Melatonin treatment timed to induce phase advances and delays has been used in the alleviation of jet lag in at least 14 real life and simulation conditions of which 11 reported beneficial effects. Field studies suggest that self-rated jet lag can be reduced on average by 50 per cent with appropriately timed treatment both westward and eastward (see (115) for a review). The improvement appears to be greater with larger numbers of time zones. The subjective impressions are reinforced by improved latency and quality of sleep, greater daytime alertness, and slightly more rapid resynchronization of melatonin and cortisol rhythms. Neither the dose nor the timing of melatonin administration has been fully optimized although the largest successful study reported, with respect to alleviating sleep problems, that 5 mg was more effective than 0.5mg and a slow release preparation taken at bedtime after flight (136). Three studies have shown no effect—a common factor in two was that the subjects were not adapted to local time before departure with consequent problems for timing the treatment. The third also appeared to use inappropriate timing of treatment. Unpredictable exposure to bright light can theoretically act in opposition to the desired result. A Cochrane review (137) recently concluded that timed melatonin was effective as a jet lag treatment; however, a metaanalysis of the effects of melatonin as a ‘nutritional supplement’ was less enthusiastic (Agency for Healthcare Research and Quality (http://www.ahrq.gov/news/press/pr2004/melatnpr.htm).

Some inconsistent work has been published on the use of melatonin in shift work, although exposure to bright light sufficient to suppress melatonin secretion during the night is clearly beneficial to night shift workers. Preliminary work suggested improved sleep and increased daytime alertness in night shift workers receiving melatonin at the desired bedtime during a night shift week compared with placebo and baseline conditions (137). A number of recent studies have successfully used melatonin to adapt to simulated or real shift work (reviewed in (138)) although it has to be said that several reports in the literature have shown no beneficial effects. Questions of posture, light environment and timing need to be resolved in field studies.

Initially encouraging results using melatonin to alleviate sleep disorder in the elderly have proved inconsistent; however, there is no doubt that some subjects will derive benefit. Dose, timing and formulation remain to be optimised (139, 140).

Patients with delayed sleep phase insomnia cannot sleep at the socially acceptable time of night and delay sleep onset until the early hours of the morning, sleeping through much of the day. This condition has been successfully treated with bright light in the early morning to induce phase advances of the clock. In others evening melatonin (5 mg at 2200 hours, or 5h ahead of endogenous melatonin onset ) also advances sleep time significantly (140, 141). Judicious, timed application of both melatonin and bright light as time cues may well be the treatment of choice for rhythm disturbances.

There is good evidence for photoperiod dependency and/or melatonin responsiveness of the initiation and evolution of certain cancers, particularly hormone-dependent cancers, in animals. Oncostatic effects are reported on some human cell lines, and in general the pineal and melatonin appear to have anti-tumor activity (142). In dimethylbenzanthracene-induced mammary tumors in rats, pinealectomy greatly increased the incidence of induced tumor growth, and daily melatonin administration in the late light phase greatly decreased incidence (143). Not all reports show positive results, however. A few early reports of positive effects of combination therapy- melatonin and tamoxifen, melatonin and interleukin, require confirmation (144, 145). Most recently, survival time and quality of life were significantly enhanced by adjunct melatonin therapy in small cell carcinoma of the lung (146).

Melatonin when appropriately administered has generally stimulatory effects on aspects of the immune system, and positive effects on cancer may be a consequence (145). The evidence that melatonin also acts as a free-radical scavenger has been discussed previously.

A recent review addresses the general question of the circadian system in relation to cancer: disruption of clock gene function is associated with increased risk of cancer in recent animal studies (7). Perhaps here may lie one aspect of the oncostatic activity of melatonin. By acting as a circadian coupling agent countering desynchrony amongst central and peripheral clocks, and optimising phase with respect to external time cues, cellular and system processes may be optimized and defense systems augmented. These considerations may also apply to risk of other major diseases associated with shift work (heart disease, metabolic syndrome, possible decreased fertility (147, 148)).