Clinical TrialParallelTreatment-Resistant Depression (TRD)PsilocybinPsilocybinCompleted

Psilocybin for Treatment-Resistant Depression

Randomised, parallel-group Phase II trial (n=30) comparing immediate vs delayed point-of-care psilocybin for treatment-resistant depression; single dosing with up to two repeat doses permitted for relapse.

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Target Enrollment
30 participants
Study Type
Phase II interventional
Design
Randomized

Detailed Description

This randomised, parallel-group study evaluates feasibility, safety, and efficacy of point-of-care psilocybin in adults with treatment-resistant depression (MDD or bipolar II).

Participants receive a single dose of psilocybin and are assessed weekly for six weeks then biweekly to 18 weeks; those who relapse may receive up to two repeat doses. Primary outcome is feasibility; secondary outcomes include depressive symptom change and tolerability.

Safety monitoring includes tracking suicidal thoughts and behaviour, adverse events, vital signs, ECG and laboratory tests; exclusion criteria screen for personal or family history of psychosis and recent substance or medical risks.

Study Arms & Interventions

Immediate treatment

experimental

Participants commence psilocybin treatment immediately upon enrollment.

Interventions

  • Psilocybin25 mg
    via Oral• single dose, repeat dosing if relapse criteria met• 3 doses total

    Fixed 25 mg oral psilocybin. Participants who relapsed could receive up to two repeat doses, for a total of up to three dosing sessions.

Delayed treatment

experimental

Participants commence psilocybin treatment two weeks after enrollment (delayed/waitlist comparator).

Interventions

  • Psilocybin25 mg
    via Oral• single dose, repeat dosing if relapse criteria met• 3 doses total

    Fixed 25 mg oral psilocybin. Participants who relapsed could receive up to two repeat doses, for a total of up to three dosing sessions.

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1. Over the age of 18 years and under the age of 65;
  • 2. Diagnosed with major depressive disorder or bipolar II disorder by a healthcare provider;
  • 3. Experiencing a major depressive episode (MDE) without psychotic features as defined in DSM-5, duration of current episode at least 3 months;
  • 4. Have failed to respond to an adequate dose and duration of at least two guideline-concordant pharmacological treatments for the current MDE (per ATHF/MGH-ATRQ);
  • 5. Able to complete all protocol assessments and comply with study visits.

Exclusion Criteria

  • Exclusion Criteria:
  • Current or past history of bipolar I disorder, schizophrenia, psychotic disorder, delusional disorder, paranoid personality disorder, or schizoaffective disorder (assessed by structured interview);
  • First-degree history of schizophrenia or any psychotic disorders, including bipolar disorder with psychotic features;
  • Currently experiencing symptoms of hypomania or mania (YMRS total score >12);
  • History of a hypomanic or manic episode in the past 3 months;
  • History of substance use and/or alcohol use disorder of moderate severity or greater in past 3 months;
  • Lifetime history of substance use disorder with a hallucinogen; lifetime history of substance-induced psychosis;
  • Currently experiencing psychotic symptoms as part of an MDE;
  • Exposure to psilocybin or any other psychedelic in the past 12 months prior to screening and/or during the current MDE;
  • Uncontrolled or insulin-dependent diabetes; seizure disorder;
  • Any personal circumstances or behaviour judged incompatible with safe exposure to psilocybin;
  • Women who are pregnant, nursing, or planning a pregnancy; refusal to use effective contraception throughout participation;
  • Recent stroke (<1 year) or myocardial infarction (<1 year); uncontrolled hypertension (BP >140/90 mmHg) or clinically significant arrhythmia within 1 year;
  • Positive urine drug screen for illicit drugs at screening, 1 week prior to treatment, or during trial;
  • Current enrolment in any investigational drug/device study or interventional depression study within 30 days of screening;
  • Abnormal and clinically significant physical exam, vital signs, ECG, or laboratory tests at screening; any other major concurrent illness that may interfere with study or pose risk.

Study Details

Study Team

Sponsors & Collaborators

Locations

Canadian Rapid Treatment Centre of Excellence (CRTCE) — Mississauga, Ontario, Canada

Related Publications

PaywallindividualPrimary

Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin

This open-label waitlist trial (n=30) assessed the feasibility of psilocybin-assisted psychotherapy (PAP/PAT) in a complex population with treatment-resistant depression (TRD), including major depressive and bipolar II disorders, baseline suicidality, and significant comorbidity. Participants received one, two, or three sessions of PAP with psilocybin (25mg), accompanied by preparation and integration psychotherapy sessions. Immediate treatment showed greater reductions in depression severity (MADRS) compared to the waitlist period, with a large effect size (g = 1.07, p < 0.01). Repeated doses were associated with further reductions in depression severity. Adverse events were transient, and the study demonstrated feasibility, preliminary antidepressant efficacy, safety, and tolerability in this population.

Published
Journal
Med
Authors
Rosenblat, J. D., Meshkat, S., Doyle, Z., Zumrova, A., Marlborough, M., Mcintyre, R. S., Kaczmarek, E., Brudner, R. M., Kratiuk, K., Mansur, R. B., Schulz-Quach, C., Sethi, R., Abate, A., Ali, S., Bawks, J., Blainey, M. G., Brietzke, E., Cronin, V., Danilewitz, J., Dhawan, S., Fonzo, A. D., Fonzo, M. D., Drzadzewski, P., Dunlop, W., Fiszter, H., Gomes, F. A., Grewal, S., Leon-Carlyle, M., Mccallum, M., Mofidi, N., Offman, H., Riva-Cambrin, J., Schmidt, J., Smolkin, M., Quinn, J. M.
PaywallindividualSecondary analysis

Psilocybin-Assisted Psychotherapy for Treatment-Resistant Depression in Bipolar II Disorder

In a subgroup analysis of four adults with treatment-resistant bipolar II disorder, one or two 25 mg psilocybin-assisted psychotherapy sessions produced rapid reductions in depressive symptoms (mean MADRS 32.5 → 20.3 at two weeks, 21.3 at six months). No treatment-emergent mania, hypomania or psychosis was observed, indicating preliminary safety and potential antidepressant efficacy that requires confirmation in larger trials.

Published
Journal
Psychedelic Medicine
Authors
Meshkat, S., Kaczmarek, E., Doyle, Z., Brudner, R. M., Gomes, F. A., Blainey, M. G., Weiglein, G., McIntyre, R. S., Mansur, R. B., Rosenblat, J. D.
Open AccessindividualSubgroup

Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation

In an open‑label trial of 27 treatment‑resistant depression patients given a single 25 mg psilocybin dose with psychotherapy, those who had discontinued antidepressants before treatment showed comparable reductions in clinician‑rated and self‑reported depression, anxiety and suicidality to patients unmedicated at screening. Both groups experienced clinically significant improvements and similar intensity of psychedelic experience, suggesting medication tapering did not alter short‑term antidepressant effects in this sample.

Published
Journal
Canadian Journal of Psychiatry
Authors
Chisamore, N., Kaczmarek, E. S., Doyle, Z., Johnson, D. E., Weiglein, G., Meshkat, S., Brudner, R. M., Blainey, M. G., Riva-Cambrin, J., Mcintyre, R. S., Rosenblat, J. D.
Open AccessindividualSecondary analysis

Examining mystical experiences as a predictor of psilocybin-assisted psychotherapy for treatment-resistant depression

In a clinical sample of 31 people with treatment‑resistant major depressive disorder or Bipolar II disorder who received one to three 25 mg psilocybin‑assisted psychotherapy sessions, greater mystical experiences during the first dosing session predicted larger reductions in depressive symptoms at two weeks, whereas this relationship was not observed for second or third doses. These findings provide preliminary support that mystical‑type experiences may contribute to the therapeutic effects of psilocybin‑assisted psychotherapy for treatment‑resistant depression.

Published
Journal
Journal of Psychopharmacology
Authors
Brudner, R. M., Kaczmarek, E., Blainey, M. G., Schulz-Quach, C., Meshkat, S., Doyle, Z., Lipsitz, O., Offman, H., Sethi, R., Weiglein, G., Mcintyre, R. S., Rosenblat, J. D.
Open AccessindividualSecondary analysis

Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression: A post-hoc analysis of a randomized, waitlist-controlled trial

This secondary analysis (n=26) of adults with treatment-resistant depression from an open-label psilocybin-assisted psychotherapy trial found statistically significant improvements in processing speed and executive function at two weeks post-treatment, with gains on Trail Making Tests remaining significant after adjusting for depressive symptoms; however, reliable change indices showed that the proportion of participants achieving meaningful improvement (4.2–12.5%) did not exceed chance expectations, suggesting observed gains may reflect practice effects rather than genuine procognitive benefits.

Published
Journal
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Authors
Johnson, D. E., Meshkat, S., Kaczmarek, E. S., Rabin, J. S., Brudner, R. M., Chisamore, N., Doyle, Z., Bawks, J., Riva-Cambrin, J., Mansur, R. B., Lipsitz, O., McIntyre, R. S., Lanctôt, K. L., Rosenblat, J. D.