This article is about melatonin as a supplement and medication. For its role as a hormone, see Melatonin.
Melatonin is a dietary supplement and medication as well as naturally occurringhormone.[9][12] As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles.[9][12] As a supplement, it is often used for the attempted short-term treatment of disrupted sleep patterns, such as from jet lagorshift work, and is typically taken orally.[13][14][15] Evidence of its benefit for this use, however, is not strong.[16] A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.[14]
Melatonin was discovered in 1958.[9] It is sold over the counter in Canada and the United States;[17][19] in the United Kingdom, it is a prescription-only medication.[15] In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.[23][8] In the European Union, it is indicated for the treatment of insomnia in children and adolescents.[18] The US Food and Drug Administration (FDA) treats melatonin as a dietary supplement and as such has not approved it for any medical uses.[17] It was approved for medical use in the European Union in 2007.[8] Besides melatonin, certain syntheticmelatonin receptor agonists like ramelteon, tasimelteon, and agomelatine are also used in medicine.[24][25] In 2021, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[26][27]
There is no good evidence that melatonin helps treat insomnia and its attempted use for this purpose is recommended against by the American Academy of Sleep Medicine.[28]
Aprolonged-release form of melatonin is approved for use as a medication in Europe for the treatment of insomnia in certain people.[11][29]
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.[30]
Melatonin appears to have limited use against the sleep problems of people who work shift work.[31] Tentative evidence suggests that it increases the length of time people are able to sleep.[31]
A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease.[36] 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.[37] Melatonin may, however, help with sundowning (increased confusion and restlessness at night) in people with dementia.[38]
Melatonin is also available as an over-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 the weight.[39] 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, or liquids. It is also available for use sublingually, or as transdermal patches.[40]
The American Academy of Sleep Medicine (AASM) said 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.[41]
Melatonin appears to cause very few side 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 and placebo.[42][43] Prolonged-release melatonin is safe with long-term use of up to 12 months.[11] Although not recommended for long-term use beyond this,[44] 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 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.[45]
There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.[46] 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.[47]
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.[53]
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.[41]
Melatonin appears to be relatively safe in overdose.[8] It has been administered at daily doses of up to 300mg without causing clinically significant adverse reactions in the literature.[8] The most commonly reported adverse effect of melatonin overdose is somnolence.[8] Upon melatonin overdose, drowsiness may be expected and the compound should be cleared within 12hours.[8] No special treatment is needed for melatonin overdose.[8]
Melatonin is metabolized mainly by CYP1Aenzymes. As such, inhibitors and inducers of CYP1A enzymes, such as CYP1A2, can modify melatonin metabolism and exposure.[8] 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.[8] CYP1A2 inducers like cigarette smoking, carbamazepine, and rifampicin may reduce melatonin exposure due to induction of CYP1A2.[8]
In those taking warfarin, some evidence suggests there may exist a potentiating interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.[54]
The bioavailability of melatonin is between 2.5 and 50%.[6][7] Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60minutes of administration, and is then eliminated.[6] Usual doses of exogenous melatonin of 1 to 12mg produce melatonin concentrations 10 to 100times higher than endogenous peak levels.[7]
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.[13] Melatonin is excreted in the urine 2 to 5% as the unchanged drug.[6][8]
The first patent for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong at Monash University,[59] and the first patent for its use as a low-dose sleep aid was granted to Richard WurtmanatMIT in 1995.[60] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[61]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."[62]
It was approved for medical use in the European Union in 2007.[8]
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.[13] FDA regulations applying to medications are not applicable to melatonin,[63] though the FDA has found false claims that it cures cancer.[64] 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.[30] In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.[65] 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.[66][67]
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.[63][68]
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.[69] In 2021, it was the 257th most commonly prescribed medication in the US, with more than 1million prescriptions.[26][27]
Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.[70] 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.[71]Bebida Beverage Company received a warning letter in 2015 for selling a melatonin-containing beverage.[72]
Melatonin, along with ramelteon, has been repurposed as a possible adjunctive treatment for manic episodes in bipolar disorder.[74] However, meta-analytic evidence is somehow inconsistent and of limited interest so far, although the small samples of trials do not allow ruling out its beneficial effect.[74] In any case, current evidence does not support the use of add-on melatonin-receptor agonists for mania.[74]
Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with benzodiazepine in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.[75]
A 2013 review by the National Cancer Institute found insufficient evidence for melatonin having anti-cancer effects.[78] A 2022 review found that melatonin supplementation had a small improvement in survival of people with cancer at one year.[79][80] One review found that melatonin may alleviate chemotherapy-related side effects.[81]
Both animal[82] and human[83][84][85] 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.[86] 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.[87]
^ abcBuscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, et al. (November 2004). "Melatonin for treatment of sleep disorders"(PDF). Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, Under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Rockville, MD: Agency for Healthcare Research and Quality (108). Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services: 1–7. doi:10.1037/e439412005-001. PMC4781368. PMID15635761. Retrieved 5 June 2013.
^ abMatheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy". American Family Physician. 96 (1): 29–35. PMID28671376.
^ abcdBritish national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 482–483. ISBN978-0-85711-338-2.
^Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, et al. (2015). "Management of Insomnia Disorder[Internet]". AHRQ Comparative Effectiveness Reviews. 15 (16): EHC027–EF. PMID26844312. Evidence for benzodiazepine hypnotics, melatonin agonists in the general adult population, and most pharmacologic interventions in older adults was generally insufficient
^ ab"Melatonin". www.drugbank.ca. Retrieved 29 January 2019.
^"Australian Public Assessment Report for Melatonin"(PDF). Australian Government Department of Health and Ageing Therapeutic Goods Administration. January 2011. pp. 2, 4. Retrieved 9 January 2019. Monotherapy for the short term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
^Carney CE, Lau PH, Kutana S (2023). "Chapter 10: Insomnia". In Hupp S, Santa Maria CL (eds.). Pseudoscience in Therapy: A Skeptical Field Guide. Cambridge University Press. pp. 147–148. doi:10.1017/9781009000611.011. ISBN9781009000611.
^ abWade A, Downie S (October 2008). "Prolonged-release melatonin for the treatment of insomnia in patients over 55 years". Expert Opin Investig Drugs. 17 (10): 1567–72. doi:10.1517/13543784.17.10.1567. PMID18808316. S2CID71158456.
^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.
^Morera AL, Henry M, de La Varga M (2001). "[Safety in melatonin use]" [Safety in melatonin use]. Actas Españolas de Psiquiatría (in Spanish). 29 (5): 334–7. PMID11602091.
^US patent 5449683, Wurtman RJ, "Methods of inducing sleep using melatonin", issued 12 September 1995, assigned to Massachusetts Institute of Technology
^Rodriguez RR (13 January 2010). "Warning Letter". Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration. Archived from the original on 12 January 2017.
^ abcBartoli 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.
^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.
^Meltz ML, Reiter RJ, Herman TS, Kumar KS (March 1999). "Melatonin and protection from whole-body irradiation: survival studies in mice". Mutation Research. 425 (1): 21–7. doi:10.1016/S0027-5107(98)00246-2. PMID10082913.
^Reiter RJ, Herman TS, Meltz ML (December 1996). "Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers". Mutation Research. 371 (3–4): 221–8. doi:10.1016/S0165-1218(96)90110-X. PMID9008723.
^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.