Melatonin is a hormone produced by the pineal gland that has multiple effects including somnolence, and is believed to play a role in regulation of the sleep-wake cycle. Melatonin is available over-the-counter and is reported to have beneficial effects on wellbeing and sleep. Melatonin has not been implicated in causing serum enzyme elevations or clinically apparent liver injury.


Melatonin is a small molecular weight amine (N-actyl-5-methoxytryptamine) synthesized in the pineal gland from serotonin (5-HT). Melatonin is released into the circulation in a circadian pattern, the plasma levels being low during the day and high at night. In persons with normal sleep-wake patterns, peak melatonin values are present between 2:00 am and 4:00 am and drop before light onset in the morning. Melatonin acts by engagement of melatonin receptors (MT-1 and MT-2) causing a reduction of body temperature and alternation of brain monoamine levels, which can induce somnolence. Melatonin also has potent antioxidant activity and may have reproductive effects and modulate immune reactions. Melatonin has been proposed as therapy of sleep disturbances including insomnia and jet lag, but it has not been approved for this or any other indication in the United States. Melatonin is considered a nutritional supplement and is available over-the-counter in multiple generic forms and formulations. Melatonin is also found in many herbal and nutrition supplement mixtures. A common dose is 10 mg once daily, taken orally one to three hours before sleep time. Side effects are few but may include daytime somnolence, dizziness, headache and nausea.


In several clinical trials, melatonin was found to be well tolerated and not associated with serum enzyme elevations or evidence of liver injury. Despite wide scale use, melatonin has not been convincingly linked to instances of clinically apparent liver injury.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Drug Class: Herbal and Dietary Supplements; Sedatives and Hypnotics

Other Drugs in the Subclass, Melatonin and its Analogues: Ramelteon, Tasimelteon



Melatonin – Generic, In Combination


Herbals and Dietary Supplements

Sedatives and Hypnotics


Fact Sheet at National Center for Complementary and Integrative Health



References updated: 10 January 2020

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    (Review of hepatotoxicity of herbal and dietary supplements [HDS] does not mention melatonin).
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    (Discussion of potential side effects and toxicities of melatonin, most of which relate to alteration in circadian rhythms; ALT elevations and hepatotoxicity are not mentioned).
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    (Potential long term adverse effects of melatonin include inhibition of reproductive function, delayed puberty and effects on circadian rhythm none of which have proven to be a problem).
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    (Controlled trial of melatonin [10 mg daily] vs placebo for 28 days in 40 volunteers found no changes or abnormalities of serum bilirubin, ALT, AST or Alk P during the 4 weeks of treatment).
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    (Systematic review of literature on efficacy and safety of melatonin for sleep disorders; in 9 randomized controlled trials there was no overall evidence of benefit; in 10 studies evaluating safety, there was no evidence of adverse effects occurring more often than with placebo with use limited to 3 months).
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  • 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. 2011;4:307–13. [PMC free article: PMC3160855] [PubMed: 21887103]
    (Controlled 3 week cross over trial of a prolonged release melatonin in 36 diabetic patients with insomnia; no serious adverse events reported and no mention of ALT levels or liver injury).
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    (Review of 3 randomized controlled trials of prolonged release melatonin for insomnia in older patients with hypertension found rate of adverse events lower in treated than placebo subjects; "hepatobiliary disorders" were reported in 15 of 1834 [0.8%] patients on melatonin versus 4 of 1558 [0.2%] receiving placebo, but no details given).
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    (Guidelines for therapy of insomnia; mentions that melatonin has been "reported to be effective in some patients with insomnia" when taken 3-5 hours before desired time to sleep, but not when taken at bedtime; the hypnotic dose and purity of melatonin available as dietary supplements have not been established).
  • Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016;36:169–75. [PubMed: 26692007]
    (Review of the safety of melatonin concludes that no studies of its use have reported serious adverse events and only mild events such as dizziness, headache, nausea and somnolence arose in short term trials; no mention of ALT elevations or hepatotoxicity despite “extensive biochemical testing” in some studies).
  • Drugs for chronic insomnia. Med Lett Drugs Ther. 2018;60(1562):201–5. [PubMed: 30625122]
    (Concise review of drugs used for insomnia mentions that melatonin has been reported to be effective “in some patients”; no mention of ALT elevations or hepatotoxicity).
  • Maras A, Schroder CM, Malow BA, Findling RL, Breddy J, Nir T, Shahmoon S, 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;28:699–710. [PMC free article: PMC6306655] [PubMed: 30132686]
    (Among 95 children with autism treated with prolonged release melatonin [2, 5 or 10 mg] or placebo once daily for 13 weeks followed by an open label period, there were no treatment related serious adverse events and no mention of ALT elevations or hepatotoxicity).
  • Madsen MT, Zahid JA, Hansen CH, Grummedal O, Hansen JR, Isbrand A, Andersen UO, et al. The effect of melatonin on depressive symptoms and anxiety in patients after acute coronary syndrome: The MEDACIS randomized clinical trial. J Psychiatr Res. 2019;119:84–94. [PubMed: 31586772]
    (Among 252 adults with acute coronary syndrome treated with melatonin [25 mg] or placebo once daily for 12 weeks, there were no differences in rates of depression or in adverse events in the two treatment groups).
  • 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. [PubMed: 30670284]
    (Systematic review of 50 randomized controlled trials found 26 articles reported no differences in rates of adverse events of melatonin compared to placebo and 24 with higher rates of minor and transient side effects with melatonin, usually drowsiness and fatigue; no mention of ALT elevations or hepatic adverse events).