Herbal Interaction

REVIEW ARTICLE
Evaluation of documented drug interactions and

contraindications associated with herbs and dietary
supplements: a systematic literature review
H.-H. Tsai,1,2 H.-W. Lin,1,2,3 A. Simon Pickard,3,4,5 H.-Y. Tsai,1,2 G. B. Mahady5
Linked Comment: Ernst. Int J Clin Pract 2012; 66: 101920.
1
School of Pharmacy and
SUMMARY
Graduate Institute, College of Review criteria
Pharmacy, China Medical Background and Aims: The use of herbs and dietary supplements (HDS) alone We conducted a structured literature search on
University, Taichung, Taiwan
2 or concomitantly with medications can potentially increase the risk of adverse tertiary literature, web resources and primary
Department of Pharmacy,
events experienced by the patients. This review aims to evaluate the documented literature, which were focusing on MEDLINE (via
China Medical University
PubMed), EMBASE and the Cochrane Library. All
Hospital, Taichung, Taiwan HDS-drug interactions and contraindications. Methods: A structured literature
3
Department of Pharmacy evidence related to drug interactions or
review was conducted on PubMed, EMBASE, Cochrane Library, tertiary literature
Administration, College of contraindications for herbal remedies and dietary
Pharmacy, University of Illinois
and Internet. Results: While 85 primary literatures, six books and two web sites supplements were selected and all relevant data
at Chicago, Chicago, IL, USA were reviewed for a total of 1,491 unique pairs of HDS-drug interactions, 213 were extracted using standardised checklists.
4
Center for Pharmacoeconomic HDS entities and 509 medications were involved. HDS products containing Possible mechanisms and severity ratings of
Research, College of Pharmacy, St. Johns Wort, magnesium, calcium, iron, ginkgo had the greatest number of documented HDSdrug interactions were identified
University of Illinois at Chicago,
documented interactions with medications. Warfarin, insulin, aspirin, digoxin, and using MicroMedex and Natural Medicines
Chicago, IL, USA
5 ticlopidine had the greatest number of reported interactions with HDS. Medications Comprehensive Database.
Department of Pharmacy
Practice, College of Pharmacy, affecting the central nervous system or cardiovascular system had more documen- Message for the clinic
University of Illinois at Chicago, ted interactions with HDS. Of the 882 HDS-drug interactions being described its Some HDS ingredients have potentially harmful
Chicago, IL, USA
mechanism and severity, 42.3% were due to altered pharmacokinetics and 240 drug interactions that are predominately moderate
Correspondence to: were described as major interactions. Of the 152 identified HDS contraindications, in their severity. HDS products containing St Johns
Hsiang-Wen (Margaret) Lin, the most frequent involved gastrointestinal (16.4%), neurological (14.5%), and Wort, magnesium, calcium, iron and ginkgo had
PhD renal genitourinary diseases (12.5%). Flaxseed, echinacea, and yohimbe had the the greatest number of documented interactions
School of Pharmacy and with other medications. Drugs affecting the central
Graduate Institute,
largest number of documented contraindications. Conclusions: Although HDS-
nervous system and cardiovascular system were
College of Pharmacy, China drug interactions and contraindications primarily concerned a relatively small subset documented to have more interactions with HDS.
Medical University of commonly used medications and HDS entities, this review provides the summary Herbal remedies were more likely to have
No. 91 Hsueh-Shih Road, to identify patients, HDS products, and medications that are more susceptible to documented drug interactions and contraindications
Taichung 40402, Taiwan
Tel.: 886-4-22053366 ext 5151
HDS-drug interactions and contraindications. The findings would facilitate the than other dietary supplements.
Fax: 886-4-22078083 health-care professionals to communicate these documented interactions and con-
Email: hsiangwl@mail.cmu. traindications to their patients and or caregivers thereby preventing serious
edu.tw, hsiangwl@yahoo.com adverse events and improving desired therapeutic outcomes.
Disclosures
None.
abdominal pain and headache (2,7,8). Because a
Introduction
majority of patients often fail to disclose that they
The marketing and consumer use of herbs and die- have taken HDS products to their healthcare provid-
tary supplements (HDS) has risen dramatically in the ers, e.g. one study estimated only 30% disclosure (9),
USA over the past two decades (1,2). It is estimated patient-provider communication concerning the risks
that > 50% of patients with chronic diseases or can- and benefits of HDS is critically important.
cers ever use HDS (3), and nearly one-fifth of A major challenge for healthcare providers in
patients take HDS products concomitantly with pre- counselling patients about HDS is that the available
scription medications (4,5). Despite their widespread clinical evidence may be ambiguous and sometimes
use, the potential risks associated with combining conflicting for HDS adverse events and drug interac-
HDS with other medications are poorly understood tions (10,11). Also, there are often practice-based
by these consumers. Although many HDS users barriers to identifying the evidence on HDSdrug
believe that HDS are safe (6), HDS products have interactions (12), including lack of familiarity or
been reported to be associated with mild-to-severe access to HDS-related textbooks and databases
adverse effects such as heart problems, chest pain, (13,14). In general, fewer and less rigorous studies
2012 Blackwell Publishing Ltd

1056 Int J Clin Pract, November 2012, 66, 11, 10561078. doi: 10.1111/j.1742-1241.2012.03008.x
Evidence evaluation of drugs with herbs and dietary supplements 1057
are available for HDS than that of prescription drugs, the HDSmedication interactions and the other for
particularly with respect to randomised controlled HDS contraindications). All pairs of HDSdrug
clinical trials (15). Many available references for interactions documented in the retrieved literature
HDS list numerous potential HDSdrug interac- sources (except for those interaction pairs with con-
tions with little clinical significance or risk. Many sequences that may benefit to users) were extracted.
reference books are replete with errors that serve Because most HDS products or ingredients are not
only to confuse healthcare practitioners or consum- recommended for use during pregnancy or lactation
ers. The aim of this review was to provide healthcare (25), documented contraindications for these condi-
professionals with a resource that concisely summa- tions were not further reviewed. All relevant data
rises the scientific evidence for HDSdrug interac- were extracted, compiled and classified all by one
tions and contraindications from 2000 to 2010. qualified reviewer, and then validated by another.
Any disagreements related to the abstraction of data
were resolved by consensus.
Methods
We grouped HDS products ingredients into three
Evidence resources and literature search categories: herb botanical, vitamin mineral amino
This review of HDSdrug interactions and contraindi- acid (VMA) and others. The most common drugs
cations focused on the evidence in the primary litera- were grouped according to the Anatomical Thera-
ture and tertiary literature (i.e. textbooks) related to peutic Chemical (ATC) classification system (26).
HDS or drug interactions (1621). Important online Possible mechanisms and the severity ratings of each
resources about HDS, including the website of National pair of interactions were retrieved using the Interac-
Center for Complementary and Alternative Medicine tions database in MicroMedex (27) and Natural
(NCCAM) (22), and Office of Dietary Supplements Product Drug Interaction Checker in Natural Medi-
(23) were also included. The definition of HDS used cines Comprehensive Database (NMCD) (28). We
for this study was the official definition of dietary sup- categorised the mechanisms for pairs of interactions
plements as stated in the Dietary Supplement Health into four types: pharmacokinetics, pharmacodynam-
and Education Act of 1994 (DSHEA) (24). HDS refers ics, both (pharmacokinetics plus pharmacodynamics)
to any herbal product or dietary supplement product and unknown. The severity of each documented
containing one of the following ingredients: vitamin, interaction was categorised as contraindicated, major,
mineral, other botanical, amino acid, or other dietary moderate and minor based upon MicroMedex, and
substance. Thus, traditional foods or fruit products, major, moderate and minor based upon NMCD,
not listed in the definition (e.g. avocado, grapefruit, respectively. The definitions of major, moderate
and onion, etc.), were not included in this review. and minor were similar in these two databases. For
The primary literature was obtained by searching instance, a major interaction may cause life-threaten-
databases, i.e. MEDLINE (via PubMed), EMBASE ing damage and or serious adverse effect(s), and a
and Cochrane Library. Search terms included, but minor interaction would result in a negligible
were not limited to the medical subject headings effect(s). However, contraindicated interactions were
(MeSH terms) or key words that encompassed herb rated as major severity in NMCD. The types of
drug interactions, dietary supplements OR vita- contraindications were categorised based on Gold-
mins OR minerals OR amino acids OR botanical man: Cecil Medicine (29). All data were compiled
OR herbal medicine OR phytotherapy combined and managed using an Excel spreadsheet. Descriptive
with contraindications OR drug interactions. The analyses to define the frequency or proportion of the
searches were performed in English only for the per- evidence associated with the interaction pairs, the
iod of January 2000 to December 2010. The articles corresponding mechanisms and severity ratings of
were selected based on the titles and abstracts and interactions and the types of contraindications for
reviewed independently by two authors (HHT, certain populations or patients was performed.
HWL). Literature without related information,
including studies regarding efficacy of HDS, regula-
Results
tion of HDS or methods of assay, was excluded. All
relevant articles were selected without restriction for Literature search
animal studies, clinical trials, observational studies Finally, 461 articles of primary literature were ini-
(including case reports) or review articles. tially identified. Eighty-five articles with full text,
including 54 review articles, other than the 6 books
Data extraction and synthesis and 2 web sites were selected for further review (Fig-
Two standardised data abstraction checklists were ure 1). The summaries of the animal studies, obser-
developed and used to perform the review (one for vational studies and clinical trials to retrieve

Int J Clin Pract, November 2012, 66, 11, 10561078
1058 Evidence evaluation of drugs with herbs and dietary supplements
MEDLINE (n = 78) Pubmed (n = 70) EMBASE (n = 328) Cochrane library (n = 71)
461 literature were identified
333 literature were excluded based on

title and abstract
128 literature were selected initially

43 literature were excluded
letters or comment: 11
interactions with benefit results: 3
no related information: 10
without full text: 16
others: 3
Original studies (n = 31)
Review articles Clinical trials Observational studies Animal studies

(n = 54) (n = 16) (n = 9) (n = 6)
Figure 1 Flow chart of primary literature search
information about HDSdrug interactions and interactions were identified for their potential mecha-
contraindications for the original studies are listed in nism and severity. In terms of contraindications,
Tables 13, respectively. The summaries of the there were 128, 15 and 9 documented HDS contrain-
retrieved books and reviewed articles to retrieve dications retrieved from books, primary articles and
information about HDSdrug interactions and con- web sites, respectively, for a total of 152.
traindications were listed in Appendices 1 and 2,
respectively. Among the original studies (n = 31), HDSdrug interactions
more than half (n = 16) were clinical trials. All of Among all included interactions between HDS and
these articles contained information about HDSdrug individual drugs, 166 different herbs botanical prod-
interactions (12,30113), but only five articles pro- ucts, 28 VMA and 19 other supplements accounted
vided descriptive information about HDS contraindi- for 890 pairs (59.7%), 529 pairs (35.5%) and 72
cations (5557,59,102). pairs (4.8%) of documented interactions, respectively
(Figure 2). The top five herbs botanical products,
Quantity of retrieved evidence which were documented to have the most interac-
After excluding the evidence regarding HDS not rec- tions with individual medications, were St Johns
ommended for human use (i.e. anvirzel, belladonna, Wort (Hypericum perforatum), ginkgo (Ginkgo
chaparral, comfrey, ephedra and pennyroyal) biloba), kava (Piper methysticum), digitalis (Digitalis
(16,19,2123) and the duplicates, a total of 1491 purpurea) and willow (Salix alba). For example, St
unique pairs of documented interactions between Johns Wort, magnesium, calcium, iron and ginkgo
HDS and individual drugs were identified. Among have been documented to interact with 147, 102, 75,
these pairs, 814 pairs (54.6%) were retrieved from the 71 and 51 individual medications, respectively. Fur-
primary literature, 1018 pairs (68.3%) from books thermore, a total of 509 unique drugs contributed to
and only 23 pairs of interactions were identified in the 1491 documented pairs of interactions with
the two reviewed web sites. Among these interactions, HDS. The majority of these medications (n = 100)
the corresponding mechanism and severity was deter- were categorised as treatment for central nervous sys-
mined for 507 pairs (34.0%) using MicroMedex and tem (CNS), second were those medications affecting
763 pairs (51.2%) in the NMCD online database. In the cardiovascular system and then systemic anti-
total, 882 pairs (59.2%) of documented HDSdrug infective drugs (n = 90 and 75, respectively)

Table 1 Summary of the included animal studies to retrieve information about HDSdrug interactions
Outcome Dose
Reference HDS Medication Animal model (number) Study design measures dependent Major findings

Chiang et al. (61) Water extract of crude Methotrexate (oral and Rats (7 in each group) Parallel design Pharmacokinetic Yes Pueraria lobata significantly
Pueraria lobata (oral) intravenous) parameters decreased the elimination
of methotrexate
Jan et al. (67) 1. Extract of dry Evodia Theophylline (intravenous) Rats (6 in each group) Randomised parallel Pharmacokinetic Yes Theophylline level was
rutaecarpa (Wu-Chu-Yu) design parameters significantly decreased

2. Commercial herbal
extract preparation of
Wu-Chu-Yu-Tang
(gastrogavage).
Tang et al. (83) Commercial extract Theophylline (oral and Rats (6 in each group) Randomised parallel Pharmacokinetic Yes Ginkgo significantly
of Ginkgo biloba (oral) intravenous) design parameters increased the total
clearance, and significantly
reduced the AUC of
theophylline
Okonta et al. (94) Extract of fresh ginger Metronidazole (oral) Rabbit (5) Crossover study Pharmacokinetic No data Ginger significantly
(oral) parameters increased the absorption
and plasma half-life, and
significantly decreased the
elimination rate constant
and clearance of
metronidazole
Chang et al. (100) Silymarin, silibinin dissolved Trazodone (intravenous) Rats (6 in each group) Randomised parallel Pharmacokinetic Yes No marked effects of
in ethanol and PEG2000 design parameters silymarin and silibinin on
(oral) Biliary excretion the pharmacokinetics of
trazodone under normal
daily doses
Chien et al. (109) Extract of crude Andrographis Theophylline (intravenous) Rats (9 in control group Randomised parallel Pharmacokinetic Yes Andrographis paniculata
paniculata and major and 6 in each studied design parameters. increased elimination of
components (oral) group) Major component theophylline, and chronic
Evidence evaluation of drugs with herbs and dietary supplements
of HDS. use of A. paniculata could

elevate the concentration
of theophylline
HDS, herbs and dietary supplements; AUC, area under concentration curve.
1059
Table 2 Summary of the included observational studies to retrieve information about HDSdrug interactions
1060
Population (number of Evidence resources of Results related to

Reference HDS Medication Study design participants) Outcome measures interactions HDSdrug interactions
Barone St Johns wort Cyclosporine Case report Transplant recipients _ No mention Cyclosporin concentrations
et al. (34) (n = 2) were consistently
subtherapeutic
Rogers Herbs General Survey Emergency department patients Prevalence and occurrence No mention Six patients were identified
et al. (38) with heart disease, diabetes, of sever herbdrug at risk for seven known
psychiatric disorders and or interactions herbdrug interactions
hypertension (n = 944)
Dergal Herbal medicines Prescription and Survey Older adults (365 years) The frequency of potential Book, medical literature There were 11 potential
et al. (40) over-the-counter attending a memory clinic interactions between identified in MEDLINE herbdrug interactions in
drugs (n = 195) herbal medicines and nine patients
conventional drug
therapies
Ly et al. (41) Dietary supplements Prescription drugs Survey Veterans 365 years (n = 285) The frequency of dietary No mention There were 15 patients
supplement use and to taking at least one
identify potential combination that could
interactions cause an interaction
Peng et al. (52) Dietary supplements Prescription drugs Survey Veteran outpatients (n = 458) The incidence and severity Tertiary references, There were 89 patients
of potential interactions newsletters, textbooks, who had a potential for
between prescription internet web pages and drugdietary supplement
medications and dietary medical literature interactions
supplements
Sood et al. (96) Dietary supplements Prescription drugs Cross-sectional, Patients in 6 different specialty The frequency of clinically MEDLINE database, Natural There were 107 interactions
point-of-care clinics (n = 1818) significant interactions Medicines Comprehensive with potential clinical
survey between dietary Database, published significance identified
supplements and textbook
prescription medication
Goldman Vitamins Prescribed or Cross-sectional Children aged 018 years The frequency and types of PubMed database, There were 193 children
et al. (101) over-the-counter study (survey) (n = 1804) potential interactions MEDLINE Plus, Drug with a potential
medications between vitamins and digest and the database vitamindrug interaction
medications of the University of identified
Maryland Medical Center
Lapi Herbal drugs and Synthetic drugs Cross-sectional Patients during preoperative The predictors of potential No mention There were 88 patients
et al. (104) dietary study (survey) anaesthesiological interactions among drugs, HDS detectable for potential
supplements visit (n = 478) and or other CAM medications interactions evaluation
Simmons Commercial Phenelzine Case report 24-Year-old male with _ No mention Hypertensive crisis
and Schneir supplement hypertension (n = 1) associated with an MAOI
(113) products interaction with
(Atrophex) beta-phenylethylamine
HDS, herbs and dietary supplements; CAM, complementary and alternative medicine; MAOI, monoamine oxidase inhibitors.

Table 3 Summary of the included clinical trials to retrieve information about HDSdrug interactions
Dose schedule Population (number

Reference HDS of HDS Medication Study design Country of participants) Outcome measures
Wang et al. Commercial product of St Single dose and Fexofenadine (oral) Open-label, USA Healthy subjects (n = 12) Pharmacokinetics (Cmax, Tmax)
(44) Johns wort (oral) long term for fixed-schedule
1415 days study

Gurley et al. Commercial products of 28 days Midazolam, caffeine, Randomised USA Healthy subjects (n = 12) Phenotypic ratio
(49) Citrus aurantium, chlorzoxazone, open-label study
Echinacea purpurea, debrisoquin (oral)
Milk thistle, Saw
palmetto (oral)

Yin et al. (53) Commercial Ginkgo biloba 12 days Omeprazole (oral) Open-label sequential Hong Kong Healthy subjects genotyped Pharmacokinetics (Cmax, Tmax)
product (oral) study for CYP2C19 (n = 18)
Yoshioka et al. Commercial product of Single dose Nifedipine (oral) Randomised crossover Japan Healthy subjects (n = 8) Pharmacokinetics (Cmax, Tmax),
(54) Ginkgo biloba (oral) study Pharmacodynamics (blood pressure).
Gurley et al. Commercial products of St 28 days Midazolam, caffeine, Randomised USA Healthy older subjects who Phenotypic metabolic ratios, serum
(62) Johns wort, garlic oil, chlorzoxazone and open-label study were extensive metabolisers of concentration
Panax ginseng and Ginkgo debrisoquine (oral) CYP2D6 (n = 12)
biloba (oral)
Gurley et al. Commercial products of 28 days Caffeine, midazolam, Randomised USA Healthy subjects who were Phenotypic ratio
(63) goldenseal, kava kava, chlorzoxazone, open-label study extensive metabolisers of
black cohosh and valerian debrisoquin (oral) CYP2D6 (n = 12)
(oral)
Gurley et al. Commercial products of 14 days Digoxin (oral) Randomised USA Healthy young adults (n = 16) Pharmacokinetic analysis, ABCB1
(71) milk thistle, black cohosh open-label study (MDR1) genotyping
(oral)
Jiang et al. (73) Commercial products of St 7 or 14 days Warfarin (oral) Two randomised, Australia Healthy subjects (n = 24) Population pharmacokinetic and
Johns wort, Asian open-label, controlled, pharmacodynamic parameter
ginseng, Ginkgo biloba or crossover studies
ginger (oral)
Gurley et al. Commercial products of 14 days Digoxin (oral) Randomised USA Healthy subjects (n = 20) Pharmacokinetic analysis,
(78) goldenseal, kava kava (oral) open-label study phytochemical analyses
Fan et al. (86) Commercial product of 14 days Rosuvastatin (oral) Randomised China Healthy subjects who were Plasma concentration and
baicalin (oral) crossover study CYP2C9*1 *1 with different pharmacokinetic parameters
OATP1B1 haplotypes (n = 18)
1061
1062
Table 3 Continued
Dose schedule Population (number

Reference HDS of HDS Medication Study design Country of participants) Outcome measures
Gurley et al. Commercial products of 14 days Midazolam (oral) Randomised USA Healthy subjects (n = 16) Pharmacokinetic parameters,
(88) goldenseal, kava kava (oral) open-label study phenotypic ratios
Gurley et al. Commercial products of 14 days Debrisoquine (oral) Randomised USA Healthy subjects who were Phenotypic ratios, phytochemical
(89) black cohosh, echinacea, open-label design extensive metabolisers of analysis and disintegration times
goldenseal, kava kava, CYP2D6 (n = 16)
milk thistle and St Johns
wort (oral)
Gurley et al. Commercial products of St 14 days Digoxin (oral) Randomised open-label USA Healthy young adults (n = 18) Pharmacokinetic parameters,
(90) Johns wort, echinacea study phytochemical analysis and
(oral) disintegration times
Mohammed Commercial products of 14 days Warfarin (oral) Randomised Australia Healthy subjects of known Pharmacokinetic parameters,
Abdul et al. garlic, cranberry (oral) open-label CYP2C9 and VKORC1 pharmacodynamics (INR)
(91) crossover study genotype (n = 12)
Kim et al. (110) Commercial product of Single dose Ticlopidine (oral) Randomised open-label, Korea Healthy subjects (n = 24) Pharmacokinetic parameters,
Ginkgo biloba (oral) crossover study pharmacodynamics (bleeding times)
Nieminen et al. Commercial product of St 15 days Oxycodone (oral) Randomised, Finland Healthy subjects (n = 12) Pharmacokinetic parameters,
(111) Johns wort (oral) balanced, pharmacodynamics (behavioural
placebo-controlled, and analgesic effects); adverse
crossover study effects
HDS, herbs and dietary supplements; Cmax, maximum plasma concentration; Tmax, time to reach Cmax; CYP, Cytochrome P450; VKORC1, vitamin K epoxide reductase subunit 1; INR, international normalised ratio.

Figure 2 Herbs and dietary supplements tended to have documented interactions with medications in each caterory.
VMA, vitamin mineral amino acid; DS, dietary supplements; DHEA, dehydroepiandrosterone
(Figure 3). The medications that most contributed to related mechanisms, and 8.5% were attributed to a
documented interactions with HDS were warfarin, combination of both mechanisms. No mechanism
insulin, aspirin, digoxin and ticlopidine. Not surpris- was identifiable for the remaining 9.1% of pairs.
ingly, warfarin was documented to have interactions Among the 373 documented HDS interaction pairs
with over 100 HDS entities (Figure 4). that were pharmacokinetic-related, 87 pairs were asso-
Among 882 pairs of interactions with identified ciated with St Johns Wort (23.3%), whereas calcium
mechanisms, a total of 373 pairs (42.3%) were attrib- supplements were involved in 47 pairs of documented
utable to pharmacokinetic-related mechanisms, i.e. interactions (12.6%), and iron was involved in 42
affected the absorption, distribution, metabolism or pairs of interactions (11.3%). St Johns Wort was doc-
excretion of the HDS drug. Approximately 40.1% of umented to reduce the effectiveness of alprazolam,
all interaction pairs accounted for pharmacodynamic- amitriptyline, imatinib, midazolam, nifedipine and
Others 32 (6.3%)
Genito urinary system and sex

19 (3.7%)
hormones
Respiratory system 21 (4.1%)

ATC classification system
Blood and blood forming organs 30 (5.9%)
Musculo-skeletal system 34 (6.7%)
Antineoplastic and
46 (9.0%)
immunomodulating agents
Alimentary tract and metabolism 62 (12.2%)
Antiinfectives for systemic use 75 (14.7%)
Cardiovascular system 90 (17.7%)
Nervous system 100 (19.6%)
0 20 40 60 80 100 120
Number of medications (n, %)
Figure 3 Distribution of medications that might have interactions with herbs and dietary supplements. ATC, anatomical
therapeutic chemical. The number of total medications was 509

120
105
100
80
Items of HDS
60
41
40 36
32
23
20 17 16
14 13
10 9 10 11 9 11 11 11 10 10 9
0
Warfarin
Aspirin
Ticlopidine
Heparin
Clopidogrel
Dipyridamole
Insulin
Glyburide
Digoxin
Spironolactone
Triamterene
Nifedipine
Theophylline
Aminophylline
Cyclosporin
Tamoxifen
Phenelzine
Phenytoin
Tetracycline
Ciprofloxacin
Blood and blood forming organs Alimentary Cardiovascular system Respiratory Antineoplastic Nervous Anti infectives
tract and system and immuno- system for systemic
metabolism modulating use
Medications agents
Figure 4 Medications with the largest number of interactions with herbs and dietary supplements. HDS, herbs and dietary
supplements
verapamil via the CYP (Cytochrome P450) 3A4 path- based on the NMCD, the majority documented
way, and the plasma levels of fexofenadine and interaction pairs were categorised as moderate
digoxin via PgP (p-glycoprotein) pathway. Some (69.2%), major (26.5%) and minor (4.3%). Approxi-
drugs (i.e. atorvastatin, cyclosporin, indinavir, nevira- mately, 240 documented HDSdrug interactions were
pine and simvastatin) were documented to interact categorised as major severity in either database
with St Johns Wort through both pathways (37,99). (Tables 4 and 5). For example, the following pairs of
Among the 354 documented interactions that were interactions were considered as being contraindicated
pharmacodynamic-related, kava accounted for 4.8% for concurrent use in MicroMedex: l-Tryptophan
pairs of interactions (17 pairs). St Johns Wort and vs. MAOI (i.e. isocarboxazid, phenelzine and tran-
ginkgo were both involved in 15 pairs of interactions ylcypromine) or venlafaxine and St Johns wort vs.
(4.2%). Risk of additive serotonergic effects were protease inhibitors (i.e. amprenavir, fosamprenavir
increased when St Johns Wort was used concurrently and indinavir), irinotecan, rasagiline or voriconazole,
with monoamine oxidase inhibitors (MAOI), selective respectively. Among the 390 documented interaction
serotonin reuptake inhibitors (SSRI), or tryptamine- pairs having severity ratings in both databases, 41.3%
based drugs causing symptoms of anxiety, dizziness, were inconsistent. For example, the combination of
restlessness, nausea and vomiting (1618,20). As a alfalfa (Medicago sativa) and warfarin were consid-
result of their pharmacological actions on the GABA ered as the minor interaction in MicroMedex;
receptor, synergism in CNS adverse events may result however, it was rated as the major interaction in
from taking barbiturates or benzodiazepines in com- NMCD. The combination of St Johns Wort with
bination with kava (16,20,98). Furthermore, kava may quetiapine, quinidine, risperidone or sildenafil gave
worsen the extrapyramidal effects associated with the severity ratings major according to NMCD, and no
use of droperidol, haloperidol, metoclopramide or ris- interaction was reported in MicroMedex.
peridone because of a dopamine (21,98).
Among the 507 documented interaction pairs HDS contraindications
identified with a severity rating in MicroMedex, Fifty-nine HDS from 152 reports were contraindi-
69.4% were categorised as the moderate interactions, cated for use among patients with specific disease
17.2% as major interactions, 10.3% as minor interac- states. The reports were classified into 19 disease
tions and 3.1% were attributable to the contraindica- states, including gastrointestinal diseases, neurologic
tions. As for the 763 pairs of documented disorders, renal genitourinary diseases, neoplastic
interactions being identified with the severity rating disorders, diseases of the liver gallbladder bile ducts

Table 4 The HDSdrug interactions with major severity* (other than St Johns Wort)
HDS Drugs Potential consequences reactions
5-Hydroxytryptophan Fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine (17) Risk of serotonin syndrome
Acacia Amoxicillin (98) Absorption of amoxicillin
Alfalfa Warfarin (21,33,43,75) The effect of warfarin
Aloe vera Digoxin (16,21,33,45) Digoxin toxicity
American ginseng Warfarin (16,70,75) The effect of warfarin
Arginine Enalapril, nitroglycerin (21) Hypotensive effects
Spironolactone (21) Risk of hyperkalemia
Bitter orange Phenelzine (22,98) Risk of hypertensive crisis
Cowhage Methyldopa (98) Hypotensive effects
Danshen Aspirin, ticlopidine, warfarin (17,20,21,31,35,43,47,6466,68,70,75,77,81,92,97,98) Risk of bleeding
Digoxin (20,21) Digoxin toxicity
Digitalis Bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, Digoxin toxicity
hydroflumethiazide, indapamide, methyclothiazide, metolazone,
polythiazide, trichlormethiazide (17,20)
Digoxin (17) Digoxin toxicity
Dong quai Aspirin, heparin, ticlopidine, warfarin (16,17,20,21,31,33,35,38,43,47,6466,70,72,75,77,92) Risk of bleeding
Evening primrose Warfarin (18,75,98) Risk of bleeding
Garlic Ritonavir (16,64,97,103) The effect of ritonavir
Saquinavir (16,22,51,64,65,77,81,85,97,98,103) The effect of saquinavir
Warfarin (1619,31,33,35,36,41,43,47,51,52,6466,68,75,77,80,81,85,87,96,98) Risk of bleeding
Ginkgo Aspirin, cilostazol, clopidogrel, dipyridamole, heparin, ibuprofen, naproxen, Risk of bleeding
ticlopidine, warfarin (12,1622,30,31,3336,38,40,47,51,52,55,60,6466,68,
75,77,80,81,85,87,98,103,105,110)
Risperidone (20,103) Risk of risperidone adverse effects
Trazodone (12,17,20,21,35,36,40,47,60,64,65,77,81,87,103) Excessive sedation and potential coma
Glucosamine Warfarin (20,75,96) Risk of bleeding
Green tea Ephedrine (17,21) Risk of stimulatory adverse effects
Guarana Ephedrine (16) Risk of stimulatory adverse effects
Hawthorn Digoxin (16,21,33,98) Digoxin toxicity
Henbane Chlorpheniramine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, promethazine (17) Risk of anticholinergic side effects
Kava Alprazolam, chlordiazepoxide, clonazepam, diazepam, estazolam, flurazepam, lorazepam, Central nervous system depression
midazolam, morphine, oxazepam, henobarbital, quazepam, temazepam, triazolam
(1620,30,35,36,42,57,64,65,69,72,80,81,85,103)
Droperidol (21,98) Central nervous system depression
Licorice Warfarin (16,43,68,75) Risk of bleeding
l-Tryptophan Citalopram, duloxetine, fluoxetine, fluvoxamine, isocarboxazid, paroxetine, phenelzine, Risk of serotonin syndrome
selegiline, sertraline, sibutramine, tranylcypromine, venlafaxine (17,20,51)
Zolpidem (17) Zolpidem-induced side effect
Melatonin Zolpidem (21) Sedative effects
N-acetylcysteine Nitroglycerin (17) Severe hypotension, intolerable headaches
Niacin Atorvastatin, cerivastatin, lovastatin, rosuvastatin, simvastatin (19,20,82,84,112) Risk of myopathy or rhabdomyolysis
PABA Dapsone, sulfamethoxazole (17,20) Antibacterial effects
Pleurisy root Digoxin (17) Digoxin toxicity
Potassium Amiloride, benazepril, captopril, enalapril, fosinopril, indomethacin, lisinopril, moexipril, Risk of hyperkalemia
quinapril, ramipril, spironolactone, trandolapril, triamterene (17,19,20,52,82)
Red yeast rice Cyclosporin (21,65,98) Creatine phosphokinase values
S-adenosylmethionine Clomipramine (16) Risk of serotonin syndrome
Scotch broom Haloperidol (98) The potential toxicity
Phenelzine (17) Risk of hypertensive crisis
Valerian Alprazolam, phenobarbital (16,20,42) Central nervous system depression
Vitamin A Acitretin, bexarotene, etretinate, isotretinoin, tretinoin (17,19,51,82,84,101,112) Risk of vitamin A toxicity
Vitamin B6 Altretamine (84) Response to altretamine

Table 4 Continued
Vitamin E Dicumarol (84) Risk of bleeding

Vitamin K Warfarin (17,19,20,23,43,47,75,82,84,112) Effect of warfarin
Willow Diclofenac, ibuprofen, naproxen, ticlopidine, warfarin (16,17,47,68,75) Risk of bleeding
*Any HDSdrug interactions with severity rated as contraindicated or major in either database of MicroMedex or NMCD were included in this table.
Potential consequences or reactions were documented according to either aforementioned database with severity rating as major or contraindicated. , increasing;
, decreasing.
and cardiovascular diseases (Figure 5). Flaxseed HDS entities have undergone more rigorous scien-
(Linum usitatissimum), echinacea (Echinacea purpu- tific evaluations. The clinical evidences for HDS are
rea) and yohimbe (Pausinystalia yohimbe) had the often mixed in terms of their support for efficacy
highest number of documented contraindications. and or effectiveness. The benefits of HDS treatment
For example, flaxseed was documented to have con- must be balanced against the potential harmful
traindications associated with gastrointestinal disor- effects including adverse events, and the potential for
ders such as acute or chronic diarrhoea, oesophageal drug interactions or disease state contraindications.
stricture, inflammatory bowel disease, hypertriglyceri- Furthermore, there often may be just a self-medicat-
demia and prostate cancer (21). Echinacea was con- ing indication creep, where patients who have a cer-
traindicated for use among patients with rheumatoid tain disease or condition unrelated to the supportive
arthritis, systemic lupus erythematosus, leukosis, therapy with these HDS. For example, WHO mono-
multiple sclerosis, tuberculosis and HIV infection graphs listed that echinacea products could be used
(16,18). Yohimbe was contraindicated in patients in supportive therapy of colds and infections but
with anxiety, bipolar disorder, depression, mania and were contraindicated for patients with autoimmune
schizophrenia, as well as benign prostate hypertrophy diseases (116). Even though the evidence to support
and kidney disease (21,22). the immunological effects of echinacea was still con-
troversial (117), 6.4% of patients with arthritis lupus
reportedly used echinacea in the 2002 NHIS (4).
Discussion
Thus, patients need to understand that advantages of
In this study, we summarised the evidence of HDS using echinacea products are outweighed by the
drug interactions and contraindications that have potential harm if they have a specific disease state.
been reported in the primary and tertiary literature. Patients using medications that have a narrow
The existing evidence suggests that some HDS prod- therapeutic range (i.e. warfarin, digoxin) were at
ucts ingredients have potentially harmful drug inter- greater risk for adverse outcomes because of HDS
actions that are predominately moderate in their drug interactions (20). This was particularly impor-
severity. HDS products containing St Johns Wort, tant for patients on anticoagulants (i.e. warfarin)
magnesium, calcium, iron, and ginkgo had the great- who concomitantly took HDS products that had
est number of documented interactions with drugs. antiplatelet or anticoagulant effects (e.g. danshen,
Medications affecting the CNS and cardiovascular dong quai, garlic, ginger and ginkgo) (70,75). In par-
system tended to have more documented interactions ticular, HDS products that contained vitamin K or
with these HDS. Of all listed medications, warfarin metabolites related to vitamin K (e.g. coenzyme
was documented to have the greatest number of Q10) had the potential to reduce the effects of warfa-
HDS interactions. HDS products containing herbal rin (75). However, some conflicting information
remedies were more likely to have documented inter- regarding warfarinHDS interactions was observed
actions with medications and the contraindications when the evidence was retrieved from different litera-
than vitamins, minerals and other types of dietary ture sources. For instance, in a case study, the inter-
supplements. national normalised ratio (INR) decreased in patients
Some of the commonly used herbal remedies such when ginseng was administered with warfarin in
as echinacea, flaxseed, ginkgo and St Johns Wort some case reports (12,66,118), but other in vitro
have featured more prominently in industry or gov- studies demonstrated that several components of
ernment sponsored clinical trials, academic studies Panax ginseng had anticoagulant effects (12).
and official monographs (114,115). Some of these Furthermore, a controlled clinical trial of healthy

Table 5 The St Johns Wort-drug interactions with major severity*
St Johns wort Amiodarone (20,37) Effect of amiodarone

Benzodiazepine: alprazolam, clonazepam, diazepam, midazolam, Benzodiazepine effectiveness
triazolam (20,36,37,49,59,62,64,65,76,77,80,81,87,93,97,99,103)
Bupropion, buspirone, eletriptan, meperidine, trazodone (17,31,37,39,65,69,99,103) Risk of serotonin syndrome
MAOI: isocarboxazid, phenelzine, tranylcypromine (17,33)
SSRI: citalopram, duloxetine, fluoxetine, fluvoxamine, nefazodone,
paroxetine, sertraline, venlafaxine
(12,1618,20,31,32,3537,47,52,59,64,65,69,72,77,81,87,99,103)
TCA: amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, nortriptyline,
protriptyline, trimipramine (12,16,17,20,36,37,59,64,65,69,72,76,
77,80,81,85,87,93,97,99,103)
Busulfan (39) Effect of busulfan
Calcium channel blockers: diltiazem, felodipine, nicardipine, nifedipine, nitrendipine, Effect of calcium channel blockers
verapamil (16,20,37,59,65,76,7981,99,102,103)
Carbamazepine (32,37,99) Effect of carbamazepine
Cyclophosphamide (16,37,93) Effect of cyclophosphamide
Cyclosporin (12,1618,2022,3032,3437,47,4951,59,64,65,69,72,76,77, Effect of cyclosporine
7981,92,93,97,99,102,103)
Dapsone (37) Effect of Dapsone
Dexamethasone (39) Effect of dexamethasone
Digoxin (12,1618,20,22,3032,34,36,37,47,51,59,6466,69,72,76,77, Effect of digoxin
7981,87,90,92,93,97,99,102,103)
Docetaxel (39,74) Effect of decetaxel
Dolasetron (39) Effect of dolasetron
Doxorubicin (39,81) Effect of doxorubicin
Erlotinib (20) Effect of erlotinib
Erythromycin (103) Effect of erythromycin
Estrogens progestogens: estradiol, gestodene, levonorgestrel, norethindrone (37,39,50,72) Effect of contraceptive
Etoposide (39,81) Effect of etoposide
Exemestane (20) Effect of exemestane
Fentanyl, Morphine, Oxycodone (21,37,99,111) Sedation
Fexofenadine (20,44,59,64,65,76,77,79,80,93,97,99,103) Effect of fexofenadine
Finasteride (39) Effect of finasteride
Flutamide (32,39) Effect of flutamide
Gliclazide (103) Effect of gliclazide
Haloperidol (37) Effect of haloperidol
Ifosfamide (39) Effect of ifosfamide
Imatinib (20,59,76,77,79,80,97,99,103) Effect of imatinib
Irinotecan (12,16,2022,49,59,64,65,76,77,80,81,97,103) Effect of irinotecan
Ivabradine (103) Effect of ivabradine
Ixabepilone (20) Effect of ixabepilone
Lapatinib (20) Effect of lapatinib
Lidocaine (37) Risk of cardiovascular collapse
Loperamide (21,30,35,36,64,77,99,103) Effect of loperamide
Maraviroc (20) Effect of maraviroc
Mephenytoin (76,97,99,103) Effect of mephenytoin
Methadone (20,21,37,64,65,77,92,93,99,103) Effect of methadone
NNRTI: delavirdine, efavirenz, nevirapine (16,18,20,32,37,69,76,77,80,99,103) NNRTI concentrations
Omeprazole (17,20,65,76,77,80,92,93,103) Effect of omeprazole
Ondansetron (39) Effect of ondansetron
Paclitaxel (37,39) Effect of paclitaxel

Table 5 Continued
Phenprocoumon (12,18,31,3537,47,65,66,77,80,81,97,103) Effect of phenprocoumon

Phenytoin (32) Effect of phenytoin
Piroxicam, rasagiline, risperidone, tetracycline, tolbutamide, tretinoin Photosensitivity reactions
(20,37,39,77,102,103)
Propofol, sevoflurane (20,99,103) Risk of cardiovascular collapse
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir, Effect of protease inhibitor
indinavir, nelfinavir, ritonavir,
saquinavir, tipranavir (12,1622,32,34,36,37,47,49,51,64,65,69,72,
76,77,7981,93,97,103)
Quetiapine (37) Effect of Quetiapine
Quinidine (37) Effect of Quinidine
Sildenafil (37,50,93) Effect of Sildenafil
Sirolimus (20) Effect of Sirolimus
Sunitinib (20) Effect of sunitinib
Tacrolimus (12,16,20,37,59,64,65,76,77,7981,92,93,97,99,103) Effect of tacrolimus
Tamoxifen (16,37,39) Effect of tamoxifen
Temsirolimus (20) Effect of sirolimus, the
active metabolite of temsirolimus
Teniposide (39) Effect of teniposide
Tramadol (96) Effect of tramadol
Vinblastin (37,39,81) Effect of vinblastin
Vincristine (39) Effect of vincristine
Voriconazole (20,76,77,99,103) Effect of voriconazole
Warfarin (1618,20,22,32,3537,43,47,51,59,6466,69, Effect of warfarin
70,72,73,7577,7981,85,87,97,99,102,103)
*Any HDSdrug interactions with severity rated as contraindicated or major in either database of MicroMedex or NMCD were included in this table. Potential
consequences or reactions were documented according to either aforementioned database with severity rating as major or contraindicated. , increasing; , decreas-
ing. MAOI, monoamine oxidase inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; NNRTI, non-nucleoside reverse transcriptase
inhibitors.
subjects revealed that there was no significant inter- then the pharmacist usually should recommend to
action when ginseng was administered with warfarin their patients to stop taking these HDS or have their
(12,17,20,31,64). This discrepancy may be attributed digoxin dose adjusted by their healthcare providers;
to the fact that there are several different species of for example, as digoxin serum concentrations are
ginseng on the market [i.e. Asian ginseng (Panax usually measured by fluorescence polarisation immu-
ginseng), American ginseng (Panax quinquefolius), noassay or microparticle enzyme immunoassay,
Siberian ginseng (Eleutherococcus senticosus)], differ- which may be influenced by ginseng and danshen
ent extract types and different doses used. Another (Salvia miltiorrhiza) (20,58). False digoxin levels may
interesting example is the concomitant use of warfa- confuse laboratory results and result in inappropriate
rin with green tea. Some studies suggested that green patient management. Furthermore, aloe vera (Aloe
tea may enhance the anticoagulant effects of warfarin barbadensis), buckthorn (Rhamnus catartica), cascara
(19,75). However, much of the literature suggested (Rhamnus purshiani), licorice (Glycyrrhiza glabra)
that the content of vitamin K in green tea might an- and senna (Cassia senna) may cause hypokalaemia
tagonise the effect of warfarin (16,17,68,70,75). and result in digoxin toxicity (16,17,33,47). As a
Regardless, it is important to regularly monitor the result, digoxin users should be told to avoid taking
INR levels of warfarin users who also use HDS prod- the aforementioned herbal remedies.
ucts that might influence the anticoagulation effect. In this study, the documented evidence of HDS
In addition, patients on a digoxin regime who drug interactions and contraindications were system-
have been taking an HDS should check to ensure atically reviewed from the published literature. This
that their plasma concentration of digoxin is indeed was done because healthcare professionals, in general,
within the therapeutic ranges. If this is not the case, use only textbooks, journal and review articles, as

Acid peptic disease(16,19,21) Betaine, guarana, iron, turmeric
Diarrhea and malabsorption(16,19,21) Barley, chitosan, flaxseed

Gastrointestinal
Diseases Inflammatory and anatomic diseases(16,19) Aloe vera, flaxseed, iron, rhubarb
(n = 25, 16.4%)
Aloe vera, cascara, flaxseed, iron,
Intestinal obstruction and ileus(16,19)
rhubarb
Others(21)* Aloe vera, flaxseed

American ginseng, Asian ginseng,
Psychiatric disorders(16,18-19,21,59,102) guarana, kava, mate, melatonin,
St. John's wort, valerian, yohimbe
Neurologic
Disorders Evening primrose, germanium, ginkgo,
Seizures and epilepsy(16,19,102) schisandra
(n = 22, 14.5%)
Others(16,18,21) Echinacea, yohimbe
Aloe vera, boron, calcium, clay,

Renal and guarana, horse chestnut, horsetail,
Renal related(16,18-19,21-22) licorice, magnesium, noni, rhubarb,
Genitourinary
Diseases sheep sorrel, vitamin D, yohimbe
(n = 19, 12.5%)
Benign prostate hypertrophy(21) Yohimbe
Identified Alfalfa, black cohosh, chasteberry,

Breast cancer(16,19,21-22,98) DHEA, red clover, soy, wild yam
contraindications
Alfalfa, chasteberry, DHEA, red
Neoplastic Gynecologic cancers(16,19,21,98) clover, soy, wild yam
Disorders
(n =18, 11.8%) Chasteberry, DHEA, flaxseed, saw
Prostate cancer(16,21,56) palmetto
Leukemia(18) Echinacea
Copper, kava, licorice, niacin, noni,

Diseases of the Liver diseases(16,19,21-22,98) rhubarb, shark cartilage
Liver,
Gallbladder, and Gallbladder diseases(16,21-22) Dandelion, turmeric
Bile Ducts
(n =16, 10.5%) Bile Ducts diseases(16,19,21-22) Copper, dandelion, turmeric
Cardiac disease(16,19,21-22) Aloe vera, bitter orange, goldenseal,

Cardiovascular guarana, huanglian, magnesium, mate
Disease
(n =14, 9.2%) American ginseng, Asian ginseng,
Hypertension(16,18-19,22,102) bitter orange, ginkgo, goldenseal, mate,
siberian ginseng
Class of HDS which should be avoided

Contraindications and/or not recommended
contraindications
Figure 5 Common contraindications for HDS use. *Other contraindications of gastrointestinal diseases included fecal
impaction for aloe vera and oesophageal stricture for flaxseed. Other contraindications of neurologic disorders included
multiple sclerosis for echinacea and posttraumatic stress disorder for yohimbe. HDS, herbs and dietary supplements
well as Internet as their major information source given HDSdrug interactions. Concerns about dis-
for HDS (119). Although the NCCAM and Office of agreements across literature resources and databases
Dietary Supplements are the two most commonly for drug interactions have been raised before (121),
used, free online resources about HDS (120), only and these increase the difficulty in implementing an
limited information is available related to HDS inter- evidence-based clinical practice for HDS products in
actions and contraindications on these sites. Further- clinical care. The intention of this review was to eval-
more, only 59% of documented HDSdrug uate the evidence of HDS interactions and contrain-
interactions could be identified with either their dications and to assist clinical practitioners in
mechanisms and or severity in either of the two identifying patients with specific disease states and
common drug interaction resources (i.e. MicroMe- drug regimens that are more susceptible to these
dex and NMCD). Among them, over 40% of the HDSdrug interactions and contraindications.
interactions differed in their severity rating, which is One of the limitations of this review was that it
likely to create confusion among healthcare providers included all relevant information identified in the
about the potential harmful effects associated with a literature, regardless of the evidence types or quality

of the studies. Although some HDSdrug interac- those pairs of interactions between any HDS prod-
tions with little or no clinical significance were ucts that contain St Johns Wort, magnesium, cal-
included in this study, their severity grading was cium, iron and ginkgo, and medications that affect
based upon the available version of MicroMedex the CNS or the cardiovascular system. These findings
and NMCD. In order to reduce any personal bias, should be helpful for healthcare professionals to
only those pairs of interactions with evidence identify the priority areas where communication
retrieved from the aforementioned two databases regarding HDS usages has the greatest potential to
were included to categorise the corresponding mech- prevent adverse events and to improve patients ther-
anisms and the severity rating. Consequently, we apeutic outcomes.
were unable to evaluate 41% of the interaction pairs
for the corresponding mechanisms and severity in
Acknowledgements
this study. Another limitation was the concern of
publication bias, which might arise as only HDS The authors express their gratitude to Jun-Fon
products and medications that have been published Wang, Yi-Ling Chen, Ying-Hung Lu, Po-Ming Hung,
in the literature on the basis of evidence-based med- Tang-Ping Shih, Chung-Hui Ku, Shan-Chieh Wu
icine. Therefore, there are many potential HDSdrug and Yi-Zhu Chen for their help on data manage-
or disease interactions that may exist but are simply ment, and Dr Chao-Ling (David) Chen, Daniel Lee,
without documented outcomes. Lastly, only reports, Vincent Lee and Matthias C. Lu for their insights
books or articles published in English were included and comments for the manuscript. This work was
in this review. Those evidence regarding traditional partially supported by the National Science Council
herbal medicine or folk therapies, which were pub- (NSC 99-2320-B-039-031-MY3), China Medical Uni-
lished in other languages (e.g. Chinese, Japanese), versity Hospital (DMR-99-140) and Committee on
might be missing. Thus, it is very likely that the Chinese Medicine and Pharmacy, Department of
amount of documented HDSdrug interactions Health, Executive Yuan, Taiwan, R.O.C. (CCMP99-
and or contraindications in this review might be RD-016).
under-reported.
Author contributions
Conclusions
HHT, HWL and ASP participated in designing the
This review provides a structured summary of the review. HHT and HWL searched databases and
evidence of the most widely documented HDS inter- retrieved the articles. HHT extracted and managed
actions and contraindications with medications. the data, while HWL validated it. HYT helped to
Although our findings primarily concern with a rela- resolve the disagreements in evidence abstraction.
tively small subset of commonly used medications HHT wrote the manuscript, HWL, ASP, HYT and
and HDS entities, it is recommended that healthcare GBM reviewed and revised the manuscript. All
professionals should be paid more attention towards authors read and approved the final manuscript.
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vastatin, substrate of organic anion-transporting what you should know. Nurse Pract 2009; 34: 21 Herbal remedies in the United States: potential
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87 Gardiner P, Phillips R, Shaughnessy AF. Herbal medicines and prescribed drugs: an updated sys- 119 Howard N, Tsourounis C, Kapusnik-Uner J. Die-
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actions in humans: effects of milk thistle, black cer Ther 2009; 8: 20827.
Paper received May 2012, accepted July 2012

Appendix 1 Summary of included books to retrieve information about HDSdrug interactions and contraindications.
HDSdrug Severity rating Cited

Reference Year interactions Medication Format of interactions Contraindications HDS references Website
Cassileth 2003 Yes Drug class or By HDS No Yes Herbal remedies, other dietary Yes Yes

(16) individual drug supplements and non-mainstream
producted promoted as
cancer treatments
Gaby 2006 Yes Individual drug By drug and No No Herbs, deitary supplements, Accessed online Yes
(17) by HDS foods and alcohol
Mahady 2001 Yes Drug class or By HDS No Yes Herbs Yes No
(18) individual drug
Mason 2001 Yes Drug class By HDS No Yes Vitamins, minerals and Yes No
(19) and or natural oils, natural
individual drug substances, enzymes, amino acid
Tatro 2010 Yes Drug class with By drug Yes No Vitamins, electrolytes and few Yes Yes
(20) individual drug common used herbs
Ulbricht 2005 Yes Drug class or By HDS No Yes Herbs and supplements Yes Yes
(21) individual drug
HDS, herbs and dietary supplements.

1073
1074
Appendix 2 Summary of review articles to retrieve information about HDSdrug interactions and contraindications.
Reference Review type HDS Medications Databases Searching period
Coxeter et al. (12) Narrative review Herbs General No mention No mention

Ernst (30) Narrative review Herbs Conventional drugs No mention No mention
Fugh-Berman (31) Narrative review Herbs General MEDLINE; EMBASE MEDLINE: 19661998;
EMBASE: 19941999
McIntyre (32) Narrative review St Johns wort General No mention No mention
Semaan (33) Narrative review Herbal medicine General No mention No mention
Fugh-Berman and Systematic review Herbs Conventional drugs MEDLINE (via PubMed), EMBASE, the Their inception to 2000
Ernst (35) Cochrane Library, CISCOM
Izzo and Ernst (36) Systematic review Herbal medicines Prescribed drugs MEDLINE (via PubMed), EMBASE, Cochrane Their inception to 2000
Library and Phytobase
Markowitz and DeVane Narrative review St Johns wort General MEDLINE, Current contents and PSYCINFO 19662000
(37)
Block and Gyllenhaal (39) Narrative review Natural inhibitors and Cancer chemotherapy No mention No mention
inducers of CYP450 drugs, adjunctive drugs
Lyons (42) Narrative review Herbal medicine Drugs used in anaesthesia No mention No mention
Myers (43) Narrative review Complementary Warfarin No mention No mention
medicines
Buehler (45) Narrative review Herbal products Conventional medicines No mention No mention
Chavez et al. (46) Narrative review Herbs General No mention No mention
Williamson (47) Narrative review Herbs Prescription medicines EMBASE, MEDLINE EMBASE: 19802003;
MEDLINE: 19662003
Zhou et al. (48) Narrative review Herbs Substrates of CYP enzymes No mention No mention
Huang and Lesko (50) Narrative review Dietary supplements General No mention No mention
Ohnishi and Yokoyama (51) Narrative review Dietary supplements General No mention No mention
Bartlett and Eperjesi (55) Narrative review Ocular nutritional General PubMed, Web of Science 19802004
supplements
Bressler (56) Narrative review Saw palmetto Prescription medications No mention No mention
Bressler (57) Narrative review Kava Prescription medications No mention No mention
Bressler (58) Narrative review Ginseng Prescription medications No mention No mention
Bressler (59) Narrative review St Johns wort Prescription medications No mention No mention
Bressler (60) Narrative review Ginkgo biloba General (prescription drugs) No mention No mention
Hu et al. (64) Narrative review Herbal medicines General (prescription drugs) MEDLINE, Biological Their inception to 2005
Abstracts, Cochrane Library,
AMED, Biosis
Previews and EMBASE
Izzo (65) Narrative review Herbal remedies General (prescription drugs) No mention No mention
Izzo et al. (66) Systematic review Herbal medicines Cardiovascular drugs MEDLINE 19662003
Marder (68) Narrative review Dietary supplements Antithrombotic agents No mention No mention
Singh (69) Narrative review Kava and St Johns wort General (prescription drugs) No mention No mention

Appendix 2 Continued
Q5
Q4
Q3
Q2
Q1
Article:
Daugherty and Smith (70) Narrative review Dietary supplements Warfarin No mention Journal:
No mention
Dear Author,
Haller (72) Narrative review Herbal and dietary General No mention No mention
Query reference
supplements

Meijerman et al. (74) Narrative review Herbs Anticancer drug No mention No mention
Nutescu et al. (75) Narrative review Herbal and dietary Warfarin No mention No mention
supplements
IJCP
3008
Venkataramanan et al. (76) Narrative review Herbal General No mention No mention
Query
instead.
Yang et al. (77) Narrative review Herbs General No mention No mention
Many thanks for your assistance.

Marchetti et al. (79) Narrative review P-gp modulators ABCB1 substrates, e.g. digoxin, No mention No mention

(e.g. St Johns wort) cyclosporin A, tacrolimus
Nekvindova and Narrative review Dietary constituents CYP substrates No mention No mention
Anzenbacher (80) affecting CYPs
Skalli et al. (81) Systematic review Common herbal General MEDLINE via PubMed, Allied and Complementary, 19662006
Discussion, Conclusion.
Medicine Database, Healthstar, AMBASE,
CINHAL, Cochrane Library
Sulli and Ezzo (82) Narrative review Vitamins and minerals General No mention No mention
whether the change is correct.

Yetley (84) Narrative review Multivitamin and General No mention No mention
multimineral dietary
supplements
Cranwell-Bruce (85) Narrative review Herbs General No mention No mention
Gardiner et al. (87) Narrative review Herbs, vitamins Anticoagulants, cardiovascular No mention No mention
medications, psychiatric
Author Query Form
medications, laxatives, diabetes

medications or medications for
human immunodeficiency virus
papers edge. Please remember that illegible mark-ups may delay publication.
edited for clarity. Please check and confirm it is correct.

(HIV) infection
Nowack (92) Narrative review Herbs CYP3A4 and transport-protein No mention No mention
dependent drug, anticoagulants or
ensure that all URLs given in this article are correct and useable.)
antiplatelets, antidiabetics,
antihypertensive agents
Nowack (93) Narrative review Herbs Immunosuppressive drugs No mention No mention
AUTHOR: Please resupply the abstract for this paper, structured under
are correct. (Please note that it is the responsibility of the author(s) to

the following headings: Background, Aims, Materials & Methods, Results,
AUTHOR: A running head short title was not supplied; please check if
AUTHOR: Please check all the website addresses and confirm that they
then the... by ginseng and danshen (Salvia miltiorrhiza). Please check
AUTHOR: Two sentences have been combined as If this is not the case,
AUTHOR: These findings should be helpful..... This sentence has been

this one is suitable and, if not, please supply a short title that can be used
Samuels et al. (95) Narrative review Herbal medicine Antiepileptic drug No mention No mention
Tomlinson et al. (97) Narrative review Herbs CYP3A4 P-gp substrates No mention No mention
rks
Re-
ma-
Ulbricht et al. (98) Systematic review Herbs General MEDLINE, EMBASE, the Cochrane Library, CINAHL, No mention
ing up your proofs with the necessary changes/additions. Please write your answers on the query
shown on the attached corrections sheet. If returning the proof by fax do not write too close to the
sheet if there is insufficient space on the page proofs. Please write clearly and follow the conventions
During the copy-editing of your paper, the following queries arose. Please respond to these by mark-
Napralert, International Pharmaceutical

Abstracts, CANCERLIT, CISCOM, HERBMED
Borrelli and Izzo (99) Narrative review St Johns wort General No mention No mention
Holcomb (102) Narrative review Herbs General No mention No mention
1075
1076
Izzo and Ernst (103) Systematic review Herbs General MEDLINE (via PubMed), EMBASE and Their inception to 2009
Cochrane Library
Shord et al. (105) Narrative review Herbs General No mention No mention
Toselli et al. (106) Narrative review Echinacea CYP450 substrate No mention No mention
Abad et al. (107) Narrative review Ginkgo biloba General No mention 20002008
Cheng et al. (108) Narrative review Herbs Anticancer drugs Ovid OLDMEDLINE, Ovid MEDLINE, Excerpta Until November 2009
Medica Database (EMBASE), Cochrane

Database of Systematic Reviews (CDSR), ACP
Journal Club, Database of Abstracts of
Reviews of Effects (DARE), Cochrane Central
Register of Controlled Trials (CCTR), Health
Technol
Rogovik et al. (112) Narrative review Vitamins General MEDLINE PubMed, MEDLINE Plus, Drug Digest, 19662009
Natural Medicine Comprehensive Database
and the database of the University of
Maryland
HDS, herbs and dietary supplements; CYP, Cytochrome P450; P-gp, P-glycoprotein.

Appendix 3 PRISMA checklist.
Reported
Section topic No. Checklist item on page no.
Title

Title 1 Identify the report as a systematic review, meta-analysis or both. P1
Abstract
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants and interventions; P2
study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number
Introduction

Rationale 3 Describe the rationale for the review in the context of what is already known P4
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes and study P4
design (PICOS)
Methods
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g. Web address), and, if available, provide registration information NA
including registration number
Eligibility criteria 6 Specify study characteristics (e.g. PICOS, length of follow-up) and report characteristics (e.g. years considered, language, publication status) P5
used as criteria for eligibility, giving rationale
Information sources 7 Describe all information sources (e.g. databases with dates of coverage, contact with study authors to identify additional studies) in the search P5
and date last searched
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated P5
Study selection 9 State the process for selecting studies (i.e. screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis) P5
Data collection process 10 Describe method of data extraction from reports (e.g. piloted forms, independently, in duplicate) and any processes for obtaining and P6
confirming data from investigators
Data items 11 List and define all variables for which data were sought (e.g. PICOS, funding sources) and any assumptions and simplifications made P6
Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or NA
studies outcome level), and how this information is to be used in any data synthesis
Summary measures 13 State the principal summary measures (e.g. risk ratio, difference in means) NA
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g. I2) for each meta-analysis NA
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g. publication bias, selective reporting within studies) NA
Additional analyses 16 Describe methods of additional analyses (e.g. sensitivity or subgroup analyses, meta-regression), if done, indicating which were prespecified NA
Results
Study selection 17 Give numbers of studies screened, assessed for eligibility and included in the review, with reasons for exclusions at each stage, ideally P7, P48 (Figure1)
with a flow diagram
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g. study size, PICOS, follow-up period) and provide the citations P2837 (Table
13); P5362
(Appendix 12)
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12) NA
1077
1078
Reported
Section topic No. Checklist item on page no.
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple NA
summary data for each intervention group (b) effect estimates and confidence intervals,
ideally with a forest plot
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures NA
of consistency
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15) NA
Additional analysis 23 Give results of additional analyses, if done [e.g. sensitivity or subgroup analyses, NA
meta-regression (see Item 16)]
Discussion
Summary of evidence 24 Summarise the main findings including the strength of evidence for each main outcome; P1114
consider their relevance to key groups (e.g. healthcare providers, users and policy makers)
Limitations 25 Discuss limitations at study and outcome level (e.g. risk of bias), and at review level (e.g. P14
incomplete retrieval of identified research, reporting bias)
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and P1415
implications for future research
Funding
Funding 27 Describe sources of funding for the systematic review and other support (e.g. supply of P15
data); role of funders for the systematic review


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REVIEW ARTICLE

Evaluation of documented drug interactions and

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

MEDLINE (n = 78) Pubmed (n = 70) EMBASE (n = 328) Cochrane library (n = 71)

461 literature were identified

333 literature were excluded based on

128 literature were selected initially

Original studies (n = 31)

Review articles Clinical trials Observational studies Animal studies

Figure 1 Flow chart of primary literature search

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

Int J Clin Pract, November 2012, 66, 11, 10561078

of HDS. use of A. paniculata could

Population (number of Evidence resources of Results related to

Int J Clin Pract, November 2012, 66, 11, 10561078

Dose schedule Population (number

2012 Blackwell Publishing Ltd

Int J Clin Pract, November 2012, 66, 11, 10561078

Dose schedule Population (number

Int J Clin Pract, November 2012, 66, 11, 10561078

Genito urinary system and sex

Respiratory system 21 (4.1%)

Blood and blood forming organs 30 (5.9%)

Musculo-skeletal system 34 (6.7%)

Alimentary tract and metabolism 62 (12.2%)

Antiinfectives for systemic use 75 (14.7%)

Cardiovascular system 90 (17.7%)

Nervous system 100 (19.6%)

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

HDS Drugs Potential consequences reactions

2012 Blackwell Publishing Ltd

HDS Drugs Potential consequences reactions

Vitamin E Dicumarol (84) Risk of bleeding

2012 Blackwell Publishing Ltd

Table 5 The St Johns Wort-drug interactions with major severity*

HDS Drugs Potential consequences reactions

St Johns wort Amiodarone (20,37) Effect of amiodarone

2012 Blackwell Publishing Ltd

HDS Drugs Potential consequences reactions

Phenprocoumon (12,18,31,3537,47,65,66,77,80,81,97,103) Effect of phenprocoumon

2012 Blackwell Publishing Ltd

Acid peptic disease(16,19,21) Betaine, guarana, iron, turmeric

Diarrhea and malabsorption(16,19,21) Barley, chitosan, flaxseed

Others(21)* Aloe vera, flaxseed

Aloe vera, boron, calcium, clay,

Identified Alfalfa, black cohosh, chasteberry,

Copper, kava, licorice, niacin, noni,

Cardiac disease(16,19,21-22) Aloe vera, bitter orange, goldenseal,

Class of HDS which should be avoided

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

2012 Blackwell Publishing Ltd

HDSdrug Severity rating Cited

Int J Clin Pract, November 2012, 66, 11, 10561078

HDS, herbs and dietary supplements.

Reference Review type HDS Medications Databases Searching period

Coxeter et al. (12) Narrative review Herbs General No mention No mention

Int J Clin Pract, November 2012, 66, 11, 10561078

2012 Blackwell Publishing Ltd

Venkataramanan et al. (76) Narrative review Herbal General No mention No mention