Araujo Gouhie et al.’s meta-analysis examines melatonin as a preventive for episodic migraine, comparing it with placebo and treatments like amitriptyline, naproxen, valproic acid, topiramate and propranolol. ^{Reference Gouhie, Silva, Parreira, Vieira, Cunha and Cezar1} Analyzing nine Randomized Controlled Trials (RCTs) with 783 participants, melatonin showed no statistically significant superior benefit over comparators in reducing headache frequency, disability, medication use or duration. Although this meta-analysis found no significant efficacy difference, it cannot prove that melatonin is inferior to other treatments for episodic migraine. The non-significant finding may result from limited sample size and power, not a true lack of effect. A larger non-inferiority or equivalence trial is needed to confirm whether melatonin is as effective as other preventive medications. The study’s strength is its robust methodology and use of network meta-analysis to synthesize data across interventions. The lack of significant differences across outcomes challenges the hypothesis that melatonin’s neuromodulatory, analgesic and cerebrovascular properties translate into superior migraine prophylaxis.

The study emphasizes melatonin’s favorable safety profile, especially compared to side effects of treatments like amitriptyline and propranolol. The authors rightly note limitations, including the small number of trials, heterogeneity in study designs and varied doses, which may obscure melatonin’s potential benefits. The lack of data on administration timing complicates interpretation, particularly since melatonin influences circadian regulation. This is worsened by the link between circadian disruption and migraine, with migraine patients showing delayed melatonin peaks and lower levels. ^{Reference Peres2} However, melatonin’s long-term safety is unknown. Melatonin’s effect on gonadal function appears biphasic and dose-dependent. ^{Reference Tamura, Jozaki and Tanabe3,Reference Kumanov, Tomova, Isidori and Nordio4} At lower, physiological doses, it often has protective antioxidant effects and is linked to improved fertility outcomes, especially in assisted reproductive technology. ^{Reference Tamura, Jozaki and Tanabe3} Conversely, higher levels can inhibit the hormonal axis that regulates reproduction. ^{Reference Kumanov, Tomova, Isidori and Nordio4} Melatonin supplements lack U.S. Food and Drug Adminstration (FDA) oversight and often contain inaccurate doses, sometimes far above or below what is labeled. ^{Reference Erland and Saxena5}

This meta-analysis underscores the need for more high-quality RCTs to elucidate melatonin’s role in migraine management. Future studies should prioritize standardized dosing, longer follow-up periods and subgroup analyses to identify patient populations that may benefit most. Additionally, exploring melatonin’s synergistic effects with other therapies could uncover novel treatment strategies. While the current evidence does not support melatonin as a first-line prophylactic, its safety profile and preliminary trends in rankogram analyses suggest it warrants further investigation. This work urges researchers to better understand melatonin’s potential in treating migraine and related conditions, such as indomethacin-responsive headaches (hemicrania continua and paroxysmal hemicrania), including its long-term use as a replacement for indomethacin. ^{Reference Cheung, Oliveira and Goadsby6}