Psilocybin therapy for mood dysfunction in Parkinson's disease: an open-label pilot trial

Abstract

Mood dysfunction is highly prevalent in Parkinson's disease (PD), a main predictor of functional decline, and difficult to treat-novel interventions are critically needed. Psilocybin shows early promise for treating depression and anxiety, but its potential in PD is unknown, as safety concerns have excluded people with neurodegenerative disease from previous trials. In this open-label pilot (NCT04932434), we examined the feasibility of psilocybin therapy among people with mild to moderate stage PD plus depression and/or anxiety. 12 participants (mean age 63.2 ± 8.2 years, 5 women) received psilocybin (one 10 mg followed by one 25 mg dose) with psychotherapy. There were no serious adverse events, no medical interventions required to manage effects of psilocybin, and no exacerbation of psychosis. Ten participants experienced treatment-emergent adverse events; the most frequent were anxiety, nausea, and increased blood pressure. We observed no worsening of PD symptomology measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). On the contrary, non-motor (MDS-UPDRS Part I: -13.8 ± 1.3, p < 0.001, Hedges' g = 3.0) and motor symptoms (Part II: -7.5 ± 0.9, p < 0.001, g = 1.2; Part III: -4.6 ± 1.3, p = 0.001; g = 0.3) as well as 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 = 0.003, g = 0.7], and Probabilistic Reversal Learning [2.9 ± 0.9, p = 0.003, g = 1.3]) improved post-treatment, and improvements were sustained until the final safety assessment one month following drug exposure. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) scores were 21.0 ± 8.7 and 17.0 ± 3.7, respectively. Both improved to a clinically meaningful degree post-treatment; these improvements persisted to the final assessment three months following drug exposure (MADRS: -9.3 ± 2.7, p = .001, g = 1.0; HAM-A: -3.8 ± 1.7; p = 0.031, g = 0.7). This study provides the first data on psilocybin's effects in any neurodegenerative disease. Results suggest that psilocybin therapy in PD warrants further investigation.

Fig. 1. Study design and participant flow diagrams.

A After screening and baseline assessments, participants completed a 10 mg psilocybin administration session (A0) followed by a 25 mg psilocybin administration session (B0) approximately two weeks later. Participants also completed a series of psychotherapy meetings as part of the treatment: two meetings were scheduled before A0, two between A0 and B0, and then three following B0. Key follow-up time points are shown: one week after the 10 mg session (A7), one week after the 25 mg session (B7), one month after the 25 mg session (B30), and three months after the 25 mg session (B90). B The five most common reasons for ineligibility after prescreening were using exclusionary medications (40), not having a diagnosis of PD (15), not meeting criteria for either depression or anxiety (11), not being able to commit to the study schedule (8), and significant cognitive impairment (7).

Fig. 2. Safety, tolerability, and preliminary efficacy outcomes.

A Vital signs during the course of the 10 mg (A0) and 25 mg (B0) psilocybin administration sessions; the x-axis indicates time since drug administration. B PD symptom severity (MDS-UPDRS) scores over time, shown for nonmotor symptoms (Part I), motor symptoms (Part II), and motor exams (Part III). Follow-up time points were one week after the 10 mg session (A7), one week after the 25 mg session (B7), and one month after the 25 mg session (B30). Lower scores indicate improvement. C Selected cognitive safety measures. Lower z-scores indicate better performance on the SWM and PAL tasks. Performance on the PRL task is indexed by the number of reversals achieved; a higher number of reversals reflects better cognitive flexibility. D Depression (MADRS) and anxiety (HAM-A); both were also assessed at three months after the 25 mg session (B90). Error bars represent 95% confidence intervals. Dotted horizontal lines indicate levels of symptom severity for reference where applicable. MDS-UPDRS Movement Disorders Society revision of the Unified Parkinson’s Disease Rating Scale, eSAPS-PD Extended Scale for the Assessment of Positive Symptoms in Parkinson’s Disease, SWM spatial working memory, PAL paired associates learning, MADRS Montgomery-Åsberg Depression Rating Scale, HAM-A Hamilton Anxiety Rating Scale, PRL Probabilistic Reversal Learning task. ***p < .001, **p < .01, *p < .05, ^┼.p < .1.