In Humans

<h2 >In humans</h2>

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

In humans, melatonin is produced by the <a href="http://en.wikipedia.org/wiki/Pineal_gland" title="Pineal gland" >pineal gland</a>, a small endocrine gland<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Reiter-23" >[24]</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-23" >[24]</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-Richardson2005-24" >[25]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Perreau-Lenz2004-25" >[26]</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 08:00 (8 AM).<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid12589109-26" >[27]</a>

In humans, 90% of melatonin is cleared in a single passage through the <a href="http://en.wikipedia.org/wiki/Liver" title="Liver" >liver</a>, a small amount is excreted in <a href="http://en.wikipedia.org/wiki/Urine" title="Urine" >urine</a>,<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-USAHRQ-27" >[28]</a> and a small amount is found in <a href="http://en.wikipedia.org/wiki/Saliva" title="Saliva" >saliva</a>.

Human melatonin production decreases as a person ages.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid3783419-28" >[29]</a> It is believed that 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-29" >[30]</a>

<h4 >Light dependence</h4>

Production of melatonin by the pineal gland is inhibited by <a href="http://en.wikipedia.org/wiki/Light" title="Light" >light</a> to the <a href="http://en.wikipedia.org/wiki/Retina" title="Retina" >retina</a> and permitted by <a href="http://en.wikipedia.org/wiki/Darkness" title="Darkness" >darkness</a>. 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_2001-30" >[31]</a> 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 nm does not suppress melatonin in bright-light conditions.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Kayumov_2005-31" >[32]</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-32" >[33]</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 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-isbn3-8055-9120-9-33" >[34]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=7" title="Edit section: Antioxidant" >edit</a>]Antioxidant</h3>

Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. In many less complex life forms, this is its only known function.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Tan_Manchester-34" >[35]</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> and the blood–brain barrier.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Hardeland2005-5" >[6]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21358970-35" >[36]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pohanka_2011-36" >[37]</a> Melatonin is a direct scavenger of OH, O2−, and NO.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid7832450-37" >[38]</a>

Unlike other antioxidants, melatonin does not undergo <a href="http://en.wikipedia.org/wiki/Redox_cycling" title="Redox cycling" class="mw-redirect" >redox cycling</a>, the ability of a <a href="http://en.wikipedia.org/wiki/Molecule" title="Molecule" >molecule</a> to undergo<a href="http://en.wikipedia.org/wiki/Reduction_(chemistry)" title="Reduction (chemistry)" class="mw-redirect" >reduction</a> and <a href="http://en.wikipedia.org/wiki/Oxidation" title="Oxidation" class="mw-redirect" >oxidation</a> 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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Tan2000-38" >[39]</a>

Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (or AFMK) rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and<a href="http://en.wikipedia.org/wiki/Metazoans" title="Metazoans" class="mw-redirect" >metazoans</a>. A single AFMK molecule can neutralize up to 10 <a href="http://en.wikipedia.org/wiki/ROS/RNS" title="ROS/RNS" class="mw-redirect" >ROS/RNS</a> (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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Tan_Manchester-34" >[35]</a>

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some <a href="http://en.wikipedia.org/wiki/Carcinogens" title="Carcinogens" class="mw-redirect" >carcinogens</a>, stopping the mechanism by which they cause cancer.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Karbownik2001-39" >[40]</a>

It also has been found to be effective in protecting against brain injury caused by <a href="http://en.wikipedia.org/wiki/Reactive_oxygen_species" title="Reactive oxygen species" >ROS</a> release in experimental hypoxic brain damage in newborn rats.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16091083-40" >[41]</a>

Melatonin's antioxidant activity may reduce damage caused by some types of <a href="http://en.wikipedia.org/wiki/Parkinson%27s_disease" title="Parkinson's disease" >Parkinson's disease</a>, play a role in preventing cardiac<a href="http://en.wikipedia.org/wiki/Arrhythmia" title="Arrhythmia" class="mw-redirect" >arrhythmia</a> and possibly increase <a href="http://en.wikipedia.org/wiki/Longevity" title="Longevity" >longevity</a>; it has been shown to increase the <a href="http://en.wikipedia.org/wiki/Average_life_span" title="Average life span" class="mw-redirect" >average life span</a> of <a href="http://en.wikipedia.org/wiki/Mouse" title="Mouse" >mice</a> by 20% in some studies.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Dean1993-41" >[42]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Anisimov2003-42" >[43]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Oaknin-Bendahan1995-43" >[44]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=8" title="Edit section: Immune system" >edit</a>]Immune system</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-Vico2005-44" >[45]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Arushanian2002-45" >[46]</a> 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 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-pmid16729718-46" >[47]</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-18" >[19]</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-Maestroni1999-47" >[48]</a>

Endogenous melatonin in human <a href="http://en.wikipedia.org/wiki/Lymphocyte" title="Lymphocyte" >lymphocytes</a> has been related to <a href="http://en.wikipedia.org/wiki/Interleukin_2" title="Interleukin 2" >interleukin-2</a> (IL-2) production and to the expression of IL-2 receptor.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-48" >[49]</a> This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human <a href="http://en.wikipedia.org/wiki/T_cell" title="T cell" >T lymphocytes</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-pmid16014678-49" >[50]</a>

Although it has not yet been clearly demonstrated whether melatonin increases non-specific <a href="http://en.wikipedia.org/wiki/Immunity_(medical)" title="Immunity (medical)" >immunity</a> with resulting <a href="http://en.wikipedia.org/wiki/Contraindication" title="Contraindication" >contraindication</a> in <a href="http://en.wikipedia.org/wiki/Autoimmune_diseases" title="Autoimmune diseases" class="mw-redirect" >autoimmune diseases</a>, an increase in the production of <a href="http://en.wikipedia.org/wiki/IL-2" title="IL-2" >IL-2</a> and <a href="http://en.wikipedia.org/wiki/IL-1" title="IL-1" >IL-1</a> was noted in cultured <a href="http://en.wikipedia.org/wiki/Splenocyte" title="Splenocyte" >splenocytes</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid12703182-50" >[51]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=9" title="Edit section: Dreaming" >edit</a>]Dreaming</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-51" >[52]</a> Many <a href="http://en.wikipedia.org/wiki/Psychoactive_drug" title="Psychoactive drug" >psychoactive drugs</a>, such as <a href="http://en.wikipedia.org/wiki/Cannabis" title="Cannabis" >cannabis</a> and <a href="http://en.wikipedia.org/wiki/Lysergic_acid_diethylamide" title="Lysergic acid diethylamide" >lysergic acid diethylamide (LSD)</a>, increase melatonin synthesis.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Lewis-51" >[52]</a> It has been suggested that nonpolar (<a href="http://en.wikipedia.org/wiki/Lipid" title="Lipid" >lipid</a>-soluble) <a href="http://en.wikipedia.org/wiki/Indolic" title="Indolic" class="mw-redirect" >indolic</a> <a href="http://en.wikipedia.org/wiki/Psychedelics,_dissociatives_and_deliriants" title="Psychedelics, dissociatives and deliriants" class="mw-redirect" >hallucinogenic drugs</a> emulate melatonin activity in the awakened state and that both act on the same areas of the brain.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Lewis-51" >[52]</a>

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

Individuals with <a href="http://en.wikipedia.org/wiki/Autism_spectrum_disorder" title="Autism spectrum disorder" class="mw-redirect" >autism spectrum disorders</a> (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 <a href="http://en.wikipedia.org/wiki/Acetylserotonin_O-methyltransferase" title="Acetylserotonin O-methyltransferase" >ASMT</a> gene, which encodes the last enzyme of melatonin synthesis.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Melke-52" >[53]</a>

Multiple small studies have demonstrated that 2 to 10 mg of melatonin may benefit children with ASD who have trouble falling asleep and/or maintaining sleep. A small 2011 randomized crossover trial found that the administration of melatonin, when compared to placebo, decreased sleep latency and increased total sleep time, but had no effect on the number of night time awakenings.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid20535539-53" >[54]</a> At this time, no guidelines exist for the use of melatonin in children with ASD.

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=11" title="Edit section: Aging" >edit</a>]Aging</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 we get older. 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-54" >[55]</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 taken by 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-pmid15009506-55" >[56]</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_2011-36" >[37]</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-pmid11270481-56" >[57]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=12" title="Edit section: Pediatrics" >edit</a>]Pediatrics</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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19486273-57" >[58]</a>

<h2 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=13" title="Edit section: Medical uses" >edit</a>]Medical uses</h2>

A bottle of melatonin tablets</div>

</div>

Melatonin has been studied as a potential treatment of <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/Wikipedia:Citation_needed" title="Wikipedia:Citation needed" >citation needed</a>] and some forms of insomnia.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19326288-58" >[59]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid21358978-59" >[60]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid15511698-60" >[61]</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-pmid17875243-61" >[62]</a> It may ameliorate <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-Lewy1987-62" >[63]</a>[<a href="http://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_(medicine)" title="Wikipedia:Identifying reliable sources (medicine)" >unreliable medical source?</a>]

Basic research indicates that melatonin may play a significant 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-Uz2003-63" >[64]</a>[<a href="http://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_(medicine)" title="Wikipedia:Identifying reliable sources (medicine)" >unreliable medical source?</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-64" >[65]</a>

A 2004 review found that melatonin significantly increased total sleep time in people suffering from <a href="http://en.wikipedia.org/w/index.php?title=Sleep_restriction&action=edit&redlink=1" class="new" title="Sleep restriction (page does not exist)" >sleep restriction</a>.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-USAHRQ-27" >[28]</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-Buscemi2006-65" >[66]</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_syndrome" title="Delayed sleep phase syndrome" class="mw-redirect" >delayed sleep phase syndrome</a>, ...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-pmid16423108-66" >[67]</a>

]Circadian rhythm disorders

Exogenous 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 <a href="http://en.wikipedia.org/wiki/Delayed_sleep_phase_syndrome" title="Delayed sleep phase syndrome" class="mw-redirect" >delayed sleep phase syndrome</a>(DSPS) and <a href="http://en.wikipedia.org/wiki/Non-24-hour_sleep-wake_syndrome" title="Non-24-hour sleep-wake syndrome" class="mw-redirect" >non-24-hour sleep-wake syndrome</a> where circadian rhythms are not <a href="http://en.wikipedia.org/wiki/Entrainment_(chronobiology)" title="Entrainment (chronobiology)" >entrained</a> 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 DSPS than in people with insomnia.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-USAHRQ-27" >[28]</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-67" >[68]</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 a small oral dose of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the ~2 hour advance achieved with light therapy.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16295212-68" >[69]</a>

The World Health Organization in 2007 named late night shift work as a probable cancer-causing agent.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19271347-69" >[70]</a> Melatonin is an anti-oxidant and suppressant of tumor development that is produced at night; when someone works in artificial light, they generally have lower melatonin and may be more likely to develop cancer. Melatonin supplements may simulate the melatonin production at different times that does not occur during regular sleeping hours for people who work night shifts.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid19271347-69" >[70]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=15" title="Edit section: Learning, memory and Alzheimer's" >edit</a>]Learning, memory and Alzheimer's</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-Larson2006-70" >[71]</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 neurotoxic substance that accumulates in the brains of patients with the disorder

.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Pappolla1997-71" >[72]</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-Pappolla1998-72" >[73]</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-Wang2005-73" >[74]</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)" >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-Volicer2001-74" >[75]</a> This may suggest a possible connection to melatonin production.

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=16" title="Edit section: Delirium" >edit</a>]Delirium</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-pmid20845391-75" >[76]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=17" title="Edit section: Stimulants" >edit</a>]Stimulants</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-Gi2003-76" >[77]</a>

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

Several clinical studies indicate that supplementation with melatonin is an effective <a href="http://en.wikipedia.org/wiki/Preventive_medicine" title="Preventive medicine" >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-Dodick2001-77" >[78]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Gagnier2001-78" >[79]</a>

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

Melatonin has been shown to be effective in treating one form of depression, <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-79" >[80]</a> 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-pmid17872420-80" >[81]</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-pmid4003592-81" >[82]</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-pmid1658841-82" >[83]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=20" title="Edit section: Cancer" >edit</a>]Cancer</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.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16207291-83" >[84]</a> Another clinical trial is due to be completed in 2012.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-84" >[85]</a> Modelling predicts that melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid15325001-85" >[86]</a> It has been suspected that women with the brightest bedrooms have an increased risk for breast cancer.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid17803517-86" >[87]</a>Reduced melatonin production has been proposed as a likely factor in the significantly higher <a href="http://en.wikipedia.org/wiki/Cancer" title="Cancer" >cancer</a> rates in night workers.<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-Schernhammer2004-87" >[88]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=21" title="Edit section: Gallbladder stones" >edit</a>]Gallbladder stones</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-pmid18338264-88" >[89]</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-pmid18338264-88" >[89]</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-pmid10622237-89" >[90]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=22" title="Edit section: Amyotrophic lateral sclerosis" >edit</a>]Amyotrophic lateral sclerosis</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-pmid17014688-90" >[91]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=23" title="Edit section: Obesity" >edit</a>]Obesity</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-Hanson2000-91" >[92]</a> It is interesting to note that the weight loss effect of melatonin does not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of <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-tan2010-92" >[93]</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/Wikipedia:Citation_needed" title="Wikipedia:Citation needed" >citation needed</a>]

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

Both animal<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid10082913-93" >[94]</a> and human<a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid9008723-94" >[95]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid9541644-95" >[96]</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-pmid18979313-96" >[97]</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-34" >[35]</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-pmid17641465-97" >[98]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=25" title="Edit section: Tinnitus" >edit</a>]Tinnitus</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-pmid21859051-98" >[99]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid16455366-99" >[100]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid9504599-100" >[101]</a><a href="http://en.wikipedia.org/wiki/Melatonin#cite_note-pmid20207491-101" >[102]</a>

<h3 >[<a href="http://en.wikipedia.org/w/index.php?title=Melatonin&action=edit&section=26" title="Edit section: Other" >edit</a>]Other</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-pmid11247054-102" >[103]</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-103" >[104]</a>