APPROVED, Melatobel, JAPAN 2020/3/25
MelatoninCAS Registry Number: 73-31-4CAS Name:N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide
Trademarks: Regulin (Young)
Molecular Formula: C13H16N2O2Molecular Weight: 232.28Percent Composition: C 67.22%, H 6.94%, N 12.06%, O 13.78%
Literature References: A hormone of the pineal gland, also produced by extra-pineal tissues, that lightens skin color in amphibians by reversing the darkening effect of MSH, q.v. Melatonin has been postulated as the mediator of photic-induced antigonadotrophic activity in photoperiodic mammals and has also been shown to be involved in thermoregulation in some ectotherms and in affecting locomotor activity rhythms in sparrows. Isoln from the pineal glands of beef cattle: Lerner et al.,J. Am. Chem. Soc.80, 2587 (1958); Wurtman et al.,Science141, 277 (1963). Structure: Lerner et al.,J. Am. Chem. Soc.81, 6084 (1959). Crystal and molecular structure: A. Wakahara, Chem. Lett.1972, 1139. Synthesis from 5-methoxyindole as starting material by two different routes: Szmuszkovicz et al.,J. Org. Chem.25, 857 (1960). Biochemical role of melatonin: Chem. Eng. News45, 40 (May 1, 1967). Pharmacological studies: Barchas et al.,Nature214, 919 (1967). Identification of antigonadal action sites in mouse brain: J. D. Glass, G. R. Lynch, Science214, 821 (1981). Binding studies in human hypothalamus: S. M. Reppert et al.,Science242, 78 (1988). Efficacy in control of estrus in red deer: G. W. Asher, Anim. Reprod. Sci.22, 145 (1990). Reviews: M. K. Vaughn, Int. J. Rev. Physiol.24, 41-95 (1981); D. C.Klein et al.,Life Sci.28, 1975-1986 (1981). Book: Advan. Biosci.vol. 29, N. Birau, W. Schlott, Eds. (Pergamon Press, New York, 1981) 420 pp. Review of etiological role in clinical disease: A. Miles, D. Philbrick, Crit. Rev. Clin. Lab. Sci.25, 231-253 (1987); in psychiatric disorders: eidem,Biol. Psychiatry23, 405-425 (1988).Properties: Pale yellow leaflets from benzene, mp 116-118°. uv max: 223, 278 nm (e 27550, 6300).Melting point: mp 116-118°Absorption maximum: uv max: 223, 278 nm (e 27550, 6300)Therap-Cat-Vet: Control of estrus.
Melatonin is a hormone primarily released by the pineal gland that regulates the sleep–wake cycle. As a dietary supplement, it is often used for the short-term treatment of insomnia, such as from jet lag or shift work, and is typically taken by mouth. Evidence of its benefit for this use, however, is not strong. A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep. The melatonin receptor agonist medication ramelteon may work as well as melatonin supplements, at greater cost but with different adverse effects, for some sleep conditions.
Side effects from melatonin supplements are minimal at low doses for short durations. They may include somnolence (sleepiness), headaches, nausea, diarrhea, abnormal dreams, irritability, nervousness, restlessness, insomnia, anxiety, migraine, lethargy, psychomotor hyperactivity, dizziness, hypertension, abdominal pain, heartburn, mouth ulcers, dry mouth, hyperbilirubinaemia, dermatitis, night sweats, pruritus, rash, dry skin, pain in the extremities, symptoms of menopause, chest pain, glycosuria (sugar in the urine), proteinuria (protein in the urine), abnormal liver function tests, increased weight, tiredness, mood swings, aggression and feeling hungover. Its use is not recommended during pregnancy or breastfeeding or for those with liver disease.
In animals (including humans), melatonin is involved in synchronizing the circadian rhythm, including sleep–wake timing, blood pressure regulation, and seasonal reproduction. Many of its effects are through activation of the melatonin receptors, while others are due to its role as an antioxidant. In plants, it functions to defend against oxidative stress. It is also present in various foods.
Melatonin was discovered in 1958. It is sold over the counter in Canada and the United States; in the United Kingdom, it is a prescription-only medication. It is not approved by the US Food and Drug Administration (FDA) for any medical use. In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54. In the European Union, it is indicated for the treatment of insomnia in children and adolescents. It was approved for medical use in the European Union in 2007.
Chemical Synthesis of Melatonin
The methods for the chemical synthesis of melatonin are generally not so complicated and do not involve more than three steps of conversion. Three synthesis reactions of melatonin from primary literatures are shown below;
In 1958 melatonin was first isolated and characterised by A.B.Lerner. It was know as one of a substituted 5-hydroxyindole derivative in the pineal gland that could lighten pigment cells. It had not been know to exist in biological tissue although it had been isolated as a urinary excretion product in rats after administration of 5-hydroxytryptamine.
Melatonin or N-acetyl-5-methoxytryptamine (40 mg) was prepared by reducing 100 mg of 5-methoxyindole-3-acetonitrile with 160 mg of sodium and 2 ml of ethanol. Then the product was acetylated with 4 ml of both glacial acetic acid and acetic anhydride at 100 oC for 1 minute. Purification was achieved by countercerrent distribution and silicic acid chromatography.
5-Methoxytryptamine hydrochloride (1g, 4.75 mmole) was dissolved in pyridine (10 ml) and acetic anhydride (10 ml) and kept overnight at 20 oC. The solution was poured onto iced, neutralised with dilute hydrochloric acid and extracted with chloroform (2×25 ml). The combined extracts were washed with water, dried in MgSO4 and evaporated to afford a liquid of N,N diacetyltryptamine derivative. The liquid was then poured into water (50 ml) and extracted with chlroform (2×25 ml). The combined organic layers were washed with water (25 ml), dried in MgSO4 and evaporated to dryness. The residual solid crystallised from benzene to afford melatonin 819 mg, 80% yield.
The more reactive indoles (1a-1d) were alkylated at the 3 position by reaction with nitroethene generated in situ by thermolysis of nitroethyl acetate. The nitroethyl acetate used for this purpose was prepared by acetylation of nitroethanol with acetic anhydride using NaOAc as a catalyst. These conditions constitute a substantial improvement of the overal yield of the reation. Reduction of the nitroethylated indoles (2a-d) by hydrogenation over PtO2, followed by acetylation fo the resluting tryptamines with acetic anhydride-pyridine completed the synthesis of melatonin and its derivatives (4a-d).
Biological Synthesis and Metabolism of Melatonin
The biosynthesis of melatonin (Fig.1) is initiated by the uptake of the essential amino acid tryptophan into pineal parenchymal cells. Tryptophan is the least abundant of essential amino acids in normal diets. It is converted to another amino acid, 5-hydroxytryptophan, through the action of the enzyme tryptopahn hydroxylase and then to 5-hydroxytryptamine (serotonin) by the enzyme aromatic amino acid decarboxylase. Serotonin concentrations are higher in the pineal than in any other organ or in any brain region. They exhibit a striking diurnal rhythm remaining at a maximum level during the daylight hours and falling by more than 80% soon after the onset of darkness as the serotonin is converted to melatonin, 5-hydroxytryptophol and other methoxyindoles. Serotonin’s conversion to melatonin involves two enzymes that are characteristic of the pineal : SNAT (serotonin-N-acetyltransferase) which converts the serotonin to N-acetylserotonin, and HIOMT (hydroxyindole-O-methyltrasferase) which trasfers a methyl group from S-adenosylmethionine to the 5-hydroxyl of the N-acetylserotonin. The activities of both enzymes rise soon after the onset of darkness because of the enhanced release of norepinephrine from sympathetic neurons terminating on the pineal parenchymal cells.
Another portion of the serotonin liberated from pineal cells after the onset of darkness is deaminated by the enzyme monoamine oxidase (MAO) and then either oxidized to form 5-hydroxyindole acetic acid or reduced to form 5-hydroxytryptophol (Fig.1). Both of these compounds are also substrates for HIOMT and can thus be converted in the pineal to 5-methoxyindole acetic acid 5-methoxytryptophol (Fig.1). The level of this latter indole, like that of melatonin, rises markedly in the pineal with the onset of darkness. Since 5-methoxytryptophol synthesis does not require the acetylation of serotonin, the nocturnal increase in pineal SNAT activity cannot be the trigger that causes pineal methoxyindole levels to rise. More likely, a single unexplained process- the intraparenchymal release of stored pineal serotonin, which then becomes accessible to both SNAT and MAO. This process ultimately controls the rates at which all three major pineal methoxyindoles are synthesized and generates the nocturnal increases in pineal melatonin and 5-methoxytryptophol. The proportion of available serotonin acetylated at any particular time of day or night depends on the relative activities of pineal SNAT and MAO at that time. The rates of methylation of all three 5-hydroxyindoles formed from pinela serotonin depends on HIOMT activity.Fig.1 Biosynthesis of pineal methoxyindoles from serotonin
Serotonin may be either acetylated to form N-acetylserotonin through the action of the enzyme serotonin-N-acetyltransferase (SNAT), or oxidatively deaminated by monoamine oxidase (MAO) to yield an unstable aldehyde. This compound is then either oxidized to 5-hydroxyindole acetic acid by the enzyme aldehyde dehydrogenase (ADH), or reduced to from 5-hydroxytryptophol by aldehyde reductase (AR). Each of these 5-hydroxyindole derivatives of serotonin is a substrate for hydroxyindole-O-methyltrasferase (HIMOT). The enzymatic trasfer of a methyl group from S-adenosylmethionine to these hydroxyindoles yields melatonin (5-hydroxy-N-acetyltryptamine), 5-methoxyindole acetic acid and 5-methoxytryptophol respectively. Pineal serotonin is synthesized from the essential amino acid tryptophan by 5-hydroxylation folloed by decarboxylation. The first step in ths enzymic sequence is catalysed by tryptophan hydroxylase. The second step is catalysed by aromatic L-amino acid decarboxylase.
In the European Union it is indicated for the treatment of insomnia in children and adolescents aged 2–18 with autism spectrum disorder (ASD) and / or Smith–Magenis syndrome, where sleep hygiene measures have been insufficient and for monotherapy for the short-term treatment of primary insomnia characterized by poor quality of sleep in people who are aged 55 or over.
Positions on the benefits of melatonin for insomnia are mixed. An Agency for Healthcare Research and Quality (AHRQ) review from 2015 stated that evidence of benefit in the general population was unclear. A review from 2017, found a modest effect on time until onset of sleep. Another review from 2017 put this decrease at six minutes to sleep onset but found no difference in total sleep time. Melatonin may also be useful in delayed sleep phase syndrome. Melatonin appears to work as well as ramelteon but costs less.
Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson’s disease and dementia with Lewy bodies. In Europe it is used for short-term treatment of insomnia in people who are 55 years old or older. It is deemed to be a first line agent in this group.
A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer’s disease. A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer’s it has little to no effect. Melatonin may, however, help with sundowning.
Jet lag and shift work
Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses.[clarification needed] Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo. Prolonged-release melatonin is safe with long-term use of up to 12 months. Although not recommended for long term use beyond this, low-dose melatonin is generally safer, and a better alternative, than many prescription and over the counter sleep aids if a sleeping medication must be used for an extended period of time. Low-doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect, but instead appear to cause drowsiness for a longer period of time.
Melatonin can cause nausea, next-day grogginess, and irritability. In the elderly, it can cause reduced blood flow and hypothermia.[needs update] In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[needs update]
When eyes receive light from the sun, the pineal gland’s production of melatonin is inhibited and the hormones produced keep the human awake. When the eyes do not receive light, melatonin is produced in the pineal gland and the human becomes tired.
In animals, melatonin plays an important role in the regulation of sleep–wake 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.
Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993. In vitro, melatonin acts as a direct scavenger of oxygen radicals and reactive nitrogen species including OH•, O2−•, and NO•. In plants, 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. Via signal transduction through melatonin receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.
Melatonin occurs at high concentrations within mitochondrial fluid which greatly exceed the plasma concentration of melatonin. Due to its capacity for free radical scavenging, indirect effects on the expression of antioxidant enzymes, and its significant concentrations within mitochondria, a number of authors have indicated that melatonin has an important physiological function as a mitochondrial antioxidant.
The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals. Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).
While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete 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.
Overview of melatonin biosynthesis
In animals, biosynthesis of melatonin occurs through hydroxylation, decarboxylation, acetylation and a methylation starting with L-tryptophan. L-tryptophan is produced in the shikimate pathway from chorismate or is acquired from protein catabolism. First L-tryptophan is hydroxylated on the indole ring by tryptophan hydroxylase to produce 5-hydroxytryptophan. This intermediate (5-HTP) is decarboxylated by pyridoxal phosphate and 5-hydroxytryptophan decarboxylase to produce serotonin.
Serotonin is itself an important neurotransmitter, but is also converted into N-acetylserotonin by serotonin N-acetyltransferase with acetyl-CoA. Hydroxyindole O-methyltransferase and S-adenosyl methionine convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.
In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimate pathway. In these cells, synthesis starts with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the synthesising reactions are similar, but with slight variations in the last two enzymes.
It has been hypothesized that melatonin is made in the mitochondria and chloroplasts.
Mechanism of melatonin biosynthesis
In order to hydroxylate L-tryptophan, the cofactor tetrahydrobiopterin (THB) must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:
1. A slow transfer of one electron from the THB to O2 could produce a superoxide which could recombine with the THB radical to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.
2. O2 could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the THB to form an iron-peroxypterin intermediate.
Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a carbocation at the C5 position of the indole ring. A 1,2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes aromaticity to furnish 5-hydroxy-L-tryptophan.
A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine. PLP forms an imine with the amino acid derivative. The amine on the pyridine is protonated and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO2. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.
It has been proposed that histidine residue His122 of serotonin N-acetyl transferase is the catalytic residue that deprotonates the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A serves as a good leaving group when attacked by a general base to give N-acetylserotonin.
In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis. Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.
Blue light, principally around 460–480 nm, suppresses melatonin biosynthesis, 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 20th century produced relatively little blue light. Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions. Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. 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.
In humans, melatonin is a full agonist of melatonin receptor 1 (picomolar binding affinity) and melatonin receptor 2 (nanomolar binding affinity), both of which belong to the class of G-protein coupled receptors (GPCRs). Melatonin receptors 1 and 2 are both Gi/o-coupled GPCRs, although melatonin receptor 1 is also Gq-coupled. Melatonin also acts as a high-capacity free radical scavenger within mitochondria which also promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase via signal transduction through melatonin receptors.
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. Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60 minutes of administration, and is then eliminated. Melatonin has a half life of 35–50 minutes. In humans, 90% of orally administered exogenous 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. The bioavalibility of melatonin is between 10 and 50%.
Melatonin is metabolized in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. 5% of melatonin is excreted in the urine as the unchanged drug.
Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).
The membrane transport proteins that move melatonin across a membrane include, but are not limited to, glucose transporters, including GLUT1, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.
For research as well as clinical purposes, melatonin concentration in humans can be measured either from the saliva or blood plasma.
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 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 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: “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.”
It was approved for medical use in the European Union in 2007.
In vertebrates, melatonin is produced in darkness, thus usually at night, 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 nuclei from retinal photosensitive ganglion cells 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 (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage 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 and follicle-stimulating hormone 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.
Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors. This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.
Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions. Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram. Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats. In some common foods and beverages, including coffee and walnuts, the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.
Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.
Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada. FDA regulations applying to medications are not applicable to melatonin, though the FDA has found false claims that it cures cancer. As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin. In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.
Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g, bananas and grapes, rice and cereals, herbs, plums, 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 increase significantly.
Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011. The FDA considered whether these food products could continue to be sold with the label “dietary supplements”. On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive. A different company selling a melatonin-containing beverage received a warning letter in 2015.
Immediate-release melatonin is not tightly regulated in countries where it is available as an over-the-counter medication. It is available in doses from less than half a milligram to 5 mg or more. Immediate-release formulations cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, or liquids. It is also available for use sublingually, or as transdermal patches.[medical citation needed]
Melatonin is the most popular over-the-counter sleep remedy in the US, resulting in sales in excess of US$400 million during 2017.
A bottle of melatonin tablets. Melatonin is available in timed-release and in liquid forms.
A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive. A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.
Protection from radiation
Both animal and human studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure. Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known, major side effects.
A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.
A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhoea secondary to endometriosis.
A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.
Gastroesophageal reflux disease
A 2011 review said melatonin is effective in relieving epigastric pain and heartburn.
Melatonin might improve sleep in people with autism. 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.
While the packaging of melatonin often warns against use in people under 18 years of age, studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD, including children. However, larger and longer studies are needed to establish long-term safety and optimal dosing.
Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with midazolam in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy. Some evidence supports an antidepressant effect.
- ^ “Melatonin – Drugs.com”. Drugs.com. Retrieved 12 October 2018.
- ^ “Melatonin”. Sleepdex. Retrieved 17 August 2011.
- ^ Jump up to:a b c d e f Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL (August 2017). “Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders” (PDF). Sleep Medicine Reviews. 34: 10–22. doi:10.1016/j.smrv.2016.06.005. PMID 28648359.
- ^ Faraone SV (2014). ADHD: Non-Pharmacologic Interventions, An Issue of Child and Adolescent Psychiatric Clinics of North America, E-Book. Elsevier Health Sciences. p. 888. ISBN 9780323326025.
- ^ Jump up to:a b c Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, et al. (November 2004). “Melatonin for treatment of sleep disorders” (PDF). Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, Under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Rockville, MD: Agency for Healthcare Research and Quality. Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services (108): 1–7. doi:10.1037/e439412005-001. PMC 4781368. PMID 15635761. Retrieved 5 June2013.
- ^ Jump up to:a b c d e f Matheson E, Hainer BL (July 2017). “Insomnia: Pharmacologic Therapy”. American Family Physician. 96 (1): 29–35. PMID 28671376.
- ^ Jump up to:a b c British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 482–483. ISBN 9780857113382.
- ^ Jump up to:a b c Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, et al. (2015). “Management of Insomnia Disorder[Internet]”. AHRQ Comparative Effectiveness Reviews. 15 (16): EHC027–EF. PMID 26844312.
Evidence for benzodiazepine hypnotics, melatonin agonists in the general adult population, and most pharmacologic interventions in older adults was generally insufficient
- ^ Adams, Katie S. (2014). “Melatonin agonists in the management of sleep disorders: A focus on ramelteon and tasimelteon”. Mental Health Clinician. 4 (2): 59–64. doi:10.9740/mhc.n190087. Retrieved 25 October 2020.
However, the clinical relevance of this objective and therefore the author’s conclusion that these results support the potential use of ramelteon in circadian rhythm sleep disorders is questionable. … It is unclear whether Takeda Pharmaceuticals will pursue FDA indications for ramelteon for circadian rhythm disorders given these results.
- ^ Jump up to:a b c d e “Melatonin: Side Effects, Uses, Dosage (Kids/Adults)”. Drugs.com. Retrieved 9 January 2019.
- ^ Jump up to:a b c d e “Circadin EPAR”. European Medicines Agency (EMA). Retrieved 31 May 2020.Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b c “Slenyto EPAR”. European Medicines Agency (EMA). Retrieved 31 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b “Summary Safety Review – MELATONIN (N-acetyl-5-methoxytryptamine) – Review of the Safety of Melatonin in Children and Adolescents”. Government of Canada. Health Canada. 10 December 2015. Retrieved 9 January 2019.
- ^ Jump up to:a b “Melatonin- Oral”. Government of Canada. Health Canada. 28 August 2018. Retrieved 9 January 2019.
- ^ Jump up to:a b c Altun A, Ugur-Altun B (May 2007). “Melatonin: therapeutic and clinical utilization”. International Journal of Clinical Practice. 61 (5): 835–45. doi:10.1111/j.1742-1241.2006.01191.x. PMID 17298593. S2CID 18050554.
- ^ Boutin JA, Audinot V, Ferry G, Delagrange P (August 2005). “Molecular tools to study melatonin pathways and actions”. Trends in Pharmacological Sciences. 26 (8): 412–9. doi:10.1016/j.tips.2005.06.006. PMID 15992934.
- ^ Hardeland R (July 2005). “Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance”. Endocrine. 27 (2): 119–30. doi:10.1385/ENDO:27:2:119. PMID 16217125.
- ^ Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S (June 2001). “Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system”. Annals of the New York Academy of Sciences. 939 (1): 200–15. Bibcode:2001NYASA.939..200R. doi:10.1111/j.1749-6632.2001.tb03627.x. PMID 11462772. S2CID 20404509.
- ^ Jump up to:a b c d Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ (January 2012). “Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science”. Journal of Experimental Botany. 63 (2): 577–97. doi:10.1093/jxb/err256. PMID 22016420.
- ^ “Australian Public Assessment Report for Melatonin” (PDF). Australian Government Department of Health and Ageing Therapeutic Goods Administration. January 2011. pp. 2, 4. Retrieved 9 January 2019.
Monotherapy for the short term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
- ^ McCarter SJ, Boswell CL, St Louis EK, Dueffert LG, Slocumb N, Boeve BF, et al. (March 2013). “Treatment outcomes in REM sleep behavior disorder”. Sleep Medicine (Review). 14 (3): 237–42. doi:10.1016/j.sleep.2012.09.018. PMC 3617579. PMID 23352028.
- ^ McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. (July 2017). “Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium”. Neurology (Review). 89 (1): 88–100. doi:10.1212/WNL.0000000000004058. PMC 5496518. PMID 28592453.
- ^ Boot BP (2015). “Comprehensive treatment of dementia with Lewy bodies”. Alzheimer’s Research & Therapy (Review). 7 (1): 45. doi:10.1186/s13195-015-0128-z. PMC 4448151. PMID 26029267.
- ^ “Circadin – Summary of Product Characteristics (SmPC) – (eMC)”. Electronic Medicines Compendium. 29 June 2007. Retrieved 1 March 2018.
- ^ Abdelgadir IS, Gordon MA, Akobeng AK (December 2018). “Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis” (PDF). Archives of Disease in Childhood. 103 (12): 1155–1162. doi:10.1136/archdischild-2017-314181. PMID 29720494. S2CID 19107081.
- ^ McCleery, Jenny; Sharpley, Ann L. (15 November 2020). “Pharmacotherapies for sleep disturbances in dementia”. The Cochrane Database of Systematic Reviews. 11: CD009178. doi:10.1002/14651858.CD009178.pub4. ISSN 1469-493X. PMID 33189083.
- ^ Spinedi E, Cardinali DP (2019). “Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer’s Disease and Melatonin”. Neuroendocrinology. 108 (4): 354–364. doi:10.1159/000494889. PMID 30368508. S2CID 53101746.
- ^ Gao C, Scullin MK, Bliwise DL (2019). “Mild Cognitive Impairment and Dementia”. In Savard J, Ouellet MC (eds.). Handbook of Sleep Disorders in Medical Conditions. Academic Press. pp. 253–276. doi:10.1016/b978-0-12-813014-8.00011-1. ISBN 978-0-12-813014-8.
- ^ Jump up to:a b Herxheimer A, Petrie KJ (2002). “Melatonin for the prevention and treatment of jet lag”. The Cochrane Database of Systematic Reviews (2): CD001520. doi:10.1002/14651858.CD001520. PMID 12076414.
- ^ Jump up to:a b Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, Ruotsalainen JH (August 2014). “Pharmacological interventions for sleepiness and sleep disturbances caused by shift work”. The Cochrane Database of Systematic Reviews. 8 (8): CD009776. doi:10.1002/14651858.CD009776.pub2. PMID 25113164.
- ^ Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, et al. (December 2005). “The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis”. Journal of General Internal Medicine. 20 (12): 1151–8. doi:10.1111/j.1525-1497.2005.0243.x. PMC 1490287. PMID 16423108.
- ^ Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, et al. (February 2006). “Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis”. BMJ. 332 (7538): 385–93. doi:10.1136/bmj.38731.532766.F6. PMC 1370968. PMID 16473858.
- ^ Lyseng-Williamson KA (November 2012). “Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years”. Drugs & Aging. 29 (11): 911–23. doi:10.1007/s40266-012-0018-z. PMID 23044640. S2CID 1403262.
- ^ Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. 2014.
- ^ Brent Bauer, M.D. “Melatonin side effects: What are the risks?”. Mayo Clinic. Retrieved 17 August 2011.
- ^ Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU (October 2001). “Melatonin treatment for age-related insomnia”. The Journal of Clinical Endocrinology and Metabolism. 86 (10): 4727–30. doi:10.1210/jc.86.10.4727. PMID 11600532.
- ^ Morera AL, Henry M, de La Varga M (2001). “[Safety in melatonin use]” [Safety in melatonin use]. Actas Espanolas de Psiquiatria (in Spanish). 29 (5): 334–7. PMID 11602091.
- ^ Terry PD, Villinger F, Bubenik GA, Sitaraman SV (January 2009). “Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research”. Inflammatory Bowel Diseases. 15 (1): 134–40. doi:10.1002/ibd.20527. PMID 18626968.
- ^ Juszczak M, Michalska M (2006). “[The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion]” [The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion]. Postepy Higieny I Medycyny Doswiadczalnej (in Polish). 60: 431–8. PMID 16921343. Archived from the original on 2 November 2014. Retrieved 24 December 2013.
- ^ Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A (December 2009). “Melatonin and human reproduction: shedding light on the darkness hormone”. Gynecological Endocrinology. 25 (12): 779–85. doi:10.3109/09513590903159649. PMID 19905996. S2CID 3442003.
- ^ Shane-McWhorter L. Melatonin. Merck Manual Professional Version. October 2018. Accessed 22 April 2019.
- ^ Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A (June 2016). “A Review of Melatonin, Its Receptors and Drugs”. The Eurasian Journal of Medicine. 48 (2): 135–41. doi:10.5152/eurasianjmed.2015.0267. PMC 4970552. PMID 27551178.
- ^ Ardura J, Gutierrez R, Andres J, Agapito T (2003). “Emergence and evolution of the circadian rhythm of melatonin in children”. Hormone Research. 59 (2): 66–72. doi:10.1159/000068571. PMID 12589109. S2CID 41937922.
- ^ Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM (1986). “Human melatonin production decreases with age”. Journal of Pineal Research. 3 (4): 379–88. doi:10.1111/j.1600-079X.1986.tb00760.x. PMID 3783419. S2CID 33664568.
- ^ Hagenauer MH, Perryman JI, Lee TM, Carskadon MA (June 2009). “Adolescent changes in the homeostatic and circadian regulation of sleep”. Developmental Neuroscience. 31(4): 276–84. doi:10.1159/000216538. PMC 2820578. PMID 19546564.
- ^ Tan DX, Chen LD, Poeggeler B, L Manchester C, Reiter RJ. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr. J. 1993, 1, 57–60 https://docs.google.com/viewer?a=v&pid=sites&srcid=ZGVmYXVsdGRvbWFpbnxkdW54aWFudGFufGd4OjVkMjA5NGZkMzFmYjRkOTU
- ^ Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR (November 1994). “Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro”. Annals of the New York Academy of Sciences. 738 (1): 419–20. Bibcode:1994NYASA.738..419P. doi:10.1111/j.1749-6632.1994.tb21831.x. PMID 7832450. S2CID 36383425.
- ^ Jump up to:a b Arnao MB, Hernández-Ruiz J (May 2006). “The physiological function of melatonin in plants”. Plant Signaling & Behavior. 1 (3): 89–95. doi:10.4161/psb.1.3.2640. PMC 2635004. PMID 19521488.
- ^ Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F (1994). “Melatonin: a peroxyl radical scavenger more effective than vitamin E”. Life Sciences. 55 (15): PL271-6. doi:10.1016/0024-3205(94)00666-0. PMID 7934611.
- ^ Jump up to:a b c Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A (2017). “Melatonin and human mitochondrial diseases”. Journal of Research in Medical Sciences. 22: 2. doi:10.4103/1735-1995.199092. PMC 5361446. PMID 28400824.
- ^ Jump up to:a b c d e f g h Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, et al. (September 2016). “Update on melatonin receptors: IUPHAR Review 20”. British Journal of Pharmacology. 173 (18): 2702–25. doi:10.1111/bph.13536. PMC 4995287. PMID 27314810.
Hence, one melatonin molecule and its associated metabolites could scavenge a large number of reactive species, and thus, the overall antioxidant capacity of melatonin is believed to be greater than that of other well‐known antioxidants, such as vitamin C and vitamin E, under in vitro or in vivo conditions (Gitto et al., 2001; Sharma and Haldar, 2006; Ortiz et al., 2013).
- ^ Jump up to:a b c Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B (November 2017). “Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas”. Cellular and Molecular Life Sciences. 74 (21): 3863–3881. doi:10.1007/s00018-017-2609-7. PMID 28864909. S2CID 23820389.
melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant … The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood.
- ^ Jump up to:a b c Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (October 2016). “Melatonin as an antioxidant: under promises but over delivers”. Journal of Pineal Research. 61 (3): 253–78. doi:10.1111/jpi.12360. PMID 27500468. S2CID 35435683.
There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant.
- ^ Jump up to:a b c Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, et al. (November 2015). “Melatonin: an ancient molecule that makes oxygen metabolically tolerable”. Journal of Pineal Research. 59 (4): 403–19. doi:10.1111/jpi.12267. PMID 26272235. S2CID 24373303.
While originally thought to be produced exclusively in and secreted from the vertebrate pineal gland , it is now known that the indole is present in many, perhaps all, vertebrate organs  and in organs of all plants that have been investigated [48, 55, 56]. That melatonin is not relegated solely to the pineal gland is also emphasized by the reports that it is present in invertebrates [57–59], which lack a pineal gland and some of which consist of only a single cell.
- ^ Jump up to:a b c d e f Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R (November 2017). “Melatonin transport into mitochondria”. Cellular and Molecular Life Sciences. 74 (21): 3927–3940. doi:10.1007/s00018-017-2616-8. PMID 28828619. S2CID 10920415.
- ^ Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (July 2005). “A review of the multiple actions of melatonin on the immune system”. Endocrine. 27 (2): 189–200. doi:10.1385/ENDO:27:2:189. PMID 16217132. S2CID 21133107.
- ^ Arushanian EB, Beĭer EV (2002). “[Immunotropic properties of pineal melatonin]”. Eksperimental’naia i Klinicheskaia Farmakologiia (in Russian). 65 (5): 73–80. PMID 12596522.
- ^ Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D (May 2006). “The modulatory role of melatonin on immune responsiveness”. Current Opinion in Investigational Drugs. 7 (5): 423–31. PMID 16729718.
- ^ Maestroni GJ (March 2001). “The immunotherapeutic potential of melatonin”. Expert Opinion on Investigational Drugs. 10 (3): 467–76. doi:10.1517/135437220.127.116.117. PMID 11227046. S2CID 6822594.
- ^ “MetaCyc serotonin and melatonin biosynthesis”.
- ^ Jump up to:a b c d e Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C (April 2017). “Melatonin: Pharmacology, Functions and Therapeutic Benefits”. Current Neuropharmacology. 15 (3): 434–443. doi:10.2174/1570159X14666161228122115. PMC 5405617. PMID 28503116.
- ^ Bochkov DV, Sysolyatin SV, Kalashnikov AI, Surmacheva IA (January 2012). “Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources”. Journal of Chemical Biology. 5 (1): 5–17. doi:10.1007/s12154-011-0064-8. PMC 3251648. PMID 22826715.
- ^ Jump up to:a b c Hardeland R (February 2015). “Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions”. Journal of Experimental Botany. 66 (3): 627–46. doi:10.1093/jxb/eru386. PMID 25240067.
- ^ Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ (March 2013). “Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes”. Journal of Pineal Research. 54 (2): 127–38. doi:10.1111/jpi.12026. PMID 23137057. S2CID 206140413.
- ^ Roberts KM, Fitzpatrick PF (April 2013). “Mechanisms of tryptophan and tyrosine hydroxylase”. IUBMB Life. 65 (4): 350–7. doi:10.1002/iub.1144. PMC 4270200. PMID 23441081.
- ^ Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T (March 1992). “Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis”. Biochemistry. 31 (8): 2229–38. doi:10.1021/bi00123a004. PMID 1540578.
- ^ Jump up to:a b Dewick PM (2002). Medicinal Natural Products. A Biosynthetic Approach (2nd ed.). Wiley. ISBN 978-0-471-49640-3.
- ^ Hickman AB, Klein DC, Dyda F (January 1999). “Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism”. Molecular Cell. 3 (1): 23–32. doi:10.1016/S1097-2765(00)80171-9. PMID 10024876.
- ^ Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC (October 1993). “Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA”. DNA and Cell Biology. 12 (8): 715–27. doi:10.1089/dna.1993.12.715. PMID 8397829.
- ^ Nesbitt AD, Leschziner GD, Peatfield RC (September 2014). “Headache, drugs and sleep”. Cephalalgia (Review). 34 (10): 756–66. doi:10.1177/0333102414542662. PMID 25053748. S2CID 33548757.
- ^ Schomerus C, Korf HW (December 2005). “Mechanisms regulating melatonin synthesis in the mammalian pineal organ”. Annals of the New York Academy of Sciences. 1057 (1): 372–83. Bibcode:2005NYASA1057..372S. doi:10.1196/annals.1356.028. PMID 16399907. S2CID 20517556.
- ^ Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD (August 2001). “Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor”. The Journal of Neuroscience. 21 (16): 6405–12. doi:10.1523/JNEUROSCI.21-16-06405.2001. PMC 6763155. PMID 11487664.
- ^ “Recent News – Program of Computer Graphics”. http://www.graphics.cornell.edu.
- ^ Kayumov L, Casper RF, Hawa RJ, Perelman B, Chung SA, Sokalsky S, Shapiro CM (May 2005). “Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work”. The Journal of Clinical Endocrinology and Metabolism. 90 (5): 2755–61. doi:10.1210/jc.2004-2062. PMID 15713707.
- ^ Burkhart K, Phelps JR (December 2009). “Amber lenses to block blue light and improve sleep: a randomized trial”. Chronobiology International. 26 (8): 1602–12. doi:10.3109/07420520903523719. PMID 20030543.
- ^ “Melatonin receptors | G protein-coupled receptors | IUPHAR/BPS Guide to Pharmacology”. http://www.guidetopharmacology.org. Retrieved 7 April 2017.
- ^ Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC (October 2005). “Phase-dependent treatment of delayed sleep phase syndrome with melatonin”. Sleep. 28 (10): 1271–8. doi:10.1093/sleep/28.10.1271. PMID 16295212.
- ^ Terman MR, Wirz-Justice A (2009). Chronotherapeutics for Affective Disorders: A Clinician’s Manual for Light and Wake Therapy. Basel: S Karger Pub. p. 71. ISBN 978-3-8055-9120-1.
- ^ “Melatonin”. http://www.drugbank.ca. Retrieved 29 January 2019.
- ^ Kennaway DJ (August 2019). “A critical review of melatonin assays: Past and present”. Journal of Pineal Research. 67 (1): e12572. doi:10.1111/jpi.12572. PMID 30919486.
- ^ Filadelfi AM, Castrucci AM (May 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. S2CID 41959214.
- ^ Sugden D, Davidson K, Hough KA, Teh MT (October 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.
- ^ Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD (2005). Encyclopedia of dietary supplements. New York, N.Y: Marcel Dekker. pp. 457–66. ISBN 978-0-8247-5504-1.
- ^ McCord CP, Allen FP (January 1917). “Evidences associating pineal gland function with alterations in pigmentation”. J Exp Zool. 23 (1): 206–24. doi:10.1002/jez.1400230108.
- ^ Lerner AB, Case JD, Takahashi Y (July 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 HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH (January 1975). “Daily rhythm in human urinary melatonin”. Science. 187 (4172): 169–71. Bibcode:1975Sci…187..169L. doi:10.1126/science.1167425. PMID 1167425.
- ^ Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC (May 1993). “Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis”. Journal of Pineal Research. 14 (4): 151–68. doi:10.1111/j.1600-079X.1993.tb00498.x. PMID 8102180. S2CID 23460208.
- ^ US patent 5449683, Wurtman RJ, “Methods of inducing sleep using melatonin”, issued 12 September 1995, assigned to Massachusetts Institute of Technology
- ^ Arendt J (August 2005). “Melatonin: characteristics, concerns, and prospects”. Journal of Biological Rhythms. 20 (4): 291–303. doi:10.1177/0748730405277492. PMID 16077149. S2CID 19011222.
There is very little evidence in the short term for toxicity or undesirable effects in humans. The extensive promotion of the miraculous powers of melatonin in the recent past did a disservice to acceptance of its genuine benefits.
- ^ Arendt J (October 2000). “Melatonin, circadian rhythms, and sleep”. The New England Journal of Medicine. 343 (15): 1114–6. doi:10.1056/NEJM200010123431510. PMID 11027748.
- ^ Reiter RJ (May 1991). “Pineal melatonin: cell biology of its synthesis and of its physiological interactions”. Endocrine Reviews. 12 (2): 151–80. doi:10.1210/edrv-12-2-151. PMID 1649044. S2CID 3219721.
- ^ Richardson GS (2005). “The human circadian system in normal and disordered sleep”. The Journal of Clinical Psychiatry. 66 Suppl 9: 3–9, quiz 42–3. PMID 16336035.
- ^ Perreau-Lenz S, Pévet P, Buijs RM, Kalsbeek A (January 2004). “The biological clock: the bodyguard of temporal homeostasis”. Chronobiology International. 21 (1): 1–25. doi:10.1081/CBI-120027984. PMID 15129821. S2CID 42725506.
- ^ Lincoln GA, Andersson H, Loudon A (October 2003). “Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis”. The Journal of Endocrinology. 179 (1): 1–13. doi:10.1677/joe.0.1790001. PMID 14529560.
- ^ Jump up to:a b Arendt J, Skene DJ (February 2005). “Melatonin as a chronobiotic”. Sleep Medicine Reviews. 9 (1): 25–39. doi:10.1016/j.smrv.2004.05.002. PMID 15649736.
Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during ‘biological daytime’, and when suitably timed (it is most effective around dusk and dawn), it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times.
- ^ Chaturvedi CM (1984). “Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis”. Australian Journal of Zoology. 32 (6): 803–09. doi:10.1071/ZO9840803.
- ^ Chen HJ (July 1981). “Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition”. Neuroendocrinology. 33 (1): 43–6. doi:10.1159/000123198. PMID 7254478.
- ^ Jump up to:a b Huelsmann M, Hecker N, Springer MS, Gatesy J, Sharma V, Hiller M (September 2019). “Genes lost during the transition from land to water in cetaceans highlight genomic changes associated with aquatic adaptations”. Science Advances. 5 (9): eaaw6671. Bibcode:2019SciA….5.6671H. doi:10.1126/sciadv.aaw6671. PMC 6760925. PMID 31579821.
- ^ Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ (1 January 2009). “Phytomelatonin: a review”. Journal of Experimental Botany. 60 (1): 57–69. doi:10.1093/jxb/ern284. PMID 19033551. S2CID 15738948.
- ^ Bonnefont-Rousselot D, Collin F (November 2010). “Melatonin: action as antioxidant and potential applications in human disease and aging”. Toxicology. 278 (1): 55–67. doi:10.1016/j.tox.2010.04.008. PMID 20417677.
- ^ Reiter RJ, Manchester LC, Tan DX (September 2005). “Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood”. Nutrition. 21 (9): 920–4. doi:10.1016/j.nut.2005.02.005. PMID 15979282.
- ^ Reiter RJ, Tan DX, Zhou Z, Cruz MH, Fuentes-Broto L, Galano A (April 2015). “Phytomelatonin: assisting plants to survive and thrive”. Molecules. 20 (4): 7396–437. doi:10.3390/molecules20047396. PMC 6272735. PMID 25911967.
- ^ Arnao MB, Hernández-Ruiz J (September 2015). “Functions of melatonin in plants: a review”. Journal of Pineal Research. 59 (2): 133–50. doi:10.1111/jpi.12253. PMID 26094813.
- ^ “187 Fake Cancer ‘Cures’ Consumers Should Avoid”. U.S. Food and Drug Administration. Archived from the original on 2 May 2017. Retrieved 20 May 2020.
- ^ Guardiola-Lemaître B (December 1997). “Toxicology of melatonin”. Journal of Biological Rhythms. 12 (6): 697–706. doi:10.1177/074873049701200627. PMID 9406047. S2CID 31090576.
- ^ Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ (October 2001). “Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus)”. Journal of Agricultural and Food Chemistry. 49 (10): 4898–902. doi:10.1021/jf010321. PMID 11600041.
- ^ González-Flores D, Velardo B, Garrido M, González-Gómez D, Lozano M, Ayuso MC, Barriga C, Paredes SD, Rodríguez AB (2011). “Ingestion of Japanese plums (Prunus salicina Lindl. cv. Crimson Globe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content”. Journal of Food and Nutrition Research. 50(4): 229–36.
- ^ Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (May 2011). “Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection”. Journal of Pineal Research. 50 (4): 374–80. doi:10.1111/j.1600-079X.2010.00853.x. PMID 21342247. S2CID 8034935.
- ^ Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, et al. (March 1995). “Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates”. Biochemistry and Molecular Biology International. 35(3): 627–34. PMID 7773197.
- ^ Sae-Teaw M, Johns J, Johns NP, Subongkot S (August 2013). “Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers”. Journal of Pineal Research. 55 (1): 58–64. doi:10.1111/jpi.12025. PMID 23137025. S2CID 979886.
- ^ Catherine Saint Louis (14 May 2011). “Dessert, Laid-Back and Legal”. The New York Times.
- ^ Rodriguez RR (13 January 2010). “Warning Letter”. Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration. Archived from the original on 12 January 2017.
- ^ Bebida Beverage Company U.S. Food and Drug Administration 4 March 2015 (Accessed 8 December 2017)
- ^ “Melatonin”. Drugs.com. Retrieved 17 August 2011.
- ^ Loria K. “Does Melatonin Really Help You Sleep?”. Consumer Reports. Retrieved 16 March 2019.
- ^ Miroddi M, Bruno R, Galletti F, Calapai F, Navarra M, Gangemi S, Calapai G (March 2015). “Clinical pharmacology of melatonin in the treatment of tinnitus: a review”. European Journal of Clinical Pharmacology. 71 (3): 263–70. doi:10.1007/s00228-015-1805-3. PMID 25597877. S2CID 16466238.
- ^ Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA (April 2006). “Potential therapeutic use of melatonin in migraine and other headache disorders”. Expert Opinion on Investigational Drugs. 15 (4): 367–75. doi:10.1517/13543718.104.22.1687. PMID 16548786. S2CID 28114683.
- ^ Evars S, Goadsby P (2005). “Review: Hypnic headache” (PDF). Practical Neurology. 5(3): 144–49. doi:10.1111/j.1474-7766.2005.00301.x. S2CID 1196313. Retrieved 12 January 2018.
- ^ Pdq Integrative, Alternative (May 2013). “Topics in complementary and alternative therapies (PDQ)”. PDQ Cancer Information Summaries [Internet]. National Cancer Institute, National Institutes of Health. PMID 26389506.
- ^ Mills E, Wu P, Seely D, Guyatt G (November 2005). “Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis”. Journal of Pineal Research. 39 (4): 360–6. doi:10.1111/j.1600-079X.2005.00258.x. PMID 16207291. S2CID 22225091.
- ^ Meltz ML, Reiter RJ, Herman TS, Kumar KS (March 1999). “Melatonin and protection from whole-body irradiation: survival studies in mice”. Mutation Research. 425 (1): 21–7. doi:10.1016/S0027-5107(98)00246-2. PMID 10082913.
- ^ Reiter RJ, Herman TS, Meltz ML (December 1996). “Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers”. Mutation Research. 371 (3–4): 221–8. doi:10.1016/S0165-1218(96)90110-X. PMID 9008723.
- ^ Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J (March 2016). “Dietary supplements for dysmenorrhoea”. The Cochrane Database of Systematic Reviews. 3 (3): CD002124. doi:10.1002/14651858.cd002124.pub2. PMC 7387104. PMID 27000311.
- ^ Reiter RJ, Herman TS, Meltz ML (February 1998). “Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes”. Mutation Research. 397 (2): 203–8. doi:10.1016/S0027-5107(97)00211-X. PMID 9541644.
- ^ Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (January 2007). “One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?”. Journal of Pineal Research. 42 (1): 28–42. doi:10.1111/j.1600-079X.2006.00407.x. PMID 17198536. S2CID 40005308.
- ^ Shirazi A, Ghobadi G, Ghazi-Khansari M (July 2007). “A radiobiological review on melatonin: a novel radioprotector”. Journal of Radiation Research. 48 (4): 263–72. Bibcode:2007JRadR..48..263S. doi:10.1269/jrr.06070. PMID 17641465.
- ^ Brigo F, Igwe SC, Del Felice A (August 2016). “Melatonin as add-on treatment for epilepsy”. The Cochrane Database of Systematic Reviews (8): CD006967. doi:10.1002/14651858.CD006967.pub4. PMC 7386917. PMID 27513702.
- ^ Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J (March 2016). “Dietary supplements for dysmenorrhoea”. The Cochrane Database of Systematic Reviews. 3: CD002124. doi:10.1002/14651858.CD002124.pub2. PMC 7387104. PMID 27000311.
- ^ Siddiqi N, Harrison JK, Clegg A, Teale EA, Young J, Taylor J, Simpkins SA (March 2016). “Interventions for preventing delirium in hospitalised non-ICU patients” (PDF). The Cochrane Database of Systematic Reviews. 3: CD005563. doi:10.1002/14651858.CD005563.pub3. PMID 26967259.
- ^ Kandil TS, Mousa AA, El-Gendy AA, Abbas AM (January 2010). “The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease”. BMC Gastroenterology. 10: 7. doi:10.1186/1471-230X-10-7. PMC 2821302. PMID 20082715.
- ^ Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM (May 2009). “Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis”. Developmental Medicine and Child Neurology (Meta-analysis). 51 (5): 340–9. doi:10.1111/j.1469-8749.2008.03244.x. PMID 19379289. S2CID 35553148.
- ^ Jump up to:a b Rossignol DA, Frye RE (September 2011). “Melatonin in autism spectrum disorders: a systematic review and meta-analysis”. Developmental Medicine and Child Neurology (Meta-analysis). 53 (9): 783–792. doi:10.1111/j.1469-8749.2011.03980.x. PMID 21518346. S2CID 9951986.
- ^ Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, Malow BA (January 2015). “Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay”. Journal of Autism and Developmental Disorders. 45 (1): 100–10. doi:10.1007/s10803-014-2197-4. PMC 4289108. PMID 25059483.
- ^ “Melatonin improves sleep quality and behavior in children with asperger disorder”. Truthly. Retrieved 15 February 2015.
- ^ Giannotti F, Cortesi F, Cerquiglini A, Bernabei P (August 2006). “An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism”. Journal of Autism and Developmental Disorders. 36 (6): 741–52. doi:10.1007/s10803-006-0116-z. PMID 16897403. S2CID 19724241.
- ^ Bendz LM, Scates AC (January 2010). “Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder”. The Annals of Pharmacotherapy. 44(1): 185–91. doi:10.1345/aph.1M365. PMID 20028959. S2CID 207263711.
- ^ Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM (April 2015). “Melatonin for pre- and postoperative anxiety in adults”. The Cochrane Database of Systematic Reviews(4): CD009861. doi:10.1002/14651858.CD009861.pub2. PMC 6464333. PMID 25856551.
- ^ Lewis A (1999). Melatonin and the Biological Clock. McGraw-Hill. p. 23. ISBN 978-0-87983-734-1.
- ^ Valdés-Tovar M, Estrada-Reyes R, Solís-Chagoyán H, Argueta J, Dorantes-Barrón AM, Quero-Chávez D, et al. (August 2018). “Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression”. British Journal of Pharmacology. 175(16): 3200–3208. doi:10.1111/bph.14197. PMC 6057892. PMID 29512136.
External links "Melatonin". Drug Information Portal. U.S. National Library of Medicine.
//////////Melatonin, Melatobel, メラトニン , JAPAN 2020, 2020 APPROVALS