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A Three Pulse Phase Response Curve to Three Milligrams of Melatonin in Humans

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A Three Pulse Phase Response Curve to Three Milligrams of Melatonin in Humans J Physiol 586.2 (2008) pp 639–647 639 A three pulse phase response curve to three milligrams of melatonin in humans Helen J. Burgess1,VictoriaL.Revell2 and Charmane I. Eastman1 1Biological Rhythms Research Laboratory, Department of Behavioural Sciences, Rush University Medical Center, Chicago, IL, USA 2Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK Exogenousmelatoninisincreasinglyusedforitsphaseshiftingandsoporificeffects.Wegenerated a three pulse phase response curve (PRC) to exogenous melatonin (3 mg) by administering it to free-running subjects. Young healthy subjects (n = 27) participated in two 5 day laboratory sessions,eachprecededbyatleastaweekofhabitual,butfixedsleep.Each5 daylaboratorysession started and ended with a phase assessment to measure the circadian rhythm of endogenous melatonin in dim light using 30 min saliva samples. In between were three days in an ultradian dim light (< 150 lux)–dark cycle (LD 2.5 : 1.5) during which each subject took one pill per day at the same clock time (3 mg melatonin or placebo, double blind, counterbalanced). Each individual’s phase shift to exogenous melatonin was corrected by subtracting their phase shift to placebo (a free-run). The resulting PRC has a phase advance portion peaking about 5 h before the dim light melatonin onset, in the afternoon. The phase delay portion peaks about 11 h after the dim light melatonin onset, shortly after the usual time of morning awakening. A dead zone of minimal phase shifts occurred around the first half of habitual sleep. The fitted maximum advance and delay shifts were 1.8 h and 1.3 h, respectively. This new PRC will aid in determining the optimal time to administer exogenous melatonin to achieve desired phase shifts and demonstrates that using exogenous melatonin as a sleep aid at night has minimal phase shifting effects. (Received 16 August 2007; accepted after revision 9 November 2007; first published online 15 November 2007) Corresponding author H. J. Burgess: Biological Rhythms Research Laboratory, Rush University Medical Center, 1645 W. Jackson Blvd, Suite 425, Chicago, IL 60612, USA. Email: helen j [email protected] The master mammalian circadian clock, contained in 3 h (Zaidan et al. 1994), but the marker of circadian the suprachiasmatic nuclei (SCN) in the hypothalamus, phase, the endogenous melatonin rhythm, may have controls circadian rhythms in a range of physiological been masked by light (< 150 lux before 23.00 h) and and behavioural functions, including the secretion of the infusion of exogenous melatonin. Furthermore, as melatonin from the pineal gland (Moore, 1978). Typically, exogenous melatonin is usually administered orally, this melatonin levels begin to increase a few hours before PRC is less relevant to the typical use of melatonin. A sleep, peak in the early hours of the morning and second PRC was to a 5 mg pill of melatonin, but as the decrease to daytime levels around the time of waking. The authors themselves state, mathematical demasking of the endogenous melatonin rhythm is considered a reliable temperature rhythm may have led to inaccuracies (Arendt marker of the human master circadian clock (Lewy et al. et al. 1999). The most commonly cited PRC to exogenous 1999; Klerman et al. 2002). However, melatonin secretion melatonin is a four pulse PRC generated in six entrained is acutely suppressed by light (Lewy et al. 1980) and so humans (1 m, 5 f) to a 0.5 mg immediate release dose of melatonin must be measured in dim light to accurately melatonin (Lewy et al. 1998). Each subject maintained his reflect the timing of the circadian clock. or her habitual sleep schedule at home for 2 weeks and It has been shown that exogenous melatonin can three times at weekly intervals they visited the laboratory phase shift the circadian clock in rats (Redman et al. to have their dim light melatonin onset (DLMO) assessed. 1983), and in humans (Arendt et al. 1985). Exogenous Subjects were instructed to take a pill once per day, at the melatonin probably produces these phase shifts by binding same time of day when they slept at home. In one week to melatonin receptors in the SCN (Reppert et al. 1988). the pill was always placebo, in the other week the last four To date, three phase response curves (PRCs) to exogenous pills were melatonin. Each subject repeated the protocol melatonin in humans have been published. In one PRC an impressive 12 times; taking the pills at one of 12 clock 20 μg of melatonin was intravenously administered for times spread evenly in 2 h intervals across the 24 h day. C 2008 The Authors. Journal compilation C 2008 The Physiological Society DOI: 10.1113/jphysiol.2007.143180 640 H. J. Burgess and others J Physiol 586.2 The resulting PRC indicates that phase delays are produced Rush University Medical Center Institutional Review when exogenous melatonin is taken in the later hours of Board. All subjects gave written informed consent prior sleep and in the morning. Phase advances result when to participation. Subjects were reimbursed for their exogenous melatonin is taken in the afternoon and early participation. evening. This important PRC has informed studies that have used exogenous melatonin to entrain free-running blind Subjects people (Lockley et al. 2000; Sack et al. 2000), treat delayed Twenty-seven healthy young subjects participated sleep phase syndrome (Nagtegaal et al. 1998; Mundey ± s.d. ± et al. 2005) and facilitate adjustment to night shift work (14 men, 13 women, mean age 28.8 6.9 years, mean body mass index ± s.d. 24.3 ± 2.8 kg m−2). To (Sharkey & Eastman, 2002) and eastward jet travel (Revell −1 et al. 2006). Nonetheless, there are limitations to this restrict the dose of exogenous melatonin (mg kg ), we PRC. These include that there was a large age range in excluded individuals who weighed more than 100 kg. the subjects (27–77 years) and there was no objective Subjects accepted into the study were non-smokers, did not habitually consume large caffeine (≤ 300 mg day−1) confirmation that subjects slept according to their usual ≤ times at home. Additionally, light levels at home were or alcohol doses ( 2 drinks per day) and reported no uncontrolled and some or all subjects may have received medical, psychiatric or sleep disorders as assessed from light during the night when they were required to wake up a telephone interview, in-person interview, medical to take the pill. As even dim light can phase shift the human history and several screening questionnaires: Minnesota circadian clock (Zeitzer et al. 2000), this light exposure may Multiphasic Personality Inventory-2 (Butcher et al. 1989), have confounded the observed phase shifts, particularly Beck Depression Inventory (Beck et al. 1961), Pittsburgh phase delays, to the melatonin. Finally, the effect of the Sleep Quality Index (Buysse et al. 1989), and part of placebo pill in each individual subject was not calculated a general health questionnaire (Tasto et al. 1978). All into the resulting PRC. These issues and the failure of a subjects were free of prescription medication, except single dose of exogenous melatonin to phase delay human three females who used hormonal birth control. A urine circadianrhythms(Wirz-Justiceetal.2002)hasledtosome drug screen confirmed that all subjects were free of questioning of the accuracy of the phase delay portion of common drugs of abuse. None reported taking melatonin this melatonin PRC. Additionally, as different durations supplements. No subject had worked night shifts or flown of light produce differently shaped PRCs (Johnson, 1992; across more than two time zones in the month preceding Comas et al. 2006), it is reasonable to assume that different the study. Morningness–eveningness was assessed (Horne doses of melatonin will produce differently shaped PRCs. & Ostberg, 1976) prior to the start of the study and there Thus the PRC of Lewy et al. (1998) generated with 0.5 mg were four moderate morning types, 22 of neither type melatonin may not indicate the best times to take higher and one moderate evening type. doses of melatonin for maximum phase advances and phase delays. In this study we generated a new PRC to a different Protocol doseofexogenousmelatoninusingadifferentprotocol.We The protocol consisted of two 5 day laboratory sessions administered pills of 3 mg of immediate release melatonin during which subjects lived in the laboratory and did not to free-running subjects. This dose and formulation of go outside (Fig. 1). Each laboratory session had a baseline exogenous melatonin is the most commonly available over phase assessment, 3 days of a 4 h ultradian light–dark (LD) the counter in the US, and is often used as a sleep aid. cycle, and then a final phase assessment. Each subject slept In generating this new PRC we aimed to confirm that at home during 7 days before the first laboratory session exogenous melatonin can phase delay the human circadian and during 9 days in between the two laboratory sessions clock and determine the best times to take this dose of (more details below). The study was a within-subjects, exogenous melatonin for phase advances and for phase counterbalanced design; in one laboratory session delays. We also aimed to determine if any phase shift will subjects took placebo pills and in the other they took occur when this dose is taken close to habitual bedtime, melatonin pills. The melatonin pills contained 3.00 mg when it is used as a sleep aid. of melatonin as verified with HPLC analysis (3 mg, immediate release, Ecological Formulas, Concord, CA, USA). Subjects participated in groups of four, and each Methods group received their pills at the same time of day, but two subjects received melatonin during the first laboratory Ethical approval session and placebo during the second laboratory session, The protocol conformed to the standards set by the while the other two subjects received the pills in reverse Declaration of Helsinki and was approved by the order.
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