Investigating the Role of Serotonin in the Mechanism of Action of Psilocybin in Patients With Major Depressive Disorder

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.