Melatonin as a hypnotic: Pro

doi:10.1016/j.smrv.2004.04.003

Sleep Medicine Reviews

Volume 9, Issue 1, February 2005, Pages 51-65

https://doi.org/10.1016/j.smrv.2004.04.003 Get rights and content

Abstract

In diurnal species, nocturnal melatonin secretion coincides with the habitual hours of sleep, in contrast to nocturnal animals which are at the peak of their activity while producing melatonin. Studies in humans, diurnal non-human primates, birds and fish show that melatonin treatment can facilitate sleep initiation during the daytime or improve altered overnight sleep. Behaviorally, the sleep-promoting effects of melatonin are distinctly different from those of common hypnotics and are not associated with alterations in sleep architecture. The effects of melatonin on sleep are mediated via specific melatonin receptors and physiologic doses of the hormone, those inducing circulating levels under 200 pg/ml, are sufficient to promote sleep in diurnal species. Aging reduces responsiveness to melatonin treatment and this correlates with reduced functional potency of melatonin receptors. Since melatonin receptors are present in different tissues and organs and involved in multiple physiologic functions, using physiologically relevant doses (0.1–0.3 mg, orally) and time of administration (at bedtime) is recommended, in order to avoid known and unknown side effects of melatonin treatment.

Introduction

Melatonin is the principal hormone of the circadian system, secreted exclusively at night in both nocturnal and diurnal species. The way this circadian signal is interpreted may depend on the animal's strategy of adaptation to periodic changes in the environmental illumination. Being a highly lipophylic hormone, melatonin reaches every cell of the body. The wide distribution of melatonin receptors also suggests that melatonin affects various tissues and organs and, thus, can be involved in multiple physiologic processes. Only some of these processes have been studied, one of them is sleep.

It took one (unrelated) clinical trial to discover that melatonin affects sleep. It has taken decades thereafter to confirm, detail and further explore this phenomenon. Major differences in experimental designs and populations studied often make it difficult to compare studies on the effects of melatonin on human sleep. However, the overall data from human and, lately, animal-based studies suggest that:

(a)
Melatonin can promote sleep in healthy humans and other diurnal animals, if administered during habitual hours of wakefulness. It can improve overnight sleep in insomniacs but does not alter sleep in healthy individuals. Melatonin can facilitate the effects of common hypnotics, thus reducing their effective dose and facilitating drug withdrawal.
(b)
The dose-dependence of melatonin's effect on sleep is within physiologic or low pharmacologic range, i.e. 50–200 pg/ml in blood plasma. Increasing melatonin above these levels does not increase melatonin efficacy but may cause side effects, e.g. circadian rhythm alterations.
(c)
The efficacy of melatonin to promote an individual's sleep depends on circulating melatonin levels and sensitivity of the individual's melatonin receptors. Sensitivity to melatonin may decline with age and as a result of neurodegenerative disorders.
(d)
Melatonin affects sleep via specific melatonin receptors, presumably MT1, and via cAMP-dependent signaling pathway. It remains to be elucidated whether one particular physiologic target or the combined response of several organs and tissues defines a behavioral picture we call the ‘sleep-promoting effect of melatonin’.

Section snippets

Melatonin can promote sleep

The first word on melatonin affecting sleep came from the ‘father’ of melatonin, Aaron Lerner, who identified and named this substance produced by the pineal gland and linked it to previously described lightening effects of pineal extracts on amphibian skin color. Since Dr Lerner studied the human pigmentation disease, vitiligo, he administered the newly-discovered endogenous substance to his patients hoping to see an effect on altered skin pigmentation. Instead, his patients became sleepy. The

Dose-dependence of melatonin's effects on sleep

The effects of biologically-active substances are always dose-dependent, although the type of dose-dependence varies. The initial studies, including those by Dr Lerner, utilized doses of melatonin in the range of 50–1000 mg orally or up to 200 mg iv.*The most important references are denoted by an asterisk.*1., 2., 3. After physiologic circulating melatonin levels have been measured in humans, it became clear that in all these studies gigantic increases in circulating melatonin were induced, to

Acute versus circadian effects of melatonin on sleep

It has been well established that melatonin can shift the circadian phase of suprachiasmatic nuclei of the hypothalamus (SCN) activity or entrain a free-running circadian rhythm to a period of melatonin administration. This action is likely to underlie the effects of melatonin on the circadian phase of sleep initiation, helpful to blind individuals with free-running rhythms or to those suffering from jet-lag.

It is, however, important to distinguish the circadian from the acute sleep-promoting

Effects of melatonin on sleep in animal models

Technical and ethical issues preclude many types of studies that could help to elucidate the mechanisms of melatonin action in humans. Initial animal-based studies on the effects of melatonin on sleep produced inconsistent results, only some being able to show that very high pharmacologic doses of melatonin produce sedative effects. However, animals used to study the effects of melatonin on sleep at that time were either those with crepuscular (cats) or nocturnal (rats) activity pattern. Unlike

Behavioral effects of melatonin differ from those of common hypnotics

The nature of melatonin's effect on sleep is such that it typically does not produce a rapid increase in subjective sleepiness, an uncontrollable urge to fall asleep or major impairments in cognitive performance.*The most important references are denoted by an asterisk.*1., 2., 3., 4., 5., 6., 7., 8., 9., 10., 11., 12., *13., 14., *15., 16., 17. In contrast to common hypnotics, and we have repeatedly underscored this, melatonin induces a behavioral state that resembles quiet wakefulness, which

Circulating melatonin levels and insomnia

Recognition that the pineal hormone produced every night can promote sleep suggested that melatonin deficiency may underlie some sleep disorders. One of the first questions to answer was whether insomniacs have lower melatonin levels than individuals with normal sleep.

Typically, melatonin secretion undergoes a predictable change over the life span. Newborn babies do not secrete melatonin for approximately the first 3 months of life. The onset of melatonin secretion appears to coincide with the

Effects of melatonin treatment in insomniacs

Observations of sleep-promoting effects of daytime melatonin administration in healthy individuals suggested that melatonin might help insomniacs to sleep better. In order to test this hypothesis, several research groups have conducted studies treating insomniacs with different melatonin doses. The results of these studies have varied, with some documenting positive effects of melatonin treatment, while others report no effect. Among possible explanations for differences in the results obtained

Mechanisms of melatonin's sleep-promoting effect

There are several critical questions regarding the mechanisms of the behavioral effects of melatonin. Do specific melatonin receptors mediate sleep-promoting effect of the hormone? If yes, which melatonin receptor subtype is responsible for the effects observed and where are these receptors localized? Which other receptors melatonin might act upon?

Conclusions

Melatonin is an exceptionally interesting hormone. Its evolutionary roots can be traced to unicellular organisms, invertebrates and lower vertebrates, which produce and use this small amine for time navigation. Every night humans and other mammals secrete melatonin and it conveys a message of darkness to every cell of the body. If an organism can perceive and translate this message, it will be prepared for complex adaptation to the periodically changing environment. Would the responses to this

Acknowledgements

This work was supported by grants AG 17636 from the National Institute on Aging and MH 65528 from the National Institute of Mental Health.

References (63)

F. Anton-Tay et al.
On the effect of melatonin upon human brain. Its possible therapeutic implications
Life Sci
(1971)
R. Nave et al.
Melatonin improves evening napping
Eur J Pharmacology
(1995)
Zhdanova et al.
Melatonin promotes sleep in three species of diurnal nonhuman primates
Physiol Behav
(2002)
Zhdanova et al.
Melatonin promotes sleep-like behavior in zebrafish
Brain Res
(2001)
N. Murakami et al.
Effect of melatonin on circadian rhythm, locomotor activity and body temperature in the intact house sparrow, Japanese quail and owl
Brain Res
(2001)
E.M. Mintz et al.
Daytime melatonin infusions induce sleep in pigeons without altering subsequent amounts of nocturnal sleep
Neurosci Lett
(1998)
D.J. Dijk et al.
Melatonin effect on daytime sleep in men: suppression of EEG low frequency activity and enhancement of spindle frequency activity
Neurosci Lett
(1995)
G. Pillar et al.
Melatonin improves sleep-wake patterns in psychomotor retarded children
Pediatr Neurol
(2000)
A. Miyamoto et al.
Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome
Brain Dev
(1999)
M.G. Smits et al.
Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial
J Am Acad Child Adolesc Psychiatry
(2003)

D. Garfinkel et al.

Improvement of sleep quality in elderly people by controlled-release melatonin

Lancet

(1995)

D.A. Golombek et al.

Melatonin effects on behavior: possible mediation by the central GABAergic system

Neurosci Biobehav Rev

(1996)

R. Nave et al.

Hypnotic and hypothermic effects of melatonin on daytime sleep in humans: lack of antagonism by flumazenil

Neurosci Lett

(1996)

R. Mason et al.

The electrophysiological effects of melatonin and a putative melatonin antagonist (N-acetyltryptamine) on rat suprachiasmatic neurons in vitro

Neurosci Lett

(1988)

K. Nakahara et al.

Effects of microinjection of melatonin into various brain regions of Japanese quail on locomotor activity and body temperature

Neurosci Lett

(2003)

B.A. Middleton et al.

Melatonin and fragmented sleep patterns

Lancet

(1996)

A.B. Lerner et al.

Melatonin

Fed Proc

(1960)

H. Cramer et al.

On the effects of melatonin on sleep and behavior in man

Adv Biochem Psychopharmacol

(1974)

F. Waldhauser et al.

Sleep laboratory investigations on hypnotic properties of melatonin

Psychopharmacology

(1990)

O. Tzischinski et al.

Melatonin possesses time-dependent hypnotic effects

Sleep

(1994)

A.B. Dollins et al.

Effect of pharmacological daytime doses of melatonin on human mood and performance

Psychopharmcology

(1993)

M. Matsumoto

The hypnotic effects of melatonin treatment on diurnal sleep in humans

Psychiatry Clin Neurosci

(1999)

T. Satomura et al.

Hypnotic action of melatonin during daytime administration and its comparison with triazolam

Psychiatry Clin Neurosci

(2001)

R.J. Hughes et al.

Sleep-promoting and hypothermic effects of daytime melatonin administration in humans

Sleep

(1997)

C. Cajochen et al.

Evening administration of melatonin and bright light: interactions on the EEG during sleep and wakefulness

J Sleep Res

(1998)

S.P. James et al.

The effect of melatonin on normal sleep

Neuropsychopharmacology

(1987)

A.B. Dollins et al.

Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance

Proc Natl Acad Sci USA

(1994)

Zhdanova et al.

Sleep-inducing effects of low doses of melatonin ingested in the evening

Clin Pharm Ther

(1995)

Zhdanova et al.

Effects of low oral doses of melatonin, given 2–4 hours before habitual bedtime, on sleep in normal young humans

Sleep

(1996)

M.E. Attenburrow et al.

Low dose melatonin improves sleep in healthy middle-aged subjects

Psychopharmacology (Berlin)

(1996)

B.M. Stone et al.

Hypnotic activity of melatonin

Sleep

(2000)

Cited by (186)

Effects of melatonin implants on locomotor activity, body temperature, and growth of lambs fed a concentrate-based diet
2023, Journal of Veterinary Behavior
Melatonin is involved in the regulation of circadian rhythms and is implicated in seasonal reproduction in sheep. In several physiological mechanisms, it acts as an antioxidant and an anti-inflammatory molecule, regulating energy metabolism. This work investigated the effects of melatonin implants at 30 days of age on locomotor activity (LA), body temperature, and growth of fattening female and male lambs. Sixty lambs were divided into two groups: one of which received melatonin (MEL, 15 males, 16 females) and a control group (CTR, 16 males, 14 females). In the melatonin group, two 18 mg melatonin implants were placed at 30 days of age. Lambs were fattened for 6 weeks from weaning (45 days of age) to slaughter (85 days). The feed conversion rate (FCR) was calculated based on live weight and the amount of concentrate consumed. LA was measured weekly by actigraphy, and circadian rhythmicity was calculated. Rectal (Trec) and surface temperatures (Tsur) were recorded in the last week of fattening, and subcutaneous fat thickness (FT) over the longissimus dorsi muscle was measured by ultrasound scanning. Treatment did not affect FCR, although MEL female lambs consumed significantly (P < 0.001) less concentrate than CTR lambs. Treatment and sex had a significant (P < 0.05) interaction effect on FT; specifically, FT was significantly (P < 0.05) higher in female MEL lambs (3.22 ± 0.21 mm) than in female CTR lambs (2.57 ± 0.24 mm), but FT in males did not differ between MEL (2.77 ± 0.21) and CTR (2.94 ± 0.24 mm) lambs. Overall activity was significantly (P < 0.001) lower in the MEL lambs (72.22 ± 0.10 counts/min) than in the CTR lambs (78.89 ± 0.12 counts/min). MEL lambs had a significantly (P < 0.01) lower Trec (CTR: 39.00 ± 0.07; MEL: 38.68 ± 0.10) and Tsur for all body regions evaluated than the CTR lambs. In conclusion, treatment with exogenous melatonin at 30 days of age increased food efficiency in fattening female lambs, probably, because of the lower metabolism in treated lambs, which was reflected by the lower body temperature and LA exhibited by these animals. In addition, the study has demonstrated the effect of exogenous melatonin in the growth performances of post-weaning lambs, and that its effects depend on animal sex, which suggests that treatments that target females might be most appropriate in the fattening period.
Neuroendocrine hormones and signaling systems in sea cucumbers
2023, The World of Sea Cucumbers: Challenges, Advances, and Innovations
Sea cucumbers occupy a special evolutionary space between Protostomia and Chordates and are widely studied in comparative endocrinology to provide insight into the evolutionary origins of neurohormone signaling systems in vertebrates. This chapter summarizes research progress in nonpeptide hormones, neuropeptides, and the signaling systems in multiple sea cucumber species, with an outlook on neuroendocrine biology in echinoderms and prospects for using neurohormone products in sea cucumber aquaculture.
Light and melatonin treatment for shift work
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
Between 10 and 30% of workers carry out night work at least once a month and 12–13% are working on rotating or regular night shifts. These atypical work schedules cause irregular, fragmented sleep patterns, as well as alertness and performance impairments at night. Atypical work schedules result in circadian misalignment, a state of desynchronization between the endogenous circadian system and the environment. Working at night also produces a state of internal desynchronization between several levels of the circadian system. Circadian adaptation to a night-oriented schedule is a gradual process requiring extended, consistent, and regular exposure to the altered work-rest cycle. There is a high degree of variability in the capacity of individuals to adapt to night schedules and it is estimated only 1 out of 4 workers is able to do so without specific interventions to facilitate circadian phase shifts. As light is the must powerful synchronizer of human circadian rhythms, countermeasures based on strategic light-dark interventions can favor circadian adaptation to atypical work schedules or modulate the secretion of melatonin at night. Melatonin, a hormone secreted by the pineal gland at night can also be administered exogenously to promote sleep in the daytime and shift human circadian rhythms. Most of our knowledge on the resetting and melatonin suppressive effects of light are based on the study of non-shift working populations in highly controlled laboratory conditions. In the field, exogenous melatonin proved useful to extend daytime sleep, although, still today, its resetting effects of shift workers' circadian rhythms remain unclear. The aim of this article is to review the latest scientific evidence on the usefulness of strategic light-dark interventions and on the use of melatonin and melatonin agonists prior to daytime sleep periods in shift working populations.
Role of melatonin in Alzheimer's disease: From preclinical studies to novel melatonin-based therapies
2022, Frontiers in Neuroendocrinology
Melatonin and novel melatonin-based therapies such as melatonin-containing hybrid molecules, melatonin analogues, and melatonin derivatives have been investigated as potential therapeutics against Alzheimer’s disease (AD) pathogenesis. In this review, we examine the developmental trends of melatonin therapies for AD from 1997 to 2021. We then highlight the neuroprotective mechanisms of melatonin therapy derived from preclinical studies. These mechanisms include the alleviation of amyloid-related burden, neurofibrillary tangle accumulation, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, and impaired neuroplasticity and neurotransmission. We further illustrate the beneficial effects of melatonin on behavior in animal models of AD. Next, we discuss the clinical effects of melatonin on sleep, cognition, behavior, psychiatric symptoms, electroencephalography findings, and molecular biomarkers in patients with mild cognitive impairment and AD. We then explore the effectiveness of novel melatonin-based therapies. Lastly, we discuss the limitations of current melatonin therapies for AD and suggest two emerging research themes for future study.
Genetic and biological factors in sleep
2022, Foundations of Sleep Health
Sleep is an extremely complex state that exhibits substantial diversity in human populations, and rapidly accumulating research indicates many of these differences are at least partially attributable to genetic contributions. Genetic polymorphisms affecting sleep timing, length, and quality have all been identified, along with other features further influencing how an individual’s sleep behavior is affected by their environment. These range from the subtle and unnoticeable without advanced analytic tools to the profound and pathologic with impacts upon everyday life. This chapter overviews findings on the breadth of genetic contributions to sleep patterns, as well as other biological factors that interact with genetics to affect sleep, such as sex, hormonal regulation, and comorbid diseases.
Melatonin for delirium prevention in hospitalized patients: A systematic review and meta-analysis
2021, Journal of Psychiatric Research
Citation Excerpt :
However, in the past decade there has been growing interest in the efficacy of melatonin on delirium prevention. Melatonin is a pineal gland hormone which has hypnotic and anti-inflammatory effect (Zhdanova, 2005; Esposito and Cuzzocrea, 2010; Hardeland et al., 2011). Melatonin modulates the circadian rhythms, sleep, and neurotransmitters (Hardeland et al., 2011), all of which are thought to be related to delirium (Trzepacz, 1999; Maclullich et al., 2008).
Melatonin, a pineal gland hormone is reported to have a protective effect against delirium. This systematic review and meta-analysis explores the effect of melatonin and melatonin receptor agonist, ramelteon on delirium prevention in adult hospitalized patients.
Randomized Controlled trials of melatonin/ramelteon published up to May 7, 2020 were identified from MEDLINE, PREMEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled trials, PubMed, and Google Scholar. The primary outcome was delirium incidence. The secondary outcomes were sleep quality, sedation score, sedatives requirement, delirium duration, length of hospital stay, length of Intensive Care Unit (ICU) stay, mortality and adverse events. A meta-analysis with a random-effects models was performed. Estimates were presented as Risk Ratio (RR) or Mean Differences (MD) with 95% Confidence Interval (CI).
Fourteen studies with 1712 participants were included. Melatonin/ramelteon significantly reduced delirium incidence (RR 0·61, 95% CI 0·42–0·89, p 0·009) with risk reduction of 49% in surgical patients and 34% in ICU patients. Non-significant reduction was found in medical patients. Melatonin/ramelteon were associated with improvement in sleep quality, increased sedation score and lower sedatives consumption. However, they did not reduce delirium duration, length of hospital stay, length of ICU stay and mortality. Hallucinations, nightmares and gastrointestinal disorders were prevalent in melatonin group.
Melatonin/ramelteon are associated with reduction in delirium incidence in hospitalized patients. However, this effect seems confined to surgical and ICU patients. The optimum dosage and formulation of melatonin, and treatment duration remain uncleared and open to further studies with larger sample sizes.

View all citing articles on Scopus

View full text

CLINICAL REVIEWMelatonin as a hypnotic: Pro

Abstract

Introduction

Section snippets

Melatonin can promote sleep

Dose-dependence of melatonin's effects on sleep

Acute versus circadian effects of melatonin on sleep

Effects of melatonin on sleep in animal models

Behavioral effects of melatonin differ from those of common hypnotics

Circulating melatonin levels and insomnia

Effects of melatonin treatment in insomniacs

Mechanisms of melatonin's sleep-promoting effect

Conclusions

Acknowledgements

Life Sci

Eur J Pharmacology

Physiol Behav

Brain Res

Brain Res

Neurosci Lett

Neurosci Lett

Pediatr Neurol

Brain Dev

J Am Acad Child Adolesc Psychiatry

Lancet

Neurosci Biobehav Rev

Neurosci Lett

Neurosci Lett

Neurosci Lett

Lancet

Melatonin

Fed Proc

On the effects of melatonin on sleep and behavior in man

Adv Biochem Psychopharmacol

Sleep laboratory investigations on hypnotic properties of melatonin

Psychopharmacology

Melatonin possesses time-dependent hypnotic effects

Sleep

Effect of pharmacological daytime doses of melatonin on human mood and performance

Psychopharmcology

The hypnotic effects of melatonin treatment on diurnal sleep in humans

Psychiatry Clin Neurosci

Hypnotic action of melatonin during daytime administration and its comparison with triazolam

Psychiatry Clin Neurosci

Sleep-promoting and hypothermic effects of daytime melatonin administration in humans

Sleep

Evening administration of melatonin and bright light: interactions on the EEG during sleep and wakefulness

J Sleep Res

The effect of melatonin on normal sleep

Neuropsychopharmacology

Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance

Proc Natl Acad Sci USA

Sleep-inducing effects of low doses of melatonin ingested in the evening

Clin Pharm Ther

Effects of low oral doses of melatonin, given 2–4 hours before habitual bedtime, on sleep in normal young humans

Sleep

Low dose melatonin improves sleep in healthy middle-aged subjects

Psychopharmacology (Berlin)

Hypnotic activity of melatonin

Sleep

CLINICAL REVIEW
Melatonin as a hypnotic: Pro