Psilocybin as a Novel Therapy for Residual Anhedonia

NCT07607938 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 26-00063R01MH142698
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Anhedonia; Emotional Blunting

Keywords

SSRI; SNR; Depression; Anhedonia; Emotional Blunting; Psilocybin

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Change in Motivation and Pleasure Scale - Self-Report (MAP-SR) Score

  Baseline (Week -3), End of Study (Week 8)

• Change in Experiential Avoidance (BEAQ) Score

  Baseline (Week -3), End of Study (Week 8)

• Change in Montgomery-Asberg Depression Scale (MADRS) Score

  Baseline (Week -3), End of Study (Week 8)

Study Arms (2)

Psilocybin

EXPERIMENTAL

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

Control

PLACEBO COMPARATOR

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

Interventions

Psilocybin DRUG

One-time dose of psilocybin 25 mg, oral, in capsule form.

Psilocybin

Placebo DRUG

One-time dose of placebo (25 mg of inert filler), oral, in capsule form.

Control

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• NYU Langone Health: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

NYU Langone Health

New York, New York, 10016, United States

Location

MeSH Terms

Conditions

Anhedonia; Depression

Interventions

Psilocybin

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Study Officials

• Joshua Siegel, MD, PhD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joshua Siegel, MD, PhD

CONTACT

646-754-4814; Joshua.Siegel@nyulangone.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2026
• First Posted: May 27, 2026
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): September 30, 2030
• Last Updated: May 27, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• 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.
• 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.

Locations

US (1)