Recruiting
Phase 2

Psilocybin

Sponsor:

Sunnybrook Health Sciences Centre

Code:

NCT06072898

Conditions

Depressive Disorder

Major Depressive Disorder

Eligibility Criteria

Sex: All

Age: 18 - 64

Healthy Volunteers: Not accepted

Interventions

Psilocybin

Microcrystalline cellulose

Supportive psychotherapy

Study Details

Brief summary:

The goal of this neuroimaging clinical trial is to test whether psilocybin produces significant immediate changes in functional brain activity in networks associated with mood regulation and depression compared to placebo in patients with depression. The trial aims to determine if psilocybin:

1. Changes connectivity within brain networks associated with mood and depression
2. Changes blood flow in brain regions associated with mood and depression

Participants will be attend two treatment sessions where they receive an oral medication and supportive psychotherapy. At each session, participants will undergo an MRI scan after drug administration but prior to psychotherapy. Participants will be randomly to assigned to one of two groups that will receive, 1) microcrystalline cellulose (25mg) at the first visit and psilocybin (25mg) at the second visit, or 2) psilocybin (25mg) at both visits, respectively. Differences between groups will be compared to understand what effects on brain activity are specific to psilocybin.

Conditions

Depressive Disorder

Major Depressive Disorder

Study ID

NCT06072898

Start date

May 28, 2025

Status verified date

Mar, 2026

Completion date

May, 2029

Anticipated

Primary completion date

May, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 64

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Able and voluntarily willing to provide written informed consent at the screening visit
  • Over 18 and under 65 years old
  • Able to complete all protocol required assessment tools without any assistance or alteration to the copyrighted assessments, and to comply with all study visits
  • Must have a responsible individual/caregiver who is able to monitor the participant at home for 24 hours after each treatment visit in the study
  • Must have a psychiatrist and/or general practitioner who is able to provide psychiatric follow-up care
  • Have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, recurrent or single episode without psychotic features where the duration of the current episode is at least 3 months
  • Depression of at least moderate severity as defined by a Hamilton Depression Rating Scale (HAMD-17) score >17

Exclusion Criteria:

  • Current or past history of bipolar I/II disorder, schizophrenia, schizoaffective disorder, psychotic disorder, or delusional disorder as assessed by a structured clinical interview (MINI)
  • A clinical diagnosis of antisocial personality disorder and/or paranoid personality disorder (defined as meeting DSM-5 criteria) based on clinical interview and the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at a clinical interview by a psychiatrist.
  • An active clinical diagnosis of borderline personality disorder as confirmed by the MINI 7.0.
  • Depression secondary to other medical conditions or bipolar I and II disorder
  • Family history of a first degree relative with a diagnosis of schizophrenia or a primary psychotic disorder and/or bipolar disorder
  • Any symptoms consistent with psychosis
  • Any symptoms consistent with hypomania and/or mania as assessed by a psychiatrist
  • Personal history of ≥ 1 suicide attempt in the past year requiring hospitalization, defined using the Columbia Suicide Severity Rating Scale (CSSRS) (Q6 (past year) = "y") and clinical interview with a psychiatrist
  • Other personal circumstances or behavior judged to be incompatible with establishment of rapport or safe exposure to psilocybin
  • Women who are pregnant (self-report or via urine test), nursing, or planning a pregnancy
  • Lifetime history of substance use disorder with a hallucinogen
  • Lifetime history of substance-induced psychosis
  • Positive urine drug screen for illicit drugs or drugs of abuse at screening, a week prior to treatment, and during the trial (any positive urine drug test will be reviewed with participants to determine the pattern of use and eligibility will be determined at the investigator's discretion)
  • Abnormal and clinically significant results on a physical examination performed within one month of study participation by a general practitioner, vital signs, ECG, or laboratory test at screening
  • QTc prolongation on ECG
  • Uncontrolled or insulin-dependent diabetes
  • History of seizure disorder except for seizures from electroconvulsive therapy and/or febrile seizures in childhood
  • Diagnosis of any mild or major neurocognitive disorder meeting DSM-5 criteria and based on clinical interview/cognitive screening by a psychiatrist
  • History of stroke, recent myocardial infarction (< 1 year from signing of ICF), uncontrolled hypertension (blood pressure > 140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF
  • Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if he/she takes part in the study
  • Exposure to psilocybin or any other psychedelic in the past 12 months prior to screening and/or during the current MDE and use of psychedelics, such as ayahuasca/LSD, during the current depressive episode
  • History of substance use and/or alcohol use disorder, of moderate severity or greater, in the past 12 months
  • Current enrolment in an interventional study for depression or participation in such within 30 days of screening
  • Serial blood counts to achieve a value to meet eligibility - abnormalities in screening/baseline blood work (complete blood counts, electrolyte panel, etc.) will be reviewed by MD, then repeated serially until abnormalities resolve.

Study Design

Enrollment

50 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

experimental: Staged Active Treatment Arm (Psilocybin-Psilocybin)

This group will receive psilocybin (25mg) at the first and second treatment visit, along with supportive psychotherapy.

experimental: Placebo to Active Delayed-Start Treatment Arm (MCC-Psilocybin)

This group will receive microcrystalline cellulose (25mg) at the first treatment visit and psilocybin (25mg) at the second treatment visit, along with supportive psychotherapy.

Interventions

Psilocybin

Psilocybin (\[3-\[2-(dimethylamino)ethyl\]-1H-indol-4-yl\] dihydrogen phosphate), 25mg PO.

Microcrystalline cellulose

MCC (excipient), 25mg PO.

Supportive psychotherapy

Supportive psychotherapy in the form of reassurance, integration, and de-escalatory techniques (if needed). Facilitating rapport and a positive environment.

Primary outcome measure

  • Regional Cerebral Blood Flow [ Time Frame: Up to 3 weeks ]
  • Montgomery-Asberg Depression Rating Scale (MADRS) Changes [ Time Frame: Up to 6 weeks ]

Central Contacts and Locations

Central contacts

EMBRACE Team

416-480-4085embrace@sunnybrook.ca

Locations

Sunnybrook Health Sciences Centre

Recruiting

Toronto, Ontario, Canada, M4N3M5

Contacts

EMBRACE Team

416-480-4085embrace@sunnybrook.ca

Principal Investigator:

Sean M Nestor, PhD MD FRCPC

More Information

Sponsor

Sunnybrook Health Sciences Centre

Last update posted

Mar 30, 2026

Last verified

Mar, 2026

Keywords

  • Psilocybin
  • Neuroimaging
  • MRI
  • Depression
  • Psychotherapy
  • Psychedelic

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Sunnybrook Health Sciences Centre on 2026-03-30.