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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Substance Use Disorders; Treatment Resistant Depression
• Intervention / Treatment: Drug: Psilocybin

Detailed Description

This is a double-blind randomized clinical trial to examine the safety and efficacy of a single dose of psilocybin (5mg or 10mg or 25mg) in reducing substance use severity and depression symptoms in N=50 veterans and first responders with treatment resistant depression (TRD) and co-occurring substance use disorder (SUD).

The study will be conducted at Goodman Hall outpatient clinic located at Indiana University, Department of Psychiatry. All participants will take part in two intake visits (one to conduct safety tests and establish eligibility, and one to collect baseline and covariate data). They will then participate in three preparatory psychotherapy sessions with a certified psilocybin counselor before receiving one of three, randomly assigned, psilocybin doses during an 8 to 10 hour administration session. Following psilocybin administration, participants will participate in three weekly integrative psychotherapy sessions. We will also conduct three, two-week bursts of Ecological Momentary Assessment (EMA) during weeks 1 and 2, weeks 5 and 6 and weeks 10 and 11 of study participation, to measure daily substance use patterns and depression symptoms both during stressful and non-stressful situations. A pre- and post- fMRI paradigm will additionally be conducted to determine psilocybin-related changes within and between the default mode network, the salience mode network and the central executive network, during both resting state and stress. We will also explore the extent to which elevations in subjective mystical and existential experience contributes to psilocybin's therapeutic and mechanistic effects.

It is anticipated that all three doses of psilocybin will be safe and well-tolerated in this sample of veterans and first responders. We additionally expect that 25mgs of psilocybin compared with 5mgs will attenuate substance use severity and depressive symptoms six weeks following administration, and during both stressful and non-stressful situations. In addition, we expect that 25mg Vs 5mg psilocybin will decrease resting state functional connectivity within the default mode network (DMN) and modulate connectivity between the DMN, salience network, central executive network, and the amygdala during stress exposure.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Helen C Fox, PhD; Phone Number: 203-671-9643; Email: helfox@iu.edu
• Study Contact Backup: Name: Susan K Conroy, MD; Phone Number: 317-948-5450; Email: sconroy@iu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • The Stark Neuroscience Building (Goodman Hall)
    • Indianapolis, Indiana, United States, 46202-3082
      • Goodman Hall, Dept of Psychiatry, Indiana University
      • Contact: Susan K Conroy, MD; Email: sconroy@iu.edu
      • Contact: Helen Fox, PhD; Phone Number: 2036719643; Email: helfox@iu.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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

Exclusion Criteria:

i) Exclusionary psychiatric conditions include schizophrenia, schizoaffective disorder, bipolar disorder, current post-traumatic stress disorder, or history of medically serious suicide attempt ii) Actively/imminently suicidal (QIDS-SR question 12 score >2, Hamilton - depression scale (HAM-D) question 3 score >3, or Montgomery-Åsberg Depression Rating Scale (MADRS) question 10 >4) ii) A family history of schizophrenia or schizoaffective disorder (first- or second-degree relatives), or bipolar disorder type 1 (first degree relatives) iii) Use of selective serotonin reuptake inhibitors (SSRIs) and other medications are acceptable if dose has remained stable for 6 months, and is not contra-indicated with psilocybin, as per the study physician, Dr Conroy iii) Individuals with any prior use of classic psychedelics, including psilocybin iv) Medical conditions that would preclude safe participation in the trial (e.g., seizure disorder, significantly impaired liver function, coronary artery disease, heart failure, history of cerebrovascular accident, severe asthma, hyperthyroidism, narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, or bladder-neck obstruction) v) Sitting blood pressure below 90/50 mmHG or above 165/95 mmHg vi) EKG evidence of any clinically significant conduction abnormalities, including a Bazett's corrected QT interval (QTc) of >450 msec for men and QTc>470 msec for women vii) Women who are pregnant or lactating

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Psilocybin Dose - Low; Experimental: Participants receive a single oral dose of psilocybin 5mgs	Drug: Psilocybin; Participants will be randomly administered a single dose of either 5mg or 10mg or 25mg psilocybin
Experimental: Psilocybin Dose - Moderate; Experimental: Participants receive a single oral dose of psilocybin 10mgs	Drug: Psilocybin; Participants will be randomly administered a single dose of either 5mg or 10mg or 25mg psilocybin
Experimental: Psilocybin Dose - High; Experimental: Participants receive a single oral dose of psilocybin 25mgs	Drug: Psilocybin; Participants will be randomly administered a single dose of either 5mg or 10mg or 25mg psilocybin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in amount of substance consumed per occasion	Self reports of alcohol and substance use, using the TLFB and brief EMA items	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	Self reports of alcohol and substance use, using the TLFB and brief EMA items	Weekly for 12-weeks TLFB and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)
Change in craving	Various standardized craving scales will be used to collect self-report craving data in addition to brief EMA items	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	The State-Trait Anxiety Inventory (STAI) will be used to collect self-report anxiety data in addition to brief momentary assessment items	Weekly for 12-weeks (STAI) and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)
Changes in emotion regulation	The Difficulties in Emotion Regulation Scale (DERS) will be used to collect emotion regulation data in addition to the DERS adapted for EMA	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)
Changes in brain functional connectivity during stress exposure	functional connectivity will be assessed during stress exposure in the scanner	Change from baseline (week 2) to post psilocybin administration (week 5)

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Susan K Conroy, PhD, Indiana University

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): January 1, 2031
• Study Completion (Estimated): February 28, 2031

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: stress; treatment resistant depression; substance abuse disorder; psilocybin assisted psychotherapy
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Mood Disorders; Depressive Disorder; Substance-Related Disorders; Depressive Disorder, Treatment-Resistant; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin
• Other Study ID Numbers: 28032

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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