Clinical TrialTreatment-Resistant Depression (TRD)PlaceboPsilocybinPsilocybinCompleted

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression

This randomised, triple-blind, active placebo-controlled Phase II study (n=144) compares oral psilocybin 25 mg and 5 mg versus a nicotinamide placebo in patients with treatment-resistant depression, with two dosing sessions and psychotherapeutic support.

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

Detailed Description

Multi-centre, randomized, parallel-group trial evaluating safety and efficacy of oral psilocybin (25 mg and 5 mg) versus nicotinamide 100 mg active placebo in adults with treatment-resistant major depression; two dosing sessions spaced six weeks apart.

Dosing is delivered under structured psychotherapeutic conditions with three preparatory and four integration sessions; participants remain hospitalised overnight after each dosing for monitoring. Outcomes include depressive symptoms (HAM-D), safety labs, ECG, and adverse events.

Study Protocol

Preparation

3 sessions
120 min each

Dosing

2 sessions
420 min each

Integration

4 sessions
120 min each

Therapeutic Protocol

supportiveother

Study Arms & Interventions

Nicotinamide

inactive

Placebo comparator arm receiving nicotinamide 100 mg at session 1 and 25 mg psilocybin at session 2 per protocol sequencing.

Interventions

  • Placebo100 mg
    via Oral• two sessions• 2 doses total

    Nicotinamide 100 mg at session 1 (placebo); session 2 receives 25 mg psilocybin per protocol.

Psilocybin low

experimental

Low-dose first session then full dose at second session (5 mg → 25 mg).

Interventions

  • Psilocybin5 mg
    via Oral• two sessions• 2 doses total

    Session 1: 5 mg; Session 2: 25 mg

Psilocybin high

experimental

High-dose sequences including 25→5 mg or 25→25 mg across two sessions.

Interventions

  • Psilocybin25 mg
    via Oral• two sessions• 2 doses total

    Sequences: 25 mg at session1 then 5 mg at session2, or 25 mg at both sessions

Participants

Ages
25 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1. 25 to 65 years of age
  • 2. Diagnosis of major depressive disorder (single and recurrent episodes) of moderate to severe degree (HAM-D score ≥ 17) according to DSM-5 without psychotic features (ICD-10: F32.1, F32.2, F33.1, F33.2). If single episode, duration must be ≥ 3 months.
  • 3. Treatment-resistance: no adequate improvement despite two adequate courses of antidepressant treatment (6 weeks each, minimum) with drugs of different pharmacological classes in the current episode (augmentation counts as second treatment).
  • 4. Discontinued any monoaminergic psychiatric medication for at least 2 weeks before first dosing; individualized down-titration allowed (minimum 2 weeks; if prior fluoxetine, minimum 5 weeks) under treating psychiatrist/study supervision.
  • 5. Abstinent from alcohol (BAC 0.00) and negative urine drug screen on dosing days.
  • 6. Medically stable by labs, history, vitals, and 12-lead ECG (QTcF ≤450 ms males, ≤470 ms females; PR <220 ms); retest allowed once for abnormal values; investigator judgement applies.
  • 7. Willing and able to adhere to prohibitions/restrictions and study procedures.
  • 8. Written informed consent including peripheral biomarker monitoring.

Exclusion Criteria

  • Exclusion Criteria:
  • 1. Current or prior DSM-5 diagnosis of major depressive episode with psychotic features, schizophrenia spectrum or other psychotic disorders, bipolar disorders, cluster A or borderline personality disorder (screen with SCID-5-PD), or PTSD (ICD-10: F43.1).
  • 2. Family history (first-degree relative) of psychosis and/or bipolar disorder.
  • 3. Current or recent clinically significant suicidal ideation within past 6 months (C-SSRS score 4–5) or history of suicidal behaviour within past 1 year; prior suicide attempt or serious ideation >6 months ago included only at investigator discretion.
  • 4. Current comorbid psychiatric diagnoses except the primary major depressive disorder; substance use disorder (except tobacco/caffeine) excluded; alcohol limits ≤40 g/day men, ≤20 g/day women.
  • 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. Significant uncontrolled medical conditions that interfere with participation (cardiac, renal, hepatic, endocrine, neurologic including epilepsy); diabetes allowed if controlled (HbA1c <7.5%).
  • 9. Women who are pregnant, nursing, or refuse effective contraception; negative pregnancy test required at screening and dosing days.
  • 10. Positive urine drug screen for illicit drugs or alcohol on dosing days.
  • 11. QTc interval >450 ms (men) or >470 ms (women) at screening or baseline.
  • 12. Receipt of investigational drug or device within 3 months prior to first administration.
  • 13. Unable/unwilling for multiple venipunctures.
  • 14. Unable to understand consent or comply with procedures; cognitive impairment excluding participation.
  • 15. Any condition making participation not in subject's best interest or likely to confound assessments.
  • 16. Major surgery within 12 weeks prior to screening or not fully recovered.
  • 17. ECT within 12 months prior or ketamine/esketamine within 6 months prior to screening.
  • 18. Prior vagal nerve stimulation or deep brain stimulation device.
  • 19. Employment relationship with investigator/site with direct study involvement or family members of employees/investigators.

Study Protocol, Arms & Participants

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Study Details

Study Team

Investigators

  • GG
    Gerhard Gründer

Locations

Charité Berlin, Campus Mitte, Department of Psychiatry and Psychotherapy — Berlin, Germany
Central Institute of Mental Health (CIMH) — Mannheim, Germany

Related Publications

Open AccessindividualMethods

Methodological challenges in psychedelic drug trials: Efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE) - Rationale and study design

This paper (2022) details the rationale and study design for an upcoming double-blind placebo-controlled trial (n=144) which will assess the safety and efficacy of using psilocybin in a cohort with treatment-resistant depression.

Published
Journal
Neuroscience Applied
Authors
Mertens, L. J., Koslowski, M., Betzler, F., Evens, R., Gilles, M., Jungaberle, A., Jungaberle, H., Maji, T., Str€ Ohle, A., Wolff, M., Wellek, S., Gründer, G.
Open AccessindividualPrimary

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial

In this triple‑blind, active placebo‑controlled randomised trial (n=144) of adults with treatment‑resistant depression, two 25 mg doses of psilocybin plus adjunct psychotherapy produced clinically meaningful reductions in depressive symptoms on exploratory secondary measures but did not significantly improve the pre‑second‑dose HAMD17 response rate versus nicotinamide.

Published
Journal
JAMA Psychiatry
Authors
Mertens, L. J., Koslowski, M., Betzler, F., Brand, M., Evens, R., Kärtner, L., Jungaberle, A., Jungaberle, H., Majić, T., Schmitz, C. N., Ströhle, A., Scharf, D., Spangemacher, M., Wolff, M., Assadi, Z., Bahri, S., Becher, L., Färber, L. V., Kirchen, N., Kulakova, E., Kunz, L., Meijer, A., Rohrmoser, B., Wellek, S., Berger, M. M., Gründer, G.
Open AccessindividualLong-term follow-up

Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial

This naturalistic follow-up of a Phase IIb randomised active placebo-controlled trial (n=144) found that one or two 25 mg doses of psilocybin with psychotherapy were linked to sustained reductions in depression symptoms in treatment-resistant major depression (TRD) at six and twelve months. Benefits were similar across groups, while restarting antidepressant medication during follow-up was associated with worse scores.

Published
Journal
Psychotherapy and Psychosomatics
Authors
Mertens, L. J., Betzler, F., Brand, M., Evens, R., Jungaberle, A., Jungaberle, H., Kärtner, L., Majić, T., Schmitz, C. N., Ströhle, A., Scharf, D., Spangemacher, M., Wolff, M., Assadi, Z., Bahri, S., Becher, L., Färber, L. V., Harder, H., Kirchen, N., Kulakova, E., Kunz, L. C., Meijer, A., Rohrmoser, B., Wellek, S., Berger, M. M., Koslowski, M., Gründer, G.

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