The pharmacokinetics of melatonin during the day-time has been studied in 4 healthy subjects after a bolus i.v. injection of 5 or 10 micrograms/person and after a 5 h infusion of 20 micrograms per person in 6 healthy subjects. In addition, a pinealomectomized patient whose nocturnal plasma melatonin had been abolished was investigated after the i.v. infusion--once during the night and once during the day. The clearance of melatonin from blood showed a biexponential decay. The pharmacokinetic parameters in the two studies were similar, except for the disappearance rate constant beta and the apparent volume of distribution at steady-state (Vss). Supplementary peaks or troughs were superimposed on the plateau and the falling part of the profile. They were not due to stimulation of endogenous secretion, because they were also seen in the pinealomectomized patient. During the melatonin infusion, the plasma hormone level reached a steady-state after 60 and 120 min, and when it was equal to the nocturnal level. The infusion regime may be valuable in replacing blunted hormonal secretion in disease states.

The plasma melatonin profile was significantly disturbed (phase-shift of the maximum melatonin level) in four out of six female sufferers from status migrainosus, compared with nine healthy controls. The number of secretion peaks was similar in both groups. A nocturnal 20 micrograms melatonin infusion (from 21.00 to 01.00 h) evoked plasma melatonin levels slightly higher than a physiological secretion peak. During infusion, the episodes of secretion were reinforced and the endogenous plasma profile was phase-advanced in two patients displaying a phase-delay. These data suggest impaired pineal function in migraine. In the absence of side effects of melatonin infusion, the relief of certain migraine symptoms described by our patients might support a controlled trial of melatonin in migraine.

An oral preparation of melatonin was administered daily at 22.00 h to 6 healthy volunteers during summer on 4 consecutive days (days 1\p=n-\4).The daily dose was 8 mg of melatonin as a single. Three 24-h melatonin, cortisol and prolactin profiles were determined in plasma by radioimmunological methods: 1) before treatment (day 0); 2) the first day after the 4-day treatment had been stopped (day 5), 3) the third day after withdrawal of this treatment (day 7). For the melatonin rhythm, an advanced phase was observed at day 7 vs day 0, whereas the amplitude and the mesor were not modified, whatever the day. For the prolactin profile, a significant increase as compared with the control day (day 0) was detected only at day 7 between 19.00 and 21.00 h. No modification was recorded for the plasma cortisol secretion.These results suggest that melatonin, when administered at a high dose over a short period, can influence the endocrine rhythms, and especially its own endogenous secretion. This effect must be investigated over several days after the treatment has ended. The pineal gland, as an endogenous clock, plays a central role in the circadian and seasonal organiza¬ tion of biological rhythms in several species (Reiter 1981). Melatonin, the main indole compound syn¬ thesized by the pineal gland, presents a very marked circadian rhythmic secretion in humans and other species: plasma melatonin levels are high at night, during the scotophase, and low or undetectable during the light period. In humans, no clearly established role has been definitively at¬ tributed to melatonin: melatonin can induce sleep (Cramer et al. 1974; Vollrath et al. 1981), and modify mood and performance (Lieberman et al. 1984) or fatigue (Arendt et al. 1984). In all these studies, however, either the doses were supraphysiological or melatonin was given during day-time. Further, in adults, hormonal effects have been observed on plasma GH levels (Smythe & Lazarus 1974) or on GH and gonadotropin levels (Nordlund & Lerne 1977) during long-term treatment, on plasma pro¬ lactin and melatonin on the day following the last oral administration of a one-month treatment (Wright et al. 1986), and in children on plasma GH and prolactin levels after an acute injection of me¬ latonin (Lissoni et al. 1986). Moreover, Arendt et al. (1986) have shown that melatonin alleviates jet-lag, suggesting an interaction between this hormone and endogenous rhythms.We report here on the 24-h plasma melatonin, prolactin and cortisol profiles of 6 normal subjects studied on three occasions, the first before treat¬ ment (day 0), the second on day 1 (day 5) and the third on day 3 (day 7) after withdrawal of a 4-day melatonin course. This study was designed to evaluate the consequence of a semi-chronic treat¬ ment on the endocrine rhythms. Subjects and MethodsSix healthy young men (22-26 years of age) were en¬ rolled for this study which was developed within the scope of a research project on the effects of melatonin in