Psilocybin-assisted Interpersonal Therapy for Depression

1. Able to give written informed consent 2. Have a confirmed DSM-5 diagnosis of Major Depressive Disorder and currently experiencing a major depressive episode and no improvement despite two adequate courses of antidepressant treatment of different pharmacological classes lasting at least 6 weeks within the current depressive episode 3. Have a baseline total score of \>13 on HAMD17 . 4. Agree to discontinue any recommended psychoactive medications, including antidepressants and lithium as part of the study. 5. Agree to refrain from using alcohol and other substances including nicotine, within 24 hours of each drug administration. 6. Be judged by study team clinicians to be at low risk for suicidality 7. Be medically stable as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests 8. Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of drug session days. 9. Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of each drug administration. 10. Agree that for one week before each drug session, he/she will refrain from taking any non-prescription medication, nutritional supplement, or herbal supplement except when approved by the study investigators. Exceptions will be evaluated by the study investigators and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals. 11. If female, they must agree to pregnancy testing and regular contraception while in study. 12. Have limited lifetime use of hallucinogens (the following criteria are preferred: no use in the past 5 years; total hallucinogen use less than 10 times) 13. Agree to participate in a 10-week combined psychotherapy and psilocybin intervention, complete required measurements (including follow-up measures at week 18) and adhere to safety protocols. Exclusion Criteria: 1. Women who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing; women who are of child-bearing potential and sexually active who are not practicing an effective means of birth control. 2. Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc \> 450 msec), artificial heart valve, or TIA in the past year 3. Epilepsy with history of seizures 4. Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia 5. Currently taking psychoactive prescription medication on a regular (e.g., daily) basis which are unable to be ceased (under supervision) during the study period. 6. Currently taking on a regular (e.g., daily) basis any medications having a primary centrally-acting serotonergic effect, including MAOIs. For individuals who have intermittent or PRN use of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose. 7. Current or past history of meeting DSM-5 criteria for schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or Bipolar I or II Disorder 8. Current or history within one year of meeting DSM-5 criteria for a moderate or severe alcohol or other drug use disorder (excluding caffeine) 9. Have a first or second-degree relative with schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or Bipolar I or II Disorder 10. Has a psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin 11. History of a medically significant suicide attempt 12. Has failed to respond to electroconvulsive therapy during the current major depressive episode 13Not fluent in English