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J Physiol Volume 561, Number 1, 339-351, November 15, 2004 DOI: 10.1113/jphysiol.2004.073742
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Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans

Shantha M. W Rajaratnam1,3, Benita Middleton1, Barbara M Stone2, Josephine Arendt1 and Derk-Jan Dijk1

1 School of Biomedical and Molecular Sciences, University of Surrey, UK
2 Centre for Human Sciences, QinetiQ Ltd, UK
3 School of Psychology, Psychiatry and Psychological Medicine, Monash University, Australia

The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00–08.00 h) in near darkness. Eight healthy male volunteers (24.4 ± 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin-induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep-facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time.

(Received 12 August 2004; accepted after revision 28 September 2004; first published online 30 September 2004)
Corresponding author S. M. W. Rajaratnam: School of Psychology, Psychiatry and Psychological Medicine, Monash University, Building 18, Victoria 3800, Australia. Email: shantha.rajaratnam{at}med.monash.edu.au




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