View source for Melatonin

{{Distinguish|Melanotan (disambiguation){{!}}Melanotan|Melanin}}
{{For|the album|Melatonin (album)}}
{{Use dmy dates|date=March 2015}}
{{drugbox
| Watchedfields = changed
| verifiedrevid = 646778032
| IUPAC_name = ''N''-[2-(5-Methoxy-1''H''-indol-3-yl)ethyl]acetamide
| image = Melatonin.svg
| image2 = Melatonin molecule ball.png

<!--Clinical data-->
| pronounce = {{IPAc-en|audio=melatonin-pronunciation.ogg|ˌ|m|ɛ|l|ə|ˈ|t|oʊ|n|ɪ|n}}
| Drugs.com = {{drugs.com|CDI|melatonin}}
| licence_EU = yes
| legal_UK = POM
| legal_AU = S4
| legal_US = OTC
| routes_of_administration = [[Oral route|Oral]], [[sublingual]], [[transdermal]]

<!--Pharmacokinetic data-->
| bioavailability = 30–50%
| metabolism = [[Liver|Hepatic]] via [[CYP1A2]] mediated 6-hydroxylation
| elimination_half-life = 35–50&nbsp;minutes
| excretion = [[Renal]]

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 73-31-4
| ATC_prefix = N05
| ATC_suffix = CH01
| PubChem = 896
| IUPHAR_ligand = 224
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01065
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 872
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = JL5DK93RCL
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08170
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16796
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 45

<!--Chemical data-->
| C=13 | H=16 | N=2 | O=2
| smiles = COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DRLFMBDRBRZALE-UHFFFAOYSA-N
}}

'''Melatonin''', also known as '''''N''-acetyl-5-methoxy tryptamine''',<ref>{{cite web| title=Melatonin| publisher=Sleepdex| accessdate=17 August 2011| url=http://www.sleepdex.org/melatonin.htm}}</ref> is a [[hormone]] that is produced by the [[pineal gland]] in animals and regulates sleep and wakefulness.<ref>{{cite journal | vauthors = Hardeland R, Pandi-Perumal SR, Cardinali DP | title = Melatonin | journal = The International Journal of Biochemistry & Cell Biology | volume = 38 | issue = 3 | pages = 313–16 | date = March 2006 | pmid = 16219483 | doi = 10.1016/j.biocel.2005.08.020 }}</ref> Melatonin is also produced in [[plants]] where it functions as a first line of defense against [[oxidative stress]].<ref name="Tan_2012">{{cite journal | vauthors = Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ | title = Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science | journal = Journal of Experimental Botany | volume = 63 | issue = 2 | pages = 577–97 | year = 2012 | pmid = 22016420 | doi = 10.1093/jxb/err256 }}</ref>

In animals, melatonin is involved in the [[Entrainment (chronobiology)|entrainment]] (synchronization) of the [[circadian rhythm]]s including sleep-wake timing, blood pressure regulation, seasonal reproduction, and many others.<ref name="Altun2007">{{cite journal |vauthors=Altun A, Ugur-Altun B | title = Melatonin: therapeutic and clinical utilization | journal = Int. J. Clin. Pract. | volume = 61 | issue = 5 | pages = 835–45 | date = May 2007 | pmid = 17298593 | doi = 10.1111/j.1742-1241.2006.01191.x }}</ref> Many of its biological effects in animals are produced through activation of [[melatonin receptor]]s,<ref name="Boutin2005">{{cite journal |vauthors=Boutin JA, Audinot V, Ferry G, Delagrange P | title = Molecular tools to study melatonin pathways and actions | journal = Trends Pharmacol. Sci. | volume = 26 | issue = 8 | pages = 412–19 | date = August 2005 | pmid = 15992934 | doi = 10.1016/j.tips.2005.06.006 }}</ref> while others are due to its role as an [[antioxidant]],<ref name="Hardeland2005">{{cite journal | author = Hardeland R | title = Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance | journal = Endocrine | volume = 27 | issue = 2 | pages = 119–30 | date = July 2005 | pmid = 16217125 | doi = 10.1385/ENDO:27:2:119 }}</ref> with a particular role in the protection of [[nuclear DNA|nuclear]] and [[mitochondrial DNA]].<ref name="Reiter2001">{{cite journal |vauthors=Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S | title = Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system | journal = Ann. N. Y. Acad. Sci. | volume = 939 | issue =  | pages = 200–15 | date = June 2001 | pmid = 11462772 | doi = 10.1111/j.1749-6632.2001.tb03627.x }}</ref>

As a medicine, it is used for the treatment of [[Insomnia#Melatonin|insomnia]]; however, scientific evidence is insufficient to demonstrate a benefit in this area.<ref name=Bra2015/> Melatonin is sold [[Over-the-counter drug|over the counter]] in the United States, Canada and some European countries. In other countries, it may require a [[Prescription drug|prescription]] or it may be unavailable.
{{TOC limit|3}}

==History==

Melatonin was first discovered in connection to the mechanism by which some [[amphibians]] and [[reptiles]] change the color of their skin.<ref name="Filadelfi1996">{{cite journal |vauthors=Filadelfi AM, Castrucci AM | title = Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates | journal = J. Pineal Res. | volume = 20 | issue = 4 | pages = 175–86 | date = May 1996 | pmid = 8836950 | doi = 10.1111/j.1600-079X.1996.tb00256.x }}</ref><ref name="Sugden2004">{{cite journal |vauthors=Sugden D, Davidson K, Hough KA, Teh MT | title = Melatonin, melatonin receptors and melanophores: a moving story | journal = Pigment Cell Res. | volume = 17 | issue = 5 | pages = 454–60 | date = October 2004 | pmid = 15357831 | doi = 10.1111/j.1600-0749.2004.00185.x }}</ref> As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark [[Epidermis (zoology)|epidermal]] [[melanophores]].<ref name="Coates">{{cite book | vauthors = Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD| title = Encyclopedia of dietary supplements | edition = | language = | publisher = Marcel Dekker | location = New York, N.Y | year = 2005 | origyear = | pages = 457–66 | quote = | isbn = 0-8247-5504-9 | url = https://books.google.com/?id=Sfmc-fRCj10C&pg=PA457&lpg=PA457&dq=Lerner+melatonin+history }}</ref><ref name="McCord">{{cite journal |vauthors=McCord CP, Allen FP |title=Evidences associating pineal gland function with alterations in pigmentation |date=January 1917 |journal=J Exptl Zool |volume= 23 |issue=1 |pages=206–24 |url=https://books.google.com/?id=OOM1AQAAMAAJ&pg=PA207 |doi=10.1002/jez.1400230108 }}</ref>

In 1958, dermatology professor [[Aaron B. Lerner]] and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.<ref name="pmid14415935">{{cite journal |vauthors=Lerner AB, Case JD, Takahashi Y | title = Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands | journal = J. Biol. Chem. | volume = 235 | issue =  | pages = 1992–97 | date = July 1960 | pmid = 14415935 | doi =  }}</ref> In the mid-70s Lynch ''et al.'' demonstrated<ref name="pmid1167425">{{cite journal |vauthors=Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH | title = Daily rhythm in human urinary melatonin | journal = Science | volume = 187 | issue = 4172 | pages = 169–71 | date = January 1975 | pmid = 1167425 | doi = 10.1126/science.1167425 | bibcode = 1975Sci...187..169L }}</ref> that the production of melatonin exhibits a circadian rhythm in human pineal glands.

The discovery that melatonin is an antioxidant was made in 1993.<ref name="scavenger">{{cite journal |vauthors=Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC | title = Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis | journal = J. Pineal Res. | volume = 14 | issue = 4 | pages = 151–68 | date = May 1993 | pmid = 8102180 | doi = 10.1111/j.1600-079X.1993.tb00498.x }}</ref>
The first [[patent]] for its use as a low-dose sleep aid was granted to [[Richard Wurtman]] at [[MIT]] in 1995.<ref>{{ cite patent | country = US | number = 5449683 | status = patent | title = Methods of inducing sleep using melatonin | gdate = 12 September 1995 | fdate = 1993-07-16 | inventor = Wurtman RJ | assign1 = Massachusetts Institute of Technology }}</ref> Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.<ref name="pmid16077149">{{cite journal | author = Arendt J | title = Melatonin: characteristics, concerns, and prospects | journal = J. Biol. Rhythms | volume = 20 | issue = 4 | pages = 291–303 | date = August 2005 | pmid = 16077149 | doi = 10.1177/0748730405277492 | 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. }}</ref> ''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."<ref name="pmid11027748">{{cite journal | author = Arendt J | title = Melatonin, circadian rhythms, and sleep | journal = N. Engl. J. Med. | volume = 343 | issue = 15 | pages = 1114–16 | date = October 2000 | pmid = 11027748 | doi = 10.1056/NEJM200010123431510 }}</ref>

==Medical uses==
[[Image:Walgreens Melatonin-2010-20-07.jpg|thumb|150px|A bottle of melatonin tablets:  additionally, melatonin is available in timed-release and in liquid forms.]]

===Sleep disorders===
Melatonin has been studied for [[insomnia]] in the elderly. Short-term treatment (up to three months) of prolonged-release melatonin was found to be effective and safe in improving [[Sleep onset latency|sleep latency]], sleep quality, and daytime alertness.<ref name="pmid22429105">{{cite journal |vauthors=Lemoine P, Zisapel N | title = Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia | journal = Expert Opin Pharmacother | volume = 13 | issue = 6 | pages = 895–905 | year = 2012 | pmid = 22429105 | doi = 10.1517/14656566.2012.667076 }}</ref>  

A 2016 review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease.<ref>{{cite journal|last1=McCleery|first1=Jenny|last2=Cohen|first2=Daniel A.|last3=Sharpley|first3=Ann L|title=Pharmacotherapies for sleep disturbances in dementia|journal=Cochrane Database of Systematic Reviews|date=16 November 2016|doi=10.1002/14651858.cd009178.pub3/full|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009178.pub3/full|publisher=John Wiley & Sons, Ltd|language=en}}</ref> 

Evidence for use of melatonin as a treatment for insomnia is, as of 2015, insufficient;<ref name=Bra2015/> low-quality evidence indicates it may speed the onset of sleep by 6 minutes.<ref name=Bra2015>{{cite journal |vauthors = Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ |title=Management of Insomnia Disorder[Internet] |journal= |volume= |issue= |pages= |year= |pmid=26844312 }}</ref>    A 2014 review found minimal evidence for efficacy in shift work.<ref name="Cochrane2014" /> 

A 2015 review of studies of melatonin in [[tinnitus]] found the quality of evidence low, but not entirely without promise.<ref>{{Cite journal|last=Miroddi|first=Marco|last2=Bruno|first2=Rocco|last3=Galletti|first3=Francesco|last4=Calapai|first4=Fabrizio|last5=Navarra|first5=Michele|last6=Gangemi|first6=Sebastiano|last7=Calapai|first7=Gioacchino|date=March 2015|title=Clinical pharmacology of melatonin in the treatment of tinnitus: a review|url=https://www.ncbi.nlm.nih.gov/pubmed/25597877|journal=European Journal of Clinical Pharmacology|volume=71|issue=3|pages=263–70|doi=10.1007/s00228-015-1805-3|issn=1432-1041|pmid=25597877}}</ref>

===Jet lag and shift work===

Melatonin is known to aid in reducing the effects of [[jet lag]], especially in eastward travel, by promoting the necessary reset of the body's sleep-wake phase. If the timing is not correct, however, it can instead delay adaption.<ref name="pubmed12076414"  >{{cite journal |pmid=12076414 | doi=10.1002/14651858.CD001520 | title=Melatonin for the prevention and treatment of jet lag | year=2002 | journal=Cochrane Database Syst Rev | pages=CD001520 |vauthors=Herxheimer A, Petrie KJ | issue=2}}</ref>

Melatonin appears also to have limited use against the sleep problems of people who work rotating or night [[shift work|shifts]].<ref name="Cochrane2014">{{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 = 8 | issue = 8 | page = CD009776 | date = August 2014 | pmid = 25113164 | doi = 10.1002/14651858.CD009776.pub2 }}</ref>

===Headaches===

Tentative evidence shows melatonin may help reduce some types of headaches including [[cluster headache|cluster]] and [[hypnic headache|hypnic]] headaches..<ref>{{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 }}</ref> <ref name="Evars05">{{cite journal |last1=Evars |first1=Stefan |last2=Goadsby |first2=Peter |year=2005 |title=Review: Hypnic headache |journal=Practical Neurology. Review |volume=5 |issue= |pages=144-49 |publisher=[[BMJ (company)|BMJ]] |url=http://pn.bmj.com/content/practneurol/5/3/144.full.pdf |accessdate=12 January 2018}}</ref>

===Cancer===
A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive.<ref>{{cite journal|last=National Cancer Institute|title=Topics in complementary and alternative therapies (PDQ)|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0053600/|publisher=National Cancer Institute, National Institutes of Health|accessdate=5 June 2013|date=May 2013|PMID=26389506}}</ref> A 2005 review of unblinded [[clinical trial]]s found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.<ref name="pmid16207291">{{cite journal |vauthors=Mills E, Wu P, Seely D, Guyatt G | title = Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis | journal = J. Pineal Res. | volume = 39 | issue = 4 | pages = 360–66 | date = November 2005 | pmid = 16207291 | doi = 10.1111/j.1600-079X.2005.00258.x }}</ref>

===Protection from radiation===

Both animal<ref name="pmid10082913">{{cite journal |vauthors=Meltz ML, Reiter RJ, Herman TS, Kumar KS | title = Melatonin and protection from whole-body irradiation: survival studies in mice | journal = Mutat. Res. | volume = 425 | issue = 1 | pages = 21–27 | date = March 1999 | pmid = 10082913 | doi = 10.1016/S0027-5107(98)00246-2 }}</ref> and human<ref name="pmid9008723">{{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 = Mutat. Res. | volume = 371 | issue = 3–4 | pages = 221–28 | date = December 1996 | pmid = 9008723 | doi= 10.1016/S0165-1218(96)90110-X }}</ref><ref>{{Cite journal|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002124.pub2/abstract|title=Dietary supplements for dysmenorrhoea|journal=Cochrane Database of Systematic Reviews|issue=3|last=Pattanittum|first=Porjai|last2=Kunyanone|first2=Naowarat|last3=Brown|first3=Julie|last4=Sangkomkamhang|first4=Ussanee S|last5=Barnes|first5=Joanne|last6=Seyfoddin|first6=Vahid|last7=Marjoribanks|first7=Jane|date=2016-03-22|publisher=John Wiley & Sons, Ltd|language=en|doi=10.1002/14651858.cd002124.pub2}}</ref><ref name="pmid9541644">{{cite journal |vauthors=Reiter RJ, Herman TS, Meltz ML | title = Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes | journal = Mutat. Res. | volume = 397 | issue = 2 | pages = 203–08 | date = February 1998 | pmid = 9541644 | doi = 10.1016/S0027-5107(97)00211-X }}</ref> 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.<ref name="Tan_Manchester"/> 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 major known side effects.<ref name="pmid17641465">{{cite journal |vauthors=Shirazi A, Ghobadi G, Ghazi-Khansari M | title = A radiobiological review on melatonin: a novel radioprotector | journal = J. Radiat. Res. | volume = 48 | issue = 4 | pages = 263–72 | date = July 2007 | pmid = 17641465 | doi = 10.1269/jrr.06070 }}</ref>

===Epilepsy===
A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.<ref name="BrigoIgwe2016">{{cite journal|last1=Brigo|first1=Francesco|last2=Igwe|first2=Stanley C|last3=Del Felice|first3=Alessandra|last4=Brigo|first4=Francesco|title=Melatonin as add-on treatment for epilepsy|year=2016|doi=10.1002/14651858.CD006967.pub4}}</ref>

===Secondary dysmenorrhoea===
A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhoea secondary to endometriosis.<ref>{{Cite book|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002124.pub2/abstract|title=Cochrane Database of Systematic Reviews|last=Pattanittum|first=Porjai|last2=Kunyanone|first2=Naowarat|last3=Brown|first3=Julie|last4=Sangkomkamhang|first4=Ussanee S|last5=Barnes|first5=Joanne|last6=Seyfoddin|first6=Vahid|last7=Marjoribanks|first7=Jane|date=2016-03-22|publisher=John Wiley & Sons, Ltd|isbn = |language=en|doi=10.1002/14651858.cd002124.pub2/full}}</ref>

===Delirium===
A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.<ref>{{Cite journal|last=Siddiqi|first=Najma|last2=Harrison|first2=Jennifer K.|last3=Clegg|first3=Andrew|last4=Teale|first4=Elizabeth A.|last5=Young|first5=John|last6=Taylor|first6=James|last7=Simpkins|first7=Samantha A.|date=2016-03-11|title=Interventions for preventing delirium in hospitalised non-ICU patients|url=http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005563.pub3/abstract| journal=The Cochrane Database of Systematic Reviews|volume=3|pages=CD005563|doi=10.1002/14651858.CD005563.pub3|issn=1469-493X|pmid=26967259}} [http://eprints.whiterose.ac.uk/99189/ Open access repository] {{Open access}}</ref>

===Gastroesophageal reflux disease===

A 2011 review said melatonin is effective line in relieving epigastric pain and heartburn.<ref name="Kandil10">{{cite journal |last1=Kandil |first1=T |last2=Moussa |first2=A |last3=El-Gendy |first3=AA |last4=Abbas |first4=AM |year=2010 |title=A The potential therapeutic effect of melatonin in Gastro-Esohageal Reflux Disease |journal=[[BMC Gastroenterology]]. Review. |volume=10 |issue= |pages=7 |publisher=BioMed Central |doi=10.1186/1471-230X-10-7 |url=https://www.ncbi.nlm.nih.gov/pubmed/20082715 |accessdate=12 January 2018}}</ref>

===Psychiatry===

Melatonin might improve sleep in [[autism spectrum|autistic]] people.<ref name=asd>{{cite journal |vauthors=Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM | title = Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis | journal = Dev Med Child Neurol | volume = 51 | issue = 5 | pages = 340–49 | date = May 2009 | pmid = 19379289 | doi = 10.1111/j.1469-8749.2008.03244.x | type = Meta-analysis }}</ref> Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin.<ref name=melatoninlevels>{{cite journal |vauthors=Rossignol DA, Frye RE | title = Melatonin in autism spectrum disorders: a systematic review and meta-analysis. | journal = Dev Med Child Neurol | volume = 53 | issue = 9 | pages = 783–92 | date = April 2011 | pmid = 21518346 | doi = 10.1111/j.1469-8749.2011.03980.x | type = Meta-analysis }}</ref><ref name=melatoninlevels2>{{cite journal | vauthors = Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, Malow BA | title = Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay. | journal = J Autism Dev Disord | volume = 45 | issue = 1 | pages = 100–10 | date = January 2015 | pmid = 25059483 | doi = 10.1007/s10803-014-2197-4 | pmc=4289108}}</ref> Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings.<ref name="melatoninlevels"/><ref>{{cite web|title=Melatonin improves sleep quality and behavior in children with asperger disorder.|url=http://www.truthlyapp.com/truths/514-melatonin-improves-sleep-quality-and-behavior-in-children-with-asperger-disorder|website=Truthly|accessdate=15 February 2015}}</ref><ref>{{cite journal |vauthors=Giannotti F, Cortesi F, Cerquiglini A, Bernabei P | title = An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. | journal = J Autism Dev Disord | volume = 36 | issue = 6 | pages = 741–52 | date = August 2006 | pmid = 16897403 | doi=10.1007/s10803-006-0116-z}}</ref> However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed.

While the packaging of melatonin often warns against use in people under 18 years of age, available studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD. However, larger and longer studies are needed to establish long-term safety and optimal dosing.<ref name="pmid20028959">{{cite journal |vauthors=Bendz LM, Scates AC | title = Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder | journal = Ann Pharmacother | volume = 44 | issue = 1 | pages = 185–91 |date=January 2010 | pmid = 20028959 | doi = 10.1345/aph.1M365 }}</ref>

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 midazolam in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.<ref>{{Cite journal |vauthors=Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM | title =Melatonin for pre- and postoperative anxiety in adults. | journal = Cochrane Database Syst Rev | issue = 4 | page = CD009861| year = 2015 | doi = 10.1002/14651858.CD009861.pub2 | pmid=25856551}}</ref>

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]].<ref name=Lewis>{{cite book |title=Melatonin and the Biological Clock |last=Lewis |first=Alan |publisher=McGraw-Hill |isbn=0-87983-734-9 |year=1999 |page=23}}</ref>

==Adverse effects==
Melatonin appears to cause very few [[Adverse effect (medicine)|side effects]] as tested in the short term, up to three months, at low doses. 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]].<ref name="pmid16423108">{{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 = 1151–58 | year = 2005 | pmid = 16423108 | pmc = 1490287 | doi = 10.1111/j.1525-1497.2005.0243.x }}</ref><ref name="Buscemi2006">{{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 }}</ref> Prolonged-release melatonin is safe with long-term use of up to 12 months.<ref name="pmid23044640">{{cite journal | author = 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 | year = 2012 | pmid = 23044640 | doi = 10.1007/s40266-012-0018-z }}</ref>

Melatonin can cause [[nausea]], next-day [[grogginess]], and irritability.<ref>{{cite web| title=Melatonin side effects: What are the risks?| publisher=Mayo Clinic| author=Brent Bauer, M.D.| accessdate=17 August 2011| url=http://www.mayoclinic.com/health/melatonin-side-effects/AN01717}}</ref> In the elderly, it can cause reduced blood flow and [[hypothermia]].<ref name="pmid11600532">{{cite journal |vauthors=Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU | title = Melatonin treatment for age-related insomnia | journal = J. Clin. Endocrinol. Metab. | volume = 86 | issue = 10 | pages = 4727–30 | date = October 2001 | pmid = 11600532 | doi = 10.1210/jc.86.10.4727 }}</ref> In [[autoimmune disorders]], evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to [[Immunomodulator|immunomodulation]].<ref name="Morera2001">{{cite journal |vauthors=Morera AL, Henry M, de La Varga M | title = Seguridad en el uso de la melatonina | language = es | journal = Actas Esp Psiquiatr | volume = 29 | issue = 5 | pages = 334–37 | year = 2001 | pmid = 11602091 | doi =  |trans-title=Safety in melatonin use }}</ref><ref name="Terry2008">{{cite journal |vauthors=Terry PD, Villinger F, Bubenik GA, Sitaraman SV | title = Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research | journal = Inflamm. Bowel Dis. | volume = 15 | issue = 1 | pages = 134–40 | date = January 2009 | pmid = 18626968 | doi = 10.1002/ibd.20527 }}</ref>

Melatonin can lower [[follicle-stimulating hormone]] levels.<ref name="pmid16921343">{{cite journal |vauthors=Juszczak M, Michalska M | title = Wpływ melatoniny na syntezę i wydzielanie prolaktyny, hormonu luteinizującego (LH) i folikulotropowego (FSH) | language = pl | journal = Postepy Hig Med Dosw (Online) | volume = 60 | issue =  | pages = 431–38 | year = 2006 | pmid = 16921343 | doi =  | 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 }}</ref> Effects of melatonin on human reproduction remain unclear,<ref name="pmid19905996">{{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 = Gynecol. Endocrinol. | volume = 25 | issue = 12 | pages = 779–85 | date = December 2009 | pmid = 19905996 | doi = 10.3109/09513590903159649 }}</ref> although it was with some effect tried as a contraceptive in the 1990s.<ref>{{cite book |vauthors=Cohen M, van Heusden AM, Verdonk HE, Wijnhamer P |chapter=Melatonin/Norethisterone contraception |veditors=Touitou Y, Arendt J, Pevet P |title=Melatonin and the Pineal Gland – From Basic Science to Clinical Application |location=Amsterdam |publisher=Elsevier |year=1993 |pages=339–45 |isbn=978-0-444-89583-7}}</ref>

Anticoagulants and other substances are known to interact with melatonin.<ref>{{cite web|title=Possible Interactions with: Melatonin|url=http://www.umm.edu/health/medical/altmed/supplement-interaction/possible-interactions-with-melatonin|website=University of Maryland Medical Center|accessdate=27 January 2016|date=2007|quote=Melatonin may increase the risk of bleeding from anticoagulant medications such as warfarin.}}</ref>

==Functions==

===Circadian rhythm===

In animals, the primary function is regulation of day-night cycles. Human infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.<ref name="pmid12589109">{{cite journal |vauthors=Ardura J, Gutierrez R, Andres J, Agapito T | title = Emergence and evolution of the circadian rhythm of melatonin in children | journal = Horm. Res. | volume = 59 | issue = 2 | pages = 66–72 | year = 2003 | pmid = 12589109 | doi = 10.1159/000068571 }}</ref> Human melatonin production decreases as a person ages.<ref name="pmid3783419">{{cite journal |vauthors=Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM | title = Human melatonin production decreases with age | journal = J. Pineal Res. | volume = 3 | issue = 4 | pages = 379–88 | year = 1986 | pmid = 3783419 | doi = 10.1111/j.1600-079X.1986.tb00760.x }}</ref> Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.<ref>{{cite web | title = Why Aren't Teens Getting Enough Sleep? | url = http://kidshealth.org/teen/your_body/take_care/how_much_sleep.html |work=How Much Sleep Do I Need? |year=2009 |vauthors=Gavin ML, Scaivina MT }}</ref>

====Antioxidant====
Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant.<ref>{{cite journal |vauthors=Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ | title = Melatonin: a potent, endogenous hydroxyl radical scavenger | journal = Endocrine J. | year = 1993 | volume = 1 | pages = 57–60 | url = https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxkdW54aWFudGFufGd4OjVkMjA5NGZkMzFmYjRkOTU}}</ref> In many less-complex life forms, this is its only known function.<ref name="Tan_Manchester">{{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 = J. Pineal Res. | volume = 42 | issue = 1 | pages = 28–42 | date = January 2007 | pmid = 17198536 | doi = 10.1111/j.1600-079X.2006.00407.x }}</ref> Melatonin is an [[antioxidant]] that can easily cross [[cell membrane]]s and the blood-brain barrier.<ref name="Hardeland2005"/><ref name="pmid21358970">{{cite journal |vauthors=Reiter RJ, Manchester LC, Tan DX | title = Neurotoxins: free radical mechanisms and melatonin protection | journal = Curr Neuropharmacol | volume = 8 | issue = 3 | pages = 194–210 | date = September 2010 | pmid = 21358970 | pmc = 3001213 | doi = 10.2174/157015910792246236 }}</ref>
This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH<sup>•</sup>, O<sup>•</sup><sub>2</sub><sup>−</sup>, and NO<sup>•</sup>.<ref name="pmid7832450">{{cite journal |vauthors=Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR | title = Melatonin – a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro | journal = Ann. N. Y. Acad. Sci. | volume = 738 | issue =  | pages = 419–20 | date = November 1994 | pmid = 7832450 | doi = 10.1111/j.1749-6632.1994.tb21831.x | bibcode = 1994NYASA.738..419P }}</ref><ref name="Melatonin Plants">{{cite journal |vauthors=Arnao MB, Hernández-Ruiz J | title = The physiological function of melatonin in plants | journal = Plant Signal Behav | volume = 1 | issue = 3 | pages = 89–95 | date = May 2006 | pmid = 19521488 | pmc = 2635004 | doi = 10.4161/psb.1.3.2640 }}</ref> Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.<ref name="Melatonin Plants" /> Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.<ref name="pmid7934611">{{cite journal |vauthors=Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F | title = Melatonin: a peroxyl radical scavenger more effective than vitamin E | journal = Life Sci. | volume = 55 | issue = 15 | pages = PL271–76 | year = 1994 | pmid = 7934611 | doi = 10.1016/0024-3205(94)00666-0 }}</ref> An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction.<ref name="Tan_Manchester" /> Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochondrial-targeted antioxidants ([[MitoQ]] and MitoE), melatonin proved to be a comparable protector against mitochondrial oxidative stress.<ref name="pmid23381720">{{cite journal |vauthors=Lowes DA, Webster NR, Murphy MP, Galley HF | title = Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis | journal = Br J Anaesth | volume = 110 | issue = 3 | pages = 472–80 | date = March 2013 | pmid = 23381720 | pmc = 3570068 | doi = 10.1093/bja/aes577 }}</ref>

===Immune system===
While it is known that melatonin interacts with the [[immune system]],<ref name="Carrillo-Vico2005">{{cite journal |vauthors=Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ | title = A review of the multiple actions of melatonin on the immune system | journal = Endocrine | volume = 27 | issue = 2 | pages = 189–200 | date = July 2005 | pmid = 16217132 | doi = 10.1385/ENDO:27:2:189 }}</ref><ref name="Arushanian2002">{{cite journal |vauthors=Arushanian EB, Beĭer EV | title = [Immunotropic properties of pineal melatonin] | language = Russian | journal = Eksp Klin Farmakol | volume = 65 | issue = 5 | pages = 73–80 | year = 2002 | pmid = 12596522 | doi =  }}</ref> the details of those interactions are unclear. [[Antiinflammatory]] effect seems to be the most relevant and most documented in the literature. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance [[cytokine]] production,<ref name="pmid16729718">{{cite journal |vauthors=Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D | title = The modulatory role of melatonin on immune responsiveness | journal = Curr Opin Investig Drugs | volume = 7 | issue = 5 | pages = 423–31 | date = May 2006 | pmid = 16729718 | doi =  }}</ref> and by doing this, counteract [[acquired immunodeficiences]]. Some studies also suggest that melatonin might be useful fighting infectious disease<ref name="Pp">{{cite journal | author = Maestroni GJ | title = The immunotherapeutic potential of melatonin | journal = Expert Opin Investig Drugs | volume = 10 | issue = 3 | pages = 467–76 | date = March 2001 | pmid = 11227046 | doi = 10.1517/13543784.10.3.467 }}</ref> including viral, such as [[HIV]], and bacterial infections, and potentially in the treatment of [[cancer]].

==Biosynthesis and pharmacology==

===Biosynthesis===

[[File:Mealtonin biosynth.jpg|thumb|Overview of Melatonin Biosynthesis]]

In animals, biosynthesis of melatonin occurs through [[hydroxylation]], [[decarboxylation]], [[acetylation]] and a [[methylation]] starting with [[L-tryptophan]].<ref>{{cite web |url=http://www.metacyc.org/META/new-image?type=PATHWAY&object=PWY-6030&detail-level=2&ENZORG=TAX-9606 |title=MetaCyc serotonin and melatonin biosynthesis |format= |work= |accessdate=}}</ref> L-tryptophan is produced in the [[shikimate pathway]] from [[chorismate]] or is acquired from [[protein catabolism]]. First L-tryptophan is hydroxylated on the [[indole ring]] by [[tryptophan hydroxylase]] to produce [[5-hydroxytryptophan]]. This intermediate (5-HTP) is decarboxylated by [[pyridoxal phosphate]] and [[5-hydroxytryptophan decarboxylase]] to produce [[serotonin]]. Serotonin is itself an important [[neurotransmitter]], but is also converted into [[N-Acetylserotonin|N-acetylserotonin]] by [[serotonin N-acetyltransferase]] and [[acetyl-CoA]]. [[Hydroxyindole O-methyltransferase]] and [[S-Adenosyl methionine|S-adenosyl methionine]] convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.

In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimate pathway. In these cells, synthesis starts with [[D-erythrose 4-phosphate]] and [[phosphoenolpyruvate]], and in [[Photosynthesis|photosynthetic cells]] with carbon dioxide. The rest of the synthesising reactions are similar, but with slight variations in the last two enzymes.<ref>{{cite journal | vauthors = Bochkov DV, Sysolyatin SV, Kalashnikov AI, Surmacheva IA | title = Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources | journal = Journal of Chemical Biology | volume = 5 | issue = 1 | pages = 5–17 | date = January 2012 | pmid = 22826715 | pmc = 3251648 | doi = 10.1007/s12154-011-0064-8 }}</ref><ref name="hardeland2015" />

===Mechanism===

[[File:Melatonin_mechanism.jpg|thumb|Mechanism of Melatonin Biosynthesis]]

In order to hydroxylate L-tryptophan, the cofactor [[tetrahydrobiopterin]] (THB) must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:

1. A slow transfer of one electron from the THB to O<sub>2</sub> could produce a [[superoxide]] which could recombine with the THB [[radical (chemistry)|radical]] to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.

2. O<sub>2</sub> could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the THB to form an iron-peroxypterin intermediate.

Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a [[carbocation]] at the C5 position of the indole ring. A 1,2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes [[aromaticity]] to furnish 5-hydroxy-L-tryptophan.<ref>{{cite journal |vauthors=Roberts KM, Fitzpatrick PF |title=Mechanisms of tryptophan and tyrosine hydroxylase |journal=IUBMB Life |volume=65 |issue=4 |pages=350–57 |year=2013 |pmid=23441081 |pmc=4270200 |doi=10.1002/iub.1144 }}</ref>

A decarboxylase with cofactor [[pyridoxal phosphate]] (PLP) removes CO<sub>2</sub> from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine.<ref>{{cite journal |vauthors=Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T |title=Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis |journal=Biochemistry |volume=31 |issue=8 |pages=2229–38 |year=1992 |pmid=1540578 |doi= 10.1021/bi00123a004}}</ref> PLP forms an [[imine]] with the amino acid derivative. The amine on the pyridine is [[protonation|protonated]] and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO<sub>2</sub>. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.<ref name="ReferenceA">{{ cite book | author = Dewick PM | year = 2002 | title = Medicinal Natural Products. A Biosynthetic Approach | edition = 2nd | publisher = Wiley | isbn = 0-471-49640-5 }}</ref>

It has been proposed that [[histidine]] residue His122 of serotonin N-acetyl transferase is the catalytic residue that [[deprotonation|deprotonates]] the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The [[thiol]] from [[coenzyme A]] serves as a good leaving group when attacked by a general base to give N-acetylserotonin.<ref>{{cite journal |vauthors=Hickman AB, Klein DC, Dyda F |title=Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism |journal=Mol. Cell |volume=3 |issue=1 |pages=23–32 |year=1999 |pmid=10024876 |doi= 10.1016/S1097-2765(00)80171-9}}</ref>

N-acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce [[S-adenosyl homocysteine]] (SAH) and melatonin.<ref name="ReferenceA"/><ref>{{cite journal |vauthors=Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC |title=Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA |journal=DNA Cell Biol. |volume=12 |issue=8 |pages=715–27 |year=1993 |pmid=8397829 |doi=10.1089/dna.1993.12.715 }}</ref>

===Regulation===

In vertebrates, melatonin secretion is regulated by [[norepinephrine]]. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by [[Proteasome|proteasomal]] [[proteolysis]].<ref>{{cite journal | vauthors = Schomerus C, Korf HW | title = Mechanisms regulating melatonin synthesis in the mammalian pineal organ | journal = Annals of the New York Academy of Sciences | volume = 1057 | issue = 1 | pages = 372–83 | date = December 2005 | pmid = 16399907 | doi = 10.1196/annals.1356.028 }}</ref> Production of melatonin is again started in the evening at the point called the [[dim-light melatonin onset]].

Blue light, principally around 460 to 480&nbsp;[[Nanometre|nm]], suppresses melatonin,<ref name="Brainard 2001">{{cite journal |vauthors=Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD | title = Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor | journal = J. Neurosci. | volume = 21 | issue = 16 | pages = 6405–12 | date = August 2001 | pmid = 11487664 | doi =  }}</ref> proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light.{{citation needed |reason=Of questionable relevance. Animals show the same pattern of blue light sensitivity | date=July 2016}} The [[incandescent light bulb]] widely used in the 20th century produced relatively little blue light.<ref>{{cite web|url=http://www.graphics.cornell.edu/online/measurements/source-spectra/index.html|title=Recent News - Program of Computer Graphics|website=www.graphics.cornell.edu}}</ref> <!-- Kayumov ''et al.'' showed that --> Light containing only wavelengths greater than 530&nbsp;nm does not suppress melatonin in bright-light conditions.<ref name="Kayumov 2005">{{cite journal |vauthors=Kayumov L, Casper RF, Hawa RJ, Perelman B, Chung SA, Sokalsky S, Shapiro CM | title = Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work | journal = J. Clin. Endocrinol. Metab. | volume = 90 | issue = 5 | pages = 2755–61 | date = May 2005 | pmid = 15713707 | doi = 10.1210/jc.2004-2062 }}</ref> Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.<ref>{{cite journal |vauthors=Burkhart K, Phelps JR | title = Amber lenses to block blue light and improve sleep: a randomized trial | journal = Chronobiol Int | volume = 26 | issue = 8 | pages = 1602–12 | date = 26 December 2009 | pmid = 20030543 | doi = 10.3109/07420520903523719 }}</ref>

===Pharmacology===
In pharmacological terms, melatonin works by activating one of two pharmacological receptors; MT1 or MT2. These are both G-protein coupled membrane receptors.<ref>{{Cite web|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=39|title=Melatonin receptors {{!}} G protein-coupled receptors {{!}} IUPHAR/BPS Guide to Pharmacology|website=www.guidetopharmacology.org|language=en|access-date=2017-04-07}}</ref>  
When used several hours before sleep according to the [[phase response curve]] for melatonin in humans, small amounts (0.3&nbsp;mg<ref name="pmid16295212">{{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 = 1271–78 | date = October 2005 | pmid = 16295212 | doi =  }}</ref>) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.<ref name="isbn 3-8055-9120-9">{{cite book |vauthors=Terman MR, Wirz-Justice A | title = Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy | publisher = S Karger Pub | location = Basel | year = 2009 | page = 71 | isbn = 3-8055-9120-9 }}</ref>  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.<ref name="USAHRQ">{{cite journal |vauthors=Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T | title = Melatonin for treatment of sleep disorders | journal = Evidence Report/Technology Assessment (Summary) | volume =  | issue = 108 | pages = 1–7 | date = November 2004 | pmid = 15635761 | doi =  | url = https://www.ncbi.nlm.nih.gov/books/NBK37431/ | pmc=4781368}}</ref>

== Animals ==

In vertebrates, melatonin is produced in darkness, thus usually at night, by the [[pineal gland]], a small endocrine gland<ref name="Reiter">{{cite journal | author = Reiter RJ | title = Pineal melatonin: cell biology of its synthesis and of its physiological interactions | journal = Endocr. Rev. | volume = 12 | issue = 2 | pages = 151–80 | date = May 1991 | pmid = 1649044 | doi = 10.1210/edrv-12-2-151 }}</ref>
located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the [[suprachiasmatic nucleus|suprachiasmatic nuclei]] <!-- (SCN) --> from retinal [[photosensitive ganglion cell]]s of the eyes<ref name="Richardson2005">{{cite journal | author = Richardson GS | title = The human circadian system in normal and disordered sleep | journal = J Clin Psychiatry | volume = 66 Suppl 9 | issue =  | pages = 3–9; quiz 42–3 | year = 2005 | pmid = 16336035 | doi =  }}</ref><ref name="Perreau-Lenz2004">{{cite journal |vauthors=Perreau-Lenz S, Pévet P, Buijs RM, Kalsbeek A | title = The biological clock: the bodyguard of temporal homeostasis | journal = Chronobiol. Int. | volume = 21 | issue = 1 | pages = 1–25 | date = January 2004 | pmid = 15129821 | doi = 10.1081/CBI-120027984 }}</ref> rather than the melatonin signal (as was once postulated). Known as "the hormone of darkness", the onset of melatonin at dusk promotes activity in [[nocturnal]] (night-active) animals and sleep in diurnal ones including humans.

Many animals use the variation in duration of melatonin production each day as a seasonal clock.<ref name="Lincoln2003">{{cite journal |vauthors=Lincoln GA, Andersson H, Loudon A | title = Clock genes in calendar cells as the basis of annual timekeeping in mammals – a unifying hypothesis | journal = J. Endocrinol. | volume = 179 | issue = 1 | pages = 1–13 | date = October 2003 | pmid = 14529560 | doi = 10.1677/joe.0.1790001 }}</ref> In animals including humans,<ref name="Arendt2005">{{cite journal |vauthors=Arendt J, Skene DJ | title = Melatonin as a chronobiotic | journal = Sleep Med Rev | volume = 9 | issue = 1 | pages = 25–39 | date = February 2005 | pmid = 15649736 | doi = 10.1016/j.smrv.2004.05.002 | quote = Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn), it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times. }}</ref> the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent ([[Photoperiodism|photoperiodic]]) seasonal functions such as reproduction, behavior, coat growth, and camouflage [[Animal colouration|coloring]] in seasonal animals.<ref name="Arendt2005"/> In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds<ref name="Chaturvedi">{{cite journal | pages = 803–09 | doi = 10.1071/ZO9840803 | url = http://www.publish.csiro.au/paper/ZO9840803.htm | title = Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis | year = 1984 | author = Chaturvedi CM | journal = Australian Journal of Zoology | volume = 32 | issue = 6}}</ref> and hamsters.<ref name="Chen1981">{{cite journal | author = Chen HJ | title = Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition | journal = Neuroendocrinology | volume = 33 | issue = 1 | pages = 43–46 | date = July 1981 | pmid = 7254478 | doi = 10.1159/000123198 }}</ref> Melatonin can suppress [[libido]] by inhibiting secretion of [[luteinizing hormone]] <!-- (LH) --> and [[follicle-stimulating hormone]] <!-- (FSH) --> from the [[anterior pituitary]] gland, especially in mammals that have a [[Reproduction|breeding]] season when daylight hours are long. The reproduction of [[Polyestrous|long-day breeders]] is [[Estrous cycle#Anestrus|repressed by melatonin]] and the reproduction of [[Polyestrous|short-day breeders]] is stimulated by melatonin.

During the night, melatonin regulates [[leptin]], lowering its levels.

== Plants ==
Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone.  When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds in varying proportions.<ref>{{cite journal | vauthors = Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ | title = Phytomelatonin: a review| journal = Journal of Experimental Botany | volume = 60 | issue = 1 | pages = 57–69 | date = 2009-01-01 | pmid = 19033551 | doi = 10.1093/jxb/ern284 }}</ref><ref name="tan2012">{{cite journal | vauthors = Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ | title = Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science| journal = Journal of Experimental Botany | volume = 63 | issue = 2 | pages = 577–97 | date = January 2012 | pmid = 22016420 | doi = 10.1093/jxb/err256 }}</ref> Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram.<ref name="Bonnefont-Rousselot 2010 55–67">{{cite journal | vauthors = Bonnefont-Rousselot D, Collin F | title = Melatonin: action as antioxidant and potential applications in human disease and aging | journal = Toxicology | volume = 278 | issue = 1 | pages = 55–67 | date = November 2010 | pmid = 20417677 | doi = 10.1016/j.tox.2010.04.008 }}</ref><ref name="hardeland2015">{{cite journal | vauthors = Hardeland R | title = Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions| journal = Journal of Experimental Botany | volume = 66 | issue = 3 | pages = 627–46 | date = February 2015 | pmid = 25240067 | doi = 10.1093/jxb/eru386 }}</ref> Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats.<ref name="tan2012"/> Melatonin is a poor direct antioxidant, it is, however, a highly efficient direct free radical scavenger and indirect antioxidant due to its ability to stimulate antioxidant enzymes.<ref name="pmid8855441">{{cite journal | vauthors = Marshall KA, Reiter RJ, Poeggeler B, Aruoma OI, Halliwell B | title = Evaluation of the antioxidant activity of melatonin in vitro | journal = Free Radical Biology & Medicine | volume = 21 | issue = 3 | pages = 307–15 | year = 1996 | pmid = 8855441 | doi = 10.1016/0891-5849(96)00046-9 }}</ref><ref>{{cite journal | vauthors = Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R | title = Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 2 | pages = 181–97 | date = February 2002 | pmid = 11899100 | doi = 10.2174/1568026023394443 }}</ref><ref name="reiter2015">{{cite journal | vauthors = Reiter RJ, Tan DX, Zhou Z, Cruz MH, Fuentes-Broto L, Galano A | title = Phytomelatonin: assisting plants to survive and thrive| journal = Molecules | volume = 20 | issue = 4 | pages = 7396–437 | date = April 2015 | pmid = 25911967 | doi = 10.3390/molecules20047396 }}</ref> Thus, melatonin in the human diet is believed to confer a number of beneficial health-related effects.<ref name="tan2012"/><ref name="Bonnefont-Rousselot 2010 55–67"/><ref>{{cite journal | vauthors = Iriti M, Varoni EM, Vitalini S | title = Melatonin in traditional Mediterranean diets| journal = Journal of Pineal Research | volume = 49 | issue = 2 | pages = 101–05 | date = September 2010 | pmid = 20536683 | doi = 10.1111/j.1600-079X.2010.00777.x  }}</ref> In some common foods and beverages, including coffee<ref name="tan2012"/> and walnuts,<ref>{{cite journal | vauthors = Reiter RJ, Manchester LC, Tan DX | title = Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood | journal = Nutrition | volume = 21 | issue = 9 | pages = 920–24 | date = September 2005 | pmid = 15979282 | doi = 10.1016/j.nut.2005.02.005 }}</ref> the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established.  Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased [[soil salinity]], drought, etc.<ref name="hardeland2015"/><ref name="reiter2015"/><ref>{{cite journal | vauthors = Arnao MB, Hernández-Ruiz J | title = Functions of melatonin in plants: a review| journal = Journal of Pineal Research | volume = 59 | issue = 2 | pages = 133–50 | date = September 2015 | pmid = 26094813 | doi = 10.1111/jpi.12253 }}</ref>

Research from the University of Buffalo has found that the substances used in the manufacturing of pesticides bind to melatonin receptors and can influence the circadian rhythm.<ref>{{Cite news|url=https://www.sleepassociation.org/patients-general-public/insomnia/melatonin/|title=Melatonin and Sleep: Hormone Uses, Dose, & Effects on Sleep|work=American Sleep Association|access-date=2018-01-14|language=en-US}}</ref>

==Exogenous melatonin==

===Dietary supplement and neurohormone===

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.<ref name = "Buscemi_2004">{{cite web|vauthors=Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T | title = Melatonin for treatment of sleep disorders | url = http://archive.ahrq.gov/downloads/pub/evidence/pdf/melatonin/melatonin.pdf | publisher = Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services | accessdate = 5 June 2013 |date=November 2004 | work = 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 }}</ref> The FDA regulations applying to medications are not applicable to melatonin.<ref name="Altun2007"/> From June 2010 onward, production of dietary supplements must comply with "current [[good manufacturing practice]]s" (cGMP) and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling."<ref>{{cite press release | title = FDA Issues Dietary Supplements Final Rule | publisher = U.S. Food and Drug Administration | date = 22 June 2007 | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108938.htm | accessdate = 4 August 2009}}</ref> The industry has also been required to report to the FDA "all serious dietary supplement related adverse events", and the FDA has (within the cGMP guidelines) begun enforcement of that requirement.<ref>{{cite web | url= http://www.medicalnewstoday.com/articles/75250.php | title = FDA Tightens Up Dietary Supplement Manufacturing And Labelling | website= Medical News Today | accessdate = 2 September 2013 | date = 26 June 2007}}</ref>

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.<ref name="pubmed12076414" />

In many countries, melatonin is recognized as a [[neurohormone]] and it cannot be sold over-the-counter.<ref name="Toxicology">{{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 }}</ref>

===Food products===
Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46&nbsp;ng/g,<ref name="pmid11600041">{{cite journal |vauthors=Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ | title = Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus) | journal = J. Agric. Food Chem. | volume = 49 | issue = 10 | pages = 4898–902 | date = October 2001 | pmid = 11600041 | doi = 10.1021/jf010321 }}</ref> bananas and grapes, rice and cereals, herbs, plums,<ref>{{cite journal | vauthors = González-Flores D, Velardo B, Garrido M, González-Gómez D, Lozano M, Ayuso MC, Barriga C, Paredes SD, Rodríguez AB | year = 2011 | url =  https://www.researchgate.net/publication/259983119 | title = Ingestion of Japanese plums (Prunus salicina Lindl. cv. Crimson Globe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content | journal = Journal of Food and Nutrition Research | volume= 50 | issue = 4 | pages = 229–36 }}</ref> olive oil, [[wine]]<ref name="pmid21342247">{{cite journal |vauthors=Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S | title = Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection | journal = J. Pi JJ Res. | volume = 50 | issue = 4 | pages = 374–80 | date = May 2011 | pmid = 21342247 | doi = 10.1111/j.1600-079X.2010.00853.x }}</ref> and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.<ref name="Hattori1995">{{cite journal |vauthors=Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ | title = Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates | journal = Biochem. Mol. Biol. Int. | volume = 35 | issue = 3 | pages = 627–34 | date = March 1995 | pmid = 7773197 }}</ref> When humans consume foods rich in melatonin such as banana, pineapple and orange, the blood levels of melatonin increase significantly.<ref name="pmid23137025">{{cite journal |vauthors=Sae-Teaw M, Johns J, Johns NP, Subongkot S | title = Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers | journal = J. Pineal Res. | volume = 55 | issue = 1 | pages = 58–64 | date = October 2012 | pmid = 23137025 | doi = 10.1111/jpi.12025 }}</ref>

As reported in the ''New York Times'' in May 2011,<ref name="NYTimes May 2011">{{cite news |url = https://www.nytimes.com/2011/05/15/us/15lazycakes.html?_r=1&scp=1&sq=lazy%20cakes&st=cse |work=New York Times |title=Dessert, Laid-Back and Legal | date=14 May 2011 |author=Catherine Saint Louis }}</ref> beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs. 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]].<ref name="FDAwarning" >{{cite web | url = https://wayback.archive-it.org/7993/20170112195035/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 }}</ref> A different company selling a melatonin-containing beverage received a Warning Letter in 2015.<ref>[https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm440953.htm Bebida Beverage Company] U.S. Food and Drug Administration March 4, 2015 (Accessed December 8, 2017)</ref>

==Commercial Availability==

[[File:Melatonin prescription.jpg|thumb|right|[[University of Helsinki]] pharmaceutical laboratory prepared melatonin available upon prescription]]

Immediate-release melatonin is not tightly regulated in countries where it is available as an over-the-counter medication.  It is available in doses from less than half a milligram to 5&nbsp;mg or more. Immediate-release formulations cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, tablets, or liquids.  It is also available for use sublingually, or as transdermal patches.

Formerly, melatonin was derived from animal pineal tissue, such as bovine.  It is now synthetic and does not carry a risk of contamination or the means of transmitting infectious material.<ref name="Altun2007"/><ref>{{cite web |url=http://www.drugs.com/melatonin.html |title=Melatonin| publisher=[[Drugs.com]]| accessdate=17 August 2011}}</ref>

Melatonin is available as a prolonged-release prescription drug. It releases melatonin gradually over 8–10 hours, intended to mimic the body's internal secretion profile.

==See also==
* [[5-Methoxytryptamine]]
* [[6-Hydroxymelatonin]]
* [[Agomelatine]]
* [[Health effects of sunlight exposure]]
* [[Melatonin receptor agonist#Drug design and development]]
* [[Ramelteon]]
* [[Sundowning]]
* [[Tasimelteon]]

==References==
{{Reflist}}

== External links ==
{{Commons category}}

* [http://tihkal.info/read.php?domain=tk&id=35 Melatonin entry in TiHKAL • info]

{{Hormones}}
{{Antioxidants}}
{{Dietary supplement}}
{{Hypnotics and sedatives}}
{{Insomnia pharmacotherapies}}
{{Melatonergics}}
{{Tryptamines}}
{{Authority control}}
{{TiHKAL}}

[[Category:Acetamides]]
[[Category:Antioxidants]]
[[Category:Aromatase inhibitors]]
[[Category:Circadian rhythm]]
[[Category:Drugs acting on the nervous system]]
[[Category:Hormones of the pineal gland]]
[[Category:Melatonin receptor agonists]]
[[Category:Phenol ethers]]
[[Category:Treatment of bipolar disorder]]
[[Category:Tryptamine alkaloids]]
[[Category:Melatonin]]