Psilocybin Assisted Psychotherapy for Treatment Resistant Depression and Co-occurring Substance Use Disorder

NCT07499583 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 28032
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 2

Brief Summary

The goal of this clinical trial is to learn if a single dose of psilocybin (5mg Vs 10mg Vs 25mg) alongside psychotherapy is safe and can help treat treatment resistant depression (TRD) with co-occurring substance use disorder (SUD) in veterans and first responders. We seek to answer:

• Whether 5mgs, 10mgs and 25mgs of psilocybin are safe in individuals with co-occurring TRD and SUD
• Whether psilocybin assisted psychotherapy will reduce substance use severity and depression symptoms
• What neurobiological processes are associated with the effects of psilocybin assisted psychotherapy. The researchers will compare the effects of a single dose of psilocybin (either 5mgs or 10mgs or 25mg) alongside psychotherapy on substance use severity and depression symptoms over six weeks in veterans and first responders with TRD and co-occurring SUD. In this 14-week study, participants will:
• Visit the clinic for two intake sessions
• Complete seven psychotherapy sessions. This will include three sessions before psilocybin administration, an 8 to 10 hour dosing session, and three sessions following psilocybin administration
• Complete short, repeated daily assessments for six weeks, in total, before and after psilocybin administration
• Complete two brain scans before and after psilocybin administration

Conditions

Treatment Resistant Depression; Substance Use Disorders

Keywords

treatment resistant depression; substance abuse disorder; psilocybin assisted psychotherapy; stress

Outcome Measures

Primary Outcomes (6)

• percentage number of participants with Adverse Events (AEs)

  AEs that occur after administration of the single psilocybin dose or worsen from a pre-treatment state.

  Weekly for 12-weeks and once during a 60-day follow-up

• Change in % number of positive urines

  urine toxicology screens for alcohol and substance use will be collected

  Weekly for 12-weeks

• Change in % number of days spent using substances

  Self reports of alcohol and substance use, using the timeline followback (TLFB) and brief ecological momentary assessment (EMA) items

  Weekly for 12-weeks TLFB and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)

• Change in severity of depression symptoms

  Self reports of depressive symptomatology, using the Quick Inventory of Depression Symptoms-Self-Report (QIDS-SR) and brief EMA items using the Positive and Negative Affect Schedule (PANAS)

  Weekly for 12-weeks QIDS and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 for PANAS

• Changes in plasma brain-derived neurotrophic factor (BDNF) during stress exposure

  Levels of BDNF in response to stress will be assessed during brain scanning

  Change from baseline (week 2) to post psilocybin administration (week 5)

• Change in resting brain functional connectivity of the default mode network (DMN).

  Resting-state functional connectivity will be assessed using functional magnetic resonance imaging (fMRI)

  Change from baseline (week 2) to post psilocybin administration (week 5)

Secondary Outcomes (6)

• Change in amount of substance consumed per occasion

  Weekly for 12-weeks TLFB and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)

• Change in number of binge episodes

  Weekly for 12-weeks TLFB and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)

• Change in craving

  Weekly for 12-weeks (various dependent upon participants substance of choice) and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)

• Change in anxiety

  Weekly for 12-weeks (STAI) and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)

• Changes in emotion regulation

  Change from baseline (week 2) to post psilocybin administration (weeks 5 and 10)and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (adapted DERS)

Study Arms (3)

Psilocybin Dose - Low

EXPERIMENTAL

Experimental: Participants receive a single oral dose of psilocybin 5mgs

Drug: Psilocybin

Psilocybin Dose - Moderate

EXPERIMENTAL

Experimental: Participants receive a single oral dose of psilocybin 10mgs

Drug: Psilocybin

Psilocybin Dose - High

EXPERIMENTAL

Experimental: Participants receive a single oral dose of psilocybin 25mgs

Drug: Psilocybin

Interventions

Psilocybin DRUG

Participants will be randomly administered a single dose of either 5mg or 10mg or 25mg psilocybin

Psilocybin Dose - High; Psilocybin Dose - Low; Psilocybin Dose - Moderate

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• i) Veterans or first responders ii) 18 -70 years of age iii) Meets criteria for TRD (current major depressive episode without psychotic features by the Mini-International Neuropsychiatric Interview - MINI, with failure to respond to 2 or more evidence-based anti-depressants in the current episode), iv) Meets moderate to severe use criteria for one primary substance (alcohol, cocaine, opioids/heroin, or cannabis). Moderate to severe co-use of nicotine also acceptable, as well as mild/recreational use of other substances, v) Able to read English and complete study evaluations and consent vi) In good health as verified by screening examination and medical history vii) able to safely receive MRI

Sponsors & Collaborators

• Indiana University: lead

Study Sites (2)

Goodman Hall, Dept of Psychiatry, Indiana University

Indianapolis, Indiana, 46202-3082, United States

Location

The Stark Neuroscience Building (Goodman Hall)

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Substance-Related Disorders

Interventions

Psilocybin

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

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

Study Officials

• Susan K Conroy, PhD

  Indiana University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Susan K Conroy, MD

CONTACT

317-948-5450; sconroy@iu.edu

Helen C Fox, PhD

CONTACT

203-671-9643; helfox@iu.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assitant Professor of Psychiatry

Model Details: Randomized, double-blind, dose trial

Study Record Dates

• First Submitted: March 24, 2026
• First Posted: March 30, 2026
• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): January 1, 2031
• Study Completion (Estimated): February 28, 2031
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)