Melatonin Systematic (IUPAC) name N-[2-(5-methoxy-1H-indol-3-yl)ethyl]
Clinical data AHFS/Drugs.com Pregnancy cat. ? Legal status Prescription Only (S4) (AU) ? (UK) OTC (US) Routes In humans: orally, as capsules, tablets or liquid, sublingually, or as transdermal patches. In lab animals: also injection. Pharmacokinetic data Bioavailability 30 – 50% Metabolism Hepatic via CYP1A2 mediated 6-hydroxylation Half-life 35 to 50 minutes Excretion Urine Identifiers CAS number ATC code N05 PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Chemical data Formula C13H16N2O2 Mol. mass 232.278 g/mol SMILES & (what is this?)
Melatonin i//, 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.
In mammals, melatonin is secreted into the blood by the pineal gland in the brain. Known as the "hormone of darkness," it is secreted in darkness in both day-active (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.
Research has shown that when bird chicks ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.  No food has been found to elevate plasma melatonin levels in humans.
Products containing melatonin have been available over-the-counter as dietary supplements in the United States since the mid-1990s. In many other countries, the over-the-counter sale of this neurohormone is not permitted or requires a prescription, and the U.S. Postal Service lists unapproved melatonin preparations among items prohibited by Germany.
- 1 Medical uses
- 2 Adverse effects
- 3 In plants
- 4 In animals
- 5 In mammals
- 6 In humans
- 7 Use as medication
- 8 History
- 9 Availability
- 10 See also
- 11 References
- 12 External links
Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders and sexual dysfunction. It may ameliorate circadian misalignment and SAD. Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine. Melatonin is also a geroprotector.
Circadian rhythm disorders
Exogenous melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts. Melatonin reduces sleep onset latency to a greater extent in people with DSPS than in people with insomnia.
Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic. It causes melatonin levels in the blood to rise earlier than the brain's own production accomplishes. This usage is now common in sleep and relaxation drinks.
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 a small oral dose of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.
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. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called sundowning, which has been shown in many studies to be effectively treated with melatonin supplements in the evening.
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.
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. However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement. One study reported that three mg of melatonin taken in the evening raised prolactin levels in six out of seven women. Melatonin also lowers FSH levels. It is believed that these hormonal changes could in some women impair fertility.
Melatonin has a very low toxicity in rats. Rat maternal toxicity: The no observable adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was ≥ 200 mg/kg/day.
Melatonin has been shown to be effective in treating one form of depression and seasonal affective disorder, and is being considered for bipolar and other disorders in which circadian disturbances are involved. It has been observed that bipolar disorder might have, as a "trait marker" (something that is characteristic of being bipolar, that does not change with state), supersensitivity to light, i.e., a greater decrease in melatonin secretion in response to light exposure at night. This could be contrasted with drug-free recovered bipolar patients not showing light hypersensitivity.
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. Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and 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.
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. 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 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 increases proliferation of cultured neural stem cells obtained from mice nervous tissue.
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.
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).
Some unwanted effects in some people, especially at high doses (~3 mg/day or more) may include: headaches, nausea, next-day grogginess or irritability, hormone fluctuations, vivid dreams or nightmares, reduced blood flow, and hypothermia.
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.
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.
Melatonin has been identified in many plants including Feverfew (Tanacetum parthenium), and St John's wort (Hypericum perforatum). It occurs in trace amounts in some foods, especially cherries to about 0.17-13.46 ng/g. 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 has been reported in foodstuffs including bananas and grapes, rice and cereals, herbs, olive oil, wine and beer. While no food has been found to elevate plasma melatonin levels in humans, when other animals consume melatonin-containing food, blood levels of melatonin do increase.
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.
Melatonin is produced in the pineal gland, which is outside of the blood-brain barrier, acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.
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 the levels; see leptin.
Light/dark information reaches the suprachiasmatic nuclei (SCN) via retinal photosensitive ganglion cells, intrinsically photosensitive photoreceptor cells, distinct from those involved in image forming (that is, these light-sensitive cells are a third type in the retina, in addition to rods and cones). These cells represent approximately 2% of the retinal ganglion cells in humans and express the photopigment melanopsin. The sensitivity of melanopsin is consistent with that of a vitamin A-based photopigment, with a peak sensitivity at 484 nm (blue light). This photoperiod cue entrains the circadian rhythm, and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate behavioral and physiological circadian rhythms. Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.
In humans, melatonin is produced by the pineal 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 (to be more specific, the 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.
Production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness." Its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual's chronotype.
Terman et al. devised a formulation that mimics that gradual washout (vs. the spikes in blood concentration and rapid washout associated with most over-the-counter melatonin tablets). When used several hours before sleep, the compound shifts the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.
It is principally blue light, around 460 to 480nm, that suppresses melatonin, 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. 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.
Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993. 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. Melatonin is a direct scavenger of OH, O2−, and NO. 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.
Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (or AFMK) rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neutralize up to 10 ROS/RNS (reactive oxygen species/reactive nitrogen species) since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade." This is not true of other, conventional antioxidants.
In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.
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 as well.
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 result from 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. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders. 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 both people with and without narcolepsy. Many psychoactive drugs, such as cannabis and lysergic acid diethylamide (LSD), increase melatonin synthesis. 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.
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 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 we 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 taken by older adults. It has been reported in one study that while elderly people have different gene expression levels in 100 of 10,000 genes, administration of melatonin may reverse this change in gene expression thus making the genes of elderly people similar to those of younger people.
One study conducted by researchers of the University of Granada’s Institute of Biotechnology found that 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. The researchers hope these results can also be applied to humans.
Along with melanocyte-stimulating hormone, melatonin controls the dispersion of melanin throughout melanocyte cells. Melatonin controls pigmentation changes by aggregation of melanin into the melanocytes within the skin, causing the skin to change color. This is responsible for the change in skin color due to amount of sleep or the appearance of those who are sleep deprived, since melatonin also controls the circadian cycle. This interaction is also responsible for the skin color of elderly people, since melatonin production reduces with age.
Use as medication
The hormone melatonin is used to treat circadian rhythm sleep disorders and some types of insomnia.
Studies have found that the use of melatonin can help entrain the circadian clock to environmental cycles and have beneficial effects for the treatment of certain forms of insomnia (2004). Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).
A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.
Other studies have found that for certain types of sleep disorders, melatonin is not effective. A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder."
In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome, ...there is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."
Melatonin tablets/capsules often contain three to ten times the amount needed to produce physiologic nocturnal blood melatonin levels for a more rapid sleep onset. Studies suggest that smaller doses (for example 0.3 mg as opposed to 3 mg) are just as effective.
Large doses of melatonin can even be counterproductive: Lewy et al. provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" (PRC). In one of their blind subjects, 0.5 mg of melatonin was effective while 20 mg was not. Solomon Labs tested initial doses of 30 and 60 milligrams and found very little efficacy even at those levels.
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, McCord and Allen discovered (J Exptl Zool, 1917) that extract of the pineal glands of cows lightened frog skin. Dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated and named the hormone melatonin in 1958. 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. 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. (...) Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."
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). The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.
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, recently begun enforcement of that requirement.
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".
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.
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.
- Risks and benefits of sun exposure
- Discovery and development of melatonin receptor agonists
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- ^ Sack, Robert L.; Brandes, Richard W.; Kendall, Adam R.; Lewy, Alfred J. (2000). "Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People". New England Journal of Medicine 343 (15): 1070–77. doi:10.1056/NEJM200010123431503. PMID 11027741.
- ^ Filadelfi, Ana Maria Caliman; Castrucci, Ana Maria de Lauro (1996). "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates". Journal of Pineal Research 20 (4): 175–86. doi:10.1111/j.1600-079X.1996.tb00256.x. PMID 8836950.
- ^ Sugden, David; Davidson, Kathryn; Hough, Kate A.; Teh, Muy-Teck (2004). "Melatonin, Melatonin Receptors and Melanophores: A Moving Story". Pigment Cell Research 17 (5): 454–60. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831.
- ^ Lerner, AB; Case, JD; Takahashi, Y (1960). "Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands". The Journal of biological chemistry 235: 1992–7. PMID 14415935.
- ^ Lynch, H.; Wurtman, R.; Moskowitz, M.; Archer, M.; Ho, M. (1975). "Daily rhythm in human urinary melatonin". Science 187 (4172): 169–71. doi:10.1126/science.1167425. PMID 1167425.
- ^ Arendt, J. (2005). "Melatonin: Characteristics, Concerns, and Prospects". Journal of Biological Rhythms 20 (4): 291–303. doi:10.1177/0748730405277492. PMID 16077149. "There is very little evidence in the short term for toxicity or undesirable effects in humans. The extraordinary “hype” of the miraculous powers of melatonin in the recent past did a disservice to acceptance of its genuine benefits."
- ^ Arendt, Josephine (2000). "Melatonin, Circadian Rhythms, and Sleep". New England Journal of Medicine 343 (15): 1114–6. doi:10.1056/NEJM200010123431510. PMID 11027748.
- ^ "FDA Issues Dietary Supplements Final Rule" (Press release). U.S. Food and Drug Administration. 2007-06-22. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108938.htm. Retrieved 2009-08-04.
- ^ url = http://www.nytimes.com/2011/05/15/us/15lazycakes.html?_r=1&scp=1&sq=lazy%20cakes&st=cse
- ^ Hoebert, Michel; Van Der Heijden, Kristiaan B.; Van Geijlswijk, Ingeborg M.; Smits, Marcel G. (2009). "Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia". Journal of Pineal Research 47 (1): 1–7. doi:10.1111/j.1600-079X.2009.00681.x. PMID 19486273.
- ^ Medical News Today Circadin (Prolonged-Release Melatonin) For Primary Insomnia Recommended For Approval In The EU (27 Apr 2007)
- Melatonin information from MedlinePlus
- Melatonin entry in TiHKAL • info
- Wade, Alan G; Ford, Ian; Crawford, Gordon; McConnachie, Alex; Nir, Tali; Laudon, Moshe; Zisapel, Nava (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 Medicine 8: 51. doi:10.1186/1741-7015-8-51. PMC 2933606. PMID 20712869. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2933606.
ligandsAfobazole • Luzindole
inhibitorsAANAT inhibitorsASMT inhibitors
Others Neurotransmitters Amino acids Endocannabinoids Gasotransmitters Monoamines Purines Trace amines OthersSee also Template:Neuropeptides AntioxidantsAcetyl-L-Carnitine (ALCAR) • Alpha-Lipoic Acid (ALA) • Ascorbic Acid (Vitamin C) • Carotenoids (Vitamin A) • Curcumin • Edaravone • Polyphenols • Glutathione • Hydroxytyrosol • L-Carnitine • Ladostigil • Melatonin • N-Acetylcysteine (NAC) • N-Acetylserotonin (NAS) • Oleocanthal • Oleuropein • Rasagiline • Resveratrol • Selegiline • Selenium • Tocopherols (Vitamin E) • Tocotrienols (Vitamin E) • Tyrosol • Ubiquinone (Coenzyme Q) • Uric Acid Endocrine system: hormones (Peptide hormones · Steroid hormones) Endocrine
glandsHeart: Natriuretic peptide (ANP, BNP)
Hypnotics/Sedatives (N05C) GABAA Agonists/PAMsBarbiturates: Allobarbital • Amobarbital • Aprobarbital • Barbital • Butabarbital • Butobarbital • Cyclobarbital • Ethallobarbital • Heptabarbital • Hexobarbital • Mephobarbital • Methohexital • Pentobarbital • Phenobarbital • Proxibarbal • Reposal • Secobarbital • Talbutal • Thiamylal • Thiopental • Vinbarbital • Vinylbital; Benzodiazepines: Brotizolam • Cinolazepam • Climazolam • Doxefazepam • Estazolam • Flunitrazepam • Flurazepam • Flutoprazepam • Haloxazolam • Loprazolam • Lormetazepam • Midazolam • Nimetazepam • Nitrazepam • Quazepam • Temazepam • Triazolam; Carbamates: Carisoprodol • Ethinamate • Hexapropymate • Meprobamate • Methocarbamol • Procymate • Tybamate; Neuroactive Steroids: Acebrochol • Allopregnanolone • Alphadolone • Alphaxolone • Eltanolone • Ganaxolone • Hydroxydione • Minaxolone • Org 20599 • Org 21465 • Tetrahydrodeoxycorticosterone; Nonbenzodiazepines: CL-218,872 • Eszopiclone • Indiplon • JM-1232 • Lirequinil • Necopidem • Pazinaclone • ROD-188 • Saripidem • Suproclone • Suriclone • SX-3228 • U-89843A • U-90042 • Zaleplon • Zolpidem • Zopiclone; Phenols: Fospropofol • Propofol; Piperidinediones: Glutethimide • Methyprylon • Pyrithyldione • Piperidione; Quinazolinones: Afloqualone • Cloroqualone • Diproqualone • Etaqualone • Mebroqualone • Mecloqualone • Methaqualone • Methylmethaqualone • Nitromethaqualone; Others: 2-Methyl-2-butanol • Acetophenone • Acetylglycinamide chloral hydrate • Bromide (Lithium bromide, Potassium bromide, Sodium bromide) • Centalun • Chloral hydrate • Chloralose • Chloralodol • Clomethiazole • Dichloralphenazone • Ethanol (Alcohol) • Ethchlorvynol • Etomidate • Gaboxadol • Loreclezole • Methylpentynol • Metomidate • Paraldehyde • Petrichloral • Sulfonmethane • Trichloroethanol • Triclofos • Valerenic acid (Valerian) GABAB Agonists H1 Inverse agonistsAntihistamines: Captodiame • Cyproheptadine • Dimenhydrinate • Diphenhydramine • Doxylamine • Hydroxyzine • Methapyrilene • Pheniramine • Promethazine • Propiomazine; Others: Tricyclic antidepressants (Amitriptyline, Doxepin, Trimipramine, etc.) • Tetracyclic antidepressants (Mianserin, Mirtazapine, etc.) • Typical antipsychotics (Chlorpromazine, Thioridazine, etc.) • Atypical antipsychotics (Olanzapine, Quetiapine, Risperidone, etc.) α1-Adrenergic Antagonists α2-Adrenergic Agonists 5-HT2A AntagonistsEplivanserin • Niaprazine • Pruvanserin • Trazodone • Volinanserin; Others: Tricyclic antidepressants (Amitriptyline, Doxepin, Trimipramine, etc.) • Tetracyclic antidepressants (Mianserin, Mirtazapine, etc.) • Typical antipsychotics (Chlorpromazine, Thioridazine, etc.) • Atypical antipsychotics (Olanzapine, Quetiapine, Risperidone, etc.) Melatonin Agonists Orexin Antagonists Others Antidepressants (N06A) Specific reuptake inhibitors (RIs), enhancers (REs), and releasing agents (RAs)Serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs)Dopamine reuptake inhibitors (DRIs)Norepinephrine-dopamine releasing agents (NDRAs)Serotonin-norepinephrine-dopamine releasing agents (SNDRAs)OthersIndeloxazine • Teniloxazine • Tramadol • Viqualine Receptor antagonists and/or reuptake inhibitorsSerotonin antagonists and reuptake inhibitors (SARIs)Serotonin modulators and stimulators (SMSs)Vortioxetine Tricyclic and tetracyclic antidepressants (TCAs/TeCAs)TricyclicsAmezepine • Amineptine • Amitriptyline# • Amitriptylinoxide • Azepindole • Butriptyline • Cianopramine • Clomipramine • Cotriptyline • Cyanodothiepin • Demexiptiline • Depramine/Balipramine • Desipramine • Dibenzepin • Dimetacrine • Dosulepin/Dothiepin • Doxepin • Enprazepine • Fluotracen • Hepzidine • Homopipramol • Imipramine • Imipraminoxide • Intriptyline • Iprindole • Ketipramine • Litracen • Lofepramine • Losindole • Mariptiline • Melitracen • Metapramine • Mezepine • Naranol • Nitroxazepine • Nortriptyline • Noxiptiline • Octriptyline • Opipramol • Pipofezine • Propizepine • Protriptyline • Quinupramine • Tampramine • Tianeptine • Tienopramine • Trimipramine; Monoamine oxidase inhibitors (MAOIs)NonselectiveMAOA-SelectiveIrreversible: Clorgiline; Reversible: Amiflamine • Bazinaprine • Befloxatone • Befol • Brofaromine • Cimoxatone • Esuperone • Harmala Alkaloids (Harmine, Harmaline, Tetrahydroharmine, Harman, Norharman, etc) • Methylene Blue • Metralindole • Minaprine • Moclobemide • Pirlindole • Sercloremine • Tetrindole • Toloxatone • Tyrima;MAOB-Selective Azapirones and other 5-HT1A receptor agonists Drugs from TiHKAL
AL-LAD • DBT • DET • DiPT • 5-MeO-α-MT • DMT • 2,α-DMT • α,N-DMT • DPT • EiPT • α-ET • ETH-LAD • Harmaline • Harmine • 4-HO-DBT • 4-HO-DET • 4-HO-DiPT • 4-HO-DMT • 5-HO-DMT • 4-HO-DPT • 4-HO-MET • 4-HO-MiPT • 4-HO-MPT • 4-HO-pyr-T • Ibogaine • LSD • MBT • 4,5-MDO-DiPT • 5,6-MDO-DiPT • 4,5-MDO-DMT • 5,6-MDO-DMT • 5,6-MDO-MiPT • 2-Me-DET • 2-Me-DMT • Melatonin • 5-MeO-DET • 5-MeO-DiPT • 5-MeO-DMT • 4-MeO-MiPT • 5-MeO-MiPT • 5,6-MeO-MiPT • 5-MeO-NMT • 5-MeO-pyr-T • 6-MeO-THH • 5-MeO-TMT • 5-MeS-DMT • MiPT • α-MT • NET • NMT • PRO-LAD • pyr-T • Tryptamine • Tetrahydroharmine • α,N,O-TMS
1-(2-Dimethylaminoethyl)dihydropyrano(3,2-e)indole • 2-Methyl-5-HT • 4-Acetoxy-DET • 4-Acetoxy-DIPT • 4-Acetoxy-DMT • 4-HO-αMT • 4-HO-DIPT • 4-HO-MET • 4-MeO-DMT • 4-Methyl-αET • 4-Methyl-αMT • 5-Benzyloxytryptamine • 5-Bromo-DMT • 5-Carboxamidotryptamine • 5-Ethoxy-αMT • 5-Fluoro-αMT • 5-HO-αMT • 5-HTP • 5-Ethoxy-DMT • 5-Ethyl-DMT • 5-Fluoro-DMT • 5-Methyl-DMT • 5-Methoxytryptamine • 5-MeO-7,N,N-TMT • 5-Methyl-αET • 5-MeO-αET • 5-MeO-αMT • 5-MeO-DALT • 5-MeO-DET • 5-MeO-DIPT • 5-MeO-DMT • 5-MeO-DPT • 5-MeO-MALT • 5-MeO-MIPT • 5,7-Dihydroxytryptamine • 5-(Nonyloxy)tryptamine • 6-Fluoro-αMT • 7-Methyl-αET • 7-Methyl-DMT • αET • αMT • Aeruginascin • AL-37350A • BW-723C86 • Baeocystin • Bufotenidine • Bufotenin • DALT • Desformylflustrabromine • DET • DiPT • DMT • DPT • Ethocybin • EiPT • EMDT • EPT • Ethocin • FGIN-127 • FGIN-143 • Ibogaine • Indorenate • Iprocin • MET • MiPT • Miprocin • Melatonin • MS-245 • NAS • NMT • Norbaeocystin • Normelatonin • Oxypertine • PiPT • Psilocin • Psilocybin • Rizatriptan • Serotonin • Sumatriptan • Tryptamine • Tryptophan • Yohimbine • Yuremamine • Zolmitriptan
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