Effects of Modafinil on Motor and Non-Motor Outcomes in Parkinson’s Disease: A Meta-Analysis and Systematic Review of Randomized, Placebo-Controlled Trials

Background: Excessive daytime sleepiness (EDS) and fatigue are prevalent non-motor symptoms of Parkinson’s disease (PD). Modafinil has been proposed as a management strategy. Evidence across individual trials remains inconsistent. This study aimed to evaluate the efficacy and safety of modafinil compared to placebo on motor and non-motor outcomes in PD. Methods: A systematic search of PubMed/Medline, Embase, and Cochrane Library databases was conducted for trials evaluating modafinil in PD up to March 2026. Inverse-variance methods with fixed-effect or random-effects models were used to determine weighted mean differences (MD) or standardized mean differences (SMD). The statistical heterogeneity was assessed using the I² statistic. Risk of bias was assessed using the Cochrane RoB 2 tool. PROSPERO (CRD420261420008). Results: Seven trials (N = 216; modafinil n = 113, placebo n = 103) met predefined eligibility criteria. Modafinil was associated with a significant reduction in EDS as measured by the Epworth Sleepiness Scale compared to placebo (MD −2.12; 95% CI −3.64 to −0.60; I2 = 65%). No significant effects were observed for fatigue (MD −0.17; 95% CI −1.12 to 0.79), depressive symptoms (SMD 1.51; 95% CI −0.10 to 3.11), or motor function (SMD 0.20; 95% CI −0.23 to 0.63). Adverse events, including insomnia, headache, dizziness, and gastrointestinal symptoms, were comparable between treatment and placebo groups. Conclusion: Modafinil may provide a modest but statistically significant improvement in EDS in PD without worsening motor function or increasing adverse events. No benefit could be elicited for fatigue or depressive symptoms. Larger, longer-duration trials with standardized outcome measures are warranted.