Circadian rhythm disturbance is associated (among other things) with shift work, jet lag, blindness, delayed and advanced sleep phase syndromes, and old age. The most obvious symptom is poor sleep. A treatment able rapidly to shift the biological clock in all its manifestations would be of substantial benefit to large numbers of people. To date bright light is the only treatment that in suitable intensity and duration is able to do this (but clearly cannot be used in the free running sleep disorder of the blind). Although melatonin has been known to have acute sleep inducing and phase shifting effects for many years, a consensus acknowledging therapeutic benefit has only emerged recently (112).

The first evidence dates from 40 years ago when Aaron Lerner, who first isolated the substance, took 100 mg and described sleepiness after the dose . Subsequently a substantial literature, generally using much lower doses (0.3-10mg), has described advance shifts in the timing of sleep after early evening administration, transient sleepiness at several different times of day within 2-4h of the dose, time dependent increases in sleep propensity, effects on the waking EEG comparable to, but not identical with, benzodiazepines, a lengthening of the first rapid eye movement (REM) episode after early evening administration, increases in the fast EEG frequencies after evening naps or night time sleep and 'beneficial effects' taken at bedtime. The latter are usually a reduction in wake after sleep onset (WASO) and an increase in total sleep time (TST) evaluated subjectively, by actigraphy and, rarely, by EEG. When melatonin was used to hasten adaptation to a 9h phase advance, TST, sleep efficiency and stage 2 sleep were increased whereas slow wave sleep (SWS) was decreased. The subject has been extensively reviewed (113-115). Recent evidence supports an effect of melatonin on sleep timing, whereby melatonin induced a redistribution of sleep during an imposed sleep opportunity of 16h without an increase in total sleep time (116).

Phase shifting of human circadian rhythms by melatonin was initially described in humans in the early 1980s. Phase advances were seen after 2mg daily at 1700h for one month. There were no significant effects on self-rated mood, or on levels of LH, FSH, testosterone, cortisol, growth hormone, or thyroxine. No deleterious effects were reported by the subjects (117). Advance shifts in sleep, endogenous melatonin, prolactin and core body temperature can be induced by oral administration (0.5- 10mg) in the 'biological afternoon/evening' (where biological night is the time of endogenous melatonin secretion). The magnitude of the shift is dose dependent. Delay shifts can be obtained by early 'biological morning' administration, and these time-dependent responses have been formalised as a phase response curve (PRC) (118). Melatonin given ca. 8-13 hours before core temperature minimum will phase advance, and given ca 1-4h after core temperature minimum will phase delay. More recently, it has become clear that the rhythms of cortisol and TSH (and no doubt other rhythmic variables) are also shifted by melatonin (119).

In addition to these acute effects, melatonin can clearly maintain synchronisation of the circadian clock to 24 hours in sighted subjects living in conditions conducive to free run, and appeared to resynchronise some subjects after a period of free run (120). In the free running blind it has been possible to stabilise the sleep wake cycle to 24 hours with improvement in sleep and mood variables, without synchronising strongly endogenous rhythms such as core body temperature. With suitable dose (0.3-10mg) and timing however, entrainment/synchronisation is possible in most subjects (121-123) (Figure 5). Success was attributed to careful timing either to the advance portion of the PRC or for the treatment to start an hour before preferred bedtime, as the subjects' free running rhythm approached a normal phase. Individual sensitivity to melatonin varies and the pharmacokinetics are very different from one individual to another. The lower dose of 0.3-0.5 mg may be more effective than higher doses in many subjects. Timing at the start of treatment may be critical; however, it is possible that subjects with a very long free running period will not, ever, synchronise to melatonin.

Even without full circadian synchronisation however, melatonin has generally positive effects on sleep in the blind (124).

The effects of melatonin on core body temperature are reported to vary in the course of the menstrual cycle and herein may lie a physiological function (125). LH pulses are amplified in early follicular phase by oral melatonin at 0800 hours (126). Attempts to develop melatonin as a contraceptive pill in combination with a synthetic progestin ‘minipill’ have not been successful (127).

A series of studies in males with and without hypogonadism has reinforced the perception that melatonin is essentially inhibitory to human reproductive function (e.g. (128, 129)), and very large doses (100 mg daily) potentiate testosterone-induced LH suppression (130). In the author's opinion, low, timed doses of melatonin used to reinforce circadian organization are likely to improve fertility in humans. Acute oral doses of melatonin stimulate prolactin secretion (131). Acute effects on other pituitary hormones are somewhat inconsistent, although recently a relationship between melatonin and and vasopressin secretion has been established (132).

Some interesting data suggests that melatonin has anti-hypertensive effects (133). Melatonin, given during the daytime, can impair performance (134). The acute pharmacological properties of melatonin in animals include sedation, hypothermia, anxiolysis, muscle hypotonia, decrease in locomotor activity with a rebound increase on increasing the dose, slight analgesia, slight protection against electroconvulsive shock, constriction of cerebral arteries, potentiation of noradrenaline-induced vasoconstriction and very low toxicity (135).