Invited Symposium: Pineal and its Hormone Melatonin
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The pineal hormone melatonin has been the subject of much recent publicity as a universal panacea and anti-aging treatment (1). Whilst there is good evidence for its potential use in disorders of biological rhythms, many of the other claims remain unsubstantiated. The result of media coverage has been that in countries such as the USA where it is freely available, it is reportedly consumed in huge quantities (2). Whether or not in the long term this is harmful remains an open question. Short term safety evaluations of melatonin have shown very low toxicity (3) but there is no long term safety data. In order to interpret the effects of melatonin it ism important to appreciate its physiological functions.
Melatonin has a major physiological function in mammals: the transmission of information about daylength for the organisation of daylength dependent seasonal functions (4). Evidently the importance in a given species depends to the extent on which that species is daylength dependent. Humans are not markedly seasonal but nevertheless they show evidence of residual photoperiodic effects in a number of ways.(5). Some powerful seasonal effects in sub human mammals include stimulation or inhibition of the reproductive system and there is certainly evidence for reproductive effects (largely inhibitory) in humans (4).
There is however very little evidence for an important function of melatonin in adult humans even though in the neonatal period it may be capable of a long term influence on circadian rhythmicity (6). A possible physiological role for melatonin in the organisation and timing of human sleep is suggested by a number of lines of correlative evidence (7). Possibly the most convincing are observations of sleep in blind subjects. Many visually impaired subjects and especially those with no light perception at all show 'free running' circadian rhythms of sleep, core temperature melatonin and cortisol secretion (8,9,10). Thus depending on individual periodicity the peak of melatonin secretion occurs intermittently during the daytime when it is strongly associated with a tendency to 'nap'. Similarly in abnormally synchronised subjects, a daytime peak of melatonin is associated with sleepiness or sleep (11). Free running sighted individuals show strong coupling between 'sleep propensity' and the melatonin peak, and sleep deprived subjects show coupling between 'maximum fatigue' and the melatonin peak (12). However melatonin is clearly not essential for the maintenance of circadian rhythms in a normal environment. Many humans take beta blockers which suppress the melatonin rhythm (13) but, whilst there are some reports of sleep disturbance this is not apparently a major problem. There is reason to believe that if the pineal or melatonin are absent, compensatory systems must operate. If however melatonin is present but with an abnormal rhythm it may cause problems.
Probably most information concerning the potential role of melatonin has been derived from its administration and early therapeutic use (4). The influence of melatonin on human circadian rhythms together with its acute effects on sleep, body temperature and performance have been extensively investigated. Aaron Lerner who first discovered melatonin in 1958 (14), was the first to report that ingestion of pharmacological amounts leads to loss of alertness/increased sleepiness during the hours following ingestion (15) Further early investigations reported effects on the EEG which proved controversial (16). Only when the importance of treatment timing was recognised was it possible to show that melatonin changes sleep timing, initially by showing advance of sleep or sleepiness when it is taken in the early evening (17).
The current upsurge of interest in the therapeutic potential of melatonin together with improvements in technology has lead to careful investigations of its effects on the EEG. It is probably too early to state a consensus view but several recent publications report that it is able in acute pharmcological doses to increase the high frequency EEG bands and possibly to decrease slow wave sleep given both in the daytime and in the evening (18, 19). Claims that in very low doses (0.1-0.3 mg) it is an effective sleep inducer (20), decreases wake after sleep onset and shortens sleep onset latency remain somewhat controversial and initial reports of therapeutic success in the elderly, for example, have been contradicted (21, 22).
In suitable conditions (seated or recumbent in a warm environment in dim light) it undoubtedly lowers body temperature in a dose dependent manner, in parallel with the increase in subjective sleepiness already mentioned (23,24). However relatively active subjects taking melatonin during the evening do not consistently show temperature changes in the author's experience.
Following evening (1700-1800h) ingestion (>0.5mg) in a controlled (dim light) but entrained environment, there is a dose dependent advance of sleep timing the same evening together with an increase in subjective sleep quality (24) and a lengthening of the first REM episode (25). During the next 24h there is an advance of the core temperature and endogenous melatonin rhythms (24). In an uncontrolled environment the same treatment provokes a significant advance of sleepiness or sleep, together with core temperature, cortisol and prolactin only after repeated dosing (3-6 days), presumably because of conflicting environmental zeitgebers (26, 27 and unpublished data). All of these observations are consistent with a circadian effect of melatonin : that it has acted to shift the timing of the central pacemaker (28).
Phase delays are seen following 'circadian' early morning administration both in an entrained environment and in free run and a phase response curve can be generated with peak advances just before core temperature maximum and peak delays shortly after core temperature minimum (29, 30, 31). The shape is an approximate mirror image of the light PRC reinforcing the concept of melatonin as a darkness hormone.
Since a PRC can be constructed it would be reasonable to assume that melatonin can fully entrain all human circadian rhythms. However to date such is not the case. It is an irony of melatonin research that much basic information has been derived from early therapeutic approaches in humans (4). One such was the demonstration that it would hasten adapatation of the endogenous clock to phase shift (both delay and advance) in jet lagged travellers (32, 33, 34) and in simulated phase shifts (34). This led directly to the delimitation of the PRC. Another was the successful use to entrain the sleep wake cycles of free running blind people to a 24 hour period (35, 36). However it was noted that whilst sleep wake could be entrained the more strongly endogenous rhythms of core temperature cortisol and endogenous melatonin were not entrained (with the possible exception of one subject) (36, 37, 38). Thus there was reason to conclude that at least in the dose and timing ranges studied melatonin was not as strong a time cue as light. The acid test for the ability to synchronise rhythms is entrainment from a free run.
Recently in collaboration with the MoD/DERA we have had the opportunity to investigate the effects of daily melatonin administration in normal sighted human volunteers free running in continuous very dim light (31). Ten normal healthy men were maintained in identical conditions in two separate groups in partial temporal isolation under constant dim light (<8lux) for two periods of 30 days.with attenuated sound and ambient temperature variations. Importantly the subjects had access to a digital clock recording real time. Knowledge of clock time is essential to timed drug administration during free run so that subjects are not disturbed by experimenters entering the unit at specified treatment times. In these circumstances the majority of individuals free run with a mean period (tau) of 24.3h (39). This tau is substantially shorter than the average tau for human circadian rhythms reported by Wever and colleagues (40), but is consistent with recent data from Campbell et al, and Czeisler et al.(41, 42) In a double blind, randomised cross-over design subjects received 5mg melatonin at 2000h for the first 15 days (melatonin 1st) followed by placebo for the second 15 days (placebo 2nd) or vice versa (placebo 1st, melatonin 2nd) during leg 1 with treatment being reversed in leg 2. The variables measured were melatonin (as 6-sulphatoxymelatonin), rectal temperature (every 6 minutes by rectal probe), activity and sleep (actigraphy and logs). Temperature was demasked mathematically.
Nine out of ten subjects showed free running rhythms in all variables (i.e. tau was significantly different from 24h by cosinor and regression analysis) when placebo was given for the first 15 days, whilst melatonin for the first 15 days stabilised the sleep wake cycle to 24h in eight of ten individuals. Two subjects showed highly irregular sleep with melatonin first and throughout the period of melatonin administration. Sleep consolidated rapidly on changing to placebo administration. In some subjects there was a shortening of the period of the temperature rhythm without synchronisation.
Melatonin, taken after a 15 day period of free run under placebo (melatonin 2nd) induced phase advances in five subjects, phase delays in two subjects and stabilisation of the sleep wake cycle in two subjects, (one subject was lost to the trial during this leg). Subsequently synchronisation of the sleep wake cycle to 24h was found in the majority (7/9) of individuals. Temperature continued clearly to free run in four subjects.
The obvious explanation for these heterogeneous results was the fact that melatonin was given at different circadian times in each subject depending on their individual free running period. Thus we calculated the time of administration relative to core temperature maximum. Maximum phase advances in core temperature were seen when the first melatonin treatment was given approximately 2 hours after the temperature acrophase and phase delays were seen with administration times 5-6 hours before core temperature maximum. These data, plotted as a conventional PRC are similar to the PRCs reported by Lewy et al and Claustrat et al (29, 30) using endogenous melatonin as a phase marker, but with a higher amplitude (31).
It is important to note however that whilst phase shifts in temperature were present, apparent synchronisation was not consistent. Moreover where the periodicity of temperature was clearly free running, the tau was shorter than that found with placebo 1st. We consider it is likely that even when apparent synchronisation of temperature was seen that the effect may well have been a shortening of tau to a period indistinguishable from 24h in this short time series. Long term studies of a blind man taking 5 mg melatonin daily have also shown synchronisation of sleep with shortening of temperature tau (43). Long term studies of a free running sighted man receiving daily melatonin in a normal environment also suggest shortening of tau rather than synchronisation (44). To what extent synchronisation of sleep is a masking effect i.e. immediate sleepines induction, rather than a circadian effect on the timing mechanisms of sleep remains an open question.
The two subjects who showed highly irregular sleep with melatonin as a first treatment raise some interesting and potentially very important questions. The initial melatonin treatment was given closer to core temperature maximum in these subjects compared to the majority of the others.
We wished to confirm this observation and performed a second shorter experiment with six subjects maintained in identical conditions. They completed a three day baseline in a normal light dark cycle (dark/sleep 2300-0700) and then took melatonin at 2000h for six days again as a double\blind crossover against placebo. These conditions were devised to time administration to within two hours of core temperature maximum. Again two subjects showed highly irregular sleep. Thus of 16 subjects taking melatonin in continuous dim light, 4 have shown this effect (45).
These observations clearly do not fit a simple model of melatonin action and evidently they need to be confirmed in a larger number of subjects. There may be an analogy with the “squashing” of the amplitude of T and cortisol and large phase jumps of the circadian system induced by bright light given at or very close to T min in a constant routine (46). Conceivably melatonin may provoke a similar response if suitably timed with respect to the sleep wake cycle. Another possible explanation may involve interactions of the circadian and homeostatic components of sleep whereby a complex combination of sleep induction by out of phase melatonin goes some way towards compensating sleep debt and a subsequent bout of sleep occurs due to the circadian component of sleep (Process C, 47) which itself may then be shifted by the melatonin administration.
However if melatonin is considered to be primarily a photoperiodic signal yet other possible interpretations are suggested. In most species melatonin secretion is related to the length of the night: the longer the night the longer the duration of secretion (4). If humans are kept strictly in darkness for 14 hours per day for a period of two months, the melatonin secretion pattern expands to cover almost the entire dark period and concomitantly, in extended periods of 16 hours of light, the rhythm contracts. In these conditions sleep is consolidated into two primary blocks with a period of wakefulness between the episodes (5). This is consistent with animal data. The sleep wake cycle is not always a consolidated block in very long or very short days or in constant conditions in animals. The phenomenon of splitting occurs (48). Effectively sleep occurs in two major episodes. Underlying this phenomenon are two theoretical oscillators, the evening (E) and morning (M), or dawn and dusk oscillators. In constant conditions they may uncouple spontaneously and run with different periods. In changing daylength they may remain coupled but as dawn occurs later and dusk occurs earlier with decreasing daylength they move apart and with increasing daylength they move together. The phase relationship will determine whether one or two episodes of sleep occur. There is reason to believe that the evening onset of melatonin is associated with the E oscillator and that the morning decline is associated with the M oscillator (49). Moreover in sufficiently long nights melatonin also shows evidence of splitting. Two peaks are seen in both sheep and humans, in the latter case extended periods of 16h darkness per day are necessary to show this clearly although two (and even three) peaks are not unknown in a normal environment (50, 51).
The fragmentation of sleep with melatonin treatment may represent spontaneous uncoupling of 2 (or more) oscillators, although it did not occur in the same subjects in the same conditions with placebo administration or in the same subjects in the same conditions with different circadian treatment times. Melatonin given close to temperature maximum affects the E oscillator (marked by onset of melatonin secretion) more than the M oscillator (marked by offset) (26, 27) and in consequence we consider that the timing of treatment may have induced such a large phase advance of E that it became dissociated from M.
The effect if confirmed may be dose related as well as circadian time related in that maximum phase advancing treatment may increase the likelihood of fragmentation. Whatever the explanation it is clear that this phenomenon would be highly undesirable if consolidated sleep and alertness is required. Moreover if human sleep is indeed controlled by two or more oscillators, theories of sleep regulation (e.g. the two process model) may have to be revised. Finally a strategy of splitting sleep into two components with melatonin may lead to more rapid adaptation to phase shift by advance of the E and delay of the M component.
These observations are important in view of the widespread self medication with melatonin in the USA, the substantial interest in melatonin for adapting to phase shift and optimising sleep and performance, and the potential therapeutic use of melatonin in various sleep and other disorders. They require confirmation and evaluation. Whatever the explanation it is clear that melatonin does not act as a conventional sleep inducing drug.
In general work to date suggests melatonin is primarily a chronobiotic with weak zeitgeber effects. It reinforces physiology and behaviour associated with darkness (in humans sleepiness, lowering of core temperature). It is able to phase shift sleep, endogenous melatonin and core temperature but is unable to synchronise core temperature consistently. In the majority of subjects sleep wake can be synchronised. The differential effects of melatonin on temperature and sleep suggest either different target control systems or a major contribution to the sleep response of acute temperature suppression, mild sleepiness and lowered alertness at the appropriate circadian phase.
Work described herein was supported primarily by the MoD, the Servier company, the MRC, The South Thames Regional Health Authority, Stockgrand Ltd, and The Wellcome Trust. Reproduced from Arendt J. Complex effects of melatonin. Medicographia 1998;20:120-127. Copyright © Les Laboratoires Servier. Updated version. With permission.
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