Microbial Metabolite; Human Endogenous Metabolite

Melatonin prevents Th17/Treg imbalance by activating the AMPK/SIRT1 pathway, which in turn reduces necrotizing enterocolitis.

Apart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it is not clear (i) whether increased PI3K/Akt phosphorylation is a concomitant event or it directly contributes to melatonin's neuroprotective effect, and (ii) how melatonin regulates PI3K/Akt signaling pathway after FCI. In this study, we showed that Akt was intensively phosphorylated at the Thr308 activation loop as compared with Ser473 by melatonin after FCI. Melatonin treatment reduced infarct volume, which was reversed by PI3K/Akt inhibition. However, PI3K/Akt inhibition did not inhibit melatonin's positive effect on brain swelling and IgG extravasation. Additionally, phosphorylation of mTOR, PTEN, AMPKα, PDK1 and RSK1 were increased, while phosphorylation of 4E-BP1, GSK-3α/β, S6 ribosomal protein were decreased in melatonin treated animals. In addition, melatonin decreased apoptosis through reduced p53 phosphorylation by the PI3K/Akt pathway[1].

Cell lines: HepG2 cells
Concentrations: 1.2 mM
Incubation Time: 24 h
Method: Cells were treated with various concentrations of drug for 24 h.

Absorption, Distribution and Excretion
The absorption and bioavailability of melatonin varies widely.
To determine whether melatonin pharmacokinetics change during puberty, ... melatonin /was infused/ iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and melatonin in serum and saliva and 6-hydroxymelatonin sulfate in urine /were measured/. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 ug/kg. All other subjects received 0.5 ug/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 per hr), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 hr), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL)hr, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 per hr). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland.
The pharmacokinetics of melatonin during the day-time has been studied in 4 healthy subjects after a bolus i.v. injection of 5 or 10 ug/person and after a 5 hr infusion of 20 ug per person in 6 healthy subjects. In addition, a pinealomectomized patient whose nocturnal plasma melatonin had been abolished was investigated after the i.v. infusion--once during the night and once during the day. The clearance of melatonin from blood showed a biexponential decay. The pharmacokinetic parameters in the two studies were similar, except for the disappearance rate constant beta and the apparent volume of distribution at steady-state (Vss). Supplementary peaks or troughs were superimposed on the plateau and the falling part of the profile. They were not due to stimulation of endogenous secretion, because they were also seen in the pinealomectomized patient. During the melatonin infusion, the plasma hormone level reached a steady-state after 60 and 120 min, and when it was equal to the nocturnal level.
... In a randomized and double-blind controlled study 10 healthy male subjects undertook an 80 min intensive hypertrophic heavy resistance exercise session (RES) for major muscles of the lower and upper extremities. The subjects were studied on two occasions receiving either melatonin (6 mg) or placebo (6 mg) in random order 60 min before each RES. Blood samples were taken from an antecubital vein both in fasting conditions in the morning and before RES (pre 60 min, pre 0 min), during RES (middle) and after RES (post 0 min, post 15 min, post 30 min, post 60 min). ... The serum melatonin concentration increased significantly (P<0.05-0.001) in the melatonin group following oral ingestion of melatonin and was elevated at every time point after that. The concentration reached a peak value of 1171.3+/-235.2 pg/mL in 60 min at pre 0. Serum melatonin increased slightly but significantly (P<0.05) also in the placebo group just before RES, in the middle of RES and after RES (post 0, post 15). There were large differences (P<0.01-0.001) in the serum melatonin concentration between the groups at all time points. ...
...Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs.
For more Absorption, Distribution and Excretion (Complete) data for MELATONIN (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine).
Most of the melatonin in the circulation is inactivated in the liver where it is first oxidized to 6-hydroxy melatonin by a P450-dependent microsomal oxidase and then largely conjugated to sulfate or glucuronide before being excreted into urine or feces.
In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 (P450s) in these pathways has not been established. /The authors/ used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2, and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19 and, to some extent CYP1A2, O-demethylated MEL. The K(m) (uM) and V(max) (k(cat), pmol/ min/ pmol P450) for 6-hydroxylation were estimated as 19.2 +/- 2.01 and 6.46 +/- 0.22 (CYP1A1), 25.9 +/- 2.47 and 10.6 +/- 0.32 (CYP1A2), and 30.9 +/- 3.76 and 5.31 +/- 0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC50 for the CYP1B1-selective inhibitor (E)-2,4,3',5'-tetramethoxystilbene was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution, and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.
Melatonin is synthesized at night in the human pineal gland and released into the blood and cerebrospinal fluid. It acts on the brains of humans to promote sleep, and also influences the phasing of sleep and various other circadian rhythms. During the day, plasma melatonin levels are low; at night, they rise 10 to 100-fold or more in young adults, but by considerably less in older people- who often may have frequent nocturnal awakenings as a consequence. Very small oral doses of melatonin raise daytime plasma melatonin to night-time levels, thus making it easier for people to fall asleep in the afternoon or evening. Such doses can also help older people remain asleep during the night. Melatonin has also occasionally been claimed to confer other medical benefits e.g. preventing such age-related diseases as atherosclerosis, cancer, and alzheimer's disease. The evidence in such claims is sparse.
Melatonin has known human metabolites that include 6-[3-(2-Acetamidoethyl)-5-methoxyindol-1-yl]-3,4,5-trihydroxyoxane-2-carboxylic acid, N-Acetyl-5-hydroxytryptamine, and 6-Hydroxymelatonin.
Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine).
Half Life: 35 to 50 minutes

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Biological Half-Life
35 to 50 minutes
...The terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 hr-1). ...

Hepatotoxicity
In several clinical trials, melatonin was found to be well tolerated and not associated with serum enzyme elevations or evidence of liver injury. Despite wide scale use, melatonin has not been convincingly linked to instances of clinically apparent liver injury.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Herbal and Dietary Supplements; Sedatives and Hypnotics
Other Drugs in the Subclass, Melatonin and its Analogues: Ramelteon, Tasimelteon

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Preliminary information and computer models indicate that canakinumab levels in milk are very low to undetectable. It is also likely to be partially destroyed in the infant's gastrointestinal tract and absorption by the infant is probably minimal. A few infants have been breastfed without noticeable harm and some professional guidelines consider canakinumab to be acceptable during breastfeeding. Until more data become available, canakinumab injection should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Waiting for at least 2 weeks postpartum to resume therapy may minimize transfer to the infant. Topical or homeopathic preparations pose little risk to the nursing infant.
◉ Effects in Breastfed Infants
In an international multicenter study of mothers exposed to interleukin-1 receptor antagonists, 4 babies were breastfed (extent not stated) by mothers receiving regular canakinumab. It is unclear if mothers received the drug postpartum or only during pregnancy. There were no reported serious infections and no developmental abnormalities at a mean follow-up of 2.2 years (range 5 months to 4 years).
A patient with Muckle-Wells syndrome received canakinumab 150 mg subcutaneously at 10 days postpartum to treat a worsening of her disease. She partially breastfed her infant. The child developed normally in the following 2 years, with a normal height and weight at 2 years of age. All vaccines were given including the first live-attenuated vaccine at 12 months of age.
Two patients, one with Muckle-Wells syndrome and one with familial Mediterranean fever, received canakinumab throughout pregnancy and lactation in doses of 150 mg given every 4 to 8 weeks. They both breastfed their infants, one for 8 months and one for 16 months (extent of nursing not stated). No infections were reported in the infants during their first 6 months and no severe or frequent infections occurred during their first 2 years. All childhood vaccines were administered on schedule except BCG, which was postponed until 3 months. Anti-hepatitis B surface antigen titers of both infants were in the normal range at 6 months and 2 years, indicating an adequate response.
Two infants were breastfed by mothers who received canakinumab during pregnancy and postpartum. No serious infections or developmental abnormalities were reported at an average follow-up of nine months.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◉ Summary of Use during Lactation
Belladonna (Atropa belladonna) contains anticholinergic alkaloids such as atropine and scopolamine. Belladonna has been used in the past for headache, airway obstruction, and irritable bowel syndrome among others, but its use has been supplanted by more specific and less toxic compounds. Long-term use of belladonna might reduce milk production by reducing serum prolactin. Application of belladonna paste to the nipple to reduce milk secretion during lactation is an extremely old use. However, it is still used this way in rural India for treating breast abscesses and may have contributed to cases of breast gangrene. Because of the narrow therapeutic index and variable potency of plant-based (i.e., nonstandardized) belladonna, it should be avoided orally and topically during lactation. Homeopathic products are not likely to interfere with breastfeeding or cause toxicity.
Dietary supplements do not require extensive pre-marketing approval from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and differences are often found between labeled and actual ingredients or their amounts. A manufacturer may contract with an independent organization to verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a product. Because of the above issues, clinical testing results on one product may not be applicable to other products. More detailed information about dietary supplements is available elsewhere on the LactMed Web site.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Specific published information in nursing mothers was not found as of the revision date. Anticholinergics can inhibit lactation in animals, apparently by inhibiting growth hormone and oxytocin secretion. Anticholinergic drugs can also reduce serum prolactin in nonnursing women. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
◉ Summary of Use during Lactation
Melatonin is the hormone produced by the pineal gland that plays a role in regulating sleep and circadian rhythm as well as a possible role in gut-brain signaling. It is a normal component of breastmilk, with concentrations higher during nighttime (peak around 3 am) than daytime. Women who work the night shift have lower milk melatonin concentrations during the midnight to 6:30 am period than on days when they are not working, which becomes larger on subsequent days of working the night shift. Elective cesarean section results in higher daytime colostrum levels than with vaginal delivery. Some authors suggest that mothers should nurse in the dark at night in order to avoid reductions in the melatonin content of breastmilk, which could disturb infant sleep patterns. Differentiating milk pumped during the day from milk pumped during darkness has also been suggested for women pumping milk for their infants. Some studies have attributed longer sleep time in breastfed infant than in formula-fed infants to melatonin in breastmilk. Another study found higher colostrum melatonin levels at night which appeared to increase the phagocytic activity of colostral cells against bacteria. A survey of 329 mothers found that infants who consumed mistimed expressed breastmilk took longer to get to sleep compared with infants who were directly breastfed, formula fed, fed timed expressed breast milk and fed breast milk/formula combined. Breastfed infants had more awakenings at night compared with infants who consumed mistimed expressed breastmilk.
Exogenous administration of melatonin has no specific use during breastfeeding and no data exist on the safety of maternal use of melatonin during breastfeeding. However, doses higher than those expected in breastmilk after maternal supplementation have been used safely in infants. It is unlikely that short-term use of usual doses of melatonin in the evening by a nursing mother would adversely affect her breastfed infant, although some authors recommend against its use in breastfeeding because of the lack of data and a relatively long half-life in preterm neonates.
Dietary supplements do not require extensive pre-marketing approval from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and differences are often found between labeled and actual ingredients or their amounts. A manufacturer may contract with an independent organization to verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a product. Because of the above issues, clinical testing results on one product may not be applicable to other products. More detailed information about dietary supplements is available elsewhere on the LactMed Web site.
◉ Effects in Breastfed Infants
A study on 54 exclusively breastfed infants (n = 54), formula-fed infants (n = 40) and their mothers questioned their mothers regarding infant behavior. Melatonin was measured in the milk of 5 of the mothers. Exclusively breastfed infants had a lower incidence of colic attacks, lower severity of irritability attacks, and a trend for longer nocturnal sleep duration. Melatonin in human milk showed a circadian curve and was unmeasurable in all artificial milks.
An 18-month-old breastfed infant was having bleeding episodes since birth. A platelet aggregation test showed that the infant had reduced platelet aggregation after breastfeeding. When the infant was fasting, platelet aggregation was normal. The infant's mother occasionally took melatonin up to 10 mg daily for sleep. After she stopped melatonin intake for 3 months, the infant's platelet aggregation was normal and the infant had no further bleeding episodes, even after major trauma. The bleeding episodes were possibly caused by melatonin in milk.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is melatonin?
Melatonin is a hormone made by the body that helps with the natural sleep-wake cycle (called circadian rhythm). Melatonin is made by the body mostly during periods of darkness in the night. During pregnancy, the body typically makes more melatonin. Studies suggest that melatonin levels are highest in the third trimester of pregnancy and levels are expected to return to normal after delivery.Melatonin is also available as a supplement sold over the counter. Taking melatonin supplements during pregnancy has not been well studied. In general, it is suggested to speak with your healthcare provider before taking any supplements. Many supplements are not recommended for use during pregnancy unless your healthcare provider has prescribed them to treat a medical condition. This is because they are not well-regulated nor studied for use in pregnancy. For more detail on supplements, please see the fact sheet at https://mothertobaby.org/fact-sheets/herbal-products-pregnancy/.
◈ I take melatonin. Can it make it harder for me to get pregnant?
It is not known if taking melatonin supplements can make it harder to get pregnant.
◈ Does taking melatonin increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Studies have not been done to see if taking melatonin supplements increases the chance for miscarriage.
◈ Does taking melatonin increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have not been done in humans to see if melatonin supplements increase the chance for birth defects above the background risk. Animal studies did not suggest an increased chance for birth defects.
◈ Does taking melatonin in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if taking melatonin supplements can increase the chance of other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking melatonin in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if taking melatonin supplements can cause behavior or learning issues for the child.
◈ Breastfeeding while taking melatonin:
Melatonin made by the body is present in breastmilk in higher amounts at night. Taking melatonin supplements while breastfeeding has not been well studied. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes melatonin, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Based on the studies reviewed, it is not known if melatonin supplements could affect fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
n/a

[1]. J Biomed Sci . 2000 Nov-Dec;7(6):444-58.

[2]. Prog Neurobiol . 1998 Oct;56(3):359-84.

[3]. Cell Biochem Biophys . 2001;34(2):237-56.

[4]. Physiol Rev . 1998 Jul;78(3):687-721.

[5]. Front Pharmacol . 2022 Sep 26:13:1007006.

[6]. Theranostics . 2020 Jun 19;10(17):7730-7746.

Melatonin is a member of the class of acetamides that is acetamide in which one of the hydrogens attached to the nitrogen atom is replaced by a 2-(5-methoxy-1H-indol-3-yl)ethyl group. It is a hormone secreted by the pineal gland in humans. It has a role as a hormone, an anticonvulsant, an immunological adjuvant, a radical scavenger, a central nervous system depressant, a human metabolite, a mouse metabolite and a geroprotector. It is a member of acetamides and a member of tryptamines. It is functionally related to a tryptamine.
Melatonin is a biogenic amine that is found in animals, plants and microbes. Aaron B. Lerner of Yale University is credited for naming the hormone and for defining its chemical structure in 1958. In mammals, melatonin is produced by the pineal gland. The pineal gland is small endocrine gland, about the size of a rice grain and shaped like a pine cone (hence the name), that is located in the center of the brain (rostro-dorsal to the superior colliculus) but outside the blood-brain barrier. The secretion of melatonin increases in darkness and decreases during exposure to light, thereby regulating the circadian rhythms of several biological functions, including the sleep-wake cycle. In particular, melatonin regulates the sleep-wake cycle by chemically causing drowsiness and lowering the body temperature. Melatonin is also implicated in the regulation of mood, learning and memory, immune activity, dreaming, fertility and reproduction. Melatonin is also an effective antioxidant. Most of the actions of melatonin are mediated through the binding and activation of melatonin receptors. Individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis. Reduced melatonin production has also been proposed as a likely factor in the significantly higher cancer rates in night workers.
Melatonin is a hormone produced by the pineal gland that has multiple effects including somnolence, and is believed to play a role in regulation of the sleep-wake cycle. Melatonin is available over-the-counter and is reported to have beneficial effects on wellbeing and sleep. Melatonin has not been implicated in causing serum enzyme elevations or clinically apparent liver injury.
Melatonin has been reported in Salvia miltiorrhiza, Gentiana macrophylla, and other organisms with data available.
Therapeutic Melatonin is a therapeutic chemically synthesized form of the pineal indole melatonin with antioxidant properties. The pineal synthesis and secretion of melatonin, a serotonin-derived neurohormone, is dependent on beta-adrenergic receptor function. Melatonin is involved in numerous biological functions including circadian rhythm, sleep, the stress response, aging, and immunity.
Melatonin is a hormone involved in sleep regulatory activity, and a tryptophan-derived neurotransmitter, which inhibits the synthesis and secretion of other neurotransmitters such as dopamine and GABA. Melatonin is synthesized from serotonin intermediate in the pineal gland and the retina where the enzyme 5-hydroxyindole-O-methyltransferase, that catalyzes the last step of synthesis, is found. This hormone binds to and activates melatonin receptors and is involved in regulating the sleep and wake cycles. In addition, melatonin possesses antioxidative and immunoregulatory properties via regulating other neurotransmitters.
Melatonin is a biogenic amine that is found in animals, plants and microbes. Aaron B. Lerner of Yale University is credited for naming the hormone and for defining its chemical structure in 1958. In mammals, melatonin is produced by the pineal gland. The pineal gland is small endocrine gland, about the size of a rice grain and shaped like a pine cone (hence the name), that is located in the center of the brain (rostro-dorsal to the superior colliculus) but outside the blood-brain barrier. The secretion of melatonin increases in darkness and decreases during exposure to light, thereby regulating the circadian rhythms of several biological functions, including the sleep-wake cycle. In particular, melatonin regulates the sleep-wake cycle by chemically causing drowsiness and lowering the body temperature. Melatonin is also implicated in the regulation of mood, learning and memory, immune activity, dreaming, fertility and reproduction. Melatonin is also an effective antioxidant. Most of the actions of melatonin are mediated through the binding and activation of melatonin receptors. Individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis. Reduced melatonin production has also been proposed as a likely factor in the significantly higher cancer rates in night workers.
A biogenic amine that is found in animals and plants. In mammals, melatonin is produced by the PINEAL GLAND. Its secretion increases in darkness and decreases during exposure to light. Melatonin is implicated in the regulation of SLEEP, mood, and REPRODUCTION. Melatonin is also an effective antioxidant.
See also: Chamomile; ginger; melatonin; thiamine; tryptophan (component of) ... View More ...

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Drug Indication
Used orally for jet lag, insomnia, shift-work disorder, circadian rhythm disorders in the blind (evidence for efficacy), and benzodiazepine and nicotine withdrawal. Evidence indicates that melatonin is likely effective for treating circadian rhythm sleep disorders in blind children and adults. It has received FDA orphan drug status as an oral medication for this use. A number of studies have shown that melatonin may be effective for treating sleep-wake cycle disturbances in children and adolescents with mental retardation, autism, and other central nervous system disorders. It appears to decrease the time to fall asleep in children with developmental disabilities, such as cerebral palsy, autism, and mental retardation. It may also improve secondary insomnia associated with various sleep-wake cycle disturbances. Other possible uses for which there is some evidence for include: benzodiazepine withdrawal, cluster headache, delayed sleep phase syndrome (DSPS), primary insomnia, jet lag, nicotine withdrawal, preoperative anxiety and sedation, prostate cancer, solid tumors (when combined with IL-2 therapy in certain cancers), sunburn prevention (topical use), tardive dyskinesia, thrombocytopenia associated with cancer, chemotherapy and other disorders.
Slenyto is indicated for the treatment of insomnia in children and adolescents aged 2-18 with Autism Spectrum Disorder (ASD) and / or Smith-Magenis syndrome, where sleep hygiene measures have been insufficient.
Melatonin Neurim is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
Circadin is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
Treatment of insomnia
Primary insomnia

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Mechanism of Action
Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. /The authors/ describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin-releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and anterior pituitary. These findings provide a neurobiological basis for the participation of melatonin in the regulation of various hypothalamic and pituitary functions. The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for stress conditions such as depression.
A major mechanism through which melatonin reduces the development of breast cancer is based on its anti-estrogenic actions by interfering at different levels with the estrogen-signalling pathways. Melatonin inhibits both aromatase activity and expression in vitro (MCF-7 cells) as well as in vivo, thus behaving as a selective estrogen enzyme modulator. The objective of this study was to study the effect of MT1 melatonin receptor overexpression in MCF-7 breast cancer cells on the aromatase-suppressive effects of melatonin. Transfection of the MT1 melatonin receptor in MCF-7 cells significantly decreased aromatase activity of the cells and MT1-transfected cells showed a level of aromatase activity that was 50% of vector-transfected MCF-7 cells. The proliferation of estrogen-sensitive MCF-7 cells in an estradiol-free media but in the presence of testosterone (an indirect measure of aromatase activity) was strongly inhibited by melatonin in those cells overexpressing the MT1 receptor. This inhibitory effect of melatonin on cell growth was higher on MT1 transfected cells than in vector transfected ones. In MT1-transfected cells, aromatase activity (measured by the tritiated water release assay) was inhibited by melatonin (20% at 1 nM; 40% at 10 microM concentrations). The same concentrations of melatonin did not significantly influence the aromatase activity of vector-transfected cells. MT1 melatonin receptor transfection also induced a significant 55% inhibition of aromatase steady-state mRNA expression in comparison to vector-transfected MCF-7 cells (p<0.001). In addition, in MT1-transfected cells melatonin treatment inhibited aromatase mRNA expression and 1 nM melatonin induced a higher and significant down-regulation of aromatase mRNA expression (p<0.05) than in vector-transfected cells. The findings presented herein point to the importance of MT1 melatonin receptor in mediating the oncostatic action of melatonin in MCF-7 human breast cancer cells and confirm MT1 melatonin receptor as a major mediator in the melatonin signalling pathway in breast cancer.
Almost all the melatonin formed in mammals is synthesized within the pineal gland... The tryptophan is first 5-hydroxylated (by the enzyme tryptophan hydroxylase) and then decarboxylated (by the enzyme aromatic L-amino acid decarboxylase) to form 5-hydroxytryptamine or serotonin. During daylight hours, the serotonin in pinealocytes tends to be stored, and is unavailable to enzymes (monoamine oxidase and the melatonin-forming enzymes) that would otherwise act on it. With the onset of darkness, postganglionic sympathetic outflow to the pineal increases, and the consequent release of norepinephrine onto pinealocytes causes stored serotonin to become accessible for intracellular metabolism. At the same time, the norepinephrine activates the enzymes (especially serotonin-N-acetyltransferase (SNAT), but also hydroxyindole-O-methyltransferase (HIOMT)) that convert serotonin to melatonin. Consequently, pineal melatonin levels rises manifold. ... The melatonin then diffuses out of the pineal gland into the blood stream and cerebrospinal fluid, rapidly raising human plasma melatonin levels from about 2-10 to 100-200 pg/mL.

C13H16N2O2

232.28

232.121

C, 67.22; H, 6.94; N, 12.06; O, 13.78

73-31-4

Melatonin-d4; 66521-38-8; Melatonin-d3; 90735-69-6; Melatonin-d7; 615251-68-8

896

White to light yellow solid powder

1.2±0.1 g/cm3

459.8±55.0 °C at 760 mmHg

116.5-118 °C(lit.)

231.9±31.5 °C

0.0±1.2 mmHg at 25°C

1.580

1.94

2

2

4

17

270

0

O(C([H])([H])[H])C1C([H])=C([H])C2=C(C=1[H])C(=C([H])N2[H])C([H])([H])C([H])([H])N([H])C(C([H])([H])[H])=O

DRLFMBDRBRZALE-UHFFFAOYSA-N

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)

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 2% DMSO + 40% PEG300 + 5% Tween80 + 53% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (10.76 mM) (saturation unknown) in 2% DMSO 98% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.

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Solubility in Formulation 6: ≥ 1.25 mg/mL (5.38 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 7: ≥ 1.25 mg/mL (5.38 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 8: 5%absolute ethyl alcohol + 95%Corn oil: 2.3mg/ml (9.90mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)