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{{Short description|Supplement and medication used to treat sleep disorders}}
{{Distinguish|Melanotan (disambiguation)|Melanin|Melanopsin|Afamelanotide}}
{{About|melatonin as a supplement and medication|its role as a hormone|Melatonin}}
{{drugbox
{{Use dmy dates|date=October 2022}}
| Verifiedfields = changed
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 420231802 | verifiedrevid = 646778032
| drug_name = Melatonin
| IUPAC_name = ''N''-<br/>acetamide
| image = Melatonin.png | image = Melatonin.svg
| width =
| image2 = Melatonin-3d-CPK.png
| alt =
| image2 = Melatonin molecule ball.png
| width2 =
| alt2 =
| caption =


<!--Clinical data--> <!-- Clinical data -->
| pronounce = {{IPAc-en|audio=En-melatonin.oga|ˌ|m|ɛ|l|ə|ˈ|t|oʊ|n|ɪ|n}}
| tradename = Circadin, Slenyto, others<ref>{{cite news|url=https://www.drugs.com/international/melatonin.html|title=Melatonin – Drugs.com|work=Drugs.com|access-date=12 October 2018}}</ref>
| Drugs.com = {{drugs.com|CDI|melatonin}} | Drugs.com = {{drugs.com|CDI|melatonin}}
| legal_UK = POM | MedlinePlus =
| DailyMedID = Melatonin
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Melatonin AusPAR" />
| pregnancy_category =
| dependency_liability = Physical: Low<ref name="auto">{{cite web |title=Pros and cons of melatonin |url=https://www.mayoclinic.org/healthy-lifestyle/adult-health/expert-answers/melatonin-side-effects/faq-20057874 |access-date=20 August 2022 |website=Mayo Clinic }}</ref>
Psychological: Low<ref name="auto"/>
| addiction_liability = Low / none<ref name="auto"/>
| routes_of_administration = ], ], ]
| class = ]
| receptors = ]
| antagonists =
| precursor = ]
| source_tissues = ]
| target_tissues = Widespread, including ], ], and ]
| ATC_prefix = N05
| ATC_suffix = CH01
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4 | legal_AU = S4
| legal_AU_comment = <ref name="Melatonin AusPAR">https://www.tga.gov.au/resources/auspar/auspar-melatonin-1 {{Bare URL inline|date=August 2024}}</ref><ref>https://www.tga.gov.au/resources/auspar/auspar-melatonin-link-immela-melakso-voquily {{Bare URL inline|date=August 2024}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = OTC
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = OTC | legal_US = OTC
| legal_US_comment =
| routes_of_administration = ], ], ]
| legal_EU = Rx, OTC
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = 30 – 50% | bioavailability = 2.5–50%<ref name=TordjmanS /><ref name="pmid33540815" /><ref name="Circadin-Label" />
| protein_bound = 60%<ref name="Circadin-Label" />
| metabolism = ] via ] mediated 6-hydroxylation
| metabolism = ] via ] mediated 6-hydroxylation
| elimination_half-life = 35 to 50 minutes
| metabolites = ], ], ]
| excretion = ]
| onset =
| elimination_half-life = {{Abbr|IR|Immediate-release}}: 20–60{{nbsp}}minutes<ref name="pmid33540815" /><ref name=Auld2017 /><ref name="pmid18368944">{{cite journal | vauthors = Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP | title = Melatonergic drugs in clinical practice | journal = Arzneimittelforschung | volume = 58 | issue = 1 | pages = 1–10 | date = 2008 | pmid = 18368944 | doi = 10.1055/s-0031-1296459 | s2cid = 38857779 | url = }}</ref><br />{{Abbr|PR|Prolonged-release}}: 3.5–4{{nbsp}}hours<ref name="pmid23044640" /><ref name="Circadin-Label" />
| duration_of_action =
| excretion = ]


<!--Identifiers--> <!-- Identifiers -->
| CASNo_Ref = {{cascite|correct|CAS}} | CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 73-31-4 | CAS_number = 73-31-4
| CAS_supplemental =
| ATC_prefix = N05
| ATC_suffix = CH01
| PubChem = 896 | PubChem = 896
| IUPHAR_ligand = 224 | IUPHAR_ligand = 224
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01065 | DrugBank = DB01065
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08170 | KEGG = D08170
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16796 | ChEBI = 16796
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 45 | ChEMBL = 45
| NIAID_ChemDB = 160011
| PDB_ligand =
| synonyms = ''N''-Acetyl-5-methoxy tryptamine<ref>{{cite web| title=Melatonin| publisher=Sleepdex| access-date=17 August 2011| url=http://www.sleepdex.org/melatonin.htm}}</ref>


<!--Chemical data--> <!-- Chemical and physical data -->
| IUPAC_name = ''N''-acetamide
| C=13 | H=16 | N=2 | O=2 | C=13 | H=16 | N=2 | O=2
| SMILES = COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
| molecular_weight = 232.278 g/mol
| smiles = COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | 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) | 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)
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DRLFMBDRBRZALE-UHFFFAOYSA-N | StdInChIKey = DRLFMBDRBRZALE-UHFFFAOYSA-N
| density =
| density_notes =
| melting_point = 117
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}


<!-- Definition and medical uses -->
'''Melatonin''' ({{IPAc-en|audio=melatonin-pronunciation.ogg|ˌ|m|ɛ|l|ə|ˈ|t|oʊ|n|ɪ|n}}), chemically '''''N''-]-5-]]''',<ref>{{cite web| title=Melatonin| publisher=Sleepdex| accessdate=2011-08-17| url=http://www.sleepdex.org/melatonin.htm}}</ref>
'''Melatonin''' is a ] ] produced in the brain that is also used as a ] and ].<ref name=Auld2017 /><ref name="Faraone2014">{{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> As a hormone, melatonin is released by the ] and is involved in ]s.<ref name=Auld2017 /><ref name="Faraone2014" /> As a supplement, it is often used for the attempted short-term treatment of disrupted sleep patterns, such as from ] or ], and is typically taken ].<ref name="Buscemi_2004">{{cite journal|vauthors=Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T | title = Melatonin for treatment of sleep disorders | url = http://archive.ahrq.gov/downloads/pub/evidence/pdf/melatonin/melatonin.pdf | publisher = Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services | access-date = 5 June 2013 |date=November 2004 | journal = Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, Under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Rockville, MD: Agency for Healthcare Research and Quality | issue = 108 | pages = 1–7 | doi = 10.1037/e439412005-001 | pmid = 15635761 | pmc = 4781368 }}</ref><ref name=AFP2017 /><ref name=BNF76 /> There is evidence of its benefit for this use, but is not strong.<ref name="Bra2015">{{cite journal | vauthors = Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ | title = Management of Insomnia Disorder | journal = AHRQ Comparative Effectiveness Reviews | volume = 15 | issue = 16 | pages = EHC027–EF | year = 2015 | pmid = 26844312 | quote = Evidence for benzodiazepine hypnotics, melatonin agonists in the general adult population, and most pharmacologic interventions in older adults was generally insufficient }}</ref> A 2017 review found that sleep onset occurred six minutes faster with use on average, but found no change in total time asleep.<ref name="AFP2017">{{cite journal | vauthors = Matheson E, Hainer BL | title = Insomnia: Pharmacologic Therapy | journal = American Family Physician | volume = 96 | issue = 1 | pages = 29–35 | date = July 2017 | pmid = 28671376 }}</ref>
is a ] found in animals, plants, fungi and bacteria.<ref>{{cite journal|last1=Hardeland|first1=Rüdiger|last2=Pandi-Perumal|first2=S.R.|last3=Cardinali|first3=Daniel P.|title=Melatonin|journal=The International Journal of Biochemistry & Cell Biology|date=2006|volume=38|issue=3|pages=313–316|doi=10.1016/j.biocel.2005.08.020|pmid=16219483}}</ref>
It is synthesized in animal cells directly from the ] ], but in other organisms through the ], in response to dark-light periods (]).<ref>{{cite journal|last1=Tan|first1=Dun-Xian|last2=Zheng|first2=Xiaodong|last3=Kong| first3=Jin|last4=Manchester|first4=Lucien |last5=Hardeland| first5=Ruediger|last6=Kim|first6=Seok|last7=Xu|first7=Xiaoying|last8=Reiter|first8=Russel|title=Fundamental Issues Related to the Origin of Melatonin and Melatonin Isomers during Evolution: Relation to Their Biological Functions|journal=International Journal of Molecular Sciences|date=9 September 2014|volume=15|issue=9|pages=15858–15890|doi=10.3390/ijms150915858|pmid=25207599|pmc=4200856}}</ref>
<ref name=acuna>{{cite book|last1=Acuna-Castroviejo|first1=D|last2=Escames|first2=G|last3=Tapias|first3=V|last4=Rivas|first4=I|editor1-last=Montilla|editor1-first=Pedro|editor2-last=Túnez|editor2-first=Isaac|title=Melatonin: Present and Future|date=2006|publisher=Nova Science Publishers|location=New York, US|isbn=9781600213748|pages=1-33|url=http://books.google.co.in/books?id=cQn9NNUinwYC&printsec|chapter=Melatonin, mitochondria and neuroprotection}}</ref>


<!-- Side effects -->
In animals, melatonin controls the daily night-day 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 | date = May 2007 | pmid = 17298593 | doi = 10.1111/j.1742-1241.2006.01191.x }}</ref>
Side effects from melatonin supplements are minimal at low doses for short durations (the studies reported about equally for both melatonin and placebo).<ref name=Auld2017 /><ref name="Drugs2019">{{cite web|title=Melatonin: Side Effects, Uses, Dosage (Kids/Adults)|url=https://www.drugs.com/melatonin.html|access-date=9 January 2019|website=Drugs.com}}</ref> Side effects of melatonin are rare but may occur in 1 to 10 patients in 1,000.<ref name="Drugs2019" /><ref name="Circadin-Label" /> They may include ], ], ], ], abnormal ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ], ] in the extremities, symptoms of ], ], ] (sugar in the urine), ] (protein in the urine), abnormal liver function tests, ], ], ], and ] after awakening.<ref name="Circadin-Label" /><ref name="Slenyto EPAR" /><ref name="Drugs2019" /><ref name="HC2015" /><ref name="HC2018Oral" /> Its use is not recommended during ] or ] or for those with ].<ref name=BNF76 /><ref name="HC2018Oral">{{cite web |title=Melatonin- Oral |url=http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=melatonin.oral&lang=eng |website=Government of Canada |publisher=Health Canada |access-date=9 January 2019 |date=28 August 2018 |archive-date=1 April 2019 |archive-url=https://web.archive.org/web/20190401003412/http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=melatonin.oral&lang=eng |url-status=dead }}</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 Pharmacol. Sci. | volume = 26 | issue = 8 | pages = 412–9 | date = August 2005 | 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 | date = July 2005 | pmid = 16217125 | doi = 10.1385/ENDO:27:2:119 }}</ref>
with a particular role in the protection of ] and ].<ref name="Reiter2001">{{cite journal | 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 = Ann. N. Y. Acad. Sci. | volume = 939 | issue = | pages = 200–15 | date = June 2001 | pmid = 11462772 | doi = 10.1111/j.1749-6632.2001.tb03627.x }}</ref>


<!-- Mechanism -->
The hormone can be used as a sleep aid and in the treatment of ]s. It can be taken orally as capsules, tablets, or liquid. It is also available in a form to be used sublingually, and there are transdermal patches. There have been few long-term clinical trials in the use of melatonin in humans.
Melatonin acts as an ] of the ] ] and ]s, the ]s of ] melatonin.<ref name="pmid34225973">{{cite book | vauthors = Pevet P, Challet E, Felder-Schmittbuhl MP | chapter = Melatonin and the circadian system: Keys for health with a focus on sleep | title = The Human Hypothalamus: Anterior Region | series = Handbook of Clinical Neurology | volume = 179 | pages = 331–343 | date = 2021 | pmid = 34225973 | doi = 10.1016/B978-0-12-819975-6.00021-2 | isbn = 9780128199756 | s2cid = 235744969 | chapter-url = }}</ref> It is thought to activate these receptors in the ] of the ] in the ] to regulate the ] and sleep–wake cycles.<ref name="pmid34225973" /> Immediate-release melatonin has a short ] of about 20 to 50{{nbsp}}minutes.<ref name="drugbank" /><ref name=Auld2017 /><ref name="pmid18368944" /> Prolonged-release melatonin used as a medication has a half-life of 3.5 to 4{{nbsp}}hours.<ref name="pmid23044640" /><ref name="Circadin-Label" />


<!-- History and culture -->
==Discovery==
Melatonin was discovered in 1958.<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> It is sold ] in Canada and the United States;<ref name=Drugs2019 /><ref name="HC2015">{{cite web |title=Summary Safety Review – MELATONIN (N-acetyl-5-methoxytryptamine) – Review of the Safety of Melatonin in Children and Adolescents |url=https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-melatonin-acetyl-methoxytryptamine-review-safety-melatonin-children-adolescents.html |website=Government of Canada |publisher=Health Canada |access-date=9 January 2019 |date=10 December 2015}}</ref> in the United Kingdom, it is a ] medication.<ref name="BNF76">{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=482–483|edition=76}}</ref> In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.<ref>{{cite web |title=Australian Public Assessment Report for Melatonin |url=https://www.tga.gov.au/sites/default/files/auspar-circadin-110118.pdf |website=Australian Government Department of Health and Ageing Therapeutic Goods Administration |access-date=9 January 2019 |pages=2, 4 |date=January 2011|quote=Monotherapy for the short term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over. }}</ref><ref name="Circadin-Label" /> In the European Union, it is indicated for the treatment of insomnia in children and adolescents.<ref name="Slenyto EPAR">{{cite web | title=Slenyto EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/slenyto | access-date=31 May 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized, provided the source is acknowledged.</ref> The U.S. ] (FDA) treats melatonin as a dietary supplement and, as such, has not approved it for any medical uses.<ref name="Drugs2019" /> It was approved for medical use in the European Union in 2007.<ref name="Circadin-Label" /> Besides melatonin, certain ] ]s like ], ], and ] are also 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|author3-link=Gabriella Gobbi | vauthors = Atkin T, Comai S, Gobbi G | 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> In 2022, it was the 217th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="Top 300 of 2022">{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref name="Clincalc Melatonin">{{cite web | title = Melatonin Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Melatonin | access-date = 30 August 2024 }}</ref>
{{TOC limit}}


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


===Insomnia===
In 1958 dermatology professor ] and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine ] extracts and named it ''melatonin''.<ref name="pmid14415935">{{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 | issue = | pages = 1992–7 | date = July 1960 | pmid = 14415935 | doi = }}</ref>
In the mid-70s Lynch ''et al.'' demonstrated<ref name="pmid1167425">{{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 | date = January 1975 | pmid = 1167425 | doi = 10.1126/science.1167425 | bibcode = 1975Sci...187..169L }}</ref>
that the production of melatonin exhibits a ] in human pineal glands.


There is no good evidence that melatonin helps treat insomnia and its attempted use for this purpose is recommended against by the ].<ref name=pseudo>{{cite book |title=Pseudoscience in Therapy: A Skeptical Field Guide |veditors=Hupp S, Santa Maria CL |chapter=Chapter 10: Insomnia |vauthors=Carney CE, Lau PH, Kutana S|pages=147–148 |year=2023 |publisher=Cambridge University Press |isbn=9781009000611 |doi=10.1017/9781009000611.011 }}</ref>
The discovery that melatonin is an antioxidant was made in 1993.<ref name="scavenger">{{cite journal | author = Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC | title = Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis | journal = J. Pineal Res. | volume = 14 | issue = 4 | pages = 151–68 | date = May 1993 | pmid = 8102180 | doi = 10.1111/j.1600-079X.1993.tb00498.x | url = }}</ref>
The first ] for its use as a low dose sleep aid was granted to ] at ] in 1995.<ref>{{ cite patent | country = US | number = 5449683 | status = patent | title = Methods of inducing sleep using melatonin | gdate = 1995-09-12 | fdate = 1993-07-16 | inventor = Wurtman RJ | assign1 = Massachusetts Institute of Technology }}</ref> Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.<ref name="pmid16077149">{{cite journal | author = Arendt J | title = Melatonin: characteristics, concerns, and prospects | journal = J. Biol. Rhythms | volume = 20 | issue = 4 | pages = 291–303 | date = August 2005 | pmid = 16077149 | doi = 10.1177/0748730405277492 | quote = There is very little evidence in the short term for toxicity or undesirable effects in humans. The 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. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."<ref name="pmid11027748">{{cite journal | author = Arendt J | title = Melatonin, circadian rhythms, and sleep | journal = N. Engl. J. Med. | volume = 343 | issue = 15 | pages = 1114–6 | date = October 2000 | pmid = 11027748 | doi = 10.1056/NEJM200010123431510 }}</ref>


A ] form of melatonin is approved for use as a medication in ] for the treatment of insomnia in certain people.<ref name="pmid23044640" /><ref name="pmid18808316" />
==Biosynthesis and Pharmacology==
Melatonin biosynthesis in humans and some other organisms involves four enzymatic steps from the essential dietary amino acid ], which follows a ].


===Circadian rhythm sleep disorders===
In the first two steps, L-tryptophan is first converted to 5-hydroxy-L-tryptophan (5-HTP) by an enzyme, tryptophan 5-hydroxylase.
Melatonin may be useful in the treatment of ].<ref name=Auld2017 />
5-HTP is then decarboxylated (] removal) by 5-hydroxytryptophan decarboxylase to produce ]. This point is the rate limiting stage such that further reaction is determined by light-dark conditions.


Melatonin is known to reduce ], especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.<ref name="pubmed12076414">{{cite journal | vauthors = Herxheimer A, Petrie KJ | title = Melatonin for the prevention and treatment of jet lag | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001520 | year = 2002 | volume = 2010 | pmid = 12076414 | doi = 10.1002/14651858.CD001520 | pmc = 8958662 }}</ref>
Only in darkness, the key enzyme, ] (AANAT) is activated and converts serotonin to N-acetyl serotonin, which is ultimately converted to melatonin by the final enzyme, acetylserotonin O-methyltransferase.<ref>{{cite web|title=MetaCyc Pathway: serotonin and melatonin biosynthesis|url=http://www.metacyc.org/META/new-image?object=PWY-6030|website=MetaCyc.org|publisher=SRI International|accessdate=2 November 2014}}</ref><ref name=norman>{{cite book|last1=Norman|first1=Anthony W.|last2=Henry|first2=Helen L.|title=Hormones|date=2012|publisher=Academic Press|location=Oxford, UK|isbn=978-0-12-369444-7|pages=352-359|edition=3|url=http://books.google.co.in/books?id=_renonjXq68C&dq}}</ref>
It is the key regulator of melatonin synthesis from tryptophan, as its gene '']'' is directly influenced by photoperiod.


Melatonin appears to have limited use against the sleep problems of people who work ].<ref name="Cochrane2014">{{cite journal | vauthors = Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, Ruotsalainen JH | title = Pharmacological interventions for sleepiness and sleep disturbances caused by shift work | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 8 | pages = CD009776 | date = August 2014 | pmid = 25113164 | doi = 10.1002/14651858.CD009776.pub2 | pmc = 10025070 }}</ref> Tentative evidence suggests that it increases the length of time people are able to sleep.<ref name="Cochrane2014" />
In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine,<ref name=USAHRQ /> and a small amount is found in saliva.


===REM sleep behavior disorder===
In bacteria, protists, fungi, and plants melatonin is synthesized indirectly with tryptophan as an intermediate product of the ]. In these cells synthesis starts with d-erythrose-4-phosphate and ], and in ] with carbon dioxide. The rest of the reactions are similar, but with slight variations in the last two enzymes.<ref>{{cite journal|last1=Bochkov|first1=Denis V.|last2=Sysolyatin|first2=Sergey V.|last3=Kalashnikov|first3=Alexander I.|last4=Surmacheva|first4=Irina A.|title=Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources|journal=Journal of Chemical Biology|date=2011|volume=5|issue=1|pages=5–17|doi=10.1007/s12154-011-0064-8|pmid=22826715|pmc=3251648}}</ref><ref>{{cite journal|last1=Hardeland|first1=R.|title=Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions|journal=Journal of Experimental Botany|date=2014|volume=18|issue=pii|pages=eru386|doi=10.1093/jxb/eru386|pmid=25240067}}</ref>
Melatonin is a safer alternative than ] in the treatment of ] – a condition associated with the ] like ] and ].<ref name="McCarter2013">{{cite journal | vauthors = McCarter SJ, Boswell CL, St Louis EK, Dueffert LG, Slocumb N, Boeve BF, Silber MH, Olson EJ, Tippmann-Peikert M | title = Treatment outcomes in REM sleep behavior disorder | journal = Sleep Medicine | volume = 14 | issue = 3 | pages = 237–42 | date = March 2013 | pmid = 23352028 | pmc = 3617579 | doi = 10.1016/j.sleep.2012.09.018 | type = Review }}</ref><ref name="McKeithConsensus2017">{{cite journal | vauthors = McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VM, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O'Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K | title = Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium | journal = Neurology | volume = 89 | issue = 1 | pages = 88–100 | date = July 2017 | pmid = 28592453 | pmc = 5496518 | doi = 10.1212/WNL.0000000000004058 | type = Review }}</ref><ref name="Boot2015">{{cite journal | vauthors = Boot BP | title = Comprehensive treatment of dementia with Lewy bodies | journal = Alzheimer's Research & Therapy | volume = 7 | issue = 1 | pages = 45 | date = 2015 | pmid = 26029267 | pmc = 4448151 | doi = 10.1186/s13195-015-0128-z | type = Review | doi-access = free }}</ref> However, clonazepam may be more effective.<ref name="pmid33410930">{{cite journal | vauthors = Gilat M, Marshall NS, Testelmans D, Buyse B, Lewis SJ | title = A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials | journal = J Neurol | volume = 269 | issue = 1 | pages = 125–148 | date = January 2022 | pmid = 33410930 | pmc = 8739295 | doi = 10.1007/s00415-020-10353-0 | doi-access=free }}</ref> In any case, the quality of evidence for both treatments is very low and it is unclear whether either is definitely effective.<ref name="pmid33410930" />


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


===Available forms===
In vertebrates, melatonin secretion is regulated by ]. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphoryates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). At daylight, noradrenergic stimulation stops and the protein is immediately destroyed by ] ].<ref>{{cite journal|last1=Schomerus|first1=C.|last2=Korf|first2=HW|title=Mechanisms regulating melatonin synthesis in the mammalian pineal organ|journal=Annals of the New York Academy of Sciences|date=2005|volume=1057|issue=1|pages=372–383|doi=10.1196/annals.1356.028|pmid=16399907}}</ref> Production is again started in the evening, which is called the dim-light melatonin onset (DLMO).
]


A ] 2{{nbsp}}mg ] formulation of melatonin sold under the brand name Circadin is approved for use in the ] in the short-term treatment of ] in people age 55 and older.<ref name="pmid23044640" /><ref name="pmid18808316">{{cite journal | vauthors = Wade A, Downie S | title = Prolonged-release melatonin for the treatment of insomnia in patients over 55 years | journal = Expert Opin Investig Drugs | volume = 17 | issue = 10 | pages = 1567–72 | date = October 2008 | pmid = 18808316 | doi = 10.1517/13543784.17.10.1567 | s2cid = 71158456 | url = }}</ref><ref name="Circadin-Label">{{cite report|url=https://www.ema.europa.eu/en/medicines/human/EPAR/circadin|title=Circadin: EPAR - Product Information ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS|date=2 February 2021|id=EMEA/H/C/000695 - IA/0066|publisher=] (EMA)}} {{Webarchive|url=https://web.archive.org/web/20221031231302/https://www.ema.europa.eu/en/documents/product-information/circadin-epar-product-information_en.pdf |date=31 October 2022 }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
It is principally blue light, around 460 to 480&nbsp;], that suppresses melatonin,<ref name="Brainard 2001">{{cite journal | author = Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD | title = Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor | journal = J. Neurosci. | volume = 21 | issue = 16 | pages = 6405–12 | date = August 2001 | pmid = 11487664 | doi = }}</ref>
proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. The ] widely used in the twentieth century produced relatively little blue light.<ref></ref>
Wearing glasses that block blue light in the hours before bedtime may decrease 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, Shapiro CM | title = Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work | journal = J. Clin. Endocrinol. Metab. | volume = 90 | issue = 5 | pages = 2755–61 | date = May 2005 | pmid = 15713707 | doi = 10.1210/jc.2004-2062 }}</ref>
Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.<ref>{{cite journal | author = Burkhart K, Phelps JR | title = Amber lenses to block blue light and improve sleep: a randomized trial | journal = Chronobiol Int | volume = 26 | issue = 8 | pages = 1602–12 | date = 26 December 2009 | pmid = 20030543 | doi = 10.3109/07420520903523719 }}</ref>


Melatonin is also available as an ] ] in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3{{nbsp}}mg to 10{{nbsp}}mg or more. It is also possible to buy raw melatonin powder by the weight.<ref>{{cite web|vauthors=Soca R|date=28 February 2021|title=Melatonin Product Availability|url=https://keldik.com/blogs/sleep-circadian-binnacle/melatonin-product-availability|website=Keldik Sleep Circadian and Performance|access-date=11 April 2022|archive-date=27 May 2022|archive-url=https://web.archive.org/web/20220527143716/https://keldik.com/blogs/sleep-circadian-binnacle/melatonin-product-availability|url-status=dead}}</ref> Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or liquids.<ref name=":0">{{cite journal | vauthors = Kolli AR, Kuczaj AK, Calvino-Martin F, Hoeng J | title = Simulated pharmacokinetics of inhaled caffeine and melatonin from existing products indicate the lack of dosimetric considerations | journal = Food and Chemical Toxicology | volume = 187 | pages = 114601 | date = May 2024 | pmid = 38493979 | doi = 10.1016/j.fct.2024.114601 | doi-access = free }}</ref> It is also available for use ], or as ]es.<ref>{{cite journal | vauthors = Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EE, Soh CK, Car J | title = Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 18 | date = February 2018 | pmid = 29397794 | pmc = 5798185 | doi = 10.1186/s12916-017-1000-8 | doi-access = free }}</ref> Several inhalation-based melatonin products with a wide range of doses are being sold but the safety remains to be evaluated.<ref name=":0" />
When used several hours before sleep according to the ] for melatonin in humans, small amounts (0.3&nbsp;mg<ref name="pmid16295212"/>) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.<ref name="isbn3-8055-9120-9">{{cite book | author = Terman MR, Wirz-Justice A | title = Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy | publisher = S Karger Pub | location = Basel | year = 2009 | page = 71 | isbn = 3-8055-9120-9 }}</ref>


The American Academy of Sleep Medicine (AASM) said that the melatonin content in unregulated (without a ] verified mark) supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.<ref name=brooks/>
== Animals ==


==Contraindications==
In vertebrates, melatonin is produced at nighttime by the pineal gland, a small endocrine gland<ref name="Reiter">{{cite journal | author = Reiter RJ | title = Pineal melatonin: cell biology of its synthesis and of its physiological interactions | journal = Endocr. Rev. | volume = 12 | issue = 2 | pages = 151–80 | date = May 1991 | pmid = 1649044 | doi = 10.1210/edrv-12-2-151 }}</ref>
]s of melatonin include ]s among others.<ref name="Circadin-Label" /> It is not recommended in people with ]s due to lack of data in these individuals.<ref name="Circadin-Label" /> Prolonged-release pharmaceutical melatonin (Circadin) contains ] and should not be used in people with the ] or ].<ref name="Circadin-Label" /> Use of melatonin is also not recommend in women who are ] or ] or in people with ].<ref name=BNF76 /><ref name="HC2018Oral" />
located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the ] (SCN) from retinal ]s of the eyes.<ref name="Richardson2005">{{cite journal | author = Richardson GS | title = The human circadian system in normal and disordered sleep | journal = J Clin Psychiatry | volume = 66 Suppl 9 | issue = | pages = 3–9; quiz 42–3 | year = 2005 | pmid = 16336035 | doi = }}</ref><ref name="Perreau-Lenz2004">{{cite journal | author = Perreau-Lenz S, Pévet P, Buijs RM, Kalsbeek A | title = The biological clock: the bodyguard of temporal homeostasis | journal = Chronobiol. Int. | volume = 21 | issue = 1 | pages = 1–25 | date = January 2004 | pmid = 15129821 | doi = 10.1081/CBI-120027984 }}</ref>
rather than the melatonin signal (as was once postulated). 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 = J. Endocrinol. | volume = 179 | issue = 1 | pages = 1–13 | date = October 2003 | pmid = 14529560 | doi = 10.1677/joe.0.1790001 }}</ref> In animals including humans<ref name="Arendt2005">{{cite journal | author = Arendt J, Skene DJ | title = Melatonin as a chronobiotic | journal = Sleep Med Rev | volume = 9 | issue = 1 | pages = 25–39 | date = February 2005 | pmid = 15649736 | doi = 10.1016/j.smrv.2004.05.002 | quote = Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times. }}</ref>
the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (]) 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 mynah birds<ref name="Chaturvedi">{{cite journal | pages = 803–9 | doi = 10.1071/ZO9840803 | url = http://www.publish.csiro.au/paper/ZO9840803.htm | title = Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis | year = 1984 | author = Chaturvedi CM | journal = Australian Journal of Zoology | volume = 32 | issue = 6}}</ref>
and hamsters.<ref name="Chen1981">{{cite journal | author = Chen HJ | title = Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition | journal = Neuroendocrinology | volume = 33 | issue = 1 | pages = 43–6 | 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. During the night, melatonin regulates ], lowering its levels.


== Plants == ==Adverse effects==
Melatonin appears to cause very few ] as tested in the short term, up to three months, at low doses.{{Clarify|reason=Specific dosages?|date=September 2019}}{{Dubious inline|reason=Common misconception-issues|date=May 2023}} Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials, and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and ].<ref name="pmid16423108">{{cite journal | vauthors = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S | title = The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis | journal = Journal of General Internal Medicine | volume = 20 | issue = 12 | pages = 1151–8 | date = December 2005 | pmid = 16423108 | pmc = 1490287 | doi = 10.1111/j.1525-1497.2005.0243.x }}</ref><ref name="Buscemi2006">{{cite journal | vauthors = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–93 | date = February 2006 | pmid = 16473858 | pmc = 1370968 | doi = 10.1136/bmj.38731.532766.F6 }}</ref> Prolonged-release melatonin is safe with long-term use of up to 12 months.<ref name="pmid23044640">{{cite journal | vauthors = Lyseng-Williamson KA | title = Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years | journal = Drugs & Aging | volume = 29 | issue = 11 | pages = 911–23 | date = November 2012 | pmid = 23044640 | doi = 10.1007/s40266-012-0018-z | s2cid = 1403262 }}</ref> Although not recommended for long-term use beyond this,<ref>{{cite web |title=Melatonin: What You Need To Know |url=https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know |website=NCCIH |publisher=National Institutes of Health |access-date=2 July 2021}}</ref> low-dose melatonin is generally safer, and a better alternative, than many prescription and over-the-counter sleep aids if a sleeping medication must be used for an extended period of time.{{Citation needed|date=August 2021}} Low doses of melatonin are usually sufficient to produce a ] effect in most people. Higher doses do not appear to result in a stronger effect but instead appear to cause drowsiness for a longer period of time.<ref>Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews . York (UK): Centre for Reviews and Dissemination (UK); 1995. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. 2014.</ref>
Melatonin is identified in many plants including ] (''Tanacetum parthenium''), ] (''Hypericum perforatum''),<ref name="Paredes2009">{{cite journal | author = Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ | title = Phytomelatonin: a review | journal = J. Exp. Bot. | volume = 60 | issue = 1 | pages = 57–69 | year = 2009 | pmid = 19033551 | doi = 10.1093/jxb/ern284 }}</ref>
rice, corn, tomato, grape<ref name="pmid19445314">{{cite journal | author = Iriti M, Faoro F | title = Bioactivity of grape chemicals for human health | journal = Nat Prod Commun | volume = 4 | issue = 5 | pages = 611–34 | year = 2009 | pmid = 19445314 | doi = }}</ref>
and other edible fruits.<ref name="pmid22016420">{{cite journal | author = Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ | title = Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science | journal = J. Exp. Bot. | volume = 63 | issue = 2 | pages = 577–97 | date = January 2012 | pmid = 22016420 | doi = 10.1093/jxb/err256 }}</ref>
The physiological roles in plants include regulation of their response to ], defense against harsh environments, and the function of an antioxidant.<ref name="pmid20039865">{{cite journal | author = Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ | title = The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness | journal = Biol Rev Camb Philos Soc | volume = 85 | issue = 3 | pages = 607–23 | date = August 2010 | pmid = 20039865 | doi = 10.1111/j.1469-185X.2009.00118.x }}</ref>
It also regulates plant growth by its ability to slow root formation, while promoting above-ground growth.<ref name="Melatonin Plants">{{cite journal | author = Arnao MB, Hernández-Ruiz J | title = The physiological function of melatonin in plants | journal = Plant Signal Behav | volume = 1 | issue = 3 | pages = 89–95 | date = May 2006 | pmid = 19521488 | pmc = 2635004 | doi = 10.4161/psb.1.3.2640 }}</ref>


There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.<ref name="pmid31901302">{{cite journal | vauthors = Garaulet M, Qian J, Florez JC, Arendt J, Saxena R, Scheer FA | title = Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy | journal = Trends in Endocrinology and Metabolism | volume = 31 | issue = 3 | pages = 192–204 | date = March 2020 | pmid = 31901302 | pmc = 7349733 | doi = 10.1016/j.tem.2019.11.011 }}</ref> Specifically, taking exogenous melatonin shortly after a meal is correlated with impaired glucose tolerance. Therefore, Rubio-Sastre and colleagues recommend waiting at least 2 hours after the last meal before taking a melatonin supplement.<ref name="Rubio-Sastre_2014">{{cite journal | vauthors = Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M | title = Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening | journal = Sleep | volume = 37 | issue = 10 | pages = 1715–9 | date = October 2014 | pmid = 25197811 | pmc = 4173928 | doi = 10.5665/sleep.4088 }}</ref>
==Functions==


Melatonin can cause ], next-day ], and irritability.<ref>{{cite web| title=Melatonin side effects: What are the risks?| publisher=Mayo Clinic| vauthors = Bauer B | access-date=17 August 2011| url=http://www.mayoclinic.com/health/melatonin-side-effects/AN01717}}</ref> In ], evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to ].<ref name="Morera2001">{{cite journal | vauthors = Morera AL, Henry M, de La Varga M | title = | language = es | journal = Actas Españolas de Psiquiatría | volume = 29 | issue = 5 | pages = 334–7 | year = 2001 | pmid = 11602091 | trans-title = Safety in melatonin use }}</ref><ref name="Terry2008">{{cite journal | vauthors = Terry PD, Villinger F, Bubenik GA, Sitaraman SV | title = Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research | journal = Inflammatory Bowel Diseases | volume = 15 | issue = 1 | pages = 134–40 | date = January 2009 | pmid = 18626968 | doi = 10.1002/ibd.20527 | doi-access = free }}</ref>{{update inline|date=April 2018}}
===Circadian rhythm===


Melatonin can lower ] levels.<ref name="pmid16921343">{{cite journal | vauthors = Juszczak M, Michalska M | title = | language = pl | journal = Postepy Higieny I Medycyny Doswiadczalnej | volume = 60 | pages = 431–8 | year = 2006 | pmid = 16921343 | url = http://www.phmd.pl/fulltxthtml.php?ICID=453297 | trans-title = The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion | access-date = 24 December 2013 | archive-url = https://web.archive.org/web/20141102054834/http://www.phmd.pl/fulltxthtml.php?ICID=453297 | archive-date = 2 November 2014 | url-status = dead }}</ref> Melatonin's effects on human reproduction remain unclear.<ref name="pmid19905996">{{cite journal | vauthors = Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A | title = Melatonin and human reproduction: shedding light on the darkness hormone | journal = Gynecological Endocrinology | volume = 25 | issue = 12 | pages = 779–85 | date = December 2009 | pmid = 19905996 | doi = 10.3109/09513590903159649 | s2cid = 3442003 }}</ref>
In animals, the primary function is regulation of day-night cycles. Human infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 AM.<ref name="pmid12589109">{{cite journal | author = Ardura J, Gutierrez R, Andres J, Agapito T | title = Emergence and evolution of the circadian rhythm of melatonin in children | journal = Horm. Res. | volume = 59 | issue = 2 | pages = 66–72 | year = 2003 | pmid = 12589109 | doi = 10.1159/000068571 }}</ref> Human melatonin production decreases as a person ages.<ref name="pmid3783419">{{cite journal | author = Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM | title = Human melatonin production decreases with age | journal = J. Pineal Res. | volume = 3 | issue = 4 | pages = 379–88 | year = 1986 | pmid = 3783419 | doi = 10.1111/j.1600-079X.1986.tb00760.x }}</ref> Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.<ref>{{cite web | title = Why Aren't Teens Getting Enough Sleep? | url = http://kidshealth.org/teen/your_body/take_care/how_much_sleep.html |work=How Much Sleep Do I Need? |year=2009 | author = Gavin ML, Scaivina MT}}</ref>


Some supplemental melatonin users report an increase in ]. Extremely high doses of melatonin increased ] time and dream activity in people both with and without ].<ref name="Lewis">{{cite book |title=Melatonin and the Biological Clock | vauthors = Lewis A |publisher=McGraw-Hill |isbn=978-0-87983-734-1 |year=1999 |page= |url-access=registration |url=https://archive.org/details/melatoninbiologi00lew_46r }}</ref>
====Antioxidant====
Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993.<ref>{{cite journal | author = Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ | title = Melatonin: a potent, endogenous hydroxyl radical scavenger | journal = Endocrine J. | year = 1993 | volume = 1 | pages = 57–60 | url = https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxkdW54aWFudGFufGd4OjVkMjA5NGZkMzFmYjRkOTU}}</ref><ref name="pmid7832450"/> In many less complex life forms, this is its only known function.<ref name="Tan_Manchester">{{cite journal | author = Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ | title = One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? | journal = J. Pineal Res. | volume = 42 | issue = 1 | pages = 28–42 | date = January 2007 | pmid = 17198536 | doi = 10.1111/j.1600-079X.2006.00407.x }}</ref>
Melatonin is an ] that can easily cross ]s<ref name = "Pohanka_2011">{{cite journal | author = Pohanka M | title = Alzheimer´s disease and related neurodegenerative disorders: implication and counteracting of melatonin | journal = Journal of Applied Biomedicine | year = 2011 | volume = 9 | pages = 185–196 | doi = 10.2478/v10136-011-0003-6|url=http://www.zsf.jcu.cz/jab/9_4/pohanka.pdf/ | issue = 4 }}</ref>
and the blood–brain barrier.<ref name="Hardeland2005"/><ref name="pmid21358970">{{cite journal | author = Reiter RJ, Manchester LC, Tan DX | title = Neurotoxins: free radical mechanisms and melatonin protection | journal = Curr Neuropharmacol | volume = 8 | issue = 3 | pages = 194–210 | date = September 2010 | pmid = 21358970 | pmc = 3001213 | doi = 10.2174/157015910792246236 }}</ref>
This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH, O<sub>2</sub><sup>−</sup>, and NO.<ref name="Melatonin Plants" /><ref name="pmid7832450">{{cite journal | author = Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR | title = Melatonin – a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro | journal = Ann. N. Y. Acad. Sci. | volume = 738 | issue = | pages = 419–20 | date = November 1994 | pmid = 7832450 | doi = 10.1111/j.1749-6632.1994.tb21831.x | bibcode = 1994NYASA.738..419P }}</ref>
Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.<ref name="Melatonin Plants" /> Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.<ref name="pmid7934611">{{cite journal | author = Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F | title = Melatonin: a peroxyl radical scavenger more effective than vitamin E | journal = Life Sci. | volume = 55 | issue = 15 | pages = PL271–6 | year = 1994 | pmid = 7934611 | doi = 10.1016/0024-3205(94)00666-0 }}</ref>
An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction.<ref name="Tan_Manchester" /> Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a better protector against mitochondrial oxidative stress.<ref name="pmid23381720">{{cite journal | author = Lowes DA, Webster NR, Murphy MP, Galley HF | title = Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis | journal = Br J Anaesth | volume = 110 | issue = 3 | pages = 472–80 | date = March 2013 | pmid = 23381720 | pmc = 3570068 | doi = 10.1093/bja/aes577 }}</ref>


Increased use of melatonin in the 21st century has significantly increased reports of melatonin overdose, calls to poison control centers, and related emergency department visits for children. The number of children who unintentionally ingested melatonin supplements in the US has increased 530% from 2012 to 2021. Over 4,000 reported ingestions required a hospital stay, and 287 children required intensive care. The ] says there is little evidence that melatonin supplementation is effective in treating insomnia in healthy children.<ref name=brooks>{{cite web | vauthors = Brooks M | title=Experts Issue Health Warning About Giving Melatonin to Kids | website=Medscape | date=23 September 2022 | url=https://www.medscape.com/viewarticle/981341}}</ref>
===Immune system===
While it is known that melatonin interacts with the ],<ref name="Carrillo-Vico2005">{{cite journal | author = Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ | title = A review of the multiple actions of melatonin on the immune system | journal = Endocrine | volume = 27 | issue = 2 | pages = 189–200 | date = July 2005 | pmid = 16217132 | doi = 10.1385/ENDO:27:2:189 }}</ref><ref name="Arushanian2002">{{cite journal | author = Arushanian EB, Beĭer EV | title = | language = Russian | journal = Eksp Klin Farmakol | volume = 65 | issue = 5 | pages = 73–80 | year = 2002 | pmid = 12596522 | doi = }}</ref> the details of those interactions are unclear. ] effect seems to be the most relevant and most documented in the literature.<ref>{{cite journal |author=Pohanka|first=M |title=Impact of melatonin on immunity: a review|journal=Central European Journal of Medicine |volume=8 |issue=4 |pages=369–376 |year=2013 |doi= 10.2478/s11536-013-0177-2|url= http://link.springer.com/article/10.2478%2Fs11536-013-0177-2}}</ref> There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance ] production,<ref name="pmid16729718">{{cite journal | author = Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D | title = The modulatory role of melatonin on immune responsiveness | journal = Curr Opin Investig Drugs | volume = 7 | issue = 5 | pages = 423–31 | date = May 2006 | pmid = 16729718 | doi = }}</ref> and by doing this counteract ]. Some studies also suggest that melatonin might be useful fighting infectious disease<ref name="Pp">{{cite journal | author = Maestroni GJ | title = The immunotherapeutic potential of melatonin | journal = Expert Opin Investig Drugs | volume = 10 | issue = 3 | pages = 467–76 | date = March 2001 | pmid = 11227046 | doi = 10.1517/13543784.10.3.467 }}</ref> including viral, such as ], and bacterial infections, and potentially in the treatment of ].


==Overdose==
In ] patients, melatonin production has been found increased when compared to age-matched healthy controls.<ref name="pmid16014678">{{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 | date = August 2005 | pmid = 16014678 | pmc = 1755599 | doi = 10.1136/ard.2005.038588 }}</ref>{{relevance-inline|date=April 2014}}
Melatonin appears to be relatively safe in ].<ref name="Circadin-Label" /> It has been administered at daily doses of up to 300{{nbsp}}mg without causing clinically significant adverse reactions in the literature.<ref name="Circadin-Label" /> The most commonly reported adverse effect of melatonin overdose is ].<ref name="Circadin-Label" /> Upon melatonin overdose, ] may be expected and the compound should be cleared within 12{{nbsp}}hours.<ref name="Circadin-Label" /> No special treatment is needed for melatonin overdose.<ref name="Circadin-Label" />


==Interactions==
===Metal Chelation===
Melatonin is ] mainly by ] ]s. As such, ]s and ]s of CYP1A enzymes, such as ], can modify melatonin metabolism and exposure.<ref name="Circadin-Label" /> As an example, the CYP1A2 and ] inhibitor ] increases melatonin peak levels by 12-fold and overall exposure by 17-fold and this combination should be avoided.<ref name="Circadin-Label" /> CYP1A2 inducers like ], ], and ] may reduce melatonin exposure due to induction of CYP1A2.<ref name="Circadin-Label" />
In vitro, melatnon can form complexes with cadmium and other metals.<ref>{{cite journal|title= The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study|last= Limson|first=J.|last2= Nyokong| first2=T.| last3= Daya|first3=S.|journal= J Pineal Res|volume= 24 |year=1998|pages=15–21}}</ref>


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


==Pharmacology==
===Dietary supplement===


===Pharmacodynamics===
Melatonin is categorized by the US ] (FDA) as a dietary supplement. It is sold freely over-the-counter in both the US and Canada without any regulation as a pharmaceutical drug.<ref name = "Buscemi_2004">{{cite web| author = Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T | title = Melatonin for treatment of sleep disorders | url = http://archive.ahrq.gov/downloads/pub/evidence/pdf/melatonin/melatonin.pdf | publisher = Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services | accessdate = 5 June 2013 |date=November 2004 | work = Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Rockville, MD: Agency for Healthcare Research and Quality }}</ref> The Food and Drug Administration (FDA) regulations applying 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> The industry has also been required to report to the FDA "all serious dietary supplement related adverse events", and the FDA has (within the cGMP guidelines) begun enforcement of that requirement.<ref>{{cite web | url= http://www.medicalnewstoday.com/articles/75250.php | title = FDA Tightens Up Dietary Supplement Manufacturing And Labelling | website= Medical News Today | accessdate = 2 September 2013 | date = 26 June 2007}}</ref>
Melatonin acts as an ] of the ] ] and ]s, the ]s of ] melatonin.<ref name="pmid34225973" /> Endogenous melatonin is normally secreted from the ] of the brain.<ref name="pmid34225973" /> Melatonin is thought to activate melatonin receptors in the ] of the ] to regulate the ] and sleep–wake cycles.<ref name="pmid34225973" /> When used several hours before sleep according to the ] for melatonin in humans, small amounts (0.3&nbsp;mg<ref name="pmid16295212">{{cite journal | vauthors = Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC | title = Phase-dependent treatment of delayed sleep phase syndrome with melatonin | journal = Sleep | volume = 28 | issue = 10 | pages = 1271–8 | date = October 2005 | pmid = 16295212 | doi = 10.1093/sleep/28.10.1271 | doi-access = free }}</ref>) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.<ref name="isbn 3-8055-9120-9">{{cite book |vauthors=Terman MR, Wirz-Justice A | title = Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy |url=https://archive.org/details/chronotherapeuti00wirz |url-access=limited | publisher = S Karger Pub | location = Basel | year = 2009 | page = | isbn = 978-3-8055-9120-1 }}</ref>


===Food products=== ===Pharmacokinetics===
Melatonin has been reported in foods including cherries to about 0.17–13.46&nbsp;ng/g,<ref name="pmid11600041">{{cite journal | author = Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ | title = Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus) | journal = J. Agric. Food Chem. | volume = 49 | issue = 10 | pages = 4898–902 | date = October 2001 | pmid = 11600041 | doi = 10.1021/jf010321 }}</ref> bananas and grapes, rice and cereals, herbs, olive oil, ]<ref name="pmid21342247">{{cite journal | author = Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S | title = Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection | journal = J. Pineal Res. | volume = 50 | issue = 4 | pages = 374–80 | date = May 2011 | pmid = 21342247 | doi = 10.1111/j.1600-079X.2010.00853.x }}</ref> and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.<ref name="Hattori1995">{{cite journal | author = Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ | title = Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates | journal = Biochem. Mol. Biol. Int. | volume = 35 | issue = 3 | pages = 627–34 | date = March 1995 | pmid = 7773197 }}</ref> When humans consume foods rich in melatonin such as banana, pineapple and orange the blood levels of melatonin significantly increase.<ref name="pmid23137025">{{cite journal | author = Sae-Teaw M, Johns J, Johns NP, Subongkot S | title = Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers | journal = J. Pineal Res. | volume = 55 | issue = 1 | pages = 58–64 | date = October 2012 | pmid = 23137025 | doi = 10.1111/jpi.12025 }}</ref>


====Absorption====
As reported in the ''New York Times'' in May 2011,<ref name="NYTimes May 2011">{{cite news |url = http://www.nytimes.com/2011/05/15/us/15lazycakes.html?_r=1&scp=1&sq=lazy%20cakes&st=cse |work=New York Times |title=Dessert, Laid-Back and Legal | date=14 May 2011 |author=Catherine Saint Louis }}</ref> beverages and snacks containing melatonin are sold in grocery stores, convenience stores, and clubs. The FDA is considering whether these food products can continue to be sold with the label "dietary supplements". On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as "relaxation drinks," stating that melatonin is not approved as a ] because it is not ].<ref name="FDAwarning"/>
The ] of melatonin is between 2.5 and 50%.<ref name=TordjmanS /><ref name="pmid33540815" /> Melatonin is rapidly ] and ], reaching ] after 60{{nbsp}}minutes of administration, and is then ].<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> Usual doses of exogenous melatonin of 1 to 12{{nbsp}}mg produce melatonin concentrations 10 to 100{{nbsp}}times higher than endogenous peak levels.<ref name="pmid33540815">{{cite journal | vauthors = Lalanne S, Fougerou-Leurent C, Anderson GM, Schroder CM, Nir T, Chokron S, Delorme R, Claustrat B, Bellissant E, Kermarrec S, Franco P, Denis L, Tordjman S | title = Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder | journal = Int J Mol Sci | volume = 22 | issue = 3 | date = February 2021 | page = 1490 | pmid = 33540815 | pmc = 7867370 | doi = 10.3390/ijms22031490 | url = | doi-access = free }}</ref>


====Distribution====
==Medical uses==
The ] of melatonin is approximately 60%.<ref name="Circadin-Label" /><ref name="pmid33540815" /> It is mainly bound to ], ], and ].<ref name="Circadin-Label" />
]
Melatonin has been studied for insomnia in the elderly.<ref name="pmid19326288">{{cite journal | author = Srinivasan V, Pandi-Perumal SR, Trahkt I, Spence DW, Poeggeler B, Hardeland R, Cardinali DP | title = Melatonin and melatonergic drugs on sleep: possible mechanisms of action | journal = Int. J. Neurosci. | volume = 119 | issue = 6 | pages = 821–46 | year = 2009 | pmid = 19326288 | doi = 10.1080/00207450802328607 }}</ref><ref name="pmid21358978">{{cite journal | author = Fornaro M, Prestia D, Colicchio S, Perugi G | title = A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation | journal = Curr Neuropharmacol | volume = 8 | issue = 3 | pages = 287–304 | date = September 2010 | pmid = 21358978 | pmc = 3001221 | doi = 10.2174/157015910792246227 }}</ref><ref name="pmid15511698">{{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 | date = November 2004 | pmid = 15511698 | doi = 10.1016/j.sleep.2004.07.009 }}</ref> Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).<ref name="pmid17875243">{{cite journal | author = Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N | 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 | date = October 2007 | pmid = 17875243 | doi = 10.1185/030079907X233098 }}</ref> It may improve ] misalignment and SAD.<ref name="pmid1701579">{{cite journal | author = Cassone VM | title = Effects of melatonin on vertebrate circadian systems | journal = Trends Neurosci. | volume = 13 | issue = 11 | pages = 457–64 | date = November 1990 | pmid = 1701579 | doi = 10.1016/0166-2236(90)90099-V }}</ref><ref name="Lewy1987">{{cite journal | author = Lewy AJ, Sack RL, Miller LS, Hoban TM | title = Antidepressant and circadian phase-shifting effects of light | journal = Science | volume = 235 | issue = 4786 | pages = 352–4 | date = January 1987 | pmid = 3798117 | doi = 10.1126/science.3798117 | bibcode = 1987Sci...235..352L }}</ref> Basic research indicates that melatonin may play a role in modulating the effects of drugs of abuse such as ].<ref name="pmid10700581">{{cite journal | author = Sircar R | title = Effect of melatonin on cocaine-induced behavioral sensitization | journal = Brain Res. | volume = 857 | issue = 1–2 | pages = 295–9 | date = February 2000 | pmid = 10700581 | doi = 10.1016/S0006-8993(99)02460-9 }}</ref><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 | date = December 2003 | pmid = 12865893 | doi = 10.1038/sj.npp.1300254 }}</ref>


The ]s that move melatonin across a membrane include, but are not limited to, ]s, including ], and the ]s ] and ].<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 | 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}}</ref><ref name="Melatonin transporters – 2017 review">{{cite journal | vauthors = Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R | title = Melatonin transport into mitochondria | journal = Cellular and Molecular Life Sciences | volume = 74 | issue = 21 | pages = 3927–3940 | date = November 2017 | pmid = 28828619 | doi = 10.1007/s00018-017-2616-8 | s2cid = 10920415 | pmc = 11107582 }}</ref>
===Sleep disorders===


====Metabolism====
A 2004 review found that "there was no evidence that melatonin had an effect on sleep onset latency or sleep efficiency" in people suffering from ], such as from shift work and rapid transmeridian travel, while it did decrease sleep onset latency in people with a primary sleep disorder and it increased sleep efficiency in people with a secondary sleep disorder.<ref name=USAHRQ />
Melatonin is ] in the ] by ] ] ] to ]. ]s are ] with ] or ] for ] in the ]. Some of the metabolites formed via the reaction of melatonin with a ] include ], ] (AFMK), and ] (AMK).<ref name="IUPHAR – melatonin receptors review" /><ref name="Melatonin transporters – 2017 review" />


====Elimination====
Short and long term treatment of prolonged-release melatonin was found to be effective and safe, improving sleep latency, sleep quality and daytime alertness in insomnia patients.<ref name="pmid22429105">{{cite journal | author = Lemoine P, Zisapel N | title = Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia | journal = Expert Opin Pharmacother | volume = 13 | issue = 6 | pages = 895–905 | year = 2012 | pmid = 22429105 | doi = 10.1517/14656566.2012.667076 }}</ref>
In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.<ref name="Buscemi_2004" /> Melatonin is excreted in the urine 2 to 5% as the unchanged drug.<ref name=TordjmanS /><ref name="Circadin-Label" />


Melatonin has an ] of about 20 to 60 minutes.<ref name="drugbank">{{cite web |title=Melatonin |url=https://www.drugbank.ca/drugs/DB01065 |website=www.drugbank.ca |access-date=29 January 2019}}</ref><ref name="pmid33540815" /><ref name=Auld2017 /><ref name="pmid18368944" /> The half-life of prolonged-release melatonin (Circadin) is 3.5 to 4{{nbsp}}hours.<ref name="pmid23044640" /><ref name="Circadin-Label" />
In exploratory studies, prolonged-release melatonin has shown sleep quality improvement in patients with chronic schizophrenia<ref name="pmid10847313">{{cite journal | author = Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N | title = Melatonin improves sleep quality of patients with chronic schizophrenia | journal = J Clin Psychiatry | volume = 61 | issue = 5 | pages = 373–7 | year = 2000 | pmid = 10847313 | doi = 10.4088/jcp.v61n0509}}</ref> as well as in patients with major depressive disorder<ref name="pmid9699707">{{cite journal | author = Dolberg OT, Hirschmann S, Grunhaus L | title = Melatonin for the treatment of sleep disturbances in major depressive disorder | journal = Am J Psychiatry | volume = 155 | issue = 8 | pages = 1119–21 |date=August 1998 | pmid = 9699707 | doi = | url = http://ajp.psychiatryonline.org/article.aspx?articleid=172965 }}</ref><ref name="pmid10721684">{{cite journal | author = Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM | title = Use of slow-release melatonin in treatment-resistant depression | journal = J Psychiatry Neurosci | volume = 25 | issue = 1 | pages = 48–52 | year = 2000 | pmid = 10721684 | pmc = 1407707 | doi = }}</ref> and treating sleep-wake cycle disorders in children with underlying neurodevelopment difficulties.<ref name="pmid10949538">{{cite journal | author = Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M | title = Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders | journal = J. Pineal Res. | volume = 29 | issue = 1 | pages = 34–9 |date=August 2000 | pmid = 10949538 | doi = 10.1034/j.1600-079X.2000.290105.x }}</ref><ref name="pmid12525548">{{cite journal | author = De Leersnyder H, Bresson JL, de Blois MC, Souberbielle JC, Mogenet A, Delhotal-Landes B, Salefranque F, Munnich A | title = Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome | journal = J. Med. Genet. | volume = 40 | issue = 1 | pages = 74–8 | year = 2003 | pmid = 12525548 | pmc = 1735264 | doi = 10.1136/jmg.40.1.74}}</ref> Additionally, as add-on to antihypertensive therapy, prolonged-release melatonin improved blood pressure control in patients with nocturnal hypertension as shown in a randomised double-blind placebo controlled study.<ref name="pmid21966222">{{cite journal | author = Grossman E, Laudon M, Zisapel N | title = Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials | journal = Vasc Health Risk Manag | volume = 7 | issue = | pages = 577–84 | year = 2011 | pmid = 21966222 | pmc = 3180511 | doi = 10.2147/VHRM.S24603 }}</ref>


==Chemistry==
Melatonin taken in the evening is, together with ] upon awakening, the standard treatment for delayed sleep phase disorder (DSPD) and ] where circadian rhythms are not ] (biologically synchronized) to the environmental cycle. 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 DSPD than in people with insomnia.<ref name="USAHRQ">{{cite journal | author = Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T | title = Melatonin for treatment of sleep disorders | journal = Evidence Report/Technology Assessment (Summary) | volume = | issue = 108 | pages = 1–7 | date = November 2004 | pmid = 15635761 | doi = | url = http://www.ncbi.nlm.nih.gov/books/NBK37431/ }}</ref>
Melatonin, also known as ''N''-acetyl-5-methoxytryptamine, is a ] and a ] of ] (5-hydroxytryptamine). It is structurally related to ] (normelatonin; ''N''-acetyl-5-hydroxytryptamine), which is the ] between serotonin and melatonin in the body. ] ]s used in medicine like ], ], ], and ] (still in clinical trials) are ]s of melatonin.


==History==
Many totally blind people can control ] by taking small amounts of melatonin in the evening.<ref name="pmid11027741">{{cite journal | author = Sack RL, Brandes RW, Kendall AR, Lewy AJ | title = Entrainment of free-running circadian rhythms by melatonin in blind people | journal = N. Engl. J. Med. | volume = 343 | issue = 15 | pages = 1070–7 | date = October 2000 | pmid = 11027741 | doi = 10.1056/NEJM200010123431503 }}</ref>
The first ] for its use in circadian rhythm disorders was granted in 1987 to Roger V Short and Stuart Armstrong at ],<ref>{{cite web |title=Method for minimizing disturbances in circadian rhythms of bodily performance and function - Patent US-4665086-A - PubChem |url=https://pubchem.ncbi.nlm.nih.gov/patent/US-4665086-A |access-date=16 April 2022 |website=pubchem.ncbi.nlm.nih.gov}}</ref> and the first patent for its use as a low-dose sleep aid was granted to ] at ] in 1995.<ref>{{cite patent | country = US | number = 5449683 | status = patent | title = Methods of inducing sleep using melatonin | gdate = 12 September 1995 | fdate = 16 July 1993 | inventor = Wurtman RJ | assign1 = Massachusetts Institute of Technology }}</ref> Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.<ref name="pmid16077149">{{cite journal | vauthors = Arendt J | title = Melatonin: characteristics, concerns, and prospects | journal = Journal of Biological Rhythms | volume = 20 | issue = 4 | pages = 291–303 | date = August 2005 | pmid = 16077149 | doi = 10.1177/0748730405277492 | s2cid = 19011222 | quote = There is very little evidence in the short term for toxicity or undesirable effects in humans. The extensive promotion of the miraculous powers of melatonin in the recent past did a disservice to acceptance of its genuine benefits. | doi-access = free }}</ref> ''The ]'' editorialized in 2000: "With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear."<ref name="pmid11027748">{{cite journal | vauthors = Arendt J | title = Melatonin, circadian rhythms, and sleep | journal = The New England Journal of Medicine | volume = 343 | issue = 15 | pages = 1114–6 | date = October 2000 | pmid = 11027748 | doi = 10.1056/NEJM200010123431510 }}</ref>


It was approved for medical use in the European Union in 2007.<ref name="Circadin-Label" />
Melatonin appears to increase the amount of sleep in people after working night shifts.<ref>{{cite journal|last1=Liira|first1=J|last2=Verbeek|first2=JH|last3=Costa|first3=G|last4=Driscoll|first4=TR|last5=Sallinen|first5=M|last6=Isotalo|first6=LK|last7=Ruotsalainen|first7=JH|title=Pharmacological interventions for sleepiness and sleep disturbances caused by shift work.|journal=The Cochrane database of systematic reviews|date=Aug 12, 2014|volume=8|pages=CD009776|pmid=25113164|doi=10.1002/14651858.CD009776.pub2}}</ref>


==Society and culture==
A very small dose taken several hours before bedtime in accordance with the ] for melatonin in humans (PRC) does not cause sleepiness but, acting as a '']'' (affecting aspects of biological time structure),<ref>{{cite book | url = http://books.google.com/?id=e-bZhuzXbK4C&pg=PA433&lpg=PA433&dq=chronobiotic+definition#v=onepage&q=chronobiotic%20definition&f=false | page = 433 | chapter = Chronobiotics: Selected Agents of Potential Value in Jet Lag and other Dyschronisms | author = Simpson HW | title = Chronobiology: Principles and Application to Shifts in Schedules | editor = Sheving FE, Hagberg F | publisher = Springer | location = Berlin | year = 1979 | isbn = 978-90-286-0940-2}} The reference discusses several chronobiotic substances, but not melatonin.</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 an oral dose of 0.3 or 3&nbsp;mg of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the ~2 hour advance achieved with light therapy. There was no difference in the average magnitude of phase shift induced by the 2 doses.<ref name="pmid16295212">{{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 | date = October 2005 | pmid = 16295212 | doi = }}</ref>


Melatonin is categorized by the US ] (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada.<ref name="Buscemi_2004" /> FDA regulations applying to medications are not applicable to melatonin,<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> though the FDA has found false claims that it cures cancer.<ref name="fda">{{cite web |url=https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm171057.htm |title=187 Fake Cancer 'Cures' Consumers Should Avoid |publisher=U.S. ] |archive-url=https://web.archive.org/web/20170502034227/https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/enforcementactivitiesbyfda/ucm171057.htm |archive-date=2 May 2017 |access-date=20 May 2020}}</ref> As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin.<ref name="pubmed12076414" /> In many countries, melatonin is recognized as a ] and it cannot be sold over-the-counter.<ref name="Toxicology">{{cite journal | vauthors = Guardiola-Lemaître B | title = Toxicology of melatonin | journal = Journal of Biological Rhythms | volume = 12 | issue = 6 | pages = 697–706 | date = December 1997 | pmid = 9406047 | doi = 10.1177/074873049701200627 | s2cid = 31090576 | doi-access = free }}</ref> According to ] caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from -83% to +478%, lot-to-lot variability was as high as 465%, and the discrepancies were not correlated to any manufacturer or product type. To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin.<ref>{{cite web |author-link = Harriet Hall | vauthors = Hall H |title=Melatonin Melatonin supplements are increasingly popular, but the evidence is weak and mixed. |url=https://sciencebasedmedicine.org/melatonin/ | work = Science-Based Medicine |date=15 December 2020 |publisher=Science Based Medicine |access-date=24 December 2020}}</ref><ref>{{cite journal | vauthors = Erland LA, Saxena PK | title = Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content | journal = Journal of Clinical Sleep Medicine | volume = 13 | issue = 2 | pages = 275–281 | date = February 2017 | pmid = 27855744 | pmc = 5263083 | doi = 10.5664/jcsm.6462 }}</ref>
===Stimulants===


Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material.<ref name="Altun2007" /><ref>{{cite web |url=https://www.drugs.com/melatonin.html |title=Melatonin| publisher=]| access-date=17 August 2011}}</ref>
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 = 7–8 | pages = 554–5 | date = July 2003 | pmid = 12783318 | doi = 10.1007/s00431-003-1207-x }}</ref>


Melatonin is the most popular over-the-counter sleep remedy in the United States, resulting in sales in excess of US$400 million during 2017.<ref>{{cite web|url=https://www.consumerreports.org/vitamins-supplements/does-melatonin-really-help-you-sleep/|title=Does Melatonin Really Help You Sleep? | vauthors = Loria K |website=Consumer Reports|access-date=16 March 2019}}</ref> In 2022, it was the 217th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="Top 300 of 2022" /><ref name="Clincalc Melatonin" />
===Headaches===


Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.<ref name="NYTimes May 2011">{{cite news |url = https://www.nytimes.com/2011/05/15/us/15lazycakes.html |work=] |title=Dessert, Laid-Back and Legal | date=14 May 2011 | vauthors = Louis CS }}</ref> The FDA considered whether these food products could continue to be sold with the label "dietary supplements". On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a ].<ref name="FDAwarning">{{cite web | url = http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm201435.htm | title = Warning Letter | vauthors = Rodriguez RR | date = 13 January 2010 | work = Inspections, Compliance, Enforcement, and Criminal Investigations | publisher = U.S. Food and Drug Administration | url-status = dead | archive-url = https://wayback.archive-it.org/7993/20170112195035/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm201435.htm | archive-date = 12 January 2017 | df = dmy-all }}</ref> ] received a warning letter in 2015 for selling a melatonin-containing beverage.<ref>{{cite web|url=https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm440953.htm|title=Bebida Beverage Company|publisher=U.S. Food and Drug Administration|date=4 March 2015|access-date=8 December 2017|archive-url=https://web.archive.org/web/20200601144105/http://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/bebida-beverage-company-03042015|archive-date=1 June 2020}}</ref>
Several clinical studies indicate that supplementation with melatonin is an effective ] for ] and ]s.<ref name="Dodick2001">{{cite journal | author = Dodick DW, Capobianco DJ | title = Treatment and management of cluster headache | journal = Curr Pain Headache Rep | volume = 5 | issue = 1 | pages = 83–91 | date = February 2001 | pmid = 11252143 | doi = 10.1007/s11916-001-0015-0 }}</ref><ref name="Gagnier2001">{{cite journal | author = Gagnier JJ | title = The therapeutic potential of melatonin in migraines and other headache types | journal = Altern Med Rev | volume = 6 | issue = 4 | pages = 383–9 | date = August 2001 | pmid = 11578254 | doi = }}</ref>


===Cancer=== ==Research==
Some research supports an ] and ] effect of melatonin.<ref>{{cite journal | vauthors = Valdés-Tovar M, Estrada-Reyes R, Solís-Chagoyán H, Argueta J, Dorantes-Barrón AM, Quero-Chávez D, Cruz-Garduño R, Cercós MG, Trueta C, Oikawa-Sala J, Dubocovich ML, Benítez-King G | title = Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression | journal = British Journal of Pharmacology | volume = 175 | issue = 16 | pages = 3200–3208 | date = August 2018 | pmid = 29512136 | pmc = 6057892 | doi = 10.1111/bph.14197 }}</ref><ref>{{cite journal|vauthors=Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM|date=8 December 2020|title=Melatonin for pre- and postoperative anxiety in adults|journal=The Cochrane Database of Systematic Reviews|volume=2020|issue=12 |pages=CD009861|doi=10.1002/14651858.CD009861.pub3|pmid=33319916|pmc=8092422}}</ref> It has also been used to aid in the treatment of manic episodes in ], although evidence for its effectiveness is still inconsistent.<ref name="repurposed2021">{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials | journal = Journal of Psychiatric Research | date = September 2021 | volume = 143 | pages = 230–238 | doi = 10.1016/j.jpsychires.2021.09.018| pmid = 34509090 | s2cid = 237485915 }}</ref>


Other studies have shown that melatonin may help reduce some types of headaches, ] and ].<ref>{{cite journal | vauthors = Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA | title = Potential therapeutic use of melatonin in migraine and other headache disorders | journal = Expert Opinion on Investigational Drugs | volume = 15 | issue = 4 | pages = 367–75 | date = April 2006 | pmid = 16548786 | doi = 10.1517/13543784.15.4.367 | s2cid = 28114683 }}</ref><ref name="Evars05">{{cite journal | vauthors = Evers S, Goadsby PJ |year=2005 |title=Review: Hypnic headache |journal=Practical Neurology |volume=5 |issue= 3|pages=144–49 |url=http://pn.bmj.com/content/practneurol/5/3/144.full.pdf |access-date=12 January 2018|doi=10.1111/j.1474-7766.2005.00301.x |s2cid=1196313 |doi-access=free }}</ref><ref name="Kandil10">{{cite journal | vauthors = Kandil TS, Mousa AA, El-Gendy AA, Abbas AM | title = The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease | journal = BMC Gastroenterology | volume = 10 | pages = 7 | date = January 2010 | pmid = 20082715 | pmc = 2821302 | doi = 10.1186/1471-230X-10-7 | doi-access = free }}</ref> There have also been studies trying to prove the effectiveness of melatonin in relation to ], ], ], and ], but little to no beneficial role has been found.<ref name="BrigoIgwe2016">{{cite journal | vauthors = Brigo F, Igwe SC, Del Felice A | title = Melatonin as add-on treatment for epilepsy | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD006967 | date = August 2016 | volume = 2016 | pmid = 27513702 | doi = 10.1002/14651858.CD006967.pub4 | pmc = 7386917 }}</ref><ref name="pmid27000311">{{cite journal | vauthors = Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J | title = Dietary supplements for dysmenorrhoea | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD002124 | date = March 2016 | issue = 3 | pmid = 27000311 | doi = 10.1002/14651858.CD002124.pub2 | pmc = 7387104 }}</ref><ref>{{cite journal | vauthors = Siddiqi N, Harrison JK, Clegg A, Teale EA, Young J, Taylor J, Simpkins SA | title = Interventions for preventing delirium in hospitalised non-ICU patients | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD005563 | date = March 2016 | issue = 3 | pmid = 26967259 | doi = 10.1002/14651858.CD005563.pub3 | pmc = 10431752 | url = http://eprints.whiterose.ac.uk/99189/7/Siddiqi_et_al-2016-The_Cochrane_Library.pdf }}</ref><ref>{{cite journal | vauthors = Miroddi M, Bruno R, Galletti F, Calapai F, Navarra M, Gangemi S, Calapai G | title = Clinical pharmacology of melatonin in the treatment of tinnitus: a review | journal = European Journal of Clinical Pharmacology | volume = 71 | issue = 3 | pages = 263–70 | date = March 2015 | pmid = 25597877 | doi = 10.1007/s00228-015-1805-3 | s2cid = 16466238 }}</ref> Melatonin has also been tested as a treatment for cancer, but the National Cancer Institute found insufficient evidence for it. However, further research found it to slightly improve survival of patients and to alleviate chemotherapy-related side effects.<ref>{{cite book | title = PDQ Cancer Information Summaries | chapter = Topics in complementary and alternative therapies |date=May 2013 |pmid=26389506 |url=https://www.ncbi.nlm.nih.gov/books/NBK126745/#CDR0000745420__16 |publisher=National Cancer Institute, National Institutes of Health| vauthors = ((PDQ Integrative, Alternative, and Complementary Therapies Editorial Board)) }}</ref><ref name="lim">{{cite journal | vauthors = Lim S, Park S, Koyanagi A, Yang JW, Jacob L, Yon DK, Lee SW, Kim MS, Il Shin J, Smith L | title = Effects of exogenous melatonin supplementation on health outcomes: An umbrella review of meta-analyses based on randomized controlled trials | journal = Pharmacological Research | volume = 176 | pages = 106052 | date = February 2022 | pmid = 34999224 | doi = 10.1016/j.phrs.2021.106052 | s2cid = 263492993 | url = https://arro.anglia.ac.uk/id/eprint/707412/1/Lim_et_al_2022.pdf | access-date = 24 January 2023 | archive-date = 31 March 2023 | archive-url = https://web.archive.org/web/20230331122137/https://arro.anglia.ac.uk/id/eprint/707412/1/Lim_et_al_2022.pdf | url-status = dead }}</ref><ref name="Posadzki2018">{{cite journal | vauthors = Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, Divakar U, Bajpai S, Soljak M, Dunleavy G, Jarbrink K, Nang EE, Soh CK, Car J | title = Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 18 | date = February 2018 | pmid = 29397794 | pmc = 5798185 | doi = 10.1186/s12916-017-1000-8 | doi-access = free }}</ref><ref name="wang2012">{{cite journal | vauthors = Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL | title = The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials | journal = Cancer Chemotherapy and Pharmacology | volume = 69 | issue = 5 | pages = 1213–1220 | date = May 2012 | pmid = 22271210 | doi = 10.1007/s00280-012-1828-8 | s2cid = 38488628 }}</ref>
A ] of unblinded ]s involving a total of 643 cancer patients using melatonin found a reduced incidence of death but that blinded and independently conducted randomized controlled trials are needed.<ref name="pmid16207291">{{cite journal | author = Mills E, Wu P, Seely D, Guyatt G | title = Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis | journal = J. Pineal Res. | volume = 39 | issue = 4 | pages = 360–6 | date = November 2005 | pmid = 16207291 | doi = 10.1111/j.1600-079X.2005.00258.x }}</ref> The National Cancer Institute's review of the evidence found that it remains inconclusive.<ref>{{cite web|last=National Cancer Institute|title=Topics in complementary and alternative therapies (PDQ)|url=http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0053600/|publisher=National Cancer Institute, National Institutes of Health|accessdate=5 June 2013|date=May 2013}}</ref>


Both animal<ref name="pmid10082913">{{cite journal | vauthors = Meltz ML, Reiter RJ, Herman TS, Kumar KS | title = Melatonin and protection from whole-body irradiation: survival studies in mice | journal = Mutation Research | volume = 425 | issue = 1 | pages = 21–7 | date = March 1999 | pmid = 10082913 | doi = 10.1016/S0027-5107(98)00246-2 | bibcode = 1999MRFMM.425...21V }}</ref> and human<ref name="pmid9008723">{{cite journal | vauthors = Reiter RJ, Herman TS, Meltz ML | title = Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers | journal = Mutation Research | volume = 371 | issue = 3–4 | pages = 221–8 | date = December 1996 | pmid = 9008723 | doi = 10.1016/S0165-1218(96)90110-X }}</ref><ref>{{cite journal | vauthors = Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J | title = Dietary supplements for dysmenorrhoea | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 3 | pages = CD002124 | date = March 2016 | pmid = 27000311 | doi = 10.1002/14651858.cd002124.pub2 | pmc = 7387104 }}</ref><ref name="pmid9541644">{{cite journal | vauthors = Reiter RJ, Herman TS, Meltz ML | title = Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes | journal = Mutation Research | volume = 397 | issue = 2 | pages = 203–8 | date = February 1998 | pmid = 9541644 | doi = 10.1016/S0027-5107(97)00211-X | bibcode = 1998MRFMM.397..203V }}</ref> studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from ] by scavenging ] which are generated during exposure.<ref name="Tan_Manchester">{{cite journal | vauthors = Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ | title = One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? | journal = Journal of Pineal Research | volume = 42 | issue = 1 | pages = 28–42 | date = January 2007 | pmid = 17198536 | doi = 10.1111/j.1600-079X.2006.00407.x | s2cid = 40005308 | doi-access = free }}</ref> Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the ] that attacks ], proteins, and ]s. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known major side effects.<ref name="pmid17641465">{{cite journal | vauthors = Shirazi A, Ghobadi G, Ghazi-Khansari M | title = A radiobiological review on melatonin: a novel radioprotector | journal = Journal of Radiation Research | volume = 48 | issue = 4 | pages = 263–72 | date = July 2007 | pmid = 17641465 | doi = 10.1269/jrr.06070 | bibcode = 2007JRadR..48..263S | doi-access = free }}</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, Tengattini S, Tamura H, Flores LJ, Tan DX, Reiter RJ | 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 | date = October 2008 | pmid = 18338264 | doi = 10.1007/s10620-007-0195-5 }}</ref> It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. 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 | date = October 1999 | pmid = 10622237 | doi = 10.1016/S0024-3205(99)00519-6 }}</ref>

===Protection from radiation===

Both animal<ref name="pmid10082913">{{cite journal | author = Meltz ML, Reiter RJ, Herman TS, Kumar KS | title = Melatonin and protection from whole-body irradiation: survival studies in mice | journal = Mutat. Res. | volume = 425 | issue = 1 | pages = 21–7 | date = March 1999 | pmid = 10082913 | doi = 10.1016/S0027-5107(98)00246-2 }}</ref> and human<ref name="pmid9008723">{{cite journal | author = Reiter RJ, Herman TS, Meltz ML | title = Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers | journal = Mutat. Res. | volume = 371 | issue = 3–4 | pages = 221–8 | date = December 1996 | pmid = 9008723 | doi = 10.1016/S0165-1218(96)90110-X }}</ref><ref name="pmid9541644">{{cite journal | author = Reiter RJ, Herman TS, Meltz ML | title = Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes | journal = Mutat. Res. | volume = 397 | issue = 2 | pages = 203–8 | date = February 1998 | pmid = 9541644 | doi = 10.1016/S0027-5107(97)00211-X }}</ref> studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than ],<ref name="pmid18979313">{{cite journal | author = Topkan E, Tufan H, Yavuz AA, Bacanli D, Onal C, Kosdak S, Yavuz MN | title = Comparison of the protective effects of melatonin and amifostine on radiation-induced epiphyseal injury | journal = Int. J. Radiat. Biol. | volume = 84 | issue = 10 | pages = 796–802 | date = October 2008 | pmid = 18979313 | doi = 10.1080/09553000802389678 }}</ref> a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of ].<ref name="Tan_Manchester"/> It is estimated that nearly 70% of biological damage caused by ionizing radiation is attributable to the free radical, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-administered, and without major known side effects.<ref name="pmid17641465">{{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 | date = July 2007 | pmid = 17641465 | doi = 10.1269/jrr.06070 }}</ref>

===Tinnitus===

Several medical studies involving adult patients indicate that melatonin can be beneficial in the treatment of ].<ref name="pmid21859051">{{cite journal | author = Hurtuk A, Dome C, Holloman CH, Wolfe K, Welling DB, Dodson EE, Jacob A | title = Melatonin: can it stop the ringing? | journal = Ann. Otol. Rhinol. Laryngol. | volume = 120 | issue = 7 | pages = 433–40 | date = July 2011 | pmid = 21859051 | doi = }}</ref><ref name="pmid16455366">{{cite journal | author = Megwalu UC, Finnell JE, Piccirillo JF | title = The effects of melatonin on tinnitus and sleep | journal = Otolaryngol Head Neck Surg | volume = 134 | issue = 2 | pages = 210–3 | date = February 2006 | pmid = 16455366 | doi = 10.1016/j.otohns.2005.10.007 }}</ref><ref name="pmid9504599">{{cite journal | author = Rosenberg SI, Silverstein H, Rowan PT, Olds MJ | title = Effect of melatonin on tinnitus | journal = Laryngoscope | volume = 108 | issue = 3 | pages = 305–10 | date = March 1998 | pmid = 9504599 | doi = 10.1097/00005537-199803000-00001 }}</ref><ref name="pmid20207491">{{cite journal | author = Pirodda A, Raimondi MC, Ferri GG | title = Exploring the reasons why melatonin can improve tinnitus | journal = Med. Hypotheses | volume = 75 | issue = 2 | pages = 190–1 | date = August 2010 | pmid = 20207491 | doi = 10.1016/j.mehy.2010.02.018 }}</ref>

===Dreaming===
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 people both with and without ].<ref name=Lewis>{{cite book |title=Melatonin and the Biological Clock |last=Lewis |first=Alan |publisher=McGraw-Hill |isbn=0-87983-734-9 |year=1999 |page=23}}</ref>

===Autism===

Melatonin might improve sleep in people with ]s (ASD).<ref name=asd>{{cite journal | author = Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM | title = Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis | journal = Dev Med Child Neurol | volume = 51 | issue = 5 | pages = 340–9 | date = May 2009 | pmid = 19379289 | doi = 10.1111/j.1469-8749.2008.03244.x | type = Meta-analysis }}</ref>

===Pediatrics===

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

==Adverse effects==
Melatonin appears to cause very few ] in the short term, up to three months, at low doses. A systematic review in 2006 showed that for sleep disorders such as ] and ], melatonin is not effective although it is safe for short term use".<ref name="pmid16423108">{{cite journal | author = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S | title = The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis | journal = J Gen Intern Med | volume = 20 | issue = 12 | pages = 1151–8 | year = 2005 | pmid = 16423108 | pmc = 1490287 | doi = 10.1111/j.1525-1497.2005.0243.x }}</ref><ref name="Buscemi2006">{{cite journal | author = Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–93 |date=February 2006 | pmid = 16473858 | pmc = 1370968 | doi = 10.1136/bmj.38731.532766.F6 }}</ref> Prolonged-release melatonin is safe with long-term use of up to 12 months.<ref name="pmid23044640">{{cite journal | author = Lyseng-Williamson KA | title = Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years | journal = Drugs Aging | volume = 29 | issue = 11 | pages = 911–23 | year = 2012 | pmid = 23044640 | doi = 10.1007/s40266-012-0018-z }}</ref>

Melatonin can cause nausea, next-day ], irritability,<ref>{{cite web| title=Melatonin side effects: What are the risks?| publisher=Mayo Clinic| author=Brent Bauer, M.D.| accessdate=2011-08-17| url=http://www.mayoclinic.com/health/melatonin-side-effects/AN01717}}</ref> reduced blood flow and ].<ref name="pmid11600532">{{cite journal | author = Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU | title = Melatonin treatment for age-related insomnia | journal = J. Clin. Endocrinol. Metab. | volume = 86 | issue = 10 | pages = 4727–30 | date = October 2001 | pmid = 11600532 | doi = 10.1210/jc.86.10.4727 }}</ref> Individuals with ], having reduced ] and ] to the brain when standing up, may benefit from the use of melatonin.<ref name="Chester2003">{{cite journal | author = Ray CA | title = Melatonin attenuates the sympathetic nerve responses to orthostatic stress in humans | journal = The Journal of Physiology | volume = 551 | issue = 3 | pages = 1043–8 | year = 2003 | pmid = 12869610 | pmc = 2343280 | doi = 10.1113/jphysiol.2003.043182 | laydate = September 16, 2003 | laysummary = http://www.sciencedaily.com/releases/2003/09/030916073900.htm | laysource = ScienceDaily }}</ref>
In ], there is conflicting evidence whether melatonin supplementation may either ameliorate or exacerbate symptoms due to ].<ref name="Morera2001">{{cite journal | author = Morera AL, Henry M, de La Varga M | title = Seguridad en el uso de la melatonina | language = es | journal = Actas Esp Psiquiatr | volume = 29 | issue = 5 | pages = 334–7 | year = 2001 | pmid = 11602091 | doi = | trans_title = Safety in melatonin use }}</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 = Inflamm. Bowel Dis. | volume = 15 | issue = 1 | pages = 134–40 | date = January 2009 | pmid = 18626968 | doi = 10.1002/ibd.20527 }}</ref>

Melatonin can lower ] levels.<ref name="pmid16921343">{{cite journal | author = Juszczak M, Michalska M | title = Wpływ melatoniny na syntezę i wydzielanie prolaktyny, hormonu luteinizującego (LH) i folikulotropowego (FSH) | language = pl | journal = Postepy Hig Med Dosw (Online) | volume = 60 | issue = | pages = 431–8 | year = 2006 | pmid = 16921343 | doi = | url = http://www.phmd.pl/fulltxthtml.php?ICID=453297 | trans_title = The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion }}</ref> Effects of the hormone on human reproduction remain unclear,<ref name="pmid19905996">{{cite journal | author = Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A | title = Melatonin and human reproduction: shedding light on the darkness hormone | journal = Gynecol. Endocrinol. | volume = 25 | issue = 12 | pages = 779–85 | date = December 2009 | pmid = 19905996 | doi = 10.3109/09513590903159649 }}</ref> although it was with some effect tried as a contraceptive in the 1990s.<ref>{{cite book |author=Cohen M, van Heusden AM, Verdonk HER, Wijnhamer P |chapter=Melatonin/Norethisterone contraception |editor=Touitou Y, Arendt J and Pevet P |title=Melatonin and the Pineal Gland – From Basic Science to Clinical Application |location=Amsterdam |publisher=Elsevier |year=1993 |pages=339–45 |isbn=978-0-444-89583-7}}</ref>

Melatonin was thought to have a very low maternal toxicity in rats.<ref name="pmid10478864">{{cite journal | author = Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C | title = Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats | journal = Toxicol. Sci. | volume = 50 | issue = 2 | pages = 271–9 | date = August 1999 | pmid = 10478864 | doi = 10.1093/toxsci/50.2.271 }}</ref> Recent studies have found results which suggested that it is toxic to photoreceptor cells in rats' retinas when used in combination with large amounts of sunlight<ref name="pmid18078931">{{cite journal | author = Wiechmann AF, Chignell CF, Roberts JE | title = Influence of dietary melatonin on photoreceptor survival in the rat retina: an ocular toxicity study | journal = Exp. Eye Res. | volume = 86 | issue = 2 | pages = 241–50 | date = February 2008 | pmid = 18078931 | pmc = 2377032 | doi = 10.1016/j.exer.2007.10.015 | url = }}</ref> and increases the incidence of tumours in white mice.<ref name="pmid11445596">{{cite journal | author = Anisimov VN, Zavarzina NY, Zabezhinski MA, Popovich IG, Zimina OA, Shtylick AV, Arutjunyan AV, Oparina TI, Prokopenko VM, Mikhalski AI, Yashin AI | title = Melatonin increases both life span and tumor incidence in female CBA mice | journal = J. Gerontol. A Biol. Sci. Med. Sci. | volume = 56 | issue = 7 | pages = B311–23 | date = July 2001 | pmid = 11445596 | doi = 10.1093/gerona/56.7.B311 | url = }}</ref><ref name="FDAwarning">{{cite web | url = http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm201435.htm | title =Warning Letter | author = Rodriguez RR | date = January 13, 2010 | work = Inspections, Compliance, Enforcement, and Criminal Investigations | publisher = U.S. Food and Drug Administration }}</ref>

In animal models, interventions that increase the bioavailability of melatonin seem to increase the severity of the symptoms of ], whereas reduction in melatonin by pinealectomy or exposure to bright light can improve recovery from those symptoms.<ref name="pmid16596313">{{cite journal | author = Schernhammer E, Chen H, Ritz B | title = Circulating melatonin levels: possible link between Parkinson's disease and cancer risk? | journal = Cancer Causes Control. | volume = 17 | issue = 4 | pages = 577–582 | date = May 2006 | pmid = 16596313 | doi = 10.1007/s10552-005-9002-9 }}</ref> Melatonin may exacerbate neurodegeneration in advanced Parkinson's disease in rats.<ref name="pmid22252727">{{cite journal | author = Meng T, Zheng ZH, Liu TT, Lin L | title = Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat | journal = Neurochem Res. | volume = 37 | issue = 5 | pages = 1050–6. | date = May 2012 | pmid = 22252727 | doi = 10.1007/s11064-012-0706-4 }}</ref>

==Availability==

The effects of long-term supplementation of melatonin in humans have not yet been thoroughly studied nor ascertained.<ref name = "Ratzburg_Vanderbilt">{{cite web | url = http://www.vanderbilt.edu/AnS/psychology/health_psychology/melatonin.htm | title = Melatonin: The Myths and Facts | author = Ratzburg C | year = n.d. | publisher = Vanderbilt University | accessdate = 2007-12-02 }}</ref> One prescription-only, prolonged-release melatonin product, trade-name ], 2&nbsp;mg, is available for up to three months use by people aged 55 and over.

] pharmaceutical laboratory prepared melatonin available upon prescription.]]

Immediate-release melatonin is scarcely regulated. It is available in doses from less than half a milligram to 5&nbsp;mg or more. It causes blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, tablets or as liquid. It is also available for use sublingually, or as transdermal patches.

The legal availability of melatonin varies widely among countries, ranging from being available without prescription (e.g. in most of North America and Finland) to being available only on prescription (e.g. in the European Union, Norway and Australia) or not at all (although its possession and use may not be illegal). Immediate-release melatonin is widely available on the Internet as a ].

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic and does not carry a risk of contamination or the means of transmitting viral material.<ref name="Altun2007"/><ref>{{cite web |url=http://www.drugs.com/melatonin.html |title=Melatonin| publisher=]| accessdate=2011-08-17}}</ref>

===Prolonged release===

Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. Containing 2&nbsp;mg melatonin, it was shown in clinical trials of older adults to decrease time to fall asleep and improve quality of sleep and daytime functioning.<ref name="pmid22429105"/><ref name="pmid23044640"/> ] It releases melatonin gradually over 8–10 hours, mimicking the body's internal secretion profile.

The ] (EMA) has approved Circadin 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><ref name = "EMA_EPAR">{{cite web| author = European Medicines Agency | title = Circadin, melatonin | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000695/human_med_000701.jsp&mid=WC0b01ac058001d124 | work = European Public Assessment Report (EPAR) | publisher = European Medicines Agency | accessdate = 5 June 2013 }}</ref>

Other countries' agencies that subsequently approved the drug include:
: --the Australian Therapeutics Goods Administration (TGA),<ref name = "TGA_APR">{{cite web | author = Therapeutic Goods Administration (TGA) | title = Australian Public Assessment Report for Melatonin | url = http://www.tga.gov.au/pdf/auspar/auspar-circadin.pdf | publisher = Department of Health and Ageing, Australian Government | accessdate = 5 June 2013 }}</ref>
: --the Swiss Agency for Therapeutics Products (SwissMedic),<ref name = "SWISSMEDIC_APR">{{cite web|author=SwissMedic|title=Circadin®, Retardtabletten, 2 mg (melatoninum)|url=https://www.swissmedic.ch/zulassungen/00153/00189/00200/01003/index.html|ref=SWISSMEDIC_APR|language=German|year=2009}}</ref>
: --the South Korean Ministry of Food and Drug Safety (MFDS)<ref name=MFDS_APP>{{cite web|title=Circadin license application|url=http://www.mfds.go.kr/jsp/common/download.jsp?fileinfo=S*2*(%C1%A4%BA%B8%B0%F8%B0%B3)_%BC%AD%C4%AB%B5%F2%BC%AD%B9%E6%C1%A42mg(%B8%E1%B6%F3%C5%E4%B4%D1)_(%BE%C8%C0%AF).pdf*bfdb417d57df46f71ca13aa03f33a890*pdf*/files/upload/1/TB_F_INFODATA/17741/bfdb417d57df46f71ca13aa03f33a890*2512375*2014:08:27%2013:58:13|publisher=MFDS|language=Korean|format=PDF|year=2014}}</ref> and
: --the Israeli Ministry of Health (MOH).<ref name=MOH_APP>{{cite web|author1=Ministry of Health Israel|title=Circadin leaflet|url=http://www.old.health.gov.il/units/pharmacy/trufot/PerutTrufa.asp?Reg_Number=139%2092%2031648%2000&safa=h}}</ref>

==See also==
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==References== ==References==
{{Reflist|35em}} {{Reflist}}


== Further reading ==

* {{cite journal | author = Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N | title = Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety | journal = BMC Med | volume = 8 | page = 51 | year = 2010 | pmid = 20712869 | pmc = 2933606 | doi = 10.1186/1741-7015-8-51 }}

== External links ==
* {{Commons category inline}}
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{{Neurotransmitters}}
{{Hormones}}
{{Antioxidants}}
{{Dietary supplement}}
{{Hypnotics and sedatives}} {{Hypnotics and sedatives}}
{{Insomnia pharmacotherapies}} {{Insomnia pharmacotherapies}}
{{Dietary supplement}}
{{Melatonergics}}
{{Melatonin receptor modulators}}
{{Tryptamines}} {{Tryptamines}}
{{Portal bar | Medicine}}
{{Authority control}}


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