Clinical TrialTreatment-Resistant Depression (TRD)PlaceboPsilocybinPsilocybinCompleted

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression

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

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

Dosing

2 sessions

Integration

4 sessions

Therapeutic Protocol

support

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 Details

Locations

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

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