The primary goal of this pilot study is to investigate whether psilocybin alters neuroplasticity in people with major depressive disorder. The primary hypothesis is that psilocybin will result in neuroplastic changes that parallel improvement in symptoms of depression.

In this placebo-controlled, blinded study, individuals with depression will participate in 2 experimental sessions approximately 4 weeks apart during which they will receive two of the following three interventions: 1) placebo, 2) low dose psilocybin (0.1 mg/kg), and 3) medium dose psilocybin (0.3 mg/kg).

Inclusion Criteria:

• Diagnosed with Major Depressive Disorder (MDD), single or recurrent episode, and currently experiencing a Major Depressive Episode (MDE)
• Failed to achieve a satisfactory clinical response to at least one adequate antidepressant trial during the current depressive episode
• Currently engaged in treatment with a mental health clinician

Exclusion Criteria:

• Axis I psychotic disorder (e.g. schizophrenia, bipolar I, depression with psychosis)
• Axis I psychotic disorder in first degree relative
• Currently taking a conventional antidepressant medication
• Unstable medical or neurological conditions
• Significant cognitive disorders
• History of intolerance to drugs known to significantly alter perception e.g., psilocybin, LSD, salvinorin A, mescaline, etc.
• Pregnant, breastfeeding, lack of adequate birth control
• Urine toxicology positive to drugs of abuse on experimental test days