Melatonin

Short description: Hormone primarily released by the pineal gland

Not to be confused with melanin. For the album, see Melatonin (album).

Melatonin

Clinical data
Pronunciation| /ˌmɛləˈtoʊnɪn/ (listen)
Trade names| Circadin, Slenyto, others[1]
Other names| N-acetyl-5-methoxy tryptamine[2]
AHFS/Drugs.com| Consumer Drug Information
License data|

* EU EMA: by INN
* US DailyMed: Melatonin

Routes of
administration| By mouth, sublingual, transdermal
ATC code|

* N05CH01 (WHO)

Physiology data
Source tissues| pineal gland
Target tissues| wide spread, including brain, retina, and circulatory system
Receptors| melatonin receptor
Precursor| N-acetylserotonin
Metabolism| Liver via CYP1A2 mediated 6-hydroxylation
Legal status
Legal status|

* AU: S3 (Pharmacist Only Medicine)
* CA: OTC
* UK: POM (Prescription only)
* US: OTC
* EU: Rx-only
* In general: ℞ (Prescription only)

Pharmacokinetic data
Bioavailability| 30–50%
Metabolism| Liver via CYP1A2 mediated 6-hydroxylation
Metabolites| 6-hydroxymelatonin, N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine
Elimination half-life| 30–50 minutes[3]
Excretion| Kidney
Identifiers

IUPAC name

* N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide

CAS Number|

* 73-31-4 Y

PubChem CID|

* 896

IUPHAR/BPS|

* 224

DrugBank|

* DB01065 Y

ChemSpider|

* 872 Y

UNII|

* JL5DK93RCL

KEGG|

* D08170 Y

ChEBI|

* CHEBI:16796 Y

ChEMBL|

* ChEMBL45 Y

Chemical and physical data
Formula| C13H16N2O2
Molar mass| 232.283 g·mol−1
3D model (JSmol)|

* Interactive image

Melting point| 117 °C (243 °F)

SMILES

* COC1=CC2=C(NC=C2CCNC(C)=O)C=C1

InChI

* InChI=1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16) Y

* Key:DRLFMBDRBRZALE-UHFFFAOYSA-N Y

(verify)

Melatonin is a hormone primarily released by the pineal gland at night, and has long been associated with control of the sleep–wake cycle.[3][4] 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 orally.[5][6][7] Evidence of its benefit for this use, however, is not strong.[8] A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.[6]

Side effects from melatonin supplements are minimal at low doses for short durations.[3][9] Melatonin side effects are rare but may occur in 1 to 10 patients in a 1000.[9][10] 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.[10][11][9][12][13] Its use is not recommended during pregnancy or breastfeeding or for those with liver disease.[7][13]

In vertebrates, melatonin is involved in synchronizing circadian rhythms, including sleep–wake timing and blood pressure regulation, and in control of seasonal rhythmicity including reproduction, fattening, moulting and hibernation.[14] Many of its effects are through activation of the melatonin receptors, while others are due to its role as an antioxidant.[15][16][17] In plants, it functions to defend against oxidative stress.[18] It is also present in various foods.[9]

Melatonin was discovered in 1958.[3] It is sold over the counter in Canada and the United States;[9][12] in the United Kingdom, it is a prescription-only medication.[7] It is not approved by the US Food and Drug Administration (FDA) for any medical use.[9] In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.[19][10] In the European Union, it is indicated for the treatment of insomnia in children and adolescents.[11] It was approved for medical use in the European Union in 2007.[10]

## Contents

* 1 Medical uses
* 1.1 Sleep disorders
* 1.2 Dementia
* 1.3 Jet lag and shift work
* 2 Adverse effects
* 3 Functions
* 3.1 Circadian rhythm
* 3.2 Antioxidant
* 3.3 Immune system
* 4 Biosynthesis
* 4.1 Mechanism
* 4.2 Regulation
* 5 Pharmacology
* 5.1 Pharmacodynamics
* 5.2 Pharmacokinetics
* 6 History
* 7 In other species
* 7.1 Other animals
* 7.2 Plants
* 7.3 Fungi
* 8 Occurrence
* 8.1 Dietary supplement
* 8.2 Food products
* 9 Commercial availability
* 10 Research
* 10.1 Psychiatry
* 10.1.1 Bipolar disorder
* 10.1.2 Other mental conditions
* 10.2 Headaches
* 10.3 Cancer
* 10.4 Protection from radiation
* 10.5 Epilepsy
* 10.6 Secondary dysmenorrhoea
* 10.7 Delirium
* 10.8 Gastroesophageal reflux disease
* 11 References
* 12 External links

## Medical uses

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[11] 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.[10]

### Sleep disorders

Positions on the benefits of melatonin for insomnia are mixed.[8] A review by the Agency for Healthcare Research and Quality (AHRQ) from 2015 stated that evidence of benefit in the general population was unclear.[8] A review from 2017 found a modest effect on time until onset of sleep.[3] Another review from 2017 put this decrease at six minutes to sleep onset but found no difference in total sleep time.[6] Melatonin may also be useful in delayed sleep phase syndrome.[3] The melatonin receptor agonist medication ramelteon may work as well as melatonin supplements,[6] at greater cost but with different adverse effects, for some sleep conditions.[20]

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.[21][22][23] In Europe it is used for short-term treatment of insomnia in people who are 55 years old or older.[24] It is deemed to be a first line agent in this group.[6]

Melatonin reduces the time until onset of sleep and increases sleep duration in children with neurodevelopmental disorders.[25]

In psychiatric research, melatonin is of interest not only for insomnia but also in the context of drug repurposing strategies to treat severe mental disorders such as bipolar disorder.[26]

### Dementia

A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease.[27] 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.[28] Melatonin may, however, help with sundowning.[29]

### Jet lag and shift work

Melatonin is known to reduce jet lag, especially in eastward travel. But, if the time it is taken is not correct, it can instead delay adaptation.[30]

Melatonin appears to have limited use against the sleep problems of people who work shift work.[31] Tentative evidence suggests that it increases the length of time people are able to sleep.[31]

## Adverse effects

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.[32][33] Prolonged-release melatonin is safe with long-term use of up to 12 months.[34] Although not recommended for long-term use beyond this,[35] 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.[36]

There is emerging evidence that the timing of taking exogenous melatonin in relation to food is also an important factor.[37] Specifically, taking exogenous melatonin shortly after a meal is correlated with impaired glucose tolerance. Therefore, Rubio-Sastre and colleagues recommend waiting at least 2 hours after the last meal before taking a melatonin supplement.[38]

Melatonin can cause nausea, next-day grogginess, and irritability.[39] In the elderly, it can cause reduced blood flow and hypothermia.[40] In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[41][42]

Melatonin can lower follicle-stimulating hormone levels.[43] Melatonin's effects on human reproduction remain unclear.[44]

In those taking warfarin, some evidence suggests there may exist a potentiating drug interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.[45]

## Functions

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.

### Circadian rhythm

In animals, melatonin plays an important role in the regulation of sleep–wake cycles.[46] Human infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.[47] Human melatonin production decreases as a person ages.[48] Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.[49]

### Antioxidant

Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993.[50] In vitro, melatonin acts as a direct scavenger of oxygen radicals and reactive nitrogen species including OH•, O2−•, and NO•.[51][52] In plants, melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.[52] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.[53] Via signal transduction through melatonin receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.[54][55]

Melatonin occurs at high concentrations within mitochondrial fluid which greatly exceed the plasma concentration of melatonin.[56][57][58] 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.[54][56][57][58][59]

The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals.[55][59] Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).[55][59]

### Immune system

While it is known that melatonin interacts with the immune system,[60][61] 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,[62] and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[63] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

## Biosynthesis

Overview of melatonin biosynthesis

In animals, biosynthesis of melatonin occurs through hydroxylation, decarboxylation, acetylation and a methylation starting with L-tryptophan.[64] 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.[65] Hydroxyindole O-methyltransferase and S-adenosyl methionine convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.[65]

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.[66][67]

It has been hypothesized that melatonin is made in the mitochondria and chloroplasts.[68]

### Mechanism

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.[69]

A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine.[70] 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.[71]

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.[72]

N-acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.[71][73]

### Regulation

In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine.[74] 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.[75] 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,[76] 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.[77] The incandescent light bulb widely used in the 20th century produced relatively little blue light.[78] Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.[79] Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss.[80] 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.[81]

## Pharmacology

### Pharmacodynamics

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).[55][82] Melatonin receptors 1 and 2 are both Gi/o-coupled GPCRs, although melatonin receptor 1 is also Gq-coupled.[55] 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.[54][55][56][57][58][59]

### Pharmacokinetics

When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg[83]) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.[84] Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60 minutes of administration, and is then eliminated.[65] Melatonin has a half life of 35–50 minutes.[85] 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.[5] The bioavalibility of melatonin is between 10 and 50%.[65]

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.[65]

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).[55][59]

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.[55][59]

For research as well as clinical purposes, melatonin concentration in humans can be measured either from the saliva or blood plasma.[86]

## History

Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin.[87][88] 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.[89][90]

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.[91] In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands.[92]

The discovery that melatonin is an antioxidant was made in 1993.[93] The first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.[94] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[95] 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."[96]

It was approved for medical use in the European Union in 2007.[10]

## In other species

### Other animals

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland[97] 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[98][99] 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.[100] In animals including humans,[101] 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.[101] 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[102] and hamsters.[103] 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.[104] This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.[104]

### Plants

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.[18][105] 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.[67][106] 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.[18] In some common foods and beverages, including coffee[18] and walnuts,[107] 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.[67][108][109]

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice.[110][111]

Fungal disease resistance is another role. Added melatonin increases resistance in Malus prunifolia against Diplocarpon mali.[111][112] Also acts as a growth inhibitor on fungal pathogens including Alternaria, Botrytis, and Fusarium spp. Decreases the speed of infection. As a seed treatment, protects Lupinus albus from fungi. Dramatically slows Pseudomonas syringae tomato DC3000 infecting Arabidopsis thaliana and infecting Nicotiana benthamiana.[112]

### Fungi

Melatonin has been observed to reduce stress tolerance in Phytophthora infestans in plant-pathogen systems.[113]

## Occurrence

### Dietary supplement

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.[5] FDA regulations applying to medications are not applicable to melatonin,[14] though the FDA has found false claims that it cures cancer.[114] 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.[30] In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.[115] According to Harriet Hall caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from -83% to +478%, lot-to-lot variability was as high as 465%, and the discrepancies were not correlated to any manufacturer or product type. To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin.[116][117]

### Food products

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,[118] bananas, plums, grapes, rice, cereals, herbs,[119] olive oil, wine,[120] and beer.[121] The consumption of milk and sour cherries may improve sleep quality.[122] When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[123] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.[124]

Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.[125] 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.[126] A different company selling a melatonin-containing beverage received a warning letter in 2015.[127]

## Commercial availability

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 0.3 mg to 10 mg or more, it is possible to buy raw melatonin powder by the pound.[128] 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.

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material.[14][129]

Melatonin is the most popular over-the-counter sleep remedy in the US, resulting in sales in excess of US$400 million during 2017.[130]

## Research

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.[131]

### Psychiatry

#### Bipolar disorder

Melatonin, along with ramelteon, has been repurposed as a possible adjunctive treatment for manic episodes in bipolar disorder.[26] However, meta-analytic evidence is somehow inconsistent and of limited interest so far, although the small samples of trials do not allow ruling out its beneficial effect.[26] In any case, current evidence does not support the use of add-on melatonin-receptor agonists for mania.[26]

#### Other mental conditions

Melatonin might improve sleep in people with autism.[132] Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin.[133][134] Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings.[133][135][136] 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.[137]

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 benzodiazepine in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.[138]

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.[139] Some evidence supports an antidepressant effect.[140]

### Headaches

Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.[141][142]

### Cancer

A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive.[143] A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.[144]

### Protection from radiation

Both animal[145] and human[146][147][148] 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.[149] 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.[150]

### Epilepsy

A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.[151]

### Secondary dysmenorrhoea

A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhoea secondary to endometriosis.[152]

### Delirium

A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.[153]

### Gastroesophageal reflux disease

A 2011 review said melatonin is effective in relieving epigastric pain and heartburn.[154]

## References

1. ↑ "Melatonin - Drugs.com". Drugs.com. https://www.drugs.com/international/melatonin.html.
2. ↑ "Melatonin". Sleepdex. http://www.sleepdex.org/melatonin.htm.
3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders". Sleep Medicine Reviews 34: 10–22. August 2017. doi:10.1016/j.smrv.2016.06.005. PMID 28648359. http://epubs.surrey.ac.uk/813219/1/Riha accepted MS 2016.pdf.
4. ↑ ADHD: Non-Pharmacologic Interventions, An Issue of Child and Adolescent Psychiatric Clinics of North America, E-Book. Elsevier Health Sciences. 2014. p. 888. ISBN 9780323326025. https://books.google.com/books?id=lNSlBAAAQBAJ&pg=PA888.
5. ↑ 5.0 5.1 5.2 "Melatonin for treatment of sleep disorders". 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. November 2004. doi:10.1037/e439412005-001. PMID 15635761. PMC 4781368. http://archive.ahrq.gov/downloads/pub/evidence/pdf/melatonin/melatonin.pdf. Retrieved 5 June 2013.
6. ↑ 6.0 6.1 6.2 6.3 6.4 "Insomnia: Pharmacologic Therapy". American Family Physician 96 (1): 29–35. July 2017. PMID 28671376.
7. ↑ 7.0 7.1 7.2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 482–483. ISBN 9780857113382.
8. ↑ 8.0 8.1 8.2 "Management of Insomnia Disorder[Internet]". AHRQ Comparative Effectiveness Reviews 15 (16): EHC027–EF. 2015. PMID 26844312. "Evidence for benzodiazepine hypnotics, melatonin agonists in the general adult population, and most pharmacologic interventions in older adults was generally insufficient".
9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Melatonin: Side Effects, Uses, Dosage (Kids/Adults)". https://www.drugs.com/melatonin.html.
10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 "Circadin EPAR". https://www.ema.europa.eu/en/medicines/human/EPAR/circadin. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
11. ↑ 11.0 11.1 11.2 "Slenyto EPAR". https://www.ema.europa.eu/en/medicines/human/EPAR/slenyto. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
12. ↑ 12.0 12.1 "Summary Safety Review – MELATONIN (N-acetyl-5-methoxytryptamine) – Review of the Safety of Melatonin in Children and Adolescents". Health Canada. 10 December 2015. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-melatonin-acetyl-methoxytryptamine-review-safety-melatonin-children-adolescents.html.
13. ↑ 13.0 13.1 "Melatonin- Oral". Health Canada. 28 August 2018. http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=melatonin.oral&lang=eng.
14. ↑ 14.0 14.1 14.2 "Melatonin: therapeutic and clinical utilization". International Journal of Clinical Practice 61 (5): 835–45. May 2007. doi:10.1111/j.1742-1241.2006.01191.x. PMID 17298593.
15. ↑ "Molecular tools to study melatonin pathways and actions". Trends in Pharmacological Sciences 26 (8): 412–9. August 2005. doi:10.1016/j.tips.2005.06.006. PMID 15992934.
16. ↑ "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine 27 (2): 119–30. July 2005. doi:10.1385/ENDO:27:2:119. PMID 16217125.
17. ↑ "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. June 2001. doi:10.1111/j.1749-6632.2001.tb03627.x. PMID 11462772. Bibcode: 2001NYASA.939..200R.
18. ↑ 18.0 18.1 18.2 18.3 "Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science". Journal of Experimental Botany 63 (2): 577–97. January 2012. doi:10.1093/jxb/err256. PMID 22016420.
19. ↑ "Australian Public Assessment Report for Melatonin". January 2011. pp. 2, 4. https://www.tga.gov.au/sites/default/files/auspar-circadin-110118.pdf. "Monotherapy for the short term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over."
20. ↑ "Melatonin agonists in the management of sleep disorders: A focus on ramelteon and tasimelteon". Mental Health Clinician 4 (2): 59–64. 2014. doi:10.9740/mhc.n190087. https://meridian.allenpress.com/mhc/article/4/2/59/37092/Melatonin-agonists-in-the-management-of-sleep. "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.".
21. ↑ "Treatment outcomes in REM sleep behavior disorder". Sleep Medicine 14 (3): 237–42. March 2013. doi:10.1016/j.sleep.2012.09.018. PMID 23352028.
22. ↑ "Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium". Neurology 89 (1): 88–100. July 2017. doi:10.1212/WNL.0000000000004058. PMID 28592453.
23. ↑ "Comprehensive treatment of dementia with Lewy bodies". Alzheimer's Research & Therapy 7 (1): 45. 2015. doi:10.1186/s13195-015-0128-z. PMID 26029267.
24. ↑ "Circadin - Summary of Product Characteristics (SmPC) - (eMC)". Electronic Medicines Compendium. 29 June 2007. https://www.medicines.org.uk/emc/product/2809.
25. ↑ "Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis". Archives of Disease in Childhood 103 (12): 1155–1162. December 2018. doi:10.1136/archdischild-2017-314181. PMID 29720494. http://clok.uclan.ac.uk/22738/1/22738 MelatoninSystematicReview ADC ( Clean copy).pdf.
26. ↑ 26.0 26.1 26.2 26.3 "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research 143: 230–238. September 2021. doi:10.1016/j.jpsychires.2021.09.018.
27. ↑ "Pharmacotherapies for sleep disturbances in dementia". The Cochrane Database of Systematic Reviews 2020 (11): CD009178. November 2020. doi:10.1002/14651858.CD009178.pub4. PMID 33189083. PMC 8094738. https://pubmed.ncbi.nlm.nih.gov/33189083.
28. ↑ "Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer's Disease and Melatonin". Neuroendocrinology 108 (4): 354–364. 2019. doi:10.1159/000494889. PMID 30368508. https://repositorio.uca.edu.ar/handle/123456789/9108.
29. ↑ "Mild Cognitive Impairment and Dementia". Handbook of Sleep Disorders in Medical Conditions. Academic Press. 2019. pp. 253–276. doi:10.1016/b978-0-12-813014-8.00011-1. ISBN 978-0-12-813014-8.
30. ↑ 30.0 30.1 "Melatonin for the prevention and treatment of jet lag". The Cochrane Database of Systematic Reviews (2): CD001520. 2002. doi:10.1002/14651858.CD001520. PMID 12076414.
31. ↑ 31.0 31.1 "Pharmacological interventions for sleepiness and sleep disturbances caused by shift work". The Cochrane Database of Systematic Reviews 8 (8): CD009776. August 2014. doi:10.1002/14651858.CD009776.pub2. PMID 25113164. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802015000100067.
32. ↑ "The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis". Journal of General Internal Medicine 20 (12): 1151–8. December 2005. doi:10.1111/j.1525-1497.2005.0243.x. PMID 16423108.
33. ↑ "Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis". BMJ 332 (7538): 385–93. February 2006. doi:10.1136/bmj.38731.532766.F6. PMID 16473858.
34. ↑ "Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years". Drugs & Aging 29 (11): 911–23. November 2012. doi:10.1007/s40266-012-0018-z. PMID 23044640.
35. ↑ "Melatonin: What You Need To Know". National Institutes of Health. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know.
36. ↑ 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.
37. ↑ "Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy". Trends in Endocrinology and Metabolism 31 (3): 192–204. March 2020. doi:10.1016/j.tem.2019.11.011. PMID 31901302.
38. ↑ "Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening". Sleep 37 (10): 1715–9. October 2014. doi:10.5665/sleep.4088. PMID 25197811.
39. ↑ "Melatonin side effects: What are the risks?". Mayo Clinic. http://www.mayoclinic.com/health/melatonin-side-effects/AN01717.
40. ↑ "Melatonin treatment for age-related insomnia". The Journal of Clinical Endocrinology and Metabolism 86 (10): 4727–30. October 2001. doi:10.1210/jc.86.10.4727. PMID 11600532.
41. ↑ "[Safety in melatonin use]" (in es). Actas Espanolas de Psiquiatria 29 (5): 334–7. 2001. PMID 11602091.
42. ↑ "Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research". Inflammatory Bowel Diseases 15 (1): 134–40. January 2009. doi:10.1002/ibd.20527. PMID 18626968.
43. ↑ "[The effect of melatonin on prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) synthesis and secretion"] (in pl). Postepy Higieny I Medycyny Doswiadczalnej 60: 431–8. 2006. PMID 16921343. http://www.phmd.pl/fulltxthtml.php?ICID=453297. Retrieved 24 December 2013.
44. ↑ "Melatonin and human reproduction: shedding light on the darkness hormone". Gynecological Endocrinology 25 (12): 779–85. December 2009. doi:10.3109/09513590903159649. PMID 19905996.
45. ↑ Shane-McWhorter L. Melatonin. Merck Manual Professional Version. October 2018. Accessed 22 April 2019.
46. ↑ "A Review of Melatonin, Its Receptors and Drugs". The Eurasian Journal of Medicine 48 (2): 135–41. June 2016. doi:10.5152/eurasianjmed.2015.0267. PMID 27551178.
47. ↑ "Emergence and evolution of the circadian rhythm of melatonin in children". Hormone Research 59 (2): 66–72. 2003. doi:10.1159/000068571. PMID 12589109.
48. ↑ "Human melatonin production decreases with age". Journal of Pineal Research 3 (4): 379–88. 1986. doi:10.1111/j.1600-079X.1986.tb00760.x. PMID 3783419.
49. ↑ "Adolescent changes in the homeostatic and circadian regulation of sleep". Developmental Neuroscience 31 (4): 276–84. June 2009. doi:10.1159/000216538. PMID 19546564.
50. ↑ "Melatonin: a potent, endogenous hydroxyl radical scavenger.". Endocr. J. 1: 57–60. 1993. https://docs.google.com/document/d/e/2PACX-1vSHolKyTREzsC-RB0H-brwbUhaVP4EZBRSoZ6F7b4cOcAkutpNX3ebh0yd_QKEWRBTYVLcqpmMit3NL/pub.
51. ↑ "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. November 1994. doi:10.1111/j.1749-6632.1994.tb21831.x. PMID 7832450. Bibcode: 1994NYASA.738..419P.
52. ↑ 52.0 52.1 "The physiological function of melatonin in plants". Plant Signaling & Behavior 1 (3): 89–95. May 2006. doi:10.4161/psb.1.3.2640. PMID 19521488.
53. ↑ "Melatonin: a peroxyl radical scavenger more effective than vitamin E". Life Sciences 55 (15): PL271-6. 1994. doi:10.1016/0024-3205(94)00666-0. PMID 7934611.
54. ↑ 54.0 54.1 54.2 "Melatonin and human mitochondrial diseases". Journal of Research in Medical Sciences 22: 2. 2017. doi:10.4103/1735-1995.199092. PMID 28400824.
55. ↑ 55.0 55.1 55.2 55.3 55.4 55.5 55.6 55.7 "Update on melatonin receptors: IUPHAR Review 20". British Journal of Pharmacology 173 (18): 2702–25. September 2016. doi:10.1111/bph.13536. 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).".
56. ↑ 56.0 56.1 56.2 "Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas". Cellular and Molecular Life Sciences 74 (21): 3863–3881. November 2017. doi:10.1007/s00018-017-2609-7. PMID 28864909. "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.".
57. ↑ 57.0 57.1 57.2 "Melatonin as an antioxidant: under promises but over delivers". Journal of Pineal Research 61 (3): 253–78. October 2016. doi:10.1111/jpi.12360. PMID 27500468. "There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant.".
58. ↑ 58.0 58.1 58.2 "Melatonin: an ancient molecule that makes oxygen metabolically tolerable". Journal of Pineal Research 59 (4): 403–19. November 2015. doi:10.1111/jpi.12267. PMID 26272235. "While originally thought to be produced exclusively in and secreted from the vertebrate pineal gland [53], it is now known that the indole is present in many, perhaps all, vertebrate organs [54] 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.".
59. ↑ 59.0 59.1 59.2 59.3 59.4 59.5 "Melatonin transport into mitochondria". Cellular and Molecular Life Sciences 74 (21): 3927–3940. November 2017. doi:10.1007/s00018-017-2616-8. PMID 28828619.
60. ↑ "A review of the multiple actions of melatonin on the immune system". Endocrine 27 (2): 189–200. July 2005. doi:10.1385/ENDO:27:2:189. PMID 16217132.
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63. ↑ "The immunotherapeutic potential of melatonin". Expert Opinion on Investigational Drugs 10 (3): 467–76. March 2001. doi:10.1517/13543784.10.3.467. PMID 11227046.
64. ↑ "MetaCyc serotonin and melatonin biosynthesis". http://www.metacyc.org/META/new-image?type=PATHWAY&object=PWY-6030&detail-level=2&ENZORG=TAX-9606.
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67. ↑ 67.0 67.1 67.2 "Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions". Journal of Experimental Botany 66 (3): 627–46. February 2015. doi:10.1093/jxb/eru386. PMID 25240067.
68. ↑ "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. March 2013. doi:10.1111/jpi.12026. PMID 23137057.
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70. ↑ "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. March 1992. doi:10.1021/bi00123a004. PMID 1540578.
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103. ↑ "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology 33 (1): 43–6. July 1981. doi:10.1159/000123198. PMID 7254478.
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119. ↑ "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. 2011. https://www.researchgate.net/publication/259983119.
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124. ↑ "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. August 2013. doi:10.1111/jpi.12025. PMID 23137025.
125. ↑ "Dessert, Laid-Back and Legal". The New York Times. 14 May 2011. https://www.nytimes.com/2011/05/15/us/15lazycakes.html.
126. ↑ "Warning Letter". Inspections, Compliance, Enforcement, and Criminal Investigations. U.S. Food and Drug Administration. 13 January 2010. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm201435.htm.
127. ↑ Bebida Beverage Company U.S. Food and Drug Administration 4 March 2015 (Accessed 8 December 2017)
128. ↑ "Melatonin Product Availability". 28 February 2021. https://keldik.com/blogs/sleep-circadian-binnacle/melatonin-product-availability.
129. ↑ "Melatonin". Drugs.com. https://www.drugs.com/melatonin.html.
130. ↑ "Does Melatonin Really Help You Sleep?". https://www.consumerreports.org/vitamins-supplements/does-melatonin-really-help-you-sleep/.
131. ↑ "Clinical pharmacology of melatonin in the treatment of tinnitus: a review". European Journal of Clinical Pharmacology 71 (3): 263–70. March 2015. doi:10.1007/s00228-015-1805-3. PMID 25597877.
132. ↑ "Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis". Developmental Medicine and Child Neurology 51 (5): 340–9. May 2009. doi:10.1111/j.1469-8749.2008.03244.x. PMID 19379289.
133. ↑ 133.0 133.1 "Melatonin in autism spectrum disorders: a systematic review and meta-analysis". Developmental Medicine and Child Neurology 53 (9): 783–792. September 2011. doi:10.1111/j.1469-8749.2011.03980.x. PMID 21518346.
134. ↑ "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. January 2015. doi:10.1007/s10803-014-2197-4. PMID 25059483.
135. ↑ "Melatonin improves sleep quality and behavior in children with asperger disorder.". http://www.truthlyapp.com/truths/514-melatonin-improves-sleep-quality-and-behavior-in-children-with-asperger-disorder.
136. ↑ "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. August 2006. doi:10.1007/s10803-006-0116-z. PMID 16897403.
137. ↑ "Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder". The Annals of Pharmacotherapy 44 (1): 185–91. January 2010. doi:10.1345/aph.1M365. PMID 20028959.
138. ↑ "Melatonin for pre- and postoperative anxiety in adults". The Cochrane Database of Systematic Reviews 12: CD009861. 8 December 2020. doi:10.1002/14651858.CD009861.pub3. PMID 33319916. PMC 8092422. https://pubmed.ncbi.nlm.nih.gov/33319916/.
139. ↑ Melatonin and the Biological Clock. McGraw-Hill. 1999. p. 23. ISBN 978-0-87983-734-1. https://archive.org/details/melatoninbiologi00lew_46r.
140. ↑ "Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression". British Journal of Pharmacology 175 (16): 3200–3208. August 2018. doi:10.1111/bph.14197. PMID 29512136.
141. ↑ "Potential therapeutic use of melatonin in migraine and other headache disorders". Expert Opinion on Investigational Drugs 15 (4): 367–75. April 2006. doi:10.1517/13543784.15.4.367. PMID 16548786.
142. ↑ "Review: Hypnic headache". Practical Neurology 5 (3): 144–49. 2005. doi:10.1111/j.1474-7766.2005.00301.x. http://pn.bmj.com/content/practneurol/5/3/144.full.pdf. Retrieved 12 January 2018.
143. ↑ PDQ Integrative, Alternative, and Complementary Therapies Editorial Board (May 2013). "Topics in complementary and alternative therapies (PDQ)". PDQ Cancer Information Summaries [Internet]. National Cancer Institute, National Institutes of Health. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0053600/.
144. ↑ "Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis". Journal of Pineal Research 39 (4): 360–6. November 2005. doi:10.1111/j.1600-079X.2005.00258.x. PMID 16207291.
145. ↑ "Melatonin and protection from whole-body irradiation: survival studies in mice". Mutation Research 425 (1): 21–7. March 1999. doi:10.1016/S0027-5107(98)00246-2. PMID 10082913.
146. ↑ "Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers". Mutation Research 371 (3–4): 221–8. December 1996. doi:10.1016/S0165-1218(96)90110-X. PMID 9008723.
147. ↑ "Dietary supplements for dysmenorrhoea". The Cochrane Database of Systematic Reviews 3 (3): CD002124. March 2016. doi:10.1002/14651858.cd002124.pub2. PMID 27000311.
148. ↑ "Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes". Mutation Research 397 (2): 203–8. February 1998. doi:10.1016/S0027-5107(97)00211-X. PMID 9541644.
149. ↑ "One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?". Journal of Pineal Research 42 (1): 28–42. January 2007. doi:10.1111/j.1600-079X.2006.00407.x. PMID 17198536.
150. ↑ "A radiobiological review on melatonin: a novel radioprotector". Journal of Radiation Research 48 (4): 263–72. July 2007. doi:10.1269/jrr.06070. PMID 17641465. Bibcode: 2007JRadR..48..263S.
151. ↑ "Melatonin as add-on treatment for epilepsy". The Cochrane Database of Systematic Reviews (8): CD006967. August 2016. doi:10.1002/14651858.CD006967.pub4. PMID 27513702.
152. ↑ "Dietary supplements for dysmenorrhoea". The Cochrane Database of Systematic Reviews 3: CD002124. March 2016. doi:10.1002/14651858.CD002124.pub2. PMID 27000311.
153. ↑ "Interventions for preventing delirium in hospitalised non-ICU patients". The Cochrane Database of Systematic Reviews 3: CD005563. March 2016. doi:10.1002/14651858.CD005563.pub3. PMID 26967259. http://eprints.whiterose.ac.uk/99189/7/Siddiqi_et_al-2016-The_Cochrane_Library.pdf.
154. ↑ "The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease". BMC Gastroenterology 10: 7. January 2010. doi:10.1186/1471-230X-10-7. PMID 20082715.

## External links

* "Melatonin". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/melatonin.
* "Melatonin". Chemwatch. https://www.chemwatch.net/resource-center/melatonin/.

* v
* t
* e

Hormones

Endocrine
glands|

| Hypothalamic-
pituitary|

| Hypothalamus|

* GnRH
* TRH
* Dopamine
* CRH
* GHRH
* Somatostatin (GHIH)
* MCH

|

Posterior pituitary|

* Oxytocin
* Vasopressin

Anterior pituitary|

* FSH
* LH
* TSH
* Prolactin
* POMC
* CLIP
* ACTH
* MSH
* Endorphins
* Lipotropin
* GH

Adrenal axis|

* Adrenal cortex
* Aldosterone
* Cortisol
* Cortisone
* DHEA
* DHEA-S
* Androstenedione
* Adrenal medulla
* Epinephrine
* Norepinephrine

Thyroid|

* Thyroid hormones
* T3
* T4
* Calcitonin
* Thyroid axis

Parathyroid|

* PTH

Gonadal axis|

| Testis|

* Testosterone
* AMH
* Inhibin

|

Ovary|

* Estradiol
* Progesterone
* Activin
* Inhibin
* Relaxin
* GnSAF

Placenta|

* hCG
* HPL
* Estrogen
* Progesterone

Pancreas|

* Glucagon
* Insulin
* Amylin
* Somatostatin
* Pancreatic polypeptide

Pineal gland|

* Melatonin
* N,N-Dimethyltryptamine
* 5-Methoxy-N,N-dimethyltryptamine

Other|

| Thymus|

* Thymosins
* Thymosin α1
* Beta thymosins
* Thymopoietin
* Thymulin

|

Digestive system|

| Stomach|

* Gastrin
* Ghrelin

|

Duodenum|

* CCK
* Incretins
* GIP
* GLP-1
* Secretin
* Motilin
* VIP

Ileum|

* Enteroglucagon
* Peptide YY

Liver/other|

* Insulin-like growth factor
* IGF-1
* IGF-2

Adipose tissue|

* Leptin
* Adiponectin
* Resistin

Skeleton|

* Osteocalcin

Kidney|

* Renin
* EPO
* Calcitriol
* Prostaglandin

Heart|

* Natriuretic peptide
* ANP
* BNP

* v
* t
* e

Antioxidants

Food antioxidants|

* 6-Hydroxymelatonin
* Acetyl-L-carnitine (ALCAR)
* Alpha-lipoic acid (ALA)
* Ascorbic acid (vitamin C)
* Carotenoids (vitamin A)
* Curcumin
* Edaravone
* Polyphenols
* Glutathione
* Hydroxytyrosol
* L-carnitine
* Ladostigil
* Melatonin
* Mofegiline
* N-Acetylcysteine (NAC)
* N-Acetylserotonin (NAS)
* Oleocanthal
* Oleuropein
* Rasagiline
* Resveratrol
* Selegiline
* Selenium
* Tocopherols (vitamin E)
* Tocotrienols (vitamin E)
* Tyrosol
* Ubiquinone (coenzyme Q)
* Uric acid

Fuel antioxidants|

* Butylated hydroxytoluene
* 2,6-Di-tert-butylphenol
* 1,2-Diaminopropane
* 2,4-Dimethyl-6-tert-butylphenol
* Ethylenediamine

Measurements|

* Folin method
* ORAC
* TEAC
* FRAP

* v
* t
* e

Dietary supplements

Types|

* Amino acids
* Bodybuilding supplement
* Energy drink
* Energy bar
* Fatty acids
* Herbal supplements
* Minerals
* Prebiotics
* Probiotics (Lactobacillus
* Bifidobacterium)
* Protein bar
* Vitamins

Vitamins and
chemical elements ("minerals")|

* Retinol (Vitamin A)
* B vitamins: Thiamine (B1)
* Riboflavin (B2)
* Niacin (B3)
* Pantothenic acid (B5)
* Pyridoxine (B6)
* Biotin (B7)
* Folic acid (B9)
* Cyanocobalamin (B12)
* Ascorbic acid (Vitamin C)
* Ergocalciferol and Cholecalciferol (Vitamin D)
* Tocopherol (Vitamin E)
* Naphthoquinone (Vitamin K)
* Calcium
* Choline
* Chromium
* Cobalt
* Copper
* Fluorine
* Iodine
* Iron
* Magnesium
* Manganese
* Molybdenum
* Phosphorus
* Potassium
* Selenium
* Sodium
* Sulfur
* Zinc

Other common ingredients|

* AAKG
* β-hydroxy β-methylbutyrate
* Carnitine
* Chondroitin sulfate
* Cod liver oil
* Copper gluconate
* Creatine
* Dietary fiber
* Echinacea
* Elemental calcium
* Ephedra
* Fish oil
* Folic acid
* Ginseng
* Glucosamine
* Glutamine
* Grape seed extract
* Guarana
* Iron supplements
* Japanese Honeysuckle
* Krill oil
* Lingzhi
* Linseed oil
* Lipoic acid
* Milk thistle
* Melatonin
* Red yeast rice
* Royal jelly
* Saw palmetto
* Spirulina
* St John's wort
* Taurine
* Wheatgrass
* Wolfberry
* Yohimbine
* Zinc gluconate

Related articles|

* Codex Alimentarius
* Enzyte
* Hadacol
* Herbal tea
* Nutraceutical
* Multivitamin
* Nutrition

* v
* t
* e

Hypnotics/sedatives (N05C)

GABAA|

| Alcohols|

* 2M2B
* Chloralodol
* Ethanol (alcohol)
* Ethchlorvynol
* Methylpentynol
* Trichloroethanol

|

Barbiturates|

* Allobarbital
* Amobarbital
* Aprobarbital
* Barbital
* Butabarbital
* Butobarbital
* Cyclobarbital
* Ethallobarbital
* Heptabarb
* Hexobarbital
* Mephobarbital
* Methohexital
* Narcobarbital
* Pentobarbital
* Phenallymal
* Phenobarbital
* Propylbarbital
* Proxibarbal
* Reposal
* Secobarbital
* Talbutal
* Thiamylal
* Thiopental
* Thiotetrabarbital
* Vinbarbital
* Vinylbital

Benzodiazepines|

* Brotizolam
* Cinolazepam
* Climazolam
* Doxefazepam
* Estazolam
* Flunitrazepam
* Flurazepam
* Flutoprazepam
* Lorazepam
* Loprazolam
* Lormetazepam
* Midazolam
* Nimetazepam
* Nitrazepam
* Phenazepam
* Quazepam
* Temazepam
* Triazolam

Carbamates|

* Carisoprodol
* Emylcamate
* Ethinamate
* Hexapropymate
* Meprobamate
* Methocarbamol
* Phenprobamate
* Procymate
* Tybamate

Imidazoles|

* Etomidate
* Metomidate
* Propoxate

Monoureides|

* Acecarbromal
* Apronal (apronalide)
* Bromisoval
* Capuride
* Carbromal
* Ectylurea

Neuroactive steroids|

* Acebrochol
* Allopregnanolone
* Alphadolone
* Alphaxolone
* Eltanolone
* Hydroxydione
* Minaxolone
* Progesterone

Nonbenzodiazepines|

* Eszopiclone
* Indiplon
* Lirequinil
* Necopidem
* Pazinaclone
* Saripidem
* Suproclone
* Suriclone
* Zaleplon
* Zolpidem
* Zopiclone

Phenols|

* Propofol

Piperidinediones|

* Glutethimide
* Methyprylon
* Pyrithyldione
* Piperidione

Quinazolinones|

* Afloqualone
* Cloroqualone
* Diproqualone
* Etaqualone
* Mebroqualone
* Mecloqualone
* Methaqualone
* Methylmethaqualone
* Nitromethaqualone

Others|

* Acetophenone
* Acetylglycinamide chloral hydrate
* Bromide compounds
* Lithium bromide
* Potassium bromide
* Sodium bromide
* Centalun
* Chloral betaine
* Chloral hydrate
* Chloralose
* Clomethiazole
* Dichloralphenazone
* Gaboxadol
* Kavalactones
* Loreclezole
* Paraldehyde
* Petrichloral
* Sulfonylalkanes
* Sulfonmethane (sulfonal)
* Tetronal
* Trional
* Triclofos
* Sesquiterpene
* Isovaleramide
* Isovaleric acid
* Valerenic acid

GABAB|

* 1,4-Butanediol
* 4-Fluorophenibut
* Aceburic acid
* Baclofen
* GABOB
* GHB (sodium oxybate)
* GBL
* GVL
* Phenibut
* Tolibut

H1|

| Antihistamines|

* Captodiame
* Cyproheptadine
* Diphenhydramine
* Doxylamine
* Hydroxyzine
* Methapyrilene
* Perlapine
* Pheniramine
* Promethazine
* Propiomazine

|

Antidepressants|

* Serotonin antagonists and reuptake inhibitors
* Etoperidone
* Nefazodone
* Trazodone
* Tricyclic antidepressants
* Amitriptyline
* Doxepin
* Trimipramine, etc.
* Tetracyclic antidepressants
* Mianserin
* Mirtazapine, etc.

Antipsychotics|

* Typical antipsychotics
* Chlorpromazine
* Thioridazine, etc.
* Atypical antipsychotics
* Olanzapine
* Quetiapine
* Risperidone, etc.

α2-Adrenergic|

* Clonidine
* Detomidine
* Dexmedetomidine
* Lofexidine
* Medetomidine
* Romifidine
* Tizanidine
* Xylazine

5-HT2A|

| Antidepressants|

* Trazodone
* Tricyclic antidepressants
* Amitriptyline
* Doxepin
* Trimipramine, etc.
* Tetracyclic antidepressants
* Mianserin
* Mirtazapine, etc.

|

Antipsychotics|

* Typical antipsychotics
* Chlorpromazine
* Thioridazine, etc.
* Atypical antipsychotics
* Olanzapine
* Quetiapine
* Risperidone, etc.

Others|

* Niaprazine

Melatonin|

* Agomelatine
* Melatonin
* Ramelteon
* Tasimelteon

Orexin|

* Almorexant
* Filorexant
* Suvorexant

α2δ VDCC|

* Gabapentin
* Gabapentin enacarbil
* Mirogabalin
* Phenibut
* Pregabalin

Others|

* Cannabidiol
* Cannabis
* Chlorophenylalkyldiols
* Fenpentadiol
* Metaglycodol
* Phenaglycodol
* Diethylpropanediol
* Evoxine
* Fenadiazole
* Guaifenesin-related muscle relaxants
* Chlorphenesin
* Mephenesin
* Mephenoxalone
* Metaxalone
* Methocarbamol
* Midaflur
* Opioids (e.g., morphine)
* Passion flower
* Scopolamine
* Trazodone
* UMB68
* Valnoctamide

* v
* t
* e

Insomnia pharmacotherapies

GABAAR PAMs|

* Benzodiazepines: Brotizolam
* Cinolazepam
* Climazolam
* Clorazepate
* Doxefazepam
* Estazolam
* Etizolam
* Flunitrazepam
* Flurazepam
* Flutoprazepam
* Haloxazolam
* Loprazolam
* Lormetazepam
* Midazolam
* Nimetazepam
* Nitrazepam
* Quazepam
* Temazepam
* Triazolam; Nonbenzodiazepines/[[Chemistry:Z-drug|]] Eszopiclone
* Zaleplon
* Zolpidem
* Zopiclone; Others: Alcohols (e.g., ethchlorvynol, amylene hydrate, ethanol)
* Barbiturates (e.g., amobarbital, pentobarbital, phenobarbital, secobarbital)
* Bromides (e.g., potassium bromide, sodium bromide)
* Carbamates (e.g., meprobamate)
* Chloral hydrate
* Clomethiazole
* Kava
* Paraldehyde
* Piperidinediones (e.g., glutethimide)
* Quinazolinones (e.g., methaqualone)
* Sulfonmethane
* Valerian

Antihistamines
(H1R inverse agonists)|

* Alimemazine
* Captodiame
* Dimenhydrinate
* Diphenhydramine
* Doxylamine
* Etodroxizine
* Hydroxyzine
* Meclizine
* Methapyrilene
* Pheniramine
* Phenyltoloxamine
* Pimethixene
* Promethazine
* Propiomazine
* Pyrilamine
* TCAs (e.g., amitriptyline, doxepin, trimipramine)
* TeCAs (e.g., mirtazapine)
* Triprolidine

OXR antagonists|

* Almorexant§
* Filorexant§
* Lemborexant§
* Suvorexant

MTR agonists|

* Agomelatine
* Melatonin
* Ramelteon
* Tasimelteon

Miscellaneous|

* Antipsychotics (e.g., quetiapine, olanzapine, chlorpromazine)
* Ashwagandha
* Benzoctamine
* Cannabinoids (e.g., cannabis, dronabinol (THC), nabilone)
* Chamomile
* Fenadiazole
* Gabapentinoids (e.g., gabapentin, pregabalin, phenibut)
* Hops
* Lavender
* Menthyl isovalerate
* Niaprazine
* Opioids (e.g., hydrocodone, oxycodone, morphine)
* Passion flower
* Scopolamine
* Serotonin precursors (tryptophan, 5-HTP)
* Sodium oxybate (GHB)
* Sympatholytics (e.g., clonidine, guanfacine)
* TCAs (e.g., amitriptyline, doxepin, trimipramine)
* TeCAs (e.g., mirtazapine)
* Theanine
* Trazodone
* Valnoctamide

* v
* t
* e

Melatonin receptor modulators

MT1|

* Agonists: 6-Hydroxymelatonin
* Agomelatine
* Fabomotizole (afobazole)
* GR-196,429
* Melatonin
* N-Acetylserotonin (normelatonin)
* Piromelatine
* Ramelteon
* Tasimelteon
* TIK-301 (LY-156,735)

* Antagonists: Luzindole

MT2|

* Agonists: 6-Hydroxymelatonin
* Agomelatine
* GR-196,429
* Melatonin
* N-Acetylserotonin (normelatonin)
* Piromelatine
* Ramelteon
* Tasimelteon
* TIK-301 (LY-156,735)

* Antagonists: Luzindole

Unsorted|

* Agonists: 2-Iodomelatonin
* 2-Phenylmelatonin
* 5-Methoxyluzindole
* 6-Chloromelatonin
* 6-Fluoromelatonin
* 6-Methoxymelatonin
* 6,7-Dichloro-2-methylmelatonin
* 8-M-PDOT
* AMMTC
* GR-135,531 (of MT3)
* N-Acetyltryptamine
* N-Butanoylmelatonin
* N-Propionylmelatonin
* S-24268
* S-25150

* Antagonists: 4-P-ADOT
* 4-P-PDOT
* DH-97
* N-Acetyltryptamine (of MT3)
* Prazosin (of MT3)
* S-20928
* S-22153
* S-24601
* S-25567
* S-26131

* See also: Receptor/signaling modulators
* Adrenergics
* Dopaminergics
* Serotonergics
* Monoamine metabolism modulators

* v
* t
* e

Tryptamines

* 1-Methylpsilocin
* 2-Methyl-5-HT
* 4,5-DHP-DMT
* 4,5-MDO-DMT
* 4,5-MDO-DiPT
* 4-AcO-DALT
* 4-AcO-DET
* 4-AcO-DMT
* 4-AcO-DiPT
* 4-AcO-NMT
* 4-AcO-MET
* 4-AcO-DPT
* 4-AcO-MiPT
* 4-HO-DALT
* 4-HO-DET
* 4-HO-DiPT
* 4-HO-DPT
* 4-HO-DSBT
* 4-HO-EPT
* 4-HO-MALT
* 4-HO-MET
* 4-HO-McPT
* 4-HO-McPeT
* 4-HO-MiPT
* 4-HO-MPT
* 4-HO-NMT
* 4-HO-αMT
* 4-Me-αET
* 4-Me-αMT
* 4-MeO-DiPT
* 4-MeO-DMT
* 5-BT
* 5-Bromo-DMT
* 5-CT
* 5-Chloro-αMT
* 5-Ethoxy-αMT
* 5-Fluoro-αMT
* 5-HO-αMT
* 5-HO-DiPT
* 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-EiPT
* 5-MeO-EPT
* 5-MeO-MALT
* 5-MeO-MiPT
* 5-MeO-NBpBrT
* 5,7-Dihydroxytryptamine
* 5-(Nonyloxy)tryptamine
* 6-Fluoro-αMT
* 6-Hydroxymelatonin
* 7-Methyl-αET
* 7-Methyl-DMT
* Acetryptine
* Aeruginascin
* αET
* AL-37350A
* αMT
* Baeocystin
* BNC-210
* Bufotenidine
* Bufotenin (5-HO-DMT)
* BW-723C86
* Convolutindole A
* DALT
* Desformylflustrabromine
* DET
* DiPT
* DMT
* DPT
* E-6801
* E-6837
* Ethocybin
* EiPT
* EMDT
* EPT
* FGIN-127
* FGIN-143
* HIOC
* Ibogaine
* Idalopirdine
* Indorenate
* Iprocin
* Lespedamine
* Luzindole
* MET
* MiPT
* MPT
* Miprocin
* Melatonin
* MS-245
* NAS
* N-Feruloylserotonin
* NMT
* Norbaeocystin
* Normelatonin
* O-4310
* Oxypertine
* Plakohypaphorine
* PiPT
* Psilocin (4-HO-DMT)
* Psilocybin (4-PO-DMT)
* Rizatriptan
* Serotonin
* ST-1936
* Sumatriptan
* Tryptamine
* Tryptophan
* Yohimbine
* Yuremamine
* Zolmitriptan

*[EU]: European Union
*[US]: United States
*[AU]: Australia
*[CA]: Canada
*[UK]: United Kingdom
*[CID]: Compound ID
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[α2δ]: alpha2delta subunit
*[VDCC]: voltage-gated calcium channel
*[GABAAR]: GABAA receptor
*[PAMs]: positive allosteric modulators
*[H1R]: H1 receptor
*[TCAs]: Tricyclic antidepressants
*[TeCAs]: Tetracyclic antidepressants
*[OXR]: Orexin receptor
*[MTR]: Melatonin receptor
*[THC]: tetrahydrocannabinol
*[5-HTP]: 5-hydroxytryptophan
*[GHB]: γ-aminobutyric acid
*[MT1]: Melatonin receptor 1
*[MT2]: Melatonin receptor 2
*[MT3]: melatonin receptor 1C