PSILOCYBIN THERAPY FOR DEPRESSION IN PARKINSON’S DISEASE

Background

Depression is common in Parkinson’s disease (PD), frequently treatment-resistant, and associated with reduced quality of life as well as accelerated physical and cognitive decline. Early evidence suggests that the serotonergic psychedelic psilocybin may be a promising novel intervention for treatment-resistant mood dysfunction in non-PD populations, but no prior psilocybin trials have enrolled participants with PD or any other neurodegenerative illness.

Methods

We aimed investigate the safety, tolerability, and preliminary efficacy of oral synthetic psilocybin paired with psychotherapeutic support for people with PD and comorbid mood dysfunction. In this open-label, single-arm pilot study (NCT04932434), we recruited people aged 40-75 with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3) who also met criteria for a depressive and and/or anxious disorder and all other inclusion/exclusion criteria. We used a dose escalation protocol where participants first received a 10 mg safety dose of psilocybin and, if this was well-tolerated, received a 25 mg treatment dose approximately 2 weeks later. Primary outcomes were safety and tolerability measured by the incidence, severity, and treatment-relatedness of adverse events (AEs) elicited through assessments of vital signs, acute subjective drug effects, changes in motor and non-motor symptoms, psychotic symptoms, suicidality, cognitive performance, and care partner distress. The secondary outcome was feasibility measured by recruitment and retention rates as well as treatment satisfaction. We explored preliminary efficacy as well as changes in blood-based markers of inflammatory activity. As this was a pilot study, no formal sample size calculation was performed. We used mixed effects linear models to examine changes in assessment scores from pre-to post-treatment. This study is registered at ClinicalTrials.gov, NCT04932434.

Results

12 participants (mean age 63.2 [SD 8.2] years, 5 women) enrolled; all completed the full protocol, receiving both doses of psilocybin. There were no serious adverse events and no medications were required to manage acute cardiovascular or psychotomimetic effects of psilocybin. Ten of 12 participants experienced treatment-emergent adverse events; the most frequent were anxiety, nausea, and increased blood pressure during the period of acute psilocybin effects. We observed no worsening of psychotic symptoms or negative effects on cognitive performance. Motor symptoms measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) improved (Part II: -7.5±0.9, p < .001, g=1.2; Part III: -4.6±1·3, p=.001; g=0.3), as did performance in select cognitive domains (Paired Associates Learning [-0.44±0.14, p=.003, g=0.4], Spatial Working Memory [-0.52±0.17, p=.003, g=0.7], and Probabilistic Reversal Learning [2.9±0.9, p=.003, g=1.3]). These improvements were sustained until the final safety assessment one month following drug exposure. Depression measured by the Mongomery-Asberg Depression Rating Scale improved post-treatment (-9.3±2.7, p=.001, g=1.0); this improvement persisted to the final assessment three months following drug exposure. Analyses of inflammatory markers are in process and anticipated to be finalized prior to this meeting.

Conclusion

This study provides the first data on psilocybin’s safety and tolerability in people with PD. Results suggest that randomized clinical trials to examine the effects of psilocybin therapy on mood dysfunction as well as other PD symptoms are warranted.

References

Bradley ER, Sakai K, Fernandes-Osterhold G, et al. “Psilocybin Therapy for Mood Dysfunction in Parkinson’s Disease: An Open-Label Pilot Trial.” Neuropsychopharmacology. 2025; 10.1038/s41386-025-02097. Weintraub D, Aarsland D, Chaudhuri KR, et al. “The Neuropsychiatry of Parkinson’s Disease: Advances and Challenges.” The Lancet Neurology. 2022; 10.1016/S14744422(21)00330-6.