daughters;
the interaction of caffeine with alcohol intake and cigarette smoking; the impact of maternal
genotype (for caffeine-metabolizing enzymes); and fetal karyotype.
Table 8-1 summarizes studies which addressed these endpoints. Coffee was the major
source of caffeine intake in most studies, with minor contribution from tea, sodas, and chocolate
beverages. In South American countries, yerba mate was a major source of caffeine, as was tea
in Japan. Some studies also evaluated caffeine intake from chocolate or candy and from medi-
cines. The highest caffeine intake group was typically ≥300 mg/d, but was >900 mg/day in a
few studies.
Conflicting results were obtained among the studies: ~20% found no caffeine-related ef-
fects, whereas the rest found an association between caffeine intake and fetal toxicity. The ad-
verse caffeine-associated fetal outcomes included an increased risk for spontaneous abortion or
stillbirth, decreased fetal growth or birth weight, premature birth, SIDS, decreased placental
weight, developmental abnormalities, genotoxicity, fetal arrhythmia, and childhood behavior
problems. Maternal coffee intake was associated with an increased risk for undescended testes at
2 years of age and decreased semen volume, testosterone and inhibin B in 21-year old sons. Ef-
fects on fetal growth and viability were often seen for only the highest intake groups (typically
≥300 mg/day), but were in some cases seen at lower intakes (~100-200 mg/day). Evidence was
marginal for a caffeine-associated increase in developmental abnormalities (cleft lip with or
without cleft palate, orofacial clefts, tetralogy of Fallot, anorectal atresia). A genotoxic effect
was suggested by the finding of placental DNA adducts, a slight increase in fetal monosomy X
and triploidy, and a reduced risk of a Down syndrome conceptus. Fetal arrhythmia was detected
from a total maternal intake of 300 mg caffeine in some studies, or from 10 cups coffee per day
in another study. Maternal intake of ≥8 cups coffee/day was associated with an increased risk of
behavioral problems in childhood.
Although maternal smoking is a known cause of fetotoxicity, a consistent effect of smok-

ing on caffeine developmental toxicity was not seen, possibly due to the fact that smoking in-
creases caffeine metabolism. In some cases, smoking obscured the contribution of caffeine to
toxicity, as caffeine-associated adverse effects were seen only in non-smokers, or were greater in
non-smokers (spontaneous abortion, decreased fetal size or birth weight, shortened gestation
time, developmental anomalies). In other cases, caffeine-associated toxicity was only seen in
smokers, or was greater in smokers. A number of studies found no statistical effect of smoking
197
on caffeine-associated spontaneous abortion. The combined effect of ethanol and caffeine intake
on developmental toxicity was not specifically addressed in many studies, but those that did gen-
erally found none. The impact of the presence of nausea during pregnancy on caffeine-
associated spontaneous abortion was evaluated in four studies. Two studies found an increased
risk in women reporting nausea, whereas the other two found that nausea was unrelated to risk.
Studies that evaluated the impact of maternal genotype or fetal karyotype on caffeine-
associated spontaneous abortion found that the risk was increased for women with the Leu/Leu
or Val/Val genotype for the CYP1B1 gene, with homozygous CYP1A21F alleles, with low
CYP1A2 enzyme activity, with the slow acetylator phenotype (NAT2 gene), and with low
GSTA1 activity (gluthatione S-transferase alpha1). One study, however, found that acetylator
phenotype had no effect. In the two studies that addressed fetal karyotype, one found no associa-
tion of caffeine intake with chromosomally normal loss, using aberrant cases as the comparison
group, and the other study found an increased risk for spontaneous abortion in non-smoking
mothers when the fetus had a normal karyotype.
Some studies found no association of caffeine intake with developmental toxicity, upon
evaluating one or more of these endpoints: spontaneous abortion, low birth weight, premature
birth, intrauterine growth retardation, SIDS, behavior during childhood, and endometriosis in
adult daughters. An explanation for these conflicting results is not immediately obvious. Some
of the discrepancy is likely due to methodological differences, both in the way that the studies
were conducted, in the characteristics of the particular population that was studied (e.g., age,
diet, location, genotype), and in the way that the data were statistically analyzed and interpreted
by the authors. For example, some investigators dismissed effects with an odds ratio of >1 if the
confidence intervals included the number 1, whereas other authors would say that the association
with caffeine intake was weak or non-significant. This difference may have had a considerable
impact, since most subjects did not have very high consumption levels during pregnancy (e.g. <3
cups/day). Additionally, the maternal genotype for caffeine-metabolizing enzymes was not con-
sidered in studies that found no caffeine-associated effects. Maternal genotype may be the key in
resolving the seeming discrepancies between the results of the studies, as no caffeine-associated
effects were seen in several studies until the women were stratified for their genotype and/or
phenotype for caffeine-metabolizing enzymes.
The overall weight of evidence indicates that a caffeine intake of >2 cups/day (~3
mg/kg/d) during pregnancy may be detrimental to the human fetus. The LOAEL for fetal toxic-
ity is therefore 3 mg/kg/day, which is about 2 cups of coffee per day, and the NOAEL is 1.5
mg/kg/day, or about 1 cup of coffee per day.
The individual study developmental toxicity data (demarcated as squares) and the derived
overall LOAEL and NOAEL (demarcated as dashed lines) are plotted below. The squares on the
plot are the lowest effect level and the no-effect level for a given endpoint of each study (the
endpoints are identified on the lower X-axis). The no-effect level for a given study was either
the upper limit or the midpoint of the lowest intake (reference) category, depending on the distri-
bution of the intake categories. The study author(s) are indicated on the upper X-axis.
198
Caffeine intake (mg/kg/day)
1.0E-01
1.0E+00
1.0E+01
1.0E+02
SI
D
S S
hy cle spi SIDS
pe ft na ID Al
ra m lip bi S m
ct icr , p fid Ar e
i v i oc a a t
ty e la Foyay al.
e ,
lo pre at phate Derd e v e 19
w t e 1 8 ly 9
lo bi rm m Jo Mat al t al 9
w r . .
lo bi th w bir o M han rco , 19, 19
w r i
lo bi th weigth Bells esen et a98 99
w r
lo bi th weight W kkh t al et al., 2
w r i .
lo bi th weight Bi sbous , 19 l., 2011
w r c e
lo bi th weight C al h r g e t a 9 3 00 9
w r h l.
lo bi th weight I n i af f o e t a l , 20
w r f a t .
lo bi th weight Roant rin al., , 19 10
w r e e
lo bi th weight Sa ndo -R et 20096
w r i
lo bi th weight Vi nto et vardal., 2
w r k s
2003; Nehlig and Debry, 1994d).

lo bi th weight Ba et et al., , 20200
w r 1
lo bi th weight Bakkeal., al., 99 07 6
w r 6
lo bi th weight Br lat r et 200 199
w r e
lo bi th weight CAack t a al., 3 8
w r e l
lo bi th weight Cl RE n e., 2 201
w r a 0
lo bi th weight Co us stu t al 03 0
w r s .
lo bi th weight M ok on dy g, 20
w r i e
lo bi th weight Pells e t a et a rou 03
w rth e h
t l
l Shacot al ., 1 l., 2p
Embryotoxic effect
sp ow birt weigh
h . 9
t E s u e c k , 1 9 9 6 00 2
spont low birt weigh t e
a h t Feken al. t a 93
spont ne birt weigh
a o h t , l.
Fonst azi 19 , 19
spont ne us weigh e 9
a o a t G rtie r e et a 5 91
spont ne us bo igh o r t l
Study author(s)
a o a r t G de et al. ., 1
spont ne us bo tion r l a , 9
a o a r V l o s s e t a l. , 1 9 9 9
spont ne us bo tion
a o a r a 1 9
Cn jin o et l., 1 99 1b
spont ne us bo tion
a o a r a 3
F e at t c e al . , 9 92
spont ne us bo tion in
a o a r Fenst giut al. 200
spont ne us bo tion
a o a r e ,
G ns t r e s e 19 1
spont ne us bo tion
a o a r e e t t 9
G org r e al. al. 7
spont ne us bo tion
a o a r i t , ,
In ann e e al. 19 20
spont ne us bo tion
a o a r f t , 9 0
Kaant elli al. 19 1a 0
spont ne us bo tion
a o a r e e , 9
K l ryp - R t a 2 0 8
spont ne us bo tion
a o e i i l 0
r M ba did vard., 2 6
spont ne us abo tion a n 0
a o a r M co off et a et 03
spont ne us bo tion
a o a r a n a
Pa tija ochet al., 2 l.,
spont ne us bo tion
a o a r 1
Raraz sev ie el., 1006 99
spont ne us bo tion
a o a r z i 3
Sa sch ini ch t al 999
spont ne us bo tion e .
a o a r
ENDPOINT: Embryotoxicity (epidemiological studies with caffeine)
T o t a e e t et a t a , 2 0
spont ne us bo tion
a o a r a l.
M lstr t al l., l., 1 , 2007
spont ne us bo tion i u . 2 9
s Polls e p e , 20 00 94 06
p
on an ou ab rtio
t
sp o aneous a ort n 3
W llac t al t al 05
on nt e s bo ion e . .
ta an ou ab rtio W n ek et , 19, 20
n e eo s a o r n e
B e ng t al al . , 9 3 03
ou us bo tio
s a b rt n .
Dl ch et a, 20 201
ab o io u e
o r rt i n
LOAEL
Do go t a l., 201 0
s l
NOAEL
ene, 2006; Christian and Brent, 2001; Golding, 1995; Hinds et al., 1996; Nehlig and Debry,
t - C on
No Effect
K h m i n z e . , 2 0 08
0
intrauterine growth retardation, and/or low birth weight was espoused in some of the reviews
YP
et al., 1998; Sosa et al., 2003; Wadge, 2009), whereas others concluded that the evidence was
Effect level
2010; Wadge, 2009), or 300 mg/day (Higdon and Frei, 2006; Hinds et al., 1996; Nawrot et al.,
Saour guet al 05
bryotoxicity were 150 mg/day (Fernandes et al., 1998; Sosa et al., 2003), 200 mg/day (ACOG,
.
topic are provided in Table 8-2. The reviews consistently agreed that there was no evidence to
1994c; Sivak, 1994). A possible association of caffeine intake with miscarriage, preterm birth,
implicate caffeine as a teratogen at doses normally ingested by humans (Brent et al., 2011; Bro-
Human studies that evaluated the effect of maternal caffeine intake during pregnancy on
Si vitzy et z-R, 19
McLaughlin, 2004). Maximum recommended levels of caffeine intake to preclude a risk of em-
(Cramer and Wise, 2000; Fernandes et al., 1998; Pacheco et al., 2007; Romo et al., 2009; Santos
the fetus are summarized in Table 8-1. Brief summaries of conclusions drawn in reviews on this
g n e a o 96
inconclusive or equivocal (Jahanfar and Sharifah, 2009; Matijasevich et al., 2005; Signorello and
199
or t a l., jas
el l., 20 e
lo 2 0 t a
et 00 4 l.,
al 8 19
., 94
20
01
TABLE 8-1. Developmental Effects of Caffeine – Human Studies
1-day experi- Adult coffee ~300 mg Maternal caffeine content linearly increased the incidence of fetal movement during active sleep Mulder et
ment n=13 F [4.3 mg/kg/d] on day 0. After coffee loading on day 2, fetuses of non- or low-caffeine consumers showed inal., 2010
(The Nether- creases in active wakefulness, general movements, and HR variation, but lower basal HR com-
lands) pared to day 0. Fetuses of habitual caffeine consumers remained unaffected, suggestive of fetal
tolerance to caffeine.
Case-control Adult caffeine, all 0, 1-400, 401- The crude ORs for SIDS for caffeine consumption >800 mg/24 hours both during and after preg- Alm et al.,
(Denmark; n=244; c=976 sources; 800, >800 nancy were significantly raised: 3.9 (95% CI, 1.9 to 8.1) and 3.1 (95% CI, 1.5 to 6.3), respectively. 1999
Norway; Swe- M+F smoking mg/d [0.01 to However, after adjustment for maternal smoking in 1st trimester, maternal age, education and par-
den) >11 mg/kg/d] ity, no significant effect of caffeine during or after pregnancy remained.
Case-control Adult coffee; tea 1, 2, >2 cups/d One or two cups of tea or coffee per day during pregnancy appears to have reduced risk for SIDS Aryayev,
(Ukraine) cases=52 F; [1.4 to >2.9 slightly, but >2 cups/d was associated with an 85% increase in univariate risk, but was accounted 1999
controls=104 mg/kg/d] for by other factors in the multivariate model. [No info on caffeine per cup coffee; assume 100
F mg/cup]
Case-control Adult caffeine, all 0, 0.5-3, ≥4 Risk of stillbirth increased only for F with slow CYP1A2, slow NAT2, and low GSTA1; no dose- Bech et al.,
(Denmark) cases=142 F; sources cups/d response - effects seen for intake of 0.5-3 cups/d and overall only. [No info on caffeine per cup; 2006
controls=157 [metabolic [0.7 to ≥5.7 assumed 100 mg/cup coffee]
F enzyme phe- mg/kg/d]
notype]
Case-control Adult caffeinated <300 or >300 There was no association between caffeine consumption during pregnancy and low birth weight, Bicalho et
(Portugal) cases=354 F; drinks mg/d [< or prematurity, or intrauterine growth retardation. al., 2002
controls=354 >4.3 mg/kg/d]
F
Case-control 12 to >35 yr caffeine, all <10, <100, Nonsignificant elevations in risk for tetralogy of Fallot (fetal malformation) overall and in non- Browne et
(USA) cases=4196 F; sources; 100-200, 200- smokers; no dose-response; no interaction with ethanol consumption; small decrease with smok- al., 2007
controls=3957 smoking 300, ≥300 ing. [Caffeine =100 mg/cup coffee, 37 mg for a cup of tea; soda caffeine was obtained from web-
F mg/d [<0.1 to sites; chocolate was assigned 10 mg per ounce]
≥4.3 mg/kg/d]
Case-control Adult caffeinated <10, 10- <100, Small, statistical elevations in adjusted OR ranging from 1.3 to 1.8 for total maternal intake or Browne et
(USA) cases=3346 F; drinks 100- <200, specific types of caffeinated beverages and anotia/microtia, esophageal atresia, small intestinal al., 2011
controls=6642 200- <300, atresia, and craniosynostosis; however, dose-response patterns were absent. [Caffeine =100
F 300+ mg/d mg/cup coffee, 37 mg for a cup of tea; soda caffeine was obtained from websites; chocolate was
[<0.1 to ≥4.3 assigned 10 mg/oz]
mg/kg/d]
200
Case-control 14-45 yr caffeinated 0, 1, ≥2 cups/d A low consumption of coffee during pregnancy did not increase risk of preterm birth of small for Chiaffarino
(Italy) cases=502 F; drinks [1.4, ≥2.9 gestational age babies. [No info on caffeine per cup; assume 100 mg/cup] et al., 2006
controls=1966 mg/kg/d]
F
Case-control Adult caffeinated >300 mg/d Daily intake of >3 cups of coffee (>300 mg caffeine) had an inverse association (OR = 0.63; CI = Christianso
(USA) cases=997 F; drinks; smok- [>4.3 mg/kg/d] 0.41-0.96) with Downs syndrome pregnancies for mothers who did not smoke only. n and Torfs,
controls=1007 ing 1998
F
Case-control caffeine, all <100, 100-299; The ingestion of ≥100 mg/d caffeine increased the risk of an early spontaneous abortion among Cnattingius
(Sweden) cases=562 F; sources; 300-499, ≥500 non-smoking women carrying fetuses with normal karyotypes; dose-response seen. et al., 2000
controls=953 smoking [nor- mg/d [<1.4 to
F mal karyotype ≥7.1 mg/kg/d]
fetuses]
Case-control Adult caffeinated <10, 10-99, Some effect estimates were elevated for moderate caffeine intake from all beverages, but estimates Collier et
(USA) cases=1531 medication; 100-199, 200- were closer to the null for high caffeine levels; cleft lip with or without cleft palate was associated al., 2009
CL/P, 813 caffeine, all 299, ≥300 with use of medications containing at least 100 mg of caffeine per dose.
CPO; con- sources mg/d [<0.1 to
trols=5711 ≥4.3 mg/kg/d]
Case-control Adult coffee < 3 cups/d; >3 High caffeine intake (>3 cups/d; OR=10.82; 95% CI, 3.78-31) increased spina bifida risk in the De Marco
(Italy) cases=133 F; cups/d (≥300 multivariate analysis; findings point out that a common underlying mechanism, a disturbed et al., 2011
controls=273 mg/d) folate/homocysteine metabolism, may be causative for the burden of spina bifida in the Italian
F population. [≥300 mg/d was considered equivalent to >3 cups/d]
Case-control Adult caffeine, all most <300 Total caffeine consumption (including food sources) during pregnancy was not associated with de Souza
(Brazil) cases=140 F; sources mg/d [<4.3 prematurity. and Si-
controls=162 mg/kg/d] chieri, 2005
F
Case-control Adult caffeine, all 0, 1-150, >150 No significant association between enzyme activity and caffeine intake during pregnancy in risk of Fenster et
(USA) cases=73 F; sources [en- mg/d spontaneous abortion: low CYP1A2 activity OR= 0.92 (0.28-3.04); low xanthine oxidase activity al., 1998
controls=141 zyme pheno- [0.01 to >2.1 OR=0.37 (0.10-1.29); low NAT2 OR=1.58 (0.48-5.13).
F type] mg/kg/d]
201
Case-control Adult caffeine, all 0-99, 100-199, Maternal consumption of ≥400 mg/d through pregnancy increased risk for SIDS; OR=1.65 (1.15 Ford et al.,
(New Zealand) cases=393 F; sources 200-399, ≥400 to 2.35) after adjusting for likely confounding factors. 1998
controls=1592 mg/d [1.4 to
F ≥5.7 mg/kg/d]
Case-control Adult caffeine, all 0-99, 100-299, There was an increased risk of repeated miscarriage among non-smoking women with intake ≥300 George et
(Sweden) cases=108 F; sources ≥300 mg/d mg/d; dose-response seen. al., 2006
controls=583 [1.4 to ≥4.3
F mg/kg/d]
Case-control Adult caffeinated 0-150, 151- Consumption of >300 mg/day doubled the risk of miscarriage relative to <151 mg/d; adjusted Giannelli et
(UK) cases=160 F; drinks 300, 301-500, OR=1.94 [95% CI 1.04, 3.63] for 301-500 mg/d and 2.18 [95% CI 1.08, 4.40] for >500 mg/d. al., 2003
controls=314 >500 mg/d [2.1
F to >7.1
mg/kg/d]
Case-control Adult caffeinated 1-100, 101- Consumption of ≥300 mg/d vs. a lower level, or using caffeine as a continuous measure, while Infante-
(Canada) cases=493 F; drinks; smok- 200, 201-300, adjusting for smoking and nausea, showed no increased risk for small-for-gestational-age (SGA) Rivard,
controls=472 ing [metabolic >300 mg/d birth. Using birth weight as the outcome and caffeine as a continuous measure, a 38 g [95% CIl - 2007
F enzyme phe- [0.01 to >4.3 68, -8] decrement for every 100 mg of daily caffeine was observed in the third trimester. Polymor-
notype] mg/kg/d] phisms in the CYP1A2 and CYP2E1 genes did not modify the effect of caffeine.
Case-control Adult caffeinated <3, ≥3 cups/d Cleft lip with or without cleft palate, not cleft palate only, was increased for ≥3 cups/d coffee; an Johansen et
(Norway) cases=573 F; drinks [<4.3, ≥4.3 effect was not seen for all sources of caffeine combined. [Caffeine was estimated as 100 mg/ cup al., 2009
controls=763 mg/kg/d] of coffee, 40 mg/ cup of tea, and 20 mg/cup of caffeinated soft drink]
F
Case-control Adult caffeine, all 0-99, 100-299, Carriers of the CYP1B1 432 Val/Val genotype (CYP1B1 Val432Leu polymorphism) were at a Karypidis et
(Sweden) cases=507 F; sources 300-499, ≥500 higher risk of miscarriage in the first trimester of pregnancy (OR=1.46; 95% CI 1.02-2.08). There al., 2006
controls=908 [metabolic mg/d [1.4 to was a significant interaction between genotype and caffeine intake.
F enzyme phe- ≥7.1 mg/kg/d]
notype]
Case-control Adult caffeine, all <30 to >1100 The adjusted OR for spontaneous abortion among F with serum paraxanthine >1845 ng/mL [16 Klebanoff
(USA) cases=591 F; sources; mg [<0.4 to 16 mg/kg/d] vs. <50 ng/mL [0.4 mg/kg/d] was 1.9 (95 CI 1.2-2.8); 1845 ng/mL paraxanthine corre- et al., 1999
controls=2558 smoking mg/kg/d] sponds to 1100 mg caffeine or 11 cups/d coffee in smokers and 6 cups/day in non-smokers [cate-
F gories were <50, 50-1845, >1845 ng/mL serum paraxanthine].
202
Case-control 18-55 yr caffeine, all 0, <151, 151- After adjustment for nausea and other variables, there was no association of caffeine consumption Maconochie
(UK) cases=603 F; sources 300, 301-500, with the risk of miscarriage. et al., 2007
controls=6116 >500 mg/d
F [<2.1 to >7.1
mg/kg/d]
Case-control Adult Coffee; yerba 0, 1-59, 60- After controlling for multiple variables, mean caffeine intake of ≥ 300 mg/day showed a signifi- Matijase-
(Uruguay) cases=382 F; mate; smok- 149, 150-299, cantly increased risk of fetal death (OR 2.33 [1.23; 4.41]) compared with no caffeine consumption vich et al.,
controls=792 ing ≥300 mg/d during pregnancy. [mate drinking was the most frequent source of caffeine in both cases and con- 2006
F [0.01 to ≥4.3 trols]
mg/kg/d]
Case-control Adult caffeine, all <10, 10-99, Anorectal atresia (birth defect) was seen for intake of ≥10-99 mg/d during pregnancy, and a Miller et al.,
(USA) cases=464 F; sources 100-299, ≥300 smaller effect was seen for intake during the prior year. 2009
controls=4940 mg/d
F [<0.14 to ≥4.3
mg/kg/d]
Case-control Adult coffee; tea 0 to <2, ≥2 No overall association between maternal coffee consumption and risk of ALL: OR=0.89 (0.61, Milne et al.,
(Australia) cases=337 F; cups/d 1.30), but a slight increase was seen in children of non-smoking mothers: OR for 2+ cups/d=1.44 2011
controls=697 [<0.6 to ≥2.9 (0.85, 2.42) and in cases with chromosomal translocations. Overall OR for maternal tea consump-
F mg/kg/d] tion was 0.82 (95% CI 0.56, 1.18), but was higher for cases with translocations OR = 1.70 (0.79-
3.68) for 2+ cups/d. [No info on caffeine per cup; assume 100 mg/cup coffee; 40 mg/cup tea]
Case-control median=31 yr coffee 0, 1, ≥2 cups/d Coffee drinking 3 mo before pregnancy had insignificant effect on fetal loss. [No info on caffeine Parazzini et
(Italy) cases=303 F; [1.4, ≥2.9 per cup; assume 100 mg/cup] al., 1994
controls=993 mg/kg/d]
F
Case-control Adult caffeinated 1-10, 11-50, Third-trimester caffeine consumption from all beverages combined showed a NS inverse associa- Pastore and
(USA) cases=408 F; drinks 151-300, >300 tion with preterm delivery. Both first- and second-trimester intake of 1-150 mg/day [0.01-2.1 Savitz,
controls=490 mg/d [0.01 to /g/kg/d], but not higher levels, were associated with a modestly increased risk of preterm delivery. 1995
F >4.3 mg/kg/d] [Assumed 146 mg/cup perked coffee, 110 mg/cup filter coffee, 66 mg/cup instant coffee, 107
mg/cup coffee of unknown preparation, 34 mg/cup tea, 42 mg/12 ounces (354.8 ml) of cola, and
46 mg/12 oz (354.8 ml) for noncola caffeinated soda.]
203
Case-control Adult caffeine, all 0-199, 200- Adjusted OR for spontaneous abortion among women who consumed ≥375 mg caffeine/d was Rasch, 2003
(Denmark) cases=330 F; sources; 374, ≥375 2.21 (1.53-3.18). Women who smoked 10-19 cigarettes and 20 or more cigarettes per day did not
controls=1168 smoking mg/day have significantly increased ORs for spontaneous abortion, after adjusting for other risk factors.
F [<2.9 to ≥5.4
mg/kg/d]
Case-control Adult coffee 0, <1, 1-2, ≥3 More interauterine growth retardation (IUGR) babies' mothers (85.4%) than appropriate for gesta- Rondo et
(Brazil) cases=356 F; cups/d [<1.4 to tional age babies' mothers (70.5%) ingested coffee in pregnancy (OR = 2.45; P < 0.001). The pro- al., 1996
controls=356 ≥4.3 mg/kg/d] portion of mothers who delivered IUGR babies increased as consumption of coffee increased (test
F for trend = 31.76; P < 0.001). The tendency for heavy coffee drinkers to deliver IUGR babies re-
mained after controlling for alcohol intake and cigarette smoking. [No info on caffeine per cup
coffee; assumed 100 mg/cup]
Case-control Adult Caffeine, all + or - The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital Samren et
(The Nether- cases=1411 F; sources; phe- monotherapy (given for epilepsy during the 1st trimester) when caffeine comedication was ex- al., 1999
lands) controls=2000 nobarbital cluded, but a significant increase in risk was found when caffeine was included. There were sig-
F [epilepsy] nificantly increased relative risks for the combination of phenobarbital + caffeine + other antiepi-
leptic drugs. [No info on caffeine exposure levels]
Case-control Adult caffeine, all <100, 100-299, Crude analyses showed no effect of caffeine on low birth weight, preterm births or intrauterine Santos et
(Brazil) cases=401 F; sources; yerba ≥300 mg/d growth retardation. The results did not change after allowing for confounders. al., 1998
controls=804 mate [<1.4 to ≥4.3
F mg/kg/d]
Case-control Adult caffeine, all 100-299 mg/d; Without consideration of the genotype, there were no significant differences of the recurrent preg- Sata et al.,
(Japan) cases=58 F; sources >300 mg/d nancy loss (RPL) risk in proportion to daily caffeine intake [<100 mg (reference); 100-299 mg: 2005
controls=147 [CYP1A21F [1.4-4.3, >4.3 OR, 1.29; 95% CI, 0.66-2.50; ≥300 mg: OR, 1.82; 95% CI, 0.72-4.58; P for trend, 0.20]. However,
F genotype] mg/kg/d] the RPL risk significantly increased only among F who had homozygous CYP1A21F alleles with
a dosage effect of daily caffeine intake [<100 mg (reference); 100-299 mg: OR, 1.94; 95% CI,
0.57-6.66; 300 mg or more: OR, 5.23; 95% CI, 1.05-25.9; P for trend, 0.03].
Case-control Adult caffeine, all 0-9, 10-99, Positive associations were observed between spina bifida and total caffeine consumption and each Schmidt et
(Canada) cases=768 F; sources; 100-199, 200- caffeine source except caffeinated tea, which showed a negative association with spina bifida. As- al., 2009
controls=4143 chocolate; 299, ≥300 sociations with modestly increased risk of neural tube defects and encephalocele were also ob-
F coffee; cola; mg/d served. The association between caffeine consumption and anencephaly differed by maternal
tea [<0.1 to ≥4.3 race/ethnicity. No dose effects were found.
mg/kg/d]
204
Case-control Adult caffeine, all 0-9, ≥10 mg/d Mothers who consumed caffeine, oxidized CYP1A2*1F quickly, and acetylized NAT2 slowly had Schmidt et
(USA) cases=768 F; sources [≤0.1 to >0.1 a non-significantly elevated estimated risk for an neural tube defect-affected pregnancy. al., 2010
controls=4143 [metabolic mg/kg/d]
F enzyme phe-
notype]
Case-control 20-29 yr caffeine, all <75, 75-300, Compared with women with a pre-pregnancy intake of <75 mg caffeine per day, the adjusted odds Tolstrup et
(Denmark) cases=303 F; sources; etha- 301-500, 501- ratio (95% confidence interval) for spontaneous abortion was 1.26 (0.77-2.06), 1.45 (0.87-2.41), al., 2003
controls=1381 nol [pre- 900, >900 1.44 (0.87-2.37) and 1.72 (1.00-2.96) for a pre-pregnancy intake on 75-300, 301-500, 501-900 and
F pregnancy] mg/d [<1.1 to >900 mg caffeine per day respectively (P = 0.05 for trend). A pre-pregnancy intake of alcohol (1-
>13 mg/kg/d] 3, 4-6, 7-13, >13 drinks/wk) was not a predictor for spontaneous abortion.
Case-control Adult caffeinated 0, ≤3, ≥ 4 An intake of ≥4 cups coffee/day reduced the risk of a Down syndrome conceptus in nonsmoking Torfs and
(USA) cases=997 F; drinks; smok- cups/d mothers. [No info on caffeine per cup; assume 100 mg/cup] Christianso
controls=1007 ing [≤4.3, ≥5.7 n, 2000
F mg/kg/d]
Case-control Adult caffeine, all 0-109, 110- Mothers of small-for-gestational-age (SGA) infants had higher mean intake of caffeine [281 ± 210 Vik et al.,
(Norway; Swe- cases=111 F; sources; 204, 205-309, mg/d] in the third trimester than mothers of non-SGA infants (212 ± 150 mg/d; P < 0.001). The 2003
den) controls=747 smoking ≥310 mg/d risk of SGA birth was nearly doubled if the mother had a high rather than a low caffeine intake in
F [<1.6 to ≥4.4 the third trimester [OR=1.8; 95% CI 1.2, 2.5]. The increased risk was mainly found in boys (OR
mg/kg/d] 2.8; 95% CI 1.5, 5.2), and not in girls (OR 1.2; 95% CI 0.7, 2.1).
Cohort prospec- Adult coffee; tea <2, 2-3.9, 4- Offspring of mothers who consumed ≥6 caffeine units/d tended to have increased risks of small- Bakker et
tive (follow-up n=7,346 F 5.9, ≥6 units/d for-gestational-age infants at birth. [1 unit=1 cup coffee with 90 mg caffeine] al., 2010
through preg- [<2.6 to ≥7.7
nancy) (The mg/kg/d]
Netherlands)
Cohort prospec- Adult caffeine, all < or >300 mg/d The pregnant non-smokers consuming >300 mg/d caffeine had lower weights of newborns and Balat et al.,
tive (follow-up n1=63 F; sources; [< or >5.0 placentas (p < 0.05), but no significant difference in the lengths, head circumferences of newborns 2003
through preg- n2=60 F smoking; tea mg/kg/d] and diameters of placentas. There were significantly lower BWs of newborns and placentas in
nancy) pregnant smokers (p < 0.05), without difference according to the diameters of placentas, and
(Turkey) lengths and head circumferences.
205
Cohort prospec- Adult Coffee 56-461 mg/d Women who switched from caff to decaf coffee during the 2nd half of pregnancy (their mean caf- Bech et al.,
tive (followed n1=568 F; [0.8-6.6 feine intake was 182 mg lower than the caffeinated group) had babies with birth weight 16 g (95% 2007a
prenatal wk <20 n2=629 F mg/kg/d] CI -40 to 73) higher; the adjusted difference (decaffeinated group-caffeinated group) of length of
to birth) (Den- gestation was -1.31 days (-2.87 to 0.25). Authors conclude that there was "no effect on birth
mark) weight or length of gestation."
Cohort prospec- Adult caffeinated 0, 33-85, 99- High (255 mg/d? - not specified) caffeine intake at 17th week of gestation slightly increased inat- Bekkhus et
tive (followed n=25,343 F drinks 251, ≥255 mg tention + overactivity in 18-month old children, and both 17th and 30th week of gestation on over- al., 2010
wk 17 of gesta- caffeine/d activity, when investigated separately from inattention. The caffeine effect was only found for soft
tion to age 18 [0.5 to ≥3.6 drinks, not tea or coffee. [mg caffeine=boiled ⁄ percolated ⁄ filtered coffee, 85/cup; instant ⁄ es-
mo) (Norway) mg/kg/d] presso coffee, 60/cup; tea, 50 mg/cup; soft drinks, 30/ cup)]
Cohort prospec- Adult coffee; decaf 0, 1-149, 150- Mean birth weight was reduced by caffeine consumption (-28 g per 100 mg/d, 95% CI: -0.10, - Bracken et
tive (follow-up n=2291 F 299, ≥300 0.46, p = 0.001) but not mean gestational age. Decaf did not increase risk for any perinatal out- al., 2003
through preg- mg/d [0.01 to come. The decreased birth weight is unlikely to be clinically important except for F consuming
nancy) ≥4.3 mg/kg/d] ≥600 mg/d (~6 cups of coffee). [a 10-ounce cup of drip coffee contained 100 mg of caffeine; tea
(USA) brewed for 3 minutes contained 42 mg of caffeine]
Cohort prospec- 18-40 yr caffeine, all + or - No significant associations were seen between intrauterine exposure to caffeine and a diagnosis of Buck Louis
tive (followed n=84 F sources endometriosis in adult daughters. [No info on caffeine amounts] et al., 2007
from in utero to
adulthood)
(USA)
Cohort prospec- 18-45 yr caffeine, all <100, 100-199, Caffeine consumption throughout pregnancy was associated with an increased risk of fetal growth CARE
tive (followed 4 n=2635 F sources 200-299, ≥300 restriction (OR=1.2 (0.9 to 1.6) for 100-199 mg/day, 1.5 (1.1 to 2.1) for 200-299 mg/day, and 1.4 Study
wk before con- mg/d [<1.4 to (1.0 to 2.0) for >300 mg/day compared with <100 mg/day; test for trend P<0.001); association was Group,
ception through ≥4.3 mg/kg/d] stronger in F with a faster caffeine clearance (test for interaction, P=0.06). [Caffeine in foods- 2008
pregnancy) Food Surveillance Information Sheet 1998:144.]
(UK)
Cohort prospec- Adult caffeine, all <100, 100-299, No effect of maternal caffeine intake on birth weight, gestational age, or fetal growth. Clausson et
tive (follow-up n=873 F sources 300-499, ≥500 al., 2002
gestation wk 6- mg/d [<1.4 to
40) (Sweden) ≥7.1 mg/kg/d]
206
Cohort prospec- Adult caffeinated ≤1000, 1001- Blood caffeine concentrations during pregnancy were not related to fetal growth, but caffeine in- Cook et al.,
tive (follow-up N1=1,500 F; drinks; smok- 2000, 2001- take was negatively associated with birth weight, only in smokers (-1.6%/1000 mg a week (-2.9% 1996
wk 28-40 of n2= 640 F ing 3000, 3001- to -0.2%) after adjustment for cotinine and -1.3% (-2.7% to 0.1%) after further adjustment for so-
pregnancy) 4000, >4000 cial class and alcohol intake). The effect remained of borderline significance after adjustment for
(UK) mg/wk [≤2.0 to other factors. [1,500 F provided a blood sample on at least one occasion; 640 women provided
>8.2 mg/kg/d] sample at booking, 28 weeks, and 36 weeks]
Cohort prospec- Adult caffeinated Serum metabo- Caffeine levels were associated with reduced risk of intrauterine growth restriction (IUGR). No Grosso et
tive (follow-up n=1,606 F drinks lite (ng/mL) associations were observed between caffeine or any metabolites and preterm delivery. al., 2006
through preg- quartiles were
nancy) (USA) provided
Cohort prospec- Adult coffee; smok- median 3.1 Sons of F who consumed 3 equivalent cups/d coffee had increased risk for undescended testes at Mongraw-
tive (≥40 yr fol- n=20,754 F ing; tea cups/d cases, birth persisting to at least age 2 years (OR for the interquartile range=1.43; 1.06, 1.93). [assumed Chaffin et
low-up) 2.1 cups/d con- that an 8-oz serving of coffee contained 135 mg of caffeine and an 8-oz serving of tea contained al., 2008
(USA) trols 43.75 mg of caffeine]
Cohort prospec- Adult caffeinated 0.8±0.8 to Caffeine consumption did not increase the risk or hazard of miscarriage. [No info on caffeine per Pollack et
tive (follow-up n=79 F drinks 1.9±0.7 bever- beverage; assumed 100 mg/beverage] al., 2010
12 menstrual ages/d [1.1-2.7
cycles) (USA) mg/kg/d]
Cohort prospec- 18-21 yr Mother: cof- Mother 0-3, 4- Sons of mothers drinking 4-7 cups coffee/day [7.9 mg/kg/d] had decreased semen volume, testos- Ramlau-
tive (~20 yr fol- n=343 M fee; Son: caf- 7, ≥8 cups/d terone and inhibin B; adult M consuming ≥8 cups/d [3.4-6.8 mg/kg/d] had increased testosterone Hansen et
low-up) feinated [2.1-14 level. [Estimated caffeine content as 100 mg/cup coffee; 50 mg/cup tea; 50 mg/0.5 L cola; set the al., 2008
(Denmark) drinks mg/kg/d]; son caffeine intake as 150, 550 and 950 mg for 0-3, 4-7 cups, and ≥8 cups/d; for tea, caffeine intake
0, <1, 1-4, 5-8, was set to 75, 275, and 475 mg for 0-3, 4-7, and ≥8 cups/d]
>8 cups/d [1.1-
14 mg/kg/d]
Cohort prospec- Adult caffeinated 0, 1-349, 350- Caffeine consumption showed no relation to fetal growth, even among heavy consumers, although Shu et al.,
tive (followed n=712 F drink, carbon- 1399, 1400- they were relatively few. 1995
through preg- ated 2099, ≥2100
nancy) (USA) mg/wk [0.01-
4.3 mg/kg/d]
207
Cohort prospec- 22-35 yr caffeine, all <20, 20-99, Maternal caffeine consumption before pregnancy, or in women without nausea, did not increase Wen et al.,
tive (followed cases=575 F; sources 100-299, ≥300 the risk of spontaneous abortion, whereas maternal caffeine consumption during the first trimester 2001
through preg- controls=75 F mg/d [<0.3 to after nausea started might increase risk of spontaneous abortion (RR=5.4, 95% CI=2.0-14.6 for
nancy) (USA) ≥4.3 mg/kg/d] caffeine consumption ≥300 mg/d vs. <20 mg/d).
Cohort prospec- Adult caffeinated 0, <200, ≥200 Caffeine intake during pregnancy was associated with an increased risk of miscarriage, compared Weng et al.,
tive (followed n=1063 F drinks mg/d with no caffeine intake, with an adjusted hazard ratio (aHR) of 1.42 (95% CI 0.93-2.15) for 200 2008
through preg- [<2.9, ≥2.9 mg/d. Nausea or vomiting during pregnancy did not affect this observed association, nor did the
nancy) mg/kg/d] change in intake pattern of caffeine during pregnancy. The magnitude of the association appeared
(USA) to be stronger among F without a history of miscarriage (aHR 2.33, 1.48-3.67) than with such a
history (aHR 0.81, 0.34-1.94).
Cross-sectional Adult coffee 1/2-3, 4-7, ≥8 Adjusted hazard ratio for fetal death associated with coffee consumption of 0 vs. 1/2-3, 4-7, and Bech et al.,
(Denmark) n=88,482 F cups/d ≥8 cups/d were 1.03 (0.89, 1.19), 1.33 (1.08, 1.63), and 1.59 (1.19, 2.13), respectively. Association 2005
was greater at >20 wk of gestation. [Assumed an average of 100 mg for 1 cup of coffee, 50 mg
for 1 cup of tea]
Cross-sectional Adult caffeinated 1-150, 151- Adjusted OR for spontaneous abortion associated with consumption of 0 vs. 1-150, 151-300, and Dlugosz et
(USA) n=2967 F drinks 300, >300 >300 mg caffeine/d were 0.81(0.54-1.20), 0.89 (0.48-1.64), and 1.75 (0.88-3.47); adjusted OR for al., 1996
mg/d ≥ 3 cups of tea or coffee was 2.33 (0.92-5.85) and 2.63 (1.29-5.34), respectively. In this study,
[0.01 to >4.3 caffeine consumption is more strongly related to spontaneous abortion than alcohol or cigarette
mg/kg/d] use in early pregnancy.
Cross-sectional 20-41 yr caffeine, all 0-140, 141- Adjusted OR of spontaneous abortion by caffeine consumption were 141-280 mg/day, 2.20 (1.22- Dominguez
(Spain) n=711 F sources; 280, 281-420, 3.96); 281-420 mg/day, 4.81 (2.28-10.14) and ≥421 mg/d, 15.43 (7.38-32.43); p < 0.05. -Rojas et
smoking ≥421 mg/d al., 1994
[1.4 to ≥6.0
mg/kg/d]
Cross-sectional Adult coffee; decaf 0, <1, 1, ≥2 Women who consumed caffeinated coffee only (amount not specified, appeared to >0) had an ad- Eskenazi et
(USA) n=7855 F cups/d justed OR of 1.3 [95% CL 1.0, 1.7] for preterm delivery, whereas those who consumed both caf- al., 1999
[<1.4 to ≥2.9 feinated and decaf coffee had an OR= 2.3 (95% CL = 1.3, 4.0). When caffeinated and decaffein-
mg/kg/d] ated coffee were considered as continuous variables, there was a reduction in adjusted mean birth
weight of -3.0 g/cup per week (95% CL = -5.9, -0.6) for caffeinated coffee and an increase of +0.4
g/cup per week (95% CL = -3.7, 4.5) for decaf. [No info on caffeine/cup]
208
Cross-sectional Adult caffeinated <150; <300; Caffeine intake was not associated with intrauterine growth retardation; not modified by cigarette Grosso et
(USA) n=2714 F drinks; smok- ≥300 mg/d smoking. al., 2001
ing [<2.1 to ≥4.3
mg/kg/d]
Cross-sectional Adult caffeine, all 1-2, >3 cups/d First trimester caffeine consumption (OR 4.5, 95% CI 1.2, 16.8) was associated with increased Khoury et
(USA) n=191 F sources; [1.4-2.9, >4.3 risk of spontaneous abortion when controlling for age, years since diagnosis of diabetes, previous al., 2004
smoking [dia- mg/kg/d] spontaneous abortion, nephropathy and retinopathy. Caffeine consumption after 20 weeks (OR
betes, type I] 0.3, 95% CI 0.1, 1.0) were associated with reduced risk of pre-eclampsia. Consumption of 0 vs. 1-
2 cups/d and >=3 cups/d had OR and 95% CI of 1.0 (0.4, 2.5) and 2.2 (0.9, 5.3), respectively, for
preterm delivery and 1.8 (0.5,7.6) and 2.7 (0.7, 10.7), respectively, for respiratory distress syn-
drome. [No info on caffeine per cup; assumed 100 mg/cup coffee]
Cross-sectional Adult caffeine, all given as serum Serum paraxanthine was greater in F who gave birth to small-for-gestational age (SGA) infants Klebanoff
(USA) n=2515 F sources; paraxanthine (754 ng/ml) than to normal size infants (653 ng/ml, p = 0.02), but the dose-response was confined et al., 2002
smoking concentration to F smokers (p = 0.03). There was no association between paraxanthine and fetal growth in non-
smokers. Adjustment for maternal age, pre-pregnant weight, education, parity, ethnicity, cigarettes
smoked/d increased the p value for trend among smokers to 0.07. [1845 ng/mL paraxanthine cor-
responds to 1100 mg caffeine or 11 cups/d coffee in smokers and 6 cups/day in non-smokers]
Cross-sectional Adult caffeinated 0, 1-3, 4-9, ≥10 Maternal exposure to ≥10 cups/d coffee was associated with a 3-fold increased risk of hyperkinetic Linnet et
(Denmark) n=24,068 F drinks; coffee cups/d [1.4 to disorder and ADHD in children (diagnosed at 3-12 yr). After adjustments for a number of con- al., 2009
≥14 mg/kg/d] founding factors, the risk decreased and became statistically insignificant (RR 2.3, 95% CI 0.9-
5.9). [Caffeine intake was categorized as <100, 100–399, 400–999, and ≥1000 mg/d; 1 cup cof-
fee=100 mg caffeine; 1 cup of tea or chocolate=50 mg; 1 bottle of cola (25 dL)=50 mg caffeine]
Cross-sectional Adult caffeinated <144; >144; Coffee and caffeine consumption at all 3 time points were unrelated to total miscarriage risk and Savitz et al.,
(USA) n=2407 F drinks >273 mg/d the risk of loss after the interview. Reported exposure at the time of the interview was associated 2008
[<2.1 to >3.9 with increased risk among those with losses before the interview.
mg/kg/d]
Cross-sectional Adult caffeine, all <100, 100-299, Slow acetylators had a nonsignificantly increased risk for spontaneous abortion (OR 1.36, 95% CI Signorello
(Sweden) n1=101 F; sources 300-499, ≥500 0.84, 2.21) and recurrent spontaneous abortion (OR 2.51, 95% CI 0.81, 7.76). In contrast, low et al., 2001
n2=953 F [metabolic mg/d [<1.4 to CYP1A2 activity was associated with a decreased risk for spontaneous abortion (OR 0.35, 95%
enzyme phe- ≥ 7.1 mg/kg/d] CI 0.20, 0.63). Caffeine was a risk factor for spontaneous abortion among women with high, but
notype] not low, CYP1A2 activity (OR 2.42, 95% CI 1.01, 5.80 for 100-299 mg/day; OR 3.17, 95% CI
1.22, 8.22 for 300 mg/day or more, among women with high CYP1A2 activity).
209
Cross-sectional Adult caffeine, all 0-10, 11-70, A significant reduction in birth weight was found to be associated with an average caffeine intake Vlajinac et
(Serbia) n=1,011 F sources 71-140, ≥141 of ≥71 mg/d, after adjustment for gestational age, infant sex, parity, and maternal height and al., 1997
mg/d [<0.1 to weight, but only in infants born to nonsmoking mothers.
≥2.0 mg/kg/d]
Cross-sectional 15 to >35 yr caffeine, all <, ≥400 mg/d Nonsmoking F had similar risk at < and ≥ 400 mg/day caffeine; women ingesting 400 mg caf- Wisborg et
(Denmark) n=4,111 F sources; [< or ≥5.7 feine/d had a 3x greater risk of preterm birth compared with nonsmokers. Women with a high inal., 1996
smoking mg/kg/d] take of caffeine had a dose-response: smoking 1-5 cigarettes/d had no increased risk of preterm
birth vs. nonsmokers with the same intake of caffeine, F smoking 6-10 cigarettes/d had almost 3x
higher risk of preterm birth, and F smoking >10 cigarettes/d had almost 5x higher risk vs. non-
smokers with the same caffeine intake.
CL=confidence limit(s); HR=heart rate; IUGR=interauterine growth retardation; OR=odds ratio; SIDS=sudden infant death syndrome
210
TABLE 8-2. Developmental Effects of Caffeine – Summaries of Reviews Reference
Animal studies indicated that long-term effects of caffeine during pregnancy and postnatally may include altered behavior and altered respiratory control in Aden, 2011
offspring, although there is currently no human data to support this. Evidence for adverse effects of caffeine in first third of pregnancy are stronger than for
later parts of pregnancy and there is currently insufficient evidence to advise women to restrict caffeine intake after the first trimester.
Moderate caffeine consumption (<200 mg/d) does not appear to be a major contributing factor in miscarriage or preterm birth, but the effect of greater intake ACOG, 2010
is uncertain; the relationship of caffeine to growth restriction is undetermined.
Moderate or even high amounts of beverages and foods containing caffeine do not increase the risks of congenital malformations, miscarriage or growth Brent et al.,
retardation. 2011
There is no evidence to support a teratogenic effect of caffeine in humans. Current epidemiologic evidence is not adequate to assess the possibility of a small Browne, 2006
change in risk of congenital anomalies resulting from maternal caffeine consumption.
Caffeine and theobromine are two important constituents of kola nuts. Although limited biological data are available for kola nut extract specifically, the Burdock et al.,
published data of the major constituents of kola nuts suggest that the pharmacological/ toxicological properties of kola nut extract parallel to those of a 2009
roughly equivalent dose of caffeine. Frank developmental/reproductive effects have not been reported and changes in offspring cannot be extrapolated to
humans. A NOEL/NOAEL cannot be defined for repeated oral exposure to kola nut extract from available data.
Caffeine intake, and subsequent inhibition of inositol 1,4,5-triphosphate receptors, might result in a biologic mechanism that could mimic inositol deficiency Cavalli et al.,
and cause neural tube defects. 2010
There is a lack of biological plausibility to support the concept that caffeine has been responsible for human malformations; findings in epidemiological Christian and
studies are inconsistent. Brent, 2001
It is controversial whether caffeine increases the risk for recurrent or spontaneous abortion. Cramer and
Wise, 2000
There was a small but statistically significant increase in the risks for spontaneous abortion and low birth weight babies in pregnant women consuming >150 Fernandes et al.,
mg caffeine/day. A possible contribution to these results of maternal age, smoking, ethanol use, or other confounders could not be excluded. 1998
It would have been more appropriate to perform a stratified analysis and examine the relation of caffeine with fetal growth restriction separately for women Geleijnse, 2009
with and without nausea (in the CARE Study Group prospective study).
A literature review showed that there was little to implicate caffeine consumption with congenital malformations or preterm delivery, but there may be asso- Golding, 1995
ciations with subfertility, miscarriage, and intrauterine growth retardation.
Coffee consumption is associated with increases in BP and plasma homocysteine; there is little evidence that coffee consumption increases the risk of cancer. Higdon and
Adults consuming moderate amounts of coffee (3-4 cups/d providing 300-400 mg/d of caffeine), have little health risk, but some groups may be more vul- Frei, 2006
nerable (people with hypertension, children, adolescents, and the elderly). It may be prudent for pregnant women to limit coffee consumption to 3 cups/d
(≤300 mg/d caffeine) to exclude any increased probability of spontaneous abortion or impaired fetal growth.
The literature review suggested that heavy caffeine use (≥300 mg/d) during pregnancy is associated with small reductions in infant birth weight that may be Hinds et al.,
especially detrimental to premature or low-birth-weight infants. Some researchers also document an increased risk of spontaneous abortion associated with 1996
caffeine consumption prior to and during pregnancy. However, overwhelming evidence indicates that caffeine is not a human teratogen, and that caffeine
appears to have no effect on preterm labor and delivery.
211
Reducing the caffeine intake of regular coffee drinkers (≥3 cups/d) during the second and third trimester by an average of 182 mg/day did not affect birth- Jahanfar and
weight or length of gestation. There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy Sharifah, 2009
outcomes.
There is wide inter-individual variation in caffeine metabolism, primarily due to variations in CYP1A2 enzyme activity. Some variability in CYP1A2 activ- Lawson and
ity is due to genetic polymorphisms in the CYP1A2 gene. Considerable evidence exists that maternal caffeine metabolism is influenced by a variety of en- LeMasters, 2005
dogenous and exogenous factors and studying the genetic polymorphisms may improve understanding of the potential effects of caffeine and its metabolites
on perinatal outcomes.
No association was found between caffeine intake during pregnancy and the risk of preterm birth for 15 cohort and 7 case-control studies. Maslova et al.,
2010
A review of four publications could not state with certainty that caffeine consumption is actually associated with fetal death because of the small number of Matijasevich et
studies addressing this subject, methodological limitations, inaccurate exposure assessment in the studies, overall risks were only marginally significant in al., 2005
most cases, and the possibility of publication bias.
The teratogenic effect of caffeine has been clearly demonstrated in rodents. In humans, caffeine does not present any teratogenic risk. However, caffeine Nehlig and De-
potentiates the teratogenic effect of other substances, such as tobacco, alcohol, and acts synergistically with ergotamine and propranolol to induce materno- bry, 1994c
fetal vasoconstrictions leading to malformations induced by ischemia. Maternal exposure to caffeine induces long-term consequences on sleep, locomotion,
learning abilities, emotivity, and anxiety in rat offspring, whereas in humans, more studies are needed to ascertain long-term behavioral effects of caffeine
ingestion by pregnant mothers.
In rodents, caffeine can induce malformations at doses never encountered in humans. Coffee ingested during gestation induces a dose-dependent decrease in Nehlig and De-
birth weight, but usually only when ingested amounts are high (i.e. >7 cups/d). Caffeine intake during gestation affects hematologic parameters of the new- bry, 1994d
born infant or rat. In animals, caffeine induces long-term consequences on sleep, locomotion, learning abilities, emotivity, and anxiety. In children, the ef-
fects of early exposure to coffee and caffeine on behavior are not clearly established. Pregnant women should limit their coffee and caffeine intake to 300 mg
caffeine/day (i.e. 2-3 cups of coffee or 2.5-3 L of coke) especially because of the increase of caffeine half-life during the third trimester and in the neonate.
In three studies, high caffeine consumption was associated with low birth weight and/or prematurity. Contradictions between studies may be due to difficul- Pacheco et al.,
ties in measuring caffeine consumption; assessment of different caffeine sources; variations in the mode of preparation and amount consumed; and sample 2007
size. Association between moderate caffeine consumption and fetal growth was not demonstrated.
Coffee consumption promotes intrauterine growth retardation. Romo et al.,
2009
Combined analysis of mean birth weight results of 11 studies showed a significant decrease in birth weight of nearly 43 g among newborns of the heaviest Santos et al.,
caffeine consumers; reliable pooled estimates could not be made for 15 studies of the effects on low birth weight, intrauterine growth retardation, and pre- 1998
term delivery due to data heterogeneity.
212
Questioning participants about caffeine intake after the miscarriage had occurred can result in recall bias generating a (false) positive result, whereas when Signorello and
caffeine exposure is ascertained before miscarriage, the findings indicate no effect of caffeine. McLaughin,
2008
Despite the fact that most epidemiologic studies have observed a positive association between maternal caffeine intake and the risk of spontaneous abortion, Signorello and
we conclude that the evidence must be considered to be equivocal, given the biases likely present, most of which would tend to overestimate any association. McLaughlin,
(Biases: selection and recall bias, confounding, exposure measurement, failure to account for fetal karyotype, caffeine metabolism, the timing of fetal de- 2004
mise, and the possibility that an effect of caffeine may be gestational age-specific.)
In animals, various results were obtained for teratogenicity of caffeine + other agents. Human studies show clearly that caffeine itself has no link to negative Sivak, 1994
birth outcome, and there appears to be no interaction between coffee consumption and either alcohol consumption or smoking on pregnancy outcome.
For 9 cohort and 5 case-control studies, an association between caffeine intake (>150 mg/d) and an increase in spontaneous abortion was found in the overall Sosa et al., 2003
outcomes (cohort studies: RR 1.16, CI 95% 1.12-1.21; case-control studies OR: 1.45 CI 95% 1.30-1.61). The analysis of studies that assessed intake before
and during first trimester showed OR 1.45 CI 95% 1.30-1.61. There was a consistency in the analysis of the different strata.
The Committee on Toxicity, after considering the results of a new study, as well as all studies previously published in peer reviewed literature on this sub- Wadge, 2009
ject, concluded that caffeine intake during pregnancy is associated with an increased risk of fetal growth restriction. The Food Standards Agency’s new ad-
vice to women on the amount of caffeine they should consume during pregnancy is below 200 mg/d (~ two mugs of coffee/d).
213
8B. Developmental Effects of Caffeine in Animals
Fetal effects resulting from maternal or paternal exposure to caffeine prior to conception
were examined in a number of studies where females were treated, and in one study where males
were treated. Females were exposed prior to pregnancy, during part or all of gestation, and/or
during gestation and lactation. Test species were primarily the rat and mouse, but several studies
also used sheep and monkeys. The animals were in general administered much higher doses than
humans normally consume. Studies in which the animals were exposed during only a portion of
the gestation period tested 0.7-375 mg/kg/day, doses administered prior to and/or throughout
gestation ranged from 5-204.5 mg/kg/day, and treatment during gestation and lactation was with
9-48 mg/kg/day in the drinking water or by gavage, and 10-1000 mg/kg/day in the diet.
Exposure of male rats for 15 days prior to mating, or female rats throughout the estrus
cycle prior to fertilization to 30 mg/kg/day caffeine resulted in relatively severe fetal effects.
Treatment of males resulted in F1 fetal growth retardation, increased postnatal mortality, and a
third of the male breeding line F2 litters were aborted (sires had testicular degeneration). Treat-
ment of females caused a decreased implantation rate (evaluated at postnatal day [PND] 5), in-
creased postnatal mortality during the first week, and decreased week 3-7 pup growth. There
was no effect, however, on gestation length, birth weight, litter size, sex ratio, or anogenital dis-
tance.
Fetal effects seen at ≥20 mg/kg/day in the one-day gestational exposure studies included
delayed ossification, skeletal abnormalities, increased resorptions, reduced cerebral oxygenation,
cardiac defects, decreased thymus weight, and degenerated lens material. Maternal effects in-
cluded reduced blood flow to the ovaries, uterus, and bladder.
Exposure of pregnant rats or mice to <10 mg/kg/day for 3-15 days of gestation did not
cause significant adverse fetal outcomes. Exposure to 10-20 mg/kg/day, however, caused de-
creased bone mineralization, delayed fetal ossification, decreased fetal body weight, altered fetal
brain development, and decreased maternal weight. Additional effects seen at 20-30 mg/kg/day
were decreased learning ability of pups, visceral and bone malformations, decreased bone
weight, impaired suckling behavior, and decreased motor activity. Exposure to 40-80 mg/kg/day
was also associated with corneal lesions, cataracts, and bone malformations including cleft pal-
ate. Fetal death or increased resorptions occurred at ≥100 mg/kg/day.
Somewhat more severe effects were seen at lower treatment doses in studies where ani-
mals were exposed throughout the entire gestation period. Offspring of mouse dams given 300
mg/mL caffeine in the drinking water (~5-6 mg/kg/d) as adults exhibited increased locomotor
activity in an open field. Macaque monkeys given 10-15 or 25-35 mg/kg/day caffeine in the
drinking water had an increase in stillbirths and miscarriages, decreased fetal growth, lower ma-
ternal body weight gain, and the infants had impaired psychomotor performance. Decreased fe-
tal brain cholesterol concentration and alkaline phosphatase activity were seen in rats at 10-20
mg/kg/day. Treatment with ≥27 mg/kg/day in the drinking water resulted in fetal malformations,
decreased fetal birth weight, decreased number of viable fetuses, and increased resorptions in
rats and mice. Adult rats exposed in utero to 50 mg/kg/day caffeine had more frequent and se-
214
vere gastric lesions from restraint stress, and all dams concurrently exposed to 120 mg/kg/day of
caffeine and restraint died during the gestation period.
In several studies, pregnant rats and macaque monkeys were exposed to caffeine
throughout all or most of gestation, and the whole lactation period. Monkeys administered 10-15
or 25-30 mg/kg/day in the drinking water had increased spontaneous abortion or stillbirth and the
offspring had decreased body weights and somatic measurements. The mothers at both doses
had decreased body weights, serum and urine creatinine, and the high-dose group had increased
serum glucose and decreased serum estrogen. Rats treated with 10-20 mg/kg/day in the diet or
drinking water had fetuses with impaired bone growth, postnatal dental enamel deterioration, de-
creased activity, and decreased plasma and pancreatic insulin content. Rats treated in one study
with 20 mg/kg/day in utero, during lactation, and in the diet until PND 93 had decreased bone
mineralization evident still at PND 388, indicating that the effect was not reversible. A study in
which a dietary intake of 1000 mg/kg/day only caused decreased fetal weight appeared to be an
outlier.
Animal studies that examined the effect of maternal or paternal caffeine intake on the fe-
tus are summarized in Table 8-3.
215
TABLE 8-3. Developmental Effects of Caffeine – Animal Studies
Rat whole 1 day pure caffeine 50-200 µg/mL Caffeine induced various morphological anomalies, but did not affect proliferation or differentiation of Iwase et al.,
embryo cul- (in vitro) cells in these experimental systems. 1994
ture
Sheep, 1 day pure caffeine 400 mg Decreased fetal cerebral oxygenation. Tomimatsu
pregnant (i.v.) et al., 2007
Mouse, 1 day pure caffeine 20 mg/kg Maternal exposure to one dose of caffeine inhibited cardiac ventricular development by 53% in hypoxia Wendler et
pregnant (i.p.); hypoxia and 37% in room air; caffeine exposure inhibited hypoxia-induced HIF1alpha protein expression in em- al., 2009
bryos by 40%; adult offspring had a 38% decrease in cardiac function by echocardiography; male mice
exposed to caffeine in utero had a 20% increase in body fat.
Mouse 1 day (GD pure caffeine; 150, 200, 250 Dose-dependent increase in the incidence of cleft palate (CP); high maternal deaths, an increased num- Reddy et
12) arachidonic mg/kg ber of resorptions, gross facial hematomas (GFH), and club foot (CF) only at 250 mg/kg. Palates from al., 1994
acid; DMSO all offspring with GFH were clefted at this dose level. None of the control or CA-treated nonclefted off-
(i.p.) spring had GFH or microscopic hematomas (MH). At 200 mg/kg caffeine + DMSO increased CA-
induced CP from 30% to 100% and also produced 100% GFH as compared to 0% by CA alone at this
dose. Greater than 50% of clefted offspring without GFH, given either dose (200 or 250 mg/kg) of CA,
had MH. Very high levels of maternal glucocorticoids (MGC) were present in CA-treated mice on GD
13 and 14. Although simultaneous administration of DMSO reduced the magnitude of CA-induced
MGC elevations on GD 14, the MGC levels remained high for greater than 24 hours following CA ex-
posure. Increase in maternal mortality and fetal resorptions, a decrease in the number of live pups and
their BWs, and no change in the incidence of CP were seen when CA-treated mice were simultaneously
exposed to arachidonic acid.
Mouse, 1 day (GD pure caffeine; 30, 60, 120 Restraint and caffeine exposure caused overall reduction of maternal BW gain and food consumption on Colomina et
pregnant 9) stress mg/kg GD 9-11 at all caffeine doses, and BW at termination for dams exposed to 120 mg/kg + restraint. No al., 1999
(gavage) significant effects of caffeine, restraint, or caffeine + restraint on embryo/fetal development were noted.
Mouse, 1 or 10 d pure caffeine; 30 mg/kg A single oral dose of caffeine or aspirin did not cause significant maternal toxicity. However, co- Colomina et
pregnant (GD 9 or aspirin; stress administration of these drugs with restraint produced a reduction in maternal weight gain and food con- al., 2001
GD 9-18) (gavage) sumption on gestational days 9-11. The incidence of some fetal skeletal defects was significantly in-
creased after exposure to caffeine, aspirin, or maternal restraint, and their binary and ternary combina-
tions. The results suggest that prenatal stress could slightly exacerbate the maternal and developmental
toxicity of the combination of these drugs in mice.
Rat 2 d (GD 8- pure caffeine 25 mg/kg Treated embryos had smaller crown-rump length and circumferential length, reduced development of the Wilkinson
9) (i.p.?) heart, eye, and limb buds, and a larger proportion of regions of open neural tube. and Pollar,
1994
216
Mouse, 3 d (GD 8- pure caffeine 12.5, 25, 50 Accelerated primitive neuroepithelium evagination into telencephalic vesicles; seen at all doses with Sahir et al.,
pregnant 10) (i.p.) mg/kg/d dose-response; seemed reversible during subsequent neuronal migration if exposure was discontinued. 2000
Mammalian 4d pure caffeine 0.16, 0.33, Developmental inhibition and embryotoxicity that was often not evident until after one to three cell cy- Scott and
cell culture (in vitro) 0.66, 1.25, 2.5, cle on mouse oocytes or embryos; occurred at concentrations commonly used to activate sperm in hu- Smith, 1995
5.0, or 10 mM man in vitro fertilization.
Rat 7d pure caffeine 30 mg/kg/d Preconceptual caffeine exposure reduced maternal fertility by the failure of a proportion of the litters to Pollard et
(throughout (gavage) implant, rather than curtailing preimplantation development or postimplantation losses. Postnatal mortal- al., 1999
estrus cy- ity between weeks 0 and 1 was elevated and the weekly incremental growth rate of the pups from wk 3-7
cle) was reduced in the preconceptually caffeine-treated offspring. F reached puberty at the same age as the
controls but at a lower BW. Gestation length, birthweight, litter size, sex ratio, and anogenital distance (a
measure of prenatal androgenization) were not affected.
Rat, preg- 3-10 d (GD pure caffeine 15, 30 mg/kg/d Delayed early postimplantation growth (both doses) somite number and the extent of neural tube clo- Jacombs et
nant 2 to 4, 10, (gavage) (pre-implant) sure; high-dose group had enlarged forebrain cavity bounded by a reduced, irregularly aligned neuroepi- al., 1999
10.5 or 11) 30, 60 mg/kg/d thelium; no effect on pre-implantation embryos.
(post-implant)
Mouse, 10 d (GD pure caffeine 10 mg/kg/d Adenosine A(2A) receptor gene expression levels of GD 11.5 embryo and GD 18.5 uterus decreased; Momoi et
pregnant 9.5-18.5) (s.c.) embryonic aortic and umbilical artery flows transiently decreased. al., 2008
Rat, preg- 12 d (GD 9- pure caffeine 20 mg/kg/d Decreased Ca, P, Mg, Zn and hydroxyproline content of the pup mandible and femur at birth; effect was Case et al.,
nant 21) (diet); ethanol greater with ethanol + caffeine than with caffeine alone (ethanol alone often had no effect). 1996
1 g/kg (gavage)
Rat, mal- 12, 15 d pure caffeine 20 mg/kg/d Dams on a low-protein diet treated with caffeine had pups with impaired suckling behavior and general Yoshino et
nourished (GD 7-18 or (diet) motor activity. al., 1994
7-21)
Mouse 13 d (GD 6- pure caffeine; 125 mg/kg Caffeine treatment resulted in reduced bone measurements or reduced ossification scores in 5/19 pa- Leblebi-
18) nicotine 3x/d rameters. The main effects for interaction of caffeine+nicotine were significant for 7 parameters; typi- cioglu-
(gavage) cally both caffeine and caffeine+nicotine were different from controls, but caffeine was not different Bekcioglu
from caffeine+nicotine. Caffeine had a significantly greater effect on fetal growth and ossification than et al., 1995
nicotine.
Rat 13 d (GD 9- pure caffeine 25, 50, 100 Maternal doses of 50 or 100 mg/kg/d caused histopathological changes in the cornea of pups at PND 1 Everek-
21) (gavage; i.p.) mg/kg/d i.p.; and 30. lioglu et al.,
50 mg/kg p.o. 2003
217
Rat 13 d (GD 9- pure caffeine 25, 50, 100 Maternal caffeine exposure to 50 or 100 mg/kg/d during pregnancy was cataractogenic for crystalline Everek-
21) (gavage; i.p.) mg/kg/d i.p.; lenses in rats at PND 1 and 30. lioglu et al.,
50 mg/kg p.o. 2004
Rat 15 d (GD 6- pure caffeine; ~84 mg/kg/d Prenatal caffeine exacerbated effects of alcohol (15 g/kg/d) on reduced birth weight, litter size, and post- Hannigan,
20) ethanol (diet) natal survival, but did not alter prenatal alcohol-induced delays in early postnatal maturation of survi- 1995
vors.
Mouse 18 d (GD 0- pure caffeine; 30, 60, 120 Maternal and embryo/fetal toxicity and malformations seen at all doses, and were enhanced by restraint, Albina et
18) stress (gavage) mg/kg/d esp. at 60 and 120 mg/kg/day; all restrained F at 120 mg/kg/d died during exposure; dose-response seen. al., 2002
Rat, preg- 20 d (GD 2- pure caffeine 83.2 mg/kg/d Metabotropic glutamate receptors were down-regulated in maternal and fetal rat heart. Iglesias et
nant 21) (DW) al., 2006
Rat 21 d (GD 1- pure caffeine 46±3 mg/kg/d Caffeine exposure during gestation did not significantly affect basal respiratory parameters in 0 to 2-day- Picard et
21) (DW); hypoxia old newborn rat, but attenuated both the early increase and the secondary decrease in ventilation trig- al., 2008
gered by moderate alveolar hypoxia (11% O2 inhaled).
Rat 21 d (GD 1- pure caffeine 10 mg/kg/d Adult offspring exposed prenatally had impaired 24-hr memory retention in the novel object recognition Soellner et
21) (DW) task and impaired working and reference memory in the radial arm maze; no change in Morris water al., 2009
maze performance.
Mouse 21 d (gesta- pure caffeine 0.3 g/L Offspring as adults exhibited increased locomotor activity in an open field; given caffeine dose produced Bjorklund
tion) (DW) blood levels in dams similar to consumption of 3-4 cups of coffee in a human. et al., 2008
Rat, preg- 21 d (gesta- pure caffeine 1 g/L (83.2 ± Brain A1 receptor down-regulated in mother and offspring after treatment throughout gestation. Leon et al.,
nant tion) (DW) 5.3 mg/kg/d) 2002
Rat, preg- 21 d (gesta- pure caffeine 1 g/L (83.2 ± Metabotropic glutamate receptors down-regulated in mother and offspring after treatment throughout Leon et al.,
nant tion) (DW) 5.3 mg/kg/d) gestation. 2005
Rat 24 d (gesta- pure caffeine 0.3 g/L Maternal ingestion of caffeine by rats in doses equivalent to 1-2 cups of coffee/day during gestation did Herlenius et
tion to PND (DW) not induce major changes in the development of respiratory control in the offspring. al., 2000
3)
Rat 28-42 d pure caffeine 1 g/L Caffeine was not able to change the age-dependent increase of acetylcholinesterase (ACH) activity or da Silva et
(gestation (DW) the age-dependent decrease of ACH expression. However, caffeine promoted an increase of ACH activ- al., 2008
to PND 7, ity (42%) without modifications on the level of acetylcholinesterase mRNA transcripts in 21-day-old
14, or 21) rats (not in 7 or 14-d old rats).
218
Rat, mal- 30 d (GD 7 pure caffeine 20 mg/kg/d Prenatal caffeine intake with protein-energy malnutrition produces permanent effects on the trigeminal Saito et al.,
nourished; to PND 15) (diet) nuclear center indicated by autoradiography and changes in biochemical parameters. 1995
pregnant
Rat 42 d (gesta- pure caffeine 0.3 g/L Brain A2A receptor mRNA levels unaffected during development by maternal caffeine intake. Aden et al.,
tion to PND (DW) 2000
21)
Rat, lactat- 42 d (gesta- pure caffeine 20 mg/kg/d Molar enamel surfaces of pups treated throughout gestation and lactation was altered microscopically, Schneider
ing; preg- tion, lacta- (diet) and the Ca and Mg therein was more acid-soluble. et al., 1995
nant tion)
Rat, lactat- 106 d (GD pure caffeine 20 mg/kg/d Cross section of femoral bone was smaller, with fewer osteocytes/area and less Ca, P, Zn, and hy- Sasahara et
ing; preg- 9 to PND (diet: dams, droxyproline (pups treated GD 9 to PND 93, and examined at day 388). al., 1994
nant 93) then pups)
Rat, preg- 123 d (ges- coffee (DW) 50 mg/mL Increased levels of calcium in the urine and plasma, decreased bone mineral density and lower volume Lacerda et
nant tation to of bone, thus delaying the bone repair process. [given dose is like ~4 cups/d coffee for humans] al., 2010
PND 102)
BW=body weight; DW=drinking water; GD=gestational day; PND=postnatal day
219
CHAPTER 9. REPRODUCTIVE EFFECTS OF CAFFEINE
9A. Reproductive Effects of Caffeine in Humans
Although conflicting evidence was found regarding the toxicity of caffeine to human go-
nads and reproduction, the weight of evidence indicates that there is a positive association with
chronic caffeine intake. Epidemiological studies showed delayed conception or decreased fe-
cundability in non-smoking men and women, and in smoking women whose only source of caf-
feine was coffee, with an intake of ≥300 mg/day (Jensen et al., 1998), in women with an intake
of ≥500 mg/day (Bolumar et al., 1997), and in non-smoking women who consumed ≥301
mg/day. Florack et al. (1994) found that fecundability was decreased in women with an intake of
5 cups of tea/day (~4 mg/kg/day) and in men with an intake of >700 mg caffeine/day (10
mg/kg/day), but was increased in women with an intake of 400-700 mg caffeine per day. Curtis
et al. (1997) observed decreased fecundability among women who were coffee drinkers and
among men who were heavy tea drinkers, but found no association with total caffeine intake. An
intake of ≥ 1 cup coffee/day had no effect by itself, but enhanced the negative effect of alcohol
on fecundability (Hakim et al., 1998).
Other caffeine-associated adverse effects in women included an increased incidence of

endometriosis with an intake of ≥300 mg/day (Berube et al., 1998), uterine leiomyomata in
women <35 years old with an intake of ≥500 mg/day, decreased menses and cycle length with an
intake of >300 mg/day (Fenster et al., 1999), increased premenstrual anxiety and mood changes
with an intake of 241-320 mg/day (4-5 mg/kg/day) (Gold et al., 2007), and dystocia from a daily
caffeine intake of 200-299 mg (3-5 mg/kg) (Kjaergaard et al., 2010). Several studies noted caf-
feine altered hormone levels in women including estradiol, progesterone, and/or sex hormone-
binding globulins from an intake of 1-3 mg/kg/day (Kotsopoulos et al., 2009; Lucero et al., 2001;
Ferrini and Barrett-Connor, 1996).
Conversely, some studies found no relationship of caffeine intake with various reproduc-
tive parameters. Caffeine intake did not affect ovulatory disorder infertility (Chavarro et al.,
2009). Kinney et al. (2006; 2007) found no effect on age at menopause from an intake of >400
mg/day, and no effect on ovarian age during the reproductive years in women with an intake of
≥160 mg/day.
Several studies noted adverse reproductive/gonadal caffeine-related effects in males. An

increase was seen in sperm aneuploidy for the X and Y chromosomes from an intake of ≥1
cup/day coffee (Robbins et al., 1997), sperm DNA double-strand breaks were increased with an
intake of >308 mg/d caffeine (Schmid et al., 2007), and there was a weak association of “high”
caffeine intake and sperm morphology alterations (Vine et al., 1997). Jensen et al. (2000) ob-
served that a high intake of cola (>14 bottles of 0.5-liter per week; ~1.4 mg/kg/day) and/or caf-
feine (>800 mg/day; 11 mg/kg/day) was associated with reduced sperm count. However,
Kobeissi and Inhorn (2007) concluded that caffeine intake was not an important risk factor for
male infertility.
220
Based on an increased risk for delayed conception, decreased fecundability, endometrio-
sis, sperm DNA double-strand breaks, and dystocia seen from intakes of 200-300 mg/day, the
LOAEL for reproductive effects for men and women is 4 mg/day (240-280 mg/kg/day), and the
NOAEL is 2 mg/kg/day (120-140 mg/day), which was not associated with adverse reproductive
effects. The reproductive toxicity data and the derived (overall) LOAEL and NOAEL are plotted
below. The squares on the plot are the lowest effect level and the no-effect level for each end-
point of each study (the endpoints are listed on the lower X-axis). The no-effect level was in
most cases the lowest (non-zero) value of the reference intake category in a given study, but was
in one case (Jensen et al., 1998) the midpoint of the no-effect reference intake category. The
study author(s) are indicated on the upper X-axis.
ENDPOINT: Reproduction (human epidemiological studies with caffeine)
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Human studies of which the primary focus was the effect of chronic caffeine exposure on
reproductive/gonadal endpoints are summarized in Table 9-1. Brief summaries of reviews on
this topic are provided in Table 9-2. Ruder et al. (2009) concluded that exposures associated
with oxidative stress and with evidence to influence the timing and maintenance of a viable
pregnancy include alcohol, tobacco, and caffeine intake. Anderson et al. (2010) asserted that a
person's time to pregnancy and their chance of having a healthy, live birth may be affected by
factors including caffeine consumption. In a comprehensive review of caffeine effects, Nawrot
et al. (2003) concluded that for healthy adults, caffeine intake up to 400 mg/d (6 mg/kg in a 65-
221
kg person) is not associated with effects on male fertility, but recommended lower consumption
for two 'at risk' subgroups: reproductive-aged women should consume ≤300 mg caffeine/day (4.6
mg/kg body weight for a 65-kg person) and children should consume ≤2.5 mg/kg body weight.
Similarly, Sadeau et al. (2010) recommended that couples trying to conceive should limit their
consumption to no more than 3 cups of coffee/day, despite the conflicting data of the effects of
caffeine on reproduction in humans. Conversely, Peck et al. (2010) felt that the weight of evi-
dence does not support a positive relationship between caffeine consumption and adverse repro-
ductive or perinatal outcomes, due to the inability to rule out plausible alternative explanations
for the observed associations, namely confounding by pregnancy symptoms and smoking, and by
exposure measurement error.
222
TABLE 9-1. Reproductive Effects of Caffeine – Human Studies
Case-control 20-39 yr caffeine, all 0-99, 100-299, The prevalence of minimal or mild endometriosis was higher in women with a caffeine Berube et al.,
(Canada) cases=329 F; sources ≥300 mg/d [<1.7 intake of ≥300 mg/d (OR = 1.33; 95% CI = 0.91-1.94). 1998
controls=262 F to ≥5.0 mg/kg/d]
Case-control ~39± 6y caffeine, all 3.2 ± 4.7 cups/d Caffeine intake was not an important risk factor for M infertility. [No info on caffeine Kobeissi and
(Lebanon) cases=120 M; sources coffee, 2.6 ±12.6 content; assumed 100 mg/cup coffee; 40 mg/bottle soft drink] Inhorn, 2007
controls=100 M bottles/d soft
drinks [1.5, 4.6
mg/kg/d]
Cohort prospec- mean 32-33 yr caffeine, all 30, 31-82, 83-160, There was no effect of caffeine intake on ovulatory disorder infertility. Chavarro et
tive (8 yr follow- n=18,555 F sources 161-332, ≥333 al., 2009
up) (USA) mg/d [0.5 to ≥5.6
mg/kg/d]
Cohort retrospec- 17 to >30 yr at caffeinated 0, 1-100, 101-300, Caffeine consumption of ≤100 vs. >100 mg was not associated with fecundability. De- Curtis et al.,
tive (30-year baseline; drinks 301-500, >500 creases were observed among F who were coffee drinkers (0.92, CI 0.84-1.00) and M 1997
evaluation) n=2,607 (45%) mg/d who were heavy tea drinkers (0.85, 0.69-1.05), regardless of caffeine content. [Assumed
(Canada) pregnancies [0.01 to >7.1 100 mg caffeine/cup coffee, 50 mg caffeine/cup tea, and 40 mg of caffeine/12 oz
among 1,277 mg/kg/d] (354.8-mL) cola]
couples (M+F)
Cohort prospec- 18-39 yr caffeinated <400, 400-700, Fecundability was decreased with F intake of 5 cups tea/d or from M intake of >700 mg Florack et al.,
tive (12 mo fol- n=259 F drinks >700 mg/d [<6.7 caffeine/d, but was increased from F intake of 400-700 mg caffeine/day. 1994
low-up) (The to >12 mg/kg/d]
Netherlands)
Cohort prospec- 23-41 yr caffeinated 0-25, 26-100, 101- Intake of ≥1 cup coffee/d [1.7 mg/kg/d] did not significantly affect the probability of Hakim et al.,
tive (100 mo fol- n=124 F drinks; ethanol 300, >300 mg/d conception but possibly enhanced alcohol's negative effect. [Converted coffee, tea, and 1998
low-up) (USA) [0.4 to >5.0 caffeinated soft drinks into 100, 50, and 40 mg of caffeine/drink, respectively]
mg/kg/d]
Cohort prospec- 20-35 yr caffeine, all 0-299, 300-699, Fecundability decreased in non-smoking F and M who consumed 300-699 or ≥ 700 Jensen et al.,
tive n=423 couples sources; smok- ≥700 mg/d [<4.3 mg/d [4.3-10 mg/kg/d], and in smoking F whose only source of caffeine was coffee, 1998
(Denmark) (M+F) ing to >10 mg/kg/d] with intake >300 mg/d [4.3 mg/kg/d]; dose-response seen.
Cohort prospec- 44-60 yr at caffeine, all >100-200, >200- Caffeine intake was not related to age at menopause. Kinney et al.,
tive (4.9 yr fol- baseline sources 400, >400 mg/d 2006
low up) (USA) n=494 F [1.7 to >6.7
mg/kg/d]
223
Cohort prospec- M=22-55 yr; caffeine, all F: 0-2, >2-50, ≥50 Not achieving a live birth was associated with F intake of >2-50 and 50 mg/d [0.03-0.8 Klonoff-
tive (5 yr follow- F=26-49 yr sources [in vitro mg/d; M: 0-50, mg/kg/d]; infant gestational age decreased if F consumed >50 mg/d [0.8 mg/kg/d]; mul- Cohen et al.,
up) n=221 couples fertilization pa- >50-200, >200 tiple gestations increased if M increased their usual intake by 100 mg/d [1.4 mg/kg/d]. 2002
(USA) (M+F) tient] mg/d [<0.1 to >2.9
mg/kg/d]
Cohort prospec- 21-69 yr at caffeine, all <50, 50-149, 150- Incidence rate ratio for uterine leiomyomata increased in F <35 yo with ≥500 mg/d in- Wise et al.,
tive (4 yr follow- baseline sources [pre- 299, 300-499, take, but not for all age groups combined. 2004
up) (USA) n=21,885 F menopausal] ≥500 mg/d [<0.7
to ≥7.1 mg/kg/d]
Cross-sectional Adult caffeinated mean 455.82 mg/d Caffeine was measured in follicular fluid; there was no association between coffee or tea Al-Saleh et
(Saudi Arabia) n=619 F drinks (range: 3.71-3561) use and pregnancy rate; the number of eggs per F decreased as the caffeine serum levels al., 2010
[0.1-59 mg/kg/d] increased; increased coffee use was positively associated with aborted pregnancy; the
number of good embryo decreased with high tea consumption.
Cross-sectional 25-44 yr caffeine, all 0-100, 101-300, Small increase in risk for subfecundity in the first pregnancy was seen for F drinking Bolumar et
(Denmark; Ger- n=3,187 F sources; smok- 301-500, ≥501 >500 mg/day, effect was stronger in smokers. al., 1997
many; Italy; Po- ing mg/d [<1.7 to ≥8.3
land; Spain) mg/kg/d]
Cross-sectional 18-39 yr caffeinated 0, 1-150, 151-300, Menses and cycle length were shorter with intake of >300 mg/d [4.3 mg/kg/d]. Fenster et al.,
(USA) n=403 F drinks >300 mg/d [0.01 1999
to >5.0 mg/kg/d]
Cross-sectional 42-90 yr caffeine, all 0, 0.1-60, 60.1- Intake of >7 g/month (~2 cups/d coffee or 4 cans/d soda) had positive association with Ferrini and
(USA) n=728 F sources [post- 144, 144.5-234, estrone and sex hormone-binding globulin, but inverse association with bioavailable Barrett-
menopausal] 234.1-880.8 mg/d testosterone in post-menopausal women. Connor, 1996
[<0.01-15
mg/kg/d]
Cross-sectional 45.8 ± 2.69 yr caffeine, all ≤80, 81-160, 161- Caffeine dietary intake was positively associated with premenstrual anxiety and mood Gold et al.,
(USA) n=3,302 F sources 240, 241-320, changes, but not in a monotonic dose-response (significant for 241-320 mg/d only [4.0- 2007
≥321 mg/d [≤1.6 5.3 mg/kg/d].
to ≥5.4 mg/kg/d]
Cross-sectional Adult caffeine, all 0-100, 101-200, High intake of cola (>14 of 0.5-L bottles/week) and/or caffeine (>800 mg/day) was as- Jensen et al.,
(Denmark) n=2,554 M sources; cola 201-800, >800 sociated with reduced sperm concentration and total sperm count, although only signifi- 2010
mg/d [<1.4 to >11 cant for cola. (0.5 L bottle=70 mg; categories were ~1, 2-7, >7 cups coffee/d; cola: 0, 1-
mg/kg/d] 7, 8-14, >14 bottles/wk)
224
Cross-sectional 22-49 yr caffeinated 0-29, 30-159, Caffeine intake had no effect on ovarian age (antral follicle count, FSH, inhibin B and Kinney et al.,
(USA) n=188 F drinks ≥160 mg/d [<0.5 estradiol levels) during the reproductive years of F. 2007
to ≥2.7 mg/kg/d]
Cross-sectional Adult caffeine, all <100, 100-199, Caffeine intake of 200-299 mg/day [2.9-4.3 mg/kg/d] was associated with dystocia. Kjaergaard et
(Denmark) n=2,810 F sources [preg- 200-299, ≥300 al., 2010
nant] mg/d [<1.4 to ≥5.0
mg/kg/d]
Cross-sectional pre-menopausal pure caffeine ≤70, >70-190, Premenopausal F had inverse relationship of caffeine/coffee intake of >70 mg/d and Kotsopoulos
(USA) 43.4 yr (524 F); >190-371, >371 luteal total and free estradiol, and caffeine was positively associated with luteal proges- et al., 2009b
post-meno- mg/d [≤1.0 to >6.2 terone levels; postmenopausal F had positive association between caffeine/coffee intake
pausal 61.6 yr mg/kg/d] and sex hormone-binding globulin levels.
(713 F)
Cross-sectional 36-45 yr caffeinated ≤100, 101-250, Coffee use >1 cup/d [2.3 mg/kg/d] was associated with higher estradiol (E2) levels; in a Lucero et al.,
(USA) n=498 F drinks 251-499, ≥500 multivariate model, total caffeine use was associated with E2 levels after adjustment for 2001
mg/d [≤1.7 to age, BMI, total calories, current smoking, alcohol, cholesterol consumption, and day of
≥8.3 mg/kg/d] sampling. Early follicular phase E2 increased ~70% for ≤100 mg/d vs. ≥500 mg/d caf-
feine [8.3 mg/kg/d]. [Intake categories were ≤1, >1 cups/d for all drinks; caffeine=140
mg/cup coffee, 50 mg/cup tea, 30 mg/12 oz cola, 40 mg/12 oz caffeinated soft drink]
Cross-sectional 19-35 yr coffee 0, 1, ≥2 cups/d Sperm aneuploidy increased for chromosomes XX18, XY18, XY18-18, and YY18-18 Robbins et al.,
(USA) n=45 M [1.4, ≥2.9 from ≥1 cup/d [2.9 mg/kg/d]; dose-response seen. [No info on caffeine per cup; as- 1997
mg/kg/d] sumed 100 mg/cup]
Cross-sectional 22-80 yr caffeine, all 0, 1-107, 107-308, Sperm DNA damage (double-strand breaks) increased with intake of >308 mg/d caf- Schmid et al.,
(USA) n=80 M sources 308-1070 mg/d feine. 2007
[0.01-15 mg/kg/d]
Cross-sectional 24-63 yr coffee 0, 1-3, 4-6, >6 Higher sperm motility, statistically increased with intake of >6 cups/d; dose-response Sobreiro et
(Brazil) n=500 M cups/d [1.4 to seen; no effect on sperm morphology or concentration. [No info on caffeine per cup; al., 2005
>8.6 mg/kg/d] assumed 100 mg/cup]
225
Cross-sectional 18-42 yr caffeine, all 0, 1-150, 151-300, Risk for delayed conception for >1 year was increased among non-smoking F who con- Stanton and
(USA) n=1430 F sources; smok- ≥ 301 mg/d sumed ≥ 301 mg/d (OR=2.65 (95% CI 1.38-5.07). Smoking was associated with an in- Gray, 1995
ing [<0.01 to ≥5.0 creased risk (OR = 1.77, 95% CI 1.33-2.37), but no effect of high caffeine consumption
mg/kg/d] was observed among F who smoked. Fecundability (per cycle probability of conception)
was reduced among nonsmokers who consumed >300 mg caffeine/d (fecundability ratio
= 0.74, 95% CI 0.59-0.92). Smoking reduced the fecundability ratio, but there was no
effect of caffeine consumption on fecundability among women who smoked.
Cross-sectional 18-35 yr caffeinated 1.1 ±1.0 to 2.8±2.1 Weak association with sperm morphology alterations and "high" caffeine intake. Vine et al.,
(USA) n=86 M drinks units/d [~1 to 9 [Caffeine intake was calculated as the sum of the number of 8 oz. cups of coffee + (0.5 x 1997
mg/kg/d] number of 8 oz. cups of tea) + (0.25 x the number of 12 oz glasses of caffeinated soft
drinks) consumed per day during the previous 3 months. The intake categories of low,
medium, and high were undefined; “high” was assumed to be ≥5.7 mg/kg/d based on an
intake of ~4 cups coffee at 100 mg caffeine/cup.]
FSH=follicle stimulating hormone; OR=odds ratio
226
TABLE 9-2. Reproductive Effects of Caffeine – Summaries of Reviews Reference
There are many studies relevant to reproductive toxicity; some suggest an adverse effect but the total data base is inconsistent. [numerous animal and human Anonymous,
results provided] 2004
The risk for development of benign prostatic hyperplasia increases with caffeine intake. Yun and Doux,
2006
Exposures associated with oxidative stress and with evidence to influence the timing and maintenance of a viable pregnancy include alcohol, tobacco, and Ruder et al.,
caffeine intake. 2009
A person's time to pregnancy and their chance of having a healthy, live birth may be affected by factors including caffeine consumption. Anderson et al.,
2010
The weight of evidence does not support a positive relationship between caffeine consumption and adverse reproductive or perinatal outcomes. This is due to Peck et al., 2010
the inability to rule out plausible alternative explanations for the observed associations, namely confounding by pregnancy symptoms and smoking, and by
exposure measurement error.
Data regarding the effect of caffeine on reproduction in humans are conflicting. For couples trying to conceive, it would be prudent to consume the equivalent Sadeu et al.,
of no more than 3 cups of coffee/d. The American College of Obstetricians and Gynecologists recommends that pregnant women limit consumption to the 2010
caffeine equivalent of 1 to 2 cups of coffee.
227
9B. Reproductive Effects of Caffeine in Animals
Only a few animal studies published since 1994 were located. In the studies, the expo-
sure duration was ≤8 weeks and exposure concentrations (7.5-150 mg/kg/day) were much higher
than in the human studies, so only a qualitative comparison with the human data is possible. Pol-
lard et al. (1999) found reduced maternal fertility in rats treated with 30 mg/kg/day throughout
the estrus cycle, but no developmental effects. Alterations in levels of LH, FSH, estrogen, and/or
testosterone were noted by Mandal et al. (2007), Ezzat and el-Gohary (1994), and Celec and Be-
huliak (2010). However, a dose of 150 mg/kg had no detrimental effects on oocyte maturation in
mice (Mailhes et al., 1996; Miao et al., 2007), and 7.5-30 mg/kg increased locomotor activity of
female rats and their return to a male following ejaculation (Guarraci and Bendon, 2005). The
animal studies are summarized in Table 9-3.
228
TABLE 9-3. Reproductive Effects of Caffeine – Animal Studies
Species; con- Exposure Test material; Caffeine
dition time route dose(s)
Rat, ovariec- 1 day pure caffeine 7.5, 15, 30 Treatment with 15 mg/kg shortened the latency to return to a male following an ejaculation and in- Guarraci and
tomized, (i.p.) mg/kg creased locomotor activity; 7.5 and 15 mg/kg (not 30 mg/kg) shortened the latency to return to a male Benson, 2005
given estro- following an ejaculation; 15 mg/kg did not disrupt preference for a sexual partner. These results suggest
gen, proges- that caffeine increased both sexual motivation and locomotor activity in F.
terone
Mouse, su- 1 day pure caffeine 150 mg/kg Caffeine neither retarded the rate of oocyte maturation nor increased the incidence of aneuploidy in Mailhes et al.,
perovulated (i.p.) mouse oocytes. 1996
Mouse; oocyte 1 day pure caffeine 150 mg/kg; Mice were given caffeine (150 mg/kg BW ip) at various times relative to hCG (-2, 0, and +2h); in an in Miao et al.,
culture (i.p.; in vitro) in vitro 1, 5, vitro study, 1, 5 or 10 mM caffeine was added to the maturation culture. Caffeine had no effect on the 2007
10 mM quality of oocytes in vivo maturation, but caffeine was detrimental to the quality of oocytes matured in
vitro.
cultured rat 1 day pure caffeine (in mM Explants exposed to caffeine differentiated normally, developing seminiferous cords made up of Sertoli Pollard et al.,
fetal testis vitro) and germ cells, soon followed by the differentiation of functionally active Leydig cells appearing in the 2001
newly formed interstitium.
Rat 7 d (through pure caffeine 30 mg/kg/d Preconceptual caffeine exposure reduced maternal fertility by the failure of a proportion of the litters to Pollard et al.,
estrus cycle (gavage) implant, rather than curtailing preimplantation development or postimplantation losses. Postnatal mortal- 1999
prior to ity between weeks 0 and 1 was elevated and the weekly incremental growth rate of the pups from wk 3-7
fertiliza- was reduced in the preconceptually caffeine-treated offspring. F reached puberty at the same age as the
tion) controls but at a lower BW. Gestation length, birthweight, litter size, sex ratio, and anogenital distance (a
measure of prenatal androgenization) were not affected.
Mouse 22-27 d pure caffeine 20 mg/kg/d Caffeine treatment increased LH (except for 27 consecutive days) and decreased FSH (except for 24 and Mandal et al.,
(gavage); EAC 27 consecutive days) and both E2 and progesterone (except for 22 and 24 consecutive days) levels; de- 2007
cells (i.p.) velopment of EAC cell for 10-15 days, significantly increased LH but decreased FSH, E2 and progester-
one levels; long-term caffeine consumption during the development of EAC cell restored the EAC cell-
or caffeine-induced induction of LH and reduction of FSH level to their normal levels and with-
drew/reduced the EAC cell-induced reduction in only E2 but not progesterone level.
Rabbit 28 d pure caffeine 30, 60 Increased plasma FSH and decreased LH at both doses; testosterone was increased at 60 mg/kg; ACTH Ezzat and el-
(i.p.?) mg/kg was not altered; had reduced sizes of the seminiferous tubules, inhibited spermatogenesis, fatty degen- Gohary, 1994
eration of the liver and hepatic lesions. The adrenal glands exhibited signs of stimulated steroidogenesis.
Rat 90 d Cola (oral) 30-60 A light-dark box showed increased locomotor activity and anxiety in all groups with cola intake. A sub- Celec and
mg/kg/d tle anti-depressive effect was seen in the forced swim test. Chronic cola intake increased both estradiol Behuliak,
and testosterone levels. 2010
229
TABLE 9-3. Reproductive Effects of Caffeine – Animal Studies
Species; con- Exposure Test material; Caffeine
dition time route dose(s)
ACTH=Adrenocorticotrophic hormone; E2=estradiol; FSH=follicle stimulating hormone; LH=luteinizing hormone
230
CHAPTER 10. EFFECTS OF CAFFEINE ON BONES AND TEETH
10A. Bone and Dental Effects of Caffeine in Humans
Only a few experimental studies examined the effect of caffeine on bone and dental pa-
rameters in adults; the vast majority of the data on this topic consist of epidemiological studies
with children and adults. Four experimental studies examined the effect of caffeine on calcium
excretion, which was increased in men and women administered 5-6 mg/kg as pure caffeine or in
coffee, or women given 1.3 mg caffeine as cola or 1.5 mg/kg as a non-cola carbonated drink.
Calcium excretion was greater in calcium stone formers than non-formers, lower in women using
OC than those not using them, and similar in normotensive and hypertensive men (Heaney and
Rafferty, 2001; Massey and Sutton, 2004; Ribioro-Alves et al., 2003; Wise et al., 1996). A
cross-sectional study also found that caffeine intake decreased calcium balance (intake and ab-
sorption efficiency) among all ages, but could be offset by a calcium intake of ~40 mg for every
177.5 ml serving of caffeine-containing coffee (Barger-Luz and Heaney, 1995). Two studies
showed that (isolated) human teeth immersed for 2 weeks in coffee, cola, or EDs had visible
changes to the surface (Kitchens and Owens, 2007; Owens and Kitchens, 2007).
An adverse effect on bone and dental-related parameters was observed in a number of

epidemiological studies. Four cross-sectional studies with children and/or adolescents who in-
gested ~1-6 mg/kg/day showed that increased caffeine consumption was a risk factor for reduced
bone mineral density (Hoch et al., 2009; Libuda et al., 2008; Ruffing et al., 2006; 2007). Three
11-14-year old children who consumed >120 mg/day caffeine in soft drinks had early initiation
and rapid progression of dental caries over a 2-year period (Majewski, 2001).
Decreased bone mineral content and/or density (BMD) or osteoporosis at one or more
sites was observed in post-menopausal middle-aged and older women with an intake of ≥1.25
cups coffee/day (~2 mg/kg) (Barrett-Connor et al., 1994); women with an intake of 200-300
mg/day caffeine (3.3-5 mg/kg/day) (Ilich et al., 2002); older women with an intake of >300
mg/day (5 mg/kg/day) or ≥5 cups/day coffee (8.3 mg/kg/day) (Rapuri et al., 2001; Korpelainen
et al., 2003). Decreased BMD was also seen in young women who used OC and had an intake of
>200 mg/day caffeine (Wetmore et al., 2008) or who drank ≥3 cups/day caffeinated drinks (2-5
mg/kg/day, depending on beverage) (Rubin et al., 1999), or with an intake of 190 ± 304
mg/kg/day (Twiss et al., 2006). Women with a low intake of calcium (<745 mg/day) who con-
sumed >450 mg/day caffeine (7.5 mg/kg/day) had increased bone loss (Harris and Dawson-
Hughes, 1994). Cola intake of >1 serving/day was associated with lower hip BMD and a lower
calcium-to-phosphorus ration in women of a variety of ages with a mean daily total intake of 235
± 194 mg/day caffeine from all sources, although the effect of caffeine intake from non-cola
sources was excluded (Tucker et al., 2006). Effects on bone density were also seen in elderly
men consuming ≥4 cups/day coffee (5.7 mg/kg/day) or ~260 mg caffeine/day (5.2 mg/kg/day)
(Hallstrom et al., 2010; Barbour et al., 2010), in men <50 years old with an intake of ~3
mg/kg/day caffeine (Atalar et al., 2009), in men of a wide age range who consumed ≥3 cups/day
coffee (4.3 mg/kg/day) (El Maghraoui et al., 2010), and in middle aged and elderly men and
women who consumed >1 cup of tea per day (Jha et al., 2010).
231
An increased risk of osteoporotic fracture was seen in older women with an intake of >2
cups/day coffee (>3 mg/kg/day) (Cummings et al., 1995), and in middle aged and older women
with an intake of >330 mg/day caffeine (5.5 mg/kg/day) with low calcium intake (<700 mg)
(Hallstrom et al., 2006).
However, some epidemiological studies found no significant association of caffeine in-

take with bone-related parameters. Caffeine intake was not correlated with the rate of bone min-
eral density and/or bone loss in middle-aged and elderly men and/or women (Guthrie et al.,
2000; Hannan et al., 2000; Cauley et al., 2005; Conlisk and Galuska, 2000; Glynn et al., 1995;
Grainge et al., 1998; Hansen, 1994; Jarupanich, 2007; Lloyd et al., 1997; Rico et al., 2002), with
biochemical markers of bone turnover in women (Ardawi et al., 2010), or with BMD in 12 and
15-year old children (McGartland et al., 2003). No association was found between caffeine in-
take and the rate of bone gain over a 4-year period in young women (Packard and Recker, 1996),
or in 12-18 year old children over a 6-year period (Lloyd et al, 1998), or between longitudinal
changes in bones in middle-aged women over a 2-year period (Lloyd et al., 2000). Several stud-
ies found no significant increase in the risk of osteoporotic fracture in men and/or women of a
wide range of ages (Cumming and Klineberg, 1994; Tavani et al., 1995; Albrand et al., 2003).
Although the data presented in the studies are not all consistent, the weight of evidence
indicates that caffeine can have an adverse effect on bone and dental-related parameters. Based
on findings of decreased bone mineral content or density, and increased risk of osteoporotic frac-
ture in men and women who consumed ≥200 mg caffeine/day (3 mg/kg/day), this dose is consid-
ered the LOAEL for adverse effects on bone integrity. The corresponding NOAEL is 1.5
mg/kg/day (100 mg/day or ~ 1 cup of coffee/day), which was not associated with adverse effects
on bone integrity. While these values are expected to apply to all beverage types for adults, data
is insufficient to determine whether these values are applicable to young children.
The bone-related toxicity data and the derived overall LOAEL and NOAEL are plotted
below, as well as the individual study data. The squares on the plot are the lowest effect level
and the no-effect level for a given endpoint of each study (the endpoints are identified on the
lower X-axis). The no-effect level for a given study was either the upper limit or the midpoint of
the lowest intake (reference) category, depending on the distribution of the intake categories.
The study author(s) are indicated on the upper X-axis.
232
Caffeine intake (mg/kg/day)
M
F; +F
os ;h
te F; ip
op h fra
F;
1.0E+00
1.0E+01
1.0E+02
1.0E-01
or ip ct
os o fr u
te F; tic act re
op h fra ur
M or ip ct e C
+F ot fra ur u
; o M F; ic f ctu e Ta mm
st +F hip rac re v i
eo ; f tu Al an ng a
po hip rac re br i e n
ro fr tu C an t a d
tic ac re u d l K
F; H mm et ., 1 line
de fra tur a i a 9 b
F
M ; d cre ct e H llstr ngs l., 2 95 erg
+F e a ur er o e 0
M ; d re e c s e Ki na m e t a 03
,1
99
+F e a d el nd t l.,
Tr et ez al. 19 4
; d cre se BM ; im a - A , 2 9
F; ec as d B D l.
po , vi 00 5
de re ed M u 1 9 la 6
M F; d crease BMD Ba et 90 et
+F e a d D rr al al
.
; cr se BM G et .
M dec eas d B D ut t-C , 20 , 19
; d re e M H hri o 91
al e nn 10
F; ec as d B D H lstr et or
r e M a o a e
M dec eas d B D R nna m e l., 2 t a
; d re e M ap n t 0 l.,
F; ec as d B D
r e W ur et al. 00 19
e i a , 94
M dec eas d BMD
; r e At tmo et a l., 201
al re l., 20 0
M dec eas d BMD Ba ar e 2 10
; d re e M e t 0
F; ec as d B D Barbo t al al. 01
d re e M u ur ., , 2
Study author(s)
F; ec as d B D C er et 20 00
de rea ed MD a e a 0 8
F; c s B
Bone adverse effect
C uley t a l., 9
d re e M on l. 2
F; ec as d B D El lis et a , 19 010
d re e M M k a l., 93
F; ec as d B D G ag n 2
de rea ed MD ly h d 0
F; c s B G nn ra Ga 05
d re e M ra e o l
F; ec as d B D H ing t al ui e usk
d re e M an e ., t a
F; ec as d B D H se et 19 al.,
de rea ed MD a n a 9 2
F; c s B Ili rris , 19 l., 5 01
d re e M ch a 1 0
F; ec as d B D Ja et nd 94 998
de rea ed MD ru a D
cr se BM Ko pa l., aw
ea d D n 2 s
se BM Kr rpe ich 002 on
d D ah lai , 2 -H
BM Ll e ne 0 ug
D oy e n 07
t he
ENDPOINT: Bone integrity (epidemiological studies with caffeine)
R d a et s.
ic e l. a ,1
R o e t al , 19 l., 2 99
ub t ., 9 0 4
a
in l., 9 1 7 03
et 2 97
0
sity because so many genetic and lifestyle factors are now known to affect bone health.
al 0
., 2
19
99
40-60 year old women. Massey (2001) concluded that most cross-sectional studies of elderly
a risk factor for negative calcium balance, poor calcium absorption, and osteoporosis (Body et
for osteoporosis in people who consume adequate calcium. Waugh et al. (2009) felt there was
al., 2011; Deal, 1997; Faine, 1995; Hata et al., 2003; Lau and Woo, 1998; Massey, 1998; Swa-
opinions. Nawrot et al. (2003) and Heaney (2002) concluded that caffeine was not a risk factor
LOAEL
are summarized in Table 10-1. Brief summaries of conclusions drawn by authors of reviews on
NOAEL
this topic are provided in Table 10-2. Most of the reviews indicate that excess caffeine intake is
populations showed no association of caffeine consumption with bone loss or bone mineral den-
Studies that evaluated the effect of caffeine intake on bone and dental-related parameters
No Effect
minathan, 1999; Ullom-Minnich, 1999; Willhite, 1998). Other authors, however, had conflicting
good or fair evidence that caffeine intake is not a risk factor for low bone mass density in healthy
233
Effect level
TABLE 10-1. Effects of Caffeine on Bones and Teeth – Human Studies
Exposure Subject age; Test material
Country number; sex [condition]
Cohort prospec- 12-18 yr at caffeine, all 3 groups by in- Caffeine intake by girls from age 12-18 was not correlated with bone mineral gain or hip Lloyd et al.,
tive (6 yr follow- baseline sources take: 14, 35, 77 bone density at age 18. [Assumed BW 40-60 kg for dose estimates] 1998
up) (USA) n=81 F mg/d [0.2-1.9
mg/kg/d]
Cohort prospec- 11 yr; 13 yr; 14 caffeinated >120 mg/d For early initiation and rapid progression of dental caries in three adolescents, a com- Majewski,
tive (2-yr fol- yr at baseline drink, carbon- [2.4 mg/kg/d] mon factor was the ingestion of high amounts of caffeinated-carbonated soft drinks. 2001
low-up) (USA) n=3 M+F ated [Assumed BW 50 kg for dose estimate]
Cross-sectional 12 yr; 15 yr cola M, 12 yr [0.7-1.5 Cola consumption and non-diet drinks were not significantly related to BMD in either McGartland et
(Ireland) n=1335 (44% M) mg/kg/d]; M, 15 yr sex; inverse relationship between intake of total carbonated soft drinks (CSD), non-cola al., 2003
[0.6-1.3 mg/kg/d]; and diet drinks and BMD in girls at the dominant heel but no consistent relationships
F, 12 yr [0.5-1.2 between CSD intake and BMD in boys. [Cola intake was given as weight of the liquid
mg/kg/d]; F, 15 yr drink, as follows: M 12 y=281.0 ± 320 g/d; M 15 y=367.0 ± 420.3 g/d; F 12 y=209.0 ±
[0.4-1.0 mg/kg/d] 269.1 g/d; F 15 y=251.3 ± 341.4 g/d; no info on caffeine content; assumed 40 mg caf-
feine/355 mL drink (0.1 mg/mL); assumed 45 kg at age 12 yr, and 60 kg at age 15 y]
Cross-sectional 13-18 yr caffeinated athletes 0.49± 6.27 Risk factors for reduced bone mineral density included being a sedentary control stu- Hoch et al.,
(USA) n=80 F; c=80 F drink, carbon- drinks/d [≤4.5; dent, low body mass index, and increased caffeine consumption. [No info on caffeine 2009
ated mg/kg/d]; others: per beverage; assumed 40 mg/12 oz can of cola and BW of 60 kg; highest dose esti-
1.10±8.65 drinks/d mated made by adding the mean + SD number of cans/d]
[≤6.5 mg/kg/d]
Cross-sectional 3-18 yr caffeinated pre-pubesc F: 10 Long-term consumption of caffeinated soft drinks was negatively associated with polar Libuda et al.,
(Germany) n=228 M+F drink, carbon- mg/d, M: 19 mg/d; strength strain index (p < 0.01) and periosteal circumference (P < 0.05), which reflect 2008
ated pubesc F: 30 bone modeling. Consumption of all soft drinks was negatively associated with total pro-
mg/d; M: 56 mg/d tein and milk intake, but was not associated with potential renal acid load. [Assumed
[0.5-2 mg/kg/d] BW 10-40 kg for pre-pubescent, and 50-60 kg for pubescent children for dose estimates]
Cross-sectional 18.7 ± 1.05 yr caffeinated 0, 1-3, >3 drinks/d Intake of caffeinated drinks/d had a negative impact on bone density and size in physi- Ruffing et al.,
(USA) n=755 M drinks [1.4 to >4.3 cally active young adult men (e.g., 2.5% lower calcaneal BMD for ≥2 cups/d). [No info 2006
mg/kg/d] on caffeine per drink; assumed 100 mg/drink]
Cross-sectional 18.4 ± 0.8 yr caffeinated 0, 1-3, >3 cups/d Caffeine intake had a borderline negative impact on tibial mineral content; no effect on Ruffing et al.,
(USA) n=135 F drinks [1.7 to >5.0 cortical thickness or calcaneal BMD; no effect from caffeine on spine or hip BMD. [No 2007
mg/kg/d] info on caffeine per cup; assumed 100 mg/cup]
234
STUDIES WITH ADULTS
1-d experiment 20-40 yr carbonated 77.5 mg from cola The excess calciuria from consumption of carbonated beverages was confined to caf- Heaney and
(USA) n=30 F drink ± caffeine [1.3 mg/kg]; 91.7 feinated beverages. Acidulant type had no acute effect. Because the caffeine effect is Rafferty, 2001
mg from non-cola known to be compensated for by reduced calciuria later in the day, it appears that the net
[1.5 mg/kg] effect of carbonated beverage constituents on calcium economy is negligible, and the
skeletal effects of carbonated beverages are likely due primarily to milk displacement.
1-d experiment n=51 ± 12 yr; pure caffeine 6 mg/kg lean body Caffeine increased urinary Ca/Cr, magnesium/Cr, citrate/Cr and sodium/Cr but not ox- Massey and
(Canada; USA) c=46 ± 15 yr [calcium kid- mass alate/Cr in stone formers and controls, and increased the Tiselius stone risk index for Sutton, 2004
n=39; c=48 M+F ney stones] calcium oxalate precipitation from 2.4 to 3.1 in stone formers and from 1.7 to 2.5 in
nonstone formers.
1-d experiment 20-29 yr Coffee [OC] 5 mg/kg Women who used OC had lower caffeine-induced excretion of calcium and other miner- Ribeiro-Alves
(Brazil) n=15 F; c=15 F als. et al., 2003
1-d experiment 65-99 yr pure caffeine 6 mg/kg lean body Calcium excretion was increased similarly in normotensives and hypertensives, but Wise et al.,
(USA) n=19 (11 M); [hypertension] mass parathyroid hormone decreased after 2-week caffeine abstinence in 14 of 18 hyperten- 1996
c=19 (11 M) sives, including the 7 consuming <700 mg calcium daily.
14-d experiment in vitro coffee; cola; Isolated teeth were Human teeth immersed for 14 d in Coca-Cola Classic, Diet Coke, Gatorade, and Red Kitchens and
(USA) ED immersed in bev- Bull all had significantly higher post treatment roughness readings than Starbucks cof- Owens, 2007
erages fee, Dasani water, and tap water. Fluoride varnish was not a significant impact factor;
however, beverage (type) and exposure time were significant impact variables immer-
sion in beverages.
14-d experiment in vitro Cola; ED Isolated teeth were Enamel specimens exhibited visual surface changes after immersion, in Red Bull and Owens and
(USA) immersed in bev- Gatorade revealing the most striking surface morphological changes. Specimens sub- Kitchens,
erages jected to Coca Cola Classic and Diet Coke immersion also displayed irregular post- 2007
treatment surface morphology.
Case-control 65-100 yr Coffee; tea 3.5, 10, 13.5, 20.5 Caffeine was not associated with hip fracture risk. [1 caffeine unit = sum of cups of Cumming and
(Australia) cases=209; con- units/wk at 20 yr; coffee + 0.5 (cups of tea)] [caffeine per unit was not reported; assumed 100 mg/unit] Klineberg,
trols=207 10, 15, 20.5, 24.5 1994
M+F units/wk at ≥50 yr
[0.5-5.0 mg/kg/d]
235
Case-control cases=65.7 ± caffeinated tea: ≤1, >1 cup/d; Regular tea drinkers and persons who drank other caffeinated beverages were at a higher Jha et al.,
(India) 16.1 yr (n=100); drinks; tea other caffeinated risk of hip fracture (OR 2.11; 95% CI .93-4.81; OR 1.88; 95% CI 1.01-3.50 respec- 2010
controls=64.7 ± drinks + or - tively). Although statistically not significant (p = 0.26), individuals who drank >1 cup of
13.8 yr (n=100) tea/d were 1.55 times more likely to have a hip fracture (95% CI 1.013- 3.50).
M+F
Case-control cases=19-74y; coffee; cola; 0, 1, 2, 3, 4, ≥5 No significant association between hip fractures and consumption of coffee, tea, or cola. Tavani et al.,
(Italy) controls=18-74 decaf; tea cups/d coffee; ± [No info on caffeine per cup; assumed 100 mg/cup coffee] 1995
yr; cases=279 F; for tea, decaf [1.7
controls=1,061 F to ≥8.3 mg/kg/d]
Cohort prospec- 59.1 ± 9.8 yr caffeinated 2.6 ± 1.8 cups/wk No consistent association between smoking, alcohol consumption, caffeine consump- Albrand et al.,
tive (5.3 yr fol- n=672 F drinks without fracture; tion, and daily intake of calcium and the risk of osteoporotic fracture. [No info on caf- 2003
low-up) [pre- 2.7 ± 1.6 cups/wk feine content; assumed 100 mg/cup]
(France) menopausal] with fracture
[4.3, 4.5 mg/kg/d]
Cohort prospec- 50-98 yr Coffee; decaf current/past drink- Significant (≥1.25 cups/d) graded association between increased lifetime intake of caf- Barrett-
tive (3 yr follow- n=980 F [post- ers cups/d: 1.0/1.2, feinated coffee and decreasing BMD at both the hip and spine, only in women who Connor et al.,
up) menopausal] 1.3/1.6, 1.8/2.3, drank < 1 cup milk/d as adults. [No info on mg caffeine per cup; assumed 100 mg/cup] 1994
(USA) 2.4/2.8, 4.1/4.6
[1.7-7.7 mg/kg/d]
Cohort prospec- 72 ± 5 yr coffee mean 172 mg/d Intake of >2 cups/d coffee (>3.3 mg/kg/day) was a risk factor for hip fracture in older Cummings et
tive (4.1-yr fol- n=9,516 F [2.9 mg/kg/d] women. al., 1995
low-up) USA)
Cohort prospec- 46-56 yr at caffeine, all 46% had intake Caffeine intake was not related to bone mineral density in women. Guthrie et al.,
tive (4-yr fol- baseline sources >360 mg/d [< or 2000
low-up) n=224 F >6 mg/kg/d]
(Australia)
Cohort prospec- 40-76 yr at caffeine, all <200, 200-330, Osteoporotic fracture risk increased with >330 mg/d intake caffeine in women with low Hallstrom et
tive (10.3 yr baseline sources; coffee; >330 mg/d calcium intake (<700 mg/day); tea drinking was not effective. al., 2006
mean follow-up) n=31,527 F tea [low cal- [<3.3 to >5.5
(Sweden) cium intake] mg/kg/d]
236
Cohort prospec- 72 yr Coffee 0-2, 3, 4, >4 Men consuming ≥4 cups coffee/day had 4% lower BMD at the proximal femur (p = Hallstrom et
tive (2-yr fol- n=717 (359 M) [CYP1A2 cups/d 0.04) than low or non-consumers; not observed in women. High consumers of coffee al., 2010
low-up) genotype] [<2.9 to >5.7 with rapid metabolism of caffeine (C/C genotype) had lower BMD than slow metaboliz-
(Sweden) mg/kg/d] ers (T/T and C/T genotypes). Calcium intake did not modify the relation between coffee
and BMD. [Mean intake 3.2 cups/d, mean caffeine intake 367 mg/d]
Cohort prospec- 67-90 yr at caffeinated 0-2, >2 cups/d Bone loss was not affected by caffeine intake in men or women. [No info on caffeine Hannan et al.,
tive (4-yr fol- baseline drinks; smok- [< or >2.9 per cup; assumed 100 mg/cup] 2000
low-up) (USA) n=764 (36% M) ing mg/kg/d]
Cohort prospec- 55-69 yr caffeinated quintiles: 0-65, 65- Wrist fractures were associated positively with caffeine intake (RR for extreme quin- Hansen et al.,
tive (6.5 yr fol- n=34,703 F drinks [post- 145, 145-343, 343- tiles=1.37, 95% CI 1.11-1.69); upper arm fractures were negatively associated with caf- 2000
low-up) menopausal] 504, ≥504 mg/d feine intake (RR=0.67, 95% CI 0.48-0.94); no dose-response.
(USA) [<1.1 to ≥8.4
mg/kg/d]
Cohort prospec- Adult caffeine, all 348 ± 243 mg/d Caffeine intake did not affect endogenous fecal calcium excretion in women. Heaney and
tive (15 yr fol- n=191 F sources [peri- [<5.8 to >9.9 Recker, 1994
low-up) (USA) menopausal] mg/kg/d]
Cohort prospec- 55-70 yr at caffeine, all 0-150, 151-300, There was no association between caffeine intake and longitudinal changes in total body Lloyd et al.,
tive (2 yr follow- baseline sources [post- >300 mg/d [<2.5 or femoral neck bone, regardless of calcium intake in women. 2000
up) (USA) n=92 F menopausal] to >5.0 mg/kg/d]
Cohort prospec- 19.0-26.0 yr at caffeine, all 7.0-809 mg/day Caffeine consumption (mean 103 ± 106 mg/d) was not associated with significant reduc- Packard and
tive (4-yr follow baseline sources [0.1-13 mg/kg/d] tion in rates of bone gain over 4 yr in young women. Recker, 1996
up) (USA) n=145 F
Cohort prospec- 65-77 yr caffeine, all low (≤300 mg/d); Women with high caffeine intakes had significantly higher rates of bone loss at the spine Rapuri et al.,
tive (3-yr fol- cross-sectional sources [vita- high (>300 mg/d) than did those with low intakes (-1.90 ± 0.97% compared with 1.19 ± 1.08%; P =0.038). 2001
low-up); Cross- n=489 F; cohort min D receptor [≤ or >5.0 When the data were analyzed according to VDR (vitamin D receptor) genotype and caf-
sectional n=96 F genotype; post- mg/kg/d] feine intake, women with the tt genotype had significantly (P = 0.054) higher rates of
(USA) menopausal] bone loss at the spine (-8.14 ± 2.62%) than did women with the TT genotype (-0.34 ±
1.42%) when their caffeine intake was >300 mg/d.
Cohort prospec- 25-64 yr at coffee 4.5±2.4 cups/d The hazard ratio for a one step increase in SD of risk for osteoporotic fracture during 20 Trimpou et
tive (20 yr fol- baseline with fracture; years was 1.07 (CI 1.01–1.13; p=0.014) for coffee consumption in models including al., 2010
low-up) n=1,396 (47% M; 4.2±2.8 cups/d current age, sex, and time since baseline examination. When these factors were analyzed
(Sweden) without [<7 to >12 in a Poisson model together with current time, age, and gender, coffee consumption lost
mg/kg/d] its significance. [No info on caffeine per cup; assumed 100 mg/cup]
237
Cohort prospec- 14-40 yr caffeine, all 0, ≤200, >200, Bone mineral content and density were decreased at >200 mg/d caffeine intake only Wetmore et
tive (2-yr fol- n=625 F sources; OC >300 mg/d [≤3.3 with co-intake of DMPA oral contraceptive. al., 2008
low-up) (USA) to >5.0 mg/kg/d]
Cross-sectional 20-79 yr (2125 caffeine, all 400 mg/d No significant correlations between total daily caffeine intakes and biochemical bone Ardawi et al.,
(Saudi Arabia) F); reference= sources [6.7 mg/kg/d] turnover markers. 2010
35-45 yr (765 F)
Cross-sectional 20-75 yr caffeine, all mg/wk: 1588± 600 In the patients < age 50, lumbar spine BMD and femoral neck BMD were negatively Atalar et al.,
(Turkey) n=131 M (71 sources for <50 yr; 1469 ± correlated with age and caffeine intake. 2009
were < 50 yr old) 561 for ≥ 50 yr
[3.2, 3.0 mg/kg/d]
Cross-sectional 69-97 yr caffeine, all mean 261 ± 259.3 A 1-standard deviation (259.3 mg/d) increase in caffeine consumption was associated Barbour et al.,
(USA) n=1,172 M sources mg/d [<3.7 to >7.4 with lower cortical volumetric bone mineral density (vBMD) of the radius. Caffeine 2010
mg/kg/d] intake also was associated with lower trabecular and cortical vBMD of the tibia.
Cross-sectional 34.8-69.3 yr coffee 262 ± 186 mg/d For every 6 fl oz (177.5 ml) serving of caffeine-containing coffee, calcium balance was Barger-Lux
(USA) n=190 F [<4.4 to >7.5 more negative by 0.114 mmol/day (4.6 mg/day) (p< 0.001). Both the calcium intake and and Heaney,
mg/kg/d] calcium absorption efficiency were independently and inversely associated with caffeine 1995
intake. There was no evidence that the effect was confined to, or greater among, subjects
with low calcium intakes or those who are older or estrogen-deprived. The magnitude
of the negative effect of caffeine on calcium balance suggests that it can be offset by
increasing calcium intake by about 1 mmol (40 mg) for every 177.5 ml serving of caf-
feine-containing coffee.
Cross-sectional ≥65 yr caffeine, all mean 214 mg/d Caffeine intake was not related to bone mineral density (BMD); African-American men Cauley et al.,
(USA) n=5,995 M sources [3.1 mg/kg/d] had 6 to 11% higher BMD than Caucasian men independent of multiple factors. 2005
Cross-sectional 19-26 yr caffeine, all mean 100 mg/d The decreases in femoral neck and lumbar spine bone mineral density were small and Conlisk and
(USA) n=177 F sources [1.7 mg/kg/d] not affected by calcium intake. Galuska, 2000
Cross-sectional 20-79 yr coffee <1, 1-2, ≥3 cups/d High coffee consumption (≥3 cups/d [4.3 mg/kg/d]) was independently associated with El Maghraoui
(Morocco) n=592 M [<1.4 to >4.3 lumbar spine osteoporosis. [No info on caffeine per cup; assumed 100 mg/cup] et al., 2010
mg/kg/d]
Cross-sectional 66.6 yr mean caffeinated 20% drank ≥4 Caffeine intake was not related to bone mineral density in men >50 yr old. [No info on Glynn et al.,
(USA) n=523 M drinks cups/wk [< or >5.7 caffeine per cup; assumed 100 mg/cup] 1995
mg/kg/d]
238
Cross-sectional 45-59 yr caffeinated median at age 20, Caffeine consumption at various ages was not associated with bone mineral density in Grainge et al.,
(Denmark; UK; n=580 F drinks [post- 30, 40, now: 180, women. 1998
USA) menopausal] 300, 360, 360
mg/d [3-6
mg/kg/d]
Cross-sectional 39 ± 6 yr Coffee; tea 0-2500 mg/d Caffeine intake did not consistently influence BMD or bone turnover in pre-menopausal Hansen, 1994
(Denmark) n=249 F [pre- [0-42 mg/kg/d] women.
menopausal]
Cross-sectional Adult caffeine, all 0-171, 182-419, Women had greater spine and total body bone loss from consumption of >450 mg/d [7.5 Harris and
(USA) n=205 F sources [post- 450-1120 mg/d mg/kg/d] caffeine while consuming <745 mg/d calcium. [caffeine intake categories for Dawson-
menopausal] [<2.9 to 19 women consuming >745 mg/d calcium were 0-157, 186-431, 431-1896 mg/d] Hughes, 1994
mg/kg/d]
Cross-sectional Adult caffeine, all 200-300 mg/d In subgroup (stratified by Ca intake) and multiple regression analysis, caffeine intake Ilich et al.,
(USA) n=136 F sources [3.3-5.0 mg/kg/d] (average ~200-300 mg/d) had a negative association with bone mineral density at most 2002
evaluated skeletal sites, which was attenuated with higher Ca intake (≥750 mg/day).
Cross-sectional 34-60 yr caffeine, all < or >2 cups caf- Caffeine intake was not associated with osteoporosis, regardless of menopausal status; Jarupanich,
(Thailand) n=1,796 F sources feine/d intake given in terms of "cups caffeine per day." [No info on caffeine per cup; assumed 2007
[< or >3.3 100 mg/cup]
mg/kg/d]
Cross-sectional 70-73 yr coffee <5, ≥5 cups/d Coffee intake ≥ 5 cups/d was associated with decreased calcaneus and bone mineral Korpelainen
(Finland) n=1222 F [< or ≥8.3 density of the radius in the leanest women (not in normal/obese women). [No info on et al., 2003
mg/kg/d] caffeine per cup; assumed 100 mg/cup]
Cross-sectional 40-50 yr caffeine, all 0.79-462 mg/d Multiple regression analysis showed that a lower femoral BMD was associated with Krahe et al.,
(Brazil) n=60 F sources [pre- [0.01-7.7 mg/kg/d] lower BMI, higher alkaline phosphatase and caffeine intake, and less frequent exercis- 1997
menopausal] ing. In this sample, the overall caffeine intake was low, and the patients who drank
more coffee were those who ate more and were heavier, thus explaining this seeming
contradiction.
Cross-sectional 55-70 yr coffee [post- 0-2, 3-4, >5 cups/d Caffeine intake was not associated with total body or hip bone mineral density. [80 Lloyd et al.,
(USA) n=138 F menopausal] [<2.7 to >6.7 mg/180 mL cup used as standard] 1997
mg/kg/d]
239
Cross-sectional 15-100 yr coffee 0, 1-2, 3-5, ≥6 Heavy coffee drinkers (≥6 cups/d) were at greater risk of sleep tooth grinding (bruxism); Ohayon et al.,
(Germany; Italy; n=13,057 (48% cups/d [1.4 to ≥8.6 more common in younger subjects. [No info on caffeine per cup; assume 100 mg/cup] 2001
UK) M) mg/kg/d]
Cross-sectional 57.3 ± 7.1 yr caffeine, all < or >100 mg/d Caffeine intake had no effect on bone mass density in healthy postmenopausal women. Rico et al.,
(Spain) n=93 F sources [post- [< or >1.7 2002
menopausal] mg/kg/d]
Cross-sectional 18-35 yr Coffee; tea; <1, 1-2, ≥3 cups/d Hip, but not spine BMD, was correlated negatively with caffeine intake of ≥3 cups/d [2- Rubin et al.,
(Canada) n=677 F cola [<0.7 to ≥5.0 5 mg/kg/d, depending on beverage]. [No info on caffeine per cup; assumed 100 mg/cup 1999
mg/kg/d] coffee and 40 mg/cup tea or cola]
Cross-sectional 45-71 yr caffeine, all ~30-228 mg/d Caffeine (3rd and 4th quartile) and family history of nephrolithiasis were positively as- Taylor and
(USA) n=3368 (30.8% sources [0.4-3.3 mg/kg/d] sociated with urinary calcium. [caffeine levels corresponding to the quartiles were not Curhan, 2009
M) [2201 stone provided; the 25th to 75th percentile caffeine intakes were 30-228, 22-229, and 30-225
formers] mg/d for the HPFS, NHS I, and NHS II cohorts, with respective mean intakes of 101,
106, and 107 mg/d]
Cross-sectional 30-87 yr Cola; caffein- 0, ≤1, >1-≥3, >3- Cola intake was associated with lower (p < 0.001-0.05) BMD at each hip site, but not Tucker et al.,
(USA) n=1413 F, 1125 ated drinks ≤7, >7 servings the spine, in women but not in men. Similar results were seen for diet cola and, although 2006
M cola/wk, in total weaker, for decaffeinated cola. No significant relations between noncola carbonated
270± 208 mg/d for beverage consumption and BMD were observed. Total phosphorus intake was not sig-
M, 235± 194 mg/d nificantly higher in daily cola consumers than in nonconsumers; however, the calcium-
for F [<4 to >7.1 to-phosphorus ratios were lower. [Non-cola sources of caffeine were adjusted for and
mg/kg/d] are not included in the caffeine intake given, which is only for cola; No info on caffeine
per cola serving; assumed 40 mg/serving]
Cross-sectional 41-75 yr caffeine, all 190 ± 304 mg/d There were significant negative relationships of daily intake of caffeine/mg or daily Twiss et al.,
(USA) n=249 F sources [obese; [<2.7 to >6.1 grams of alcohol with bone mass (g/cm2) at the total hip. About half of the women had 2006
breast cancer mg/kg/d] low intake of vitamin D. [Assumed BW 70 kg for the obese women.]
survivor; post-
menopausal]
BMD=bone mass density; OR=odds ratio; RR=relative risk
240
TABLE 10-2. Bone and Dental Effects of Caffeine – Summaries of Reviews Reference
An excessive consumption of sodium, caffeine, or fibers exerts negative effects on calcium balance. Body et al., 2011
Excessive consumption of protein, caffeine, and alcohol are risk factors for osteoporosis Deal, 1997
The deleterious effects of caffeine on bone mineral density appear to have been overstated, especially in respect of the positive effects of flavonoids on Dew et al., 2007
bone health.
ED + alcohol are gaining popularity in young adults, which poses significant concerns about health risks; ED-related health concerns include case reports Duchan et al., 2010
of seizures and cardiac arrest following ED consumption and dental enamel erosion resulting from the acidity of ED.
In older women, high sodium, protein, alcohol, and caffeine intakes will cause increased urinary losses and negative calcium balance. Faine, 1995
Too much intake of caffeine or alcohol, as well as smoking, are risk factors for osteoporosis. Hata et al., 2003
All of the observations implicating caffeine-containing beverages as a risk factor for osteoporosis have been made in populations consuming substantially Heaney, 2002
less than optimal calcium intakes. There is no evidence that caffeine has any harmful effect on bone status or on the calcium economy in individuals who
ingest the currently recommended daily allowances of calcium.
Dietary caffeine intake may have a small negative effect on calcium absorption. Lau and Woo, 1998
Although caffeine consumption increases urinary calcium levels similarly in both younger and older individuals, the preponderance of data suggest that Massey, 1998
caffeine has a greater impact on calcium metabolism and bone in older people. Caffeine appears to affect metabolic and neurological responses similarly in
both young and elderly individuals, when differences in baseline performance are taken into account.
Most cross-sectional studies of elderly populations showed no association of caffeine consumption with bone loss or bone mineral density because so Massey, 2001
many genetic and lifestyle factors are now known to affect bone health. Previous prospective studies of elderly populations yielded conflicting results re-
garding caffeine and bone loss.
For healthy adults, caffeine intake up to 400 mg/d (6 mg/kg BW in a 65-kg person) is not associated with general toxicity, cardiovascular effects, effects Nawrot et al., 2003
on bone status and calcium balance (with consumption of adequate calcium), changes in adult behavior, incidence of cancer, or effects on male fertility.
Lower consumption is recommended for two 'at risk' subgroups: reproductive-aged women should consume ≤300 mg caffeine/d (4.6 mg/kg BW for a 65-
kg person) and children should consume ≤2.5 mg/kg BW.
A moderate reduction in intake of caffeine is likely to be of benefit against osteoporosis. Swaminathan, 1999
The use of caffeine, tobacco and steroids is associated with a decrease in bone density. Ullom-Minnich,
1999
There was good or fair evidence that alcohol and caffeine intake, and reproductive history, are not risk factors for low bone mass density in healthy 40-60 Waugh et al., 2009
year old women.
Modifying caffeine intake can help prevent osteoporosis and fractures. Willhite, 1998
Caffeine, a known inhibitor of cAMP phosphodiesterase, may affect bone metabolism by activating cAMP-dependent protein kinase A (PKA) pathway. Zhou et al., 2009
Caffeine may exert its undesirable influences on bone only in absence or low level of estrogen in vivo and estrogen may antagonize the adverse effect of
caffeine on bone. This assumes that estrogen may block the cAMP-dependent PKA pathway, which is shared by caffeine, to exhibit its antagonistic roles.
241
10B. Bone and Dental Effects of Caffeine in Animals (post-natal exposure)
Animal studies examined the effect of caffeine on serum and urinary calcium levels, bone
mineral content and mechanical strength, on the parathyroid glands, and on dental parameters.
Rats were tested in all but two studies, which used hamsters. Most exposures were short-term,
used females, and tested pure caffeine; one chronic study was available which administered cof-
fee. Adverse effects similar to those seen in humans were seen in most studies.
In the only single-dose study, female hamsters had decreased serum calcium and parathy-
roid gland changes indicative of increased hormone secretion two hours after gavage with 25 or
100 mg/kg caffeine (Jamali et al., 2000a). More extensive parathyroid gland changes were seen
after giving the same doses for 17 or 32 days, and hamsters given 100 mg/kg/day had decreased
bone mineral content and lower mean body weight (Jamali et al., 2000b).
Caffeine intake during lactation and in the diet for PND 0-52 (40 mg/kg/diet) resulted in
decreased bone mechanical strength and mineral content (Ohta et al., 2002). Exposure of male
or female rats for 6-10 weeks to 100 mg/kg/day caused decreased bone mineral content, in-
creased secretion of serum parathyroid hormone, and increased urinary calcium secretion (Chen
and Whitford, 1999; Bezerra et al., 2008; Duarte et al, 2009; Huang et al., 2002). Dosing for 90
days with 20 mg/kg/day via the diet decreased the strength of the femur and its mineral content
in old, ovariectomized rats (Ohta et al., 1999). Of particular interest is a study in which female
rats treated for 8 months with ~0.75 or 1.5 mg/kg/day caffeine in the drinking water had bone
density loss in the femur that was detected by dual-energy X-ray absorptiometry (Lu et al.,
2008). The doses tested in this study were comparable to human caffeine intake, and suggest a
cause of concern from long-term caffeine intake.
Pups exposed to caffeine during gestation and/or lactation from dams given 20 mg/kg day
via the diet had decreased tooth germ calcium content at PND 15, higher dental enamel caries
scores at PND 50, and demineralized tooth enamel at PND 22 (Schneider et al., 1995). Male rats
given 100 mg/kg/day caffeine in the drinking water for 56 days had enhanced ligature-induced
periodontitis (Bezerra et al., 2008). These studies indicated that caffeine has an adverse effect on
tooth development and integrity.
Studies that evaluated the effect of caffeine intake on bone and dental-related parameters
in animals are summarized in Table 10-3. These studies in general support the findings in the
human studies of a potential for caffeine to adversely affect bone and tooth mineralization.
242
TABLE 10-3. Effects of Caffeine on Bones and Teeth – Animal Studies (Post-Natal Exposure)
Species; Exposure Test mate- Caffeine
Effects; Comments (sorted by exposure time) Reference
condition time rial; route dose(s)
Hamster 1 day pure caffeine 25, 100 mg/kg Two hours after dosing, had decreased serum calcium and parathyroid gland structural changes; no signifi- Jamali et
(gavage) cant effect on bone mineral content or density. al., 2000a
Mammalian 1 day pure caffeine 0.2, 0.5, 1.0, Decreased vitamin D receptor protein expression and vitamin D-stimulated alkaline phosphatase activity. Rapuri et
cell culture (in vitro) 10 mM al., 2007
Rat bone 1 day pure caffeine 0.1-1 mM Cell viability decreased (concentration-dependent) primarily due to necrosis and, to a small extent, apop- Zhou et al.,
marrow (in vitro) tosis. Genes including Cbfa1/Runx2, collagen I, alkaline phosphatase and its protein were down-regulated; 2010
stromal cell inhibited calcium deposition (concentration- and time-dependent manner), but increased intracellular cAMP
culture (concentration-dependent).
Mammalian 7d pure caffeine 10 mM The viability of the osteoblasts (MTT assay), the formation of alkaline phosphatase (ALP) positive staining Tsuang et
osteoblastic (in vitro) colonies, and mineralization nodules formation decreased significantly in the presence of 10 mM caffeine. al., 2006
cell culture The intracellular LDH, ALP and prostaglandin E2 (PGE2) content decreased significantly, the LDH and
PGE2 secreted into the medium increased significantly. The activation of an irreversible commitment to cell
death by caffeine was clearly demonstrated by DNA ladder staining.
Rat 20 d (PND cola (DW) ~50 mg/kg Decrease in the osteogenic process within the tooth sockets, which had thinner and sparser new bone trabe- Teofilo et
23-42) culae; alveolar bone healing was significantly delayed in cola-fed rats at 3 wk after tooth extraction [fluid al., 2010
intake was similar in the control and cola beverage consuming groups]
Rat 30 d (3 pure caffeine 100 mg/kg/d Caffeine seemed to stimulate the growth of long bone. However, it caused more serious negative effects on Huang et
d/wk for 10 (DW); exer- bone, including bone mineral loss, lower bone mineral density, and lower calcium content. Exercise training al., 2002
wk) cise at 70% VO(2)max had little antagonizing effect on caffeine-induced impairment of bone formation. Exer-
cise and caffeine significantly lowered the BW gain.
Rat 42 d pure caffeine 3, 25, 100 Increased urinary Ca excretion not sufficient to significantly alter calcium balance; ash content of femur Chen and
(gavage) mg/kg/d epiphysis and bone mineral content of the tibia were reduced at 100 mg/kg/d, unrelated to Ca or P balance. Whitford,
1999
Hamster 17 or 32 d pure caffeine 25, 100 Both groups had parathyroid gland structural changes indicative of hormone secretion; high dose had lower Jamali et
(gavage) mg/kg/d mean BW, decreased bone mineral content; no microscopic changes in tibia or effect on serum calcium al., 2000b
level.
Rat, ovari- PND 0-52 pure caffeine 40 mg/kg diet Decreased femoral mechanical strength and elasticity; decreased Ca, Mg, and phosphorous content. Ohta et al.,
ectomized at (lactation + (~2 mg/kg/d 2002
PND 32 diet) caffeine)
Rat 56 d pure caffeine 100 mg/kg/d Caffeine intake did not have a direct effect on the alveolar bone loss in unligated teeth. But on the ligated Bezerra et
(DW) tooth, a greater area of bone loss was observed in the animals that ingested caffeine (P <0.05). Thus daily al., 2008
intake of high doses of caffeine may enhance ligature-induced periodontitis progression.
243
TABLE 10-3. Effects of Caffeine on Bones and Teeth – Animal Studies (Post-Natal Exposure)
Species; Exposure Test mate- Caffeine
Effects; Comments (sorted by exposure time) Reference
condition time rial; route dose(s)
Rat 56 d [8 d pure caffeine 100 mg/kg/d Caffeine intake caused a lower area of new bone formation 8 days after injury, but had no effect on bone Duarte et
after tibial (DW) density. [Forty-eight days after the beginning of caffeine intake, a critical-size surgical defect was created in al., 2009
surgery] the right tibia of both groups, while the contralateral tibia was left without defect. Eight days later, the ani-
mals were sacrificed.]
Rat, ovari- 60 d cola (DW) 141-144 ± 5 Rats consuming cola had a 3-fold higher liquid intake than rats consuming water and half the intake of solid Garcia-
ectomized mL cola/d food. They developed hypocalcemia and had lower femoral mineral density; a pair-fed group had lower BW Contreras et
(~55 mg/kg) but did not develop bone mineral reduction or hypocalcemia. [cola was not described; estimate 10 mg caf- al., 2000
feine/100 mL cola; BW 250 mg]
Rat, ovari- 90 d pure caffeine 20 mg/kg/d Femur strength and Zinc, Sr, and crystallite size decreased, but increased Si content. Ohta et al.,
ectomized, (diet) 1999
old
Rat 140 d coffee (diet) 0.62%, 1.36% Urinary phosphorus excretion was increased with no effects on bone metabolism or histomorphometry. Sakamoto
coffee diet et al., 2001
Rat; Mam- 8 mo pure caffeine 10, 20 μM Bone mineral density loss in femur of rats (both concentrations). [caffeine dose calculated assuming 78 Lu et al.,
malian cell (DW) (~0.75, 1.5 mL/d liquid intake, molecular weight of caffeine of 194.19, and BW of 0.2 kg] 2008
culture mg/kg/d)
ALP=alkaline phosphatase; BW=body weight; DW=drinking water; LDH=lactate dehydrogenase
244
CHAPTER 11. EFFECT OF CAFFEINE ON THE KIDNEY, URINARY
BLADDER, AND ELECTROLYTE BALANCE
11A. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance in Humans
A number of experimental studies reported increased urination (diuresis) after caffeine

intakes of 3.4-6 mg/kg/day, which was in some cases associated with increased natriuresis or the
excretion of sulfate (Benicosa et al., 1995; Lohsiriwat et al., 2011; Rachima-Maoz et al., 1998;
Reisenhuber et al., 2006; Shirley et al., 2002; Bird et al., 2005). Although 6 mg/kg caffeine in-
creased urine flow and sweat electrolyte excretion in response to exercise, there was no overall
effect on hydration status (Del Coso et al., 2009). The diuretic response to 6 mg/kg caffeine was
diminished by the third day of treatment (Bird et al., 2005).
Case reports of adults who consumed excessive amounts of caffeine in beverages (900-
3000 mg/d or ~12-43 mg/kg caffeine) noted effects including renal dysfunction and failure, hy-
ponatremia, hypokalemia, markedly increased serum creatine phosphokinase (indicative of rhab-
domyolysis), muscle weakness, and paralysis (Kamijo et al., 1999; Rigato et al., 2010; Young et
al., 2001). The effect of caffeine on urinary incontinence in women was evaluated in a case-
control study which found that women with detrusor instability had greater mean caffeine intake
than controls (484 ± 123 mg/day vs. 194 ± 84 mg/day, P =0.002) (Arya et al., 2000). Caffeine
intake by pregnant women (amount not reported) was associated with increased frequency of
urination of smaller voided volumes (Thorp et al., 1999). Cross-sectional studies found that cof-
fee intake (amount not specified) increased the voided volume but did not change the peak flow
rate of men (Cohen et al., 2002), and that drinking ≥1 cup coffe/day increased estimated glome-
rular filtration rates compared to non-coffee drinkers (Kotani et al., 2010; Nakajima et al., 2010).
Consumption of ≥2 cups coffe/day was a risk factor for urinary incontinence in healthy pregnant
Brazilian women (Martins et al., 2010), and decreasing caffeine intake reduced incontinence epi-
sodes in 55-87 year old women (Tomlinson et al., 1999). Plasma renin activity had an inverse
relationship to coffee consumption in mild hypertensive men (Palatini et al., 1996). Kincade et
al. (2007) found that urine loss increased weakly with the amount of fluids consumed, irrespec-
tive of caffeine intake. A cross-sectional study with 5-12 year old children found that intake of 2-
3.6 mg/kg caffeine was not significantly correlated with enuresis (Warzak et al., 2010).
NOAEL values; it is unclear that the addressed endpoints are adverse for overall human health.
Cancer studies for the kidneys and urinary bladder are discussed in Chapter 15. Studies
of which the primary focus was the effect of caffeine on the kidneys, urinary tract, and electro-
lyte balance are summarized in Table 11-1. Brief summaries of conclusions of reviews on this
topic are presented in Table 11-2. Several authors noted that caffeine can increase bladder activ-
ity, and that caffeine reduction may be beneficial in managing overactive bladder syndrome (Al-
bertsen, 1997; Hashim and Mousa, 2009; Bolignano et al., 2007). Greer et al. (2009) noted that
caffeine does not exhibit a diuretic effect during exercise performance. Osswald and Schner-
mann (2011) described the mechanism of caffeine diuresis as mainly resulting from inhibition of
tubular fluid reabsorption along the renal proximal tubule, which is mediated mainly by antago-
nism of adenosine A1 receptors (A1AR) in the proximal tubule.
245
TABLE 11-1. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Human Studies
Cross-sectional 5-7 yr caffeinated N1=52 mg/d [2.1 Caffeine consumption and hours slept were significantly negatively correlated, but caf- Warzak et al.,
(USA) (n1=104) drinks mg/kg/d] feine consumption and enuresis were not significantly correlated. [Assumed BW 25 kg 2010
8-12 yr N2=109 mg/d for 5-7 year olds, and 30-40 kg for 8-12 year olds for dose estimates]
(n2=97) M+F [2.7-3.6 mg/kg/d]
STUDIES WITH ADULTS
1-d experiment 39-78 yr pure caffeine; 6 mg/kg lean Caffeine ingestion increased the urinary excretion of sulfate, an effect that may be re- Benincosa et
(USA) n=39 F decaf; estrogen body mass lated to the diuretic effect of caffeine or due to a caffeine-induced alteration in the renal al., 1995
replacement reabsorption of sulfate.
hormones
1-d experiment Adult pure caffeine; 6 mg/kg Caffeine ingested alone or in combination with water or a sports drink was not ther- Del Coso et
(Spain) n=7 M exercise; heat mogenic or impaired heat dissipation. However, caffeine + carbohydrate-electrolytes al., 2009
solution (CES) tended to have a higher final rectal temperature than CES alone. Caffeine
increased urine flow and sweat electrolyte excretion, but these effects are not enough to
affect dehydration or blood electrolyte levels when exercising for 120 min in a hot envi-
ronment.
1-d experiment 21-40 yr pure caffeine 4.5 mg/kg Caffeine caused diuresis and decreased the threshold of sensation at filling phase, with Lohsiriwat et
(Thailand) n=12 (3 M) [overactive an increase in flow rate and voided volume. Thus, caffeine promoted early urgency and al., 2011
bladder] frequency of urination.
1-d experiment 21-72 yr pure caffeine 250 mg Older hypertensive subjects (58 ± 10.4 yr) had increased systolic and diastolic BP; non- Rachima-
(Israel) n=23 (17 M) [hypertension] [3.6 mg/kg] responders were younger (44.5 ± 15.8 years); for 60 min after intake both groups had Maoz et al.,
decreased HR, diuresis, and natriuresis; no effect on renin and endothelin levels. 1998
1-d experiment 18-28 yr ED ± caffeine, 240 mg Diuretic and natriuretic effects of the tested ED were largely mediated by caffeine; Riesenhuber
(Austria) n=12 M taurine [3.4 mg/kg] taurine played no significant role. [ED not identified; it contained 240 mg caffeine and et al., 2006
3 g taurine; the three other test drinks either lacked caffeine, taurine or both]
1-d experiment 21-52 yr pure caffeine; 400 mg In caffeine-treated subjects, the fractional excretion of sodium rose from 1.00±0.25% in Shirley et al.,
(UK) n=8 M lithium [5.7 mg/kg] the control period to 1.47±0.18% in the experimental period, while corresponding values 2002
on the placebo day were 1.04±0.16% and 0.70±0.07% respectively. The glomerular fil-
tration rate was unchanged after caffeine or placebo. When compared with the placebo
day, caffeine caused increases in lithium clearance, the fractional excretion of lithium
and the sodium/lithium clearance ratio.
246
3-d experiment 18-50 yr pure caffeine 6 mg/kg/d Diuresis was seen first 2 days only of the 3-day treatment. Bird et al.,
(USA) n=80 (12 M) 2005
6 or 12 d ex- 21.6 ± 0.4 yr pure caffeine; 3 mg/kg, then 0, There were no between-group differences in plasma, urinary, thermoregulatory, cardio- Roti et al.,
periment n=59 M exercise; heat 3, or 6 mg/kg vascular, and perceptual variables across time pre- vs. post-exercise in an exercise heat 2006
(USA) tolerance test, although some of these variables increased significantly over time (p <
0.05). The test time was significantly greater at 3 mg/kg vs. 0 mg/kg caffeine.
Case report 36 yr tea, oolong ≤ 3 g/d [43 Effects after exposure for ~8 days included delirium, acute renal failure, markedly ele- Kamijo et al.,
(Japan) n=1 M [schizophrenia] mg/kg/d] vated CPK (rhabdomyolysis); renal dysfunction, and hyponatremia. 1999
Case report 18 yr coffee; cola; ED 18 cups/d caf- Effects after 6 days of exposure included collapse, intense fatigue, weakness, nausea, Rigato et al.,
(Italy) n=2 M feinated drink vomiting, headache, diffused paresthesia, changes in electrocardiogram, severe hypo- 2010
[≤26 mg/kg/d] kalemia. [No info on caffeine per drink; assumed ≤100 mg/drink]
Case report Adult caffeinated 8-9 servings/d Effects included severely increased CPK (rhabdomyolysis), dehydration, diuresis, and Young et al.,
(USA) n=1 F drink, carbona- [~12 mg/kg/d] hypokalemia. [2 days of symptoms; intake duration unspecified; no info on caffeine per 2001
ted; tea [preg- serving; assumed 100 mg caffeine/serving]
nant]
Case-control cases=55.6 yr caffeinated <100 mg/d, 100- Mean caffeine intake of women with detrusor instability (484 ± 123 mg/day) was sig- Arya et al.,
(USA) (n=131 F); drinks [urinary 400 mg/d, >400 nificantly higher than that of controls (194 ± 84 mg/day, P =.002); multivariate analysis 2000
controls=45.3 incontinence] mg/d [<1.7 to showed an association between high caffeine intake and detrusor instability after con-
yr >6.7 mg/kg/d] trolling for age and smoking (OR= 2.4,CI= 1.1, 6.5; P =.018).
(n=128 F)
Cohort prospec- Adult caffeine, all + or - In pregnant women, caffeine intake did not affect the total volume voided per day, but it Thorp et al.,
tive (follow-up n=123 F sources [preg- was associated both with a significant increase in the mean number of micturition epi- 1999
through pregnant] sodes each day and with a significant decrease in the mean volume voided at each epi-
nancy and 8 wk sode. [No info on caffeine intake per day]
after) (USA)
Cross-sectional 36-59 yr Coffee; stress + or - Coffee intake significantly increased the voided volume but did not change the peak Cohen et al.,
(Canada) n=31 M flow rate. Uroflowmetry parameters and voided volume were highly variable in a nor- 2002
mal asymptomatic population. Subjective stress level did not seem to have an influence
on these parameters. [No info on caffeine amounts]
247
Cross-sectional 55.0 ± 13.6 yr caffeine, all most had ≥1 Urine loss increased weakly with the amount of all fluids consumed and the intake of Kincade et al.,
(USA) n=525 F sources drink/d caffeinated fluids, but not with the amount of caffeine itself. Nearly three-quarters of the 2007
[≥1.4 mg/kg/d] sample (71.5%) drank 12 ounces or more of caffeinated beverages in 24 hours. [No info
on caffeine per beverage; assumed subjects drank coffee containing 100 mg /cup.]
Cross-sectional Adult coffee + or - Coffee drinkers had higher estimated glomerular filtration rate than non-coffee drinkers, Kotani et al.,
(Japan) n1=114 (46 independently of clinical variables (body mass index, BP, blood glucose, lipids and 2010
M); n2=114 high-sensitivity C-reactive protein); the rates among coffee drinkers were similar with
(46 M) and without use of sugar.
Cross-sectional Adult coffee ≤1, ≥2 cups/d Drinking ≥2 cups/d coffee was a risk factor for urinary incontinence in healthy pregnant Martins et al.,
(Brazil) n=500 F [≤1.4 to ≥2.9 Brazilian women. [No info on caffeine per cup; assumed 100 mg/cup] 2010
mg/kg/d]
Cross-sectional 30-80 yr coffee <1, ≥1 cup/d Habitual coffee consumption (≥ 1 cup/d) was associated with normal or increased esti- Nakajima et
(Japan) 182 consumers, [<1.4, ≥1.4 mated glomerular filtration rate, but not proteinuria, even after adjustment for age, sex, al., 2010
160 abstainers mg/kg/d] smoking, tea consumption and other cardiovascular risks. [No info on caffeine per cup;
M+F assumed 100 mg/cup]
Cross-sectional 18-45 yr Coffee [hyper- 0, 1-3, >3 cups/d BP, HR, and urinary catecholamines did not differ according to coffee intake; chronic Palatini et al.,
(Italy) n=351 M tension] [1.4 to >4.3 coffee intake and physical training showed an inverse relationship with plasma renin 1996
mg/kg/d] activity in mild hypertensive men. [Italian coffee averages 100 mg caffeine per cup]
Cross-sectional 55-87 yr caffeinated mean 829 mL/d Decreasing caffeine intake reduced incontinence episodes. [No info on caffeine per mL; Tomlinson et
(USA) n=41 F drinks [8.6 mg/kg/d] assumed 100 mg caffeine/137 mL coffee (1 cup)] al., 1999
BP=blood pressure; CPK=creatine phosphokinase; ED=energy drink; HR=heart rate
248
TABLE 11-2. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Summaries of Reviews Reference
Bladder hyperactivity can be induced by stress and caffeine. Albertsen,

1997
There are no epidemiological data that implicate caffeine in analgesic-associated nephropathy, or evidence that caffeine increases analgesics papillotoxicity Bach et al.,
directly. The presence of caffeine in mixtures of analgesics are no more addictive than other sources of caffeine. 1998
As yet, there is no evidence contraindicating the consumption of the equivalent of 3-4 cups of coffee per day in healthy or nephropathic subjects. However, Bolignano et
particular attention should be paid to the elderly, children, and patients on concomitant treatment with analgesics or diuretics, whereas in subjects with a al., 2007
family or clinical history of calcium lithiasis, a moderate caffeine consumption should be associated with an adequate fluid intake.
Caffeine does not exhibit a diuretic effect during exercise performance. Greer, 2010
Caffeine reduction may be beneficial in the management of patients with overactive bladder syndrome. Hashim and
Mousa, 2009
The mildly diuretic actions of caffeine and theophylline are mainly the result of inhibition of tubular fluid reabsorption along the renal proximal tubule. Osswald and
This is mediated mainly by antagonism of adenosine A1 receptors (A1AR) in the proximal tubule. Methylxanthines are weak renal vasodilators and act as Schnermann,
competitive antagonists against adenosine-induced preglomerular vasoconstriction. Caffeine and theophylline stimulate the secretion of renin by inhibition 2011
of adenosine receptors and removal of the general inhibitory brake function of endogenous adenosine.
249
11B. Effect of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance in Animals
A one-day rat study showed that 5 mg/kg caffeine administered intraportally increased
urine flow, but the effect was abolished upon liver denervation (Ming and Lautt, 2010). Renin
secretion was increased in rats treated for 10 days (1% solution in the drinking water) but not
from a single i.v. dose (Tofovic et al., 1999). Treatment of rats having diabetes, hypertension,
and/or kidney nephrosis for 8-30 weeks via the drinking water (0.1% caffeine solution) caused
renal toxicity, manifested as increased proteinuria, reduced creatinine and inulin clearance, in-
creased renal vascular resistance, and glomerular pathological changes (Tofovic et al., 2000;
2001; 2002; 2007; Tofovic and Jackson, 1999). These studies assert that prolonged administra-
tion of 0.1% caffeine in the drinking water results in plasma levels of caffeine (5-10 µg/mL) that
are seen in humans after an intake of 2-3 cups coffee. Tanner and Tanner (2001) found no effect
on kidney glomerular filtration rate in rats with polycystic kidney disease that were exposed for 5
months to 0.1 to 0.32 mg/mL caffeine in their drinking water. Based on other studies in which
rats were administered 0.1% caffeine in the drinking water, this corresponds to a dose to the
animals of ~100 mg/kg (Sudakov et al., 2001; 2003b). This is much higher than normal human
intake, rendering questionable the utility of these studies in predicting effects in humans.
Animal studies that evaluated the effect of caffeine intake on the kidney and urinary
bladder are summarized in Table 11-3.
250
TABLE 11-3. Effects of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Animal Studies
Species; con- Exposure Test mate- Caffeine
dition time rial (route) dose(s)
Rat 1 day pure caffeine 5 mg/kg Intraportal caffeine increased urine flow (~82%) in healthy rats; effect was abolished by liver denervation. Ming and
(intraportal); Intraportal infusion of adenosine decreased urine production; effect was abolished by intraportal caffeine. Lautt, 2010
adenosine Intraportal caffeine improved basal urine production and renal ability to increase urine production in re-
(i.v.) sponse to saline overload. Effects not seen with intravenous dosing.
Rat; heart 1 day; 10 pure caffeine 10 mg/kg +150 Caffeine infusion increased HR, systolic pressure, and workload in hypertensive but not normotensive rats Tofovic et
failure, hyper- d (DW; i.v.) µg/min over 40 without affecting cardiac contractility; caffeine increased plasma renin activity, norepinephrine, and epi- al., 1999
tension min; 0.1% in nephrine levels, the most in hypertensive rats; 10-day DW treatment only changed (increased) renal renin
DW [~100 secretion. [Prolonged administration of 0.1% caffeine in the DW results in plasma levels of caffeine (5-10
mg/kg] µg/mL) that are seen in humans after an intake of 2-3 cups coffee]
Rat; diabetes; 8 wk pure caffeine 0.1% in DW Reduced food and fluid consumption; proteinuria; decreased creatine clearance; no effect on plasma renin Tofovic et
hypertension; (DW) [~100 mg/kg] activity, BP, renal blood flow or renal vascular resistance; BW or weight gain decrease; plasma al., 2001
overweight (nor)epinephrine increased; glucose tolerance/absorption enhanced; plasma lipids increase [Prolonged
administration of 0.1% caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that are seen
in humans after an intake of 2-3 cups coffee]
Rat; diabetes, 9 wk pure caffeine 0.1% in DW Caffeine reduced BW and glycosuria, improved glucose tolerance, increased plasma cholesterol, proteinu- Tofovic et
kidney dis- (DW); tem- [~100 mg/kg] ria, renal vascular resistance and HR, augmented the influx of glomerular and interstitial macrophages al., 2007
ease, over- pol (ED1+ cells), glomerular and tubular proliferative response, and glomerular collagen IV content. Caffeine
weight had no effect on elevated plasma triglycerides, plasma cholesterol, and BP. Tempol (1 mmol/L) attenu-
ated caffeine-induced increase in HR and RVR, and renal inflammation, proliferation, and fibrosis. [Pro-
longed administration of 0.1% caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that
are seen in humans after an intake of 2-3 cups coffee]
Rat; high- 20 wk pure caffeine 0.1% in DW Time-related decline in renal function and augmented urinary protein excretion; decreased creatinine Tofovic and
renin hyper- (DW) [~100 mg/kg] clearance; lower glomerular filtration rate. [Prolonged administration of 0.1% caffeine in the DW results Jackson,
tension in plasma levels of caffeine (5-10 µg/mL) that are seen in humans after an intake of 2-3 cups coffee] 1999
Rat; polycys- 5 mo pure caffeine 0.1, 0.2, 0.32 No effect on kidney GFR or cyst development in rats with PKD; BP was greater in rats with PKD than Tanner and
tic kidney (DW) mg/mL normal rats and was increased more by caffeine. Tanner,
disease 2001
Rat; PAN- 23 wk pure caffeine 0.1% solution Caffeine adversely affected renal function in puromycin-aminonucleoside (PAN)-nephrotic rats, that may Tofovic et
induced neph- (DW) [~100 mg/kg] be due in part to increased activity of the renin angiotensin system. [Prolonged administration of 0.1% al., 2000
ropathy caffeine in the DW results in plasma levels of caffeine (5-10 µg/mL) that are seen in humans after an in-
take of 2-3 cups coffee]
251
TABLE 11-3. Effects of Caffeine on the Kidney, Urinary Bladder, and Electrolyte Balance – Animal Studies
Species; con- Exposure Test mate- Caffeine
dition time rial (route) dose(s)
Rat; diabetes, 30 wk pure caffeine 0.1% in DW Caffeine reduced BW, glycosuria, fasting glucose and insulin levels, improved glucose tolerance, slightly Tofovic et
type I (DW) [~100 mg/kg] increased mean arterial BP and HR, increased proteinuria, reduced creatinine clearance, increased plasma al., 2002
cholesterol, renal vascular resistance and decreased inulin clearance, and potentiated severe tubulointersti-
tial changes and focal glomerulosclerosis. Thus, despite improving insulin sensitivity, caffeine exacer-
bated renal failure in obese, diabetic rats. [Prolonged administration of 0.1% caffeine in the DW results in
plasma levels of caffeine (5-10 µg/mL) that are seen in humans after an intake of 2-3 cups coffee]
BP=blood pressure; DW=drinking water; BW=body weight; GFR=glomerular filtration rate; HR=heart rate; PKD=polycystic kidney disease; RVR= renal vascular resistance
252
CHAPTER 12. IMMUNOLOGICAL, GI, OCULAR, AND MAMMARY
(NON-CANCER) EFFECTS OF CAFFEINE
12A. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects in Humans
The adverse effects of caffeine on immunological, ocular, GI and breast parameters (ex-
cluding cancer) were addressed in a relatively small number of studies. Studies that evaluated
cancer-related effects on these organ systems are presented in Chapter 15. Two studies deter-
mined that 180-300 mg (2.6-4.3 mg/kg) caffeine inhibited platelet aggregation by ADP, collagen
and/or arachidonic acid (Lev et al., 2007; Natella et al., 2008), whereas a third study found no
effect of 11 mg/kg/day caffeine (given in 3 doses/day) for 7 days on platelet aggregation by
ADP, collagen, or adrenaline (Cavalcante et al., 2000). An increase in lymphocyte count, MCV,
thrombocytosis, and plasma alanine transaminase activity was observed from ingestion of 5
mg/kg pure caffeine prior to exercise, possibly due to muscle injury (Bassini-Cameron et al.,
2007). A cross-sectional study of 18-44 year old women found no association of mastalgia with
consumption of caffeinated beverages (Ader et al., 2001).
Increased intra-ocular pressure was observed for several minutes after a single intake of
coffee in a healthy Nigerian population of (30-50 mg; 0.4-0.7 mg/kg) (Ajayi and Ukwade, 2001).
Subjects with glaucoma or ocular hypertension had increased intraocular pressure (IOP) from an
intake of 180 mg caffeine as coffee (2.6 mg/kg/d) for 7-10 days (Avisar et al., 2002). An intake
of 100 and 200 mg pure caffeine (1.4, 2.9 mg/kg) caused a dose-related increase in visual distur-
bance, i.e., instability when viewing grid patterns (Coren, 2002). A case report of “months” of
daily intake of 600 mg caffeine (8.6 mg/kg/day) as a weight-loss supplement by a 42-year old
male noted hypertensive retinopathy and increased BP (Willis et al., 2006). An Australian cross-
sectional study found that subjects with open-angle glaucoma who regularly drank coffee (≥200
mg caffeine/d or 2.9 mg/kg/day) had significantly higher mean IOP than non-drinkers, but there
was no association between coffee or caffeine consumption and IOP in subjects with ocular hy-
pertension or without open-angle glaucoma (Chandrasekaran et al., 2005). In a cohort study with
a 2-year follow-up, an increased risk for primary open-angle glaucoma was associated with con-
sumption of ≥5 cups/d coffee (7.1 mg caffeine/kg/d), especially in those with a family history of
glaucoma in a cohort study (Kang et al., 2008). Caffeine intake was unrelated to cataract forma-
tion in diabetic and non-diabetic subjects who ingested up to 45 mg/kg/day caffeine (Klein et al.,
1999).
An intake of 2 or 3.5 g caffeine in a dietary supplement (~30, 50 mg/kg/day) caused ad-

verse GI affects (irritation or pain, nausea, vomiting) as well as sinus tachycardia in two adoles-
cents (Kromhout et al., 2008). A cross-sectional study of 10-16 year old children associated high
(undefined) caffeine intake with increased somatic complaints including stomachache, headache,
backache, and morning fatigue (Ghandour et al., 2004). Experimental studies with adults
showed that ingestion of an ED (1.7 mg caffeine/kg) lowered midespohageal pressure with no
effect on gastric pH or reflux during or after exercise (Van Nieuwenhoven et al., 2000). An in-
take of 3.5 mg/kg diminished lower esophageal pressure and peristaltic contractions but
strengthened anal sphincter contractions and led to an earlier desire to defecate (Lohsiriwat et al.,
2006; 2008). Ingestion of caffeinated coffee (3.0 mg caffeine/kg), but not decaf (0.2 mg caf-
253
feine/kg) aggravated existing gastroesophageal reflux (Pehl et al., 1997). No GI complaints were
noted from four intakes of a caffeinated drink containing 90 mg caffeine during an 18-km run
(van Nieuwenhoven et al., 2005). Consuming an herbal preparation containing caffeine (0.3 mg
caffeine/kg/day) for 10 days to 12 months delayed gastric emptying and reduced the time to per-
ceived fullness, and led to significant body weight loss (Anderson and Fogh, 2001).
A case report of intake for four days of 400 mg/day caffeine as an ED (5.7 mg/kg/day)
noted nausea, vomiting, headache, hypertension, and a ruptured aneurysm (Argano et al., 2011).
In epidemiological studies, caffeine intake was not associated with an increased risk of duodenal
ulcer in men or women, or of symptomatic diverticular disease in men, but patients with nonul-
cer dyspepsia were more likely to experience dyspeptic symptoms after ingesting coffee (Aldoori
et al., 1995; 1997). Coffee intake (0.7-3.7 mg caffeine/kg/day) was positively associated with
vomiting in pregnant women but not with nausea or appetite loss (Lawson, 2002). A multi-
country cross-sectional study concluded that upper GI symptoms were not associated with caf-
feine consumption (Stanghellini, 1999). Minor GI symptoms were commonly seen among 43
hospital admissions due to deliberate excessive caffeine ingestion (Waring et al., 2009).
The available data on the immunological, ocular, mammary, and GI effects of caffeine
were insufficient to allow a reliable estimate of LOAEL or NOAEL values for these endpoints.
Human studies that evaluated the effect of caffeine on immunological, GI, ocular, and
non-cancer breast parameters are summarized in Table 12-1. Brief summaries of conclusions of
reviews on this topic are provided in Table 12-2. O'Connor and Irwin (2010) concluded that epi-
demiologic studies show a relationship between high consumption of non-filtered coffee and in-
creases in C-reactive protein, TNF-a, IL-6 and homocysteine, whereas filtered coffee drinking
appeared to have minimal impact on markers of inflammation. Norlock (2002) noted that some
investigations have found associations between breast pain and premenstrual syndrome, fibro-
cystic breast disease, and caffeine intake. Intraocular pressure measured at 0.5, 1, and 1.5 hours
post-ingestion in 6 randomized controlled trials was not affected by caffeine in normal subjects
but increased significantly for patients with glaucoma or ocular hypertension (Li et al., 2010).
Drinking coffee was not associated with peptic ulcer disease or functional dyspepsia, but there
was evidence that coffee may promote gastro-esophageal reflux, stimulate gallbladder contrac-
tion and colonic activity (Boekema et al., 1999), and is a risk factor for uninvestigated dyspepsia
(Mahadeva and Goh, 2006).
254
TABLE 12-1. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Human Studies
Subject age; Test material Caffeine
Study type Effects; Comments Reference
number; sex [condition] dose(s)
IMMUNOLOGICAL EFFECTS
1-d experiment 19-40 yr pure caffeine; 5 mg/kg Lymphocyte count increase, MCV increase, thrombocytosis increase; plasma alanine transaminase Bassini-
(Brazil) n=22 M exercise increase; increase in white cell count possibly caused by greater muscle cell injury. Cameron et
al., 2007
1-d experiment CVD=64.6 ± pure caffeine; 300 mg In healthy subjects, caffeine decreased ADP-induced platelet aggregation at 4 hr, lowered activa- Lev et al.,
(USA) 9 yr, n=40 aspirin; clopi- [4.3 mg/kg] tion markers at 2 hr, and lowered vasodilator-stimulated phosphoprotein at 4 hr after clopidogrel, 2007
Controls= dogrel [CVD] but had no effect on the platelet surface biomarkers. In patients with CAD receiving aspirin and
33.5 ± 6 yr, clopidogrel, caffeine was associated with lower platelet activation markers (P-selectin, PAC-1
n=12 M+F binding), without significant effect on aggregation.
1-d experiment 24-35 yr pure caffeine; 180 mg Coffee drinking, but not pure caffeine intake, inhibited collagen and arachidonic acid induced Natella et
(Italy) n=10 (5 M) coffee [2.6 mg/kg] platelet aggregation, and induced a significant increase of platelet phenolic acids and caffeic acid; al., 2008
caffeine was not detectable in platelets.
7-d experiment 21-27 yr pure caffeine 750 mg/d (in 3 Diastolic pressure increased 24 hours after the first intake, but not on subsequent days; platelet Cavalcante
(Brazil) n=13 M+F doses) aggregation tests did not reveal significant alterations at any time during the study. et al., 2000
[11 mg/kg/d]
MAMMARY EFFECTS
Cross-sectional 18-44 yr caffeinated ≤1, >1 caffein- Caffeine consumption (>1 caffeinated beverage per day) was associated with mastalgia (p < 0.05; Ader et al.,
(USA) n=874 F drinks ated beverage/d OR= 1.53 (1.04-2.24)). 2001
OCULAR EFFECTS
1-d experiment 20-27 yr coffee; decaf Coffee 30-50 Caffeine increased intraocular pressure which was variable across patients, and was sustained for Ajayi and
(Nigeria) n=20; c=20 mg [0.4-0.7 several minutes. The mean increase across patients rose monotonically with the post-ingestion Ukwade,
M+F mg/kg]; Decaf 2 time and by almost 4 mm Hg. There was a corresponding increase in systolic and diastolic BP. 2001
mg [0.03 mg/kg] There was relatively no change in intraocular pressure or BP with time in the decaf group. The
difference between groups was statistically significant (P < 0.05).
1-d experiment 18-20 yr pure caffeine 100, 200 mg With increasing caffeine dosage the level of reported visual disturbances increased. The increased Coren, 2002
(Canada) n=20 (10 M) [1.4, 2.9 mg/kg] cortical arousal associated with caffeine intake may interact with the structural properties of the
visual cortex to increase the perceptual instability associated with viewing grid patterns.
255
7-10 d experi- Adult M+F coffee; decaf Coffee 180 mg The difference in the change in intra-ocular pressure from baseline after ingestion of regular vs. Avisar et
ment n1=6 nor- [glaucoma or [2.6 mg/kg/d]; decaf coffee was significant in each group at 60 and 90 minutes. Subjects who drank regular coffee al., 2002
(Israel) motensive; ocular hyper- Decaf 3.6 mg demonstrated a greater elevation in pressure; this elevation may be clinically significant.
n2=22 hy- tension] [0.05 mg/kg]
pertensive
Case report 42 yr caffeine, in 600 mg/d [8.6 Supplement intake for “months” resulted in hypertensive retinopathy and increased BP. [Supple- Willis et al.,
(USA) n=1 M supplement mg/kg] ment= Hydroxycut, a caffeine-based ephedra-free weight loss supplement] 2006
Cross-sectional ≥49 yr caffeinated ≥100, 200, 300 Participants with open-angle glaucoma (OAG) who reported regular coffee drinking had signifi- Chandrasek
(Australia) n=3654 M+F drinks [glau- mg/d [≥1.4 to cantly higher mean intraocular pressure (IOP) than non-drinkers (19.63 vs. 16.84 mm Hg), after aran et al.,
coma or ocu- 4.3 mg/kg/d] multivariate adjustment, P = 0.03. Those consuming ≥200 mg caffeine/d had higher mean IOP 2005
lar hyperten- than those consuming < 200 mg caffeine/d (19.47 vs. 17.11 mm Hg), after adjusting for age, sex,
sion] and systolic BP, P = 0.06. No association between coffee or caffeine consumption and higher IOP
was found in subjects with ocular hypertension or without open-angle glaucoma.
Cohort prospec- 43-84 yr caffeine, all 0, 1-102, 103- None of the cataract types in non-diabetic and in diabetic subjects were related to caffeine intake Klein et al.,
tive (5-yr fol- n=3684 M+F sources 205, 206-308, (a significant relationship between current caffeine intake and nuclear cataract was found in right 1999
low-up) 309-3162 mg/d eyes but not when considering data from both eyes).
(USA) [1-45 mg/kg/d]
Cohort prospec- mean ~58-60 coffee; cola; <150, 150-299, Intake of ≥5 cups/d coffee had RR of 1.61 (1.00-2.59; P for trend = 0.02) for primary open-angle Kang et al.,
tive (2 yr fol- yr tea [family 300-499, 450- glaucoma; risk was not increased for tea or caffeinated cola; association was stronger among those 2008
low-up) n=42,052 M, history of 559, ≥600 mg/d with a family history of glaucoma, esp. with elevated intraocular pressure.
(USA) 79,120 F glaucoma] [<2.1 to ≥8.6
mg/kg/d]
GI EFFECTS – CHILDREN
Case report 15 yr; 17 yr caffeine, in ~2.1 g; 3.5 g Sinus tachycardia; GI irritation or pain; hypokalemia; nausea or vomiting; plasma glucose in- Kromhout
(The Nether- n=2 M supplement [30, 50 mg/kg] crease. [Supplement='herbal energy capsules' containing 200 mg each] et al., 2008
lands)
Cross-sectional 10-16 yr caffeinated none; "high" Somatic complaints of headache, stomachache, backache, and morning fatigue are common among Ghandour
(USA) n=8,250 F drinks U.S. adolescent girls. Heavy alcohol use, high caffeine intake, and smoking cigarettes every day et al., 2004
were strongly associated with all symptoms. A dose-response was observed between the preva-
lence of symptoms and caffeine consumption. For example, the proportion of frequent headache
sufferers increased 30 percentage points between low- and high-caffeine consumers (data not pro-
vided). [No further info on caffeine intake]
256
GI EFFECTS – ADULTS
1-d experiment Adult ED; exercise ~120 mg [1.7 In the postexercise episode, midesophageal pressure was significantly lower in the ED trial com- Van Nieu-
(The Nether- n=10 M mg/kg] pared with the water trial. There was no effect on gastric pH and reflux during the preexercise, the wenhoven
lands) cycling, and the postexercise episode, respectively, or on gastric emptying, orocecal transit time, et al., 2000
and intestinal permeability. Glucose absorption was significantly increased in the ED trial com-
pared with CHO-electrolyte solution only. [ED=carbohydrate-electrolyte solution with 150 mg/L
caffeine]
1-d experiment 35.5 ± 1.5 yr pure caffeine; 1.0, 3.0 g tea; 52 3.0 g tea drink caused GI symptoms; plasma glucose concentrations <60 min in response to the Bryans et
(UK) n=16 (4 M) CHO; instant mg pure caf- drinks were similar, but were reduced at 120 min with the 1.0 g tea drink relative to the control and al., 2007
black tea feine [0.7 caffeine drinks. Tea consumption resulted in elevated insulin concentrations compared with the
mg/kg] control and caffeine drinks at 90 min and compared with caffeine drink alone at 150 min (P<0.01).
1-d experiment 20-46 yr pure caffeine 250, 500 mg Pleasant subjective effects at 250 mg and unpleasant at 500 mg (anxiety, irritability, nausea, palpi- Kaplan et
(USA) n=12 (5 M) [3.6, 7.1 mg/kg] tations); enhanced performance on digit symbol substitution test and tapping speed test at 250 mg al., 1997
greater than at 500 mg; EEG changes at both doses; metabolism impaired at 500 mg.
1-d experiment 45-78 yr coffee; decaf 300 mL [0.2; 3.0 For regular coffee the fraction time was a median of 17.9% (0.7-56.6%). The fraction time was Pehl et al.,
(Germany) n=17 (11 M) [reflux dis- mg/kg] significantly reduced to 3.1% (0-49.9%) after ingestion of decaffeinated coffee. Therefore, the 1997
ease] amount of gastro-esophageal reflux induced by the intake of regular coffee in patients with reflux
disease can be reduced by the decaffeination of coffee. [Caffeine content of coffee was 0.69
mg/mL (regular) and 0.05 mg/mL (decaf)]
1-d experiment 41 ± 8 yr pure caffeine; 4 x 150 mL (90 Caffeine had no effect on GI complaints or performance (no difference from sports drink effects) van Nieu-
(The Nether- n=98 (90 M) exercise mg) during an 18-km run. [150 mg caffeine per liter] wenhoven
lands) [1.3 mg/kg] et al., 2005
1-d experiment 29.4 ± 9.5 yr pure caffeine 3.5 mg/kg Caffeine 3.5 mg/kg BW in 200 mL of water resulted in stronger anal sphincter contractions both at Lohsiriwat
(Thailand) n=10 (5 M) basal period and during voluntary squeeze. The sensory threshold was also decreased, leading to et al., 2008
an earlier desire to defecate.
1-d experiment 19-31 yr pure caffeine 3.5 mg/kg There was no change in basal lower esophageal sphincter (LES) pressure after a water drink while Lohsiriwat
(Thailand) n=12 (6 M) caffeine consumption significantly lowered the pressure at 10, 15, 20 and 25 min. The mean am- et al., 2006
plitude of contractions and peristaltic velocity were decreased at the distal esophagus at 3 and 8 cm
above LES. The mean duration of contraction was decreased at the distal part but increased at the
more proximal esophagus. The HR, systolic and diastolic BP were increased significantly at 10-20
min after caffeine ingestion.
257
1, 10, 45 d; 12 Adult caffeine, in 3 capsules/d The herbal preparation significantly delayed gastric emptying, reduced the time to perceived gas- Andersen
mo experiment n=51; c=47 supplement [13-24 mg caf- tric fullness and induced significant weight loss over 10 and 45 days in overweight patients, and and Fogh,
(Denmark) M+F [overweight] feine] maintained the loss for 12 mo. [Supplement= herbal preparation 'YGD'; each capsule contained 2001
[0.3 mg/kg/d] 112 mg Yerbe Mate (3-6% caffeine), 95 mg Guarana (1-1.5% caffeine) and 36 mg Damiana ex-
tract.]
Case report 38 yr ED 400 mg/d [5.7 Intake of ~400 mg/d caffeine for 4 d resulted in headache, nausea, vomiting, hypertension, and a Argano et
(Italy) n=1 M mg/kg/d] ruptured aneurysm of the anterior communicating artery. [ED=Red Bull] al., 2011
Cohort prospec- 40-75 yr Caffeine, all Median 8, 59, There was no association between the intake of caffeine, caffeine-containing beverages, and the Aldoori et
tive (6 yr fol- n=47,806 M sources 154, 322, 581 risk of duodenal ulcer. [Intake categories were 0, 1 cup/mo to 1 cup/d, 2-3, ≥4-5 cups/d for coffee al., 1997
low-up) mg/d [0.1-8.3 and decaf; 0, 1 cup/mo to 1 cup/d, 2 to ≥3 cups/d]
(USA) mg/kg/d]
Cohort prospec- 40-75 yr Caffeine, all Median 6, 82, There was no association between the intake of caffeine, caffeinated beverages, and the risk of Aldoori et
tive (4 yr fol- n=47,678 M sources 165, 355, 615 symptomatic diverticular disease in men. [Intake categories were 0, 1 cup/mo to 1 cup/d, 2-3, ≥4- al., 1995
low-up) mg/d [0.1-8.8 5 cups/d]
(USA) mg/kg/d]
Cross-sectional 18-40 yr coffee; decaf 20-107 oz/wk Coffee intake had inverse association with estrone-3-glucuronide and human chorionic gonadotro- Lawson et
(USA) n=92 F [pregnant] [0.7-3.7 pin; positive association with vomiting but not with nausea or appetite loss; pregnanediol-3- al., 2002
mg/kg/d] glucuronide was lower in subjects who drank at least 8 ounces of coffee/d at last menstrual period.
[No info on caffeine/oz coffee; assumed 137 mg/8 oz]
Cross-sectional mean 44 yr caffeinated none, occa- Upper GI symptoms were not associated with caffeine consumption. Countries involved in study: Stanghel-
(multiple coun- n=5581 drinks sional, light, Canada, Denmark, Finland, Italy, Japan, Norway, Sweden, Switzerland, The Netherlands, and lini, 1999
tries) (40.6% M) moderate, heavy USA. [Consumption was evaluated as cups/glasses per day, or occasionally, each of coffee, tea or
cola; before analysis, intake was classified as none, occasional, light, moderate, heavy, but there
was no info on actual caffeine content]
Cross-sectional 25-39 yr pure caffeine 600-1500 mg There were 43 hospital attendances due to deliberate caffeine ingestion, representing 0.2% of all Waring et
(UK) n=38 (15 M) [8.6-25 mg/kg] poisoning cases. The median (interquartile range) stated dose was 1040 mg (600-1500 mg). Minor al., 2009
gastrointestinal symptoms were common, and no patient developed features of severe toxicity.
258
TABLE 12-2. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Summaries of Reviews Reference
No evidence for an association of coffee ingestion with peptic ulcer disease or functional dyspepsia; coffee may promote gastro-esophageal reflux, stimu- Boekema et al.,
lates gallbladder contraction, and stimulates colonic activity in some people. 1999
Some investigations found associations between breast pain and premenstrual syndrome, fibrocystic breast disease, and caffeine intake. Norlock, 2002
No association between daily caffeine intake and the development of rheumatoid arthritis. Mikuls et al.,
2002b
Caffeine intake is a risk factor for uninvestigated dyspepsia. Mahadeva and
Goh, 2006
Intraocular pressure (IOP) was measured at 0.5 h, 1 hr and 1.5 hr post-ingestion in 6 randomized controlled trials (total 103 normal, 41 with glaucoma or Li et al., 2010
ocular hypertension). IOP was not affected by caffeine in normal subjects but increased significantly for patients with glaucoma or ocular hypertension.
In epidemiologic studies, non-filtered coffee consumed at moderate to high doses has been found to be related to increases in C-reactive protein, TNF-a, IL- O'Connor and
6, and homocysteine. In contrast, filtered coffee drinking appears to have minimal impact on markers of inflammation. Irwin, 2010
At pharmacologically relevant concentrations most of the effects of caffeine and theophylline are attributable to adenosine receptor blockade and histone Hasko and Cron-
deacetylase activation. In addition, at higher concentrations methylxanthines can suppress inflammation by inhibiting phosphodiesterases, thereby elevating stein, 2011
intracellular cyclic adenosine monophosphate levels.
Methyxanthines interrupt the immunosuppressive adenosine–A2AR signaling and may enhance the antipathogen immunity and pathogen destruction by Ohta and
immune cells. Caffeine can prevent the inhibition of antitumor T cells in a hypoxic tumor microenvironment. On the other hand, caffeine may exacerbate Sitkovsky, 2011
liver damage by weakening the tissue-protecting A2A adenosine receptor signaling during episodes of acute liver inflammation.
259
12B. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects in Animals
The animal studies in general supported the findings in humans regarding caffeine effects
on immunological, GI, ocular, and mammary (non-cancer) parameters. Effects reported included
increased serum lysozyme activity, spleen weight, and levels of monocytes and neutrophils (≥40
mg/kg, gavage) (Ramanaviciene et al., 2004). Dogs infused i.v. with 30 mg/kg caffeine had in-
creased intra-ocular pressure (Kurata et al., 1998), and newborn rats of dams treated i.p. or p.o.
with 50 mg/kg/day caffeine during gestation had corneal lesions and catarogenic effects on the
crystalline lens (Evereklioglu et al., 2003; 2004). Caffeine increased colonic motility (spike ac-
tivity) in dogs (≥7 mg/kg i.v.) (Abo et al., 2000). Rats gavaged with green tea extract for 28 days
had decreased body weight and food consumption and gastric lesions at ≥1000 and 2000
mg/kg/day, respectively (containing 37 and 74 mg/kg/day caffeine) (Chengelis et al., 2008).
Animal studies of which a major focus was the effect of caffeine on immunological, GI,
ocular, and mammary (non-cancer) parameters are summarized in Table 12-3.
260
TABLE 12-3. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Animal Studies
Exposure Test material;
Species Caffeine dose(s) Effects; Comments Reference
time route
IMMUNOLOGICAL EFFECTS
Mouse 1 day pure caffeine 2, 20, 40, 200 Serum lysozyme activity and the number of monocytes and neutrophils increased; spleen weight Ramanaviciene
(gavage) mg/kg increased; dose-response seen. et al., 2004
OCULAR EFFECTS
Dog 1 day pure caffeine 30 mg/kg Caffeine (i.v.) significantly increased the intraocular pressure (IOP) at 0.25 and 1 hr after a single Kurata et al.,
(i.v.); befunolol dose, which resolved within 2 hr. Over time, there were no differences in the outflow between the 1998
(topical) caffeine and control groups. Instillation of the topical beta-blocker befunolol (which inhibits aqueous
humor formation in the ciliary body) lowered outflow and produced ocular hypotension. The levels
of the IOP and outflow in dogs treated with caffeine + befunolol were almost the same as with be-
funolol alone. This suggests that i.v. caffeine increases the IOP in normal beagle dogs by increasing
aqueous humor formation and not by the inhibition of aqueous humor drainage through the trabecu-
lar meshwork.
Rat 12 d (GD 9- pure caffeine 25, 50, 100 Maternal doses of 50 or 100 mg/kg/d caused histopathological changes in the cornea of pups at PND Evereklioglu et
21) (i.p.; gavage) mg/kg/d i.p.; 50 1 and 30. al., 2003
mg/kg p.o.
Rat 12 d (GD 9- pure caffeine 25, 50, 100 Maternal caffeine exposure to 50 or 100 mg/kg/d during pregnancy was cataractogenic for crystal- Evereklioglu et
21) (i.p.; gavage) mg/kg/d i.p.; 50 line lenses in rats at PND 1 and 30. al., 2004
mg/kg p.o.
GI EFFECTS
Dog 1 day pure caffeine 125, 250 mg In the colon there was a significant increase in the number of spike bursts per minute after the injec- Abo et al.,
(i.v.) tion of both the low and the high dose of caffeine. The increase in the total energy of spikes per min- 2000
ute after the injection of the high dose of caffeine was significantly higher than that after the low
dose of caffeine. The gastric and jejeunal slow waves were not affected.
261
TABLE 12-3. Immunological, GI, Ocular, and Mammary (Non-Cancer) Effects of Caffeine – Animal Studies
Exposure Test material;
Species Caffeine dose(s) Effects; Comments Reference
time route
Rat 28 d green tea cate- 0, 500, 1000, The clinical condition of the animals, functional observational battery, motor activity, clinical pa- Chengelis et
chins (GTC) 2000 mg/kg/d thology evaluations, organ weights, and gross necropsy findings were unaffected by any of the green al., 2008
(gavage) GTC (3.7% caf- tea catechin (GTC) preparations. GTC-HDC (decaffeinated) or GTC-UH (non-heat-sterilized) dos-
feine), decaf ing had no effects on BWs or microscopic findings, whereas lower BWs and food consumption were
GTC, 2000 observed in the 1000 and 2000 mg/kg/day GTC-hr (heat-sterilized) group males. The NOAEL for
mg/kg/d localized gastric effects for GTC-hr was 1000 mg/kg/day. No other target organs were identified.
Thus, the NOAEL for systemic toxicity following oral administration was 2000 mg/kg/day for GTC-
H, GTC HDC, and GTC-UH in this study.
262
CHAPTER 13. THE IMPACT OF HUMAN GENOTYPE ON CAFFEINE
EFFECTS
A number of experimental and epidemiological studies evaluated the impact of human

genetic differences on the toxicity and disposition of caffeine. Many of these studies have been
included in other Chapters of this document, per their subject area. The studies examined the
distribution and effects of polymorphic forms of the key caffeine-metabolizing enzymes
CYP1A2, N-acetyltransferase (fast/slow acetylator NAT2 gene), and XO among populations
(geographic; ethnic; racial), among males and females, among various age groups, and in persons
with concurrent medical conditions (Down’s syndrome; biliary cirrhosis). In metabolic studies,
subjects were treated with a single low dose (typically 100-300 mg) of caffeine, which was used
as an enzyme substrate.
The studies showed that acetylator phenotype (NAT2 gene) was distributed bimodally,
being approximately 60% slow and 40% fast in with French, American, and German Caucasian
populations. An Arabic population was 72% slow acetylator phenotype. Asian populations
(Japanese and Chinese) were predominantly rapid acetylators (~80-90%), although a group of
Hmong living in Minnesota was primarily of the slow acetylator phenotype (92%). Both sexes
had similar acetylator phenotype distribution. CYP1A2 activity was distributed unimodally,
with only a small fraction (5-15%) of people having the low activity phenotype, and activity
tending to be greater in men than women. Xanthine oxidase activity was also distributed unimo-
dally and was comparable in both sexes and among various populations.
Several studies evaluated the association of specific polymorphic enzymes (or combina-
tions thereof) or adenosine (A2A) or dopamine receptors with various toxic effects/medical con-
ditions. No association was found of specific CYP or NAT2 genotypes with urinary bladder car-
cinoma. However, specific metabolic enzyme or receptor genotypes were associated with in-
creased (or decreased) risk of ovarian cancer, spontaneous abortion, hypertension, myocardial
infarction, caffeine-induced anxiety sensitivity, inhibition of melatonin metabolism, and high
habitual caffeine intake.
Caffeine effects were also influenced by other, uncharacterized, heritable factors. For
example, African-American adolescents had a greater caffeine-induced increase in BP, and
adults recovered more slowly from a caffeine-induced BP increase than non-Hispanic whites
given the same dose. Relatives of panic disorder patients were more sensitive to caffeine-
induced panic attacks, and those with a family history of hypertension had a greater caffeine-
induced BP increase than subjects without a family history.
Studies that addressed a genetic component of caffeine disposition and/or toxicity are
summarized in Table 13-1. Brief summaries of reviews published on this topic are provided in
Table 13-2.
263
TABLE 13-1. The Impact of Human Genotype on Caffeine Effects
Study type; Subject age; Subject Test mate-
country number; sex variable(s) rial(s)
1-day experi- 3-8 yr cystic fibro- caffeinated 35 mg Mild cystic fibrosis did not alter the activities of CYP1A2, NAT-2, XO, or CYP2D6 in Kennedy
ment n=12; c=12 sis; CYP, drink, car- [1.2-2.3 mg/kg] children, per standard caffeine and dextromethorphan (0.5 mg/kg) phenotyping meth- et al.,
(USA) M+F NAT activity bonated ods [Assumed BW 15-30 kg for dose estimates] 2004a
1-day experi- 7-16 yr; 21-46 CYP, NAT, pure caf- 35 mg child A significantly higher CYP1A2 ratio was found for M than F; no differences in activi- Krul and
ment (The yr XO activity feine; OC; [0.5-1.4 ties of N-acetyltransferase (NAT), XO, or CYP2A6 among groups (healthy, non- Hageman,
Netherlands) n=26 M+F smoking mg/kg]; 80-140 smoking F using OC or not; healthy nonsmoking M, and children). [Assumed BW 25- 1998
mg adult [1.1- 65 kg for ages 7-16 yr dose estimates ]
2.0 mg/kg]
1-day experi- 2-6 yr cystic fibro- pure caf- 3 mg/kg The cumulative percentage of labeled caffeine exhaled as carbon dioxide measured Parker et
ment (UK) n=8 (4 M); c=9 sis feine over two hours was significantly higher in the patients with cystic fibrosis than in con- al., 1997
trols.
1-day experi- 1 mo-17 yr Overweight; pure caf- 2.5 mg/kg Xanthine oxidase (XO) activity was elevated in pediatric obese volunteers compared to Zielinska
ment obese (n = 9); CYP1A2, feine; Coca- non-obese pediatric volunteers (XO metabolic ratio of 0.7 ± 0.06 vs. 0.6 ± 0.06, respec- et al.,
(Poland) lean (n = 16) XO, NAT2 Cola tively; (95% CI 0.046, 0.154) (p < 0.001). NAT activity was 5-fold higher in the obese 1999
M+F phenotype (1 ± 0.4) vs. non-obese children (0.2 ± 0.1) (95% CI 0.26, 1.34)(p < 0.05). No differ-
ence was observed in CYP1A2 activity between the groups (95% CI -2.72, 0.12) (p
>0.05).
Cross-sectional 15-19 yr race caffeine, all 0-50, >50-100, The positive association between systolic BP and caffeine category varied by race, be- Savoca et
(USA) n=159 M+F sources >100 mg/d [0.8 ing higher in African Americans consuming >100 mg/d of caffeine. [Assumed a BW al., 2004
to >1.5 of 65 kg for dose estimates.]
mg/kg/d]
Cross-sectional 15-19 yr race caffeine, all 0-50, >50-100, The level of dietary caffeine was positively associated with daytime systolic and dia- Savoca et
(USA) n=82 M+F sources >100 mg/d [0.8 stolic BP; effect on systolic BP was most pronounced for African-American subjects. al., 2005
to >1.5 [Assumed a BW of 65 kg for dose estimates.]
mg/kg/d]
STUDIES WITH ADULTS
1-day experi- Adult XO pheno- pure caf- 100 mg [1.4 XO activity was higher in Ethiopians living in Ethiopia than in Sweden; no significant Aklillu et
ment (Ethiopia; n1=100 (57 type; country feine; mg/kg/d] difference in XO metabolic ratio between men and women or between smokers and al., 2003
Sweden) M); n2=73 (43 of residence smoking non-smokers.
M)
264
1-day experi- ~21 ± 3.5 yr A2a receptor pure caf- 150 mg [2.1 An adenosine receptor gene polymorphism that has been associated with panic disorder Alsene et
ment (USA) n=94 (51 M) gene poly- feine mg/kg/d] (linked polymorphisms on the A2a receptor gene, 1976C>T and 2592C>Tins) is also al., 2003
morphism associated with an anxiogenic responses to an acute dose of caffeine.
1-day experi- 19-39 yr NAT2 phe- pure caf- 200 mg [2.9 Frequency distribution analysis of the metabolic ratios AFMU/1X revealed two distinct Asprodini
ment n=83 (34 M) notype feine mg/kg] groups with 66.3% slow acetylators and 33.7% rapid acetylators. No statistical differ- et al.,
(Greece) ence was found between slow and fast acetylators in terms of gender, smoking habits 1998
and caffeine-intake habits.
1-day experi- Adult; NAT2 phe- pure caf- (100-300 mg) In the three main racial/ethnic groups living in Tunisia (Arabs, Berbers and Numides), Attitallah
ment n=?? M+F notype feine [1.4-4.3 mg/kg] the frequency of slow acetylators appears identical and NAT-2 activity as a whole is et al.,
(Tunisia) lower in Tunisians than in Caucasians. 2000
1-day experi- 29-48 yr sleep disor- pure caf- 140 mg [2.0 Caffeine pharmacokinetic parameters and EEG data differed between sleep-sensitive Bchir et
ment (Tunisia) n1=4 M; n2=4 der feine; mg/kg] and control subjects. al., 2006
M smoking
1-day experi- 18-86 yr age, sex, pure caf- 100 mg [1.4 Gender had no effect on CYP1A2, CYP2C19, or CYP2E1 activity; CYP2C19 activity Bebia et
ment n=161 M+F CYP pheno- feine mg/kg] decreased with age; and CYP2E1 activity increased with age and developed earlier in al., 2004
(USA) type life in M than F.
1-day experi- 32-75 yr alcoholism; pure caf- 200 mg [2.9 Caffeine metabolism was reduced by half in patients with alcoholic cirrhosis, mainly Bechtel et
ment (France) n=226 (178 liver disease feine mg/kg/d] due to decreased CYP1A2 activity. al., 2000a
M)
1-day experi- 20-91 yr NAT2 geno- pure caf- 1 cup coffee or Found arylamine N-acetyltransferase (NAT2) slow acetylation (58.9%) in German un- Cascorbi
ment (Ger- n=844 M+F type; pheno- feine; cof- 100 mg tablet related population; 6.7% of the cases deviated in genotype and phenotype; all mutant et al.,
many) (563 phenotype fee [1.4 mg/kg] alleles showed low in vivo acetylation capacities. [1 cup assumed = 100 mg] 1995
typed)
1-day experi- Adult CYP1A2 pure caf- 100 mg [1.4 CYP1A2 activity was low for G-3113A polymorphism and haplotype pairs 5, 8, 9, 12, Chen et
ment (China) n=27 M+F polymor- feine mg/kg] and 15, but was high for haplotype pairs 10 and 13 in Chinese subjects. al., 2005
phism
1-day experi- 18-35 yr Adenosine pure caf- 0, 50, 150, 450 An intake of ≥150 mg caused anxiety, which was associated with gene variants Childs et
ment (USA) n=102 (51 M) and dopa- feine mg [0.7-6.4 ADORA2A rs5751876 (1976C/T), rs2298383 (intron 1a) and rs4822492 (3'-flank), and al., 2008
mine recep- mg/kg] DRD2 rs1110976 (intron 6), as well as two-loci interactions of selected ADORA2A
tor genotype and DRD2 polymorphism.
265
1-day experi- 18-46 yr CYP2A6, pure caf- 100 mg [1.4 A 21-fold variation in the urinary 17U/17X ratio was observed (indicates CYP2A6 ac- Djordjevic
ment (Serbia) n=140 (72 M) XO pheno- feine; mg/kg] tivity) and a 4-fold urinary 1U/(1U + 1X) ratio (indicates XO activity); CYP2A6 geno- et al.,
type smoking type and cigarette smoking, but not sex, influenced CYP2A6 enzyme activity; XO ac- 2010
tivity was not influenced by sex or cigarette smoking.
1-day experi- 18-60 yr CYP1A2 pure caf- 100 mg [1.4 The 4-hr plasma 17X/137X ratio (CYP1A2 activity) was higher in Swedes (1.5x) than Ghotbi et
ment (Korea; Swedes n=194 phenotype feine mg/kg] Koreans, and in smokers, but was lower in OC users; no gender effect. al., 2007
Sweden) Koreans n=150
M+F
1-day experi- Adult 7 CYP1A2 coffee 1 cup [1.4 Smoking had the strongest impact on CYP1A2 activity, while gender (higher in men) Gunes et
ment n=146 M+F polymor- mg/kg] and CYP1A2 haplotype H4 (higher activity) showed marginal effects. [No info on al., 2009
(Turkey) phisms caffeine/cup coffee; assumed 100 mg/cup]
1-day experi- 21 ± 1 yr Arg allele in pure caf- 4 mg/kg At baseline, subjects with the Arg/Arg genotype had a significantly lower energy ex- Hamada et
ment n=44 F beta(3)-AR feine penditure (EE) level than those with the Trp/Trp or Trp/Arg genotype. There were al., 2010
(Japan) gene similar caffeine-induced increases in EE in all genotypes. [Arg allele in the beta(3)-
adrenergic receptor gene (beta(3)-AR) is a marker for obesity-related traits.]
1-day experi- 22-46 yr NAT2 geno- pure caf- 150-200 mg The urinary NAT2 ratios before and after caffeine intake correlated well in 65 volun- Jetter et
ment n=77 (60 M) type feine [2.1-2.9 mg/kg] teers; NAT2 genotyping, done in 41 volunteers for four SNPs, corroborated the pheno- al., 2004
(Germany) typing results.
1-day experi- Adult developmen- pure caf- 3 mg/kg A composite measure of developmental instability (minor physical anomalies and fluc- Jung et al.,
ment n=100 M+F tal instability feine tuating asymmetry) predicted the magnitude of caffeine-induced verbal memory dec- 2000
(USA) rement.
1-day experi- 41-79 yr primary bil- pure caf- 200 mg [2.9 CYP1A2 activity was decreased but XO and mainly CYP2A6 activities were increased; Lelouet et
ment n=67 (10 M) iary cirrho- feine mg/kg] clear-cut bimodal distribution in NAT-2 index, most patients being fast acetylators. al., 2001
(France) sis; CYP,
NAT, XO
activity
1-day experi- Adult Race; CYP, pure caf- (100-300 mg) Found 20 slow acetylators and 100 rapid phenotypic acetylators in 120 Chinese people; Lu et al.,
ment (China) n=120 M+F NAT, XO feine; [1.4-4.3 mg/kg] similar CYP1A2 and XO activity in Chinese and European volunteers; CYP1A2 index 1997
activity smoking was much higher in smokers.
266
1-day experi- Adult adenosine caffeine, all 0, ≥1 cup (the Carriers of the A allele (adenosine deaminase polymorphism) who consumed caffeine Mazzotti
ment n=958 M+F deaminase sources previous day) in the day prior to polysomnography had higher sleep efficiency and REM sleep per- et al.,
(Brazil) polymor- [≥1.4 mg/kg/d] centage, after adjustment for confounders. No effect was observed without caffeine. 2011
phism Thus caffeine may modulate the function of this gene. [No info on caffeine content;
assumed 100 mg/cup]
1-day experi- ~34 yr race; CYP, coffee 7 tb instant The putative low risk phenotype for transitional cell carcinoma of the urinary bladder Muscat et
ment n1=165 (82 NAT2 phe- coffee [7.5 (slow CYP1A2/rapid NAT2) was more common in blacks than in whites (25% vs. al., 2008
(USA) M); n2=183 notype mg/kg] 15%); no significant racial differences in slow and rapid CYP1A2 phenotypes, or in the
(89 M) slow NAT2/rapid CYP1A2 phenotype. [No info provided on caffeine content of instant
coffee; assumed 75 mg/tb]
1-day experi- 17-50 yr CYP1A2 coffee; in- 114 mg [1.6 Found 14.1% were poor CYP1A2 activity phenotype, which is inherited as an auto- Nakajima
ment n1=147; n2=58 phenotype stant coffee; mg/kg] somal recessive trait; CYP1A2 activity was induced by cigarette smoking, and was et al.,
(Japan) M+F smoking higher in M than F. 1994
1-day experi- 18-66 yr CYP1A2 pure caf- 114 mg [1.6 Human CYP1A2 gene point mutation in 5'-flanking region caused decreased CYP1A2 Nakajima
ment n=116 (62 M) genotype feine; cof- mg/kg] activity in Japanese smokers; mutant allele frequency was 0.23. et al.,
(Japan) fee; smok- 1999
ing
1-day experi- ~32 ± 13 yr predisposed pure caf- 480 mg [6.9 Panic disorder (PD) patients and their first-degree relatives were more sensitive than Nardi et
ment n1=25 (PD); to PD feine mg/kg] healthy volunteers to the panic attack symptoms from caffeine intake, but less sensitive al., 2008
(Brazil) n2=27 (relati- to headache, increase in BP, and insomnia.
ves); c=22
M+F
1-day experi- 18- 23 yr CYP1A2 pure caf- 300 mg [4.3 A 16-fold variation of CYP1A2 activity (range 0.09 to 1.46) was found; coefficient of Ou-Yang
ment (China) n=229 (120 phenotype feine mg/kg] variation was 62.9%. Non-normal distribution of CYP1A2 activity showed 5.24% were et al.,
M) poor CYP1A2 metabolizers; overall, men had higher CYP1A2 activity than women. 2000
1-day experi- 18-60 yr CYP1A2 pure caf- 200 mg [2.9 The CYP1A2 phenotype was unimodally distributed in Faroese residents; caffeine me- Petersen et
ment n=305 M+F phenotype feine; PCB; mg/kg] tabolism was increased in all smokers, decreased in non-smoking women using OC, but al., 2006
(Denmark) smoking was unaffected by polychlorinated biphenyls (PCB) exposure.
1-day experi- 49.0 ± 10.7 yr CYP1A2 no caffeine no caffeine CYP1A2 F21L and F186L polymorphisms [formerly CYP1A2(*)2 and (*)11 alleles] Pucci et
ment n=500 M+F polymor- (DNA se- (DNA sequenc- were absent in 500 Italian healthy subjects. al., 2007
(Italy) phisms quencing) ing)
267
1-day experi- 17-64 yr CYP1A2 pure caf- 200 mg [2.9 CYP1A2 activity was higher in men, in smokers, and in women not taking OC; com- Rasmus-
ment n=378 (187 M) activity feine; OC; mg/kg] parison of twins yielded heritability estimate of 0.725. sen et al.,
(Denmark) smoking 2002
1-day experi- Adult C-->A pure caf- 100 mg [1.4 Overall 46% were homozygous for variant A, 44% were heterozygous, and 10% were Sachse et
ment n1=185 non- polymor- feine; mg/kg] homozygous for variant C. The 5 hr plasma 17X/caffeine ratios in non-smokers did not al., 1999a
(Germany) smokers; phism in smoking differ between the three CYP1A2 genotypes. In the smokers, there were significant
n2=51 smokers intron 1 of differences in the 5 hr plasma 17X/caffeine ratios between the genotypes. The mean
(sex NR) the cyto- ratio was 1.37 in carriers of the A/A genotype, 0.88 in heterozygotes and 0.82 in carri-
chrome P450 ers of C/C. The mean difference between A/A and C/A groups was 0.48 (0.15-0.81;
CYP1A2 p=0.01).
gene
1-day experi- 19-85 yr schizophre- pure caf- 100 mg [1.4 FMO3 (flavin monooxygenase 3) amino acid variants K158, G308, and M257 were Sachse et
ment n=204; c=192 nia; FMO3 feine mg/kg] found and linkage analysis revealed 7 different alleles; subjects with these variants did al., 1999b
(Germany) M+F polymor- not differ in clozapine N-oxidation or caffeine oxidation compared with the wild-type.
phism
1-day experi- 18-65 yr NAT2 phe- cola 46 mg (0.7 Found 92.2% slow and 7.8% rapid acetylators in 51 urine samples from 61 Hmnong Straka et
ment (Minne- n=51 (27 M) notype mg/kg] subjects living in Minnesota; a urinary caffeine metabolic ratio AFMU/1X (<0.6) was al., 2006
sota Hmong) used to classify subjects as slow acetylators.
1-day experi- mean 39 yr CYP1A2 coffee; OC; 204 ± 169 CYP1A2 activity was lower in OC users and residents of Bulgaria and Slovakia (than Tantcheva
ment (Bulgaria; n=786 (371 M) phenotype smoking mg/d [<2.9 to Germany), and was higher in cigarette smokers. Mean coffee intake was 0.46 ± 0.38 -Poor et
Slovakia; Ger- >5.3 mg/kg] L/d. al., 1999
many)
1-day experi- Adult NAT2 geno- coffee; tea 1 cup [1.4 Found single locus control of N-acetyltransferase (NAT2) activity, with recessive allele Vincent-
ment n=281 M+F type mg/kg] for the homozygous slow phenotype; slow allelic frequencies were 0.739, 0.753, and Viry et al.,
(France) 0.724, respectively, phenotypic concordance was 90 to 92% with the AFMU/1X ratio. 1994
[No info on caffeine/cup coffee; assumed 100 mg/cup]
1-day experi- 18-50 yr CYP1A2 pure caf- 2 cups (~200 CYP1A2 did not show functionally significant polymorphism but the wide interindi- Welfare et
ment n=92 (43 M) polymor- feine mg) [2.9 vidual variation in activity may be due to environmental factors. al., 1999
(UK) non-smokers phism mg/kg]
12-day experi- 21-35 yr CYP1A2 pure caf- 100 mg [1.4 Human hepatic CYP1A2 activity may be assayed as the caffeine metabolic ratio Kall et al.,
ment n=16 (14 M) phenotype feine mg/kg] (CMR) value. Broccoli causes increased CYP1A2 activity, as the mean CMR value 1996
(Denmark) non-smokers increased by 19% (P < 0.0005) after 12 days on the broccoli diet. The average increase
in the CMR, however, covered a 0-82% inter-individual range of induction.
268
Case-control ~57 ± 11 yr CYP1A2 coffee <1, 1, 2-3, ≥4 Found 55% of cases and 54% of controls were carriers of the slow *1F allele for Cornelis et
(Costa Rica) cases= con- genotype cups/d [<1.4 to CYP1A2, for whom the intake of ≥2 cups/d coffee was associated with an increased al., 2006
trols= 2,014 ≥5.7 mg/kg/d] risk of nonfatal MI. [No info on caffeine per cup; assumed 100 mg/cup]
(74% M)
Case-control Adult CYP1A2 coffee <1, 1, 2-3, ≥4 Individuals homozygous for the CYP1A2*1A allele (A/A) are ‘‘rapid’’ caffeine me- El-
(Canada) cases=2,014; genotype cups/d [<1.4 to tabolizers; carriers of CYP1A2*1F are ‘‘slow’’ caffeine metabolizers. Risk of MI was Sohemy et
controls=2,014 ≥5.7 mg/kg/d] increased in slow metabolizers with intake of ≥2 cups/d, and was greater in those <50 al., 2007
(M+F) yr old; protective effect but no linear dose-response was seen in fast metabolizers <50
yr old. [No info on caffeine per cup coffee.]
Case-control 66 yr CYP1A2 caffeine, all 1.24 g/wk [2.5 Increased risk of ovarian cancer for regular coffee drinkers, and for overall caffeine Goodman
(USA) cases=164 F; genotype sources; mg/kg/d] intake of ≥0.43 g/wk, but not for tea or soda drinking; risk was greater for F with et al.,
controls=194 F coffee; tea CYP1A2 A/A genotype than with any C allele. 2003
Case-control Adult CYP1B1 caffeine, all 0-99, 100-299, Carriers of the CYP1B1 432 Val/Val genotype (CYP1B1 Val432Leu polymorphism) Karypidis
(Sweden) cases=507 F; Val432Leu sources 300-499, ≥500 were at a higher risk of miscarriage in the first trimester of pregnancy (OR=1.46; 95% et al.,
controls=908 F polymor- mg/d [<1.4 to CI 1.02-2.08). There was a significant interaction between genotype and caffeine in- 2006
phism ≥7.1 mg/kg/d] take.
Case-control cases=52.4 ± BRCA1 mu- coffee never; ever Females with a variant C allele in the CYP1A2 gene (AC or CC; associated with de- Kotsopou-
(USA) 12.3 yr (n=170 tation carri- creased enzyme inducibility and impaired caffeine metabolism) who consumed coffee los et al.,
F); controls= ers; CYP1A2 had a 64% reduction in breast cancer risk compared with non-consumers; protective 2007
43.1 ± 13.2 yr genotype effect was not seen among women with the CYP1A2 AA genotype
(n=241 F)
Case-control ~ 51 yr; ~60 yr CYP19, caffeine, all < or ≥ 410 Increased risk of ovarian cancer in premenopausal F in the NECC study population Kotsopou-
(USA) cases=1,354 F; CYP1A1, sources mg/d [< or only; carrying one or both of the variant CYP19 genes (CYP19013 A or CYP19027 G los et al.,
controls=1,851 CYP1A2, or ≥6.8 mg/kg/d] alleles) was associated with an 18% increased and 15% decreased risk of ovarian can- 2009a
F CYP2A6 cer, respectively. Variation in CYP1A1, CYP1A2, or CYP2A6 did not explain the in-
genotype consistent reports of coffee intake and risk.
Case-control mean =63 yr bladder can- coffee 0, ≤3, 4, ≥5 Increased risk of bladder cancer among heavy coffee drinkers (>5 cups/day; OR 3.1, Pavanello
(Italy) for cases (185 cer; CYP1A2 cups/d [≤4.3 to 95% CI: 1.2-7.9) [and heavy smokers]. Case-only analysis showed no interaction be- et al.,
M); 62 yr for genotype ≥7.1 mg/kg/d] tween CYP1A2 polymorphisms and coffee consumption. No overall effect of CYP1A2 2010
controls (180 by itself on bladder cancer risk. [No info on caffeine per cup coffee; assumed 100
M) mg/cup]
269
Case-control most >55 yr bladder can- caffeine, all 0, 1, 2, 3, ≥4 There was a modest increased bladder cancer risk among coffee drinkers (≥4 cups/d) Villanueva
(Spain) cases=1,136 cer; NAT2, sources cups/d [1.4 to that may, in part, be explained by residual confounding by smoking; gene-coffee inter- et al.,
(88.1% M); CYP1A2, ≥5.7 mg/kg/d] actions for NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified. [No 2009
controls=1,138 CYP2E1-02, info on caffeine per cup; assumed 100 mg/cup]
(87.2% M) CYP1A1
genotype
Cohort pro- 42-60 yr at COMT gene coffee median mL/d: OR (90% CI)=3.2 (1.2-8.4) comparing heavy coffee drinkers with the low activity Happonen
spective (13 yr baseline n=773 polymor- 269, 579, 938 COMT (catechol-O-methyltransferase) genotype vs. high activity or heterozygotic et al.,
mean follow- M phism [3.8, 8.3, 13 genotypes; urinary adrenaline excretion increased with increasing coffee intake, being 2006
up) mg/kg/d] over two-fold in heavy drinkers vs. nondrinkers. [If estimate coffee=0.5-1 mg caf-
(Finland) feine/mL, then caffeine= 135-269 mg, 290-579 mg, 469-938 mg for light, moderate,
and heavy consumption, respectively]
Cohort pro- 18-45 yr at CYP1A2 coffee 0, 1-3, ≥4 BP and urinary epinephrine increased (dose-response) only in carriers of slow *1F al- Palatini et
spective (8.2 yr baseline n=553 genotype cups/d lele of CYP1A2 who drank coffee. [The caffeine content per cup of 'espresso' Italian al., 2009
follow-up) M+F) [1.4-4.3, ≥5.7 coffee averages 100 mg]
(Italy) mg/kg/d]
Cohort pro- 65-77 yr post-meno- caffeine, all >300 mg/d Women with high caffeine intake had higher rates of bone loss at the spine than did Rapuri et
spective (3-yr n=489 F; pausal; vita- sources [>5.0 mg/kg/d] those with low intake. After analysis according to vitamin D receptor genotype and al., 2001
follow-up); cohort n=96 F min D recep- caffeine intake, women with the tt genotype had higher (P = 0.054) rates of bone loss at
Cross-section- tor genotype the spine than with the tt genotype if their caffeine intake was >300 mg/d.
al (USA)
Cross-sectional Mixed ages PNKD caffeine, all + or - Caffeine, alcohol, and emotional stress were prominent precipitants of paroxysmal Bruno et
(various coun- n=71 M+F (14 sources; nonkinesigenic dyskinesia (PNKD) attacks. Attacks had a favorable response to ben- al., 2007
tries) kindreds) diazepam; zodiazepines, such as clonazepam and diazepam. (participating countries: Russia;
clonazepam Denmark; Germany; Italy; Poland; USA) [Caffeine intake not reported]
Cross-sectional ≥65 yr race caffeine, all mean 214 mg/d Caffeine intake was not related to bone mineral density (BMD); African-American men Cauley et
(USA) n=5,995 M sources [3.1 mg/kg/d] had 6 to 11% higher BMD than Caucasian men independent of multiple factors. al., 2005
Cross-sectional ~57 ± 11 yr ADORA2A caffeine, all 200-400, >400 The adenosine A2A (ADORA2A) but not the CYP1A2 genotype was associated with Cornelis et
(Costa Rica) n=2,735 and CYP1A2 sources mg/d [2.9 to the amount of habitual caffeine intake, particularly for current smokers; those with the al., 2007
(~80% M) genotype >5.7 mg/kg/d] ADORA2A tt genotype were more likely to consume less caffeine than carriers of the
C allele.
270
Cross-sectional 18-46 yr CYP1A2 pure caf- coffee <3, ≥3 Among non-smokers and non-OC users, heavy coffee consumption (≥3 cups/d) in- Djordjevic
(Serbia; Swe- (n=100); 18-60 phenotype feine; cof- cups/d [< or creased CYP1A2 activity; Serbs had lower 17X/137X ratio than Swedes. [no info on et al.,
den) yr (n=149) fee; OC; ≥4.3 mg/kg/d]; caffeine content of coffee] [No info on caffeine content; assume 100 mg/d] 2008
M+F smoking 100 mg [1.4
mg/kg]
Cross-sectional ~36 ± 8 yr genotype for caffeine, all heavy use was The resemblance in twin pairs for total caffeine consumption, caffeine use, caffeine Kendler
(USA) n=1,934 F caffeine in- sources ≥625 mg/d intoxication, caffeine tolerance, and caffeine withdrawal were greater in monozygotic and Pres-
take and tol- [10 mg/kg/d] than in dizygotic twin pairs; model fitting suggested broad heritabilities of between cott, 1999
erance 35% and 77%. [Assumed estimates of caffeine content: brewed coffee, 125 mg/cup;
instant coffee, 90 mg/cup; tea, 60 mg/cup; caffeinated soft drinks, 40 mg/can]
Cross-sectional 53.9 ± 7.8 yr Mt5178 C/A coffee <1, 1-3, ≥4 Among subjects who consumed <1 cup of coffee/d, OR for hyper-LDL cholesterolemia Kokaze et
(Japan) n=397 M polymor- cups/d was lower in those with mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) al., 2010
phism [<1.4 to ≥5.7 polymorphism than with the Mt5178C allele; coffee consumption was positively asso-
mg/kg/d] ciated with serum LDL cholesterol only in subjects with Mt5178A (for 1-3 and ≥4
cups/d). [No info on caffeine per cup; assumed 100 mg/cup]
BP= blood pressure; EEG=electroencephalogram; MI=myocardial infarction; NR=not reported; OC=OC; SNP=single nucleotide polymorphism
271
TABLE 13- 2. The Impact of Human Genotype on Caffeine Effects – Summaries of Reviews Reference
(sorted by publication date)
A 24-hr urine collection after a caffeine dose allows quantification of the metabolites excreted. The ratios of selected metabolites can be used to classify the Crews et al.,
volunteers into fast, intermediate or slow caffeine metabolizers by CYP1A2 phenotype. 2001
There is wide inter-individual variation in caffeine metabolism, primarily due to variations in CYP1A2 enzyme activity. Some variability in CYP1A2 activity Lawson and
is due to genetic polymorphisms in the CYP1A2 gene. Considerable evidence exists that maternal caffeine metabolism is influenced by a variety of endoge- LeMasters, 2005
nous and exogenous factors and studying the genetic polymorphisms may improve understanding of the potential effects of caffeine and its metabolites on
perinatal outcomes.
In children and adolescents who are not habitual caffeine users, vulnerability to caffeine intoxication may be markedly increased due to an absence of phar- Reissig et al.,
macological tolerance. Genetic factors may also contribute to an individual's vulnerability to caffeine-related disorders including caffeine intoxication, de- 2009
pendence, and withdrawal. The combined use of caffeine and alcohol may increase the rate of alcohol-related injury. Several studies suggest that EDs may
serve as a gateway to other forms of drug dependence.
Twin studies find the heritability of caffeine-related traits to range between 0.36 and 0.58. Analysis of polysubstance use shows that predisposition to caffeine Yang et al.,
use is highly specific to caffeine itself and shares little common disposition to use of other substances. Genome association studies link variations in adeno- 2010
sine and dopamine receptors to caffeine-induced anxiety and sleep disturbances. Polymorphism in the metabolic enzyme cytochrome P-450 is associated with
risk of myocardial infarction in caffeine users.
Two DNA sequence variants were significantly associated with increased coffee consumption, one located between CYP1A1 and CYP1A2 at 15q24 and one Sulem et al.,
near the aryl hydrocarbon receptor (AHR) at 7p21. An effect of ~0.2 cups a day per allele was observed for both single nucleotide polymorphisms (SNPs). 2011
The association was present in both smokers and non-smokers.
272
CHAPTER 14. CAFFEINE GENOTOXICITY
The small number of relevant human studies indicated that increased consumption of cof-
fee and/or tea was associated with genotoxic effects. Endpoints included formation of DNA ad-
ducts in the placenta, chromosome aberrations and sister chromatid exchanges (SCE) in lympho-
cytes, micronucleus formation in erythrocytes, sperm aneuploidy and double-strand breaks, and
mutations in tumors. The data set was too small, however, to definitively conclude that caffeine
as typically used by humans is mutagenic.
Whole animal studies were also scarce. One mouse study obtained results consistent with
the human data, namely, that gavage with 2-6 mg/kg caffeine increased chromosome aberrations
in the bone marrow. The other animal studies tested caffeine concentrations (25-200 mg/kg)
higher than typically consumed by humans, and found that caffeine by itself did not induce bone
marrow chromosome aberrations, micronuclei in erythrocytes, aneuploidy in mouse oocytes, or
dominant lethal mutations in mice. However, caffeine potentiated chromosome aberrations in-
duced by thiotepa, fenfluramine, and cyclophosphamide; and micronucleus formation by folate
deficiency, mitomycin C, and cyclophosphamide. Based on this principle, caffeine has been
used therapeutically in humans as an adjuvant in cancer therapy (these studies were considered
out of the scope of the present review).
Cell culture studies were abundant, and those conducted prior to 1994 were summarized
in a review (D’Ambrosio, 1994). Effects ascribed to caffeine in this review and by other studies
include inhibition of DNA elongation and excision repair, induction of protein synthesis, cell
transformation, SCE, and aneuploidy, and relieving the G1, S, and G2 checkpoint delays in re-
sponse to a DNA-damaging agent. These effects decreased cell survival.
Human and animal genotoxicity studies are presented in Table 14-1, as well as selected
studies with non-mammalian systems and with cell cultures. Brief summaries of conclusions
drawn by reviews on this topic are provided in Table 14-2. Nehlig and Debry (1994b; 1996)
concluded that coffee and caffeine have been shown to be mutagenic in lower organisms, but
usually at doses several orders of magnitude greater than the estimated lethal dose for caffeine in
humans, and the chances of coffee and caffeine consumption in moderate to normal amounts to
induce mutagenic effects in humans are almost nil.
273
TABLE 14- 1. Caffeine Genotoxicity Studies
Species; Test material
Exposure time Caffeine dose(s) Effects; Comments Reference
other (route)
Human chronic Coffee (oral) <2, 2-7, 8-14, ≥15 Mutations were found in tumors from 94 of 121 patients, and were more common in those with Porta et al.,
64.5±2.4 yr cups/wk [<0.3 to intake of ≥2 cups/wk; mean intake in patients with a mutated tumor was 14.5 cups/week vs. 8.8 in 1999
n=121 M+F ≥3.1 mg/kg/d] those with a wild type tumor. [A cup of coffee is 35-50 mL and contains 95-115 mg caffeine.]
Human chronic coffee 0, 1, ≥2 cups/d Sperm aneuploidy increased for chromosomes XX18, XY18, XY18-18, and YY18-18 from ≥1 Robbins et al.,
19-35 yr [1.4, ≥2.9 cup/d [2.9 mg/kg/d]; dose-response seen. [No info on caffeine per cup; assumed 100 mg/cup] 1997
n=45 M mg/kg/d]
Human chronic caffeine, all 0, 1-107, 107-308, Sperm DNA damage (double-strand breaks) increased with intake of >308 mg/d caffeine. Schmid et al.,
22-80 y sources 308-1070 mg/d 2007
n=80 M [0.01-15 mg/kg/d]
Mammalian 1 day pure caffeine; mM Caffeine caused oxidative DNA breakage with transition metal ions. Azam et al.,
cell culture metal ions (in 2003
vitro)
Mammalian 1 day pure caffeine mM Caffeine induced aneuploidy through asymmetrical cell division. Katsuki et al.,
cell culture (in vitro) 2008
Mammalian 1 day pure caffeine; 1.5-10 mM Caffeine inhibited DNA repair in response to uv radiation. Link et al.,
cell culture uv (in vitro) 1995
Mammalian 1 day pure caffeine; mM Yerba mate extract induced in lymphocytes a concentration-dependent increase in apoptotic and Wnuk et al.,
cell culture yerba mate (in necrotic cells, decreased nuclear division and transcriptional rDNA activity, and increased pro- 2009
vitro) duction of acrocentric micronuclei (aneugenic); caffeine at the same concentrations was more
cyto- and genotoxic.
Mouse 1 day; 21 d pure caffeine; 2.0, 4.0, 6.0 mg/kg Caffeine increased chromosome aberrations with dose- and duration-dependence at 2.0, 4.0 and Sen et al.,
fenfluramine 6.0 mg/kg. Caffeine post-treatment (4.0 and 6.0 mg/kg) 2 hr after fenfluramine application caused 1994
(gavage) a strong synergism in the late treatment period. The results suggest that prolonged Fen application
increases post-replication repair that is inhibited by caffeine.
Mouse, su- 1 day pure caffeine 150 mg/kg Caffeine neither retarded the rate of oocyte maturation nor increased the incidence of aneuploidy Mailhes et al.,
perovulated (i.p.) in mouse oocytes. 1996
Rat ≥50 d pure caffeine 0.3 or 1 g/L ~40, Caffeine consumption and chronic stress increased anxiety-like behavior (no interaction when Noschang et
(DW); stress ~108 mg/kg/d given together) as well as DNA breaks in the hippocampus (less than additive effect when given al., 2009b
together) in male; no effects in females.
Rat; bacteria 2-14 d Coffee; PhIP diet (0, 1, 5% Caffeine treatment inhibited CYP1A2 activity in bacteria but induced activity in rats; caffeine did Turesky et al.,
(diet) w/w) not increase PhIP-DNA adduct formation in the colon and pancreas while liver adducts were de- 2003
creased 50% over controls [PhIP=2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine].
274
TABLE 14- 2. Caffeine Genotoxicity – Summaries of Reviews Reference
The mutagenic potential of coffee and caffeine has been demonstrated in lower organisms, but usually at doses several orders of magnitude greater than Nehlig and Debry,
the estimated lethal dose for caffeine in humans. Therefore, the chances of coffee and caffeine consumption in moderate to normal amounts to induce 1994b
mutagenic effects in humans are almost nonexistent.
At the doses usually consumed by man, coffee does not have any potential genotoxic, mutagenic or carcinogenic effect. There is still some debate on the Nehlig and Debry,
role of coffee in the carcinogenesis of the pancreas, colon, bladder and urinary tract. 1996
275
CHAPTER 15. CAFFEINE AND CANCER
15A. Caffeine and Cancer in Humans
The effect of chronic caffeine intake on cancer development in humans was evaluated in
a number of organs. These include the pancreas, colon, rectum, ovaries, uterus, breast, urinary
bladder, kidney, lungs, and prostate. Also examined were the association between chronic caf-
feine intake and non-Hodgkin’s lymphoma, childhood acute leukemia (from maternal intake),
and death due to cancer. Studies that evaluated the carcinogenic potential of caffeine in humans
For every site of cancer evaluated, conflicting studies were found regarding the associa-
tion of cancer with caffeine intake via coffee, tea, and/or cola. The site most consistently posi-
tively associated with an increased cancer risk was the urinary bladder. A modestly increased
risk in bladder cancer was found in men from an intake of ≥4 cups/day coffee (Villanueva et al.,
2009), although confounding by smoking was not excluded; from an intake of ≥5 cups/day cof-
fee in men (Pavanello et al., 2010); or from an intake of ≥ 1 cup/day coffee in never or formerly
smoking men (Kurahashi et al., 2008).
The association of caffeine with breast cancer was evaluated in many epidemiological
studies. The majority of the studies found either no association or a slight protective effect of
consumption of caffeinated tea and/or coffee with breast cancer. This included a number of
case-control studies (by Smith et al., 1994c; Tavani et al., 1998; Nkondjock et al., 2006; and
Kotsopoulos et al., 2007); cohort prospective studies (Michels et al., 2002; Ishitano et al., 2008;
Boggs et al., 2010, and Bhoo Pathy et al., 2010); and a cross-sectional study (Jernstrom et al.,
2008). An increased risk for breast cancer was, however, found for women who drank ≥1
cup/day coffee (13 mg/kg/d) in a case-control study (Bissonauth et al., 2009). Pre-menopausal
women had an increased risk that was not dose-related from an intake of ≥ 4 mg/kg/day caffeine.
The cohort study by Larsson et al. (2009) found that an intake of ≥ 2 cups/day black tea was
positively associated with the overall risk of breast cancer, although there was no association of
coffee consumption with breast cancer. One cohort study found that an intake of ≥ 382 mg/day
caffeine (~6.4 mg/kg/day) increased the risk of atypical hyperplasia, which is a benign breast
disease marker of increased cancer risk (Webb et al., 2004).
The risk of cancer of the ovaries, endometrium, or uterus was associated with caffeine in-
take in several case-control studies. Goodman et al. (2003) found that regular coffee drinkers, or
a total caffeine intake of ≥ 0.43 g/week (~1 mg/kg/d) was associated with an increased risk of
ovarian cancer, especially for women with a CYP1A2 genotype. A positive association of ovar-
ian cancer in pre-menopausal but not post-menopausal women was found for an intake of ≥2
cups/day coffee if the subjects carried CYP19 variant genes (Kuper et al., 2000), and for an in-
take of ≥ 410 mg/day caffeine (~8.5 mg/kg/day) (Kotsopoulos et al., 2009a). The cohort study of
Leuth et al. (2008) found in increased risk of ovarian cancer in women who consumed ≥ 5
cups/day coffee. Other studies, however, found no association or a decreased risk of cancer with
caffeine intake by coffee and/or tea. The case-control studies of Tavani et al. (2001b), Baker et
al. (2007), and Song et al. (2008) found a decreased risk for ovarian cancer. The case-control
276
studies of Jordan et al. (2004) and Bandera et al. (2010), and the cohort study of Friberg et al.
(2009) found a decreased risk for endometrial cancer.
Only two studies were located that evaluated the effect of caffeine intake on prostate can-
cer. The cohort study of Nilsson et al. (2010) found no association of coffee or tea intake with
the risk of prostate cancer.
Most studies that evaluated the association of caffeine intake with colon or colorectal
cancer found no association or an inverse relationship, including the case-control study of Munoz
et al. (1998) and several cohort prospective studies (Michels et al., 2005; Larsson et al., 2006a;
Naganuma et al., 2007; and Peterson et al., 2010). However, a positive association with rectal
cancer was identified for an intake of >6 cups/day coffee (>8.6 mg/kg/day) in men and women in
the cohort study of by Simons et al. (2010). An increased risk of colon cancer was found at low
levels of caffeine intake (0.2-1.4 mg/kg/day) but a decreased risk for high intake (>7.4
mg/kg/day) in a case-control study by Slattery et al. (1999).
Conflicting results were obtained regarding the impact of caffeine intake on pancreatic
cancer risk. A recent case-control study found that an intake of ≥3 servings/day doubled the
pancreatic cancer risk in men and women (Anderson et al., 2009), and a Swedish cohort study
found an increased risk of pancreatic cancer for subjects who ingested boiled coffee (Nilsson et
al., 2010). Mutations were found more commonly in pancreas exocrine tumors from patients
with an intake of ≥2 cups/week coffee (Porta et al., 1999). Conversely, the recent case-control
study of Polesel et al. (2009) and the cohort study of Michaud et al. (2001) found no association
between caffeine intake and pancreatic cancer risk.
Intake of caffeinated drinks had an inverse relationship with the risk of cancer of the oral
cavity, pharynx, and/or esophagus in three epidemiological studies (Galeone et al., 2010; Na-
ganuma et al., 2008; Ren et al., 2010). A marginal increase in the risk for gastric cancer was
found by Gallus et al. (2009) for an intake of ≥ 4 cups coffe/day in men and women, and by Re-
net al. (2010) for an intake of >3 cups/day coffee.
The risk of caffeine intake on the lung, kidney, CNS, and the immune system was exam-
ined in few studies. A positive association was found for lung cancer from an intake of ≥ 2
cups/day coffee (Baker et al., 2005); for respiratory tract cancer from drinking boiled coffee
(Nilsson et al., 2009); for CNS ependymomas from intake of >3 cups/day coffee (Munoz et al.,
1998); for childhood acute leukemia from an intake of >3 cups/day coffee by non-smoking
mother during pregnancy (Menegaux et al., 2007); and a borderline association for non-
Hodgkin’s lymphoma from intake of cola. There was no association of caffeine intake with renal
cancer (Nilsson et al., 2009; Montella et al., 2009). Caffeine intake was not significantly associ-
ated with the risk of cancer death in women or men (Lopez-Garcia et al., 2008; Tamakoshi et al.,
2011).
Conclusions drawn by review articles regarding the association of caffeine intake and the
risk of cancer are summarized in Table 15-2. After a meta-analysis of 34 case-control and 3 co-
hort studies, Zeegers et al. (2001) concluded that coffee consumption increases the risk of uri-
nary tract cancer by about 20%, whereas tea had no effect. Pelucchi and La Vecchia (2009) con-
277
cluded that a strong association between coffee intake and bladder cancer could be excluded, and
that the moderate risk seen in some studies might be attributed to confounding by smoking, alco-
hol, or other unidentified factors. A meta-analysis of prospective cohort studies (Je et al., 2009)
and a meta-analysis of case-control studies (Galeone et al., 2010a) found no increase in the risk
of colorectal cancer from caffeine intake and possibly a slight protective effect. Prostate cancer
was concluded to probably not be associated with caffeine intake by Lee et al. (2009). Park et al.
(2010) found a significant association of caffeine intake and prostate cancer in case-control but
not in cohort studies, and concluded that the latter were more important, and thus coffee con-
sumption did not increase prostate cancer risk. Several reviews concluded that caffeine intake
was either not associated with cancer risk, or was protective, including the risk of cancer of the
liver, kidney, prostate, pancreas, ovary, endometrium, colon, oral cavity/pharynx; and/or pan-
creas (Nkondjock et al., 2009; Arab, 2010; Zhang et al., 2010; Turati et al., 2010; and Gallus et
al., 2011).
278
TABLE 15- 1. Caffeine and Cancer – Human Studies
Study type; Subject age; Test material Effects; Comments
Caffeine dose(s) Reference
country number; sex [condition] (sorted by study type; then publication year)
BREAST
Case-control <36 yr caffeinated 0-100, 101-200, There was no association between caffeine consumption at ages 16 and 25, and risk of Smith et al.,
(UK) cases=755 F; drinks [age] 201-300, >300 breast cancer diagnosed before the age of 36; risk was reduced non-significantly at each 1994c
controls=755 F mg/d [<1.7 to level of consumption above baseline.
>5.0 mg/kg/d]
Case-control cases=22-74 yr; coffee; decaf; Coffee <2, 2, >2 No relationship was observed between coffee or tea intake and the risk of breast cancer. Tavani et
(Italy) controls=15-74 tea to <4, ≥4 cups/d [Decaf and tea intake were categorized as + or -; no info on caffeine per cup; assumed al., 1998
yr [<3.4 to ≥6.7 100 mg/cup coffee]
cases=5,984 F; mg/kg/d]
controls=5,504 F
Case-control <30-64 yr Coffee 0, 1-3, 4-5, ≥6 Among women with BRCA gene mutation diagnosed before age 50 yr, caffeinated coffee Nkondjock
(Canada; Israel; cases=1,690 F; [BRCA1 or cups/d [1.7 to consumption may be related to reduced breast cancer risk; effect not seen for decaf or for et al., 2006
Poland; USA) controls=1,690 F BRCA2 muta- ≥10 mg/kg/d] total (decaf + caff) coffee. [No info on caffeine per cup; assumed 100 mg/cup]
tion carrier]
Case-control cases=52.4 ± coffee never; never; ever F with a variant C allele in the CYP1A2 gene (AC or CC; associated with decreased en- Kotsopoulos
(USA) 12.3 yr (170 F); ever [BRCA1 zyme inducibility and impaired caffeine metabolism) who consumed coffee had a 64% et al., 2007
controls=43.1 ± mutation car- reduction in breast cancer risk compared with non-consumers; protective effect was not
13.2 yr (241 F) riers; CYP1A2 seen among women with the CYP1A2 AA genotype.
AA genotype]
Case-control Adult Coffee [non- ≤2, >2 and 8 Women who drank more than eight cups of coffee per day had an increased risk of breast Bissonauth
(Canada) cases=280 F; carrier of cups/d [≤3.3 to cancer: OR = 1.40 (95% CI: 1.09-2.24; p = 0.03). [No info on caffeine per cup; assumed et al., 2009
controls=280 F BRCA1/2 mu- 13 mg/kg/d] 100 mg/cup coffee]
tations]
Cohort prospec- 40-76 yr coffee; tea Quintiles: 83.8, Consumption of coffee, tea, or caffeine were not associated with breast cancer incidence. Michels et
tive (508,267 n=59,036 F 186.6, 196.3, [Intake categories were ≤1, 2-4 cups/wk, 1, 2-3, ≥4 cups/d] al., 2002
person-yr fol- 253.5, 308.8
low-up) mg/d [1.4-5.1
(Sweden) mg/kg/d]
279
Cohort prospec- mean 35-37 yr at caffeine, all <62, 63-171, High caffeine consumption (≥382 mg/d) was positively associated (RR = 2.46, 95% CI Webb et al.,
tive (6 yr follow- baseline sources 172-381, ≥382 1.11-5.49 for the highest quartile) with increased risk of atypical hyperplasia (benign 2004
up) (USA) n=56,628 F mg/d [<1.0 to breast disease marker of increased breast cancer risk) although these analyses were based
≥6.4 mg/kg/d] on small numbers.
Cohort prospec- mean 54-55 yr at caffeine, all 0, <1, 1, 2-3, ≥4 Caffeine intake was not associated with overall risk of breast cancer; F with benign breast Ishitani et
tive (10 yr mean baseline sources; coffee cups/d disease had borderline association with breast cancer risk at ≥4 cups/d coffee; caffeine al., 2008
follow-up) n=38,432 F intake was associated with risk of estrogen receptor-negative and progesterone receptor-
(USA) negative breast cancer and breast tumors >2 cm. [Assumptions: 1 cup = 137 mg (coffee),
47 mg (tea), 46 mg (bottle of cola), 7 mg (chocolate candy)]
Cohort prospec- 40-76 yr at coffee; tea, coffee: <1, 1, 2– Coffee intake was not associated with risk of overall breast cancer (for ≥4 vs. <1 cups/d Larsson et
tive (17.4 yr baseline black 3, ≥4 cups/d; tea: RR=.02 [0.87-1.20]) or with tumor estrogen receptor (ER) and progesterone receptor al., 2009
follow-up) n=61,433 F 0, <1, 1, ≥2 (PR) status; black tea intake was positively associated with risk of overall breast cancer
(Sweden) cups/d [<1.7 to (for ≥2 vs. 0 cups/d RR=1.22 [1.05-1.42] and for ER+/PR+ tumors RR=1.36 [1.09-1.69]).
≥6.7 mg/kg/d] [Assumed caffeine content was 120 mg per cup coffee and 52 mg per cup tea]
Cohort prospec- 21-69 yr at caffeine, all <16, 16-42, 43- Intakes of tea, coffee, and caffeine were not associated with the risk of breast cancer Boggs et al.,
tive (6 yr follow- baseline sources; coffee; 92, 93-208, ≥209 among African-American women. [Intake categories for coffee or tea: <1/mo, <1, 1, 2-3, 2010
up) (USA) n=52,062 F tea [post- mg/d [<0.3 to ≥ 4 cups/d; decaf: <1/mo, <1, 1, ≥ 2 cups/d]
menopausal] ≥3.5 mg/kg/d]
Cohort prospec- 20-70 yr at coffee; tea 0, 0.1-1.0, 1.1- Coffee intake increased the risk of breast cancer (consumers vs. non-consumers HR=2.25 Bhoo Pathy
tive (9.6 yr fol- baseline 2.0, 2.1-3.0, 3.1- (1.30-3.90)), but the association did not hold after multivariate adjustment (HR=1.17 et al., 2010
low-up) (The n=27,323 F 5.0, >5 cups/d (0.65-2.12)). [No info on caffeine per cup; assumed 100 mg/cup coffee and 40 mg/cup
Netherlands) [<0.1 to >8.3 tea]
mg/kg/d]
Cross-sectional n1=24-33 yr, 136 Coffee [famil- 0, <1, 1.0-1.9, Intake of ≥3 cups per day was associated with lower breast volume (and lower cancer Jernstrom et
(Sweden) F (A/A allele); ial breast can- 2.0-2.9, 3.0-3.9, risk) only in C-allele carriers; no association between coffee and breast volume was ob- al., 2008
n2=24-36 yr, 131 cer risk; 4.0-4.9. 5.0-5.0, served in women with the CYP1A2*1F A/A genotype or in women who used hormonal
F (C allele) CYP1A2 geno- ≥6 cups/d [<1.7 contraception. [No info on caffeine per cup; assumed 100 mg/cup]
type] to >10 mg/kg/d]
280
OVARIES / ENDOMETRIUM / UTERUS
Case-control Adult caffeinated 0, <1, 1, 2-3, ≥4 Coffee/caffeine intake of ≥2 cups/d (≥280 mg/d) was associated with increased risk for Kuper et al.,
(USA) cases=549 F; drinks cups/d [<1.7 to ovarian cancer in only premenopausal women. [Used 140 mg/cup coffee, 50 mg/cup tea, 2000
controls=516 F ≥6.7 mg/kg/d] 40 mg/8 oz of caffeinated soft drinks, 30 mg/8 oz cola and 2.5 mg/cup decaf to divide
caffeine intake into quintiles, of which the caffeine intake was not provided; here as-
sumed 100 mg/cup coffee for dose estimates]
Case-control 17-79 yr coffee; decaf; Coffee <1, 1 to There was no association of ovarian cancer with intake of coffee (mostly espresso and Tavani et
(Italy) cases=1,031 F; tea <2, 2 to <3, 3 to mocha), cappuccino, decaffeinated coffee, or tea. [Decaf and tea intake were categorized al., 2001b
controls=2,411 F <4, ≥4 cups/d as + or -; no info on caffeine per cup; assumed 100 mg/cup coffee]
[<1.7 to ≥6.7
mg/kg/d]
Case-control 66 yr caffeine, all <0.43, 0.43-1.24, Increased risk of ovarian cancer for regular coffee drinkers, and for overall caffeine in- Goodman et
(USA) cases=164 F; sources; coffee; >1.24 g/wk [<1.0 take of ≥0.43 g/wk, but not for tea or soda drinking; risk was greater for F with CYP1A2 al., 2003
controls=194 F tea [CYP1A2 to >3.0 mg/kg/d] A/A genotype than with any C allele.
genotype]
Case-control 18-79 yr coffee; tea 0, <1, 1, 2-3, ≥4 Coffee (or total caffeine) intake was associated with decreased risk of invasive epithelial Jordan et
(Australia) cases=696 F; cups/d coffee or ovarian cancer (EOC) at 0 vs. ≥4 cups/d [4.7 mg/kg/d], or ≤130 vs. ≥330 mg/d [5.5 al., 2004
controls=786 F tea; caffeine mg/kg/d] for serous and endometrioid or clear cell histological subtypes; no association
quintiles ≤130, with borderline tumors; tea was not related to EOC. [Intake categories 0, [Caffeine con-
131-199, 200- tent: 70 mg/250 mL cup coffee; 50 mg/250 mL cup tea; 36 mg/375 mL can cola; 10
259, 260-329, mg/50 g bar of chocolate]
≥330 mg/d
Case-control n=55.6 ± 13.7 yr; coffee; decaf; Coffee 0, ≤1, 2-3, Black tea and decaf consumption were associated with a linear decline in ovarian cancer Baker et al.,
(USA) c=55.4 ± 13.7 yr tea, black ≥4 cups/d [≤1.4 risk (intake of ≥2 cups/day had 30% lower risk), but there was no association between 2007
cases=414 F; to ≥5.7 mg/kg/d] regular coffee consumption and risk. Intake categories were 0, <1, 1, ≥2 cups/d for black
controls=868 F tea and 0, ≤1, ≥2 cups/d for decaf. [No info on caffeine content of coffee; assumed 100
mg/cup]
281
Case-control 35-74 yr coffee; tea; Coffee: <1, 1-<2, Neither caffeinated nor decaffeinated coffees were associated with ovarian cancer risk; Song et al.,
(USA) cases=781 F; cola 2-<3, ≥3 cups/d there was no association of total caffeine with risk using the combined intake from cof- 2008
controls=1,263 F [<1.7 to ≥5 fee, tea, and carbonated soft drinks. Among teas, neither herbal nor decaffeinated nor
mg/kg/d] black teas were associated with risk; however, women who reported drinking ≥1 cup/d of
green tea had a 54% reduction in risk (P trend = 0.01). [Intake categories for tea were <1
to ≥1 cup/d, and for colas were <1, 1-<2, ≥2 cans/d; coffee serving equivalent = 137 mg;
values for tea and cola not provided; and total caffeine not provided]
Case-control means 51-52 yr; caffeine, all <410 mg/d, ≥410 Increased risk of ovarian cancer in premenopausal F in the NECC study population only Kotsopoulos
(USA) 59-60 yr sources [CYP mg/d (not NHS I or II); carrying one or both of the variant CYP19 genes (CYP19013 A or et al., 2009a
cases=1,354 F; genotype] CYP19027 G alleles) was associated with an 18% increased and 15% decreased risk of
controls=1,851 F ovarian cancer, respectively. Variation in CYP1A1, CYP1A2, or CYP2A6 did not ex-
plain the inconsistent reports of coffee intake and risk.
Case-control cases mean= 61.6 coffee; tea coffee: 0, ≤1, >1- Moderate inverse association of endometrial cancer risk with coffee consumption Bandera et
(USA) yr (417 F); con- 2, >2 cups/d; (OR=0.65 (0.36-1.17)) for 0 vs. >2cups/d [3.3 mg/kg/d]; tea increased risk for 0 vs. >1 al., 2010
trols mean=64.3 Tea: 0, ≤1, >1 cup/d [0.7 mg/kg/d] (OR: 1.93 (1.08-3.45)) but not after including the variables added
yr (395 F) cup/d sugar/honey and cream/milk. [No info on mg caffeine per cup; assumed 100 mg/cup
[≤0.7 to >3.3 coffee and 40 mg/cup tea]
mg/kg/d]
Cohort prospec- 55-68 yr at caffeine, all 0-20, 21-115, An increased risk of ovarian cancer was observed in the multivariate model for F who Lueth et al.,
tive (18 yr fol- baseline sources [post- 116-344, 345- drank 0 vs. ≥5 cups/day [8.3 mg/kg/d] of caffeinated coffee (HR = 1.81, 95% CI: 1.10- 2008
low-up) n=29,060 F menopausal] 463, 464-1162 2.95). Decaffeinated coffee, total coffee, and caffeine were not significantly associated
(USA) mg/d [<0.3-19 with ovarian cancer incidence. [Coffee intake categories were 0, <1, 1-2, 3-4, ≥5 cups/d;
mg/kg/d] 1 cup= 8 oz = 237 mL=237 mg; caffeine content used was 21 mg/100 g chocolate, 27
mg/100 g tea; 58 mg/100 g coffee (137 mg/cup); 13 mg/100 g soda; 88% of total caffeine
intake was contributed by coffee]
Cohort prospec- mean 51-59 yr at coffee ≤1, 2-3, ≥4 In women drinking ≥4 cups/d coffee, the RR for the risk reduction of endometrial cancer Friberg et
tive (17.6 yr baseline cups/d [≤1.7 to was 0.75 (95% CI, 0.58-0.97) when compared with those who drank ≤1 cup/d. The asso- al., 2009
follow-up) n=60,634 F ≥6.7 mg/kg/d] ciation seemed largely confined to overweight and obese women. [No info on caffeine
(Sweden) per cup; assumed 100 mg/cup coffee]
282
PROSTATE
Cohort prospec- 39-59 yr filtered or <1 (reference), 1- No associations for all cancer sites combined, or for prostate or colorectal cancer. For Nilsson et
tive (15 yr fol- n=64,603 (50% boiled coffee 3, ≥4 occasions/d breast cancer, boiled coffee (≥4 vs. <1/d) was associated with a reduced risk; an increased al., 2010
low-up) M) [<1 to ≥5.7 risk of premenopausal and a reduced risk of postmenopausal breast cancer held for both
(Sweden) mg/kg/d] total and filtered coffee. Boiled coffee was positively associated with the risk of respira-
tory tract cancer in M; total coffee was associated with a lower risk for renal cell cancer;
boiled coffee was associated with a higher risk of pancreatic cancer. [No info on caffeine
intake per occasion; assumed 100 mg]
COLON / RECTUM
Case-control 23-79 yr coffee; tea; Coffee or tea: 0, The consumption of coffee, maté, and tea were not related to colorectal cancer; the odds Munoz et
(Argentina) cases=190; con- yerba mate ≥1 cup/d [≥1.4 ratios were <1 [(0.9 (0.7-1.3) for coffee, 0.9 (0.6-1.2) for maté and 0.8 (0.6-1.2) for tea al., 1998
trols=393 M+F mg/kg/d]; mate: drinkers]. [No info on caffeine per cup; assumed 100 mg/cup coffee, 50 mg/cup mate,
0, ≤5, >5 cups/d and 40 mg/cup tea]
[≤ or >3.6
mg/kg/d]
Case-control 30-79 yr coffee; smok- Coffee: ≤2.0, 2.1- Among men, low levels of coffee intake were associated with an increased risk of colon Slattery et
(USA) cases=1993; con- ing 4.0, 4.1-6.0, >6.0 cancer relative to non-consumers (OR 1.32, 95% CI 1.02-1.67), but an inverse associa- al., 1999
trols=2410 cups/d]; total tion was observed for high consumers (OR 0.81, 95% CI 0.58-1.12). Changing the refer-
(M+F) caffeine 15-96, ent group to those consuming ≤ 1 cup/d coffee resulted in a stronger association and a
97-273, 274-519, more significant inverse linear trend (OR 0.71, 95% CI 0.53-0.96). There was a signifi-
>519 mg/d [0.2 cant interaction between smoking and coffee and colon cancer risk for both men and
to >7.4 mg/kg/d] women.
Cohort prospec- mean 55-60 yr coffee; decaf; Coffee: 0, ½, 1, Caffeinated coffee or tea, or total caffeine intake were not associated with colon or rectal Michels et
tive (follow-up M=46,099; tea 2-3, 4-5, >5 cancer; ≥2 cups/d decaf coffee was associated with a reduced incidence of rectal cancer al., 2005
M=12 yr, F=18 F=87,794 cups/d [1.0 to (decaf intake categories were 0, ¼, ½, 1-1.9, ≥2 cups/d; caffeine content not provided).
yr) >9.8 mg/kg/d] [Used mg/cup: coffee, 137; tea, 47; 1 can/bottle of cola, 46; 1 serving of chocolate, 7;
(USA) caffeine intakes in the quintiles were not provided]
Cohort prospec- M:45-79 yr at coffee <1, 1, 2–3, 4–5, Coffee consumption was not associated with risk of colorectal cancer, colon cancer, or Larsson et
tive (6 yr follow- baseline; F:40-76 ≥6 cups/d [<1.4 rectal cancer in either women or men. For both cohorts combined, the multivariate rate al., 2006a
up for M, 17 yr yr at baseline to ≥8.6 mg/kg/d] ratio for colorectal cancer for each additional cup of coffee per day was 1.00 (95% confi-
for F) n=106,739 (42% dence interval: 0.97, 1.04). [No info on caffeine per cup coffee; assumed 100 mg/cup]
(Sweden) M)
283
Cohort prospec- 40-64 yr at coffee 0, occasional, 1- Coffee consumption was not associated with the incidence of colorectal, colon (proximal Naganuma
tive (11.6 yr baseline 2, ≥3 cups/d [1.4 or distal) or rectal cancer. The adjusted Hazard Ratio (95% CI) of colorectal cancer inci- et al., 2007
follow-up) n=47,605 (48% to ≥4.3 mg/kg/d] dence for 0 vs. ≥3 cups/d coffee was 0.95 (0.65-1.39) for men and women (p for trend =
(Japan) M) 0.55). [No info on caffeine per cup; assumed 100 mg/cup]
Cohort prospec- 40-64 yr coffee never, occasion- Inverse association between coffee consumption and mortality due to coronary heart dis- Sugiyama et
tive (10.3 yr n=37,742 (48% ally, 1-2, ≥3 ease in women but not in men; death due to colorectal cancer was associated with coffee al., 2010
follow-up) (Ja- M) cups/d [1.4 to consumption in women. [No info on caffeine per cup; assumed 100 mg/cup]
pan) ≥4.3 mg/kg/d]
Cohort prospec- 45-74 yr coffee 0, <1, 1, ≥2 No overall association between coffee intake and colorectal cancer; ever smokers with Peterson et
tive (12 yr fol- N=61,321 (43- cups/d [<1.4 to advanced disease had an inverse association (P for trend = 0.01; HR=0.56 (0.35-0.90) for al., 2010
low-up) 52% M) ≥2.9 mg/kg/d] 0 or <1 cup vs. ≥ 2 cups/d. [No info on caffeine per cup; assumed 100 mg/cup]
(Singapore)
Cohort prospec- 55-69 yr at coffee; dietary ≤2 (ref.), >2–4, For rectal cancer risk in M, there was a significant positive trend for coffee intake (>6 vs. Simons et
tive (13.3 yr baseline fiber >4–6, >6 cups/d ≤2 cups/day Hazard Ratio HR= 1.60, 95% CI = 0.96-2.66, P trend = 0.05). There was no al., 2010
follow-up) (The n=120,852 (48% [≤2.9 to >8.6 evidence that fiber intake modified associations. [No info on caffeine per cup; assumed
Netherlands) M) mg/kg/d] 100 mg/cup coffee]
Cohort prospec- 26-74 yr at coffee 0, 1-2, 3-4, 5-6, No association between coffee consumption and the risk of colorectal, colon and rectal Bidel et al.,
tive (18-yr fol- baseline 7-9, ≥10 cups/d cancer for 0 vs. ≥ 10 cups/d in M (0.98; 0.47-2.03), or F (1.24; 0.49-3.14); or in M+F 2010
low-up) n=60,041 (48.6% [1.4 to ≥14 (1.03, 0.58-1.83). [No info on caffeine per cup; assumed 100 mg/cup coffee]
(Finland) M) mg/kg/d]
URINARY BLADDER
Case-control most were >55 yr Coffee [CYP 0, 1, 2, 3, ≥4 There was a modest increased bladder cancer risk among coffee drinkers (≥4 cups/d) that Villanueva
(Spain) cases=1,136 and NAT2 cups/d [1.4 to may, in part, be explained by residual confounding by smoking; gene-coffee interactions et al., 2009
(88.1% M); con- phenoptype] ≥5.7 mg/kg/d] for NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified. [No info on
trols=1,138 caffeine per cup; assumed 100 mg/cup]
(87.2% M)
Case-control cases mean 63 yr Coffee 0, ≤3, 4, ≥5 Increased risk of bladder cancer among heavy coffee drinkers (>5 cups/day; OR 3.1, 95% Pavanello et
(Italy) (n=185 M); con- [CYP1A2 phe- cups/d [≤4.3 to CI: 1.2-7.9) [and heavy smokers]. Case-only analysis showed no interaction between al., 2010
trols mean 62 yr notype] ≥7.1 mg/kg/d] CYP1A2 polymorphisms and coffee consumption. No overall effect of CYP1A2 by itself
(n=180 M) on cancer risk. [No info on caffeine/cup; assumed 100 mg/cup]
284
Cohort prospec- 40-69 yr coffee; smok- median caffeine Coffee was positively associated with bladder cancer risk in men, without statistical sig- Kurahashi
tive (15 yr fol- n=104,440 (47% ing; tea, green mg/d M: 40, 130, nificance. When stratified by smoking status, coffee and caffeine consumption were as- et al., 2009
low-up) M) 180, 320 mg/d; F: sociated with an increased risk of bladder cancer in never- or former-smoking men, with
(Japan) 50, 130, 240 hazard ratios in the highest categories of coffee (≥ 1 cup/d) and caffeine consumption vs.
[M: 0.6-4.6 the lowest of 2.24 (95% CI = 1.21-4.16) and 2.05 (95% CI = 1.15-3.66), respectively.
mg/kg/d; F: 0.8- [Intake categories were coffee: 0, 1-4 cups/wk, 1-2, ≥3 cups/d; tea: <1/wk, 1-2, 3-4, ≥5
4.0 mg/kg/d] cups/d]
PANCREAS
Case-control 63 ± 9.9 yr caffeinated <1, 1-2, ≥3 serv- Intake of ≥3 servings/d caffeinated drinks doubled the pancreatic cancer risk. [No info on Anderson et
(Canada) cases=422; con- drinks ings/d [<0.6 to mg caffeine per cup; assumed 100 mg/cup coffee and 40 mg/cup tea or soft drink] al., 2009
trols=312; 56% ≥5.0 mg/kg/d]
M
Case-control 34-80 yr Coffee and quintiles median Milk, yogurt, coffee, and tea were not related to the risk of pancreatic cancer. [No info Polesel et
(Italy) cases=326; con- cappuccino servings/wk: 0.5, on caffeine per cup; assumed 100 mg/cup coffee or cappuccino] al., 2009
trols=652 M+F 7, 14, 21, 28
[<1.4 to 5.7
mg/kg/d]
Cross-sectional 64.5 ± 2.4 yr coffee <2, 2-7, 8-14, Mutations were found in the K-ras gene in exocrine pancreatic tumors from 94 of 121 Porta et al.,
(Spain) case-case; n=121 ≥15 cups/wk patients, and were more common in those with intake of ≥2 cups/wk; mean intake among 1999
M+F [<0.3 to ≥3.1 patients with a mutated tumor was 14.5 cups/week vs. 8.8 among those with a wild type
mg/kg/d] tumor. [In Spain, it is estimated that an average cup of coffee is 35-50 mL and contains
95-115 mg caffeine.]
Cohort prospec- M=40-75 yr caffeine, all 0, 1-3, >3 cups/d Coffee (≥4 vs. 0 cups/d), tea, and total caffeine intakes were not associated with an in- Michaud et
tive (follow-up (n=47,794); sources; coffee; [1.4 to >4.3 creased risk of pancreatic cancer in either cohort or after pooling the results (examined al., 2001
M=12 yr, F=16 F=30-55 yr decaf; tea mg/kg/d] various latency periods). [Total caffeine intake was calculated by summing the amount
yr) (n=88,799) in coffee (77%), tea (13%), soda (6.6%), decaf (3%), chocolate (0.3%), and candies
(USA) (0.1%); caffeine corresponding to quintiles of total caffeine intake were not provided.]
[Caffeine/cup was not provided; assumed 100 mg/cup]
285
ORAL / PHARYNGEAL / GASTRIC
Case-control 19-80 yr coffee; decaf; 0, 1, 2, 3, ≥4 Compared with coffee non-drinkers, risk of gastric cancer OR=0.94 (0.73-1.22) for 1 Gallus et al.,
(Italy) cases=999 (61% tea, black cups/d coffee; 0, cup/d, 1.03 (0.80-1.32) for 2 cups/d, 1.07 (0.82-1.40) for 3 cups/d, and 1.24 (0.94-1.65) 2009
M); con- 1 ≥2 cups/d tea for ≥4 cups/d; no association with duration of coffee consumption, or consumption of
trols=2,628 (57% [0.6 to ≥5.7 decaf. Compared with tea non-drinkers, OR= 0.89 (0.56-1.42) for ≥2 cups/d. [No info on
M) mg/kg/d] caffeine/cup; assumed 100 mg/cup coffee and 40 mg/cup tea]
Case-control 18-80 yr coffee 1, 2, 3, 4, >4 Inverse association between caffeinated coffee drinking and risk of cancer of the oral Galeone et
(Puerto Rico; cases=5,139 cups/d [1.4 to cavity and pharynx. [No info on caffeine per cup; assumed 100 mg/cup coffee] al., 2010
France; Italy; (79% M); con- >5.7 mg/kg/d]
Switzerland; trols= 9,028
USA) (70.3% M)
Cohort prospec- 40-64 yr at coffee 0, occasional, ≥1 The risk of oral, pharyngeal, and esophageal cancers was inversely associated with coffee Naganuma
tive (13.6 yr baseline cup/d [< or ≥1.4 consumption. The multivariate-adjusted hazard ratio of these cancers for ≥1 cups of cof- et al., 2008
follow-up) (Ja- n=38,679 (47- mg/kg/d] fee/d vs. 0 cup/d was 0.51 (95% CI 0.33, 0.77). This inverse association was consistent
pan) 51% M) regardless of sex and cancer site and was observed both for subjects who did not drink or
smoke and for those who currently drank or smoked at baseline. [No info on caffeine per
cup; assumed 100 mg/d]
Cohort prospec- 50-71 yr at caffeinated Coffee <1, 1, 2-3, Compared to non-drinking, the hazard ratio for hot tea intake of ≥1 cup/day was 0.37 Ren et al.,
tive (2,584,953 baseline drink, carbon- >3 cups/d [<1.4 (95% CI: 0.20, 0.70) for pharyngeal cancer. There was a significant association between 2010
person-years of n=481,563 (59% ated; coffee; to >4.3 mg/kg/d]; coffee drinking and risk of gastric cardia cancer (compared to <1 cup/day, the hazard
follow-up) M) tea Hot tea 0, <1, 1-3 ratio for drinking >3 cups/day was 1.57 (95% CI: 1.03, 2.39), and an inverse association
(USA) cups/mo, 1-6 between coffee drinking and esophageal adenocarcinoma for the cases occurring in the
cups/wk, ≥1 last 3 years of follow-up (compared to <1 cup/day, the hazard ratio for drinking >3
cup/day [<0.3 to cups/day was 0.54 (95% CI: 0.31, 0.92)), but no association in earlier follow-up. [No info
≥0.7 mg/kg/d] on caffeine per cup; assumed 100 mg/cup coffee; 40 mg/cup tea, and minimum of 0.5 cup
hot tea consumed/day for dose estimates]
286
IMMUNE SYSYEM
Case-control 17-79 yr Coffee; caf- Coffee: 0, 1, 2, 3, Compared with non-drinkers, the RR for non-Hodgkin's lymphoma was 1.2 (95% CI, Tavani et
(Italy) cases=429 feinated drinks 4, ≥5 cups/d [1.4 0.8-1.7) for coffee drinkers. No trend in risk emerged with number of cups of coffee con- al., 1994
(58.0% M); con- to ≥7.1 mg/kg/d] sumed/day (RR = 1.1 for one and three cups; RR = 1.2 for two; or RR = 0.9 for four
trols=1157 cups/day), or duration of coffee intake (RR = 1.2 for less than 20 years; RR = 1.3 for 21-
(61.3% M) 30 years; and RR = 1.1 for more than 30 years). No significant association was observed
with consumption of decaffeinated coffee (RR = 0.9) or tea (RR = 1.2). Consumption of
cola was associated with a borderline risk (RR = 1.7; 95% CI 1.0-2.7). [Other drinks
were categorized as + or -]
Case-control Adult coffee ≤3, >3 cups/d [≤ Childhood acute leukaemia (diagnosed before age 15) risk increased if the mother con- Menegaux
(France) cases=472 F; or >5.0 mg/kg/d] sumed >3 cups/d during pregnancy and did not smoke. [No info on caffeine per cup; et al., 2007
controls=567 F assumed 100 mg/cup]
LUNG, KIDNEY, and CNS

Case-control 26 to 75+ yr coffee; decaf; ≤1, 2-3, ≥4 Lung cancer risk was elevated from coffee intake of ≥2 cups/d but was unrelated to black Baker et al.,
(USA) cases=993 (624 tea, black cups/d [≤1.7 to tea consumption; decaf coffee decreased lung cancer risk. [No info on caffeine per cup; 2005
M); controls=986 ≥6.7 mg/kg/d] assumed 100 mg/cup coffee]
(619 M)
Case-control cases: 24-79 yr coffee; decaf; <1,1-3, ≥4 cups/d No evidence that coffee, decaffeinated coffee, or tea consumption are related to renal cell Montella et
(Italy) n=767 (494 M); tea [<1.4 to ≥5.7 carcinoma risk. [No info on caffeine per cup; assumed 100 mg/cup for dose estimates] al., 2009
controls: 22-79 mg/kg/d]
yr
n=1534 (988 M)
287
Case-control Adult coffee; tea coffee ≤3, >3 Associations between ependymomas and the highest consumption of coffee [OR: 2.7 Plichart et
(France) cases=208 F; cups/d; tea ≤1, >1 (0.9-8.1)] and tea [OR: 2.5 (1.1-5.9)] were observed. A strong association between CNS al., 2008
controls=1,681 F cup/d tumors and the highest maternal consumption coffee + tea during pregnancy was ob-
[0.6 to >4.3 served [OR: 4.4 (1.5-13)]. [No info on caffeine per cup; assumed 100 mg/cup coffee, 40
mg/kg/d] mg/cup tea]
MORTALITY (DUE TO CANCER)

Cohort prospec- 40-79 yr at coffee <1, 1, 2-3, ≥4 All-cause mortality risk decreased with increasing coffee consumption in M and F, with a Tamakoshi
tive (16 yr fol- baseline cups/d [<1.4 to risk elevation at the highest coffee consumption (≥4 cups/d [5.7 mg/kg/d]) compared with et al., 2011
low-up) n=97,753 (41.6% ≥5.7 mg/kg/d] the 2nd highest consumption level in F, but the number of subjects was small; no associa-
(Japan) M) tion between coffee consumption and total cancer mortality in M, but a weak inverse as-
sociation was found among F. [No info on caffeine per cup; assumed 100 mg/cup]
Cohort prospec- M=52-53 yr coffee; decaf <1 cup/mo; ≤4, Coffee consumption was not associated with risk for cancer or CVD death, or with an Lopez-
tive (18 yr fol- mean at baseline 5-7 cups/wk, 2-3, increased overall mortality rate in either M or F; decaf consumption was associated with Garcia et
low-up in M; 24 (n=41,736); 4-5, ≥6 cups/d a small reduction in all-cause and CVD mortality. [Estimated: 137 mg/cup of coffee, 47 al., 2008
yr in F) F= 45-46 yr [coffee: <0.1 to mg/cup of tea, 46 mg per can or 12-oz bottle of soft drink, 7 mg per 1-oz serving of
(USA) mean at baseline ≥8.7 mg/kg/d] chocolate candy.]
(n= 86,214)
288
TABLE 15- 2. Caffeine and Cancer – Summaries of Reviews Reference
At the doses usually consumed by man, coffee does not have any potential genotoxic, mutagenic or carcinogenic effect. There is still some debate on the effect Nehlig and
of coffee in the carcinogenesis of the pancreas, colon, bladder and urinary tract. Debry, 1996
Analysis of 34 case-control and 3 follow-up studies found that coffee consumption increases the risk of urinary tract cancer by ~20% (adjusted summary OR Zeegers et al.,
(95% CI)=1.26 (1.09-1.46) for M, 1.08 (0.79-1.46) for F, and 1.18 (1.01-1.38) for M+F. Neither unadjusted nor adjusted summary OR showed a positive asso- 2001
ciation between tea consumption and urinary tract cancer.
Several early studies suggested that coffee consumption could result in a marked increase in risk of coronary heart disease and several types of cancer. How- van Dam,
ever, more recent prospective cohort studies that are less prone to selection and information bias have not confirmed these findings. High consumption of unfil- 2008b
tered types of coffee, such as French press and boiled coffee, has been shown to increase low-density-lipoprotein-cholesterol concentrations.
Results from epidemiological studies allow excluding a strong association between coffee and bladder cancer. Several studies reported a moderate increase in Pelucchi and
risk in coffee drinkers as compared with nondrinkers, but no trend with dose has been established. The moderate increase in risk observed in some investiga- La Vecchia,
tions might be attributed to residual confounding by smoking, or to an association between alcohol, coffee, and yet unidentified risk factors for bladder cancer. 2009
Coffee consumption probably has no relationship with prostate cancer. Tea, especially green tea, has shown some potential in the prevention of prostate cancer. Lee et al.,
While evidence from epidemiologic studies is currently inconclusive, strong evidence has emerged from animal and in vitro studies. We consider the evidence 2009
strong enough to recommend tea as a healthier alternative to coffee.
Current evidence suggests that coffee consumption is associated with a reduced risk of liver, kidney, and to a lesser extent, premenopausal breast and colorec- Nkondjock,
tal cancers, while it is unrelated to prostate, pancreas and ovary cancers. 2009
A systematic meta-analysis of prospective cohort studies found no significant effect of coffee consumption on colorectal cancer risk (RR = 0.91; 95% CI: 0.81- Je et al., 2009
1.02). The RR was 0.93 (0.71-1.22) for 4 U.S. studies, 0.91 (0.76-1.10) for 5 European studies, and 0.83 (0.62-1.10) for 3 Japanese studies. No significant dif-
ferences by sex and cancer-site.
For 9 cohort and 9 case-control studies, the combined RR showed a borderline significant influence of highest coffee consumption (RR, 0.95; 95% CI, 0.90- Tang et al.,
1.00) or an increment of 2 cups/day of coffee consumption (RR, 0.98; 95% CI, 0.96-1.00) on the risk of breast cancer. In stratified analysis, borderline signifi- 2009
cant associations were observed among cohort and case-control studies and studies conducted in Europe and the United States. However, no significant asso-
ciation was noted among studies conducted in Asia. [Note: This author’s conclusions do not make sense given the provided statistical analysis]
For hepatocellular and endometrial cancers, there appears to be a strong and consistent protective association; for colorectal cancer, the direction of association Arab, 2010
is borderline protective. There appears to be no association with breast, pancreatic, kidney, ovarian, prostate, or gastric cancer. Risk of bladder cancer appears
to be associated with heavy coffee consumption in some populations and among men. The associations with childhood leukemia and mother's consumption of
coffee were ambiguous, with some suggestion of risk at high levels of daily consumption.
289
TABLE 15- 2. Caffeine and Cancer – Summaries of Reviews Reference
Analysis of 13 cohort studies (n=731,441 (33% M); follow-up 6-20 yr) found that drinking coffee or sugar-sweetened carbonated soft drinks was not associ- Zhang et al.,
ated with colon cancer risk; a modest positive association with higher tea consumption was possible (RR=1.28 [95% CI = 1.02-1.61, P(trend)=0.01]) for >900 2010
mL/d (~ four 8-oz cups)).
In a meta-analysis of 8 case-control and 4 cohort studies, the overall RR of prostate cancer for the highest vs. lowest consumption was 1.16 (95% CI=1.01- Park et al.,
1.33). There was a significant positive association between coffee consumption and prostate cancer risk in the case-control studies using both crude and ad- 2010
justed data (RR 1.20, 95% CI 1.02-1.40; and RR 1.21, 95% CI 1.03-1.43, respectively), but not in the cohort studies (RR=0.97, 95% CI 0.68-1.38; and
RR=1.06, 95% CI 0.83-1.35, respectively). Since cohort studies give a higher level of evidence, there is no support for a harmful effect of coffee consumption
on prostate cancer risk.
Coffee drinking was inversely related to oral cavity/pharynx cancer risk (pooled RR=0.64; CI 0.51-0.80; 2633 cases from one cohort and 8 case-control stud- Turati et al.,
ies), while there was no association with laryngeal cancer (732 cases from three case-control studies), esophageal squamous cell carcinoma (2115 cases from 2010
one cohort and six case-control studies), or esophageal adenocarcinoma (415 cases from three case-control studies).
The meta-analysis of 24 case-control studies, including a total of 14,846 cases of colorectal, colon or rectal cancer, suggests a moderate favorable effect of cof- Galeone et al.,
fee consumption on colorectal cancer risk. For drinkers vs. non/occasional drinkers, OR= 0.83 (95% CI 0.73-0.95) for colorectal, 0.93 (95% CI 0.81-1.07) for 2010a
colon and 0.98 (95% CI 0.85-1.13) for rectal cancer, with significant heterogeneity among studies. This may reflect a real protection but also partly or largely
be due to reverse causation, i.e. decreased coffee consumption among cases following the onset of bowel symptoms.
Analysis of combined results of 5 prospective studies and 8 case-control studies (5,347 cases and 104,911 non-cases) indicated a significant positive associa- Tang et al.,
tion between highest coffee intake (≥2 to ≥7 cups/d) and lung cancer [RR=1.27, 1.04-1.54]. An increase of 2 cups/d was associated with a 14% increased risk 2010
of developing lung cancer (RR=1.14, 95% CI=1.04-1.26). Decaf was associated with decreased lung cancer risk but the number of studies was small. Resid-
ual confounding effects of smoking or other factors may still exist.
Soft drink consumption was not related to pancreatic cancer risk; the pooled relative risks (RR) for soft drink consumers vs. non-consumers were 0.97 (95% CI Gallus et al.,
0.81-1.16) for case-control, 1.05 (0.94-1.17) for cohort, and 1.02 (0.93-1.12) for all studies. The pooled RRs for heavy drinkers were 1.08 (0.73-1.60) for case- 2011
control, 1.21 (0.90-1.63) for cohort, and 1.16 (0.93-1.45) for all studies combined.
290
15B. Caffeine and Cancer in Animals
No studies were located in which animals were treated with pure caffeine for an extended
period of time. In a study by Belpoggi et al. (2006), rats given caffeinated cola instead of drink-
ing water starting in utero or at the age of 30, 39 or 55 weeks until death consumed twice as
much fluid as controls and ate 40% less food over their lifetime. There was an increase in body
weight in all treated animals, as well as an increased incidence of malignant mammary tumors,
exocrine pancreas adenomas, and pancreatic islet cell carcinomas in one or both sexes. The in-
creased neoplasia may be largely due to the increased body weight from the high intake of sugar,
and cannot be solely ascribed to caffeine. This study is summarized in Table 15-3.
A number of animal studies examined the effect of caffeine co-exposure on the toxicity
of other substances, including those known to be genotoxic. These studies were considered to be
out of the scope of the present review.
TABLE 15- 3. Caffeine and Cancer – Animal Studies

Test ma-
Exposure Caffeine
Species terial; Effects; Comments Reference
time dose(s)
route
Rat 1-2 yr Cola (DW) Estimate Cola-treated animals consumed >2x as much fluid as controls Belpoggi
(start in 30 and 40% less food (breeders and offspring) over their lifetime. et al., 2006
utero or mg/kg/d This resulted in (a) an increase in BW in all treated animals; (b)
at age 30, increase of the incidence of malignant mammary tumors in F
39, or 55 breeders and offspring; (c) increase in the incidence of exocrine
wk, until adenomas of the pancreas in M and F breeders and offspring;
death) and (d) a non-sign increase of pancreatic islet cell carcinomas
in females. No differences in survival were observed among
treated breeders but female offspring had a slight decrease in
survival compared to the controls. [caffeine intake=100 mL/d
est intake x 0.1 mg/mL caffeine / 0.3 kg BW]
291
FUTURE RESEARCH NEEDS
Areas of priority for future research include the following:
 Studies of the effect of caffeine on bone integrity in children, young adults, and older
adults, when the source of caffeine is a carbonated beverage or an ED. The geno-
type/phenotype for caffeine metabolic enzymes of the subjects should be determined.
 The effect of caffeine on blood lipids, and the association of caffeine-elevated blood lip-
ids with heart disease, and how this is influenced by genotype/phenotype for caffeine
metabolic enzymes.
 Prospective studies that evaluate the effect of caffeine intake on individuals with cardio-
vascular disease, to include consumers of caffeine as EDs and colas. The geno-
 Studies quantifying the effect of caffeine on intraocular pressure in individuals with and
without eye disease, to include consumers of caffeine as EDs and colas. The geno-
 Prospective studies designed to evaluate the effect of aging and sex on the body’s cardio-
vascular response to caffeine. Should include a range of ages, particularly >60 years old.
The genotype/phenotype for caffeine metabolic enzymes of the subjects should be deter-
mined.
 Studies that focus on the effect of high caffeine intake (≥5 cups/day), which look at end-
points including cardiovascular disease, reproductive and developmental toxicity, bone
integrity, and cancer. The genotype/phenotype for caffeine metabolic enzymes of the
subjects should be determined.
 Studies that evaluate the effect of caffeine intake on “health-compromised” individuals,

to look at endpoints including cardiovascular disease, reproductive and developmental
toxicity, and bone integrity. “Health-compromised” subjects include those with chronic
diseases such as AIDS, cancer, liver, or kidney disease; individuals who are malnour-
ished; and those who are under stress for a prolonged period. The genotype/phenotype
for caffeine metabolic enzymes of the subjects should be determined.
292
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377
APPENDIX I : FDA WORK ASSIGNMENT # 2008-39
OFFICE OF FOOD ADDITIVE SAFETY

FDA INTERAGENCY AGREEMENT 224-00-2615
WORK ASSIGNMENT INSTRUCTION SHEET
ASSIGNMENT #: 2008 - 39 DATE ISSUED: 10/15/08 WORK PLAN DUE DATE:
DESCRIPTION OF DATA: SEE BELOW GOVERNMENT TOTAL ESTIMATED TECHNICAL REVIEW HOURS:
TECHNICAL INSTRUCTIONS:
Issued by__Scott Thurmond___________Date

Materials Received by Signature______________________Date________
FDA Contact person:

Scott Thurmond – 301-436-1268
Secondary contact – Ali Abdel-Rahman – 301-436-1853
Assignment Type: Literature review and evaluation of the safety of caffeine and related xanthenes in sensitive populations.
See “Additional Instructions” for complete statement of work.
Draft assignment due: TBD

Final assignment due: TBD
Additional Instructions:
Adverse Health Effects of Caffeine:

A review of recent human and animal research
Statement of work (SOW).
A.-CFSAN Administrative Structure
Dr. Scott Thurmond from the Office of Food Additive Safety (OFAS) will be the Project Officer
(P.O.) and will serve ex officio on the Technical Evaluation Panel (TEP). Dr. Ali Abdel Rahman
of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS) will chair the TEP and
copy the P.O. on all communications with the contractor. The TEP will communicate directly
with the Contractor (Oak Ridge National Laboratories, ONRL) to discuss development and pro-
gress of the work assignment. The final work assignment and any changes to the work assign-
ment will be communicated to ONRL by the P.O.
B-Schedule of tasks
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1- Kick-Off Call with contractor
The objective of this kick-off call is to discuss this work plan and specific elements of
work to be performed.
2-First Conference Call with TEP
The TEP will arrange an initial conference call with ORNL to discuss the following:
a) The full list of key questions; b) key word approaches to the literature search and report
and; c) any modification of the work assignment.
3-Revised Work Plan
a) Following the initial conference call, P.O will meet with TEP to revise any changes to the
work plan according to the first conference call list.
b) P.O. will submit a revised work plan highlighting any changes from the initial draft work
plan regarding; the questions, key words, proposed literature search and review.
4- Contractor Starts
Contractor starts initial literature search according to the revised work plan. Contractor will
identify and search relevant databases such as MEDLINE, Cochrane Database of Systematic Re-
views, EMBASE. Literature retrieved will include scientific studies of caffeine and related me-
thylxanthines (e.g. theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine).
Once the search is conducted, contractors will submit the results to the P.O.
The results will consist of the list of articles retrieved, annotated to designate the key questions
(see § C6, below) to which the articles are responsive, an appendix containing the abstracts of the
articles, and an estimate of the resources needed to complete the analysis of the literature that has
been retrieved.
5-Revision
P.O will meet with TEP to discuss the results and make any necessary revisions to the work
plan. The results of this discussion will be transmitted to the contractor as appropriate.
7-Monthly Conference Calls and Status Reports
After the second conference call, P.O. will participate in a monthly conference call along
with the TEP, as needed, to update progress. Calls may be scheduled more or less frequently,
as requested by the P.O. Participation includes scheduling the call in advance and circulating
an agenda at least two working days prior to the call. The P.O will request that the agenda in-
cludes attachments of working documents, such as reference lists, literature retrieval figures,
draft summary tables, etc. Within one week after the call, an electronic summary of the call
will be submitted, which will serve as a status report. The Submission should be sent via e-
mail to the P.O and to the TEP.
This report must document the following:
progress during the prior period in completing tasks
Any problems or major issues encountered during the conference calls: how they came to be
and how they were addressed.
379
Major issues include those that involve changes in scope of work, timeline, outcomes, inclu-
sion/exclusion criteria, resources and cost.
Any foreseeable problems and plans to eliminate or mitigate those problems, and any ex-
pected change to the delivery schedule, including rationale.
8 -Literature Review
Search should cover literature published between 1994 and the date of the final report.
Systematically search, abstract, review and analyze the scientific evidence for each key term,
question and the variance, if any, of the evidence according to age, gender, and
race/ethnicity. Specifically
Develop appropriate data collection forms;
Review abstracts against pre-established inclusion/exclusion criteria to determine potential
eligibility for inclusion in the evidence synthesis;
Retrieve and review full articles on eligible studies, extracting key data from each eligible
study and entering the abstracted data into an electronic database
Maintain a file of excluded studies with reasons for exclusion;
Review each eligible study and assess its quality according to predetermined criteria;
Use appropriate procedures to reduce bias, enhance consistency, and to check accuracy of
study reviewed;
Assess/rate the strength of the overall body of evidence according to predetermined criteria;
Prepare summary evidence tables to include key data and important findings, including, as
appropriate, as these relate to the patient population, their age, gender, and race/ethnicity;
Identify priorities for future research.
The entire study bibliography, including database from which each reference was first identi-
fied.
9- Draft Review
Contractors submitted draft report in MS Word format with line numbers with literature at-
tached in PDF format.
TEP has 90-days to review and submit comments.
10- Update Literature Search and respond to comments.
During the draft review time period, contractors should perform an updated literature search,
using the same search strategy as originally done, to ensure that the search is current (i.e., no
more than one year old when the final report is anticipated to be published). Discuss the find-
ings of the updated search with the P.O and TEP, particularly findings that may change the
results of the systematic review. Incorporate the findings into the final report.
11-Final Report
Contractors will finalize the reports and submit the final evidence report and appendices to
the P.O electronically using MS Word, MS Excel or searchable PDF format. Tables and
charts must be delinked from underlying databases unless the databases are fully accessible
from public or FDA computers. Identify and use references cited in articles revised.
C.-Scope of search, Key Words and Definitions:
380
:
1- Caffeine and related methylxanthenes

a. Caffeine: 3, 7-dihydro-1, 3, 7-trimethyl-1H-purine-2, 6-dione,
1, 3, 7-trimethylxanthine;
1, 3, 7-trimethyl-2, 6-dioxopurine
b. 1-methyl-3-isobutylxanthine.
c. 1-methyl-3-(2- methylpropyl)-7H-purine-2,6-dione
d. 1, 3-dimethylxanthine (theophylline)
e. 3, 7-dimethylxanthine (theobromine)
f. Others as recommended by ONRL..
2) Product Types:
1-Conventional Food:
a) Coffee, Tea, Cocoa, Milk chocolate, Guarana, Yerba mate, Kola etc.
b) Energy drinks
2-: Dietary supplements

a) Weight control
b) Sport performance
c) Mental alertness
d) Products derived from Coffea (coffee), camellia (tea), Cocoa, Yerba and Guarana spp.,
3-Interactions products containing (or taken with foods containing):
a) Ethyl Alcohol
b) Biogenic /sympathomimetic amines
c) Multiple methylxanthines
d) Polyphenols
e) Others as recommended by ONRL
3) Sensitive Populations:
1) Children very young (2-3 years old); young (4-13years old); teenager, (14-18) years old);
young adults, (19-25 years old) and women of childbearing age, (18- 45years old).
2) Pregnant and lactating women
3) Mood disorders (e.g. Attention Deficit Disorder or) especially in children
4) Adults with underlying cardiovascular disease (e.g., heart disease, high blood pressure,
stroke) and diabetics,
5) Slow metabolizer of caffeine or other genetic polymorphisms TBD
6) Adults with urinary incontinence
7) Patients taking pharmaceuticals (list TBD)
8) Any other sensitive population the contractor identifies during search of literature.
4 Adverse events:
Adverse events, Blood glucose, C-reactive protein, Insulin levels, ,Blood lipid levels (TG, LDL,
HDL, cholesterol), unwanted weight changes Urine volume (diuresis), GI polyps, Nervousness,
381
Agitation, tremors, Insomnia Tachycardia, Gastrointestinal upsets, Stillbirths, Low-birth weight,
Spontaneous abortions, Intrauterine growth retardation, overdose, Cancer, Death.
5- Types of studies to be reviewed
A) Research involving animals: yes__x__no_____
B) Research involving Human subjects: yes__x__no_____
C) Research involving both gender male and female: yes x__no_____
D) Research involving in vivo and/or in vitro: yes x__no_____
6- Key questions
1. What is the evidence that the caffeine or caffeine-related xanthine (s) as a single ingredient or
as an ingredient in a product such as: dietary supplements (See list p4 (2) 2, drink, powder,
conventional, food, etc in all delivery vehicles (and formulations) when used as stimulant by
“sensitive population as listed above” are safe in the short-term? And long-term?
a. What adverse events of caffeine consumption are reported in epidemiological and an-
imal studies?
b. What harms are reported in epidemiological studies and case reports?
c. What pharmacokinetics, pharmacodynamics and metabolic products of caffeine or re-
lated compound reported to affect in any sensitive population?
d. What fatalities have been reported in sensitive populations describe mechanism of ac-
tion?
e. What interactions between caffeine and alcohol or any other ingredients products
have been reported? (See list p4 (2) 3
f. What disease (addiction, mental disorder, anxiety, sleep disorder, headache, psychosis
and high blood pressures) related to adverse effects secondary to caffeine or caffeine
related product intake reported to occur in sensitive populations?
g. What is the scientific evidence that mortality, pharmacokinetics, hepatic injury, car-
diovascular disease, CNS, development, reproduction, cancer, and mutagenicity differ
occur between sensitive and insensitive population?
h. What is the scientific evidence that harms differ between caffeinated and decaffein-
ated products?
i. What is pharmacological aspect reported by sensitive populations following exposure
to caffeine or caffeine related products?
2. Does harm such as (Restlessness, Anxiety, Irritability, Muscle tremors, Sleeplessness, Headaches, Nau-
sea, diarrhea or other gastrointestinal problems and abnormal heart rhythms) differ by products con-
taining single caffeine ingredient vs. Caffeine products or any other related?
3. How do the adverse effects of caffeine vary based on (a) dose; (b) timing; (c) caffeine related
products; (d) age (all ages), gender, ethnicity, disease; (e) relationship to efficacy; (f) source
of caffeine or as an ingredient in product such as drink, powder, conventional food etc…?
a. Is there a threshold or dose-response relationship between caffeine and other formula-
tion containing caffeine (please see above) and an adverse event? Does the amount
of daily intake relate to adverse event?
382
b. Is there a relationship to time of exposure periods- acute (14 days or less), intermedi-
ate (15-364 days), and chronic (365 days or more) and harm and time of caffeine ad-
ministration (e.g., prior to onset of disease under study, after disease onset)? How
does time of exposure affect harm? Is harm sustained after the intervention or expo-
sure stops?
c. Does an overdose of caffeine or its content administration relate to harm?
d. How does harm relate to subpopulations; children (2-13 years old), teenagers (14-21
years old), women of childbearing age (18- 45years old), 46 and older and women,
ethnic/race subgroups, or health status, (healthy to high risk)?
e. Do adverse events or safety differ in studies showing efficacy vs. protection of caf-
feine or caffeine related products.
f. Do adverse events vary according to the source of caffeine such as dose, product
(e.g., coffee, Tea, dietary supplement and energy drink or any other to be deter-
mined)?
D. Outcome
1-The goal of the overall analysis of the literature is to help the public health professional and
others who raised the question what is the relationship between caffeine consumption and related
health effects?
To addresses the above question, the information’s in this reviews will be organized as follows:
2) The data will include the source of caffeine, consumption and the health effects (sensitive
populations) as described in section B of this SOW.
3- The data will be discussed in terms of three exposure periods - acute (14 days or less), inter-
mediate (15-364 days), and chronic (365 days or more).
4-The levels of significant exposure for each caffeine sources and duration should be presented
in tables and illustrated in figure.
5- The points in the figure that show no-observed-adverse-effect levels (NOAEL) and Lowest –
observed-adverse effects levels (LOAEL). Reflect the actual doses (levels of exposure) used in
the studies. LOAELS have been classified into “less serious” or “serious effects”. “Serious ef-
fects” are those that evoke failure in a biological system and can lead to morbidity or mortality.
6- The significance of the exposure levels should be shown in the Levels of Significant Exposure
(LSE) table and figure may differ depending on the a) source of caffeine; b) exposure period and
c) the daily intake.
383
APPENDIX II: FDA REVIEW COMMENTS ON THE DRAFT #1
CAFFEINE REPORT
CFSAN (ONLDS / OFAS) Review/ Comments on the draft report “Health Hazard Evalua-
tion of Caffeine” submitted to the FDA by Oak Ridge National Laboratory (ORNL) on
January 26, 2010.
Date: June 8, 2010
Based on an interagency agreement, the Food and Drug Administration (Office of Food Additive
Safety) requested Oak Ridge National Laboratories (ORNL) to conduct a review of the scientific
literature on the adverse health effects of caffeine in sensitive populations (work assignment #
2008-39, dated 10/15/08). Oak Ridge systemically review the relevant scientific literature on top-
ics assigned to them by CFSAN. The goal of this report was to provide CFSAN with comprehen-
sive, science- based information on the health risk of caffeine or caffeine- related products in
sensitive populations, such as pregnant women, individuals with cardiovascular disease, and
children with Attention Deficit Hypersensitivity Disorders. The funding for this evidence-based
review was provided by the Office of Food Additive Safety (OFAS) and the Office of Nutrition,
Labeling and Dietary Supplements (ONLDS).
Oak Ridge National Laboratory (ORNL) submitted a draft report titled “Health Hazard Evalua-
tion of Caffeine” to CFSAN on January 26, 2010, for review and comments. Oak Ridge empha-
size that the first draft contains imperfections and formatting inconsistencies. Oak Ridge is also
willing to edit or add any information deemed necessary after receiving the FDA’s comments.
OFAS and ONLDS of the Center for Food Safety and Applied Nutrition (CFSAN) have re-
viewed this draft report and have listed below our comments under the comments section.
FDA’s comments are focused mostly on scientific and technical issues and do not address all the
typographical errors or format issues. In our comments, CFSAN will discuss the larger issues of
concern and identify specific targeted concerns, highlighting draft text and provide input and
recommendations, where appropriate.
Overall, the data is vast and extensive; the various physiological effects of Caffeine are well
documented in tabular form. However, all the six key questions in the work statement were
not clearly discussed in the Summary. The effects of caffeine seen in animals should be summa-
rized separately rather than combining them with those in humans. The effects of caffeine when
consumed along with other substances such as ethyl alcohol have not been sufficiently covered
in the summary. Since FDA is concerned about the possible adverse effects due to potential in-
teractions with alcohol, it would be helpful to discuss such interactions in more detail (currently
one paragraph on page 25). Similarly, the effects of caffeine consumption in sensitive popula-
tions, such as the effect on adults with underlying cardiovascular disease, are not discussed in
detail in the summary. It would be more helpful to address the effects of caffeine on sleep in
teens in a separate section. Finally, if there is a lack of dose response (page 6, second para-
graph), it is not clear how the effect could be explained.
384
CFSAN encourages Oak Ridge to evaluate and address the weaknesses, uncertainty and specific
limitations of the use of the body of literature, models for the estimation of a dose-response rela-
tionships, identification of the mode and mechanism of action, assessment of the carcinogenicity
risk, and setting of the NOAEL and the LOAEL
Comments
A. Page 1 (cover page) of the draft report:

 Should read: “Prepared for Office of Nutrition, Labeling and Dietary Supplements and Office
of Food Additive Safety”.
 The title of the report should be revised from HHE of caffeine to a more appropriate title, such
as “Adverse Health Effects of Caffeine: A review of recent human and animal research.”
B. Table of contents: The draft report provided by ORNL covers the following
areas regarding the effects of caffeine:
1. Effect of caffeine on CNS in human- children, adults, sleep-deprived adults and animals.
2. Effect of caffeine intake on sleep in children and adults.
3. Effect of caffeine intake on cardiovascular system in humans and animals.
(Note: Not enough studies provided in the draft report that covered the effect of caffeine in indi-
viduals with CVD).
4. Effect of caffeine intake on physical (excercise, sports) performance.
5. Effect of maternal caffeine intake on fetus (human and animal data),
6. Effect of chronic caffeine exposure on reproductive / gonadal endpoints (human and animals).
7. Effect of caffeine exposure on bone and dental parameters (human and animals).
8. Effect of caffeine on kidney (human data only)
9. Effect of caffeine on body weight, Glucose, lipids (human and animals)
10. Effect of caffeine on immunological, GI, Ocular, and mammary (non-cancer) system
(human and animal).
11. Case Reports
12. Impact of human genotype on caffeine disposition and toxicity (human).
13. Metabolism and disposition of caffeine in humans and animals.
14. Genotoxicity.
It would be helpful to compartmentalize these effects based on the sensitive populations (chil-
dren, pregnant and lactating women, adults with underlying cardiovascular disease) as stated in
the SOW (Section C (3)).
C. Literature Review:
1. The first draft of Health hazard evaluation of caffeine covered published literature before and
after 1994 which is inconsistent with our SOW section 8. The literature summarized appears to
be outside the date range as stated in the work assignment (1994 to date of final report). For ex-
ample, Table 1 lists studies from 1975, Table 3 has studies from 1976, and it is not clear that re-
cent literature is summarized. FDA has not agreed to changes in the work assignment therefore,
385
the literature within the date range specified in the work assignment should be summarized in the
report.
2. ORNL should summarize the outstanding scientific issues, supported by specific examples
from the draft text rather than provide line by line review.
3 Searching "all dates" as indicated on page 5 (Preface) for information on caffeine resulted in a
very large number of articles (~3400 potentially useful articles), which had to be reduced to
~1800 for review, utilizing a lot of time and resources. Studies on sub-cellular effects of caffeine
which were omitted may be useful for addressing the mechanism of action of caffeine. The
SOW includes review of data from in vitro studies. ORNL should also summarize in vitro stud-
ies on caffeine from 1994 to present.
4. In studies where multiple caffeine dose levels were administered to subjects, it is not clear in
some instances, the dose levels at which the reported effects occurred. ORNL should present the
data as dose-related effects. Additionally, ORNL should state the exact duration, number of serv-
ings, and dose levels in the tables (e.g. duration = 364+d; dose <18 mg; 5.3 x 130 mg, >0 cups,
what do these really mean). The NOAEL and LOAEL for each of the sensitive populations
should be determined and stated in the review.
5. ORNL should include the details of the study type (e.g., epidemiology, placebo controlled,
randomized, double blind crossover design, national study, case reports), duration of the study,
number of subjects, gender, age, and race/ethnicity (if known) in each study to give a better un-
derstanding of the quality of the studies summarized in the tables. For example, studies on hu-
man subjects should state whether subjects are healthy, if not state their health condition;
this helps to put the results in perspective.
6. Some of the summary sections include the citation (to the literature) in the written synopsis
prior to the table (e.g., see page 30, 54, 84). Citations to statements in the synopsis are helpful as
a guide. For consistency, citations should be included for all the summary sections.
7. Opinions should be removed from the report. For example, a statement that serious toxicity
has not been associated with green tea extracts appears to be an opinion (page 98).
8. Tables 1- 32, on pages 10 - 142: ONLDS and OFAS groups found the listing of the studies
confusing and it would be better if the studies are listed using a format based on the SOW, key
question No. 3. For example the listing can be arranged starting with single dose studies and in-
creasing levels of caffeine tested. We also recommend that the repeat-dose studies be handled
similarly but under a separate listing (Table 19, page 96).
9. Selection of literature must support the basic study question. Criteria to use or exclude specific
studies can have a profound effect on the results of the risk assessment. The draft lacks this clari-
fying information and statement of scientific key question. For example, there were several stud-
ies included in which the dose of caffeine was not specified table 1 page 12, table 7 page 50, ta-
ble 10 page 64; table 17, page 91; table 21 page 104; 105; table 22 page 107 and 109; table 23
386
page 110; table 24 page 119; table 25 page 122; table 30 page 139and 140; table 31 page 142 and
143.
10. It would be more helpful to organize the list of studies in each table similar to table 16. How-
ever, the listing can be arranged starting with single dose studies and increasing levels of caffeine
tested and in a chronological order within a given dose.
11. The studies conducted in children are interspersed with those done in adults. It would be bet-
ter to have them under a separate sub-heading as stated in the SOW.
12. Under the "Exposure variables" column where test substance is listed only as "caffeine" or
"caffeine, dietary", did the subjects ingest pure caffeine or dietary supplements in liquid, pow-
dered, or capsule form? The timing of caffeine intake, before or after exercise and the source of
caffeine will be beneficial.
13. In cases where caffeine is consumed along with other variables e.g. taurine, ephedrine, exer-
cise, it’s not clear as to whether the effects summarized in the table are due to caffeine alone or
the combination of components
14. In cases where the observed effects of caffeine are different from the usual, for example, the
heart rate is increased when caffeine is consumed in conjunction with exercise. However, there
are certain studies which indicate that the heart rate decreased or synergistic/ additive interac-
tions were observed when consumed with other variables. Such differences would be of interest
and should be highlighted in the table.
15. ORNL should include a “Comments” column for all the tables.
16. Tables 1 to 32, pages 10 to 142: ONLDS and OFAS groups would prefer that the negative
and mixed results cited in the tables be categorized in different groups as this will have an impact
on the estimated risk assessment of caffeine.
17. ORNL should include the most recent publications that are relevant to the key questions
posed in the SOW that are available in the scientific literature.
Additional suggestions:
1. It will be useful to include search strategy for primary studies, data extraction forms and qual-
ity assessment checklists, and a list of excluded references.
2. Page 73, paragraph 2 in part reads “The highest caffeine intake group was typically ≥300
mg/d, but was ranged to >900 mg/day in a few studies.” Please clarify the range of intake.
3. We suggest that the contractor check report for typos (e.g., see page 88, first line "chromic"
caffeine intake); the word "Data" missing on page 67, paragraph 6; Column 1 header "Time" on
pages 60-64 incorrectly spelt; abbreviations on some pages need to be defined when they are first
used (e.g., page 20: ANS, CRT, p3b, NT, n2b; page 23: AA).
387
Comments Sent from Ali Abdel-Rahman (via Felicia Ellison) to ORNL (Robert Ross) on
September 1, 2010
Major deficiencies of the draft report submitted to the FDA by Oak Ridge National Laboratories
on January 26, 2010 based on the Statement of Work (SOW) dated 10/15/08.
1. Section B. 8 (literature review) of the SOW reads as follows: “Search should cover litera-
ture published between 1994 and the date of the final report”. However, approximately
31% of references cited in thirty-one (31) tables in the draft review of the Health Hazard
Evaluation of Caffeine submitted by ORNL were published before 1994. This is inconsis-
tent with section 8 of the SOW.
2. Section D.4 (outcome) of the SOW reads as follows: “The levels of significant exposure
for each caffeine sources and duration should be presented in tables and illustrated in fig-
ures”. However, all the data submitted was in tabular form.
3. Section D. 5 (outcome) of the SOW reads as follows: “The points in the figure that show
no-observed-adverse-effect levels (NOAEL) and Lowest –observed-adverse effects levels
(LOAEL); Reflect the actual doses (levels of exposure) used in the studies”. However,
the review does not include any of the above analyses.
388
APPENDIX III: FDA REVIEW COMMENTS ON THE DRAFT #2
CAFFEINE REPORT
The Center for Food Safety and Applied Nutrition (CFSAN) Comments on “Health Hazard
Evaluation of Caffeine” draft report #2 submitted to the FDA by Oak Ridge National La-
boratory (ORNL) on May 13, 2011.
Date: October 7, 2011
On January 26, 2010, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN, submitted to
CFSAN / FDA the first draft report on the Health Hazard Evaluation of Caffeine. The Office of
Nutrition, Labeling and Dietary Supplements (ONLDS) and the Office of Food Additive Safety
(OFAS) of CFSAN reviewed this 1st draft report and sent their comments to ORNL on June 8,
2010. These comments were based on inconsistencies with keywords listed in the Statement of
Work (SOW) (work assignment # 2008-39, dated 10/15/08).
In response to our comments, ORNL revised the 1st draft report (now draft report 2) and sent to
the Chair of the Technical Expert Panel (TEP), Dr. Ali Abdel-Rahman of ONLDS, on May 13,
2011.
ONLDS and OFAS have reviewed this 2nd draft report and have listed their comments below.
FDA’s comments are focused mostly on scientific and technical issues and do not address all the
typographical errors or format issues.
A. ONLDS and OFAS Comments on Draft Caffeine Report #2

In our comments, ONLDS and OFAS will discuss the larger issues of concern and identify spe-
cific targeted concerns, provide input and recommendations, where appropriate.
Strengths
Overall, it appears that ORNL is expert in conducting literature reviews. The 2nd draft “Health
Hazard Evaluation of Caffeine” is very well written, well-organized and comprehensive (395
pages, including Appendices). The review includes 15 chapters; each describes human studies
and animal studies separately in tabulated format and brief summaries of conclusions.
Most of the comments submitted by the FDA on the first draft report seem to have been ade-
quately addressed by ORNL in Draft Report 2. For example:
1. All cited references were updated and only articles published from 1994 to present were in-
cluded.
2. Studies published since the first Draft Report through early March 2011 were added.
3. A summary table of review articles on the various subject areas is included in each chapter.
Each table of individual studies has an “Effect; Comments column.”
389
4. NOAEL and LOAEL values were addressed for all subject areas, and where appropriate, val-
ues were determined.
5. Plots, using Excel software, were made of study data in subject areas for which NOAEL and
LOAEL values were developed (CNS anxiety; reproductive toxicity, embryotoxicity; effects on
bone).
6. The text descriptions of each study were expanded and information was added regarding caf-
feine content of various drinks.
7. The age, gender, number, and country of origin of human subjects were added.
8. Text descriptions in each chapter were expanded.
Weaknesses
1. The cover page states: “Prepared for Center for Food Safety and Applied Nutrition, Office
of Food Additive Safety……” ONLDS is omitted.
2. The title of the report should be revised from "Health Hazard Evaluation of Caffeine" to a
more appropriate title, such as “Adverse Health Effects of Caffeine: A review of recent
human and animal research.”
3. We suggest the current Chapter 12 “Metabolism and Disposition of Caffeine” be made

Chapter 1.
4. The document does not identify areas of priority for future research as stated in the work
statement.
5. The contractor needs to identify in the report the pre-established inclusion/exclusion crite-
ria to determine potential eligibility of studies for inclusion in the report.
6. Currently, there are instances where the same abbreviations are defined differently in differ-
ent sections and other instances where abbreviations are not defined. For example, CAD is
defined as 2-chloroadenosine on page 106, and as coronary artery disease on page 134; RER,
on pages 74 and 111, is not defined.
7. We noted that most of the cited animal toxicology data in tables 1-15 are inadequate because
they were conducted following intraperitoneal (ip), intravenous (iv) and intramuscular injec-
tion (im). It would be better if these studies were conducted using the appropriate route of
administration (oral) and if specific information such as duration of exposure, timing of ex-
posure, life stages and susceptible subpopulations be included. It would be better if ORNL
cites adequate animal studies to establish the relevance of the animal data for predicting hu-
man response (specifically, the dose response data for the NOAEL and LOAEL value).
8. The document does not provide information on the criteria used to determine the NOAELs or
the LOAELs, when there was enough data to determine one. Please provide information on
how the NOAELs or the LOAELs were determined.
9. We noted that the NOAEL and LOAEL values were determined only from human
390
studies. Some of these human studies were not adequate for determination of the NOAEL
and LOAEL; where this is true, it is important to include data from animal studies which
could be used to establish the NOAEL and LOAEL.
10. We noted that in some cases the NOAEL and LOAEL were determined based on a
single dose of caffeine
11. We noted that presenting the NOAEL and LOAEL for each section separately makes it diffi-
cult to come up with conclusion for comparison. It would be better if ORNL included a
summary table which contains the target organs for all defined LOAEL and NOAEL. For
Example;
_______________________________________________________________________
Exposure cardiovascular Neurotoxicity reproductive effects etc ……
Duration toxicity
______________________________________________________________________
Acute
Human (NOAEL)
(LOAEL)
Rat (NOAEL)
(LOAEL)
Mouse (NOAEL)
(LOAEL)
________________________________________________________________________
Intermediate
Human (NOAEL)
(LOAEL)
Rat (NOAEL)
(LOAEL)
Mouse (NOAEL)
(LOAEL)
_______________________________________________________________________
Chronic
Human (NOAEL),
(NOAEL)
Rat (NOAEL),
(NOAEL)
Mouse (NOAEL),
(NOAEL)
391
12. Please clarify what these mean:
i- P240, 2nd paragraph: "Minor GI symptoms were commonly seen among
43 hospital admissions due to deliberate caffeine ingestion (Waring et al.,
2009)." What does this mean? As opposed to accidental ingestion?
ii- P269, 4th paragraph: "The degree of subjects’ inherent developmental sta-
bility predicted the magnitude of their caffeine-induced memory decre-
ments." It is not clear what this means.
iii- P291, Table 15-1, Portaet al., study: "Mutations were found in mutations
in the K-ras gene..." What does this mean?
iv- The term pure caffeine ….” What you mean by pure caffeine?
13. These studies need to be reconsidered for placement in a more appropriate section of the re-
port:
ii. P248: Table 11-3 is on non-cancer effects of caffeine. However, the
Wanget al., (2008) study (2nd row) shows tumors.
iii. P253, Table 12-1: It is not clear if the Tiffinet al., 1995 study is addressing caf-
feine metabolism and disposition.
iv. P196: The Gilbert-Barness 2000 chick embryos study is in Table 7-2, De-
velopmental Effects of Caffeine - Summaries of Reviews. (Why not,
chick embryo studies are intended to assess potential reproductive effects.)
14. Please proof-read report for typos and other errors before issuing the final report. We anticipate that
this will be performed at the end of the text modification process. (some examples of typing errors, miss-
ing words/letter, or incomplete sentences are listed below).
ii) P11, 2nd paragraph; page 230, 2nd paragraph; page 240, 2nd paragraph;
page 284 (line 5), the word "coffee" is missing an "e"
iii) P79: 1st paragraph, line 7, and page 233, row 7, "IN" should be “In”
iv) P83: Table 3-4, row 5, what is "Its"
v) P109, 2nd paragraph: "Several cross-sectional studies in evaluated the ef-
fects of caffeine on blood pressure."
vi) P110: "genetic profile of medication use"
vii) P143: 2nd paragraph, "There was insufficient to determine which caffeine
medium was most potent."
viii) P160: 2nd paragraph, "Studies with children consisted of two case reports
in which 25-27 year old adolescents…"
ix) P180: paragraph 3, "Fetal arrhythmia was detected from a maternal intake
of 300 mg caffeine, or 10 cups coffee per day." I was under the impres-
sion that a cup of coffee contains 100-150 mg caffeine. Please clarify how
this cup of coffee contains only 30 mg caffeine.
x) P193: row 5, "Caffeine was not t related to birth weight, length, or---."
xi) P215 3rd paragraph: "Effects on bone density were also seen in elderly
men consuming ≥4 cups/day coffee (5.7 mg/kg/day) or~260 mg caf-
feine/day (5.2 mg/kg/day (Hallstrom et al., 2010; Barbour et al., 2010), in
men <50 years old with an intake of ~3 mg/kg/day caffeine (Atalar et al.,
2009), in men of a wide age range who consumed ≥3 cups/day coffee (4.3
mg/kg/day) (El Maghraoui et al., 2010), and in middle aged and elderly
men and women who consumed >1 cup of tea per day and in (Jha et al.,
2010).” This sentence appears to be incomplete.
392

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ADVERSE HEALTH EFFECTS OF CAFFEINE:

REVIEW AND ANALYSIS OF RECENT HUMAN AND ANIMAL

Office of Nutrition, Labeling and Dietary Supplements

Sylvia Milanez, Ph.D., D.A.B.T.

CHAPTER 1. METABOLISM AND DISPOSITION OF CAFFEINE ................................................................11

CHAPTER 2. EFFECTS OF CAFFEINE ON COGNITIVE AND PSYCHOMOTOR FUNCTION ..................31

CHAPTER 3. EFFECTS OF CAFFEINE ON SLEEP AND ON SLEEP-DEPRIVED HUMANS......................77

CHAPTER 4. INTERACTION OF CAFFEINE WITH OTHER CHEMICALS..................................................92

CHAPTER 5. CARDIOVASCULAR EFFECTS OF CAFFEINE......................................................................126

CHAPTER 6. EFFECTS OF CAFFEINE ON EXERCISE−RELATED PARAMETERS .................................160

CHAPTER 8. DEVELOPMENTAL EFFECTS OF CAFFEINE........................................................................197

CHAPTER 9. REPRODUCTIVE EFFECTS OF CAFFEINE ............................................................................220

CHAPTER 10. EFFECTS OF CAFFEINE ON BONES AND TEETH .............................................................230

CHAPTER 11. EFFECT OF CAFFEINE ON THE KIDNEY, URINARY BLADDER, AND

CHAPTER 13. THE IMPACT OF HUMAN GENOTYPE ON CAFFEINE EFFECTS ....................................262

CHAPTER 14. CAFFEINE GENOTOXICITY ..................................................................................................272

CHAPTER 15. CAFFEINE AND CANCER ......................................................................................................275

FUTURE RESEARCH NEEDS ...........................................................................................................................291

APPENDIX I : FDA WORK ASSIGNMENT # 2008-39 ...................................................................................377

APPENDIX III: FDA REVIEW COMMENTS ON THE DRAFT #2 CAFFEINE REPORT............................388

TABLE 1-1. Caffeine Metabolism and Disposition in Humans ................................................................ 12

TABLE 6-1. Impact of Caffeine on Exercise−Related Parameters ......................................................... 161

TABLE 8-1. Developmental Effects of Caffeine – Human Studies ........................................................ 200

TABLE 9-1. Reproductive Effects of Caffeine – Human Studies ........................................................... 223

TABLE 13- 1. The Impact of Human Genotype on Caffeine Effects...................................................... 263

TABLE 14- 1. Caffeine Genotoxicity Studies ......................................................................................... 273

TABLE 15- 1. Caffeine and Cancer – Human Studies ............................................................................ 278

Final Report date: October 27, 2011

Studies of caffeine pharmacokinetics showed a linear dose-response for up to at least 5

1A. Caffeine Metabolism and Disposition in Humans

Caffeine metabolism and/or clearance were linear up to a dose of at least 5 mg/kg/day in

STUDIES WITH ADULTS

In healthy adults, caffeine pharmacokinetics was not significantly affected by treatment

A number of commonly taken medications were found to impair caffeine metabolism

Caffeine itself is capable of disrupting the metabolism and/or disposition of a number of

Caffeine metabolism and/or disposition were inhibited by treatment with alprazolam

2A. Effects on Cognitive and Psychomotor Function in Humans

Al ith al. 200 att , 1 94

C ella and Par , 2

N iero and 200 08

1.0E+02 Study author(s) No Effect

1.0E+01 Significant increase

1.0E+00 NOAEL for anxiety NOAEL

Epidemiological studies showed an increased frequency of headaches, premenstrual anx-

A number of experimental studies examined the effect of caffeine on brain activity.

STUDIES WITH ADULTS

STUDIES WITH CHILDREN

4A. Interaction of Caffeine and Ethanol – Human Studies

Brief summaries of conclusions drawn by authors of reviews addressing the interaction of

Co-exposure of caffeine with acetominophen reduced the incidence of caffeine-induced

Caffeine increased the hyperthermic response of MDMA (“Ecstasy”) and MDA

5A. Cardiovascular Effects of Caffeine – Human Studies

The cardiovascular effects of caffeine were assessed in many single-exposure experimen-

Epidemiological studies provided conflicting findings regarding the effects of caffeine on

Conversely, a number of cohort studies found no association or an inverse association be-

Experimental studies that evaluated the cardiovascular effects of caffeine in humans

STUDIES WITH CHILDREN

There is a long-standing interest in the ability of caffeine to enhance performance in

A number of experimental and epidemiological studies examined the effect of caffeine on

Repeat-exposure experimental studies found similar effect as the single-day studies.

8A. Developmental Effects of Caffeine in Humans

Although maternal smoking is a known cause of fetotoxicity, a consistent effect of smok-

2003; Nehlig and Debry, 1994d).

Issued byScott Thurmond_________Date

A) Research involving animals: yesxno_____

B) Research involving Human subjects: yesxno_____

C) Research involving both gender male and female: yes xno___

D) Research involving in vivo and/or in vitro: yes xno___