Table 5.

Melatonin Studies in Children in Canada

Reference	N (Age range, yr)	Melatonin Dosage	Duration	Summary/Comments
ADHD
Weiss60	19 (6–14)	5 mg Give 20 min before bedtime. Melatonin was manufactured by Circa Dia BV.	30-day cross over (10-day tx periods) with 3-mo post open-label study)	Nineteen children with ADHD and comorbid insomnia, who did not respond to sleep hygiene, were randomly assigned to receive melatonin vs placebo. Sleep onset latency was measured via actigraphy and somnolog (sleep diary). Actigraphy indicated superiority of melatonin by 16 min of decreased sleep latency (p < 0.01). Somnolog results noted a change from baseline (mean of 91.7 min) to a mean of 62.1 min on placebo (p < 0.05) and 46.4 min on melatonin (p < 0.01). SEs were similar (20% with melatonin, 23% with placebo). Except for migraine, all SEs were mild.
Insomnia
Carr61	44 (2–18)	5, 10, and 15 mg depending on response. Melatonin was obtained from Circa Dia BV.	Up to 9.6 yr, mean 4.3 yr	Open-label study obtained from 41 caregivers regarding long-term efficacy and safety of melatonin in children with neurodevelopmental disorders and refractory circadian rhythm sleep disorders. Mean age at enrollment was 6 yr. Mean duration and dose of melatonin was 4.3 yr and 10 mg, respectively. For part of the study, 5 mg SR melatonin was given (1 mg FR and 4 mg SR). At an unspecified time, the company manufactured a new 5-mg FR formulation. For the CR product: 19 children began 5 mg; 21 began 10 mg, and 4 began 15 mg. Efficacy with the FR formulation was less; hence, the dose was increased for the majority of the participants. All caregivers reported benefits on sleep difficulties and positive effects on overall health. Negative feedback related to the change in perceived effectiveness when CR formulation was changed to FR (9/41 caregivers, 22%). Although excessive morning sedation, nausea, diarrhea, irritability, nasal allergy, and rash were the most reported, they were mild. Limitations: Open-label with efficacy/safety determined by caregiver reports.
Neurodevelopmental disorders
Wasdell62	50 and 47 (2–18)	A range from 5 to 15 mg of CR melatonin. Given 20–30 min before bedtime. Melatonin was provided by Circa Dia BV, a 5-mg formulation (1 mg FR melatonin and 4 mg CR melatonin).	10 days of tx; 3–5 days washout period; 10 days of alternative tx; then 3 mo open-labeled study	A randomized, placebo-controlled trial of melatonin for delayed sleep phase syndrome and impaired sleep maintenance in 50 children with neurodevelopmental disorders. Forty-seven children then participated in a 3-mo open-label trial. A significant correlation was noted between the actigraphy and somnologs results for total night-time sleep and sleep latency. For actigraphy, night-time sleep (p < 0.01) and sleep latency (p < 0.01) improved. SEs reported were cold/flu/infection (20%), seizures (16%), and gastrointestinal illness (50%). Authors report similar SEs in the placebo group, but the quantity and frequency were not provided.
Jan63	42 (0.5–21)	A range from 2 to 25 mg of melatonin FR. FR was from Sigma Company (St Louis, MO) and CR was from Neurim Pharmaceuticals. In the subsequent study, FR and CR were obtained from Twin Laboratories (Ronkonkoma, NY).	Average duration of FR and CR was 2.2 and 2.8 yr, respectively.	Clinical trials of CR melatonin in 16 children with sleep-wake cycle disorders who were previously tx with FR melatonin. Patients could begin with CR melatonin and transition to FR, or vice versa. The final average doses for FR and CR melatonin was 7 mg and 5 mg, respectively. Younger children were started at smaller doses in the beginning of the trial but ended on larger doses than older patients, suggesting that dose and dose response is not directly proportional to age. CR tx resulted in ~50% reduction in dose from FR. Children had very complex neurodevelopmental disorders, which made determining SEs difficult. Some patients required a change in the doses of seizure medication following melatonin.

ADHD, attention-deficit/hyperactivity disorder; CR, controlled release; FR, fast release; SE, side effect; SR, sustained release; tx, treatment