Melatonin as a medication and supplement

An extended-release pharmaceutical formulation of melatonin is approved under the brand name Circadin for the treatment of insomnia in certain settings, such as in people over 55{{nbsp}}years of age.{{cite web | title=Circadin | website=ALZFORUM | date=9 October 2015 | url=https://www.alzforum.org/therapeutics/circadin | access-date=12 June 2025}}{{cite web | title=Melatonin controlled-release | website=AdisInsight | date=8 April 2025 | url=https://adisinsight.springer.com/drugs/800018177 | access-date=12 June 2025}} It is approved in the European Union, Israel, Australia, and countries in Asia and elsewhere in the world, but not in the United States (where it reached phase 3 trials but was not approved). The medication has been licensed since 2007.

The 2023 European Insomnia Guideline recommended use of prolonged-release melatonin for treatment of insomnia in people age 55 or older for up to 3{{nbsp}}months.{{cite journal | vauthors = Riemann D, Espie CA, Altena E, Arnardottir ES, Baglioni C, Bassetti CL, Bastien C, Berzina N, Bjorvatn B, Dikeos D, Dolenc Groselj L, Ellis JG, Garcia-Borreguero D, Geoffroy PA, Gjerstad M, Gonçalves M, Hertenstein E, Hoedlmoser K, Hion T, Holzinger B, Janku K, Jansson-Fröjmark M, Järnefelt H, Jernelöv S, Jennum PJ, Khachatryan S, Krone L, Kyle SD, Lancee J, Leger D, Lupusor A, Marques DR, Nissen C, Palagini L, Paunio T, Perogamvros L, Pevernagie D, Schabus M, Shochat T, Szentkiralyi A, Van Someren E, van Straten A, Wichniak A, Verbraecken J, Spiegelhalder K | title = The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023 | journal = J Sleep Res | volume = 32 | issue = 6 | pages = e14035 | date = December 2023 | pmid = 38016484 | doi = 10.1111/jsr.14035 | url = | hdl = 11250/3121742 | hdl-access = free }} It recommended against fast-release or over-the-counter melatonin for treatment of insomnia. These recommendations were based on several meta-analyses published in 2022 and 2023.

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of melatonin in the treatment of insomnia due to poor effectiveness and very low quality of evidence.{{cite journal | vauthors = Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL | title = Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline | journal = J Clin Sleep Med | volume = 13 | issue = 2 | pages = 307–349 | date = February 2017 | pmid = 27998379 | pmc = 5263087 | doi = 10.5664/jcsm.6470 | url = }}{{cite book |title=Pseudoscience in Therapy: A Skeptical Field Guide |veditors=Hupp S, Santa Maria CL |chapter=Chapter 10: Insomnia |vauthors=Carney CE, Lau PH, Kutana S|pages=147–148 |year=2023 |publisher=Cambridge University Press |isbn=9781009000611 |doi=10.1017/9781009000611.011 }}

Melatonin may be useful in the treatment of delayed sleep phase syndrome.

Melatonin is known to reduce jet lag, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.{{cite journal | vauthors = Herxheimer A, Petrie KJ | title = Melatonin for the prevention and treatment of jet lag | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001520 | year = 2002 | volume = 2010 | pmid = 12076414 | doi = 10.1002/14651858.CD001520 | pmc = 8958662 }}

Melatonin appears to have limited use against the sleep problems of people who work shift work.{{cite journal | vauthors = Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, Ruotsalainen JH | title = Pharmacological interventions for sleepiness and sleep disturbances caused by shift work | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 8 | pages = CD009776 | date = August 2014 | pmid = 25113164 | doi = 10.1002/14651858.CD009776.pub2 | pmc = 10025070 }} Tentative evidence suggests that it increases the length of time people are able to sleep.

Meta-analyses, published between 2005 and 2017, appear to show different results as to whether melatonin is effective for circadian rhythm sleep disorders or not.{{cite journal | vauthors = Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL | title = Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders | journal = Sleep Med Rev | volume = 34 | issue = | pages = 10–22 | date = August 2017 | pmid = 28648359 | doi = 10.1016/j.smrv.2016.06.005 | hdl = 20.500.11820/0e890bda-4b1d-4786-a907-a03b1580fd07 | hdl-access = free }}{{cite journal | vauthors = van Geijlswijk IM, Korzilius HP, Smits MG | title = The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis | journal = Sleep | volume = 33 | issue = 12 | pages = 1605–14 | date = December 2010 | pmid = 21120122 | pmc = 2982730 | doi = 10.1093/sleep/33.12.1605 | url = }}{{cite journal | vauthors = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–393 | date = February 2006 | pmid = 16473858 | pmc = 1370968 | doi = 10.1136/bmj.38731.532766.F6 | url = }}{{cite journal | vauthors = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S | title = The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis | journal = J Gen Intern Med | volume = 20 | issue = 12 | pages = 1151–1158 | date = December 2005 | pmid = 16423108 | pmc = 1490287 | doi = 10.1111/j.1525-1497.2005.0243.x | url = }} Some found that it was effective, while others found no evidence of effectiveness. Meta-analyses of melatonin for delayed sleep phase syndrome that found it effective have reported that it improves time to sleep onset by about 40{{nbsp}}minutes (0.67{{nbsp}}hours) and advances onset of endogenous melatonin secretion by about 1.2{{nbsp}}hours (72{{nbsp}}minutes). One meta-analysis found that melatonin was notably more effective in improving sleep onset latency in people with delayed sleep phase syndrome than in people with insomnia (improvement of 39{{nbsp}}minutes vs. 7{{nbsp}}minutes, respectively). One meta-analysis found that melatonin was probably effective for jet lag syndrome.{{cite journal | vauthors = Tortorolo F, Farren F, Rada G | title = Is melatonin useful for jet lag? | journal = Medwave | volume = 15 Suppl 3 | issue = | pages = e6343 | date = December 2015 | pmid = 26731279 | doi = 10.5867/medwave.2015.6343 | url = | doi-access = free }}

Low doses of melatonin may be advantageous to high doses in the treatment of sleep-cycle disorders.

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson's disease and dementia with Lewy bodies.{{cite journal | vauthors = McCarter SJ, Boswell CL, St Louis EK, Dueffert LG, Slocumb N, Boeve BF, Silber MH, Olson EJ, Tippmann-Peikert M | title = Treatment outcomes in REM sleep behavior disorder | journal = Sleep Medicine | volume = 14 | issue = 3 | pages = 237–42 | date = March 2013 | pmid = 23352028 | pmc = 3617579 | doi = 10.1016/j.sleep.2012.09.018 | type = Review }}{{cite journal | vauthors = McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VM, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O'Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K | title = Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium | journal = Neurology | volume = 89 | issue = 1 | pages = 88–100 | date = July 2017 | pmid = 28592453 | pmc = 5496518 | doi = 10.1212/WNL.0000000000004058 | type = Review }}{{cite journal | vauthors = Boot BP | title = Comprehensive treatment of dementia with Lewy bodies | journal = Alzheimer's Research & Therapy | volume = 7 | issue = 1 | pages = 45 | date = 2015 | pmid = 26029267 | pmc = 4448151 | doi = 10.1186/s13195-015-0128-z | type = Review | doi-access = free }} However, clonazepam may be more effective.{{cite journal | vauthors = Gilat M, Marshall NS, Testelmans D, Buyse B, Lewis SJ | title = A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials | journal = J Neurol | volume = 269 | issue = 1 | pages = 125–148 | date = January 2022 | pmid = 33410930 | pmc = 8739295 | doi = 10.1007/s00415-020-10353-0 | doi-access=free }} In any case, the quality of evidence for both treatments is very low and it is unclear whether either is definitely effective.

A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease.{{cite journal | vauthors = McCleery J, Sharpley AL | title = Pharmacotherapies for sleep disturbances in dementia | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | pages = CD009178 | date = November 2020 | issue = 11 | pmid = 33189083 | doi = 10.1002/14651858.CD009178.pub4 | pmc = 8094738 }} A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect.{{cite journal | vauthors = Spinedi E, Cardinali DP | title = Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer's Disease and Melatonin | journal = Neuroendocrinology | volume = 108 | issue = 4 | pages = 354–364 | date = 2019 | pmid = 30368508 | doi = 10.1159/000494889 | url = https://repositorio.uca.edu.ar/handle/123456789/9108 | s2cid = 53101746 | doi-access = free | hdl = 11336/86560 | hdl-access = free | archive-date = 27 April 2021 | access-date = 11 April 2022 | archive-url = https://web.archive.org/web/20210427113359/https://repositorio.uca.edu.ar/handle/123456789/9108 | url-status = dead }} Melatonin may, however, help with sundowning (increased confusion and restlessness at night) in people with dementia.{{cite book |vauthors=Gao C, Scullin MK, Bliwise DL |chapter=Mild Cognitive Impairment and Dementia |date=2019 |title=Handbook of Sleep Disorders in Medical Conditions |pages=253–276 |veditors=Savard J, Ouellet MC|publisher=Academic Press |doi=10.1016/b978-0-12-813014-8.00011-1 |isbn=978-0-12-813014-8|s2cid=88265944 }}

File:Walgreens Melatonin-2010-20-07.jpg

A prolonged-release 2{{nbsp}}mg oral formulation of melatonin sold under the brand name Circadin is approved for use in the European Union in the short-term treatment of insomnia in people age 55 and older.{{cite journal | vauthors = Wade A, Downie S | title = Prolonged-release melatonin for the treatment of insomnia in patients over 55 years | journal = Expert Opin Investig Drugs | volume = 17 | issue = 10 | pages = 1567–72 | date = October 2008 | pmid = 18808316 | doi = 10.1517/13543784.17.10.1567 | s2cid = 71158456 | url = }}{{cite report|url=https://www.ema.europa.eu/en/medicines/human/EPAR/circadin|title=Circadin: EPAR - Product Information ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS|date=2 February 2021|id=EMEA/H/C/000695 - IA/0066|publisher=European Medicines Agency (EMA)}} [https://www.ema.europa.eu/en/documents/product-information/circadin-epar-product-information_en.pdf As PDF.] {{Webarchive|url=https://web.archive.org/web/20221031231302/https://www.ema.europa.eu/en/documents/product-information/circadin-epar-product-information_en.pdf |date=31 October 2022 }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Melatonin is also available as an over-the-counter dietary supplement in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3{{nbsp}}mg to 10{{nbsp}}mg or more. It is also possible to buy raw melatonin powder by weight.{{cite web|vauthors=Soca R|date=28 February 2021|title=Melatonin Product Availability|url=https://keldik.com/blogs/sleep-circadian-binnacle/melatonin-product-availability|website=Keldik Sleep Circadian and Performance|access-date=11 April 2022|archive-date=27 May 2022|archive-url=https://web.archive.org/web/20220527143716/https://keldik.com/blogs/sleep-circadian-binnacle/melatonin-product-availability|url-status=dead}} Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or as a liquid.{{cite journal | vauthors = Kolli AR, Kuczaj AK, Calvino-Martin F, Hoeng J | title = Simulated pharmacokinetics of inhaled caffeine and melatonin from existing products indicate the lack of dosimetric considerations | journal = Food and Chemical Toxicology | volume = 187 | pages = 114601 | date = May 2024 | pmid = 38493979 | doi = 10.1016/j.fct.2024.114601 | doi-access = free }} It is also available for use sublingually, or as transdermal patches.{{cite journal | vauthors = Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EE, Soh CK, Car J | title = Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 18 | date = February 2018 | pmid = 29397794 | pmc = 5798185 | doi = 10.1186/s12916-017-1000-8 | doi-access = free }} Several inhalation-based melatonin products with a wide range of doses are available but their safety remains to be evaluated.

The American Academy of Sleep Medicine (AASM) says that the melatonin content in unregulated (without a USP verified mark) supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.

Contraindications to the use of melatonin include hypersensitivity reactions among others. It is not recommended in people with autoimmune diseases due to lack of data in these individuals. Prolonged-release pharmaceutical melatonin (Circadin) contains lactose and should not be used in people with the lactase deficiency or glucose–galactose malabsorption. Use of melatonin is also not recommend in women who are pregnant or breastfeeding or in people with liver disease.

Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses.{{Clarify|reason=Specific dosages?|date=September 2019}}{{Dubious inline|reason=Common misconception-issues|date=May 2023}} Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials, and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo.{{cite journal | vauthors = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S | title = The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis | journal = Journal of General Internal Medicine | volume = 20 | issue = 12 | pages = 1151–8 | date = December 2005 | pmid = 16423108 | pmc = 1490287 | doi = 10.1111/j.1525-1497.2005.0243.x }}{{cite journal | vauthors = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–93 | date = February 2006 | pmid = 16473858 | pmc = 1370968 | doi = 10.1136/bmj.38731.532766.F6 }} Prolonged-release melatonin is safe with long-term use of up to 12 months.{{cite journal | vauthors = Lyseng-Williamson KA | title = Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years | journal = Drugs & Aging | volume = 29 | issue = 11 | pages = 911–23 | date = November 2012 | pmid = 23044640 | doi = 10.1007/s40266-012-0018-z | s2cid = 1403262 }} Although not recommended for long-term use beyond this,{{cite web |title=Melatonin: What You Need To Know |url=https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know |website=NCCIH |publisher=National Institutes of Health |access-date=2 July 2021}} low-dose melatonin is generally safer, and a better alternative, than many prescription and over-the-counter sleep aids if a sleeping medication must be used for an extended period of time.{{Citation needed|date=August 2021}} Low doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect but instead appear to cause drowsiness for a longer period of time.Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. 2014.

There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.{{cite journal | vauthors = Garaulet M, Qian J, Florez JC, Arendt J, Saxena R, Scheer FA | title = Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy | journal = Trends in Endocrinology and Metabolism | volume = 31 | issue = 3 | pages = 192–204 | date = March 2020 | pmid = 31901302 | pmc = 7349733 | doi = 10.1016/j.tem.2019.11.011 }} Specifically, taking exogenous melatonin shortly after a meal is correlated with impaired glucose tolerance. Therefore, Rubio-Sastre and colleagues recommend waiting at least 2 hours after the last meal before taking a melatonin supplement.{{cite journal | vauthors = Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M | title = Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening | journal = Sleep | volume = 37 | issue = 10 | pages = 1715–9 | date = October 2014 | pmid = 25197811 | pmc = 4173928 | doi = 10.5665/sleep.4088 }}

Melatonin can cause nausea, next-day grogginess, and irritability.{{cite web| title=Melatonin side effects: What are the risks?| publisher=Mayo Clinic| vauthors = Bauer B | access-date=17 August 2011| url=http://www.mayoclinic.com/health/melatonin-side-effects/AN01717}} In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.{{cite journal | vauthors = Morera AL, Henry M, de La Varga M | title = [Safety in melatonin use] | language = es | journal = Actas Españolas de Psiquiatría | volume = 29 | issue = 5 | pages = 334–7 | year = 2001 | pmid = 11602091 | trans-title = Safety in melatonin use }}{{cite journal | vauthors = Terry PD, Villinger F, Bubenik GA, Sitaraman SV | title = Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research | journal = Inflammatory Bowel Diseases | volume = 15 | issue = 1 | pages = 134–40 | date = January 2009 | pmid = 18626968 | doi = 10.1002/ibd.20527 | doi-access = free }}{{update inline|date=April 2018}}

Melatonin can lower follicle-stimulating hormone levels.{{cite journal | vauthors = Juszczak M, Michalska M | title = [The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion] | language = pl | journal = Postepy Higieny I Medycyny Doswiadczalnej | volume = 60 | pages = 431–8 | year = 2006 | pmid = 16921343 | url = http://www.phmd.pl/fulltxthtml.php?ICID=453297 | trans-title = The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion | access-date = 24 December 2013 | archive-url = https://web.archive.org/web/20141102054834/http://www.phmd.pl/fulltxthtml.php?ICID=453297 | archive-date = 2 November 2014 | url-status = dead }} Melatonin's effects on human reproduction remain unclear.{{cite journal | vauthors = Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A | title = Melatonin and human reproduction: shedding light on the darkness hormone | journal = Gynecological Endocrinology | volume = 25 | issue = 12 | pages = 779–85 | date = December 2009 | pmid = 19905996 | doi = 10.3109/09513590903159649 | s2cid = 3442003 }}

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy.{{cite book |title=Melatonin and the Biological Clock | vauthors = Lewis A |publisher=McGraw-Hill |isbn=978-0-87983-734-1 |year=1999 |page=[https://archive.org/details/melatoninbiologi00lew_46r/page/23 23] |url-access=registration |url=https://archive.org/details/melatoninbiologi00lew_46r }}

Increased use of melatonin in the 21st century has significantly increased reports of melatonin overdose, calls to poison control centers, and related emergency department visits for children. The number of children who unintentionally ingested melatonin supplements in the US has increased 530% from 2012 to 2021. Over 4,000 reported ingestions required a hospital stay, and 287 children required intensive care. The American Academy of Sleep Medicine says there is little evidence that melatonin supplementation is effective in treating insomnia in healthy children.{{cite web | vauthors = Brooks M | title=Experts Issue Health Warning About Giving Melatonin to Kids | website=Medscape | date=23 September 2022 | url=https://www.medscape.com/viewarticle/981341}}

Melatonin appears to be relatively safe in overdose. It has been administered at daily doses of up to 300{{nbsp}}mg without causing clinically significant adverse reactions in the literature. However, doses of 200 to 1,200{{nbsp}}mg daily were reported to cause sleeping and emotional problems.{{cite journal | vauthors = Dawson D, Encel N | title = Melatonin and sleep in humans | journal = J Pineal Res | volume = 15 | issue = 1 | pages = 1–12 | date = August 1993 | pmid = 8229640 | doi = 10.1111/j.1600-079x.1993.tb00503.x | url = }}{{cite journal | vauthors = Carman JS, Post RM, Buswell R, Goodwin FK | title = Negative effects of melatonin on depression | journal = Am J Psychiatry | volume = 133 | issue = 10 | pages = 1181–1186 | date = October 1976 | pmid = 788529 | doi = 10.1176/ajp.133.10.1181 | url = }} The most commonly reported adverse effect of melatonin overdose is somnolence. Upon melatonin overdose, drowsiness may be expected and the compound should be cleared within 12{{nbsp}}hours. No special treatment is needed for melatonin overdose.

Melatonin is metabolized mainly by CYP1A enzymes. As such, inhibitors and inducers of CYP1A enzymes, such as CYP1A2, can modify melatonin metabolism and exposure. As an example, the CYP1A2 and CYP2C19 inhibitor fluvoxamine increases melatonin peak levels by 12-fold and overall exposure by 17-fold and this combination should be avoided. CYP1A2 inducers like cigarette smoking, carbamazepine, and rifampicin may reduce melatonin exposure due to induction of CYP1A2.

In those taking warfarin, some evidence suggests there may exist a potentiating interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.{{cite web|url=https://www.merckmanuals.com/professional/special-subjects/dietary-supplements/melatonin?query=melatonin|title=Melatonin – Special Subjects|website=Merck Manuals Professional Edition}}

Melatonin acts as an agonist of the melatonin MT₁ and MT₂ receptors, the biological targets of endogenous melatonin. Endogenous melatonin is normally secreted from the pineal gland of the brain. Melatonin is thought to activate melatonin receptors in the suprachiasmatic nucleus of the hypothalamus to regulate the circadian clock and sleep–wake cycles. When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3{{nbsp}}mg{{cite journal | vauthors = Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC | title = Phase-dependent treatment of delayed sleep phase syndrome with melatonin | journal = Sleep | volume = 28 | issue = 10 | pages = 1271–8 | date = October 2005 | pmid = 16295212 | doi = 10.1093/sleep/28.10.1271 | doi-access = free }}) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.{{cite book |vauthors=Terman MR, Wirz-Justice A | title = Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy |url=https://archive.org/details/chronotherapeuti00wirz |url-access=limited | publisher = S Karger Pub | location = Basel | year = 2009 | page = [https://archive.org/details/chronotherapeuti00wirz/page/n83 71] | isbn = 978-3-8055-9120-1 }}

Normal melatonin production is approximately 30{{nbsp}}μg (0.03{{nbsp}}mg) per day/night.{{cite journal | vauthors = Macchi MM, Bruce JN | title = Human pineal physiology and functional significance of melatonin | journal = Front Neuroendocrinol | volume = 25 | issue = 3-4 | pages = 177–195 | date = 2004 | pmid = 15589268 | doi = 10.1016/j.yfrne.2004.08.001 | url = | quote = Using radioimmunoassay (RIA) methods, mean melatonin production in healthy adults has been estimated at 28.8 μg/day [113], and at 39.2 and 14.8 μg/night, respectively, in a group of young healthy men and in women in the follicular phase of the menstrual cycle [70]. Similarly, gas chromatography-mass spectrometry techniques have shown slightly lower daily plasma concentrations in women (21.6 μg) than in men (35.7 μg), with constant rates of secretion at night (μg/h: 4.6 in males, 2.8 in females) and no differences related to age [66]. While very stable within individuals [137], the timing, duration and amount of nocturnal melatonin production, show pronounced individual differences, such that very low concentrations may be observed even in healthy, young individuals (low secretors) [9,21].}} In adults in temperate zones, the onset of melatonin secretion is around 21:00 to 22:00{{nbsp}}h, the peak is around 02:00 to 04:00{{nbsp}}h, and the offset is around 07:00 to 09:00{{nbsp}}h.{{cite journal | vauthors = Zawilska JB, Skene DJ, Arendt J | title = Physiology and pharmacology of melatonin in relation to biological rhythms | journal = Pharmacol Rep | volume = 61 | issue = 3 | pages = 383–410 | date = 2009 | pmid = 19605939 | doi = 10.1016/s1734-1140(09)70081-7 | url = | quote = Individual sensitivity to melatonin varies and the pharmacokinetics are very different from one individual to another. The lower dose of 0.3–0.5 mg may be more effective than higher doses in many subjects [113, 176]. [...] The peak concentrations of melatonin in plasma normally occur between 02.00 and 04.00 h. The onset of secretion is usually around 21.00 to 22.00 h and the offset at 07.00 to 09.00 h in adults in temperate zones [12]. [...] Several studies have demonstrated a progressive decline in the amplitude of melatonin rhythm in the elderly, especially in subjects over 70 years of age [38, 130, 202, 218, 293, 330, 345, 366].}} There is marked variability (e.g., 10-fold) in melatonin secretion and levels between individuals.{{cite journal | vauthors = Kennaway DJ | title = A critical review of melatonin assays: Past and present | journal = J Pineal Res | volume = 67 | issue = 1 | pages = e12572 | date = August 2019 | pmid = 30919486 | doi = 10.1111/jpi.12572 | url = | quote = Interestingly, the amount of melatonin produced varies enormously in normal healthy individuals. For example, a study of melatonin levels at 03:00 hours in 129 healthy subjects gave a range from 18.5 to 180 pg/mL.4 Similarly, a study of melatonin production in 75 healthy adults using 24 hours 6‐sulphatoxymelatonin excretion (a validated measure of total melatonin production 5) reported a range of 7.5‐58.1 μg per day.6 A study of peak saliva melatonin levels in 170 healthy subjects reported a range of 2.4‐83.6 pg/mL.7}} Melatonin levels may decline with age.{{cite journal | vauthors = Scholtens RM, van Munster BC, van Kempen MF, de Rooij SE | title = Physiological melatonin levels in healthy older people: A systematic review | journal = J Psychosom Res | volume = 86 | issue = | pages = 20–27 | date = July 2016 | pmid = 27302542 | doi = 10.1016/j.jpsychores.2016.05.005 | url = }} Doses of melatonin even above 300{{nbsp}}μg (0.3{{nbsp}}mg) have been shown to produce supraphysiological melatonin levels.{{cite journal | vauthors = Vural EM, van Munster BC, de Rooij SE | title = Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature | journal = Drugs Aging | volume = 31 | issue = 6 | pages = 441–451 | date = June 2014 | pmid = 24802882 | doi = 10.1007/s40266-014-0178-0 | url = | quote = In younger adults, it is amply proven that low exogenous doses of melatonin, even above 0.3 mg, produce supra-physiological levels [16,20–22,26–30,35] as well as in older adults [33].}} Usual doses of exogenous melatonin of 1 to 12{{nbsp}}mg produce circulating melatonin concentrations that are 10 to 100{{nbsp}}times higher than endogenous peak levels, which remain elevated for 4 to 8{{nbsp}}hours.{{cite journal | vauthors = Lalanne S, Fougerou-Leurent C, Anderson GM, Schroder CM, Nir T, Chokron S, Delorme R, Claustrat B, Bellissant E, Kermarrec S, Franco P, Denis L, Tordjman S | title = Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder | journal = Int J Mol Sci | volume = 22 | issue = 3 | date = February 2021 | page = 1490 | pmid = 33540815 | pmc = 7867370 | doi = 10.3390/ijms22031490 | url = | doi-access = free }} Melatonin levels with Circadin, an approved 4-mg controlled-release pharmaceutical drug, are also supraphysiological.{{cite journal | vauthors = Gooneratne NS, Edwards AY, Zhou C, Cuellar N, Grandner MA, Barrett JS | title = Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults | journal = Journal of Pineal Research | volume = 52 | issue = 4 | pages = 437–445 | date = May 2012 | pmid = 22348451 | pmc = 3682489 | doi = 10.1111/j.1600-079X.2011.00958.x }}

The oral bioavailability of melatonin ranges between 2.5% and 50%. In one study, the bioavailability of melatonin ranged from 10% to 56% between different individuals, with an average of 33%. A systematic review found that the bioavailability of melatonin was approximately 15%, with a range across studies of 9% to 33%.{{cite journal | vauthors = Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J | title = Clinical pharmacokinetics of melatonin: a systematic review | journal = Eur J Clin Pharmacol | volume = 71 | issue = 8 | pages = 901–909 | date = August 2015 | pmid = 26008214 | doi = 10.1007/s00228-015-1873-4 | url = }}

Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60{{nbsp}}minutes of administration, and is then eliminated.{{cite journal | vauthors = Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C | title = Melatonin: Pharmacology, Functions and Therapeutic Benefits | journal = Current Neuropharmacology | volume = 15 | issue = 3 | pages = 434–443 | date = April 2017 | pmid = 28503116 | pmc = 5405617 | doi = 10.2174/1570159X14666161228122115 }} A single 0.5{{nbsp}}mg dose of melatonin achieved peak melatonin levels ranging between 2 and 395{{nbsp}}nmol/L between different individuals.

The plasma protein binding of melatonin is approximately 60%. It is mainly bound to albumin, α₁-acid glycoprotein, and high-density lipoprotein.

The membrane transport proteins that move melatonin across a membrane include, but are not limited to, glucose transporters, including GLUT1, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.{{cite journal | vauthors = Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP | title = Update on melatonin receptors: IUPHAR Review 20 | journal = British Journal of Pharmacology | volume = 173 | issue = 18 | pages = 2702–25 | date = September 2016 | pmid = 27314810 | pmc = 4995287 | doi = 10.1111/bph.13536}}{{cite journal | vauthors = Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R | title = Melatonin transport into mitochondria | journal = Cellular and Molecular Life Sciences | volume = 74 | issue = 21 | pages = 3927–3940 | date = November 2017 | pmid = 28828619 | doi = 10.1007/s00018-017-2616-8 | s2cid = 10920415 | pmc = 11107582 }}

Melatonin is metabolized in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).

In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva. Melatonin is excreted in the urine 2 to 5% as the unchanged drug.

Melatonin has an elimination half-life of about 20 to 60 minutes.{{cite web |title=Melatonin |url=https://www.drugbank.ca/drugs/DB01065 |website=www.drugbank.ca |access-date=29 January 2019}} The half-life of prolonged-release melatonin (Circadin) is 3.5 to 4{{nbsp}}hours.

Melatonin, also known as N-acetyl-5-methoxytryptamine, is a substituted tryptamine and a derivative of serotonin (5-hydroxytryptamine). It is structurally related to N-acetylserotonin (normelatonin; N-acetyl-5-hydroxytryptamine), which is the chemical intermediate between serotonin and melatonin in the body. Synthetic melatonin receptor agonists used in medicine like ramelteon, tasimelteon, agomelatine, and piromelatine (still in clinical trials) are analogues of melatonin.

The first patent for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong at Monash University,{{cite web |title=Method for minimizing disturbances in circadian rhythms of bodily performance and function - Patent US-4665086-A - PubChem |url=https://pubchem.ncbi.nlm.nih.gov/patent/US-4665086-A |access-date=16 April 2022 |website=pubchem.ncbi.nlm.nih.gov}} and the first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.{{cite patent | country = US | number = 5449683 | status = patent | title = Methods of inducing sleep using melatonin | gdate = 12 September 1995 | fdate = 16 July 1993 | inventor = Wurtman RJ | assign1 = Massachusetts Institute of Technology }} Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.{{cite journal | vauthors = Arendt J | title = Melatonin: characteristics, concerns, and prospects | journal = Journal of Biological Rhythms | volume = 20 | issue = 4 | pages = 291–303 | date = August 2005 | pmid = 16077149 | doi = 10.1177/0748730405277492 | s2cid = 19011222 | quote = There is very little evidence in the short term for toxicity or undesirable effects in humans. The extensive promotion of the miraculous powers of melatonin in the recent past did a disservice to acceptance of its genuine benefits. | doi-access = free }} The New England Journal of Medicine editorialized in 2000: "With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear."{{cite journal | vauthors = Arendt J | title = Melatonin, circadian rhythms, and sleep | journal = The New England Journal of Medicine | volume = 343 | issue = 15 | pages = 1114–6 | date = October 2000 | pmid = 11027748 | doi = 10.1056/NEJM200010123431510 }}

It was approved for medical use in the European Union in 2007.

Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada. FDA regulations applying to medications are not applicable to melatonin,{{cite journal | vauthors = Altun A, Ugur-Altun B | title = Melatonin: therapeutic and clinical utilization | journal = International Journal of Clinical Practice | volume = 61 | issue = 5 | pages = 835–45 | date = May 2007 | pmid = 17298593 | doi = 10.1111/j.1742-1241.2006.01191.x | s2cid = 18050554 | doi-access = free }} though the FDA has found false claims that it cures cancer.{{cite web |url=https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm171057.htm |title=187 Fake Cancer 'Cures' Consumers Should Avoid |publisher=U.S. Food and Drug Administration |archive-url=https://web.archive.org/web/20170502034227/https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/enforcementactivitiesbyfda/ucm171057.htm |archive-date=2 May 2017 |access-date=20 May 2020}} As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin. In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.{{cite journal | vauthors = Guardiola-Lemaître B | title = Toxicology of melatonin | journal = Journal of Biological Rhythms | volume = 12 | issue = 6 | pages = 697–706 | date = December 1997 | pmid = 9406047 | doi = 10.1177/074873049701200627 | s2cid = 31090576 | doi-access = free }} According to Harriet Hall, caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from –83% to +478%, lot-to-lot variability was as high as 465%, and the discrepancies were not correlated to any manufacturer or product type. To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin.{{cite web |author-link = Harriet Hall | vauthors = Hall H |title=Melatonin Melatonin supplements are increasingly popular, but the evidence is weak and mixed. |url=https://sciencebasedmedicine.org/melatonin/ | work = Science-Based Medicine |date=15 December 2020 |publisher=Science Based Medicine |access-date=24 December 2020}}{{cite journal | vauthors = Erland LA, Saxena PK | title = Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content | journal = Journal of Clinical Sleep Medicine | volume = 13 | issue = 2 | pages = 275–281 | date = February 2017 | pmid = 27855744 | pmc = 5263083 | doi = 10.5664/jcsm.6462 }}

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material.{{cite web |url=https://www.drugs.com/melatonin.html |title=Melatonin| publisher=Drugs.com| access-date=17 August 2011}}

Melatonin is the most popular over-the-counter sleep remedy in the United States, resulting in sales in excess of US$400 million during 2017.{{cite web|url=https://www.consumerreports.org/vitamins-supplements/does-melatonin-really-help-you-sleep/|title=Does Melatonin Really Help You Sleep? | vauthors = Loria K |website=Consumer Reports|access-date=16 March 2019}} In 2022, it was the 217th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.

Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.{{cite news |url = https://www.nytimes.com/2011/05/15/us/15lazycakes.html |work=The New York Times |title=Dessert, Laid-Back and Legal | date=14 May 2011 | vauthors = Louis CS }} The FDA considered whether these food products could continue to be sold with the label "dietary supplements". On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive.{{cite web | url = http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm201435.htm | title = Warning Letter | vauthors = Rodriguez RR | date = 13 January 2010 | work = Inspections, Compliance, Enforcement, and Criminal Investigations | publisher = U.S. Food and Drug Administration | url-status = dead | archive-url = https://wayback.archive-it.org/7993/20170112195035/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm201435.htm | archive-date = 12 January 2017 | df = dmy-all }} Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage.{{cite web|url=https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm440953.htm|title=Bebida Beverage Company|publisher=U.S. Food and Drug Administration|date=4 March 2015|access-date=8 December 2017|archive-url=https://web.archive.org/web/20200601144105/http://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/bebida-beverage-company-03042015|archive-date=1 June 2020}}

Some research supports an antidepressant and anxiolytic effect of melatonin.{{cite journal | vauthors = Valdés-Tovar M, Estrada-Reyes R, Solís-Chagoyán H, Argueta J, Dorantes-Barrón AM, Quero-Chávez D, Cruz-Garduño R, Cercós MG, Trueta C, Oikawa-Sala J, Dubocovich ML, Benítez-King G | title = Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression | journal = British Journal of Pharmacology | volume = 175 | issue = 16 | pages = 3200–3208 | date = August 2018 | pmid = 29512136 | pmc = 6057892 | doi = 10.1111/bph.14197 }}{{cite journal|vauthors=Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM|date=8 December 2020|title=Melatonin for pre- and postoperative anxiety in adults|journal=The Cochrane Database of Systematic Reviews|volume=2020|issue=12 |pages=CD009861|doi=10.1002/14651858.CD009861.pub3|pmid=33319916|pmc=8092422}} It has also been used to aid in the treatment of manic episodes in bipolar disorder, although evidence for its effectiveness is still inconsistent.{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials | journal = Journal of Psychiatric Research | date = September 2021 | volume = 143 | pages = 230–238 | doi = 10.1016/j.jpsychires.2021.09.018| pmid = 34509090 | s2cid = 237485915 }}

Other studies have shown that melatonin may help reduce some types of headaches, epigastric pain and heartburn.{{cite journal | vauthors = Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA | title = Potential therapeutic use of melatonin in migraine and other headache disorders | journal = Expert Opinion on Investigational Drugs | volume = 15 | issue = 4 | pages = 367–75 | date = April 2006 | pmid = 16548786 | doi = 10.1517/13543784.15.4.367 | s2cid = 28114683 }}{{cite journal | vauthors = Evers S, Goadsby PJ |year=2005 |title=Review: Hypnic headache |journal=Practical Neurology |volume=5 |issue= 3|pages=144–49 |url=http://pn.bmj.com/content/practneurol/5/3/144.full.pdf |access-date=12 January 2018|doi=10.1111/j.1474-7766.2005.00301.x |doi-broken-date=20 May 2025 |s2cid=1196313 |doi-access=free }}{{cite journal | vauthors = Kandil TS, Mousa AA, El-Gendy AA, Abbas AM | title = The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease | journal = BMC Gastroenterology | volume = 10 | pages = 7 | date = January 2010 | pmid = 20082715 | pmc = 2821302 | doi = 10.1186/1471-230X-10-7 | doi-access = free }} There have also been studies trying to prove the effectiveness of melatonin in relation to epilepsy, dysmenorrhea, delirium, and tinnitus, but little to no beneficial role has been found.{{cite journal | vauthors = Brigo F, Igwe SC, Del Felice A | title = Melatonin as add-on treatment for epilepsy | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD006967 | date = August 2016 | volume = 2016 | pmid = 27513702 | doi = 10.1002/14651858.CD006967.pub4 | pmc = 7386917 }}{{cite journal | vauthors = Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J | title = Dietary supplements for dysmenorrhoea | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD002124 | date = March 2016 | issue = 3 | pmid = 27000311 | doi = 10.1002/14651858.CD002124.pub2 | pmc = 7387104 }}{{cite journal | vauthors = Siddiqi N, Harrison JK, Clegg A, Teale EA, Young J, Taylor J, Simpkins SA | title = Interventions for preventing delirium in hospitalised non-ICU patients | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD005563 | date = March 2016 | issue = 3 | pmid = 26967259 | doi = 10.1002/14651858.CD005563.pub3 | pmc = 10431752 | url = http://eprints.whiterose.ac.uk/99189/7/Siddiqi_et_al-2016-The_Cochrane_Library.pdf }}{{cite journal | vauthors = Miroddi M, Bruno R, Galletti F, Calapai F, Navarra M, Gangemi S, Calapai G | title = Clinical pharmacology of melatonin in the treatment of tinnitus: a review | journal = European Journal of Clinical Pharmacology | volume = 71 | issue = 3 | pages = 263–70 | date = March 2015 | pmid = 25597877 | doi = 10.1007/s00228-015-1805-3 | s2cid = 16466238 }} Melatonin has also been tested as a treatment for cancer, but the National Cancer Institute found insufficient evidence for it. However, further research found it to slightly improve survival of patients and to alleviate chemotherapy-related side effects.{{cite book | title = PDQ Cancer Information Summaries [Internet] | chapter = Topics in complementary and alternative therapies |date=May 2013 |pmid=26389506 |url=https://www.ncbi.nlm.nih.gov/books/NBK126745/#CDR0000745420__16 |publisher=National Cancer Institute, National Institutes of Health| vauthors = ((PDQ Integrative, Alternative, and Complementary Therapies Editorial Board)) }}{{cite journal | vauthors = Lim S, Park S, Koyanagi A, Yang JW, Jacob L, Yon DK, Lee SW, Kim MS, Il Shin J, Smith L | title = Effects of exogenous melatonin supplementation on health outcomes: An umbrella review of meta-analyses based on randomized controlled trials | journal = Pharmacological Research | volume = 176 | pages = 106052 | date = February 2022 | pmid = 34999224 | doi = 10.1016/j.phrs.2021.106052 | s2cid = 263492993 | url = https://arro.anglia.ac.uk/id/eprint/707412/1/Lim_et_al_2022.pdf | access-date = 24 January 2023 | archive-date = 31 March 2023 | archive-url = https://web.archive.org/web/20230331122137/https://arro.anglia.ac.uk/id/eprint/707412/1/Lim_et_al_2022.pdf | url-status = dead }}{{cite journal | vauthors = Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EE, Soh CK, Car J | title = Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 18 | date = February 2018 | pmid = 29397794 | pmc = 5798185 | doi = 10.1186/s12916-017-1000-8 | doi-access = free }}{{cite journal | vauthors = Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL | title = The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials | journal = Cancer Chemotherapy and Pharmacology | volume = 69 | issue = 5 | pages = 1213–1220 | date = May 2012 | pmid = 22271210 | doi = 10.1007/s00280-012-1828-8 | s2cid = 38488628 }}

Both animal{{cite journal | vauthors = Meltz ML, Reiter RJ, Herman TS, Kumar KS | title = Melatonin and protection from whole-body irradiation: survival studies in mice | journal = Mutation Research | volume = 425 | issue = 1 | pages = 21–7 | date = March 1999 | pmid = 10082913 | doi = 10.1016/S0027-5107(98)00246-2 | bibcode = 1999MRFMM.425...21V }} and human{{cite journal | vauthors = Reiter RJ, Herman TS, Meltz ML | title = Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers | journal = Mutation Research | volume = 371 | issue = 3–4 | pages = 221–8 | date = December 1996 | pmid = 9008723 | doi = 10.1016/S0165-1218(96)90110-X }}{{cite journal | vauthors = Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J | title = Dietary supplements for dysmenorrhoea | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 3 | pages = CD002124 | date = March 2016 | pmid = 27000311 | doi = 10.1002/14651858.cd002124.pub2 | pmc = 7387104 }}{{cite journal | vauthors = Reiter RJ, Herman TS, Meltz ML | title = Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes | journal = Mutation Research | volume = 397 | issue = 2 | pages = 203–8 | date = February 1998 | pmid = 9541644 | doi = 10.1016/S0027-5107(97)00211-X | bibcode = 1998MRFMM.397..203V }} studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure.{{cite journal | vauthors = Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ | title = One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? | journal = Journal of Pineal Research | volume = 42 | issue = 1 | pages = 28–42 | date = January 2007 | pmid = 17198536 | doi = 10.1111/j.1600-079X.2006.00407.x | s2cid = 40005308 | doi-access = free }} Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known major side effects.{{cite journal | vauthors = Shirazi A, Ghobadi G, Ghazi-Khansari M | title = A radiobiological review on melatonin: a novel radioprotector | journal = Journal of Radiation Research | volume = 48 | issue = 4 | pages = 263–72 | date = July 2007 | pmid = 17641465 | doi = 10.1269/jrr.06070 | bibcode = 2007JRadR..48..263S | doi-access = free }}

Melatonin has been found to possess anti-inflammatory effects.{{cite journal | vauthors = Cho JH, Bhutani S, Kim CH, Irwin MR | title = Anti-inflammatory effects of melatonin: A systematic review and meta-analysis of clinical trials | journal = Brain Behav Immun | volume = 93 | issue = | pages = 245–253 | date = March 2021 | pmid = 33581247 | pmc = 7979486 | doi = 10.1016/j.bbi.2021.01.034 | url = }} It has been found to reduce levels of several pro-inflammatory cytokines in clinical studies, with large effect sizes. Melatonin might be useful in the treatment of inflammatory disorders.

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