Psilocybin-Assisted Therapy in Treatment-Resistant Depression

Inclusion Criteria:

• Provision of signed and dated informed consent form.

• Willingness to comply with all study procedures and availability for the study.

• Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-V) diagnosis of majordepressive disorder.

• Currently experiencing a major depressive episode, lasting at least 3 months

• Failure to respond or inability to tolerate at least 2 guideline-concordantpharmacological treatments from different pharmacologic classes during the currentmajor depressive episode

• Good health evidenced by medical history and routine lab tests

• No central nervous system (CNS) or neurocognitive impairment

• Ability to take oral medication and to follow to the psilocybin-assisted therapyprotocol

• Identified support person to accompany patient home after dosing

• Use of effective contraception throughout the study by those with child-bearingpotential

• Use of condoms or other effective contraceptive methods by males with reproductivepotential

• Fully vaccinated and up to date on vaccination against COVID-19, as defined byCenter for Disease Control guidelines

• Following Lifestyle Considerations throughout study (no nicotine containing productsin clinical unit, refrain from operating heavy machinery for the duration oftreatment day, no more than two servings 8 hours prior to treatment, no psychoactivedrugs 72 hours before treatment, refrain from consuming foods that would interferewith drug absorption, minimize interaction with household immunocompromisedcontacts)

Exclusion Criteria:

• Family history (first- or second-degree relatives) or diagnosis of bipolar disorderwith psychotic features, schizophrenia, schizoaffective disorder,hallucinogen-induced psychosis, anti-social personality disorder, or other psychoticdisorder.

• Borderline personality disorder, defined by DSM-V criteria, that in the judgement ofthe Investigator is likely to complicate the assessment of clinical response tostudy treatments or limits the patient's ability to comply with study procedures.

• Alcohol or other substance use disorder (except tobacco/nicotine) that has beenactive within the 6 months prior to enrollment.

• Recent use (within past 6 months) of esketamine, ketamine or classic hallucinogens (psilocybin-containing mushrooms or LSD) or use of psychedelics more than 10 timesin lifetime.

• Participants with active suicidal ideation or plan with a Columbia Suicide SeverityRating Scale (C-SSRS) score greater than or equal to 4.

• Current active self-injurious behavior, requiring medical attention or perinvestigator discretion.

• Diagnosis of Obsessive-compulsive disorder or post-traumatic stress disorder.

• Within 72 hours of psilocybin administration, use of nicotine, alcohol, or othercontrolled substances.

• Current delirium, dementia, amnestic disorder, or other cognitive disorders.

• Any current or past medical or neurological illness (including chronic painsyndromes and/or history of cerebrovascular event (excluding migraine)) that, in theopinion of the investigator, may confound the interpretation of study assessments

• Known allergic reactions to components of psilocybin.

• Medically instability at screening, including hepatic, renal, circulatory, cardiac (arrhythmia, uncontrolled hypertension, systolic BP > 140 mmHg or diastolic BP > 90mmHg, abnormal QTc), pulmonary or CNS (seizure disorder or treatment withantiepileptic drugs) impairment.

• Current pregnancy or lactation.

• Febrile illness in last 3 weeks.

• Current use or use within 4 weeks of psilocybin administration of Monoamine oxidaseinhibitors (MAOIs), alcohol dehydrogenase inhibitors and antipsychotics (concomitantmedications will be allowed per investigator discretion).

• Current treatment with buproprion greater than 300mg/day.

• Current use of tramadol.

• Prior participation in psilocybin-assisted therapy trial and or regular use ofhallucinogens

• Treatment with another investigational drug or other intervention during studyperiod.