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Role of Melatonin in the Regulation of Human Circadian
Rhythms and Sleep
C. Cajochen, K. Kra
¨uchi and A. Wirz-Justice
Center for Chronobiology, Psychiatric University Clinic, Basel, Switzerland.
Key words: chronobiotic, soporific, EEG power density, thermoregulation, sleepiness.
Abstract
The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels.
The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of
the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans,
and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is
evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is
insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce
phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new,
desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a
chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous
melatonin to treat sleep or circadian rhythm disorders.
Endogenous melatonin and the circadian sleep–wake
cycle and thermoregulation
Under entrained conditions, the phase relationship between the
endogenous circadian rhythm of melatonin and the sleep–wake
cycle is such that during the usual 16-h waking day,stable levels of
neurobehavioural function can be maintained. This occurs
because the circadian pacemaker opposes the decrements in
neurobehavioural function associated with increased homeostatic
drive for sleep accumulating with sustained wakefulness. Exten-
sion of the wake episode into the biological night (i.e. past the
evening rise of melatonin) is associated with marked decrements
in neurobehavioural function, because the circadian pacemaker no
longer opposes the wake-dependent deterioration but, instead,
promotes sleep at this circadian phase (1). Thus, shortly after
habitual bedtime, a sharp increase in subjective sleepiness and its
electrophysiological correlates occurs (Fig. 1) (2). This latter
phenomenon has been referred to as ‘the opening of the sleep
gate’ (3). In parallel, the entire thermoregulatory cascade (i.e.
decrease in heat production and increase in heat loss leading to
decrease in core body temperature) starts with the rise in endo-
genous melatonin levels in the evening (Fig. 2) (4). Melatonin
onset seems to be the hormonal signal timing the rise in blood flow
in distal skin regions and hence heat loss, the degree of which
(measured by the distal–proximal skin temperature gradient) is the
best physiological predictor for the rapid onset of sleep (5).
The association of sleep with the melatonin rhythm has been
confirmed in blind people in whom the circadian pacemaker is not
entrained (6, 7) and in sighted subjects with non 24-sleep–wake
cycle syndrome (8, 9). Even more impressive are the results
obtained from studies using the forced desynchrony protocol to
separate out circadian- and wake-dependent components of beha-
viour. The daily circadian increase in melatonin secretion coin-
cides with a decrease in wake episodes during scheduled sleep
episodes (Fig. 3) (10). Sleep consolidation gradually deteriorates
during that phase of the circadian cycle with low melatonin
production. Electroencephalogram (EEG) activation during wake-
fulness is also timed at a specific phase relative to the circadian
melatonin rhythm (11).
These carefully controlled experiments clearly show that the
circadian pacemaker drives the rhythms of melatonin synthesis,
thermoregulation, sleep consolidation and EEG activation during
wakefulness. There may also be feedback from the pineal gland to
both the circadian pacemaker and thermoregulatory centres in the
hypothalamus. The interpretation is that melatonin weakens the
circadian signal from the suprachiasmatic nuclei (SCN), promot-
ing heat loss which induces sleepiness via the preoptic area of the
anterior hypothalamus. Any effect of melatonin on sleepiness and
sleep must be relative rather than absolute, however, because indi-
viduals who secrete no melatonin at all seem to sleep normally (12).
Effects of exogenous melatonin on sleep and
thermoregulation
There is ample evidence for a close temporal relationship between
the melatonin secretory phase and thermoregulation and circadian
Journal of Neuroendocrinology, 2003, Vol. 15, 432–437
#2003 Blackwell Publishing Ltd
Correspondence to: Dr Christian Cajochen, Center for Chronobiology, Psychiatric University Clinic, Wilhelm Kleinstrasse 27, CH-4025 Basel, Switzerland
(e-mail: christian.cajochen@pukbasel.ch).
sleep propensity. However, is melatonin causally involved in sleep
and thermoregulatory mechanisms? Is it necessary, or sufficient?
Initially, the answer is no. The ability to sleep is still possible in the
absence of detectable endogenous melatonin during the day, or in
tetraplegic patients (13), and only a moderate incidence of sleep
disturbance has been reported in pinealectomized patients (14).
Absolute melatonin production (which varies enormously between
individuals) does not correlate with sleep quality in the elderly
(15) or elderly sleep-maintenance insomniacs (16). To our
knowledge, whether thermoregulatory mechanisms are changed
in low melatonin secretors, pinealectomized patients and in trau-
matic spinal cord injury subjects whose melatonin production is
absent, has not been investigated. At least in patients with spinal
injuries above T6, thermoregulation is impaired because of the
interruption of neuronal pathways to and from the hypothalamus
(17). By contrast, numerous laboratory studies under stringent
conditions clearly demonstrate that administration of melatonin
acutely affects sleep and thermoregulation in humans. Therefore,
on second glance, the answer to the question of the causal role of
melatonin would be yes. Exogenous melatonin elicits all the
physiological effects which occur in the evening during endogen-
ous melatonin secretion. Indeed, exogenous melatonin is most
effective when endogenous levels are low during the biological
day. It elicits time-dependent soporific effects, which have been
corroborated with electrophysiological measures of sleepiness
such as electroencephalographic theta activity during wakefulness
(18). The soporific effect is paralleled by a time- and dose-
dependent hypothermic action, mediated by an increase in heat loss
FIG. 1. Time courses of subjective sleepiness as assessed on the Karolinska
sleepiness scale (highest possible score ¼9, lowest possible score ¼1),
plasma melatonin, mean eye blink rate per 30-s epoch during the Karolinska
drowsiness test, incidence of slow eye movements (SEMs, percentage of 30-s
epochs containing at least 1 SEM per 5-min interval), and incidence of stage 1
sleep (percentage of 30-s epochs containing at least 15 s of stage 1 sleep per
5-min interval) are shown, averaged across 10 subjects (SE). All data were
binned in 2-h intervals and expressed with respect to elapsed time since
scheduled waketime. Vertical reference line indicates transition of subjects’
habitual wake- and bedtime. Adapted with permission from Cajochen et al. (2).
FIG. 2. Time courses of subjective sleepiness (forinformation on the Karolinska
sleepiness scale, see Fig.1), core body temperature, distal and proximal
skin temperatures, the distal-to-proximal skin temperature gradient and sali-
vary melatonin in a baseline 7.5-h constant routine followed by a 7.5-h sleep
episode. Continuously measured data are plotted in 30-min bins. Mean values
of n ¼18 subjects (SE). Adapted with permission from Kra
¨uchi et al. (4).
Melatonin, sleep and circadian rhythms 433
#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432–437
(19, 20). In an experiment where we blocked this natural evening
increase in heat loss, subjective sleepiness, and melatonin secre-
tion by light exposure, we could show that melatonin replacement
(5 mg) acutely recovered the evening increase in heat loss, sub-
jective sleepiness and also theta activity in the waking EEG (21,
22). Together, these data suggest a causal relationship between
melatonin and sleepiness, probably mediated by thermoregulatory
mechanisms (4). This supports the hypothesis that the onset of
melatonin secretion might contribute to the rise in sleepiness and
sleep propensity that occurs in the evening. It remains to be
established whether exogenous melatonin acts via the SCN and
the thermoregulatory centres in the preoptic area of the anterior
hypothalamus, or whether it is a peripheral effect on receptors in
the arterio-venous anastomoses, or both.
Quantitative analysis of the sleep EEG based on the fast Fourier
transform (FFT) has revealed that 5 mg melatonin, given shortly
before a daytime sleep episode, suppresses low EEG components
and increases EEG activity in the sleep-spindle frequency range
(23). Interestingly, similar changes in the sleep EEG spectra occur
in sleep during the melatonin secretory phase (biological night)
when compared with sleep occurring outside the melatonin secre-
tory phase (biological day). Two different experimental paradigms
have revealed this: a forced desynchrony protocol (10) and a nap
protocol (24). The two top panels in Fig. 4 illustrate the similarity
in relative EEG power spectra during night-time sleep (high
endogenous melatonin levels) and during daytime sleep after
melatonin administration (5 mg). The bottom panel shows EEG
power density during night-time sleep after melatonin ingestion
(5 mg), which did not differ significantly from a baseline placebo
night-time sleep recording (22). These studies suggest that as soon
melatonin is secreted (biological night), an extra dose of mela-
tonin (5 mg) has no further effect on the spectral composition of
the sleep EEG. Sleep spindles are presumably generated in the
nucleus reticularis of the thalamus (25) and are enhanced by
GABA
A
-receptor agonists (26). The effects of melatonin are, to
some extent, and to a much lower degree, similar to the changes
induced by GABA
A
agonists such as benzodiazepine hypnotics
(27). Both agents increase EEG activity in the frequency range of
sleep spindles. However, given that melatonin’s action (3 mg) on
sleep EEG spectra was not blocked by flumanzenil (10 mg), a
GABA
A
antagonist which blocks benzodiazepine effects, the
mechanisms may be dissimilar (28).
Most studies on the role of melatonin in sleep have been
confined to classical sleep scoring analyses. Therefore, replication
of the above mentioned FFT findings are required. The most
consistent effect found in those studies was that sleep latency was
shorter after melatonin, even at rather low doses (29). On the other
hand, sleep consolidation or sleep efficiency was not affected by
night-time melatonin administration whereas, during daytime, an
improvement in sleep efficiency could be found. Recent data from
a forced desynchrony protocol, where melatonin was given to
healthy young adults across a full range of circadian phases,
confirm that exogenous melatonin can only increase sleep effi-
ciency outside the time window of its normal production (30).
FIG. 3. Phase relationships between the circadian rhythms of plasma
melatonin and sleep consolidation. Data are plotted against circadian phase
of the plasma melatonin rhythm (08corresponds to the fitted maximum,
bottom x-axis). To facilitate comparison with the situation in which the
circadian system is entrained to the 24-h day, the top x-axis indicates the
average clock time of the circadian melatonin rhythm during the first day of
the forced desynchronization protocol (i.e. immediately upon release from
entrainment). Plasma melatonin data were expressed as Z-scores to correct for
interindividual differences in mean values. Wakefulness is expressed as a
percentage of recording time. Data are double-plotted (i.e. all data plotted left
from the dashed vertical line are repeated to the right of this vertical line)
(n ¼7) (SE). Adapted with permission from Dijk et al. (53).
FIG. 4. Effects of endogenous and exogenous melatonin on electroencepha-
logram power density in non-rapid eye movement sleep. For each frequency
bin and subject, the values were expressed either as a percentage of the
corresponding values during daytime naps (top panel) (24) or relative to the
corresponding placebo values (bottom panels) (22, 23). Top panel: adapted
with permission from Knoblauch et al. (24); middle panel: adapted with
permission from Dijk et al. (23); bottom panel: adapted with permission from
Cajochen et al. (22).
#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432–437
434 Melatonin, sleep and circadian rhythms
Similar findings come from an extended sleep protocol. Chronic
administration of melatonin in a slow-release formulation during a
16-h sleep opportunity beginning at 16.00 h resulted in a redis-
tribution of sleep so that sleep efficiency during the first half of the
sleep opportunity was substantially higher during melatonin treat-
ment compared to placebo (31). These two recent studies provide
strong support for the hypothesis that exogenous melatonin
attenuates the wake-promoting signal of the endogenous circadian
pacemaker, allowing for increased sleep efficiency at circadian
phases corresponding to the habitual wake episode. In summary,
endogenous melatonin has an important role in the circadian
regulation of sleep (sleep timing), and exogenous melatonin exerts
effects on the main characteristics of human sleep (i.e. slow
waves, sleep spindles, sleep latency and sleep consolidation).
Effects of exogenous melatonin on circadian rhythms
In a variety of animal species melatonin is a ‘zeitgeber’, which
induces phase shifts and entrainment of the circadian clock
underlying the expression of many 24-h rhythms (32). Melatonin
is also a major entraining signal for the circadian systems of fetal
and neonatal mammals (33). Daily exposure to circulating mel-
atonin allows fetuses to be synchronized with each other and with
their mother long before they can directly perceive the environ-
mental light/dark cycle on their own. Overall, the animal literature
clearly supports the role of melatonin as a chronobiotic.
In sighted humans, under real life conditions, exogenous mel-
atonin may not be able to sufficiently override the most important
‘zeitgeber’light to produce a robust consistent, statistically sig-
nificant phase-shifting effect on the day after administration. An
elegant approach to elaborate phase-shifting capacities of mela-
tonin has been in totally blind people. In such individuals, light/
dark information fails to reach the endogenous circadian pace-
maker. In a proportion of these individuals, circadian rhythms (e.g.
melatonin and core body temperature) do not synchronize with the
environment and free run usually with a period length >24 h.
Recently, it was demonstrated that melatonin treatment (0.5–
10 mg) can entrain the circadian system (melatonin or cortisol
rhythms) of some free-running blind people if initiated at an
appropriate time relative to internal time (34, 35). In addition,
melatonin can stabilize sleep/wake timing even without entraining
the circadian system (36). As for the ‘zeitgeber’light, a number of
studies have begun to delineate a phase–response curve (PRC) for
melatonin. A ‘classic’PRC measures phase shifts following a
single exposure to a ‘zeitgeber’under free-running conditions.
Repeated doses of melatonin do yield a PRC, with the direction of
the phase shift dependent on the time of administration (37, 38).
Unfortunately, in these studies, light, a much more powerful
‘zeitgeber’on the human circadian pacemaker than melatonin,
was not controlled, or was of too high an intensity to provide
unmasked melatonin onset times. However, in a double-blind,
placebo-controlled, crossover study in which subjects were stu-
died under dim light and constant posture conditions, we and
others showed that a single melatonin dose at 18.00 h induced an
advance of the circadian nocturnal decline in core body tempera-
ture (19), heart rate and the dim-light melatonin onset as assessed
on the second day (more than 24 h) after melatonin administration
(39). In the same study, an earlier offset of sleep was observed in
the second night after melatonin administration. Because this
sleep episode was initiated 29 h after melatonin administration,
these effects have been interpreted as reflecting a phase advance of
the circadian timing system similar to the effects of bright light
exposure in the morning hours (40). Interestingly, in our similarly
designed constant routine study of 5 mg melatonin given in the
morning (07.00 h), no evidence for a phase delay in the above
circadian rhythms was found (41). This means that either we have
missed the appropriate timing for a phase delay [selected accord-
ing to Zaidan et al. (37)] which might be later in the morning (i.e.
after endogenous melatonin levels had declined) or that the dose
was too high and overlapped into the phase advance portion of the
hypothetical PRC. To our knowledge, there is only one other
randomized, double-blind, placebo-controlled trial under con-
trolled light conditions that investigated the capacity of melatonin
to induce phase delays. The authors reported delays in the onset of
the melatonin secretory phase after administration of melatonin at
07.00 h; however, no significant phase shift in the offset of
secretion could be determined (42). These data suggest that it
is difficult to phase delay human circadian rhythms by exogenous
melatonin. In fact, the evidence that melatonin has phase-delaying
effects (>30 min) in humans is based on very limited data (38). It
appears that the precise timing of melatonin administration is
crucial in order to exploit its chronobiotic properties. Therefore,
there is an urgent need for a complete PRC for a single dose of
melatonin carried out under stringently controlled laboratory
conditions.
Implications for the treatment of insomnia and
circadian rhythms disorders
The soporific and chronobiotic properties of melatonin make it an
optimal candidate for treating sleep, in addition to circadian
rhythm disorders. In our view, the most successful attempt to
treat insomnia and changes in circadian phase position by mel-
atonin has been carried out in free-running blind people. Optimal
melatonin treatment in those people should utilize not only its
soporific effects by administration close to the desired bedtime,
but also its chronobiotic properties, in order to entrain sleep/wake
behaviour (43). Another promising patient group are elderly
patients with insomnia. However, compared to the excellent
studies in the blind, randomized, double-blind, placebo-controlled
trials are rare (n ¼6). In those six studies, the results of melatonin
treatment (0.5–6 mg) administered before bedtime were not con-
sistent: sleep latency decreased in four studies and sleep efficiency
improved in three studies, whereas subjective sleep quality did not
improve in any of the studies (44). Reviewing 78 articles on
melatonin treatment in elderly insomniacs, Olde Rikkert and
Rigaud (44) concluded that melatonin is most effective in elderly
insomniacs who chronically use benzodiazepines and/or with
documented low melatonin secretion during sleep.
Abnormal timing of sleep with respect to circadian phase occurs
in the delayed sleep phase syndrome (DSPS), in which sleep
occurs at a delayed clock time relative to the light/dark cycle,
social, work, and family demands. In the first use of melatonin in
patients with DSPS, it was found that, when administered 5 h
before sleep onset for a period of 4 weeks, melatonin (5 mg)
advanced sleep onset and wake times compared to placebo
(45). A more recent study confirmed this, showing that melatonin
induces an advance in sleep onset in patients with DSPS (46), and
is most effective in DSPS patients with shorter habitual sleep time
and later clinical onset (47).
#2003 Blackwell Publishing Ltd, Journal of Neuroendocrinology,15, 432–437
Melatonin, sleep and circadian rhythms 435
The first application of melatonin using chronobiological prin-
ciples was to alleviate the perceived effects of jet lag. There have
been many placebo-controlled and uncontrolled studies that have
recently been summarized by Cochrane (48). This stringent ana-
lysis concludes that nine of 10 trials of melatonin, taken close to
the target bedtime at destination, decreased jet lagsymptoms arising
after flights crossing five or more time zones. One difficulty in
using melatonin for jet lag is that its use may require adminis-
tration at times when it will have undesired soporific properties.
There is also a great interest in whether melatonin can facilitate
phase-shifting in night-shift workers; however, few studies have
measured such phase shifts. In two laboratory studies, circadian
rhythms were measured before and after a large shift in the sleep/
wake schedule (49, 50). Melatonin (5 mg) was administered
during the phase-advance portion of the PRC and produced larger
circadian phase shifts than placebo (49). In the other study,
subjects took 4 mg melatonin (or placebo) before and during their
daytime sleep (50) and melatonin did not produce a larger phase
delay than placebo. In a night-shift field study, melatonin pro-
duced larger circadian phase shifts than placebo in only seven of
the first 24 subjects studied (51). Overall, these studies do not
provide strong evidence that melatonin can help phase shift the
circadian rhythms of night-shift workers, in particular, when
comparing its action as being less strong than exposure to light.
One problem has been the lack of control over time of melatonin
administration, and of the subjects’sleep schedules. In a recent
study where the timing of melatonin administration, the sleep/
wake schedule and, to some extent, the light/dark cycle could be
controlled in a field setting, melatonin produced larger phase
advances than placebo in the circadian rhythms of melatonin and
core body temperature (52). Additional caution is required in this
setting to avoid the soporific effects of melatonin during work
requiring vigilance, or driving home after the shift.
Conclusions
A remarkably tight association between the circadian rhythms of
melatonin and sleep propensity and thermoregulation has been
described in humans. Together with the observation that daytime
administration of melatonin increases sleep propensity and
decreases core body temperature via heat loss induction, this
suggests that melatonin has direct effects on sleep-inducing
thermoregulatory mechanisms. The circadian rhythm of melato-
nin secretion may be part of the pathway by which the circadian
pacemaker drives the circadian rhythm of sleep propensity, sleep
structure and core body temperature.
There is clear evidence that melatonin induces phase shifts,
particularly phase advances, in human circadian rhythms, and pre-
cisely-timed melatonin can be useful for the treatment of insomnia
related to jet lag or shift work. However, there is the need for a
detailed PRC to single doses of melatonin in humans under
stringently-controlled laboratory conditions. Furthermore, further
studies are required using physiological doses and/or delivery
systems that generate ‘natural’melatonin profiles, while at the
same time scheduling sleep at a variety of circadian phases to
establish the role of melatonin in the circadian regulation of sleep.
In summary, the combined circadian and soporific properties of
melatonin make it an attractive tool not only for basic circadian/
sleep research, but also as an attractive candidate for the treatment
of sleep disorders related to inappropriate circadian timing.
Acknowledgements
C.C. is supported by Swiss National Foundation Grants START # 3130-054991.98
and #3100-055385.98.
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