Since melatonin does show the characteristics of a zeitgeber in that a PRC can be generated, it would be expected to entrain fully the circadian clock in suitable circumstances. Human tau is on average 24.3 h or less in constant dim light (34,35,36) and thus the clock needs to be phase advanced on average by 0.3 h or less each day. Acute phase shifts induced by melatonin in an entrained or free running environment are of at least this magnitude when sleep is permitted. However it has proved impossible so far to demonstrate entrainment in humans, with the exception of apparent entrainment or "stabilisation to 24h" of the sleep wake cycle (30,37). Given to blind subjects free running in a normal environment a pharmacological dose of melatonin induces phase shifts (38) and can stabilise sleep onset in some subjects (39,40). There is no good evidence for entrainment of strongly endogenous rhythms such as core temperature and endogenous melatonin itself (30,39).
It is possible to maintain the sleep-wake cycle of the majority of sighted subjects transferred to a free run in constant dim light (<8lux) on a cycle indistinguishable from 24 h by daily administration of a pharmacological dose of melatonin (5 mg, 2000 h) at 24 h intervals for periods of 15 days (30). Less successful was an attempt to reentrain subjects after free running with different periodicities for 15 days in constant dim light by daily melatonin at the same clock time (30). The initial melatonin administration at 2000 h occurred at different circadian phases. Both phase advances and phase delays of sleep and core temperature were seen according to a PRC. However the data indicated that the effects observed were complex and variable. Some subjects showed a stabilization of sleep onset with little effect on sleep offset for periods of several days. There was some evidence for splitting of sleep such that some components delayed and others advanced to resynchronise. One subject showed a double phase delay and appeared to entrain to melatonin given at sleep offset for several days. Core temperature indicated that tau was shortened, in one case to significantly less than 24h, rather than fully entrained, in many subjects. Since the time series was short (15 days) some taus indistinguishable from 24 h may well not have been synchronised. Similarly a longer study time might have shown synchronisation of temperature in more subjects. Only a very long time series would resolve this question.
The lack of entrainment of strongly endogenous rhythms by melatonin in free running blind and sighted humans remains difficult to explain. The fact that an apparent phase shift is produced by evening melatonin in a normal environment may simply be an artifact of the unnatural experimental situation. If melatonin were given naturalistically such as to extend the duration both in the morning and the evening, no overall phase shift should be seen in endogenous melatonin in an entrained environment. The effects of different doses, with pharmacokinetic evaluation, require detailed exploration. The magnitude of the published PRCs may simply be wrong. As yet there is no single pulse PRC for melatonin in free running conditions and this urgently needs to be measured. The stabilisation of sleep to 24h may simply be a masking effect-but much data is inconsistent with this hypothesis.
Most surprising of all in the free running study mentioned above (30) was a phenomenon of fragmentation of sleep in two subjects taking 5 mg melatonin close to core temperature maximum immediately after transferring to a dim light environment. Cross-over from melatonin to placebo led to consolidated sleep. A subsequent attempt to time melatonin specifically to be close to core temperature maximum provided two further subjects showing fragmented sleep with melatonin compared to placebo (41). Thus, of a total of 16 subjects studied in dim light in this way, 4 showed sleep fragmentation. There was evidence by spectral analysis for the presence of two components with different periodicity's in 3 of the 4 subjects.
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