Clinical TrialParallelMajor Depressive Disorder (MDD)PsilocybinPlaceboNot yet recruiting

Psilocybin as a Novel Therapy for Residual Anhedonia

This Phase I, randomised, triple-masked, parallel-group trial (n=90) will evaluate whether a single oral dose of psilocybin 25 mg can improve residual anhedonia and emotional blunting in adults with major depressive disorder who remain symptomatic despite ongoing SSRI or SNRI treatment. The study will compare psilocybin with placebo and will assess whether treatment can restore fronto-striatal reward circuit function and reduce anhedonia. Participants in both arms will complete six MRI sessions, with two scans before the administration day and four afterwards. The psilocybin group will receive a supervised one-time 25 mg capsule dose, while the control group will receive a matching placebo capsule containing 25 mg of inert filler. Key outcomes include change in Dimensional Anhedonia Rating Scale score and change in fronto-striatal connectivity (pgACC-NAcc functional connectivity) from baseline to end of study, with assessments planned from week -3 to week 8.

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Target Enrollment
90 participants
Study Type
Phase I interventional
Design
Randomized, triple Blind

Detailed Description

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 Arms & Interventions

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).

Interventions

  • Psilocybin25 mg
    via Oral• one-time dose• 1 doses total

Control

inactive

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.

Interventions

  • Placebo25 mg
    via Oral• one-time dose• 1 doses total

Participants

Ages
18 – 65
Sexes
Male & Female

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 Details

Study Team

Sponsors & Collaborators

Locations

NYU Langone Health — New York, New York, United States