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.