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Physiology and available preparations of melatonin

Richard Wurtman, MD
Section Editor
David S Cooper, MD
Deputy Editor
Kathryn A Martin, MD


Melatonin is a hormone produced in the pineal gland from the amino acid tryptophan and secreted into the blood and cerebrospinal fluid. It conveys signals to distant organs, principally the brain, and affects the synthesis of second messengers and, ultimately, sleep and circadian rhythms.

The physiology of melatonin and an overview of its clinical uses are reviewed here. Additional information on clinical uses of melatonin are found separately. (See "Treatment of insomnia in adults", section on 'Melatonin agonists' and "Jet lag" and "Complementary and alternative therapies for cancer", section on 'Melatonin'.)


The human pineal gland is an important structure that transmits signals to the brain and other organs by secreting its unique hormone, melatonin. However, this concept is only a few decades old. In 1975, it was discovered that melatonin production in humans, like that in all other mammals studied, exhibits a pronounced circadian rhythm such that nocturnal plasma melatonin concentrations are at least 10-fold higher than daytime concentrations [1,2]. In humans, nocturnal serum concentrations of melatonin decline across puberty [3], but no reproductive effects of exogenous melatonin have been clearly demonstrated [4].

Much pineal research has concerned the human brain's responses to melatonin rhythms. The most compelling evidence supports two roles for melatonin in humans: the involvement of nocturnal melatonin secretion in initiating and maintaining sleep, and control by the day/night melatonin rhythm of the timing of other 24-hour rhythms. Melatonin's effect on sleep underlies most of its current use as a drug and the development of melatonin analogs as new drugs [5,6]. (See 'Circadian rhythm' below and 'Melatonin agonists' below.)


Synthesis and metabolism — Almost all of the melatonin formed in mammals is synthesized within the pineal gland from the essential amino acid tryptophan (figure 1) [7]. Plasma melatonin and its circadian rhythm largely or completely disappear among pinealectomized animals [8] or human subjects post-pinealectomy [9]. Tryptophan is first 5-hydroxylated by the enzyme tryptophan hydroxylase and then decarboxylated by the enzyme aromatic L-amino acid decarboxylase to form 5-hydroxytryptamine, or serotonin (figure 1) [7].


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  1. Lynch HJ, Wurtman RJ, Moskowitz MA, et al. Daily rhythm in human urinary melatonin. Science 1975; 187:169.
  2. Lynch HJ, Jimerson DC, Ozaki Y, et al. Entrainment of rhythmic melatonin secretion in man to a 12-hour phase shift in the light/dark cycle. Life Sci 1978; 23:1557.
  3. Waldhauser F, Weiszenbacher G, Frisch H, et al. Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet 1984; 1:362.
  4. Srinivasan V, Spence WD, Pandi-Perumal SR, et al. Melatonin and human reproduction: shedding light on the darkness hormone. Gynecol Endocrinol 2009; 25:779.
  5. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med 2006; 7:17.
  6. Hardeland R. Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. Curr Opin Investig Drugs 2009; 10:691.
  7. Axelrod J, Shein HM, Wurtman RJ. Stimulation of C14-melatonin synthesis from C14-tryptophan by noradrenaline in rat pineal in organ culture. Proc Natl Acad Sci U S A 1969; 62:544.
  8. Ozaki Y, Lynch HJ. Presence of melatonin in plasma and urine or pinealectomized rats. Endocrinology 1976; 99:641.
  9. Neuwelt EA, Lewy AJ. Disappearance of plasma melatonin after removal of a neoplastic pineal gland. N Engl J Med 1983; 308:1132.
  10. Klein DC. The pineal gland: A model of neuroendocrine regulation. In: The Hypothalamus, Reichlin S, Baldessarini RJ, Martin JB (Eds), Raven Press, New York 1978. p.303.
  12. AXELROD J, WEISSBACH H. Enzymatic O-methylation of N-acetylserotonin to melatonin. Science 1960; 131:1312.
  13. Lynch HJ. Diurnal oscillations in pineal melatonin content. Life Sci I 1971; 10:791.
  14. Skene DJ, Vivien-Roels B, Sparks DL, et al. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease. Brain Res 1990; 528:170.
  15. Tricoire H, Locatelli A, Chemineau P, Malpaux B. Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 2002; 143:84.
  17. Cardinali DP, Lynch HJ, Wurtman RJ. Binding of melatonin to human and rat plasma proteins. Endocrinology 1972; 91:1213.
  18. KOPIN IJ, PARE CM, AXELROD J, WEISSBACH H. 6-Hydroxylation, the major metabolic pathway for melatonin. Biochim Biophys Acta 1960; 40:377.
  19. Witt-Enderby PA, Bennett J, Jarzynka MJ, et al. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci 2003; 72:2183.
  20. Gerdin MJ, Masana MI, Rivera-Bermúdez MA, et al. Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J 2004; 18:1646.
  21. Gerdin MJ, Masana MI, Dubocovich ML. Melatonin-mediated regulation of human MT(1) melatonin receptors expressed in mammalian cells. Biochem Pharmacol 2004; 67:2023.
  22. Lewy AJ, Wehr TA, Goodwin FK, et al. Light suppresses melatonin secretion in humans. Science 1980; 210:1267.
  24. Klein DC, Moore RY. Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus. Brain Res 1979; 174:245.
  25. Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992; 9:380.
  26. Deacon S, Arendt J. Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res 1995; 688:77.
  27. Arendt J, Wirz-Justice A, Bradtke J, Kornemark M. Long-term studies on immunoreactive human melatonin. Ann Clin Biochem 1979; 16:307.
  28. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186.
  29. Farez MF, Mascanfroni ID, Méndez-Huergo SP, et al. Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. Cell 2015; 162:1338.
  30. Jin Y, de Pedro-Cuesta J, Söderström M, et al. Seasonal patterns in optic neuritis and multiple sclerosis: a meta-analysis. J Neurol Sci 2000; 181:56.
  31. Steinman L. Immunology of relapse and remission in multiple sclerosis. Annu Rev Immunol 2014; 32:257.
  32. Rosenthal NE, Sack DA, Gillin JC, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41:72.
  33. Kennaway DJ, Stamp GE, Goble FC. Development of melatonin production in infants and the impact of prematurity. J Clin Endocrinol Metab 1992; 75:367.
  34. Waldhauser F, Lynch HJ, Wurtman RJ. Melatonin in human body fluids: Clinical significance. In: The Pineal Gland (Comprehensive Endocrinology), Reiter RJ (Ed), Raven Press, New York 1984. p.345.
  35. Mayeda A, Mannon S, Hofstetter J, et al. Effects of indirect light and propranolol on melatonin levels in normal human subjects. Psychiatry Res 1998; 81:9.
  36. Garde E, Micic S, Knudsen K, et al. 8-methoxypsoralen increases daytime plasma melatonin levels in humans through inhibition of metabolism. Photochem Photobiol 1994; 60:475.
  37. Wright KP Jr, Badia P, Myers BL, et al. Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans. Brain Res 1997; 747:78.
  38. Röjdmark S, Wikner J, Adner N, et al. Inhibition of melatonin secretion by ethanol in man. Metabolism 1993; 42:1047.
  39. Ekman AC, Leppäluoto J, Huttunen P, et al. Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind cross-over study. J Clin Endocrinol Metab 1993; 77:780.
  40. Brainard GC, Rollag MD, Hanifin JP. Photic regulation of melatonin in humans: ocular and neural signal transduction. J Biol Rhythms 1997; 12:537.
  41. Aoki H, Yamada N, Ozeki Y, et al. Minimum light intensity required to suppress nocturnal melatonin concentration in human saliva. Neurosci Lett 1998; 252:91.
  42. Brainard GC, Hanifin JP, Greeson JM, et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 2001; 21:6405.
  43. Chang AM, Aeschbach D, Duffy JF, Czeisler CA. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc Natl Acad Sci U S A 2015; 112:1232.
  44. Jonas M, Garfinkel D, Zisapel N, et al. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press 2003; 12:19.
  45. Arangino S, Cagnacci A, Angiolucci M, et al. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Am J Cardiol 1999; 83:1417.
  46. Burgess HJ, Sletten T, Savic N, et al. Effects of bright light and melatonin on sleep propensity, temperature, and cardiac activity at night. J Appl Physiol (1985) 2001; 91:1214.
  47. Cagnacci A, Cannoletta M, Renzi A, et al. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens 2005; 18:1614.
  48. Grossman E, Laudon M, Yalcin R, et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med 2006; 119:898.
  49. Jansen SL, Forbes DA, Duncan V, Morgan DG. Melatonin for cognitive impairment. Cochrane Database Syst Rev 2006; :CD003802.
  50. European Food Safety Authority. Scientific opinion on the substantiation of a health claim related to melatonin and reduction of sleep onset latency (ID 1698, 1780, 4080) pursuant to article 13(1) of regulation (EC) No 1924/2006. EFSA Journal 2011; 9:2241. http://www.efsa.europa.eu/en/efsajournal/doc/2241.pdf (Accessed on September 23, 2011).
  51. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev 2005; 9:41.
  52. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Summary, evidence report/technology assessment: Number 108. AHRQ Publication Number 05-E002-1, November 2004. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/melatsum.htm (Accessed on September 23, 2011).
  53. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005; 20:1151.
  54. Dollins AB, Zhdanova IV, Wurtman RJ, et al. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci U S A 1994; 91:1824.
  55. Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleep-promoting agent. J Biol Rhythms 1997; 12:644.
  56. Cramer H, Rudolph J, Consbruch U, Kendel K. On the effects of melatonin on sleep and behavior in man. Adv Biochem Psychopharmacol 1974; 11:187.
  57. James SP, Mendelson WB, Sack DA, et al. The effect of melatonin on normal sleep. Neuropsychopharmacology 1987; 1:41.
  58. James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacology 1990; 3:19.
  59. Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology (Berl) 1990; 100:222.
  60. Dahlitz M, Alvarez B, Vignau J, et al. Delayed sleep phase syndrome response to melatonin. Lancet 1991; 337:1121.
  61. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995; 18:598.
  62. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995; 346:541.
  63. Wurtman RJ, Zhdanova I. Improvement of sleep quality by melatonin. Lancet 1995; 346:1491.
  64. Zhdanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995; 57:552.
  65. Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berl) 1996; 126:179.
  66. Zhdanova IV, Wurtman RJ, Morabito C, et al. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep 1996; 19:423.
  67. Hughes RJ, Badia P. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep 1997; 20:124.
  68. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 1998; 21:52.
  69. Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001; 86:4727.
  70. Shamir E, Laudon M, Barak Y, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000; 61:373.
  71. Singer C, Tractenberg RE, Kaye J, et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep 2003; 26:893.
  72. Vural EM, van Munster BC, de Rooij SE. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. Drugs Aging 2014; 31:441.
  73. Atkinson G, Jones H, Edwards BJ, Waterhouse JM. Effects of daytime ingestion of melatonin on short-term athletic performance. Ergonomics 2005; 48:1512.
  74. Waldhauser F, Lieberman HR, Lynch HJ, et al. A pharmacological dose of melatonin increases PRL levels in males without altering those of GH, LH, FSH, TSH, testosterone or cortisol. Neuroendocrinology 1987; 46:125.
  75. Di WL, Kadva A, Johnston A, Silman R. Variable bioavailability of oral melatonin. N Engl J Med 1997; 336:1028.
  76. Zhdanova, I, Wurtman, RJ, Balcioglu, A, Kartashov, AI, et al. Endogenous melatonin levels and the fate of exogenous melatonin: Age effects. J Gerontology 1998; 53:293.
  77. Lyseng-Williamson KA. Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years. Drugs Aging 2012; 29:911.
  78. Wade AG, Ford I, Crawford G, et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med 2010; 8:51.
  79. Morera AL, Henry M, de La Varga M. [Safety in melatonin use]. Actas Esp Psiquiatr 2001; 29:334.