In patients with Parkinson disease (PD) and comorbid mood dysfunction, psilocybin-assisted therapy is well-tolerated and associated with sustained improvements in depression, anxiety, motor symptoms, and cognitive flexibility. These are the results of a study published in Neuropsychopharmacology.

Mood dysfunction, including depression and anxiety, are common nonmotor symptoms of PD due to the accumulation of α-synuclein. Psilocybin has demonstrated early promise for the treatment of anxiety and depression, but its effect on PD is unknown.

In the single-arm, open-label study (ClinicalTrials.gov Identifier: NCT04932434), researchers aimed to evaluate the safety, feasibility, and preliminary efficacy of psilocybin therapy for adults (N=12; mean age, 63.2 years; women, 41.7%) with mild to moderate PD and a concurrent depressive or anxiety disorder. Participants received 2 oral doses of psilocybin (10 mg followed by 25 mg) paired with structured psychotherapy.

Key exclusion criteria included moderate to severe cognitive impairment, high-risk comorbidities, and current use of medications with potential pharmacodynamic interactions with psilocybin, such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors. The majority of participants (n=9) were on a stable carbidopa-levodopa regimen throughout the study.

[R]esults of this initial pilot study suggest that psilocybin therapy may have promise as a new treatment for mood dysfunction in PD, but rigorous efficacy testing is a crucial
next step.

he primary objective was to assess the safety and tolerability of psilocybin therapy in patients with PD. Common treatment-emergent adverse events (AEs) included transient anxiety (67% at 10 mg; 25% at 25 mg), nausea (50%), and elevated blood pressure (25% and 50% at 10 mg and 25 mg, respectively), all of which resolved spontaneously. No serious AEs were observed and none required medical intervention.

Severe anxiety was experienced by 2 participants during dosing sessions, with 1 reporting increased tremor and transient suicidal ideation post-treatment. Psychotic symptoms, as measured by the enhanced scale for the assessment of positive symptoms in PD, decreased post-treatment (B30: –1.3; P =.016; Hedges’ g =0.5), and no exacerbation of PD-related hallucinations or psychosis was recorded.

Secondary analyses revealed significant improvements across several clinical endpoints.

  • Depression scores declined by –9.3 at 3 months (B90; P =.001; g =1.0), and
  • Anxiety scores decreased by –3.8 (P =.031; g =0.7).

These changes exceeded minimal clinically important difference (MCID) thresholds for mood measures. Improvements were also observed in nonmotor symptoms (Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part I: –13.8 at B30; P <.001; g =3.0) and motor symptoms (Part II: –7.5; P <.001; g =1.2; Part III: –4.6; P =.001; g =0.3), all of which met MCID criteria.

Cognitive performance showed statistically significant post-treatment gains in spatial working memory (–0.52; P =.003; g =0.7), visual learning (–0.44; P =.003; g =0.4), and probabilistic reversal learning (+2.9; P =.003; g =1.3).

Improvements in neuropsychiatric symptom burden were corroborated by care partner reports (Neuropsychiatric Inventory Questionnaire severity at B90: –5.2; P <.001; g= 1.8), with participants also rating the treatment as helpful and acceptable.

Study limitations included the small sample size, lack of a control group, and limited racial and ethnic diversity. The open-label design also raises the possibility of expectancy effects.

“… [R]esults of this initial pilot study suggest that psilocybin therapy may have promise as a new treatment for mood dysfunction in PD, but rigorous efficacy testing is a crucial next step,” the researchers concluded.

This research was supported by an anonymous donor. Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.