Clinical TrialMajor Depressive Disorder (MDD)PsilocybinPsilocybinCompleted

Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms

Randomised double-blind Phase II trial (n=59) comparing psilocybin versus escitalopram for major depressive disorder, assessing efficacy and mechanisms.

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

Detailed Description

Randomised, double-blind, parallel-group study comparing psilocybin dosing days with daily escitalopram or placebo over a 6-week comparator period in adults with moderate-to-severe major depressive disorder.

Outcomes include clinical depression measures and mechanistic investigations (neuroimaging and related biomarkers); eligibility required HAM-D ≥17 and excluded current or familial psychotic disorders and significant medical contraindications.

Study Arms & Interventions

Psilocybin + placebo

experimental

Psilocybin dosing with daily placebo for comparator period.

Interventions

  • Psilocybin
    via Oral• multiple dosing days

    Psilocybin administered on dosing days; daily placebo for 6 weeks.

Psilocybin + escitalopram

active comparator

Psilocybin dosing with daily escitalopram for comparator period.

Interventions

  • Psilocybin
    via Oral• multiple dosing days

    Psilocybin administered on dosing days.

  • Compound
    via Oral• daily

    Escitalopram daily for 6 weeks (active comparator).

Participants

Ages
18 – 80
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1. Major depressive disorder (DSM-IV)
  • 2. Depression of moderate to severe degree (17+ on the 17-item Hamilton Depression Scale (HAM-D)).
  • 3. No Magnetic Resonance Imaging (MRI) contraindications
  • 4. No SSRI contraindications
  • 5. Has a general practitioner (GP) or other mental healthcare professional who can confirm diagnosis
  • 6. 18-80 years of age
  • 7. Males and females
  • 8. Sufficiently competent with English language

Exclusion Criteria

  • Key exclusion criteria:
  • 1. Current or previously diagnosed psychotic disorder
  • 2. Immediate family member with a diagnosed psychotic disorder
  • 3. Medically significant condition rendering unsuitability for the study (e.g., diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure e.g. creatine clearance:renal clearance (CLRC) < 30 ml/min etc.)
  • 4. History of serious suicide attempts requiring hospitalisation.
  • 5. Significant history of mania (determined by study psychiatrist and medical records)
  • 6. Psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g. borderline personality disorder
  • 7. Blood or needle phobia
  • 8. Positive pregnancy test at screening or during the study, women who are planning a pregnancy and/or women who are nursing/breastfeeding.
  • 9. Participants who do not agree to use an acceptable contraceptive method throughout their participation in study.
  • 10. Current drug or alcohol dependence
  • 11. No email access
  • 12. Use of contraindicated medication
  • 13. Patients presenting with abnormal QT interval prolongation at screening or with a history of this (QTc at screening above 440ms for men and above 470ms for women)

Primary Results(10 publications)

Participants

N = 59Mean age: 39.1–43.3 across armsL. et al. 2021 →
N = 59M. et al. 2023 →
N = 59B. et al. 2023 →
N = 55B. et al. 2024 →
N = 59B. et al. 2024 →
N = 59M. et al. 2024 →
N = 59Mean age: 39.1–43.3 across armsD. et al. 2024 →
N = 41R. et al. 2025 →
N = 59Mean age: 38.7–41.9 across armsM. et al. 2025 →
N = 59J. et al. 2025 →

Δ in QIDS-SR from Baseline

Change from Baseline

Psilocybin + placeboΔ2 [-0.8, 5]Day 42·M. et al. 2023 →
Psilocybin + escitalopram—Day 42·M. et al. 2023 →

Adverse Events (from all publications)

Arm / GroupnAny TEAESevereSeriousDiscont.
Psilocybin + placeboexperimental3026(86.7%)—0(0.0%)3(10.0%)
Psilocybin + escitalopramactive_comparator2924(82.8%)—0(0.0%)5(17.2%)
Psilocybin + placeboexperimental59————
Psilocybin + escitalopramactive_comparator59————
Psilocybin + placeboexperimental30————
Psilocybin + escitalopramactive_comparator29————
Psilocybin + placeboexperimental27————
Psilocybin + escitalopramactive_comparator28————
Psilocybin + placeboexperimental30————
Psilocybin + escitalopramactive_comparator29————
Psilocybin + placeboexperimental30————
Psilocybin + escitalopramactive_comparator29————
Psilocybin + placeboexperimental30———1(3.3%)
Psilocybin + escitalopramactive_comparator29———4(13.8%)
Psilocybin + placeboexperimental22————
Psilocybin + escitalopramactive_comparator19————
Psilocybin + placeboexperimental30————
Psilocybin + escitalopramactive_comparator29————

* 3 patients did not complete all dosing procedures: 2 due to Covid-19 restrictions and 1 stopped placebo due to guessing content. Most common AE was headache.

* 5 patients did not complete protocol: 4 stopped due to adverse events, 1 missed dosing due to Covid-19. One patient halved dose due to perceived adverse events.

* The paper is a Bayesian reanalysis of a previous trial; summary TEAE counts are not provided in this document. Total participants (n=59) is mentioned in the Abstract.

* Safety data (TEAE counts) not explicitly reported in the provided text/tables; paper focuses on personality outcomes.

* n=27 based on Figure 2 legend for Psilocybin arm.

* n=28 based on Figure 2 legend for Escitalopram arm.

* Safety summary counts (TEAEs) not explicitly provided in the text or tables; only acute experience scores and efficacy outcomes are reported.

* The paper focuses on the 'inner healer' construct and depressive symptoms (BDI) rather than reporting a summary table of treatment-emergent adverse events (TEAEs).

* 1 participant discontinued taking placebo capsules without informing the team. Safety in the follow-up period was not assessed.

* 4 participants discontinued escitalopram completely due to side-effects. Safety in the follow-up period was not assessed.

* The paper focuses on secondary fMRI analysis and subjective measures; specific TEAE counts are not reported in the provided text.

* Safety data summary is deferred to Carhart-Harris et al., 2021 as stated in Section 3.

Study Details

Study Team

Sponsors & Collaborators

Locations

Imperial College Hammersmith campus — London, United Kingdom

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