The primary objectives of this clinical investigation are to (1) determine the acceptability and feasibility of joining psilocybin-assisted therapy with cognitive-behavioral therapy (PA-CBT) for patients with depression, (2) optimize CBT to most effectively integrate the psilocybin experience with psychotherapy and (3) examine the clinical benefit of psilocybin as an adjunct to cognitive-behavioral therapy (CBT) for major depressive disorder.

This study will involve an open trial of PA-CBT where participants will receive two doses of psilocybin (10mg and then 25mg, separated by one month) plus 12 sessions of cognitive behavioral therapy.

Inclusion Criteria:

• • Ages 21-60,

  • Able to swallow capsules,
  • Patients with 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 (HAM-D) covering the prior 2 weeks; Hamilton, 1986),
  • Have an identified support person 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
  • Patient has been medically cleared for the study by a physician.

Exclusion Criteria:

• • A personal or family history (first or second-degree) of psychosis or bipolar disorder

  • Resting blood pressure above 140 systolic, 90 diastolic (averaged across four separate measurements)
  • Meeting criteria for a DSM-5 cluster B personality disorder (narcissistic, histrionic, borderline, antisocial personality disorder),
  • Active suicidality (as indicated by a 3 or greater on item 3 of the HAM-D) 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),
  • 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
  • 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
  • Positive urine drug screen for illicit substances
  • Use of other psychedelics or ketamine within prior 12 months
  • Adverse prior reaction to a psychedelic agent
  • Pregnant, trying to get pregnant, or nursing

From enrollment until end of follow-up (i.e., 7 months)

There was no comparator to the PA-CBT condition. Additionally, the sample size was modest and follow-up was brief, limiting our ability to ascertain mechanisms of treatment effects. The study design would have been strengthened by measuring psilocybin mood states just prior to each psilocybin dose to better account for the psilocybin-specific antidepressant effects, since participants rated their pre-psilocybin mood states at the study's baseline assessment.