Efficacy and safety of cannabinoids in the treatment of spasticity in multiple sclerosis: A systematic review of randomized clinical trials.

Aims: This work aimed to evaluate the efficacy and safety of cannabinoids for the treatment of MS-related spasticity. Methods: Systematic searches were conducted in PubMed, EMBASE, and LILACS on 2 December 2025. Randomized controlled trials evaluating natural or synthetic cannabinoids for MS-related spasticity were included. Studies published in non-Roman characters and those assessing recreational cannabis use were excluded. Two reviewers independently performed study selection, data extraction, and risk of bias assessment using the RoB 2 tool. Qualitative synthesis, pairwise random-effects meta-analyses, and Bayesian network meta-analysis were conducted. Certainty of evidence was assessed using GRADE and CINeMA. Results: Twenty-seven studies (>3000 participants) were included. Interventions comprised tetrahydrocannabinol:cannabidiol (THC:CBD) extracts, other cannabis extracts, isolated cannabinoids (natural or synthetic), and smoked cannabis. In pairwise meta-analysis (7 studies), THC:CBD extracts reduced patient-reported spasticity versus placebo (MD -0.82; 95% CI -1.24 to -0.40; I(2) = 53%). Network meta-analysis confirmed superiority of THC:CBD (MD -0.80; 95% CrI -1.61 to -0.32). Adverse events were frequent but mostly mild to moderate, while serious events were rare. Certainty of evidence was low, and substantial clinical and methodological heterogeneity was observed. Conclusions: Cannabinoids provide modest improvements in patient-reported spasticity in MS, with more consistent effects for THC:CBD extracts. Given the low certainty of evidence and limited objective benefits, cannabinoids should be considered cautiously as adjunctive therapy with appropriate safety monitoring.