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Melatonin as a hypnotic: Con
Sleep Medicine Reviews (2005) 9, 71–80
www.elsevier.com/locate/smrv
CLINICAL REVIEW
Melatonin as a hypnotic: Con Cameron J. van den Heuvela,*, Sally A. Fergusona, M. Mila Macchib,1, Drew Dawsona a
Centre for Sleep Research, University of South Australia, 5th Floor, Basil Hetzel Institute, The Queen Elizabeth Hospital, 11–23 Woodville Road, Woodville, SA 5011, Australia b New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University, Unit 50, 1051 Riverside Drive, New York, NY 10032, USA KEYWORDS Melatonin; Hypnotic; Sleep; Soporific; Exogenous; Endogenous; Circadian rhythms
Summary The physiological roles of melatonin are still unclear despite almost 50 years of research. Elevated melatonin levels from either endogenous nocturnal production or exogenous daytime administration are associated in humans with effects including increased sleepiness, reduced core temperature, increased heat loss and other generally anabolic physiological changes. This supports the idea that endogenous melatonin increases nocturnal sleep propensity, either directly or indirectly via physiological processes associated with sleep. The article “Melatonin as a hypnotic—Pro”, also in this issue, presents evidence to support this viewpoint. We do not entirely disagree, but nevertheless feel this is an overly simplistic interpretation of the available data. Our interpretation is that melatonin is primarily a neuroendocrine transducer promoting an increased propensity for ‘dark appropriate’ behavior. Thus, it is our view that exogenous melatonin is only hypnotic in those species or individuals for which endogenous melatonin increases sleep propensity and is consequently a dark appropriate outcome. Evidence supporting this position is drawn primarily from studies of exogenous administration of melatonin and its varied effects on sleep/wake behavior based on dose, time of administration, age and other factors. From this perspective, it will be shown that melatonin can exert hypnotic-like effects but only under limited circumstances. q 2004 Elsevier Ltd. All rights reserved.
Introduction Abbreviations: EEG, electroencephalograph; (GABA)A, gaminobutyric acid receptor complex; NREM, non-rapid eye movement (sleep); REM, rapid eye movement (sleep). * Corresponding author. Tel.: C61-8-8222-6624; fax: C61-88222-6623. E-mail addresses: [email protected] (C.J. van den Heuvel), [email protected] (S.A. Ferguson), [email protected] (M. Mila Macchi), [email protected] (D. Dawson). 1 Tel.: C1-212-543-5469; fax: C1-212-543-6540.
The initial isolation of the pineal hormone melatonin1 marked the start of an increasing research effort to identify the endogenous role of melatonin and the mechanisms by which it regulates the physiology of both mammalian and non-mammalian species. While our current understanding of melatonin has therefore increased substantially, especially regarding melatonin’s involvement in the circadian timing system, the putative role that
1087-0792/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2004.07.001
72 endogenous melatonin may play in regulating sleep and how this role is mediated remains unclear. In diurnal species, the nocturnal production of melatonin and occurrence of sleep are closely related. In humans, the onset of melatonin production typically coincides with an increase in the propensity to fall asleep (sometimes termed the ‘sleep gate’) and follows a forbidden zone for sleep in the early evening.2 This relationship may not be purely coincidental. Under conditions that force the circadian system to free run (i.e. an ultra-short sleep/wake cycle), the onset of melatonin production and the timing of the sleep gate have been observed to remain time-locked to each other.3 While such data do not confirm a causal role of endogenous melatonin in the regulation of normal sleep/wake behavior, they are generally consistent with studies examining the effect of exogenous melatonin on sleep propensity.
Potential mechanisms by which melatonin may increase sleep propensity Whether melatonin regulates sleep/wake behavior by increasing sleep propensity or by inhibiting wakefulness,4 studies with daytime oral administration of either melatonin or hypnotics typically show that increased sleepiness occurs in association with decreasing core temperature.5–8 In contrast, agents such as caffeine, amphetamines, nicotine and cocaine decrease sleepiness and increase body temperature.9 This association has been documented in humans for at least half a century, leading to consistent suggestions that circadian changes in body temperature, at least partly mediated by endogenous melatonin secretion, are involved in the regulation of sleep/wake behavior.9–11 Nevertheless, evidence of a causal link between core hypothermic effects and sleep-induction following ingestion of melatonin is lacking and should be addressed in future research. In addition, it has been suggested that melatonin may exert sleeppromoting effects via indirect chronobiotic effects on the circadian timing system12 or directly through occupation of the g-aminobutyric acid (GABA)A receptor complex, although there is some evidence that central GABA receptors are not involved in mediating melatonin’s effects in humans.13 While it is important here to introduce possible mechanisms, a detailed exploration is, however, beyond the scope of the current paper. This review instead aims to examine the evidence that is inconsistent with melatonin acting as a hypnotic agent when administered exogenously.
C.J. van den Heuvel et al. While ingested melatonin may sometimes have effects compatible with a hypnotic mode of action, we contend that these are only apparent under a limited set of circumstances. In Section 3, we briefly present some evidence that has historically led to suggestions that melatonin possesses significant hypnotic effects. However, we anticipate that this area will be covered extensively in the article “Melatonin as a Hypnotic—Pro”, also in this issue. Thereafter, we present some key exceptions to the rule, or in other words, evidence that supports the suggestion that melatonin may be hypnotic, but only under specific conditions. In particular, we present evidence from various studies suggesting that the effects of exogenous daytime melatonin are attenuated or absent completely in nocturnal species, at physiologically relevant levels, at different times of the day or phases of the menstrual cycle, in conditions not conducive to sleep or where there is motivation not to initiate sleep, and in elderly individuals and insomniacs.
Hypnotic-like effects following melatonin administration In a letter to the editor of the Journal of Sleep Research, Wirz-Justice and Armstrong14 referred to a hypnotic as, “A drug which produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electroencephalogram (EEG) characteristics, and from which the recipient can be aroused easily”. They point out, however, that the classical hypnotic drugs (e.g. benzodiazepines) do not fully comply with this definition, as the sleep-induced does not typically resemble ‘natural’ sleep. Specifically, benzodiazepine administration typically decreases the amount of REM sleep, slow wave sleep and EEG power in the delta and theta range when compared with normal (unmedicated) sleep. In addition, with increasing dose hypnotics tend to produce greater sedation and eventually, coma and death. This appears not to be the case with melatonin, as even with large pharmacological doses15,16 no involuntary loss of consciousness has ever been reported. In any case, Wirz-Justice and Armstrong14 favor the term soporific to hypnotic in description of melatonin’s effects on humans, and we use it hereafter to refer specifically to its ability to increase sleep propensity and induce sleep. Studies with human volunteers to whom melatonin has been administered exogenously, typically report a dose–response effect on sleep propensity across doses that produce physiological and low
Melatonin as a hypnotic: Con supraphysiological circulating levels. This is unlike the benzodiazepine hypnotics, which cause a proportionally higher sleep-inducing response with increasing dose. Daytime oral melatonin doses that elevate plasma melatonin into the supraphysiological range often result in closely associated acute hypothermic effects and hypnoticlike effects5–8,13 but not always.17 In general, melatonin administered orally at doses above 0.5 mg will produce blood levels in the pharmacological range (i.e. above the normal nocturnal production range of around 30–200 pg mlK1).18 However, this varies greatly between individuals due to variable first-pass metabolism19 and also depends on the speed of release of the preparation. In addition, there have been no systematic attempts in previous studies to administer a consistent dose by subjects’ body weight, which may also contribute to the large variability in circulating levels following oral melatonin ingestion. In most studies, melatonin has demonstrated soporific effects only at oral doses of 0.1–0.3 mg or more.6–7,20–22 However, these effects are generally subtle, typically including a shorter latency to sleep onset but not changes to the architecture of subsequent sleep bouts. In addition, most studies have given doses that elevate peak melatonin levels above the nocturnal physiological range. For example, 5 mg oral melatonin administered during the daytime (12:00, 17:00, 19:00 or 21:00 h) subsequently shortened latency to sleep onset at each time,3 but the effect became increasingly rapid with later times of ingestion. Also, at each trial, ingestion of melatonin was observed to increase theta and delta power, while decreasing wakefulness (alpha activity) compared to placebo. The authors concluded that melatonin did indeed display some hypnotic properties, but that the effects in humans were time-dependent, increasing in proportion with later administration into the evening. A study by Hughes and Badia20 found that doses of 1, 10 and 40 mg all reduced sleep onset latencies when administered at 10:00 h. While significant, note that the reduced sleep latencies were of quite a small magnitude, from 4.8G0.9 (placebo) to 2.9G0.4 (1 mg), 2.6G0.4 (10 mg), and 3.2G 0.4 min (40 mg), respectively. A similar study using oral administration of melatonin at 09:30 h was only effective at a dose of 9 mg and not 3 mg.23 In this instance, however, only six young male subjects were studied suggesting insufficient power may have been responsible for a lack of statistical significance. Finally, at doses of 0.3 and 1 mg, melatonin was also found to significantly reduce sleep latencies when given in the evening at 18:00, 20:00 and 22:00 h.21
73 In summary, studies of melatonin that result in circulating levels at or above the observed endogenous production, typically find significant objective and subjective increases in sleepiness when given to healthy young adults with ‘normal’ sleep. Furthermore, in the majority of these studies, only latencies to sleep onset were significantly impacted while sleep architecture (where examined) is largely observed to be unaffected, or have only subtle changes in stages 1 and 2 sleep at the expense of wakefulness (i.e. stage 0). Melatonin can therefore be seen to be hypnotic or at least soporific, as it may not exactly mimic the EEG characteristics of normal nocturnal sleep in closely controlled laboratory studies in humans. In the following sections, however, we explore several exceptional circumstances that provide evidence against melatonin acting as a hypnotic substance.
Exception 1: Nocturnal versus diurnal species The most prominent feature of melatonin production is that it has been found to occur only during the hours of darkness in all species in which it has been studied. The endogenous nocturnal production of melatonin and its association with physiological and behavioral changes associated with the nocturnal period has led to it being dubbed variously the ‘chemical expression of darkness’24 and the ‘hormone of darkness’.25 The secretion of melatonin in humans coincides with systematic changes including increased sleepiness, lowering of core temperature, increased heat loss, decreased cardiovascular output and enhanced immune responsiveness. However, it has been suggested that nocturnal species have evolved to use the stable, nocturnal timing signal provided by melatonin to promote wakefulness and motor activity, increase core temperature and sustain other catabolic processes.26 Whereas the evening rise in melatonin secretion has been suggested to act as a ‘gating’ mechanism for sleep onset in humans,2 in nocturnal animals entrained to normal light/dark schedules melatonin production coincides with the major period of wakefulness and motor activity.27 Together, the evidence from naturalistic observations supports the suggestion by Mendelson and co-workers28 that the endogenous role of melatonin may be to enhance behaviors normally associated with night in both diurnal and nocturnal species. In other words, melatonin can be viewed as a neuroendocrine transducer promoting an increased propensity for ‘dark appropriate’ behavior.
74 Experimental evidence that melatonin is involved in promotion of wakefulness in nocturnal laboratory animals such as rats and hamsters, generally supports this suggestion. For example, surgical excision of the pineal gland, locus of mammalian melatonin production, causes a significant but modest increase in the amount of NREM sleep in rats,29 consistent with the loss of endogenous melatonin production increasing sleep propensity. It has also been recognized for 30 years that pinealectomy in rats reduces the amplitude of the sleep/wake circadian rhythm, which is to say that the ratio of sleep during the day to that at night, normally a factor of 2–3, is significantly reduced and sleep periods becomes more equally distributed across the 24-h day.30 The role of melatonin in sleep has also been investigated directly by administering the hormone in rats. Amongst the earliest studies of this kind, Mendelson and co-workers28 injected rats with melatonin at a dose of 833 mg kgK1 , a large pharmacological dose but comparable to those used in contemporary human studies. Melatonin given at 07:45 h, just prior to the lights coming on at 08:00 h for 12 h, was observed to decrease total sleep time by an average of 52 min, mainly at the expense of NREM sleep (48 min). A comparative increase in wake after sleep onset was consistent with melatonin decreasing sleep propensity in these nocturnal animals. In a separate group given melatonin at 19:45 h, when endogenous melatonin production was expected to be increasing, no significant effects on sleep architecture were observed. Referring to earlier experiments with other species, the authors concluded that melatonin (given during the day) may induce “the customary nighttime behavior for each species (waking for the rat, sleep for humans and chickens)”. Subsequent studies of melatonin’s effects on sleep in rats produced contradictory results, ranging along a continuum from sleep promoting to sleep reducing effects.31,32 More recent reports, however, typically fail to find significant effects of melatonin on brain temperature or sleep architecture in nocturnal rodents.32,33 For example, Langebartels and co-workers34 found that large pharmacological melatonin doses (5 or 10 mg kgK1) injected intraperitoneally in rats at 13:30 h (middle of the 12 h light period), did not exert significant effects on brain temperature, sleep architecture or sleep EEG. Interestingly, melatonin also failed to attenuate the promotion of wakefulness observed with administration of the (GABA)A receptor agonist picrotoxin. The authors concluded therefore, “that melatonin hardly influences sleep–wake behavior in rats”.
C.J. van den Heuvel et al. It should be noted that a limitation of similar studies in nocturnal laboratory animals is that melatonin is often administered during the light phase, when melatonin is not endogenously produced but the animals are most likely asleep. Nevertheless, rats display intermittent periods of sleep and wakefulness in both light and dark phases rather than a single consolidated sleep period such as observed in humans. This situation clearly has no analogue in humans; therefore the conclusions drawn from laboratory studies in rats may be of limited value when extrapolated to other species. In addition, the doses typically employed in rats (i.e. 2–20 mg kgK1) produce pharmacological circulating levels, several orders of magnitude greater than what is observed naturally, so like many of the human studies these may not reflect the endogenous physiological role of the hormone.
Practice Point 1 Melatonin is produced by the mammalian pineal gland during the hours of darkness. Both the normal nocturnal production of melatonin or administration of melatonin during the day, when endogenous levels are low, are generally associated with increased sleep propensity in humans and other diurnal species, and decreased sleep propensity in nocturnal laboratory animals. From this perspective, melatonin may be viewed as a nocturnal timing signal to which different species have adapted their particular physiology to produce dark appropriate behaviors.
Exception 2: Issues related to dose and mode of administration Previous melatonin administration protocols with human subjects have mostly used large oral doses that do not appropriately mimic either the achieved peak level or duration of endogenous nocturnal melatonin production. Several authors have therefore suggested that the conclusions drawn from exogenous oral melatonin administration studies would be strengthened if the profile of nocturnal melatonin production were better reproduced during the day.11,35 In an attempt to reproduce the peak level and duration of nocturnal physiological melatonin production, a previous study by our group infused small daytime intravenous doses of melatonin continuously between 10:00 and 16:30 h.36 Melatonin
Melatonin as a hypnotic: Con infused at rates of 0.04 and 0.08 mg hK1 kgK1 body weight raised the daytime plasma and saliva melatonin levels into the normal physiological range observed in young adults at night.37 Despite achieving physiological melatonin levels, however, these dose rates did not significantly affect rectal, hand, forehead or tympanic temperatures or subjective sleepiness. Only a high dose infusion rate of 8.0 mg h K1 kgK1 , producing supraphysiological levels in plasma and saliva, was associated with an approximately 4-fold increase in subjects’ selfreported sleepiness, compared to a saline control condition. Also associated with the highest melatonin dose for the first half of the infusion period was significantly attenuated rectal temperature and increased hand temperature for 2 h after the start of the melatonin infusion. Nevertheless, this study is still only one of two published studies employing infusion of melatonin in human volunteers to examine the effects on sleep propensity or body temperature,35,36 so the results have not yet been independently replicated or even shown with objective sleepiness measures. Another previous study from our group, using physiological bolus intravenous doses of melatonin during the day suggests that melatonin with a rapid onset to physiological levels has thermoregulatory effects and supports the hypothesis that the hormone plays a role in the circadian regulation of body temperature. 38 However, the fact that soporific effects of melatonin were not apparent except at steady supraphysiological levels using intravenous infusion36 supports the suggestion that regulating sleep propensity may not be a physiological role of melatonin. Alternately, the threshold for acute effects of melatonin may be increased during the day, such that varying doses of melatonin are required across the day proportional to the sensitivity of melatonin receptors or other tissues responsive to the presence of melatonin. Taken together, the above studies nevertheless show that at physiologically relevant levels, melatonin may not always elicit demonstrable effects on sleep propensity in human subjects, as has been shown for low oral melatonin doses (e.g. 0.1–0.3 mg).
Practice Point 2 Daytime exogenous melatonin, producing similar peak levels and duration as endogenous nocturnal melatonin, does not affect either subjective sleepiness or core and peripheral body temperatures. Many of the experimental observations of soporific and thermoregulatory
75 effects of exogenous melatonin may therefore be related to the high circulating levels detected in various body fluids (e.g. CSF, plasma, saliva, urine) achieved with ingestion
Exception 3: Issues related to timing of administration In 1997, Lavie suggested that the time of melatonin administration appeared to be the most crucial factor in determining the sleepinducing effects of the hormone.2 Central to this suggestion was this group’s previous research finding that 5 mg of oral melatonin significantly shortened sleep onset latencies after ingestion at 12:00, 17:00, 19:00 or 21:00 h,3 with the effect occurring more rapidly the later melatonin was administered. As the subjects in this study were healthy young students entrained to normal schedules, it is unlikely (but nevertheless unclear) whether exogenous melatonin, especially at 21:00 h, would have overlapped the endogenous nocturnal production of the hormone. This is important, as it has been suggested that the soporific effects of melatonin, together with a time- and dose-dependent hypothermic action, are manifested only when circulating levels of endogenous melatonin are low.11,39 This suggestion is supported by the findings of a conference abstract employing forced desynchrony, where melatonin was administered to young adults over a range of circadian phases.40 This study found that significant improvements in sleep efficiency occurred only when exogenous melatonin was administered outside of its endogenous production phase. It has also been shown that melatonin administration in normally entrained subjects at night, when endogenous melatonin is being produced concomitantly, has little or no effect on sleep propensity.41,42 Whereas Cramer and colleagues41 reported decreased sleep latency in 10 young male subjects following nighttime injection of 50 mg melatonin, no other changes in sleep architecture were observed. This paper, however, does not state what time injections were performed, and therefore it is not possible to even speculate whether endogenous melatonin production had yet commenced at that time. In contrast, doses of 1 and 5 mg at 22:45 h—likely to be close to the endogenous onset of melatonin production, elicited no significant effects in healthy subjects on polysomnographic sleep measures.42 In general, the lower pharmacological doses (1–5 mg) at night
76 typically do not affect sleep propensity or architecture in either healthy-sleeping adults42 or insomniac subjects.43,44 One of the few studies with contrasting results was conducted by Waldhauser and colleagues,16 who administered 80 mg oral melatonin to 20 healthy young volunteers at 21:00 h and found significant decreases in sleep latency and other changes in sleep architecture, but again it was not clear whether the onset of endogenous melatonin had already occurred in these subjects. More recent studies employing patients with dementia typically show no significant therapeutic effects of melatonin on nighttime sleep. Serfaty and colleagues45 administered slow release melatonin (6 mg) at habitual bedtime to elderly patients with dementia and disturbance of sleep and Singer’s group46 administered 2.5 mg of sustained-release or 10 mg of immediate release melatonin to Alzheimer’s patients at 1 h before habitual bedtime. Unlike most prior studies, these groups recruited relatively large initial subject groups (nZ44 and 157, respectively), yet still found no objective evidence for an improvement in sleep measures between treated and untreated (placebo) groups. It is presumed that in both these studies, oral melatonin was given after the onset of endogenous melatonin, which in normally entrained individuals occurs about 2 h before sleep onset. Thus, it may be that patients with sleep disturbance related to dementia may not generally be insensitive to the soporific effects of melatonin, but rather that the time of administration after endogenous melatonin onset in these studies precluded any chance of detecting any significant effects of the hormone on measures of sleep propensity or sleep architecture. Finally, there is some evidence that exogenous melatonin may have varying sleep-inducing and thermoregulatory effects not only according to circadian (24-h) phase, but also according to phase of the menstrual cycle.47 While not investigating the sleepiness effects of exogenous melatonin, this group did find that daytime administration of 2.5 mg melatonin in seven healthy, pre-menopausal women significantly decreased core temperature during the follicular phase of the menstrual cycle, but was ineffective in the luteal phase. Their observations indicated that higher progesterone levels and an attenuated and phase-delayed circadian core temperature rhythm in the luteal phase may account for the lack of effects of administered melatonin. As the soporific effects of melatonin are typically associated with concomitant changes in core and
C.J. van den Heuvel et al. peripheral temperatures, these results also suggest that melatonin may not modify sleep propensity in women during the luteal phase. It should be noted, however, that this suggestion has not yet been supported by any empirical evidence.
Practice Point 3 Exogenous melatonin has time-dependent effects on both sleep propensity and body temperatures. Soporific effects in humans are typically observed only when circulating levels of endogenous melatonin are lowest (i.e. during the day).
Exception 4: Abolition of melatonin effects by motivation and posture Based on their experimental observations, Zhdanova and Wurtman48 have suggested that physiological levels of melatonin, due to either daytime ingestion or endogenous production, “is not an imperative signal for sleep but is rather a gentle promoter of general relaxation and sedation, elements of sleepiness that, in favorable conditions, might significantly facilitate sleep onset and that are typical for a period of what conventionally is called ‘quiet wakefulness’”. They also state that adequate motivation in an individual may allow them to overcome the feelings of increased sleepiness and, “be both alert and productive for some time”. While it has not yet been shown with quantitative analysis that exogenous melatonin only induces sleep in a sleepconducive environment, it might suggest that the soporific effects of melatonin, unlike traditional hypnotics, can be overridden with conscious effort. This agrees with the observation mentioned earlier, that melatonin has never been reported to cause an involuntary loss of consciousness. If endogenous melatonin does mediate the increase in sleep propensity occurring in the evening, then it would also explain why a decision to extend wakefulness past habitual bedtime can be made without undue difficulty. It is also unclear, if melatonin and hypnotics like the benzodiazepine drugs share a common mechanism (e.g. via GABA receptor occupation and/or changes in thermoregulation), how melatonin’s effects on sleep can be overcome if those of hypnotic drugs cannot, particularly at large pharmacological doses of melatonin. A more active approach to attenuate the effects on sleep propensity of daytime melatonin
Melatonin as a hypnotic: Con administration has been demonstrated by Cajochen and co-workers.39 As the soporific effects of melatonin in humans require heat loss via distal skin regions,49 the ability to lose heat was manipulated using an orthostatic challenge (changing posture from supine to upright). It was observed that the significant effects of 5 mg melatonin at 13:00 h on subjective sleepiness and objective measures (waking EEG) were suppressed when the young male subjects were standing from 13:00 to 15:00 h, compared to data for subjects kept supine. A posture-dependent soporific and core hypothermic effect of melatonin only became apparent when subjects lay down at 15:00 h, coinciding with decreased sympathetic activation. In summary, it would appear that similar to the possibility that motivation may overcome the sleep-inducing effects of melatonin, simply adopting an upright posture might be another means to achieve the same goal.
Practice Point 4 There is a limited amount of evidence that nevertheless suggests the soporific effects of melatonin may be suppressed by either adequate motivated effort, or the adoption of an upright posture; neither of which has any demonstrated efficacy in countering the effects of traditional hypnotic drugs.
Exception 5: Effects of age, gender and sleep status Reiter50 stated in his recent review that, “the nighttime rises in circulating levels of melatonin seem to promote sleep onset and maintain restful sleep”, but added the epithet, “in some individuals”. Sack and colleagues51 concluded their review with a similarly suggestive remark, “that melatonin may benefit sleep by correcting circadian phase abnormalities and/or by a modest direct soporific effect that is most evident following daytime administration to younger subjects”. There is considerable experimental evidence underlying these statements that supports the suggestion that soporific (and underlying thermoregulatory) effects of administered melatonin are not universally observed in all adults. For instance, research from our laboratory has demonstrated that administered melatonin has significantly less effect on core temperature in older, compared with younger women.52 In this study, 5 mg oral melatonin or placebo was taken at
77 14:00 h, after which the core temperature of six younger women (aged around 20–30 years) declined at a significantly faster rate (0.09 8C hK1) than that of 10 older women (aged around 60–70 years; 0.05 8C hK1). Although no significant difference with age was observed in the maximum change in core temperature following melatonin in this study, Cagnacci and colleagues53 had shown previously that melatonin did elicit disparate temperature effects in young and older volunteers. They found that significant decreases in core temperature observed in a group of young women were completely absent in older women, after both groups received 100 mg melatonin at 08:00 h. While there were discrepancies between these two studies, respectively, in terms of core temperature measurement site (rectal versus vaginal and tympanic), timing of administration (14:00 versus 08:00 h) and analyses of temperatures (relative to time of administration versus absolute), it is nevertheless apparent that advancing age may reduce the thermoregulatory effect of administered melatonin. It follows that if melatonin exerts its effects on sleep via thermoregulatory effects that soporific effects may also decline with age. However, based on the few studies specifically investigating agerelated decreases in melatonin’s effects, it is not yet possible to make a definitive statement about whether the efficacy of exogenous melatonin decreases with age, as it is not clear whether the case is similar for older males as has been observed for older females. Thus, if the effect is robust it may represent either a gender- or age-related phenomena. The demonstrated soporific and chronobiotic effects of melatonin have often been suggested as desirable qualities in the treatment of insomnia. However, in insomniacs, especially elderly subjects with sleep disturbance, the efficacy of melatonin is not clear. Previous research has suggested that the sleep of melatonin-deficient elderly insomniacs might be improved with 1–2 mg oral melatonin, with administration continuing for between 7 days and 2 months.54 Still, a review of 78 studies examining the effect of melatonin on sleep in elderly insomniacs55 found that melatonin was most effective in elderly individuals also being treated with benzodiazepines or who showed low melatonin secretion during sleep. In younger adults with chronic insomnia, only one study has reported positive effects of melatonin (75 mg) on subsequent sleep.56 Other studies have not found any objective therapeutic effect of 1–5 mg oral melatonin given in the evening for up to a week in similar cohorts.43,44
78 A study by our group has shown that elderly female sleep maintenance insomniacs receiving 0.5 mg sustained release (transbuccal) melatonin on four consecutive nights had significantly decreased rectal core temperature but had no positive effects on any polysomnographic (PSG) (measure of sleep quality.57 This was consistent with an earlier study where we administered 5 mg melatonin orally at 14:00 h to a group of 12 elderly female sleep maintenance insomniacs during the day. Subjects displayed significant lowering of core temperature and decreased sleep onset latencies,58 however, compared to the magnitude of effects observed in younger subjects in other previous studies the effects were attenuated in older subjects. Therefore, while melatonin may decrease sleep onset latency and depending on dose and the target population may mildly improve other sleep parameters, its therapeutic efficacy is generally limited in elderly insomniacs. As suggested by Sack et al.,51 “IroniIronically, it may be the young who are more sensitive to melatonin’s soporific effects”.
Practice Point 5 There appears to be a complex interaction between age, gender and sleep status in determining the effects of melatonin. Older women are less responsive than younger women to soporific and thermoregulatory effects of melatonin, and younger insomniacs are less responsive than healthy young adults. It has not yet been investigated, however, whether melatonin has attenuated effects on sleep and body temperatures in older men.
Conclusions Wirz-Justice and Armstrong14 suggested that melatonin partially fits the definition of a hypnotic, “since it induces sleepiness and facilitates the onset of a ‘natural’ sleep EEG”. They nevertheless recommended that melatonin might better be called a soporific, and based on the evidence available 8 years since publication of their letter, we not only support their claim but further maintain that to class melatonin as a hypnotic is oversimplified and lacks sophistication. There is certainly a large body of evidence consistent with the suggestion that daytime melatonin ingestion results in, among other physiological changes, an increase in sleep propensity and
C.J. van den Heuvel et al. initiation of sleep in humans. However, we have presented compelling evidence to support the view that exogenous melatonin is only hypnotic in those species for which endogenous melatonin increases sleep propensity and is therefore a dark appropriate outcome. This review has also presented evidence in other key areas that demonstrates that melatonin does not have hypnotic properties under most conditions. In summary, there is evidence that melatonin at large pharmacological or supraphysiological doses appears to have limited or no soporific effects when given either during the day to nocturnal species, women in the luteal phase (just prior to menstruation), older women, or insomniacs, or to healthy subjects at night when endogenous production is high. Furthermore, daytime intravenous administration of melatonin that produces circulating levels equivalent to peak endogenous levels observed at night in young adults does not elicit significant changes in core temperature or subjective sleepiness. Finally, whereas the effects of traditional hypnotic agents cannot be easily counteracted, it would appear that only mild interventions such as adequate motivation or a change from supine to an upright posture are required to counteract the soporific effects of administered melatonin.
Research agenda While melatonin has chronobiotic effects which can be exploited in the treatment of sleep disturbance in circadian rhythm sleep disorders,59 or which occurs with jet-lag, shift work and blindness, it is still not clear what the precise physiological role of melatonin is concerning the regulation of body temperature and sleep. Acute soporific effects of melatonin are apparent in healthy young adults with daytime administration, but may not reflect its physiological role. Melatonin may nevertheless have some therapeutic use as a sleeppromoting or soporific agent.The circumstances raised in this review which suggest that melatonin administration is not always hypnotic indicate that many basic research studies still need to be conducted. Specifically, there are unresolved issues with melatonin and its efficacy relating to issues such as dosage, timing, age and gender, as well as long-term safety. Similarly, further investigation is required to define the effects of melatonin on the immune, reproductive and circadian systems.
Melatonin as a hypnotic: Con
Acknowledgements This work was supported by grants from the National Health and Medical Research Council and the Australian Research Council.
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79 18. Dawson D, Gibbon S, Singh P. The hypothermic effect of melatonin on core body temperature: is more better? J Pineal Res 1996;20(4):192–7. 19. Aldhous M, Franey C, Wright J, Arendt J. Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol 1985;19(4): 517–21. 20. Hughes RJ, Badia P. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep 1997;20:124–31. 21. Zhdanova IV, Wurtman RJ, Lynch HJ, Ives JR, Dollins AB, Morabito C, Matheson JK, Schomer DL. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995;57(5):552–8. 22. Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Effects of low oral doses of melatonin, given 2– 4 hours before habitual bedtime, on sleep in normal young humans. Sleep 1996;19(5):423–31. 23. Mishima K, Satoh K, Shimizu T, Hishikawa Y. Hypnotic and hypothermic action of daytime-administered melatonin. Psychopharmacology (Berl) 1997;133(2):168–71. 24. Reiter RJ. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol 1991;79(1–3):C153–C158. 25. Utiger RD. Melatonin—the hormone of darkness. N Engl J Med 1992; 327(19):1377–9. * 26. Dawson D, van den Heuvel CJ. Integrating the actions of melatonin on human physiology. Ann Med 1998;30(1): 95–102. 27. Yellon SM, Hilliker S. Influence of acute melatonin treatment and light on the circadian melatonin rhythm in the Djungarian hamster. J Biol Rhythms 1994;9(1):71–81. 28. Mendelson WB, Gillin JC, Dawson SD, Lewy AJ, Wyatt RJ. Effects of melatonin and propranolol on sleep of the rat. Brain Res 1980;201(1):240–4. 29. Mendelson WB, Bergmann BM. Effects of pinealectomy on baseline sleep and response to sleep deprivation. Sleep 2001;24(4):369–73. 30. Mouret J, Coindet J, Chouvet G. Effect of pinealectomy on sleep stages and rhythms of the male rat. Brain Res 1974; 81(1):97–105. 31. Mirmiran M, Pe ´vet P. Effects of melatonin and 5-methoxytryptamine on sleep–wake patterns in the male rat. J Pineal Res 1986;3(2):135–41. 32. Tobler I, Jaggi K, Borbely AA. Effects of melatonin and the melatonin receptor agonist S-20098 on the vigilance states, EEG spectra, and cortical temperature in the rat. J Pineal Res 1994;16(1):26–32. 33. Huber R, Deboer T, Schwierin B, Tobler I. Effect of melatonin on sleep and brain temperature in the Djungarian hamster and the rat. Physiol Behav 1998;65(1):77–82. 34. Langebartels A, Mathias S, Lancel M. Acute effects of melatonin on spontaneous and picrotoxin-evoked sleep– wake behaviour in the rat. J Sleep Res 2001;10(3):211–7. * 35. Strassman RJ, Qualls CR, Lisansky EJ, Peake GT. Elevated rectal temperature produced by all-night bright light is reversed by melatonin infusion in men. J Appl Physiol 1991; 71(6):2178–82. * 36. van den Heuvel CJ, Kennaway DJ, Dawson D. Effects of daytime melatonin infusion in young adults. Am J Physiol 1998;275(1 Pt 1):E19–E26. 37. Voultsios A, Kennaway DJ, Dawson D. Salivary melatonin as a circadian phase marker: validation and comparison to plasma melatonin. J Biol Rhythms 1997;12(5):457–66. 38. van den Heuvel CJ, Kennaway DJ, Dawson D. Thermoregulatory and soporific effects of very low dose melatonin injection. Am J Physiol 1999;276(2 Pt 1):E249–E254.
80 * 39. Cajochen C, Krauchi K, Wirz-Justice A. The acute soporific action of daytime melatonin administration: effects on the EEG during wakefulness and subjective alertness. J Biol Rhythms 1997;12(6):636–43. 40. Wyatt JK, Dijk DJ, Ritz-De Cecco A, Ronda JM, Czeisler CA. Effects of physiologic doses of exogenous melatonin on sleep propensity and consolidation in healthy young men and women are circadian phase-dependent. Sleep Res Online 1999;2(Suppl. 1):636. 41. Cramer H, Kendel K, Beck U. Influence of melatonin on sleep in humans. In: Sleep: physiology, biochemistry, psychology, pharmacology, clinical implications. 1st European Congress of Sleep Research, 1972. Basel: Karger; 1973 p. 488–91. 42. James SP, Mendelson WB, Sack DA, Rosenthal NE, Wehr TA. The effect of melatonin on normal sleep. Neuropsychopharmacology 1987;1(1):41–4. 43. James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacology 1990;3(1):19–23. 44. Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 1996;5(1):61–5. 45. Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P. Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry 2002;17:1120–7. 46. Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, Thomas R, Thal LJ. A multicenter, placebocontrolled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 2003;26(7):893–901. * 47. Cagnacci A, Soldani R, Laughlin GA, Yen SS. Modification of circadian body temperature rhythm during the luteal menstrual phase: role of melatonin. J Appl Physiol 1996; 80(1):25–9. 48. Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleeppromoting agent. J Biol Rhythms 1997;12(6):644–50. * 49. Krauchi K, Cajochen C, Wirz-Justice A. A relationship between heat loss and sleepiness: effects of postural change
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www.elsevier.com/locate/smrv
CLINICAL REVIEW
Melatonin as a hypnotic: Con Cameron J. van den Heuvela,*, Sally A. Fergusona, M. Mila Macchib,1, Drew Dawsona a
Centre for Sleep Research, University of South Australia, 5th Floor, Basil Hetzel Institute, The Queen Elizabeth Hospital, 11–23 Woodville Road, Woodville, SA 5011, Australia b New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University, Unit 50, 1051 Riverside Drive, New York, NY 10032, USA KEYWORDS Melatonin; Hypnotic; Sleep; Soporific; Exogenous; Endogenous; Circadian rhythms
Summary The physiological roles of melatonin are still unclear despite almost 50 years of research. Elevated melatonin levels from either endogenous nocturnal production or exogenous daytime administration are associated in humans with effects including increased sleepiness, reduced core temperature, increased heat loss and other generally anabolic physiological changes. This supports the idea that endogenous melatonin increases nocturnal sleep propensity, either directly or indirectly via physiological processes associated with sleep. The article “Melatonin as a hypnotic—Pro”, also in this issue, presents evidence to support this viewpoint. We do not entirely disagree, but nevertheless feel this is an overly simplistic interpretation of the available data. Our interpretation is that melatonin is primarily a neuroendocrine transducer promoting an increased propensity for ‘dark appropriate’ behavior. Thus, it is our view that exogenous melatonin is only hypnotic in those species or individuals for which endogenous melatonin increases sleep propensity and is consequently a dark appropriate outcome. Evidence supporting this position is drawn primarily from studies of exogenous administration of melatonin and its varied effects on sleep/wake behavior based on dose, time of administration, age and other factors. From this perspective, it will be shown that melatonin can exert hypnotic-like effects but only under limited circumstances. q 2004 Elsevier Ltd. All rights reserved.
Introduction Abbreviations: EEG, electroencephalograph; (GABA)A, gaminobutyric acid receptor complex; NREM, non-rapid eye movement (sleep); REM, rapid eye movement (sleep). * Corresponding author. Tel.: C61-8-8222-6624; fax: C61-88222-6623. E-mail addresses: [email protected] (C.J. van den Heuvel), [email protected] (S.A. Ferguson), [email protected] (M. Mila Macchi), [email protected] (D. Dawson). 1 Tel.: C1-212-543-5469; fax: C1-212-543-6540.
The initial isolation of the pineal hormone melatonin1 marked the start of an increasing research effort to identify the endogenous role of melatonin and the mechanisms by which it regulates the physiology of both mammalian and non-mammalian species. While our current understanding of melatonin has therefore increased substantially, especially regarding melatonin’s involvement in the circadian timing system, the putative role that
1087-0792/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2004.07.001
72 endogenous melatonin may play in regulating sleep and how this role is mediated remains unclear. In diurnal species, the nocturnal production of melatonin and occurrence of sleep are closely related. In humans, the onset of melatonin production typically coincides with an increase in the propensity to fall asleep (sometimes termed the ‘sleep gate’) and follows a forbidden zone for sleep in the early evening.2 This relationship may not be purely coincidental. Under conditions that force the circadian system to free run (i.e. an ultra-short sleep/wake cycle), the onset of melatonin production and the timing of the sleep gate have been observed to remain time-locked to each other.3 While such data do not confirm a causal role of endogenous melatonin in the regulation of normal sleep/wake behavior, they are generally consistent with studies examining the effect of exogenous melatonin on sleep propensity.
Potential mechanisms by which melatonin may increase sleep propensity Whether melatonin regulates sleep/wake behavior by increasing sleep propensity or by inhibiting wakefulness,4 studies with daytime oral administration of either melatonin or hypnotics typically show that increased sleepiness occurs in association with decreasing core temperature.5–8 In contrast, agents such as caffeine, amphetamines, nicotine and cocaine decrease sleepiness and increase body temperature.9 This association has been documented in humans for at least half a century, leading to consistent suggestions that circadian changes in body temperature, at least partly mediated by endogenous melatonin secretion, are involved in the regulation of sleep/wake behavior.9–11 Nevertheless, evidence of a causal link between core hypothermic effects and sleep-induction following ingestion of melatonin is lacking and should be addressed in future research. In addition, it has been suggested that melatonin may exert sleeppromoting effects via indirect chronobiotic effects on the circadian timing system12 or directly through occupation of the g-aminobutyric acid (GABA)A receptor complex, although there is some evidence that central GABA receptors are not involved in mediating melatonin’s effects in humans.13 While it is important here to introduce possible mechanisms, a detailed exploration is, however, beyond the scope of the current paper. This review instead aims to examine the evidence that is inconsistent with melatonin acting as a hypnotic agent when administered exogenously.
C.J. van den Heuvel et al. While ingested melatonin may sometimes have effects compatible with a hypnotic mode of action, we contend that these are only apparent under a limited set of circumstances. In Section 3, we briefly present some evidence that has historically led to suggestions that melatonin possesses significant hypnotic effects. However, we anticipate that this area will be covered extensively in the article “Melatonin as a Hypnotic—Pro”, also in this issue. Thereafter, we present some key exceptions to the rule, or in other words, evidence that supports the suggestion that melatonin may be hypnotic, but only under specific conditions. In particular, we present evidence from various studies suggesting that the effects of exogenous daytime melatonin are attenuated or absent completely in nocturnal species, at physiologically relevant levels, at different times of the day or phases of the menstrual cycle, in conditions not conducive to sleep or where there is motivation not to initiate sleep, and in elderly individuals and insomniacs.
Hypnotic-like effects following melatonin administration In a letter to the editor of the Journal of Sleep Research, Wirz-Justice and Armstrong14 referred to a hypnotic as, “A drug which produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electroencephalogram (EEG) characteristics, and from which the recipient can be aroused easily”. They point out, however, that the classical hypnotic drugs (e.g. benzodiazepines) do not fully comply with this definition, as the sleep-induced does not typically resemble ‘natural’ sleep. Specifically, benzodiazepine administration typically decreases the amount of REM sleep, slow wave sleep and EEG power in the delta and theta range when compared with normal (unmedicated) sleep. In addition, with increasing dose hypnotics tend to produce greater sedation and eventually, coma and death. This appears not to be the case with melatonin, as even with large pharmacological doses15,16 no involuntary loss of consciousness has ever been reported. In any case, Wirz-Justice and Armstrong14 favor the term soporific to hypnotic in description of melatonin’s effects on humans, and we use it hereafter to refer specifically to its ability to increase sleep propensity and induce sleep. Studies with human volunteers to whom melatonin has been administered exogenously, typically report a dose–response effect on sleep propensity across doses that produce physiological and low
Melatonin as a hypnotic: Con supraphysiological circulating levels. This is unlike the benzodiazepine hypnotics, which cause a proportionally higher sleep-inducing response with increasing dose. Daytime oral melatonin doses that elevate plasma melatonin into the supraphysiological range often result in closely associated acute hypothermic effects and hypnoticlike effects5–8,13 but not always.17 In general, melatonin administered orally at doses above 0.5 mg will produce blood levels in the pharmacological range (i.e. above the normal nocturnal production range of around 30–200 pg mlK1).18 However, this varies greatly between individuals due to variable first-pass metabolism19 and also depends on the speed of release of the preparation. In addition, there have been no systematic attempts in previous studies to administer a consistent dose by subjects’ body weight, which may also contribute to the large variability in circulating levels following oral melatonin ingestion. In most studies, melatonin has demonstrated soporific effects only at oral doses of 0.1–0.3 mg or more.6–7,20–22 However, these effects are generally subtle, typically including a shorter latency to sleep onset but not changes to the architecture of subsequent sleep bouts. In addition, most studies have given doses that elevate peak melatonin levels above the nocturnal physiological range. For example, 5 mg oral melatonin administered during the daytime (12:00, 17:00, 19:00 or 21:00 h) subsequently shortened latency to sleep onset at each time,3 but the effect became increasingly rapid with later times of ingestion. Also, at each trial, ingestion of melatonin was observed to increase theta and delta power, while decreasing wakefulness (alpha activity) compared to placebo. The authors concluded that melatonin did indeed display some hypnotic properties, but that the effects in humans were time-dependent, increasing in proportion with later administration into the evening. A study by Hughes and Badia20 found that doses of 1, 10 and 40 mg all reduced sleep onset latencies when administered at 10:00 h. While significant, note that the reduced sleep latencies were of quite a small magnitude, from 4.8G0.9 (placebo) to 2.9G0.4 (1 mg), 2.6G0.4 (10 mg), and 3.2G 0.4 min (40 mg), respectively. A similar study using oral administration of melatonin at 09:30 h was only effective at a dose of 9 mg and not 3 mg.23 In this instance, however, only six young male subjects were studied suggesting insufficient power may have been responsible for a lack of statistical significance. Finally, at doses of 0.3 and 1 mg, melatonin was also found to significantly reduce sleep latencies when given in the evening at 18:00, 20:00 and 22:00 h.21
73 In summary, studies of melatonin that result in circulating levels at or above the observed endogenous production, typically find significant objective and subjective increases in sleepiness when given to healthy young adults with ‘normal’ sleep. Furthermore, in the majority of these studies, only latencies to sleep onset were significantly impacted while sleep architecture (where examined) is largely observed to be unaffected, or have only subtle changes in stages 1 and 2 sleep at the expense of wakefulness (i.e. stage 0). Melatonin can therefore be seen to be hypnotic or at least soporific, as it may not exactly mimic the EEG characteristics of normal nocturnal sleep in closely controlled laboratory studies in humans. In the following sections, however, we explore several exceptional circumstances that provide evidence against melatonin acting as a hypnotic substance.
Exception 1: Nocturnal versus diurnal species The most prominent feature of melatonin production is that it has been found to occur only during the hours of darkness in all species in which it has been studied. The endogenous nocturnal production of melatonin and its association with physiological and behavioral changes associated with the nocturnal period has led to it being dubbed variously the ‘chemical expression of darkness’24 and the ‘hormone of darkness’.25 The secretion of melatonin in humans coincides with systematic changes including increased sleepiness, lowering of core temperature, increased heat loss, decreased cardiovascular output and enhanced immune responsiveness. However, it has been suggested that nocturnal species have evolved to use the stable, nocturnal timing signal provided by melatonin to promote wakefulness and motor activity, increase core temperature and sustain other catabolic processes.26 Whereas the evening rise in melatonin secretion has been suggested to act as a ‘gating’ mechanism for sleep onset in humans,2 in nocturnal animals entrained to normal light/dark schedules melatonin production coincides with the major period of wakefulness and motor activity.27 Together, the evidence from naturalistic observations supports the suggestion by Mendelson and co-workers28 that the endogenous role of melatonin may be to enhance behaviors normally associated with night in both diurnal and nocturnal species. In other words, melatonin can be viewed as a neuroendocrine transducer promoting an increased propensity for ‘dark appropriate’ behavior.
74 Experimental evidence that melatonin is involved in promotion of wakefulness in nocturnal laboratory animals such as rats and hamsters, generally supports this suggestion. For example, surgical excision of the pineal gland, locus of mammalian melatonin production, causes a significant but modest increase in the amount of NREM sleep in rats,29 consistent with the loss of endogenous melatonin production increasing sleep propensity. It has also been recognized for 30 years that pinealectomy in rats reduces the amplitude of the sleep/wake circadian rhythm, which is to say that the ratio of sleep during the day to that at night, normally a factor of 2–3, is significantly reduced and sleep periods becomes more equally distributed across the 24-h day.30 The role of melatonin in sleep has also been investigated directly by administering the hormone in rats. Amongst the earliest studies of this kind, Mendelson and co-workers28 injected rats with melatonin at a dose of 833 mg kgK1 , a large pharmacological dose but comparable to those used in contemporary human studies. Melatonin given at 07:45 h, just prior to the lights coming on at 08:00 h for 12 h, was observed to decrease total sleep time by an average of 52 min, mainly at the expense of NREM sleep (48 min). A comparative increase in wake after sleep onset was consistent with melatonin decreasing sleep propensity in these nocturnal animals. In a separate group given melatonin at 19:45 h, when endogenous melatonin production was expected to be increasing, no significant effects on sleep architecture were observed. Referring to earlier experiments with other species, the authors concluded that melatonin (given during the day) may induce “the customary nighttime behavior for each species (waking for the rat, sleep for humans and chickens)”. Subsequent studies of melatonin’s effects on sleep in rats produced contradictory results, ranging along a continuum from sleep promoting to sleep reducing effects.31,32 More recent reports, however, typically fail to find significant effects of melatonin on brain temperature or sleep architecture in nocturnal rodents.32,33 For example, Langebartels and co-workers34 found that large pharmacological melatonin doses (5 or 10 mg kgK1) injected intraperitoneally in rats at 13:30 h (middle of the 12 h light period), did not exert significant effects on brain temperature, sleep architecture or sleep EEG. Interestingly, melatonin also failed to attenuate the promotion of wakefulness observed with administration of the (GABA)A receptor agonist picrotoxin. The authors concluded therefore, “that melatonin hardly influences sleep–wake behavior in rats”.
C.J. van den Heuvel et al. It should be noted that a limitation of similar studies in nocturnal laboratory animals is that melatonin is often administered during the light phase, when melatonin is not endogenously produced but the animals are most likely asleep. Nevertheless, rats display intermittent periods of sleep and wakefulness in both light and dark phases rather than a single consolidated sleep period such as observed in humans. This situation clearly has no analogue in humans; therefore the conclusions drawn from laboratory studies in rats may be of limited value when extrapolated to other species. In addition, the doses typically employed in rats (i.e. 2–20 mg kgK1) produce pharmacological circulating levels, several orders of magnitude greater than what is observed naturally, so like many of the human studies these may not reflect the endogenous physiological role of the hormone.
Practice Point 1 Melatonin is produced by the mammalian pineal gland during the hours of darkness. Both the normal nocturnal production of melatonin or administration of melatonin during the day, when endogenous levels are low, are generally associated with increased sleep propensity in humans and other diurnal species, and decreased sleep propensity in nocturnal laboratory animals. From this perspective, melatonin may be viewed as a nocturnal timing signal to which different species have adapted their particular physiology to produce dark appropriate behaviors.
Exception 2: Issues related to dose and mode of administration Previous melatonin administration protocols with human subjects have mostly used large oral doses that do not appropriately mimic either the achieved peak level or duration of endogenous nocturnal melatonin production. Several authors have therefore suggested that the conclusions drawn from exogenous oral melatonin administration studies would be strengthened if the profile of nocturnal melatonin production were better reproduced during the day.11,35 In an attempt to reproduce the peak level and duration of nocturnal physiological melatonin production, a previous study by our group infused small daytime intravenous doses of melatonin continuously between 10:00 and 16:30 h.36 Melatonin
Melatonin as a hypnotic: Con infused at rates of 0.04 and 0.08 mg hK1 kgK1 body weight raised the daytime plasma and saliva melatonin levels into the normal physiological range observed in young adults at night.37 Despite achieving physiological melatonin levels, however, these dose rates did not significantly affect rectal, hand, forehead or tympanic temperatures or subjective sleepiness. Only a high dose infusion rate of 8.0 mg h K1 kgK1 , producing supraphysiological levels in plasma and saliva, was associated with an approximately 4-fold increase in subjects’ selfreported sleepiness, compared to a saline control condition. Also associated with the highest melatonin dose for the first half of the infusion period was significantly attenuated rectal temperature and increased hand temperature for 2 h after the start of the melatonin infusion. Nevertheless, this study is still only one of two published studies employing infusion of melatonin in human volunteers to examine the effects on sleep propensity or body temperature,35,36 so the results have not yet been independently replicated or even shown with objective sleepiness measures. Another previous study from our group, using physiological bolus intravenous doses of melatonin during the day suggests that melatonin with a rapid onset to physiological levels has thermoregulatory effects and supports the hypothesis that the hormone plays a role in the circadian regulation of body temperature. 38 However, the fact that soporific effects of melatonin were not apparent except at steady supraphysiological levels using intravenous infusion36 supports the suggestion that regulating sleep propensity may not be a physiological role of melatonin. Alternately, the threshold for acute effects of melatonin may be increased during the day, such that varying doses of melatonin are required across the day proportional to the sensitivity of melatonin receptors or other tissues responsive to the presence of melatonin. Taken together, the above studies nevertheless show that at physiologically relevant levels, melatonin may not always elicit demonstrable effects on sleep propensity in human subjects, as has been shown for low oral melatonin doses (e.g. 0.1–0.3 mg).
Practice Point 2 Daytime exogenous melatonin, producing similar peak levels and duration as endogenous nocturnal melatonin, does not affect either subjective sleepiness or core and peripheral body temperatures. Many of the experimental observations of soporific and thermoregulatory
75 effects of exogenous melatonin may therefore be related to the high circulating levels detected in various body fluids (e.g. CSF, plasma, saliva, urine) achieved with ingestion
Exception 3: Issues related to timing of administration In 1997, Lavie suggested that the time of melatonin administration appeared to be the most crucial factor in determining the sleepinducing effects of the hormone.2 Central to this suggestion was this group’s previous research finding that 5 mg of oral melatonin significantly shortened sleep onset latencies after ingestion at 12:00, 17:00, 19:00 or 21:00 h,3 with the effect occurring more rapidly the later melatonin was administered. As the subjects in this study were healthy young students entrained to normal schedules, it is unlikely (but nevertheless unclear) whether exogenous melatonin, especially at 21:00 h, would have overlapped the endogenous nocturnal production of the hormone. This is important, as it has been suggested that the soporific effects of melatonin, together with a time- and dose-dependent hypothermic action, are manifested only when circulating levels of endogenous melatonin are low.11,39 This suggestion is supported by the findings of a conference abstract employing forced desynchrony, where melatonin was administered to young adults over a range of circadian phases.40 This study found that significant improvements in sleep efficiency occurred only when exogenous melatonin was administered outside of its endogenous production phase. It has also been shown that melatonin administration in normally entrained subjects at night, when endogenous melatonin is being produced concomitantly, has little or no effect on sleep propensity.41,42 Whereas Cramer and colleagues41 reported decreased sleep latency in 10 young male subjects following nighttime injection of 50 mg melatonin, no other changes in sleep architecture were observed. This paper, however, does not state what time injections were performed, and therefore it is not possible to even speculate whether endogenous melatonin production had yet commenced at that time. In contrast, doses of 1 and 5 mg at 22:45 h—likely to be close to the endogenous onset of melatonin production, elicited no significant effects in healthy subjects on polysomnographic sleep measures.42 In general, the lower pharmacological doses (1–5 mg) at night
76 typically do not affect sleep propensity or architecture in either healthy-sleeping adults42 or insomniac subjects.43,44 One of the few studies with contrasting results was conducted by Waldhauser and colleagues,16 who administered 80 mg oral melatonin to 20 healthy young volunteers at 21:00 h and found significant decreases in sleep latency and other changes in sleep architecture, but again it was not clear whether the onset of endogenous melatonin had already occurred in these subjects. More recent studies employing patients with dementia typically show no significant therapeutic effects of melatonin on nighttime sleep. Serfaty and colleagues45 administered slow release melatonin (6 mg) at habitual bedtime to elderly patients with dementia and disturbance of sleep and Singer’s group46 administered 2.5 mg of sustained-release or 10 mg of immediate release melatonin to Alzheimer’s patients at 1 h before habitual bedtime. Unlike most prior studies, these groups recruited relatively large initial subject groups (nZ44 and 157, respectively), yet still found no objective evidence for an improvement in sleep measures between treated and untreated (placebo) groups. It is presumed that in both these studies, oral melatonin was given after the onset of endogenous melatonin, which in normally entrained individuals occurs about 2 h before sleep onset. Thus, it may be that patients with sleep disturbance related to dementia may not generally be insensitive to the soporific effects of melatonin, but rather that the time of administration after endogenous melatonin onset in these studies precluded any chance of detecting any significant effects of the hormone on measures of sleep propensity or sleep architecture. Finally, there is some evidence that exogenous melatonin may have varying sleep-inducing and thermoregulatory effects not only according to circadian (24-h) phase, but also according to phase of the menstrual cycle.47 While not investigating the sleepiness effects of exogenous melatonin, this group did find that daytime administration of 2.5 mg melatonin in seven healthy, pre-menopausal women significantly decreased core temperature during the follicular phase of the menstrual cycle, but was ineffective in the luteal phase. Their observations indicated that higher progesterone levels and an attenuated and phase-delayed circadian core temperature rhythm in the luteal phase may account for the lack of effects of administered melatonin. As the soporific effects of melatonin are typically associated with concomitant changes in core and
C.J. van den Heuvel et al. peripheral temperatures, these results also suggest that melatonin may not modify sleep propensity in women during the luteal phase. It should be noted, however, that this suggestion has not yet been supported by any empirical evidence.
Practice Point 3 Exogenous melatonin has time-dependent effects on both sleep propensity and body temperatures. Soporific effects in humans are typically observed only when circulating levels of endogenous melatonin are lowest (i.e. during the day).
Exception 4: Abolition of melatonin effects by motivation and posture Based on their experimental observations, Zhdanova and Wurtman48 have suggested that physiological levels of melatonin, due to either daytime ingestion or endogenous production, “is not an imperative signal for sleep but is rather a gentle promoter of general relaxation and sedation, elements of sleepiness that, in favorable conditions, might significantly facilitate sleep onset and that are typical for a period of what conventionally is called ‘quiet wakefulness’”. They also state that adequate motivation in an individual may allow them to overcome the feelings of increased sleepiness and, “be both alert and productive for some time”. While it has not yet been shown with quantitative analysis that exogenous melatonin only induces sleep in a sleepconducive environment, it might suggest that the soporific effects of melatonin, unlike traditional hypnotics, can be overridden with conscious effort. This agrees with the observation mentioned earlier, that melatonin has never been reported to cause an involuntary loss of consciousness. If endogenous melatonin does mediate the increase in sleep propensity occurring in the evening, then it would also explain why a decision to extend wakefulness past habitual bedtime can be made without undue difficulty. It is also unclear, if melatonin and hypnotics like the benzodiazepine drugs share a common mechanism (e.g. via GABA receptor occupation and/or changes in thermoregulation), how melatonin’s effects on sleep can be overcome if those of hypnotic drugs cannot, particularly at large pharmacological doses of melatonin. A more active approach to attenuate the effects on sleep propensity of daytime melatonin
Melatonin as a hypnotic: Con administration has been demonstrated by Cajochen and co-workers.39 As the soporific effects of melatonin in humans require heat loss via distal skin regions,49 the ability to lose heat was manipulated using an orthostatic challenge (changing posture from supine to upright). It was observed that the significant effects of 5 mg melatonin at 13:00 h on subjective sleepiness and objective measures (waking EEG) were suppressed when the young male subjects were standing from 13:00 to 15:00 h, compared to data for subjects kept supine. A posture-dependent soporific and core hypothermic effect of melatonin only became apparent when subjects lay down at 15:00 h, coinciding with decreased sympathetic activation. In summary, it would appear that similar to the possibility that motivation may overcome the sleep-inducing effects of melatonin, simply adopting an upright posture might be another means to achieve the same goal.
Practice Point 4 There is a limited amount of evidence that nevertheless suggests the soporific effects of melatonin may be suppressed by either adequate motivated effort, or the adoption of an upright posture; neither of which has any demonstrated efficacy in countering the effects of traditional hypnotic drugs.
Exception 5: Effects of age, gender and sleep status Reiter50 stated in his recent review that, “the nighttime rises in circulating levels of melatonin seem to promote sleep onset and maintain restful sleep”, but added the epithet, “in some individuals”. Sack and colleagues51 concluded their review with a similarly suggestive remark, “that melatonin may benefit sleep by correcting circadian phase abnormalities and/or by a modest direct soporific effect that is most evident following daytime administration to younger subjects”. There is considerable experimental evidence underlying these statements that supports the suggestion that soporific (and underlying thermoregulatory) effects of administered melatonin are not universally observed in all adults. For instance, research from our laboratory has demonstrated that administered melatonin has significantly less effect on core temperature in older, compared with younger women.52 In this study, 5 mg oral melatonin or placebo was taken at
77 14:00 h, after which the core temperature of six younger women (aged around 20–30 years) declined at a significantly faster rate (0.09 8C hK1) than that of 10 older women (aged around 60–70 years; 0.05 8C hK1). Although no significant difference with age was observed in the maximum change in core temperature following melatonin in this study, Cagnacci and colleagues53 had shown previously that melatonin did elicit disparate temperature effects in young and older volunteers. They found that significant decreases in core temperature observed in a group of young women were completely absent in older women, after both groups received 100 mg melatonin at 08:00 h. While there were discrepancies between these two studies, respectively, in terms of core temperature measurement site (rectal versus vaginal and tympanic), timing of administration (14:00 versus 08:00 h) and analyses of temperatures (relative to time of administration versus absolute), it is nevertheless apparent that advancing age may reduce the thermoregulatory effect of administered melatonin. It follows that if melatonin exerts its effects on sleep via thermoregulatory effects that soporific effects may also decline with age. However, based on the few studies specifically investigating agerelated decreases in melatonin’s effects, it is not yet possible to make a definitive statement about whether the efficacy of exogenous melatonin decreases with age, as it is not clear whether the case is similar for older males as has been observed for older females. Thus, if the effect is robust it may represent either a gender- or age-related phenomena. The demonstrated soporific and chronobiotic effects of melatonin have often been suggested as desirable qualities in the treatment of insomnia. However, in insomniacs, especially elderly subjects with sleep disturbance, the efficacy of melatonin is not clear. Previous research has suggested that the sleep of melatonin-deficient elderly insomniacs might be improved with 1–2 mg oral melatonin, with administration continuing for between 7 days and 2 months.54 Still, a review of 78 studies examining the effect of melatonin on sleep in elderly insomniacs55 found that melatonin was most effective in elderly individuals also being treated with benzodiazepines or who showed low melatonin secretion during sleep. In younger adults with chronic insomnia, only one study has reported positive effects of melatonin (75 mg) on subsequent sleep.56 Other studies have not found any objective therapeutic effect of 1–5 mg oral melatonin given in the evening for up to a week in similar cohorts.43,44
78 A study by our group has shown that elderly female sleep maintenance insomniacs receiving 0.5 mg sustained release (transbuccal) melatonin on four consecutive nights had significantly decreased rectal core temperature but had no positive effects on any polysomnographic (PSG) (measure of sleep quality.57 This was consistent with an earlier study where we administered 5 mg melatonin orally at 14:00 h to a group of 12 elderly female sleep maintenance insomniacs during the day. Subjects displayed significant lowering of core temperature and decreased sleep onset latencies,58 however, compared to the magnitude of effects observed in younger subjects in other previous studies the effects were attenuated in older subjects. Therefore, while melatonin may decrease sleep onset latency and depending on dose and the target population may mildly improve other sleep parameters, its therapeutic efficacy is generally limited in elderly insomniacs. As suggested by Sack et al.,51 “IroniIronically, it may be the young who are more sensitive to melatonin’s soporific effects”.
Practice Point 5 There appears to be a complex interaction between age, gender and sleep status in determining the effects of melatonin. Older women are less responsive than younger women to soporific and thermoregulatory effects of melatonin, and younger insomniacs are less responsive than healthy young adults. It has not yet been investigated, however, whether melatonin has attenuated effects on sleep and body temperatures in older men.
Conclusions Wirz-Justice and Armstrong14 suggested that melatonin partially fits the definition of a hypnotic, “since it induces sleepiness and facilitates the onset of a ‘natural’ sleep EEG”. They nevertheless recommended that melatonin might better be called a soporific, and based on the evidence available 8 years since publication of their letter, we not only support their claim but further maintain that to class melatonin as a hypnotic is oversimplified and lacks sophistication. There is certainly a large body of evidence consistent with the suggestion that daytime melatonin ingestion results in, among other physiological changes, an increase in sleep propensity and
C.J. van den Heuvel et al. initiation of sleep in humans. However, we have presented compelling evidence to support the view that exogenous melatonin is only hypnotic in those species for which endogenous melatonin increases sleep propensity and is therefore a dark appropriate outcome. This review has also presented evidence in other key areas that demonstrates that melatonin does not have hypnotic properties under most conditions. In summary, there is evidence that melatonin at large pharmacological or supraphysiological doses appears to have limited or no soporific effects when given either during the day to nocturnal species, women in the luteal phase (just prior to menstruation), older women, or insomniacs, or to healthy subjects at night when endogenous production is high. Furthermore, daytime intravenous administration of melatonin that produces circulating levels equivalent to peak endogenous levels observed at night in young adults does not elicit significant changes in core temperature or subjective sleepiness. Finally, whereas the effects of traditional hypnotic agents cannot be easily counteracted, it would appear that only mild interventions such as adequate motivation or a change from supine to an upright posture are required to counteract the soporific effects of administered melatonin.
Research agenda While melatonin has chronobiotic effects which can be exploited in the treatment of sleep disturbance in circadian rhythm sleep disorders,59 or which occurs with jet-lag, shift work and blindness, it is still not clear what the precise physiological role of melatonin is concerning the regulation of body temperature and sleep. Acute soporific effects of melatonin are apparent in healthy young adults with daytime administration, but may not reflect its physiological role. Melatonin may nevertheless have some therapeutic use as a sleeppromoting or soporific agent.The circumstances raised in this review which suggest that melatonin administration is not always hypnotic indicate that many basic research studies still need to be conducted. Specifically, there are unresolved issues with melatonin and its efficacy relating to issues such as dosage, timing, age and gender, as well as long-term safety. Similarly, further investigation is required to define the effects of melatonin on the immune, reproductive and circadian systems.
Melatonin as a hypnotic: Con
Acknowledgements This work was supported by grants from the National Health and Medical Research Council and the Australian Research Council.
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