Clinical TrialMajor Depressive Disorder (MDD)PsilocybinPsilocybinPlaceboRecruiting

Psilocybin Mechanism of Action (MOA)

Randomised, quadruple-blind, placebo-controlled parallel trial (n=60) testing whether 5-HT2A blockade with pimavanserin (34 mg) alters the subjective and antidepressant effects of a single 25 mg oral dose of psilocybin in people with MDD.

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

Detailed Description

This is a randomised, quadruple-blind, parallel-group treatment study in adults (21–80 y) with Major Depressive Disorder. Participants receive a single 25 mg oral dose of psilocybin plus either pimavanserin 34 mg or matching placebo.

Assessments occur before dosing and at multiple post-dose timepoints up to five weeks, including clinical depression scales and neuroimaging to probe the role of 5-HT2A signalling in subjective psychedelic effects versus antidepressant response.

Safety precautions include withdrawal of serotonergic drugs prior to dosing, ECG and lab monitoring, and MRI compatibility screening.

Study Protocol

Preparation

sessions

Dosing

1 sessions

Integration

sessions

Study Arms & Interventions

Psilocybin + Pimavanserin

active comparator

Single oral dose psilocybin (25 mg) with single oral pimavanserin (34 mg).

Interventions

  • Psilocybin25 mg
    via Oral• single dose
  • Compound
    via Oral• single dose

    Pimavanserin 34 mg (Nuplazid)

Psilocybin + Placebo

inactive

Single oral dose psilocybin (25 mg) with matching placebo.

Interventions

  • Psilocybin25 mg
    via Oral• single dose
  • Placebo
    via Oral• single dose

    Matching placebo

Participants

Ages
21 – 80
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Age 21-80 years, any gender
  • Current primary diagnosis of Unipolar Major Depressive Disorder (MDD) without psychotic features using DSM-5 criteria
  • 24-item Hamilton Rating Scale for Depression (HRSD) ≥16
  • Current diagnosis of Major Depressive Episode (MDE)
  • Capable of providing informed consent and complying with study procedures
  • Currently using or agreeing to use a highly effective contraception, if person of childbearing potential; male participants agree to use highly effective contraception with partners of childbearing potential
  • Discontinuation of any serotonergic drug for at least 2 weeks or 5 half-lives (whichever is longer) prior to psilocybin exposure

Exclusion Criteria

  • Exclusion Criteria:
  • Any severity of substance use disorder in the last 6 months (excluding tobacco use disorder) as determined by DSM-V criteria via the SCID
  • Current psychiatric hospitalization or psychiatric hospitalization within the last 6 months
  • Use of psychedelics in the last 12 months
  • Non-medical or illicit use of ketamine in the past 12 months
  • Negative reaction after prior use of psychedelics
  • Past or current psychotic disorder (including psychotic MDD), mania, or bipolar disorder
  • Severe depression as indicated by CGI-Severity score ≥5 at baseline
  • Significant suicidal ideation as indicated by C-SSRS > 2 in the past 6 months at time of screening
  • Suicide attempt in the past 2 years, or clinician concern that the patient poses a risk to self or others
  • Acute, severe, or unstable medical illness
  • Weight > 300 lbs., or girth size incompatible with scanner bore
  • Any conditions/qualities that make participation in MRI imaging unsafe
  • Any physical or intellectual disability adversely affecting ability to complete assessments
  • Current pregnancy or currently breast feeding
  • Any clinically significant abnormal lab test result, including clinically significant abnormal baseline liver and/or renal function tests
  • Currently being treated with a contraindicated medication (including antipsychotics, serotonergic antidepressants, mood stabilizers, strong CYP3A4 inhibitors/inducers, UGT1A9/UGT1A10 inhibitors, MAO inhibitors, aldehyde or alcohol dehydrogenase inhibitors)
  • History of abnormal QT prolongation or QTc interval >450 ms on screening
  • Use of medications known to prolong the QT interval
  • Any congenital prolongation of the QT interval or a family history of long QT syndrome
  • A family history of sudden cardiac or unexplained death
  • A family history in a first-degree relative of psychosis/schizophrenia or related disorders
  • A first-degree family history of bipolar disorder
  • A history of cardiac arrhythmias or who require treatment with an antiarrhythmic medication
  • A history of any cardiovascular disorder/condition known to increase the possibility of QT prolongation, or any other risk factors for prolonged QT interval/torsades de pointes
  • Baseline vital sign parameters exceeding SBP >139 mmHg, DBP >89 mmHg, or HR >90 bpm
  • Hypersensitivity to either psilocybin or pimavanserin
  • Psychiatric or other condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin
  • Positive urine toxicology at screening
  • Any clinically significant abnormalities on 12-lead electrocardiogram (ECG)
  • MMSE score <25
  • BPRS-6 >5
  • Potential fall risk

Study Details

Locations

Icahn School of Medicine at Mount Sinai, Center for Psychedelic Therapy Research — New York, New York, United States

Your Library