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CNS Drugs

, Volume 33, Issue 12, pp 1167–1186 | Cite as

Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review

  • Frank M. C. BesagEmail author
  • Michael J. Vasey
  • Kim S. J. Lao
  • Ian C. K. Wong
Systematic Review

Abstract

Background

Melatonin is widely available either on prescription for the treatment of sleep disorders or as an over-the-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jetlag. Little is known about the potential for adverse events (AEs), in particular AEs resulting from long-term use. Concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma.

Objectives

The aim of this systematic review was to assess the evidence for AEs associated with short-term and longer-term melatonin treatment for sleep disorders.

Methods

A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of < 1 week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk-of-bias criteria.

Results

37 RCTs met criteria for inclusion. Daily melatonin doses ranged from 0.15 mg to 12 mg. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (4 weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%). Very few AEs considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. Most AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged ‘good’ overall with respect to the Cochrane risk-of-bias criteria. Of the remaining papers, 16 were considered ‘fair’ and 13 ‘poor’ but publication of almost half of the papers preceded that of the earliest version of the guidelines.

Conclusion

Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinically significant adverse effects in potentially at-risk populations. Future studies should be designed to comply with appropriate quality standards for RCTs, which most past studies have not.

Notes

Compliance with Ethical Standards

Conflict of interest

Frank M. C. Besag, Michael J. Vasey, Kim S. J. Lao and Ian C. K. Wong declare that they have no conflicts of interest.

Funding

No funding was received in relation to the preparation of this manuscript.

Supplementary material

40263_2019_680_MOESM1_ESM.docx (66 kb)
Supplementary material 1 (DOCX 66 kb)

References

  1. 1.
    Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336(3):186–95.PubMedGoogle Scholar
  2. 2.
    Cassone VM. Effects of melatonin on vertebrate circadian systems. Trends Neurosci. 1990;13(11):457–64.PubMedGoogle Scholar
  3. 3.
    Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Med Rev. 2005;9(1):25–39.PubMedGoogle Scholar
  4. 4.
    Maestroni GJ, Conti A, Pierpaoli W. Role of the pineal gland in immunity: II. Melatonin enhances the antibody response via an opiatergic mechanism. Clin Exp Immunol. 1987;68(2):384–91.Google Scholar
  5. 5.
    Maestroni GJM. The immunoneuroendocrine role of melatonin. J Pineal Res. 1993;14(1):1–10.PubMedGoogle Scholar
  6. 6.
    Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem. 2002;2(2):167–79.PubMedGoogle Scholar
  7. 7.
    Bonnefont-Rousselot D, Collin F. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology. 2010;278(1):55–67.PubMedGoogle Scholar
  8. 8.
    Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM. Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res. 2010;48(4):297–310.PubMedGoogle Scholar
  9. 9.
    Acuna Castroviejo D, C Lopez L, Escames G, Lopez A, A Garcia J, J Reiter R. Melatonin-mitochondria interplay in health and disease. current topics in medicinal chemistry. 2011;11(2):221–40.PubMedGoogle Scholar
  10. 10.
    Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci. 2000;917(1):376–86.PubMedGoogle Scholar
  11. 11.
    Cuzzocrea S, Reiter RJ. Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol. 2001;426(1):1–10.PubMedGoogle Scholar
  12. 12.
    Reiter RJ, Rosales-Corral SA, Tan D-X, Acuna-Castroviejo D, Qin L, Yang S-F, et al. Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. Int J Mol Sci. 2017;18(4):843.PubMedCentralGoogle Scholar
  13. 13.
    Reiter RJ, Melchiorri D, Sewerynek E, Poeggeler B, Barlow-Walden L, Chuang J, et al. A review of the evidence supporting melatonin’s role as an antioxidant. J Pineal Res. 1995;18(1):1–11.PubMedGoogle Scholar
  14. 14.
    Reiter RJ. Melatonin and human reproduction. Ann Med. 1998;30(1):103–8.PubMedGoogle Scholar
  15. 15.
    Reiter RJ, Maestroni GJM. Melatonin in relation to the antioxidative defense and immune systems: possible implications for cell and organ transplantation. J Mol Med. 1999;77(1):36–9.PubMedGoogle Scholar
  16. 16.
    Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. J Biomed Sci. 2000;7(6):444–58.PubMedGoogle Scholar
  17. 17.
    Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36(1):1–9.PubMedGoogle Scholar
  18. 18.
    Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, et al. Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. BMC Med. 2018;16(1):18.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Tamarkin L, Baird C, Almeida O. Melatonin: a coordinating signal for mammalian reproduction? Science. 1985;227(4688):714–20.PubMedGoogle Scholar
  20. 20.
    Reiter RJ, Tan D-X, Manchester LC, Paredes SD, Mayo JC, Sainz RM. Melatonin and reproduction revisited. Biol Reprod. 2009;81(3):445–56.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A. Melatonin and human reproduction: shedding light on the darkness hormone. Gynecol Endocrinol. 2009;25(12):779–85.PubMedGoogle Scholar
  22. 22.
    Arendt J. Melatonin and human rhythms. Chronobiol Int. 2006;23(1–2):21–37.PubMedGoogle Scholar
  23. 23.
    Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms. 2006;21(6):482–93.PubMedGoogle Scholar
  24. 24.
    Dijk D-J, Cajochen C. Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms. 1997;12(6):627–35.PubMedGoogle Scholar
  25. 25.
    Zhdanova IV, Tucci V. Melatonin, circadian rhythms, and sleep. Curr Treat Options Neurol. 2003;5(3):225–9.PubMedGoogle Scholar
  26. 26.
    Zhdanova IV. Melatonin as a hypnotic: pro. Sleep Med Rev. 2005;9(1):51–65.PubMedGoogle Scholar
  27. 27.
    Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology. 1990;100(2):222–6.PubMedGoogle Scholar
  28. 28.
    Dawson D, Encel N. Melatonin and sleep in humans. J Pineal Res. 1993;15(1):1–12.PubMedGoogle Scholar
  29. 29.
    Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9(1):11–24.PubMedGoogle Scholar
  30. 30.
    Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, et al. Melatonin for treatment of sleep disorders. Evid Rep Technol Assess (Summ). 2004;108:1–7.Google Scholar
  31. 31.
    Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Dietary Supplement Health and Education Act of 1994. 1994. https://www.govinfo.gov/content/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdf. Cited 10 Oct 2019.
  33. 33.
    Health Canada. Drugs and Health Products. Natural Health Products Ingredients Database–Melatonin. 2019. http://webprod.hc-sc.gc.ca/nhpid-bdipsn/ingredReq.do?id=1773&lang=eng. Cited 10 Oct 2019.
  34. 34.
    Health Canada. Summary Safety Review—Melatonin (N-acetyl-5-methoxytryptamine)—Review of the Safety of Melatonin in Children and Adolescents. 2015. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-melatonin-acetyl-methoxytryptamine-review-safety-melatonin-children-adolescents.html. Cited 10 Oct 2019.
  35. 35.
    National Institute for Health and Care Excellence (NICE). Sleep disorders in children and young people with attention deficit hyperactivity disorder: melatonin. Evidence summary [ESUOM2]. 2013. https://www.nice.org.uk/advice/esuom2/chapter/overview-for-healthcare-professionals#regulatory-status-of-melatonin. Cited 10 Oct 2019.
  36. 36.
    Danish Medicines Agency. Are you considering to buy melatonin online? 2018. laegemiddelstyrelsen.dk/en/pharmacies/medicines-imported-from-abroad/are-you-considering-to-buy-melatonin-online. Cited 10 Oct 2019.Google Scholar
  37. 37.
    French Agency for Food, Environmental and Occupational Health and Safety (ANSES). Relatif aux risques liés à la consommation de compléments alimentaires contenant de la mélatonine—on the risks associated with the consumption of food supplements containing melatonin (in French). 2018. https://www.anses.fr/fr/system/files/NUT2016SA0209.pdf. Cited 10 Oct 2019.
  38. 38.
    Grigg-Damberger MM, Ianakieva D. Poor quality control of over-the-counter melatonin: what they say is often not what you get. J Clin Sleep Med. 2017;13(2):163–5.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Medsafe New Zealand. Reclassification of melatonin. 2019. medsafe.govt.nz/profs/class/ReclassificationOfMelatonin.asp. Cited 10 Oct 2019.Google Scholar
  40. 40.
    French Agency for Food, Environmental and Occupational Health and Safety (ANSES). Assessment of the risks associated with food supplements containing melatonin. 2018. anses.fr/en/glossaire/1541. Cited 4 Oct 2019.Google Scholar
  41. 41.
    Chu W. Side effects prompt French authorities to issue melatonin supplement warning. 2018. nutraingredients.com/Article/2018/04/23/Side-effects-prompt-French-authorities-to-issue-melatonin-supplement-warning. Cited 4 Oct 2019.Google Scholar
  42. 42.
    electronic Medicines Compendium (eMC). Circadin Summary of Product Characteristics (SmPC). 2018. https://www.medicines.org.uk/EMC/medicine/25643/SPC/Circadin/. Cited 4 Aug 2019.
  43. 43.
    European Medicines Agency (EMA). Slenyto. 2018. http://ema.europa.eu/en/medicines/human/EPAR/slenyto. Cited 4 Oct 2019.Google Scholar
  44. 44.
    Neurim Pharmaceuticals. Slenyto. 2019. http://neurim.com/products/pedprm. 2019. Cited 4 Oct 2019.Google Scholar
  45. 45.
    National Institute for Health and Care Excellence (NICE). Sleep disorders in children and young people with attention deficit hyperactivity disorder: melatonin. 2013. http://nice.org.uk/advice/esuom2/chapter/overview-for-healthcare-professionals. Cited 4 Oct 2019.Google Scholar
  46. 46.
    National Institute for Health and Care Excellence (NICE). Melatonin. 2019. http://bnf.nice.org.uk/drug/melatonin.html#sideEffects. Cited 4 Oct 2019.Google Scholar
  47. 47.
    Electronic Medicines Compendium (EMC). SmPC Melatonin 3 mg film-coated tablets. 2019. http://medicines.org.uk/emc/product/10405/smpc. Cited 4 Oct 2019.Google Scholar
  48. 48.
    Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin Drug Investig. 2016;36(3):169–75.PubMedGoogle Scholar
  49. 49.
    Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2015;11(10):1199–236.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Kennaway DJ. Potential safety issues in the use of the hormone melatonin in paediatrics. J Paediatr Child Health. 2015;51(6):584–9.PubMedGoogle Scholar
  51. 51.
    Boafo A, Greenham S, Alenezi S, Robillard R, Pajer K, Tavakoli P, et al. Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective. Nat Sci Sleep. 2019;11:1–10.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Stores G. Medication for sleep-wake disorders. Arch Dis Child. 2003;88(10):899–903.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Gitto E, Aversa S, Reiter RJ, Barberi I, Pellegrino S. Update on the use of melatonin in pediatrics. J Pineal Res. 2011;50(1):21–8.PubMedGoogle Scholar
  54. 54.
    Appleton RE, Jones AP, Gamble C, Williamson PR, Wiggs L, Montgomery P, et al. The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS). Health Technol Assess. 2012;16(40):i-239.PubMedGoogle Scholar
  55. 55.
    Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado ME, Lima-Cabello E, Lopez LC, et al. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014;71(16):2997–3025.PubMedGoogle Scholar
  56. 56.
    Hardeland R, Reiter RJ, Poeggeler B, Tan DX. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev. 1993;17(3):347–57.PubMedGoogle Scholar
  57. 57.
    Claustrat B, Leston J. Melatonin: physiological effects in humans. Neurochirurgie. 2015;61(2):77–84.PubMedGoogle Scholar
  58. 58.
    Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002;2(2):113–32.PubMedGoogle Scholar
  59. 59.
    Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39(4):360–6.PubMedGoogle Scholar
  60. 60.
    Vijayalaxmi CRT Jr, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol. 2002;20(10):2575–601.PubMedGoogle Scholar
  61. 61.
    Brusco LI, Márquez M, Cardinali DP. Monozygotic twins with Alzheimer’s disease treated with melatonin: case report. J Pineal Res. 1998;25(4):260–3.PubMedGoogle Scholar
  62. 62.
    Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer’s disease. Neuro Endocrinol Lett. 2002;23(Suppl 1):20–3.PubMedGoogle Scholar
  63. 63.
    Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. 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):334–41.PubMedGoogle Scholar
  64. 64.
    Mayo JC, Sainz RM, Tan D-X, Antolín I, Rodríguez C, Reiter RJ. Melatonin and Parkinson’s disease. Endocrine. 2005;27(2):169–78.PubMedGoogle Scholar
  65. 65.
    Srinivasan V, Pandi-Perumal SR, Cardinali DP, Poeggeler B, Hardeland R. Melatonin in Alzheimer’s disease and other neurodegenerative disorders. Behav Brain Funct. 2006;2(1):15.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Rosales-Corral SA, Acuña-Castroviejo D, Coto-Montes A, Boga JA, Manchester LC, Fuentes-Broto L, et al. Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res. 2012;52(2):167–202.PubMedGoogle Scholar
  67. 67.
    Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res. 2011;51(1):1–16.PubMedGoogle Scholar
  68. 68.
    Maestroni GJM. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs. 2001;10(3):467–76.PubMedGoogle Scholar
  69. 69.
    Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, Rodríguez-Rodríguez A, Guerrero JM. Melatonin: buffering the immune system. Int J Mol Sci. 2013;14(4):8638–83.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Lin G-J, Huang S-H, Chen S-J, Wang C-H, Chang D-M, Sytwu H-K. Modulation by melatonin of the pathogenesis of inflammatory autoimmune diseases. Int J Mol Sci. 2013;14(6):11742–66.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002.  https://doi.org/10.1002/14651858.CD001520.CrossRefPubMedGoogle Scholar
  72. 72.
    Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65–81.PubMedGoogle Scholar
  73. 73.
    Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2017;56(11):948–57.PubMedGoogle Scholar
  74. 74.
    Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis. Arch Dis Child. 2018;103(12):1155–62.PubMedGoogle Scholar
  75. 75.
    Esposito S, Laino D, D’Alonzo R, Mencarelli A, Di Genova L, Fattorusso A, et al. Pediatric sleep disturbances and treatment with melatonin. J Transl Med. 2019;17(1):77.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Parker A, Beresford BA, Dawson V, Elphick H, Fairhurst CM, Hewitt CE, et al. Oral melatonin for non-respiratory sleep disturbance in children with neurodisabilities: systematic review and meta-analyses. Dev Med Child Neurol. 2019;61:880–90.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Soares N, Kanungo S. Management of adverse effects of sleep medications in pediatrics. Curr Psychopharmacol. 2018;7(1):36–48.Google Scholar
  78. 78.
    Wei S, Smits MG, Tang X, Kuang L, Meng H, Ni S et al. Efficacy and safety of melatonin for sleep onset insomnia in children and adolescents: a meta-analysis of randomized controlled trials. Sleep Med. 2019. Available online 09 Mar 2019 (in press).Google Scholar
  79. 79.
    Baskett JJ, Broad JB, Wood PC, Duncan JR, Pledger MJ, English J, et al. Does melatonin improve sleep in older people? A randomised crossover trial. Age Ageing. 2003;32(2):164–70.PubMedGoogle Scholar
  80. 80.
    Braam W, Didden R, Smits M, Curfs L. Melatonin treatment in individuals with intellectual disability and chronic insomnia: a randomized placebo-controlled study. J Intellect Disabil Res. 2008;52(3):256–64.PubMedGoogle Scholar
  81. 81.
    Campos FL, da Silva-Júnior FP, de Bruin VMS, de Bruin PFC. Melatonin improves sleep in asthma. Am J Respir Crit Care Med. 2004;170(9):947–51.PubMedGoogle Scholar
  82. 82.
    Chang Y, Lin M, Lee J, et al. Melatonin supplementation for children with atopic dermatitis and sleep disturbance: a randomized clinical trial. JAMA Pediatrics. 2016;170(1):35–42.PubMedGoogle Scholar
  83. 83.
    Coppola G, Iervolino G, Mastrosimone M, La Torre G, Ruiu F, Pascotto A. Melatonin in wake–sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Brain Dev. 2004;26(6):373–6.PubMedGoogle Scholar
  84. 84.
    Cortesi F, Giannotti F, Sebastiani T, Panunzi S, Valente D. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res. 2012;21(6):700–9.PubMedGoogle Scholar
  85. 85.
    Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in children with developmental disabilities. J Child Neurol. 2001;16(8):581–4.PubMedGoogle Scholar
  86. 86.
    Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry. 1998;155(8):1119–21.PubMedGoogle Scholar
  87. 87.
    Dowling GA, Mastick J, Aminoff MJ. Melatonin treatment for insomnia in Parkinson’s disease: a pilot study. Sleep Res Online. 2003;5(3):99–103.Google Scholar
  88. 88.
    Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res. 1996;5(1):61–5.PubMedGoogle Scholar
  89. 89.
    Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346(8974):541–4.PubMedGoogle Scholar
  90. 90.
    Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes Targets Therapy. 2011;4:307–13.Google Scholar
  91. 91.
    Garzón C, Guerrero JM, Aramburu O, Guzmán T. Effect of melatonin administration on sleep, behavioral disorders and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study. Aging Clin Exp Res. 2009;21(1):38.PubMedGoogle Scholar
  92. 92.
    Jain SV, Horn PS, Simakajornboon N, Beebe DW, Holland K, Byars AW, et al. Melatonin improves sleep in children with epilepsy: a randomized, double-blind, crossover study. Sleep Med. 2015;16(5):637–44.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med. 2001;63(1):40–8.PubMedGoogle Scholar
  94. 94.
    Kunz D, Mahlberg R, Müller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. J Clin Endocrinol Metab. 2004;89(1):128–34.PubMedGoogle Scholar
  95. 95.
    Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. J Sleep Res. 2010;19(4):591–6.PubMedGoogle Scholar
  96. 96.
    Kurdi MS, Muthukalai SP. The efficacy of oral melatonin in improving sleep in cancer patients with insomnia: a randomized double-blind placebo-controlled study. Indian J Palliat Care. 2016;22(3):295–300.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Luthringer R, Muzet M, Zisapel N, Staner L. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol. 2009;24(5):239–49.PubMedGoogle Scholar
  98. 98.
    McArthur AJ, Budden SS. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol. 1998;40(3):186–92.PubMedGoogle Scholar
  99. 99.
    Medeiros CAM, Carvalhedo de Bruin PF, Lopes LA, Magalhães MC, de Lourdes Seabra M, Sales de Bruin VM. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. J Neurol. 2007;254(4):459–64.PubMedGoogle Scholar
  100. 100.
    Nunes DM, Mota RMS, Machado MO, Pereira EDB, de Bruin VMS, de Bruin PFC. Effect of melatonin administration on subjective sleep quality in chronic obstructive pulmonary disease. Braz J Med Biol Res. 2008;41:926–31.PubMedGoogle Scholar
  101. 101.
    O’Callaghan FJ, Clarke AA, Hancock E, Hunt A, Osborne JP. Use of melatonin to treat sleep disorders in tuberous sclerosis. Dev Med Child Neurol. 1999;41(2):123–6.PubMedGoogle Scholar
  102. 102.
    Roth T, Nir T, Zisapel N. Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial. Nat Sci Sleep. 2015;7:13–23.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Scheer FAJL, Morris CJ, Garcia JI, Smales C, Kelly EE, Marks J, et al. Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. Sleep. 2012;35(10):1395–402.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Serfaty MA, Osborne D, Buszewicz MJ, Blizard R, Raven PW. A randomized double-blind placebo-controlled trial of treatment as usual plus exogenous slow-release melatonin (6 mg) or placebo for sleep disturbance and depressed mood. Int Clin Psychopharmacol. 2010;25(3):132–42.PubMedGoogle Scholar
  105. 105.
    Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, et al. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med. 2018;15(6):e1002587.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol. 2001;16(2):86–92.PubMedGoogle Scholar
  107. 107.
    Van der Heijden KB, Smits MG, Van Someren EJW, Ridderinkhof KR, Gunning WB. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry. 2007;46(2):233–41.PubMedGoogle Scholar
  108. 108.
    van Geijlswijk IM, van der Heijden KB, Egberts ACG, Korzilius HPLM, Smits MG. Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT. Psychopharmacology. 2010;212(3):379–91.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin. 2007;23(10):2597–605.PubMedGoogle Scholar
  110. 110.
    Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, 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.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Wade AG, Farmer M, Harari G, Fund N, Laudon M, Nir T, et al. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 2014;9:947–61.Google Scholar
  112. 112.
    Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008;44(1):57–64.PubMedGoogle Scholar
  113. 113.
    Wirojanan J, Jacquemont S, Diaz R, Bacalman S, Anders TF, Hagerman RJ, et al. The efficacy of melatonin for sleep problems in children with autism, fragile x syndrome, or autism and fragile x syndrome. J Clin Sleep Med. 2009;5(2):145–50.PubMedPubMedCentralGoogle Scholar
  114. 114.
    De Leersnyder H, Bresson J, de Blois MC, Souberbielle J, Mogenet A, Delhotal-Landes B, et al. ß(1)-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J Med Genet. 2003;40(1):74–8.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord. 2006;36(6):741–52.PubMedGoogle Scholar
  116. 116.
    Hoebert M, van der Heijden KB, Van Geijlswijk IM, Smits MG. Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia. J Pineal Res. 2009;47(1):1–7.PubMedGoogle Scholar
  117. 117.
    Jan MMS. Melatonin for the treatment of handicapped children with severe sleep disorders. Pediatr Neurol. 2000;23(3):229–32.PubMedGoogle Scholar
  118. 118.
    Lemoine P, Garfinkel D, Laudon M, Nir T, Zisapel N. Prolonged-release melatonin for insomnia—an open-label long-term study of efficacy, safety, and withdrawal. Ther Clin Risk Manag. 2011;7:301–11.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Maras A, Schroder CM, Malow BA, Findling RL, Breddy J, Nir T, et al. Long-term efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Child Adolesc Psychopharmacol. 2018;28(10):699–710.PubMedCentralGoogle Scholar
  120. 120.
    Nagtegaal J, Smits M, Van Der Meer Y, Fischer-Steenvoorden M. Melatonin: a survey of suspected adverse drug reactions. Sleep Wake Res Nether. 1996;7:115–8.Google Scholar
  121. 121.
    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):319–25.PubMedGoogle Scholar
  122. 122.
    Tomoda A, Miike T, Iwatani N, Ninomiya T, Mabe H, Kageshita T, et al. Effect of long-term melatonin administration on school-phobic children and adolescents with sleep disturbances. Curr Ther Res. 1999;60(11):607–12.Google Scholar
  123. 123.
    van Geijlswijk IM, Mol RH, Egberts TC, Smits MG. Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Psychopharmacology. 2011;216(1):111–20.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Zwart TC, Smits MG, Egberts TCG, Rademaker CMA, van Geijlswijk IM. Long-term melatonin therapy for adolescents and young adults with chronic sleep onset insomnia and late melatonin onset: evaluation of sleep quality, chronotype, and lifestyle factors compared to age-related randomly selected population cohorts. Healthcare. 2018;6(1):23.PubMedCentralGoogle Scholar
  125. 125.
    Hajak G, Lemme K, Zisapel N. Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. Int Clin Psychopharmacol. 2015;30(1):36–42.PubMedGoogle Scholar
  126. 126.
    Jones C, Huyton M, Hindley D. Melatonin and epilepsy. Arch Dis Child. 2005;90(11):1203.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet. 1998;351(9111):1254.PubMedGoogle Scholar
  128. 128.
    Nordlund JJ, Lerner AB. The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. 1977;45(4):768–74.PubMedGoogle Scholar
  129. 129.
    Webley GE, Böhle A, Leidenberger FA. Positive relationship between the nocturnal concentrations of melatonin and prolactin, and a stimulation of prolactin after melatonin administration in young men. J Pineal Res. 1988;5(1):19–33.PubMedGoogle Scholar
  130. 130.
    Wright J, Aldhous M, Franey C, English J, Arendt J. The effects of exogenous melatonin on endocrine function in man. Clin Endocrinol. 1986;24(4):375–82.Google Scholar
  131. 131.
    Voordouw BC, Euser R, Verdonk RE, Alberda BT, de Jong FH, Drogendijk AC, et al. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab. 1992;74(1):108–17.PubMedGoogle Scholar
  132. 132.
    Garaulet M, Gómez-Abellán P, Rubio-Sastre P, Madrid JA, Saxena R, Scheer FAJL. Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism. 2015;64(12):1650–7.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Rubio-Sastre P, Scheer FAJL, Gómez-Abellán P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep. 2014;37(10):1715–9.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, et al. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol. 2001;54(3):339–46.Google Scholar
  135. 135.
    Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol. 2000;49(5):423–7.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Rechciński T, Trzos E, Wierzbowska-Drabik K, Krzemińska-Pakuła M, Kurpesa M. Melatonin for nondippers with coronary artery disease: assessment of blood pressure profile and heart rate variability. Hypertens Res. 2010;33(1):56–61.PubMedGoogle Scholar
  137. 137.
    Baandrup L, Lindschou J, Winkel P, Gluud C, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: a randomised, placebo-controlled, blinded trial. World J Biol Psychiatry. 2016;17(7):514–24.PubMedGoogle Scholar
  138. 138.
    Goyal A, Terry PD, Superak HM, Nell-Dybdahl CL, Chowdhury R, Phillips LS, et al. Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial. Diabetol Metab Syndr. 2014;6:124.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Hansen MV, Andersen LT, Madsen MT, Hageman I, Rasmussen LS, Bokmand S, et al. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2014;145(3):683–95.PubMedGoogle Scholar
  140. 140.
    Suhner A, Schlagenhauf P, Tschopp A, Hauri-Bionda R, Friedrich-Koch A, Steffen R. Impact of melatonin on driving performance. J Travel Med. 1998;5(1):7–13.PubMedGoogle Scholar
  141. 141.
    Ashrafi MR, Mohammadi M, Tafarroji J, Shabanian R, Salamati P, Zamani GR. Melatonin versus chloral hydrate for recording sleep EEG. Eur J Paediatric Neurol. 2010;14(3):235–8.Google Scholar
  142. 142.
    Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms. 1997;12(6):604–17.PubMedGoogle Scholar
  143. 143.
    Costello RB, Lentino CV, Boyd CC, O’Connell ML, Crawford CC, Sprengel ML, et al. The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature. Nutr J. 2014;13:106.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Phillips L, Appleton RE. Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. Dev Med Child Neurol. 2004;46(11):771–5.PubMedGoogle Scholar
  145. 145.
    Crowley SJ, Eastman CI. Melatonin in the afternoons of a gradually advancing sleep schedule enhances the circadian rhythm phase advance. Psychopharmacology. 2013;225(4):825–37.PubMedGoogle Scholar
  146. 146.
    Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA. 1994;91(5):1824–8.PubMedGoogle Scholar
  147. 147.
    Graw P, Werth E, Krauchi K, Gutzwiller F, Cajochen C, Wirz-Justice A. Early morning melatonin administration impairs psychomotor vigilance. Behav Brain Res. 2001;121(1–2):167–72.PubMedGoogle Scholar
  148. 148.
    Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007;16(4):372–80.PubMedGoogle Scholar
  149. 149.
    Otmani S, Demazières A, Staner C, Jacob N, Nir T, Zisapel N, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Human Psychopharmacol Clin Exp. 2008;23(8):693–705.Google Scholar
  150. 150.
    Carman JS, Post RM, Buswell R, Goodwin FK. Negative effects of melatonin on depression. Am J Psychiatry. 1976;133(10):1181–6.PubMedGoogle Scholar
  151. 151.
    Seabra MdLV, Bignotto M, Pinto Jr LR, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29(4):193–200.PubMedGoogle Scholar
  152. 152.
    Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WG, Van Someren EW. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008;299(22):2642–55.PubMedGoogle Scholar
  153. 153.
    Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci. 2000;25(1):48–52.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Weiss MD, Wasdell MB, Bomben MM, Rea KJ, Freeman RD. Sleep hygiene and melatonin treatment for children and adolescents with adhd and initial insomnia. J Am Acad Child Adolesc Psychiatry. 2006;45(5):512–9.PubMedGoogle Scholar
  155. 155.
    Carvalho LA, Gorenstein C, Moreno R, Pariante C, Markus RP. Effect of antidepressants on melatonin metabolite in depressed patients. J Psychopharmacol. 2009;23(3):315–21.PubMedGoogle Scholar
  156. 156.
    Childs PA, Rodin I, Martin NJ, Allen NH, Plaskett L, Smythe PJ, et al. Effect of fluoxetine on melatonin in patients with seasonal affective disorder and matched controls. Br J Psychiatry. 1995;166(2):196–8.PubMedGoogle Scholar
  157. 157.
    Härtter S, Wang X, Weigmann H, Friedberg T, Arand M, Oesch F, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol. 2001;21(2):167–74.PubMedGoogle Scholar
  158. 158.
    Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine and norfluoxetine mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19 and CYP3A4. Clin Pharmacol Ther. 2014;95(6):653–62.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Dowling GA, Burr RL, Van Someren EJW, Hubbard EM, Luxenberg JS, Mastick J, et al. Melatonin and bright-light treatment for rest–activity disruption in institutionalized patients with alzheimer’s disease. J Am Geriatr Soc. 2008;56(2):239–46.PubMedGoogle Scholar
  160. 160.
    Härtter S, Grözinger M, Weigmann H, Röschke J, Hiemke C. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther. 2000;67(1):1–6.PubMedGoogle Scholar
  161. 161.
    Härtter S, Nordmark A, Rose D-M, Bertilsson L, Tybring G, Laine K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br J Clin Pharmacol. 2003;56(6):679–82.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Hilli J, Korhonen T, Turpeinen M, Hokkanen J, Mattila S, Laine K. The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2g.-163C>A polymorphism. J Clin Pharmacol. 2008;48(8):986–94.PubMedGoogle Scholar
  163. 163.
    Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vascular Health Risk Manag. 2011;7:577–84.Google Scholar
  164. 164.
    McGrane IR, Leung JG, St. Louis EK, Boeve BF. Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. Sleep Med. 2014;16(1):19–26.PubMedGoogle Scholar
  165. 165.
    Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol. 2011;53(9):783–92.PubMedGoogle Scholar
  166. 166.
    Foster BC, Cvijovic K, Boon HS, Tam TW, Liu R, Murty M, et al. Melatonin interaction resulting in severe sedation. J Pharm Pharm Sci. 2015;18(2):124–31.PubMedGoogle Scholar
  167. 167.
    Skene D, Bojkowski C, Arendt J. Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans. Br J Clin Pharmacol. 1994;37(2):181–6.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Monteleone P, Tortorella A, Borriello R, Natale M, Cassandro P, Maj M. Suppression of nocturnal plasma melatonin levels by evening administration of sodium valproate in healthy humans. Biol Psychiat. 1997;41(3):336–41.PubMedGoogle Scholar
  169. 169.
    McIntyre IM, Norman TR, Burrows GD, Armstrong SM. Alterations to plasma melatonin and cortisol after evening alprazolam administration in humans. Chronobiol Int. 1993;10(3):205–13.PubMedGoogle Scholar
  170. 170.
    National Institute for Health and Care Excellence (NICE). Melatonin (interactions). 2019. http://bnf.nice.org.uk/interaction/melatonin-2.html. Cited 04 Oct 2019.Google Scholar
  171. 171.
    Waldhauser F, Boepple PA, Schemper M, Mansfield MJ, Crowley WF Jr. Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children*. J Clin Endocrinol Metab. 1991;73(4):793–6.PubMedGoogle Scholar
  172. 172.
    Kolata G. Puberty mystery solved. Science. 1984;223:272–3.PubMedGoogle Scholar
  173. 173.
    Kocher L, Lornage J, Claustrat B. Persistence of fertility despite semen alterations in a pinealectomised patient treated with melatonin. Neuroendocrinol Lett. 2013;34(8):763–6.PubMedGoogle Scholar
  174. 174.
    Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P. Melatonin administration alters semen quality in healthy men. J Androl. 2002;23(4):572–83.PubMedGoogle Scholar
  175. 175.
    Valcavi R, Zini M, Maestroni GJ, Conti A, Portioli I. Melatonin stimulates growth hormone secretion through pathways other than the growth hormone-releasing hormone. Clin Endocrinol. 1993;39(2):193–9.Google Scholar
  176. 176.
    Forsling ML, Wheeler MJ, Williams AJ. The effect of melatonin administration on pituitary hormone secretion in man. Clin Endocrinol. 1999;51(5):637–42.Google Scholar
  177. 177.
    Luboshitzky R, Shen-Orr Z, Shochat T, Herer P, Lavie P. Melatonin administered in the afternoon decreases next-day luteinizing hormone levels in men. J Mol Neurosci. 1999;12(1):75–80.PubMedGoogle Scholar
  178. 178.
    Kripke DF, Kline LE, Shadan FF, Dawson A, Poceta JS, Elliott JA. Melatonin effects on luteinizing hormone in postmenopausal women: a pilot clinical trial NCT00288262. BMC Women’s Health. 2006;6:8.PubMedPubMedCentralGoogle Scholar
  179. 179.
    Bellipanni G, Bianchi P, Pierpaoli W, Bulian D, Ilyia E. Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study. Exp Gerontol. 2001;36(2):297–310.PubMedGoogle Scholar
  180. 180.
    Waldhauser F, Lieberman HJ, Frisch H, Herckner K, Crowley WF, Wurtman RJ. Melatonin does not alter human serum gondotropin and testosterone levels, but it increases prolactin levels. Pediatr Res. 1984;18(11):1228.Google Scholar
  181. 181.
    Waldhauser F, Lieberman HR, Lynch HJ, Waldhauser M, Herkner K, Frisch H, et al. A pharmacological dose of melatonin increases prl levels in males without altering those of GH, LH, FSH, TSH. Testosterone Cortisol Neuroendocrinol. 1987;46(2):125–30.Google Scholar
  182. 182.
    Mauri R, Lissoni P, Resentini M, De Medici C, Morabito F, Djemal S, et al. Effects of melatonin on PRL secretion during different photoperiods of the day in prepubertal and pubertal healthy subjects. J Endocrinol Invest. 1985;8(4):337–41.PubMedGoogle Scholar
  183. 183.
    Lisoni P, Resentini M, Mauri R, De Medici C, Morabito F, Esposti D, et al. Effect of an acute injection of melatonin on the basal secretion of hypophyseal hormones in prepubertal and pubertal healthy subjects. Acta Endocrinol. 1986;111(3):305–11.PubMedGoogle Scholar
  184. 184.
    Mallo C, Zaidan R, Faure A, Brun J, Chazot G, Claustrat B. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol. 1988;119(4):474–80.PubMedGoogle Scholar
  185. 185.
    Piovesan A, Terzolo M, Revelli A, Guidetti D, Puligheddu B, Codegone A, et al. Sex-related effects of exogenous melatonin on the pulsatile secretion of prolactin, TSH and LH in healthy human subjects. In: Touitou Y, Arendt J, Pevet P, editors. Melatonin and the pineal gland, from basic science to clinical application: proceedings of the international symposium on melatonin and the pineal gland: from basic science to clinical application, Paris, 6–9 September 1992. New York: Excerpta Medica Amsterdam; 1993. p. 355–8Google Scholar
  186. 186.
    Sutherland ER, Ellison MC, Kraft M, Martin RJ. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol. 2003;112(3):513–7.PubMedGoogle Scholar
  187. 187.
    Sutherland ER, Martin RJ, Ellison MC, Kraft M. Immunomodulatory effects of melatonin in asthma. Am J Respir Crit Care Med. 2002;166(8):1055–61.PubMedGoogle Scholar
  188. 188.
    Andersen IM, Kaczmarska J, McGrew SG, Malow BA. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol. 2008;23(5):482–5.PubMedGoogle Scholar
  189. 189.
    Carr R, Wasdell MB, Hamilton D, Weiss MD, Freeman RD, Tai J, et al. Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. J Pineal Res. 2007;43(4):351–9.PubMedGoogle Scholar
  190. 190.
    Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res. 2000;29(1):34–9.PubMedGoogle Scholar
  191. 191.
    Elkhayat HA, Hassanein SM, Tomoum HY, Abd-Elhamid IA, Asaad T, Elwakkad AS. Melatonin and sleep-related problems in children with intractable epilepsy. Pediatr Neurol. 2010;42(4):249–54.PubMedGoogle Scholar
  192. 192.
    Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in children with severe neurologic deficit disorders. Epilepsia. 2001;42(9):1208–10.PubMedGoogle Scholar
  193. 193.
    Ross C, Davies P, Whitehouse W. Melatonin treatment for sleep disorders in children with neurodevelopmental disorders: an observational study. Dev Med Child Neurol. 2002;44(5):339–44.PubMedGoogle Scholar
  194. 194.
    Bojkowski CJ, Arendt J, Shih MC, Markey SP. Melatonin secretion in humans assessed by measuring its metabolite, 6-sulfatoxymelatonin. Clin Chem. 1987;33(8):1343–8.PubMedGoogle Scholar
  195. 195.
    Sadeh A. Sleep and melatonin in infants: a preliminary study. Sleep. 1997;20(3):185–91.PubMedGoogle Scholar
  196. 196.
    Waldhauser F, Frisch H, Waldhauser M, Weiszenbacher G, Zeitlhuber U, Wurtman R. Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet. 1984;323(8373):362–5.Google Scholar
  197. 197.
    Puig-Domingo M, Webb SM, Serrano J, Peinado M-A, Corcoy R, Ruscalleda J, et al. Melatonin-related hypogonadotropic hypogonadism. N Engl J Med. 1992;327(19):1356–9.PubMedGoogle Scholar
  198. 198.
    Jain S, Besag FM. Does melatonin affect epileptic seizures? Drug Saf. 2013;36(4):207–15.PubMedGoogle Scholar
  199. 199.
    Bazil CW, Short D, Crispin D, Zheng W. Patients with intractable epilepsy have low melatonin, which increases following seizures. Neurology. 2000;55(11):1746–8.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Reiter RJ, Tan D-x, Leon J, Kilic Ü, Kilic E. When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med. 2005;230(2):104–17.PubMedGoogle Scholar
  201. 201.
    Samantaray S, Das A, Thakore NP, Matzelle DD, Reiter RJ, Ray SK, et al. Therapeutic potential of melatonin in traumatic central nervous system injury. J Pineal Res. 2009;47(2):134–42.PubMedGoogle Scholar
  202. 202.
    Ardura J, Andres J, Garmendia JR, Ardura F. Melatonin in epilepsy and febrile seizures. J Child Neurol. 2010;25(7):888–91.PubMedGoogle Scholar
  203. 203.
    Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol. 1994;36(2):97–107.PubMedGoogle Scholar
  204. 204.
    Jan JE, O’Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res. 1996;21(4):193–9.PubMedGoogle Scholar
  205. 205.
    Mason TBA, Arens R, Sharman J, Bintliff-Janisak B, Schultz B, Walters AS, et al. Sleep in children with Williams Syndrome. Sleep Med. 2011;12(9):892–7.PubMedPubMedCentralGoogle Scholar
  206. 206.
    Molina-Carballo A, Muñoz-Hoyos A, Reiter RJ, Sánchez-Forte M, Moreno-Madrid F, Rufo-Campos M, et al. Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: two years’ experience. J Pineal Res. 1997;23(2):97–105.PubMedGoogle Scholar
  207. 207.
    Brigo F, Igwe SC, Del Felice A. Melatonin as add-on treatment for epilepsy. Cochrane Database Syst Rev. 2016.  https://doi.org/10.1002/14651858.CD006967.pub4 CrossRefPubMedGoogle Scholar
  208. 208.
    Woolfenden SUE, Sarkozy V, Ridley G, Coory M, Williams K. A systematic review of two outcomes in autism spectrum disorder–epilepsy and mortality. Dev Med Child Neurol. 2012;54(4):306–12.PubMedGoogle Scholar
  209. 209.
    Goldberg-Stern H, Oren H, Peled N, Garty B-Z. Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study. J Child Neurol. 2012;27(12):1524–8.PubMedGoogle Scholar
  210. 210.
    Waldhauser F, Gisinger B, Tatzer E, Weiszenbacher G, Frisch H, Schemper M, et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging*. J Clin Endocrinol Metab. 1988;66(3):648–52.PubMedGoogle Scholar
  211. 211.
    Cavallo A. Plasma melatonin rhythm in normal puberty: interactions of age and pubertal stages. Neuroendocrinology. 1992;55(4):372–9.PubMedGoogle Scholar
  212. 212.
    Cavallo A, Ritschel WA. Pharmacokinetics of melatonin in human sexual maturation. J Clin Endocrinol Metab. 1996;81(5):1882–6.PubMedGoogle Scholar
  213. 213.
    Cavallo A, Dolan LM. 6-Hydroxymelatonin sulfate excretion in human puberty. J Pineal Res. 1996;21(4):225–30.PubMedGoogle Scholar
  214. 214.
    Commentz JC, Uhlig H, Henke A, Hellwege HH, Willig RP. Melatonin and 6-hydroxymelatonin sulfate excretion is inversely correlated with gonadal development in children. Hormone Res Paediatr. 1997;47(3):97–101.Google Scholar
  215. 215.
    Crowley SJ, Acebo C, Carskadon MA. Human puberty: salivary melatonin profiles in constant conditions. Dev Psychobiol. 2012;54(4):468–73.PubMedGoogle Scholar
  216. 216.
    Cavallo A. Melatonin and human puberty: current perspectives. J Pineal Res. 1993;15(3):115–21.PubMedGoogle Scholar
  217. 217.
    Berga SL, Mortola JF, Yen SSC. Amplification of nocturnal melatonin secretion in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1988;66(1):242–4.PubMedGoogle Scholar
  218. 218.
    Brzezinski A, Lynch HJ, Seibel MM, Deng MH, Nader TM, Wurtman RJ. The circadian rhythm of plasma melatonin during the normal menstrual cycle and in amenorrheic women*. J Clin Endocrinol Metab. 1988;66(5):891–5.PubMedGoogle Scholar
  219. 219.
    Arendt J. Safety of melatonin in long-term use. J Biol Rhythms. 1997;12(6):673–81.PubMedGoogle Scholar
  220. 220.
    Roy D, Belsham DD. Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GnRH neurons. Signal Transduct Mech J Biol Chem. 2002;277(1):251–8.Google Scholar
  221. 221.
    Szeinberg A, Borodkin K, Dagan Y. Melatonin treatment in adolescents with delayed sleep phase syndrome. Clin Pediatr. 2006;45(9):809–18.Google Scholar
  222. 222.
    Han S-K, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25(49):11349–56.PubMedPubMedCentralGoogle Scholar
  223. 223.
    Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351(2):152–66.PubMedPubMedCentralGoogle Scholar
  224. 224.
    Shi L, Li N, Bo L, Xu Z. Melatonin and hypothalamic-pituitary-gonadal axis. Curr Med Chem. 2013;20(15):2017–31.PubMedGoogle Scholar
  225. 225.
    Johnston JD, Skene DJ. 60 years of neuroendocrinology: regulation of mammalian neuroendocrine physiology and rhythms by melatonin. J Endocrinol. 2015;226(2):T187–98.PubMedGoogle Scholar
  226. 226.
    Luboshitzky R, Levi M, Shen-Orr Z, Blumenfeld Z, Herer P, Lavie P. Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men. Human Reprod. 2000;15(1):60–5.Google Scholar
  227. 227.
    Rajaratnam SMW, Dijk D-J, Middleton B, Stone BM, Arendt J. Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-hour production of reproductive hormones. J Clin Endocrinol Metab. 2003;88(9):4303–9.PubMedGoogle Scholar
  228. 228.
    Cagnacci A, Elliott JA, Yen SSC. Amplification of pulsatile LH secretion by exogenous melatonin in women. J Clin Endocrinol Metab. 1991;73(1):210–2.PubMedGoogle Scholar
  229. 229.
    Siegrist C, Benedetti C, Orlando A, Beltrán JM, Tuchscherr L, Noseda CMJ, et al. Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. J Pineal Res. 2001;30(1):34–42.PubMedGoogle Scholar
  230. 230.
    Corbalán-Tutau D, Madrid JA, Nicolás F, Garaulet M. Daily profile in two circadian markers “melatonin and cortisol” and associations with metabolic syndrome components. Physiol Behav. 2014;123:231–5.PubMedGoogle Scholar
  231. 231.
    Mäntele S, Otway DT, Middleton B, Bretschneider S, Wright J, Robertson MD, et al. Daily rhythms of plasma melatonin, but not plasma leptin or leptin mRNA, vary between lean, obese and type 2 diabetic men. PLoS One. 2012;7(5):e37123.PubMedPubMedCentralGoogle Scholar
  232. 232.
    Nagorny C, Lyssenko V. Tired of diabetes genetics? Circadian rhythms and diabetes: the MTNR1B story. Curr DiabRep. 2012;12(6):667–72.Google Scholar
  233. 233.
    Robeva R, Kirilov G, Tomova A, Kumanov P. Melatonin–insulin interactions in patients with metabolic syndrome. J Pineal Res. 2008;44(1):52–6.PubMedGoogle Scholar
  234. 234.
    McMullan CJ, Curhan GC, Schernhammer ES, Forman JP. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. Am J Epidemiol. 2013;178(2):231–8.PubMedPubMedCentralGoogle Scholar
  235. 235.
    Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2008;41:77.PubMedPubMedCentralGoogle Scholar
  236. 236.
    Tam CHT, Ho JSK, Wang Y, Lee HM, Lam VKL, Germer S, et al. Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects. PLoS One. 2010;5(7):e11428.PubMedPubMedCentralGoogle Scholar
  237. 237.
    Müssig K, Staiger H, Machicao F, Häring H-U, Fritsche A. Genetic variants in MTNR1B affecting insulin secretion. Ann Med. 2010;42(6):387–93.PubMedGoogle Scholar
  238. 238.
    Bruderman I, Rahamimoff R. Alterations in tracheobronchial smooth muscle activity following melatonin. J Appl Physiol. 1967;23(6):938–43.PubMedGoogle Scholar
  239. 239.
    Doolen S, Krause DN, Dubocovich ML, Duckles SP. Melatonin mediates two distinct responses in vascular smooth muscle. Eur J Pharmacol. 1998;345(1):67–9.PubMedGoogle Scholar
  240. 240.
    Conti A, Maestroni GJM. The clinical neuroimmunotherapeutic role of melatonin in oncology. J Pineal Res. 1995;19(3):103–10.PubMedGoogle Scholar
  241. 241.
    Zhang Z, Inserra PF, Liang B, Ardestani SK, Elliott KK, Molitor M, et al. Melatonin, immune modulation and aging. Autoimmunity. 1997;26(1):43–53.PubMedGoogle Scholar
  242. 242.
    Maksoud A, Moore C, Harshkowitz M. The effect of melatonin administration on patients with sleep apnea. Sleep Res. 1997;26:114.Google Scholar
  243. 243.
    Hong YG, Riegler JL. Is Melatonin associated with the development of autoimmune hepatitis? J Clin Gastroenterol. 1997;25(1):376–8.PubMedGoogle Scholar
  244. 244.
    Erden S. Hypothermia associated with melatonin ingestion in a child with autism. Clin Neuropharmacol. 2019;42(5):179–80.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.East London Foundation NHS TrustBedfordUK
  2. 2.University College LondonLondonUK
  3. 3.King’s College LondonLondonUK
  4. 4.Department of Pharmacology and PharmacyUniversity of Hong KongPok Fu LamHong Kong
  5. 5.BedfordUK

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