Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression

Inclusion Criteria: * Veteran of the U.S. military who is English-speaking * Signed informed consent and HIPAA * Adults \</= 75 years of age * Meets DSM-5 criteria for current major depressive episode (MDE) * MADRS \>/= 20 at baseline * Failure to respond satisfactorily to \>/= 2 antidepressant treatments for \>/= 8 weeks, including \>/= 2 weeks at an adequate dose (\>/= 50% of the FDA-approved uppermost dose) for major depression. Augmentation with a medication for depression (e.g., neuroleptics, lithium, levothyroxine) is considered a separate course of treatment. * If applicable, concurrent \& permitted antidepressants must be at stable doses for \>/= 4 weeks prior to baseline (see allowed \& prohibited medication list) * Participants of child-bearing potential must have negative pregnancy test \& agree to adhere to a medically acceptable method of birth control during the study * Has a responsible adult who will provide transportation to the participant's home or place of lodging on the days of psilocybin administration Exclusion Criteria: Exclusion Criteria: * Lifetime bipolar, schizophrenia spectrum, or other psychotic disorders * First-degree relative with history of bipolar I, schizophrenia spectrum or other psychotic disorder * Presence of psychotic symptoms (e.g., MDE with psychotic symptoms) * Sedative-hypnotic, stimulant, inhalant and/or opioid use disorder within past 6 months (lifetime substance use disorder is allowed at the discretion of the LSI) * Severe alcohol and/or cannabis use disorder within the past 6 months (mild or moderate alcohol and/or cannabis use is allowed at the discretion of the LSI) * Lifetime hallucinogen persisting perception or hallucinogen use disorders * Use of psilocybin, ayahuasca, mescaline, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), peyote, or 3,4-methylenedioxymethamphetamine (MDMA) within past 6 months * Participant agrees to not use psychedelics (listed above) during the study, except as prescribed by the study protocol * Taking prohibited medication within 2 weeks of baseline (see allowed and prohibited concomitant medication list) * History of severe traumatic brain injury (TBI) * Diagnosis of dementia or related progressive neurocognitive disorder * Suicidal ideation/behavior Type 4 or Type 5 intensity on C-SSRS within past 6 months of baseline * Psychiatric inpatient treatment within past 3 months of baseline * Treatment with electroconvulsive therapy, deep brain stimulation, vagus nerve stimulation, or transcranial magnetic stimulation within 3 months of baseline * Implanted central nervous system device * Treatment with evidence-based psychotherapy (EBP) for MDD or PTSD within 2 weeks prior to baseline. If receiving EBP therapy, he/she must complete treatment at least 2 weeks prior to baseline. Other forms of non-EBP psychotherapy for MDD or PTSD are allowed to continue during the study period. * Pregnancy or lactation, or anticipated pregnancy or breastfeeding during the active treatment phase * History of myocardial infarction, congestive heart failure, diabetic ketoacidosis, brain cancer, stroke and/or severe cardiac disease * Clinically significant cardiac, pulmonary, renal, liver and/or other medical disease that, in the opinion of the investigator, may contraindicate the use of psilocybin, interfere with the interpretation of study results and/or constitute a health risk for the participant if they take part in the study * Seizure disorder, except for seizures due to fever or withdrawal from a substance * Clinically significant hypertension (\>160/95 mmHg), hypotension (\<90/60 mmHg) tachycardia (\>100 bpm at rest), QTc prolongation (\>450 msec men; \>470 msec women) or clinically significant arrhythmia on ECG * Clinically significant abnormal laboratory results on chemistry panel, liver function tests, complete blood count, and/or thyroid stimulating hormone * Positive urine drug screen for illicit drugs of abuse (except for THC) at screening or baseline * Prior allergic, adverse reaction or adverse experience to a psilocybin formulation * Litigating for disability income for a mental disorder outside the VA compensation and pension process