A systematic literature search was conducted across MEDLINE (PubMed), Cochrane Central Register of Controlled Trials, Scopus, and Web of Science until May 2025. Randomized controlled trials (RCTs) of melatonin for migraine prophylaxis in patients aged 2-17 years were included. Exclusion criteria comprised other headache types, combination therapies, and non-trial publications. Two independent reviewers performed the study selection and data extraction.

Three RCTs (113 participants) met the inclusion criteria. Melatonin was consistently well tolerated, with no serious adverse events reported. In one RCT (n = 42) comparing melatonin with placebo, there was no significant difference in the reduction of monthly headache frequency (mean difference: melatonin -10.3 ± 6.3 vs. placebo -10.0 ± 7.2; p = 0.93). In two RCTs comparing melatonin with amitriptyline, amitriptyline demonstrated significantly greater efficacy, leading to a larger reduction in monthly headache frequency (Study 1: melatonin -7.67 ± 4.8 vs. amitriptyline -11.52 ± 6.9 attacks/month; p < 0.001; Study 2: melatonin -10.44 ± 4.2 vs. amitriptyline -12.54 ± 4.6 attacks/month; p < 0.0001) and a higher rate of ≥50% reduction in headache frequency (“good response”) (Study 1: melatonin 62.5% vs. amitriptyline 82.5%; Study 2: melatonin 66.7% vs. amitriptyline 84.4%; p < 0.04 for both).