Melatonin, Circadian Rhythms, and Sleep

Article (PDF Available)inCurrent Treatment Options in Neurology 5(3):225-229 · June 2003with 693 Reads
DOI: 10.1007/s11940-003-0013-0 · Source: PubMed
Abstract
Experimental data show a close relationship among melatonin, circadian rhythms, and sleep. Low-dose melatonin treatment, increasing circulating melatonin levels to those normally observed at night, promotes sleep onset and sleep maintenance without changing sleep architecture. Melatonin treatment can also advance or delay the phase of the circadian clock if administered in the evening or in the morning, respectively. If used in physiologic doses and at appropriate times, melatonin can be helpful for those suffering from insomnia or circadian rhythm disorders. This may be especially beneficial for individuals with low melatonin production, which is established by measuring individual blood or saliva melatonin levels. However, high melatonin doses (over 0.3 mg) may cause side effects and disrupt the delicate mechanism of the circadian system, dissociating mutually dependent circadian body rhythms. A misleading labeling of the hormone melatonin as a "food supplement" and lack of quality control over melatonin preparations on the market continue to be of serious concern.
Melatonin, Circadian
Rhythms, and Sleep
Irina V. Zhdanova, MD, PhD
*
Valter Tucci
Address
*
Department of Anatomy and Neurobiology, Boston University Medical
School, 715 Albany Street R-913, Boston, MA 02118, USA.
E-mail: zhdanova@bu.edu
Current Treatment Options in Neurology 2003, 5:225–229
Current Science Inc. ISSN 1092-8480
Copyright © 2003 by Current Science Inc.
Introduction
The major structures of the biologic clock system—
the pineal gland (epiphysis cerebri), the eyes, and the
suprachiasmatic nuclei (SCN) of the hypothalamus—
develop from the roof of the diencephalon. Together
these structures allow the perception or the translation
of changes in illumination caused by the earth’s daily
rotation and the organism’s adaptive adjustment to it.
Melatonin (N-acetyl-5-methoxytryptamine) is the
major hormone of the pineal gland and is secreted
exclusively at night. The circulating amino acid L-
tryptophan is the precursor of melatonin. Within cells
in the pineal gland, it is converted to serotonin by a
two-step process catalyzed by tryptophan hydroxylase
and 5-hydroxytryptophan decarboxylase. This process
involves serotonin’s N-acetylation, catalyzed by N-
acetyltransferase, and its methylation by hydroxyindole-
O-methyltransferase to produce melatonin. The
hormone is released directly into the blood stream and
the cerebrospinal fluid as it is synthesized and, because
it is lipid soluble, it has ready access to every cell of
the body. Approximately 50% to 70% of circulating
melatonin is reportedly bound to plasma albumin; the
physiologic significance of this binding is yet unknown.
Inactivation of melatonin occurs in the liver where
it is converted to 6-hydroxymelatonin by the P450-
dependent microsomal mixed-function oxidase enzyme
system. Most of the 6-hydroxymelatonin is excreted in
the urine and feces as a sulfate conjugate (6-sulfatoxy-
melatonin), and a much smaller amount is excreted as a
glucuronide. Some melatonin may be converted to N-
acetyl-5-methoxykynurenamine in the central nervous
system. Approximately 2% to 3% of the melatonin that
is produced is excreted unchanged in the urine.
Regular activation of the pineal gland is defined by a
periodic signal from SCN, which is the master biologic
clock.” The SCN is active during the day and slowed
down at night. A gradual reduction of SCN activity in
the evening promotes the onset of nocturnal melatonin
production. An abrupt imposition of bright light
at night activates SCN and suppresses melatonin
secretion. However, the exposure to darkness during the
daytime does not induce melatonin production.
Opinion statement
Experimental data show a close relationship among melatonin, circadian rhythms, and
sleep. Low-dose melatonin treatment, increasing circulating melatonin levels to those
normally observed at night, promotes sleep onset and sleep maintenance without
changing sleep architecture. Melatonin treatment can also advance or delay the phase
of the circadian clock if administered in the evening or in the morning, respectively.
If used in physiologic doses and at appropriate times, melatonin can be helpful for
those suffering from insomnia or circadian rhythm disorders. This may be especially
beneficial for individuals with low melatonin production, which is established by
measuring individual blood or saliva melatonin levels. However, high melatonin doses
(over 0.3 mg) may cause side effects and disrupt the delicate mechanism of the circa-
dian system, dissociating mutually dependent circadian body rhythms. A misleading
labeling of the hormone melatonin as a “food supplement” and lack of quality control
over melatonin preparations on the market continue to be of serious concern.
226 Sleep Disorders
The temporal pattern of melatonin production by
the pineal gland correlates with the timing of human
sleep. The onset of nighttime melatonin secretion is
initiated approximately 2 hours before individual’s
habitual bedtime and correlates with the onset of
evening sleepiness [1,2••]. Observations in human
infants also reveal that the timing of consolidation of
nocturnal sleep coincides with the onset of rhythmic
melatonin secretion, which occur when infants are
approximately 3 months old. Furthermore, a typical
reduction of melatonin secretion and sleep efficiency
with aging could be related phenomenon.
Acute reduction in circulating melatonin levels after
pinealectomy or from the suppression of melatonin
production by, for example, treatment with adrenergic
beta-blockers is reported to cause insomnia. In
contrast, an increase in circulating melatonin induced
by suppression of melatonin-metabolizing liver
enzymes results in increased sleepiness.
Two major effects of melatonin treatment on sleep,
a direct sleep promoting effect and a circadian phase
shifting effect, may occur jointly or separately. Physio-
logic (3 to 5 µg/kg) and higher, pharmacologic oral doses
of melatonin promote sleep onset or sleep maintenance
when administered at different time of the day [2••,3–5,
Class II]. The effect of melatonin on sleep initiation is
typically manifest 30 to 60 minutes after the treatment.
Studies in animal models suggest that this effect
results from the activation of specific melatonin recep-
tors. However, the exact brain structures conveying the
sleep-promoting effect of melatonin remain to be eluci-
dated. One of the candidate structures is SCN, although
presence of melatonin receptors in thalamic nuclei and
hindbrain may indicate that other sleep-related pathways
may be involved. Melatonin appears to also produce an
anxiolytic effect [6••, Class II], which could facilitate its
hypnotic property. Compared with the majority of the
existing hypnotics, the effects of melatonin on sleep
initiation are not accompanied by any dramatic changes
in electrophysiologic sleep architecture. Nevertheless,
some decrease of stage 4 and an increase in stage 2 may
occur in some individuals.
Although sleep-promoting effect of melatonin does
not significantly depend on the time of administration,
the timing of melatonin treatment is critical for its
effect on the phase of the circadian clock. Hormone
administration in the morning causes a phase delay,
although evening treatment results in phase advance.
Because sleep is under control of the circadian clock,
these changes in the circadian phase will cause a delay
in the onset of evening sleepiness or advance it to an
earlier hour.
Treatment
The sleep-promoting effect of melatonin is helpful in treating insomnia
of different origin, especially in individuals with low melatonin secretion.
The phase-shifting effect of melatonin can be beneficial to those suffering
from circadian rhythm disorders, including phase delay or phase advance
syndromes and blindness [7••, Class II]. The latter is associated with a
“free-running” circadian rhythm (ie, with a period of more or less than
24 hours) and results in sleep alterations. This effect of melatonin can
also help individuals with circadian rhythm alterations after transmeridian
flight or shift work to resynchronize their circadian body rhythms with the
environmental light-dark cycle. Moreover, patients with psychiatric and
neurologic disorders, especially those experiencing anxiety, could benefit
from melatonin treatment caused by hypnotic and anxiolytic effects of the
pineal hormone. Melatonin treatment may also attenuate the subjective
effects of drug withdrawal [6••, Class II].
Despite melatonin being currently sold in the US under a peculiar label as a
“dietary supplement,” it is highly unlikely that any kind of diet can modify
circulating melatonin levels. The amounts of melatonin in food are so
negligibly low that in order to consume enough food to match the lowest
physiologic oral dose used in human studies (eg, 0.1 mg) one would need
to ingest hundreds of bananas, tomatoes, or hundreds of pounds of rice
during one meal. Furthermore, melatonin is rapidly metabolized in the
body, with a half-life less than an hour, making its accumulation over days
Indications for melatonin therapy
Diet and lifestyle
Melatonin, Circadian Rhythms, and Sleep Zhdanova and Tucci 227
or weeks from consumption of melatonin-containing food impossible.
Hence, dietary control of circulating melatonin levels is unrealistic, and
calling the pineal hormone a food supplement is misleading.
Under normal conditions, melatonin secretion does not occur during
daytime and, thus, never coincides with bright environmental light. This
temporal dissociation is also assured by nighttime melatonin secretion
being significantly inhibited by the environmental light of relatively low
intensity, within the range of regular room illumination. Thus, an irregular
lifestyle or shift work would alter melatonin secretion and contribute to an
overall disruption of the circadian rhythms and sleep.
Melatonin administration induces high circulating levels of the hormone
that could not be opposed by light, which permits these two stimuli to
coincide in time. A combination of bright light and high circulating mela-
tonin levels is likely to cancel or significantly attenuate the effect of melato-
nin treatment. More importantly, this could produce an adverse effect on
the visual system, because melatonin has been reported to increase photo-
receptor susceptibility to light-induced damage in animals [8] and may
have a similar effect in humans [9••]. Thus, it is important not to expose
an individual to bright light during melatonin treatment.
Melatonin
Standard dosage Physiologic doses of melatonin (0.1 to 0.3 mg) are efficient in promoting sleep
and shifting the phase of the circadian clock in humans. After the administration
of a 0.3-mg dose of the hormone, blood melatonin levels typically reach 100 to
150 pg/mL, which is similar to those observed normally in the middle of the night.
However, in older individuals, the same dose can produce much higher melatonin
levels, because of alterations in melatonin metabolism in the liver. Thus, even a
relatively low melatonin dose may induce supraphysiologic circulating levels of
the hormone in some people over 50 years of age, and the appropriate dose should
be determined by measuring individual melatonin levels after treatment.
Typically, using an immediate-release (“fast”) melatonin preparation can
assure its overnight efficacy. In some patients, however, such fast-release prepara-
tions may not be able to sustain a high enough level of the hormone in the second
half of the night. If this is the case and the symptoms of the sleep disorder include
early morning awakening, an additional half-dose of melatonin (
eg,
0.1 mg) on
early morning awakening may be recommended.
Contraindications There are no known contraindications in using physiologic doses of melatonin
at nighttime in individuals with low melatonin secretion. However, melatonin
deficiency and individual physiologic dose should be determined based on blood
or saliva endogenous melatonin measurements at night or induced melatonin
levels reached 1 hour after treatment.
Main drug interactions Melatonin secretion depends on sympathetic innervation of the pineal gland.
Thus, it can be inhibited by beta-blockers [10]. In contrast, alpha-2-adrenoceptor
antagonists can enhance melatonin secretion at night [11].
Having a hypnotic property of its own, melatonin can also potentiate the
effects of other hypnotic agents. A preliminary study showed that melatonin can
facilitate a hypnotic effect of benzodiazepines and may allow reducing benzodiaze-
pine therapeutic doses [12••].
Because serotonin is a precursor for melatonin synthesis in the pineal gland,
substances that alter serotonin metabolism can affect melatonin production.
So far, studies produced somewhat conflicting results on the effects of serotonin
reuptake inhibitors,
eg,
fluvoxamine or fluoxetine, on melatonin synthesis; some
studies reported the increase in melatonin production [13] and others documented
Pharmacologic treatment
228 Sleep Disorders
its decline [14••]. Such results may be partially explained by different effects of
these drugs, ranging from increased extracellular serotonin levels to intracellular
serotonin depletion, depending on the doses and duration of treatment.
Other hormones can affect melatonin secretion or metabolism. For example,
a controlled trial found that a single dose of the synthetic corticosteroid dexa-
methasone suppressed production of melatonin in nine of 11 healthy volunteers
[15, Class I].
Main side effects The available pharmacologic doses of fast-release melatonin (eg, 3 mg) and low-
dose slow-release (or controlled) preparations (eg, 0.5 mg) tend to increase
hormone levels over a 24-hour period, thus altering the circadian pattern of
circulating melatonin [16••, Class II]. Abnormally high melatonin levels at night
and in the day after consumption of a pharmacologic dose of the hormone may
disrupt the delicate mechanism of the circadian system and dissociate mutually
dependent circadian body rhythms, which is described in a recent study [17]. Thus,
if administered in high doses or at inappropriate times, melatonin may induce a
circadian rhythm disorder rather than cure one.
Cost/cost effectiveness The price of melatonin on the market is relatively low, because of its label of a
“food supplement” and its wide availability. Unfortunately, lack of quality and
quantity control over the melatonin preparations sold on the US market does not
allow estimating its cost or cost effectiveness.
Recent studies suggest that melatonin therapy can be beneficial to children
and adults with a wide range of neurologic disorders associated with
seizures, mental retardation, attention deficit, and hyperactivity [18••,
Class II]. Another potentially important area of melatonin application is
anxiety disorders, for example, those associated with acute withdrawal
from drug abuse [17,19]. These new emerging applications of melatonin
may be related to its anxiolytic, myorelaxant, and hypnotic properties.
The human fetus and newborn infant do not produce melatonin but rely
on the hormone supplied via the placental blood and, postnatally, via the
mother’s milk. In infants older than 9 to 12 weeks, rhythmic melatonin
production increases rapidly; the highest nocturnal melatonin levels are
documented in children of 3 to 5 years of age. These data suggest that
melatonin may play an important role in development and that prenatal
and postnatal melatonin deficiency may have significant negative effects.
However, the role of melatonin in development is poorly understood and
requires further investigation before compensation of melatonin deficiency
during pregnancy or at early age can be recommended.
Melatonin treatment was successfully applied in children with a number
of neurologic disorders, including those affected by Angelman syndrome
[18••, Class II; 20••, Class II]. In such children, an increase in sleep quantity
and quality after melatonin (0.3 mg) administration was not accompanied
by significant changes in their daytime behavior. However, in some patients,
parents and teachers noticed a decrease in hyperactivity, and this effect
correlated with an increase in the children’s attention. Because children with
neurologic disorders are often prone to seizures, the reported antiseizure
properties of melatonin may provide an additional benefit for such patients.
If long-term melatonin treatment in these children is initiated, it is important
to use physiologic rather than pharmacologic doses of the hormone, because
excess melatonin may affect the development of the reproductive system.
Emerging therapies
Pediatric considerations
Melatonin, Circadian Rhythms, and Sleep Zhdanova and Tucci 229
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    Nocturnal frequency of urination (nocturia) is common in the elderly, and it is one of the most troublesome urologic symptoms. Urinary frequency interferes with daily activities, while nocturia may also result in sleep disturbance that can cause daytime fatigue as well as worsening the quality of life (QOL). Multiple factors may contribute to the occurrence of nocturia, including pathological conditions such as cardiovascular disease, diabetes mellitus, lower urinary tract obstruction, anxiety disorders or primary sleep disorders, and various other behavioral and environmental factors. Recently published guidelines have attributed the occurrence of nocturia to nocturnal polyuria and/or diminished nocturnal bladder capacity. However, since these factors may express the states of nocturia rather than the causes, it remains difficult to develop effective treatments for nocturia if the underlying etiology is not determined. Accordingly, in order to investigate which factors are strongly related to occurrence of nocturia, we performed a suite of examinations in elderly persons who had nocturia without any other diseases (elderly nocturia group) and two (young adult and elderly) control groups. As the results, sleep disturbance (a decrease of the nighttime plasma melatonin level), hypertension (an increase of nighttime plasma catecholamine levels), and excessive fluid intake (an increase of total urine volume) were major factors contributing to nocturia in the elderly. On the other hand, some elderly persons do not consider nocturnal urination to be bothersome even if they have a number of episodes. So, as a next step, the factors related to nocturnal urination that was not considered bothersome by comparing biochemistry tests were investigated between subjects who felt nocturnal urination (≤ twice per night) as bothersome and those who did not. As the results, the plasma melatonin level was lower in the bothersome group than in the non-bothersome group. Therefore, nocturnal urination might be not considered bothersome when subjects maintain sufficient levels of melatonin. As the third step, the effects of melatonin and the hypnotic, rilmazafone, on nocturia were compared in the elderly patients. After 4 weeks' treatment, the number of nocturnal urinations was decreased and the QOL score was improved in both groups. Melatonin and rilmazafone were equally effective for nocturia in the elderly, and the plasma melatonin level was increased in the melatonin-treated group. Therefore, the decrease of the plasma melatonin level may be one of the most important causes of nocturia, and sleep disturbance should be considered when choosing a therapy for nocturia.
  • Article
    There is no conclusive evidence supporting an interaction between the pineal gland and the hypothalamic-pituitary-adrenal axis. In this study, 11 healthy adults (six women, five men; aged 18–47 years) received a placebo the first night and 1 mg dexamethasone the next night at either 1800 or 2300 h. Administration of 1 mg of dexamethasone was followed by an attenuation of the nocturnal production of melatonin in 9 of 11 subjects. A significant reduction was found between melatonin plasma levels before and after dexamethasone at 0400h (P < 0.01, t test for dependent groups). It is suggested that dexamethasone affects nocturnal production of melatonin by means of mechanisms within the pineal gland.
  • Article
    Melatonin is an indolamine hormone synthesized in the retina and pineal gland. It is thought to act as a paracrine neurohormone in the mammalian retina. Pinealectomy has been shown to protect photoreceptors from light-induced damage, and melatonin treatment has been reported to increase the degree of photoreceptor damage in albino rats. To determine how melatonin influences photoreceptor survival, the effect of melatonin administration on light-induced retinal damage was studied. Melatonin was administered to albino rats by intraperitoneal injections at various times before or after light exposure. The rats were exposed to high-intensity illumination (1600 lux) for 24 hr to induce photodamage, then returned to cyclic lighting for 12 days. After this, they were killed, and their eyes were removed and examined histologically. Measurements of the outer nuclear layer (ONL) thickness were taken at 12 different loci around the circumference of the retinal sections. The animals that received daily melatonin injections (100 micrograms) in the late afternoon (3 hr before lights off) for 1-3 days before photodamage showed an approximate 30% greater reduction compared with sham control animals in ONL thickness in the superior quadrant, the area most susceptible to light damage. Melatonin injections given after the photodamage did not affect ONL thickness. Although retinal susceptibility to light damage varied with time of day, the degree to which melatonin increased the degree of damage appeared unaffected by the time of day. These results suggest that melatonin may be involved in some aspects of photoreceptor sensitivity to light damage.
  • Article
    Nocturnal plasma melatonin concentration was significantly increased in ten normal volunteers following the administration of an alpha 2 adrenoceptor antagonist, Org 3770 (30 mg). This result supports the existence of an alpha 2 adrenergic influence on melatonin secretion in man and provides a possible clinical neuroendocrine marker of the action of an alpha 2 antagonist.
  • Article
    There is no conclusive evidence supporting an interaction between the pineal gland and the hypothalamic-pituitary-adrenal axis. In this study, 11 healthy adults (six women, five men; aged 18-47 years) received a placebo the first night and 1 mg dexamethasone the next night at either 1800 or 2300 h. Administration of 1 mg of dexamethasone was followed by an attenuation of the nocturnal production of melatonin in 9 of 11 subjects. A significant reduction was found between melatonin plasma levels before and after dexamethasone at 0400 h (P less than 0.01, t test for dependent groups). It is suggested that dexamethasone affects nocturnal production of melatonin by means of mechanisms within the pineal gland.
  • Article
    The aim was to investigate the secretion profile of melatonin and seasonal affective disorder before and after treatment with fluoxetine. A six-week case-controlled study with repeated overnight blood sampling was conducted. Ten patients fulfilling the criteria for major depressive disorder, seasonal type, with a 29-item Hamilton Depression Rating Scale (HDRS) score of at least 20 were compared with ten age- and sex-matched healthy controls in a clinical laboratory. The effects of fluoxetine (20 mg/day) on the HDRS and melatonin concentration were measured. Fluoxetine significantly reduced melatonin levels in both groups. There was no significant difference in melatonin secretion between the groups. The effect of fluoxetine differs from tricyclics and fluvoxamine, both of which increase melatonin.
  • Article
    We previously observed tht low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using and involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced "hangover" effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.
  • Article
    Full-text available
    We examined effects of very low doses of melatonin (0.1-10 mg, orally) or placebo, administered at 1145 h, on sleep latency and duration, mood, performance, oral temperature, and changes in serum melatonin levels in 20 healthy male volunteers. A repeated-measure double-blind Latin square design was used. Subjects completed a battery of tests designed to assess mood and performance between 0930 and 1730 h. The sedative-like effects of melatonin were assessed by a simple sleep test: at 1330 h subjects were asked to hold a positive pressure switch in each hand and to relax with eyes closed while reclining in a quiet darkened room. Latency and duration of switch release, indicators of sleep, were measured. Areas under the time-melatonin concentration curve varied in proportion to the different melatonin doses ingested, and the 0.1- and 0.3-mg doses generated peak serum melatonin levels that were within the normal range of nocturnal melatonin levels in untreated people. All melatonin doses tested significantly increased sleep duration, as well as self-reported sleepiness and fatigue, relative to placebo. Moreover, all of the doses significantly decreased sleep-onset latency, oral temperature, and the number of correct responses on the Wilkinson auditory vigilance task. These data indicate that orally administered melatonin can be a highly potent hypnotic agent; they also suggest that the physiological increase in serum melatonin levels, which occurs around 2100 h daily, may constitute a signal initiating normal sleep onset.
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    Full-text available
    The ability of melatonin (MLT) to potentiate the effects of gamma-aminobutyric acid and the benzodiazepines has been demonstrated repeatedly in animal models, and recent experimental data favored the hypothesis that MLT, given together with threshold doses of benzodiazepines, could significantly improve the quality of sleep. This preliminary study was designed to compare the effects of MLT (100 mg) with those of a benzodiazepine hypnotic [triazolam (TRI) 0.125 mg] and to explore the effects of a combination of MLT and TRI at a low dose in healthy volunteers. No significant changes in the classical polysomnographic variables were observed following MLT, TRI and MLT + TRI, whereas MLT and especially MLT + TRI resulted in significant modulation of some microstructural parameters. These changes were paralleled by ameliorated subjective sleep quality. A combination of MLT and low benzodiazepine doses could avoid the residual, dose-related benzodiazepine effects.
  • Article
    The present study investigated the relationship between the time of nocturnal onset of urinary 6-sulfatoxymelatonin (aMT6s) secretion, and the timing of the steepest increase in nocturnal sleepiness ("sleep gate"), as determined by an ultrashort sleep-wake cycle test (7 min sleep, 13 min wake). Twenty-nine men (mean age 23.8 +/- 2.7 years) participated. The ultrashort sleep-wake paradigm started at 0700 hr after a night of sleep deprivation and continued for 24 hr until 0700 hr the next day. Electrophysiological recordings were carried out during the 7-min sleep trials, which were then scored conventionally for sleep stages. Urinary aMT6s was measured every 2 hr. The results showed that the timing of the sleep gate was significantly correlated with the onset of aMT6s secretion. These results are discussed in light of the possible role of melatonin in sleep-wake regulation.
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    Full-text available
    Low oral doses of melatonin raise serum melatonin concentrations to those normally occurring nocturnally and facilitate polysomnographically assessed sleep onset when given at different time points throughout the day, without altering mood or performance on the morning following treatment. In the present study, 12 young healthy volunteers, free of sleep disturbances, received 0.3 or 1.0 mg of melatonin or placebo at 2100 hours, 2-4 hours prior to their habitual bedtime. Polysomnographic recording of overnight sleep began at 2200 hours and continued until 0700 hours the following morning, when subjects were awakened. Sleep onset latency and latency to stage 2 sleep were significantly decreased as a result of melatonin treatment. Neither dose of melatonin significantly altered sleep architecture. Administration of the lower dose of melatonin (0.3 mg) at 2100 hours elevated serum melatonin to levels within the normal nocturnal range (113 +/- 13.5 pg/ml) at the time the sleep test was initiated. Neither melatonin dose caused "hangover effects", as assessed by self-reports or by mood and performance tests administered on the morning following treatment. These observations provide additional evidence that nocturnal melatonin secretion has a sleep-promoting function. They also indicate that an increase in serum melatonin concentrations, within the normal physiologic range, does not significantly alter sleep architecture in subjects with normal sleep who receive the treatment several hours prior to their habitual bedtime.