Clinical TrialSingle-armMajor Depressive Disorder (MDD)PsilocybinNot yet recruiting

Psilocybin-Assisted Therapy as a Treatment for Depression

This Phase 2b open-label, single-arm pilot mechanistic trial (n=50) evaluates psilocybin-assisted therapy (PAT) for adults with mild-to-moderate depression at Washington University in St. Louis. Each participant receives the Usona Institute PAT protocol: 2 preparation sessions (~8 hours total), one Dosing Day with a single 25 mg oral psilocybin capsule, and 3 integration sessions at Trial Days 2, 8 and 15 (~80 min each) with two trained facilitators. Participants on a stable antidepressant monotherapy may continue their medication, and those with a MADRS score ≥7 at Trial Day 30 are eligible for one optional re-administration. Primary endpoints are change in depression severity (MADRS) and psychological flexibility (MPFI) at ~1 week (Trial Day 8) and ~30 days after dosing. Exploratory aims characterise neural mechanisms via up to 10 fMRI sessions per participant (including imaging during dosing using precision functional brain mapping), proteomic blood biomarkers (the senescence-associated secretory phenotype, SASP), and cognitive functioning via the NIH Toolbox. The study is designed to estimate feasibility, effect sizes and operational parameters — it is not powered for confirmatory hypothesis testing — to inform a subsequent adequately-powered trial.

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Target Enrollment
50 participants
Study Type
Phase II interventional
Design
Non-randomized

Detailed Description

Depression is the leading cause of disability worldwide, affecting an estimated 300 million people. Despite available treatments, response rates remain modest, and treatment resistance is common. Novel treatments are needed that act rapidly, produce lasting effects and work differently than existing antidepressants.

In clinical trials, psilocybin has shown promise as a treatment for depression due to its rapid onset of antidepressant effects and sustained benefits.

This study will use MRI scanning of the brain and other biological measures (biomarkers) to investigate how psilocybin affects brain activity and psychological flexibility before, during, and after receiving psilocybin in participants with depressive symptoms.

Study Protocol

Preparation

2 sessions
240 min each

Dosing

1 sessions
420 min each

Integration

3 sessions
80 min each

Therapeutic Protocol

supportive

Study Arms & Interventions

25mg Open Label dose of synthetic psilocybin

experimental

Open-label psilocybin-assisted therapy (PAT) delivered per the Usona Institute Phase III (PSIL301 / UAspire) protocol. Each participant receives ~20 hours of psychological support from two trained Facilitators (Lead + Assistant), comprising: 2 preparation sessions (~8 hours total) up to two weeks before dosing; one Dosing Day with a single 25 mg oral psilocybin capsule taken with ~8 oz of water, supported by two Facilitators in a dedicated room (eye shades, headphones, pre-selected music); and 3 integration sessions on approximately Trial Days 2, 8, and 15 (~80 minutes each). When feasible, fMRI scanning is performed during the dosing session. Participants on a stable antidepressant monotherapy may continue their medication. Participants with a MADRS score ≥7 at the Trial Day 30 Visit are eligible for one optional open-label re-administration of 25 mg psilocybin, preceded by one ~90-minute preparation session and followed by 3 further integration sessions.

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total

Participants

Ages
18 – ?
Sexes
Male & Female

Inclusion Criteria

  • 1. Age > 18 years
  • 2. Participants of childbearing potential must agree to practice 2 forms of effective birth control throughout the duration of the study
  • 3. Females of childbearing potential must have a negative urine pregnancy test at Screening and prior to dosing on Dosing Day
  • 4. Diagnosis of depression at Screening via the SCID-5-CT interview and MADRS score of ≥7
  • 5. Have an identified support person Agree to be accompanied home (or to an otherwise safe destination) by the support person, or another responsible party, following dosing

Exclusion Criteria

  • 1. Unable to read or understand English
  • 2. Is currently pregnant or breastfeeding, or plan to become pregnant or breastfeed within the study period
  • 3. Has had Electroconvulsive Therapy, Transmagnetic Stimulation, Vagus Nerve Stimulation or Deep Brain Stimulation treatment within the last 12 months
  • a. Participants with VNS or DBS devices in place- including devices that are inactive or turned off will not be eligible to participate in the imaging portion of the study
  • 4. Is currently taking a medication on the prohibited medications list, such as heterocyclic (tricyclic, tetracyclic) antidepressants, monoamine oxidase inhibitors (MAOIs), antipsychotic augmentation therapy, or is taking more than one medication for the treatment of depression:
  • 1. Participants who are taking a single prescription medication for depression must be on a stable, minimally therapeutic/tolerated dose for at least 4 weeks prior to Screening.
  • 2. Psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) are allowed, if used at a stable dose or pattern for at least 6-weeks prior to Screening and not used on Dosing Day(s).
  • 5. Has a primary psychotic disorder diagnosis
  • 6. Has a first-degree relative with a known history of a psychotic disorder
  • 7. Meets criteria for substance use disorder or diagnosis of substance use disorder within 6 months prior to Screening
  • 8. Has an unstable medical condition or serious abnormalities of complete blood count, chemistries, or ECG, or taking medications that in the opinion of the study clinician would preclude safe participation in the trial
  • 9. Is at risk for hypertensive crisis defined as:
  • 1. BP at Screening AND Baseline \>140/90 mmHG
  • 2. BP on Dosing Day prior to dosing \>140/90 mmHG
  • 10. Has used a serotonergic hallucinogenic substance (e.g., psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine, 3,4-methylenedioxymethamphetamine (MDMA), or other related substances) within 6 months of Screening.
  • 11. Has a known sensitivity to psychedelic medications
  • 12. Has a positive urine drug test including amphetamines, barbiturates, buprenorphine, benzodiazepines, cocaine, methamphetamine (unless prescribed), MDMA, methadone, opiates, and phencyclidine (PCP)
  • 13. Is at high risk for suicide (e.g., active suicidal ideation and or current intent or plan) and unable to be managed safely (i.e., unwilling to be hospitalized)

Study Details

Study Team

Sponsors & Collaborators

Locations

Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine — St. Louis, Missouri, United States
Mallinckrodt Institute of Radiology, Washington University School of Medicine (neuroimaging) — St. Louis, Missouri, United States