CNS Drugs

, Volume 21, Issue 12, pp 995–1018 | Cite as

Role of the Melatonin System in the Control of Sleep

Therapeutic Implications
  • Seithikurippu R. Pandi-Perumal
  • Venkatramanujan Srinivasan
  • D. Warren Spence
  • Daniel P. Cardinali
Review Article


The circadian rhythm of pineal melatonin secretion, which is controlled by the suprachiasmatic nucleus (SCN), is reflective of mechanisms that are involved in the control of the sleep/wake cycle. Melatonin can influence sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of MT1 (melatonin la) and MT2 (melatonin 1b) receptors, the two major melatonin receptor subtypes found in mammals. Both receptors are highly concentrated in the SCN. In diurnal animals, exogenous melatonin induces sleep over a wide range of doses. In healthy humans, melatonin also induces sleep, although its maximum hypnotic effectiveness, as shown by studies of the timing of dose administration, is influenced by the circadian phase.

In both young and elderly individuals with primary insomnia, nocturnal plasma melatonin levels tend to be lower than those in healthy controls. There are data indicating that, in affected individuals, melatonin therapy may be beneficial for ameliorating insomnia symptoms. Melatonin has been successfully used to treat insomnia in children with attention-deficit hyperactivity disorder or autism, as well as in other neurodevelopmental disorders in which sleep disturbance is commonly reported.

In circadian rhythm sleep disorders, such as delayed sleep-phase syndrome, melatonin can significantly advance the phase of the sleep/wake rhythm. Similarly, among shift workers or individuals experiencing jet lag, melatonin is beneficial for promoting adjustment to work schedules and improving sleep quality.

The hypnotic and rhythm-regulating properties of melatonin and its agonists (ramelteon, agomelatine) make them an important addition to the armamentarium of drugs for treating primary and secondary insomnia and circadian rhythm sleep disorders.


Melatonin Sleep Onset Melatonin Receptor Agomelatine Melatonin Secretion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to acknowledge the comments provided by anonymous reviewers, which considerably improved the paper.

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Lerner AB, Case JD, Takahashi Y, et al. Isolation of melatonin, a pineal factor that lightens melanocytes [letter]. J Am Chem Soc 1958; 80: 2587CrossRefGoogle Scholar
  2. 2.
    Pandi-Perumal SR, Srinivasan V, Maestroni GJ, et al. Melatonin: nature’s most versatile biological signal? FEBS J 2006; 273(13): 2813–38PubMedCrossRefGoogle Scholar
  3. 3.
    Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005; 9(1): 11–24PubMedCrossRefGoogle Scholar
  4. 4.
    Wurtman RJ. The pineal as a neuroendocrine transducer. Hosp Pract 1980; 15(1): 82–86, 91-92PubMedGoogle Scholar
  5. 5.
    Zisapel N. Circadian rhythm sleep disorders: pathophysiology and potential approaches to management. CNS Drugs 2001; 15(4): 311–28PubMedCrossRefGoogle Scholar
  6. 6.
    Liu C, Weaver DR, Jin X, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 1997; 19(1): 91–102PubMedCrossRefGoogle Scholar
  7. 7.
    Jin X, von Gall C, Pieschl RL, et al. Targeted disruption of the mouse Mel1b melatonin receptor. Mol Cell Biol 2003; 23(3): 1054–60PubMedCrossRefGoogle Scholar
  8. 8.
    Dijk DJ, Cajochen C. Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms 1997; 12(6): 627–35PubMedCrossRefGoogle Scholar
  9. 9.
    Lavie P. Melatonin: role in gating nocturnal rise in sleep propensity. J Biol Rhythms 1997; 12(6): 657–65PubMedCrossRefGoogle Scholar
  10. 10.
    Wehr TA. Photoperiodism in humans and other primates: evidence and implications. J Biol Rhythms 2001; 16(4): 348–64PubMedCrossRefGoogle Scholar
  11. 11.
    Cajochen C, Krauchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol 2003; 15(4): 432–7PubMedCrossRefGoogle Scholar
  12. 12.
    Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 2004; 25(3–4): 177–95PubMedCrossRefGoogle Scholar
  13. 13.
    Zhdanova IV, Tucci V. Melatonin, circadian rhythms, and sleep. Curr Treat Options Neurol 2003; 5(3): 225–9PubMedCrossRefGoogle Scholar
  14. 14.
    Baskett JJ, Wood PC, Broad JB, et al. Melatonin in older people with age-related sleep maintenance problems: a comparison with age matched normal sleepers. Sleep 2001; 24(4): 418–24PubMedGoogle Scholar
  15. 15.
    Lushington K, Dawson D, Kennaway DJ, et al. The relationship between 6-sulphatoxymelatonin and polysomnographic sleep in good sleeping controls and wake maintenance insomniacs, aged 55–80 years. J Sleep Res 1999; 8(1): 57–64PubMedCrossRefGoogle Scholar
  16. 16.
    Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people [letter]. BMJ 1994; 309(6948): 167PubMedCrossRefGoogle Scholar
  17. 17.
    Hajak G, Rodenbeck A, Adler L, et al. Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia. Pharmacopsychiatry 1996; 29(5): 187–92PubMedCrossRefGoogle Scholar
  18. 18.
    Rodenbeck A, Huether G, Hajak G. Sleep disorders and aging: understanding the causes. In: Touitou Y, editor. Biological clocks, mechanisms and application. Amsterdam: Elsevier, 1998: 329–32Google Scholar
  19. 19.
    Leger D, Laudon M, Zisapel N. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med 2004; 116(2): 91–5PubMedCrossRefGoogle Scholar
  20. 20.
    MacFarlane J, Cleghorn J, Brown G. Melatonin and core temperature rhythm in chronic insomnia. Adv Biosci 1984; 53: 303–6Google Scholar
  21. 21.
    Kripke DF, Elliot JA, Youngstedt SD, et al. Melatonin: marvel or marker? Ann Med 1998; 30(1): 81–7PubMedCrossRefGoogle Scholar
  22. 22.
    Pandi-Perumal SR, Zisapel N, Srinivasan V, et al. Melatonin and sleep in aging population. Exp Gerontol 2005; 40(12): 911–25PubMedCrossRefGoogle Scholar
  23. 23.
    Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001; 86(10): 4727–30PubMedCrossRefGoogle Scholar
  24. 24.
    Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Med Rev 2005; 9(1): 25–39PubMedCrossRefGoogle Scholar
  25. 25.
    Srinivasan V, Smits G, Kayumov L, et al. Melatonin in circadian rhythm sleep disorders. In: Cardinali DP, Pandi-Perumal SR, editors. Neuroendocrine correlates of sleep/wakefulness. New York: Springer, 2006: 269–94CrossRefGoogle Scholar
  26. 26.
    Cardinali DP, Furio AM, Reyes MP, et al. The use of chronobiotics in the resynchronization of the sleep-wake cycle. Cancer Causes Control 2006; 17(4): 601–9PubMedCrossRefGoogle Scholar
  27. 27.
    Cardinali DP, Rosner JM. Metabolism of serotonin by the rat retina “in vitro”. J Neurochem 1971; 18: 1769–70PubMedCrossRefGoogle Scholar
  28. 28.
    Tosini G, Menaker M. The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration. Brain Res 1998; 789(2): 221–8PubMedCrossRefGoogle Scholar
  29. 29.
    Raikhlin NT, Kvetnoy IM, Tolkachev VN. Melatonin may be synthesised in enterochromaffin cells. Nature 1975; 255(5506): 344–5PubMedCrossRefGoogle Scholar
  30. 30.
    Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002; 47(10): 2336–48PubMedCrossRefGoogle Scholar
  31. 31.
    Slominski A, Fischer TW, Zmijewski MA, et al. On the role of melatonin in skin physiology and pathology. Endocrine 2005; 27(2): 137–48PubMedCrossRefGoogle Scholar
  32. 32.
    Carrillo-Vico A, Calvo JR, Abreu P, et al. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J 2004; 18(3): 537–9PubMedGoogle Scholar
  33. 33.
    Champier J, Claustrat B, Besancon R, et al. Evidence for tryptophan hydroxylase and hydroxy-indole-O-methyl-transferase mRNAs in human blood platelets. Life Sci 1997; 60(24): 2191–7PubMedCrossRefGoogle Scholar
  34. 34.
    Conti A, Conconi S, Hertens E, et al. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 2000; 28(4): 193–202PubMedCrossRefGoogle Scholar
  35. 35.
    Tricoire H, Moller M, Chemineau P, et al. Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod. Reprod Suppl 2003; 61: 311–21PubMedGoogle Scholar
  36. 36.
    Cardinali DP, Pévet P. Basic aspects of melatonin action. Sleep Med Rev 1998; 2(3): 175–90PubMedCrossRefGoogle Scholar
  37. 37.
    Reiter RJ. Melatonin: clinical relevance. Best Pract Res Clin Endocrinol Metab 2003; 17(2): 273–85PubMedCrossRefGoogle Scholar
  38. 38.
    Touitou Y. Human aging and melatonin: clinical relevance. Exp Gerontol 2001; 36(7): 1083–100PubMedCrossRefGoogle Scholar
  39. 39.
    Hirata F, Hayaishi O, Tokuyama T, et al. In vitro and in vivo formation of two new metabolites of melatonin. J Biol Chem 1974; 249(4): 1311–3PubMedGoogle Scholar
  40. 40.
    Tan DX, Manchester LC, Terron MP, et al. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007; 42(1): 28–42PubMedCrossRefGoogle Scholar
  41. 41.
    Fourtillan JB, Brisson AM, Gobin P, et al. Bioavailability of melatonin in humans after day-time administration of D7 melatonin. Biopharm Drug Dispos 2000; 21(1): 15–22PubMedCrossRefGoogle Scholar
  42. 42.
    Hartter S, Grozinger M, Weigmann H, et al. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther 2000; 67(1): 1–6PubMedCrossRefGoogle Scholar
  43. 43.
    Hartter S, Nordmark A, Rose DM, et al. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br J Clin Pharmacol 2003; 56(6): 679–82PubMedCrossRefGoogle Scholar
  44. 44.
    Morin LP, Allen CN. The circadian visual system, 2005. Brain Res Brain Res Rev 2006; 51(1): 1–60CrossRefGoogle Scholar
  45. 45.
    Hannibal J. Roles of PACAP-containing retinal ganglion cells in circadian timing. Int Rev Cytol 2006; 251: 1–39PubMedCrossRefGoogle Scholar
  46. 46.
    Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002; 295(5557): 1070–3PubMedCrossRefGoogle Scholar
  47. 47.
    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(16): 6405–12PubMedGoogle Scholar
  48. 48.
    Saper CB, Lu J, Chou TC, et al. The hypothalamic integrator for circadian rhythms. Trends Neurosci 2005; 28(3): 152–7PubMedCrossRefGoogle Scholar
  49. 49.
    Moore RY. Neural control of the pineal gland. Behav Brain Res 1996; 73(1–2): 125–30PubMedGoogle Scholar
  50. 50.
    Klein DC, Weller JL, Moore RY. Melatonin metabolism: neural regulation of pineal serotonin: acetyl coenzyme A N-acetyl-transferase activity. Proc Natl Acad Sci U S A 1971; 68(12): 3107–10PubMedCrossRefGoogle Scholar
  51. 51.
    Vacas MI, Lowenstein P, Cardinali DP. Dihydroergocryptine binding sites in bovine and rat pineal glands. J Auton Nerv Syst 1980; 2: 305–13PubMedCrossRefGoogle Scholar
  52. 52.
    Ho AK, Klein DC. Activation of alpha1-adrenoceptors, protein kinase C, or treatment with intracellular free Ca2+ elevating agents increases pineal phospholipase A2 activity: evidence that protein kinase C may participate in Ca2+-dependent alpha1-adrenergic stimulation of pineal phospholipase A2 activity. J Biol Chem 1987; 262(24): 11764–70PubMedGoogle Scholar
  53. 53.
    Krause DN, Dubocovich ML. Regulatory sites in the melatonin system of mammals. Trends Neurosci 1990; 13(11): 464–70PubMedCrossRefGoogle Scholar
  54. 54.
    Korf HW, Schomerus C, Maronde E, et al. Signal transduction molecules in the rat pineal organ: Ca2+, pCREB, and ICER. Naturwissenschaften 1996; 83(12): 535–43PubMedCrossRefGoogle Scholar
  55. 55.
    Klein DC, Schaad NL, Namboordiri MA, et al. Regulation of pineal serotonin N-acetyltransferase activity. Biochem Soc Trans 1992; 20(2): 299–304PubMedGoogle Scholar
  56. 56.
    Ribelayga C, Pévet P, Simonneaux V. HIOMT drives the photo-periodic changes in the amplitude of the melatonin peak of the Siberian hamster. Am J Physiol Regul Integr Comp Physiol 2000; 278(5): R1339–45PubMedGoogle Scholar
  57. 57.
    Ceinos RM, Chansard M, Revel F, et al. Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT. Neurosignals 2004; 13(6): 308–17PubMedCrossRefGoogle Scholar
  58. 58.
    Liu T, Borjigin J. N-acetyltransferase is not the rate-limiting enzyme of melatonin synthesis at night. J Pineal Res 2005; 39(1): 91–6PubMedCrossRefGoogle Scholar
  59. 59.
    Reppert SM, Godson C, Mahle CD, et al. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Me1b melatonin receptor. Proc Natl Acad Sci U S A 1995; 92(19): 8734–8PubMedCrossRefGoogle Scholar
  60. 60.
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 1994; 13(5): 1177–85PubMedCrossRefGoogle Scholar
  61. 61.
    Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2005; 27(2): 101–10PubMedCrossRefGoogle Scholar
  62. 62.
    Weaver DR, Reppert SM. The Mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei. Neuroreport 1996; 8(1): 109–12PubMedCrossRefGoogle Scholar
  63. 63.
    McArthur AJ, Hunt AE, Gillette MU. Melatonin action and signal transduction in the rat suprachiasmatic circadian clock: activation of protein kinase C at dusk and dawn. Endocrinology 1997; 138(2): 627–34PubMedCrossRefGoogle Scholar
  64. 64.
    Nosjean O, Ferro M, Coge F, et al. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 2000; 275(40): 31311–7PubMedCrossRefGoogle Scholar
  65. 65.
    Wu YH, Zhou JN, Van Heerikhuize J, et al. Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging 2006; 28(8): 1239–47PubMedCrossRefGoogle Scholar
  66. 66.
    Borbely AA. A two process model of sleep regulation. Hum Neurobiol 1982; 1(3): 195–204PubMedGoogle Scholar
  67. 67.
    Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005; 437(7063): 1257–63PubMedCrossRefGoogle Scholar
  68. 68.
    Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nature Neurosci Rev 2002; 3: 591–605Google Scholar
  69. 69.
    Dijk DJ, von Schantz M. Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators. J Biol Rhythms 2005; 20(4): 279–90PubMedCrossRefGoogle Scholar
  70. 70.
    Dijk DJ, Lockley SW. Integration of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol 2002; 92(2): 852–62PubMedGoogle Scholar
  71. 71.
    Zee PC, Manthena P. The brain’s master circadian clock: implications and opportunities for therapy of sleep disorders. Sleep Med Rev 2007; 11(1): 59–70PubMedCrossRefGoogle Scholar
  72. 72.
    Lynch HJ, Wurtman RJ, Moskowitz MA, et al. Daily rhythm in human urinary melatonin. Science 1975; 187(4172): 169–71PubMedCrossRefGoogle Scholar
  73. 73.
    Pandi-Perumal SR, Smits M, Spence W, et al. Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1–11PubMedCrossRefGoogle Scholar
  74. 74.
    Gorfine T, Assaf Y, Goshen-Gottstein Y, et al. Sleep-anticipating effects of melatonin in the human brain. Neuroimage 2006; 31(1): 410–8PubMedCrossRefGoogle Scholar
  75. 75.
    Tzischinsky O, Shlitner A, Lavie P. The association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulfatoxymelatonin. J Biol Rhythms 1993; 8(3): 199–209PubMedCrossRefGoogle Scholar
  76. 76.
    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(5): 423–31PubMedGoogle Scholar
  77. 77.
    Brismar K, Mogensen L, Wetterberg L. Depressed melatonin secretion in patients with nightmares due to beta-adrenoceptor blocking drugs. Acta Med Scand 1987; 221(2): 155–8PubMedCrossRefGoogle Scholar
  78. 78.
    van den Heuvel CJ, Reid KJ, Dawson D. Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin. Physiol Behav 1997; 61(6): 795–802CrossRefGoogle Scholar
  79. 79.
    Hartter S, Wang X, Weigmann H, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol 2001; 21(2): 167–74PubMedCrossRefGoogle Scholar
  80. 80.
    Haimov I, Lavie P. Melatonin: a chronobiotic and soporific hormone. Arch Gerontol Geriatr 1997; 24(2): 167–73PubMedCrossRefGoogle Scholar
  81. 81.
    Strogatz SH, Kronauer RE, Czeisler CA. Circadian regulation dominates homeostatic control of sleep length and prior wake length in humans. Sleep 1986; 9(2): 353–64PubMedGoogle Scholar
  82. 82.
    Lavie P. Ultrashort sleep-waking schedule: III. ‘Gates’ and ‘forbidden zones’ for sleep. Electroencephalogr Clin Neurophysiol 1986; 63(5): 414–25PubMedCrossRefGoogle Scholar
  83. 83.
    Buysse DJ, Nofzinger EA, Germain A, et al. Regional brain glucose metabolism during morning and evening wakefulness in humans: preliminary findings. Sleep 2004; 27(7): 1245–54PubMedGoogle Scholar
  84. 84.
    Long MA, Jutras MJ, Connors BW, et al. Electrical synapses coordinate activity in the suprachiasmatic nucleus. Nat Neurosci 2005; 8(1): 61–6PubMedCrossRefGoogle Scholar
  85. 85.
    Birkeland AJ. Plasma melatonin levels and nocturnal transitions between sleep and wakefulness. Neuroendocrinology 1982; 34(2): 126–31PubMedCrossRefGoogle Scholar
  86. 86.
    Sack RL, Hughes RJ, Edgar DM, et al. Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? Sleep 1997; 20(10): 908–15PubMedGoogle Scholar
  87. 87.
    Hunt AE, Al Ghoul WM, Gillette MU, et al. Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J Physiol Cell Physiol 2001; 280(1): C110–8PubMedGoogle Scholar
  88. 88.
    Zhdanova IV, Cantor ML, Leclair OU, et al. Behavioral effects of melatonin treatment in non-human primates. Sleep Res Online 1998; 1(3): 114–8PubMedGoogle Scholar
  89. 89.
    Zhdanova IV, Geiger DA, Schwagerl AL, et al. Melatonin promotes sleep in three species of diurnal nonhuman primates. Physiol Behav 2002; 75(4): 523–9PubMedCrossRefGoogle Scholar
  90. 90.
    Mintz EM, Phillips NH, Berger RJ. Daytime melatonin infusions induce sleep in pigeons without altering subsequent amounts of nocturnal sleep. Neurosci Lett 1998; 258(2): 61–4PubMedCrossRefGoogle Scholar
  91. 91.
    Murakami N, Kawano T, Nakahara K, et al. Effect of melatonin on circadian rhythm, locomotor activity and body temperature in the intact house sparrow, Japanese quail and owl. Brain Res 2001; 889(1–2): 220–4PubMedCrossRefGoogle Scholar
  92. 92.
    Zhdanova IV, Wang SY, Leclair OU, et al. Melatonin promotes sleep-like state in zebrafish. Brain Res 2001; 903(1–2): 263–8PubMedCrossRefGoogle Scholar
  93. 93.
    Zhdanova IV. Melatonin as a hypnotic: pro. Sleep Med Rev 2005; 9(1): 51–65PubMedCrossRefGoogle Scholar
  94. 94.
    Lerner AB, Case MD. Melatonin. Fed Proc 1960; 19: 590–2Google Scholar
  95. 95.
    Anton-Tay F, Diaz JL, Fernandez-Guardiola A. On the effect of melatonin upon human brain: its possible therapeutic implications. Life Sci I 1971; 10(15): 841–50PubMedCrossRefGoogle Scholar
  96. 96.
    Cramer H, Rudolph J, Consbruch U, et al. On the effects of melatonin on sleep and behavior in man. Adv Biochem Psychopharmacol 1974; 11: 187–91PubMedGoogle Scholar
  97. 97.
    Vollrath L, Semm P, Gammel G. Sleep induction by intranasal administration of melatonin. Adv Biosci 1981; 29: 327–9Google Scholar
  98. 98.
    Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology (Berl) 1990; 100(2): 222–6CrossRefGoogle Scholar
  99. 99.
    Dollins AB, Lynch HJ, Wurtman RJ, et al. Effect of pharmacological daytime doses of melatonin on human mood and performance. Psychopharmacology (Berl) 1993; 112(4): 490–6CrossRefGoogle Scholar
  100. 100.
    Nave R, Peled R, Lavie P. Melatonin improves evening napping. Eur J Pharmacol 1995; 275(2): 213–6PubMedCrossRefGoogle Scholar
  101. 101.
    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(5): 1824–8PubMedCrossRefGoogle Scholar
  102. 102.
    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(5): 552–8PubMedCrossRefGoogle Scholar
  103. 103.
    Stone BM, Turner C, Mills SL, et al. Hypnotic activity of melatonin. Sleep 2000; 23(5): 663–9Google Scholar
  104. 104.
    Tzischinsky O, Lavie P. Melatonin possesses time-dependent hypnotic effects. Sleep 1994; 17(7): 638–45PubMedGoogle Scholar
  105. 105.
    Lewy AJ. Melatonin as a marker and phase-resetter of circadian rhythms in humans. Adv Exp Med Biol 1999; 460: 425–34PubMedCrossRefGoogle Scholar
  106. 106.
    Rajaratnam SM, Middleton B, Stone BM, et al. Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans. J Physiol 2004; 561 (Pt 1): 339–51PubMedCrossRefGoogle Scholar
  107. 107.
    Lockley S, Tabandeh H, Skene D, et al. Day-time naps and melatonin in blind people [letter]. Lancet 1995; 346(8988): 1491PubMedCrossRefGoogle Scholar
  108. 108.
    Lockley SW, Skene DJ, James K, et al. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000; 164(1): R1–6PubMedCrossRefGoogle Scholar
  109. 109.
    Sack RL, Brandes RW, Kendall AR, et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000; 343(15): 1070–7PubMedCrossRefGoogle Scholar
  110. 110.
    Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev2005; 9(1): 41–50PubMedCrossRefGoogle Scholar
  111. 111.
    Wyatt JK, Dijk DJ, Ritz-de Cecco A, et al. Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep 2006; 29(5): 609–18PubMedGoogle Scholar
  112. 112.
    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(12): 1151–8PubMedCrossRefGoogle Scholar
  113. 113.
    Hughes RJ, Badia P. Sleep-promoting and hypothermie effects of daytime melatonin administration in humans. Sleep 1997; 20(2): 124–31PubMedGoogle Scholar
  114. 114.
    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(1): 52–68PubMedGoogle Scholar
  115. 115.
    MacKenzie RS, Melan MA, Passey DK, et al. Dual coupling of MT1 and MT2 melatonin receptors to cyclic AMP and phosphoinositide signal transduction cascades and their regulation following melatonin exposure. Biochem Pharmacol 2002; 63(4): 587–95PubMedCrossRefGoogle Scholar
  116. 116.
    Witt-Enderby PA, Jarzynka MJ, Krawitt BJ, et al. Knock-down of RGS4 and beta tubulin in CHO cells expressing the human MT2 melatonin receptor prevents melatonin-induced receptor desensitization. Life Sci 2004; 75(22): 2703–15PubMedCrossRefGoogle Scholar
  117. 117.
    Ying SW, Rusak B, Mocaer E. Chronic exposure to melatonin receptor agonists does not alter their effects on suprachiasmatic nucleus neurons. Eur J Pharmacol 1998; 342(1): 29–37PubMedCrossRefGoogle Scholar
  118. 118.
    Gerdin MJ, Masana MI, Rivera-Bermudez 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(14): 1646–56PubMedCrossRefGoogle Scholar
  119. 119.
    Gerdin MJ, Masana MI, Dubocovich ML. Melatonin-mediated regulation of human MT1 melatonin receptors expressed in mammalian cells. Biochem Pharmacol 2004; 67(11): 2023–30PubMedCrossRefGoogle Scholar
  120. 120.
    Masana MI, Benloucif S, Dubocovich ML. Circadian rhythm of mt1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse. J Pineal Res 2000; 28(3): 185–92PubMedCrossRefGoogle Scholar
  121. 121.
    Jarzynka MJ, Passey DK, Ignatius PF, et al. Modulation of melatonin receptors and G-protein function by microtubules. J Pineal Res 2006; 41(4): 324–36PubMedCrossRefGoogle Scholar
  122. 122.
    Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 2005; 48(2): 301–10PubMedCrossRefGoogle Scholar
  123. 123.
    Wurtman R. Ramelteon: a novel treatment for the treatment of insomnia. Expert Rev Neurother 2006; 6(7): 957–64PubMedCrossRefGoogle Scholar
  124. 124.
    Karim A, Tolbert D, Cao C. Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol 2006; 46(2): 140–8PubMedCrossRefGoogle Scholar
  125. 125.
    Cagnacci A, Elliott JA, Yen SS. Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab 1992; 75(2): 447–52PubMedCrossRefGoogle Scholar
  126. 126.
    Dawson D, Encel N. Melatonin and sleep in humans. J Pineal Res 1993; 15(1): 1–12PubMedCrossRefGoogle Scholar
  127. 127.
    Krauchi K, Cajochen C, Pache M, et al. Thermoregulatory effects of melatonin in relation to sleepiness. Chronobiol Int 2006; 23(1–2): 475–84PubMedCrossRefGoogle Scholar
  128. 128.
    Summers MO, Crisostomo MI, Stepanski EJ. Recent developments in the classification, evaluation, and treatment of insomnia. Chest 2006; 130(1): 276–86PubMedCrossRefGoogle Scholar
  129. 129.
    Lam RW. Sleep disturbances and depression: a challenge for antidepressants. Int Clin Psychopharmacol 2006; 21 Suppl. 1: S25–9PubMedCrossRefGoogle Scholar
  130. 130.
    Cricco M, Simonsick EM, Foley DJ. The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc 2001; 49(9): 1185–9PubMedCrossRefGoogle Scholar
  131. 131.
    Manabe K, Matsui T, Yamaya M, et al. Sleep patterns and mortality among elderly patients in a geriatric hospital. Gerontology 2000; 46(6): 318–22PubMedCrossRefGoogle Scholar
  132. 132.
    Kamel NS, Gammack JK. Insomnia in the elderly: cause, approach, and treatment. Am J Med 2006; 119(6): 463–9PubMedCrossRefGoogle Scholar
  133. 133.
    Garfinkel D, Laudon M, Zisapel N. Improvement of sleep quality by controlled-release melatonin in benzodiazepinetreated elderly insomniacs. Arch Gerontol Geriatr 1997; 24(2): 223–31PubMedCrossRefGoogle Scholar
  134. 134.
    Haimov I, Lavie P. Potential of melatonin replacement therapy in older patients with sleep disorders. Drugs Aging 1995; 7(2):75–8PubMedCrossRefGoogle Scholar
  135. 135.
    Monti JM, Alvarino F, Cardinali DP, et al. Polysomnographic study of the effect of melatonin on sleep in elderly patients with chronic primary insomnia. Arch Gerontol Geriatr 1999; 28: 85–98PubMedCrossRefGoogle Scholar
  136. 136.
    Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 2005; 28(3): 303–7PubMedGoogle Scholar
  137. 137.
    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(1): 17–24PubMedCrossRefGoogle Scholar
  138. 138.
    Pandi-Perumal SR, Srinivasan V, Cardinali DP, et al. Could agomelatine be the ideal antidepressant? Expert Rev Neurother 2006; 6(11): 1595–608PubMedCrossRefGoogle Scholar
  139. 139.
    Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs 2006; 20(12): 981–92PubMedCrossRefGoogle Scholar
  140. 140.
    James SP, Sack DA, Rosenthal NE, et al. Melatonin administration in insomnia. Neuropsychopharmacology 1990; 3(1): 19–23PubMedGoogle Scholar
  141. 141.
    Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995; 18(7): 598–603PubMedGoogle Scholar
  142. 142.
    Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 1996; 5(1): 61–5PubMedCrossRefGoogle Scholar
  143. 143.
    Shamir E, Rotenberg VS, Laudon M, et al. First-night effect of melatonin treatment in patients with chronic schizophrenia. J Clin Psychopharmacol 2000; 20(6): 691–4PubMedCrossRefGoogle Scholar
  144. 144.
    Andrade C, Srihari BS, Reddy KP, et al. Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001; 62(1): 41–5PubMedCrossRefGoogle Scholar
  145. 145.
    Smits MG, Nagtegaal EE, van der Heijden J, et al. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol 2001; 16(2): 86–92PubMedGoogle Scholar
  146. 146.
    Smits MG, van Stel HF, van der Heijden K, et al. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2003; 42(11): 1286–93PubMedCrossRefGoogle Scholar
  147. 147.
    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(7): 893–901PubMedGoogle Scholar
  148. 148.
    Asayama K, Yamadera H, Ito T, et al. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 2003; 70(4): 334–41PubMedCrossRefGoogle Scholar
  149. 149.
    Ivanenko A, Crabtree VM, Tauman R, et al. Melatonin in children and adolescents with insomnia: a retrospective study. Clin Pediatr (Phila) 2003; 42(1): 51–8CrossRefGoogle Scholar
  150. 150.
    Campos FL, Silva-Junior FP, de Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2004; 170(9): 947–51PubMedCrossRefGoogle Scholar
  151. 151.
    Dowling GA, Mastick J, Colling E, et al. Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med 2005; 6(5): 459–66PubMedCrossRefGoogle Scholar
  152. 152.
    Weiss M, Wasdell M, Bomben M, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 2006; 45(5): 512–9PubMedGoogle Scholar
  153. 153.
    Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med 2004; 5(6): 523–32PubMedCrossRefGoogle Scholar
  154. 154.
    Hirai K, Kita M, Ohta H, et al. Ramelteon (TAK-375) accelerates re-entrainment of circadian rhythm after a phase advance of the light-dark cycle in rats. J Biol Rhythms 2005; 20(1): 27–37PubMedCrossRefGoogle Scholar
  155. 155.
    Cajochen C. TAK-375 Takeda. Curr Opin Investig Drugs 2005; 6(1): 114–21PubMedGoogle Scholar
  156. 156.
    Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med 2006; 7(4): 312–8PubMedCrossRefGoogle Scholar
  157. 157.
    Bellon A. Searching for new options for treating insomnia: are melatonin and ramelteon beneficial? J Psychiatr Pract 2006; 12(4): 229–43PubMedCrossRefGoogle Scholar
  158. 158.
    Stevenson S, Bryson S, Amayke D, et al. Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects [abstract]. Clin Pharmacol Ther 2004; 75: 22Google Scholar
  159. 159.
    Rozerem™ (prescribing information). Lincolnshire (IL): Takeda Pharmaceuticals America, Inc., 2005, rev. 2006 AprGoogle Scholar
  160. 160.
    Ying SW, Rusak B, Delagrange P, et al. Melatonin analogues as agonists and antagonists in the circadian system and other brain areas. Eur J Pharmacol 1996; 296(1): 33–42PubMedCrossRefGoogle Scholar
  161. 161.
    Loo H, Hale A, D’haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002; 17(5): 239–47PubMedCrossRefGoogle Scholar
  162. 162.
    Millan MJ. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie 2005; 60(5): 441–60PubMedCrossRefGoogle Scholar
  163. 163.
    Delagrange P, Boutin JA. Therapeutic potential of melatonin ligands. Chronobiol Int 2006; 23(1–2): 413–8PubMedCrossRefGoogle Scholar
  164. 164.
    Leproult R, Van Onderbergen A, L’hermite-Baleriaux M, et al. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 2005; 63(3): 298–304CrossRefGoogle Scholar
  165. 165.
    Quera-Salva MA, Vanier B, Chapotot F. Effect of agomelatine on the sleep EEG in patients with major depressive disorders (MDD) [abstract]. Eur Neuropsychopharmacol 2005; 15Suppl. 3: S435Google Scholar
  166. 166.
    Dubocovich ML. Agomelatine targets a range of major depressive disorder symptoms. Curr Opin Investig Drugs 2006; 7(7):670–80PubMedGoogle Scholar
  167. 167.
    Liu RY, Zhou JN, van Heerikhuize J, et al. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab 1999; 84: 323–7PubMedCrossRefGoogle Scholar
  168. 168.
    McCurry SM, Reynolds CF, Ancoli-Israel S, et al. Treatment of sleep disturbance in Alzheimer’s disease. Sleep Med Rev 2000; 4(6): 603–28PubMedCrossRefGoogle Scholar
  169. 169.
    Wu YH, Feenstra MG, Zhou JN, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 2003; 88(12): 5898–906PubMedCrossRefGoogle Scholar
  170. 170.
    Mishima K, Tozawa T, Satoh K, et al. Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biol Psychiatry 1999; 45(4): 417–21PubMedCrossRefGoogle Scholar
  171. 171.
    Fainstein I, Bonetto A, Brusco LI, et al. Effects of melatonin in elderly patients with sleep disturbance: a pilot study. Curr Ther Res 1997; 58: 990–1000CrossRefGoogle Scholar
  172. 172.
    Jean-Louis G, von Gizycki H, Zizi F. Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J Pineal Res 1998; 25(3): 177–83PubMedCrossRefGoogle Scholar
  173. 173.
    Brusco LI, Marquez M, Cardinali DP. Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuroendocrinol Lett 1998; 19: 111–5Google Scholar
  174. 174.
    Cardinali DP, Brusco LI, Liberczuk C, et al. The use of melatonin in Alzheimer’s disease. Neuroendocrinol Lett 2002; 23Suppl. 1: 20–3PubMedGoogle Scholar
  175. 175.
    Mahlberg R, Kunz D, Sutej I, et al. Melatonin treatment of day-night rhythm disturbances and sundowning in Alzheimer disease: an open-label pilot study using actigraphy. J Clin Psychopharmacol 2004; 24(4): 456–9PubMedCrossRefGoogle Scholar
  176. 176.
    Jan JE, Freeman RD. Melatonin therapy for circadian rhythm sleep disorders in children with multiple disabilities: what have we learned in the last decade? Dev Med Child Neurol 2004; 46(11): 776–82PubMedCrossRefGoogle Scholar
  177. 177.
    Van der Heijden KB, Smits MG, Van Someren EJ, et al. Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia. J Sleep Res 2005; 14(2): l17–94CrossRefGoogle Scholar
  178. 178.
    Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol 1994; 36(2): 97–107PubMedCrossRefGoogle Scholar
  179. 179.
    De Leersnyder H, Bresson JL, de Blois MC, et al. Beta1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J Med Genet 2003; 40(1): 74–8PubMedCrossRefGoogle Scholar
  180. 180.
    De Leersnyder H. Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. Trends Endocrinol Metab 2006; 17(7): 291–8PubMedCrossRefGoogle Scholar
  181. 181.
    Asato MR, Hardan AY. Neuropsychiatric problems in tuberous sclerosis complex. J Child Neurol 2004; 19(4): 241–9PubMedCrossRefGoogle Scholar
  182. 182.
    O’Callaghan FJ, Clarke AA, Hancock E, et al. Use of melatonin to treat sleep disorders in tuberous sclerosis. Dev Med Child Neurol 1999; 41(2): 123–6PubMedCrossRefGoogle Scholar
  183. 183.
    Tordjman S, Anderson GM, Pichard N, et al. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biol Psychiatry 2005; 57(2): 134–8PubMedCrossRefGoogle Scholar
  184. 184.
    Giannotti F, Cortesi F, Cerquiglini A, et al. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord 2006; 36(6): 741–52PubMedCrossRefGoogle Scholar
  185. 185.
    Jan MM. Melatonin for the treatment of handicapped children with severe sleep disorders. Pediatr Neurol 2000; 23(3):229–32PubMedCrossRefGoogle Scholar
  186. 186.
    Wassmer E, Whitehouse WP. Melatonin and sleep in children with neurodevelopmental disabilities and sleep disorders. Current Paediatrics 2006; 16(2): 132–8CrossRefGoogle Scholar
  187. 187.
    Weitzman ED, Czeisler CA, Coleman RM, et al. Delayed sleep phase syndrome: a chronobiological disorder with sleep-onset insomnia. Arch Gen Psychiatry 1981; 38(7): 737–46PubMedCrossRefGoogle Scholar
  188. 188.
    Regestein QR, Monk TH. Delayed sleep phase syndrome: a review of its clinical aspects. Am J Psychiatry 1995; 152(4):602–8PubMedGoogle Scholar
  189. 189.
    Wyatt JK, Stepanski EJ, Kirkby J. Circadian phase in delayed sleep phase syndrome: predictors and temporal stability across multiple assessments. Sleep 2006; 29(8): 1075–80PubMedGoogle Scholar
  190. 190.
    Oren DA, Turner EH, Wehr TA. Abnormal circadian rhythms of plasma melatonin and body temperature in the delayed sleep phase syndrome [letter]. J Neurol Neurosurg Psychiatry 1995; 58(3): 379PubMedCrossRefGoogle Scholar
  191. 191.
    Hohjoh H, Takasu M, Shishikura K, et al. Significant association of the arylalkylamine N-acetyltransferase (AA-NAT) gene with delayed sleep phase syndrome. Neurogenetics 2003; 4(3): 151–3PubMedGoogle Scholar
  192. 192.
    Dahlitz M, Alvarez B, Vignau J, et al. Delayed sleep phase syndrome response to melatonin. Lancet 1991; 337(8750):1121–4PubMedCrossRefGoogle Scholar
  193. 193.
    Lewy AJ, Ahmed S, Jackson JM, et al. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992; 9(5): 380–92PubMedCrossRefGoogle Scholar
  194. 194.
    Oldani A, Ferini-Strambi L, Zucconi M, et al. Melatonin and delayed sleep phase syndrome: ambulatory polygraphic evaluation. Neuroreport 1994; 6(1): 132–4PubMedCrossRefGoogle Scholar
  195. 195.
    Nagtegaal E, Peeters T, Swart W, et al. Correlation between concentrations of melatonin in saliva and serum in patients with delayed sleep phase syndrome. Ther Drug Monit 1998; 20(2): 181–3PubMedCrossRefGoogle Scholar
  196. 196.
    Kayumov L, Brown G, Jindal R, et al. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med 2001; 63(1): 40–8PubMedGoogle Scholar
  197. 197.
    Mundey K, Benloucif S, Harsanyi K, et al. Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep 2005; 28(10): 1271–8PubMedGoogle Scholar
  198. 198.
    Reid KJ, Chang AM, Dubocovich ML, et al. Familial advanced sleep phase syndrome. Arch Neurol 2001; 58(7): 1089–94PubMedCrossRefGoogle Scholar
  199. 199.
    Jones CR, Campbell SS, Zone SE, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 1999; 5(9): 1062–5PubMedCrossRefGoogle Scholar
  200. 200.
    Satoh K, Mishima K, Inoue Y, et al. Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 2003; 26(4): 416–7PubMedGoogle Scholar
  201. 201.
    Toh KL, Jones CR, He Y, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001; 291(5506): 1040–3PubMedCrossRefGoogle Scholar
  202. 202.
    Czeisler CA, Kronauer RE, Mooney JJ, et al. Biologic rhythm disorders, depression, and phototherapy: a new hypothesis. Psychiatr Clin North Am 1987; 10(4): 687–709PubMedGoogle Scholar
  203. 203.
    Lockley SW, Skene DJ, Tabandeh H, et al. Relationship between napping and melatonin in the blind. J Biol Rhythms 1997; 12(1): 16–25PubMedCrossRefGoogle Scholar
  204. 204.
    Shibui K, Okawa M, Uchiyama M, et al. Continuous measurement of temperature in non-24 hour sleep-wake syndrome. Psychiatry Clin Neurosci 1998; 52(2): 236–7PubMedCrossRefGoogle Scholar
  205. 205.
    McArthur AJ, Lewy AJ, Sack RL. Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment. Sleep 1996; 19(7): 544–53PubMedGoogle Scholar
  206. 206.
    Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 1997; 39(5): 319–25PubMedCrossRefGoogle Scholar
  207. 207.
    Folkard S, Arendt J, Aldhous M, et al. Melatonin stabilises sleep onset time in a blind man without entrainment of cortisol or temperature rhythms. Neurosci Lett 1990; 113(2): 193–8PubMedCrossRefGoogle Scholar
  208. 208.
    Arendt J, Marks V. Physiological changes underlying jet lag. Br Med J (Clin Res Ed) 1982; 284(6310): 144–6CrossRefGoogle Scholar
  209. 209.
    Cardinali DP, Brusco LI, Lloret SP, et al. Melatonin in sleep disorders and jet-lag. Neuroendocrinol Lett 2002; 23 Suppl. 1:9–13PubMedGoogle Scholar
  210. 210.
    Oxenkrug GF, Requintina PJ. Melatonin and jet lag syndrome: experimental model and clinical implications. CNS Spectr 2003; 8(2): 139–48PubMedGoogle Scholar
  211. 211.
    Cardinali DP, Bortman GP, Liotta G, et al. A multifactorial approach employing melatonin to accelerate resynchronization of sleep-wake cycle after a 12 time-zone westerly transmeridian flight in elite soccer athletes. J Pineal Res 2002; 32(1): 41–6PubMedCrossRefGoogle Scholar
  212. 212.
    Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998; 15(6): 655–66PubMedCrossRefGoogle Scholar
  213. 213.
    Burch JB, Yost MG, Johnson W, et al. Melatonin, sleep, and shift work adaptation. J Occup Environ Med 2005; 47(9): 893–901PubMedCrossRefGoogle Scholar
  214. 214.
    Drake CL, Roehrs T, Richardson G, et al. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep 2004; 27(8): 1453–62PubMedGoogle Scholar
  215. 215.
    Akerstedt T. Shift work and sleep disorders. Sleep 2005; 28(1):9–11PubMedGoogle Scholar
  216. 216.
    Van Reeth O. Sleep and circadian disturbances in shift work: strategies for their management. Horm Res 1998; 49(3–4):158–62PubMedCrossRefGoogle Scholar
  217. 217.
    Sack RL, Blood ML, Lewy AJ. Melatonin rhythms in night shift workers. Sleep 1992; 15(5): 434–41PubMedGoogle Scholar
  218. 218.
    Roden M, Koller M, Pirich K, et al. The circadian melatonin and cortisol secretion pattern in permanent night shift workers. Am J Physiol 1993; 265 (1 Pt 2): R261–7PubMedGoogle Scholar
  219. 219.
    Weibel L, Spiegel K, Gronfier C, et al. Twenty-four-hour melatonin and core body temperature rhythms: their adaptation in night workers. Am J Physiol 1997; 272 (3 Pt 2): R948–54PubMedGoogle Scholar
  220. 220.
    Folkard_S, Arendt J, Clark M. Can melatonin improve shift workers’ tolerance of the night shift? Some preliminary findings. Chronobiol Int 1993; 10(5): 315–20PubMedCrossRefGoogle Scholar
  221. 221.
    Jorgensen KM, Witting MD. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med 1998; 31(6): 699–704PubMedCrossRefGoogle Scholar
  222. 222.
    Burgess HJ, Sharkey KM, Eastman CI. Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Sleep Med Rev 2002; 6(5): 407–20PubMedGoogle Scholar
  223. 223.
    Quera-Salva MA, Guilleminault C, Claustrat B, et al. Rapid shift in peak melatonin secretion associated with improved performance in short shift work schedule. Sleep 1997; 20(12):1145–50PubMedGoogle Scholar
  224. 224.
    Cavallo A, Ris MD, Succop P, et al. Melatonin treatment of pediatric residents for adaptation to night shift work. Ambul Pediatr 2005; 5(3): 172–7PubMedCrossRefGoogle Scholar
  225. 225.
    Arendt J. Safety of melatonin in long-term use (?). J Biol Rhythms 1997; 12(6): 673–81PubMedCrossRefGoogle Scholar
  226. 226.
    Guardiola-Lemaitre B. Toxicology of melatonin. J Biol Rhythms 1997; 12(6): 697–706PubMedCrossRefGoogle Scholar
  227. 227.
    Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002; (2): CD001520PubMedGoogle Scholar
  228. 228.
    Jacob S, Poeggeler B, Weishaupt JH, et al. Melatonin as a candidate compound for neuroprotection in amyotrophic lateral sclerosis (ALS): high tolerability of daily oral melatonin administration in ALS patients. J Pineal Res 2002; 33(3): 186–7PubMedCrossRefGoogle Scholar
  229. 229.
    Weishaupt JH, Bartels C, Polking E, et al. Reduced oxidative damage in ALS by high-dose enterai melatonin treatment. J Pineal Res 2006; 41(4): 313–23PubMedCrossRefGoogle Scholar
  230. 230.
    Maestroni GJM, Cardinali DP, Esquifino AI, et al. Does melatonin play a disease-promoting role in rheumatoid arthritis? J Neuroimmunol 2004; 158: 106–11CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Seithikurippu R. Pandi-Perumal
    • 1
  • Venkatramanujan Srinivasan
    • 2
  • D. Warren Spence
    • 3
  • Daniel P. Cardinali
    • 4
  1. 1.Comprehensive Center for Sleep Medicine, Department of Pulmonary, Critical Care, and Sleep MedicineMt Sinai School of MedicineNew YorkUSA
  2. 2.Department of Physiology, School of Medical SciencesUniversity Sains MalaysiaKubang Kerian, KelantanMalaysia
  3. 3.Sleep and Alertness ClinicUniversity Health NetworkTorontoCanada
  4. 4.Departamento de Fisiologia, Facultad de MedicinaUniversidad de Buenos AiresBuenos AiresArgentina

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