Nabiximols in Multiple Sclerosis: Beyond Spasticity—An Exploratory Systematic Review and Meta-Analysis of Symptomatic Outcomes

Background/Objectives: Nabiximols, a standardized extract of Cannabis sativa, has been approved as an add-on therapy for patients with moderate to severe spasticity associated with multiple sclerosis (MS). Moreover, current Italian treatment algorithms suggest that cannabis-based therapies may have further relevance in the management of MS. The aim of our systematic review and meta-analysis was to assess the effectiveness of nabiximols in relieving symptoms other than spasticity in adult MS patients. Methods: A systematic search was conducted in Web of Science, MEDLINE (via PubMed), Cochrane CENTRAL and Embase on September 10, 2025. Study selection was performed according to the predefined PROSPERO protocol (CRD42022329952). Data were combined into a common denominator and examined using a random-effects model with meta-regression expressed as mean difference (MD) and a 95% confidence interval (CI). Risk of bias was assessed using the Cochrane risk of bias instrument (RoB2) and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Results: Of the 49 eligible articles, 25 were included in the statistical analysis (2949 patients). Significant improvements in spasm quality (MD = −16.87; 95% CI = (−29.75)–(−3.99)), bladder function (MD = −16.38; 95% CI = (−22.18)–(−10.58)), sleep disruption (MD = −15.75; 95% CI = (−22.02)–(−9.49)) and gait function (timed walk MD(s) = −5.31; 95% CI(s) = (−9.88)–(−0.74)) were observed. Time-dependency was not significant. The subject global impression of change (SGIC) improved significantly after the first month (odds ratio (OR) = 1.69; 95% CI = (1.30)–(2.18)). Conclusion: Beyond spasticity, nabiximols may represent a signal of benefit for bladder function, sleep disruption, spasm quality, and gait function in MS, in line with the “spasticity-plus” concept. However, the evidence certainty was low to very low, and these findings should be considered exploratory.