Psilocybin Mechanism of Action (MOA)

This randomised, quadruple-blind, placebo-controlled trial (n=60) will investigate the role of the 5-HT2A receptor in mediating the subjective and antidepressant effects of psilocybin in individuals with Major Depressive Disorder (MDD). Participants will receive a single dose of psilocybin (25mg) combined with either pimavanserin (34mg; atypical antipsychotic) or a placebo.

Conducted by the Icahn School of Medicine at Mount Sinai, this study aims to determine whether the antidepressant effects of psilocybin are independent of its psychedelic experience. Evaluations will be conducted before dosing and at multiple timepoints up to five weeks post-dosing.

The primary outcome measure is the Mystical Experience Questionnaire (MEQ-30) score, while secondary outcomes include changes in depressive symptoms assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). The trial is expected to run from February 2025 to January 2028.

Topic Depression
Compound Psilocybin Placebo
Country United States of America
Visit trial
Status Recruiting
Results Published No
Start date 01 February 2025
End date 01 January 2028
Phase Phase II
Design Blinded
Type Interventional
Generation First
Participants 60
Sex All
Age 21- 80
Therapy No

Trial Details

This is an interventional, parallel arm assignment treatment study in individuals with Major Depressive Disorder (MDD). Each individual will be treated with a single dose of pimavanserin or placebo plus a single dose of psilocybin. Evaluations will be taken before dosing and following dosing at several timepoints up to 5 weeks post-dosing. In this study, the researchers want to probe the role of the 5-HT2A receptor in mediating the subjective effects of psilocybin. While previous studies have shown that blockage of the 5-HT2A receptor reduces the psychedelic experience in humans, an animal study revealed that blockage of the 5- HT2A receptor abolished the psychedelic effects without affecting the antidepressant response. This suggests that the pathway responsible for the antidepressant response is dissociated from the psychedelic experience pathway, which is mediated by 5-HT2A signaling.

Trial Number NCT06592833

Sponsors & Collaborators

Icahn School of Medicine at Mount Sinai
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Data attribution

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