Clinical TrialTreatment-Resistant Depression (TRD)PsilocybinPsilocybinPlaceboPlaceboRecruiting

Swinburne Three-dose Psilocybin Assisted Psychotherapy (3PAP): a clinical trial of 2 vs 3 doses of psilocybin-assisted psychotherapy vs psychotherapy with placebo for Treatment-Resistant Depression

This randomised, double-blind, 3-arm Phase II trial (n=160) compares three 25 mg psilocybin sessions vs two 25 mg psilocybin + one placebo session vs three placebo sessions, all paired with preparatory and integrative psychotherapy for treatment-resistant depression.

Target Enrollment
160 participants
Study Type
Phase II interventional
Design
Randomized, single Blind

Detailed Description

Randomised, parallel-group Phase IIb trial enrolling 160 participants with treatment-resistant major depressive disorder to compare two versus three dosing schedules of 25 mg oral psilocybin administered under clinical supervision alongside structured psychotherapy.

Each participant receives preparatory sessions (two), three supervised dosing sessions (weeks 1, 5 and 18) of 6–8 hours, and integration sessions (three) after each dose; primary outcome is change in MADRS after the second dosing session and at 3-month follow-up.

Psychotherapy is delivered face-to-face by a trained co-therapist dyad (a medical practitioner and a psychologist) using supportive, largely non-directive approaches; medication tapering prior to baseline is required where appropriate.

Study Protocol

Preparation

2 sessions

Dosing

3 sessions
480 min each

Integration

3 sessions

Therapeutic Protocol

support

Study Arms & Interventions

3× Psilocybin

experimental

Three 25 mg oral psilocybin sessions plus preparatory and integrative psychotherapy (co-therapist dyad). Sessions at weeks 1, 5 and 18.

Interventions

  • Psilocybin25 mg
    via Oral• three sessions• 3 doses total

    Tablets with neutral excipient; supervised by medical practitioner at site

2× Psilocybin + 1× Placebo

experimental

Two 25 mg oral psilocybin sessions and one inactive placebo session plus psychotherapy; sessions at weeks 1, 5 and 18.

Interventions

  • Psilocybin25 mg
    via Oral• two sessions• 2 doses total
  • Placebo
    via Oral• single session• 1 doses total

    Inactive matching tablet

3× Placebo

inactive

Three inactive placebo oral sessions plus preparatory and integrative psychotherapy (identical schedule to active arms).

Interventions

  • Placebo
    via Oral• three sessions• 3 doses total

    Inactive matching tablet; supervised dosing

Participants

Ages
18 – 65
Sexes
Male & Female

Inclusion Criteria

  • Adults aged 18 to 65 years.
  • Those currently experiencing major depressive disorder (DSM-5) as determined by the SCID-5.
  • Those with current moderate to severe depression according to the MADRS.
  • Treatment-resistance using criteria adapted from current literature of research in major depression.
  • Under the care of a psychiatrist, psychologist, physician, or GP.
  • Proficiency in English.
  • Safe tapering and wash-out of current antidepressant pharmacotherapy prior to baseline assessment, as confirmed by treating GP, psychiatrist, or physician.
  • Abstinence from illicit or extra-medical drug and alcohol use for at least 2 days prior to each dose session.
  • Participants who agree to have their drug dosing sessions recorded to video for treatment fidelity and clinical supervision within the study team.
  • Participants who are able to swallow tablets.

Exclusion Criteria

  • Key General Medical Exclusion Criteria:
  • Patients in treatment in another clinical trial involving an investigational product.
  • Any disorder with known CNS involvement, or other major CNS disease.
  • Hepatic dysfunction.
  • Known conditions putting participant at risk for hypercalcaemia.
  • Cardiovascular conditions: uncontrolled hypertension, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation), TIA in the last 6 months, stroke, or cerebrovascular disease, peripheral or pulmonary vascular disease.
  • A diagnosis of epilepsy or previous seizures.
  • Renal insufficiency.
  • Insulin-dependent diabetes.
  • Females who are pregnant or nursing or are trying to get pregnant, or become pregnant during the study.
  • Current hypothyroidism.
  • Weight less than 40 kg.
  • Contraindicated medication (SSRIs, SNRIs, MAOIs), and either 1) do not wish to be tapered off this medication, or 2) it is deemed by trial psychiatrists or the participant’s usual treatment team that tapering the participant off their current medication would be inappropriate.
  • Use of any illicit or extra-medical drugs or alcohol within the 2 days prior to each psilocybin dosing.
  • Current use of any potent metabolic inducers or inhibitors.
  • Significant, uncorrected visual impairments (to ensure that they can read all study material).
  • Key Psychiatric Exclusion Criteria:
  • Current or past history of meeting DSM-5 criteria for Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), Bipolar I or II Disorder, or Mania.
  • First degree relative with diagnosed Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), Bipolar I or II Disorder or Mania.
  • Currently meets DSM-5 criteria for Dissociative Disorder, Anorexia Nervosa, Bulimia Nervosa, or any psychiatric conditions judged to be incompatible with establishment of rapport or safe exposure to psilocybin.
  • Unable to give adequate informed consent.

Study Details

Locations

Unknown facility — Australia

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