Refractory DepressionPhase 3NCT06303739

Psilocybin-Assisted Therapy in Treatment-Resistant Depression

A Phase 3 study testing psilocybin in people with Refractory Depression and Treatment Resistant Depression, run by University of North Carolina, Chapel Hill at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

The goal of this clinical trial is to test how well psilocybin-assisted therapy works in treating people with depression. The main questions this study aims to answer are: Does psilocybin with assisted therapy help improve symptoms for people with depression? How long do the effects of this treatment last?… Read more about this study

Who is it for?: Ages 18 to 70 years
Conditions the study is for: Refractory Depression, Treatment Resistant Depression
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: 20 participants
Where: 1 siteUnited States
Study dates: 19 Apr 2024to 26 Mar 2027
Phase: Phase 3
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

Provision of signed and dated informed consent form.
Willingness to comply with all study procedures and availability for the study.
Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-V) diagnosis of major depressive disorder.
Currently experiencing a major depressive episode, lasting at least 3 months
Failure to respond or inability to tolerate at least 2 guideline-concordant pharmacological treatments from different pharmacologic classes during the current major depressive episode
Good health evidenced by medical history and routine lab tests

Show all 13Show fewer

No central nervous system (CNS) or neurocognitive impairment
Ability to take oral medication and to follow to the psilocybin-assisted therapy protocol
Identified support person to accompany patient home after dosing
Use of effective contraception throughout the study by those with child-bearing potential
Use of condoms or other effective contraceptive methods by males with reproductive potential
Fully vaccinated and up to date on vaccination against COVID-19, as defined by Center for Disease Control guidelines
Following Lifestyle Considerations throughout study (no nicotine containing products in clinical unit, refrain from operating heavy machinery for the duration of treatment day, no more than two servings 8 hours prior to treatment, no psychoactive drugs 72 hours before treatment, refrain from consuming foods that would interfere with drug absorption, minimize interaction with household immunocompromised contacts)

Who cannot join

Family history (first- or second-degree relatives) or diagnosis of bipolar disorder with psychotic features, schizophrenia, schizoaffective disorder, hallucinogen-induced psychosis, anti-social personality disorder, or other psychotic disorder.
Borderline personality disorder, defined by DSM-V criteria, that in the judgement of the Investigator is likely to complicate the assessment of clinical response to study treatments or limits the patient's ability to comply with study procedures.
Alcohol or other substance use disorder (except tobacco/nicotine) that has been active within the 6 months prior to enrollment.
Recent use (within past 4 weeks) of esketamine, ketamine or classic hallucinogens (psilocybin-containing mushrooms or LSD) or use of psychedelics within the past 6 months or more than 10 times in lifetime.
Participants with active suicidal ideation or plan with a Columbia Suicide Severity Rating Scale (C-SSRS) score greater than or equal to 4.
Current active self-injurious behavior, requiring medical attention or per investigator discretion.

Show all 19Show fewer

Diagnosis of Obsessive-compulsive disorder or post-traumatic stress disorder.
Within 72 hours of psilocybin administration, use of nicotine, alcohol, or other controlled substances (use related to over-the-counter or prescribed medications may be allowed per the Primary Investigator's discretion).
Current delirium, dementia, amnestic disorder, or other cognitive disorders.
Any current or past medical or neurological illness (including chronic pain syndromes and/or history of cerebrovascular event (excluding migraine)) that, in the opinion of the investigator, may confound the interpretation of study assessments
Known allergic reactions to components of psilocybin.
Medically instability at screening, including hepatic, renal, circulatory, cardiac (arrhythmia, uncontrolled hypertension, systolic BP > 140 mmHg or diastolic BP > 90 mmHg, abnormal QTc), pulmonary or CNS (seizure disorder or treatment with antiepileptic drugs) impairment.
Current pregnancy or lactation.
Febrile illness in last 3 weeks.
Current use or use within 4 weeks of psilocybin administration of Monoamine oxidase inhibitors (MAOIs), alcohol dehydrogenase inhibitors and antipsychotics (concomitant medications will be allowed per investigator discretion).
Current treatment with buproprion greater than 300mg/day.
Current use of tramadol.
Prior participation in psilocybin-assisted therapy trial and or regular use of hallucinogens
Treatment with another investigational drug or other intervention during study period.

Trial locations and contacts

1 site in 1 country.

United States1 site

UNC Chapel Hill Medical Center
Chapel Hill, North Carolina, 27514

Other trials in United States

About this study

Official title: Induction Protocol for Psilocybin-Assisted Therapy in Treatment-Resistant Depression (TRD): A Pilot Study

The goal of this clinical trial is to test how well psilocybin-assisted therapy works in treating people with depression. The main questions this study aims to answer are:

Does psilocybin with assisted therapy help improve symptoms for people with depression?
How long do the effects of this treatment last?

Participants will:

Take part in a couple of screening and preparation visits.
Be given psilocybin in one or two treatment sessions.
Attend a series of follow-up sessions over the following year.
Complete forms and surveys to test how their symptoms have changed and what they thought of their experience.

Researchers will also compare whether one treatment or two treatments help improve symptoms more for participants.

Read the detailed description

Major depressive disorder (MDD) ranks fourth in global disease burden and has significant morbidity, mortality, societal and financial costs. However, few adequate and effective treatments exist with 60% of MDD patients not responding sufficiently to an initial oral antidepressant treatment. These patients who experience treatment resistant depression (TRD), defined as an intolerance or lack of response to two antidepressants of different classes, have limited treatment options beyond the antidepressant treatments that often yield insufficient results or relapse. Psilocybin, a novel treatment, has been found to relieve symptoms of TRD, but there are limited studies on specific dosing and long term treatment follow-up. In this study, the investigators will look closer at the effectiveness of one treatment with psilocybin versus two treatments with psilocybin, as well as the long term effectiveness over the first 12 months after treatment.

Conditions: Refractory Depression, Treatment Resistant Depression
Being tested: psilocybin
Keywords: psilocybin, psychedelic, refractory depression, psychedelic-assisted therapy, treatment-resistant depression, TRD, depression
Medical subject headings: Depressive Disorder, Treatment-Resistant, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

psilocybinDrug
25mg of psilocybin administered during treatment session, accompanied by preparation before, integration after, and assistive therapy during the session.

Study groups in NCT06303739
Study group	Role	What they receive
Single Psilocybin Treatment	Experimental	Participants will be administered one dose of a 25mg capsule of psilocybin. This will be administered one time. Receives: Drug: psilocybin
Two Psilocybin Treatments	Active comparator	Participants will be administered one dose of a 25mg capsule of psilocybin. Two weeks later, the participant will be administered one more dose of a 25mg capsule of psilocybin. Receives: Drug: psilocybin

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in HAM-D-17 Scores between Baseline and 2 Weeks after Treatment
The change in Hamilton Depression Rating Scale 17 item (HAM-D-17) scores between baseline and 2 weeks after treatment
The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Measured: Baseline, 2 weeks
Change in QIDS SR-16 Scores between Baseline and 2 Weeks after Treatment
The change between depression scores as reported by Quick Inventory of Depressive Symptomatology Short Response-16 (QIDS SR-16) scores between baseline and 2 weeks after treatment
The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Measured: Baseline, 2 weeks
Number of Participants Achieving Remission 2 Weeks after Treatment
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 2 weeks after treatment
Measured: up to 2 weeks
Number of Participants Achieving Response 2 weeks after treatment
Number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) 2 weeks after treatment
Measured: up to 2 weeks

Secondary outcomes (22)

Number of Participants Achieving Remission at 6 Weeks
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 6 weeks after treatment
Measured: up to 6 weeks
Number of Participants Achieving Response at 6 Weeks
Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 6 weeks after treatment
Measured: up to 6 weeks
Number of Participants Achieving Remission at 3 Months
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 3 months after treatment
Measured: up to 3 months
Number of Participants Achieving Response at 3 Months
Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 3 months after treatment
Measured: up to 3 months
Number of Participants Achieving Remission at 6 Months
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 6 months after treatment
Measured: up to 6 months
Number of Participants Achieving Response at 6 Months
Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 6 months after treatment
Measured: up to 6 months
Number of Participants Achieving Remission at 9 Months
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 9 months after treatment
Measured: up to 9 months
Number of Participants Achieving Response at 9 Months
Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 9 months after treatment
Measured: up to 9 months
Number of Participants Achieving Remission at 12 Months
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 12 months after treatment
Measured: up to 12 months
Number of Participants Achieving Response at 12 Months
Estimate the number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) at 12 months after treatment
Measured: up to 12 months
Time to Relapse in Participants Who Showed Remission at 2 weeks
Of the number of participants achieving remission (defined as a HAM-D-17 score less than 10) 2 weeks after treatment, the amount of time until a relapse occurring thereafter occurs.
Relapse is defined as a HAM-D-17 score greater than or equal to 17 and will be measured up to the study follow-up visit at 1 year.
Measured: up to 1 year after treatment
Time to Relapse in Participants Who Showed Response at 2 Weeks
Of the number of participants achieving remission (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) 2 weeks after treatment, the amount of time until a relapse occurring thereafter occurs.
Relapse is defined as a HAM-D-17 score greater than or equal to 17 and will be measured up to the study follow-up visit at 1 year.
Measured: up to 1 year after treatment
Change in HAM-D-17 Scores between Baseline and 6 Weeks after Treatment
The change in HAM-D-17 scores between baseline and 2 weeks after treatment
The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Measured: Baseline, 6 weeks
Change in HAM-D-17 Scores between Baseline and 3 Months after Treatment
The change in HAM-D-17 scores between baseline and 2 weeks after treatment
The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Measured: Baseline, 3 Months
Change in HAM-D-17 Scores between Baseline and 6 Months after Treatment
The change in HAM-D-17 scores between baseline and 2 weeks after treatment
The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Measured: Baseline, 6 Months
Change in HAM-D-17 Scores between Baseline and 9 Months after Treatment
The change in HAM-D-17 scores between baseline and 2 weeks after treatment
The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Measured: Baseline, 9 Months
Change in HAM-D-17 Scores between Baseline and 12 Months after Treatment
The change in HAM-D-17 scores between baseline and 2 weeks after treatment
The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Measured: Baseline, 12 months
Change in QIDS SR-16 Scores between Baseline and 6 Weeks after Treatment
The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment
The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Measured: Baseline, 6 weeks
Change in QIDS SR-16 Scores between Baseline and 3 Months after Treatment
The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment
The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Measured: Baseline, 3 Months
Change in QIDS SR-16 Scores between Baseline and 6 Months after Treatment
The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment
The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Measured: Baseline, 6 Months
Change in QIDS SR-16 Scores between Baseline and 9 Months after Treatment
The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment
The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Measured: Baseline, 9 Months
Change in QIDS SR-16 Scores between Baseline and 12 Months after Treatment
The change between depression scores as reported by QIDS SR-16 scores between baseline and 2 weeks after treatment
The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Measured: Baseline, 12 Months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

19 Apr 202426 Mar 2027

First posted12 Mar 2024
Study start19 Apr 2024
Primary completion9 Apr 2026
Study completion26 Mar 2027 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (15)Papers the sponsor has linked to this study.
Other trials for Refractory DepressionStudies of the same condition, open and under way.
More trials run by University of North Carolina, Chapel HillThe 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 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: Participants are randomized into one of two groups and will receive either one single treatment of psilocybin-assisted therapy with follow-up therapy and assessments or two treatments spaced two weeks apart with follow-up therapy and assessments.
Masking: Single blind
Who is masked: Outcomes assessor
Enrolment: 20 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT06303739
Sponsor's protocol ID: 22-1421
Status last verified: May 2026
First submitted: 27 Feb 2024
Last updated: 6 May 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

Publications

Demyttenaere K, Van Duppen Z. The Impact of (the Concept of) Treatment-Resistant Depression: An Opinion Review. Int J Neuropsychopharmacol. 2019 Feb 1;22(2):85-92. doi: 10.1093/ijnp/pyy052.
PubMed 29961822
Dold M, Kasper S. Evidence-based pharmacotherapy of treatment-resistant unipolar depression. Int J Psychiatry Clin Pract. 2017 Mar;21(1):13-23. doi: 10.1080/13651501.2016.1248852. Epub 2016 Nov 16.
PubMed 27848269
Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016 Dec;30(12):1165-1180. doi: 10.1177/0269881116675512.
PubMed 27909164
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.
PubMed 17074942
Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depressive disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982 Aug;39(8):905-10. doi: 10.1001/archpsyc.1982.04290080025004.
PubMed 7103679
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.
PubMed 27909165
Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994.
PubMed 33852780
Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul;3(7):619-27. doi: 10.1016/S2215-0366(16)30065-7. Epub 2016 May 17.
PubMed 27210031
Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, Kaelen M, Giribaldi B, Bloomfield M, Pilling S, Rickard JA, Forbes B, Feilding A, Taylor D, Curran HV, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018 Feb;235(2):399-408. doi: 10.1007/s00213-017-4771-x. Epub 2017 Nov 8.
PubMed 29119217
Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021 May 1;78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285.
PubMed 33146667
Gukasyan N, Davis AK, Barrett FS, Cosimano MP, Sepeda ND, Johnson MW, Griffiths RR. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. J Psychopharmacol. 2022 Feb;36(2):151-158. doi: 10.1177/02698811211073759.
PubMed 35166158
Barrett FS, Johnson MW, Griffiths RR. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol. 2015 Nov;29(11):1182-90. doi: 10.1177/0269881115609019. Epub 2015 Oct 6.
PubMed 26442957
Maclean KA, Leoutsakos JM, Johnson MW, Griffiths RR. Factor Analysis of the Mystical Experience Questionnaire: A Study of Experiences Occasioned by the Hallucinogen Psilocybin. J Sci Study Relig. 2012 Dec;51(4):721-737. doi: 10.1111/j.1468-5906.2012.01685.x.
PubMed 23316089
Murphy R, Kettner H, Zeifman R, Giribaldi B, Kartner L, Martell J, Read T, Murphy-Beiner A, Baker-Jones M, Nutt D, Erritzoe D, Watts R, Carhart-Harris R. Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression. Front Pharmacol. 2022 Mar 31;12:788155. doi: 10.3389/fphar.2021.788155. eCollection 2021.
PubMed 35431912
Bond FW, Hayes SC, Baer RA, Carpenter KM, Guenole N, Orcutt HK, Waltz T, Zettle RD. Preliminary psychometric properties of the Acceptance and Action Questionnaire-II: a revised measure of psychological inflexibility and experiential avoidance. Behav Ther. 2011 Dec;42(4):676-88. doi: 10.1016/j.beth.2011.03.007. Epub 2011 May 25.
PubMed 22035996

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Refractory Depression trials

Study at a glance

From the registry record, last updated by the sponsor on 6 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Induction Protocol for Psilocybin-Assisted Therapy in Treatment-Resistant Depression (TRD): A Pilot Study
ClinicalTrials.gov ID: NCT06303739
Acronym / sponsor ID: 22-1421
Conditions: Refractory Depression, Treatment Resistant Depression
Keywords: psilocybin, psychedelic, refractory depression, psychedelic-assisted therapy, treatment-resistant depression, TRD, depression
Phase: Phase 3
Study type: Interventional
Recruitment status: Active, not recruiting
Enrolment: 20 participants (actual)
Lead sponsor: University of North Carolina, Chapel HillUniversity, hospital or other
Collaborators: Foundation of Hope, North Carolina
Study start: 19 Apr 2024 (actual)
Primary completion: 9 Apr 2026 (actual)
Study completion: 26 Mar 2027 (estimated)
First posted: 12 Mar 2024 (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 test how well psilocybin-assisted therapy works in treating people with depression. The main questions this study aims to answer are:

Does psilocybin with assisted therapy help improve symptoms for people with depression?
How long do the effects of this treatment last?

Participants will:

Take part in a couple of screening and preparation visits.
Be given psilocybin in one or two treatment sessions.
Attend a series of follow-up sessions over the following year.
Complete forms and surveys to test how their symptoms have changed and what they thought of their experience.

Researchers will also compare whether one treatment or two treatments help improve symptoms more for participants.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Single blind (outcomes assessor)
Number of arms: 2
Model description: Participants are randomized into one of two groups and will receive either one single treatment of psilocybin-assisted therapy with follow-up therapy and assessments or two treatments spaced two weeks apart with follow-up therapy and assessments.

Arm	Type	Receives
Single Psilocybin Treatment	Experimental	Drug: psilocybinParticipants will be administered one dose of a 25mg capsule of psilocybin. This will be administered one time.
Two Psilocybin Treatments	Active comparator	Drug: psilocybinParticipants will be administered one dose of a 25mg capsule of psilocybin. Two weeks later, the participant will be administered one more dose of a 25mg capsule of psilocybin.

Who may qualify

Ages: 18 to 70 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (13 listed)

Provision of signed and dated informed consent form.
Willingness to comply with all study procedures and availability for the study.
Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-V) diagnosis of major depressive disorder.
Currently experiencing a major depressive episode, lasting at least 3 months
Failure to respond or inability to tolerate at least 2 guideline-concordant pharmacological treatments from different pharmacologic classes during the current major depressive episode

Key exclusion criteria (19 listed)

Family history (first- or second-degree relatives) or diagnosis of bipolar disorder with psychotic features, schizophrenia, schizoaffective disorder, hallucinogen-induced psychosis, anti-social personality disorder, or other psychotic disorder.
Borderline personality disorder, defined by DSM-V criteria, that in the judgement of the Investigator is likely to complicate the assessment of clinical response to study treatments or limits the patient's ability to comply with study procedures.
Alcohol or other substance use disorder (except tobacco/nicotine) that has been active within the 6 months prior to enrollment.
Recent use (within past 4 weeks) of esketamine, ketamine or classic hallucinogens (psilocybin-containing mushrooms or LSD) or use of psychedelics within the past 6 months or more than 10 times in lifetime.
Participants with active suicidal ideation or plan with a Columbia Suicide Severity Rating Scale (C-SSRS) score greater than or equal to 4.

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
psilocybin25mg of psilocybin administered during treatment session, accompanied by preparation before, integration after, and assistive therapy during the session.	Drug	Single Psilocybin Treatment, Two Psilocybin Treatments

Primary outcome

Change in HAM-D-17 Scores between Baseline and 2 Weeks after Treatment
Time frame: Baseline, 2 weeks
The change in Hamilton Depression Rating Scale 17 item (HAM-D-17) scores between baseline and 2 weeks after treatment The HAM-D-17 is a 17-item questionnaire used to measure severity of depression. The score ranges from 0 to 52. Higher scores indicate more severe depression.
Change in QIDS SR-16 Scores between Baseline and 2 Weeks after Treatment
Time frame: Baseline, 2 weeks
The change between depression scores as reported by Quick Inventory of Depressive Symptomatology Short Response-16 (QIDS SR-16) scores between baseline and 2 weeks after treatment The QIDS SR-16 is a 16-item questionnaire used to measure severity of depression. The scores range from 0 to 45. Higher scores indicate more severe depression.
Number of Participants Achieving Remission 2 Weeks after Treatment
Time frame: up to 2 weeks
Number of participants achieving remission (defined as a HAM-D-17 score less than 10) 2 weeks after treatment
Number of Participants Achieving Response 2 weeks after treatment
Time frame: up to 2 weeks
Number of participants achieving response (defined as a HAM-D-17 score that has decreased by greater than or equal to 50 percent compared to baseline) 2 weeks after treatment

22 secondary outcomes

Number of Participants Achieving Remission at 6 Weeks
Time frame: up to 6 weeks
Number of Participants Achieving Response at 6 Weeks
Time frame: up to 6 weeks
Number of Participants Achieving Remission at 3 Months
Time frame: up to 3 months
Number of Participants Achieving Response at 3 Months
Time frame: up to 3 months
Number of Participants Achieving Remission at 6 Months
Time frame: up to 6 months
Number of Participants Achieving Response at 6 Months
Time frame: up to 6 months
Number of Participants Achieving Remission at 9 Months
Time frame: up to 9 months
Number of Participants Achieving Response at 9 Months
Time frame: up to 9 months
Number of Participants Achieving Remission at 12 Months
Time frame: up to 12 months
Number of Participants Achieving Response at 12 Months
Time frame: up to 12 months
Time to Relapse in Participants Who Showed Remission at 2 weeks
Time frame: up to 1 year after treatment
Time to Relapse in Participants Who Showed Response at 2 Weeks
Time frame: up to 1 year after treatment
Change in HAM-D-17 Scores between Baseline and 6 Weeks after Treatment
Time frame: Baseline, 6 weeks
Change in HAM-D-17 Scores between Baseline and 3 Months after Treatment
Time frame: Baseline, 3 Months
Change in HAM-D-17 Scores between Baseline and 6 Months after Treatment
Time frame: Baseline, 6 Months
Change in HAM-D-17 Scores between Baseline and 9 Months after Treatment
Time frame: Baseline, 9 Months
Change in HAM-D-17 Scores between Baseline and 12 Months after Treatment
Time frame: Baseline, 12 months
Change in QIDS SR-16 Scores between Baseline and 6 Weeks after Treatment
Time frame: Baseline, 6 weeks
Change in QIDS SR-16 Scores between Baseline and 3 Months after Treatment
Time frame: Baseline, 3 Months
Change in QIDS SR-16 Scores between Baseline and 6 Months after Treatment
Time frame: Baseline, 6 Months
Change in QIDS SR-16 Scores between Baseline and 9 Months after Treatment
Time frame: Baseline, 9 Months
Change in QIDS SR-16 Scores between Baseline and 12 Months after Treatment
Time frame: Baseline, 12 Months

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 6 May 2026.
Background: PubMed 29961822Demyttenaere K, Van Duppen Z. The Impact of (the Concept of) Treatment-Resistant Depression: An Opinion Review. Int J Neuropsychopharmacol. 2019 Feb 1;22(2):85-92. doi: 10.1093/ijnp/pyy052.
Background: PubMed 27848269Dold M, Kasper S. Evidence-based pharmacotherapy of treatment-resistant unipolar depression. Int J Psychiatry Clin Pract. 2017 Mar;21(1):13-23. doi: 10.1080/13651501.2016.1248852. Epub 2016 Nov 16.
Background: PubMed 27909164Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016 Dec;30(12):1165-1180. doi: 10.1177/0269881116675512.
Background: PubMed 17074942Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.
Background: PubMed 7103679Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depressive disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982 Aug;39(8):905-10. doi: 10.1001/archpsyc.1982.04290080025004.
Background: PubMed 27909165Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.
Background: PubMed 33852780Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994.
Background: PubMed 27210031Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul;3(7):619-27. doi: 10.1016/S2215-0366(16)30065-7. Epub 2016 May 17.
Background: PubMed 29119217Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, Kaelen M, Giribaldi B, Bloomfield M, Pilling S, Rickard JA, Forbes B, Feilding A, Taylor D, Curran HV, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018 Feb;235(2):399-408. doi: 10.1007/s00213-017-4771-x. Epub 2017 Nov 8.
Background: PubMed 33146667Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021 May 1;78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285.
Background: PubMed 35166158Gukasyan N, Davis AK, Barrett FS, Cosimano MP, Sepeda ND, Johnson MW, Griffiths RR. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. J Psychopharmacol. 2022 Feb;36(2):151-158. doi: 10.1177/02698811211073759.
Background: PubMed 26442957Barrett FS, Johnson MW, Griffiths RR. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol. 2015 Nov;29(11):1182-90. doi: 10.1177/0269881115609019. Epub 2015 Oct 6.
Individual participant dataSharing planned: Yes. Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

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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. This study is not recruiting at the moment.

Robert K McClure, MD principal investigator

Director of Interventional Psychiatry

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing psilocybin in people with Refractory Depression and Treatment Resistant Depression, run by University of North Carolina, Chapel Hill at 1 site 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 13 inclusion and 19 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: under way, not looking for participants, as of the sponsor's last update on 6 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in HAM-D-17 Scores between Baseline and 2 Weeks after Treatment (time frame: Baseline, 2 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06303739, which also lists 15 linked publications.

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 6 May 2026.