|This article relies on references to primary sources. (March 2012)|
|Systematic (IUPAC) name|
|Legal status||Prescription Only (S4) (AU) OTC (US)|
|Routes||In humans: orally, as capsules, tablets or liquid, sublingually, or as transdermal patches. In lab animals: also injection.|
|Bioavailability||30 – 50%|
|Metabolism||Hepatic via CYP1A2 mediated 6-hydroxylation|
|Half-life||35 to 50 minutes|
|Mol. mass||232.278 g/mol|
| (what is this?)
Melatonin i//, is also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions.
Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA.
Products containing melatonin have been available over-the-counter in the United States since the mid-1990s. In many other countries, the sale of this neurohormone is not permitted or requires a prescription.
Melatonin has been identified in many plants including feverfew (Tanacetum parthenium), St John's wort (Hypericum perforatum)., rice, corn, tomato and edible fruits. The physiological roles of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution. Melatonin also regulates plant growth by its ability to slow root formation, while promoting above ground growth.
When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. When humans consume foods rich in melatonin such as banana, pineapple and orange the blood levels of melatonin significantly increased.
Many animals use the variation in duration of melatonin production each day as a seasonal clock. In animals including humans 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 (photoperiodic) seasonal functions such as reproduction, behaviour, coat growth and camouflage colouring in seasonal animals. In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds and hamsters.
In mammals, melatonin is biosynthesized in four enzymatic steps from the essential dietary amino acid tryptophan, with serotonin produced at the second step. 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 (diurnal) and night-active (nocturnal) animals. It may also be produced by a variety of peripheral cells such as bone marrow cells, lymphocytes, and 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 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 breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin. During the night, melatonin regulates leptin, lowering its levels.
Light/dark information reaches the suprachiasmatic nuclei (SCN) from retinal photosensitive ganglion cells, which are intrinsically photosensitive photoreceptor cells that are distinct from those involved in the primary (at least, from one point of view) image formation function of the eye (that is the rods and cones of the retina). These cells represent approximately 2% of all retinal ganglion cells in humans and express the photopigment melanopsin.
Melanopsin, often confused with melatonin because of its similar name, is structurally unrelated to the hormone. It is a conventional 7-transmembrane opsin protein with the usual vitamin A-like cis-retinal cofactor having a peak absorption at 484 nm, in the blue light part of the visible spectrum. The photoperiod cue created by blue light (from a blue image of the sky) entrains a circadian rhythm, and thus governs resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate behavioral and physiological circadian rhythms associated with melatonin. Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.
Circadian rhythm 
In humans, melatonin is produced by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier. The melatonin signal forms part of the system that regulates the sleep–wake cycle by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system (specifically the suprachiasmatic nuclei, or SCN) that controls the daily cycle in most components of the paracrine and endocrine systems 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).
Human melatonin production decreases as a person ages. It is believed that as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.
Light dependence 
It is principally blue light, around 460 to 480 nm, that suppresses melatonin, proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. The incandescent light bulb widely used in the twentieth century produced relatively little blue light. Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Kayumov et al. showed that light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions. 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.
When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.
Besides its function as synchronizer of the biological clock, melatonin was found to be a powerful free-radical scavenger and wide-spectrum antioxidant in 1993. In many less complex life forms, this is its only known function. Melatonin is an antioxidant that can easily cross cell membranes and the blood–brain barrier. This antioxidant is a direct scavenger of radical oxygen and nitrogen species including: OH, O2−, and NO. Melatonin works with other antioxidants to improve the overall effectiveness from each antioxidant. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo 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.:p.189
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) because 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.
It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage in newborn rats. Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease, play a role in preventing cardiac arrhythmia and possibly increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.
Immune system 
While it is known that melatonin interacts with the immune system, 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 cytokine production, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor. This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.
Although it has not yet been clearly demonstrated whether melatonin increases non-specific immunity with resulting contraindication in autoimmune diseases, an increase in the production of IL-2 and IL-1 was noted in cultured splenocytes.
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased REM sleep time and dream activity in people both with and without narcolepsy. It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.
Some individuals with autism spectrum disorders (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 ASMT gene, which encodes the last enzyme of melatonin synthesis.
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. At this time, no official guidelines exist for the use of melatonin in children with ASD.
Research has supported the anti-aging properties of melatonin. Younger children hit their peak melatonin production at night, and some researchers believe that the level of melatonin peaks earlier as people get older. This may explain why older adults go to bed earlier, wake up earlier, and have more sleep problems than children do.
Some studies have shown that melatonin plays a crucial part in the aging process and that it may act as an anti-aging agent when administered to older mice. It has been reported in one study that administration of melatonin in elderly mice may reverse this change in expression of some 13 genes, thus making them similar to those of younger mice. Consuming melatonin may neutralize oxidative damage and delay the neurodegenerative process of aging. 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.
Single-nucleotide polymorphisms of the human melatonin MT2 receptor have been linked to an increased risk of developing type 2 diabetes. Furthermore women with low levels of melatonin secretion have been found to more likely to develop type 2 diabetes than women with high levels.
While the packaging of melatonin often warns against use in children, at least one long-term study does assess effectiveness and safety in children. No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents. With a mean follow-up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases. Other studies warn against potential side effects
Medical uses 
Melatonin has been studied as a potential treatment of gastroesophageal reflux disease, cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders, sexual dysfunction and insomnia in the elderly. Prolonged release melatonin has shown good results in treating insomnia in older adults (2007). It may ameliorate circadian misalignment and SAD. Basic research indicates that melatonin may play a role in modulating the effects of drugs of abuse such as cocaine. Melatonin is also a geroprotector.
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 jet lag and shiftwork disorder."
In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome(DSPS), ...there is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."
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 where circadian rhythms are not entrained to the environmental cycle. 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 shifts. Melatonin reduces sleep onset latency to a greater extent in people with DSPS than in people with insomnia.
A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a chronobiotic (affecting aspects of biological time structure), advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and an oral dose of 0.3 or 3 mg of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the ~2 hour advance achieved with light therapy. There was no difference in the average magnitude of phase shift induced by the 2 doses.
The World Health Organization in 2007 named late night shift work as a probable cancer-causing agent. 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.
Learning, memory and Alzheimer's 
Melatonin receptors appear to be important in mechanisms of learning and memory in mice, 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. 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 neurofibrillary tangles, the other neuropathological landmark of Alzheimer's disease.
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. 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 sundowning, with a phase delay in core body temperature. This may suggest a possible connection to melatonin production.
Research shows that after melatonin is administered to 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.
Mood disorders 
Melatonin has been shown to be effective in treating seasonal affective disorder, a form of depression, and is being considered for bipolar and other disorders in which circadian disturbances are involved. It was observed in 1985 that bipolar disorder 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). This could be contrasted with drug-free recovered bipolar patients showing normal light sensitivity.
A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death. Another clinical trial is due to be completed in 2012.[dated info] Modelling predicts that melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes. Studies have shown that melatonin prevents DNA fragmentation in brain tissue caused by dexamethasone neurotoxicity in mice, it is hypothesized it has similar affects on the human brain. Melatonin is hypothesized to inhibit breast cancer-causing fibroblasts, as the main metabolite of melatonin is statistically significantly linked to lower risk of developing breast cancer. It has been suspected that women with the brightest bedrooms have an increased risk for breast cancer. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers.
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. 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. 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.
Amyotrophic lateral sclerosis 
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 ALS patients, high-dose rectal melatonin (300 mg/day for 2 years) was shown to be tolerated well.
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 and the weight loss effect did not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of brown adipose tissue (BAT) as well as enhances its activity. This effect would raise the basal metabolic rate by stimulating thermogenesis, heat generation through uncoupling oxidative phosphorylation in mitochondria. 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.
Protection from radiation 
Both animal and human studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than amifostine, a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of free radicals. 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.
Melatonin was used to treat periodic limb movement disorder, 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.
Adverse effects 
Melatonin appears to cause very few side-effects in the short term, up to three months, when healthy people take it at low doses. A systematic review in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances that are secondary to other diagnoses and, second, for sleep disorders such as jet lag and shift work that accompany sleep restriction.
The study concluded that "There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use".
A similar analysis 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)."
While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for months.
Melatonin can cause somnolence (drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc.
Individuals experiencing 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 experiencing the condition, the study found.
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. One study reported that melatonin taken in the evening raised prolactin levels in six out of seven women. Melatonin has been found to lower FSH levels. Effects of the hormone on human reproduction remain unclear, although it was with some effect tried as a contraceptive in the 1990s.
Melatonin was thought to have a very low maternal toxicity in rats. Newer studies, though, have found that it is toxic to photoreceptor cells in rats' retinas and increases tumours in white mice.
Legal availability of melatonin varies in different countries, ranging from being available without prescription (e.g. in most of North America) to being available only on prescription or not at all (although its possession and use may not be illegal). In the UK it is available on prescription only.
The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.
The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material. The synthetic form of this medication does not carry this risk.
Dietary supplement 
In the USA, because it is sold as a dietary supplement, sometimes combined with other ingredients, such as vitamins and herbal extracts, and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin. However, new FDA rules required that by June 2010 all production of dietary supplements must comply with "current good manufacturing practices" (cGMP), and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling." 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, begun enforcement of that requirement.
Food products 
As reported in the New York Times in May 2011, melatonin is sold in grocery stores, convenience stores, and clubs in both beverage and snack forms. The FDA is considering whether these food products can continue to be sold with the label "dietary supplements". On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as "relaxation drinks," stating that melatonin is not approved as a food additive because it is not generally recognized as safe.
Prolonged release 
Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The European Medicines Agency (EMA) has approved Circadin 2 mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.
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. As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores. In 1958 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 the hormone from rat urine and named it melatonin. In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993. The first patent for its use as a low dose sleep aid was granted to Richard Wurtman at MIT in 1995. Around the same time, the hormone got a lot of press as a possible treatment for many illnesses. The New England Journal of Medicine editorialized in 2000: "The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."
See also 
|Wikimedia Commons has media related to: Melatonin|
- Discovery and development of melatonin receptor agonists
- Risks and benefits of sun exposure
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Further reading 
- Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N (2010). "Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety". BMC Med 8: 51. doi:10.1186/1741-7015-8-51. PMC 2933606. PMID 20712869.