The purpose of this study is to understand whether people with Parkinson's Disease and depression have improvement in their symptoms after psilocybin therapy.

This is a randomized controlled trial of oral psilocybin therapy for depression in people with Parkinson's disease (PD). The primary goal is to examine efficacy of psilocybin therapy in this patient population. We will enroll 60 people ages 40 to 80 with clinically diagnosed early to moderate stage Parkinson's disease (Hoehn and Yahr Stage 1-3 during an "on" period), who meet criteria for moderate or greater depression severity and meet all other inclusion and exclusion criteria at screening. Participants will complete two drug administration sessions where they will each receive a dose of oral psilocybin ranging from low ("microdose") to high in a medically monitored setting with psychotherapeutic support. Participants will also complete a series of psychotherapy sessions before and after each drug administration session. Clinical assessments, neuroimaging, non-invasive brain stimulation, and peripheral blood draws will be used to quantify changes in depression, other non-motor and motor symptoms of PD, quality of life, and selected neural and blood-based biomarkers at multiple time points. Follow-up will continue to 3 months after the second session. Primary endpoints will evaluate efficacy, safety, and tolerability of study procedures.

Inclusion Criteria:

• Age 40 to 80
• Comfortable speaking and writing in English
• Have neurologist-diagnosed idiopathic Parkinson's disease (PD), Hoehn and Yahr stages 1 to 3 during an "on" phase (time when medication/DBS for parkinsonian motor feature, including bradykinesia and rigidity is in effect)
• Currently experiencing depressive symptoms
• Able to attend all in-person visits at UCSF as well as virtual visits
• Have a primary care provider, neurologist, or psychiatrist who is actively managing or coordinating

Exclusion Criteria:

• Psychotic symptoms involving loss of insight
• Significant cognitive impairment
• Regular use of medications that may have problematic interactions with psilocybin
• A health condition that makes this study unsafe or unfeasible, determined by study physicians

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

This trial is testing various doses of psilocybin. Participants, study staff and clinical assessors will be blinded to individual treatment conditions until study close-out. The clinician administered instruments will be administered by different clinical study staff than the facilitators who provide the preparation, psilocybin therapy, and integration sessions.