1Department of Psychiatry, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
2Department of Psychiatry, Pusan National University School of Medicine, Yangsan, Korea
3Department of Pediatrics, Kosin University College of Medicine, Busan, Korea
Copyright © 2022 Kosin University College of Medicine.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author contributions
Conceptualization: EM, JHL. Data curation: JHL. Formal analysis: EM, JHL. Methodology: EM, JHL. Project administration: EM, JHL. Visualization: EM, JHL. Writing - original draft: EM, JHL. Writing - review & editing: EM, JHL. Approval of final manuscript: all authors.
Study (year) | Design/duration | Sample | Age (yr)a) | Diagnosis | Dose | Administration time | Principal adverse effects |
---|---|---|---|---|---|---|---|
Palm et al. (1997) [28] | Case series (1–6 yr) | 8 | 3–23 | Blindness and intellectual disability with non-24-hr sleep-wake syndrome | Initial dose: 0.5–2 mg | 30–60 min before bedtime | Reflux esophagitis complaints and increasing sleep disturbance |
Maximal dose: 4 mg | |||||||
Carr et al. (2007) [29] | Placebo-controlled, double-blind cross-over trial | 44 | 4.3 | Neurodevelopmental disability and treatment-resistant circadian rhythm sleep disorders | Sustained melatonin: mean 1.4 mg | NA | No serious adverse effects |
Open-label study (3 mo–3.8 yr) | |||||||
Hoebert et al. (2009) [30] | Randomized, double-blind, placebo-controlled trials | 101 | 6–12 | ADHD and chronic sleep onset insomnia | 3 mg/day (<40 kg) | NA | Dizziness (4.3%), bedwetting (3.2%), and sleep maintenance insomnia (3.2%) |
Open-label follow-up study (mean 3.7 yr) | 6 mg/day (≥40 kg) | ||||||
Yuge et al. (2020) [31] | 26-wk open-label study | 99 | 6–15 | Neurodevelopmental disorders with longer sleep onset latency (≥30 min for 3 or more mo) | Starting dose: 1 mg | 30–60 min before bedtime | TEAEs: 14.1% |
Final dose: 1, 2, 4 mg | All TEAEs: mild | ||||||
No TEAEs after 16 wk | |||||||
Withdrawal symptoms (–) | |||||||
Rebound phenomenon (–) | |||||||
Rebound | |||||||
Maras et al. (2018) [32] | Total 52 wk | 95 | 2–17.5 | ASD and neurogenetic disorders (with/without ADHD) with insomnia | Prolonged-release melatonin 2, 5, 10 mg | 30–60 min before bedtime | At least 1 TEAEs 17.9%, fatigue (5.3%), and mood swings (3.2%) |
13-wk double-blind phase + 39-wk continuous phase | |||||||
Malow et al. (2021) [33] | Total 104 wk | 80 | 2–17.5 | ASD with insomnia | Starting dose: 2 mg | 30–60 min before bedtime | Fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%) |
3-mo double-blind phase + 2-wk withdrawal phase + 90-wk continuous phase | After 3 wk: 2–5 mg | No significant changes on children's growth and pubertal development such as weight, height, body mass index, or pubertal status | |||||
After 12 wk: 5–10 mg |
Study (year) | Design/duration | Sample | Age (yr) |
Diagnosis | Dose | Administration time | Principal adverse effects |
---|---|---|---|---|---|---|---|
Palm et al. (1997) [28] | Case series (1–6 yr) | 8 | 3–23 | Blindness and intellectual disability with non-24-hr sleep-wake syndrome | Initial dose: 0.5–2 mg | 30–60 min before bedtime | Reflux esophagitis complaints and increasing sleep disturbance |
Maximal dose: 4 mg | |||||||
Carr et al. (2007) [29] | Placebo-controlled, double-blind cross-over trial | 44 | 4.3 | Neurodevelopmental disability and treatment-resistant circadian rhythm sleep disorders | Sustained melatonin: mean 1.4 mg | NA | No serious adverse effects |
Open-label study (3 mo–3.8 yr) | |||||||
Hoebert et al. (2009) [30] | Randomized, double-blind, placebo-controlled trials | 101 | 6–12 | ADHD and chronic sleep onset insomnia | 3 mg/day (<40 kg) | NA | Dizziness (4.3%), bedwetting (3.2%), and sleep maintenance insomnia (3.2%) |
Open-label follow-up study (mean 3.7 yr) | 6 mg/day (≥40 kg) | ||||||
Yuge et al. (2020) [31] | 26-wk open-label study | 99 | 6–15 | Neurodevelopmental disorders with longer sleep onset latency (≥30 min for 3 or more mo) | Starting dose: 1 mg | 30–60 min before bedtime | TEAEs: 14.1% |
Final dose: 1, 2, 4 mg | All TEAEs: mild | ||||||
No TEAEs after 16 wk | |||||||
Withdrawal symptoms (–) | |||||||
Rebound phenomenon (–) | |||||||
Rebound | |||||||
Maras et al. (2018) [32] | Total 52 wk | 95 | 2–17.5 | ASD and neurogenetic disorders (with/without ADHD) with insomnia | Prolonged-release melatonin 2, 5, 10 mg | 30–60 min before bedtime | At least 1 TEAEs 17.9%, fatigue (5.3%), and mood swings (3.2%) |
13-wk double-blind phase + 39-wk continuous phase | |||||||
Malow et al. (2021) [33] | Total 104 wk | 80 | 2–17.5 | ASD with insomnia | Starting dose: 2 mg | 30–60 min before bedtime | Fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%) |
3-mo double-blind phase + 2-wk withdrawal phase + 90-wk continuous phase | After 3 wk: 2–5 mg | No significant changes on children's growth and pubertal development such as weight, height, body mass index, or pubertal status | |||||
After 12 wk: 5–10 mg |
Safety issue | Current conclusion |
---|---|
What are the adverse effects of melatonin use in children and adolescents? | There were no serious adverse effects. Most TEAEs were mild. Frequent adverse effects were fatigue, somnolence, mood swings. |
Are there studies on safety of long-term melatonin use in children and adolescents? | Several studies on the long-term use of melatonin in children and adolescents reported no serious TEAEs and no significant changes in children’s growth and pubertal development. |
Does the use of melatonin inhibit the natural secretion of melatonin? | There was no evidence for the inhibition of endogenous melatonin rhythm. |
What drug interactions should be considered when using melatonin? | Melatonin is mainly metabolized through CYP1A2, and the expression of the CYP1A2 enzyme in children is low. When CYP1A2 inhibitors and enhancers are used together with melatonin, appropriate dose adjustment is required. In addition, when using melatonin in younger children, the bioavailability can be higher than would otherwise be expected. |
Can the adverse effects of melatonin use appear differently depending on the individual child or adolescent? | The adverse effects of melatonin use might be somewhat different based on individual characteristics, such as medical condition, endogenous melatonin level, melatonin dosage, and administration timing. |
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; NA, not assessed; TEAEs, treatment-emergent adverse events. Range or mean.
TEAEs, treatment-emergent adverse events; CYP1A2, cytochrome P450 1A2.