Melatonin

Melatonin is a hormone synthesized from the amino acid tryptophan in the pineal gland, a small endocrine structure in the brain. Its production is regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, the body's master circadian clock. Melatonin secretion increases in darkness and decreases with light exposure, providing the primary hormonal signal for nighttime physiology.

The "darkness hormone" serves multiple functions beyond sleep induction. It helps synchronize circadian rhythms throughout the body, acts as a potent antioxidant, supports immune function, and influences various physiological processes including core body temperature, blood pressure regulation, and hormone secretion. Melatonin receptors are found not only in the brain but in many peripheral tissues, reflecting its widespread biological roles.

As a dietary supplement, melatonin has been extensively studied for sleep disorders. Its primary established use is for jet lag, where it helps reset the circadian clock to the new time zone. It is also effective for delayed sleep phase syndrome and some other circadian rhythm disorders. In older adults, whose natural melatonin production declines with age, supplementation can improve sleep quality and duration.

Melatonin differs fundamentally from prescription sleep medications. Rather than sedating the brain like benzodiazepines or Z-drugs, melatonin provides a "chemical signal" of darkness that promotes the natural onset of sleep. This mechanism explains why it is most effective for circadian rhythm problems rather than general insomnia caused by stress or anxiety. It has minimal impact on sleep architecture and does not cause the "hangover" effect common with conventional sleep aids.

The safety profile of melatonin is excellent, especially compared to pharmaceutical sleep medications. It is not associated with dependency, tolerance, or withdrawal. Side effects are generally mild and dose-related. However, optimal dosing is lower than many people assume - doses of 0.5-5 mg are typically as effective as higher doses, with fewer side effects.

Melatonin acts primarily through specific membrane receptors MT1 and MT2, which are G-protein coupled receptors found in the brain and peripheral tissues. These receptors mediate most of melatonin's effects on circadian rhythms and sleep.

The MT1 receptor appears responsible for sleep onset effects. Activation of MT1 receptors in the suprachiasmatic nucleus (SCN) inhibits neuronal firing, reducing the alerting signal and promoting sleep. MT2 receptors are more involved in phase-shifting effects - resetting the circadian clock. This receptor-specific action explains why melatonin can both help people fall asleep and adjust their circadian timing.

For circadian entrainment, melatonin provides a "darkness signal" to the SCN. When taken at the appropriate time, it shifts the circadian phase: evening doses shift rhythms earlier (earlier sleep onset), while morning doses shift rhythms later. This phase-response curve is utilized for jet lag, where timing of melatonin administration depends on travel direction and time zones crossed.

Beyond receptor-mediated effects, melatonin is a potent direct antioxidant. It is both water- and fat-soluble, allowing it to access all cellular compartments. Melatonin scavenges hydroxyl and peroxyl radicals, stimulates antioxidant enzymes, and inhibits pro-oxidant enzymes. Its metabolites also possess antioxidant activity, creating an antioxidant cascade. This antioxidant function is independent of its hormonal actions and occurs in all cells.

Melatonin also influences thermoregulation by promoting peripheral vasodilation and lowering core body temperature, which facilitates sleep onset. This temperature-lowering effect is mediated through MT1 receptors in the hypothalamus and contributes to melatonin's sleep-promoting properties.

Pharmacokinetically, melatonin is rapidly absorbed after oral administration, with peak plasma levels within 30-60 minutes for immediate-release formulations. It has a short half-life (20-50 minutes) due to rapid hepatic metabolism, primarily by CYP1A2. This short half-life means immediate-release melatonin may not maintain sleep throughout the night, leading to development of extended-release formulations for sleep maintenance.

Melatonin is found in small amounts in various foods, particularly tart cherries, nuts, grains, and some fruits. However, dietary intake is insufficient to significantly affect plasma melatonin levels compared to supplementation.

Melatonin naturally declines with age. Low melatonin is associated with difficulty falling asleep, poor sleep quality, and circadian rhythm disruptions. Night shift workers may have suppressed melatonin due to light exposure at night.

No established RDA. Effective doses range from 0.5-5 mg for most applications. Lower doses (0.5-1 mg) are often as effective as higher doses with fewer side effects. Timing is more important than dose.

Melatonin comes in immediate-release and extended-release formulations, as well as sublingual and liquid forms. Immediate-release helps with sleep onset; extended-release helps with sleep maintenance.