Efficacy and Safety of Melatonin in Migraine Prophylaxis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Migraine is a chronic, disabling brain disorder. Melatonin, a circadian regulator with anti-inflammatory and antinociceptive actions, has been proposed for migraine prevention. We evaluated the efficacy and safety of melatonin for prophylaxis. Methods We systematically searched PubMed, Cochrane, Scopus, Embase, and Web of Science (September 29, 2024) for randomised controlled trials (RCTs) comparing melatonin with placebo or other active drugs. Outcomes were analysed as change from baseline to last follow-up using mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI). Results Nine RCTs ( n = 788) were included. Versus placebo, melatonin reduced attack duration (MD -4.98 h; 95% CI -9.30 to -0.67; p = 0.02), headache days (MD -1.54 days; 95% CI -2.50 to -0.58; p < 0.01), headache severity (MD -2.08; 95% CI -2.91 to -1.26; p < 0.01), and analgesic use (MD -1.38; 95% CI -2.41 to -0.36; p < 0.01). Melatonin also increased the response rate (≥ 50% reduction in monthly headache frequency) (RR 1.38; 95% CI 1.11–1.70; p < 0.01) and improved sleep quality (PSQI: MD -1.64; 95% CI -2.85 to -0.42; p = 0.008) and disability (MIDAS: SMD − 4.07; 95% CI -5.45 to -2.69; p < 0.001). Compared with amitriptyline, melatonin was generally less effective for attack duration and severity, with no consistent advantage on analgesic use or response; however, melatonin showed a more favourable tolerability profile, including lower risk of sleepiness (RR 0.49; 95% CI 0.28–0.87; p = 0.01). Conclusions Melatonin demonstrates benefits over placebo for reducing migraine burden and improving patient-reported outcomes, with a favourable safety profile. While amitriptyline remains more potent for several efficacy endpoints, melatonin represents a reasonable preventive option, particularly as an adjunct during titration of first-line agents. Further head-to-head trials with standardised dosing and longer follow-up are warranted.