Psilocybin-assisted Treatment for Cannabis Use Disorder

Inclusion Criteria:

• ≥ 18 years of age.

• Capable of providing written informed consent for participation into the study.

• Willingness to allow the study team to review past medical records.

• Currently meets criteria for The Diagnostic and Statistical Manual of MentalDisorders, Fifth Edition (DSM-5) diagnosis of Cannabis Use Disorder.

• Be medically stable as determined by screening for medical problems via a personalinterview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests.

• Concurrent pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs), and/or bupropion is allowed ifthe type and frequency of the therapy has been stable for at least two months priorto screening. Allowable bupropion doses for participants will be ≤300mg/day.

Exclusion Criteria:

• Meeting DSM-5 criteria for another moderate or severe substance use disorder (excluding tobacco) within the past 5 years.

• Currently taking antipsychotics, monoamine oxidase (MAO) inhibitors, orantidepressant medications other than SSRIs, SNRIs, or bupropion. Allowablebupropion doses for participants will be ≤300mg/day.

• Currently taking lithium or other primary centrally-acting serotonergic medications,whether over-the-counter or prescription (e.g., efavirenz, 5-hydroxytryptophan, St.John's wort).

• Cardiovascular conditions: angina, a clinically significant ECG abnormality (e.g.atrial fibrillation or corrected QT interval (QTc) > 450 msec), transient ischemicattack (TIA) in the last 6 months, stroke, artificial heart valves, or uncontrolledhypertension with resting blood pressure systolic >139 or diastolic >89, or heartrate >90 bpm.

• Body weight at screening <50kg.

• Renal disease (creatinine clearance < 60 ml/min using the Cockraft and Gaultequation).

• Abnormal screening labs values for hemoglobin, white blood count, creatinine,potassium, and bilirubin outside of the normal lab reference rage.

• Transaminases greater than x2 the upper limit of normal lab reference range.

• Current or past history of meeting DSM-5 criteria for Schizophrenia, PsychoticDisorder (unless substance-induced or due to a medical condition), or Bipolar I orII Disorder.

• Family (i.e., 1st degree relative) history of Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), or Bipolar I Disorder.

• Epilepsy with history of seizures.

• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history ofhypoglycemia.

• Current dementia or related disorders including but not limited to, Alzheimer'sDisease, vascular dementia, Lewy body dementia, and frontotemporal disorders.

• Current or past major immunosuppressive illness or medications.

• Currently pregnant or nursing.

• Currently of childbearing potential and not using effective methods of contraception (i.e., intrauterine systems/devices, hormonal methods including implant, shot,patch, ring, or oral contraceptive, condom, diaphragm, sterilization, abstinence,and fertility-awareness methods).

• Not fluent in English.

• High risk for suicidal ideation or behavior (i.e., individuals who report suicidalideation with intent or behavior on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening, or individuals with a suicide attempt within the past 3years).