The Efficacy of Psilocybin Therapy for Depression in Parkinson's Disease (PSI-PD)

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

Study Overview

• Status: Not yet recruiting
• Conditions: Depression; Parkinson's Disease (PD)
• Intervention / Treatment: Drug: Psilocybin (drug)

Detailed Description

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. Investigators will enroll participants 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 will be used to quantify changes in depression as well as other relevant outcomes (non-motor and motor symptoms of PD, cognitive performance, quality of life). Follow-up will continue to 3 months after the second session. Endpoints will evaluate efficacy, safety, and tolerability of study procedures.

After posting of these trial results, this data will be combined with the data from the trial at UCSF (NCT06455293) for publication purposes.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sophie Holmes, PhD; Phone Number: 203-685-4066; Email: sophie.holmes@yale.edu
• Study Contact Backup: Name: Gerard Sanacora, MD; Email: gerard.sanacora@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University
      • Principal Investigator: Sophie Holmes, PhD
      • Contact: Sophie Holmes, PhD; Phone Number: 203-685-4066; Email: sophie.holmes@yale.edu
      • Principal Investigator: Gerard Sanacora, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able to understand and provide informed consent
• 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)
• Have no changes in medication or major surgical procedures anticipated for treatment duration
• Have a score >/=20 on the Beck Depression Inventory-2 (BDI-2), consistent with moderate or greater depressive symptom severity, at Baseline.
• For people who can become pregnant: agree to use highly effective contraception from entry into the trial through Day B30 assessments (4 weeks after the second psilocybin administration session) and agree to not breastfeed. Acceptable methods of contraception are: An intrauterine device (IUD), hormone-based contraceptives (birth control pills) , condoms (internal or external) must be used with another method (other than spermicide), and complete abstinence from sexual activity that could result in pregnancy.
• Agree that for one week preceding each psilocybin session, they will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the research team. Exceptions will be evaluated by the research team and assessed for safety. Agree to abstain from all tobacco and nicotine use for the duration of the study.
• Agree to consume approximately the same amount of caffeine-containing beverages that they usually consume before arriving at the research unit on the mornings of psilocybin administration sessions.
• Agree to avoid sedative-hypnotic medications (e.g., benzodiazepines, zolpidem, zopiclone, zaleplon) taken on an as-needed basis for a minimum of 5 half-lives prior to each psilocybin administration session and for 24 hours after each psilocybin administration session.
• Agree to avoid opioid medications taken on an as-needed basis for a minimum of 5 half-lives prior to each psilocybin administration session and for 24 hours after each psilocybin administration session.
• Agree not to use products or substances containing Δ9-tetrahydrocannabinol (THC) and/or cannabidiol for at least 7 days prior to each psilocybin administration session and for 24 hours after each psilocybin administration session.
• Agree to not use non-prescribed narcotics (eg. heroine, fentanyl), depressants (eg. Barbiturates, benzodiazepines) and/or inhalants for the duration of participation in the trial.
• Agree not to consume alcoholic beverages for at least 24 hours prior to and 24 hours following each psilocybin administration session.
• Have a primary care provider, neurologist, or psychiatrist who is actively managing or coordinating care and is available for consultation with the study medical monitor.

Exclusion Criteria:

• Any indication of forms of parkinsonism other than idiopathic Parkinson's disease.
• Cognitive impairment, defined as a Montreal Cognitive Assessment (MoCA) score <24.
• Symptomatic orthostatic hypotension.
• Currently receiving electroconvulsive therapy (ECT) or treatment via transcranial magnetic stimulation (TMS). Previous treatment with ECT and/or TMS is permitted; last treatment must be at least 30 days prior to entry into this trial.
• Treatment in a clinical trial within 30 days of entry into this trial or treatment with another investigational drug or other intervention within 30 days or 5 half-lives, whichever is longer, prior to entry into this trial.
• Pregnancy as indicated by a positive urine pregnancy test during screening, lactation, or the intention of becoming pregnant within 3 months of entry into this trial.
• Current severity of psychiatric symptoms warranting immediate treatment as determined by the study medical staff (e.g. due to inability to provide for basic needs/safety). The study medical staff will assess these individuals, determine the appropriate level of care, and coordinate with the individual's primary providers to ensure close follow-up.
• High risk of self-harm/suicide, as determined by the Columbia-Suicide Severity Rating Scale (C-SSRS) risk screen, specifically: participant answers "yes" to item 4 or 5 suggesting intent to act on suicidal thoughts OR participant has made a serious suicide attempt within the 12 months prior to entry into this trial.
• History of meeting DSM-5 criteria for a schizophrenia spectrum disorder, other psychotic disorder, or a mood disorder with psychotic features.
• History of delusional symptoms or any other psychotic symptoms accompanied by a loss of insight. Exceptions may be made at the investigators' discretion in cases of a history of psychotic symptoms that were attributable to substance or medication use.
• Current delusional symptoms or any other psychotic symptoms accompanied by a loss of insight.
• History of a schizophrenia spectrum disorder in a first-degree relative.
• History of bipolar disorder 1 in a first-degree relative, in whom illness onset was prior to age 40.
• Current or history of meeting DSM-5 criteria for a bipolar disorder.
• Current or history within the last 2 years of meeting DSM-5 criteria for a moderate or severe alcohol or drug use disorder, excluding caffeine.
• Currently meeting DSM-5 criteria for another psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin treatment procedures as determined by the investigators.
• History of meeting DSM-5 criteria for Hallucinogen Persisting Perception Disorder (HPPD).
• History of using any psychedelic substances including psilocybin, lysergic acid diethylamide (LSD), mescaline (and natural products containing mescaline including peyote and San Pedro cactus), N,N-Dimethyltryptamine (DMT), natural products containing DMT including ayahuasca and 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine, 2C compounds, 3,4-methylenedioxy-methamphetamine (MDMA), or methylone during the past 6 months at dosages and/or frequencies determined clinically significant by the investigators.
• Cancer with known central nervous system (CNS) involvement, CNS infection, or other major CNS disease aside from PD.
• Epilepsy or other seizure disorder in adulthood.
• Supplemental oxygen requirement.
• Allergy or intolerance to any of the materials contained in the drug products.
• Renal insufficiency defined as creatinine clearance < 40 ml/min using Cockraft and Gault equation
• Insufficiently managed endocrine conditions, including diabetes mellitus and clinically significant thyroid dysfunction.

• Cardiovascular conditions, including:

  • Elevated blood pressure defined as systolic blood pressure (SBP) >150 or diastolic blood pressure (DBP) >95 taken during Enrollment
  • Tachycardia defined as heart rate (HR) >90 beats per minute taken during Enrollment
  • Bradycardia defined as HR <50 bpm taken during Enrollment
  • Angina
  • History of stroke within the past year
  • Clinically significant ECG abnormality as determined by the investigators, including but not limited to QTc > 450

• Hepatic dysfunction as indicated by any of the following laboratory values:

  • AST > 3 x upper limit of normal
  • ALT > 3 x upper limit of normal
  • Total bilirubin > 3.0 mg/dl

• Use of any of the following concomitant medications AND inability/unwillingness to discontinue for at least 5 times the elimination half-life of the agent (specific exceptions are noted) prior to psilocybin administration, including:

  • Agents that may be associated with serotonin syndrome:

    • MAO inhibitors (participants must have discontinued 2 weeks prior to baseline)
    • St. John's Wort
    • S-adenosyl-methionine (SAM-e)
    • 5-Hydroxytryptophan (5-HTP)
    • Dextromethorphan
    • Opioids (e.g., codeine, fentanyl, hydrocodone, meperidine, tramadol)
    • Lithium
    • Linezolid
    • Buspirone

  • Agents that may interact with psilocybin metabolism/effects:

    • Serotonin antagonists (e.g., cyclobenzaprine, ondansetron)
    • Antipsychotics
    • Other dopamine antagonists (e.g., metoclopramide, promethazine, prochlorperazine)
    • Nicotine
    • Modulators of uridine diphosphate (UDP) or glucuronosyltransferase (UGT) (e.g. valproate, diclofenac, mefenamic acid, verapamil, ketoconazole, itraconazole, probenecid, phenobarbital, protease inhibitors)
    • L-methyl folate (>/= 7.5mg/day)
    • Efavirenz

  • Agents that may increase the risk of psychotic symptoms:

    • Stimulants (e.g. modafinil, methylphenidate, atomoxetine, methamphetamine, cocaine, amphetamine derivatives)
    • Anticholinergics (e.g. benztropine, trihexyphenidyl, scopolamine, hyoscyamine)
    • Systemic steroids
  • Tricyclic antidepressants
• Other medical condition or diagnosis, concomitant medication(s), physical exam finding, laboratory abnormality or health risk identified that precludes participation in study procedures due to safety or feasibility concerns at the discretion of the investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Psilocybin Administration Session 1; Participants will receive one dose of psilocybin ranging from low ("microdose") to high in a monitored setting with preparation sessions before and integration sessions after.	Drug: Psilocybin (drug); Single dose of psilocybin ranging from low ("microdose") to high delivered orally with psychological support and monitoring; Other Names: 4-phosphoryloxy- N, N-dimethyltryptamine
Experimental: Psilocybin Administration Session 2; Participants will receive one dose of psilocybin ranging from low ("microdose") to high in a monitored setting with preparation sessions before and integration sessions after.	Drug: Psilocybin (drug); Single dose of psilocybin ranging from low ("microdose") to high delivered orally with psychological support and monitoring; Other Names: 4-phosphoryloxy- N, N-dimethyltryptamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in depression as measured by the Montgomery-Asberg Depression Rating Scale (MADRS)	MADRS is a 10-item clinician-administered scale used to measure the severity of depressive symptoms. Total scores range from 0 to 60 with higher scores indicating more severe depression.	Baseline to 30 days after first drug dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Incidence, severity, and frequency of all Adverse Events (AEs) including Treatment-Emergent AEs (TEAEs) and Serious AEs (SAEs)	Baseline to 90 days after second drug dose
Changes in clinician-rated psychotic symptoms as measured by the Enhanced Scale for the Assessment of Positive Symptoms for Parkinson's Disease (eSAPS-PD)	The eSAPS-PD is a clinician-administered scale used to track Parkinson's Disease symptom severity. Scores range from 25 to 125, where higher scores indicate more impairment.	Baseline to 90 days after second drug dose
Subjective effects of psilocybin as measured by the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC)	The 5D-ASC is a patient-reported scale used to measure the intensity of an experience during altered states of conciousness. Scores range from 0 to 100, where higher scores indicate more intense psychedelic effects.	Up to 30 and 60 days after Baseline
Suicidality as measured using the Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is a clinician-administered scale used to assess suicide risk. Scores range from 0 to 6, where higher scores indicate more severe suicide risk.	Baseline to 90 days after second drug dose
Participant -reported acceptability of study procedures as measured by the study-specific Treatment Satisfaction Questionnaire-Participant (TSQ-P)	TSQ-P is a patient-reported 7-point scale used to measure patients' satisfaction with their medication. Scores range from 0 to 7, where higher scores indicate greater satisfaction.	30 days after second drug dose
Changes in depression severity as measured by Montgomery-Asberg Depression Rating Scale (MADRS)	MADRS is a 10-item clinician-administered scale used to measure the severity of depression symptoms. Overall score ranges from 0 to 60, where higher scores indicate more severe depression.	Baseline to 90 days after second drug dose
Proportion of participants with a response (defined as a >/=50% decrease in MADRS total score) as measured by the Montgomery-Asberg Depression Rating Scale (MADRS)	MADRS is a 10-item clinician-administered scale used to measure the severity of depression symptoms. Overall score ranges from 0 to 60, where higher scores indicate more severe depression.	7 days after first drug dose and up to 90 days after second drug dose
Changes in participant reported depression as measured by the Beck Depression Inventory (BDI-II)	BDI-II is a 21-item patient-reported questionnaire used to assess the severity of depressive symptoms. Total scores range from 0 to 63, with higher scores indicating more severe depression.	Baseline up to 90 days after second drug dose
Changes in anxiety as measured by the Parkinson Anxiety Scale (PAS)	PAS is a 12-item, PD-specific scale used to assess anxiety in adults with Parkinson's disease. Total scores range from 0 to 50 with higher scores indicating more severe anxiety.	Baseline to 90 days after second drug dose
Changes in PD symptom severity as measured by the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)	MDS-UPDRS is a 50-item scale used for assessing both motor and non-motor aspects of Parkinson's disease. Total scores range from 0 to 176 with higher scores indicating more severe disease.	Baseline to 90 days after second drug dose
Changes in cognitive performance as measured by multi-task assessments to include Probabilistic Reversal Task, Category Switch Task, Simon Task, Delay Discounting Task, California Verbal Learning Test-II, Digit span forward and backward	Probabilistic Reversal Task measures flexible learning, Category Switch Task measures mental set shifting, Simon Task measures selective attention, Delay Discounting Task measures impulse control/waiting for rewards, California Verbal Learning Test (CVLT-II) measures short- and long-term memory, Digit Span Forward and Backward measures working memory.	Baseline to 90 days after second drug dose
Changes in Quality of Life as measured by the 36-item Short Form survey (SF-36)	SF-36 is a patient-reported 36-item scale used to measure health-related quality of life. Total scores range from 0 to 100 with higher scores indicating better health.	Baseline to 90 days after second drug dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in sleep parameters as measured using passive sensing via an Oura ring (exploratory)	The Oura ring is a wearable device that synchronizes with a smartphone application. It records sleep by combining infrared photoplethysmography (PPG) sensors, a sensitive accelerometer, and temperature monitoring to track heart rate, movement, and body temperature, which are analyzed by machine learning algorithms to determine sleep stages and patterns.	Baseline to 30 days after the second drug dose
Changes in physical activity as measured using passive sensing via an Oura ring (exploratory)	The Oura ring is a wearable device that synchronizes with a smartphone application. It records physical activity using using a combination of a 3D accelerometer, heart rate sensors, and activity algorithms to track movement, steps, calories burned, and exercise intensity.	Baseline to 30 days after the second drug dose
Changes in body temperature as measured using passive sensing via an Oura ring (exploratory)	The Oura ring is a wearable device that synchronizes with a smartphone application. It records average nighttime skin temperature to track deviations from personal baseline, providing insights into readiness, health changes, and menstrual cycle trends.	Baseline to 30 days after the second drug dose
Changes in heart rate as measured using passive sensing via an Oura ring (exploratory)	The Oura ring is a wearable device that synchronizes with a smartphone application. It records resting heart rate and heart rate variability, primarily during sleep and select daytime sessions.	Baseline to 30 days after the second drug dose
Changes in participant-reported sleep as measured by the Parkinson's Disease Sleep Scale-2 (exploratory)	The PDSS-2 is a scale used to assess sleep disturbances in individuals with Parkinson's disease, with scores indicating the severity of sleep problems ranging from 0 to 60. Higher scores reflect more severe sleep issues.	Baseline to 90 days after second drug dose
Evaluation of treatment expectancy as measured by the Treatment Expectancy Questionnaire (TEQ) (exploratory)	The TEQ is a patient-reported scale used to measure and compare patients' expectations across diverse treatment contexts. Scores range from 0 to 75, where higher scores indicate stronger overall treatment expectations.	Baseline
Evaluation of masking procedures as measured by a study-specific Masking Questionnaire (exploratory)	The Masking Questionnaire is completed by participants and facilitators/clinical assessors to formally define, document, and evidence the blinding (masking) strategy for the study.	At first and second drug dose

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Michael J. Fox Foundation for Parkinson's Research
• Investigators: Principal Investigator: Sophie Holmes, PhD, Yale University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): May 1, 2030

Study Registration Dates

• First Submitted: May 15, 2026
• First Submitted That Met QC Criteria: May 21, 2026
• First Posted (Actual): May 28, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Psilocybin; Movement disorder; Psilocybin therapy; Parkinson's Diesease
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Behavioral Symptoms; Neurodegenerative Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Behavior; Depression; Movement Disorders; Parkinson Disease; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Amines; Indoles; Indole Alkaloids; Indolizidines; Indolizines; Biogenic Monoamines; Biogenic Amines; Tryptamines; Psilocybin; N,N-Dimethyltryptamine; Pharmaceutical Preparations
• Other Study ID Numbers: 2000042396

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Any data, code and software needed for independent verification of research results will be shared freely and publicly per the funder's open access publication policy.
• IPD Sharing Time Frame: The IPD will be shared at the end of the research project and for 1 year after that.
• IPD Sharing Access Criteria: The public will be able to access the IPD and supporting information, the IPD accessed will be data and code generated from the project and they will be able to access it from a community-recognized repository.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No