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Melatonin Phase-Shifts Human Circadian Rhythms with No Evidence of Changes in the Duration of Endogenous Melatonin Secretion or the 24-Hour Production of Reproductive Hormones

Centre for Chronobiology (S.M.W.R., D.-J.D., B.M., J.A.), School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom; Centre for Human Sciences (B.M.S.), QinetiQ Ltd., Farnborough GU14 0LX, United Kingdom; and School of Psychology, Psychiatry and Psychological Medicine (S.M.W.R.), Monash University, Victoria 3800, Australia

Address all correspondence and requests for reprints to: Dr. Shantha Rajaratnam, School of Psychology, Psychiatry and Psychological Medicine, P.O. Box 17, Monash University, Victoria 3800, Australia. E-mail: shantha.rajaratnam{at}med.monash.edu.au.

The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Melatonin administered at optimal times of the day for treatment often results in a prolonged melatonin profile. In photoperiodic (day length-dependent) species, changes in melatonin profile duration influence the timing of seasonal rhythms. We investigated the effects of an artificially prolonged melatonin profile on endogenous melatonin and cortisol rhythms, wrist actigraphy, and reproductive hormones in humans. Eight healthy men took part in this double-blind, crossover study. Surge/sustained release melatonin (1.5 mg) or placebo was administered for 8 d at the beginning of a 16-h sleep opportunity (1600 h to 0800 h) in dim light. Compared with placebo, melatonin administration advanced the timing of endogenous melatonin and cortisol rhythms. Activity was reduced in the first half and increased in the second half of the sleep opportunity with melatonin; however, total activity during the sleep opportunities and wake episodes was not affected. Melatonin treatment did not affect the endogenous melatonin profile duration, pituitary/gonadal hormone levels (24-h), or sleepiness and mood levels on the subsequent day. In the short term, suitably timed sustained-release melatonin phase-shifts circadian rhythms and redistributes activity during a 16-h sleep opportunity, with no evidence of changes in the duration of endogenous melatonin secretion or pituitary/gonadal hormones.

This work was supported by a joint grant from the Medical Research Council and the Ministry of Defense (G9810584) and funding from Stockgrand Ltd. (University of Surrey, United Kingdom).

Abbreviations: CR, Constant routine; CV, coefficient of variation; D, study day; LD, limit of detection; PRL, prolactin.

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