Methylsulfonylmethane as a Bioactive Nutraceutical: Molecular Mechanisms, Clinical Evidence, Combination Therapy, Dosing, and Safety.

Methylsulfonylmethane (MSM; dimethyl sulfone) is an organosulfur nutraceutical used primarily for joint symptoms, although its molecular actions and clinical applicability beyond osteoarthritis remain uncertain. This narrative review integrates pharmacological, preclinical, and human evidence on MSM, with emphasis on musculoskeletal disorders, multi-ingredient formulations, dosing, safety, toxicology, and clinical monitoring. Experimental studies implicate NF-κB and NLRP3 signaling, redox regulation, sulfur metabolism, and AMPK/mTOR/ULK1-related autophagy; however, most pathway-level evidence remains preclinical. Human clinical evidence is comparatively most developed for knee osteoarthritis, although it remains limited to small, short-term randomized trials reporting modest symptomatic improvement rather than established structural or disease-modifying benefit. Recent evidence syntheses also identify signals for glucosamine-MSM and glucosamine-chondroitin-MSM combinations, although certainty is limited and the independent contribution of MSM cannot be determined. Tendon studies largely evaluate multi-ingredient products, preventing attribution of benefit to MSM alone. Evidence in cardiometabolic disease, gastrointestinal health, exercise recovery, and toxicant exposure is preliminary. MSM is not a direct metal chelator and should not replace established chelation therapy. Short-term studies have used approximately 1-6 g/day with generally mild gastrointestinal adverse effects, whereas long-term safety, formal drug-interaction data, and clinically validated biomarker-guided dosing remain undefined. MSM should therefore be considered an adjunct with indication-dependent evidence rather than a broadly applicable anti-inflammatory or detoxification supplement.