Phase Shifting Effects Of Melatonin

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Following an acute dose of melatonin (0.5-10mg) core body temperature declines and causal links have been suggested between this effect, the induction of sleepiness and, in the case of early evening administration, a subsequent phase advance of melatonin onset and/or core body temperature (23,24,25). Substance has been added to this speculation by the observation that both the temperature decline and the sleepiness are dependent on posture (26). Subjects who remain upright and/or active after the dose do not show either the sleepiness or the temperature drop. However the induced phase shift may not depend on changes in core temperature. In early work, subjects taking 2mg melatonin daily at 1700h for 30 days and remaining active only showed significant evening sleepiness after 4 days as a group (22,27) and rarely slept in the early evening. Moreover in conditions where very little acute change in temperature was found, phase shifts still occurred (22,27).

Fast release melatonin (0.5 mg-5 mg, or less in divided doses) phase advances and delays the circadian system (endogenous melatonin, core temperature, sleep timing) according to a PRC (28,29,30). In our experiments this is a dose related phenomenon for advance phase shifts in the range 0.05-5 mg (25). Infusion experiments with controlled plasma levels indicated that melatonin can phase advance and delay the circa-dian system in physiological concentrations, however the distinction between endogenous (marker rhythm) and exogenous melatonin in parts of this study was mathematical rather than real (29). The duration of endogenous melatonin may be increased by evening oral administration since the onset can be advanced more than the offset (27,31). In this way the circadian and photoperiodic effects become confounded, if indeed they are distinguishable at all.

It is absolutely relevant to the argument for a photoperiodic function of melatonin in humans that (in an entrained environment) phase advances are seen when oral administration is timed such that the exogenous dose adds to the duration of the endogenous dose by advancing the evening rise, that a dead zone exists in the middle of the night when no duration change would be anticipated (with low doses) and that phase delays are seen when the exogenous dose adds to the duration by delaying the morning offset. An exception to this is the phase delay (in acrophase) reported after infusion of night time levels from 12-15h (29). However the episodic nature of the profiles reported in this study may have unduly influenced the acrophase estimates.

It is the author's opinion that endogenous melatonin indicates dark onset (the rise) and offset (the decline) and reinforces physiological functions associated with darkness, in humans as in other mammals. Pharmacological doses of melatonin may well act differently. What constitutes a physiological dose of melatonin remains problematic. In the authors' experience fast release doses of melatonin in gelatine-lactose or in corn oil/1% ethanol from 0.05-0.2 mg give, on average, "physiological", i.e. night time plasma concentrations of melatonin during the day (25,27,31,32). Individual pharmacokinetics are extremely variable with plasma levels varying up to 25 fold (33) and this may account for some of the variability in the literature.

Whether target tissue concentrations are comparable to blood or not remains debatable and it is possible that higher doses are required to give physiological target tissue concentrations. This is unlikely since when given by infusion to create "physiological profiles" melatonin has clear photoperiodic effects in rodents and sheep and generates phase shifts in humans (6,29).

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