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

Inclusion Criteria:

• Age 21-80 years, any gender

• Current primary diagnosis of Unipolar Major Depressive Disorder (MDD) withoutpsychotic 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 ofchildbearing potential (such as condoms, IUD, or oral contraceptive), for durationof the study. Male participants agree to use highly effective contraception withpartners of childbearing potential

• Discontinuation of any serotonergic drug for at least 2 weeks or 5 half-lives (whichever of the two is longer) prior to psilocybin exposure

Exclusion Criteria:

• Any severity of substance use disorder in the last 6 months (excluding tobacco usedisorder) as determined by DSM-V criteria via the SCID

• Current psychiatric hospitalization or psychiatric hospitalization within the last 6months

• 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 bipolardisorder

• Severe depression as indicated by Clinical Global Impressions (CGI)-Severity score ≥ 5 at baseline

• Significant suicidal ideation as indicated by C-SSRS > 2 in the past 6 months attime of screening

• Suicide attempt in the past 2 years, or clinician concern that the patient poses arisk 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 completeassessments.

• Current pregnancy or currently breast feeding.

• Any clinically significant abnormal lab test result, including clinicallysignificant abnormal baseline liver and/or renal function tests

• Currently being treated with a contraindicated medication. Contraindicatedmedications include antipsychotic medications, serotonergic antidepressantmedications, and mood stabilizers that may attenuate the effects of psilocybin.Strong CYP3A4 inhibitors and inducers are also contraindicated. UGT1A9 and UGT1A10inhibitors, monoamine oxidase, and aldehyde or alcohol dehydrogenase inhibitors areprohibited concomitant medications.

• 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 QTsyndrome

• A family history of sudden cardiac or unexplained death

• A family history in a first-degree relative of psychosis/schizophrenia or relateddisorders

• A first-degree family history of bipolar disorder

• A history of cardiac arrhythmias or who require treatment with an antiarrhythmicmedication

• A history of any cardiovascular disorder/condition known to increase the possibilityof QT prolongation, or any other risk factors for prolonged QT interval/tosades depointes (including symptomatic bradycardia, hypokalemia, hypomagnesemia,hypocalcemia, heart failure, or Brugada Syndrome)

• Preexisting cardiovascular conditions, including cardiac valvulopathy, pulmonaryhypertension, hypertension, tachycardia, and any cardiovascular conditions that maybe worsened/exacerbated by elevated blood pressure or heart rate.

• Baseline vital sign parameters at screening and on day of dosing prior to dose thatexceed to the following values for systolic blood pressure (SBP), diastolic (DBP),and heart rate (HR): SBP > 139 mmHg, DBP 89 mmHg, and HR > 90 bpm

• Hypersensitivity to either psilocybin or pimavanserin

• Psychiatric or other condition judged to be incompatible with establishment ofrapport with therapy team and/or safe exposure to psilocybin

• Positive urine toxicology at screening

• Any clinically significant abnormalities on 12-lead electrocardiogram (ECG)

• Mini-Mental State Examination (MMSE) score < 25

• Brief Psychiatric Rating Scale (BPRS-6) > 5

• Potential fall risk