Psilocybin as a Novel Therapy for Residual Anhedonia

Targeting Reward Circuits: Psilocybin as a Novel Therapy for Residual Anhedonia

The primary objective is to evaluate whether a single dose of psilocybin (25 mg), compared to placebo, can restore fronto-striatal reward circuit function and thereby improve anhedonia and emotional blunting in individuals with residual symptoms despite ongoing SSRI or SNRI treatment. This will be assessed using precision functional mapping (PFM), task-based fMRI, and clinical rating scales (DARS).

Study Overview

• Status: Not yet recruiting
• Conditions: Anhedonia; Emotional Blunting
• Intervention / Treatment: Drug: Psilocybin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Joshua Siegel, MD, PhD; Phone Number: 646-754-4814; Email: Joshua.Siegel@nyulangone.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Health

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age between 18 and 65 years
• Able to provide voluntary signed and dated informed consent.
• Females of childbearing potential (FOCBP) must agree to practice an effective means of birth control throughout the duration of the trial
• Males who have FOCBPs as partners must agree to practice an effective means of birth control throughout the duration of the trial
• State willingness to comply and be available for all study requirements, including psychological, cognitive, imaging and procedural evaluations for the duration of the study
• Meet DSM-5 criteria for major depressive disorder (MDD)
• Screening Dimensional Anhedonia Rating Scale (DARS) total score of < 28.5 points
• Have an identified support person
• Agree to refrain from taking all non-prescription medications and supplements (nutritional and herbal) for at least 1 week prior to the IP administration session unless approved by the Investigator.

Exclusion Criteria:

• Inability to speak and understand English sufficiently to complete informed consent and study procedures.
• Inability to provide informed consent.
• Women who are pregnant or who intend to become pregnant or nurse during the study duration.
• Prior exposure to classic psychedelics (i.e., psilocybin, LSD, ayahuasca, and/or mescaline) within the past 1 year.
• Current or previous psychiatric conditions that meet DSM-5 criteria for psychotic disorders (i.e., schizophrenia, schizoaffective disorder, MDD with psychosis), bipolar 1 or 2 disorder, or current diagnosis of active substance use disorder.
• Have active suicidal ideation with intent, based on Columbia-Suicide Severity Rating Scale (C-SSRS assessment (severity score > 3) at the Screening visit, confirmed by the Investigator.
• Have made a medically significant suicide attempt (i.e., one that had a significant possibility of causing death or permanent harm in the absence of intervention) within the past 12 months, based on Screening C-SSRS assessment and confirmation by the Investigator.
• Immediate family history (i.e., parents, full siblings, or half siblings) with known or suspected psychotic disorder.
• Presence of medical conditions that may confound results of imaging study or that are contraindications to or psilocybin exposure (i.e., neurological, renal, hypertension, metabolic or cardiovascular disease or pregnancy);
• Presence of contraindications to MRI scanning (implantable devices, bone hardware, various IUD).
• Participants who received electroconvulsive therapy (ECT), trans magnetic cranial stimulation (TMS), and/or ketamine in the past 90 days.
• Has any other physical or psychological symptom, medication, or other relevant finding prior to randomization that, based on the clinical judgment of trial personnel, would make a participant unsuitable for the trial.
• Are unable or unwilling to discontinue taking any protocol-prohibited medications and supplements.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Psilocybin; Participants will complete a total of six MRI sessions; two sessions prior to psilocybin administration day and four sessions after. On administration day, the psilocybin arm will receive psilocybin (25 mg single dose, under supervision).	Drug: Psilocybin; One-time dose of psilocybin 25 mg, oral, in capsule form.
Placebo Comparator: Control; Participants will complete a total of six MRI sessions; two sessions prior to placebo administration day and four sessions after. The control arm will receive placebo on administration day.	Drug: Placebo; One-time dose of placebo (25 mg of inert filler), oral, in capsule form.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Dimensional Anhedonia Rating Scale (DARS) Score	DARS is a 17-item, patient-reported instrument designed to measure "state" anhedonia (how a person is feeling right now). The total score is the sum of responses and ranges from 0-68; lower scores indicate more severe anhedonia.	Baseline (Week -3), End of Study (Week 8)
Change in Fronto-Striatal Connectivity (pgACC-NAcc FC)	This outcome measures the change in functional connectivity (FC) between the pregenual anterior cingulate cortex (pgACC) and the nucleus accumbens (NAcc). PgACC-NAcc FC will be measured using fMRI sequencing. The standard deviation of FC is assumed to be 0.1.	Baseline (Week -3), End of Study (Week 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Motivation and Pleasure Scale - Self-Report (MAP-SR) Score	MAP-SR is an 15-item self-report assessment designed to measure the "experiential" negative symptoms of psychiatric disorders. Each item is rated on a scale from 0-4; the total score is the sum of responses and ranges from 0-60; lower scores indicate more severe psychiatric symptoms.	Baseline (Week -3), End of Study (Week 8)
Change in Experiential Avoidance (BEAQ) Score	The Brief Measure of Experimental Avoidance Questionnaire (BEAQ) is a 15-item assessment of experiential avoidance. Each item is rated on a scale from 1-6; the total score is the sum of responses and ranges from 15 to 90. Higher scores indicate greater levels of experiential avoidance (and lower psychological flexibility).	Baseline (Week -3), End of Study (Week 8)
Change in Montgomery-Asberg Depression Scale (MADRS) Score	The MADRS is a 10-item assessment of depression severity. Each item is rated on a scale from 0-6; the total score is the sum of responses and ranges from 0-60. Higher scores indicate greater severity of depression.	Baseline (Week -3), End of Study (Week 8)

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Joshua Siegel, MD, PhD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: May 19, 2026
• First Submitted That Met QC Criteria: May 19, 2026
• First Posted (Actual): May 27, 2026

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Anhedonia; Psilocybin; SSRI; Emotional Blunting; SNR
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Behavioral Symptoms; Neurobehavioral Manifestations; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Depression; Anhedonia; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin
• Other Study ID Numbers: 26-00063; R01MH142698 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The de-identified participant data from the final research dataset will be shared with researchers who provide a methodologically sound proposal, or investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose, beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's Data Sharing Strategy Board (DSSB). Requests should be directed to: Joshua Siegel, MD, PhD, Joshua.Siegel@nyulangone.org. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal, or investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose, will be granted access upon reasonable request, including to achieve aims in the approved proposal and for individual participant data meta-analysis. Requests should be directed to Joshua.Siegel@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

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