Efficacy and safety of supplemental melatonin for delayed sleep–wake phase disorder in children: an overview

Abstract

Delayed sleep–wake phase disorder (DSPD) is the most frequently occurring intrinsic circadian rhythm sleep–wake disorder, with the highest prevalence in adolescence. Melatonin is the first-choice drug treatment. However, to date melatonin (in a controlled-release formulation) is only authorised for the treatment of insomnia in children with autism or Smiths-Magenis syndrome. Concerns have been raised with respect to the safety and efficacy of melatonin for more general use in children, as melatonin has not undergone the formal safety testing required for a new drug, especially long-term safety in children. Melatonin 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. The objective of the present article was therefore to establish the efficacy and safety of exogenous melatonin for use in children with DSPD, based on in vitro, animal model and clinical studies by reviewing the relevant literature in the Medline database using PubMed. Acute toxicity studies in rats and mice showed toxic effects only at extremely high melatonin doses (>400 mg/kg), some tens of thousands of times more than the recommended dose of 3–6 mg in a person weighing 70 kg. Longer-term administration of melatonin improved the general health and survival of ageing rats or mice. A full range of in vitro/in vivo genotoxicity tests consistently found no evidence that melatonin is genotoxic. Similarly long term administration of melatonin in rats or mice did not have carcinogenic effects, or negative effects on cardiovascular, endocrine and reproductive systems. With regard to clinical studies, in 19 randomised controlled trials comprising 841 children and adolescents with DSPD, melatonin treatment (usually of 4 weeks duration) consistently improved sleep latency by 22–60 min, without any serious adverse effects. Similarly, 17 randomised controlled trials, comprising 1374 children and adolescents, supplementing melatonin for indications other than DSPD, reported no relevant adverse effects. In addition, 4 long-term safety studies (1.0–10.8 yr) supplementing exogenous melatonin found no substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores. Finally, post-marketing data for an immediate-release melatonin formulation (Bio-melatonin), used in the UK since 2008 as an unlicensed medicine for sleep disturbance in children, recorded no adverse events to date on sales of approximately 600,000 packs, equivalent to some 35 million individual 3 mg tablet doses (MHRA yellow card adverse event recording scheme). In conclusion, evidence has been provided that melatonin is an efficacious and safe chronobiotic drug for the treatment of DSPD in children, provided that it is administered at the correct time (3–5 h before endogenous melatonin starts to rise in dim light (DLMO)), and in the correct (minimal effective) dose. As the stat...

Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

“…This variability could be due to differing or overlapping etiologies of ADHD, whether it is a manifestation of genetic SNPs related to sleep disturbance and circadian rhythm dysfunction or attributed to the melatonin-signaling deficiency. More research is needed to determine appropriate dosage protocols specific to the pathophysiology of ADHD under the supervision of a qualified healthcare professional [ 114 , 115 ].…”

Analysis and Evaluation of the Effects of Melatonin on Oral Keratinocytes: A Pilot Study

“…Most of the rest of the evidence regarding melatonin and the potential cellular effects comes from our understanding of melatonin supplementation and these relationships with circadian rhythms and sleep [57,58]. Of particular interest has been the effects of melatonin on children and adolescents, who may be treated with melatonin for sleepwake and sleep phase disorders that have recently been observed at increasingly higher rates [59,60]. Research that seeks to understand the effects of melatonin and how normal oral cells and tissues function in response to melatonin without injury or insult is therefore of increasing importance [61].…”

Melatonin Treatment for Pediatric Patients with Insomnia: Is There a Place for It?

“…A review of 19 randomized controlled trials of IR melatonin daily treatment on a total of 841 children and adolescents with DSPD showed a consistent improvement of sleep latency by 22 to 60 min without serious adverse effects. 47 A meta-analysis of seven RCTs assessing efficacy and safety of melatonin in 387 children and adolescents with sleep-onset insomnia associated with DSPD from 6 to 19 years old concluded that melatonin advanced mean sleep-onset time by 37 min and DLMO by 49 min, 46 including two RCTS on children and adolescents with ADHD (see Table 1 ). 134 , 135 Another study from Mohammadi et al in 2012 evaluated the effect of combined treatment of melatonin (3–6 mg) and methylphenidate (1 mg/kg) in a group of 26 children with ADHD whose sleep symptoms were assessed using the Sleep Disturbance Scale for Children (SDSC) parent-questionnaire, with a placebo group of 24 children treated with placebo+methylphenidate (1 mg/kg).…”

“…Alternatively, for a combination of the chronobiotic, chronohypnotic and soporific effect of IR melatonin (see Part I, above), a prescription of 1 to 3 mg at bedtime is equally interesting (though the degree of the induced phase shift will be less than if given several hours earlier, see Figure 2 ). 47 , 132 Even though the benign safety profile of melatonin is established (see above), as chronotype varies across lifespan and endogenous circadian rhythm may change during long-term treatment, it is recommended to stop and reassess the indication of melatonin treatment regularly (at least once a year, for example during the summer holidays).…”

“…Across studies, melatonin (IR as well as PR) has overall displayed a very benign safety profile (for studies and reviews in children and adolescents, see references. [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] In terms of toxicology, melatonin has a good safety profile event at extremely high doses (up to 1600 mg) in adults, as shown by a recent meta-analysis, 62 even though some authors suggest possible effects on the hypothalamic pituitary gonadal axis and the cardiovascular system in healthy adults. 63 No suicide has ever been reported with melatonin even with very high doses (Texas Poison Centers, 779 cases between 1998 and 2003).…”