Summary: The present study investigated the hypnotic effects of 5 mg melatonin ... These findings indicate that melatonin possesses a time-dependent hypnotic.
Sleep, 17(7):638--{j45 © 1994 American Sleep Disorders Association and Sleep Research Society
Melatonin Possesses Time-Dependent Hypnotic Effects O. Tzischinsky and P. Lavie Sleep Laboratory, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Israel
The present study investigated the hypnotic effects of 5 mg melatonin in comparison with placebo when administered at 1200, 1700, 1900 and 2100 hours. Eighteen young adults were studied with the 7/13 ultrashort sleep-wake paradigm after an overnight sleep deprivation. Melatonin was administered according to a double-blind Latin square design. After each administration, melatonin significantly increased sleep propensity, the spectral power in the theta, delta and spindles bands, and subjective sleepiness. It significantly decreased the power in the alpha and beta bands and oral temperature. The latency to maximum effect varied linearly from 3 hours 40 minutes at 1200 hours to 1 hour at 2100 hours. These findings indicate that melatonin possesses a time-dependent hypnotic effect and suggest that endogenous melatonin may participate in sleep-wake regulation. Key Words: MelatoninHypnotic-7/13 paradigm-Normal young adults.
Summary:
Melatonin, a neurohormone produced by the pineal gland during the dark phase ofthe day-night cycle, has been implicated in the regulation of the mammalian circadian system (1). In humans melatonin has been shown to ameliorate sleep disturbances in blind people (2,3) and in patients suffering from delayed sleep phase syndrome (4,5). It also facilitates adaptation to jet lag (6,7). Recently, it was shown that the response of endogenous production of melatonin to exogenous administration in humans follows a phase response curve that mirrors the melatonin phase response curve to light (8). The question of whether melatonin actually possesses any hypnotic effects is still controversial. Although pharmacological dosages of exogenous melatonin have been found to produce some hypnotic effects (9), lower dosages were ineffective or were reported to produce some sensation of fatigue and sedation (10,11). In the present study, we utilized an ultrashort sleepwake paradigm to test this hypothesis. The results showed that the time interval to maximal effect is dependent on the time of melatonin administration.
pleted the Technion Sleep Questionnaire and a morning/evening questionnaire (Hebrew translation of the Home and Ostberg questionnaire) to exclude sleep disturbances and/or extreme morning or evening types. All were students living on campus and had approximately the same daily schedule. None used any kind of drugs or medications on a regular basis. To investigate the hypnotic effects of melatonin, subjects were studied five times with the 7/13 ultrashort sleep-wake paradigm under different treatment conditions in a crossover, placebo-controlled, double-blind design. Each experimental period started at 0700 hours after an overnight sleep deprivation, and continued for 24 hours. The 7/13 sleep-wake paradigm has already been described in detail (12). The reason for imposing a sleep deprivation period before the 7113 paradigm was to increase sleep propensity. Previous studies showed that the pattern of 24-hour variations in sleep propensity after a night of sleep deprivation can be reliably reproduced and has distinct temporal features that can be easily identified. These include the "sleep gate" and the "forbidden zone for sleep" (13). Melatonin was administered during four of the five experimental periods; in each period, four identical-looking METHODS AND DESIGN pills were administered at 1200, 1700, 1900 and 2100 Eight healthy males (age 27.06 ± 3.7 years) partic- hours. One pill contained 5 mg melatonin and the ipated. All were individually interviewed, and all com- remainder were placebos. The reason for the uneven distribution of administrations was to examine the effect of melatonin before the midafternoon sleepiness Accepted for publication June 1994. peak (1200 hours) during the forbidden zone for sleep Address correspondence and reprint requests to P. Lavie, Ph.D., (1700 and 1900 hours) and just before the nocturnal Sleep Laboratory, Gutwirth Building, Technion City, Haifa, Israel 32000. sleep gate (2100 hours). The timing of melatonin ad638
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