background
Melatonin is a biogenic amine found in animals, plants and microorganisms. In mammals, melatonin is produced by the pineal gland. The pineal gland is a small endocrine gland, about the size of a grain of rice and shaped like a pine cone, located in the center of the brain but outside the blood: the blood-brain barrier. Melatonin secretion increases in darkness and decreases in light, thereby regulating circadian rhythms in multiple biological functions including sleep-wake cycles. In particular, melatonin regulates the sleep-wake cycle by chemically causing drowsiness and lowering body temperature. Melatonin is also associated with the regulation of mood, learning and memory, immune activity, dreaming, fertility and reproduction. Melatonin is also a potent antioxidant.
Most of the effects of melatonin are mediated through the binding and activation of melatonin receptors. People with autism spectrum disorder (ASD) may have lower than normal levels of melatonin. A 2008 study found that the unaffected parents of people with ASD also had lower melatonin levels, and that the defect was associated with low activity in the ASMT gene, which codes for the last enzyme in melatonin synthesis. Reductions in melatonin have also been implicated as a possible factor in the significant increase in cancer rates among night shift workers.
chemical formula
C 13 H 16 N 2 O 2
pharmacology
Orally used to treat jet lag, insomnia, shift work disorder, circadian rhythm disorders in blind people (evidence of efficacy), and benzodiazepine and nicotine withdrawal.
There is evidence that melatonin may be effective in treating circadian rhythm sleep disorders in blind children and adults. It has received FDA orphan drug status as an oral drug for this purpose. Many studies suggest that melatonin may be effective in treating sleep-wake cycle disorders in children and adolescents with mental retardation, autism, and other central nervous system disorders. It appears to reduce the time it takes for children with developmental disabilities, such as cerebral palsy, autism and mental retardation, to fall asleep. It can also improve secondary insomnia associated with various sleep-wake cycle disorders.
pharmacodynamics
Melatonin is a hormone normally produced in the pineal gland and released into the bloodstream. The essential amino acid L-tryptophan ( L-tryptophan) is the precursor for the synthesis of melatonin. It helps regulate the sleep-wake cycle, or circadian rhythm. Melatonin production is stimulated by darkness and inhibited by light. High levels of melatonin cause sleep, so taking this medication can combat insomnia and jet lag. MT1 and MT2 receptors may be targets for the treatment of circadian and noncircadian sleep disorders because of their pharmacological and functional differences within the SCN. The SCN is responsible for maintaining a 24-hour cycle that regulates many different body functions from sleep to immune function
Mechanism
Melanin is a derivative of tryptophan . It binds to the type 1A melatonin receptor, which then acts on adenylyl cyclase and inhibits the cAMP signaling pathway. Melatonin not only inhibits adenylate cyclase , but also activates phosphilpase C. This enhances the release of arachidonic acid ( arachidonate) . By binding to melatonin receptors 1 and 2, downstream signaling cascades produce various effects in the body. Melatonin receptors are G protein-coupled receptors expressed in various tissues of the body. There are two receptor subtypes in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, either on the market or in clinical trials, bind and activate both receptor types. The binding of agonists to receptors has been studied for more than two decades or since 1986. It is known by some but still not fully understood. When melatonin receptor agonists bind to and activate their receptors, it causes a number of physiological processes. MT1 receptors are expressed in many areas of the central nervous system (CNS): hypothalamic suprachiasmatic nucleus (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 immune system. The MT2 receptor is expressed primarily in the CNS but also in lung, heart, coronary and aortic tissues, myometrium and granulosa cells, immune cells, duodenum, and adipocytes. The binding of melatonin to melatonin receptors activates several signaling pathways. MT1 receptor activation inhibits adenylyl cyclase, and its inhibition causes a ripple effect of non-activation; starting with a reduction in cyclic adenosine monophosphate (cAMP) formation and then progressively reducing protein kinase A (PKA) activity, which in turn Blocks the phosphorylation of cAMP response element binding protein (CREB binding protein) to P-CREB. The MT1 receptor also activates phospholipase C (PLC), which affects ion channels and regulates intracellular ion flux. Binding of melatonin to MT2 receptors inhibits adenylyl cyclase, thereby reducing cAMP formation. It also blocks guanylyl cyclase, thereby preventing the formation of cyclic guanosine monophosphate (cGMP). Binding to the MT2 receptor may affect PLC, thereby increasing protein kinase C (PKC) activity.
absorb
Melatonin absorption and bioavailability vary widely.
metabolism
Hepatic metabolism to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetyl 5-hydroxytryptamine glucuronide, N -Acetyl serotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin, melatonin cyclic melatonin, cyclic N-acetyl 5- Serotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, dihydroxymelatonin and its glucuronic acid conjugates. 6-Hydroxymelatonin glucuronide is the major metabolite in mouse urine (accounting for 65-88% of the total melatonin metabolites in urine).
half life
35 to 50 minutes
toxicity
It is generally well tolerated when taken orally. The most common side effects, daytime drowsiness, headache and dizziness, appeared to occur with the same frequency as placebo. Other reported side effects include transient depressive symptoms, mild tremors, mild anxiety, abdominal cramping, irritability, decreased alertness, confusion, nausea, vomiting, and hypotension.
Safety in Adults: There is evidence that oral and parenteral forms may be safe for up to two months if used appropriately. Some evidence suggests it can be used safely by mouth in some patients for up to 9 months. Topical use may also be safe if used appropriately. Safety in Children: Melatonin appears to be safe to use in the small number of children who participated in short-term clinical trials. However, concerns about children's safety have arisen based on their developmental status. People under the age of 20 produce higher levels of melatonin than adults over the age of 20. Melatonin levels are inversely related to gonadal development, and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during pregnancy: High doses of melatonin administered orally or parenterally may suppress ovulation. Not recommended for use by people who are pregnant or trying to become pregnant. Safety during breastfeeding: Not recommended as safety has not been established. Melatonin levels are inversely related to gonadal development, and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during pregnancy: High doses of melatonin administered orally or parenterally may suppress ovulation. Not recommended for use by people who are pregnant or trying to become pregnant. Safety during breastfeeding: Not recommended as safety has not been established. Melatonin levels are inversely related to gonadal development, and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during pregnancy: High doses of melatonin administered orally or parenterally may suppress ovulation. Not recommended for use by people who are pregnant or trying to become pregnant.
Safety during breastfeeding: Not recommended as safety has not been established.
medicine interactions
1,2-Benzodiazepine The risk or severity of adverse effects can be increased when melatonin is combined with 1,2-benzodiazepine.
Concomitant use of abamepyr with abamepyr may increase the serum concentration of melatonin.
The metabolism of melatonin can be increased when Abatacept is combined with Abatacept.
The serum concentration of melatonin may be increased when Abiraterone is used concomitantly with Abiraterone.
Acamprosate excretion can be decreased when Acamprosate is combined with Melatonin.
Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Melatonin.
Acetaminophen The metabolism of melatonin can be decreased when combined with acetaminophen.
Acetazolamide The risk or severity of adverse effects can be increased when Acetazolamide is combined with Melatonin.
Acetylphenazine The risk or severity of adverse effects can be increased when Acetylphenazine is combined with melatonin.
food interactions
Avoid alcohol. Alcohol intake may reduce the effects of melatonin.
Take after meals. Taking melatonin after eating can slow absorption and lower melatonin Cmax.
