ARTICLE IN PRESS

Current Paediatrics (2006) 16, 132138

Available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/cupe

Melatonin and sleep in children with

neurodevelopmental disabilities and sleep disorders
E. Wassmera, W.P. Whitehouseb,
a

Neurology Department, Birmingham Childrens Hospital, Birmingham, UK

School of Human Development, University of Nottingham, Nottingham, UK

KEYWORDS
Melatonin;
Sleep;
Children;
Neurodevelopmental
disorders

Summary
Sleep disorders impair the quality of life for children with neurodevelopmental disabilities
and their families. Melatonin, a natural regulator of sleep, may be an effective therapy in
this area. Numerous studies in children report that melatonin may be beneficial for
sleep. Studies differ widely from each other with respect to the dosage and time of
administration. The effectiveness of melatonin depends on a number of factors, including
dose, the individual sensitivity of the patient and the time of administration. Few acute
adverse effects have been reported. Long-term adverse effects have not been systematically studied. Well-designed, randomised, controlled studies with long-term follow-up
in children are needed.
& 2006 Elsevier Ltd. All rights reserved.

Introduction
Practice points

 Melatonin is used effectively in children with




neurodevelopmental disabilities and various sleep

problems
A large randomised placebo controlled trial is being
funded in the UK through the Department of Health
in this population
Melatonin has a very good safety profile in the short
and medium term

Corresponding author. School of Human Development, University

of Nottingham, E Floor, East Block, Queens Medical Centre,
Nottingham NG7 2UH, UK. Tel.: +44 (0) 115 924 9924x 44476; fax:
+44 (0) 115 823 0626.
E-mail address: william.whitehouse@nottingham.ac.uk
(W.P. Whitehouse).

0957-5839/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cupe.2006.01.001

Sleep is important for children. Sleep disorders, i.e., sleep

loss and excessive daytime sleepiness are associated with
behavioural and performance deficits.1,2 Impaired vigilance,
memory, mood and increased upper airway collapsibility,
and decreased respiratory drive are adverse effects of sleep
loss.3 These deficits will increase pre-existing morbidity and
decrease the quality of life of the child and his family.4 Many
children with neurodevelopmental disabilities and visual
impairment suffer from sleep disorders. Prevalence rates of
severe sleep disorders in this population have been assessed
as 86% up to age 6 years, 81% in 611 years olds and 77% in
1216 years olds.5 Difficulty going to sleep and repeated
waking in the night are the most common sleep problems in
the neurologically disabled child and young adult.5 Intrinsic
and extrinsic factors play a role. Intrinsic factors include an
immature brain;6 sensory dysfunction, especially visual;7
disturbance of circadian rhythm;8 disturbing nocturnal

ARTICLE IN PRESS
Melatonin and sleep in children with neurodevelopmental disabilities
seizures9; hypotonia and structural changes giving rise to
obstructive sleep apnoea syndrome.10 Other factors are
brainstem maldevelopment leading to central apnoea,10
pain due to orthopaedic problems and gastroesophageal
reflux.11 Extrinsic factors include medications that can
disturb normal sleep9 and parental expectations of the
vulnerable child. The consequences of impaired sleep can
be severe for the neurodevelopmentally disabled child and
his or her family. Parents and siblings of affected children
are awakened and also suffer sleep deprivation. Sleep
disorders can lead to learning and behavioural problems in
the affected child, parenting difficulties, high levels of
maternal stress and marital discord.9,12,13 They affect the
health, social, emotional and economic functioning of the
entire family14 and treatment can be difficult. When
treatment is successful it is associated with improved
behaviour, maternal health and family functioning.15 Behavioural treatments can be effective,16,17 however, this form
of treatment is not given frequently as it requires time and
effort and access to well-trained professionals for assessment and treatment. Sedative drugs are often not very
effective and can cause unwelcome adverse effects. In the
UK, melatonin is currently being used to help children with
neurodevelopmental disabilities to sleep. It seems to be
effective and have very few adverse effects, and parents
claim it improves their quality of life. Over 100 published
open-label trials have shown that melatonin can be
effective and safe,11 however, there are few good quantitative studies.18 Despite little evidence, melatonin is a
commonly prescribed drug for children with neurodisabilities and sleep disorders.

Basic physiology
Melatonin or N-acetyl-5-methoxytryptamine is a small lipidsoluble indolamine molecule,11,19,20 which can easily cross
most membrane barriers. It is produced mainly by the pineal
gland, but is also secreted in the retina, gastrointestinal
tract, skin, lacrimal glands and other tissues. However, in
these tissues the actions of melatonin appear to be
restricted only to the local areas.
In the pineal gland melatonin is synthesised by the
pinealocytes. Tryptophan is converted to serotonin, then to
N-acetylserotonin and finally to melatonin. Arylakylamine
N-acetytransferase and hydroxyindole-O-methyltransferase
are the enzymes responsible for the daynight rhythm of
melatonin production. The rate limiting enzyme for synthesis
of melatonin is N-acetyltransferase, which is produced mainly
during the night resulting in 100-fold greater nighttime than
daytime plasma levels. Norepinephrine mainly initiates the
production through adrenergic receptors on the pinealocytes.
Melatonin secretion has a circadian rhythm and is
influenced by environmental light. Pineal melatonin secretion depends on light being transmitted to the retina, which
through the retinohypothalamic tract influences the function
of the suprachiasmatic nucleus (SCN), the anterior hypothalamic region, the paraventricular nucleus and the lateral
hypothalamus area. Through the sympathetic nervous system, superior cervical ganglion, and norepinephrine, the
pineal gland secretes melatonin into the circulation (Fig. 1).
The melatonin will then attach to specific melatonin

Figure 1.

133

The control of endogenous melatonin secretion.

receptors. Melatonin receptors are found in the brain, visual

system, heart, lung, arteries, adrenal gland and many other
organs. The exact molecular mechanisms involved in the
retinal-SCN communication are still unclear. Darkness stimulates the synthesis and release of melatonin and light inhibits
this process. However, the circadian rhythm of melatonin
secretion is of endogenous origin, environmental light then
entrains the rhythm. The SCN is responsible for the
production of melatonin in the pineal gland. Additional input
from the brain influences melatonin production. In humans
melatonin secretion increases soon after the onset of
darkness, peaks in the middle of the night (24 a.m.) and
then gradually falls. The average day time plasma level in
young adults is 10 pg/ml, rising to 60 pg/ml at night.
Melatonin secretion varies with age. Babies less than 3
months secrete very little at all. Then it increases and
becomes circadian in older infants. The peak nocturnal
concentrations are highest age 13 years (mean 325 pg/ml)
after which they decline. The elderly have very little
melatonin secretion.

Melatonin as a drug
Exogenous melatonin is absorbed in the small intestine.
Absorption is decreased in the presence of food. Melatonin is
transported by the portal circulation to the liver. It is
disseminated throughout the body by the systemic circulation. The absolute bioavailability is about 15%. Ingestion of
0.10.3 mg results in an increase in plasma melatonin to a
level that is within the normal range of endogenous
melatonin.21 One to 5 mg exogenous oral melatonin given
at night will give 10100 times higher than usual nighttime
peak, within 1 h of ingestion. The bioavailablity varies due
to variation in first pass metabolism, melatonin receptor
density, and variable endogenous circulating levels.

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134

E. Wassmer, W.P. Whitehouse

Melatonin is metabolised in the liver. It is hydroxylated to

6-hydroxymelatonin. Exogenous melatonin is rapidly metabolised with a plasma half-life 0.51 h.22 Melatonin metabolites conjugated with sulphuric (80%) or glucoronic acid
(20%) are excreted in the urine (75%) and faeces (25%) with
the major metabolite being 6-sulphatoxy melatonin. Ingestion of 1 g melatonin at bedtime would lead to complete
metabolism and excretion by morning.22 Low-dose exogenous oral melatonin (15 mg) declines to baseline plasma
melatonin levels within 48 h.

Mendelsons38 review of placebo-controlled studies concluded that there was no evidence that melatonin administration improved sleep in insomniacs. Zhadanova and
Wurtman39 established a hypnotic effect of exogenous
melatonin in humans. The studies differ widely with respect
to subjects (healthy adults or insomniacs), the dosage (from
0.1 to 1000 mg), the route of administration (intravenous,
nasal or oral) and the time of administration (day or night).
The effectiveness of any biologically active molecule will
depend on a number of factors including dose, the individual
sensitivity of the organism and the time of administration.

Function of melatonin
The role of melatonin in humans is unclear. The pineal gland
is essential for animals to survive, as without this they are
unable to respond to seasonal and circadian cues. However,
humans with pinealectomy survive. Because melatonin is
secreted at night and has a circadian rhythm, it may play a
role in indicating to humans day and night and in inducing
sleep. The distribution of melatonin receptors has suggested
many other functions. Many organs such as the retina,
bowel, heart, liver and bone marrow have their own
circadian clocks and produce minute amounts of melatonin,
which only act locally. However, pineal melatonin is the
internal synchroniser of these local circadian rhythms.23
Besides regulating the sleepwake cycle and its hypnotic
properties, melatonin may have anxiolytic properties in
mood disorders.24 Melatonin may have antioxidant properties, which may have a therapeutic effect in infections,
ischaemia, chemotherapy and aging.25 Melatonin has been
used to treat osteoporosis,26 headache,27 hypertension,28
inhibit sexual maturation and reproduction29,30 and has been
claimed to have a preventive and therapeutic role in
cancer31 through its antiproliferative properties32 and
enhancement of the immune system.33 There is some
evidence supporting these claims (Table 1).

Melatonin and sleep

Studies in adults show that melatonin regulates the
sleepwake cycle.3437 Besides the phase-shifting effect,
melatonin may have a somnogenic effect; however, studies
of exogenous melatonin have given inconsistent results.
Table 1

Studies of the use of melatonin in children

Melatonin has been used to treat sleep disorders since the
early 1990s. In 1991 Palm et al.40 described the first
melatonin treatment of a blind child with multiple disabilities, who had a fragmented sleep pattern. Subsequently
numerous case reports and studies have been published on
the use of melatonin in paediatric sleepwake cycle
disorders. Table 219,41 lists the larger case series and
studies.4271 Most of these children were neurologically
impaired with or without visual problems. Ages ranged from
0.5 to 18 years. The doses ranged from 2 to 10 mg at
nocturnal bedtime. None of the authors noted significant
adverse effects even though some children had used
melatonin for 57 years. Few studies of melatonin treatment
of non-circadian sleep disorders have been published. In
most studies melatonin was beneficial for sleep. Few studies
have been published reporting the contrary (possibly
because of reporting bias). However, there have been very
few well-designed controlled and long-term studies.18 A
systematic review of randomised, controlled trials identified
only three studies involving a total of 35 children.18
Clinical experience suggests that melatonin can induce
and maintain sleep. However, it is unclear exactly how
melatonin does this, although there is increasing understanding of some of the multitude of mechanisms involved.11
Melatonin is thought, for example, to inhibit neuronal
excitability in the central nervous system directly.
Sleep disorders in children with neurodevelopmental
disabilities are not just simply due to a deficiency of
melatonin secretion, which can be treated by replacing the

Potential effects of melatonin.

Functions

Mechanism

Evidence

Sleep-hypnotic

Hypothermic
Retina-mediated action on limbic system
Melatonin response to SCN input
Retina-mediated action on neural & peripheral
tissues
Unknown
Inhibition of hypothalamicpituitarygonadal axis

Placebo-controlled clinical trials

Circadian Rhythm control

Mood-cyclic disorders
Sex. maturation & reproductioninhibition
Cancer-antiproliferative
Immune system-enhanced
Aging-decreased cell damage

Direct effect
Scavenging of free radicals
Increased Interleukin production by T-helper cells
Scavenging of free radicals

Human & animal studies

Comparitive clinical studies

Human & animal studies
In vitro & in vivo animal studies
Few clinical studies
Human & animal studies
In vitro & in vivo animal studies

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Melatonin and sleep in children with neurodevelopmental disabilities

Table 2

135

Treatment of children with melatonin: series of more than five children.

Author

Year

Study

Number of
subjects

Response (good/
moderate/poor)

Sleep effected P/E/I

Jan et al.42
Jan and ODonnell43
Zhdanova et al.44
Camfield et al.45
Masters46
Palm et al.47
Schmitt-Mechelke48
Ross et al.49
Hung et al.50
Jan et al.51
Vancouver study
Edmonton study
Wassmer et al.52
Ross and Whitehouse53
McArthur and Budden54
OCallaghan et al.55
Zhdanova et al.56
Okawa et al.57
Ishizaki et al.58
Jan et al.59
Jan60
Dodge and Wilson61
Wassmer et al.62
Smits et al.63
Wassmer et al.64
Ross et al.65
Ramstad and Loge66
Paavonen et al.67
Ivanenko et al.68
Coppola et al.69
Hancock et al.70
Gupta et al.71

1994
1996
1996
1996
1996
1997
1997
1997
1998
1998

PC
UCT
UCT
DBP
UCT
UCT
UCT
UCT
UCT

15
100
12
6
20
8
36
16
37

Moderate (12/15)
Moderate (82%)
Good
Poor (3/6)
Good
Good (7/8)
Good (94%)
Poor (44%)
Good (86%)

P
P
I
E
P
P

UCT
PC
UCT
UCT
DBP
DBP
UCT
UCT
UCT
UCT
UCT
DBP
CT
DBP
UCT
UCT
UCT
UCT
UCT
DBP
DBCO
DBP

90
16
12
43
9
7
13
20
50
42
10
20
68
40

Good (87%)
Moderate (79%)
Good (11/12)
Moderate (77%)
Good
Good (6/7)
Good
Poor (2/20)
Good (42/50)
Good
Good (80%)
Good (18/20)
Good (80%)
Good
Good (80%)
Moderate 34/46
Good 13/15
Good
Good (91%)
Good
Good
Good

1998
1998
1998
1999
1999
1999
1999
2000
2000
2001
2001
2001
2001
2002
2002
2003
2003
2004
2005
2005

46
15
15
32
25
8
31

I (&P)
I, E &P
I, E
I
E
P&I
I, E, P
P
P
I, E
I
P
I
E
P
I
I, E
P
I, E,
E

CT, controlled trial; I, induces sleep onset; UCT, uncontrolled clinical trial; P, shifts phases of sleep; PC, placebo controlled; E,
improves sleep efficiency/quality; BCO, double-blind crossover (not placebo); DBP, double blind placebo.

missing hormone. Sleep is regulated by the autonomic

nervous system, as it stimulates melatonin secretion. Brain
damage can affect the autonomic nervous system. However,
melatonin levels can be elevated and patients may still
experience sleep disturbance. Sleep is a complex neurological function. Normal sleep is a learned behaviour in
response to environmental cues. Children with disabilities
may not respond adequately to environmental cues and then
retain an infantile fragmented sleep pattern. Sleep can be
disturbed due to excessive excitatory input. In order to fall
asleep, the brain must inhibit the arousal state. This
inhibition may be inefficient in children with neurodevelopmental disabilities, for example, due to brain damage.

Sleep induction for medical investigations

Melatonin was found effective in inducing sleep for sleep EEG
recording72 and was also found to be effective in children,
inducing stage III or IV sleep in about 80%, and increasing the
yield of epileptiform abnormalities without any alteration in

sleep macro-structure.62 In this respect it compared favourably with sleep-deprivation, but was significantly better
tolerated by the patients and their families.73 It is used
routinely by several clinical neurophysiology departments in
the UK now, especially for children who may be uncooperative and have neurodisabilities. Melatonin has been
used to induce sleep for auditory brainstem evoked potentials,74,75 however, it was not so reliable in this setting,
probably because auditory stimuli are so arousing.
Melatonin is starting to be used in paediatric neuroimaging, where sleep can often effectively prevent movement
and anxiety. In one series it was successful in inducing sleep
and enabling successful brain magnetic resonance imaging
(MRI) in about 50% of children, many of whom were too old
for the local sedation protocol (over 7 years of age) and had
severe learning and behavioural difficulties.76 When it
worked it avoided the need for formal sedation or general
anaesthetics with their attendant costs and risks. Melatonin
seems to switch on normal sleep (as seen in the EEG)
and if a child is safe in normal sleep at home then no
special monitoring or supervision is needed in hospital for

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136
melatonin-assisted sleep. Melatonin has even been used as a
preoperative premedication.77

Sleep assistance in other medical settings

We have used melatonin to good effect, in inpatients with
acutely severely disrupted sleep to re-establish more normal
circadian rhythms. Sometimes it is combined with phototherapy during the day to suppress endogenous melatonin
and try and normalise reversed sleepwake cycles. This has
been a noticeable problem in a minority of children
recovering from a variety of illnesses, including acquired
brain injuries, on the paediatric intensive care unit. So far
this experience remains anecdotal.

Adverse effects
One of the problems is that melatonin is available in many
countries over the counter and is regarded as a food
supplement. The purity and exact dosage of melatonin is
therefore unknown for many products, available without the
strict quality control regulation applied to drugs. At one time
melatonin was even obtained from the pineal glands of cattle.
This confuses the beneficial and the adverse effects of the
hormone. It is recommended that the synthetic form is used
and that the manufacturers follow Good Manufacturing
Practise (GMP) rules, so that the consumer obtains safe and
consistent products, avoiding adverse effects from impurities.
Melatonin appears to have extremely low acute toxicity.78
In rats and mice oral doses of melatonin in excess of
1000 mg/kg were needed to cause death. These doses are far
above the recommended doses for human consumption
(maximum is 5 mg/kg). Overdose experience with melatonin
in humans is limited, but significant toxicity has not been
observed. In human clinical studies daily administration
short-term seems to be well tolerated.79 Mild adverse effects
have been reported such as drowsiness, headache, confusion
or agitation, depression, cramps and rashes. None of the
paediatric studies have reported serious adverse effects.
There are case reports of apparent adverse effects from
ingestion of melatonin including psychosis80 and autoimmune hepatitis.81 Adverse events reported to the Food and
Drug Associations (FDAs) special nutritional adverse event
monitoring system (SN/AEMS) included, amongst others,
hypertension, stroke, pneumonia, adult respiratory distress
syndrome, dizziness, depression, confusion, headache,
sleep disturbance and gastrointestinal disturbance. These
adverse events could be true rare effects of melatonin or
they could be coincidental or could be due to using
unregulated products with impurities.
Long-term adverse effects have still not been ruled out.
Just as there are many potential beneficial effects, there
could be, theoretically, as yet unknown serious adverse
effects. As melatonin can cross the placenta, teratogenic
effects are possible. In animals receiving large doses, no
effects were noted in the offspring.82 Melatonin may affect
sexual maturation and reproductive function,30,8385 Large
doses of up 300 mg were given to women in one study as a
contraceptive, without the desired effect.30 There is some
evidence that chronic melatonin use may exacerbate gastric
ulcer disease,86 hypertension,87 glucose intollerance88 and

E. Wassmer, W.P. Whitehouse

mood disorders.80 Melatonin may have an adverse immunomodulatory effect in asthma.89
The most concerning adverse effect reported is the effect
on epilepsy. Many children with epilepsy have been treated
with melatonin for sleep disorders with no pro-convulsant
effect. Sheldon90 warned of pro-convulsant effects of
melatonin in neurologically disabled children in a small,
uncontrolled case series of six children. However, suppression of seizure activity has been shown to occur after
melatonin administration71,9193 and melatonin has been
used to treat seizures.94,95

Concomitant medication and disease

There is very little information on the drug interactions of
melatonin. It is metabolised by the classic reaction
sequence of hydroxylation and conjugation, common to
steroids and many drugs. Haloperidol, phenothiazines and
benzodiazepines inhibit melatonin metabolism. Fluvoxamine increases melatonin while fluoxetin reduces endogenous melatonin. Melatonin is an antagonist of calcium
channel blockers such as nifedipine.
The effects of concomitant disease, e.g., liver or kidney
disease on melatonin physiology or pharmacology are
unknown. As melatonin is metabolised by the liver,
melatonin use in patients with liver disease could lead to
elevated levels of the hormone. In patients with liver
cirrhosis the half-life of melatonin was twice the half-life
than healthy subjects.

Conclusions
The effect of melatonin on sleep in adults is inconsistent,
but the studies differ with respect to subjects, dosage and
the time of administration. There seems to be a consensus
that melatonin may be useful in the treatment of paediatric
sleep disorders. The exact mechanism is complex. Although
melatonin seems to be safe, caution is warranted. We are
currently helping to set up a double-blind, placebocontrolled trial with colleagues in other hospitals in the
UK, and hope to add to the increasing information about this
exciting treatment.

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Further reading
1. Gordon N. The therapeutics of melatonin: a paediatric perspective. Brain Dev 2000;22:2137.
2. Sweis D. The uses of melatonin. Arch Dis Child Educ Practice Ed
2005;90(3):ep747.