Melatonin and Sleep

Garrick Wang, M.D., Ph.D.

Stanford Sleep Disorders Clinic
Stanford Dept. of Psychiatry
 What is melatonin?
• Hormone that is naturally produced by the
pineal gland
• Conveys information to various parts of the
body
• Chemical structure identified in 1958
• Expressed rhythmically throughout the day
 Regulation of Melatonin
• In the US, the FDA considers melatonin a
“dietary supplement”
• No need for a prescription
• No regulation of dosing and preparations
may have additives that affect
bioavailibility, side effects, drug
interactions
• Not detected in food
 Making Melatonin
• Generated from amino acid tryptophan and
serotonin
• Is made predominantly at night in the pineal
gland
• Freely diffuses into bloodstream and crosses
blood-brain barrier
•
 Making Melatonin
• Generated from amino acid tryptophan and
serotonin
• Is made predominantly at night in the pineal
gland
• Freely diffuses into bloodstream and crosses
blood-brain barrier
 Where Melatonin Binds
• Works by binding 3 receptors
• MT1 = Found in the SCN of hypothalamus,
pituitary gland, cardiac blood vessels
• MT2 = Retina and hippocampus
• MT3 = Kidney, brain, other organs
 SCN: Our internal clock
• Suprachiasmatic Nucleus (SCN) is the site
of internal biological clock
• Many intrinsic properties cycle: cortisol,
body temperature
• Melatonin binding MT1 inhibits neuron
activity
 How Melatonin Works
• Melatonin levels cycle
• Low levels during daylight, rise during
nighttime
• Peak levels between 11PM and 3AM
• Levels continue to cycle in constant
darkness
• Can slowly adjust to environmental changes
 Melatonin Activity
• Light acts indirectly, likely through retina,
to inhibit melatonin synthesis and release
• MT1 and MT2 receptors desensitize:
activity decreases after exposure to
excessively high levels of melatonin
 Melatonin Secretion

• Melatonin secretion starts at 3-4 months of

age when nighttime sleeping consolidates
• Peak levels at 1-3 years of age
• Slightly lower levels through early
adulthood
• Marked decline in levels afterwards
• Peak levels for 70 year olds is ¼ of levels
for young adults
 Melatonin Levels
• Exogenous melatonin of 1-10mg raise
levels 3-60x normal nighttime levels
• Doses as low as 0.1 to 0.3 mg caused dose-
related decreases in sleep latency and self-
reported sleepiness and fatigue
• Blood levels did not go above nighttime
levels
 Melatonin Activity

• Metabolized by the liver

• Propranolol, caffeine, and alcohol can
interfere with melatonin activity
• Vitamin B6 needed for synthesis. Estrogen,
OCPs, hydralazine, lasix may affect levels
• Levels can also be affected by preparation.
Those in oil-based preparation lead to
higher blood levels
 Adverse Effects
• Excess melatonin can lead to daytime
sleepiness, impaired mental and physical
performance, hypothermia, and high levels
of prolactin
• Menstrual irregularities, galactorrhea,
impotence, decreased libido
 Melatonin and Sleep Promotion
• Analysis of 17 separate studies looking at
people who slept normally or insomnia
from a number of causes (e.g. age, jet lag,
Alzheimer’s, schizophrenia)
• Melatonin can decrease sleep latency (time
between laying down and onset of sleep)
• 4 minute decrease on average
• Works in afternoon and evening as well
 Melatonin and Sleep Promotion
• Melatonin also increased sleep efficiency.
• Sleep efficiency = amount of time asleep as
percentage of total time in bed
• Increase in total sleep duration of 12
minutes
 Significance?
• Hard to determine significance due to wide
variations of studies
• Doses ranging from 0.1 to 80 mg
• Wide variety of subjects: sleep latency
normal for most elderly, sleep efficiency not
very affected for jet lag
 Melatonin and Insomnia
• Looking more closely at those with
insomnia secondary to neurologic or
psychiatric disease, as well as jet lag or
shiftwork, melatonin did not help
• Implies effectiveness for primary insomnia
 Other Studies
• Doses as low as 0.3 mg can decrease sleep
latency, increase sleep duration and sleep
efficiency without affecting body
temperature.
• Melatonin at early evening to help for
prolonging elevated nocturnal melatonin
levels (useful for shift workers and jet lag)
 Melatonin and Insomnia
• One study showed improved sleep
efficiency in adults >50 yo vs. controls
• No changes seen in total sleep time or sleep
architecture
• No changes seen in patients without
insomnia
• 0.3 mg effective and resulted in peak
concentrations similar to young adult peaks
 Melatonin and Insomnia
• One study showed improved sleep
efficiency in adults >50 yo vs. controls
• No changes seen in total sleep time or sleep
architecture
• No changes seen in patients without
insomnia
• 0.3 mg effective and resulted in peak
concentrations similar to young adult peaks
 Melatonin and Insomnia
• One study showed improved sleep
efficiency in adults >50 yo vs. controls
• No changes seen in total sleep time or sleep
architecture
• No changes seen in patients without
insomnia
• 0.3 mg effective and resulted in peak
concentrations similar to young adult peaks
Melatonin and Sleep Architecture
• No consistent changes in sleep architecture
• Unlike hypnotic medications used to
promote sleep, subjects reported they could
fight off sleep if they wanted to
• In addition, no reports of cognitive
impairment in the morning
 Ramelteon (Rozerem)
• Synthetic melatonin agonist that acts at
MT1 and MT2 receptors
• Approved for treatment of insomnia
• No potential for abuse
 Melatonin and Phase Shifting
• At night, advances the clock. In early AM,
delays clock
• If given at 5PM, can advance nighttime
melatonin secretion
• 0.5 mg can also shift body temperature
rhythms
• Can also entrain rhythms in blind
individuals who did not have endogenous
rhythms
 Melatonin and jet lag
• Especially useful for Eastbound travel
• Shown effective if taken at bedtime of
destination when crossing >5 time zones.
• Improved total sleep time
• Less effective westbound
• Adverse effects include dizziness,
headache, decreased appetite, daytime
sleepiness
 Other uses of melatonin
• Although thought to have antioxidant
properties and thus useful for
atherosclereosis, cancer, and Alzheimer’s,
no controlled clinical data supports this.
• In vitro studies needed concentrations 1000
to 100,000 times normal levels
• At such levels, may impair sleep and
circadian rhythms by desensitization
 Other uses of melatonin
• No improvement in cognitive impairment in
Alzheimer’s patients
• No evidence as helpful for anti-aging
• Small studies suggest melatonin may reduce
blood pressure
 Adverse Effects
• Daytime sleepiness, Hypothermia
• Desensitzation of melatonin receptors if
doses too high
• Possible adverse events in those with
seizure disorders
• Possible interaction with those taking
coumadin/warfarin
 Conclusions
• For problems of sleep efficiency (such as
age-related insomnia), melatonin starting at
0.3 mg. If no effect after a week, can double
dosage.
• If initial response but stops being effective
after a few weeks, recommend “drug
holiday”
 Conclusions
• For traveling > 5 time zones, take melatonin
at bedtime of destination up to 4 days after
arrival
• May also consider for travel < 5 time zones
if jet lag would be serious interference
• 0.3 to 0.5 mg recommended starting dose
 Conclusions
• Effectiveness may depend on cause of sleep
problems
• Must be aware of different forms of
packaging and dosing
• Inform physicians if interested in a trial of
melatonin
Thank You !