CLINICAL REVIEW Melatonin as a chronobiotic Josephine Arendt * ,2,3 , Debra Jean Skene 1,2 School of Biomedical and Molecular Sciences, Centre for Chronobiology, University of Surrey, Guildford, Surrey GU2 7XH, UK KEYWORDS Melatonin; Circadian; Rhythm; Sleep; Phase shift Summary Melatonin, hormone of the pineal gland, is concerned with biological timing. It is secreted at night in all species and in ourselves is thereby associated with sleep, lowered core body temperature, and other night time events. The period of melatonin secretion has been described as ‘biological night’. Its main function in mammals is to ‘transduce’ information about the length of the night, for the organisation of daylength dependent changes, such as reproductive competence. Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during ‘biological daytime’, and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times. The shifts induced are sufficient to synchronise to 24 h most blind subjects suffering from non-24 h sleep –wake disorder, with consequent benefits for sleep. Successful use of melatonin’s chronobiotic properties has been reported in other sleep disorders associated with abnormal timing of the circadian system: jetlag, shiftwork, delayed sleep phase syndrome, some sleep problems of the elderly. No long- term safety data exist, and the optimum dose and formulation for any application remains to be clarified. q 2004 Elsevier Ltd. All rights reserved. Introduction The word chronobiotic does not yet figure in the Oxford English dictionary. A practical definition would be ‘a substance that adjusts the timing of internal biological rhythms’ or more specifically ‘a substance that adjusts the timing of the central biological clock’. Conditions in which adjustment of the timing of circadian (ca. 24 h) rhythms is of practical benefit include non-24 h sleep –wake dis- order, delayed sleep phase syndrome (DSPS), shift work, jet lag, living in very dim light, possibly some sleep disorders in the elderly and probably many other situations yet to be investigated (Fig. 1). There is good evidence that exogenous melato- nin can change the timing of some overt rhythms such as sleep, core body temperature, endogenous melatonin and cortisol, and that in vitro it will shift the timing of activity (electrophysiological and metabolic) within the suprachiasmatic nuclei (SCN), the central circadian rhythm generator or pacemaker. In some circumstances melatonin can synchronise or ‘entrain’ to the 24 h day circadian rhythms in individuals who are ‘free-running’, 1087-0792/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2004.05.002 Sleep Medicine Reviews (2005) 9, 25–39 www.elsevier.com/locate/smrv 1 Tel.: þ44-1483-689706; fax: þ 44-1483-300374. 2 Josephine Arendt and Debra Skene are directors of Stockgrand Ltd, which measures melatonin and related products and conducts clinical trials and basic research on the effects of melatonin. Josephine Arendt is the major shareholder and Debra Skene is a minor shareholder. 3 Josephine Arendt is a member of the Sleep Advisory Board of Alliance Pharmaceuticals. * Corresponding author. Tel.: þ44-1483-689701; fax: þ 44- 1483-689712. E-mail addresses: j.arendt@surrey.ac.uk, arendtjo@aol.com (J. Arendt), d.skene@surrey.ac.uk (D.J. Skene).