Treatment Resistant DepressionPhase 1/2NCT07499583
Psilocybin Assisted Psychotherapy for Treatment Resistant Depression and Co-occurring Substance Use Disorder
A Phase 1/2 study testing Psilocybin in people with Treatment Resistant Depression and Substance Use Disorders, run by Indiana University at 2 sites in United States.
Trial 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). The participant sample will be enriched for veterans and first responders. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Treatment Resistant Depression, Substance Use Disorders
- What is being tested?
- Psilocybin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 2 sitesUnited States
- Study dates
- 1 Feb 2027to 1 Feb 2031
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and Women 18 years or over (veterans and first responders encouraged)
- 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)
- 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
- Able to read English and complete study evaluations and consent
- In good health as verified by screening examination and medical history
- Able to safely receive MRI
Who cannot join
- Exclusionary psychiatric conditions include schizophrenia, schizoaffective disorder, bipolar disorder, current post-traumatic stress disorder, or history of medically serious suicide attempt
- 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)
- A family history of schizophrenia or schizoaffective disorder (first- or second-degree relatives), or bipolar disorder type 1 (first degree relatives)
- 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
- Any prior use of classic psychedelics, including psilocybin
- 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)
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- Sitting blood pressure below 90/50 mmHg or above 165/95 mmHg
- 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
- Women who are pregnant or lactating
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites
Goodman Hall, Dept of Psychiatry, Indiana University
Indianapolis, Indiana, 46202-3082
Susan K Conroy, MD, psycrsch@iu.edu
Helen Fox, PhD, 2036719643, psycrsch@iu.edu
The Stark Neuroscience Building (Goodman Hall)
Indianapolis, Indiana, 46202
About this study
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). The participant sample will be enriched for veterans and first responders. Investigators 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.
Read more
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 a sample of individuals 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
Read the 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 individuals with treatment resistant depression (TRD) and co-occurring substance use disorder (SUD). The study sample will be enriched for veterans and first responders.
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). Subjects 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, subjects will participate in three weekly integrative psychotherapy sessions. Three, two-week bursts of Ecological Momentary Assessment (EMA) will additionally be administered 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. Investigators 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, and that 25mgs of psilocybin compared with 5mgs will attenuate substance use severity and depressive symptoms six weeks following administration, during both stressful and non-stressful situations. In addition, it is expected 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.
- Being tested
- Psilocybin
- Keywords
- treatment resistant depression, substance abuse disorder, psilocybin assisted psychotherapy, stress
- Medical subject headings
- Depressive Disorder, Treatment-Resistant, Substance-Related Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PsilocybinDrug
Participants will be randomly administered a single dose of either 5mg or 10mg or 25mg psilocybin
| Study group | Role | What they receive |
|---|---|---|
| Psilocybin Dose - Low | Experimental | Experimental: Participants receive a single oral dose of psilocybin 5mgs Receives: Drug: Psilocybin |
| Psilocybin Dose - Moderate | Experimental | Experimental: Participants receive a single oral dose of psilocybin 10mgs Receives: Drug: Psilocybin |
| Psilocybin Dose - High | Experimental | Experimental: Participants receive a single oral dose of psilocybin 25mgs Receives: Drug: Psilocybin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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
Measured: 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)
Measured: 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
Measured: 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)
Measured: Change from baseline (week 2) to post psilocybin administration (week 5)
Secondary outcomes (6)
Change in amount of substance consumed per occasion
Self reports of alcohol and substance use, using the TLFB and brief EMA items
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Change from baseline (week 2) to post psilocybin administration (week 5)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2026
- Study start1 Feb 2027 (estimated)
- Primary completion1 Feb 2031 (estimated)
- Study completion1 Feb 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Treatment Resistant DepressionStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, double-blind, dose trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Susan K. Conroy, Indiana University
- Investigators
- Susan K Conroy, MD, PhD, Principal investigator, Indiana UniversityHelen C Fox, PhD, Principal investigator, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07499583
- Sponsor's protocol ID
- 28032
- Status last verified
- Oct 2026
- First submitted
- 24 Mar 2026
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Psilocybin Assisted Psychotherapy for Treatment Resistant Depression and Co-occurring Substance Use Disorder
- ClinicalTrials.gov ID
- NCT07499583
- Acronym / sponsor ID
- 28032
- Keywords
- treatment resistant depression, substance abuse disorder, psilocybin assisted psychotherapy, stress
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Study start
- 1 Feb 2027 (estimated)
- Primary completion
- 1 Feb 2031 (estimated)
- Study completion
- 1 Feb 2031 (estimated)
- First posted
- 30 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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). The participant sample will be enriched for veterans and first responders. Investigators 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 a sample of individuals 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
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 individuals with treatment resistant depression (TRD) and co-occurring substance use disorder (SUD). The study sample will be enriched for veterans and first responders.
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). Subjects 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, subjects will participate in three weekly integrative psychotherapy sessions. Three, two-week bursts of Ecological Momentary Assessment (EMA) will additionally be administered 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. Investigators 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, and that 25mgs of psilocybin compared with 5mgs will attenuate substance use severity and depressive symptoms six weeks following administration, during both stressful and non-stressful situations. In addition, it is expected 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- Randomized, double-blind, dose trial
| Arm | Type | Receives |
|---|---|---|
| Psilocybin Dose - Low | Experimental | Drug: PsilocybinExperimental: Participants receive a single oral dose of psilocybin 5mgs |
| Psilocybin Dose - Moderate | Experimental | Drug: PsilocybinExperimental: Participants receive a single oral dose of psilocybin 10mgs |
| Psilocybin Dose - High | Experimental | Drug: PsilocybinExperimental: Participants receive a single oral dose of psilocybin 25mgs |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Men and Women 18 years or over (veterans and first responders encouraged)
- 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)
- 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
- Able to read English and complete study evaluations and consent
- In good health as verified by screening examination and medical history
Key exclusion criteria (9 listed)
- Exclusionary psychiatric conditions include schizophrenia, schizoaffective disorder, bipolar disorder, current post-traumatic stress disorder, or history of medically serious suicide attempt
- 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)
- A family history of schizophrenia or schizoaffective disorder (first- or second-degree relatives), or bipolar disorder type 1 (first degree relatives)
- 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
- Any prior use of classic psychedelics, including psilocybin
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PsilocybinParticipants will be randomly administered a single dose of either 5mg or 10mg or 25mg psilocybin | Drug | Psilocybin Dose - High, Psilocybin Dose - Low, Psilocybin Dose - Moderate |
Primary outcome
percentage number of participants with Adverse Events (AEs)
Time frame: Weekly for 12-weeks and once during a 60-day follow-up
AEs that occur after administration of the single psilocybin dose or worsen from a pre-treatment state.
Change in % number of positive urines
Time frame: Weekly for 12-weeks
urine toxicology screens for alcohol and substance use will be collected
Change in % number of days spent using substances
Time frame: Weekly for 12-weeks TLFB and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)
Self reports of alcohol and substance use, using the timeline followback (TLFB) and brief ecological momentary assessment (EMA) items
Change in severity of depression symptoms
Time frame: Weekly for 12-weeks QIDS and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 for PANAS
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)
Changes in plasma brain-derived neurotrophic factor (BDNF) during stress exposure
Time frame: Change from baseline (week 2) to post psilocybin administration (week 5)
Levels of BDNF in response to stress will be assessed during brain scanning
Change in resting brain functional connectivity of the default mode network (DMN).
Time frame: Change from baseline (week 2) to post psilocybin administration (week 5)
Resting-state functional connectivity will be assessed using functional magnetic resonance imaging (fMRI)
6 secondary outcomes
Change in amount of substance consumed per occasion
Time frame: 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
Time frame: Weekly for 12-weeks TLFB and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)
Change in craving
Time frame: 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
Time frame: Weekly for 12-weeks (STAI) and 5 times per day in weeks 1, 2, 5, 6, 10 & 11 (brief items)
Changes in emotion regulation
Time frame: 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
Time frame: Change from baseline (week 2) to post psilocybin administration (week 5)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Susan K Conroy, MD, PhD principal investigator
Indiana University
Helen C Fox, PhD principal investigator
Indiana University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Psilocybin in people with Treatment Resistant Depression and Substance Use Disorders, run by Indiana University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 23 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Susan K Conroy, MD (317-948-5450, psycrsch@iu.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
percentage number of participants with Adverse Events (AEs) (time frame: Weekly for 12-weeks and once during a 60-day follow-up). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2026.