The Therapeutic Potential of Melatonin: A Review of the Science PART 1

Summary

Melatonin is a ubiquitous natural neurotransmitter-like compound produced primarily by the pineal gland. This agent is involved in numerous aspects of the biological and physiologic regulation of body functions. The role of endogenous melatonin in circadian rhythm disturbances and sleep disorders is well established. Some studies have shown that melatonin may also be effective in breast cancer, fibrocystic breast diseases, and colon cancer. Melatonin has been shown to modify immunity, the stress response, and certain aspects of the aging process; some studies have demonstrated improvements in sleep disturbances and “sundowning” in patients with Alzheimer's disease. The antioxidant role of melatonin may be of potential use for conditions in which oxidative stress is involved in the pathophysiologic processes. The multiplicity of actions and variety of biological effects of melatonin suggest the potential for a range of clinical and wellness-enhancing uses. This review summarizes the physiology of melatonin and discusses the potential therapeutic uses of melatonin.Melatonin is a widely occurring neurotransmitter-like compound derived primarily from the pineal gland. It is also produced in a number of other areas, for example the gastrointestinal tract. Once labeled as a master hormone, it has been found to be involved in numerous aspects of biological and physiologic regulation.Synthesis and Physiologic Role in HumansMelatonin is an indole hormone, widely distributed in both plant and animal sources, such as human milk, bananas, beets, cucumbers, and tomatoes.Chemically, melatonin is N-acetyl-5-methoxytryptamine, a derivative of serotonin, which in turn is derived from tryptophan. Serotonin is first acetylated by N-acetyltransferase (probably the rate-limiting step) and then methylated by hydroxyindole orthomethyltransferase to form melatonin.Melatonin synthesis depends on intact beta-adrenergic receptor function. Norepinephrine activates the N-acetyltransferase and beta-receptor blockers depress melatonin secretion.The enzymes of melatonin synthesis are activated and depressed, respectively, by darkness and light. Release of melatonin follows a circadian (circa: about; dias: a day) rhythm generated by the suprachiasmatic nuclei in response to daylight alterations.Through melatonin release, the pineal gland maintains the internal clock governing the natural rhythms of body function. This apparent clock-setting property of melatonin has led to the suggestion that it is a “chronobiotic” substance that alters and potentially normalizes biological rhythms and adjusts the timing of other critical processes and biomolecules (hormones, neurotransmitters, etc) that, in turn, exert numerous peripheral actions.

Sleep Disturbances

Studies  have suggested that a relationship exists among sleep, pineal function, and melatonin levels. Nocturnal melatonin levels and the quality of sleep both decline at puberty; in elderly populations, periods of sleep tend to become shorter and the quality of sleep poorer. Controlled clinical trials have shown that melatonin is effective as a chronobiotic in a number of circadian rhythm sleep disorders.Jet LagWhen melatonin is taken at the destination, between 10 pm and midnight, it can correct the sleep disturbances, mental inefficiency, and daytime fatigue (cumulatively known as “jet lag”) that occur after flights across several time zones. The biological rhythm disorganization caused by the rapid change of environment (and associated light/dark cues) apparently can be corrected by melatonin. The benefit is likely to be greater as more time zones are crossed and less for westward flights. However, melatonin taken before travel can actually worsen symptoms as opposed to the benefit of melatonin initiated immediately upon arrival. Parry has reviewed the use and effectiveness of melatonin as a ‘dark pulse’ at night, with appropriately timed bright light to reduce symptoms of jet lag.InsomniaNocturnal melatonin levels are reduced in primary insomnia. Supplemental melatonin has been used successfully as a hypnotic for delayed sleep-phase syndrome, a type of insomnia characterized by wakefulness and the inability to fall asleep before 2:00 to 3:00 am. In several small studies, 5-mg doses of melatonin given at 10 pm resulted in an advance of the sleep phase (shortening of time to sleep) by about 1.5 hours and reduced sleep duration by about 30 minutes, suggesting a lowered sleep requirement as a consequence of improved sleep quality.NarcolepsyMelatonin has also been used to alter sleep architecture in narcolepsy, a disorder of disturbed circadian sleep/wake rhythm and rapid-eye-movement (REM) sleep deficit. Changes in REM sleep patterns similar to those of narcolepsy also occur in animals and humans after removal of the pineal gland. Pharmacologic doses of melatonin (50 mg) dramatically increased REM sleep time in both narcoleptics and normals and greatly intensified subjective dream phenomena.Several studies using varying doses of melatonin (2–20 mg/daily) have reported improved sleep quality, accelerated sleep initiation, and improved sleep maintenance without significantly altering memory, in contrast to benzodiazepines.

Sleep Disorders in Children

Melatonin has also been used successfully to treat serious sleep disorders in hyperactive and neurologically compromised children, such as those with attention-deficit/hyperactivity disorder. In 1 study, doses of 2.5–5 mg nightly provided prompt sedation and improved sleep quality, noted in almost all the 15 subjects, with no side effects. Irritability has been reduced, children have tended to become more alert and sociable, and developmental gains have been reported in children treated with melatonin.