Melatonin supplementation in multiple sclerosis: a systematic review of clinical, imaging, biomarker, and safety outcomes

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Purpose Melatonin may act on immune, oxidative, and circadian pathways relevant to multiple sclerosis (MS), yet its clinical benefits and safety profile remain unclear. This systematic review assessed the efficacy and safety of oral melatonin supplementation in adults with MS. Methods We searched MEDLINE (via PubMed), Scopus, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception through August 15, 2026, and included randomized and prospective non-randomized intervention studies. Two reviewers independently selected studies, extracted data, and assessed risk of bias using RoB 2 or ROBINS-I. Given substantial clinical and methodological heterogeneity, we synthesized findings without meta-analysis, following SWiM guidance, and rated certainty of evidence with GRADE. We registered the protocol in PROSPERO (CRD420251167112). Results We included 10 independent studies, reported across 17 publications, covering 435 participants. Nine were randomized trials (two of them crossover designs), and one was a prospective non-randomized intervention study. Melatonin doses spanned 0.5–300 mg/day, with treatment durations from 2 weeks to 14 months. The evidence did not show reductions in relapse activity, disability progression, or new MRI activity. Small studies suggested possible improvements in sleep, fatigue, pain, physical function, cognition, mood, autonomic function, body composition, and inflammatory, metabolic, or oxidative-stress biomarkers, but these results were inconsistent and rarely replicated. Doses of 0.5–25 mg/day were generally well tolerated, though some participants discontinued treatment and adverse-event reporting remained incomplete. At 300 mg/day, three of four melatonin-treated participants developed hypertransaminasemia, which resolved after withdrawal and recurred on rechallenge in one case. Certainty of evidence was low or very low for every outcome assessed. Conclusion Current evidence does not support a disease-modifying effect of melatonin in MS. Any symptomatic or biomarker benefits need confirmation in larger, well-designed trials, and high-dose melatonin may carry meaningful hepatic risk.

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