Psilocybin With Pimavanserin Compared to Psilocybin Alone for the Treatment of Major Depressive Disorder

This study is comparing two treatments for major depression: psilocybin (a psychedelic compound) given alone versus psilocybin given together with pimavanserin (a drug that may reduce the hallucinogenic effects). The goal is to see whether combining the two works better or differently. **You may be eligible if...** - You are between 21 and 80 years old - You have been diagnosed with major depressive disorder (without psychotic features) - Your depression is currently moderate to severe based on a rating scale - You are not currently taking serotonin-affecting medications, or have stopped them for at least 2 weeks - You are willing to use effective contraception during the study **You may NOT be eligible if...** - You have a substance use disorder (other than tobacco) in the past 6 months - You were hospitalized for psychiatric reasons in the past 6 months - You have used psychedelics or ketamine in the past 12 months - You have a history of psychosis, mania, or bipolar disorder - You have had serious thoughts of suicide in the past 6 months Talk to your doctor to see if this trial is right for you.