Therapeutic effects of cannabinoids on Parkinson's disease: an updated systematic review and meta-analysis of randomized controlled trials.
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PURPOSE: Current treatments for Parkinson's disease (PD) are primarily symptomatic and may lead to motor fluctuations and levodopa-induced dyskinesia over time, highlighting the need to repurpose other medications. Cannabinoids have gained attention as potential repurposed treatments. This systematic review and meta-analysis evaluated their efficacy in PD while addressing limitations of previous reviews, including low statistical power and inclusion of cannabinoid antagonists in pooled analyses. METHODS: A literature search was conducted through PubMed, Scopus, and Web of Science, identifying randomized controlled trials (RCTs) evaluating the use of cannabinoids in PD. Quality assessment was done via RoB-2. A random-effects meta-analysis was performed using the meta and metafor packages in R, with mean differences (MD) or standardized mean differences (SMD; Hedges' g) reported with 95% confidence interval (CI). A sensitivity analysis was carried out to assess the robustness of our findings. In crossover trials, effect sizes and standard errors were extrapolated from the reported CIs, considering the paired design. RESULTS: Eleven RCTs were identified, six of which were eligible for meta-analysis due to the absence of poolable outcomes in the remainder. Cannabinoids did not significantly improve PD severity (SMD = 0.16, 95% CI[-0.13 to 0.44], p = 0.27, I²=0%), motor examination (SMD=-0.08, 95% CI[-0.35 to 0.20], p = 0.57, I²=0%), motor experiences of daily living (SMD=-0.08, 95% CI[-0.49 to 0.33], p = 0.71, I²=0%), non-motor symptoms (SMD= -0.03, 95% CI[-0.72 to 0.67], p = 0.94, I²= 64.3%). Sensitivity analysis excluding Peball et al. showed that the pooled estimate of non-motor symptoms was largely driven by nabilone (SMD = 0.34, 95%CI [-0.19 to 0.88], p = 0.21, I²=0%), suggesting a drug-specific benefit signal. CONCLUSION: Cannabinoids have not shown significant benefit in PD; however, our findings should be interpreted with caution. The nabilone benefit signal for non-motor symptoms represents a distinct question warranting dedicated trials. Future studies should use standardized, pharmacologically stratified protocols.