Melatonin

In humans, melatonin primarily acts as a potent full agonist of two types of melatonin receptors: melatonin receptor 1, with picomolar binding affinity, and melatonin receptor 2, with nanomolar binding affinity. Both receptors are part of the G-protein coupled receptors (GPCRs) family, specifically the G_i/o alpha subunit GPCRs,{{cite journal | vauthors = Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP| title = Update on melatonin receptors: IUPHAR Review 20 | journal = British Journal of Pharmacology | volume = 173 | issue = 18 | pages = 2702–25 | date = September 2016 | pmid = 27314810 | pmc = 4995287 | doi = 10.1111/bph.13536 | quote = 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}}{{cite web|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=39|title=Melatonin receptors {{!}} G protein-coupled receptors {{!}} IUPHAR/BPS Guide to Pharmacology|website=www.guidetopharmacology.org|access-date=7 April 2017}} although melatonin receptor 1 also exhibits coupling with G_q alpha subunit.

Furthermore, melatonin functions as a high-capacity antioxidant, or free radical scavenger, within mitochondria, playing a dual role in combating cellular oxidative stress. First, it directly neutralizes free radicals, and second, it promotes the gene expression of essential antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. This increase in antioxidant enzyme expression is mediated through signal transduction pathways activated by the binding of melatonin to its receptors. Through these mechanisms, melatonin protects the cell against oxidative stress in two ways, highlighting how it serves human health beyond regulating the sleep-wake cycle.{{cite journal |vauthors=Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A |date=2017 |title=Melatonin and human mitochondrial diseases |journal=Journal of Research in Medical Sciences |volume=22 |pages=2 |doi=10.4103/1735-1995.199092 |pmc=5361446 |pmid=28400824 |doi-access=free}}{{cite journal |vauthors=Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B |date=November 2017 |title=Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas |journal=Cellular and Molecular Life Sciences |volume=74 |issue=21 |pages=3863–3881 |doi=10.1007/s00018-017-2609-7 |pmid=28864909 |s2cid=23820389 |quote=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.|pmc=11107735 }}{{cite journal |vauthors=Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L |date=October 2016 |title=Melatonin as an antioxidant: under promises but over delivers |journal=Journal of Pineal Research |volume=61 |issue=3 |pages=253–78 |doi=10.1111/jpi.12360 |pmid=27500468 |s2cid=35435683 |doi-access=free}}{{cite journal |vauthors=Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ |date=November 2015 |title=Melatonin: an ancient molecule that makes oxygen metabolically tolerable |journal=Journal of Pineal Research |volume=59 |issue=4 |pages=403–19 |doi=10.1111/jpi.12267 |pmid=26272235 |s2cid=24373303 |quote=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|doi-access=free}}{{cite journal |vauthors=Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R |date=November 2017 |title=Melatonin transport into mitochondria |journal=Cellular and Molecular Life Sciences |volume=74 |issue=21 |pages=3927–3940 |doi=10.1007/s00018-017-2616-8 |pmid=28828619 |s2cid=10920415|pmc=11107582 }}

File:Circadian rhythm.svg

{{Main|Circadian rhythm}}

In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms.{{cite journal | vauthors = Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A | title = A Review of Melatonin, Its Receptors and Drugs | journal = The Eurasian Journal of Medicine | volume = 48 | issue = 2 | pages = 135–41 | date = June 2016 | pmid = 27551178 | pmc = 4970552 | doi = 10.5152/eurasianjmed.2015.0267 }} The establishment of regular melatonin levels in human infants occurs around the third month after birth, with peak concentrations observed between midnight and 8:00 am.{{cite journal | vauthors = Ardura J, Gutierrez R, Andres J, Agapito T | title = Emergence and evolution of the circadian rhythm of melatonin in children | journal = Hormone Research | volume = 59 | issue = 2 | pages = 66–72 | year = 2003 | pmid = 12589109| s2cid = 41937922 }} It has been documented that melatonin production diminishes as a person ages.{{cite journal | vauthors = Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM | title = Human melatonin production decreases with age | journal = Journal of Pineal Research | volume = 3 | issue = 4 | pages = 379–88 | year = 1986 | pmid = 3783419 | doi = 10.1111/j.1600-079X.1986.tb00760.x | s2cid = 33664568 }} Additionally, a shift in the timing of melatonin secretion is observed during adolescence, resulting in delayed sleep and wake times, increasing their risk for delayed sleep phase disorder during this period.{{cite journal | vauthors = Hagenauer MH, Perryman JI, Lee TM, Carskadon MA | title = Adolescent changes in the homeostatic and circadian regulation of sleep | journal = Developmental Neuroscience | volume = 31 | issue = 4 | pages = 276–84 | date = June 2009 | pmid = 19546564 | pmc = 2820578 | doi = 10.1159/000216538 }}

The antioxidant properties of melatonin were first recognized in 1993.{{cite journal | vauthors = Tan DX, Chen LD, Poeggeler B, L Manchester C, Reiter RJ | title = Melatonin: a potent, endogenous hydroxyl radical scavenger. | journal = Endocr. J. | date = 1993 | volume = 1 | pages = 57–60 | url = https://docs.google.com/document/d/e/2PACX-1vSHolKyTREzsC-RB0H-brwbUhaVP4EZBRSoZ6F7b4cOcAkutpNX3ebh0yd_QKEWRBTYVLcqpmMit3NL/pub }} In vitro studies reveal that melatonin directly neutralizes various reactive oxygen species, including hydroxyl (OH•), superoxide (O2−•), and reactive nitrogen species such as nitric oxide (NO•).{{cite journal |vauthors=Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR |date=November 1994 |title=Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro |journal=Annals of the New York Academy of Sciences |volume=738 |issue=1 |pages=419–20 |bibcode=1994NYASA.738..419P |doi=10.1111/j.1749-6632.1994.tb21831.x |pmid=7832450 |s2cid=36383425}}{{cite journal |vauthors=Arnao MB, Hernández-Ruiz J |date=May 2006 |title=The physiological function of melatonin in plants |journal=Plant Signaling & Behavior |volume=1 |issue=3 |pages=89–95 |bibcode=2006PlSiB...1...89A |doi=10.4161/psb.1.3.2640 |pmc=2635004 |pmid=19521488}} In plants, melatonin works synergistically with other antioxidants, enhancing the overall effectiveness of each antioxidant. This compound has been found to be twice as efficacious as vitamin E, a known potent lipophilic antioxidant, at scavenging peroxyl radicals.{{cite journal | vauthors = Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F | title = Melatonin: a peroxyl radical scavenger more effective than vitamin E | journal = Life Sciences | volume = 55 | issue = 15 | pages = PL271-6 | year = 1994 | pmid = 7934611 | doi = 10.1016/0024-3205(94)00666-0 }} The promotion of antioxidant enzyme expression, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase, is mediated through melatonin receptor-triggered signal transduction pathways.

Melatonin's concentration in the mitochondrial matrix is significantly higher than that found in the blood plasma, emphasizing its role not only in direct free radical scavenging but also in modulating the expression of antioxidant enzymes and maintaining mitochondrial integrity. This multifaceted role shows the physiological significance of melatonin as a mitochondrial antioxidant, a notion supported by numerous scholars.

Furthermore, the interaction of melatonin with reactive oxygen and nitrogen species results in the formation of metabolites capable of reducing free radicals. These metabolites, including cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK), contribute to the broader antioxidative effects of melatonin through further redox reactions with free radicals.

Melatonin's interaction with the immune system is recognized, yet the specifics of these interactions remain inadequately defined.{{cite journal | vauthors = Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ | title = A review of the multiple actions of melatonin on the immune system | journal = Endocrine | volume = 27 | issue = 2 | pages = 189–200 | date = July 2005 | pmid = 16217132 | doi = 10.1385/ENDO:27:2:189 | s2cid = 21133107 }}{{cite journal | vauthors = Arushanian EB, Beĭer EV | title = [Immunotropic properties of pineal melatonin] | language = ru | journal = Eksperimental'naia i Klinicheskaia Farmakologiia | volume = 65 | issue = 5 | pages = 73–80 | year = 2002 | pmid = 12596522 }}{{Update inline|date=March 2024}} An anti-inflammatory effect appears to be the most significant.{{Citation needed|date=July 2023}} The efficacy of melatonin in disease treatment has been the subject of limited trials, with most available data deriving from small-scale, preliminary studies. It is posited that any beneficial immunological impact is attributable to melatonin's action on high-affinity receptors (MT1 and MT2), which are present on immunocompetent cells. Preclinical investigations suggest that melatonin may augment cytokine production and promote the expansion of T cells,{{cite journal | vauthors = Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D | title = The modulatory role of melatonin on immune responsiveness | journal = Current Opinion in Investigational Drugs | volume = 7 | issue = 5 | pages = 423–31 | date = May 2006 | pmid = 16729718 }} thereby potentially mitigating acquired immunodeficiencies.{{cite journal | vauthors = Maestroni GJ | title = The immunotherapeutic potential of melatonin | journal = Expert Opinion on Investigational Drugs | volume = 10 | issue = 3 | pages = 467–76 | date = March 2001 | pmid = 11227046 | doi = 10.1517/13543784.10.3.467 | s2cid = 6822594 }}

Melatonin's potential to regulate weight gain is posited to involve its inhibitory effect on leptin, a hormone that serves as a long-term indicator of the body's energy status.{{cite journal | vauthors = Suriagandhi V, Nachiappan V | title = Protective Effects of Melatonin against Obesity-Induced by Leptin Resistance | journal = Behavioural Brain Research | volume = 417 | pages = 113598 | date = January 2022 | pmid = 34563600 | doi = 10.1016/j.bbr.2021.113598 | s2cid = 237603177 }}{{cite journal | vauthors = Kelesidis T, Kelesidis I, Chou S, Mantzoros CS | title = Narrative review: the role of leptin in human physiology: emerging clinical applications | journal = Annals of Internal Medicine | volume = 152 | issue = 2 | pages = 93–100 | date = January 2010 | pmid = 20083828 | pmc = 2829242 | doi = 10.7326/0003-4819-152-2-201001190-00008 }} Leptin is important for regulating energy balance and body weight by signaling satiety and reducing food intake. Melatonin, by modulating leptin's actions outside of waking hours, may contribute to the restoration of leptin sensitivity during daytime, thereby counteracting leptin resistance.

File:Mealtonin biosynth.jpg

The biosynthesis of melatonin in animals involves a sequence of enzymatic reactions starting with L-tryptophan, which can be synthesized through the shikimate pathway from chorismate, found in plants, or obtained from protein catabolism. The initial step in the melatonin biosynthesis pathway is the hydroxylation of L-tryptophan's indole ring by the enzyme tryptophan hydroxylase, resulting in the formation of 5-hydroxytryptophan (5-HTP). Subsequently, 5-HTP undergoes decarboxylation, facilitated by pyridoxal phosphate and the enzyme 5-hydroxytryptophan decarboxylase, yielding serotonin.{{cite web |url=http://www.metacyc.org/META/new-image?type=PATHWAY&object=PWY-6030&detail-level=2&ENZORG=TAX-9606 |title=MetaCyc serotonin and melatonin biosynthesis }}

Serotonin, an essential neurotransmitter, is further converted into N-acetylserotonin by the action of serotonin N-acetyltransferase, using acetyl-CoA.{{cite journal | vauthors = Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C | title = Melatonin: Pharmacology, Functions and Therapeutic Benefits | journal = Current Neuropharmacology | volume = 15 | issue = 3 | pages = 434–443 | date = April 2017 | pmid = 28503116 | pmc = 5405617 | doi = 10.2174/1570159X14666161228122115 }} The final step in the pathway involves the methylation of N-acetylserotonin's hydroxyl group by hydroxyindole O-methyltransferase, with S-adenosyl methionine as the methyl donor, to produce melatonin.

In bacteria, protists, fungi, and plants, the synthesis of melatonin also involves tryptophan as an intermediate but originates indirectly from the shikimate pathway. The pathway commences with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells, additionally involves carbon dioxide. While the subsequent biosynthetic reactions share similarities with those in animals, there are slight variations in the enzymes involved in the final stages.{{cite journal | vauthors = Bochkov DV, Sysolyatin SV, Kalashnikov AI, Surmacheva IA | title = Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources | journal = Journal of Chemical Biology | volume = 5 | issue = 1 | pages = 5–17 | date = January 2012 | pmid = 22826715 | pmc = 3251648 | doi = 10.1007/s12154-011-0064-8 }}

The hypothesis that melatonin synthesis occurs within mitochondria and chloroplasts suggests an evolutionary and functional significance of melatonin in cellular energy metabolism and defense mechanisms against oxidative stress, reflecting the molecule's ancient origins and its multifaceted roles across different domains of life.{{cite journal | vauthors = Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ | title = Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes | journal = Journal of Pineal Research | volume = 54 | issue = 2 | pages = 127–38 | date = March 2013 | pmid = 23137057 | doi = 10.1111/jpi.12026 | s2cid = 206140413 | doi-access = free }}

File:Melatonin mechanism.jpg

The mechanism of melatonin biosynthesis initiates with the hydroxylation of L-tryptophan, a process that requires the cofactor tetrahydrobiopterin (THB) to react with oxygen and the active site iron of tryptophan hydroxylase. Although the complete mechanism is not entirely understood, two main mechanisms have been proposed:

The first mechanism involves a slow transfer of one electron from THB to molecular oxygen (O₂), potentially producing a superoxide ({{chem2|O2-}}). This superoxide could then recombine with the THB radical to form 4a-peroxypterin. 4a-peroxypterin may either react with the active site iron (II) to create an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron, facilitating the hydroxylation of L-tryptophan.

Alternatively, the second mechanism proposes that oxygen interacts with the active site iron (II) first, forming iron (III) superoxide. This molecule could then react with THB to form an iron-peroxypterin intermediate.

Following the formation of iron (IV) oxide from the iron-peroxypterin intermediate, this oxide selectively attacks a double bond to yield a carbocation at the C5 position of the indole ring. A subsequent 1,2-shift of the hydrogen and the loss of one of the two hydrogen atoms on C5 would restore aromaticity, producing 5-hydroxy-L-tryptophan.{{cite journal | vauthors = Roberts KM, Fitzpatrick PF | title = Mechanisms of tryptophan and tyrosine hydroxylase | journal = IUBMB Life | volume = 65 | issue = 4 | pages = 350–7 | date = April 2013 | pmid = 23441081 | pmc = 4270200 | doi = 10.1002/iub.1144 }}

The decarboxylation of 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine is then facilitated by a decarboxylase enzyme with pyridoxal phosphate (PLP) as a cofactor.{{cite journal | vauthors = Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T | title = 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 | journal = Biochemistry | volume = 31 | issue = 8 | pages = 2229–38 | date = March 1992 | pmid = 1540578 | doi = 10.1021/bi00123a004 }} PLP forms an imine with the amino acid derivative, facilitating the breaking of the carbon–carbon bond and release of carbon dioxide. The protonation of the amine derived from tryptophan restores the aromaticity of the pyridine ring, leading to the production of 5-hydroxytryptamine and PLP.{{cite book | vauthors = Dewick PM | year = 2002 | title = Medicinal Natural Products. A Biosynthetic Approach | edition = 2nd | publisher = Wiley | isbn = 978-0-471-49640-3 }}

Serotonin N-acetyltransferase, with histidine residue His122, is hypothesized to deprotonate the primary amine of 5-hydroxytryptamine. This deprotonation allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A then acts as a leaving group when attacked by a general base, producing N-acetylserotonin.{{cite journal | vauthors = Hickman AB, Klein DC, Dyda F | title = Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism | journal = Molecular Cell | volume = 3 | issue = 1 | pages = 23–32 | date = January 1999 | pmid = 10024876 | doi = 10.1016/S1097-2765(00)80171-9 | doi-access = free }}

The final step in the biosynthesis of melatonin involves the methylation of N-acetylserotonin at the hydroxyl position by SAM, resulting in the production of S-adenosyl homocysteine (SAH) and melatonin.{{cite journal | vauthors = Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC | title = Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA | journal = DNA and Cell Biology | volume = 12 | issue = 8 | pages = 715–27 | date = October 1993 | pmid = 8397829 | doi = 10.1089/dna.1993.12.715 | url = https://zenodo.org/record/1235255 }}

In vertebrates, the secretion of melatonin is regulated through the activation of the beta-1 adrenergic receptor by the hormone norepinephrine.{{cite journal | vauthors = Nesbitt AD, Leschziner GD, Peatfield RC | title = Headache, drugs and sleep | journal = Cephalalgia | volume = 34 | issue = 10 | pages = 756–66 | date = September 2014 | pmid = 25053748 | doi = 10.1177/0333102414542662 | s2cid = 33548757 | type = Review }} Norepinephrine increases the concentration of intracellular cAMP via beta-adrenergic receptors, which in turn activates the cAMP-dependent protein kinase A (PKA). PKA then phosphorylates arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme in the melatonin synthesis pathway. When exposed to daylight, noradrenergic stimulation ceases, leading to the immediate degradation of the protein by proteasomal proteolysis.{{cite journal | vauthors = Schomerus C, Korf HW | title = Mechanisms regulating melatonin synthesis in the mammalian pineal organ | journal = Annals of the New York Academy of Sciences | volume = 1057 | issue = 1 | pages = 372–83 | date = December 2005 | pmid = 16399907 | doi = 10.1196/annals.1356.028 | bibcode = 2005NYASA1057..372S | s2cid = 20517556 }} The production of melatonin recommences in the evening, a phase known as the dim-light melatonin onset.

Blue light, especially within the {{nowrap|460–480 nm}} range, inhibits the biosynthesis of melatonin,{{cite journal | vauthors = Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD | title = Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor | journal = The Journal of Neuroscience | volume = 21 | issue = 16 | pages = 6405–12 | date = August 2001 | pmid = 11487664 | pmc = 6763155 | doi = 10.1523/JNEUROSCI.21-16-06405.2001 }} with the degree of suppression being directly proportional to the intensity and duration of light exposure. Historically, humans in temperate climates experienced limited exposure to blue daylight during winter months, primarily receiving light from sources that emitted predominantly yellow light, such as fires.{{cite journal | vauthors = Holzman DC | title = What's in a color? The unique human health effect of blue light | journal = Environmental Health Perspectives | volume = 118 | issue = 1 | pages = A22-7 | date = January 2010 | pmid = 20061218 | pmc = 2831986 | doi = 10.1289/ehp.118-a22 }} The incandescent light bulbs used extensively throughout the 20th century emitted relatively low levels of blue light.{{cite web|url=http://www.graphics.cornell.edu/online/measurements/source-spectra/index.html|title=Recent News – Program of Computer Graphics|website=www.graphics.cornell.edu}} It has been found that light containing only wavelengths greater than 530 nm does not suppress melatonin under bright-light conditions.{{cite journal | vauthors = Kayumov L, Casper RF, Hawa RJ, Perelman B, Chung SA, Sokalsky S, Shapiro CM | title = Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 5 | pages = 2755–61 | date = May 2005 | pmid = 15713707 | doi = 10.1210/jc.2004-2062 | doi-access = free }} The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression.{{cite web|title=University of Houston study shows blue light glasses at night increase melatonin by 58%|url=https://designeroptics.com/blogs/news/university-of-houston-study-shows-blue-light-glasses-at-night-increase-melatonin-by-58|access-date=2021-08-26|website=designeroptics.com|date=25 August 2021 |language=en}} Additionally, wearing blue-blocking goggles during the last hours before bedtime is recommended for individuals needing to adjust to an earlier bedtime since melatonin facilitates the onset of sleep.{{cite journal | vauthors = Burkhart K, Phelps JR | title = Amber lenses to block blue light and improve sleep: a randomized trial | journal = Chronobiology International | volume = 26 | issue = 8 | pages = 1602–12 | date = December 2009 | pmid = 20030543 | doi = 10.3109/07420520903523719 | s2cid = 145296760 }}

Melatonin is metabolized with an elimination half-life ranging from 20 to 50 minutes.{{cite web |title=Melatonin |url=https://www.drugbank.ca/drugs/DB01065 |access-date=29 January 2019 |website=www.drugbank.ca}}{{cite journal |vauthors=Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP |date=2008 |title=Melatonergic drugs in clinical practice |url= |journal=Arzneimittelforschung |volume=58 |issue=1 |pages=1–10 |doi=10.1055/s-0031-1296459 |pmid=18368944 |s2cid=38857779}} The primary metabolic pathway transforms melatonin into 6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine as a waste product.{{cite journal |last1=Ma |first1=Xiaochao |last2=Idle |first2=Jeffrey R. |last3=Krausz |first3=Kristopher W. |last4=Gonzalez |first4=Frank J. |title=Metabolism of Melatonin by Human Cytochromes P450 |journal=Drug Metabolism and Disposition |date=April 2005 |volume=33 |issue=4 |pages=489–494 |doi=10.1124/dmd.104.002410 |pmid=15616152 |s2cid=14555783 |url=https://dmd.aspetjournals.org/content/33/4/489 |access-date=25 January 2023|url-access=subscription }} It is primarily metabolized by the liver enzyme CYP1A2 and to a lesser extent by CYP1A1, CYP2C19, and CYP1B1.

For both research and clinical purposes, melatonin levels in humans can be determined through saliva or blood plasma analysis.{{cite journal | vauthors = Kennaway DJ | title = A critical review of melatonin assays: Past and present | journal = Journal of Pineal Research | volume = 67 | issue = 1 | pages = e12572 | date = August 2019 | pmid = 30919486 | doi = 10.1111/jpi.12572 | doi-access = free }}

{{Main|Melatonin as a medication and supplement}}

There is evidence of melatonin’s benefit for insomnia, but the evidence is not strong.{{cite journal |vauthors=Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ |year=2015 |title=Management of Insomnia Disorder[Internet] |journal=AHRQ Comparative Effectiveness Reviews |volume=15 |issue=16 |pages=EHC027–EF |pmid=26844312}} A 2017 review found that sleep onset occurred six minutes faster with use on average, but found no change in total time asleep.{{cite journal |vauthors=Matheson E, Hainer BL |date=July 2017 |title=Insomnia: Pharmacologic Therapy |journal=American Family Physician |volume=96 |issue=1 |pages=29–35 |pmid=28671376}}

Melatonin is used both as a prescription medication and an over-the-counter dietary supplement for the management of sleep disorders, including insomnia and various circadian rhythm sleep disorders such as delayed sleep phase disorder, jet lag disorder, and shift work sleep disorder.{{cite journal | vauthors = Riha RL | title = The use and misuse of exogenous melatonin in the treatment of sleep disorders | journal = Curr Opin Pulm Med | volume = 24 | issue = 6 | pages = 543–548 | date = November 2018 | pmid = 30148726 | doi = 10.1097/MCP.0000000000000522 | s2cid = 52096729 | url = }} In addition to melatonin, a range of synthetic melatonin receptor agonists, namely ramelteon, tasimelteon, and agomelatine, are used in medicine.{{cite journal | vauthors = Williams WP, McLin DE, Dressman MA, Neubauer DN | title = Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders | journal = Pharmacotherapy | volume = 36 | issue = 9 | pages = 1028–41 | date = September 2016 | pmid = 27500861 | pmc = 5108473 | doi = 10.1002/phar.1822 | url = }}{{cite journal | vauthors = Atkin T, Comai S, Gobbi G |author3-link=Gabriella Gobbi| title = Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery | journal = Pharmacol Rev | volume = 70 | issue = 2 | pages = 197–245 | date = April 2018 | pmid = 29487083 | doi = 10.1124/pr.117.014381 |s2cid=3578916 | url = | doi-access = free }}

A study published by the Journal of the American Medical Association (JAMA) in April 2023 found that only 12% of the 30 melatonin gummy product preparations analyzed had melatonin quantities within ±10% of the amounts specified on their labels. Some gummy supplements were found to contain up to 347% of the declared melatonin content. In Europe, melatonin is classified as an active pharmaceutical ingredient, highlighting the regulatory oversight of its use and distribution. Conversely, {{As of|lc=y|2022}}, the United States was considering the inclusion of melatonin in pharmacy compounding practices. A preceding study from 2022 concluded that consuming unregulated melatonin products can expose individuals, including children, to melatonin quantities ranging from 40 to 130 times higher than the recommended levels when products are used 'as directed'.Cohen PA, Avula B, Wang Y, Katragunta K, Khan I. (April 2023) [https://jamanetwork.com/journals/jama/fullarticle/2804077?guestAccessKey=f66dce36-77ca-4bdc-a6bc-4978d8a66ed2 "Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US"] JAMA. 329 (16): 1401–1402. doi:10.1001/jama.2023.2296. PMID [https://pubmed.ncbi.nlm.nih.gov/37097362/37097362 37097362]

Anecdotal reports and formal research studies over the past few decades have established a link between melatonin supplementation and more vivid dreams.{{citation |title=Effects of melatonin on dream bizarreness among male and female college students.|last=Kahan |first=Tracey L. |journal=Psychology |year=2000 |publisher=Sleep and Hypnosis, 2(2), 74-83.|url=https://scholarcommons.scu.edu/psych/102/}}

{{Main|History of the pineal gland}}

Melatonin's discovery is linked to the study of skin color changes in some amphibians and reptiles, a phenomenon initially observed through the administration of pineal gland extracts.{{cite journal | vauthors = Filadelfi AM, Castrucci AM | title = Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates | journal = Journal of Pineal Research | volume = 20 | issue = 4 | pages = 175–86 | date = May 1996 | pmid = 8836950 | doi = 10.1111/j.1600-079X.1996.tb00256.x | s2cid = 41959214 }}{{cite journal | vauthors = Sugden D, Davidson K, Hough KA, Teh MT | title = Melatonin, melatonin receptors and melanophores: a moving story | journal = Pigment Cell Research | volume = 17 | issue = 5 | pages = 454–60 | date = October 2004 | pmid = 15357831 | doi = 10.1111/j.1600-0749.2004.00185.x | doi-access = free }} In 1917, Carey Pratt McCord and Floyd P. Allen found that feeding extracts from the pineal glands of cows caused the skin of tadpoles to lighten by contracting the dark epidermal melanophores.{{cite book | vauthors = Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD| title = Encyclopedia of dietary supplements | publisher = Marcel Dekker | location = New York, N.Y | year = 2005 | pages = 457–66 | isbn = 978-0-8247-5504-1 | url = https://books.google.com/books?id=Sfmc-fRCj10C&q=Lerner+melatonin+history&pg=PA457 }}{{cite journal |vauthors=McCord CP, Allen FP |title=Evidences associating pineal gland function with alterations in pigmentation |date=January 1917 |journal=J Exp Zool |volume= 23 |issue=1 |pages=206–24 |url=https://books.google.com/books?id=OOM1AQAAMAAJ&pg=PA207 |doi=10.1002/jez.1400230108 |bibcode=1917JEZ....23..207M }}

The hormone melatonin was isolated in 1958 by Aaron B. Lerner, a dermatology professor, and his team at Yale University. Motivated by the possibility that a substance from the pineal gland could be beneficial in treating skin diseases, they extracted and identified melatonin from bovine pineal gland extracts.{{cite journal | vauthors = Lerner AB, Case JD, Takahashi Y | title = Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands | journal = The Journal of Biological Chemistry | volume = 235 | pages = 1992–7 | date = July 1960 | issue = 7 | doi = 10.1016/S0021-9258(18)69351-2 | pmid = 14415935 | doi-access = free }} Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.{{cite journal | vauthors = Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH | title = Daily rhythm in human urinary melatonin | journal = Science | volume = 187 | issue = 4172 | pages = 169–71 | date = January 1975 | pmid = 1167425 | doi = 10.1126/science.1167425 | bibcode = 1975Sci...187..169L }}

The first patent for the therapeutic use of melatonin as a low-dose sleep aid was awarded to Richard Wurtman at the Massachusetts Institute of Technology in 1995.{{cite patent|country=US|number=5449683|title=Methods of inducing sleep using melatonin|status=patent|fdate=16 July 1993|gdate=12 September 1995|inventor=Wurtman RJ|assign1=Massachusetts Institute of Technology}}

The etymology of melatonin stems from its skin-lightening properties. As detailed in their publication in the Journal of the American Chemical Society,{{Cite journal |last1=Lerner |first1=Aaron B. |last2=Case |first2=James D. |last3=Takahashi |first3=Yoshiyata |last4=Lee |first4=Teh H. |last5=Mori |first5=Wataru |date=1958 |title=Isolation of melatonin, the pineal gland factor that lightens melanocytes |url=https://pubs.acs.org/doi/abs/10.1021/ja01543a060 |journal=Journal of the American Chemical Society |language=en |volume=80 |issue=10 |pages=2587 |doi=10.1021/ja01543a060 |bibcode=1958JAChS..80Q2587L |issn=0002-7863|url-access=subscription }} Lerner and his colleagues proposed the name melatonin, derived from the Greek words melas, meaning 'black' or 'dark', and tonos, meaning 'labour',{{Cite journal |last1=Goeser |first1=Suzanne |last2=Ruble |first2=James |last3=Chandler |first3=Linda |date=1997 |title=Melatonin: Historical and Clinical Perspectives |url=http://www.tandfonline.com/doi/full/10.1300/J088v05n01_04 |journal=Journal of Pharmaceutical Care in Pain & Symptom Control |language=en |volume=5 |issue=1 |pages=37–49 |doi=10.1300/J088v05n01_04|url-access=subscription }} 'colour'{{Cite journal |last1=Beyer |first1=C. E. |last2=Steketee |first2=J. D. |last3=Saphier |first3=D. |date=1998 |title=Antioxidant properties of melatonin–an emerging mystery |journal=Biochemical Pharmacology |volume=56 |issue=10 |pages=1265–1272 |doi=10.1016/s0006-2952(98)00180-4 |issn=0006-2952 |pmid=9825724}} or 'suppress'.{{Cite journal |last1=Liebmann |first1=P. M. |last2=Wölfler |first2=A. |last3=Felsner |first3=P. |last4=Hofer |first4=D. |last5=Schauenstein |first5=K. |date=1997 |title=Melatonin and the immune system|journal=International Archives of Allergy and Immunology |volume=112 |issue=3 |pages=203–211 |doi=10.1159/000237455 |issn=1018-2438 |pmid=9066504}} This naming convention follows that of serotonin, another agent affecting skin color, discovered in 1948 as a modulator of vascular tone, which influenced its name based on its serum vasoconstrictor effect.{{cite journal |vauthors=Rapport MM, Green AA, Page IH |date=December 1948 |title=Serum vasoconstrictor, serotonin; isolation and characterization |url=http://www.jbc.org/content/176/3/1243.short |journal=The Journal of Biological Chemistry |volume=176 |issue=3 |pages=1243–1251 |doi=10.1016/S0021-9258(18)57137-4 |pmid=18100415 |doi-access=free}} Melatonin was thus aptly named to reflect its role in preventing the darkening of the skin, highlighting the intersection of biochemistry and linguistics in scientific discovery.

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland{{cite journal | vauthors = Reiter RJ | title = Pineal melatonin: cell biology of its synthesis and of its physiological interactions | journal = Endocrine Reviews | volume = 12 | issue = 2 | pages = 151–80 | date = May 1991 | pmid = 1649044 | doi = 10.1210/edrv-12-2-151 | s2cid = 3219721 }}

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{{cite journal | vauthors = Richardson GS | title = The human circadian system in normal and disordered sleep | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 9 | pages = 3–9; quiz 42–3 | year = 2005 | pmid = 16336035 }}{{cite journal | vauthors = Perreau-Lenz S, Pévet P, Buijs RM, Kalsbeek A | title = The biological clock: the bodyguard of temporal homeostasis | journal = Chronobiology International | volume = 21 | issue = 1 | pages = 1–25 | date = January 2004 | pmid = 15129821 | doi = 10.1081/CBI-120027984 | s2cid = 42725506 }} 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.{{cite journal | vauthors = Foster RG | title = Sleep, circadian rhythms and health | journal = Interface Focus | volume = 10 | issue = 3 | pages = 20190098 | date = June 2020 | pmid = 32382406 | pmc = 7202392 | doi = 10.1098/rsfs.2019.0098 }}

In humans, ~30 μg of melatonin is produced daily and 80% of the total amount is produced in the night (W). The plasma maximum concentration of melatonin at night are 80–120 pg/mL and the concentrations during the day are between 10–20 pg/mL.{{Cite journal |last1=Karasek |first1=M. |last2=Winczyk |first2=K. |date=2006 |title=Melatonin in humans |url=https://pubmed.ncbi.nlm.nih.gov/17218758/ |journal=Journal of Physiology and Pharmacology|volume=57 Suppl 5 |pages=19–39 |issn=1899-1505 |pmid=17218758}}{{Cite journal |last1=Kolli |first1=Aditya R. |last2=Kuczaj |first2=Arkadiusz K. |last3=Calvino-Martin |first3=Florian |last4=Hoeng |first4=Julia |date=2024 |title=Simulated pharmacokinetics of inhaled caffeine and melatonin from existing products indicate the lack of dosimetric considerations |journal=Food and Chemical Toxicology |volume=187 |pages=114601 |doi=10.1016/j.fct.2024.114601 |issn=0278-6915|doi-access=free |pmid=38493979 }}

Many animals and humans use the variation in duration of melatonin production each day as a seasonal clock.{{cite journal | vauthors = Lincoln GA, Andersson H, Loudon A | title = Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis | journal = The Journal of Endocrinology | volume = 179 | issue = 1 | pages = 1–13 | date = October 2003 | pmid = 14529560 | doi = 10.1677/joe.0.1790001 | doi-access = free }} In animals including humans,{{cite journal | vauthors = Arendt J, Skene DJ | title = Melatonin as a chronobiotic | journal = Sleep Medicine Reviews | volume = 9 | issue = 1 | pages = 25–39 | date = February 2005 | pmid = 15649736 | doi = 10.1016/j.smrv.2004.05.002 | quote = 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. }} 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{{cite journal | pages = 803–09 | doi = 10.1071/ZO9840803 | title = Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis | year = 1984 | vauthors = Chaturvedi CM | journal = Australian Journal of Zoology | volume = 32 | issue = 6}} and hamsters.{{cite journal | vauthors = Chen HJ | title = Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition | journal = Neuroendocrinology | volume = 33 | issue = 1 | pages = 43–6 | date = July 1981 | pmid = 7254478 | doi = 10.1159/000123198 }} 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. In sheep, melatonin administration has also shown antioxidant and immune-modulatory regime in prenatally stressed offspring helping them survive the crucial first days of their lives.{{Cite journal |last1=Bouroutzika |first1=Efterpi |last2=Ciliberti |first2=Maria Giovanna |last3=Caroprese |first3=Mariangela |last4=Theodosiadou |first4=Ekaterini |last5=Papadopoulos |first5=Serafeim |last6=Makri |first6=Sotiria |last7=Skaperda |first7=Zoi-Vasiliki |last8=Kotsadam |first8=Georgios |last9=Michailidis |first9=Marios-Lazaros |last10=Valiakos |first10=George |last11=Chadio |first11=Stella |last12=Kouretas |first12=Dimitris |last13=Valasi |first13=Irene |date=2021-11-05 |title=Association of Melatonin Administration in Pregnant Ewes with Growth, Redox Status and Immunity of Their Offspring |journal=Animals |language=en |volume=11 |issue=11 |pages=3161 |doi=10.3390/ani11113161 |doi-access=free |issn=2076-2615 |pmc=8614450 |pmid=34827893}}

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.{{cite journal | vauthors = Huelsmann M, Hecker N, Springer MS, Gatesy J, Sharma V, Hiller M | title = Genes lost during the transition from land to water in cetaceans highlight genomic changes associated with aquatic adaptations | journal = Science Advances | volume = 5 | issue = 9 | pages = eaaw6671 | date = September 2019 | pmid = 31579821 | pmc = 6760925 | doi = 10.1126/sciadv.aaw6671 | bibcode = 2019SciA....5.6671H }} 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.{{cite journal | vauthors = Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ | title = Phytomelatonin: a review | journal = Journal of Experimental Botany | volume = 60 | issue = 1 | pages = 57–69 | date = 1 January 2009 | pmid = 19033551 | doi = 10.1093/jxb/ern284 | s2cid = 15738948 | doi-access = free }} 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.{{cite journal | vauthors = Hardeland R | title = Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions | journal = Journal of Experimental Botany | volume = 66 | issue = 3 | pages = 627–46 | date = February 2015 | pmid = 25240067 | doi = 10.1093/jxb/eru386 | doi-access = }}{{cite journal | vauthors = Bonnefont-Rousselot D, Collin F | title = Melatonin: action as antioxidant and potential applications in human disease and aging | journal = Toxicology | volume = 278 | issue = 1 | pages = 55–67 | date = November 2010 | pmid = 20417677 | doi = 10.1016/j.tox.2010.04.008 | bibcode = 2010Toxgy.278...55B }} 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,{{cite journal | vauthors = Reiter RJ, Manchester LC, Tan DX | title = Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood | journal = Nutrition | volume = 21 | issue = 9 | pages = 920–4 | date = September 2005 | pmid = 15979282 | doi = 10.1016/j.nut.2005.02.005 }} 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.{{cite journal | vauthors = Reiter RJ, Tan DX, Zhou Z, Cruz MH, Fuentes-Broto L, Galano A | title = Phytomelatonin: assisting plants to survive and thrive | journal = Molecules | volume = 20 | issue = 4 | pages = 7396–437 | date = April 2015 | pmid = 25911967 | pmc = 6272735 | doi = 10.3390/molecules20047396 | doi-access = free }}{{cite journal | vauthors = Arnao MB, Hernández-Ruiz J | title = Functions of melatonin in plants: a review | journal = Journal of Pineal Research | volume = 59 | issue = 2 | pages = 133–50 | date = September 2015 | pmid = 26094813 | doi = 10.1111/jpi.12253 | doi-access = free }}

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice.{{cite journal | vauthors = Park S, Lee DE, Jang H, Byeon Y, Kim YS, Back K | title = Melatonin-rich transgenic rice plants exhibit resistance to herbicide-induced oxidative stress | journal = Journal of Pineal Research | volume = 54 | issue = 3 | pages = 258–63 | date = April 2013 | pmid = 22856683 | doi = 10.1111/j.1600-079x.2012.01029.x | publisher = Wiley | s2cid = 6291664 }}{{cite journal | vauthors = Arnao MB, Hernández-Ruiz J | title = Melatonin: plant growth regulator and/or biostimulator during stress? | journal = Trends in Plant Science | volume = 19 | issue = 12 | pages = 789–97 | date = December 2014 | pmid = 25156541 | doi = 10.1016/j.tplants.2014.07.006 | publisher = Elsevier | bibcode = 2014TPS....19..789A | s2cid = 38637203 }}{{cite journal |first1= Hemat A. |last1= EL-Bauome | first2= Samar M. |last2= Doklega | first3= Said A. |last3= Saleh |first4= Ahmed S. |last4= Mohamed |last5= Suliman| first5= Ahmad A. | first6= Mahmoud A.M. |last6= Abd El-Hady | title = Effects of melatonin on lettuce plant growth, antioxidant enzymes and photosynthetic pigments under salinity stress conditions | journal = Folia Horticulturae | volume = 36 | issue = 1 | pages = 1–17 | date = February 2024 | pmid = | doi = 10.2478/fhort-2024-0001 | publisher = Polish Society of Horticultural Science | s2cid = 19887642 | doi-access = free }} Studies conducted on lettuce grown in saline soil conditions have shown that the application of melatonin significantly mitigates the harmful effects of salinity. Foliar application increases the number of leaves, their surface area, increases fresh weight and the content of chlorophyll a and chlorophyll b, and the content of carotenoids compared to plants not treated with melatonin.

Fungal disease resistance is another role. Added melatonin increases resistance in Malus prunifolia against Diplocarpon mali.{{cite journal | vauthors = Arnao MB, Hernández-Ruiz J | title = Functions of melatonin in plants: a review | journal = Journal of Pineal Research | volume = 59 | issue = 2 | pages = 133–50 | date = September 2015 | pmid = 26094813 | doi = 10.1111/jpi.12253 | publisher = Wiley | s2cid = 19887642 | doi-access = free }} 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.

Melatonin has been observed to reduce stress tolerance in Phytophthora infestans in plant-pathogen systems.{{cite journal | vauthors = Socaciu AI, Ionuţ R, Socaciu MA, Ungur AP, Bârsan M, Chiorean A, Socaciu C, Râjnoveanu AG | title = Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases | journal = Reviews in Endocrine & Metabolic Disorders | volume = 21 | issue = 4 | pages = 465–478 | date = December 2020 | pmid = 32691289 | doi = 10.1007/s11154-020-09570-9 | s2cid = 220657247 }} Danish pharmaceutical company Novo Nordisk have used genetically modified yeast (Saccharomyces cerevisiae) to produce melatonin.{{Cite journal |last1=Germann |first1=Susanne M. |last2=Baallal Jacobsen |first2=Simo A. |last3=Schneider |first3=Konstantin |last4=Harrison |first4=Scott J. |last5=Jensen |first5=Niels B. |last6=Chen |first6=Xiao |last7=Stahlhut |first7=Steen G. |last8=Borodina |first8=Irina |last9=Luo |first9=Hao |last10=Zhu |first10=Jiangfeng |last11=Maury |first11=Jérôme |last12=Forster |first12=Jochen |date=2016 |title=Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae |journal=Biotechnology Journal |language=en |volume=11 |issue=5 |pages=717–724 |doi=10.1002/biot.201500143 |pmc=5066760 |pmid=26710256}}

Melatonin is produced by α-proteobacteria and photosynthetic cyanobacteria. There is no report of its occurrence in archaea which indicates that melatonin originated in bacteria most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.

Novo Nordisk have used genetically modified Escherichia coli to produce melatonin.{{Cite journal |last1=Luo |first1=Hao |last2=Schneider |first2=Konstantin |last3=Christensen |first3=Ulla |last4=Lei |first4=Yang |last5=Herrgard |first5=Markus |last6=Palsson |first6=Bernhard Ø. |date=2020 |title=Microbial Synthesis of Human-Hormone Melatonin at Gram Scales |url=https://pubs.acs.org/doi/10.1021/acssynbio.0c00065 |journal=ACS Synthetic Biology |language=en |volume=9 |issue=6 |pages=1240–1245 |doi=10.1021/acssynbio.0c00065 |pmid=32501000 |s2cid=219331624 |issn=2161-5063|url-access=subscription }}{{Cite journal |last1=Arnao |first1=Marino B. |last2=Giraldo-Acosta |first2=Manuela |last3=Castejón-Castillejo |first3=Ana |last4=Losada-Lorán |first4=Marta |last5=Sánchez-Herrerías |first5=Pablo |last6=El Mihyaoui |first6=Amina |last7=Cano |first7=Antonio |last8=Hernández-Ruiz |first8=Josefa |date=2023 |title=Melatonin from Microorganisms, Algae, and Plants as Possible Alternatives to Synthetic Melatonin |journal=Metabolites |volume=13 |issue=1 |pages=72 |doi=10.3390/metabo13010072 |pmc=9862825 |pmid=36676997 |doi-access=free }}

In 2022, the discovery of serotonin N-acetyltransferase (SNAT)—the penultimate, rate-limiting enzyme in the melatonin biosynthetic pathway—in the archaeon Thermoplasma volcanium{{Cite journal |last1=Lee |first1=Kyungjin |last2=Choi |first2=Geun-Hee |last3=Back |first3=Kyoungwhan |date=2022-03-21 |title=Functional Characterization of Serotonin N-Acetyltransferase in Archaeon Thermoplasma volcanium |journal=Antioxidants |volume=11 |issue=3 |pages=596 |doi=10.3390/antiox11030596 |doi-access=free |issn=2076-3921 |pmc=8945778 |pmid=35326246}} firmly places melatonin biosynthesis in all three major domains of life, dating back to ~4 Gya.{{Cite journal |last1=Hoshino |first1=Yosuke |last2=Villanueva |first2=Laura |date=2023-03-10 |title=Four billion years of microbial terpenome evolution |url=https://pubmed.ncbi.nlm.nih.gov/36941124/ |journal=FEMS Microbiology Reviews |volume=47 |issue=2 |pages=fuad008 |doi=10.1093/femsre/fuad008 |issn=1574-6976 |pmid=36941124}}

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,{{cite journal | vauthors = Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ | title = Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus) | journal = Journal of Agricultural and Food Chemistry | volume = 49 | issue = 10 | pages = 4898–902 | date = October 2001 | pmid = 11600041 | doi = 10.1021/jf010321 }} bananas, plums, grapes, rice, cereals, herbs,{{cite journal | vauthors = González-Flores D, Velardo B, Garrido M, González-Gómez D, Lozano M, Ayuso MC, Barriga C, Paredes SD, Rodríguez AB | year = 2011 | url = https://www.researchgate.net/publication/259983119 | title = 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 = Journal of Food and Nutrition Research | volume= 50 | issue = 4 | pages = 229–36 }} olive oil, wine,{{cite journal | vauthors = Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S | title = Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection | journal = Journal of Pineal Research | volume = 50 | issue = 4 | pages = 374–80 | date = May 2011 | pmid = 21342247 | doi = 10.1111/j.1600-079X.2010.00853.x | s2cid = 8034935 }} and beer.{{cite journal|vauthors=Salehi B|date=5 July 2019|title=Melatonin in Medicinal and Food Plants|url=https://schlaf.fit/Melatonin_in_Plants_and_Food.pdf|journal=Cells|volume=681|access-date=2 July 2021|archive-date=29 November 2021|archive-url=https://web.archive.org/web/20211129060429/https://schlaf.fit/Melatonin_in_Plants_and_Food.pdf|url-status=dead}} The consumption of milk and sour cherries may improve sleep quality.{{cite journal | vauthors = Pereira N, Naufel MF, Ribeiro EB, Tufik S, Hachul H | title = Influence of Dietary Sources of Melatonin on Sleep Quality: A Review | journal = Journal of Food Science | volume = 85 | issue = 1 | pages = 5–13 | date = January 2020 | pmid = 31856339 | doi = 10.1111/1750-3841.14952 | publisher = Wiley | doi-access = free }} When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.{{cite journal | vauthors = Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ| title = Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates | journal = Biochemistry and Molecular Biology International | volume = 35 | issue = 3 | pages = 627–34 | date = March 1995 | pmid = 7773197 }} When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.{{cite journal | vauthors = Sae-Teaw M, Johns J, Johns NP, Subongkot S | title = Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers | journal = Journal of Pineal Research | volume = 55 | issue = 1 | pages = 58–64 | date = August 2013 | pmid = 23137025 | doi = 10.1111/jpi.12025 | s2cid = 979886 | doi-access = free }}

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