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Chapter: Basic & Clinical Pharmacology : Dietary Supplements & Herbal Medications


Melatonin, a serotonin derivative produced by the pineal gland and some other tissues, is believed to be responsible for regulating sleep-wake cycles.


Melatonin, a serotonin derivative produced by the pineal gland and some other tissues, is believed to be responsible for regulating sleep-wake cycles. Release coincides with darkness; it typically begins around 9 PM and lasts until about 4 AM. Melatonin release is suppressed by daylight. Melatonin has also been studied for a number of other functions, including contraception, protection against endogenous oxidants, prevention of aging, treatment of depression, HIV infection, and a variety of cancers. Currently, melatonin is most often used to prevent jet lag and to induce sleep.

Pharmacologic Effects & Clinical Uses


A. Jet Lag


Jet lag, a disturbance of the sleep-wake cycle, occurs when there is a disparity between the external time and the traveler’s endogenous circadian clock (internal time). The internal time regulates not only daily sleep rhythms but also body temperature and many metabolic systems. The synchronization of the circadian clock relies on light as the most potent “zeitgeber” (time giver).


Jet lag is especially common among frequent travelers and airplane cabin crews. Typical symptoms of jet lag may include daytime drowsiness, insomnia, frequent awakenings, and gastroin-testinal upset. Clinical studies with administration of melatonin have reported subjective reduction in daytime fatigue, improved mood, and a quicker recovery time (return to normal sleep patterns, energy, and alertness). Although taking melatonin has not been shown to adjust circadian patterns of melatonin release, it may have a role in helping people fall asleep once they arrive at their new destination. When traveling across five or more time zones, jet lag symptoms are reduced when taking melatonin close to the target bedtime (10 PM to midnight) at the new destination. The benefit of melatonin is thought to be greater as more time zones are crossed. In addition, melatonin appears more effective for eastbound travel than for westward travel. Finally, maximizing exposure to daylight on arrival at the new destination can also aid in resetting the internal clock.


B. Insomnia


Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syn-drome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observa-tions have been applied to the development of ramelteon, a prescription hypnotic, which is an agonist at melatonin receptors .


Clinical studies in patients with primary insomnia have shown that oral melatonin supplementation may alter sleep architecture. Subjective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. Specifically, melatonin taken at the desired bedtime, with bedroom lights off, has been shown to improve morning alertness and quality of sleep as compared to placebo. These effects have been observed in both young and older adults (18–80 years of age). Interestingly, baseline endogenous melatonin levels were not predictive of exogenous melatonin efficacy.


C. Female Reproductive Function


Melatonin receptors have been identified in granulosa cell mem-branes, and significant amounts of melatonin have been detected in ovarian follicular fluid. Melatonin has been associated with midcycle suppression of luteinizing hormone surge and secretion. This may result in partial inhibition of ovulation. Nightly doses of melatonin (75–300 mg) given with a progestin through days 1–21 of the menstrual cycle resulted in lower mean luteinizing hormone levels. Therefore, melatonin should not be used by women who are pregnant or attempting to conceive. Furthermore, melatonin supplementation may decrease prolactin release in women and therefore should be used cautiously or not at all while nursing.


D. Male Reproductive Function


In healthy men, chronic melatonin administration (≥ 6 months) decreased sperm quality, possibly by aromatase inhibition in the testes. However, when endogenous melatonin levels were measured in healthy men, high endogenous melatonin concentrations were associated with enhanced sperm quality and short-term in vitro exposure to melatonin improved sperm motility. Until more is known, melatonin should not be used by couples who are actively trying to conceive.

Adverse Effects


Melatonin appears to be well tolerated and is often used in pref-erence to over-the-counter “sleep-aid” drugs. Although mela-tonin is associated with few adverse effects, some next-day drowsiness has been reported as well as fatigue, dizziness, head-ache, and irritability. Melatonin may affect blood pressure as both increases and decreases in blood pressure have been observed. Careful monitoring is recommended, particularly in patients initiating melatonin therapy while taking antihyperten-sive medications.

Drug Interactions


Melatonin drug interactions have not been formally studied. Various studies, however, suggest that melatonin concentrations are altered by a variety of drugs, including nonsteroidal anti-inflammatory drugs, antidepressants, β-adrenoceptor agonists and antagonists, scopolamine, and sodium valproate. The relevance of these effects is unknown. Melatonin is metabolized by CYP450 1A2 and may interact with other drugs that either inhibit or induce the 1A2 isoenzyme, including fluvoxamine. Melatonin may decrease prothrombin time and may theoretically decrease the effects of warfarin therapy. A dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested according to one in vitro analysis. If combination therapy is desired, careful monitoring is recom-mended especially if melatonin is being used on a short-term basis. Melatonin may interact with nifedipine, possibly leading to an increased blood pressure and heart rate. The exact mechanism is unknown.




A. Jet Lag


Daily doses of 0.5–5 mg appear to be equally effective for jet lag; however, the 5-mg dose resulted in a faster onset of sleep and better sleep quality than lower doses. The immediate-release formulation is preferred and should be given at the desired sleep time (10 PM–midnight) upon arrival at the new destination and for 1–3 nights after arrival. The value of extended-release formulations remains unknown, as evidence suggests the short-acting, high-peak effect of the immediate-release formulation to be more effective. Exposure to daylight at the new time zone is also important to regulate the sleep-wake cycle.


B. Insomnia


Doses of 0.3–10 mg of the immediate-release formulation orally given once nightly have been tried. The lowest effective dose should be used first and may be repeated in 30 minutes up to a maximum of 10–20 mg. Sustained-release formulations are effec-tive and may be used but currently do not appear to offer any advantages over the immediate-release formulations. Sustained-release formulations are also more costly.


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