Clinical ReviewMelatonin as a chronobiotic
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 disorder, 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 melatonin 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’, i.e. expressing the natural period of their internal clock. To what extent the effects of melatonin on the SCN dictate overt changes in circadian rhythms remains to be determined. Likewise direct effects of melatonin masking on overt rhythms may well feedback to modify SCN activity. The receptors involved in these effects remain to be properly characterised in humans. This review will evaluate the evidence for phase shifting and entrainment by melatonin, the influence of dose, timing of treatment and formulation, and the therapeutic applications of these properties.
Section snippets
Production and physiological role of melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is synthesised primarily in the pineal gland of mammals. It is secreted with a robust circadian rhythm, which in all species, whether nocturnal or diurnal, normally peaks during the dark phase of the day (Fig. 2). The rhythm is generated in the SCN and synchronised (entrained) to the 24 h day largely by the alternation of light and darkness. Light exposure during the dark phase also suppresses melatonin production.1 Light of suitable intensity, spectral
Phase response curves
A stimulus of any nature, which shifts circadian rhythms is known as a zeitgeber (time cue).18 Zeitgebers advance or delay circadian rhythms according to the time they are experienced. The direction and magnitude of the change in timing (phase shift) is described by a phase response curve (PRC). The time base of a PRC is ‘circadian time’ (CT) which is effectively internal biological time usually defined in humans by the timing of the core body temperature rhythm or melatonin secretion (see Fig.
Dose and formulation
The question of appropriate dose and formulation of melatonin for the adjustment of circadian rhythms has not been resolved. Most information derives from fast release preparations. Acute phase advances derived from single dose administration at 17:00 h, in normally synchronised individuals, are clearly dose dependent with respect to sleepiness, endogenous melatonin and cBT (core body temperature), in the range of 0.05–5 mg in controlled conditions (dim light, 50 lux, recumbency following the
Phase shift conditions: jet lag and shift work
Melatonin administered from about 6 h before to about 4 h after the initial onset of endogenous secretion will normally induce an advance shift of sleep, cBT and the endogenous melatonin rhythm. Delays occur when melatonin is given on the declining phase of the endogenous rhythm such as to extend high levels into the morning hours. There are minor differences between authors and rather large individual differences. The scatter of data is such20 that it is difficult to determine precise times
Therapeutic benefits in the blind
There is no doubt that melatonin treatment improves sleep in blind subjects suffering from non-24 h sleep–wake disorder.38., 42., *44., *47. It is probably the treatment of choice in this situation, and may in future be combined with behavioural therapy with regard to reinforcing the treatment by appropriate behaviour, e.g. regular bedtime and structured daytime activities. In principle entrainment of all circadian rhythms is desirable for optimising the treatment effects. However, sleep
Delayed sleep phase syndrome
The ability of exogenous melatonin to phase advance circadian rhythms suggests that it will be effective in the treatment of instrinsic DSPS. In the first placebo controlled crossover study, melatonin (5 mg fast release) was given at 22:00 h (5 h before sleep onset) to eight men with DSPS.68 Compared to placebo, melatonin advanced sleep onset and wake time (P<0.01). Later studies using 5 mg melatonin have agreed with the first report.69., *70., 71. Nagtegaal et al.70 demonstrated beneficial
Future
There is no doubt that melatonin has chronobiotic properties, as well as the ability to induce transient sleepiness or sleep. Very few reports of deleterious effects exist, however the vast majority of subjects have been normal healthy volunteers and experimenters use rigorous exclusion criteria. The safety of melatonin in long-term use has still not been evaluated. Little is known of possible drug interactions with melatonin. In virtually all of the applications described here the dose,
Acknowledgements
This review was written during the tenure of grants from the Health and Safety Executive (UK), the Institute of Petroleum (UK), the Antarctic Funding Initiative, the BBSRC, the European Union Framework 5 (QLK6-CT-2000-00499) and the National Grid plc (UK).
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- 1
Tel.: +44-1483-689706; fax: +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.