This study will seek to determine the (1) acceptability and (2) feasibility of psilocybin as an adjunct to cognitive-behavioral therapy, delivered as a group treatment (G-PACBT) for major depressive disorder and (3) explore the clinical effects of G-PACBT on depressive symptoms and psychosocial functioning.

Inclusion Criteria:

• Ages 21-60,
• Fluent in English
• Able to swallow capsules,
• Meets for a current major depressive episode or a history of major depressive episodes based on the DSM-5 criteria (American Psychiatric Association, 2013),
• Active current depressive symptoms (i.e., scores >16 on the Hamilton-Depression Rating Scale covering the prior 2 weeks; Hamilton, 1986),
• Have an identified support person (i.e., trusted adult friend or relative) who can pick up the individual from UCLA Semel Institute and drive individual home following psilocybin sessions,
• For women of child-bearing potential - using one form of highly effective contraception (e.g., oral contraceptive pill) and willingness to continue contraceptive use for duration of study. Must be willing to take on-site pregnancy tests.
• Agree to refrain from any psychoactive drug (including alcohol) within 24 hours of each drug session and during the drug sessions. Participants will be allowed to consume their usual amount of caffeine prior to and after the drug sessions.
• Agree to not take any PRN medications on the mornings of the drug sessions
• Has been medically cleared for the study by a physician
• Participants must remain on anti-hypertensive medications if prescribed previously to manage hypertension

Exclusion Criteria:

• A personal or family history (first-degree) of psychosis or mania
• Resting blood pressure above 140 systolic, 90 diastolic or heart rate > 90 beats per minute (averaged across four separate measurements)
• Meeting criteria for a DSM-5 cluster B personality disorder (narcissistic, histrionic, borderline, antisocial personality disorder),
• Active suicidality (i.e., HAM-D item 3 score of greater than 3) or other psychiatric disturbance requiring acute treatment
• Current use of antidepressants or other serotonergic-affecting substances (e.g., St. John's Wort and 5-hydroxytryptophan), lithium, or efavirenz [regardless of whether the drug(s) is/are prescribed for MDD or other conditions]
• Current use of opioids (e.g., codeine, fentanyl, hydrocodone, meperidine, tramadol)
• Currently receiving cognitive behavioral therapy,
• Any of the following cardiovascular conditions: uncontrolled hypertension, coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction, tachycardia, artificial heart valve, a clinically significant screening ECG abnormality, or any other significant cardiovascular condition
• QTc interval measurement of > 450 ms in males or > 460 ms in females as measured by the baseline ECG
• A history of stroke or Transient Ischemic Attack (TIA)
• Epilepsy or history of seizures
• Insulin-dependent diabetes
• Meeting criteria for a DSM-5 substance abuse or dependence within prior 6 months (including for nicotine and cannabis)
• Positive urine drug screen for illicit substances (not including cannabis)
• Use of other psychedelics or ketamine within prior 12 months
• Adverse prior reaction to a 5-HT2A receptor agonist psychedelic agent
• Pregnant, trying to get pregnant, or nursing