Major DepressionPhase 2PACTNCT07895134
Psilocybin for Depression in Veterans
A Phase 2 study testing Psilocybin, modafinil and zolpidem in people with Major Depression, run by VA Office of Research and Development at 4 sites in United States.
Trial summary
More efficacious treatments for Major Depressive Disorder (MDD) in Veterans are urgently needed. Psilocybin is a promising novel treatment that is likely to be the first FDA-approved psychedelic, but its safety and efficacy remain unclear. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Major Depression
- What is being tested?
- Psilocybin, modafinil and zolpidem
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 150 participants
- Where
- 4 sitesUnited States
- Study dates
- 1 Jan 2027to 31 Dec 2031
- Phase
- Phase 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 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Veteran
- Depression determined by the Structured Clinical Interview for DSM-5 (SCID) collected at screening visit
- Hamilton Depression Rating Scale (HAMD-6) of 8 or higher, assessed at screening visit
- No medication changes or psychiatric hospitalization in the past month (30 days prior to informed consent)
- No planned medication changes or psychotherapy treatment changes for duration of trial
- At least one attempt with a antidepressant medication
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- Agree to consume the same amount of caffeine-containing beverages that they usually consume before arriving at the research space on the mornings of their drug administration session
- Agree to refrain from taking any non-prescription medication, nutritional supplement, or herbal supplement except those approved by the study medical provider
- Agree to abstain from all tobacco and nicotine use for the at least 24 hours before and after the drug administration session
- Agree to avoid sedative-hypnotic medications (e.g., benzodiazepines, zolpidem, zopiclone, zaleplon) taken on an as-needed basis for a minimum of 5 half-lives prior and for 24 hours after the drug administration session, or the duration chosen by the study medical provider
- Agree to avoid opioid medications taken on an as-needed basis for a minimum of 5 half-lives prior and for 24 hours after each drug administration session, or the duration chosen by the study medical provider
- Agree not to use products or substances containing 9-tetrahydrocannabinol (THC) and/or cannabidiol for at least 7 days prior to and for 24 hours after each drug administration session
- Agree not to consume alcoholic beverages for at least 24 hours prior to and 24 hours following each drug administration session
- Agree to have a trusted adult accompany them from the research space upon discharge after drug administration
Who cannot join
- Meeting DSM-5 criteria for moderate or higher substance use disorder in the past 6 months, measured at screening visit. Nicotine and cannabis is permissible as long as inclusion criteria can be met
- Meeting DSM-5 criteria for a lifetime history of a bipolar or psychotic disorder determined at screening (family history permissible)
- Medical conditions contraindicated for psilocybin, modafinil, pimavanserin, or zolpidem, including uncontrolled hypertension, significant cardiac abnormality, or cognitive disorder (Mini-Mental State Examination <23) determined at screening
- Severe traumatic brain injury (Glasgow Outcome Scale-Extended Interview "Severe disability" or worse) determined at screening visit
- History of meeting DSM-5 criteria for Hallucinogen Persisting Perception Disorder (HPPD) determined at screening visit
- Active suicidal ideation with plan and intent requiring immediate emergency management at any point in the study
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- Suicide attempt requiring hospitalization in last year determined at screening visit
- High dose psychedelic use in past 3 years or ≥10 lifetime uses determined at screening visit
- Current use of any of the following medications or inability or unwillingness to stop (see Medication Exclusions and Restrictions section below):
- Clozapine
- Tricyclic antidepressants
- Monoamine oxidase inhibitors
- Pregnancy as indicated by a positive urine pregnancy test during screening or prior to drug administration; lactation, or the intention of becoming pregnant within 3 months of entry into this trial
- Refusal to use highly effective contraception from entry into the trial through Day 90 and refuse to not breastfeed. Acceptable methods of contraception are: An intrauterine device (IUD), hormone-based contraceptives (birth control pills), condoms (internal or external) must be used with another method (other than spermicide), complete abstinence from sexual activity that could result in pregnancy.
- Currently in another therapeutic interventional clinical trial (e.g. a study focused on improving symptoms using a drug or non-drug treatment)
- Other medical condition or diagnosis, physical exam finding, laboratory abnormality, or health risk identified that precludes participation in study procedures due to safety or feasibility concerns at the discretion of the investigators
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States4 sites
Minneapolis VA Health Care System, Minneapolis, MN
Minneapolis, Minnesota, 55417-2309
Holly Hamilton, PhD, holly.hamilton@va.gov
VA Salt Lake City Health Care System, Salt Lake City, UT
Salt Lake City, Utah, 84148-0001
Jennifer Romesser, PsyD, Jennifer.Romesser@va.gov
Lauren Thurgood, Lauren.Thurgood@va.gov
VA San Diego Healthcare System, San Diego, CA
San Diego, California, 92161-0002
Matthew Herbert, PhD, matthew.herbert2@va.gov
San Francisco VA Medical Center, San Francisco, CA
San Francisco, California, 94121-1563
Josh Woolley, BS PhD MD, (415) 221-4810 ext. 4117, Josh.Woolley@ucsf.edu
Josh Woolley, BS PhD MD
About this study
Official title: Safety, Efficacy, and Mechanisms of Psilocybin-assisted Acceptance and Commitment Therapy (PACT) in Treating Major Depressive Disorder (MDD) Among Veterans
More efficacious treatments for Major Depressive Disorder (MDD) in Veterans are urgently needed. Psilocybin is a promising novel treatment that is likely to be the first FDA-approved psychedelic, but its safety and efficacy remain unclear. To address this gap, the investigators propose a randomized controlled trial of a single dose of psilocybin paired with a brief course of a VA-endorsed evidence-based psychotherapy (Acceptance and Commitment Therapy) in Veterans with MDD. Our trial addresses key limitations of previous studies including the challenge of management of expectancy effects, a focus on Veterans with input from Veterans, and a study population that reflects the demographics and medical and psychiatric complexity of the VHA patient population. Our study also explores psilocybin's antidepressant mechanisms focusing on changes in psychological flexibility and synaptic plasticity. In sum, this study will provide critical and timely data to determine if psilocybin treatment is a safe and efficacious treatment for MDD in Veterans.
Read the detailed description
Major depressive disorder (MDD) affects 1 in 8 Veterans, leading to functional impairment, increased mortality, and high suicide risk. Veterans face complex psychiatric and medical comorbidities that often render conventional treatments inadequate, creating critical gaps in their mental health care. Psilocybin has emerged as a promising candidate treatment for MDD, but its safety and efficacy remain unclear. To address this gap, the investigators propose a four-site randomized clinical trial (RCT; N=120) to evaluate psilocybin-assisted Acceptance and Commitment Therapy (PACT) specifically for Veterans with MDD. The trial will determine if and how PACT decreases depressive and related symptoms, providing essential data that may lead to the development of a novel, efficacious treatment and guide potential VHA implementation. Our study incorporates Veteran input to ensure real-world relevance and addresses key limitations of previous psilocybin trials. The investigators will systematically evaluate safety, tolerability, and acceptability using gold-standard measures. PACT combines a single dose of psilocybin with a brief course of standardized, VA-endorsed ACT, overcoming issues of non-standardized psychotherapy that have hindered reproducibility and scalability. To tackle ineffective masking-which has plagued prior trials-the investigators employ a rigorous control condition pairing identical psychotherapy with a psychoactive multidrug placebo that mimics psilocybin's subjective effects, along with incomplete disclosure to minimize expectancy biases. A representative sample ensures generalizability to the VHA population, while mechanistic evaluations will inform a precision medicine approach that may extend to other disorders with similar neurobiological dysfunctions.
- Conditions
- Major Depression
- Being tested
- Psilocybin, modafinil, zolpidem, pimavanserin
- Keywords
- Psychedelic, Psilocybin, Depression, Veteran, Clinical Trial, Mental Health
- Medical subject headings
- Depressive Disorder, Major, Depression, Psychological Well-Being
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PsilocybinDrug
1-30mg
modafinilDrug
FDA-approved dosage
zolpidemDrug
FDA approved dosage
pimavanserinDrug
FDA-approved dosage
| Study group | Role | What they receive |
|---|---|---|
| Psilocybin, modafanil, zolpidem, pimavanserin arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 3 other drugs: modafinil, zolpidem, pimavanserin. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: modafinil; Drug: zolpidem; Drug: pimavanserin |
| Psilocybin, modafanil, zolpidem arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: modafinil and zolpidem and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: modafinil; Drug: zolpidem |
| Psilocybin, modafanil, pimavanserin arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: modafinil, pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: modafinil; Drug: pimavanserin |
| Psilocybin, modafanil arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: modafinil, and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: modafinil |
| Psilocybin, zolpidem, arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: zolpidem, and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: zolpidem |
| Psilocybin, pimavanserin arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: pimavanserin |
| Psilocybin arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin |
| Psilocybin, zolpidem, pimavanserin arm | Experimental | Participants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: zolpidem, pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm Receives: Drug: Psilocybin; Drug: zolpidem; Drug: pimavanserin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hamilton Depression Rating Scale-6 (HAMD-6)
A clinician-administered, 6-item version of the Hamilton Depression Rating Scale that assesses core depressive symptoms including depressed mood, guilt, work and activities, psychomotor retardation, psychic anxiety, and somatic symptoms. Scores range from 0-22, with higher scores indicating greater depression severity. Administered at Baseline, Day 1, Day 7, Day 30, and Day 90.
Measured: Baseline to 30 and 90 days post-drug administration
Secondary outcomes (8)
Change in EEG-measured LTP-like visual plasticity from baseline to Day 7, assessed by P1-N1b visual evoked potential amplitude (micro volts)
LTP-like cortical plasticity will be assessed using an EEG-based visual stimulation paradigm. Visual evoked potential (VEPs) will be recorded before and after 10 minutes of repetitive checkerboard stimulation at 2 Hz. Within-session potentiation will be quantified as the change in P1-N1b peak-to-peak VEP amplitude (micro-volts) from pre- to post-stimulation. The outcome measure is the change in within-session potentiation from baseline to Day 7 following study drug administration, calculated as the D7 potentiation minus baseline potentiation..
Measured: Baseline to 7 days post-drug administration
Change in Multidimensional Psychological Flexibility Inventory (MPFI)
The Multidimensional Psychological Flexibility Inventory (MPFI) is a self-report questionnaire assessing psychological flexibility, the core therapeutic process in Acceptance and Commitment Therapy (ACT). The psychological flexibility score is calculated as the mean of six subscales: acceptance, present moment awareness, self as context, defusion, values, and committed action. Scores range from 1 to 6, with higher scores indicating greater psychological flexibility (better outcome).
Measured: Baseline to 30 and 90 days post-drug administration
Change in Symptoms of Depression Questionnaire (SDQ)
The Symptoms of Depression Questionnaire (SDQ) is a 44-item self-report questionnaire assessing depressive symptoms across five domains: lassitude, mood, and cognitive functioning; anxiety, agitation, irritability, and anger; suicidal ideation; sleep disturbances; and appetite and weight changes. Each item is scored from 1 to 6, yielding a total score ranging from 44 to 264. Higher scores indicate greater depressive symptom severity (worse outcome). Administered at Baseline, Day 30, and Day 90. Endpoints include change from Baseline to Days 30 and 90 post-treatment.
Measured: Baseline to 30 and 90 days post-drug administration
Change in Columbia-Suicide Severity Rating Scale - Suicidal Ideation Subscale (C-SSRS-SI)
The Columbia-Suicide Severity Rating Scale - Suicidal Ideation Subscale (C-SSRS-SI) is a structured assessment of suicidal ideation across five levels of increasing severity: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods, active suicidal ideation with intent, and active suicidal ideation with plan and intent. Scores range from 0 (no suicidal ideation) to 5 (active suicidal ideation with specific plan and intent), based on the highest severity level endorsed. Higher scores indicate more severe suicidal ideation (worse outcome). The score will be analyzed as a numerical measure of suicidal ideation severity. Trained study staff will administer the assessment at Baseline, Day 30, and Day 90. Endpoints include change from Baseline to Days 30 and 90 post-treatment.
Measured: Baseline to 30 and 90 days post-drug administration
Change in WHO Disability Assessment 2.0 (WHODAS 2.0)
The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a self-report questionnaire assessing functional disability across six domains: cognition, mobility, self-care, getting along, life activities, and participation. Standardized total scores range from 0 (no disability) to 100 (complete disability), with higher scores indicating greater functional disability (worse outcome). Administered at Baseline, Day 30, and Day 90. Endpoints include change from Baseline to Days 30 and 90 post-treatment.
Measured: Baseline to 30 and 90 days post-drug administration
Change in EEG Theta Band Phase Synchrony
Change in EEG theta-band (4-8 Hz) phase synchrony induced by repetitive visual stimulation, measured using intertrial coherence (ITC). ITC is a unitless measure ranging from 0 to 1, with higher values indicating greater consistency of neural oscillatory phase across trials. EEG assessments are performed at Baseline and Day 7, with changes in stimulation-induced ITC compared between visits.
Measured: Baseline to 7 days post-drug administration.
Change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a centrally administered structured clinical interview assessing the 20 DSM-5 PTSD symptoms. The CAPS-5 provides both categorical PTSD diagnoses and continuous symptom severity scores. Each symptom is rated from 0 to 4, yielding a total severity score ranging from 0 to 80, with higher scores indicating greater PTSD symptom severity (worse outcome). Administered by trained, licensed clinical staff at Baseline and Day 30. The endpoint is change from Baseline to Day 30 post-drug administration.
Measured: Baseline to 30 days post-drug administration
Change in EEG Theta Band Power
Change in EEG theta-band (4-8 Hz) power induced by repetitive visual stimulation, measured using a visual long-term potentiation (LTP)-like plasticity paradigm. EEG assessments are performed at Baseline and Day 7, with changes in stimulation-induced theta power compared between visits.
Measured: Baseline to 7 days post-drug administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Oct 2026
- Study start1 Jan 2027 (estimated)
- Primary completion31 Dec 2031 (estimated)
- Study completion31 Dec 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major DepressionStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants will complete a course of Acceptance and Commitment Therapy and a single drug treatment session. Participants will be randomized to receive 1-30mg of psilocybin, in addition to up to 3 other drugs: modafinil, zolpidem, pimavanserin, or a placebo (no drug).
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Josh Woolley, BS PhD MD, Principal investigator, San Francisco VA Medical Center, San Francisco, CA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07895134
- Sponsor's protocol ID
- MHBC-003-25S
- Other IDs
- 1903662, 1I01RD001521-01-A1, 181208
- Acronym
- PACT
- Status last verified
- Oct 2026
- First submitted
- 8 Oct 2026
- Last updated
- 26 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 26 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety, Efficacy, and Mechanisms of Psilocybin-assisted Acceptance and Commitment Therapy (PACT) in Treating Major Depressive Disorder (MDD) Among Veterans
- ClinicalTrials.gov ID
- NCT07895134
- Acronym / sponsor ID
- PACT / MHBC-003-25S
- Conditions
- Major Depression
- Keywords
- Psychedelic, Psilocybin, Depression, Veteran, Clinical Trial, Mental Health
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 1 Jan 2027 (estimated)
- Primary completion
- 31 Dec 2031 (estimated)
- Study completion
- 31 Dec 2031 (estimated)
- First posted
- 26 Oct 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.
More efficacious treatments for Major Depressive Disorder (MDD) in Veterans are urgently needed. Psilocybin is a promising novel treatment that is likely to be the first FDA-approved psychedelic, but its safety and efficacy remain unclear. To address this gap, the investigators propose a randomized controlled trial of a single dose of psilocybin paired with a brief course of a VA-endorsed evidence-based psychotherapy (Acceptance and Commitment Therapy) in Veterans with MDD. Our trial addresses key limitations of previous studies including the challenge of management of expectancy effects, a focus on Veterans with input from Veterans, and a study population that reflects the demographics and medical and psychiatric complexity of the VHA patient population. Our study also explores psilocybin's antidepressant mechanisms focusing on changes in psychological flexibility and synaptic plasticity. In sum, this study will provide critical and timely data to determine if psilocybin treatment is a safe and efficacious treatment for MDD in Veterans.
Detailed description
Major depressive disorder (MDD) affects 1 in 8 Veterans, leading to functional impairment, increased mortality, and high suicide risk. Veterans face complex psychiatric and medical comorbidities that often render conventional treatments inadequate, creating critical gaps in their mental health care. Psilocybin has emerged as a promising candidate treatment for MDD, but its safety and efficacy remain unclear. To address this gap, the investigators propose a four-site randomized clinical trial (RCT; N=120) to evaluate psilocybin-assisted Acceptance and Commitment Therapy (PACT) specifically for Veterans with MDD. The trial will determine if and how PACT decreases depressive and related symptoms, providing essential data that may lead to the development of a novel, efficacious treatment and guide potential VHA implementation. Our study incorporates Veteran input to ensure real-world relevance and addresses key limitations of previous psilocybin trials. The investigators will systematically evaluate safety, tolerability, and acceptability using gold-standard measures. PACT combines a single dose of psilocybin with a brief course of standardized, VA-endorsed ACT, overcoming issues of non-standardized psychotherapy that have hindered reproducibility and scalability. To tackle ineffective masking-which has plagued prior trials-the investigators employ a rigorous control condition pairing identical psychotherapy with a psychoactive multidrug placebo that mimics psilocybin's subjective effects, along with incomplete disclosure to minimize expectancy biases. A representative sample ensures generalizability to the VHA population, while mechanistic evaluations will inform a precision medicine approach that may extend to other disorders with similar neurobiological dysfunctions.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 8
- Model description
- Participants will complete a course of Acceptance and Commitment Therapy and a single drug treatment session. Participants will be randomized to receive 1-30mg of psilocybin, in addition to up to 3 other drugs: modafinil, zolpidem, pimavanserin, or a placebo (no drug).
| Arm | Type | Receives |
|---|---|---|
| Psilocybin, modafanil, zolpidem, pimavanserin arm | Experimental | Drug: Psilocybin, Drug: modafinil, Drug: zolpidem, Drug: pimavanserinParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 3 other drugs: modafinil, zolpidem, pimavanserin. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin, modafanil, zolpidem arm | Experimental | Drug: Psilocybin, Drug: modafinil, Drug: zolpidemParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: modafinil and zolpidem and placebo. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin, modafanil, pimavanserin arm | Experimental | Drug: Psilocybin, Drug: modafinil, Drug: pimavanserinParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: modafinil, pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin, modafanil arm | Experimental | Drug: Psilocybin, Drug: modafinilParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: modafinil, and placebo. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin, zolpidem, arm | Experimental | Drug: Psilocybin, Drug: zolpidemParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: zolpidem, and placebo. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin, pimavanserin arm | Experimental | Drug: Psilocybin, Drug: pimavanserinParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin arm | Experimental | Drug: PsilocybinParticipants will receive a single dose of 1-30mg of psilocybin, and placebo. All participants will be masked to the probability of being assigned to a specific arm |
| Psilocybin, zolpidem, pimavanserin arm | Experimental | Drug: Psilocybin, Drug: zolpidem, Drug: pimavanserinParticipants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: zolpidem, pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Veteran
- Depression determined by the Structured Clinical Interview for DSM-5 (SCID) collected at screening visit
- Hamilton Depression Rating Scale (HAMD-6) of 8 or higher, assessed at screening visit
- No medication changes or psychiatric hospitalization in the past month (30 days prior to informed consent)
- No planned medication changes or psychotherapy treatment changes for duration of trial
Key exclusion criteria (16 listed)
- Meeting DSM-5 criteria for moderate or higher substance use disorder in the past 6 months, measured at screening visit. Nicotine and cannabis is permissible as long as inclusion criteria can be met
- Meeting DSM-5 criteria for a lifetime history of a bipolar or psychotic disorder determined at screening (family history permissible)
- Medical conditions contraindicated for psilocybin, modafinil, pimavanserin, or zolpidem, including uncontrolled hypertension, significant cardiac abnormality, or cognitive disorder (Mini-Mental State Examination <23) determined at screening
- Severe traumatic brain injury (Glasgow Outcome Scale-Extended Interview "Severe disability" or worse) determined at screening visit
- History of meeting DSM-5 criteria for Hallucinogen Persisting Perception Disorder (HPPD) determined at screening visit
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 |
|---|---|---|
| Psilocybin1-30mg | Drug | Psilocybin arm, Psilocybin, modafanil arm, Psilocybin, modafanil, pimavanserin arm, Psilocybin, modafanil, zolpidem arm, Psilocybin, modafanil, zolpidem, pimavanserin arm, Psilocybin, pimavanserin arm, Psilocybin, zolpidem, arm, Psilocybin, zolpidem, pimavanserin arm |
| modafinilFDA-approved dosage | Drug | Psilocybin, modafanil arm, Psilocybin, modafanil, pimavanserin arm, Psilocybin, modafanil, zolpidem arm, Psilocybin, modafanil, zolpidem, pimavanserin arm |
| zolpidemFDA approved dosage | Drug | Psilocybin, modafanil, zolpidem arm, Psilocybin, modafanil, zolpidem, pimavanserin arm, Psilocybin, zolpidem, arm, Psilocybin, zolpidem, pimavanserin arm |
| pimavanserinFDA-approved dosage | Drug | Psilocybin, modafanil, pimavanserin arm, Psilocybin, modafanil, zolpidem, pimavanserin arm, Psilocybin, pimavanserin arm, Psilocybin, zolpidem, pimavanserin arm |
Primary outcome
Hamilton Depression Rating Scale-6 (HAMD-6)
Time frame: Baseline to 30 and 90 days post-drug administration
A clinician-administered, 6-item version of the Hamilton Depression Rating Scale that assesses core depressive symptoms including depressed mood, guilt, work and activities, psychomotor retardation, psychic anxiety, and somatic symptoms. Scores range from 0-22, with higher scores indicating greater depression severity. Administered at Baseline, Day 1, Day 7, Day 30, and Day 90.
8 secondary outcomes
Change in EEG-measured LTP-like visual plasticity from baseline to Day 7, assessed by P1-N1b visual evoked potential amplitude (micro volts)
Time frame: Baseline to 7 days post-drug administration
Change in Multidimensional Psychological Flexibility Inventory (MPFI)
Time frame: Baseline to 30 and 90 days post-drug administration
Change in Symptoms of Depression Questionnaire (SDQ)
Time frame: Baseline to 30 and 90 days post-drug administration
Change in Columbia-Suicide Severity Rating Scale - Suicidal Ideation Subscale (C-SSRS-SI)
Time frame: Baseline to 30 and 90 days post-drug administration
Change in WHO Disability Assessment 2.0 (WHODAS 2.0)
Time frame: Baseline to 30 and 90 days post-drug administration
Change in EEG Theta Band Phase Synchrony
Time frame: Baseline to 7 days post-drug administration.
Change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
Time frame: Baseline to 30 days post-drug administration
Change in EEG Theta Band Power
Time frame: Baseline to 7 days post-drug administration
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 26 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.
Josh Woolley, BS PhD MD principal investigator
San Francisco VA Medical Center, San Francisco, CA
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Psilocybin, modafinil and zolpidem in people with Major Depression, run by VA Office of Research and Development at 4 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 14 inclusion and 16 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 26 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 4 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 phase mean?
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 Josh Woolley, BS PhD MD ((415) 221-4810 ext. 4117, Josh.Woolley@ucsf.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hamilton Depression Rating Scale-6 (HAMD-6) (time frame: Baseline to 30 and 90 days post-drug administration). 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 26 Oct 2026.