Melatonin

1. Melatonin Deepti Sinha April 1, 2009

2. Outline Melatonin: where, why, how it is manufactured by the brain, and for what purpose Where does melatonin act, and what does it do? How can this system be manipulated by pharmacologic and behavioral interventions to improve - or worsen - sleep?

3. Circadian Rhythms French astronomer Jean Jacques d'Ortous de Mairan discovered in 1729 that when a Mimosa plant was placed in the constant darkness of a closet, the opening and closing of the leaves still occurred on the basis of an intrinsic rhythm (de Mairan 1729) First description in nature of endogenously generated biological rhythms of the light-dark cycle However, to stay aligned to precise environmental changes, biological rhythms keep pace with a time-clock linked to the external environment

4. Circadian Rhythms in Humans Examples: Core body temperature, blood pressure, heart rate, and hormone production fluctuate in cycles lasting about 24 hours, known as the circadian cycle The sleep-wake cycle is a well-recognized example in humans Such cycles are governed by a biological “clock”, or timekeeping system, located in the anterior hypothalamus of the brain: this is the Suprachiasmatic nucleus (SCN)

6. SCN: links internal rhythms and external environment The SCN is the master clock, ensuring that various biological rhythms are keeping pace with one another and with the external environment The SCN is entrained to light-dark cues, thus maintaining a “lock” on a 24-hr day Humans’ “free-running” clock is actually greater than 24 hours

7. SCN and Melatonin The SCN responds to environmental light/dark cues to regulate melatonin production Melatonin plays a critical role in synchronizing internal biological events to external environmental clues: it acts inside and outside the brain to synchronize various circadian rhythms

8. Melatonin and Regulation of Sleep The master clock is set by light signals traveling from the retina (eye) to the SCN, which in turn sends signals to the pineal gland. In the pineal gland, release of norepinephrine stimulates melatonin synthesis In vertebrates, melatonin synthesis and release are stimulated by darkness In humans, melatonin release begins after darkness and peaks between 2-4 am.

9. Melatonin 5-methoxy-N- acetyltryptamine Secreted by the pineal gland Secretion increases in darkness, decreases in light Melatonin feeds back to the brain -importantly, the SCN- to decrease alertness; it also acts on the pituitary gland and other peripheral locations to fine tune timing of biological rhythms. Melatonin also has antioxidant properties

10. Melatonin synthesis and release by the pineal gland are inhibited by light and stimulated by darkness. Neural signals from stimulated retinal ganglion cells are transferred to the anterior hypothalamus and SCN via the retinohypothalamic tract (RHT), then to the superior cervical ganglion, and finally to the pineal gland

11. Melatonin and the Shifting Clock Therefore, the daily rhythm of melatonin secretion is dictated by daily light/dark cycles Melatonin is a “darkness signal” for the body: Melatonin shifts the endogenous circadian cycle according to a phase-response curve that is nearly opposite in phase to light exposure Endogenous circadian rhythms can be delayed with melatonin treatment in the morning, and can be advanced with treatment in the evening

12. Uses for Melatonin Melatonin’s ability to synchronize the circadian clock by acting on the SCN has led to the idea that melatonin can be used to treat jet lag, some types of insomnia, and shift work sleep disorder Also a known antioxidant – but little clinical evidence of effectiveness Has been tried for sleep disturbances in children with neuropsychiatric disorders; insomnia in the elderly; and sleep enhancement in healthy sleepers

13. Use of Melatonin Circadian Rhythmn Sleep Disorders (eg. shift work, jetlag, blind) Insomnia Parasomnias (eg. REM Behavior Disorder) Currently available in health stores as a dietary supplement

14. Non-circadian, Homeostatic Regulation of Sleep is Also Important As the day goes on, we increase our “sleep pressure” – our drive towards sleep. Sleep need accumulates during wakefulness and diminishes during sleep The circadian process, which is driven by light and dark via the SCN, can oppose homeostatic sleep drive at times – e.g., 2-3 hours before one’s habitual bedtime, circadian alertness is at peak levels.

15. Circadian and Homeostatic Regulation of Sleep. The circadian cycle and the homeostatic drive interact to produce sleep and wakefulness at the appropriate times. The need for sleep (ie, sleep load) accumulates during wakefulness and dissipates during sleep.

16. Homeostatic and Circadian Sleep Drives During the evening, the circadian alerting signal is diminished, in part because of increased melatonin levels. Sleep occurs when homeostatic need is high and circadian alertness ebbs. Homeostatic drive is also impacted by neuromodulators like adenosine, which accumulates during wakefulness.

17. Melatonin as a Hypnotic In addition to phase shifting properties, melatonin has soporific properties Lowers core body temperature Induces mild sedation Mute alerting signals emitted by the SCN Thus, nighttime melatonin works in concert with homeostatic drive to allow sleep * Melatonin works in both the circadian and homeostatic systems!

18. The SCN and Melatonin Receptors Melatonin released in the pineal gland travels back to the SCN, where it interacts with MT1 and MT2 receptors MT1 suppresses SCN firing, reducing alertness MT2 is responsible for circadian phase shifts Both MT1 and MT2 are expressed in many other organs

19. Melatonin and Hormonal Effects

20. Melatonin - Clinical Efficacy and Safety Because of circadian-shifting and hypnotic effects, melatonin treatments have been studied to treat circadian disorders (phase delay, phase advance, jet lag, etc) and insomnia Melatonin is a neurohormone classified by the FDA as a dietary supplement and first approved in 1994 Half life 0.5-6 minutes – effects are short-lived Dosages range 0.1 – 10mg, ½ hour to 2 hours before bedtime

21. Conflicting Results Differences in purity and properties of commercially available products lead to differences in biological and pharmocological properties Studies vary in timing, frequency, and duration of administration Inclusion and exclusion criteria for insomnia vary widely between studies

24. Melatonin Studies Some meta-analyses and reviews have supported the hypothesis that it reduces sleep onset latency, increases sleep efficiency, and daytime alertness/ performance But other analyses have not supported the effectiveness of melatonin for primary or secondary insomnia with short-term use, except in the case of delayed sleep phase syndrome Most studies report that it is safe for short-term use – most common side effects were headache, dizziness, and drowsiness – no different than placebo High dose use can lead to “hangover” effect and perhaps suppress ovulation Longterm safety unknown

25. Melatonin Receptor Agonists Lack of consistent efficacy of melatonin thought to be due to pharmacological properties – short half-life, multiple sites of action, high first-pass metabolism Thus, MT-1 and MT-2 targeted compounds have been developed to selectively treat insomnia and circadian rhythm disorders

26. Ramelteon (Rozarem) Approved by FDA in 2005 for use in sleep initiation insomnia Selective MT1/MT2 agonist Low bioavailability but longer ½ life, 0.8-2.6 hours, with metabolite half-life 2-5 hours Recommended dose is 8 mg Only non-scheduled hypnotic; no addictive potential; also no rebound and no withdrawal ? No next-day residual effects in studies, although somnolence (2%) and fatigue (2%) are most common SEs Should not be used with fluvoxamine (Luvox), an antidepressant metabolized by the same liver enzyme

27. Ramelteon II Placebo-controlled study of 107 adults with DSM-IV insomnia, 5-period crossover design, with doses of 4, 8, 16, and 32 mg doses – 2 nights at each dose: PSG sleep latency was reduced all doses vs placebo (P<0.001) Placebo-controlled study of 405 adults with chronic insomnia, 8 vs 16 mg x 5 weeks: both doses decreased PSG sleep latency In older patients (age 64-93), 5 weeks of either 4 or 8 mg reduced self-reported sleep latency

28. Future Melatonin Receptor Agonists Agomelatine is a serotonergic antidepressant that also works on MT-1 and MT-2 – some promise that it is also a chronobiotic that will relieve sleep complaints in depressed patients LY 156735: a new investigational melatonin (MT-1 and MT-2) agonist VEC-162: in early development, appears to phase advance melatonin secretion after one dose.

29. Melatonin and Side Effects Common adverse effects: fatigue, dizziness, irritability, headache; less commonly, nightmares, vivid dreams, disorientation, confusion. Avoid if taking warfarin or other anti-blood clotting medications May cause a drop in blood pressure Hormonal effects have been reported, and should not be used by pregnant or breastfeeding women

30. Melatonin and Jet Lag Melatonin taken by mouth. Started on the day of travel, close to the target bedtime at the destination and continued for several days, has been shown to reduce days to establish a normal sleep pattern, and reduce sleep latency

31. Melatonin and Blindness Even without light cues, melatonin tends to rise and fall in a circadian pattern, but the cycle tends to drift in those who are totally blind Often wide awake at night, sleepy during the day Exogenous melatonin at night can reset the 24 hour sleep pattern

32. Melatonin and Popularity google.com search for “melatonin”: 6.82 million results pubmed search for “melatonin”: 14,000 results Amazon.com: 48 results. Almost all dietary supplements

33. Questions