Melatonin was discovered in 1958.[12] It is soldover-the-counter in Canada and the United States;[19][21] in the United Kingdom, it is aprescription-only medication.[18] In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.[25][11] Slenyto is a prolonged-release melatonin medicine used in the E.U. to treat insomnia in children and adolescents withautism spectrum disorder, neurogenetic disorders, orADHD.[20] The U.S.Food and Drug Administration (FDA) treats melatonin as a dietary supplement and, as such, has not approved it for any medical uses.[19] It was approved for medical use in the European Union in 2007.[11] Besides melatonin, certainsyntheticmelatonin receptor agonists likeramelteon,tasimelteon, andagomelatine are also used in medicine.[26][27] In 2023, it was the 164th most commonly prescribed medication in the United States, with more than 3million prescriptions.[28][29]
The 2023 European Insomnia Guideline recommended use of prolonged-release melatonin for treatment of insomnia in people age 55 or older for up to 3months.[34] It recommended againstfast-release orover-the-counter melatonin for treatment of insomnia.[34] These recommendations were based on severalmeta-analyses published in 2022 and 2023.[34]
Melatonin is known to reducejet lag, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.[37]
Melatonin appears to have limited use against the sleep problems of people who workshift work.[38] Tentative evidence suggests that it increases the length of time people are able to sleep.[38]
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.[39][40][41][42] Some found that it was effective,[39][40][42] while others found no evidence of effectiveness.[41] Meta-analyses of melatonin for delayed sleep phase syndrome that found it effective have reported that it improves time to sleep onset by about 40minutes (0.67hours) and advances onset of endogenous melatonin secretion by about 1.2hours (72minutes).[40][42] 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 39minutes vs. 7minutes, respectively).[42] One meta-analysis found that melatonin was probably effective forjet lag syndrome.[43]
Low doses of melatonin may be advantageous to high doses in the treatment of sleep-cycle disorders.[44]
A 2020Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severedementia due toAlzheimer's disease.[49] A 2019 review found that while melatonin may improve sleep inminimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect.[50] Melatonin may, however, help withsundowning (increased confusion and restlessness at night) in people with dementia.[51]
Melatonin is also available as anover-the-counterdietary 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 0.3mg to 10mg or more. It is also possible to buy raw melatonin powder by weight.[52] 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.[53] It is also available for usesublingually, or astransdermal patches.[54] Several inhalation-based melatonin products with a wide range of doses are available but their safety remains to be evaluated.[53]
The American Academy of Sleep Medicine (AASM) says that the melatonin content in unregulated (without aUSP 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.[55]
Melatonin appears to cause very fewside effects as tested in the short term, up to three months, at low doses.[clarification needed][dubious –discuss] 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 andplacebo.[56][57] Prolonged-release melatonin is safe with long-term use of up to 12 months.[14] Although not recommended for long-term use beyond this,[58] 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] Low doses of melatonin are usually sufficient to produce ahypnotic 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.[59]
There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.[60] 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.[61]
Some supplemental melatonin users report an increase invivid dreaming. Extremely high doses of melatonin increasedREM sleep time and dream activity in people both with and withoutnarcolepsy.[67]
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. TheAmerican Academy of Sleep Medicine says there is little evidence that melatonin supplementation is effective in treating insomnia in healthy children.[55]
Melatonin appears to be relatively safe inoverdose.[11] It has been administered at daily doses of up to 300mg without causing clinically significant adverse reactions in the literature.[11] However, doses of 200 to 1,200mg daily were reported to cause sleeping and emotional problems.[68][69] The most commonly reported adverse effect of melatonin overdose issomnolence.[11] Upon melatonin overdose,drowsiness may be expected and the compound should be cleared within 12hours.[11] No special treatment is needed for melatonin overdose.[11]
In those takingwarfarin, some evidence suggests there may exist a potentiating interaction, increasing theanticoagulant effect of warfarin and the risk of bleeding.[70]
Normal melatonin production is approximately 30μg (0.03mg) per day/night.[73] In adults in temperate zones, the onset of melatonin secretion is around 21:00 to 22:00h, the peak is around 02:00 to 04:00h, and the offset is around 07:00 to 09:00h.[44] There is marked variability (e.g., 10-fold) in melatonin secretion and levels between individuals.[74][73] Melatonin levels may decline with age.[44][75] Doses of melatonin even above 300μg (0.3mg) have been shown to produce supraphysiological melatonin levels.[76] Usual doses of exogenous melatonin of 1 to 12mg produce circulating melatonin concentrations that are 10 to 100times higher than endogenous peak levels, which remain elevated for 4 to 8hours.[9][10] Melatonin levels with Circadin, an approved 4-mgcontrolled-releasepharmaceutical drug, are also supraphysiological.[77] Clinical studies have found melatonin to have maximal effectiveness and the fewestside effects at a once-nightly dose of 0.3mg.[76][78][79] In elderly people, this dose resulted in similar melatonin spikes in magnitude and duration to those that occur in healthy young people.[76]
Theoralbioavailability of melatonin ranges between 2.5% and 50%.[9][10] In one study, the bioavailability of melatonin ranged from 10% to 56% between different individuals, with an average of 33%.[9] Asystematic review found that the bioavailability of melatonin was approximately 15%, with a range across studies of 9% to 33%.[8]
Melatonin is rapidlyabsorbed anddistributed, reachingpeak plasma concentrations after 60minutes of administration, and is theneliminated.[9] A single 0.5mg dose of melatonin achievedpeak melatonin levels ranging between 2 and 395nmol/L between different individuals.[9]
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.[16] Melatonin is excreted in the urine 2 to 5% as the unchanged drug.[9][11]
The firstpatent for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong atMonash University,[82] and the first patent for its use as a low-dose sleep aid was granted toRichard Wurtman atMIT in 1995.[83] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[84]TheNew 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."[85]
It was approved for medical use in the European Union in 2007.[11]
Melatonin is categorized by the USFood and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada.[16] FDA regulations applying to medications are not applicable to melatonin,[86] though the FDA has found false claims that it cures cancer.[87] 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.[37] In many countries, melatonin is recognized as aneurohormone and it cannot be sold over-the-counter.[88] According toHarriet Hall, caution is advisable, since quality control is a documented problem, particularly with respect to the actually dosage as opposed to label-stated dosage.[89]: 30 To make matters worse, 8 out of 31 products were contaminated with the neurotransmitterserotonin.[90][91]
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.[86][92]
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.[93] In 2022, it was the 217th most commonly prescribed medication in the United States, with more than 1million prescriptions.[94][29]
Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.[95] 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 afood additive.[96]Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage.[97]
Some research supports anantidepressant andanxiolytic effect of melatonin.[98][99] It has also been used to aid in the treatment of manic episodes inbipolar disorder, although evidence for its effectiveness is still inconsistent.[100]
Other studies have shown that melatonin may help reduce some types of headaches,epigastric pain andheartburn.[101][102][103] There have also been studies trying to prove the effectiveness of melatonin in relation toepilepsy,dysmenorrhea,delirium, andtinnitus, but little to no beneficial role has been found.[104][105][106][107] 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.[108][109][54][110]
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^abcRiemann D, Espie CA, Altena E, Arnardottir ES, Baglioni C, Bassetti CL, et al. (December 2023). "The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023".J Sleep Res.32 (6) e14035.doi:10.1111/jsr.14035.hdl:11250/3121742.PMID38016484.
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^abcZawilska JB,Skene DJ, Arendt J (2009). "Physiology and pharmacology of melatonin in relation to biological rhythms".Pharmacol Rep.61 (3):383–410.doi:10.1016/s1734-1140(09)70081-7.PMID19605939.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].
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^abMacchi MM, Bruce JN (2004). "Human pineal physiology and functional significance of melatonin".Front Neuroendocrinol.25 (3–4):177–195.doi:10.1016/j.yfrne.2004.08.001.PMID15589268.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].
^Kennaway DJ (August 2019). "A critical review of melatonin assays: Past and present".J Pineal Res.67 (1) e12572.doi:10.1111/jpi.12572.PMID30919486.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
^Scholtens RM, van Munster BC, van Kempen MF, de Rooij SE (July 2016). "Physiological melatonin levels in healthy older people: A systematic review".J Psychosom Res.86:20–27.doi:10.1016/j.jpsychores.2016.05.005.PMID27302542.
^abcVural EM, van Munster BC, de Rooij SE (June 2014). "Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature".Drugs Aging.31 (6):441–451.doi:10.1007/s40266-014-0178-0.PMID24802882.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].
^Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, et al. (February 2005). "Effects of exogenous melatonin on sleep: a meta-analysis".Sleep Med Rev.9 (1):41–50.doi:10.1016/j.smrv.2004.06.004.PMID15649737.
^Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU (October 2001). "Melatonin treatment for age-related insomnia".J Clin Endocrinol Metab.86 (10):4727–4730.doi:10.1210/jcem.86.10.7901.PMID11600532.
^US patent 5449683, Wurtman RJ, "Methods of inducing sleep using melatonin", issued 12 September 1995, assigned to Massachusetts Institute of Technology
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^Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, et al. (September 2021). "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 of Psychiatric Research.143:230–238.doi:10.1016/j.jpsychires.2021.09.018.PMID34509090.S2CID237485915.
^Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA (April 2006). "Potential therapeutic use of melatonin in migraine and other headache disorders".Expert Opinion on Investigational Drugs.15 (4):367–75.doi:10.1517/13543784.15.4.367.PMID16548786.S2CID28114683.
^Miroddi M, Bruno R, Galletti F, Calapai F, Navarra M, Gangemi S, et al. (March 2015). "Clinical pharmacology of melatonin in the treatment of tinnitus: a review".European Journal of Clinical Pharmacology.71 (3):263–70.doi:10.1007/s00228-015-1805-3.PMID25597877.S2CID16466238.
^PDQ Integrative, Alternative, and Complementary Therapies Editorial Board (May 2013). "Topics in complementary and alternative therapies".PDQ Cancer Information Summaries [Internet]. National Cancer Institute, National Institutes of Health.PMID26389506.
^Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, et al. (May 2012). "The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials".Cancer Chemotherapy and Pharmacology.69 (5):1213–1220.doi:10.1007/s00280-012-1828-8.PMID22271210.S2CID38488628.
