Clinical TrialTreatment-Resistant Depression (TRD)PsilocybinPsilocybinPlaceboCompleted

A phase II randomized, double-blind, active placebo-controlled parallel group trial to examine the efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE)

Randomized, double-blind, parallel-group Phase II trial (n=144) comparing 25 mg psilocybin vs 5 mg psilocybin (low-dose active placebo) vs nicotinamide 100 mg in adults (25–65) with treatment-resistant major depression, delivered with psychotherapy.

Target Enrollment
144 participants
Study Type
Phase II interventional
Design
Randomized, double Blind

Detailed Description

EPIsoDE is a Phase II randomized, double-blind, active placebo-controlled parallel-group trial assessing the efficacy and safety of a single 25 mg oral psilocybin dose compared with a 5 mg low psilocybin dose and 100 mg nicotinamide in adults with treatment-resistant major depression, delivered within a psychotherapeutic framework.

Primary outcome is responder rate (≥50% reduction in HAM-D) at six weeks after first dose; secondary outcomes include BDI-II, remitter rates, additional responder analyses at 1 week, 12 weeks and follow-ups at 6 and 12 months, plus safety measures (vitals, ECG, labs, C-SSRS, UKU, DSS-4, AEs/SAEs).

Study Protocol

Preparation

sessions

Dosing

2 sessions

Integration

sessions

Therapeutic Protocol

support

Study Arms & Interventions

Psilocybin 25 mg

experimental

Single oral 25 mg psilocybin dose administered in a psychotherapeutic context (second-dose schedules per protocol).

Interventions

  • Psilocybin25 mg
    via Oral• single dose

    Capsule; second dose administered per protocol in some sequences.

Psilocybin 5 mg (low dose)

active comparator

Sub-therapeutic active placebo: 5 mg oral psilocybin capsule.

Interventions

  • Psilocybin5 mg
    via Oral• single dose

    Low-dose active placebo (5 mg).

Nicotinamide 100 mg

active comparator

Nicotinamide (niacinamide) 100 mg oral capsule used as negative control.

Interventions

  • Placebo100 mg
    via Oral• single dose

    Nicotinamide (niacinamide) 100 mg; recorded as comparator in notes.

Participants

Ages
25 – 65
Sexes
Male & Female

Inclusion Criteria

  • 1) Aged 25–65 years.
  • 2) Major depressive disorder (single or recurrent) of moderate to severe degree without psychotic features (DSM-5); ICD-10: F32.1, F32.2, F33.1, F33.2.
  • 3) HAM-D score ≥ 17.
  • 4) Treatment-resistant as defined by lack of adequate improvement after two adequate antidepressant courses (≥6 weeks each) of different classes; augmentation counts as a second treatment.
  • 5) Discontinuation of monoaminergic psychiatric medication for at least 2 weeks prior to dosing (fluoxetine: 5 weeks) or supervised down-titration.
  • 6) Abstinent from alcohol (BAC 0.00) and negative urine drug screen on dosing day.
  • 7) Medically stable by labs, vitals and 12-lead ECG (QTcF ≤450 ms males, ≤470 ms females; PR <220 ms) or acceptable per investigator.
  • 8) Willing and able to adhere to protocol restrictions and provide informed consent.

Exclusion Criteria

  • 1) Current or prior DSM-5 diagnosis of: depressive episode with psychotic features; schizophrenia spectrum or other primary psychotic disorders; bipolar disorder; cluster A personality disorders and/or borderline personality disorder (assessed with SCID-5-PD); PTSD.
  • 2) First-degree family history of psychosis and/or bipolar disorder.
  • 3) Current or recent clinically significant suicidal ideation within past 6 months (C-SSRS score 4–5) or suicidal behaviour within past 1 year; prior attempts or serious ideation >6 months require careful screening and investigator discretion.
  • 4) Current comorbid psychiatric diagnoses (except the index MDD) as specified under exclusion 1; substance use disorder (except tobacco/caffeine). Alcohol consumption >40 g/day men or >20 g/day women excluded.
  • 5) Use of classical psychedelics in past year or >5 lifetime uses.
  • 6) Failure to establish sufficient rapport with therapists after first two preparation sessions.
  • 7) Lithium intake.
  • 8) ECT within 12 months or ketamine/esketamine within 6 months prior to screening.
  • 9) Prior vagal nerve stimulation or deep brain stimulation.

Study Details

Locations

Germany

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