Therapeutic Dilemma: Melatonin or not?

ABSTRACT

THE DILEMMA

A 4-year-old child who you have been following is seen in the clinic with her parents. She was born at term and is developmentally normal. She has had three episodes of otitis media and has no other medical history. Her parents are concerned that she is not sleeping well in that she takes a long time to go to sleep. They were wondering if it might be worthwhile to try a course of melatonin to help improve her sleep.

BACKGROUND

Over the past decade, there has been a significant increase in the use of melatonin, primarily for sleep disorders, increasing significantly over the past decades in Canada, the USA, and Europe (1,2). Current estimates are that every month more than 9 million people in the USA use melatonin (1). Use has increased in both adults and children, with melatonin now being one of the commonest used natural products taken by children in Canada. This increase in use has been accompanied by a sharp increase in overdoses; a recent study by researchers in Michigan and Boston demonstrated a greater than 500% increase in melatonin overdoses in children reported to US Poison Control Centres from 2012 to 2020 (3).

WHAT IS MELATONIN?

This raises a number of questions. First, what is melatonin? Melatonin is a hormone that is present in a number of species. With specific reference to humans, melatonin is made in the brain—specifically in the pineal gland—from serotonin, an important neurotransmitter that the body produces from the amino acid tryptophan (2). Melatonin undergoes circadian variation, in that the pineal gland releases melatonin in response to darkness, with peak levels being attained approximately 2 h before sleep and then declining rapidly an hour or so before awakening (4). When released, melatonin has sleep-inducing effects mediated by the interaction of melatonin with specific receptors in certain parts of the brain.

THERAPEUTIC USES

Since the observation of the effect of light on melatonin release in humans in 1981, there has been a keen interest in whether melatonin could have a therapeutic role as a sleep-inducing agent (4). Recent estimates by the Centers for Disease Control are that 70 million Americans have some form of chronic sleep disorder. The consequences of disordered sleep are profound, both for the unfortunate individuals impacted and for society as a whole. Despite the large number of patients involved, there are very few truly effective and safe therapies for sleep, notably for chronic sleep disorders. Thus it should be no surprise that melatonin would be considered as a potential therapy.

Work with melatonin has demonstrated that in adults with circadian rhythm disorders—notably jet lag—melatonin is modestly effective in restoring normal sleep patterns (4). In low doses and for short periods of time melatonin therapy for adults appears to be fairly safe, while the safety and efficacy of melatonin for long-term use in the general population remain unclear.

THERAPEUTIC USE IN CHILDREN

How does this apply to children? First, it should be appreciated that sleep issues with children are surprisingly common. When we surveyed physicians in Southwestern Ontario—40% of who were paediatricians—we found that the vast majority had recommended or prescribed medications, both over-the-counter and prescription, for sleep promotion in children (5). While many of the children for whom these medications were recommended had conditions such as developmental delay or attention deficit hyperactivity disorder, many were otherwise healthy children. Of the medications used, the one most commonly used—in fact, 73% of the time for over-the-counter medication—was melatonin.

Sleep disturbances in children can be due to multiple causes. Behavioural insomnia in childhood is the commonest one in which psycho-physiological insomnia is characterized by heightened arousal and learned sleep prevention. Other causes include (i) circadian rhythm abnormalities, (ii) biological, medical, or behavioural causes, and (iii) delayed sleep-wake phase disorder in adolescents. Sleep disturbances are more common in children with developmental disabilities and, depending on the condition, can be seen in 13% to 86% of neurodivergent children.

Melatonin rhythm begins to be set around 3 months of age in typical development, at the same time that infants begin to have more regular sleep-wake cycles associated with nighttime sleep lasting 6 to 8 h. Final stabilization of the sleep-wake rhythm typically occurs by 3 years of age, which corresponds to a regular melatonin secretion rhythm.

This raises the question, does melatonin work for children? While there is less data than in adults, there is an emerging body of knowledge that demonstrates that children who are neurodivergent with conditions such as autism spectrum disorder or other developmental disorders have a very high rate of sleep disorders. Furthermore, children with autism spectrum and Trisomy 21 appear to have low melatonin concentrations which suggests that these can be improved by low-dose melatonin therapy (6). This may be due to differences in the rate of conversion of serotonin to melatonin, which results in a relative melatonin deficiency which produces a circadian rhythm disturbance (7).

A small study of the effect of melatonin on sleep in 26 children with autism spectrum disorder demonstrated statistically significant improvements in sleep-onset latency and sleep efficiency (7). In contrast, while melatonin can have a powerful placebo effect, there is no evidence that melatonin has similar efficacy in otherwise healthy children. What makes this an issue is the concern over the issue of melatonin overdose noted earlier. While melatonin is natural it is not non-toxic. The symptoms of overdose include drowsiness, nausea, vomiting, headache, and changes in blood pressure (https://doi-org.proxy1.lib.uwo.ca/10.1089/cap.2019.0108). Of particular note, of the melatonin overdoses reported by the US investigators 15% resulted in a hospital stay and nearly 300 children required an Intensive Care Unit admission (3).

Why do overdoses occur? There are two important factors. The first is that while low-dose melatonin is effective in children with certain conditions, lack of a response can be taken as the need for a higher dose, and thus well-intentioned parents may give their children an overly large dose. The second is that, unlike Europe, Japan, and Australia, in Canada and the USA, melatonin is considered a herbal medication or a dietary supplement, and thus is available over the counter and not subject to the strict quality control measures applied to prescription medications. As an example, a very large variation in melatonin content among over-the-counter products has been demonstrated by Saxena and Erland from the University of Guelph, with the majority of products having significant differences (−83% to +478%) in content from that stated on the label (8). Variability was greatest in lower doses (1 and 1.5 mg) and chewable formulations (8).

CONCLUSIONS AND RETURNING TO OUR PATIENT

What then should we do? For parents with children who are neurodivergent, low-dose melatonin—and this is often in the 1 to 2 mg/day range—may be a viable option to be pursued with their health care providers (7,9). Dosage recommendations for melatonin can vary depending on the type of sleep problem and the child’s age. Suggested doses for different age groups are 1 to 2 mg/h before going to sleep for preschool children, 2 to 3 mg for school-age children, and 5 mg for adolescents. As a caveat, children should always be started with the lowest dose of melatonin available, increasing the amount only if necessary based on inadequate response after a several-week trial (https://www.sleepfoundation.org/melatonin/melatonin-dosage-for-kids).

For otherwise healthy children, non-pharmacological remedies such as establishing a regular and consistent sleep routine are more likely to be rewarding over the long term, albeit being more demanding of parents. Groups such as the Sleep Foundation have useful resources on their website to help families with the all too common problem of helping children to go to sleep and stay asleep (https://www.sleepfoundation.org/baby-sleep).

ACKNOWLEDGEMENTS

The authors hold research support from external granting agencies including CIHR and NSERC and not in conflict of interest with the recommendations of this manuscript.

FUNDING

No funding to report.

POTENTIAL CONFLICT OF INTEREST

All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

REFERENCES