Melatonin

<h1 id="firstHeading" class="firstHeading" lang="en" >Melatonin</h1>

<div id="siteSub" >From Wikipedia, the free encyclopedia</div>

<div class="hatnote" >Not to be confused with <a href="http://en.wikipedia.org/wiki/Melanotan_(disambiguation)" title="Melanotan (disambiguation)" class="mw-redirect" >Melanotan (disambiguation)</a>, <a href="http://en.wikipedia.org/wiki/Melanin" title="Melanin" >Melanin</a>, or <a href="http://en.wikipedia.org/wiki/Afamelanotide" title="Afamelanotide" >Afamelanotide</a>.</div>

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<td class="mbox-text" >This article relies on <a href="http://en.wikipedia.org/wiki/Wikipedia:Verifiability" title="Wikipedia:Verifiability" >references</a> to <a href="http://en.wikipedia.org/wiki/Wikipedia:No_original_research#Primary.2C_secondary_and_tertiary_sources" title="Wikipedia:No original research" >primary sources</a>. Please add references to <a href="http://en.wikipedia.org/wiki/Wikipedia:No_original_research#Primary.2C_secondary_and_tertiary_sources" title="Wikipedia:No original research" >secondary or tertiary sources</a>. (March 2012)</td>

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<caption >Melatonin</caption>

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<th colspan="2" >Systematic (<a href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" title="International Union of Pure and Applied Chemistry nomenclature" class="mw-redirect" >IUPAC</a>) name</th>

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<td colspan="2" >N-[2-(5-methoxy-1H-indol-3-yl)ethyl]

acetamide</td>

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<th colspan="2" >Clinical data</th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists" >AHFS</a>/<a href="http://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com" >Drugs.com</a></th>

<td ><a rel="nofollow" class="external text" href="http://www.drugs.com/cdi/melatonin.html" >Consumer Drug Information</a></td>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods" >Legal status</a></th>

<td ><a href="http://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" title="Standard for the Uniform Scheduling of Drugs and Poisons" class="mw-redirect" >Prescription Only (S4)</a> (<a href="http://en.wikipedia.org/wiki/Australia" title="Australia" >AU</a>)<a href="http://en.wikipedia.org/wiki/Over-the-counter_drug" title="Over-the-counter drug" >OTC</a> (<a href="http://en.wikipedia.org/wiki/United_States" title="United States" >US</a>)</td>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration" >Routes</a></th>

<td >In humans: orally, as capsules, tablets, or liquid, sublingually, or as transdermal patches. In lab animals: also injection.</td>

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<th colspan="2" >Pharmacokinetic data</th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/Bioavailability" title="Bioavailability" >Bioavailability</a></th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism" >Metabolism</a></th>

<td ><a href="http://en.wikipedia.org/wiki/Liver" title="Liver" >Hepatic</a> via <a href="http://en.wikipedia.org/wiki/CYP1A2" title="CYP1A2" >CYP1A2</a> mediated 6-hydroxylation</td>

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<td >35 to 50 minutes</td>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/Excretion" title="Excretion" >Excretion</a></th>

<td ><a href="http://en.wikipedia.org/wiki/Urine" title="Urine" >Urine</a></td>

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<th colspan="2" >Identifiers</th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/CAS_registry_number" title="CAS registry number" >CAS number</a></th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/PubChem" title="PubChem" >PubChem</a></th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/International_Union_of_Basic_and_Clinical_Pharmacology" title="International Union of Basic and Clinical Pharmacology" >IUPHAR ligand</a></th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/DrugBank" title="DrugBank" >DrugBank</a></th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider" >ChemSpider</a></th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/ChEBI" title="ChEBI" >ChEBI</a></th>

<td ><a rel="nofollow" class="external text" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:16796" >CHEBI:16796</a> <img src="/eeb3edaf-56ab-53e1-9446-af958028c8bd.png"/></td>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL" >ChEMBL</a></th>

<td ><a rel="nofollow" class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL45" >CHEMBL45</a> <img src="/3ba36e0f-455d-57d3-94e3-a0ea1f438b21.png"/></td>

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<th colspan="2" >Chemical data</th>

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<th scope="row" ><a href="http://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula" >Formula</a></th>

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<div class="NavHead" ><a href="http://en.wikipedia.org/wiki/Simplified_molecular_input_line_entry_specification" title="Simplified molecular input line entry specification" class="mw-redirect" >SMILES</a><a class="NavToggle" id="NavToggle1" href="http://en.wikipedia.org/wiki/Melatonin#" >[show]</a></div>

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<div class="NavHead" ><a href="http://en.wikipedia.org/wiki/International_Chemical_Identifier" title="International Chemical Identifier" >InChI</a><a class="NavToggle" id="NavToggle2" href="http://en.wikipedia.org/wiki/Melatonin#" >[show]</a></div>

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<th colspan="2" > <img src="/dd48a214-858b-5277-9382-2cee518498af.png"/> <a href="http://en.wikipedia.org/wiki/Wikipedia:WikiProject_Chemicals/Chembox_validation" title="Wikipedia:WikiProject Chemicals/Chembox validation" >(what is this?)</a>  <a class="external text" href="http://en.wikipedia.org/w/index.php?title=Special:ComparePages&rev1=420231802&page2=Melatonin" >(verify)</a></th>

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Melatonin <a href="http://upload.wikimedia.org/wikipedia/commons/5/5f/Melatonin-pronunciation.ogg" title="Listen" ><img src="/cca981b9-8b78-515a-83a4-794781d373f3.png"/></a><a href="http://en.wikipedia.org/wiki/File:Melatonin-pronunciation.ogg" title="File:Melatonin-pronunciation.ogg" >i</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English" >/</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English#Key" title="Help:IPA for English" >ˌmɛləˈtoʊnɪn</a><a href="http://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English" >/</a>, also known chemically as N-<a href="http://en.wikipedia.org/wiki/Acetyl" title="Acetyl" >acetyl</a>-5-<a href="http://en.wikipedia.org/wiki/Methoxy" title="Methoxy" >methoxy</a><a href="http://en.wikipedia.org/wiki/Tryptamine" title="Tryptamine" >tryptamine</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-1" >[1]</a> is a <a href="http://en.wikipedia.org/wiki/Hormone" title="Hormone" >hormone</a> found in animals, plants, and microbes.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Caniato2003-2" >[2]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Paredes2009-3" >[3]</a> In animals, circulating levels of melatonin vary in a daily cycle, thereby allowing the <a href="http://en.wikipedia.org/wiki/Entrainment_(chronobiology)" title="Entrainment (chronobiology)" >entrainment</a> of the <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >circadian rhythms</a> of several biological functions.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Altun2007-4" >[4]</a>

Many biological effects of melatonin are produced through activation of <a href="http://en.wikipedia.org/wiki/Melatonin_receptor" title="Melatonin receptor" >melatonin receptors</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Boutin2005-5" >[5]</a> while others are due to its role as a pervasive and powerful<a href="http://en.wikipedia.org/wiki/Antioxidant" title="Antioxidant" >antioxidant</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Hardeland2005-6" >[6]</a> with a particular role in the protection of <a href="http://en.wikipedia.org/wiki/Nuclear_DNA" title="Nuclear DNA" >nuclear</a> and <a href="http://en.wikipedia.org/wiki/Mitochondrial_DNA" title="Mitochondrial DNA" >mitochondrial DNA</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Reiter2001-7" >[7]</a>

The full effects of long-term exogenous (dietary) supplementation in humans have not yet been ascertained.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Ratzburg_Vanderbilt-8" >[8]</a> Melatonin is categorized by the US <a href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration" >Food and Drug Administration</a> (FDA) as a <a href="http://en.wikipedia.org/wiki/Dietary_supplement" title="Dietary supplement" >dietary supplement</a> and is not regulated as a pharmaceutical drug.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Buscemi_2004-9" >[9]</a> A prescription-only, timed release melatonin product for people aged 55 and over was approved for use by the European Medicines Agency in 2007, despite having shown only small effects,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-EMA_EPAR-10" >[10]</a> and in Australia in 2009.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-TGA_APR-11" >[11]</a>

<h2 >Contents</h2>

[<a href="http://en.wikipedia.org/wiki/Melatonin#" class="internal" id="togglelink" >hide</a>] </div>

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<li class="toclevel-1 tocsection-1" ><a href="http://en.wikipedia.org/wiki/Melatonin#Plants" >1 Plants</a></li>

<li class="toclevel-1 tocsection-2" ><a href="http://en.wikipedia.org/wiki/Melatonin#Animals" >2 Animals</a></li>

<li class="toclevel-1 tocsection-3" ><a href="http://en.wikipedia.org/wiki/Melatonin#Mammals" >3 Mammals</a></li>

<li class="toclevel-1 tocsection-4" ><a href="http://en.wikipedia.org/wiki/Melatonin#Humans" >4 Humans</a>

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<li class="toclevel-2 tocsection-5" ><a href="http://en.wikipedia.org/wiki/Melatonin#Circadian_rhythm" >4.1 Circadian rhythm</a>

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<li class="toclevel-3 tocsection-6" ><a href="http://en.wikipedia.org/wiki/Melatonin#Light_dependence" >4.1.1 Light dependence</a></li>

<li class="toclevel-3 tocsection-7" ><a href="http://en.wikipedia.org/wiki/Melatonin#Antioxidant" >4.1.2 Antioxidant</a></li>

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<li class="toclevel-2 tocsection-8" ><a href="http://en.wikipedia.org/wiki/Melatonin#Immune_system" >4.2 Immune system</a></li>

<li class="toclevel-2 tocsection-9" ><a href="http://en.wikipedia.org/wiki/Melatonin#Dreaming" >4.3 Dreaming</a></li>

<li class="toclevel-2 tocsection-10" ><a href="http://en.wikipedia.org/wiki/Melatonin#Autism" >4.4 Autism</a></li>

<li class="toclevel-2 tocsection-11" ><a href="http://en.wikipedia.org/wiki/Melatonin#Aging" >4.5 Aging</a></li>

<li class="toclevel-2 tocsection-12" ><a href="http://en.wikipedia.org/wiki/Melatonin#Diabetes" >4.6 Diabetes</a></li>

<li class="toclevel-2 tocsection-13" ><a href="http://en.wikipedia.org/wiki/Melatonin#Pediatrics" >4.7 Pediatrics</a></li>

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<li class="toclevel-1 tocsection-14" ><a href="http://en.wikipedia.org/wiki/Melatonin#Medical_uses" >5 Medical uses</a>

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<li class="toclevel-2 tocsection-15" ><a href="http://en.wikipedia.org/wiki/Melatonin#Circadian_rhythm_disorders" >5.1 Circadian rhythm disorders</a></li>

<li class="toclevel-2 tocsection-16" ><a href="http://en.wikipedia.org/wiki/Melatonin#Learning.2C_memory_and_Alzheimer.27s" >5.2 Learning, memory and Alzheimer's</a></li>

<li class="toclevel-2 tocsection-17" ><a href="http://en.wikipedia.org/wiki/Melatonin#Delirium" >5.3 Delirium</a></li>

<li class="toclevel-2 tocsection-18" ><a href="http://en.wikipedia.org/wiki/Melatonin#Stimulants" >5.4 Stimulants</a></li>

<li class="toclevel-2 tocsection-19" ><a href="http://en.wikipedia.org/wiki/Melatonin#Headaches" >5.5 Headaches</a></li>

<li class="toclevel-2 tocsection-20" ><a href="http://en.wikipedia.org/wiki/Melatonin#Mood_disorders" >5.6 Mood disorders</a></li>

<li class="toclevel-2 tocsection-21" ><a href="http://en.wikipedia.org/wiki/Melatonin#Cancer" >5.7 Cancer</a></li>

<li class="toclevel-2 tocsection-22" ><a href="http://en.wikipedia.org/wiki/Melatonin#Gallbladder_stones" >5.8 Gallbladder stones</a></li>

<li class="toclevel-2 tocsection-23" ><a href="http://en.wikipedia.org/wiki/Melatonin#Amyotrophic_lateral_sclerosis" >5.9 Amyotrophic lateral sclerosis</a></li>

<li class="toclevel-2 tocsection-24" ><a href="http://en.wikipedia.org/wiki/Melatonin#Obesity" >5.10 Obesity</a></li>

<li class="toclevel-2 tocsection-25" ><a href="http://en.wikipedia.org/wiki/Melatonin#Protection_from_radiation" >5.11 Protection from radiation</a></li>

<li class="toclevel-2 tocsection-26" ><a href="http://en.wikipedia.org/wiki/Melatonin#Tinnitus" >5.12 Tinnitus</a></li>

<li class="toclevel-2 tocsection-27" ><a href="http://en.wikipedia.org/wiki/Melatonin#Other" >5.13 Other</a></li>

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<li class="toclevel-1 tocsection-28" ><a href="http://en.wikipedia.org/wiki/Melatonin#Adverse_effects" >6 Adverse effects</a></li>

<li class="toclevel-1 tocsection-29" ><a href="http://en.wikipedia.org/wiki/Melatonin#Availability" >7 Availability</a>

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<li class="toclevel-2 tocsection-30" ><a href="http://en.wikipedia.org/wiki/Melatonin#Dietary_supplement" >7.1 Dietary supplement</a></li>

<li class="toclevel-2 tocsection-31" ><a href="http://en.wikipedia.org/wiki/Melatonin#Food_products" >7.2 Food products</a></li>

<li class="toclevel-2 tocsection-32" ><a href="http://en.wikipedia.org/wiki/Melatonin#Prolonged_release" >7.3 Prolonged release</a></li>

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<li class="toclevel-1 tocsection-33" ><a href="http://en.wikipedia.org/wiki/Melatonin#History" >8 History</a></li>

<li class="toclevel-1 tocsection-35" ><a href="http://en.wikipedia.org/wiki/Melatonin#References" >10 References</a></li>

<li class="toclevel-1 tocsection-36" ><a href="http://en.wikipedia.org/wiki/Melatonin#Further_reading" >11 Further reading</a></li>

<li class="toclevel-1 tocsection-37" ><a href="http://en.wikipedia.org/wiki/Melatonin#External_links" >12 External links</a></li>

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<h2 >Plants[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=1" title="Edit section: Plants" >edit</a>]</h2>

Melatonin has been identified in many plants including <a href="http://en.wikipedia.org/wiki/Tanacetum_parthenium" title="Tanacetum parthenium" >feverfew</a> (Tanacetum parthenium), <a href="http://en.wikipedia.org/wiki/Hypericum_perforatum" title="Hypericum perforatum" >St John's wort</a> (Hypericum perforatum),<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Paredes2009-3" >[3]</a> rice, corn, tomato, grape<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-12" >[12]</a> and other edible fruits.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid22016420-13" >[13]</a> The physiological roles of melatonin in plants involve regulation of their response to <a href="http://en.wikipedia.org/wiki/Photoperiod" title="Photoperiod" class="mw-redirect" >photoperiod</a>, defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid20039865-14" >[14]</a> Melatonin also regulates plant growth by its ability to slow root formation, while promoting above ground growth.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Melatonin_Plants-15" >[15]</a>

Melatonin has been reported in foodstuffs including cherries to about 0.17–13.46 ng/g,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11600041-16" >[16]</a> bananas and grapes, rice and cereals, herbs, olive oil, <a href="http://en.wikipedia.org/wiki/Wine" title="Wine" >wine</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21342247-17" >[17]</a> and beer.

When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Hattori1995-18" >[18]</a> When humans consume foods rich in melatonin such as banana, pineapple and orange the blood levels of melatonin significantly increase.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid23137025-19" >[19]</a>

<h2 >Animals[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=2" title="Edit section: Animals" >edit</a>]</h2>

Many animals use the variation in duration of melatonin production each day as a seasonal clock.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Lincoln2003-20" >[20]</a> In animals including humans<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Arendt2005-21" >[21]</a> 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 (<a href="http://en.wikipedia.org/wiki/Photoperiodism" title="Photoperiodism" >photoperiodic</a>) seasonal functions such as reproduction, behavior, coat growth and camouflage <a href="http://en.wikipedia.org/wiki/Animal_colouration" title="Animal colouration" class="mw-redirect" >coloring</a> in seasonal animals.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Arendt2005-21" >[21]</a> 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<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Chaturvedi-22" >[22]</a> and hamsters.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Chen1981-23" >[23]</a>

In mammals, melatonin is biosynthesized in four enzymatic steps from the essential dietary amino acid <a href="http://en.wikipedia.org/wiki/Tryptophan" title="Tryptophan" >tryptophan</a>, with <a href="http://en.wikipedia.org/wiki/Serotonin" title="Serotonin" >serotonin</a> produced at the third step. Melatonin is secreted into the blood by the<a href="http://en.wikipedia.org/wiki/Pineal_gland" title="Pineal gland" >pineal gland</a> in the brain. Known as the "hormone of darkness," it is secreted in darkness in both day-active (<a href="http://en.wikipedia.org/wiki/Diurnality" title="Diurnality" >diurnal</a>) and night-active (<a href="http://en.wikipedia.org/wiki/Nocturnality" title="Nocturnality" >nocturnal</a>) animals.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Challet2007-24" >[24]</a> It may also be produced by a variety of peripheral cells such as <a href="http://en.wikipedia.org/wiki/Bone_marrow" title="Bone marrow" >bone marrow cells</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pp-25" >[25]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-26" >[26]</a> lymphocytes, and <a href="http://en.wikipedia.org/wiki/Epithelium" title="Epithelium" >epithelial cells</a>. Usually, the melatonin concentration in these cells is much higher than that found in the blood, but it does not seem to be regulated by the photoperiod.

<h2 >Mammals[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=3" title="Edit section: Mammals" >edit</a>]</h2>

Melatonin, produced in the pineal gland which is outside of the <a href="http://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier" title="Blood–brain barrier" >blood–brain barrier</a>, acts as an <a href="http://en.wikipedia.org/wiki/Endocrine" title="Endocrine" class="mw-redirect" >endocrine</a> hormone since it is released into the blood.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19075654-27" >[27]</a>

Melatonin can suppress <a href="http://en.wikipedia.org/wiki/Libido" title="Libido" >libido</a> by inhibiting secretion of <a href="http://en.wikipedia.org/wiki/Luteinizing_hormone" title="Luteinizing hormone" >luteinizing hormone</a> (LH) and <a href="http://en.wikipedia.org/wiki/Follicle-stimulating_hormone" title="Follicle-stimulating hormone" >follicle-stimulating hormone</a> (FSH) from the <a href="http://en.wikipedia.org/wiki/Anterior_pituitary" title="Anterior pituitary" >anterior pituitary</a> gland, especially in mammals that have a <a href="http://en.wikipedia.org/wiki/Reproduction" title="Reproduction" >breeding</a> season when daylight hours are long. The reproduction of <a href="http://en.wikipedia.org/wiki/Polyestrous" title="Polyestrous" class="mw-redirect" >long-day breeders</a> is <a href="http://en.wikipedia.org/wiki/Estrous_cycle#Anestrus" title="Estrous cycle" >repressed by melatonin</a> and the reproduction of <a href="http://en.wikipedia.org/wiki/Polyestrous" title="Polyestrous" class="mw-redirect" >short-day breeders</a> is stimulated by melatonin. During the night, melatonin regulates<a href="http://en.wikipedia.org/wiki/Leptin" title="Leptin" >leptin</a>, lowering its levels.

Light/dark information reaches the <a href="http://en.wikipedia.org/wiki/Suprachiasmatic_nucleus" title="Suprachiasmatic nucleus" >suprachiasmatic nuclei</a> (SCN) from retinal <a href="http://en.wikipedia.org/wiki/Photosensitive_ganglion_cell" title="Photosensitive ganglion cell" class="mw-redirect" >photosensitive ganglion cells</a>, which are intrinsically photosensitive <a href="http://en.wikipedia.org/wiki/Photoreceptor_cell" title="Photoreceptor cell" >photoreceptor cells</a> that are distinct from those involved in the primary (at least, from one point of view) image formation function of the eye (that is the <a href="http://en.wikipedia.org/wiki/Rod_cell" title="Rod cell" >rods</a> and <a href="http://en.wikipedia.org/wiki/Cone_cell" title="Cone cell" >cones</a> of the retina). These cells represent approximately 2% of all retinal ganglion cells in humans and express the photopigment melanopsin.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid17160354-28" >[28]</a>

<a href="http://en.wikipedia.org/wiki/Melanopsin" title="Melanopsin" >Melanopsin</a>, often confused with melatonin because of its similar name, is structurally unrelated to the hormone. It is a conventional 7-transmembrane <a href="http://en.wikipedia.org/wiki/Opsin" title="Opsin" >opsin</a> protein with the usual vitamin A-like cis-retinal cofactor having a peak absorption at 484 nm, in the blue light part of the visible spectrum.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid15656701-29" >[29]</a> The photoperiod cue created by blue light (from a blue image of the sky) entrains a <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >circadian rhythm</a>, and thus governs resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate behavioral and physiological circadian rhythms associated with melatonin. Melatonin is secreted in darkness in both day-active (<a href="http://en.wikipedia.org/wiki/Diurnality" title="Diurnality" >diurnal</a>) and night-active (<a href="http://en.wikipedia.org/wiki/Nocturnality" title="Nocturnality" >nocturnal</a>) animals.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Challet2007-24" >[24]</a>

<h2 >Humans[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=4" title="Edit section: Humans" >edit</a>]</h2>

<h3 >Circadian rhythm[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=5" title="Edit section: Circadian rhythm" >edit</a>]</h3>

In humans, melatonin is produced by the pineal gland, a small endocrine gland<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Reiter-30" >[30]</a> located in the center of the brain but outside the blood–brain barrier. The melatonin signal forms part of the system that regulates the <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >sleep–wake cycle</a> by chemically causing drowsiness and lowering the body temperature, but it is the <a href="http://en.wikipedia.org/wiki/Central_nervous_system" title="Central nervous system" >central nervous system</a> (specifically the suprachiasmatic nuclei, or <a href="http://en.wikipedia.org/wiki/Suprachiasmatic_nucleus" title="Suprachiasmatic nucleus" >SCN</a>)<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Reiter-30" >[30]</a> that controls the daily cycle in most components of the <a href="http://en.wikipedia.org/wiki/Paracrine" title="Paracrine" class="mw-redirect" >paracrine</a> and <a href="http://en.wikipedia.org/wiki/Endocrine" title="Endocrine" class="mw-redirect" >endocrine</a> systems<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Richardson2005-31" >[31]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Perreau-Lenz2004-32" >[32]</a> rather than the melatonin signal (as was once postulated).

Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 AM.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid12589109-33" >[33]</a>

In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-USAHRQ-34" >[34]</a> and a small amount is found in saliva.

Human melatonin production decreases as a person ages.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid3783419-35" >[35]</a> Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-36" >[36]</a>

<h4 >Light dependence[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=6" title="Edit section: Light dependence" >edit</a>]</h4>

Production of melatonin by the pineal gland is inhibited by light to the <a href="http://en.wikipedia.org/wiki/Retina" title="Retina" >retina</a> and permitted by darkness. Its onset each evening is called the dim-light melatonin onset (DLMO).

It is principally blue light, around 460 to 480 <a href="http://en.wikipedia.org/wiki/Nanometre" title="Nanometre" >nm</a>, that suppresses melatonin,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Brainard_2001-37" >[37]</a> 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 <a href="http://en.wikipedia.org/wiki/Incandescent_light_bulb" title="Incandescent light bulb" >incandescent light bulb</a> widely used in the twentieth century produced relatively little blue light.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-38" >[38]</a> 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 nm does not suppress melatonin in bright-light conditions.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Kayumov_2005-39" >[39]</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-40" >[40]</a>

When used several hours before sleep according to the <a href="http://en.wikipedia.org/wiki/Phase_response_curve" title="Phase response curve" >phase response curve</a> for melatonin in humans, small amounts (0.3 mg<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16295212-41" >[41]</a>) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-isbn3-8055-9120-9-42" >[42]</a>

<h4 >Antioxidant[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=7" title="Edit section: Antioxidant" >edit</a>]</h4>

Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-43" >[43]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid7832450-44" >[44]</a> In many less complex life forms, this is its only known function.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Tan_Manchester-45" >[45]</a> Melatonin is an <a href="http://en.wikipedia.org/wiki/Antioxidant" title="Antioxidant" >antioxidant</a> that can easily cross <a href="http://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane" >cell membranes</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pohanka_2011-46" >[46]</a> and the blood–brain barrier.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Hardeland2005-6" >[6]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21358970-47" >[47]</a> This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH, O2−, and NO.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Melatonin_Plants-15" >[15]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid7832450-44" >[44]</a> Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Melatonin_Plants-15" >[15]</a> Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid7934611-48" >[48]</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Tan_Manchester-45" >[45]</a> Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochodrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a better protector against mitochondrial oxidative stress.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid23381720-49" >[49]</a>

<h3 >Immune system[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=8" title="Edit section: Immune system" >edit</a>]</h3>

While it is known that melatonin interacts with the <a href="http://en.wikipedia.org/wiki/Immune_system" title="Immune system" >immune system</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Carrillo-Vico2005-50" >[50]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Arushanian2002-51" >[51]</a> the details of those interactions are unclear. <a href="http://en.wikipedia.org/wiki/Antiinflammatory" title="Antiinflammatory" class="mw-redirect" >Antiinflammatory</a> effect seems to be the most relevant and most documented in the literature.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-52" >[52]</a> 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 <a href="http://en.wikipedia.org/wiki/Cytokine" title="Cytokine" >cytokine</a> production,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16729718-53" >[53]</a>and by doing this counteract <a href="http://en.wikipedia.org/wiki/Acquired_immunodeficiences" title="Acquired immunodeficiences" class="mw-redirect" >acquired immunodeficiences</a>. Some studies also suggest that melatonin might be useful fighting infectious disease<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pp-25" >[25]</a> including viral, such as <a href="http://en.wikipedia.org/wiki/HIV" title="HIV" >HIV</a>, and bacterial infections, and potentially in the treatment of <a href="http://en.wikipedia.org/wiki/Cancer" title="Cancer" >cancer</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Maestroni1999-54" >[54]</a>

In <a href="http://en.wikipedia.org/wiki/Rheumatoid_arthritis" title="Rheumatoid arthritis" >rheumatoid arthritis</a> patients, melatonin production has been found increased when compared to age-matched healthy controls.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16014678-55" >[55]</a>[<a href="http://en.wikipedia.org/wiki/Wikipedia:TOPIC" title="Wikipedia:TOPIC" class="mw-redirect" >relevant?</a> – <a href="http://en.wikipedia.org/wiki/Talk:Melatonin" title="Talk:Melatonin" >discuss</a>]

<h3 >Dreaming[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=9" title="Edit section: Dreaming" >edit</a>]</h3>

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased <a href="http://en.wikipedia.org/wiki/REM_sleep" title="REM sleep" class="mw-redirect" >REM sleep</a> time and dream activity in people both with and without <a href="http://en.wikipedia.org/wiki/Narcolepsy" title="Narcolepsy" >narcolepsy</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Lewis-56" >[56]</a>

<h3 >Autism[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=10" title="Edit section: Autism" >edit</a>]</h3>

Melatonin improves sleep in people with intellectual disabilities and <a href="http://en.wikipedia.org/wiki/Autism_spectrum_disorder" title="Autism spectrum disorder" class="mw-redirect" >autism spectrum disorders</a> (ASD).<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-asd-57" >[57]</a>

<h3 >Aging[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=11" title="Edit section: Aging" >edit</a>]</h3>

Research has supported the anti-aging properties of melatonin. Younger children hit their peak melatonin production at night, and some researchers believe that the level of melatonin peaks earlier as people get older.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-58" >[58]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-59" >[59]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-60" >[60]</a> This may explain why older adults go to bed earlier, wake up earlier, and have more sleep problems than children do.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-urlMelatonin-61" >[61]</a>

Some studies have shown that melatonin plays a crucial part in the aging process and that it may act as an anti-aging agent when administered to older mice. It has been reported in one study that administration of melatonin in elderly mice may reverse this change in expression of some 13 genes, thus making them similar to those of younger mice.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid15009506-62" >[62]</a> Consuming melatonin may neutralize oxidative damage and delay the neurodegenerative process of aging.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pohanka_2011-46" >[46]</a> When small amounts of melatonin were administered to lab mice, it reduced the oxidative damage caused by aging and delayed the inflammatory process, which in turn increased the longevity of the mice.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11270481-63" >[63]</a>

<h3 >Diabetes[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=12" title="Edit section: Diabetes" >edit</a>]</h3>

<a href="http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism" title="Single-nucleotide polymorphism" >Single-nucleotide polymorphisms</a> of the human melatonin <a href="http://en.wikipedia.org/wiki/Melatonin_receptor_1B" title="Melatonin receptor 1B" >MT2</a> receptor have been linked to an increased risk of developing <a href="http://en.wikipedia.org/wiki/Type_2_diabetes" title="Type 2 diabetes" class="mw-redirect" >type 2 diabetes</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21112029-64" >[64]</a> Furthermore women with low levels of melatonin secretion have been found to more likely to develop type 2 diabetes than women with high levels.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid23549584-65" >[65]</a>

<h3 >Pediatrics[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=13" title="Edit section: Pediatrics" >edit</a>]</h3>

While the packaging of melatonin often warns against use in children, at least one long-term study does assess effectiveness and safety in children. No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents. With a mean follow-up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases. Other studies warn against potential side effects<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19486273-66" >[66]</a>

<h2 >Medical uses[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=14" title="Edit section: Medical uses" >edit</a>]</h2>

A bottle of melatonin tablets</div>

</div>

Melatonin has been studied as a potential treatment of <a href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease" title="Gastroesophageal reflux disease" >gastroesophageal reflux disease</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid20082715-67" >[67]</a> <a href="http://en.wikipedia.org/wiki/Cancer" title="Cancer" >cancer</a>, <a href="http://en.wikipedia.org/wiki/Immune_System#Disorders_of_the_human_immune_system" title="Immune System" class="mw-redirect" >immune disorders</a>, <a href="http://en.wikipedia.org/wiki/Cardiovascular_disease" title="Cardiovascular disease" >cardiovascular diseases</a>, <a href="http://en.wikipedia.org/wiki/Clinical_depression" title="Clinical depression" class="mw-redirect" >depression</a>, <a href="http://en.wikipedia.org/wiki/Seasonal_affective_disorder" title="Seasonal affective disorder" >seasonal affective disorder</a> (SAD), <a href="http://en.wikipedia.org/wiki/Circadian_rhythm_sleep_disorder" title="Circadian rhythm sleep disorder" >circadian rhythm sleep disorders</a>, <a href="http://en.wikipedia.org/wiki/Sexual_dysfunction" title="Sexual dysfunction" >sexual dysfunction</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-mayoclinic.com-68" >[68]</a> and insomnia in the elderly.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-mayoclinic.com-68" >[68]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19326288-69" >[69]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21358978-70" >[70]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid15511698-71" >[71]</a> Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid17875243-72" >[72]</a> It may improve <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >circadian</a> misalignment and SAD.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid1701579-73" >[73]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Lewy1987-74" >[74]</a> Basic research indicates that melatonin may play a role in modulating the effects of drugs of abuse such as <a href="http://en.wikipedia.org/wiki/Cocaine" title="Cocaine" >cocaine</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid10700581-75" >[75]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Uz2003-76" >[76]</a> Melatonin is also a <a href="http://en.wikipedia.org/wiki/Geroprotector" title="Geroprotector" >geroprotector</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16678784-77" >[77]</a>

A 2004 review found that melatonin significantly increased total sleep time in people suffering from <a href="http://en.wikipedia.org/wiki/Sleep_deprivation" title="Sleep deprivation" >sleep restriction</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-USAHRQ-34" >[34]</a>

For many types of sleep disorders, melatonin is not effective. A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as <a href="http://en.wikipedia.org/wiki/Jet_lag" title="Jet lag" >jet lag</a> and <a href="http://en.wikipedia.org/wiki/Shiftwork_disorder" title="Shiftwork disorder" class="mw-redirect" >shiftwork disorder</a>."<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Buscemi2006-78" >[78]</a>

In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating <a href="http://en.wikipedia.org/wiki/Delayed_sleep_phase_disorder" title="Delayed sleep phase disorder" >delayed sleep phase disorder</a> (DSPD), there is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16423108-79" >[79]</a>

<h3 >Circadian rhythm disorders[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=15" title="Edit section: Circadian rhythm disorders" >edit</a>]</h3>

<div class="hatnote" >Further information: <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >Circadian rhythm</a></div>

Exogenous (externally derived) melatonin taken in the evening is, together with <a href="http://en.wikipedia.org/wiki/Light_therapy" title="Light therapy" >light therapy</a> upon awakening, the standard treatment for delayed sleep phase disorder (DSPD) and <a href="http://en.wikipedia.org/wiki/Non-24-hour_sleep%E2%80%93wake_disorder" title="Non-24-hour sleep–wake disorder" >non-24-hour sleep–wake disorder</a> where circadian rhythms are not <a href="http://en.wikipedia.org/wiki/Entrainment_(chronobiology)" title="Entrainment (chronobiology)" >entrained</a> (biologically synchronized) to the environmental cycle. It appears to have some use against other circadian rhythm sleep disorders as well, such as<a href="http://en.wikipedia.org/wiki/Jet_lag" title="Jet lag" >jet lag</a> and the problems of people who work rotating or night <a href="http://en.wikipedia.org/wiki/Shift_work" title="Shift work" >shifts</a>. Melatonin reduces <a href="http://en.wikipedia.org/wiki/Sleep_onset_latency" title="Sleep onset latency" >sleep onset latency</a> to a greater extent in people with DSPD than in people with insomnia.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-USAHRQ-34" >[34]</a>

A very small dose taken several hours before bedtime in accordance with the <a href="http://en.wikipedia.org/wiki/Phase_response_curve#Melatonin_PRC" title="Phase response curve" >phase response curve</a> for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a <a href="http://en.wikipedia.org/wiki/Chronobiotic" title="Chronobiotic" >chronobiotic</a> (affecting aspects of biological time structure),<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-80" >[80]</a> 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 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16295212-41" >[41]</a>

<h3 >Learning, memory and Alzheimer's[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=16" title="Edit section: Learning, memory and Alzheimer's" >edit</a>]</h3>

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Larson2006-81" >[81]</a> and melatonin can alter electrophysiological processes associated with memory, such as <a href="http://en.wikipedia.org/wiki/Long-term_potentiation" title="Long-term potentiation" >long-term potentiation</a> (LTP). The first published evidence that melatonin may be useful in <a href="http://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease" >Alzheimer's disease</a> was the demonstration that this neurohormone prevents neuronal death caused by exposure to the<a href="http://en.wikipedia.org/wiki/Amyloid_beta" title="Amyloid beta" class="mw-redirect" >amyloid beta</a> protein, a <a href="http://en.wikipedia.org/wiki/Neurotoxic" title="Neurotoxic" class="mw-redirect" >neurotoxic</a> substance that accumulates in the brains of patients with the disorder.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pappolla1997-82" >[82]</a> Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of <a href="http://en.wikipedia.org/wiki/Neurofibrillary_tangle" title="Neurofibrillary tangle" >neurofibrillary tangles</a>, the other neuropathological landmark of Alzheimer's disease.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pappolla1998-83" >[83]</a>

Melatonin has been shown to prevent the <a href="http://en.wikipedia.org/wiki/Hyperphosphorylation" title="Hyperphosphorylation" >hyperphosphorylation</a> of the <a href="http://en.wikipedia.org/wiki/Tau_protein" title="Tau protein" >tau protein</a> in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Wang2005-84" >[84]</a> These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Another study has implicated heightened afternoon agitation found in many Alzheimer's patients, called <a href="http://en.wikipedia.org/wiki/Sundowning_(dementia)" title="Sundowning (dementia)" class="mw-redirect" >sundowning</a>, with a <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >phase delay</a> in core body temperature.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Volicer2001-85" >[85]</a> This may suggest a possible connection to melatonin production.

<h3 >Delirium[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=17" title="Edit section: Delirium" >edit</a>]</h3>

A randomized placebo-controlled trial showed that low-dose melatonin supplementation to 72 elderly patients admitted to acute medicine services significantly reduced <a href="http://en.wikipedia.org/wiki/Delirium" title="Delirium" >delirium</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid20845391-86" >[86]</a>

<h3 >Stimulants[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=18" title="Edit section: Stimulants" >edit</a>]</h3>

Research shows that after melatonin is administered to <a href="http://en.wikipedia.org/wiki/Attention-deficit_hyperactivity_disorder" title="Attention-deficit hyperactivity disorder" class="mw-redirect" >ADHD</a> patients on <a href="http://en.wikipedia.org/wiki/Methylphenidate" title="Methylphenidate" >methylphenidate</a>, 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Gi2003-87" >[87]</a>

<h3 >Headaches[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=19" title="Edit section: Headaches" >edit</a>]</h3>

Several clinical studies indicate that supplementation with melatonin is an effective <a href="http://en.wikipedia.org/wiki/Preventive_medicine" title="Preventive medicine" class="mw-redirect" >preventive treatment</a> for <a href="http://en.wikipedia.org/wiki/Migraines" title="Migraines" class="mw-redirect" >migraines</a> and <a href="http://en.wikipedia.org/wiki/Cluster_headache" title="Cluster headache" >cluster headaches</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Dodick2001-88" >[88]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Gagnier2001-89" >[89]</a>

<h3 >Mood disorders[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=20" title="Edit section: Mood disorders" >edit</a>]</h3>

Melatonin has been shown to be effective in treating <a href="http://en.wikipedia.org/wiki/Seasonal_affective_disorder" title="Seasonal affective disorder" >seasonal affective disorder</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-90" >[90]</a> a form of depression, and is being considered for <a href="http://en.wikipedia.org/wiki/Bipolar_disorder" title="Bipolar disorder" >bipolar</a> and other disorders in which circadian disturbances are involved.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid17872420-91" >[91]</a> It was observed in 1985 that <a href="http://en.wikipedia.org/wiki/Bipolar_disorder" title="Bipolar disorder" >bipolar disorder</a> might have elevated sensitivity to light, i.e., a greater decrease in melatonin secretion in response to light exposure at night, as a "trait marker" (a characteristic of being bipolar, which does not change with state).<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid4003592-92" >[92]</a> This could be contrasted with drug-free recovered bipolar patients showing normal light sensitivity.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid1658841-93" >[93]</a>

<h3 >Cancer[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=21" title="Edit section: Cancer" >edit</a>]</h3>

A <a href="http://en.wikipedia.org/wiki/Systematic_review" title="Systematic review" >systematic review</a> of unblinded <a href="http://en.wikipedia.org/wiki/Clinical_trial" title="Clinical trial" >clinical trials</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16207291-94" >[94]</a> The National Cancer Institute's review of the evidence found that it remains inconclusive.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-95" >[95]</a>

<h3 >Gallbladder stones[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=22" title="Edit section: Gallbladder stones" >edit</a>]</h3>

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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid18338264-96" >[96]</a> It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced <a href="http://en.wikipedia.org/wiki/Cholecystitis" title="Cholecystitis" >cholecystitis</a>, whether administered before or after onset of inflammation.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid18338264-96" >[96]</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid10622237-97" >[97]</a>

<h3 >Amyotrophic lateral sclerosis[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=23" title="Edit section: Amyotrophic lateral sclerosis" >edit</a>]</h3>

In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, it is presumed due to its antioxidant effects. In a clinical safety study involving 31 <a href="http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis" title="Amyotrophic lateral sclerosis" >ALS</a> patients, high-dose rectal melatonin (300 mg/day for 2 years) was shown to be tolerated well.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid17014688-98" >[98]</a>

<h3 >Obesity[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=24" title="Edit section: Obesity" >edit</a>]</h3>

Melatonin is involved in energy metabolism and body weight control in small animals. Many studies show that chronic melatonin supplementation in drinking water reduces body weight and abdominal fat in experimental animals, especially in the middle-aged rats<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Wolden-Hanson2000-99" >[99]</a> and the weight loss effect did not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of <a href="http://en.wikipedia.org/wiki/Brown_adipose_tissue" title="Brown adipose tissue" >brown adipose tissue</a> (BAT) as well as enhances its activity.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-tan2010-100" >[100]</a> This effect would raise the <a href="http://en.wikipedia.org/wiki/Basal_metabolic_rate" title="Basal metabolic rate" >basal metabolic rate</a> by stimulating <a href="http://en.wikipedia.org/wiki/Thermogenesis" title="Thermogenesis" >thermogenesis</a>, heat generation through uncoupling <a href="http://en.wikipedia.org/wiki/Oxidative_phosphorylation" title="Oxidative phosphorylation" >oxidative phosphorylation</a> in <a href="http://en.wikipedia.org/wiki/Mitochondria" title="Mitochondria" class="mw-redirect" >mitochondria</a>. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult humans.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-101" >[101]</a>

<h3 >Protection from radiation[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=25" title="Edit section: Protection from radiation" >edit</a>]</h3>

Both animal<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid10082913-102" >[102]</a> and human<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid9008723-103" >[103]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid9541644-104" >[104]</a> studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than <a href="http://en.wikipedia.org/wiki/Amifostine" title="Amifostine" >amifostine</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid18979313-105" >[105]</a> a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of <a href="http://en.wikipedia.org/wiki/Free_radicals" title="Free radicals" class="mw-redirect" >free radicals</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Tan_Manchester-45" >[45]</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid17641465-106" >[106]</a>

<h3 >Tinnitus[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=26" title="Edit section: Tinnitus" >edit</a>]</h3>

Several medical studies involving adult patients indicate that melatonin can be beneficial in the treatment of <a href="http://en.wikipedia.org/wiki/Tinnitus" title="Tinnitus" >tinnitus</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21859051-107" >[107]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16455366-108" >[108]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid9504599-109" >[109]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid20207491-110" >[110]</a>

<h3 >Other[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=27" title="Edit section: Other" >edit</a>]</h3>

Melatonin was used to treat <a href="http://en.wikipedia.org/wiki/Periodic_limb_movement_disorder" title="Periodic limb movement disorder" >periodic limb movement disorder</a>, a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11247054-111" >[111]</a>

In recent trial for use in <a href="http://en.wikipedia.org/wiki/Irritable_bowel_syndrome" title="Irritable bowel syndrome" >irritable bowel syndrome</a> treatment, melatonin relieved some symptoms, as published in 2010.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-112" >[112]</a>

A research team in <a href="http://en.wikipedia.org/wiki/Italy" title="Italy" >Italy</a> has found that melatonin supplementation in the evening in <a href="http://en.wikipedia.org/wiki/Perimenopausal" title="Perimenopausal" class="mw-redirect" >perimenopausal</a> women produces an improvement in thyroid function and <a href="http://en.wikipedia.org/wiki/Gonadotropin" title="Gonadotropin" >gonadotropin</a> levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Bellipanni2005-113" >[113]</a> One study reported that melatonin taken in the evening raised <a href="http://en.wikipedia.org/wiki/Prolactin" title="Prolactin" >prolactin</a> levels in six out of seven women.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid8370131-114" >[114]</a>

<h2 >Adverse effects[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=28" title="Edit section: Adverse effects" >edit</a>]</h2>

Melatonin appears to cause very few <a href="http://en.wikipedia.org/wiki/Adverse_effect_(medicine)" title="Adverse effect (medicine)" class="mw-redirect" >side-effects</a> in the short term, up to three months, when healthy people take it at low doses. A systematic review<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Buscemi2006-78" >[78]</a> in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances that are secondary to other diagnoses and, second, for sleep disorders such as <a href="http://en.wikipedia.org/wiki/Jet_lag" title="Jet lag" >jet lag</a> and <a href="http://en.wikipedia.org/wiki/Shift_work" title="Shift work" >shift work</a> that accompany sleep restriction.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Buscemi2006-78" >[78]</a>

The study concluded that "There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use".<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Buscemi2006-78" >[78]</a>

A similar analysis<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16423108-79" >[79]</a> by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of primary sleep disorders found that: "There is evidence to suggest that melatonin is safe with short-term use (3 months or less)."

Unwanted effects in some people may include nausea, next-day <a href="http://en.wikipedia.org/wiki/Grogginess" title="Grogginess" class="mw-redirect" >grogginess</a>, irritability,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-115" >[115]</a> reduced blood flow and <a href="http://en.wikipedia.org/wiki/Hypothermia" title="Hypothermia" >hypothermia</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11600532-116" >[116]</a>

While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for months.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11027741-117" >[117]</a>

Melatonin can cause <a href="http://en.wikipedia.org/wiki/Somnolence" title="Somnolence" >somnolence</a> (drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc.

In individuals with <a href="http://en.wikipedia.org/wiki/Auto-immune_disorders" title="Auto-immune disorders" class="mw-redirect" >auto-immune disorders</a>, there is conflicting evidence whether melatonin supplementation may either ameliorate or exacerbate symptoms due to <a href="http://en.wikipedia.org/wiki/Immunomodulator" title="Immunomodulator" class="mw-redirect" >immunomodulation</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Morera2001-118" >[118]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Terry2008-119" >[119]</a>

Individuals experiencing <a href="http://en.wikipedia.org/wiki/Orthostatic_intolerance" title="Orthostatic intolerance" >orthostatic intolerance</a>, a <a href="http://en.wikipedia.org/wiki/Cardiovascular" title="Cardiovascular" class="mw-redirect" >cardiovascular</a> condition that results in reduced <a href="http://en.wikipedia.org/wiki/Blood_pressure" title="Blood pressure" >blood pressure</a> and <a href="http://en.wikipedia.org/wiki/Blood_flow" title="Blood flow" >blood flow</a> to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at <a href="http://en.wikipedia.org/wiki/Penn_State_College_of_Medicine" title="Penn State College of Medicine" class="mw-redirect" >Penn State College of Medicine</a>'s Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those experiencing the condition, the study found.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Chester2003-120" >[120]</a>

Melatonin has been found to lower <a href="http://en.wikipedia.org/wiki/Follicle-stimulating_hormone" title="Follicle-stimulating hormone" >FSH</a> levels.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16921343-121" >[121]</a>[<a href="http://en.wikipedia.org/wiki/Wikipedia:NOTRS" title="Wikipedia:NOTRS" class="mw-redirect" >better source needed</a>] Effects of the hormone on human reproduction remain unclear,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19905996-122" >[122]</a> although it was with some effect tried as a contraceptive in the 1990s.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-123" >[123]</a>

Melatonin was thought to have a very low maternal toxicity in rats.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid10478864-124" >[124]</a> 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<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid18078931-125" >[125]</a> and increases the incidence of tumours in white mice.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11445596-126" >[126]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-FDAwarning-127" >[127]</a>

In animal models, interventions that increase the bioavailability of melatonin seem to increase the severity of parkinsonian symptoms, whereas reduction in melatonin by pinealectomy or exposure to bright light can improve recovery from parkinsonisms symptoms.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16596313-128" >[128]</a> Melatonin may exacerbate neurodegeneration in advanced <a href="http://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease" >Parkinson's disease</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid22252727-129" >[129]</a>

<h2 >Availability[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=29" title="Edit section: Availability" >edit</a>]</h2>

<a href="http://en.wikipedia.org/wiki/Helsinki_university" title="Helsinki university" class="mw-redirect" >Helsinki university</a>pharmaceutical laboratory prepared melatonin available upon prescription.</div>

</div>

Legal availability of melatonin varies in different countries, ranging from being available without prescription (e.g. in most of <a href="http://en.wikipedia.org/wiki/North_America" title="North America" >North America</a> and Finland) to being available only on prescription (e.g. in the UK) or not at all (although its possession and use may not be illegal). It is widely available on the Internet.

The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.

The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material. The synthetic form of this medication does not carry this risk.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Altun2007-4" >[4]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-130" >[130]</a>

<h3 >Dietary supplement[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=30" title="Edit section: Dietary supplement" >edit</a>]</h3>

In the US it is sold as a dietary supplement (sometimes combined with other ingredients, such as vitamins and herbal extracts) and not as a drug. The Food and Drug Administration (FDA) regulations applying to medications are not applicable to melatonin.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Altun2007-4" >[4]</a> However, new FDA rules required that by June 2010 all production of dietary supplements must comply with "current <a href="http://en.wikipedia.org/wiki/Good_manufacturing_practice" title="Good manufacturing practice" >good manufacturing practices</a>" (cGMP) and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling."<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-131" >[131]</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-132" >[132]</a>

<h3 >Food products[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=31" title="Edit section: Food products" >edit</a>]</h3>

As reported in the New York Times in May 2011,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-NYTimes_May_2011-133" >[133]</a> melatonin is sold in grocery stores, convenience stores, and clubs in both beverage and snack forms. 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 <a href="http://en.wikipedia.org/wiki/Food_additive" title="Food additive" >food additive</a> because it is not <a href="http://en.wikipedia.org/wiki/Generally_recognized_as_safe" title="Generally recognized as safe" >generally recognized as safe</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-FDAwarning-127" >[127]</a>

<h3 >Prolonged release[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=32" title="Edit section: Prolonged release" >edit</a>]</h3>

Circadin 2mg, prolonged-release melatonin</div>

</div>

Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The <a href="http://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency" >European Medicines Agency</a> (EMA) has approved Circadin 2 mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-134" >[134]</a>

<h2 >History[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=33" title="Edit section: History" >edit</a>]</h2>

Melatonin was first discovered in connection to the mechanism by which some <a href="http://en.wikipedia.org/wiki/Amphibians" title="Amphibians" class="mw-redirect" >amphibians</a> and <a href="http://en.wikipedia.org/wiki/Reptiles" title="Reptiles" class="mw-redirect" >reptiles</a> change the color of their skin.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Filadelfi1996-135" >[135]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Sugden2004-136" >[136]</a> As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark <a href="http://en.wikipedia.org/wiki/Epidermis(zoology)" title="Epidermis (zoology)" >epidermal</a> <a href="http://en.wikipedia.org/wiki/Melanophores" title="Melanophores" class="mw-redirect" >melanophores</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Coates-137" >[137]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-McCord-138" >[138]</a> In 1958 dermatology professor <a href="http://en.wikipedia.org/wiki/Aaron_B.Lerner" title="Aaron B. Lerner" >Aaron B. Lerner</a> and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid14415935-139" >[139]</a> In the mid-70s Lynch et al. demonstrated<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid1167425-140" >[140]</a> that the production of melatonin exhibits a <a href="http://en.wikipedia.org/wiki/Circadian_rhythm" title="Circadian rhythm" >circadian rhythm</a> in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-scavenger-141" >[141]</a> The first <a href="http://en.wikipedia.org/wiki/Patent" title="Patent" >patent</a> for its use as a low dose sleep aid was granted to <a href="http://en.wikipedia.org/wiki/Richard_Wurtman" title="Richard Wurtman" >Richard Wurtman</a> at <a href="http://en.wikipedia.org/wiki/MIT" title="MIT" class="mw-redirect" >MIT</a> in 1995.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-142" >[142]</a> Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16077149-143" >[143]</a> 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."<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid11027748-144" >[144]</a>

<tr>

<td class="mbox-text plainlist" >Wikimedia Commons has media related to<a href="http://commons.wikimedia.org/wiki/Category:Melatonin" class="extiw" title="commons:Category:Melatonin" >Melatonin</a>.</td>

</tr>

</tbody></table>

<ul >

<li ><a href="http://en.wikipedia.org/wiki/5-Methoxytryptamine" title="5-Methoxytryptamine" >5-Methoxytryptamine</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Agomelatine" title="Agomelatine" >Agomelatine</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Discovery_and_development_of_melatonin_receptor_agonists" title="Discovery and development of melatonin receptor agonists" class="mw-redirect" >Discovery and development of melatonin receptor agonists</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Ramelteon" title="Ramelteon" >Ramelteon</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Risks_and_benefits_of_sun_exposure" title="Risks and benefits of sun exposure" class="mw-redirect" >Risks and benefits of sun exposure</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Tasimelteon" title="Tasimelteon" >Tasimelteon</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Sundowning" title="Sundowning" >Sundowning</a></li>

</ul>

<h2 >References[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=35" title="Edit section: References" >edit</a>]</h2>

<li id="cite_note-1" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-1" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.sleepdex.org/melatonin.htm" >"Melatonin"</a>. Sleepdex. Retrieved 2011-08-17.</li>

<li id="cite_note-Caniato2003-2" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Caniato2003_2-0" >Jump up^{</a>&nbsp};Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti EM (2003). "Melatonin in plants". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology 527: 593–7. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2F978-1-4615-0135-0_68" >10.1007/978-1-4615-0135-0_68</a>. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/978-0-306-47755-3" title="Special:BookSources/978-0-306-47755-3" >978-0-306-47755-3</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15206778" >15206778</a>.</li>

<li id="cite_note-Paredes2009-3" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Paredes2009_3-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Paredes2009_3-1" >b</a> Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ (2009). "Phytomelatonin: a review". J. Exp. Bot. 60 (1): 57–69.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fjxb%2Fern284" >10.1093/jxb/ern284</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19033551" >19033551</a>.</li>

<li id="cite_note-Altun2007-4" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Altun2007_4-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Altun2007_4-1" >b</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Altun2007_4-2" >c</a> Altun A, Ugur-Altun B (May 2007). "Melatonin: therapeutic and clinical utilization". Int. J. Clin. Pract. 61 (5): 835–45.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1742-1241.2006.01191.x" >10.1111/j.1742-1241.2006.01191.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17298593" >17298593</a>.</li>

<li id="cite_note-Boutin2005-5" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Boutin2005_5-0" >Jump up^{</a>&nbsp};Boutin JA, Audinot V, Ferry G, Delagrange P (August 2005). "Molecular tools to study melatonin pathways and actions". Trends Pharmacol. Sci. 26 (8): 412–9. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.tips.2005.06.006" >10.1016/j.tips.2005.06.006</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15992934" >15992934</a>.</li>

<li id="cite_note-Hardeland2005-6" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Hardeland2005_6-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Hardeland2005_6-1" >b</a> Hardeland R (July 2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine 27 (2): 119–30.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1385%2FENDO%3A27%3A2%3A119" >10.1385/ENDO:27:2:119</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16217125" >16217125</a>.</li>

<li id="cite_note-Reiter2001-7" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Reiter2001_7-0" >Jump up^{</a>&nbsp};Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S; Acuña-Castroviejo; Tan; Burkhardt (June 2001). "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system". Ann. N. Y. Acad. Sci. 939: 200–15. <a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2001NYASA.939..200R" >2001NYASA.939..200R</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1749-6632.2001.tb03627.x" >10.1111/j.1749-6632.2001.tb03627.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11462772" >11462772</a>.</li>

<li id="cite_note-Ratzburg_Vanderbilt-8" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Ratzburg_Vanderbilt_8-0" >Jump up^{</a>&nbsp};Ratzburg C (Undated). <a rel="nofollow" class="external text" href="http://www.vanderbilt.edu/AnS/psychology/health_psychology/melatonin.htm" >"Melatonin: The Myths and Facts"</a>. Vanderbilt University. Retrieved 2007-12-02.</li>

<li id="cite_note-Buscemi_2004-9" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Buscemi_2004_9-0" >Jump up^{</a>&nbsp};Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T (November 2004).<a rel="nofollow" class="external text" href="http://archive.ahrq.gov/downloads/pub/evidence/pdf/melatonin/melatonin.pdf" >"Melatonin for treatment of sleep disorders"</a>. 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. Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services. Retrieved 5 June 2013.</li>

<li id="cite_note-EMA_EPAR-10" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-EMA_EPAR_10-0" >Jump up^{</a>&nbsp};European Medicines Agency. <a rel="nofollow" class="external text" href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000695/human_med_000701.jsp&mid=WC0b01ac058001d124" >"Circadin, melatonin"</a>. European Public Assessment Report (EPAR). European Medicines Agency. Retrieved 5 June 2013.</li>

<li id="cite_note-TGA_APR-11" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-TGA_APR_11-0" >Jump up^{</a>&nbsp};Therapeutic Goods Administration (TGA). <a rel="nofollow" class="external text" href="http://www.tga.gov.au/pdf/auspar/auspar-circadin.pdf" >"Australian Public Assessment Report for Melatonin"</a>. Department of Health and Ageing, Australian Government. Retrieved 5 June 2013.</li>

<li id="cite_note-12" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-12" >Jump up^{</a>&nbsp};Bioactivity of grape chemicals for human health. Iriti M and Faoro F, Nat Prod Commun., 2009 May, 4(5), pages 611-634, <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19445314" >PubMed</a></li>

<li id="cite_note-pmid22016420-13" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid22016420_13-0" >Jump up^{</a>&nbsp};Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ (January 2012). "Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science". J. Exp. Bot. 63 (2): 577–97. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fjxb%2Ferr256" >10.1093/jxb/err256</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/22016420" >22016420</a>.</li>

<li id="cite_note-pmid20039865-14" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid20039865_14-0" >Jump up^{</a>&nbsp};Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ (August 2010). "The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness". Biol Rev Camb Philos Soc 85 (3): 607–23. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1469-185X.2009.00118.x" >10.1111/j.1469-185X.2009.00118.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20039865" >20039865</a>.</li>

<li id="cite_note-Melatonin_Plants-15" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Melatonin_Plants_15-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Melatonin_Plants_15-1" >b</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Melatonin_Plants_15-2" >c</a> Arnao MB, Hernández-Ruiz J (May 2006). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635004" >"The physiological function of melatonin in plants"</a>. Plant Signal Behav 1 (3): 89–95.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.4161%2Fpsb.1.3.2640" >10.4161/psb.1.3.2640</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635004" >2635004</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19521488" >19521488</a>.</li>

<li id="cite_note-pmid11600041-16" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid11600041_16-0" >Jump up^{</a>&nbsp};Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ (October 2001). "Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus)". J. Agric. Food Chem. 49 (10): 4898–902.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1021%2Fjf010321" >10.1021/jf010321</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11600041" >11600041</a>.</li>

<li id="cite_note-pmid21342247-17" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid21342247_17-0" >Jump up^{</a>&nbsp};Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (May 2011). "Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection". J. Pineal Res. 50 (4): 374–80. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1600-079X.2010.00853.x" >10.1111/j.1600-079X.2010.00853.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/21342247" >21342247</a>.</li>

<li id="cite_note-Hattori1995-18" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Hattori1995_18-0" >Jump up^{</a>&nbsp};Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ (March 1995). "Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates". Biochem. Mol. Biol. Int. 35 (3): 627–34. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/7773197" >7773197</a>.</li>

<li id="cite_note-pmid23137025-19" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid23137025_19-0" >Jump up^{</a> Sae}-Teaw M, Johns J, Johns NP, Subongkot S (October 2012). "Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers". J. Pineal Res. 55 (1): 58–64. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fjpi.12025" >10.1111/jpi.12025</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23137025" >23137025</a>.</li>

<li id="cite_note-Lincoln2003-20" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Lincoln2003_20-0" >Jump up^{</a>&nbsp};Lincoln GA, Andersson H, Loudon A (October 2003). "Clock genes in calendar cells as the basis of annual timekeeping in mammals – a unifying hypothesis". J. Endocrinol. 179 (1): 1–13.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1677%2Fjoe.0.1790001" >10.1677/joe.0.1790001</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/14529560" >14529560</a>.</li>

<li id="cite_note-Arendt2005-21" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Arendt2005_21-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Arendt2005_21-1" >b</a> Arendt J, Skene DJ (February 2005). "Melatonin as a chronobiotic". Sleep Med Rev 9 (1): 25–39.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.smrv.2004.05.002" >10.1016/j.smrv.2004.05.002</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15649736" >15649736</a>. "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."</li>

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<li id="cite_note-Chen1981-23" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Chen1981_23-0" >Jump up^{</a>&nbsp};Chen HJ (July 1981). "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology 33 (1): 43–6. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1159%2F000123198" >10.1159/000123198</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/7254478" >7254478</a>.</li>

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<li id="cite_note-Arushanian2002-51" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Arushanian2002_51-0" >Jump up^{</a>&nbsp};Arushanian EB, Beĭer EV (2002). "[Immunotropic properties of pineal melatonin]". Eksp Klin Farmakol (in Russian) 65 (5): 73–80.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/12596522" >12596522</a>.</li>

<li id="cite_note-52" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-52" >Jump up^{</a> Pohanka}, M (2013). <a rel="nofollow" class="external text" href="http://link.springer.com/article/10.2478%2Fs11536-013-0177-2" >"Impact of melatonin on immunity: a review"</a>.Central European Journal of Medicine 8 (4): 369–376.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.2478%2Fs11536-013-0177-2" >10.2478/s11536-013-0177-2</a>.</li>

<li id="cite_note-pmid16729718-53" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16729718_53-0" >Jump up^{</a> Carrillo}-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D (May 2006). "The modulatory role of melatonin on immune responsiveness". Curr Opin Investig Drugs 7 (5): 423–31. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16729718" >16729718</a>.</li>

<li id="cite_note-Maestroni1999-54" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Maestroni1999_54-0" >Jump up^{</a>&nbsp};Maestroni GJ (1999). "Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology 467: 217–26. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2F978-1-4615-4709-9_28" >10.1007/978-1-4615-4709-9_28</a>. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/978-1-4613-7133-5" title="Special:BookSources/978-1-4613-7133-5" >978-1-4613-7133-5</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10721059" >10721059</a>.</li>

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<li id="cite_note-59" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-59" >Jump up^{</a>&nbsp};Brown GM, Young SN, Gauthier S, Tsui H, Grota LJ (September 1979). "Melatonin in human cerebrospinal fluid in daytime: its origin and variation with age". Life Science 25 (11): 929–936.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2F0024-3205%2879%2990498-3" >10.1016/0024-3205(79)90498-3</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/513940" >513940</a>.</li>

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<li id="cite_note-urlMelatonin-61" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-urlMelatonin_61-0" >Jump up^{</a>&nbsp};Ehrlich SD (2012-01-20). <a rel="nofollow" class="external text" href="http://www.umm.edu/altmed/articles/melatonin-000315.htm" >"Melatonin"</a>. University of Maryland Medical Center.</li>

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<li id="cite_note-pmid23549584-65" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid23549584_65-0" >Jump up^{</a>&nbsp};McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP (April 2013). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804914" >"Melatonin secretion and the incidence of type 2 diabetes"</a>. JAMA 309 (13): 1388–96.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1001%2Fjama.2013.2710" >10.1001/jama.2013.2710</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804914" >3804914</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23549584" >23549584</a>.<a rel="nofollow" class="external text" href="http://www.sciencedaily.com/releases/2013/04/130402162420.htm" >Lay summary</a> – ScienceDaily.</li>

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<li id="cite_note-pmid10700581-75" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid10700581_75-0" >Jump up^{</a>&nbsp};Sircar R (February 2000). "Effect of melatonin on cocaine-induced behavioral sensitization". Brain Res. 857 (1–2): 295–9.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2FS0006-8993%2899%2902460-9" >10.1016/S0006-8993(99)02460-9</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10700581" >10700581</a>.</li>

<li id="cite_note-Uz2003-76" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Uz2003_76-0" >Jump up^{</a>&nbsp};Uz T, Akhisaroglu M, Ahmed R, Manev H (December 2003). "The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice".Neuropsychopharmacology 28 (12): 2117–23.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fsj.npp.1300254" >10.1038/sj.npp.1300254</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/12865893" >12865893</a>.</li>

<li id="cite_note-pmid16678784-77" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16678784_77-0" >Jump up^{</a>&nbsp};Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA (2006). "Melatonin as antioxidant, geroprotector and anticarcinogen". Biochim. Biophys. Acta 1757 (5–6): 573–89. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.bbabio.2006.03.012" >10.1016/j.bbabio.2006.03.012</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16678784" >16678784</a>.</li>

<li id="cite_note-Buscemi2006-78" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Buscemi2006_78-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Buscemi2006_78-1" >b</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Buscemi2006_78-2" >c</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Buscemi2006_78-3" >d</a> Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G (February 2006). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1370968" >"Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis"</a>.BMJ 332 (7538): 385–93. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1136%2Fbmj.38731.532766.F6" >10.1136/bmj.38731.532766.F6</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1370968" >1370968</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16473858" >16473858</a>.</li>

<li id="cite_note-pmid16423108-79" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16423108_79-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16423108_79-1" >b</a> Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S (December 2005). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490287" >"The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis"</a>. J Gen Intern Med 20 (12): 1151–8.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1525-1497.2005.0243.x" >10.1111/j.1525-1497.2005.0243.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490287" >1490287</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16423108" >16423108</a>.</li>

<li id="cite_note-80" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-80" >Jump up^{</a>&nbsp};Simpson HW (1979). <a rel="nofollow" class="external text" href="http://books.google.com/?id=e-bZhuzXbK4C&pg=PA433&lpg=PA433&dq=chronobiotic+definition#v=onepage&q=chronobiotic%20definition&f=false" >"Chronobiotics: Selected Agents of Potential Value in Jet Lag and other Dyschronisms"</a>. In Sheving FE, Hagberg F. Chronobiology: Principles and Application to Shifts in Schedules. Berlin: Springer. p. 433. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/978-90-286-0940-2" title="Special:BookSources/978-90-286-0940-2" >978-90-286-0940-2</a>. The reference discusses several chronobiotic substances, but not melatonin.</li>

<li id="cite_note-Larson2006-81" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Larson2006_81-0" >Jump up^{</a>&nbsp};Larson J, Jessen RE, Uz T, Arslan AD, Kurtuncu M, Imbesi M, Manev H (January 2006). "Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice". Neurosci. Lett. 393 (1): 23–6. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.neulet.2005.09.040" >10.1016/j.neulet.2005.09.040</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16203090" >16203090</a>.</li>

<li id="cite_note-Pappolla1997-82" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Pappolla1997_82-0" >Jump up^{</a>&nbsp};Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK (March 1997). "Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide". J. Neurosci. 17 (5): 1683–90. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9030627" >9030627</a>.</li>

<li id="cite_note-Pappolla1998-83" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Pappolla1998_83-0" >Jump up^{</a>&nbsp};Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J (March 1998). "Inhibition of Alzheimer beta-fibrillogenesis by melatonin". J. Biol. Chem. 273 (13): 7185–8.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1074%2Fjbc.273.13.7185" >10.1074/jbc.273.13.7185</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9516407" >9516407</a>.</li>

<li id="cite_note-Wang2005-84" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Wang2005_84-0" >Jump up^{</a>&nbsp};Wang XC, Zhang J, Yu X, Han L, Zhou ZT, Zhang Y, Wang JZ (February 2005). "Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat". Sheng Li Xue Bao 57(1): 7–12. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15719129" >15719129</a>.</li>

<li id="cite_note-Volicer2001-85" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Volicer2001_85-0" >Jump up^{</a>&nbsp};Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A (May 2001). "Sundowning and circadian rhythms in Alzheimer's disease".Am J Psychiatry 158 (5): 704–11. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1176%2Fappi.ajp.158.5.704" >10.1176/appi.ajp.158.5.704</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11329390" >11329390</a>.</li>

<li id="cite_note-pmid20845391-86" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid20845391_86-0" >Jump up^{</a> Al}-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M (July 2011). "Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial". Int J Geriatr Psychiatry 26 (7): 687–94. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1002%2Fgps.2582" >10.1002/gps.2582</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20845391" >20845391</a>.</li>

<li id="cite_note-Gi2003-87" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Gi2003_87-0" >Jump up^{</a>&nbsp};Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG (July 2003). "Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study".Eur. J. Pediatr. 162 (7–8): 554–5. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs00431-003-1207-x" >10.1007/s00431-003-1207-x</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/12783318" >12783318</a>.</li>

<li id="cite_note-Dodick2001-88" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Dodick2001_88-0" >Jump up^{</a>&nbsp};Dodick DW, Capobianco DJ (February 2001). "Treatment and management of cluster headache". Curr Pain Headache Rep 5 (1): 83–91. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs11916-001-0015-0" >10.1007/s11916-001-0015-0</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11252143" >11252143</a>.</li>

<li id="cite_note-Gagnier2001-89" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Gagnier2001_89-0" >Jump up^{</a>&nbsp};Gagnier JJ (August 2001). "The therapeutic potential of melatonin in migraines and other headache types". Altern Med Rev 6 (4): 383–9.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11578254" >11578254</a>.</li>

<li id="cite_note-90" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-90" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.nimh.nih.gov/science-news/2006/properly-timed-light-melatonin-lift-winter-depression-by-syncing-rhythms.shtml" >"Properly Timed Light, Melatonin Lift Winter Depression By Syncing Rhythms"</a>. National Institute of Mental Health. 2006-05-01. Retrieved 2011-08-17.</li>

<li id="cite_note-pmid17872420-91" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid17872420_91-0" >Jump up^{</a>&nbsp};Bhattacharjee Y (September 2007). "Psychiatric research. Is internal timing key to mental health?". Science 317 (5844): 1488–90.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1126%2Fscience.317.5844.1488" >10.1126/science.317.5844.1488</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17872420" >17872420</a>.</li>

<li id="cite_note-pmid4003592-92" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid4003592_92-0" >Jump up^{</a>&nbsp};Lewy AJ, Nurnberger JI, Wehr TA, Pack D, Becker LE, Powell RL, Newsome DA (June 1985). "Supersensitivity to light: possible trait marker for manic-depressive illness". Am J Psychiatry 142 (6): 725–7. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/4003592" >4003592</a>.</li>

<li id="cite_note-pmid1658841-93" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid1658841_93-0" >Jump up^{</a>&nbsp};Whalley LJ, Perini T, Shering A, Bennie J (July 1991). "Melatonin response to bright light in recovered, drug-free, bipolar patients".Psychiatry Res 38 (1): 13–9. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2F0165-1781%2891%2990048-T" >10.1016/0165-1781(91)90048-T</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1658841" >1658841</a>.</li>

<li id="cite_note-pmid16207291-94" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16207291_94-0" >Jump up^{</a>&nbsp};Mills E, Wu P, Seely D, Guyatt G (November 2005). "Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis". J. Pineal Res. 39 (4): 360–6.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1600-079X.2005.00258.x" >10.1111/j.1600-079X.2005.00258.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16207291" >16207291</a>.</li>

<li id="cite_note-95" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-95" >Jump up^{</a>&nbsp};National Cancer Institute (May 2013). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0053600/" >"Topics in complementary and alternative therapies (PDQ)"</a>. National Cancer Institute, National Institutes of Health. Retrieved 5 June 2013.</li>

<li id="cite_note-pmid18338264-96" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid18338264_96-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid18338264_96-1" >b</a> Koppisetti S, Jenigiri B, Terron MP, Tengattini S, Tamura H, Flores LJ, Tan DX, Reiter RJ (October 2008). "Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review". Dig. Dis. Sci. 53(10): 2592–603. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs10620-007-0195-5" >10.1007/s10620-007-0195-5</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18338264" >18338264</a>.</li>

<li id="cite_note-pmid10622237-97" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid10622237_97-0" >Jump up^{</a>&nbsp};Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ (October 1999). "High physiological levels of melatonin in the bile of mammals". Life Sci. 65 (23): 2523–9. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2FS0024-3205%2899%2900519-6" >10.1016/S0024-3205(99)00519-6</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10622237" >10622237</a>.</li>

<li id="cite_note-pmid17014688-98" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid17014688_98-0" >Jump up^{</a>&nbsp};Weishaupt JH, Bartels C, Pölking E, Dietrich J, Rohde G, Poeggeler B, Mertens N, Sperling S, Bohn M, Hüther G, Schneider A, Bach A, Sirén AL, Hardeland R, Bähr M, Nave KA, Ehrenreich H (November 2006). "Reduced oxidative damage in ALS by high-dose enteral melatonin treatment". J. Pineal Res. 41 (4): 313–23.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1600-079X.2006.00377.x" >10.1111/j.1600-079X.2006.00377.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17014688" >17014688</a>.</li>

<li id="cite_note-Wolden-Hanson2000-99" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Wolden-Hanson2000_99-0" >Jump up^{</a> Wolden}-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen DD (February 2000). "Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat". Endocrinology 141(2): 487–97. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1210%2Fen.141.2.487" >10.1210/en.141.2.487</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10650927" >10650927</a>.</li>

<li id="cite_note-tan2010-100" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-tan2010_100-0" >Jump up^{</a>&nbsp};Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ (March 2011). "Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity". Obes Rev 12 (3): 167–88. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1467-789X.2010.00756.x" >10.1111/j.1467-789X.2010.00756.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20557470" >20557470</a>.</li>

<li id="cite_note-101" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-101" >Jump up^{</a>&nbsp};Nedergaard J, Bengtsson T, Cannon B (August 2007). "Unexpected evidence for active brown adipose tissue in adult humans". Am J Physiol Endocrinol Metab. 293 (2): E444–E452.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1152%2Fajpendo.00691.2006" >10.1152/ajpendo.00691.2006</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17473055" >17473055</a>.</li>

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<li id="cite_note-pmid11445596-126" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid11445596_126-0" >Jump up^{</a>&nbsp};Anisimov VN, Zavarzina NY, Zabezhinski MA, Popovich IG, Zimina OA, Shtylick AV, Arutjunyan AV, Oparina TI, Prokopenko VM, Mikhalski AI, Yashin AI (July 2001). "Melatonin increases both life span and tumor incidence in female CBA mice". J. Gerontol. A Biol. Sci. Med. Sci. 56 (7): B311–23. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fgerona%2F56.7.B311" >10.1093/gerona/56.7.B311</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11445596" >11445596</a>.</li>

<li id="cite_note-FDAwarning-127" >^ <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-FDAwarning_127-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-FDAwarning_127-1" >b</a> Rodriguez RR (January 13, 2010). <a rel="nofollow" class="external text" href="http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm201435.htm" >"Warning Letter"</a>.Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration.</li>

<li id="cite_note-pmid16596313-128" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16596313_128-0" >Jump up^{</a>&nbsp};Schernhammer E, Chen H, Ritz B. (May 2006). "Circulating melatonin levels: possible link between Parkinson's disease and cancer risk?". Cancer Causes Control. 17 (4): 577–582.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs10552-005-9002-9" >10.1007/s10552-005-9002-9</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16596313" >16596313</a>.</li>

<li id="cite_note-pmid22252727-129" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid22252727_129-0" >Jump up^{</a>&nbsp};Meng T, Zheng ZH, Liu TT, Lin L. (May 2012). "Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat". Neurochem Res. 37 (5): 1050–6.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs11064-012-0706-4" >10.1007/s11064-012-0706-4</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/22252727" >22252727</a>.</li>

<li id="cite_note-130" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-130" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.drugs.com/melatonin.html" >"Melatonin"</a>. <a href="http://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com" >Drugs.com</a>. Retrieved 2011-08-17.</li>

<li id="cite_note-131" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-131" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108938.htm" >"FDA Issues Dietary Supplements Final Rule"</a> (Press release). U.S. Food and Drug Administration. 2007-06-22. Retrieved 2009-08-04.</li>

<li id="cite_note-132" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-132" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.medicalnewstoday.com/articles/75250.php" >"FDA Tightens Up Dietary Supplement Manufacturing And Labelling"</a>. Medical News Today. 26 June 2007. Retrieved 2 September 2013.</li>

<li id="cite_note-NYTimes_May_2011-133" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-NYTimes_May_2011_133-0" >Jump up^{</a>&nbsp};Catherine Saint Louis (14 May 2011). <a rel="nofollow" class="external text" href="http://www.nytimes.com/2011/05/15/us/15lazycakes.html?_r=1&scp=1&sq=lazy%20cakes&st=cse" >"Dessert, Laid-Back and Legal"</a>. New York Times.</li>

<li id="cite_note-134" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-134" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.medicalnewstoday.com/articles/69195.php" >Medical News Today</a> Circadin (Prolonged-Release Melatonin) For Primary Insomnia Recommended For Approval In The EU (27 Apr 2007)</li>

<li id="cite_note-Filadelfi1996-135" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Filadelfi1996_135-0" >Jump up^{</a>&nbsp};Filadelfi AM, Castrucci AM (May 1996). "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates". J. Pineal Res. 20 (4): 175–86. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1600-079X.1996.tb00256.x" >10.1111/j.1600-079X.1996.tb00256.x</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/8836950" >8836950</a>.</li>

<li id="cite_note-Sugden2004-136" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Sugden2004_136-0" >Jump up^{</a>&nbsp};Sugden D, Davidson K, Hough KA, Teh MT (October 2004). "Melatonin, melatonin receptors and melanophores: a moving story".Pigment Cell Res. 17 (5): 454–60. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1600-0749.2004.00185.x" >10.1111/j.1600-0749.2004.00185.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15357831" >15357831</a>.</li>

<li id="cite_note-Coates-137" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-Coates_137-0" >Jump up^{</a>&nbsp};Coates PM, Blackman MR, Cragg GM, LevineM, Moss J, White JD (2005). <a rel="nofollow" class="external text" href="http://books.google.com/?id=Sfmc-fRCj10C&pg=PA457&lpg=PA457&dq=Lerner+melatonin+history" >Encyclopedia of dietary supplements</a>. New York, N.Y: Marcel Dekker. pp. 457–66. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/0-8247-5504-9" title="Special:BookSources/0-8247-5504-9" >0-8247-5504-9</a>.</li>

<li id="cite_note-McCord-138" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-McCord_138-0" >Jump up^{</a>&nbsp};McCord CP, Allen FP (January 1917). <a rel="nofollow" class="external text" href="http://books.google.com/?id=OOM1AQAAMAAJ&pg=PA207" >"Evidences associating pineal gland function with alterations in pigmentation"</a>. J Exptl Zool23 (1): 206–24. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1002%2Fjez.1400230108" >10.1002/jez.1400230108</a>.</li>

<li id="cite_note-pmid14415935-139" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid14415935_139-0" >Jump up^{</a>&nbsp};Lerner AB, Case JD, Takahashi Y (July 1960). "Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands". J. Biol. Chem. 235: 1992–7. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/14415935" >14415935</a>.</li>

<li id="cite_note-pmid1167425-140" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid1167425_140-0" >Jump up^{</a>&nbsp};Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH; Wurtman; Moskowitz; Archer; Ho (January 1975). "Daily rhythm in human urinary melatonin". Science 187 (4172): 169–71.<a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/1975Sci...187..169L" >1975Sci...187..169L</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1126%2Fscience.1167425" >10.1126/science.1167425</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1167425" >1167425</a>.</li>

<li id="cite_note-scavenger-141" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-scavenger_141-0" >Jump up^{</a>&nbsp};Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC (May 1993). "Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis". J. Pineal Res. 14 (4): 151–68.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1600-079X.1993.tb00498.x" >10.1111/j.1600-079X.1993.tb00498.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/8102180" >8102180</a>.</li>

<li id="cite_note-142" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-142" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US5449683" >US patent 5449683</a>, Wurtman RJ, "Methods of inducing sleep using melatonin", issued 1995-09-12, assigned to Massachusetts Institute of Technology</li>

<li id="cite_note-pmid16077149-143" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid16077149_143-0" >Jump up^{</a>&nbsp};Arendt J (August 2005). "Melatonin: characteristics, concerns, and prospects". J. Biol. Rhythms 20 (4): 291–303.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1177%2F0748730405277492" >10.1177/0748730405277492</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16077149" >16077149</a>. "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."</li>

<li id="cite_note-pmid11027748-144" ><a href="http://en.wikipedia.org/wiki/Melatonin#cite_ref-pmid11027748_144-0" >Jump up^{</a>&nbsp};Arendt J (October 2000). "Melatonin, circadian rhythms, and sleep".N. Engl. J. Med. 343 (15): 1114–6.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1056%2FNEJM200010123431510" >10.1056/NEJM200010123431510</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11027748" >11027748</a>.</li>

</ol>

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<h2 >Further reading[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=36" title="Edit section: Further reading" >edit</a>]</h2>

<ul >

<li >Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N (2010). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933606" >"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"</a>. BMC Med 8: 51. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1186%2F1741-7015-8-51" >10.1186/1741-7015-8-51</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933606" >2933606</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20712869" >20712869</a>.</li>

</ul>

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<h2 >External links[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=37" title="Edit section: External links" >edit</a>]</h2>

<ul >

<li ><a rel="nofollow" class="external text" href="http://gmd.mpimp-golm.mpg.de/Spectrums/5c07b02a-6ada-4428-9a58-a739a3177f45.aspx" >Melatonin MS Spectrum</a></li>

<li ><a rel="nofollow" class="external text" href="http://tihkal.info/read.php?domain=tk&id=35" >Melatonin entry in TiHKAL • info</a></li>

</ul>

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Melatonin

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