Clinical TrialTreatment-Resistant Depression (TRD)PsilocybinPsilocybinActive not recruiting

Effects of Psilocybin With Psychological Support on Anhedonia in Treatment-resistant Depression: a Randomized Controlled Pilot Trial

Randomised, quadruple‑blind, parallel Phase II trial (n=40) comparing a single 25 mg oral psilocybin dose versus a 1 mg active‑placebo with psychological support to treat anhedonia in treatment‑resistant MDD.

Target Enrollment
40 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

This Phase II randomised, quadruple‑blind, parallel study evaluates whether a single 25 mg oral dose of psilocybin plus psychological support reduces anhedonia in participants with treatment‑resistant major depressive disorder compared with an ultra‑low (1 mg) active‑placebo.

Primary efficacy is measured with MADRS (including item 8 for interest/ability to feel); secondary assessments include safety labs, ECG, adverse events, and neuroimaging (fMRI) outcomes. Psychological support is provided pre, during and post dosing.

Study Protocol

Preparation

sessions

Dosing

1 sessions

Integration

sessions

Therapeutic Protocol

support

Study Arms & Interventions

Psilocybin 25mg

experimental

Single oral 25 mg psilocybin capsule with psychological support.

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total

    Psychological support provided pre/during/post dosing.

Active placebo 1mg

active

Single oral 1 mg psilocybin (active placebo) capsule with psychological support.

Interventions

  • Psilocybin1 mg
    via Oral• single dose• 1 doses total

    Ultra‑low dose psilocybin used as active placebo; psychological support provided.

Participants

Ages
21 – 75
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Adults ≥ 21 years of age at Screening
  • Diagnosis of Major Depressive Disorder (MDD)
  • Score of at least 12 (symptomatic depression) on administration of the Montgomery Asberg Depression Rating Scale (MADRS)
  • Score of at least a 3 on question 8 on the MADRS evaluating loss of interest and ability to feel at both Screening and Baseline Visit 1
  • The participant's Major depressive disorder meets the criteria for being treatment-resistant, defined as not experiencing a 50% improvement to two or more antidepressant treatments for adequate duration (6 weeks minimum) within the current episode, as determined by the Antidepressant Treatment Response Questionnaire (Desseilles et al., 2011; Posternak et al., 2004)
  • Sufficiently competent in English Language
  • Currently under the care of a psychiatric practitioner (MD, DO, NP, PA) OR under the consistent care of a clinician within the UCHealth/CUMedicine health system
  • Right-handed
  • Women of childbearing potential must agree to practice effective birth control throughout the study
  • Have an identified support person and agree to be accompanied home following dosing
  • Written informed consent obtained and ability to comply with study requirements
  • Ability to abstain from caffeine and nicotine for 2 hours prior to fMRI scan visits

Exclusion Criteria

  • Exclusion Criteria:
  • Unstable medical conditions or serious abnormalities of complete blood count, chemistries, or EKG that in the opinion of the study physician would preclude safe participation (examples: congestive heart failure; clinically significant arrhythmias or EKG abnormality, e.g. QTc > 450; recent acute myocardial infarction; malignant hypertension; congenital long QT syndrome; acute renal failure; severe hepatic impairment; respiratory failure)
  • Risk for hypertensive crisis defined as BP >140/90 mmHg at Screening, Baseline, or prior to dosing
  • High resting heart rate defined as >90 BPM at Screening, Baseline, or prior to dosing
  • Significant CNS pathology (e.g., neoplasm, epilepsy, history of stroke, cerebral aneurysm, dementia, delirium)
  • Current or lifetime primary psychotic disorder, bipolar affective disorder, affective disorder with psychotic features (e.g., schizophrenia spectrum, schizoaffective, bipolar I/II, history of mania)
  • Family history of first-degree relative with psychotic or serious bipolar spectrum illness
  • High risk of adverse emotional or behavioural reaction based on investigator assessment (e.g., agitation, violent behaviour)
  • Active substance use disorders (DSM-5 moderate/severe) in past year (excluding caffeine/nicotine)
  • Extensive recent or heavy use of serotonergic hallucinogens (any use in last 6 months or >25 lifetime uses)
  • History of hallucinogen persisting perception disorder (HPPD)
  • Women who are pregnant or nursing or intend to become pregnant during the study
  • History of severe suicide attempt requiring hospitalization in the past year
  • Any suicidal ideation or thoughts judged to present serious risk of imminent suicidal or self-injurious behaviour
  • Use of drugs or supplements that may interfere with study drug (examples listed in protocol); certain prescribed meds allowed at PI discretion with washout of 5 half-lives as required
  • Psychiatric condition incompatible with rapport or safe exposure to psilocybin per PI
  • Allergy or intolerance to study product materials
  • Positive urine drug screen for listed substances (exceptions noted for stable prescribed benzodiazepines)
  • Claustrophobia, lack of internet access, weight over 300 pounds, metal unsafe for MRI, or other contraindications to MRI
  • Known contraindication to clonidine, diazepam, or olanzapine (examples listed in protocol)

Primary Results(2 publications)

Participants

N = 26Mean age: 45.3–45.7 across armsN. et al. 2025 →
N = 31Mean age: 44.4 across armsM. et al. 2025 →

MADRS

Score at Timepoint

Psilocybin 25mg—Day 60·N. et al. 2025 →
Psilocybin 25mg—Day 60·N. et al. 2025 →
Psilocybin 25mg21Day 14·M. et al. 2025 →

Response Rates

complete mystical experience

8/28(28.6%)·M. et al. 2025 →
8/17(47.1%)·M. et al. 2025 →
3/5(60.0%)·M. et al. 2025 →

Adverse Events (from all publications)

Arm / GroupnAny TEAESevereSeriousDiscont.
Psilocybin 25mgexperimental1728(164.7%)—0(0.0%)—
Active placebo 1mgactive9——0(0.0%)—
Psilocybin 25mgexperimental30————
Active placebo 1mgactive—————

* The paper states 28/30 participants in the original study experienced an AE. For this specific analysis of 26 patients, the text notes AEs were frequently reported but mostly mild to moderate and transient. The '28/30' refers to the total study population; specific arm-level counts for TEAEs are not provided in the summary text, but the total study sample is mentioned. However, the text explicitly states 'No serious AEs were reported throughout the study'.

* No serious AEs were reported throughout the study.

* nAtRisk is 30 (total participants receiving at least 1 dose). TEAESI refers to participants with a 'complete mystical experience' at dose 1 as defined in the text/Table 2.

* The paper describes a waitlist-control design rather than an active placebo arm for this specific analysis; no data provided for 'arm2'.

Study Details

Study Team

Sponsors & Collaborators

Locations

University of Colorado Anschutz Medical Campus — Aurora, Colorado, United States

Related Publications

Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation

Published
Authors
Chisamore, N., Kaczmarek, E. S., Doyle, Z., Johnson, D. E., Weiglein, G., Meshkat, S., Brudner, R. M., Blainey, M. G., Riva-Cambrin, J., Mcintyre, R. S., Rosenblat, J. D.

Examining mystical experiences as a predictor of psilocybin-assisted psychotherapy for treatment-resistant depression

Published
Authors
Brudner, R. M., Kaczmarek, E., Blainey, M. G., Schulz-Quach, C., Meshkat, S., Doyle, Z., Lipsitz, O., Offman, H., Sethi, R., Weiglein, G., Mcintyre, R. S., Rosenblat, J. D.

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