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			{{Short description|Hormone released by the pineal gland}}
	{{Primary sources|date=March 2011}}
			{{Hatnote|Not to be confused with ]. For the album, see ''Melatonin'' (album). For the video game see ]}}
	{{Distinguish|melanin|Melanotan (disambiguation)|}}
			{{About|melatonin as a hormone|its role as a supplement and medication|Melatonin as a medication and supplement}}
	{{drugbox
			{{cs1 config|name-list-style=vanc}}
	| verifiedrevid = 419141674
			{{Use dmy dates|date=March 2023}}
	| IUPAC_name = ''N''-<br/>ethanamide
			{{Chembox
	| image = Melatonin2.svg
			<!-- Images -->| ImageFile = Melatonin.svg
	| ImageSize = 200px
			| ImageSize =
	| image2 = Melatonin-3d-CPK.png
			| ImageClass = skin-invert
	| CASNo_Ref = {{cascite|correct|CAS}}
			| ImageFile2 = Melatonin molecule ball.png
	| UNII_Ref = {{fdacite|correct|FDA}}
			| ImageSize2 = <!-- Names -->
	| UNII = JL5DK93RCL
			| IUPACName = N-acetamide
	| ChEMBL_Ref = {{ebicite|correct|EBI}}
			| OtherNames = 5-Methoxy-N-acetyltryptamine; N-Acetyl-5-methoxytryptamine; NSC-113928
			<!-- Sections -->| Section1 = {{Chembox Identifiers
			| CASNo = 73-31-4
			| ChEBI = 16796
	| ChEMBL = 45		| ChEMBL = 45
	| 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
	| CAS_number = 73-31-4
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 872		| ChemSpiderID = 872
	| ATC_prefix = N05		| DrugBank = DB01065
	| ATC_suffix = CH01		| EINECS = 200-797-7
			| EC_number = 200-797-7
	| ATC_supplemental =
			| InChI = 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)
			| InChIKey = DRLFMBDRBRZALE-UHFFFAOYSA-N
			| KEGG = C01598
			| MeSHName = Melatonin
	| PubChem = 896		| PubChem = 896
			| SMILES = CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC
	| IUPHAR_ligand = 1357
			| UNII = JL5DK93RCL
	| IUPHAR_ligand = 224
			}}
	| DrugBank = APRD00742
			| Section2 = {{Chembox Properties
	| KEGG_Ref = {{keggcite|correct|kegg}}
			| C=13 | H=16 | N=2 | O=2
	| KEGG = D08170
			| MolarMass = 232.281 g/mol
	| smiles = CC(=O)NCCc1cc2c1cc(cc2)OC
			| Appearance =
	| C = 13 | H = 16 | N = 2 | O = 2
			| Density =
	| molecular_weight = 232.278 g/mol
			| MeltingPt = 117
	| bioavailability = 30 – 50%
	| protein_bound =		| BoilingPt =
			| Solubility =
	| metabolism = ] via ] mediated 6-hydroxylation
			}}
	| elimination_half-life = 35 to 50 minutes
			| Section3 = {{Chembox Hazards
	| pregnancy_category =
	| legal_AU = S4		| MainHazards =
	| legal_UK = POM		| FlashPt =
			| AutoignitionPt =
	| legal_US = OTC
			}}
	| routes_of_administration = In humans: orally, as capsules, tablets or liquid, sublingually, or as transdermal patches. In lab animals: also injection.
			| Section6 = <!-- {{Chembox Pharmacology
	| excretion = ]
			See and populate infobox at ] rather for pharmacokinetic, pharmacodynamic, etc.
			}} -->
	}}		}}
			'''Melatonin''', an ], is a ] produced by various ], including ] and ].<ref>{{cite journal |doi=10.20945/2359-3997000000066 |title=A brief review about melatonin, a pineal hormone |year=2018 |last1=Amaral |first1=Fernanda Gaspar do |last2=Cipolla-Neto |first2=José |journal=Archives of Endocrinology and Metabolism |volume=62 |issue=4 |pages=472–479 |pmid=30304113 |pmc=10118741 |s2cid=52954755 }}</ref> Its discovery in 1958 by ] and colleagues stemmed from the isolation of a substance from the ] of cows that could induce ] in ]. This compound was later identified as a ] secreted in the ] during the night, playing a crucial role in regulating the ], also known as the circadian rhythm, in ].<ref name="Auld2017">{{cite journal | vauthors = Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL | title = Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders | journal = Sleep Medicine Reviews | volume = 34 | pages = 10–22 | date = August 2017 | pmid = 28648359 | doi = 10.1016/j.smrv.2016.06.005 | hdl = 20.500.11820/0e890bda-4b1d-4786-a907-a03b1580fd07 | url = http://epubs.surrey.ac.uk/813219/1/Riha%20accepted%20MS%202016.pdf | hdl-access = free }}</ref><ref>{{cite book | vauthors = Faraone SV |title=ADHD: Non-Pharmacologic Interventions, An Issue of Child and Adolescent Psychiatric Clinics of North America, E-Book |date=2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-32602-5 |page=888 |url=https://books.google.com/books?id=lNSlBAAAQBAJ&pg=PA888}}</ref>
	'''Melatonin''' ({{pron-en|ˌmɛləˈtoʊnɪn|melatonin-pronunciation.ogg}}), also known chemically as '''''N''-acetyl-5-methoxytryptamine''',<ref>http://www.sleepdex.org/melatonin.htm</ref> is a naturally occurring compound found in animals, plants, and microbes.<ref name="Caniato2003">{{Cite journal|author=Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti EM |title=Melatonin in plants |journal=Advances in Experimental Medicine and Biology |volume=527 |issue= |pages=593–7 |year=2003 |pmid=15206778}}</ref><ref name="Paredes2009">{{Cite journal|author=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 |year=2009 |pmid=19033551 |doi=10.1093/jxb/ern284}}</ref> In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the ] of the ]s of several biological functions.<ref name="Altun2007">{{Cite journal|author=Altun A, Ugur-Altun B |title=Melatonin: therapeutic and clinical utilization |journal=Int. J. Clin. Pract. |volume=61 |issue=5 |pages=835–45 |year=2007 |pmid=17298593 |doi=10.1111/j.1742-1241.2006.01191.x}}</ref>
	Many biological effects of melatonin are produced through activation of ]s,<ref name="Boutin2005">{{Cite journal|author=Boutin JA, Audinot V, Ferry G, Delagrange P |title=Molecular tools to study melatonin pathways and actions |journal=Trends in Pharmacological Sciences |volume=26 |issue=8 |pages=412–9 |year=2005 |month=August |pmid=15992934 |doi=10.1016/j.tips.2005.06.006}}</ref> while others are due to its role as a pervasive and powerful ],<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 |year=2005 |month=July |pmid=16217125 |doi=10.1385/ENDO:27:2:119}}</ref> with a particular role in the protection of ] and ].<ref name="Reiter2001">{{Cite journal|doi=10.1111/j.1749-6632.2001.tb03627.x |author=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=Annals of the New York Academy of Sciences |volume=939 |issue= 1|pages=200–15 |year=2001 |month=June |pmid=11462772}}</ref>		In vertebrates, melatonin's functions extend to ] sleep-wake cycles, encompassing sleep-wake timing and ], as well as controlling seasonal rhythmicity (]), which includes reproduction, fattening, molting, and hibernation.<ref name="Altun2007">{{cite journal | vauthors = Altun A, Ugur-Altun B | title = Melatonin: therapeutic and clinical utilization | journal = International Journal of Clinical Practice | volume = 61 | issue = 5 | pages = 835–45 | date = May 2007 | pmid = 17298593 | doi = 10.1111/j.1742-1241.2006.01191.x | s2cid = 18050554 | doi-access = free }}</ref> Its effects are mediated through the activation of ]s and its role as an ].<ref name="Boutin2005">{{cite journal |vauthors=Boutin JA, Audinot V, Ferry G, Delagrange P |date=August 2005 |title=Molecular tools to study melatonin pathways and actions |journal=Trends in Pharmacological Sciences |volume=26 |issue=8 |pages=412–9 |doi=10.1016/j.tips.2005.06.006 |pmid=15992934}}</ref><ref name="Hardeland2005">{{cite journal |vauthors=Hardeland R |date=July 2005 |title=Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance |journal=Endocrine |volume=27 |issue=2 |pages=119–30 |doi=10.1385/ENDO:27:2:119 |pmid=16217125 |s2cid=46984486}}</ref><ref name="Reiter2001">{{cite journal |vauthors=Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S |date=June 2001 |title=Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system |journal=Annals of the New York Academy of Sciences |volume=939 |issue=1 |pages=200–15 |bibcode=2001NYASA.939..200R |doi=10.1111/j.1749-6632.2001.tb03627.x |pmid=11462772 |s2cid=20404509}}</ref> In plants and bacteria, melatonin primarily serves as a defense mechanism against ], indicating its evolutionary significance.<ref name="Tan_2012">{{cite journal |vauthors=Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ |date=January 2012 |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 |doi=10.1093/jxb/err256 |pmid=22016420 |doi-access=free}}</ref> The ], key ] within cells, are the main producers of antioxidant melatonin,<ref>{{Cite journal |last1=Reiter |first1=Russel J. |last2=Tan |first2=Dun Xian |last3=Rosales-Corral |first3=Sergio |last4=Galano |first4=Annia |last5=Zhou |first5=Xin Jia |last6=Xu |first6=Bing |date=2018 |title=Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions |journal=Molecules |volume=23 |issue=2 |pages=509 |doi=10.3390/molecules23020509 |pmc=6017324 |pmid=29495303 |doi-access=free }}</ref> underscoring the molecule's "ancient origins" and its fundamental role in protecting the earliest cells from ].<ref name=":0">{{Cite journal |last1=Manchester |first1=Lucien C. |last2=Coto-Montes |first2=Ana |last3=Boga |first3=Jose Antonio |last4=Andersen |first4=Lars Peter H. |last5=Zhou |first5=Zhou |last6=Galano |first6=Annia |last7=Vriend |first7=Jerry |last8=Tan |first8=Dun-Xian |last9=Reiter |first9=Russel J. |date=2015 |title=Melatonin: an ancient molecule that makes oxygen metabolically tolerable |journal=Journal of Pineal Research |volume=59 |issue=4 |pages=403–419 |doi=10.1111/jpi.12267 |pmid=26272235|s2cid=24373303 |doi-access=free }}</ref><ref name=":1">{{Cite journal |last1=Zhao |first1=Dake |last2=Yu |first2=Yang |last3=Shen |first3=Yong |last4=Liu |first4=Qin |last5=Zhao |first5=Zhiwei |last6=Sharma |first6=Ramaswamy |last7=Reiter |first7=Russel J. |date=2019 |title=Melatonin Synthesis and Function: Evolutionary History in Animals and Plants |journal=Frontiers in Endocrinology |volume=10 |pages=249 |doi=10.3389/fendo.2019.00249 |pmc=6481276 |pmid=31057485 |doi-access=free }}</ref>
			In addition to its ] functions as a hormone and antioxidant, melatonin is also administered exogenously as a ]. It is utilized in the treatment of ]s, including ] and various ].{{TOC limit}}
	In mammals, melatonin is secreted into the blood by the ] in the brain. Known as the "hormone of darkness", it is secreted in darkness in both day-active (]) and night-active (]) animals.<ref name="Challet2007" />
			==Biological activity==
	It may also be produced by a variety of peripheral cells such as ],<ref>{{Cite journal|author=Maestroni GJ |title=The immunotherapeutic potential of melatonin |journal=Expert Opin Investig Drugs |volume=10 |issue=3 |pages=467–76 |year=2001 |month=March |pmid=11227046 |doi=10.1517/13543784.10.3.467 |url=}}</ref><ref>{{Cite journal|author=Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM |title=Evidence for melatonin synthesis in mouse and human bone marrow cells |journal=J. Pineal Res. |volume=28 |issue=4 |pages=193–202 |year=2000 |month=May |pmid=10831154 |doi=10.1034/j.1600-079X.2000.280401.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0742-3098&date=2000&volume=28&issue=4&spage=193}}</ref> lymphocytes and ]. Usually, the melatonin concentration in these cells is much higher than that found in the blood but it does not seem to be regulated by the photoperiod.
			In humans, melatonin primarily acts as a potent ] of two types of ]: ], with ] ], and ], with nanomolar binding affinity. Both receptors are part of the ] (GPCRs) family, specifically the ] GPCRs,<ref name="IUPHAR – melatonin receptors review">{{cite journal | vauthors = Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP | display-authors = 6 | title = Update on melatonin receptors: IUPHAR Review 20 | journal = British Journal of Pharmacology | volume = 173 | issue = 18 | pages = 2702–25 | date = September 2016 | pmid = 27314810 | pmc = 4995287 | doi = 10.1111/bph.13536 | quote = Hence, one melatonin molecule and its associated metabolites could scavenge a large number of reactive species, and thus, the overall antioxidant capacity of melatonin is believed to be greater than that of other well-known antioxidants, such as vitamin C and vitamin E, under in vitro or in vivo conditions (Gitto et al., 2001; Sharma and Haldar, 2006; Ortiz et al., 2013). }}</ref><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|access-date=7 April 2017}}</ref> although melatonin receptor 1 also exhibits coupling with ].<ref name="IUPHAR – melatonin receptors review" />
			Furthermore, melatonin functions as a high-capacity ], or free radical scavenger, within ], playing a dual role in combating cellular ]. First, it directly neutralizes ], and second, it promotes the ] of essential antioxidant enzymes, such as ], ], ], and ]. This increase in antioxidant enzyme expression is mediated through ] activated by the binding of melatonin to its receptors. Through these mechanisms, melatonin protects the cell against oxidative stress in two ways, and plays other roles in human health than only regulating the sleep-wake cycle.<ref name="pmid28400824">{{cite journal |vauthors=Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A |date=2017 |title=Melatonin and human mitochondrial diseases |journal=Journal of Research in Medical Sciences |volume=22 |pages=2 |doi=10.4103/1735-1995.199092 |pmc=5361446 |pmid=28400824 |doi-access=free}}</ref><ref name="IUPHAR – melatonin receptors review" /><ref name="Melatonin as a mitochondrial antioxidant – 2017 Review">{{cite journal |vauthors=Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B |date=November 2017 |title=Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas |journal=Cellular and Molecular Life Sciences |volume=74 |issue=21 |pages=3863–3881 |doi=10.1007/s00018-017-2609-7 |pmid=28864909 |s2cid=23820389 |quote=melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant&nbsp;... The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood.|pmc=11107735 }}</ref><ref name="Melatonin – 2016 Review">{{cite journal |vauthors=Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L |date=October 2016 |title=Melatonin as an antioxidant: under promises but over delivers |journal=Journal of Pineal Research |volume=61 |issue=3 |pages=253–78 |doi=10.1111/jpi.12360 |pmid=27500468 |s2cid=35435683 |quote=There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. |doi-access=free}}</ref><ref name="pmid26272235">{{cite journal |display-authors=6 |vauthors=Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ |date=November 2015 |title=Melatonin: an ancient molecule that makes oxygen metabolically tolerable |journal=Journal of Pineal Research |volume=59 |issue=4 |pages=403–19 |doi=10.1111/jpi.12267 |pmid=26272235 |s2cid=24373303 |quote=While originally thought to be produced exclusively in and secreted from the vertebrate pineal gland , it is now known that the indole is present in many, perhaps all, vertebrate organs and in organs of all plants that have been investigated . That melatonin is not relegated solely to the pineal gland is also emphasized by the reports that it is present in invertebrates , which lack a pineal gland and some of which consist of only a single cell. |doi-access=free}}</ref><ref name="Melatonin transporters – 2017 review">{{cite journal |vauthors=Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R |date=November 2017 |title=Melatonin transport into mitochondria |journal=Cellular and Molecular Life Sciences |volume=74 |issue=21 |pages=3927–3940 |doi=10.1007/s00018-017-2616-8 |pmid=28828619 |s2cid=10920415|pmc=11107582 }}</ref>
	Melatonin-rich plant feed, such as rice, ingested by chicks has been shown to reach and bind to melatonin receptors in their brains.<ref name="Hattori1995">{{Cite journal|author=Hattori A, Migitaka H, Iigo M, ''et al.'' |title=Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates |journal=Biochemistry and Molecular Biology International |volume=35 |issue=3 |pages=627–34 |year=1995 |month=March |pmid=7773197}}</ref> No food has been found to elevate plasma melatonin levels in humans.<ref name="Coates">{{Cite book|last= Coates |first= Paul M. |others= Marc R. Blackman, Gordon M. Cragg, Mark Levine, Joel Moss, Jeffrey D. White |title= Encyclopedia of Dietary Supplements |url= http://books.google.com/?id=Sfmc-fRCj10C&pg=PA457&lpg=PA457&dq=Lerner+melatonin+history |format= |accessdate= 2009-03-31 |edition= |series= |date= |year= 2005 |publisher= CRC Press |location= |isbn= 0824755049 |pages= 457–466 |chapter= |chapterurl= |quote= }}</ref>
			==Biological functions==
	Products containing melatonin have been available ] as a ] in the United States since the mid-1990s.<ref>{{Cite web| url = http://www.vanderbilt.edu/AnS/psychology/health_psychology/melatonin.htm | title = Melatonin: The Myths and Facts | first = Courtney | last = Ratzburg | year = Undated | publisher = Vanderbilt University | accessdate = 2007-12-02 }}</ref> In many other countries, the over-the-counter sale of this ] is not permitted or requires a prescription, and the ] lists unapproved melatonin preparations among items prohibited by Germany.<ref>{{Cite web|url= http://pe.usps.gov/text/imm/fh_011.htm |title= Country Conditions for Mailing — Germany |accessdate=2008-01-15 |author= USPS |last= |first= |authorlink= |coauthors= |date= |year= |month= |work= |publisher= |pages= |language= |doi= |archiveurl= |archivedate= |quote= }}</ref> In 2008, a prolonged release form of melatonin (Circadin®) by ] has been approved in European countries and Israel as a ] for the treatment of ].<ref></ref>
			]
	==History==
	Melatonin is related to the mechanism by which some ] and ] change the color of their skin and, indeed, it was in this connection the substance first was discovered.<ref name="Filadelfi1996">{{Cite journal|author=Filadelfi AM, Castrucci AM |title=Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates |journal=Journal of Pineal Research |volume=20 |issue=4 |pages=175–86 |year=1996 |month=May |pmid=8836950 |doi=10.1111/j.1600-079X.1996.tb00256.x}}</ref><ref name="Sugden2004">{{Cite journal|author=Sugden D, Davidson K, Hough KA, Teh MT |title=Melatonin, melatonin receptors and melanophores: a moving story |journal=Pigment Cell Research |volume=17 |issue=5 |pages=454–60 |year=2004 |month=October |pmid=15357831 |doi=10.1111/j.1600-0749.2004.00185.x}}</ref> As early as 1917, McCord and Allen discovered (J Exptl Zool, 1917) that extract of the pineal glands of cows lightened frog skin.<ref name="Coates"/> Dermatology professor ] and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated and named the hormone ''melatonin'' in 1958.<ref>{{Cite journal| author = 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 | pages = 1992–7 | year = 1960 | pmid = 14415935}}</ref> In the mid-70s Lynch ''et al.'' demonstrated<ref>{{Cite journal|author=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 |year=1975 |month=January |pmid=1167425 |doi=10.1126/science.1167425}}</ref> that the production of melatonin exhibits a ] in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993.<ref name="scavenger">Tan D.X., L.D. Chen, B. Poeggeler, L.C. Manchester, R.J. Reiter (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocrine J. 1: 57-60</ref> Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.<ref>{{Cite journal | unused_data = vol. 20 no. 4 291-303 | last = Arendt | first = Josephine | date = | year = 2005 | month = August | title = Melatonin: Characteristics, Concerns, and Prospects | journal = J Biol Rhythms | volume = 20 | issue = 4 | pages = 291–303 | publisher = SagePub | pmid = 16077149| doi = 10.1177/0748730405277492 | id = | url = | format = Review | accessdate = 2010-10-10 | quote = There is very little evidence in the short term for toxicity or undesirable effects in humans. The extraordinary “hype” 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: "The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. (...) Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."<ref>{{Cite journal | last = Arendt | first = Josephine | date = 12 | year = October | month = 2000 | title = Melatonin, Circadian Rhythms, and Sleep | journal = N Engl J Med | volume = 343 | issue = 15| pages = 1114–1116 | publisher = The New NEJM | issn = | pmid = 11027748| doi = 10.1056/NEJM200010123431510 | format = Editorial | accessdate = 2010-11-30 | quote = }}</ref>
	==In plants==
	Melatonin has been identified in many plants.<ref name="Paredes2009"/> It occurs in trace amounts in some foods, especially ] to about 0.17-13.46&nbsp;ng/g.<ref>Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ (2001). “Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus).” ''J Agric Food Chem.'' '''49''' (10) : 4898-902. </ref> The physiological roles of melatonin in plants involve regulation of their response to ], defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution.<ref>Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ. | The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol Rev Camb Philos Soc. 2010 Aug;85(3):607-23.| PMID 20039865</ref> Melatonin has been reported in foodstuffs including bananas and grapes, rice and cereals, herbs, olive oil, wine and beer. While no food has been found to elevate plasma melatonin levels in humans,<ref name="Coates" /> when other animals consume melatonin-containing food, blood levels of melatonin do increase.<ref name="Hattori1995"/>
	==In animals==
	Many animals use the variation in duration of melatonin production each day as a seasonal clock.<ref name="Lincoln2003">{{Cite journal|author=Lincoln GA, Andersson H, Loudon A |title=Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis |journal=The Journal of Endocrinology |volume=179 |issue=1 |pages=1–13 |year=2003 |month=October |pmid=14529560 |doi=10.1677/joe.0.1790001}}</ref> In animals including humans<ref name="Arendt2005">{{Cite journal|author=Arendt J, Skene DJ |title=Melatonin as a chronobiotic |journal=Sleep Med Rev |volume=9 |issue=1 |pages=25–39 |year=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 organisation of daylength-dependent (]) seasonal functions such as reproduction, behaviour, coat growth and camouflage ] 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
	| author = CM Chaturvedi
	| title = Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis
	| journal = Australian Journal of Zoology
	| volume = 32
	| issue = 6
	| pages = 803–809
	| doi =10.1071/ZO9840803
	| url = http://www.publish.csiro.au/paper/ZO9840803.htm
	| year = 1984
	}}</ref> and hamsters.<ref name="Chen1981">{{Cite journal
	| author = Chen H
	| 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 = 43–6
	| year = 1981
	| pmid = 7254478
	| doi = 10.1159/000123198
	}}</ref>
	==In mammals==
	Melatonin is produced in the ], which is outside of the ], acts as an ] hormone since it is released into the ].
	By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a ] hormone.{{Citation needed|date=May 2010}}
	Melatonin can suppress ] by inhibiting secretion of ] (LH) and ] (FSH) from the ] gland, especially in mammals that have a ] season when daylight hours are long. The reproduction of ] is ] and the reproduction of ] is stimulated by melatonin. During the night, melatonin regulates leptin, lowering the levels; see ].
	Light/dark information reaches the ] (SCN) via retinal ]s, intrinsically photosensitive ]s, distinct from those involved in image forming (that is, these light-sensitive cells are a third type in the retina, in addition to ] and ]). These cells represent approximately 2% of the retinal ganglion cells in humans and express the photopigment ].<ref>{{Cite journal|author=Nayak SK, Jegla T, Panda S |title=Role of a novel photopigment, melanopsin, in behavioral adaptation to light |journal=Cell. Mol. Life Sci. |volume=64 |issue=2 |pages=144–54 |year=2007 |month=January |pmid=17160354 |doi=10.1007/s00018-006-5581-1 |url=}}</ref> The sensitivity of melanopsin is consistent with that of a ]-based photopigment, with a peak sensitivity at 484&nbsp;nm (blue light).<ref>{{Cite journal|author=Roberts JE |title=Update on the positive effects of light in humans |journal=Photochem. Photobiol. |volume=81 |issue=3 |pages=490–2 |year=2005 |pmid=15656701 |doi=10.1562/2004-12-02-IR-391 |url=}}</ref> This photoperiod cue entrains the ], and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate behavioral and physiological circadian rhythms. Melatonin is secreted in darkness in both day-active (]) and night-active (]) animals.<ref name="Challet2007">{{Cite journal|author=Challet E |title=Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals |journal=Endocrinology |volume=148 |issue=12 |pages=5648–55 |year=2007 |month=December |pmid=17901231 |doi=10.1210/en.2007-0804}}</ref>
	==In humans==
	===Circadian rhythm===		===Circadian rhythm===
			{{Main|Circadian rhythm}}
	In humans, melatonin is produced by the ], a gland about the size of a ], located in the center of the brain but outside the blood-brain barrier. The melatonin signal forms part of the system that regulates the ] by chemically causing drowsiness and lowering the body temperature, but it is the ] (to be more specific, the ]) that controls the daily cycle in most components of the ] and ] systems<ref name="Richardson2005">{{Cite journal
			In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms.<ref name="EmetM">{{cite journal | vauthors = Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A | title = A Review of Melatonin, Its Receptors and Drugs | journal = The Eurasian Journal of Medicine | volume = 48 | issue = 2 | pages = 135–41 | date = June 2016 | pmid = 27551178 | pmc = 4970552 | doi = 10.5152/eurasianjmed.2015.0267 }}</ref> The establishment of regular melatonin levels in human infants occurs around the third month after birth, with ] observed 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 = Hormone Research | volume = 59 | issue = 2 | pages = 66–72 | year = 2003 | pmid = 12589109 | doi = 10.1159/000068571 | doi-broken-date = 10 December 2024 | s2cid = 41937922 }}</ref> It has been documented that melatonin production diminishes 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 = Journal of Pineal Research | volume = 3 | issue = 4 | pages = 379–88 | year = 1986 | pmid = 3783419 | doi = 10.1111/j.1600-079X.1986.tb00760.x | s2cid = 33664568 }}</ref> Additionally, a shift in the timing of melatonin secretion is observed during adolescence, resulting in delayed sleep and wake times, increasing their risk for ] during this period.<ref>{{cite journal | vauthors = Hagenauer MH, Perryman JI, Lee TM, Carskadon MA | title = Adolescent changes in the homeostatic and circadian regulation of sleep | journal = Developmental Neuroscience | volume = 31 | issue = 4 | pages = 276–84 | date = June 2009 | pmid = 19546564 | pmc = 2820578 | doi = 10.1159/000216538 }}</ref>
	| author = Richardson G
	| title = The human circadian system in normal and disordered sleep
	| series = 66
	| journal = J Clin Psychiatry
	| volume = Suppl 9
	| pages = 3–9; quiz 42–3
	| year = 2005
	| pmid = 16336035
	}}</ref><ref name="Perreau-Lenz2004">{{Cite journal
	| author = Perreau-Lenz S, Pévet P, Buijs R, Kalsbeek A
	| title = The biological clock: the bodyguard of temporal homeostasis
	| journal = Chronobiol Int
	| volume = 21
	| issue = 1
	| pages = 1–25
	| year = 2004
	| pmid = 15129821
	| doi = 10.1081/CBI-120027984
	}}</ref> rather than the melatonin signal (as was once postulated).
	Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 08:00 (8 AM).<ref>{{Cite journal| last = Ardura | first = Julio | date = | year = 2002 | month = | title = Emergence and Evolution of the Circadian Rhythm of Melatonin in Children | journal = Hormone Research | volume = 59 | issue = 2 | pages = 66–72 | publisher = S. Karger AG, Basel | issn = | pmid = 12589109| doi = 10.1159/000068571 | id = | url = http://content.karger.com/ProdukteDB/produkte.asp?Doi=68571 | format = Free abstract | accessdate = 2009-11-08 | quote = | last2 = Gutierrez | first2 = R | last3 = Andres | first3 = J | last4 = Agapito | first4 = T }}</ref>
	In humans, 90% of melatonin is cleared in a single passage through the ], a small amount is excreted in ],<ref name=USAHRQ /> and a small amount is found in ].
	Human melatonin production decreases as a person ages.<ref>
	{{cite web
	| title = www.ncbi.nlm.nih.gov/pubmed/3783419
	| url = http://www.ncbi.nlm.nih.gov/pubmed/3783419
	| accessdate = February 9, 2011
	}} ''Human melatonin production decreases with age,'' 1986, Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM.</ref>
	====Light dependence====
	Production of melatonin by the pineal gland is inhibited by ] and permitted by ]. For this reason melatonin has been called "the hormone of darkness". Its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual's ].<ref>]</ref> Terman ''et al.'' devised a formulation that mimics that gradual washout (vs. the spikes in blood concentration and rapid washout associated with most over-the-counter melatonin tablets). When used several hours before sleep, the compound shifts the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.<ref>{{Cite book | title=Chronotherapeutics for Affective Disorders: A Clinician’s Manual for Light and Wake Therapy| last1=Wirz-Justice |first1=A|last2= Benedetti|first2= F|last3=Terman|first3=M |year=2009| publisher=Karger| location=Basel| isbn=978-3-8055-9120-1|accessdate=12-13-10.}}</ref>
	It is principally blue light, around 460 to 480], that suppresses melatonin,<ref name="Brainard 2001">{{Cite journal| author =Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag | title = Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor | journal = J Neurosci. | volume =15;21
	| issue =16 | pages =6405–12 |date=August 15, 2001 | pmid = 11487664
	}}</ref> increasingly with increased 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. Wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. 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| author =Kayumov L, Casper RF, Hawa RJ, Perelman B Chung SA, Sokalsky S, Shipiro | 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 | month=May | year=2005 | pmid = 15713707 | doi =10.1210/jc.2004-2062 }}</ref> 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.
			The antioxidant properties of melatonin were first recognized in 1993.<ref>{{cite journal | vauthors = Tan DX, Chen LD, Poeggeler B, L Manchester C, Reiter RJ | title = Melatonin: a potent, endogenous hydroxyl radical scavenger. | journal = Endocr. J. | date = 1993 | volume = 1 | pages = 57–60 | url = https://docs.google.com/document/d/e/2PACX-1vSHolKyTREzsC-RB0H-brwbUhaVP4EZBRSoZ6F7b4cOcAkutpNX3ebh0yd_QKEWRBTYVLcqpmMit3NL/pub }}</ref> ] studies reveal that melatonin directly neutralizes various ], including ] (OH•), ] (O2−•), and ] such as ] (NO•).<ref name="pmid7832450">{{cite journal |vauthors=Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR |date=November 1994 |title=Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro |journal=Annals of the New York Academy of Sciences |volume=738 |issue=1 |pages=419–20 |bibcode=1994NYASA.738..419P |doi=10.1111/j.1749-6632.1994.tb21831.x |pmid=7832450 |s2cid=36383425}}</ref><ref name="Melatonin Plants">{{cite journal |vauthors=Arnao MB, Hernández-Ruiz J |date=May 2006 |title=The physiological function of melatonin in plants |journal=Plant Signaling & Behavior |volume=1 |issue=3 |pages=89–95 |bibcode=2006PlSiB...1...89A |doi=10.4161/psb.1.3.2640 |pmc=2635004 |pmid=19521488}}</ref> In plants, melatonin works ] with other antioxidants, enhancing the overall effectiveness of each antioxidant.<ref name="Melatonin Plants" /> This compound has been found to be twice as efficacious as ], a known potent ] antioxidant, in combating oxidative stress.<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 Sciences | volume = 55 | issue = 15 | pages = PL271-6 | year = 1994 | pmid = 7934611 | doi = 10.1016/0024-3205(94)00666-0 }}</ref> The promotion of antioxidant enzyme expression, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase, is mediated through melatonin receptor-triggered signal transduction pathways.<ref name="IUPHAR – melatonin receptors review" /><ref name="pmid28400824" />
	===Antioxidant===
	Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993.<ref name="scavenger" /> In many less complex life forms, this is its only known purpose.<ref name="Tan_Manchester">{{Cite journal| author = Dun-Xian Tan, Lucien C. Manchester, Maria P. Terron, Luis J. Flores, Russel J. Reiter | title = One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?| journal = Journal of Pineal Research| volume = 42 | issue = 1 | pages = 28–42 | year = 2007 | pmid = 17198536 | doi = 10.1111/j.1600-079X.2006.00407.x }}</ref> Melatonin is an ] that can easily cross ]s and the blood-brain barrier.<ref name="Hardeland2005"/> Melatonin is a direct scavenger of OH, O<sub>2</sub><sup>−</sup>, and NO.<ref>{{Cite journal|author=Poeggeler B, Saarela S, Reiter RJ |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= 1|pages=419–20 |year=1994 |pmid=7832450 |doi=10.1111/j.1749-6632.1994.tb21831.x}}</ref> Unlike other antioxidants, melatonin does not undergo ], the ability of a ] to undergo ] and ] repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.<ref name="Tan2000">{{Cite journal
	| author = Tan DX, Manchester LC, Reiter RJ, Qi W, Karbownik M, Calvo JR
	| title = Significance of melatonin in anti oxidative defense system: reactions and products
	| journal = Biol Signals Recept
	| volume = 9 | issue = 3–4 | pages = 137–59 | year = 2000
	| pmid = 10899700
	| doi = 10.1159/000014635
	}}</ref>
			Melatonin's concentration in the ] is significantly higher than that found in the ],<ref name="Melatonin as a mitochondrial antioxidant – 2017 Review" /><ref name="Melatonin – 2016 Review" /><ref name="pmid26272235" /> emphasizing its role not only in direct free radical scavenging but also in modulating the expression of antioxidant enzymes and maintaining mitochondrial integrity. This multifaceted role shows the physiological significance of melatonin as a mitochondrial antioxidant, a notion supported by numerous scholars.<ref name="pmid28400824" /><ref name="Melatonin as a mitochondrial antioxidant – 2017 Review" /><ref name="Melatonin – 2016 Review" /><ref name="pmid26272235" /><ref name="Melatonin transporters – 2017 review" />
	Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (or AFMK) rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and ]. A single AFMK molecule can neutralize up to 10 ] (reactive oxygen species/reactive nitrogen species) since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.<ref name="Tan_Manchester"/>
			Furthermore, the interaction of melatonin with reactive oxygen and nitrogen species results in the formation of metabolites capable of reducing free radicals.<ref name="IUPHAR – melatonin receptors review" /><ref name="Melatonin transporters – 2017 review" /> These metabolites, including ], ] (AFMK), and ] (AMK), contribute to the broader antioxidative effects of melatonin through further ] with free radicals.<ref name="IUPHAR – melatonin receptors review" /><ref name="Melatonin transporters – 2017 review" />
	In animal models, melatonin has been demonstrated to prevent the damage to DNA by some ], stopping the mechanism by which they cause cancer.<ref name="Karbownik2001">{{Cite journal
	| author = Karbownik M, Reiter R, Cabrera J, Garcia J
	| title = Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage
	| journal = Mutat Res
	| volume = 474
	| issue = 1–2
	| pages = 87–92
	| year = 2001
	| pmid = 11239965
	}}</ref>
	It also has been found to be effective in protecting against brain injury caused by ] release in experimental hypoxic brain damage in newborn rats.<ref>{{Cite journal|author=Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U |title=The protective role of melatonin in experimental hypoxic brain damage |journal=Pediatr Int |volume=47 |issue=4 |pages=434–9 |year=2005 |pmid=16091083 |doi=10.1111/j.1442-200x.2005.02085.x}}</ref> Melatonin's antioxidant activity may reduce damage caused by some types of ], may play a role in preventing cardiac ] and may increase ]; it has been shown to increase the ] of ] by 20% in some studies.<ref name="Dean1993">{{Cite book
	| author = Ward Dean, John Morgenthaler, Steven William Fowkes
	| title = Smart Drugs II: The Next Generation : New Drugs and Nutrients to Improve Your Memory and Increase Your Intelligence (Smart Drug Series, V. 2)
	| publisher = Smart Publications
	| year = 1993
	| isbn = 0-9627418-7-6
	}}</ref><ref name="Anisimov2003">{{Cite journal
	| author = Anisimov V, Alimova I, Baturin D, Popovich I, Zabezhinski M, Rosenfeld S, Manton K, Semenchenko A, Yashin A
	| title = Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice
	| journal = Exp Gerontol
	| volume = 38
	| issue = 4
	| pages = 449–61
	| year = 2003
	| pmid = 12670632
	| doi = 10.1016/S0531-5565(02)00240-1
	}}</ref><ref name="Oaknin-Bendahan1995">{{Cite journal
	| author = Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N
	| title = Effects of long-term administration of melatonin and a putative antagonist on the ageing rat
	| journal = Neuroreport
	| volume = 6
	| issue = 5
	| pages = 785–8
	| year = 1995
	| pmid = 7605949
	| doi = 10.1097/00001756-199503270-00020
	}}</ref>
	===Immune system===		===Immune system===
			Melatonin's interaction with the ] is recognized, yet the specifics of these interactions remain inadequately defined.<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 | s2cid = 21133107 }}</ref><ref name="Arushanian2002">{{cite journal | vauthors = Arushanian EB, Beĭer EV | title = | language = ru | journal = Eksperimental'naia i Klinicheskaia Farmakologiia | volume = 65 | issue = 5 | pages = 73–80 | year = 2002 | pmid = 12596522 }}</ref>{{Update inline|date=March 2024}} An anti-inflammatory effect appears to be the most significant.{{Citation needed|date=July 2023}} The efficacy of melatonin in disease treatment has been the subject of limited trials, with most available data deriving from small-scale, preliminary studies. It is posited that any beneficial immunological impact is attributable to melatonin's action on high-affinity receptors (MT1 and MT2), which are present on immunocompetent cells. Preclinical investigations suggest that melatonin may augment ] production and promote the expansion of ]s,<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 = Current Opinion in Investigational Drugs | volume = 7 | issue = 5 | pages = 423–31 | date = May 2006 | pmid = 16729718 }}</ref> thereby potentially mitigating ].<ref name="Pp">{{cite journal | vauthors = Maestroni GJ | title = The immunotherapeutic potential of melatonin | journal = Expert Opinion on Investigational Drugs | volume = 10 | issue = 3 | pages = 467–76 | date = March 2001 | pmid = 11227046 | doi = 10.1517/13543784.10.3.467 | s2cid = 6822594 }}</ref>
	While it is known that melatonin interacts with the ],<ref name="Carrillo-Vico2005">{{Cite journal
	| author = Carrillo-Vico A, Guerrero J, Lardone P, Reiter R
	| title = A review of the multiple actions of melatonin on the immune system
	| journal = Endocrine
	| volume = 27
	| issue = 2
	| pages = 189–200
	| year = 2005
	| pmid = 16217132
	| doi = 10.1385/ENDO:27:2:189
	}}</ref><ref name="Arushanian2002">{{Cite journal
	| author = Arushanian E, Beier E
	| title = Immunotropic properties of pineal melatonin
	| journal = Eksp Klin Farmakol
	| volume = 65
	| issue = 5
	| pages = 73–80
	| year = 2002
	| pmid = 12596522 }}</ref> the details of those interactions are unclear. 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 result from melatonin acting on high affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance ] production,<ref>{{Cite journal|author=Carrillo-Vico A, Reiter RJ, Lardone PJ |title=The modulatory role of melatonin on immune responsiveness |journal=Curr Opin Investig Drugs |volume=7 |issue=5 |pages=423–31 |year=2006 |pmid=16729718 |doi=}}</ref> and by doing this counteract ]. Some studies also suggest that melatonin might be useful fighting infectious disease<ref>{{Cite journal|author=Maestroni GJ |title=The immunotherapeutic potential of melatonin |journal=Expert Opin Investig Drugs |volume=10 |issue=3 |pages=467–76 |year=2001 |pmid=11227046 |doi=10.1517/13543784.10.3.467}}</ref> including viral, such as ], and bacterial infections, and potentially in the treatment of ].<ref name="Maestroni1999">{{Cite journal
	| author = Maestroni G
	| title = Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer
	| journal = Adv Exp Med Biol
	| volume = 467
	| pages = 217–26
	| year = 1999
	| pmid = 10721059 }}</ref>
			=== Weight regulation ===
	Endogenous melatonin in human ]s has been related to ] (IL-2) production and to the expression of IL-2 receptor.<ref>{{Cite journal|author=Carrillo-Vico A, Lardone PJ, Fernández-Santos JM |title=Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=2 |pages=992–1000 |year=2005 |pmid=15562014 |doi=10.1210/jc.2004-1429}}</ref> This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human ]. When taken in conjunction with ], it is an ]{{Citation needed|date=November 2007}} and is used as an ] in some ]s{{Citation needed|date=November 2007}}; conversely, the increased immune system activity may aggravate ]s. In ] patients, melatonin production has been found increased when compared to age-matched healthy controls.<ref>{{Cite journal|author=Cutolo M, Maestroni GJ |title=The melatonin-cytokine connection in rheumatoid arthritis |journal=Ann. Rheum. Dis. |volume=64 |issue=8 |pages=1109–11 |year=2005 |pmid=16014678 |doi=10.1136/ard.2005.038588 |pmc=1755599}}</ref>
			Melatonin's potential to regulate weight gain is posited to involve its inhibitory effect on ], a hormone that serves as a long-term indicator of the body's energy status.<ref name=":2">{{cite journal | vauthors = Suriagandhi V, Nachiappan V | title = Protective Effects of Melatonin against Obesity-Induced by Leptin Resistance | journal = Behavioural Brain Research | volume = 417 | pages = 113598 | date = January 2022 | pmid = 34563600 | doi = 10.1016/j.bbr.2021.113598 | s2cid = 237603177 }}</ref><ref>{{cite journal | vauthors = Kelesidis T, Kelesidis I, Chou S, Mantzoros CS | title = Narrative review: the role of leptin in human physiology: emerging clinical applications | journal = Annals of Internal Medicine | volume = 152 | issue = 2 | pages = 93–100 | date = January 2010 | pmid = 20083828 | pmc = 2829242 | doi = 10.7326/0003-4819-152-2-201001190-00008 }}</ref> Leptin is important for regulating ] and body weight by signaling satiety and reducing food intake. Melatonin, by modulating leptin's actions outside of waking hours, may contribute to the restoration of leptin sensitivity during daytime, thereby counteracting ].
	===Dreaming===		==Biochemistry==
	Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50&nbsp;mg) dramatically increased ] time and dream activity in both people with and without ].<ref name=Lewis/> Many ]s, such as ] and ], increase melatonin synthesis.<ref name=Lewis>{{Cite book| title = Melatonin and the Biological Clock | last = Lewis | first = Alan | publisher = McGraw-Hill | isbn = 0879837349 | year = 1999 | pages = 23}}</ref> It has been suggested that nonpolar (]-soluble) ] ] emulate melatonin activity in the awakened state and that both act on the same areas of the brain.<ref name=Lewis/>
	===Autism===		===Biosynthesis===
			]
	Individuals with ]s (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ] gene, which encodes the last enzyme of melatonin synthesis.<ref name=Melke>{{Cite journal|title= Abnormal melatonin synthesis in autism spectrum disorders |author= Melke J, Botros HG, Chaste P |journal= Mol Psychiatry |volume=13 |issue=1 |year=2008 |pages=90–8 |doi=10.1038/sj.mp.4002016 |pmid=17505466 |last12= Mouren-Simeoni |first12= MC |last13= Fauchereau |first13= F |last14= Durand |first14= CM |last15= Chevalier |first15= F |last16= Drouot |first16= X |last17= Collet |first17= C |last18= Launay |first18= JM |last19= Leboyer |first19= M |last20= Gillberg |first20= C |last21= Bourgeron |first21= T |pmc= 2199264}}</ref>
			The ] of melatonin in animals involves a sequence of ] starting with ], which can be synthesized through the ] from ], found in plants, or obtained from ]. The initial step in the melatonin biosynthesis pathway is the ] of <small>L</small>-tryptophan's ] by the enzyme ], resulting in the formation of ] (5-HTP). Subsequently, 5-HTP undergoes ], facilitated by ] and the enzyme ], yielding ].<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 }}</ref>
	==Therapeutic uses==
	Melatonin has been studied for the treatment of ], ], ]s, ], ] (SAD), ]s and ]. Studies by ] at ] and other researchers have found that it may ameliorate circadian misalignment and SAD.<ref name="Lewy1987">{{Cite journal| author = Lewy A, Sack R, Miller L, Hoban T
	| title = Antidepressant and circadian phase-shifting effects of light | journal = Science | volume = 235 | issue = 4786 | pages = 352–4 | year = 1987 | pmid = 3798117
	| doi = 10.1126/science.3798117
	}}</ref> Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as ].<ref name="Uz2003">{{Cite journal
	| author = Uz T, Akhisaroglu M, Ahmed R, Manev H
	| title = The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice
	| journal = Neuropsychopharmacology
	| volume = 28
	| issue = 12
	| pages = 2117–23
	| year = 2003
	| pmid = 12865893
	| doi = 10.1038/sj.npp.1300254
	}}</ref>
			Serotonin, an essential ], is further converted into ] by the action of ], utilizing ].<ref name="TordjmanS">{{cite journal | vauthors = Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C | title = Melatonin: Pharmacology, Functions and Therapeutic Benefits | journal = Current Neuropharmacology | volume = 15 | issue = 3 | pages = 434–443 | date = April 2017 | pmid = 28503116 | pmc = 5405617 | doi = 10.2174/1570159X14666161228122115 }}</ref> The final step in the pathway involves the ] of ]'s ] by ], with ] as the ] donor, to produce melatonin.<ref name="TordjmanS" />
	====Circadian rhythm disorders====
	Exogenous melatonin taken in the evening is, together with ] upon awakening, the standard treatment for ] (DSPS) and ]. It appears to have some use against other circadian rhythm sleep disorders as well, such as ] and the problems of people who work rotating or night ]. Melatonin reduces ] to a greater extent in people with DSPS than in people with insomnia.<ref name=USAHRQ>{{Cite web|url= http://www.ahrq.gov/clinic/epcsums/melatsum.htm |title= Melatonin for Treatment of Sleep Disorders. Summary, Evidence Report/Technology Assessment: Number 108 |accessdate= 2010-05-25 |author= Buscemi, N. ''et al.'' |year= 2004 |format= Review |work= |publisher= U.S. Department of Health & Human Services, Agency for Healthcare Research and Quality |doi= |quote= }}</ref>
			In ], ], ], and plants, the synthesis of melatonin also involves tryptophan as an intermediate but originates indirectly from the shikimate pathway. The pathway commences with <small>]</small>] and ], and in ] cells, additionally involves ]. While the subsequent biosynthetic reactions share similarities with those in animals, there are slight variations in the enzymes involved in the final stages.<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" />
	Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic. It causes melatonin levels in the blood to rise earlier than the brain's own production accomplishes. This usage is now commonly used in sleep and relaxation drinks.<ref>{{Cite news| url=http://www.nydailynews.com/lifestyle/2010/02/07/2010-02-07_these_drinksll_knock_you_out_dozeinducing_concoctions_include_dose_of_hormones.html | location=New York | work=Daily News | title=New melatonin-based drinks help restless sleepers hit the hay with just a gulp - but pack hormones | first=Simone | last=Weichselbaum | date=2010-02-07}}</ref>
			The hypothesis that melatonin synthesis occurs within mitochondria and ] suggests an evolutionary and functional significance of melatonin in cellular ] and defense mechanisms against oxidative stress, reflecting the molecule's ancient origins and its multifaceted roles across different ].<ref name="Mitochondrial biosynthesis">{{cite journal | vauthors = Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ | title = Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes | journal = Journal of Pineal Research | volume = 54 | issue = 2 | pages = 127–38 | date = March 2013 | pmid = 23137057 | doi = 10.1111/jpi.12026 | s2cid = 206140413 | doi-access = free }}</ref>
	A very small dose taken several hours before bedtime in accordance with the ] for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a ''chronobiotic'' (affecting aspects of biological time structure),<ref>. Retrieved September 23, 2009.</ref> advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and a small oral dose melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.<ref>{{Cite journal|author=Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC |title=Phase-dependent treatment of delayed sleep phase syndrome with melatonin |journal=Sleep |volume=28 |issue=10 |pages=1271–8 |year=2005 |month=October |pmid=16295212}}</ref>
			=== Mechanism ===
	====Learning, memory and Alzheimer's====
			]
	Melatonin receptors appear to be important in mechanisms of learning and memory in mice,<ref name="Larson2006">{{Cite journal
	| author = Larson J, Jessen R, Uz T, Arslan A, Kurtuncu M, Imbesi M, Manev H
	| title = Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice
	| journal = Neurosci Lett
	| volume = 393
	| issue = 1
	| pages = 23–6
	| year = 2006
	| pmid = 16203090
	| doi = 10.1016/j.neulet.2005.09.040
	}}</ref> and melatonin can alter electrophysiological processes associated with memory, such as ] (LTP). The first published evidence that melatonin may be useful in ] was the demonstration that this neurohormone prevents neuronal death caused by exposure to the ] protein, a neurotoxic substance that accumulates in the brains of patients with the disorder.<ref name="Pappolla1997">{{Cite journal| author = Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK.| title = Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide | journal = J Neurosci| volume = 17 | issue = 5 | pages = 1683–1690 | year = 1997 | pmid = 9030627 }}</ref> Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of ]s, the other neuropathological landmark of Alzheimer's disease.<ref name="Pappolla1998">{{Cite journal| doi = 10.1074/jbc.273.13.7185| author = Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J.| title = Inhibition of Alzheimer beta-fibrillogenesis by melatonin | journal = J Biol Chem| volume = 273 | issue = 13 | pages = 7185–7188 | year = 1998 | pmid = 9516407 }}</ref>
			The mechanism of melatonin biosynthesis initiates with the hydroxylation of <small>L</small>-tryptophan, a process that requires the ] ] (THB) to react with oxygen and the active site iron of tryptophan hydroxylase. Although the complete mechanism is not entirely understood, two main mechanisms have been proposed:
	Melatonin has been shown to prevent the ] of the ] in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease.<ref name="Wang2005">{{Cite journal| author = Wang X, Zhang J, Yu X, Han L, Zhou Z, Zhang Y, Wang J | title = Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat | journal = Sheng Li Xue Bao | volume = 57 | issue = 1 | pages = 7–12 | year = 2005 | pmid = 15719129 }}</ref> These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called '']'', which has been shown in many studies to be effectively treated with melatonin supplements in the evening.<ref name="Volicer2001">{{Cite journal| author = Volicer L, Harper D, Manning B, Goldstein R, Satlin A | title = Sundowning and circadian rhythms in Alzheimer's disease | journal = Am J Psychiatry | volume = 158 | issue = 5 | pages = 704–11 | year = 2001 | pmid = 11329390 | doi = 10.1176/appi.ajp.158.5.704 }}</ref>
			The first mechanism involves a slow transfer of one ] from THB to molecular oxygen (O<sub>2</sub>), potentially producing a superoxide ({{chem2|O2-}}). This superoxide could then recombine with the THB ] to form 4a-peroxypterin. 4a-peroxypterin may either react with the active site iron (II) to create an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron, facilitating the hydroxylation of <small>L</small>-tryptophan.
	====Delirium====
	A randomized placebo-controlled trial, showed that low-dose (0.5&nbsp;mg) melatonin supplementation to elderly patients admitted to acute Medicine services, significantly reduced ].<ref>Al-Aama, T., Brymer, C., Gutmanis, I., Woolmore-Goodwin, S. M., Esbaugh, J. and Dasgupta, M. , Melatonin decreases delirium in elderly patients: A randomized, placebo-controlled trial. International Journal of Geriatric Psychiatry, n/a. doi: 10.1002/gps.2582</ref>
			Alternatively, the second mechanism proposes that oxygen interacts with the active site iron (II) first, forming iron (III) superoxide. This molecule could then react with THB to form an iron-peroxypterin intermediate.
	====ADHD====
	Research shows that after melatonin is administered to ] patients on ], the time needed to fall asleep is significantly reduced. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.<ref name="Gi2003">{{Cite journal
	| author = Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG
	| title = Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study
	| journal = Eur J Pediatr. | volume = 162 | issue = 7 | pages = 554–555 | year = 2003 | pmid = 12783318
	| doi = 10.1007/s00431-003-1207-x
	}}</ref>
			Following the formation of iron (IV) oxide from the iron-peroxypterin intermediate, this oxide selectively ] a ] to yield a ] at the C5 position of the indole ring. A subsequent ] of the hydrogen and the loss of one of the two hydrogen atoms on C5 would restore ], producing 5-hydroxy-<small>L</small>-tryptophan.<ref>{{cite journal | vauthors = Roberts KM, Fitzpatrick PF | title = Mechanisms of tryptophan and tyrosine hydroxylase | journal = IUBMB Life | volume = 65 | issue = 4 | pages = 350–7 | date = April 2013 | pmid = 23441081 | pmc = 4270200 | doi = 10.1002/iub.1144 }}</ref>
	====Fertility====
	A research team in ] has found that melatonin supplementation in the evening in ] women produces an improvement in thyroid function and ] levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.<ref name="Bellipanni2005">{{Cite journal
	| author = Bellipanni G, DI Marzo F, Blasi F, Di Marzo A
	| title = Effects of melatonin in perimenopausal and menopausal women: our personal experience
	| journal = Ann N Y Acad Sci
	| volume = 1057
	| issue = Dec
	| pages = 393–402
	| year = 2005
	| pmid = 16399909
	| doi = 10.1196/annals.1356.030
	}}</ref> However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement.<ref name="About.com">{{Cite journal
	| title = Melatonin
	| journal = About.com: Sleep Disorders
	| pages = 4
	| link = http://sleepdisorders.about.com/cs/melatonin/a/melatonin_4.htm
	}}</ref> One study reported that three mg of melatonin taken in the evening raised ] levels in six out of seven women.<ref>Terzolo M, et al., 1993."Evening administration of melatonin enhances the pulsatile secretion of ] but not of LH and TSH in normally cycling women." ''Clinical Endocrinology'', 39(2):185–191.</ref> Melatonin also lowers ] levels. It is believed that these hormonal changes could in some women impair fertility.
			The decarboxylation of 5-hydroxy-<small>L</small>-tryptophan to produce 5-hydroxytryptamine is then facilitated by a decarboxylase enzyme with ] (PLP) as a cofactor.<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 | date = March 1992 | pmid = 1540578 | doi = 10.1021/bi00123a004 }}</ref> PLP forms an ] with the amino acid derivative, facilitating the breaking of the ] and release of carbon dioxide. The ] of the amine derived from tryptophan restores the aromaticity of the ], leading to the production of 5-hydroxytryptamine and PLP.<ref name="ReferenceA">{{cite book | vauthors = Dewick PM | year = 2002 | title = Medicinal Natural Products. A Biosynthetic Approach | edition = 2nd | publisher = Wiley | isbn = 978-0-471-49640-3 }}</ref>
	====Toxicology====
	Melatonin has a very low toxicity in rats. Rat maternal toxicity: The no observable adverse effect level (]) and lowest observed adverse effect level (]) were 100 and 200&nbsp;mg/kg/day, respectively, and the developmental toxicity NOAEL was >= 200&nbsp;mg/kg/day.<ref>Jahnke G, Marr M, Myers C, Wilson R, Travlos G and Price C, 1999. "Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats." ''Toxicological Sciences'',50(2):271-9. PMID: 10478864.</ref>
			Serotonin ''N''-acetyltransferase, with ] residue His122, is hypothesized to ] the primary amine of 5-hydroxytryptamine. This deprotonation allows the ] on the amine to attack acetyl-CoA, forming a ]. The ] from ] then acts as a ] when attacked by a general base, producing ''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 = Molecular Cell | volume = 3 | issue = 1 | pages = 23–32 | date = January 1999 | pmid = 10024876 | doi = 10.1016/S1097-2765(00)80171-9 | doi-access = free }}</ref>
	====Headaches====
	Several clinical studies indicate that supplementation with melatonin is an effective ] for ] and ]s.<ref name="Dodick2001">{{Cite journal
	| author = Dodick D, Capobianco D
	| title = Treatment and management of cluster headache
	| journal = Curr Pain Headache Rep
	| volume = 5
	| issue = 1
	| pages = 83–91
	| year = 2001
	| pmid = 11252143
	| doi = 10.1007/s11916-001-0015-0
	}}</ref><ref name="Gagnier2001">{{Cite journal
	| author = Gagnier J
	| title = The therapeutic potential of melatonin in migraines and other headache types
	| journal = Altern Med Rev
	| volume = 6
	| issue = 4
	| pages = 383–9
	| year = 2001
	| pmid = 11578254
	}}</ref>
			The final step in the biosynthesis of melatonin involves the methylation of ''N''-acetylserotonin at the hydroxyl position by SAM, resulting in the production of ] (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 and Cell Biology | volume = 12 | issue = 8 | pages = 715–27 | date = October 1993 | pmid = 8397829 | doi = 10.1089/dna.1993.12.715 | url = https://zenodo.org/record/1235255 }}</ref>
	====Mood disorders====
	Melatonin has been shown to be effective in treating one form of depression and ],<ref>http://www.nimh.nih.gov/press/sad-melatonin.cfm</ref> and is being considered for ] and other disorders in which circadian disturbances are involved.<ref>{{Cite journal
	| last = Bhattacharjee | first = Yudhijit
	| date = 14 September 2007
	| title = Is Internal Timing Key to Mental Health?
	| journal = ScienceMag | volume = 317 | pages = 1488–90
	| publisher = AAAS | location = | issn = | doi = | bibcode = | oclc = | id = | url = http://www.ohsu.edu/ohsuedu/academic/som/images/Al-Lewy-Science.pdf
	| format = PDF | accessdate = 2008-02-18
	| quote = }}</ref> It has been observed that ] might have, as a "trait marker" (something that is characteristic of being bipolar, that does not change with state), supersensitivity to light, i.e., a greater decrease in melatonin secretion in response to light exposure at night.<ref name="pmid4003592">{{Cite journal|author=Lewy AJ, Nurnberger JI, Wehr TA |title=Supersensitivity to light: possible trait marker for manic-depressive illness |journal=Am J Psychiatry |volume=142 |issue=6 |pages=725–7 |year=1985 |month=June |pmid=4003592 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=4003592}}</ref> This could be contrasted with drug-free recovered bipolar patients not showing light hypersensitivity.<ref name="pmid1658841">{{Cite journal|author=Whalley LJ, Perini T, Shering A, Bennie J |title=Melatonin response to bright light in recovered, drug-free, bipolar patients |journal=Psychiatry Res |volume=38 |issue=1 |pages=13–9 |year=1991 |month=July |pmid=1658841 |doi= 10.1016/0165-1781(91)90048-T|url=}}</ref>
	====Cancer====		=== Regulation ===
			In vertebrates, the secretion of melatonin is regulated through the activation of the ] by the hormone ].<ref name="Nesbitt2014">{{cite journal | vauthors = Nesbitt AD, Leschziner GD, Peatfield RC | title = Headache, drugs and sleep | journal = Cephalalgia | volume = 34 | issue = 10 | pages = 756–66 | date = September 2014 | pmid = 25053748 | doi = 10.1177/0333102414542662 | s2cid = 33548757 | type = Review }}</ref> Norepinephrine increases the concentration of intracellular ] via ], which in turn activates the ] (PKA). PKA then ] ] (AANAT), the penultimate enzyme in the melatonin synthesis pathway. When exposed to daylight, noradrenergic stimulation ceases, leading to the immediate degradation of the protein by ] ].<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 | bibcode = 2005NYASA1057..372S | s2cid = 20517556 }}</ref> The production of melatonin recommences in the evening, a phase known as the ].
	A ] of unblinded ]s involving a total of 643 cancer patients using melatonin found a reduced incidence of death.<ref>{{Cite journal| last = Mills E, Wu P, Seely D,4; Guyatt G | year = 2005 | title = Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis | journal = Journal of pineal research | volume = 39 | issue = 4 | pages = 360 | doi = 10.1111/j.1600-079X.2005.00258.x | url = http://pt.wkhealth.com/pt/re/jpin/abstract.00005208-200511000-00005.htm | pmid = 16207291 | last1 = Mills | first1 = E | last2 = Wu | first2 = P | last3 = Seely | first3 = D | last4 = Guyatt | first4 = G}}</ref> Another clinical trial is due to be completed in 2012.<ref>CCNM. .</ref> Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and it has been suspected that women with the brightest bedrooms have an increased risk for breast cancer.<ref>{{Cite journal| last = Navara | first = Kristen J. | year = 2007 | title = The dark side of light at night: physiological, epidemiological, and ecological consequences | journal = J. Pineal Res. | volume = 43| issue = 43 | pages = 215–224| doi = 10.1111/j.1600-079X.2007.00473.x | id = | url = http://www.psy.ohio-state.edu/nelson/documents/JPinealRes2007.pdf | format = Review, PDF: full text | accessdate = 2008-05-07 | quote = | pmid = 17803517 | last1 = Navara | first1 = KJ | last2 = Nelson | first2 = RJ }}</ref> Reduced melatonin production has been proposed as a likely factor in the significantly higher ] rates in night workers.<ref name="Schernhammer2004">{{Cite journal| author = Schernhammer E, Rosner B, Willett W, Laden F, Colditz G, Hankinson S | title = Epidemiology of urinary melatonin in women and its relation to other hormones and night work | journal = Cancer Epidemiol Biomarkers Prev | volume = 13 | issue = 62 | pages = 936–43 | year = 2004 | pmid = 15184249 }}</ref>
			Blue light, especially within the {{nowrap|460–480&nbsp;]}} range, inhibits the biosynthesis of 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 = The Journal of Neuroscience | volume = 21 | issue = 16 | pages = 6405–12 | date = August 2001 | pmid = 11487664 | pmc = 6763155 | doi = 10.1523/JNEUROSCI.21-16-06405.2001 }}</ref> with the degree of suppression being directly proportional to the intensity and duration of light exposure. Historically, humans in temperate climates experienced limited exposure to blue daylight during winter months, primarily receiving light from sources that emitted predominantly yellow light, such as fires.<ref>{{cite journal | vauthors = Holzman DC | title = What's in a color? The unique human health effect of blue light | journal = Environmental Health Perspectives | volume = 118 | issue = 1 | pages = A22-7 | date = January 2010 | pmid = 20061218 | pmc = 2831986 | doi = 10.1289/ehp.118-a22 }}</ref> The ] used extensively throughout the 20th century emitted relatively low levels of 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 --> It has been found that light containing only wavelengths greater than 530&nbsp;nm does not suppress melatonin under 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 = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 5 | pages = 2755–61 | date = May 2005 | pmid = 15713707 | doi = 10.1210/jc.2004-2062 | doi-access = free }}</ref> The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression.<ref>{{cite web|title=University of Houston study shows blue light glasses at night increase melatonin by 58%|url=https://designeroptics.com/blogs/news/university-of-houston-study-shows-blue-light-glasses-at-night-increase-melatonin-by-58|access-date=2021-08-26|website=designeroptics.com|date=25 August 2021 |language=en}}</ref> Additionally, wearing blue-blocking goggles during the last hours before bedtime is recommended for individuals needing to adjust to an earlier bedtime since melatonin facilitates the onset of sleep.<ref>{{cite journal | vauthors = Burkhart K, Phelps JR | title = Amber lenses to block blue light and improve sleep: a randomized trial | journal = Chronobiology International | volume = 26 | issue = 8 | pages = 1602–12 | date = December 2009 | pmid = 20030543 | doi = 10.3109/07420520903523719 | s2cid = 145296760 }}</ref>
	====Gallbladder stones====
	Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder.<ref name="pmid18338264">{{Cite journal|author=Koppisetti S, Jenigiri B, Terron MP |title=Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review |journal=Dig. Dis. Sci. |volume=53 |issue=10 |pages=2592–603 |year=2008 |month=October |pmid=18338264 |doi=10.1007/s10620-007-0195-5 |url=}}</ref> It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced ], whether administered before or after onset of inflammation.<ref name="pmid18338264"/> Concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.<ref name="pmid10622237">{{Cite journal|author=Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ |title=High physiological levels of melatonin in the bile of mammals |journal=Life Sci. |volume=65 |issue=23 |pages=2523–9 |year=1999 |month=October |pmid=10622237 |doi= 10.1016/S0024-3205(99)00519-6|url=http://linkinghub.elsevier.com/retrieve/pii/S0024320599005196}}</ref>
			===Metabolism===
	====Amyotrophic lateral sclerosis====
			Melatonin is ] with an ] ranging from 20 to 50 minutes.<ref name="drugbank">{{cite web |title=Melatonin |url=https://www.drugbank.ca/drugs/DB01065 |access-date=29 January 2019 |website=www.drugbank.ca}}</ref><ref name="Auld2017" /><ref name="pmid18368944">{{cite journal |vauthors=Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP |date=2008 |title=Melatonergic drugs in clinical practice |url= |journal=Arzneimittelforschung |volume=58 |issue=1 |pages=1–10 |doi=10.1055/s-0031-1296459 |pmid=18368944 |s2cid=38857779}}</ref> The primary metabolic pathway transforms melatonin into ], which is then conjugated with sulfate and excreted in urine as a waste product.<ref name="metabolism">{{cite journal |last1=Ma |first1=Xiaochao |last2=Idle |first2=Jeffrey R. |last3=Krausz |first3=Kristopher W. |last4=Gonzalez |first4=Frank J. |title=Metabolism of Melatonin by Human Cytochromes P450 |journal=Drug Metabolism and Disposition |date=April 2005 |volume=33 |issue=4 |pages=489–494 |doi=10.1124/dmd.104.002410 |pmid=15616152 |s2cid=14555783 |url=https://dmd.aspetjournals.org/content/33/4/489 |access-date=25 January 2023}}</ref> It is primarily metabolized by the liver enzyme ] and to a lesser extent by ], ], and ].<ref name="metabolism"/>
	In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, it is presumed due to its antioxidant effects. In a clinical safety study involving 31 ] patients, high-dose rectal melatonin (300&nbsp;mg/day for 2 years) was shown to be tolerated well.<ref>{{Cite journal| last = Weishaupt | first = J. H. | coauthors = et al | date = | year = 2006 | month = November | title = Reduced oxidative damage in ALS by high-dose enteral melatonin treatment | journal = J Pineal Res. | volume = 41 | issue = 4 | pages = 313–23 | publisher = | issn = | pmid = 17014688 | doi = 10.1111/j.1600-079X.2006.00377.x| bibcode = | oclc =| id = | url = http://www.ncbi.nlm.nih.gov/pubmed/17014688 | format = | accessdate = 2010-07-03 | laysummary = | laysource = | laydate = | quote = }}</ref>
	====Obesity====		===Measurement===
			For both research and clinical purposes, melatonin levels in humans can be determined through saliva or blood plasma analysis.<ref name="pmid30919486">{{cite journal | vauthors = Kennaway DJ | title = A critical review of melatonin assays: Past and present | journal = Journal of Pineal Research | volume = 67 | issue = 1 | pages = e12572 | date = August 2019 | pmid = 30919486 | doi = 10.1111/jpi.12572 | doi-access = free }}</ref>
	Melatonin is involved in energy metabolism and body weight control in small animals. Many studies show that chronic melatonin supplementation in drinking water reduces body weight and abdominal fat in experimental animals, especially in the middle-aged rats.<ref name="Wolden-Hanson2000">Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.Endocrinology.141 (2)487-497, 2000 PMID=10650927.</ref> It is interesting to note that the weight loss effect of melatonin does not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of ] (BAT) as well as enhances its activity.<ref name="tan2010">Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity.Obes Rev. 2010 Jun 16. ] by stimulating ], heat generation through uncoupling ] in ]. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult humans.
			==Use as a medication and supplement==
	====Protection from radiation====
			{{Main|Melatonin as a medication and supplement}}
	Radioactive fallout from nuclear accidents is potentially a worldwide problem and we are ill-equipped to protect against this low dose and persistent ionizing radiation, for example, after ] ingestion or inhalation. Both animal <ref>Vijayalaxmi, Meltz ML, Reiter RJ, Herman TS, Kumar KS Melatonin and protection from whole-body irradiation: survival studies in mice.Mutat Res. 1999 Mar 10;425(1):21-7.PMID:10082913</ref> and human<ref>Vijayalaxmi, Reiter RJ, Herman TS, Meltz ML.Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers.Mutat Res. 1996 Dec 20;371(3-4):221-8.PMID:9008723</ref><ref>Vijayalaxmi, Reiter RJ, Herman TS, Meltz ML.Mutat Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes.Res. 1998 Feb 2;397(2):203-8 PMID:9541644</ref> studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than amifostine,<ref>Topkan E, Tufan H, Yavuz AA, Bacanli D, Onal C, Kosdak S, Yavuz MN.Comparison of the protective effects of melatonin and amifostine on radiation-induced epiphyseal injury.Int J Radiat Biol. 2008 Oct;84(10):796-802.PMID:18979313</ref> a commonly used agent for this purpose. The mechanism of melatonin in protection of ionizing radiation is thought to involve scavenging of free radicals.<ref>Dun-Xian Tan, Lucien C. Manchester, Maria P. Terron, Luis J. Flores, Russel J. Reiter (2007). "One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?". Journal of Pineal Research 42 (1): 28–42. doi:10.1111/j.1600-079X.2006.00407.x. PMID 17198536</ref> It is estimated that nearly 70% biological damages caused by ionizing radiation are attributed to the free radical, especially the hydroxyl radical attacking to DNA, proteins and cellular membrane. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-adminsted, and without major known side effects.<ref>{{cite journal |author=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 |year=2007 |month=July |pmid=17641465 |doi= |url=}}</ref>
			Melatonin is used both as a ] and an ] ] for the management of ]s, including ] and various ] such as ], ], and ].<ref name="pmid30148726">{{cite journal | vauthors = Riha RL | title = The use and misuse of exogenous melatonin in the treatment of sleep disorders | journal = Curr Opin Pulm Med | volume = 24 | issue = 6 | pages = 543–548 | date = November 2018 | pmid = 30148726 | doi = 10.1097/MCP.0000000000000522 | s2cid = 52096729 | url = }}</ref> In addition to melatonin, a range of synthetic ], namely ], ], and ], are used in medicine.<ref name="pmid27500861">{{cite journal | vauthors = Williams WP, McLin DE, Dressman MA, Neubauer DN | title = Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders | journal = Pharmacotherapy | volume = 36 | issue = 9 | pages = 1028–41 | date = September 2016 | pmid = 27500861 | pmc = 5108473 | doi = 10.1002/phar.1822 | url = }}</ref><ref name="pmid29487083">{{cite journal | vauthors = Atkin T, Comai S, Gobbi G |author3-link=Gabriella Gobbi| title = Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery | journal = Pharmacol Rev | volume = 70 | issue = 2 | pages = 197–245 | date = April 2018 | pmid = 29487083 | doi = 10.1124/pr.117.014381 |s2cid=3578916 | url = | doi-access = free }}</ref>
	====Other====
	It is believed that melatonin has some effects for sexual development in higher organisms.,<ref>From Ross' ''Histology'' and Wheater's ''Functional Histology''.{{full citations needed}}</ref> and is involved in the seasonal timing of reproduction in rodents.{{Citation needed|date=February 2011}}
			A study published by the ] (JAMA) in April 2023 found that only 12% of the 30 melatonin gummy product preparations analyzed had melatonin quantities within ±10% of the amounts specified on their labels. Some gummy supplements were found to contain up to 347% of the declared melatonin content. In Europe, melatonin is classified as an ], highlighting the regulatory oversight of its use and distribution. Conversely, {{As of|lc=y|2022}}, the United States was considering the inclusion of melatonin in ] practices. A preceding study from 2022 concluded that consuming unregulated melatonin products can expose individuals, including children, to melatonin quantities ranging from 40 to 130 times higher than the recommended levels when products are used 'as directed'.<ref>Cohen PA, Avula B, Wang Y, Katragunta K, Khan I. (April 2023) ''JAMA''. '''329''' (16): 1401–1402. ]:10.1001/jama.2023.2296. PMID </ref>
	Melatonin increases proliferation of cultured neural stem cells obtained from mice nervous tissue.<ref>Areechun Sotthibundhu, Pansiri Phansuwan-Pujito, Piyarat Govitrapong (2010). “Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone”. ''Journal of Pineal Research 49 (3)'': 291-300. PMID 20663047 </ref>
			Anecdotal reports and formal research studies over the past few decades have established a link between melatonin supplementation and more vivid ].<ref>{{citation |title=Effects of melatonin on dream bizarreness among male and female college students.|last=Kahan |first=Tracey L. |journal=Psychology |year=2000 |publisher=Sleep and Hypnosis, 2(2), 74-83.|url=https://scholarcommons.scu.edu/psych/102/}}</ref>
	Melatonin was used in to treat ], a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.<ref>Kunz D, Bes F. "Exogenous melatonin in periodic limb movement disorder: an open clinical trial and a hypothesis." Sleep. 2001 Mar 15; 24(2): 183-7. PMID 11247054</ref>
			==History==
	In recent trial for use in ] treatment, melatonin relieved some symptoms, as published in 2010<ref>Basu P.P., Pacana T., Shah N., Hampole H., Krishnaswamy N., Rayapudi K. "Role of melatonin in colonic motility in irritable bowel syndrome - Constipation MIMI-C-a double blinded randomized placebocontrol clinical trial" Neurogastroenterology and Motility 2010 22 SUPPL. 1 (67)</ref>
			{{Main|History of the pineal gland}}
			=== Discovery ===
	Veterinarians may recommend melatonin for dogs suffering from aggression or separation anxiety.{{Citation needed|date=July 2010}}
			Melatonin's discovery is linked to the study of skin color changes in some amphibians and reptiles, a phenomenon initially observed through the administration of pineal gland extracts.<ref name="Filadelfi1996">{{cite journal | vauthors = Filadelfi AM, Castrucci AM | title = Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates | journal = Journal of Pineal Research | volume = 20 | issue = 4 | pages = 175–86 | date = May 1996 | pmid = 8836950 | doi = 10.1111/j.1600-079X.1996.tb00256.x | s2cid = 41959214 }}</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 Research | volume = 17 | issue = 5 | pages = 454–60 | date = October 2004 | pmid = 15357831 | doi = 10.1111/j.1600-0749.2004.00185.x | doi-access = free }}</ref> In 1917, Carey Pratt McCord and Floyd P. Allen found that feeding extracts from the pineal glands of cows caused the skin of tadpoles to lighten by contracting the dark ] ].<ref name="Coates">{{cite book | vauthors = Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD| title = Encyclopedia of dietary supplements | publisher = Marcel Dekker | location = New York, N.Y | year = 2005 | pages = 457–66 | isbn = 978-0-8247-5504-1 | url = https://books.google.com/books?id=Sfmc-fRCj10C&q=Lerner+melatonin+history&pg=PA457 }}</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 Exp Zool |volume= 23 |issue=1 |pages=206–24 |url=https://books.google.com/books?id=OOM1AQAAMAAJ&pg=PA207 |doi=10.1002/jez.1400230108 |bibcode=1917JEZ....23..207M }}</ref>
			The hormone melatonin was isolated in 1958 by ], a ] professor, and his team at ]. Motivated by the possibility that a substance from the pineal gland could be beneficial in treating ], they extracted and identified melatonin from bovine pineal gland extracts.<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 = The Journal of Biological Chemistry | volume = 235 | pages = 1992–7 | date = July 1960 | issue = 7 | doi = 10.1016/S0021-9258(18)69351-2 | pmid = 14415935 | doi-access = free }}</ref> Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.<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>
	==Use as medication==
	]
	The hormone melatonin is used to treat ]s and some types of insomnia.
			The first patent for the therapeutic use of melatonin as a low-dose sleep aid was awarded to ] at the ] in 1995.<ref>{{cite patent|country=US|number=5449683|title=Methods of inducing sleep using melatonin|status=patent|fdate=16 July 1993|gdate=12 September 1995|inventor=Wurtman RJ|assign1=Massachusetts Institute of Technology}}</ref>
	Studies have found that the use of melatonin can help ] the circadian clock to environmental cycles and have beneficial effects for the treatment of certain forms of insomnia (2004).<ref>{{Cite journal|author=Turek FW, Gillette MU |title=Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists |journal=Sleep Med. |volume=5 |issue=6 |pages=523–32 |year=2004 |month=November |pmid=15511698 |doi=10.1016/j.sleep.2004.07.009 |url=}}</ref> Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).<ref>{{Cite journal|author=Wade AG, Ford I, Crawford G |title=Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes |journal=Curr Med Res Opin |volume=23 |issue=10 |pages=2597–605 |year=2007 |month=October |pmid=17875243 |doi=10.1185/030079907X233098 |url=}}</ref>
			=== Etymology ===
	A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.<ref name=USAHRQ />
			The etymology of ''melatonin'' stems from its skin-lightening properties. As detailed in their publication in the '']'',<ref name=":3">{{Cite journal |last1=Lerner |first1=Aaron B. |last2=Case |first2=James D. |last3=Takahashi |first3=Yoshiyata |last4=Lee |first4=Teh H. |last5=Mori |first5=Wataru |date=1958 |title=Isolation of melatonin, the pineal gland factor that lightens melanocytes |url=https://pubs.acs.org/doi/abs/10.1021/ja01543a060 |journal=Journal of the American Chemical Society |language=en |volume=80 |issue=10 |pages=2587 |doi=10.1021/ja01543a060 |bibcode=1958JAChS..80Q2587L |issn=0002-7863}}</ref> Lerner and his colleagues proposed the name melatonin, derived from the Greek words ''melas'', meaning 'black' or 'dark', and ''tonos'', meaning 'labour',<ref>{{Cite journal |last1=Goeser |first1=Suzanne |last2=Ruble |first2=James |last3=Chandler |first3=Linda |date=1997 |title=Melatonin: Historical and Clinical Perspectives |url=http://www.tandfonline.com/doi/full/10.1300/J088v05n01_04 |journal=Journal of Pharmaceutical Care in Pain & Symptom Control |language=en |volume=5 |issue=1 |pages=37–49 |doi=10.1300/J088v05n01_04}}</ref> 'colour'<ref>{{Cite journal |last1=Beyer |first1=C. E. |last2=Steketee |first2=J. D. |last3=Saphier |first3=D. |date=1998 |title=Antioxidant properties of melatonin–an emerging mystery |journal=Biochemical Pharmacology |volume=56 |issue=10 |pages=1265–1272 |doi=10.1016/s0006-2952(98)00180-4 |issn=0006-2952 |pmid=9825724}}</ref> or 'suppress'.<ref>{{Cite journal |last1=Liebmann |first1=P. M. |last2=Wölfler |first2=A. |last3=Felsner |first3=P. |last4=Hofer |first4=D. |last5=Schauenstein |first5=K. |date=1997 |title=Melatonin and the immune system|journal=International Archives of Allergy and Immunology |volume=112 |issue=3 |pages=203–211 |doi=10.1159/000237455 |issn=1018-2438 |pmid=9066504}}</ref> This naming convention follows that of ], another agent affecting skin color, discovered in 1948 as a modulator of ], which influenced its name based on its serum ] effect.<ref name="pmid18100415">{{cite journal |vauthors=Rapport MM, Green AA, Page IH |date=December 1948 |title=Serum vasoconstrictor, serotonin; isolation and characterization |url=http://www.jbc.org/content/176/3/1243.short |journal=The Journal of Biological Chemistry |volume=176 |issue=3 |pages=1243–1251 |doi=10.1016/S0021-9258(18)57137-4 |pmid=18100415 |doi-access=free}}</ref> Melatonin was thus aptly named to reflect its role in preventing the darkening of the skin, highlighting the intersection of biochemistry and linguistics in scientific discovery.<ref name=":3" />
	Other studies have found that for certain types of sleep disorders, melatonin is not effective. A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as ] and ]."<ref name="Buscemi2006">{{Cite journal| last = Buscemi | first = Nina | date = 2006-02-18 | year = | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–393 | publisher = | pmid = 16473858| doi = 10.1136/bmj.38731.532766.F6 | url =http://www.bmj.com/cgi/content/full/332/7538/385 | accessdate = 2008-05-17 | quote = | last2 = Vandermeer | first2 = B | last3 = Hooton | first3 = N | last4 = Pandya | first4 = R | last5 = Tjosvold | first5 = L | last6 = Hartling | first6 = L | last7 = Vohra | first7 = S | last8 = Klassen | first8 = TP | last9 = Baker | first9 = G | pmc = 1370968 }}</ref>
			==Occurrence==
	In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating ]", ... "There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."<ref name="Buscemi N, Vandermeer B, Hooton N, et al. 2005 1151–8">{{Cite journal|author=Buscemi N, Vandermeer B, Hooton N, ''et al.'' |title=The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis |journal=Journal of General Internal Medicine |volume=20 |issue=12 |pages=1151–8 |year=2005 |month=December |pmid=16423108 |pmc=1490287 |doi=10.1111/j.1525-1497.2005.0243.x}}</ref>
	====Dosage====		===Animals and Humans===
			In vertebrates, melatonin is produced in darkness, thus usually at night, by the ], a small ]<ref name="Reiter">{{cite journal | vauthors = Reiter RJ | title = Pineal melatonin: cell biology of its synthesis and of its physiological interactions | journal = Endocrine Reviews | volume = 12 | issue = 2 | pages = 151–80 | date = May 1991 | pmid = 1649044 | doi = 10.1210/edrv-12-2-151 | s2cid = 3219721 }}</ref>
	Melatonin tablets/capsules often contain three to ten times the amount needed to produce physiologic nocturnal blood melatonin levels for a more rapid sleep onset. Studies suggest that smaller doses (for example 0.3&nbsp;mg as opposed to 3&nbsp;mg) are just as effective.<ref name="Zhdanova2001">{{Cite journal
			located in the center of the brain but outside the ]. Light/dark information reaches the ] <!-- (SCN) --> from retinal ]s of the eyes<ref name="Richardson2005">{{cite journal | vauthors = Richardson GS | title = The human circadian system in normal and disordered sleep | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 9 | pages = 3–9; quiz 42–3 | year = 2005 | pmid = 16336035 }}</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 = Chronobiology International | volume = 21 | issue = 1 | pages = 1–25 | date = January 2004 | pmid = 15129821 | doi = 10.1081/CBI-120027984 | s2cid = 42725506 }}</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 ] (night-active) animals and sleep in ] ones including humans.<ref>{{cite journal | vauthors = Foster RG | title = Sleep, circadian rhythms and health | journal = Interface Focus | volume = 10 | issue = 3 | pages = 20190098 | date = June 2020 | pmid = 32382406 | pmc = 7202392 | doi = 10.1098/rsfs.2019.0098 }}</ref>
	| author = Zhdanova I, Wurtman R, Regan M, Taylor J, Shi J, Leclair O
	| title = Melatonin treatment for age-related insomnia
	| journal = J Clin Endocrinol Metab
	| volume = 86 | issue = 10 | pages = 4727–30
	| year = 2001 | pmid = 11600532
	| doi = 10.1210/jc.86.10.4727
	}}</ref>
			In humans, ~30 μg of melatonin is produced daily and 80% of the total amount is produced in the night (W). The plasma maximum concentration of melatonin at night are 80–120 pg/mL and the concentrations during the day are between 10–20 pg/mL.<ref>{{Cite journal |last1=Karasek |first1=M. |last2=Winczyk |first2=K. |date=2006 |title=Melatonin in humans |url=https://pubmed.ncbi.nlm.nih.gov/17218758/ |journal=Journal of Physiology and Pharmacology|volume=57 Suppl 5 |pages=19–39 |issn=1899-1505 |pmid=17218758}}</ref><ref>{{Cite journal |last1=Kolli |first1=Aditya R. |last2=Kuczaj |first2=Arkadiusz K. |last3=Calvino-Martin |first3=Florian |last4=Hoeng |first4=Julia |date=2024 |title=Simulated pharmacokinetics of inhaled caffeine and melatonin from existing products indicate the lack of dosimetric considerations |journal=Food and Chemical Toxicology |volume=187 |pages=114601 |doi=10.1016/j.fct.2024.114601 |issn=0278-6915|doi-access=free |pmid=38493979 }}</ref>
	Large doses of melatonin can even be counterproductive: Lewy ''et al.''<ref name="Lewy2002">{{Cite journal
	| author = Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA
	| title = Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period
	| journal = Chronobiol Int.
	| volume = 19 | issue = 3 | pages = 649–58
	| year = 2002 | pmid = 12069043
	| doi = 10.1081/CBI-120004546
	}}</ref> provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" (]). In one of their blind subjects, 0.5&nbsp;mg of melatonin was effective while 20&nbsp;mg was not. Solomon Labs tested initial doses of 30 and 60 milligrams and found very little efficacy even at those levels.<ref name="Lewy2002" /><ref>{{Cite journal | last = Sack | first = Robert L. | coauthors = Richard W. Brandes, Adam R. Kendall, Alfred J. Lewy | date = | year = 2000 | month = October | title = Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People | journal = New England Journal of Medicine | volume = | issue = 343 | pages = 1070–77 | publisher =
	| issn = | pmid = | doi = | url = http://www.nejm.org/doi/full/10.1056/NEJM200010123431503#t=article | format = Full text | accessdate = 2010-12-01 | quote = }}</ref>
			Many animals and humans 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 = The Journal of Endocrinology | volume = 179 | issue = 1 | pages = 1–13 | date = October 2003 | pmid = 14529560 | doi = 10.1677/joe.0.1790001 | doi-access = free }}</ref> In animals including humans,<ref name="Arendt2005">{{cite journal | vauthors = Arendt J, Skene DJ | title = Melatonin as a chronobiotic | journal = Sleep Medicine Reviews | 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 (]) seasonal functions such as reproduction, behavior, coat growth, and camouflage ] 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 ]<ref name="Chaturvedi">{{cite journal | pages = 803–09 | doi = 10.1071/ZO9840803 | title = Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis | year = 1984 | vauthors = Chaturvedi CM | journal = Australian Journal of Zoology | volume = 32 | issue = 6}}</ref> and hamsters.<ref name="Chen1981">{{cite journal | vauthors = 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 = 43–6 | date = July 1981 | pmid = 7254478 | doi = 10.1159/000123198 }}</ref> Melatonin can suppress ] by inhibiting secretion of ] <!-- (LH) --> and ] <!-- (FSH) --> from the ] gland, especially in mammals that have a ] season when daylight hours are long. The reproduction of ] is ] and the reproduction of ] is stimulated by melatonin. In sheep, melatonin administration has also shown antioxidant and immune-modulatory regime in prenatally stressed offspring helping them survive the crucial first days of their lives.<ref>{{Cite journal |last1=Bouroutzika |first1=Efterpi |last2=Ciliberti |first2=Maria Giovanna |last3=Caroprese |first3=Mariangela |last4=Theodosiadou |first4=Ekaterini |last5=Papadopoulos |first5=Serafeim |last6=Makri |first6=Sotiria |last7=Skaperda |first7=Zoi-Vasiliki |last8=Kotsadam |first8=Georgios |last9=Michailidis |first9=Marios-Lazaros |last10=Valiakos |first10=George |last11=Chadio |first11=Stella |last12=Kouretas |first12=Dimitris |last13=Valasi |first13=Irene |date=2021-11-05 |title=Association of Melatonin Administration in Pregnant Ewes with Growth, Redox Status and Immunity of Their Offspring |journal=Animals |language=en |volume=11 |issue=11 |pages=3161 |doi=10.3390/ani11113161 |doi-access=free |issn=2076-2615 |pmc=8614450 |pmid=34827893}}</ref>
	==Availability and safety==
	Legal availability of melatonin varies in different countries, ranging from being available without prescription (e.g., in most of ]) to being available only on prescription or not at all (although its possession and use may not be illegal). The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.
			During the night, melatonin regulates ], lowering its levels.
	====Dietary supplement====
	In the USA, because it is sold as a dietary supplement, sometimes combined with other ingredients, such as vitamins and herbal extracts, and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin.<ref name="Altun2007"/> However, new FDA rules required that by June 2010 all production of dietary supplements must comply with "current ]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 = 2007-06-22 | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108938.htm | accessdate = 2009-08-04}}</ref> In addition, the industry has been required to report to the FDA "all serious dietary supplement related adverse events" and the FDA has, within the cGMP guidelines, recently begun enforcement of that requirement.
			]s have lost all the genes for melatonin synthesis as well as those for melatonin receptors.<ref name="Huelsmann2019">{{cite journal | vauthors = Huelsmann M, Hecker N, Springer MS, Gatesy J, Sharma V, Hiller M | title = Genes lost during the transition from land to water in cetaceans highlight genomic changes associated with aquatic adaptations | journal = Science Advances | volume = 5 | issue = 9 | pages = eaaw6671 | date = September 2019 | pmid = 31579821 | pmc = 6760925 | doi = 10.1126/sciadv.aaw6671 | bibcode = 2019SciA....5.6671H }}</ref> This is thought to be related to their ] pattern (one ] at a time). Similar trends have been found in ]ns.<ref name="Huelsmann2019" />
	====Pediatrics====
	While the packaging of melatonin often warns against use in children, at least one long-term study<ref>{{Cite journal|author=Hoebert M, van der Heijden KB, van Geijlswijk IM, Smits MG |title=Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia |journal=Journal of Pineal Research |volume=47 |issue=1 |pages=1–7 |year=2009 |month=August |pmid=19486273 |doi=10.1111/j.1600-079X.2009.00681.x}}</ref> does assess effectiveness and safety in children. No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents. With a mean follow-up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases.
			===Plants===
	====Prolonged release for older patients====
			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 name="Tan_2012"/><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 = 1 January 2009 | pmid = 19033551 | doi = 10.1093/jxb/ern284 | s2cid = 15738948 | doi-access = free }}</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="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 | doi-access = }}</ref><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 | bibcode = 2010Toxgy.278...55B }}</ref> Notably high melatonin concentrations have been measured in popular beverages such as coffee, ], ], and ], and crops including ], ], ], ], and ].<ref name="Tan_2012" /> In some common foods and beverages, including coffee<ref name="Tan_2012" /> and ],<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 = 920–4 | 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.
	Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The ] (EMA) has approved Circadin 2&nbsp;mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.<ref> Circadin (Prolonged-Release Melatonin) For Primary Insomnia Recommended For Approval In The EU (27 Apr 2007)</ref>
			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 ], drought, etc.<ref name="hardeland2015" /><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 | pmc = 6272735 | doi = 10.3390/molecules20047396 | doi-access = free }}</ref><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 | doi-access = free }}</ref>
	====Side-effects====
	Melatonin appears to cause very few ] in the short term, up to three months, when healthy people take it at low doses. A systematic review<ref name="Buscemi2006" /> in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances that are secondary to other diagnoses and, second, for sleep disorders such as ] and ] that accompany sleep restriction.
			]-induced ] has been experimentally mitigated ''in vivo'' in a high-melatonin ].<ref name="Park-et-al-2012">{{cite journal | vauthors = Park S, Lee DE, Jang H, Byeon Y, Kim YS, Back K | title = Melatonin-rich transgenic rice plants exhibit resistance to herbicide-induced oxidative stress | journal = Journal of Pineal Research | volume = 54 | issue = 3 | pages = 258–63 | date = April 2013 | pmid = 22856683 | doi = 10.1111/j.1600-079x.2012.01029.x | publisher = ] | s2cid = 6291664 }}</ref><ref name="Arnao-Hernandez-Ruiz-2014">{{cite journal | vauthors = Arnao MB, Hernández-Ruiz J | title = Melatonin: plant growth regulator and/or biostimulator during stress? | journal = Trends in Plant Science | volume = 19 | issue = 12 | pages = 789–97 | date = December 2014 | pmid = 25156541 | doi = 10.1016/j.tplants.2014.07.006 | publisher = ] | bibcode = 2014TPS....19..789A | s2cid = 38637203 }}</ref><ref name="FH">{{cite journal |first1= Hemat A. |last1= EL-Bauome | first2= Samar M. |last2= Doklega | first3= Said A. |last3= Saleh |first4= Ahmed S. |last4= Mohamed |last5= Suliman| first5= Ahmad A. | first6= Mahmoud A.M. |last6= Abd El-Hady | title = Effects of melatonin on lettuce plant growth, antioxidant enzymes and photosynthetic pigments under salinity stress conditions | journal = ] | volume = 36 | issue = 1 | pages = 1–17 | date = February 2024 | pmid = | doi = 10.2478/fhort-2024-0001 | publisher = Polish Society of Horticultural Science | s2cid = 19887642 | doi-access = free }}</ref> Studies conducted on lettuce grown in saline soil conditions have shown that the application of melatonin significantly mitigates the harmful effects of salinity. Foliar application increases the number of leaves, their surface area, increases fresh weight and the content of chlorophyll a and chlorophyll b, and the content of carotenoids compared to plants not treated with melatonin.<ref name="FH" />
	The study concluded that ''There is evidence that melatonin is safe with short term use''.
			Fungal disease resistance is another role. Added melatonin increases ] in '']'' against '']''.<ref name="Arnao-Hernandez-Ruiz-2014" /><ref name="Arnao-Hernandez-Ruiz-2015">{{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 | publisher = ] | s2cid = 19887642 | doi-access = free }}</ref> Also acts as a ] on ] including '']'', '']'', and '']'' spp. Decreases the speed of infection. As a ], protects '']'' from fungi. Dramatically slows ] and ].<ref name="Arnao-Hernandez-Ruiz-2015" />
	A similar analysis<ref name="Buscemi N, Vandermeer B, Hooton N, et al. 2005 1151–8"/> by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of ''primary'' sleep disorders found that: ''There is evidence to suggest that melatonin is safe with short-term use (3 months or less).''
			===Fungi===
	Some unwanted effects in some people, especially at high doses (~3&nbsp;mg/day or more) may include: headaches, nausea, next-day ] or irritability, hormone fluctuations, vivid dreams or nightmares,<ref>{{Cite web|url=http://www.melatonin.com/melatonin-cautions.php|title=melatonin cautions|publisher=www.melatonin.com}}</ref> and reduced blood flow.
			Melatonin has been observed to reduce stress tolerance in '']'' in plant-pathogen systems.<ref name="Socaciu-et-al-2020">{{cite journal | vauthors = Socaciu AI, Ionuţ R, Socaciu MA, Ungur AP, Bârsan M, Chiorean A, Socaciu C, Râjnoveanu AG | display-authors = 6 | title = Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases | journal = Reviews in Endocrine & Metabolic Disorders | volume = 21 | issue = 4 | pages = 465–478 | date = December 2020 | pmid = 32691289 | doi = 10.1007/s11154-020-09570-9 | s2cid = 220657247 }}</ref> Danish pharmaceutical company ] have used genetically modified yeast ('']'') to produce melatonin.<ref>{{Cite journal |last1=Germann |first1=Susanne M. |last2=Baallal Jacobsen |first2=Simo A. |last3=Schneider |first3=Konstantin |last4=Harrison |first4=Scott J. |last5=Jensen |first5=Niels B. |last6=Chen |first6=Xiao |last7=Stahlhut |first7=Steen G. |last8=Borodina |first8=Irina |last9=Luo |first9=Hao |last10=Zhu |first10=Jiangfeng |last11=Maury |first11=Jérôme |last12=Forster |first12=Jochen |display-authors=8 |date=2016 |title=Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae |journal=Biotechnology Journal |language=en |volume=11 |issue=5 |pages=717–724 |doi=10.1002/biot.201500143 |pmc=5066760 |pmid=26710256}}</ref>
			=== Bacteria ===
	While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for years.<ref>{{Cite journal| last = Sack | first = Robert L. | date = 12 October 2000 | title = Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People | journal = The NEW ENGLAND JOURNAL of MEDICINE | volume = 343 | issue = 15 | pages = 1070–1077 | publisher = | location = | pmid = 11027741| doi = 10.1056/NEJM200010123431503| bibcode = | oclc = | id = | url = http://content.nejm.org/cgi/content/abstract/343/15/1070 | format = | accessdate = 2008-04-13 | quote = | last2 = Brandes | first2 = RW | last3 = Kendall | first3 = AR | last4 = Lewy | first4 = AJ }}</ref>
			Melatonin is produced by α-proteobacteria and photosynthetic cyanobacteria. There is no report of its occurrence in archaea which indicates that melatonin originated in bacteria<ref name=":1" /> most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.<ref name=":0" />
			Novo Nordisk have used genetically modified '']'' to produce melatonin.<ref>{{Cite journal |last1=Luo |first1=Hao |last2=Schneider |first2=Konstantin |last3=Christensen |first3=Ulla |last4=Lei |first4=Yang |last5=Herrgard |first5=Markus |last6=Palsson |first6=Bernhard Ø. |date=2020 |title=Microbial Synthesis of Human-Hormone Melatonin at Gram Scales |url=https://pubs.acs.org/doi/10.1021/acssynbio.0c00065 |journal=ACS Synthetic Biology |language=en |volume=9 |issue=6 |pages=1240–1245 |doi=10.1021/acssynbio.0c00065 |pmid=32501000 |s2cid=219331624 |issn=2161-5063}}</ref><ref>{{Cite journal |last1=Arnao |first1=Marino B. |last2=Giraldo-Acosta |first2=Manuela |last3=Castejón-Castillejo |first3=Ana |last4=Losada-Lorán |first4=Marta |last5=Sánchez-Herrerías |first5=Pablo |last6=El Mihyaoui |first6=Amina |last7=Cano |first7=Antonio |last8=Hernández-Ruiz |first8=Josefa |date=2023 |title=Melatonin from Microorganisms, Algae, and Plants as Possible Alternatives to Synthetic Melatonin |journal=Metabolites |volume=13 |issue=1 |pages=72 |doi=10.3390/metabo13010072 |pmc=9862825 |pmid=36676997 |doi-access=free }}</ref>
	Melatonin can cause ] (drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc.
			=== Archaea ===
	In individuals with ], there is concern that melatonin supplementation may ameliorate or exacerbate symptoms due to ].<ref name="Morera2001">{{Cite journal| author = Morera A, Henry M, de La Varga M | title = Safety in melatonin use | journal = Actas Esp Psiquiatr | volume = 29 | issue = 5 | pages = 334–7 | year = 2001 | pmid = 11602091 }}</ref><ref name="Terry2008">{{Cite journal|author=Terry PD, Villinger F, Bubenik GA, Sitaraman SV |title=Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research |journal=Inflammatory Bowel Diseases |volume=15 |issue=1 |pages=134–40 |year=2009 |month=January |pmid=18626968 |doi=10.1002/ibd.20527}}</ref>
			In 2022, the discovery of serotonin N-acetyltransferase (SNAT)'''—'''the penultimate, rate-limiting enzyme in the melatonin biosynthetic pathway'''—'''in the archaeon '']'' <ref>{{Cite journal |last1=Lee |first1=Kyungjin |last2=Choi |first2=Geun-Hee |last3=Back |first3=Kyoungwhan |date=2022-03-21 |title=Functional Characterization of Serotonin N-Acetyltransferase in Archaeon Thermoplasma volcanium |journal=Antioxidants |volume=11 |issue=3 |pages=596 |doi=10.3390/antiox11030596 |doi-access=free |issn=2076-3921 |pmc=8945778 |pmid=35326246}}</ref> firmly places melatonin biosynthesis in all three major domains of life, dating back to ~4 Gya.<ref>{{Cite journal |last1=Hoshino |first1=Yosuke |last2=Villanueva |first2=Laura |date=2023-03-10 |title=Four billion years of microbial terpenome evolution |url=https://pubmed.ncbi.nlm.nih.gov/36941124/ |journal=FEMS Microbiology Reviews |volume=47 |issue=2 |pages=fuad008 |doi=10.1093/femsre/fuad008 |issn=1574-6976 |pmid=36941124}}</ref>
			=== Food products ===
	Individuals experiencing ], a ] condition that results in reduced ] and ] to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at ]'s Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those experiencing the condition, the study found.<ref name="Chester2003">{{cite press release |publisher=Penn State College of Medicine, Milton S. Hershey Medical Center |date = September 2003|url = http://www.hmc.psu.edu/news/pr/2003/sept/Ray_melatonin.doc | title = Study Shows Melatonin Supplements May Make Standing A Hazard For The Cardiovascular-Challenged |accessdate=2006-07-21 |format=DOC}} (MS Word Format)</ref>
			Naturally-occurring melatonin has been reported in foods including ] 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 = Journal of Agricultural and Food Chemistry | volume = 49 | issue = 10 | pages = 4898–902 | date = October 2001 | pmid = 11600041 | doi = 10.1021/jf010321 }}</ref> ], ], ], rice, ], ],<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> ], 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 = Journal of Pineal Research | volume = 50 | issue = 4 | pages = 374–80 | date = May 2011 | pmid = 21342247 | doi = 10.1111/j.1600-079X.2010.00853.x | s2cid = 8034935 }}</ref> and beer.<ref>{{cite journal|vauthors=Salehi B|date=5 July 2019|title=Melatonin in Medicinal and Food Plants|url=https://schlaf.fit/Melatonin_in_Plants_and_Food.pdf|journal=]|volume=681|access-date=2 July 2021|archive-date=29 November 2021|archive-url=https://web.archive.org/web/20211129060429/https://schlaf.fit/Melatonin_in_Plants_and_Food.pdf|url-status=dead}}</ref> The consumption of ] and sour cherries may improve sleep quality.<ref>{{cite journal | vauthors = Pereira N, Naufel MF, Ribeiro EB, Tufik S, Hachul H | title = Influence of Dietary Sources of Melatonin on Sleep Quality: A Review | journal = Journal of Food Science | volume = 85 | issue = 1 | pages = 5–13 | date = January 2020 | pmid = 31856339 | doi = 10.1111/1750-3841.14952 | publisher = Wiley | doi-access = free }}</ref> 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 | display-authors = 6 | title = Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates | journal = Biochemistry and Molecular Biology International | volume = 35 | issue = 3 | pages = 627–34 | date = March 1995 | pmid = 7773197 }}</ref> When humans consume foods rich in melatonin, such as banana, ], and ], 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 = Journal of Pineal Research | volume = 55 | issue = 1 | pages = 58–64 | date = August 2013 | pmid = 23137025 | doi = 10.1111/jpi.12025 | s2cid = 979886 | doi-access = free }}</ref>
	The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material. The synthetic form of this medication does not carry this risk.<ref name= "Altun2007"/><ref>{{Cite web|url= http://www.drugs.com/melatonin.html|title= Melatonin Information from Drugs.com}}</ref>
	==See also==
	{{Commons category}}
	* ]
	* ]
	* ]
	* ]
	* ]
	* ]
	==References==		==References==
	{{Reflist|colwidth=30em}}		{{Reflist}}
	==External links==		==External links==
			{{Commons category}}
	* from ]
			* {{cite web | url = https://www.chemwatch.net/resource-center/melatonin/ | publisher = Chemwatch | title = Melatonin }}
	*
			{{Hormones}}
	{{Melatonergics}}
	{{Neurotransmitters}}
	{{Antioxidants}}		{{Antioxidants}}
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