Melatonin

Hormone released by the pineal gland

This article is about melatonin as a hormone. For its role as a supplement and medication, see Melatonin as a medication and supplement. For other uses, see Melatonin (disambiguation).

Not to be confused with melanin.

Melatonin

Names
IUPAC name

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

Other names

5-Methoxy-N-acetyltryptamine; N-Acetyl-5-methoxytryptamine; NSC-113928

Identifiers

CAS Number

* 73-31-4

3D model (JSmol)

* Interactive image

ChEBI |

* CHEBI:16796

ChEMBL |

* ChEMBL45

ChemSpider |

* 872

DrugBank |

* DB01065

ECHA InfoCard | 100.000.725
EC Number |

* 200-797-7200-797-7

KEGG |

* C01598

MeSH | Melatonin

PubChem CID

* 896

UNII |

* JL5DK93RCL

CompTox Dashboard (EPA)

* DTXSID1022421

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)

Key: DRLFMBDRBRZALE-UHFFFAOYSA-N

SMILES

* CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC

Properties

Chemical formula

| C13H16N2O2
Molar mass | 232.283 g·mol−1
Melting point | 117 °C (243 °F; 390 K)

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Infobox references

Chemical compound

Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes.[1] Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cows that could induce skin lightening in common frogs. This compound was later identified as a hormone secreted in the brain during the night, playing a crucial role in regulating the sleep-wake cycle, also known as the circadian rhythm, in vertebrates.[2][3]

In vertebrates, melatonin's functions extend to synchronizing sleep-wake cycles, encompassing sleep-wake timing and blood pressure regulation, as well as controlling seasonal rhythmicity (circannual cycle), which includes reproduction, fattening, molting, and hibernation.[4] Its effects are mediated through the activation of melatonin receptors and its role as an antioxidant.[5][6][7] In plants and bacteria, melatonin primarily serves as a defense mechanism against oxidative stress, indicating its evolutionary significance.[8] The mitochondria, key organelles within cells, are the main producers of antioxidant melatonin,[9] underscoring the molecule's "ancient origins" and its fundamental role in protecting the earliest cells from reactive oxygen species.[10][11]

In addition to its endogenous functions as a hormone and antioxidant, melatonin is also administered exogenously as a dietary supplement and medication. Melatonin may help people fall asleep about six minutes faster, but it does not significantly increase total sleep time and the overall evidence of its effectiveness for insomnia is weak. It is used in the treatment of sleep disorders, including insomnia and various circadian rhythm sleep disorders.

## Biological activity

[edit]

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 Gi/o alpha subunit GPCRs,[12][13] although melatonin receptor 1 also exhibits coupling with Gq alpha subunit.[12]

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.[14][12][15][16][17][18]

## Biological functions

[edit]

Visible light entering the eye and the cascading positive and negative signalling pathways to neuronal structures in the mamallian brain that may follow: When the eyes are exposed to sunlight, the pineal gland's melatonin production is suppressed, resulting in the secretion of hormones that promote wakefulness. Conversely, in the absence of light, the pineal gland synthesizes melatonin unabated, leading to feelings of drowsiness and facilitating the onset of sleep.

### Circadian rhythm

[edit]

Main article: Circadian rhythm

In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms.[19] 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.[20] It has been documented that melatonin production diminishes as a person ages.[21] 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.[22]

The antioxidant properties of melatonin were first recognized in 1993.[23] 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•).[24][25] In plants, melatonin works synergistically with other antioxidants, enhancing the overall effectiveness of each antioxidant.[25] This compound has been found to be twice as efficacious as vitamin E, a known potent lipophilic antioxidant, at scavenging peroxyl radicals.[26] 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.[12][14]

Melatonin's concentration in the mitochondrial matrix is significantly higher than that found in the blood plasma,[15][16][17] 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.[14][15][16][17][18]

Furthermore, the interaction of melatonin with reactive oxygen and nitrogen species results in the formation of metabolites capable of reducing free radicals.[12][18] 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.[12][18]

### Immune system

[edit]

Melatonin's interaction with the immune system is recognized, yet the specifics of these interactions remain inadequately defined.[27][28][needs update] An anti-inflammatory effect appears to be the most significant.[citation needed] 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,[29] thereby potentially mitigating acquired immunodeficiencies.[30]

### Weight regulation

[edit]

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.[31][32] 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.

## Biochemistry

[edit]

### Biosynthesis

[edit]

Melatonin biosynthesis

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.[33]

Serotonin, an essential neurotransmitter, is further converted into N-acetylserotonin by the action of serotonin N-acetyltransferase, using acetyl-CoA.[34] 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.[34]

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.[35][36]

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.[37]

### Mechanism

[edit]

Mechanism of melatonin biosynthesis

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 (O−2). 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.[38]

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.[39] 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.[40]

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.[41]

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.[40][42]

### Regulation

[edit]

In vertebrates, the secretion of melatonin is regulated through the activation of the beta-1 adrenergic receptor by the hormone norepinephrine.[43] 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.[44] The production of melatonin recommences in the evening, a phase known as the dim-light melatonin onset.

Blue light, especially within the 460–480 nm range, inhibits the biosynthesis of melatonin,[45] 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.[46] The incandescent light bulbs used extensively throughout the 20th century emitted relatively low levels of blue light.[47] It has been found that light containing only wavelengths greater than 530 nm does not suppress melatonin under bright-light conditions.[48] The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression.[49] 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.[50]

### Metabolism

[edit]

Melatonin is metabolized with an elimination half-life ranging from 20 to 50 minutes.[51][2][52] The primary metabolic pathway transforms melatonin into 6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine as a waste product.[53] It is primarily metabolized by the liver enzyme CYP1A2 and to a lesser extent by CYP1A1, CYP2C19, and CYP1B1.[53]

### Measurement

[edit]

For both research and clinical purposes, melatonin levels in humans can be determined through saliva or blood plasma analysis.[54]

## Use as a medication and supplement

[edit]

Main article: Melatonin as a medication and supplement

There is evidence of melatonin’s benefit for insomnia, but the evidence is not strong.[55] A 2017 review found that sleep onset occurred six minutes faster with use on average, but found no change in total time asleep.[56]

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.[57] In addition to melatonin, a range of synthetic melatonin receptor agonists, namely ramelteon, tasimelteon, and agomelatine, are used in medicine.[58][59]

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 2022[update], 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'.[60]

Anecdotal reports and formal research studies over the past few decades have established a link between melatonin supplementation and more vivid dreams.[61]

## History

[edit]

Main article: History of the pineal gland

### Discovery

[edit]

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.[62][63] 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.[64][65]

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.[66] Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.[67]

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.[68]

### Etymology

[edit]

The etymology of melatonin stems from its skin-lightening properties. As detailed in their publication in the Journal of the American Chemical Society,[69] Lerner and his colleagues proposed the name melatonin, derived from the Greek words melas, meaning 'black' or 'dark', and tonos, meaning 'labour',[70] 'colour'[71] or 'suppress'.[72] 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.[73] 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.[69]

## Occurrence

[edit]

### Animals and Humans

[edit]

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland[74] 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[75][76] 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.[77]

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.[78][79]

Many animals and humans use the variation in duration of melatonin production each day as a seasonal clock.[80] In animals including humans,[81] 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.[81] 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[82] and hamsters.[83] 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.[84]

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.[85] This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.[85]

### Plants

[edit]

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.[8][86] 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.[36][87] 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.[8] In some common foods and beverages, including coffee[8] and walnuts,[88] 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.[36][89][90]

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice.[91][92][93] 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.[93]

Fungal disease resistance is another role. Added melatonin increases resistance in Malus prunifolia against Diplocarpon mali.[92][94] 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.[94]

### Fungi

[edit]

Melatonin has been observed to reduce stress tolerance in Phytophthora infestans in plant-pathogen systems.[95] Danish pharmaceutical company Novo Nordisk have used genetically modified yeast (Saccharomyces cerevisiae) to produce melatonin.[96]

### Bacteria

[edit]

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[11] most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.[10]

Novo Nordisk have used genetically modified Escherichia coli to produce melatonin.[97][98]

### Archaea

[edit]

In 2022, the discovery of serotonin N-acetyltransferase (SNAT)—the penultimate, rate-limiting enzyme in the melatonin biosynthetic pathway—in the archaeon Thermoplasma volcanium[99] firmly places melatonin biosynthesis in all three major domains of life, dating back to ~4 Gya.[100]

### Food products

[edit]

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,[101] bananas, plums, grapes, rice, cereals, herbs,[102] olive oil, wine,[103] and beer.[104] The consumption of milk and sour cherries may improve sleep quality.[105] When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[106] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.[107]

## References

[edit]

1. ^ Amaral FG, Cipolla-Neto J (2018). "A brief review about melatonin, a pineal hormone". Archives of Endocrinology and Metabolism. 62 (4): 472–479\. doi:10.20945/2359-3997000000066. PMC 10118741. PMID 30304113. S2CID 52954755.
2. ^ a b Auld F, Maschauer EL, Morrison I, et al. (August 2017). "Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders" (PDF). Sleep Medicine Reviews. 34: 10–22\. doi:10.1016/j.smrv.2016.06.005. hdl:20.500.11820/0e890bda-4b1d-4786-a907-a03b1580fd07. PMID 28648359.
3. ^ Faraone SV (2014). ADHD: Non-Pharmacologic Interventions, An Issue of Child and Adolescent Psychiatric Clinics of North America, E-Book. Elsevier Health Sciences. p. 888\. ISBN 978-0-323-32602-5.
4. ^ Altun A, Ugur-Altun B (May 2007). "Melatonin: therapeutic and clinical utilization". International Journal of Clinical Practice. 61 (5): 835–45\. doi:10.1111/j.1742-1241.2006.01191.x. PMID 17298593. S2CID 18050554.
5. ^ Boutin JA, Audinot V, Ferry G, et al. (August 2005). "Molecular tools to study melatonin pathways and actions". Trends in Pharmacological Sciences. 26 (8): 412–9\. doi:10.1016/j.tips.2005.06.006. PMID 15992934.
6. ^ Hardeland R (July 2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine. 27 (2): 119–30\. doi:10.1385/ENDO:27:2:119. PMID 16217125. S2CID 46984486.
7. ^ Reiter RJ, Acuña-Castroviejo D, Tan DX, et al. (June 2001). "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system". Annals of the New York Academy of Sciences. 939 (1): 200–15\. Bibcode:2001NYASA.939..200R. doi:10.1111/j.1749-6632.2001.tb03627.x. PMID 11462772. S2CID 20404509.
8. ^ a b c d Tan DX, Hardeland R, Manchester LC, et al. (January 2012). "Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science". Journal of Experimental Botany. 63 (2): 577–97\. doi:10.1093/jxb/err256. PMID 22016420.
9. ^ Reiter RJ, Tan DX, Rosales-Corral S, et al. (2018). "Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions". Molecules. 23 (2): 509. doi:10.3390/molecules23020509. PMC 6017324. PMID 29495303.
10. ^ a b Manchester LC, Coto-Montes A, Boga JA, et al. (2015). "Melatonin: an ancient molecule that makes oxygen metabolically tolerable". Journal of Pineal Research. 59 (4): 403–419\. doi:10.1111/jpi.12267. PMID 26272235. S2CID 24373303.
11. ^ a b Zhao D, Yu Y, Shen Y, et al. (2019). "Melatonin Synthesis and Function: Evolutionary History in Animals and Plants". Frontiers in Endocrinology. 10: 249. doi:10.3389/fendo.2019.00249. PMC 6481276. PMID 31057485.
12. ^ a b c d e f Jockers R, Delagrange P, Dubocovich ML, et al. (September 2016). "Update on melatonin receptors: IUPHAR Review 20". British Journal of Pharmacology. 173 (18): 2702–25\. doi:10.1111/bph.13536. PMC 4995287. PMID 27314810. "Hence, one melatonin molecule and its associated metabolites could scavenge a large number of reactive species, and thus, the overall antioxidant capacity of melatonin is believed to be greater than that of other well-known antioxidants, such as vitamin C and vitamin E, under in vitro or in vivo conditions"
13. ^ "Melatonin receptors | G protein-coupled receptors | IUPHAR/BPS Guide to Pharmacology". www.guidetopharmacology.org. Retrieved 7 April 2017.
14. ^ a b c Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, et al. (2017). "Melatonin and human mitochondrial diseases". Journal of Research in Medical Sciences. 22: 2. doi:10.4103/1735-1995.199092. PMC 5361446. PMID 28400824.
15. ^ a b c Reiter RJ, Rosales-Corral S, Tan DX, et al. (November 2017). "Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas". Cellular and Molecular Life Sciences. 74 (21): 3863–3881\. doi:10.1007/s00018-017-2609-7. PMC 11107735. PMID 28864909. S2CID 23820389. "melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant ... The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood."
16. ^ a b c Reiter RJ, Mayo JC, Tan DX, et al. (October 2016). "Melatonin as an antioxidant: under promises but over delivers". Journal of Pineal Research. 61 (3): 253–78\. doi:10.1111/jpi.12360. PMID 27500468. S2CID 35435683.
17. ^ a b c Manchester LC, Coto-Montes A, Boga JA, et al. (November 2015). "Melatonin: an ancient molecule that makes oxygen metabolically tolerable". Journal of Pineal Research. 59 (4): 403–19\. doi:10.1111/jpi.12267. PMID 26272235. S2CID 24373303. "While originally thought to be produced exclusively in and secreted from the vertebrate pineal gland, it is now known that the indole is present in many, perhaps all, vertebrate organs"
18. ^ a b c d Mayo JC, Sainz RM, González-Menéndez P, et al. (November 2017). "Melatonin transport into mitochondria". Cellular and Molecular Life Sciences. 74 (21): 3927–3940\. doi:10.1007/s00018-017-2616-8. PMC 11107582. PMID 28828619. S2CID 10920415.
19. ^ Emet M, Ozcan H, Ozel L, et al. (June 2016). "A Review of Melatonin, Its Receptors and Drugs". The Eurasian Journal of Medicine. 48 (2): 135–41\. doi:10.5152/eurasianjmed.2015.0267. PMC 4970552. PMID 27551178.
20. ^ Ardura J, Gutierrez R, Andres J, et al. (2003). "Emergence and evolution of the circadian rhythm of melatonin in children". Hormone Research. 59 (2): 66–72\. PMID 12589109. S2CID 41937922.
21. ^ Sack RL, Lewy AJ, Erb DL, et al. (1986). "Human melatonin production decreases with age". Journal of Pineal Research. 3 (4): 379–88\. doi:10.1111/j.1600-079X.1986.tb00760.x. PMID 3783419. S2CID 33664568.
22. ^ Hagenauer MH, Perryman JI, Lee TM, et al. (June 2009). "Adolescent changes in the homeostatic and circadian regulation of sleep". Developmental Neuroscience. 31 (4): 276–84\. doi:10.1159/000216538. PMC 2820578. PMID 19546564.
23. ^ Tan DX, Chen LD, Poeggeler B, et al. (1993). "Melatonin: a potent, endogenous hydroxyl radical scavenger". Endocr. J. 1: 57–60.
24. ^ Poeggeler B, Saarela S, Reiter RJ, et al. (November 1994). "Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro". Annals of the New York Academy of Sciences. 738 (1): 419–20\. Bibcode:1994NYASA.738..419P. doi:10.1111/j.1749-6632.1994.tb21831.x. PMID 7832450. S2CID 36383425.
25. ^ a b Arnao MB, Hernández-Ruiz J (May 2006). "The physiological function of melatonin in plants". Plant Signaling & Behavior. 1 (3): 89–95\. Bibcode:2006PlSiB...1...89A. doi:10.4161/psb.1.3.2640. PMC 2635004. PMID 19521488.
26. ^ Pieri C, Marra M, Moroni F, et al. (1994). "Melatonin: a peroxyl radical scavenger more effective than vitamin E". Life Sciences. 55 (15): PL271-6. doi:10.1016/0024-3205(94)00666-0. PMID 7934611.
27. ^ Carrillo-Vico A, Guerrero JM, Lardone PJ, et al. (July 2005). "A review of the multiple actions of melatonin on the immune system". Endocrine. 27 (2): 189–200\. doi:10.1385/ENDO:27:2:189. PMID 16217132. S2CID 21133107.
28. ^ Arushanian EB, Beĭer EV (2002). "[Immunotropic properties of pineal melatonin]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 65 (5): 73–80\. PMID 12596522.
29. ^ Carrillo-Vico A, Reiter RJ, Lardone PJ, et al. (May 2006). "The modulatory role of melatonin on immune responsiveness". Current Opinion in Investigational Drugs. 7 (5): 423–31\. PMID 16729718.
30. ^ Maestroni GJ (March 2001). "The immunotherapeutic potential of melatonin". Expert Opinion on Investigational Drugs. 10 (3): 467–76\. doi:10.1517/13543784.10.3.467. PMID 11227046. S2CID 6822594.
31. ^ Suriagandhi V, Nachiappan V (January 2022). "Protective Effects of Melatonin against Obesity-Induced by Leptin Resistance". Behavioural Brain Research. 417: 113598. doi:10.1016/j.bbr.2021.113598. PMID 34563600. S2CID 237603177.
32. ^ Kelesidis T, Kelesidis I, Chou S, et al. (January 2010). "Narrative review: the role of leptin in human physiology: emerging clinical applications". Annals of Internal Medicine. 152 (2): 93–100\. doi:10.7326/0003-4819-152-2-201001190-00008. PMC 2829242. PMID 20083828.
33. ^ "MetaCyc serotonin and melatonin biosynthesis".
34. ^ a b Tordjman S, Chokron S, Delorme R, et al. (April 2017). "Melatonin: Pharmacology, Functions and Therapeutic Benefits". Current Neuropharmacology. 15 (3): 434–443\. doi:10.2174/1570159X14666161228122115. PMC 5405617. PMID 28503116.
35. ^ Bochkov DV, Sysolyatin SV, Kalashnikov AI, et al. (January 2012). "Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources". Journal of Chemical Biology. 5 (1): 5–17\. doi:10.1007/s12154-011-0064-8. PMC 3251648. PMID 22826715.
36. ^ a b c Hardeland R (February 2015). "Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions". Journal of Experimental Botany. 66 (3): 627–46\. doi:10.1093/jxb/eru386. PMID 25240067.
37. ^ Tan DX, Manchester LC, Liu X, et al. (March 2013). "Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes". Journal of Pineal Research. 54 (2): 127–38\. doi:10.1111/jpi.12026. PMID 23137057. S2CID 206140413.
38. ^ Roberts KM, Fitzpatrick PF (April 2013). "Mechanisms of tryptophan and tyrosine hydroxylase". IUBMB Life. 65 (4): 350–7\. doi:10.1002/iub.1144. PMC 4270200. PMID 23441081.
39. ^ Sumi-Ichinose C, Ichinose H, Takahashi E, et al. (March 1992). "Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis". Biochemistry. 31 (8): 2229–38\. doi:10.1021/bi00123a004. PMID 1540578.
40. ^ a b Dewick PM (2002). Medicinal Natural Products. A Biosynthetic Approach (2nd ed.). Wiley. ISBN 978-0-471-49640-3.
41. ^ Hickman AB, Klein DC, Dyda F (January 1999). "Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism". Molecular Cell. 3 (1): 23–32\. doi:10.1016/S1097-2765(00)80171-9. PMID 10024876.
42. ^ Donohue SJ, Roseboom PH, Illnerova H, et al. (October 1993). "Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA". DNA and Cell Biology. 12 (8): 715–27\. doi:10.1089/dna.1993.12.715. PMID 8397829.
43. ^ Nesbitt AD, Leschziner GD, Peatfield RC (September 2014). "Headache, drugs and sleep". Cephalalgia (Review). 34 (10): 756–66\. doi:10.1177/0333102414542662. PMID 25053748. S2CID 33548757.
44. ^ Schomerus C, Korf HW (December 2005). "Mechanisms regulating melatonin synthesis in the mammalian pineal organ". Annals of the New York Academy of Sciences. 1057 (1): 372–83\. Bibcode:2005NYASA1057..372S. doi:10.1196/annals.1356.028. PMID 16399907. S2CID 20517556.
45. ^ Brainard GC, Hanifin JP, Greeson JM, et al. (August 2001). "Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor". The Journal of Neuroscience. 21 (16): 6405–12\. doi:10.1523/JNEUROSCI.21-16-06405.2001. PMC 6763155. PMID 11487664.
46. ^ Holzman DC (January 2010). "What's in a color? The unique human health effect of blue light". Environmental Health Perspectives. 118 (1): A22-7. doi:10.1289/ehp.118-a22. PMC 2831986. PMID 20061218.
47. ^ "Recent News – Program of Computer Graphics". www.graphics.cornell.edu.
48. ^ Kayumov L, Casper RF, Hawa RJ, et al. (May 2005). "Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work". The Journal of Clinical Endocrinology and Metabolism. 90 (5): 2755–61\. doi:10.1210/jc.2004-2062. PMID 15713707.
49. ^ "University of Houston study shows blue light glasses at night increase melatonin by 58%". designeroptics.com. 25 August 2021. Retrieved 26 August 2021.
50. ^ Burkhart K, Phelps JR (December 2009). "Amber lenses to block blue light and improve sleep: a randomized trial". Chronobiology International. 26 (8): 1602–12\. doi:10.3109/07420520903523719. PMID 20030543. S2CID 145296760.
51. ^ "Melatonin". www.drugbank.ca. Retrieved 29 January 2019.
52. ^ Hardeland R, Poeggeler B, Srinivasan V, et al. (2008). "Melatonergic drugs in clinical practice". Arzneimittelforschung. 58 (1): 1–10\. doi:10.1055/s-0031-1296459. PMID 18368944. S2CID 38857779.
53. ^ a b Ma X, Idle JR, Krausz KW, et al. (April 2005). "Metabolism of Melatonin by Human Cytochromes P450". Drug Metabolism and Disposition. 33 (4): 489–494\. doi:10.1124/dmd.104.002410. PMID 15616152. S2CID 14555783. Retrieved 25 January 2023.
54. ^ Kennaway DJ (August 2019). "A critical review of melatonin assays: Past and present". Journal of Pineal Research. 67 (1): e12572. doi:10.1111/jpi.12572. PMID 30919486.
55. ^ Brasure M, MacDonald R, Fuchs E, et al. (2015). "Management of Insomnia Disorder[Internet]". AHRQ Comparative Effectiveness Reviews. 15 (16): EHC027–EF. PMID 26844312.
56. ^ Matheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy". American Family Physician. 96 (1): 29–35\. PMID 28671376.
57. ^ Riha RL (November 2018). "The use and misuse of exogenous melatonin in the treatment of sleep disorders". Curr Opin Pulm Med. 24 (6): 543–548\. doi:10.1097/MCP.0000000000000522. PMID 30148726. S2CID 52096729.
58. ^ Williams WP, McLin DE, Dressman MA, et al. (September 2016). "Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders". Pharmacotherapy. 36 (9): 1028–41\. doi:10.1002/phar.1822. PMC 5108473. PMID 27500861.
59. ^ Atkin T, Comai S, Gobbi G (April 2018). "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacol Rev. 70 (2): 197–245\. doi:10.1124/pr.117.014381. PMID 29487083. S2CID 3578916.
60. ^ Cohen PA, Avula B, Wang Y, Katragunta K, Khan I. (April 2023) "Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US" JAMA. 329 (16): 1401–1402. doi:10.1001/jama.2023.2296. PMID 37097362
61. ^ Kahan TL (2000), "Effects of melatonin on dream bizarreness among male and female college students.", Psychology, Sleep and Hypnosis, 2(2), 74-83.
62. ^ Filadelfi AM, Castrucci AM (May 1996). "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates". Journal of Pineal Research. 20 (4): 175–86\. doi:10.1111/j.1600-079X.1996.tb00256.x. PMID 8836950. S2CID 41959214.
63. ^ Sugden D, Davidson K, Hough KA, et al. (October 2004). "Melatonin, melatonin receptors and melanophores: a moving story". Pigment Cell Research. 17 (5): 454–60\. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831.
64. ^ Coates PM, Blackman MR, Cragg GM, et al. (2005). Encyclopedia of dietary supplements. New York, N.Y: Marcel Dekker. pp. 457–66\. ISBN 978-0-8247-5504-1.
65. ^ McCord CP, Allen FP (January 1917). "Evidences associating pineal gland function with alterations in pigmentation". J Exp Zool. 23 (1): 206–24\. Bibcode:1917JEZ....23..207M. doi:10.1002/jez.1400230108.
66. ^ Lerner AB, Case JD, Takahashi Y (July 1960). "Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands". The Journal of Biological Chemistry. 235 (7): 1992–7\. doi:10.1016/S0021-9258(18)69351-2. PMID 14415935.
67. ^ Lynch HJ, Wurtman RJ, Moskowitz MA, et al. (January 1975). "Daily rhythm in human urinary melatonin". Science. 187 (4172): 169–71\. Bibcode:1975Sci...187..169L. doi:10.1126/science.1167425. PMID 1167425.
68. ^ US patent 5449683, Wurtman RJ, "Methods of inducing sleep using melatonin", issued 12 September 1995, assigned to Massachusetts Institute of Technology
69. ^ a b Lerner AB, Case JD, Takahashi Y, et al. (1958). "Isolation of melatonin, the pineal gland factor that lightens melanocytes". Journal of the American Chemical Society. 80 (10): 2587. Bibcode:1958JAChS..80Q2587L. doi:10.1021/ja01543a060. ISSN 0002-7863.
70. ^ Goeser S, Ruble J, Chandler L (1997). "Melatonin: Historical and Clinical Perspectives". Journal of Pharmaceutical Care in Pain & Symptom Control. 5 (1): 37–49\. doi:10.1300/J088v05n01_04.
71. ^ Beyer CE, Steketee JD, Saphier D (1998). "Antioxidant properties of melatonin–an emerging mystery". Biochemical Pharmacology. 56 (10): 1265–1272\. doi:10.1016/s0006-2952(98)00180-4. ISSN 0006-2952. PMID 9825724.
72. ^ Liebmann PM, Wölfler A, Felsner P, et al. (1997). "Melatonin and the immune system". International Archives of Allergy and Immunology. 112 (3): 203–211\. doi:10.1159/000237455. ISSN 1018-2438. PMID 9066504.
73. ^ Rapport MM, Green AA, Page IH (December 1948). "Serum vasoconstrictor, serotonin; isolation and characterization". The Journal of Biological Chemistry. 176 (3): 1243–1251\. doi:10.1016/S0021-9258(18)57137-4. PMID 18100415.
74. ^ Reiter RJ (May 1991). "Pineal melatonin: cell biology of its synthesis and of its physiological interactions". Endocrine Reviews. 12 (2): 151–80\. doi:10.1210/edrv-12-2-151. PMID 1649044. S2CID 3219721.
75. ^ Richardson GS (2005). "The human circadian system in normal and disordered sleep". The Journal of Clinical Psychiatry. 66 (Suppl 9): 3–9, quiz 42–3. PMID 16336035.
76. ^ Perreau-Lenz S, Pévet P, Buijs RM, et al. (January 2004). "The biological clock: the bodyguard of temporal homeostasis". Chronobiology International. 21 (1): 1–25\. doi:10.1081/CBI-120027984. PMID 15129821. S2CID 42725506.
77. ^ Foster RG (June 2020). "Sleep, circadian rhythms and health". Interface Focus. 10 (3): 20190098. doi:10.1098/rsfs.2019.0098. PMC 7202392. PMID 32382406.
78. ^ Karasek M, Winczyk K (2006). "Melatonin in humans". Journal of Physiology and Pharmacology. 57 Suppl 5: 19–39\. ISSN 1899-1505. PMID 17218758.
79. ^ Kolli AR, Kuczaj AK, Calvino-Martin F, et al. (2024). "Simulated pharmacokinetics of inhaled caffeine and melatonin from existing products indicate the lack of dosimetric considerations". Food and Chemical Toxicology. 187: 114601. doi:10.1016/j.fct.2024.114601. ISSN 0278-6915. PMID 38493979.
80. ^ Lincoln GA, Andersson H, Loudon A (October 2003). "Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis". The Journal of Endocrinology. 179 (1): 1–13\. doi:10.1677/joe.0.1790001. PMID 14529560.
81. ^ a b Arendt J, Skene DJ (February 2005). "Melatonin as a chronobiotic". Sleep Medicine Reviews. 9 (1): 25–39\. doi:10.1016/j.smrv.2004.05.002. PMID 15649736. "Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn), it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times."
82. ^ Chaturvedi CM (1984). "Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis". Australian Journal of Zoology. 32 (6): 803–09\. doi:10.1071/ZO9840803.
83. ^ Chen HJ (July 1981). "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology. 33 (1): 43–6\. doi:10.1159/000123198. PMID 7254478.
84. ^ Bouroutzika E, Ciliberti MG, Caroprese M, et al. (5 November 2021). "Association of Melatonin Administration in Pregnant Ewes with Growth, Redox Status and Immunity of Their Offspring". Animals. 11 (11): 3161. doi:10.3390/ani11113161. ISSN 2076-2615. PMC 8614450. PMID 34827893.
85. ^ a b Huelsmann M, Hecker N, Springer MS, et al. (September 2019). "Genes lost during the transition from land to water in cetaceans highlight genomic changes associated with aquatic adaptations". Science Advances. 5 (9): eaaw6671. Bibcode:2019SciA....5.6671H. doi:10.1126/sciadv.aaw6671. PMC 6760925. PMID 31579821.
86. ^ Paredes SD, Korkmaz A, Manchester LC, et al. (1 January 2009). "Phytomelatonin: a review". Journal of Experimental Botany. 60 (1): 57–69\. doi:10.1093/jxb/ern284. PMID 19033551. S2CID 15738948.
87. ^ Bonnefont-Rousselot D, Collin F (November 2010). "Melatonin: action as antioxidant and potential applications in human disease and aging". Toxicology. 278 (1): 55–67\. Bibcode:2010Toxgy.278...55B. doi:10.1016/j.tox.2010.04.008. PMID 20417677.
88. ^ Reiter RJ, Manchester LC, Tan DX (September 2005). "Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood". Nutrition. 21 (9): 920–4\. doi:10.1016/j.nut.2005.02.005. PMID 15979282.
89. ^ Reiter RJ, Tan DX, Zhou Z, et al. (April 2015). "Phytomelatonin: assisting plants to survive and thrive". Molecules. 20 (4): 7396–437\. doi:10.3390/molecules20047396. PMC 6272735. PMID 25911967.
90. ^ Arnao MB, Hernández-Ruiz J (September 2015). "Functions of melatonin in plants: a review". Journal of Pineal Research. 59 (2): 133–50\. doi:10.1111/jpi.12253. PMID 26094813.
91. ^ Park S, Lee DE, Jang H, et al. (April 2013). "Melatonin-rich transgenic rice plants exhibit resistance to herbicide-induced oxidative stress". Journal of Pineal Research. 54 (3). Wiley: 258–63\. doi:10.1111/j.1600-079x.2012.01029.x. PMID 22856683. S2CID 6291664.
92. ^ a b Arnao MB, Hernández-Ruiz J (December 2014). "Melatonin: plant growth regulator and/or biostimulator during stress?". Trends in Plant Science. 19 (12). Elsevier: 789–97\. Bibcode:2014TPS....19..789A. doi:10.1016/j.tplants.2014.07.006. PMID 25156541. S2CID 38637203.
93. ^ a b EL-Bauome HA, Doklega SM, Saleh SA, et al. (February 2024). "Effects of melatonin on lettuce plant growth, antioxidant enzymes and photosynthetic pigments under salinity stress conditions". Folia Horticulturae. 36 (1). Polish Society of Horticultural Science: 1–17\. doi:10.2478/fhort-2024-0001. S2CID 19887642.
94. ^ a b Arnao MB, Hernández-Ruiz J (September 2015). "Functions of melatonin in plants: a review". Journal of Pineal Research. 59 (2). Wiley: 133–50\. doi:10.1111/jpi.12253. PMID 26094813. S2CID 19887642.
95. ^ Socaciu AI, Ionuţ R, Socaciu MA, et al. (December 2020). "Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases". Reviews in Endocrine & Metabolic Disorders. 21 (4): 465–478\. doi:10.1007/s11154-020-09570-9. PMID 32691289. S2CID 220657247.
96. ^ Germann SM, Baallal Jacobsen SA, Schneider K, et al. (2016). "Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae". Biotechnology Journal. 11 (5): 717–724\. doi:10.1002/biot.201500143. PMC 5066760. PMID 26710256.
97. ^ Luo H, Schneider K, Christensen U, et al. (2020). "Microbial Synthesis of Human-Hormone Melatonin at Gram Scales". ACS Synthetic Biology. 9 (6): 1240–1245\. doi:10.1021/acssynbio.0c00065. ISSN 2161-5063. PMID 32501000. S2CID 219331624.
98. ^ Arnao MB, Giraldo-Acosta M, Castejón-Castillejo A, et al. (2023). "Melatonin from Microorganisms, Algae, and Plants as Possible Alternatives to Synthetic Melatonin". Metabolites. 13 (1): 72. doi:10.3390/metabo13010072. PMC 9862825. PMID 36676997.
99. ^ Lee K, Choi GH, Back K (21 March 2022). "Functional Characterization of Serotonin N-Acetyltransferase in Archaeon Thermoplasma volcanium". Antioxidants. 11 (3): 596. doi:10.3390/antiox11030596. ISSN 2076-3921. PMC 8945778. PMID 35326246.
100. ^ Hoshino Y, Villanueva L (10 March 2023). "Four billion years of microbial terpenome evolution". FEMS Microbiology Reviews. 47 (2): fuad008. doi:10.1093/femsre/fuad008. ISSN 1574-6976. PMID 36941124.
101. ^ Burkhardt S, Tan DX, Manchester LC, et al. (October 2001). "Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus)". Journal of Agricultural and Food Chemistry. 49 (10): 4898–902\. doi:10.1021/jf010321. PMID 11600041.
102. ^ González-Flores D, Velardo B, Garrido M, et al. (2011). "Ingestion of Japanese plums (Prunus salicina Lindl. cv. Crimson Globe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content". Journal of Food and Nutrition Research. 50 (4): 229–36.
103. ^ Lamont KT, Somers S, Lacerda L, et al. (May 2011). "Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection". Journal of Pineal Research. 50 (4): 374–80\. doi:10.1111/j.1600-079X.2010.00853.x. PMID 21342247. S2CID 8034935.
104. ^ Salehi B (5 July 2019). "Melatonin in Medicinal and Food Plants" (PDF). Cells. 681. Archived from the original (PDF) on 29 November 2021. Retrieved 2 July 2021.
105. ^ Pereira N, Naufel MF, Ribeiro EB, et al. (January 2020). "Influence of Dietary Sources of Melatonin on Sleep Quality: A Review". Journal of Food Science. 85 (1). Wiley: 5–13\. doi:10.1111/1750-3841.14952. PMID 31856339.
106. ^ Hattori A, Migitaka H, Iigo M, et al. (March 1995). "Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates". Biochemistry and Molecular Biology International. 35 (3): 627–34\. PMID 7773197.
107. ^ Sae-Teaw M, Johns J, Johns NP, et al. (August 2013). "Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers". Journal of Pineal Research. 55 (1): 58–64\. doi:10.1111/jpi.12025. PMID 23137025. S2CID 979886.

## External links

[edit]

Wikimedia Commons has media related to Melatonin.

* "Melatonin". Chemwatch.

* 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
* Adrenaline
* 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
* GIP
* Secretin
* Motilin
* VIP

Ileum|

* Enteroglucagon
* Peptide YY
* GLP-1

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 hydroxyanisole
* 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

Tryptamines

Tryptamines|

* 1-Methyl-T
* 2-HO-NMT
* 2-Methyl-DET
* 2,N,N-TMT (2-Me-DMT)
* 3-IAAR
* 4-Fluoro-DMT
* 4-Fluoro-T
* 5-Bromo-DMT
* 5-Bromo-T
* 5-Chloro-DMT
* 5-Chloro-T
* 5-CT
* 5-Ethyl-DMT
* 5-Fluoro-DET
* 5-Fluoro-DMT
* 5-Fluoro-EPT
* 5-Fluoro-T
* 5-Me-MiPT
* 5-MeS-DMT
* 5-Methyl-DMT
* 5-Methyl-T
* 6-Fluoro-DET
* 6-Fluoro-DMT
* 6-Fluoro-T
* 6-MeO-DMT
* 6-MeO-T
* 6-Methyl-T
* 6,7-DHT
* 7-Chloro-T
* 7-MeO-T
* 7-Methyl-DMT
* 7-Methyl-T
* Acetryptine (5-AT)
* Benzotript (4-CB-Trp)
* BGE
* Bretisilocin (5-fluoro-MET; GM-2505)
* Convolutindole A (2,4,6-TBr,1,7-DiMeO-DMT)
* DALT
* DAT
* DBT
* Desformylflustrabromine
* DET (T-9)
* DHT
* DiPT
* DMT
* DPT
* E-6801
* E-6837
* EiPT
* EPT
* FGIN-127
* FGIN-143
* Idalopirdine
* iPALT (ALiPT)
* Lespedamine (1-MeO-DMT)
* MBT
* MET
* MiPT
* MPT
* MSBT
* N-DEAOP-NET
* N-DEAOP-NMT
* NBoc-DMT
* NET/NETP
* NiPT
* NMT
* NSBT
* NTBT
* PALT
* PiPT
* ST-1936 (2-Me-5-Cl-DMT)
* Tryptamine (T; indolylethylamine)
* Tryptophan (Trp)
* Yuremamine
* Z2876442907

4-Hydroxytryptamines
and esters/ethers|

* 1-Methylpsilocin (CMY-16)
* 4-AcO-DALT
* 4-AcO-DET (ethacetin, ethylacybin)
* 4-AcO-DiPT (ipracetin)
* 4-AcO-DMT (psilacetin; O-acetylpsilocin)
* 4-AcO-DPT (depracetin)
* 4-AcO-EPT
* 4-AcO-MALT
* 4-AcO-MET (metacetin)
* 4-AcO-MiPT (mipracetin)
* 4-AcO-NMT
* 4-AcO-TMT
* 4-HO-5-MeO-T
* 4-HO-DALT (dalocin)
* 4-HO-DBT
* 4-HO-DET (ethocin; CZ-74)
* 4-HO-DPT (deprocin)
* 4-HO-DSBT
* 4-HO-EiBT (eibucin)
* 4-HO-EPT
* 4-HO-MALT
* 4-HO-MET (metocin)
* 4-HO-McPT
* 4-HO-McPeT
* 4-HO-MiPT (miprocin)
* 4-HO-MPT (meprocin)
* 4-HO-MsBT
* 4-HO-NALT
* 4-HO-NiPT
* 4-HO-PiPT (piprocin)
* 4-HO-TMT
* 4-HT (dinorpsilocin)
* 4-MeO-DiPT
* 4-MeO-DMT
* 4-MeO-MiPT
* 4-MeO-T
* 4-PrO-DMT
* 4,5-DHT
* 4,5-MDO-DMT
* 4,5-MDO-DiPT
* Aeruginascin (4-PO-TMT)
* Baeocystin (4-PO-NMT)
* EB-002 (EB-373)
* Ethocybin (4-PO-DET; CEY-19)
* Iprocin (4-HO-DiPT)
* MSP-1014
* Norbaeocystin (4-PO-T)
* Norpsilocin (4-HO-NMT)
* O-4310 (1-iPrO-6-F-psilocin)
* Psilocin (4-HO-DMT; CX-59)
* Psilocybin (4-PO-DMT; CY-39)
* Psilomethoxin (4-HO-5-MeO-DMT)
* Psilomethoxybin (4-PO-5-MeO-DMT)
* RE-104 (FT-104; 4-GO-DiPT)
* RE-109 (4-GO-DMT)

5-Hydroxy- and
5-methoxytryptamines|

* 2-Methyl-5-HT
* 4-HO-5-MeO-T
* 4-F-5-MeO-DMT
* 4,5-DHP-DMT
* 4,5-DHT
* 4,5-MDO-DMT
* 4,5-MDO-DiPT
* 5-BT
* 5-Ethoxy-DMT
* 5-HO-DiPT
* 5-HO-NiPT
* 5-HTP (oxitriptan)
* 5-MeO-2-TMT
* 5-MeO-34MPEMT
* 5-MeO-7,N,N-TMT
* 5-MeO-DALT
* 5-MeO-DBT
* 5-MeO-DET
* 5-MeO-DiPT
* 5-MeO-DMT (N,N,O-TMS; O-methylbufotenine)
* 5-MeO-DPT
* 5-MeO-EiPT
* 5-MeO-EPT
* 5-MeO-MALT
* 5-MeO-MET
* 5-MeO-MiPT
* 5-MeO-NET
* 5-MeO-NiPT
* 5-MeO-NMT (O,N-DMS)
* 5-MeO-PiPT
* 5-MeO-NBpBrT
* 5-MeO-T (5-MT; mexamine; O-methylserotonin)
* 5-MeO-T-NBOMe
* 5-MT-NB3OMe
* 5-NOT
* 5,6-DHT
* 5,6-MDO-DiPT
* 5,6-MDO-DMT
* 5,6-MDO-MiPT
* 5,6-MeO-MiPT
* 5,7-DHT
* Arachidonoyl serotonin
* ASR-3001 (5-MeO-iPALT)
* BAB
* Benanserin (BAS; SQ-4788)
* BGC20-761
* Bufotenidine (5-HTQ; N,N,N-TMS)
* Bufotenin (5-HO-DMT; N,N-DMS; mappine)
* Bufoviridine (5-SO-DMT)
* CP-132,484
* Cqd 280
* Cqd 285
* Cqdd 280
* EMDT (2-Et-5-MeO-DMT)
* HIOC
* Indorenate (TR-3369)
* Isamide (N-CA-5-MT)
* L-741604
* MS-245
* N-DEAOP-5-MeO-NET
* N-DEAOP-5-MeO-NMT
* N-Feruloylserotonin (moschamine)
* Norbufotenin (5-HO-NMT; NMS)
* O-Acetylbufotenine (5-AcO-DMT)
* O-Pivalylbufotenine (5-(t-BuCO)-DMT)
* Psilomethoxin (4-HO-5-MeO-DMT)
* Psilomethoxybin (4-PO-5-MeO-DMT)
* Serotonin (5-HT)

N-Acetyltryptamines|

* 2-Iodomelatonin
* 2-Phenylmelatonin
* 5-Methoxyluzindole
* 6-Chloromelatonin
* 6-Fluoromelatonin
* 6-Hydroxymelatonin
* 6-Methoxymelatonin
* 6,7-Dichloro-2-methylmelatonin
* α-Methylmelatonin
* Luzindole
* Melatonin (N-Ac-O-Me-serotonin; N-Ac-5-MeO-T)
* Normelatonin (N-acetylserotonin; NAS)
* N-Acetyltryptamine
* N-Butanoylmelatonin
* N-Propionylmelatonin
* Piromelatine
* TIK-301 (LY-156735)

α-Alkyltryptamines|

* 1-Methyl-AMT
* 2,α-DMT (2-Me-AMT)
* 4-HO-αMT (MP-14)
* 4-Methyl-αET
* 4-Methyl-αMT (MP-809)
* 5-Chloro-αET (PAL-526)
* 5-Chloro-αMT (PAL-542)
* 5-Fluoro-αET (PAL-545)
* 5-Fluoro-αMT (PAL-212; PAL-544)
* 5-Methyl-αET
* 6-Fluoro-αMT
* 7-Chloro-αMT
* 7-Me-αET
* α-Methyltryptophan (αMTP)
* α,N-DMT (N-Me-αMT; SKF-7024, Ro 3-1715)
* α,N,N-TMT (α-Me-DMT; Alpha-N)
* αET (etryptamine; Monase)
* αMT (Indopan; IT-290; 3-API; 3-IT)
* IPAP (α,N-DPT)
* Soclenicant (BNC-210; Ile–Trp)

* 5-Hydroxy- and 5-alkoxy-α-alkyltryptamines: 1-Pr-5-MeO-AMT
* 5-Allyloxy-AMT
* 5-Ethoxy-αMT
* 5-iPrO-αMT
* 5-MeO-αET
* 5-MeO-αMT (α,O-DMS; Alpha-O)
* α-Methyl-5-HTP
* α-Methylmelatonin
* α-Methylserotonin (5-HO-αMT; α-Me-5-HT)
* α,N,O-TMS (5-MeO-α,N-DMT)
* α,N,N,O-TeMS (5-MeO-α,N,N-TMT)
* AL-37350A (4,5-DHP-αMT)
* BW-723C86

* β-Keto-α-alkyltryptamines: BK-5Br-NM-AMT
* BK-5Cl-NM-AMT
* BK-5F-NM-AMT
* BK-NM-AMT

Triptans|

* Almotriptan
* Donitriptan
* Eletriptan
* Frovatriptan
* L-694247
* Rizatriptan
* Sumatriptan
* Zolmitriptan

Cyclized tryptamines|

* Barettin
* Bufothionine
* Ciclindole
* Cyclic 3-OHM
* Ergolines and lysergamides (e.g., LSD)
* Flucindole
* Frovatriptan
* Harmala alkaloids and β-carbolines (e.g., 6-MeO-THH, 9-Me-BC, β-carboline (norharman), fenharmane, harmaline, harmalol, harmane, harmine, pinoline, tetrahydroharmine, tryptoline)
* Iboga alkaloids (e.g., ibogaine, ibogamine, noribogaine, tabernanthine)
* Ibogalogs (e.g., fluorogainalog, ibogainalog, ibogaminalog (DM-506), LS-22925, noribogainalog, noribogaminalog, PNU-22394, tabernanthalog)
* Imidazolylindoles (e.g., AGH-107, AGH-192, AH-494)
* LY-266,097
* LY-344864
* Metralindole
* O-Methylnordehydrobufotenine
* Partial ergolines and lysergamides (e.g., NDTDI, RU-27849, RU-28251, RU-28306, FHATHBIN, LY-178210, Bay R 1531 (LY-197206), LY-293284, 10,11-seco-LSD, 10,11-secoergoline (α,N-Pip-T), CT-5252)
* Pertines (e.g., alpertine, milipertine, oxypertine, solypertine)
* PHA-57378
* Piperidinylethylindoles (e.g., Pip-T, indolylethylfentanyl)
* Pyrrolidinylethylindoles (e.g., Pyr-T, 4-HO-pyr-T, 5-MeO-pyr-T, 4-F-5-MeO-pyr-T)
* Pyrrolidinylmethylindoles (e.g., MPMI, 4-HO-MPMI (lucigenol), 5F-MPMI, 5-MeO-MPMI, CP-135807, eletriptan)
* Tetrahydropyridinylindoles (e.g., RS134-49, RU-28253)
* Yohimbans (e.g., yohimbine, rauwolscine, spegatrine, corynanthine, ajmalicine, reserpine, deserpidine, rescinnamine)

Isotryptamines|

* 5-MeO-isoDMT
* 6-MeO-isoDMT
* isoAMT (1-API; 1-IT; α-Me-isoT)
* isoDMT
* Isotryptamine (isoT)
* Ro60-0175
* VER-3323
* Zalsupindole (DLX-001, AAZ-A-154)

* Cyclized isotryptamines: JRT
* PNU-181731

Related compounds|

* 2-Azapsilocin
* 4-Aza-5-MeO-DPT
* 5-Aza-4-MeO-DiPT
* 5-HIAA
* 5-HIAL
* 5-HITCA
* 5-MIAL
* 7-Aza-5-MeO-DiPT
* Amedalin
* Benzindopyrine
* Benzofurans (e.g., 3-APB, 5-MeO-DiBF, BPAP, 3-F-BPAP, dimemebfe, mebfap)
* Benzothiophenes (e.g., 3-APBT)
* CP-94253
* CT-4436
* Daledalin
* Gramine
* Histamine
* I-32
* IAL
* IN-399
* Indazoles (e.g., AL-34662, AL-38022A, O-methyl-AL-34662, VU6067416, YM-348)
* Indenes (e.g., C-DMT)
* Indolizines (e.g., TACT908 (2ZEDMA), 1ZP2MA, 1Z2MAP1O)
* Indolylaminopropanes (e.g., 1-API, 2-API, 4-API, 5-API (5-IT; PAL-571), 6-API (6-IT), 7-API)
* Iprindole
* Latrepirdine
* Masupirdine
* Medmain
* Molindone
* Non-tryptamine triptans (e.g., avitriptan, LY-334370, naratriptan)
* Phenethylamines (e.g., phenethylamine, amphetamine)
* Piperidinylindoles (e.g., BRL-54443, LY-334370, naratriptan, sertindole, SN-22)
* Pirlindole
* Pyridinylindoles (e.g., tepirindole)
* Pyrrolylethylamines (e.g., 2-pyrrolylethylamine (NEA), 3-pyrrolylethylamine (3-NEA), 3-pyrrolylpropylamine)
* Quinolinylethylamines (e.g., mefloquine)
* (R)-69 (3IQ)
* Ro60-0213
* Selisistat
* Tetrahydropyridinylindoles (e.g., EMD-386088, LY-367265, RU-24,969)
* Tetrindole
* Tiflucarbine
* Tipindole
* Zilpaterol (RU-42173)

* See also: Phenethylamines
* Ergolines and lysergamides
* Psychedelics

Portal:

* Medicine

Authority control databases: National |

* Germany
* United States
* France
* BnF data
* Japan
* Czech Republic
* Israel

|

*[CID]: Compound ID
*[EPA]: U.S. Environmental Protection Agency
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template