Reconsidering Placebo Effects in Neuromodulation for Parkinson's Disease: Lessons for Clinical Trials and Therapeutic Translation.

Background: Placebo effects are well documented in Parkinson's disease (PD) clinical trials and represent a major methodological challenge in interpreting neuromodulation studies. Although sham stimulation has been associated with clinical improvement, the magnitude, durability, and outcome specificity of placebo-related effects across non-invasive neuromodulation trials remain incompletely characterized. Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD1272381). PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library were searched from inception through September 2025. Randomized, sham-controlled trials of non-invasive neuromodulation in adults with PD were included. Results: Seventeen randomized sham-controlled trials (n = 654 participants) involving repetitive transcranial magnetic stimulation and transcranial direct current stimulation were included. Sham stimulation was associated with small but statistically significant improvements in UPDRS Part III (motor examination) at post-intervention and follow-up, whereas no significant placebo-related improvement was observed for UPDRS Total score. Placebo effects were modest and did not increase over time. In contrast, active neuromodulation produced larger and more durable improvements in both UPDRS Total and Part III, with statistically significant effects maintained at follow-up. Conclusions: Placebo effects contribute to short-term clinical improvement in non-invasive neuromodulation trials for PD, particularly for motor examination outcomes, but do not fully account for the sustained benefits observed with active stimulation. Placebo responsiveness is outcome- and time-dependent, underscoring the importance of rigorous trial design, including careful outcome selection, assessment timing, expectancy management, and comparator structures, to accurately estimate neuromodulation efficacy and support clinical translation.