Melatonin

Several pharmacological actions were reported for melatonin:

-Hypnotic/Sedative -Phase-shifting -Immunomodulation -Antiproliferative -Antioxidant -Hormonal effects -Anti-inflammatory -Anticonvulsant -Hypotensive

Melatonin: Side Effects

-Adverse effects of melatonin are few and it is generally regarded as safe in recommended dosages. -There are isolated case reports of psychomotor disturbances (disorientation, fatigue, headache, dizziness, etc.), increased seizure risk, and blood clotting abnormalities associated with melatonin alone or in combination with other medications.

Phase-shifting: MOA

-Both endogenous and exogenous melatonin can shift circadian rhythms if given at the appropriate time of day. -Retinal light exposure appears to regulate the circadian rhythm of melatonin secretion. -When trying to advance the sleep phase, melatonin should be given 1-2 hours before 9 pm and when trying to delay the sleep phase, melatonin should be given in the early morning. -Melatonin administration also results in a slight decrease in core body temperature, a factor contributing to sleep. The mechanism behind this effect is not known, but may be attributed to melatonin's effect on the hypothalamus and its thermoregulatory centers.

Melatonin: Contraindications and Dosage

-Contraindications: Based on its hormonal effects, women who are pregnant should consult a health care practitioner prior to supplementing with melatonin -Dosage: Evening oral doses of melatonin as low as 0.3 mg have been shown to be adequate in improving sleep quality, although doses as high as 5-10 mg have been used successfully as well

Melatonin-Drug Interactions

-Hepatic metabolism of melatonin is primarily via the cytochrome P450 enzyme CYP1A2. Therefore, drugs that alter CYP1A2 enzyme activity may have an effect on melatonin metabolism. -Drugs that inhibit CYP1A2 and can increase serum melatonin include fluvoxamine, cimetidine, ciprofloxacin, erythromycin, and tricyclic antidepressants. -Endogenous melatonin levels are increased by caffeine consumption. Therefore, melatonin supplementation may have an additive effect, necessitating a decrease in dosage in persons consuming significant amounts of caffeine. -NSAIDs, such as ibuprofen and naproxen, can suppress endogenous melatonin production, necessitating supplemental melatonin. -Preliminary evidence indicates melatonin use in conjunction with blood-thinning agents, such as warfarin, may increase the risk of bleeding -Melatonin administration has been shown to lower blood pressure 4-10 mm Hg, even at 1-mg dosages; therefore, using melatonin in conjunction with beta-blockers and other anti-hypertensives may result in a potentiation of hypotensive action. -Melatonin's sedative properties may potentiate the effect of sedative medications. -Melatonin's hormonal effects may impact blood glucose and insulin levels; therefore, caution should be used when prescribing melatonin in conjunction with glucose-lowering medications

Sleep Disturbances

-It has been noted that patients with insomnia have decreased nocturnal melatonin secretion. -Several clinical trials studied the use of both high (75 mg at 10 pm) and low (0.1-2.0 mg nightly) doses of melatonin in the treatment of insomnia. Subjects receiving melatonin (regardless of dose) had significant increases in total sleep time as well as improved daytime alertness and decreases in time needed to fall asleep, compared to placebo.

Hypnotic/Sedative: MOA

-Melatonin administration, regardless of dosage time, exerts a hypnotic and sedative effect when given in doses of 0.3-5.0 mg (close to the physiologic range of endogenous melatonin). -If taken before onset of endogenous melatonin secretion, even low doses can induce sleep. -Melatonin can act either by interacting with specific receptors or directly in the absence of such interactions. Melatonin also acts through melatonin receptors. There are two types of melatonin receptors in mammals—MT1 and MT2. -Promotion of sleep by melatonin correlates with reductions in stimulated brain cAMP levels. -Melatonin is also thought to potentiate the affects of gamma-aminobutyric acid (GABA) via direct interaction with GABA receptors. -Research indicates melatonin exerts a sleep-promoting action by accelerating sleep initiation, improving sleep maintenance, and marginally altering sleep architecture. -The nature of melatonin's effect on sleep is such that it typically does not produce a rapid increase in subjective sleepiness, an uncontrollable urge to fall asleep or major impairments in cognitive performance. In contrast to common hypnotics, melatonin induces a behavioral state that resembles quiet wakefulness, which normally predisposes to normal sleep initiation, rather than sleepiness or drowsiness

Jet Lag

-Seventeen participants were flying from San Francisco eastward to London. For three days before their flight, eight participants took a 5 mg daily dose of melatonin, and nine subjects took placebo, at 18:00 local (San Francisco) time, and then at bedtime (London) 22:00-24:00 for the first four days after their return to Britain. Jet lag was significantly less severe among subjects treated with melatonin as rated on day seven after the flight. -Visual analogue scores (0=insignificant, 100=very bad) showing severity of jet lag among eight subjects given melatonin and nine subjects given placebo.

Melatonin: Clinical Indications

-Sleep disturbances -Jet lag -Shift work -Neuropsychiatric conditions and sleep disorders -Preoperative sedation

Melatonin: Biochemistry

-The production of melatonin (N-acetyl-5-methoxytryptamine) from the amino acid tryptophan is primarily nocturnal and is controlled by exposure to cycles of light and dark, independent of sleep. -Melatonin synthesis is inhibited by exposure to light; production is stimulated during periods of darkness by way of a multi-synaptic neural pathway connecting the pineal gland to the external environment via the retina. Serum melatonin levels are highest prior to bedtime. -In addition to the pineal gland, some melatonin is synthesized in the retina, bone marrow, gastrointestinal tract, and bile. The gut appears to produce proportionally more melatonin than the pineal gland. -Melatonin secretion undergoes a predictable change over the life span. Young children are reported to have the highest circulating melatonin levels, which start declining around the time of puberty. Mean circulating melatonin levels in aged individuals are significantly lower than in young healthy adults

Melatonin

-is a ubiquitous natural neurotransmitter-like compound secreted by the pineal gland in the brain . Melatonin has diverse functions that regulate the circadian rhythm, energy metabolism, and the immune system; it also inhibits oxidative stress and participates in the aging process . In vertebrates, melatonin is produced in some tissues; however, most melatonin is produced by the pineal gland, secreted into the blood, and acts as a hormone . -In mammals, the pineal gland is a neuroendocrine gland located near the thalamus, and consists of pinealocytes that produce melatonin

melatonin, the primary hormone of the pineal gland, is the principal hormone of the circadian system, secreted exclusively at night in both nocturnal and diurnal species

being a highly lipophilic hormone , melatonin reaches every cell of the body. The wide distribution of melatonin receptors also suggests that melatonin affects various tissue and organs and , thus can be involved in multiple physiologic processes. only some of these processes have been studied, on of them is sleep