Melatonin
Melatonin is an endogenous hormone and indoleamine compound naturally produced by the pineal gland in response to darkness, regulating sleep-wake cycles and circadian rhythms.12 First isolated and characterized by Aaron B. Lerner in 1958,1 it is widely available as an over-the-counter supplement for treating insomnia and promoting healthier sleep patterns.3 Beyond sleep regulation, melatonin functions as an antioxidant and influences mood, seasonal rhythms, and immune activity.24
Contents
Dosage & Duration
Dosage
Supplement products are available across a wide range, from 0.3 mg to 10 mg or more, and a prolonged-release 2 mg oral formulation is used medically. Doses of roughly 2-10 mg have been explored for circadian rhythm disruption such as jet lag; relatively large doses of 75-80 mg have been described as producing a more pronounced soporific effect. Administration after eating slows absorption and lowers peak concentrations. Alcohol may reduce the effects.
Duration
Subjective Effects
Melatonin produces a subtle shift toward sleepiness rather than a distinct intoxication, and at typical low doses it is often indistinguishable from placebo. Its primary action is to shorten the time taken to fall asleep rather than to sedate outright, and it is described as a sleep catalyst at modest doses that only becomes genuinely soporific at much larger ones. Reports from recreational contexts note that it is not particularly hypnotic when used to close out a drug experience. Residual drowsiness can carry into the following day, though large doses have been described as producing increased total sleep without hangover.
Physical
The dominant physical effect is drowsiness accompanied by a lowering of body temperature; headache, dizziness, mild tremor, abdominal cramps, and nausea are also reported.
Uncomfortable
Cognitive
Reduced alertness, confusion, and mild anxiety have been reported, alongside transient depressive symptoms and irritability.
Emotional
Impairment
Reagent Testing
Loading reagent data
Pharmacology
Pharmacodynamics
Melatonin acts as a potent full agonist at melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2), both G protein-coupled receptors of the Gi/o subtype, with MT1 also exhibiting Gq coupling.5 MT1 receptor activation inhibits adenylyl cyclase, reducing cyclic AMP formation and downstream protein kinase A activity,6 while also activating phospholipase C and modulating ion channel flux.5 MT2 receptor activation similarly inhibits adenylyl cyclase and guanylyl cyclase while increasing protein kinase C activity.6 These receptors are expressed throughout the central nervous system, including the suprachiasmatic nucleus responsible for circadian rhythm regulation, as well as in peripheral tissues including the retina, cardiovascular system, and immune cells.6
Beyond receptor-mediated effects, melatonin functions as a high-capacity free radical scavenger within mitochondria, directly neutralizing reactive oxygen and nitrogen species while promoting expression of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and catalase through receptor-triggered signal transduction pathways.7
Pharmacokinetics
Melatonin absorption and bioavailability vary widely between individuals.1 It is hepatically metabolized primarily by CYP1A2, with lesser contributions from CYP1A1, CYP2C19, and CYP1B1. The primary metabolic pathway transforms melatonin into 6-hydroxymelatonin, which is then conjugated with sulfate or glucuronide and excreted in urine.1 Immediate-release formulations cause blood levels to peak in approximately one hour.1
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Harm Potential
Addiction & Dependence
Toxicity
Psychosis Risk
Transient mild anxiety, confusion, and irritability have been reported as uncommon side effects,9 but these occur at similar frequencies to placebo. No psychotic episodes have been documented.
History & Culture
Discovery and Isolation
The discovery of melatonin traces back to early twentieth-century research on skin pigmentation in amphibians. In 1917, Carey Pratt McCord and Floyd P. Allen observed that feeding extracts from bovine pineal glands to tadpoles caused their skin to lighten through contraction of dark epidermal…
Legality
By Country
References
Source Pages
Citations
- (n.d.). Melatonin: Pharmacology, Functions and Therapeutic Benefits. https://pmc.ncbi.nlm.nih.gov/articles/PMC5405617/123456
- (n.d.). Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders. https://pmc.ncbi.nlm.nih.gov/articles/PMC9907215/12
- (n.d.). Pediatric Melatonin Ingestions — United States, 2012–2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC9169525/1
- (n.d.). Melatonin: Buffering the Immune System. https://pmc.ncbi.nlm.nih.gov/articles/PMC3645767/1
- (n.d.). Update on melatonin receptors: IUPHAR Review 20. https://pmc.ncbi.nlm.nih.gov/articles/PMC4995287/12
- (n.d.). MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. https://pmc.ncbi.nlm.nih.gov/articles/PMC5091650/123
- (n.d.). Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions. https://pmc.ncbi.nlm.nih.gov/articles/PMC6017324/1
- (n.d.). New approaches in the management of insomnia: weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists. https://pmc.ncbi.nlm.nih.gov/articles/PMC2699659/1
- (n.d.). Chronic Administration of Melatonin: Physiological and Clinical Considerations. https://pmc.ncbi.nlm.nih.gov/articles/PMC10053496/12
- (n.d.). Melatonin and 6-hydroxymelatonin sulfate excretion is inversely correlated with gonadal development in children. https://pubmed.ncbi.nlm.nih.gov/9050947/1
- (n.d.). Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician's perspective. https://pmc.ncbi.nlm.nih.gov/articles/PMC6362935/12
- (January 1917). Evidences associating pineal gland function with alterations in pigmentation. J Exp Zool, 23(1), 206–24. https://doi.org/10.1002/jez.14002301081
- (December 1948). Serum vasoconstrictor, serotonin; isolation and characterization. The Journal of Biological Chemistry, 176(3), 1243–1251. https://doi.org/10.1016/s0021-9258(18)57137-41
- (January 1975). Daily rhythm in human urinary melatonin. Science, 187(4172), 169–71. https://doi.org/10.1126/science.11674251
- Richard J. Wurtman. (September 12, 1995). Methods of inducing sleep using melatonin. USPTO. https://patents.google.com/patent/US5449683A/en12
- (January 2012). Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. Journal of Experimental Botany, 63(2), 577–97. https://doi.org/10.1093/jxb/err25612
- Aaron B. Lerner, James D. Case, Yoshiyata Takahashi, Teh H. Lee, & Wataru Mori. (1958). Isolation of melatonin, the pineal gland factor that lightens melanocytes. Journal of the American Chemical Society, 80(10), 2587. https://doi.org/10.1021/ja01543a0601
- (n.d.). Circadin 2 mg Prolonged-release Tablets – Summary of Product Characteristics (SmPC). https://www.medicines.org.uk/emc/product/2809/smpc12
- (n.d.). Melatonin: What You Need To Know – National Center for Complementary and Integrative Health (NIH). https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know1234
Further Reading
Automated synthesisInformation aggregated and synthesized using an autonomous workflow built by Josie Kins.
Suggest an edit
Spotted a mistake, an outdated claim, or something missing from the Melatonin article? Send the editors a private note. Feedback lands in a moderation queue and is never shown on the site.