Abstract
Graphical abstract.
This is a visual representation of the abstract.
Keywords: melatonin, OTC melatonin, pediatric, circadian rhythm, insomnia, DLMO, DSPS, DSWPD
Melatonin is a naturally occurring hormone in humans produced primarily by the pineal gland. The natural rise of melatonin occurs in the early evening and “sends a message” for the person to go to sleep in approximately three hours. Melatonin is a versatile neurohormone that has been recognized to have multiple functions in children and adolescents.1 The purified forms of melatonin are widely used as prescription medications in sleep clinics around the globe (but not widely available in Canada) to treat Delayed Sleep Phase Syndrome (DSPS), which affects up to 16% of teenagers.2 In children, it is primarily used to treat insomnia and circadian rhythm disorders.3 Over-the-counter (OTC) and off-label melatonin have been increasingly used to treat pediatric insomnia in North America because of its supposed benign safety profile. The COVID-19 pandemic caused an increase in sleep disorders and mental health conditions in the general population and led to a skyrocketing of OTC melatonin's popularity. This was amplified by the lack of safety warnings. Are the present-day OTC melatonin products safe for consumers? In our search for answers to this question, we came across a selection of articles, which are presented below.
Current Recommendation for Melatonin Use in Children and Adolescents
Owens et al.3 recently outlined the recommendations for using melatonin to treat insomnia in typically developing children. Melatonin used as a hypnotic agent for the treatment of insomnia is controversial. Pediatric insomnia may be exacerbated by another sleep disorder such as obstructive sleep apnea, restless legs syndrome, periodic leg movement disorder and comorbid medical and psychiatric disorders. Before using melatonin to treat pediatric insomnia, it is reasonable to rule out other disorders, which may precipitate and perpetuate sleep disruptions. A sleep diary or actigraphy may shed light on sleep patterns and regularity.
If an adolescent shows signs of DSPS, such as frequently getting up late in the morning and catching up on sleep on weekends, it is important to evaluate them using the Dim Light Melatonin Onset (DLMO) test to gauge the extent of the phase shift. Treating DSPS with melatonin, with close monitoring by a physician, improves sleep. For optimal chronobiotic use, melatonin should be taken about three hours before bedtime and it can be effective in DSPS when given for 4 to 6 weeks at 7 PM.
Although melatonin is often viewed by parents as “natural” and safe, it should still be considered a hormonal medication.3 Furthermore, there are limited data on long-term effects of melatonin in children and adolescents. Notably, the effects of melatonin on bones and sexual maturation are not adequately understood. Therefore, a reliably produced melatonin should be used clinically for a short term and not as a long term “supplement”.
Is the Use of OTC Melatonin Sold in North America Safe?
Melatonin used as a hypnotic agent for the treatment of insomnia is controversial. Melatonin is available as an unregulated OTC supplement often used in children and adolescents in Canada and the United States (US). Erland and Saxena4 tested 31 OTC melatonin supplements purchased from grocery stores and pharmacies in Guelph, Ontario, Canada, and analyzed their content. The study showed that there is a high variability in melatonin concentrations, ranging from −83% to +478% of the labelled concentration.4 In addition, serotonin was also detected in 8 of 30 products tested.4
More recently, Cohen et al.5 analyzed 25 melatonin gummy products available in the US market. Of these, one product did not contain detectable levels of melatonin, but had 31.3 mg of Cannabidiol (CBD). In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving size. In products that contained melatonin, the quantity of melatonin ranged from 74% to 347% of the labeled quantity. Furthermore, the authors found that 22 of 25 products (88%) were inaccurately labeled, and only 3 products (12%) contained a quantity of melatonin that was within ±10% of the declared quantity.5 Five products declared CBD as an ingredient, and the quantity of CBD ranged from 10.6 mg to 31.3 mg per portion. The quantity of CBD ranged from 104% to 118% of the labeled quantity. From a clinician's perspective, such variability in quantity and the presence of contaminants in OTC melatonin limit its use as a reliable therapeutic option for consistent outcomes in both children and adults.
There have been deaths reported in young children in the US after taking off-label melatonin supplements.6,7 Since 2015, seven deaths of infants and toddlers, aged 2 months to 3 years, were investigated in North Carolina, USA.6 Melatonin levels in these children's post-mortem whole blood ranged from 3 to 1,400 ng/mL, far exceeding the endogenous concentrations. Notably, the unit of normal melatonin concentrations at different ages is in picograms or 10−12 per milliliter of serum. The amounts found in these children were at least a thousand times greater than that of the physiological levels. While the cause and the manner of all seven deaths were classified as “undetermined”, these findings are noteworthy. Endogenous melatonin production does not begin until the pineal gland matures at around 3 months of age. 6 These tragic cases show that administering children OTC melatonin may result in markedly greater levels of melatonin than that from endogenous sources (see Table 1 for current dosing recommendations3). Although lethal outcomes were not solely attributed to exogenous melatonin overdose, this should now be a focus in toxicology. Labay et al.7 pointed out that severe adverse effects or fatal consequences as a direct result of OTC melatonin use are not recorded due to a lack of awareness. Melatonin is presumed to be safe and is not included in routine toxicology panels designed for post-mortem investigations. According to Lelak et al.,8 between 2012 and 2021 there was a 530% rise in calls to US Poison Control Centers for pediatric melatonin ingestions. This resulted in 27,795 emergency department and clinic visits, 4,097 hospitalizations, 287 intensive care unit admissions and 2 deaths.8 According to a survey by Bock et al.,9 of 67 pediatricians and family physicians in Southwestern Ontario included in their study, a total of 30% recommended OTC supplement or prescription medication to otherwise healthy children with sleep problems. OTC melatonin (73%), OTC antihistamines (41%), antidepressants (37%) and benzodiazepines (29%) were the most commonly recommended and prescribed medications.9
Table 1.
Age-Dependent Melatonin Dosage Recommendations for Children.3
| Age | Recommended Dose |
|---|---|
| Infants (0–2 years) | Not recommended |
| Toddler (2–3 years) | Up to 1 mg |
| Preschool (4–5 years) | Up to 2 mg |
| School-Age (6–10 years) | Up to 3 mg |
| Older School-Age and Adolescents | Up to 5 mg |
The Figure 1 infographic summarizes the potential causes for the variability and contamination in OTC melatonin. It is clear that there is a paucity of surveillance and statistics in Canada and both the general public and clinicians are under-informed and unaware of the potential dangers of OTC melatonin. There is a need for manufacturers to engage in rigorous testing and quality assurance to minimize the risk of variability and contamination in melatonin supplements. Regulatory efforts should be implemented to mandate manufacturers to perform rigorous testing.
Figure 1.
A Graphic Summary of the Possible Reasons for Variability and Contamination in OTC Melatonin. CBD = Cannabidiol.
Acknowledgments
We would like to thank Dr. Praveen Saxena of the University of Guelph for providing input regarding important concepts and the possible reasons for variability and contamination in OTC melatonin. We would also like to thank Ms. Ilana Rosen, who created the infographics.
Footnotes
Author Contributions: CK is the primary author, performing the majority of the literature search, reviewing, writing the major details of this article and formatting the article for submission. PY and RG are the second and third authors, respectively, helping with the literature search, reviewing, adding specific details, reorganizing portions of the text, providing feedback and editing. Dr. Colin Shapiro is the overviewing author and professor with expertise in psychiatry, sleep medicine and has published in this area. He also provided feedback, guidance on key references, editing, adding essential details and orchestrating the article's direction.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Chris Y. Kim https://orcid.org/0009-0006-9393-5201
Persis Yousef https://orcid.org/0009-0003-7994-4564
Royi Gilad https://orcid.org/0000-0001-9045-3932
Colin M. Shapiro https://orcid.org/0000-0002-2231-0427
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