Melatonin

Pale yellow leaflets from benzene

White-cream to yellowish crystalline powder

In water, 2 g/L at 20 °C; 5 g/L at 50 °C

>34.8 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Complementary Therapies; Central Nervous System Depressants; Antioxidants

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

FDA approved animal drugs -> Active ingredient

Pharmaceuticals -> UK Veterinary Medicines Directorate List

116-118 °C

117 °C

153.3 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID1022421]

153.53 Ų [M-H]- [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

153.2 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]

155.82 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

153.4 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

152 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 96.5% (139 of 144) of all reports.

Not Classified

Aggregated GHS information provided per 144 reports by companies from 6 notifications to the ECHA C&L Inventory.

Chemical: Acetamide, N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-

Melatonin: Does not have an individual approval but may be used under an appropriate group standard

Implantation or injectable dosage form new animal drugs. Melatonin implant. ... Indications for use: For use in healthy male and female kit and adult female mink (Mustela vison) to accelerate the fur priming cycle. Limitations: For subcutaneous implantation in mink only. Do not implant potential breeding stock. Do not use in food-producing animals.

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

... This prospective, randomized, double-blind study included 200 adults with American Society of Anesthesiologists (ASA) physical status I. Patients received either 0.2 mg/kg melatonin or a placebo orally for premedication (n = 100 per group). Approximately 50 min later, subgroups of 10 melatonin and 10 placebo patients were administered various doses of propofol (0.5, 1.0, 1.5, 2.0, or 2.4 mg/kg) or thiopental (2.0, 3.0, 4.0, 5.0, or 6.0 mg/kg) for anesthetic induction. The ability of each patient to respond to the command, "open your eyes," and the disappearance of the eyelash reflex were assessed 60 sec after the end of the injection of propofol or thiopental. Dose-response curves were determined by probit analysis. RESULTS: Melatonin premedication decreased thiopental ED50 values for loss of response to verbal command and eyelash reflex from 3.4 mg/kg (95% confidence interval, 3.2-3.5 mg/kg) and 3.7 mg/kg (3.5-3.9 mg/kg) to 2.7 mg/kg (2.6-2.9 mg/kg) and 2.6 mg/kg (2.5-2.7 mg/kg), respectively (P < 0.05). Corresponding propofol ED50 values decreased from 1.5 mg/kg (1.4-1.6 mg/kg) and 1.6 mg/kg (1.5-1.7 mg/kg) to 0.9 mg/kg (0.8-0.96 mg/kg) and 0.9 mg/kg (0.8-0.95 mg/kg), respectively (P < 0.05). CONCLUSIONS: Melatonin premedication significantly decreased the doses of both propofol and thiopental required to induce anesthesia.

Diadenosine tetraphosphate (Ap(4)A, 0.03 nmol) applied topically to the cornea of New Zealand white rabbits, evoked an increase in tear secretion of 9.7 +/- 2.60% (N=7). Melatonin (1 nmol) had no significant effect. Application of Ap(4)A in combination with melatonin, evoked a significantly greater increase in tear secretion of 34.2 +/- 5.8% (N=11). This potentiating effect of melatonin was blocked by pretreating the cornea with a topical application of the melatonin receptor antagonist, luzindole (240 nmol). Melatonin combined with Ap(4)A may be useful for treating dry eye conditions.

The present study was designed to investigate the potential protective effect of melatonin against the hepatic and renal toxicity of lead in male rats. Three groups of animals were used in this study (control, lead acetate-treated (100 mg/kg), and lead acetate plus melatonin (10 mg/kg) for 30 days. Levels of lipid peroxidation (LPO) products, superoxide dismutase (SOD) activity, total glutathione (GSH), histopathological changes in the liver and kidneys were investigated. In addition, nuclear area (NA), nuclear volume (NV) and the ratio of nuclear volume/cellular volume (N/C) were measured in the liver. The results revealed increased LPO and decreased SOD, GSH, NA, NV and N/C in the studied organs of lead-treated rats. Histopathological observations showed severe damage in the liver and kidneys. Melatonin co-treatment to the lead-administered rats attenuated the increase of LPO and restored the activity of SOD and levels of GSH as well as the mean values of NA, NV and N/C. Also, the morphological damage in the liver and kidneys was reduced and the tissues appeared like those of controls. The present study suggests that melatonin may be useful in combating free radical-induced damage due to lead toxicity.

... In this study, the effect of melatonin against the toxicity of doxorubicin (DOX) was investigated in rats. Hemodynamic function, pathological and biochemical changes were determined in different treated hearts. /The/ findings showed that a significant protection by melatonin (6 mg/kg for 15 days, cumulative dose of 90 mg/kg) against the DOX-induced toxicity was observed. Cardiac function was improved and lipid peroxidation decreased after melatonin treatment. It is concluded that melatonin provides protection against doxorubicin toxicity via an attenuation of lipid peroxidation.

For more Interactions (Complete) data for MELATONIN (38 total), please visit the HSDB record page.

Tolerance can develop, in which the person needs larger doses to achieve the desired effect; this can lead to overdose and death. Accidents or injury can also occur due to the side effects of loss of coordination, slowed reaction time, sleepiness and impaired judgment. Drugs in this category have a high potential for physical and psychological dependence. May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.

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.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 904(SRC), determined from a structure estimation method(2), indicates that melatonin is expected to have low mobility in soil(SRC). Melatonin has pKa values of 16.51 and -0.69 and is uncharged in the entire pH-range(3); therefore, sorption in soil will be determined by the neutral form of melatonin(SRC). Volatilization of melatonin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.6X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Melatonin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.4X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Melatonin absorbs at wavelengths >290 nm(4,5) and, therefore, may be susceptible to direct photolysis on soil surfaces exposed to sunlight(SRC). A strain of bacterium (Shewanella putrefaciens) isolated from an estuarine wetland sediment was able to use melatonin as a sole source of carbon and energy under aerobic conditions and completely degrade melatonin at initial of concentrations 25-150 mg/L within a 144-hr incubation period(6).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 904(SRC), determined from a structure estimation method(2), indicates that melatonin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.6X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of 1.18(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Melatonin absorbs at wavelengths >290 nm(6,7) and, therefore, may be susceptible to direct photolysis in waters exposed to sunlight(SRC). With the exception of the amide function, melatonin does not contain functional groups that hydrolyze under environmental conditions(3), and the amide group of melatonin is expected to have a hydrolysis half-life on the order of years under environmental conditions (pH 5-9)(2,SRC). A strain of bacterium (Shewanella putrefaciens) isolated from an estuarine wetland sediment was able to use melatonin as a sole source of carbon and energy under aerobic conditions and completely degrade melatonin at initial of concentrations 25-150 mg/L within a 144-hr incubation period(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), melatonin, which has an estimated vapor pressure of 1.4X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2),will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase melatonin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2 hours(SRC), calculated from its rate constant of 2.1X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase melatonin may be removed from the air by wet and dry deposition(SRC). Melatonin absorbs UV light at wavelengths >290 nm(3,4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Melatonin concentrations of 2.06 and 13.46 ng/g were detected in Balaton and Montmorency cherries obtained from commercial growers in Tranverse City, MI(1). Melatonin has been detected in bananas, grapes, rice, cereals, herbs, olive oil and wine(2).

Melatonin is relatively nontoxic, although some mild adverse effects have been reported with higher doses and extended-release formulations, including drowsiness, daytime sedation, nausea, and headaches. No evidence suggests that patients develop tolerance to melatonin. However, impaired glucose tolerance has been reported in some cases.

The pineal hormone melatonin exhibits a circadian rhythm in body fluids. No data are available on melatonin in human milk. The present study was undertaken to determine whether melatonin is detectable in human milk and, if so, whether it exhibits a daily rhythm. Blood and milk were sampled between 1400-1700 h and again between 0200-0400 h from 10 mothers 3-4 days after delivery. Melatonin in both fluids was beyond the limit of detection during the day, whereas during the night, its concentration was 280 pmol/L in serum and 99 pmol/L in milk. Six mothers collected milk after each feeding throughout 1 24-h period within 3 months after delivery. Melatonin in the milk of all subjects exhibited a pronounced daily rhythm, with high levels during the night and undetectable levels during the day. The presence of the rhythm in milk suggests that melatonin fluctuations in milk might communicate time of day information to breast-fed infants.

Toxicity due to melatonin might present as follows:

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.

EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; See the data in Chemical Explorer/[USEPA; ICSS Dashboard Application; Available from, as of March 28, 2014: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of March 19, 2014: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=73-31-4]

Implantation or injectable dosage form new animal drugs. Melatonin implant. ... Indications for use: For use in healthy male and female kit and adult female mink (Mustela vison) to accelerate the fur priming cycle. Limitations: For subcutaneous implantation in mink only. Do not implant potential breeding stock. Do not use in food-producing animals.

N05CH01

N - Nervous system

QN - Nervous system

Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions

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.

35 to 50 minutes

...The terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 hr-1). ...

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

Naturally occurring or synthetic substances that inhibit or retard oxidation reactions. They counteract the damaging effects of oxidation in animal tissues.

A very loosely defined group of drugs that tend to reduce the activity of the central nervous system. The major groups included here are ethyl alcohol, anesthetics, hypnotics and sedatives, narcotics, and tranquilizing agents (antipsychotics and antianxiety agents).

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.

Melatonin regulates biological rhythms and neuroendocrine functions.

In the United States, the hormone melatonin is sold, without regulation by the FDA, as a dietary supplement. In most of the rest of the world, it is not sold at all, because it is regulated as a drug and no pharmaceutical company has presented an appropriate regulatory body with a successful new drug application for its use. Some countries allow very low doses-less than 100 mg-to be sold without regulatory approval.

Derivatives and analogs of melatonin are being used in the development of preventive therapies of Alzheimer's disease.

Melatonin drugs and supplements have use in treating insomnia, sleep disorders and jet lag; treatment for reducing pain of "cluster headaches; some evidence that melatonin might improve the effectiveness of cancer drugs used to fight tumors in the breast, lung, kidney, liver, pancreas, stomach and colon.

For more Uses (Complete) data for MELATONIN (7 total), please visit the HSDB record page.

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.

Formed from serotonin (5-HT).

Melatonin is synthesized endogenously by the pinealocytes of the pineal gland. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. In this synthesis, L-tryptophan first gets metabolized to 5-hydroxytryptophan from which 5-hydroxytryptamine, also known as serotonin, is made. 5-hydroxytryptamine is converted to melatonin in a two-step process, occurring mainly in the pineal gland.

Melatonex (Sun source); Mela-T (Alacer); Night Rest (Source Naturals)[PDRhealth

Regulin

To evaluate and compare the quality of a sample of melatonin products, as measured by the United States Pharmacopeial Convention (USP) General Tests and Assays for Nutritional Supplements (other than Microbial Limits) and certain other tests. ..five immediate-release, two sublingual, and two controlled-release products were randomly gathered from a health food store, groceries, and pharmacies in the Baltimore-Washington metropolitan area. MAIN OUTCOME MEASURES: Weight variation, disintegration (not applicable for controlled-release products), and drug dissolution, based on USP standards. Twelve-hour dissolution profiles were obtained from the controlled-release products. All tablets were also evaluated for friability following the USP procedure and for hardness following unofficial procedures. RESULTS: All products passed the weight variation test. Two products showed excessive friability. Three immediate-release products failed both the disintegration and the dissolution tests. One of the three products demonstrated a threefold difference in hardness. One controlled-release product released 90% of melatonin in four hours in the dissolution test; the other released 90% of its content in 12 hours. ... Some products showed evidence of poor formulation and/or poor quality control as indicated by excessive friability, failure to disintegrate and dissolve, and excessive variation in hardness. In vitro release profiles of the two controlled-release products were substantially different. The poor quality of some supplements should be a concern to consumers and health care providers.