Melatonin (), chemically N-acetyl-5-methoxytryptamine, is a hormone found in animals, plants, fungi and bacteria in anticipation of the daily onset of darkness. It is synthesized in animal cells directly from the [[amino acid]] [[tryptophan]], but in other organisms through the [[Shikimic acid pathway]]. In animals, melatonin is involved in the [[Entrainment (chronobiology)|entrainment]] of the [[circadian rhythm]]s of physiological functions including sleep timing, blood pressure regulation, seasonal reproduction and many others. Many biological effects of melatonin are produced through activation of [[melatonin receptor]]s, while others are due to its role as a pervasive and powerful [[antioxidant]], with a particular role in the protection of [[nuclear DNA|nuclear]] and [[mitochondrial DNA]]. The hormone can be used as a sleep aid and in the treatment of [[sleep disorder]]s. It can be taken orally as capsules, tablets, or liquid. It is also available in a form to be used sublingually, and there are transdermal patches. There have been few long-term clinical trials in the use of melatonin in humans. ==Discovery== Melatonin was first discovered in connection to the mechanism by which some [[amphibians]] and [[reptiles]] change the color of their skin. As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the [[pineal gland]]s of cows lightened tadpole skin by contracting the dark [[Epidermis (zoology)|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 bovine [[pineal gland]] extracts 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.” ==Biosynthesis and Pharmacology== Melatonin biosynthesis in humans and some other organisms involves four enzymatic steps from the essential dietary amino acid [[tryptophan]], which follows a [[serotonin pathway]]. In the first two steps, L-tryptophan is first converted to 5-hydroxy-L-tryptophan (5-HTP) by an enzyme, tryptophan 5-hydroxylase. 5-HTP is then decarboxylated ([[Carbon dioxide|CO2]] removal) by 5-hydroxytryptophan decarboxylase to produce [[serotonin]]. This point is the rate limiting stage such that further reaction is determined by light-dark conditions. Only in darkness, the key enzyme, [[aralkylamine N-acetyltransferase]] (AANAT) is activated and converts serotonin to N-acetyl serotonin, which is ultimately converted to melatonin by the final enzyme, acetylserotonin O-methyltransferase. It is the key regulator of melatonin synthesis from tryptophan, as its gene ”[[AANAT (gene)|AANAT]]” is directly influenced by photoperiod. In bacteria, protists, fungi, and plants melatonin is synthesized indirectly with tryptophan as an intermediate product of the [[shikimic acid pathway]]. In these cells synthesis starts with d-erythrose-4-phosphate and [[phosphoenolpyruvate]], and in [[Photosynthesis|photosynthetic cells]] with carbon dioxide. The rest of the reactions are similar, but with slight variations in the last two enzymes. ===Regulation=== In vertebrates, melatonin secretion is regulated by [[norepinephrine]]. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphoryates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). At daylight, noradrenergic stimulation stops and the protein is immediately destroyed by [[Proteasome|proteasomal]] [[proteolysis]]. Production is again started in the evening, which is called the dim-light melatonin onset (DLMO). It is principally blue light, around 460 to 480 [[Nanometre|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. ===Pharmacology=== 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. In humans, 90% of orally administered melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva. == Animals == In vertebrates, melatonin is produced at nighttime by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the [[suprachiasmatic nucleus|suprachiasmatic nuclei]] (SCN) from retinal [[photosensitive ganglion cell]]s of the eyes rather than the melatonin signal (as was once postulated). Known as “the hormone of darkness”, the onset of melatonin at dusk promotes activity in [[nocturnal]] (night active) animals and sleep in diurnal ones including humans. 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 organization of daylength-dependent ([[Photoperiodism|photoperiodic]]) seasonal functions such as reproduction, behavior, coat growth and camouflage [[Animal colouration|coloring]] 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. 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 [[Polyestrous|long-day breeders]] is [[Estrous cycle#Anestrus|repressed by melatonin]] and the reproduction of [[Polyestrous|short-day breeders]] is stimulated by melatonin. During the night, melatonin regulates [[leptin]], lowering its levels. == Plants == Melatonin is identified in many plants including [[Tanacetum parthenium|feverfew]] (”Tanacetum parthenium”), [[Hypericum perforatum|St John’s wort]] (”Hypericum perforatum”), rice, corn, tomato, grape and other edible fruits. The physiological roles in plants include regulation of their response to [[photoperiod]], defense against harsh environments, and the function of an antioxidant. It also regulates plant growth by its ability to slow root formation, while promoting above-ground growth. ==Functions== ===Circadian rhythm=== In animals, the primary function is regulation of day-night cycles. Human infants’ melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 AM. Human melatonin production decreases as a person ages. Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times. ====Antioxidant==== Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993. In many less complex life forms, this is its only known function. Melatonin is an [[antioxidant]] that can easily cross [[cell membrane]]s 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 of each antioxidant. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction. Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a better protector against mitochondrial oxidative stress. ===Immune system=== While it is known that melatonin interacts with the [[immune system]], the details of those interactions are unclear. [[Antiinflammatory]] effect seems to be the most relevant and most documented in the literature. 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]]. In [[rheumatoid arthritis]] patients, melatonin production has been found increased when compared to age-matched healthy controls.{{relevance-inline|date=April 2014}} ===Metal Chelation=== In vitro, melatonin can form complexes with cadmium and other metals. ==Exogenous melatonin== ===Dietary supplement=== Melatonin is categorized by the US [[Food and Drug Administration]] (FDA) as a dietary supplement. It is sold freely over-the-counter in both the US and Canada without any regulation as a pharmaceutical drug. The Food and Drug Administration (FDA) regulations applying 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 practice]]s” (cGMP) and be manufactured with “controls that result in a consistent product free of contamination, with accurate labeling.” The industry has also been required to report to the FDA “all serious dietary supplement related adverse events”, and the FDA has (within the cGMP guidelines) begun enforcement of that requirement. ===Food products=== Melatonin has been reported in foods including cherries to about 0.17–13.46 ng/g, bananas and grapes, rice and cereals, herbs, olive oil, [[wine]] and beer. 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 increase. As reported in the ”New York Times” in May 2011, beverages and snacks containing melatonin are sold in grocery stores, convenience stores, and clubs. The FDA is considering whether these food products can continue to be sold with the label “dietary supplements”. On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as “relaxation drinks,” stating that melatonin is not approved as a [[food additive]] because it is not [[generally recognized as safe]]. ==Medical uses== Melatonin has been studied for insomnia in the elderly. Prolonged release melatonin has shown good results in treating insomnia in older adults (2007). It may improve [[circadian rhythm|circadian]] misalignment and SAD. Basic research indicates that melatonin may play a role in modulating the effects of drugs of abuse such as [[cocaine]]. ===Sleep disorders=== A 2004 review found that “there was no evidence that melatonin had an effect on sleep onset latency or sleep efficiency” in people suffering from [[sleep deprivation|sleep restriction]], such as from shift work and rapid transmeridian travel, while it did decrease sleep onset latency in people with a primary sleep disorder and it increased sleep efficiency in people with a secondary sleep disorder. Short and long term treatment of prolonged-release melatonin was found to be effective and safe, improving sleep latency, sleep quality and daytime alertness in insomnia patients. In exploratory studies, prolonged-release melatonin has shown sleep quality improvement in patients with chronic schizophrenia as well as in patients with major depressive disorder and treating sleep-wake cycle disorders in children with underlying neurodevelopment difficulties. Additionally, as add-on to antihypertensive therapy, prolonged-release melatonin improved blood pressure control in patients with nocturnal hypertension as shown in a randomised double-blind placebo controlled study. Melatonin taken in the evening is, together with [[light therapy]] upon awakening, the standard treatment for delayed sleep phase disorder (DSPD) and [[non-24-hour sleep–wake disorder|Non-24]] where circadian rhythms are not [[entrainment (chronobiology)|entrained]] (biologically synchronized) 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 [[shift work|shifts]]. Melatonin reduces [[sleep onset latency]] to a greater extent in people with DSPD than in people with insomnia. Many totally blind people can control [[non-24-hour sleep–wake disorder|Non-24]] by taking small amounts of melatonin in the evening. Melatonin appears to increase the amount of sleep in people after working night shifts. 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) does not 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. ===Stimulants=== 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. ===Headaches=== Several clinical studies indicate that supplementation with melatonin is an effective [[Preventive medicine|preventive treatment]] for [[migraines]] and [[cluster headache]]s. ===Cancer=== A [[systematic review]] of unblinded [[clinical trial]]s involving a total of 643 cancer patients using melatonin found a reduced incidence of death but that blinded and independently conducted randomized controlled trials are needed. The National Cancer Institute’s review of the evidence found that it remains inconclusive. ===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. 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. ===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. ===Tinnitus=== Several medical studies involving adult patients indicate that melatonin can be beneficial in the treatment of [[tinnitus]]. ===Dreaming=== 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]]. ===Autism=== Melatonin might improve sleep in people with [[autism spectrum disorder]]s (ASD). Research has shown that children with autism have abnormal melatonin pathways and below average physiological levels of melatonin. Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings. However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed. ===Pediatrics=== While the packaging of melatonin often warns against use in children, available studies suggest that melatonin is an efficacious and safe treatment for ADHD and sleep-onset insomnia. However larger and longer studies are needed to establish long-term safety and optimal dosing. ==Adverse effects== Melatonin appears to cause very few [[Adverse effect (medicine)|side-effects]] in the short term, up to three months, at low doses. A systematic review in 2006 showed that for sleep disorders such as [[jet lag]] and [[shift work]], melatonin is not effective although it is safe for short term use”. Prolonged-release melatonin is safe with long-term use of up to 12 months. Melatonin can cause nausea, next-day [[grogginess]], irritability, reduced blood flow and [[hypothermia]]. Individuals with [[orthostatic intolerance]], having reduced [[blood pressure]] and [[blood flow]] to the brain when standing up, may benefit from the use of melatonin. In [[auto-immune disorders]], there is conflicting evidence whether melatonin supplementation may either ameliorate or exacerbate symptoms due to [[Immunomodulator|immunomodulation]]. Melatonin can lower [[Follicle-stimulating hormone|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. Recent studies have found results which suggested that it is toxic to photoreceptor cells in rats’ retinas when used in combination with large amounts of sunlight and increases the incidence of tumours in white mice. In animal models, interventions that increase the bioavailability of melatonin seem to increase the severity of the symptoms of [[Parkinson’s disease]], whereas reduction in melatonin by pinealectomy or exposure to bright light can improve recovery from those symptoms. Melatonin may exacerbate neurodegeneration in advanced Parkinson’s disease in rats. ==Availability== The effects of long-term supplementation of melatonin in humans have not yet been thoroughly studied nor ascertained. One prescription-only, prolonged-release melatonin product, trade-name [[Circadin]], 2 mg, is available for up to three months use by people aged 55 and over. Immediate-release melatonin is scarcely regulated. It is available in doses from less than half a milligram to 5 mg or more. It causes blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, tablets or as liquid. It is also available for use sublingually, or as transdermal patches. The legal availability of melatonin varies widely among countries, ranging from being available without prescription (e.g. in most of North America and Finland) to being available only on prescription (e.g. in the European Union, Norway and Australia) or not at all (although its possession and use may not be illegal). Immediate-release melatonin is widely available on the Internet as a [[dietary supplement]]. Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic and does not carry a risk of contamination or the means of transmitting viral material. ===Prolonged release=== Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. Containing 2 mg melatonin, it was shown in clinical trials of older adults to decrease time to fall asleep and improve quality of sleep and daytime functioning. It releases melatonin gradually over 8–10 hours, mimicking the body’s internal secretion profile. The [[European Medicines Agency]] (EMA) has approved Circadin for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep. Other countries’ agencies that subsequently approved the drug include: : –the Australian Therapeutics Goods Administration (TGA), : –the Swiss Agency for Therapeutics Products (SwissMedic), : –the South Korean Ministry of Food and Drug Safety (MFDS) and : –the Israeli Ministry of Health (MOH). ==See also== * [[5-Methoxytryptamine]] * [[Agomelatine]] * [[Discovery and development of melatonin receptor agonists]] * [[Ramelteon]] * [[Risks and benefits of sun exposure]] * [[Tasimelteon]] * [[Sundowning]] ==References== {{Reflist|35em}} == Further reading == * {{cite journal | author = Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N | title = Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety | journal = BMC Med | volume = 8 | page = 51 | year = 2010 | pmid = 20712869 | pmc = 2933606 | doi = 10.1186/1741-7015-8-51 }} == External links == * {{Commons category inline}} * [http://gmd.mpimp-golm.mpg.de/Spectrums/5c07b02a-6ada-4428-9a58-a739a3177f45.aspx Melatonin MS Spectrum] * [http://tihkal.info/read.php?domain=tk&id=35 Melatonin entry in TiHKAL • info] {{Neurotransmitters}} {{Hormones}} {{Antioxidants}} {{Dietary supplement}} {{Hypnotics and sedatives}} {{Insomnia pharmacotherapies}} {{Melatonergics}} {{Tryptamines}} [[Category:Antioxidants]] [[Category:Circadian rhythm]] [[Category:Hormones of the pineal gland]] [[Category:Tryptamine alkaloids]] [[Category:Treatment of bipolar disorder]] [[Category:Acetamides]] [[Category:Phenol ethers]] [[Category:Drugs acting on the nervous system]] [[Category:Melatonin receptor agonists]]