A review of melatonin as a chronobiotic agent: therapeutic use in the treatment of sleep disorders in shift-workers

The pineal hormone, melatonin, has been widely promoted as a chronobiotic agent that may be used to adjust circadian rhythms under a variety of conditions including jet-lag, shift-work disorder, insomnia, delayed sleep phase syndrome (DSPS), in blind and sighted individuals with free-running sleep-wake cycles, and even for space travel. Melatonin has also been promoted as an antioxidant to prevent aging, a contraceptive, and as an adjunct in chemotherapy for cancer (Webb & Puig-Domingo, 1995). \ud In North America, the Food and Drug Administration (FDA) classify melatonin as a nutritive or dietary supplement (Cowley, 1995). Products listed under this classification require only limited review, thus quality and concentrations are not regulated. Analysis of six melatonin products showed that four had impurities (Medical Letters, 1995). Melatonin manufacturers are often not identified on product labels. Some melatonin is made from bovine pineal glands, but most is synthesized chemically. Melatonin has not undergone the clinical trials for safety and efficacy required for FDA drug approval. Melatonin can be purchased in health food stores, pharmacies and via the Internet in many countries, and it is sold as a “natural” substance (Caldwell, 2000). Patients often ask physicians about its use, but not all physicians are able to provide “accurate” advice about the appropriate use of melatonin (Caldwell, 2000). \ud Melatonin secretion follows a circadian rhythm with blood plasma levels high at night and low during the day (Brown, 1994). Bright light in the evening suppresses melatonin secretion and delays the melatonin rhythm (Brown, 1994). Melatonin has a soporific effect at higher doses and can entrain the sleep-wake rhythm (Brown, 1994). The available data, suggest that, melatonin may be effective for a variety of sleep-related disorders. However, there are few well-controlled clinical studies, and no studies on the effects of chronic melatonin administration (Avery, Lenz & Landis, 1998). The optimal dose of melatonin is not clear; and most studies have used doses that produce supraphysiologic blood levels (Avery et al. 1998). Studies have shown that the timing of melatonin administration is of critical importance (Lewy, Bauer Ahmed, Thomas, Cutler, Singer, Moffit & Sack, 1998). Sack and Lewy (1998) propose that melatonin promotes sleep by producing corrective circadian phase shifts, improving the alignment of the endogenous sleep-wake rhythm with the desired external sleep schedule. Sack and Lewy (1998) also note that melatonin has a direct soporific effect, particularly when administered during the day. This effect is explained in terms of the direct action resulting from the release of accumulated sleep drive by attenuation of the circadian alerting signal