The Effect of Polyphenol Supplementation in People with Multiple Sclerosis: A Systematic Review of Clinical Trials

Background/Objectives: Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease affecting 2.9 million worldwide. Current immunosuppressive treatments offer limited neuroprotection and often cause adverse effects. Polyphenols with antioxidant and anti-inflammatory properties have been investigated as adjuncts in MS. Methods: On 19 June 2025, Embase, Medline, and ClinicalTrials.gov were systematically searched. Eligible clinical trials assessing polyphenol supplementation in MS were included. Outcomes of interest were Expanded Disability Status Scale (EDSS), annualised relapse rate (ARR), magnetic resonance imaging (MRI) changes, safety, and tolerability. Risk of bias was evaluated using the Cochrane tool, and certainty of evidence was appraised with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The protocol was registered with PROSPERO (CRD420251052042). Results: Of 870 records identified, 13 trials (n = 785) met inclusion. Nanocurcumin consistently improved EDSS in relapsing-remitting MS (3 trials, n = 150; p = 0.039-0.041), while epigallocatechin-3-gallate, silymarin (SM), cranberry extract, and bio-enhanced curcumin extract (BCM-95) curcumin showed no significant impact on disability, relapse rates, or MRI outcomes. Intervention adverse events were generally mild. SM showed potential hepatoprotective effects. Risk of bias was determined as low risk for seven of the trials and of some concern for five of the studies. Most often raising concerns because of selective reporting. Certainty of evidence, assessed using GRADE, was generally moderate, indicating some uncertainty regarding the outcomes. Meta-analysis was not possible due to the heterogeneity of included studies. Conclusions: Nanocurcumin may contribute to improvements in disability outcomes in Relapse Remitting Multiple Sclerosis (RRMS), whereas other polyphenols lack consistent efficacy. However, the evidence base remains limited by small sample sizes and methodological concerns. Larger, multicentre randomised controlled trials are required to establish optimal dosing, long-term safety, and therapeutic potential.