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Melatonin and Sleep

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Title: Melatonin and Sleep


1
Melatonin and Sleep
  • Garrick Wang, M.D., Ph.D.
  • Stanford Sleep Disorders Clinic
  • Stanford Dept. of Psychiatry

2
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

3
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

4
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

5

6
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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8
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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10
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

11
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

12
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

13
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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15
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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17
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

18
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

19
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

20
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

21
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

22
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

23
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)

24
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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26
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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28
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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30
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

31
Ramelteon (Rozerem)
  • Synthetic melatonin agonist that acts at MT1 and
    MT2 receptors
  • Approved for treatment of insomnia
  • No potential for abuse

32
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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34
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

35
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

36
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

37
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

38
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

39
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

40
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

41
Thank You !
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