Potential safety issues in the use of the hormone melatonin in paediatrics

Abstract

Melatonin is a hormone produced by the pineal gland during the night in response to light/dark information received by the retina and its integration by the suprachiasmatic nucleus. When administered to selected populations of adults, in particular those displaying delayed sleep phase disorder, melatonin may advance the time of sleep onset. It is, however, being increasingly prescribed for children with sleep disorders despite the fact that (i) it is not registered for use in children anywhere in the world; (ii) it has not undergone the formal safety testing expected for a new drug, especially long-term safety in children; (iii) it is known to have profound effects on the reproductive systems of rodents, sheep and primates, as well as effects on the cardiovascular, immune and metabolic systems; and (iv) there is the potential for important interactions with drugs sometimes prescribed for children. In this review, I discuss properties of melatonin outside its ability to alter sleep timing that have been widely ignored but which raise questions about the safety of its use in infants and adolescents.

Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015

“…Long-term physiologic studies are needed to accurately ascertain any serious chronic risks, particularly as melatonin supplements are not subject to FDA oversight. 94 In January of 2014, the FDA approved the melatonin agonist Hetlioz TM (tasimelteon) for the treatment of N24SWD among the blind. This is the first FDA-approved drug for any CRSWD.…”

“…Optimal results were obtained with a dose of 0.15 mg/kg, taken 1.5-2.0 hours prior to habitual bedtime, for 6 nights. Although no serious adverse reactions have been described in relation to melatonin use to date, relevant concerns have been raised by select studies with respect to the pediatric/adolescent population, 94 and rigorous long-term data are lacking (see separate "Harms and Adverse Effects" section). As such, the benefits/harms assessment is uncertain.…”

“…As such, it may not generalize to all children/adolescents with ISWRD/neurologic disorders. Although no serious adverse reactions have been described in relation to melatonin use to date, relevant concerns have been raised by select studies with respect to the pediatric/adolescent population, 94 and rigorous long-term data are lacking (see separate "Harms and Adverse Effects" section). Nevertheless, clinical experience suggests that a majority of patients and caregivers would accept this treatment option (versus no treatment), particularly taking into account significant burdens associated with the neurologic disabilities and severe associated sleep disturbances.…”

Quality control and determination of melatonin in food supplements

“…On the other hand, melatonin or its contaminants have also been reported to induce eosinophilia in patients with cancer (Lissoni et al, 1993a;1993b) and to affect the reproductive systems of rodents, sheep and primates (Kennaway, 2015). Despite this, melatonin has been widely used as a food supplement for the alleviation of jet-lag and other disorders resulting from sleep delay (Brzezinski et al, 2005;Herxheimer & Petrie, 2002).…”

Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content

“…[6][7][8]10 Though melatonin consumption is generally considered to be of little risk, there have been reports of interaction of melatonin with other botanical and medicinal products, as well as negative side effects if taken in excess in the short term. [21][22][23][24][25] In contrast with melatonin, serotonin has much more significant health concerns if taken in excess, leading to a condition known as serotonin syndrome, which ranges from very mild to fatal in its outcome, which can be exacerbated by interactions with other medications, such as selective serotonin reuptake inhibitors (SSRIs) and the analgesic tramadol. 18,19,26,27 The large discrepancy in melatonin content compared to label claim and the presence of serotonin in a large percentage of supplements indicates that current best practices for production of melatonin supplements may require further attention, and further emphasizes that natural over-the-counter supplements do not always equal zero-risk alternatives to traditional medications.…”