View source for Melatonin

{{Distinguish|melanin|Melanotan (disambiguation)|}}
{{drugbox
| verifiedrevid = 268373882
| IUPAC_name = ''N''-[2-(5-methoxy-1''H''-indol-3-yl)ethyl]<br/>ethanamide
| image = Melatonin2.svg
| image2 = Melatonin-3d-CPK.png
| CASNo_Ref = {{cascite}}
| CAS_number = 73-31-4
| ChemSpiderID = 872
| ATC_prefix = N05
| ATC_suffix = CH01
| ATC_supplemental =
| PubChem = 896
| IUPHAR_ligand = 1357
| IUPHAR_ligand = 224
| DrugBank = APRD00742
| SMILES = CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC
| C = 13 | H = 16 | N = 2 | O = 2
| molecular_weight = 232.278 g/mol
| bioavailability = 30 – 50%
| protein_bound =
| metabolism = [[Liver|Hepatic]] via [[CYP1A2]] mediated 6-hydroxylation
| elimination_half-life = 35 to 50 minutes
| pregnancy_category =
| legal_AU = S4
| legal_UK = POM
| legal_US = OTC
| routes_of_administration = In humans: orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.  In lab animals: also injection.
| excretion = [[Urine]]
}}

'''Melatonin''' ({{pron-en|ˌmɛləˈtoʊnɪn|melatonin-pronunciation.ogg}}), also known chemically as '''''N''-acetyl-5-methoxytryptamine''',<ref>http://www.sleepdex.org/melatonin.htm</ref> is a naturally occurring compound found in animals, plants, and microbes.<ref name="Caniato2003">{{cite journal |author=Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti EM |title=Melatonin in plants |journal=Advances in Experimental Medicine and Biology |volume=527 |issue= |pages=593–7 |year=2003 |pmid=15206778}}</ref><ref name="Paredes2009">{{cite journal |author=Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ |title=Phytomelatonin: a review |journal=Journal of Experimental Botany |volume=60 |issue=1 |pages=57–69 |year=2009 |pmid=19033551 |doi=10.1093/jxb/ern284}}</ref> In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the [[entrainment]] of the [[circadian rhythm]]s of several biological functions.<ref name="Altun2007">{{cite journal |author=Altun A, Ugur-Altun B |title=Melatonin: therapeutic and clinical utilization |journal=Int. J. Clin. Pract. |volume=61 |issue=5 |pages=835–45 |year=2007 |pmid=17298593 |doi=10.1111/j.1742-1241.2006.01191.x}}</ref>

Many biological effects of melatonin are produced through activation of [[melatonin receptor]]s,<ref name="Boutin2005">{{cite journal |author=Boutin JA, Audinot V, Ferry G, Delagrange P |title=Molecular tools to study melatonin pathways and actions |journal=Trends in Pharmacological Sciences |volume=26 |issue=8 |pages=412–9 |year=2005 |month=August |pmid=15992934 |doi=10.1016/j.tips.2005.06.006}}</ref> while others are due to its role as a pervasive and powerful [[antioxidant]],<ref name="Hardeland2005">{{cite journal |author=Hardeland R |title=Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance |journal=Endocrine |volume=27 |issue=2 |pages=119–30 |year=2005 |month=July |pmid=16217125 |doi=10.1385/ENDO:27:2:119}}</ref> with a particular role in the protection of [[nuclear DNA|nuclear]] and [[mitochondrial DNA]].<ref name="Reiter2001">{{cite journal |doi=10.1111/j.1749-6632.2001.tb03627.x |author=Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S |title=Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system |journal=Annals of the New York Academy of Sciences |volume=939 |issue= |pages=200–15 |year=2001 |month=June |pmid=11462772}}</ref>

In mammals, melatonin is secreted into the blood by the [[pineal gland]] in the brain.  Known as the "hormone of darkness", it is secreted in darkness in both day-active ([[Diurnality|diurnal]]) and night-active ([[Nocturnality|nocturnal]]) animals.<ref name="Challet2007" /> 

It may also be produced by a variety of peripheral cells such as [[Bone marrow|bone marrow cells]],<ref>{{cite journal |author=Maestroni GJ |title=The immunotherapeutic potential of melatonin |journal=Expert Opin Investig Drugs |volume=10 |issue=3 |pages=467–76 |year=2001 |month=March |pmid=11227046 |doi=10.1517/13543784.10.3.467 |url=}}</ref><ref>{{cite journal |author=Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM |title=Evidence for melatonin synthesis in mouse and human bone marrow cells |journal=J. Pineal Res. |volume=28 |issue=4 |pages=193–202 |year=2000 |month=May |pmid=10831154 |doi=10.1111/j.1600-079X.2000.280401.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0742-3098&date=2000&volume=28&issue=4&spage=193 |doi_brokendate=2009-03-03}}</ref> lymphocytes and [[Epithelium|epithelial cells]]. 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.

Melatonin-rich plant feed, such as rice, ingested by chicks has been shown to reach and bind to melatonin receptors in their brains.<ref name="Hattori1995">{{cite journal |author=Hattori A, Migitaka H, Iigo M, ''et al.'' |title=Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates |journal=Biochemistry and Molecular Biology International |volume=35 |issue=3 |pages=627–34 |year=1995 |month=March |pmid=7773197}}</ref>  No food has been found to elevate plasma melatonin levels in humans.<ref name="Coates">{{cite book |last= Coates |first= Paul M. |others= Marc R. Blackman, Gordon M. Cragg, Mark Levine, Joel Moss, Jeffrey D. White  |title= Encyclopedia of Dietary Supplements |url= http://books.google.com/?id=Sfmc-fRCj10C&pg=PA457&lpg=PA457&dq=Lerner+melatonin+history |format= |accessdate= 2009-03-31 |edition= |series= |date= |year= 2005  |publisher= CRC Press |location= |isbn= 0824755049 |pages= 457–466 |chapter= |chapterurl= |quote= }}</ref>

Products containing melatonin have been available [[Over-the-counter drug|over-the-counter]] as a [[dietary supplement]] in the United States since before 1994.<ref>{{cite web | url = http://www.vanderbilt.edu/AnS/psychology/health_psychology/melatonin.htm | title = Melatonin: The Myths and Facts | first = Courtney | last = Ratzburg | year = Undated | publisher = Vanderbilt University | accessdate = 2007-12-02 }}</ref>  In many other countries, sale of the hormone remains illegal or requires a prescription, and the [[U.S. Postal Service]] lists melatonin among items prohibited by Germany.<ref>{{cite web |url= http://pe.usps.gov/text/imm/fh_011.htm |title= Country Conditions for Mailing — Germany |accessdate=2008-01-15 |author= USPS |last= |first= |authorlink= |coauthors= |date= |year= |month= |work= |publisher= |pages= |language= |doi= |archiveurl= |archivedate= |quote= }}</ref>

== History ==
Melatonin is related to the mechanism by which some [[amphibians]] and [[reptiles]] change the color of their skin and, indeed, it was in this connection the substance first was discovered.<ref name="Filadelfi1996">{{cite journal |author=Filadelfi AM, Castrucci AM |title=Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates |journal=Journal of Pineal Research |volume=20 |issue=4 |pages=175–86 |year=1996 |month=May |pmid=8836950 |doi=10.1111/j.1600-079X.1996.tb00256.x}}</ref><ref name="Sugden2004">{{cite journal |author=Sugden D, Davidson K, Hough KA, Teh MT |title=Melatonin, melatonin receptors and melanophores: a moving story |journal=Pigment Cell Research |volume=17 |issue=5 |pages=454–60 |year=2004 |month=October |pmid=15357831 |doi=10.1111/j.1600-0749.2004.00185.x}}</ref>   As early as 1917, McCord and Allen discovered (J Exptl Zool, 1917) that extract of the pineal glands of cows lightened frog skin.<ref name="Coates"/>  Dermatology professor [[Aaron B. Lerner]] and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated and named the hormone ''melatonin'' in 1958.<ref>{{cite journal | author =  Lerner AB, Case JD, Takahashi Y | title = Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands | journal = J Biol Chem | volume = 235 | pages = 1992–7 | year = 1960 | pmid = 14415935}}</ref>  In the mid-70s Lynch ''et al.'' demonstrated<ref>{{cite journal |author=Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH |title=Daily rhythm in human urinary melatonin |journal=Science |volume=187 |issue=4172 |pages=169–71 |year=1975 |month=January |pmid=1167425 |doi=10.1126/science.1167425}}</ref> that the production of melatonin exhibits a [[circadian rhythm]] in human pineal glands.  The discovery that melatonin is an antioxidant was made in 1993.<ref name="Tan">{{cite journal | authors = Tan DX, Chen LD, Poggeler B, Manchester LC, Reiter RJ | date = | year = 1993 | month = | title = Melatonin: a potent, endogenous hydroxyl radical scavenger | journal = Endocr J | volume = | issue = 1 | pages = 57–60 | publisher = | issn = | pmid = | doi = | url = | format = | accessdate = | quote =  }}</ref>

== In plants ==
Melatonin in plants has multiple roles including regulation of the [[photoperiod]], in plant defense responses, and as a scavenger of [[reactive oxygen species]].<ref name="Paredes2009"/>

== In animals ==
Many animals use the variation in duration of melatonin production each day as a seasonal clock.<ref name="Lincoln2003">{{cite journal |author=Lincoln GA, Andersson H, Loudon A |title=Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis |journal=The Journal of Endocrinology |volume=179 |issue=1 |pages=1–13 |year=2003 |month=October |pmid=14529560 |doi=10.1677/joe.0.1790001}}</ref> In animals including humans<ref name="Arendt2005">{{cite journal |author=Arendt J, Skene DJ |title=Melatonin as a chronobiotic |journal=Sleep Med Rev |volume=9 |issue=1 |pages=25–39 |year=2005 |pmid=15649736 |doi= 10.1016/j.smrv.2004.05.002 |quote=Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times. }}</ref> the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organisation of daylength-dependent ([[Photoperiodism|photoperiodic]]) seasonal functions such as reproduction, behaviour, coat growth and camouflage [[Animal colouration|colouring]] in seasonal animals.<ref name="Arendt2005"/> In seasonal breeders which do not have long gestation periods and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds<ref name="Chaturvedi">{{cite journal
 | author = CM Chaturvedi
 | title = Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis
 | journal = Australian Journal of Zoology
 | volume = 32
 | issue = 6
 | pages = 803–809
 | doi =10.1071/ZO9840803
 | url = http://www.publish.csiro.au/paper/ZO9840803.htm
 | year = 1984
}}</ref> and hamsters.<ref name="Chen1981">{{cite journal
| author = Chen H
| title = Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition
| journal = Neuroendocrinology
| volume = 33
| issue = 1
| pages = 43–6
| year = 1981
| pmid = 7254478
| doi = 10.1159/000123198
}}</ref>

== In mammals ==
Melatonin produced in the [[pineal gland]], which is outside of the blood-brain barrier, acts as an [[endocrine]] hormone since it is released into the [[blood]].
By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a [[paracrine]] hormone.{{Citation needed|date=May 2010}}

Melatonin can suppress [[libido]] by inhibiting secretion of [[luteinizing hormone]] (LH) and [[follicle stimulating hormone]] (FSH) from the [[anterior pituitary]] gland, especially in mammals that have a [[Reproduction|breeding]] season when daylight hours are long. The reproduction of [[Estrous cycle#Frequency|long-day breeders]] is [[Estrous cycle#Anestrus|repressed by melatonin]] and the reproduction of [[Estrous cycle#Frequency|short-day breeders]] is stimulated by melatonin.  During the night, melatonin regulates leptin, lowering the levels; see [[leptin]].

Light/dark information reaches the [[suprachiasmatic nucleus|suprachiasmatic nuclei]] (SCN) via retinal [[photosensitive ganglion cell]]s, intrinsically photosensitive [[photoreceptor cell]]s, distinct from those involved in image forming (that is, these light sensitive cells are a third type in the retina, in addition to [[rod cell|rods]] and [[cone cell|cones]]). These cells represent approximately 2% of the retinal ganglion cells in humans and express the photopigment [[melanopsin]].<ref>{{cite journal |author=Nayak SK, Jegla T, Panda S |title=Role of a novel photopigment, melanopsin, in behavioral adaptation to light |journal=Cell. Mol. Life Sci. |volume=64 |issue=2 |pages=144–54 |year=2007 |month=January |pmid=17160354 |doi=10.1007/s00018-006-5581-1 |url=}}</ref> The sensitivity of melanopsin is consistent with that of a [[vitamin A]]-based photopigment with a peak sensitivity at 484&nbsp;nm (blue light).<ref>{{cite journal |author=Roberts JE |title=Update on the positive effects of light in humans |journal=Photochem. Photobiol. |volume=81 |issue=3 |pages=490–2 |year=2005 |pmid=15656701 |doi=10.1562/2004-12-02-IR-391 |url=}}</ref> This photoperiod cue entrains the [[circadian rhythm]], and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals which regulate behavioral and physiological circadian rhythms.  Melatonin is secreted in darkness in both day-active ([[Diurnality|diurnal]]) and night-active ([[Nocturnality|nocturnal]]) animals.<ref name="Challet2007">{{cite journal |author=Challet E |title=Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals |journal=Endocrinology |volume=148 |issue=12 |pages=5648–55 |year=2007 |month=December |pmid=17901231 |doi=10.1210/en.2007-0804}}</ref>

==In humans==
===Circadian rhythm===
In humans, melatonin is produced by the [[pineal gland]], a gland about the size of a [[pea]], located in the center of the brain but outside the [[blood-brain barrier]]. The melatonin signal forms part of the system that regulates the [[Circadian rhythm|sleep-wake cycle]] by chemically causing drowsiness and lowering the body temperature, but it is the [[central nervous system]] (more specifically, the SCN) that controls the daily cycle in most components of the [[paracrine]] and [[endocrine]] systems<ref name="Richardson2005">{{cite journal
| author = Richardson G
| title = The human circadian system in normal and disordered sleep
| journal = J Clin Psychiatry
| volume = 66 Suppl 9
| pages = 3 – 9; quiz 42–3
| year = 2005
| pmid = 16336035
}}</ref><ref name="Perreau-Lenz2004">{{cite journal
| author = Perreau-Lenz S, Pévet P, Buijs R, Kalsbeek A
| title = The biological clock: the bodyguard of temporal homeostasis
| journal = Chronobiol Int
| volume = 21
| issue = 1
| pages = 1–25
| year = 2004
| pmid = 15129821
| doi = 10.1081/CBI-120027984
}}</ref> rather than the melatonin signal (as was once postulated).

Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 08:00 (8 AM).<ref>{{cite journal | last = Ardura | first = Julio | date = | year = 2002 | month = | title = Emergence and Evolution of the Circadian Rhythm of Melatonin in Children | journal = Hormone Research | volume = 59 | issue = 2 | pages = 66–72 | publisher = S. Karger AG, Basel | issn = | pmid = 12589109| doi = 68571 | id = | url = http://content.karger.com/ProdukteDB/produkte.asp?Doi=68571 | format = Free abstract | accessdate = 2009-11-08 | quote = | last2 = Gutierrez | first2 = R | last3 = Andres | first3 = J | last4 = Agapito | first4 = T | doi_brokendate = 2009-11-14  }}</ref>

In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine,<ref name=USAHRQ /> and a small amount is found in saliva.

====Light dependence====
Production of melatonin by the pineal gland is inhibited by [[light]] and permitted by [[darkness]]. For this reason melatonin has been called "the hormone of darkness".  Its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual's [[chronotype]].

It is principally blue light, around 480[[Nanometre|nm]], that suppresses melatonin,<ref name="Brainard 2001">{{cite journal | author =Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag | title = Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor | journal = J Neurosci. | volume =15;21
 | issue =16 | pages =6405–12 |date=August 15, 2001 | pmid = 11487664
 }}</ref> increasingly with increased light intensity and length of exposure.  Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. Wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. Kayumov ''et al.'' showed that light containing only wavelengths greater than 530&nbsp;nm does not suppress melatonin in bright-light conditions.<ref name="Kayumov 2005">{{cite journal | author =Kayumov L, Casper RF, Hawa RJ, Perelman B Chung SA, Sokalsky S, Shipiro | title = Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work | journal = J Clin Endocrinol Metab. | volume =90 | issue =5 | pages =2755–61 | month=May | year=2005 | pmid = 15713707 | doi =10.1210/jc.2004-2062 }}</ref>  Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.

===Antioxidant===
Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993.<ref name="Tan" /> In many less complex life forms, this is its only known purpose.<ref name="Tan_Manchester">{{cite journal | author = Dun-Xian Tan, Lucien C. Manchester, Maria P. Terron, Luis J. Flores, Russel J. Reiter | title = One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?| journal = Journal of Pineal Research| volume = 42 | issue = 1 | pages = 28–42 | year = 2007 | pmid = 17198536 | doi = 10.1111/j.1600-079X.2006.00407.x }}</ref> Melatonin is an [[antioxidant]] that can easily cross [[cell membrane]]s and the blood-brain barrier.<ref name="Hardeland2005"/> Melatonin is a direct scavenger of OH, O<sub>2</sub><sup>−</sup>, and NO.<ref>{{cite journal |author=Poeggeler B, Saarela S, Reiter RJ |title=Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro |journal=Ann. N. Y. Acad. Sci. |volume=738 |issue= |pages=419–20 |year=1994 |pmid=7832450 |doi=10.1111/j.1749-6632.1994.tb21831.x}}</ref> Unlike other antioxidants, melatonin does not undergo [[redox cycling]], the ability of a [[molecule]] to undergo [[reduction (chemistry)|reduction]] and [[oxidation]] repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.<ref name="Tan2000">{{cite journal
| author = Tan DX, Manchester LC, Reiter RJ, Qi W, Karbownik M, Calvo JR
| title = Significance of melatonin in anti oxidative defense system: reactions and products
| journal = Biol Signals Recept
| volume = 9 | issue = 3–4 | pages = 137–59 | year = 2000
| pmid = 10899700
| doi = 10.1159/000014635
}}</ref>

Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (or AFMK) rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and [[metazoans]]. A single AFMK molecule can neutralize up to 10 [[ROS/RNS]] (reactive oxygen species/reactive nitrogen species) since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.<ref name="Tan_Manchester"/>

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some [[carcinogens]], stopping the mechanism by which they cause cancer.<ref name="Karbownik2001">{{cite journal
| author = Karbownik M, Reiter R, Cabrera J, Garcia J
| title = Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage
| journal = Mutat Res
| volume = 474
| issue = 1–2
| pages = 87–92
| year = 2001
| pmid = 11239965
}}</ref>
It also has been found to be effective in protecting against brain injury caused by [[Reactive oxygen species|ROS]] release in experimental hypoxic brain damage in newborn rats.<ref>{{cite journal |author=Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U |title=The protective role of melatonin in experimental hypoxic brain damage |journal=Pediatr Int |volume=47 |issue=4 |pages=434–9 |year=2005 |pmid=16091083 |doi=10.1111/j.1442-200x.2005.02085.x}}</ref> Melatonin's antioxidant activity may reduce damage caused by some types of [[Parkinson's disease]], may play a role in preventing cardiac [[arrhythmia]] and may increase [[longevity]]; it has been shown to increase the [[average life span]] of [[mouse|mice]] by 20% in some studies.<ref name="Dean1993">{{cite book
| author = Ward Dean, John Morgenthaler, Steven William Fowkes
| title = Smart Drugs II: The Next Generation : New Drugs and Nutrients to Improve Your Memory and Increase Your Intelligence (Smart Drug Series, V. 2)
| publisher = Smart Publications
| year = 1993
| isbn = 0-9627418-7-6
}}</ref><ref name="Anisimov2003">{{cite journal
| author = Anisimov V, Alimova I, Baturin D, Popovich I, Zabezhinski M, Rosenfeld S, Manton K, Semenchenko A, Yashin A
| title = Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice
| journal = Exp Gerontol
| volume = 38
| issue = 4
| pages = 449–61
| year = 2003
| pmid = 12670632
| doi = 10.1016/S0531-5565(02)00240-1
}}</ref><ref name="Oaknin-Bendahan1995">{{cite journal
| author = Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N
| title = Effects of long-term administration of melatonin and a putative antagonist on the ageing rat
| journal = Neuroreport
| volume = 6
| issue = 5
| pages = 785–8
| year = 1995
| pmid = 7605949
| doi = 10.1097/00001756-199503270-00020
}}</ref>

===Immune system===
While it is known that melatonin interacts with the [[immune system]],<ref name="Carrillo-Vico2005">{{cite journal
| author = Carrillo-Vico A, Guerrero J, Lardone P, Reiter R
| title = A review of the multiple actions of melatonin on the immune system
| journal = Endocrine
| volume = 27
| issue = 2
| pages = 189–200
| year = 2005
| pmid = 16217132
| doi = 10.1385/ENDO:27:2:189
}}</ref><ref name="Arushanian2002">{{cite journal
| author = Arushanian E, Beier E
| title = Immunotropic properties of pineal melatonin
| journal = Eksp Klin Farmakol
| volume = 65
| issue = 5
| pages = 73–80
| year = 2002
| pmid = 12596522 }}</ref> the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to result from melatonin acting on high affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance [[cytokine]] production,<ref>{{cite journal |author=Carrillo-Vico A, Reiter RJ, Lardone PJ |title=The modulatory role of melatonin on immune responsiveness |journal=Curr Opin Investig Drugs |volume=7 |issue=5 |pages=423–31 |year=2006 |pmid=16729718 |doi=}}</ref> and by doing this counteract [[acquired immunodeficiences]].  Some studies also suggest that melatonin might be useful fighting infectious disease<ref>{{cite journal |author=Maestroni GJ |title=The immunotherapeutic potential of melatonin |journal=Expert Opin Investig Drugs |volume=10 |issue=3 |pages=467–76 |year=2001 |pmid=11227046 |doi=10.1517/13543784.10.3.467}}</ref> including viral, such as [[HIV]], and bacterial infections, and potentially in the treatment of [[cancer]].<ref name="Maestroni1999">{{cite journal
| author = Maestroni G
| title = Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer
| journal = Adv Exp Med Biol
| volume = 467
| pages = 217–26
| year = 1999
| pmid = 10721059 }}</ref>

Endogenous melatonin in human [[lymphocyte]]s has been related to [[Interleukin 2|interleukin-2]] (IL-2) production and to the expression of IL-2 receptor.<ref>{{cite journal |author=Carrillo-Vico A, Lardone PJ, Fernández-Santos JM |title=Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=2 |pages=992–1000 |year=2005 |pmid=15562014 |doi=10.1210/jc.2004-1429}}</ref> This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human [[T cell|T lymphocytes]]. When taken in conjunction with [[calcium]], it is an [[immunostimulator]]{{Citation needed|date=November 2007}} and is used as an [[adjuvant]] in some [[clinical protocol]]s{{Citation needed|date=November 2007}}; conversely, the increased immune system activity may aggravate [[autoimmune disorder]]s. In [[rheumatoid arthritis]] patients, melatonin production has been found increased when compared to age-matched healthy controls.<ref>{{cite journal |author=Cutolo M, Maestroni GJ |title=The melatonin-cytokine connection in rheumatoid arthritis |journal=Ann. Rheum. Dis. |volume=64 |issue=8 |pages=1109–11 |year=2005 |pmid=16014678 |doi=10.1136/ard.2005.038588 |pmc=1755599}}</ref>

===Dreaming===
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50&nbsp;mg) dramatically increased [[REM sleep]] time and dream activity in both people with and without [[narcolepsy]].<ref name=Lewis/> Many [[psychoactive drug]]s, such as [[cannabis]] and [[Lysergic acid diethylamide|lysergic acid diethylamide (LSD)]], increase melatonin synthesis.<ref name=Lewis>{{cite book | title = Melatonin and the Biological Clock | last = Lewis | first = Alan | publisher = McGraw-Hill | isbn = 0879837349 | year = 1999 | pages = 23}}</ref> It has been suggested that nonpolar ([[lipid]]-soluble) [[indolic]] [[Psychedelics, dissociatives and deliriants|hallucinogenic drugs]] emulate melatonin activity in the awakened state and that both act on the same areas of the brain.<ref name=Lewis/>

===Autism===
Individuals with [[autism spectrum disorder]]s (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the [[Acetylserotonin O-methyltransferase|ASMT]] gene, which encodes the last enzyme of melatonin synthesis.<ref name=Melke>{{cite journal |title= Abnormal melatonin synthesis in autism spectrum disorders |author= Melke J, Botros HG, Chaste P |journal= Mol Psychiatry |volume=13 |issue=1 |year=2008 |pages=90–8 |doi=10.1038/sj.mp.4002016 |pmid=17505466 |last12= Mouren-Simeoni |first12= MC |last13= Fauchereau |first13= F |last14= Durand |first14= CM |last15= Chevalier |first15= F |last16= Drouot |first16= X |last17= Collet |first17= C |last18= Launay |first18= JM |last19= Leboyer |first19= M |last20= Gillberg |first20= C |last21= Bourgeron |first21= T |pmc= 2199264}}</ref>

==Current and potential medical indications==
Melatonin has been studied for the treatment of [[cancer]], [[Immune System#Disorders of the human immune system|immune disorders]], [[cardiovascular disease]]s, [[clinical depression|depression]], [[seasonal affective disorder]] (SAD), [[circadian rhythm sleep disorder]]s and [[sexual dysfunction]]. Studies by [[Alfred J. Lewy]] at [[Oregon Health & Science University]] and other researchers have found that it may ameliorate circadian misalignment and SAD.<ref name="Lewy1987">{{cite journal | author = Lewy A, Sack R, Miller L, Hoban T
| title = Antidepressant and circadian phase-shifting effects of light | journal = Science | volume = 235 | issue = 4786 | pages = 352–4 | year = 1987 | pmid = 3798117
 | doi = 10.1126/science.3798117
}}</ref> Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as [[cocaine]].<ref name="Uz2003">{{cite journal
| author = Uz T, Akhisaroglu M, Ahmed R, Manev H
| title = The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice
| journal = Neuropsychopharmacology
| volume = 28
| issue = 12
| pages = 2117–23
| year = 2003
| pmid = 12865893
| doi = 10.1038/sj.npp.1300254
}}</ref>

====Treatment of circadian rhythm disorders====
Exogenous melatonin taken in the evening is, together with [[light therapy]] upon awakening, the standard treatment for [[delayed sleep phase syndrome]] (DSPS) and [[non-24-hour sleep-wake syndrome]].  It appears to have some use against other circadian rhythm sleep disorders as well, such as [[jet lag]] and the problems of people who work rotating or night [[shift work|shifts]].  Melatonin reduces [[sleep onset latency]] to a greater extent in people with DSPS than in people with insomnia.<ref name=USAHRQ>{{cite web |url= http://www.ahrq.gov/clinic/epcsums/melatsum.htm |title= Melatonin for Treatment of Sleep Disorders. Summary, Evidence Report/Technology Assessment: Number 108 |accessdate= 2010-05-25 |author= Buscemi, N. ''et al.'' |year= 2004 |format= Review |work= |publisher= U.S. Department of Health & Human Services, Agency for Healthcare Research and Quality |doi=  |quote= }}</ref>

Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic.  It causes melatonin levels in the blood to rise earlier than the brain's own production accomplishes. This usage is now commonly used in sleep and relaxation drinks, such as [[Dream Water]].<ref>{{cite news| url=http://www.nydailynews.com/lifestyle/2010/02/07/2010-02-07_these_drinksll_knock_you_out_dozeinducing_concoctions_include_dose_of_hormones.html | location=New York | work=Daily News | title=New melatonin-based drinks help restless sleepers hit the hay with just a gulp - but pack hormones | first=Simone | last=Weichselbaum | date=2010-02-07}}</ref>

A very small dose taken several hours before bedtime in accordance with the [[Phase_response_curve#Melatonin_PRC|phase response curve]] for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a ''chronobiotic'' (affecting aspects of biological time structure),<ref>[http://books.google.co.uk/books?id=e-bZhuzXbK4C&pg=PA433&lpg=PA433&dq=chronobiotic+definition&source=bl&ots=boAbbe_1-r&sig=H0ICqtUEACE9FK6d6dwiAIHF-Mw&hl=en&ei=bkO6SpuEJ5PajQfmo_n3BQ&sa=X&oi=book_result&ct=result&resnum=7#v=onepage&q=chronobiotic%20definition&f=false  ''Chronobiotics: Selected Agents of Potential Value in Jet Lag and other Dyschronisms'', H. W. Simpson, of Glasgow University, in ''Chronobiology: Principles and Application to Shifts in Schedules'', ed: L.E. Sheving and F. Hagberg, Springer, Berlin, 1979]. Retrieved September 23, 2009.</ref> advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and a small oral dose melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.<ref>{{cite journal |author=Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC |title=Phase-dependent treatment of delayed sleep phase syndrome with melatonin |journal=Sleep |volume=28 |issue=10 |pages=1271–8 |year=2005 |month=October |pmid=16295212}}</ref>

====Preventing ischemic damage====
Melatonin has been shown to reduce tissue damage in rats due to [[ischemia]] in both the brain<ref>Lee MY, Kuan YH, Chen HY, Chen TY, Chen ST, Huang CC, Yang IP, Hsu YS, Wu TS, Lee EJ. Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal [[cerebral ischemia]] in rats. J Pineal Res. 2007 Apr;42(3):297 – 309. PMID 17349029</ref> and the heart;<ref>Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC, Reiter RJ, Jimenez-Sosa A. A unicenter, randomized, [[double-blind]], parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with [[Myocardial infarction|acute myocardial infarction]] undergoing primary Angioplasty The Melatonin Adjunct in the acute myocardial infarction treated with Angioplasty (MARIA) trial: Study design and rationale. Contemp Clin Trials. 2006 Oct 17. PMID 17123867.</ref> however, this has not been tested in humans.

====Learning, memory and Alzheimer's====
Melatonin receptors appear to be important in mechanisms of learning and memory in mice,<ref name="Larson2006">{{cite journal
| author = Larson J, Jessen R, Uz T, Arslan A, Kurtuncu M, Imbesi M, Manev H
| title = Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice
| journal = Neurosci Lett
| volume = 393
| issue = 1
| pages = 23–6
| year = 2006
| pmid = 16203090
| doi = 10.1016/j.neulet.2005.09.040
}}</ref> and melatonin can alter electrophysiological processes associated with memory, such as [[long-term potentiation]] (LTP). The first published evidence that melatonin may be useful in [[Alzheimer's disease]] was the demonstration that this neurohormone prevents neuronal death caused by exposure to the [[amyloid beta]] protein, a neurotoxic substance that accumulates in the brains of patients with the disorder.<ref name="Pappolla1997">{{cite journal | author = Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK.| title = Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide | journal = J Neurosci| volume = 17 | issue = 5 | pages = 1683–1690 | year = 1997 | pmid = 9030627 }}</ref> Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates which seem to underlie the neurotoxicity of this protein, causing death of neurons and formation of [[neurofibrillary tangle]]s, the other neuropathological landmark of Alzheimer's disease.<ref name="Pappolla1997">{{cite journal | author = Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J.| title = Inhibition of Alzheimer beta-fibrillogenesis by melatonin.| journal = J Biol Chem. 1998.Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Neurosci| volume = 273 | issue = 13 | pages = 7185–7188 | year = 1998 | pmid = 9516407 }}</ref>

Melatonin has been shown to prevent the [[hyperphosphorylation]] of the [[tau protein]] in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease.<ref name="Wang2005">{{cite journal | author = Wang X, Zhang J, Yu X, Han L, Zhou Z, Zhang Y, Wang J | title = Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat | journal = Sheng Li Xue Bao | volume = 57 | issue = 1 | pages = 7–12 | year = 2005 | pmid = 15719129 }}</ref> These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called ''sundowning'', which has been shown in many studies to be effectively treated with melatonin supplements in the evening.<ref name="Volicer2001">{{cite journal | author = Volicer L, Harper D, Manning B, Goldstein R, Satlin A | title = Sundowning and circadian rhythms in Alzheimer's disease | journal = Am J Psychiatry | volume = 158 | issue = 5 | pages = 704–11 | year = 2001 | pmid = 11329390 | doi = 10.1176/appi.ajp.158.5.704 }}</ref>

====ADHD====
Research shows that after melatonin is administered to [[Attention-deficit hyperactivity disorder|ADHD]] patients on [[methylphenidate]], the time needed to fall asleep is significantly reduced. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.<ref name="Gi2003">{{cite journal
| author = Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG
| title = Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study
| journal = Eur J Pediatr. | volume = 162 | issue = 7 | pages = 554–555 | year = 2003 | pmid = 12783318
| doi = 10.1007/s00431-003-1207-x
}}</ref>

====Fertility====
A research team in [[Italy]] has found that melatonin supplementation in the evening in [[perimenopausal]] women produces an improvement in thyroid function and [[gonadotropin]] levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.<ref name="Bellipanni2005">{{cite journal
| author = Bellipanni G, DI Marzo F, Blasi F, Di Marzo A
| title = Effects of melatonin in perimenopausal and menopausal women: our personal experience
| journal = Ann N Y Acad Sci
| volume = 1057
| issue = Dec
| pages = 393–402
| year = 2005
| pmid = 16399909
| doi = 10.1196/annals.1356.030
}}</ref> However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement.<ref name="About.com">{{cite journal
| title = Melatonin
| journal = About.com: Sleep Disorders
| pages = 4
| link = http://sleepdisorders.about.com/cs/melatonin/a/melatonin_4.htm
}}</ref> One study reported that three mg of melatonin taken in the evening raised [[prolactin]] levels in six out of seven women.<ref>Terzolo M, et al., 1993."Evening administration of melatonin enhances the pulsatile secretion of [[prolactin]] but not of LH and TSH in normally cycling women."  ''Clinical Endocrinology'', 39(2):185–191.</ref>  Melatonin also lowers [[Follicle-stimulating hormone|FSH]] levels.  It is believed that these hormonal changes could in some women impair fertility.[http://www.wddty.com/the-infertility-drug.html]

====Toxicology====
Melatonin has a very low toxicity in rats. Rat maternal toxicity: the no observable adverse effect level ([[NOAEL]]) and lowest observed adverse effect level ([[LOAEL]]) were 100 and 200&nbsp;mg/kg/day, respectively, and the developmental toxicity NOAEL was >= 200&nbsp;mg/kg/day.<ref>Jahnke G, Marr M, Myers C, Wilson R, Travlos G and Price C, 1999. "Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats." ''Toxicological Sciences'',50(2):271-9. PMID: 10478864.</ref>

====Headaches====
Several clinical studies indicate that supplementation with melatonin is an effective [[Preventive medicine|preventive treatment]] for [[migraines]] and [[cluster headache]]s.<ref name="Dodick2001">{{cite journal
| author = Dodick D, Capobianco D
| title = Treatment and management of cluster headache
| journal = Curr Pain Headache Rep
| volume = 5
| issue = 1
| pages = 83–91
| year = 2001
| pmid = 11252143
| doi = 10.1007/s11916-001-0015-0
}}</ref><ref name="Gagnier2001">{{cite journal
| author = Gagnier J
| title = The therapeutic potential of melatonin in migraines and other headache types
| journal = Altern Med Rev
| volume = 6
| issue = 4
| pages = 383–9
| year = 2001
| pmid = 11578254
}}</ref>

====Mood disorders====
Melatonin has been shown to be effective in treating one form of depression, [[seasonal affective disorder]],<ref>http://www.nimh.nih.gov/press/sad-melatonin.cfm</ref> and is being considered for [[Bipolar disorder|bipolar]] and other disorders where circadian disturbances are involved.<ref>{{cite journal
 | last = Bhattacharjee | first = Yudhijit
 | date = 14 September 2007
 | title = Is Internal Timing Key to Mental Health?
 | journal = ScienceMag | volume = 317 | pages = 1488–90
 | publisher = AAAS | location = | issn = | doi = | bibcode = | oclc = | id = | url = http://www.ohsu.edu/ohsuedu/academic/som/images/Al-Lewy-Science.pdf
 | format = PDF | accessdate = 2008-02-18
 | quote = }}</ref> It has been observed that [[bipolar disorder]] might have, as a "trait marker" (something which is characteristic of being bipolar, that does not change with state), supersensitivity to light, i.e. a greater decrease in melatonin secretion in response to light exposure at night.<ref name="pmid4003592">{{cite journal |author=Lewy AJ, Nurnberger JI, Wehr TA |title=Supersensitivity to light: possible trait marker for manic-depressive illness |journal=Am J Psychiatry |volume=142 |issue=6 |pages=725–7 |year=1985 |month=June |pmid=4003592 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=4003592}}</ref> This could be contrasted with drug-free recovered bipolar people not showing light hypersensitivity.<ref name="pmid1658841">{{cite journal |author=Whalley LJ, Perini T, Shering A, Bennie J |title=Melatonin response to bright light in recovered, drug-free, bipolar patients |journal=Psychiatry Res |volume=38 |issue=1 |pages=13–9 |year=1991 |month=July |pmid=1658841 |doi= 10.1016/0165-1781(91)90048-T|url=}}</ref>

====Cancer====
A [[systematic review]] of unblinded [[clinical trial]]s involving a total of 643 cancer patients using melatonin found a reduced incidence of death.<ref>{{cite journal | last = Mills E, Wu P, Seely D,4; Guyatt G | year = 2005 | title = Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis | journal = Journal of pineal research | volume = 39 | issue = 4 | pages = 360 | doi = 10.1111/j.1600-079X.2005.00258.x | url = http://pt.wkhealth.com/pt/re/jpin/abstract.00005208-200511000-00005.htm | pmid = 16207291 | last1 = Mills | first1 = E | last2 = Wu | first2 = P | last3 = Seely | first3 = D | last4 = Guyatt | first4 = G}}</ref> Another clinical trial is due to be completed in 2012.<ref>CCNM. [http://www.ccnm.edu/?q=current_research Current Research].</ref> Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and it has been shown that women with the brightest bedrooms have an increased risk for breast cancer.<ref>{{cite journal | last = Navara | first = Kristen J. | year = 2007 | title = The dark side of light at night: physiological, epidemiological, and ecological consequences | journal = J. Pineal Res. | volume = 43| issue = 43 | pages = 215–224| doi = 10.1111/j.1600-079X.2007.00473.x | id = | url = http://www.psy.ohio-state.edu/nelson/documents/JPinealRes2007.pdf | format = Review, PDF: full text | accessdate = 2008-05-07 | quote = | pmid = 17803517 | last1 = Navara | first1 = KJ | last2 = Nelson | first2 = RJ }}</ref> Reduced melatonin production has been proposed as a likely factor in the significantly higher [[cancer]] rates in night workers.<ref name="Schernhammer2004">{{cite journal | author = Schernhammer E, Rosner B, Willett W, Laden F, Colditz G, Hankinson S | title = Epidemiology of urinary melatonin in women and its relation to other hormones and night work | journal = Cancer Epidemiol Biomarkers Prev | volume = 13 | issue = 62 | pages = 936–43 | year = 2004 | pmid = 15184249 }}</ref>

====Gallbladder stones====
Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder.<ref name="pmid18338264">{{cite journal |author=Koppisetti S, Jenigiri B, Terron MP |title=Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review |journal=Dig. Dis. Sci. |volume=53 |issue=10 |pages=2592–603 |year=2008 |month=October |pmid=18338264 |doi=10.1007/s10620-007-0195-5 |url=}}</ref> It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced [[Cholecystitis]], whether administered before or after onset of inflammation.<ref name="pmid18338264"/>  Relatively speaking, concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.<ref name="pmid10622237">{{cite journal |author=Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ |title=High physiological levels of melatonin in the bile of mammals |journal=Life Sci. |volume=65 |issue=23 |pages=2523–9 |year=1999 |month=October |pmid=10622237 |doi= 10.1016/S0024-3205(99)00519-6|url=http://linkinghub.elsevier.com/retrieve/pii/S0024320599005196}}</ref>

====Amyotrophic lateral sclerosis====
In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, possibly due to its antioxidant effects. In a clinical safety study involving 31 [[Amyotrophic lateral sclerosis|ALS]] patients, high-dose rectal melatonin (300&nbsp;mg/day for 2 years) was shown to be tolerated well.<ref>{{cite journal | last = Weishaupt | first = J. H. | coauthors = et al | date = | year = 2006 | month = November | title = Reduced oxidative damage in ALS by high-dose enteral melatonin treatment | journal = J Pineal Res. | volume = 41 | issue = 4 | pages = 313–23 | publisher =  | issn = | pmid = 17014688 | doi = 10.1111/j.1600-079X.2006.00377.x| bibcode = | oclc =| id = | url = http://www.ncbi.nlm.nih.gov/pubmed/17014688 | format = | accessdate = 2010-07-03 | laysummary = | laysource = | laydate = | quote = }}</ref>

====Obesity====
Melatonin is involved in energy metabolism and body weight control in small animals. Many studies show that chronic melatonin supplementation in drinking water reduces body weight and abdominal fat in experimental animals, especially in the middle-aged rats.<ref name="Wolden-Hanson2000">Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.Endocrinology.141 (2)487-497, 2000 PMID=10650927.</ref> Interestingly, the weight loss effect of melatonin does not require the animals to eat less and to be physically  more active. A potential mechanism is that melatonin promotes the recruitment of brown adipose tissue (BAT) as well as enhances its activity.<ref name="tan2010">Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity.Obes Rev. 2010 Jun 16. [Epub ahead of print.|PMID.20557470|.</ref> BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. In this way, the fat is burned. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials since substantial amounts of active BAT have been identified in adult humans.

====Other====
Histologically, it is believed that melatonin has some effects for sexual development in higher organisms.<ref>From Ross' ''Histology'' and Wheater's ''Functional Histology''.{{full citations needed}}</ref>  It is involved in the seasonal timing of reproduction in rodents, at least.

Exogenous melatonin has also been used in a small clinical trial by Kunz D and Bes F to treat Periodic Limb Movement Disorder, a common neurological condition which, when severe, adversely affects sleep and causes excessive daytime fatigue. The sufferer is affected by mini arousals (often without noticing) during sleep when the limb movements occur in a frequent rhythmic fashion, often involving leg kicking but sometimes also involving the arms. Partners are often the first to notice the condition. In the trial, 7 out of the 9 taking part showed significant improvement.{{Citation needed|date=July 2010}}

A veterinarian may recommend melatonin for dogs suffering from aggression or separation anxiety.{{Citation needed|date=July 2010}}

== Use as medication ==
[[Image:Walgreens Melatonin-2010-20-07.jpg|thumb|A bottle of melatonin tablets]]
The hormone melatonin is used to treat [[circadian rhythm sleep disorder]]s and some types of insomnia.

Studies have found that the use of melatonin can help [[Entrainment (chronobiology)|entrain]] the circadian clock to environmental cycles and have beneficial effects for the treatment of certain forms of insomnia.<ref>{{cite journal |author=Turek FW, Gillette MU |title=Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists |journal=Sleep Med. |volume=5 |issue=6 |pages=523–32 |year=2004 |month=November |pmid=15511698 |doi=10.1016/j.sleep.2004.07.009 |url=}}</ref> Prolonged release melatonin has shown good results in treating insomnia in older adults.<ref>{{cite journal |author=Wade AG, Ford I, Crawford G |title=Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes |journal=Curr Med Res Opin |volume=23 |issue=10 |pages=2597–605 |year=2007 |month=October |pmid=17875243 |doi=10.1185/030079907X233098 |url=}}</ref>

Other studies have found that for certain types of sleep disorders, melatonin is not effective.  A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as [[jet lag]] and [[shiftwork disorder]]."<ref>{{cite journal | last = Buscemi | first = Nina | date = 2006-02-18 | year = | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–393 | publisher = | pmid = 16473858| doi = 10.1136/bmj.38731.532766.F6 | url =http://www.bmj.com/cgi/content/full/332/7538/385 | accessdate = 2008-05-17 | quote = | last2 = Vandermeer | first2 = B | last3 = Hooton | first3 = N | last4 = Pandya | first4 = R | last5 = Tjosvold | first5 = L | last6 = Hartling | first6 = L | last7 = Vohra | first7 = S | last8 = Klassen | first8 = TP | last9 = Baker | first9 = G | pmc = 1370968 }}</ref> However, a 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.<ref name=USAHRQ />

In another study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating [[delayed sleep phase syndrome]]", ... "There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."<ref name="Buscemi N, Vandermeer B, Hooton N, et al. 2005 1151–8">{{cite journal |author=Buscemi N, Vandermeer B, Hooton N, ''et al.'' |title=The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis |journal=Journal of General Internal Medicine |volume=20 |issue=12 |pages=1151–8 |year=2005 |month=December |pmid=16423108 |pmc=1490287 |doi=10.1111/j.1525-1497.2005.0243.x}}</ref>

====Dosage====
Studies from [[Massachusetts Institute of Technology]] have said that melatonin pills sold as supplements contain three to ten times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for a more rapid sleep onset. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses (for example 0.3&nbsp;mg as opposed to 3&nbsp;mg) are just as effective.<ref name="Zhdanova2001">{{cite journal
| author = Zhdanova I, Wurtman R, Regan M, Taylor J, Shi J, Leclair O
| title = Melatonin treatment for age-related insomnia
| journal = J Clin Endocrinol Metab
| volume = 86 | issue = 10 | pages = 4727–30
| year = 2001 | pmid = 11600532
| doi = 10.1210/jc.86.10.4727
}}</ref> Large doses of melatonin can even be counterproductive: Lewy ''et al.''<ref name="Lewy2002">{{cite journal
| author = Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA
| title = Low, but not high, doses of melatonin entrained a free-running blind person with
a long circadian period
| journal = Chronobiol Int.
| volume = 19 | issue = 3 | pages = 649–58
| year = 2002 | pmid = 12069043
| doi = 10.1081/CBI-120004546
}}</ref> provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" ([[Phase_response_curve#Melatonin_PRC|PRC]]). In one of their subjects, 0.5&nbsp;mg of melatonin was effective while 20&nbsp;mg was not.

== Availability and safety ==
Melatonin is available without prescription in most cases in the United States and Canada, while it is available only by prescription or not at all in some other countries. The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.

====Dietary supplement====
In the USA, because it is sold as a dietary supplement and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin.<ref name="Altun2007"/> However, new FDA rules required that by June 2010 all production of dietary supplements must comply with "current [[good manufacturing practice]]s" (cGMP), and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling."<ref>{{cite press release | title = FDA Issues Dietary Supplements Final Rule | publisher = U.S. Food and Drug Administration | date = 2007-06-22 | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108938.htm | accessdate = 2009-08-04}}</ref> In addition, the industry has been required to report to the FDA "all serious dietary supplement related adverse events" and the FDA has, within the cGMP guidelines, recently begun enforcement of that requirement.

==== Pediatrics ====
While the packaging of melatonin often warns against use in children, at least one long-term study<ref>{{cite journal |author=Hoebert M, van der Heijden KB, van Geijlswijk IM, Smits MG |title=Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia |journal=Journal of Pineal Research |volume=47 |issue=1 |pages=1–7 |year=2009 |month=August |pmid=19486273 |doi=10.1111/j.1600-079X.2009.00681.x}}</ref> does assess effectiveness and safety in children.  No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents.  With a mean follow up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases.

====Prolonged release for older patients====
Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, distributed by Neurim Pharmaceuticals. The [[European Medicines Agency]] (EMEA) has approved Circadin 2&nbsp;mg (prolonged-release melatonin) for patients who are aged 55 or over, as monotherapy for the short-term treatment of primary insomnia characterized by poor quality of sleep .<ref>[http://www.medicalnewstoday.com/articles/69195.php Medical News Today] Circadin (Prolonged-Release Melatonin) For Primary Insomnia Recommended For Approval In The EU (27 Apr 2007)</ref>

====Side effects====
Melatonin appears to cause very few [[Adverse effect (medicine)|side effects]] in the short term, up to three months, when healthy people take it at low doses. A systematic review<ref>{{cite journal | last = Buscemi | first = Nina | date = 2006-02-18 | year = | title = Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis | journal = BMJ | volume = 332 | issue = 7538 | pages = 385–393 | publisher = | pmid = 16473858| doi = 10.1136/bmj.38731.532766.F6 | url = http://www.bmj.com/cgi/content/full/332/7538/385 | accessdate = 2008-05-17 | quote = | last2 = Vandermeer | first2 = B | last3 = Hooton | first3 = N | last4 = Pandya | first4 = R | last5 = Tjosvold | first5 = L | last6 = Hartling | first6 = L | last7 = Vohra | first7 = S | last8 = Klassen | first8 = TP | last9 = Baker | first9 = G | pmc = 1370968 }}</ref> in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances which are secondary to other diagnoses and, second, for sleep disorders such as jet lag and [[shift work]] which accompany sleep restriction.

The study concluded that ''There is evidence that melatonin is safe with short term use''.

A similar analysis<ref name="Buscemi N, Vandermeer B, Hooton N, et al. 2005 1151–8"/> by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of ''primary'' sleep disorders found that: ''There is evidence to suggest that melatonin is safe with short-term use (3 months or less).''

Some unwanted effects in some people, especially at high doses (~3&nbsp;mg/day or more) may include: headaches, nausea, next-day grogginess or irritability, hormone fluctuations, vivid dreams or nightmares<ref>{{cite web|url=http://www.melatonin.com/melatonin-cautions.php|title=melatonin cautions|publisher=www.melatonin.com}}</ref> and reduced blood flow.

While no large, long-term studies which might reveal side effects have been conducted, there do exist case reports about patients who have taken melatonin for years.<ref>{{cite journal | last = Sack | first = Robert L. | date = 12 October 2000 | title = Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People | journal = The NEW ENGLAND JOURNAL of MEDICINE | volume = 343 | issue = 15 | pages = 1070–1077 | publisher = | location = | pmid =  11027741| doi = 10.1056/NEJM200010123431503| bibcode = | oclc = | id = | url = http://content.nejm.org/cgi/content/abstract/343/15/1070 | format = | accessdate = 2008-04-13 | quote = | last2 = Brandes | first2 = RW | last3 = Kendall | first3 = AR | last4 = Lewy | first4 = AJ }}</ref>

Melatonin can cause [[somnolence]] (drowsiness), and therefore caution should be shown when driving, operating machinery, etc.

In individuals with [[auto-immune disorders]], there is concern that melatonin supplementation may ameliorate or exacerbate symptoms due to [[Immunomodulator|immunomodulation]].<ref name="Morera2001">{{cite journal | author = Morera A, Henry M, de La Varga M | title = Safety in melatonin use | journal = Actas Esp Psiquiatr | volume = 29 | issue = 5 | pages = 334–7 | year = 2001 | pmid = 11602091 }}</ref><ref name="Terry2008">{{cite journal |author=Terry PD, Villinger F, Bubenik GA, Sitaraman SV |title=Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research |journal=Inflammatory Bowel Diseases |volume=15 |issue=1 |pages=134–40 |year=2009 |month=January |pmid=18626968 |doi=10.1002/ibd.20527}}</ref>

Individuals who experience [[orthostatic intolerance]], a [[cardiovascular]] condition that results in reduced [[blood pressure]] and [[blood flow]] to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at [[Penn State College of Medicine]]'s Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those who experience the condition, the study found.<ref name="Chester2003">{{cite press release |publisher=Penn State College of Medicine, Milton S. Hershey Medical Center |date=September 2003 |url = http://www.hmc.psu.edu/news/pr/2003/sept/Ray_melatonin.doc | title = Study Shows Melatonin Supplements May Make Standing A Hazard For The Cardiovascular-Challenged |accessdate=2006-07-21 |format=DOC}} (MS Word Format)</ref>

The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material. The synthetic form of this medication does not carry this risk.<ref name= "Altun2007"/><ref>{{cite web |url= http://www.drugs.com/melatonin.html|title= Melatonin Information from Drugs.com}}</ref>

==See also==
{{Commons category}}
* [[Ramelteon]]
* [[Agomelatine]]
* [[Tasimelteon]]
* [[Risks and benefits of sun exposure]]

==References==
{{Reflist|colwidth=30em}}

==External links==
* [http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-melatonin.html Melatonin information] from [[MedlinePlus]]
* [http://tihkal.info/read.php?domain=tk&id=35 Melatonin entry in TiHKAL • info]

{{Melatonergics}}
{{Neurotransmitters}}
{{Antioxidants}}
{{Dietary supplement}}
{{Hormones}}
{{Hypnotics and sedatives}}
{{Antidepressants}}
{{TiHKAL}}
{{Tryptamines}}

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