Psilocybin-Assisted Psychotherapy for Treatment-Resistant Depression: Comparing One Versus Two Doses of Psilocybin

NCT06341426 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: 23-5872
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to see if one or two doses of psilocybin is more effective in relieving depressive symptoms in patients with treatment-resistant depression (TRD). Researchers also want to know if a second dose of psilocybin is safe and well-tolerated. This study will see if psilocybin is effective, safe, and well-tolerated by tracking changes in depressive symptoms, suicidality, and side effects. This study will also see if a second dose of psilocybin has an effect on quality of life, functioning, cognition (thinking, reasoning, remembering), and how long depressive symptoms improve (or worsen) after psilocybin is administered.

Conditions

Major Depressive Disorder; Depression; Treatment-Resistant Depression; Mood Disorders

Keywords

Depression; Major Depressive Disorder; Treatment-Resistant Depression; Mood Disorders; Psilocybin; Psychedelics; Psychotherapy; Psilocin; Mental Disorders; Hallucinogen; Antidepressant; Phase 2; Phase II

Outcome Measures

Primary Outcomes (1)

• Antidepressant Efficacy

  Antidepressant efficacy will be evaluated using change in Montgomery-Åsberg Depression Rating Scale (MADRS) score, a clinician-administered depression severity rating scale where higher scores indicate greater severity of depression symptoms. The MADRS has been validated extensively in major depressive disorder (MDD) and treatment-resistant depression (TRD) patient population samples, and specifically in psilocybin trials.

  Baseline to Week 8 (Primary Endpoint)

Secondary Outcomes (12)

• Self-Reported Depression Symptoms

  Baseline to 6 month follow-up

• Anxiety Symptoms

  Baseline to 6 month follow-up

• Self-Reported Quality of Life

  Baseline to 6 month follow-up

• Subjective Functioning

  Baseline to 6 month follow-up

• Incidence of Treatment Emergent Adverse Events (Safety and Tolerability)

  Baseline to 6 month follow-up

Other Outcomes (6)

• Participant Blinding Success

  Baseline to 6 month follow-up

• Expectancy Effects

  Baseline to 6 month follow-up

• Quality of Clinician-Patient Therapeutic Relationship

  Baseline to 6 month follow-up

Study Arms (2)

Two Doses of Psilocybin

ACTIVE COMPARATOR

Two psychedelic doses (25mg of psilocybin + 25mg of psilocybin) taken in conjunction with psilocybin-assisted psychotherapy

Drug: Two Psychedelic Doses Psilocybin

Single Dose of Psilocybin

PLACEBO COMPARATOR

One psychedelic dose (1mg of psilocybin + 25mg of psilocybin) taken in conjunction with psilocybin-assisted psychotherapy

Drug: Single Psychedelic Dose Psilocybin

Interventions

Single Psychedelic Dose Psilocybin DRUG

One psychedelic dose (1mg of psilocybin + 25mg of psilocybin) taken in conjunction with psilocybin-assisted psychotherapy

Single Dose of Psilocybin

Two Psychedelic Doses Psilocybin DRUG

Two psychedelic doses (25 mg of psilocybin + 25mg of psilocybin) taken in conjunction with psilocybin-assisted psychotherapy

Two Doses of Psilocybin

Eligibility Criteria

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

You may qualify if:

• Adults 18 to 65 years old.
• Must be deemed to have capacity to provide informed consent.
• Must sign and date the informed consent form.
• Stated willingness to comply with all study procedures.
• Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent.
• Meets DSM-5 criteria for MDD, currently experiencing a Major Depressive Episode (MDE) without psychotic features, as diagnosed by a mood disorder specialist. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI).
• Current MDE must be moderate to severe, as determined by a MADRS score greater than 21.
• Have not responded to at least two trials of antidepressants at an adequate dosage and duration based on the Antidepressant Treatment History Form Short Form (ATHF-SF) with no upper limit on the number of treatment failures.
• Ability to take oral medication.
• Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 1 months prior to screening and agreement to use such a method during study participation in addition to monthly check-ins by study staff to determine the first day of their last menstrual period;
• Individuals who are capable of making their partner pregnant: use of condoms or other methods for the duration of study participation to ensure effective contraception with partner.
• Individuals who are willing to taper off concomitant medications (antidepressants, antipsychotics, mood stabilizers, ketamine, esketamine, monoaminergic medicines, and stimulants) for a minimum of 1-month prior to Baseline (V2, Day 0) and whose physician confirms that it is safe for them to do so.
• Individuals who are willing to not receive additional psychotherapy (outside of the therapy provided as part of the study) during the 8-week trial and whose physician confirms that it is safe for them to do so; however, they may continue seeing their therapist before and after this time period.
• Individuals who have a caregiver that will be able to bring them home after treatment sessions and stay with them for a minimum of 24 hours after discharge;
• Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration.

You may not qualify if:

• Lifetime history of mania, hypomania or psychosis as determined by clinical psychiatric assessment and the MINI.
• Current symptoms of mania, hypomania or mixed features, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
• Substance, cannabis, or alcohol use disorder within the past 3 months or lifetime history of hallucinogen use disorder as determined by the MINI and urine drug screen.
• Major neurocognitive disorder, as determined by clinical assessment, including administration of the Montreal Cognitive Assessment (MoCA).
• Have active suicidal ideation as determined by the C-SSRS and/or clinical interview (significant suicide risk is defined by suicidal ideation as endorsed by items 4 or 5 of the C-SSRS) or active suicidality requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
• Presence of a relative or absolute contraindication to psilocybin (within the past 12 months),, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction (within the past 12 months),, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal (Glomerular Filtration Rate (GFR) less than 45ml/min/1.73 m2) or hepatic impairment (Child-Pugh B: 7 to 9 points and Child-Pugh C: 10 to 15 points).
• Pregnant as assessed by a urine pregnancy test at Screening (V1) or individual's that intend to become pregnant during the study or are breastfeeding.
• Treatment with another investigational drug or other intervention within 30 days of Baseline (V2).
• Participants who will receive any form of brain stimulation (e.g., rTMS, ECT) during the trial or have within 30 days before Baseline (V2).
• Individuals who have had changes to psychiatric medications 30 days before entering the trial, outside of as needed (PRN) medications.
• Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; obsessive- compulsive disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, or borderline personality disorder as determined by medical history, the M.I.N.I clinical interview, and the International Personality Disorder Examination (IPDE) administered at Screening (V1).
• Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder as determined by the family medical history form and discussions with the participant.
• Uncontrolled seizure disorder or a seizure within the past 12 months
• Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors.
• Use of classic psychedelic drugs within the previous 6 months, including but not limited to psilocybin, psilocin, DMT, LSD, ayahuasca, mescaline, peyote, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Centre for Addiction and Mental Health: collaborator

Study Sites (2)

Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

Location

Centre for Addiction and Mental Health (CAMH)

Toronto, Ontario, M6J 1H4, Canada

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depression; Depressive Disorder, Treatment-Resistant; Mood Disorders; Mental Disorders

Condition Hierarchy (Ancestors)

Depressive Disorder; Behavioral Symptoms; Behavior

Study Officials

• Joshua Rosenblat, MD, MSc

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The first dose will be randomized and blinded (1mg psilocybin versus 25mg psilocybin), while the second dose will be open-label (25mg psilocybin).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Psychiatrist, Assistant Professor, Clinician-Investigator

Model Details: Participants will be randomized to two groups for the first dosing session in a 1:1 allocation: 1) non-psychedelic/placebo dose (psilocybin 1mg) or 2) psychedelic dose (psilocybin 25mg). All participants will receive a psychedelic dose (psilocybin 25mg) for their second dosing session.

Study Record Dates

• First Submitted: March 4, 2024
• First Posted: April 2, 2024
• Study Start: February 5, 2024
• Primary Completion: July 28, 2026
• Study Completion (Estimated): December 28, 2026
• Last Updated: July 9, 2026

Record last verified: 2026-07

Locations

CA (2)