If humans remain photoperiodic, some of these effects of melatonin may be explicable. Animal data (42,43) and some human evidence (44,45) show that extending the night length can lead to a bimodal pattern of sleep/activity and sometimes of the endogenous melatonin profile itself. Classical photoperiodic theory attributes this bimodality to two theoretical oscillators, the evening (E) and morning (M) components of a rhythm (42,45). Expansion of a rhythm such as sleep or, in rodents, activity in short days (i.e. long nights) is postulated to be due to an advance of the E and a delay of the M oscillators. Melatonin given only in the early evening (advancing the perceived onset) would be expected to differentially affect these theoretical rhythm generators such that the E is influenced more than the M (or vice versa if given in the morning). The possible differential effect of evening melatonin on melatonin onset (27,31) and, to some extent, on the timing of sleepiness/ alertness (22), lends support to this theory. The evidence for this differential effect with regard to light induced phase shifts is very solid (46).
A possible explanation for the fragmentation of sleep in the free running experiments described above is implicit in this theory if indeed sleep consists of two bouts controlled by two coupled oscillators. Given close to core temperature maximum, a maximum phase advance is induced by the first dose of melatonin, with the greatest effect on the E oscillator. The dose used (5 mg) is not necessarily completely cleared by the end of sleep and a phase delaying effect related to the late decline of melatonin may be simultaneously induced on the M oscillator. In these circumstances it is conceivable that the "sleep oscillators" are uncoupled or literally pulled apart, subsequently free running in the very dim light environment with different periodicies as seen in animal experiments. Another possible explanation may involve interactions of the circadian and homeostatic components of sleep (47) whereby a complex combination of sleep induction by out of phase melatonin goes some way towards compensating sleep debt and a subsequent bout of sleep occurs due to the circadian component of sleep (Process C) which itself may then be shifted by the melatonin administration. The effect if confirmed may be dose related as well as circadian time related.
Whatever the explanation it is clear that this phenomenon would be highly undesirable if consolidated sleep and alertness is required. However a strategy of splitting sleep into two components with melatonin may lead to more rapid adaptation to phase shift by advance of the E and delay of the M component.
The majority of published data indicate that melatonin has therapeutic benefits in circadian rhythm-related sleep disorders. However as yet its mechanism of action remains unclear, the appropriate dose for any given condition and individual is uncertain, the contraindications remain to be defined, there is no data on long term safety, use with concomitant medication or organic disease and very little information concerning its most important function as a photoneuroendocrine transducer in humans. Since it does appear to have some photoperiodic effects, and since in principle daylength has the potential to affect many if not all physiological systems, much further research is needed on its physiological role and pharmacological effects in humans.
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