Melatonin and Sleep

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Melatonin and Sleep

• Garrick Wang, M.D., Ph.D.
• Stanford Sleep Disorders Clinic
• Stanford Dept. of Psychiatry

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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, Alzheimers,
  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

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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

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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

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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

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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)

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Melatonin and Insomnia

• One study showed improved sleep efficiency in
  adults gt50 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

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Melatonin and Insomnia

• One study showed improved sleep efficiency in
  adults gt50 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

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Melatonin and Insomnia

• One study showed improved sleep efficiency in
  adults gt50 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

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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

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Ramelteon (Rozerem)

• Synthetic melatonin agonist that acts at MT1 and
  MT2 receptors
• Approved for treatment of insomnia
• No potential for abuse

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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

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Melatonin and jet lag

• Especially useful for Eastbound travel
• Shown effective if taken at bedtime of
  destination when crossing gt5 time zones.
• Improved total sleep time
• Less effective westbound
• Adverse effects include dizziness, headache,
  decreased appetite, daytime sleepiness

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Other uses of melatonin

• Although thought to have antioxidant properties
  and thus useful for atherosclereosis, cancer, and
  Alzheimers, 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

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Other uses of melatonin

• No improvement in cognitive impairment in
  Alzheimers patients
• No evidence as helpful for anti-aging
• Small studies suggest melatonin may reduce blood
  pressure

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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

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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

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Conclusions

• For traveling gt 5 time zones, take melatonin at
  bedtime of destination up to 4 days after arrival
• May also consider for travel lt 5 time zones if
  jet lag would be serious interference
• 0.3 to 0.5 mg recommended starting dose

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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

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Thank You !