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Melatonin is a hormone, produced by the pineal gland among other locations, which regulates wakefulness.
Side effects from supplements are minimal at low doses.
Melatonin was discovered in 1958.
1 Medical use
1.1 Sleep disorders
1.2 Jet lag and shift work
2 Adverse effects
3.1 Circadian rhythm
3.3 Immune system
7 Other animals
9.1 Dietary supplement
9.2 Food products
10 Commercial availability
11.3 Protection from radiation
11.5 Secondary dysmenorrhoea
11.7 Gastroesophageal reflux disease
12 See also
14 External links
Positions on the benefits of melatonin for insomnia are mixed.
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.
Melatonin reduces the time until onset of sleep and increases sleep duration in children with neurodevelopmental disorders.
A 2016 review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer’s disease.
Jet lag and shift work
Melatonin is known to aid in reducing the effects of jet lag, especially in eastward travel, by promoting the necessary reset of the body’s sleep-wake phase. If the timing is not correct, however, it can instead delay adaption.
Melatonin appears to have limited use against the sleep problems of people who work rotating or night shifts.
Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses. 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.
Melatonin can cause nausea, next-day grogginess, and irritability.
Melatonin can lower follicle-stimulating hormone levels.
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.
Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993.
Melatonin occurs at high concentrations within mitochondrial fluid, greatly exceeding the concentration of melatonin in blood plasma.
The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals.
While it is known that melatonin interacts with the immune system, 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 and 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 O 2 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. O 2 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 CO 2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine.
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.
N-acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.
In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine. Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.
Blue light, principally around 460 to 480 nm, suppresses melatonin,
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).
This section needs expansion with: metabolites from enzymatic metabolism of melatonin. You can help by adding to it. (July 2018)
When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg
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.
Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin.
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. 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.
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. 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.
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. 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.
Research from the University of Buffalo has found that the substances used in the manufacturing of pesticides bind to melatonin receptors and can influence the circadian rhythm.
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.
Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,
As reported in the New York Times in May 2011,
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, tablets, or liquids. It is also available for use sublingually, or as transdermal patches.
Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic and does not carry a risk of contamination or the means of transmitting infectious material.
A bottle of melatonin tablets. Melatonin is available in timed-release and in liquid forms.
Various uses and effects of melatonin have been studied. A 2015 review of studies of melatonin in tinnitus found the quality of evidence low, but not entirely without promise.
Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.
A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive.
Protection from radiation
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. 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, available studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD. 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.
Health effects of sunlight exposure
Melatonin receptor agonist#Drug design and development
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