This pilot study will collect preliminary data that measures the effects of psilocybin-assisted psychotherapy vs ketamine-assisted psychotherapy on patients struggling with alcohol use.

This pilot study will be a double blind, randomized, active-comparator controlled trial with two study arms. Subjects randomized to Arm 1 (n=10) will receive individual psychotherapy sessions plus a 25mg dose of psilocybin, while Arm 2 subjects (n=10) will receive individual psychotherapy sessions and a 200mg dose of ketamine. Psychotherapy sessions will involve integrative psychotherapy modalities.

At baseline, subjects will be consented, randomized into one of the two arms, complete psychiatric and medical evaluations, and will undergo an MRI scan. The first two therapy sessions (week 1 and week 2) will be used to learn about the participant's life story, engage the patient, and evoke their reasons for wanting to change their pattern of alcohol use. At week 3, participants will undergo a psilocybin-assisted therapy session or a ketamine-assisted therapy session. The last 2 psychotherapy sessions will be focused on integration of their experiences in the drug administration session and will include a second MRI scan and more assessments. Therefore, each arm receives 4 psychotherapy sessions, and the primary difference between the groups is which drug participants receive. After the psychotherapy sessions are completed at the end of week 4, subjects will be followed weekly for 4 weeks. At the last follow-up (week 8), they will undergo a third MRI scan and a final assessment. At the conclusion of the study, those randomized to the ketamine group will be offered a psilocybin-assisted therapy session, and two follow-up/integration sessions in an open-label extension. The open-label extension will also include an additional 4 weeks of follow-up.

Inclusion Criteria:

• 25-65 years old
• Male
• English fluency
• Meets criteria for DSM-V moderate or severe AUD.
• Have at least 4 heavy drinking days (5 or more standard drinks in a day) in the past 30 days.
• No history of a of cerebrovascular accident, asthma, or significant alcohol withdrawal history
• No seizure disorder, coronary artery disease, heart failure, uncontrolled hypertension, insulin-dependent diabetes
• No current substance use disorder other than AUD
• Negative drug screen (other than THC) on drug administration day
• No prescription medications classified as UGT1A9 inhibitors, UGT1A10 inhibitors, aldehyde or alcohol dehydrogenase inhibitors.
• At least a high-school level of education or equivalent (e.g. GED).
• Lived at current residence for at least 3 months.
• Family member/friend for pick-up, overnight post-drug session monitoring.
• No hallucinogen or ketamine use in past 1 year
• No self-reported, personal, or familial history of specific psychotic disorders/episodes as subjects who take psilocybin may experience a worsening and/or persistent psychotic state. Therefore, these subjects are excluded due to an abundance of caution since even a family history may create a vulnerability to psychosis.
• No serious traumatic brain injury (TBI) in the past 2 years.
• No known allergies to rescue medication (diazepam)
• Weight between 110 and 330 lbs

Exclusion Criteria:

• Drug/medication assessment that yields: nonprescription medication use, nutritional supplement, or herbal supplement (except when approved by the study investigators), medically unstable, current medication use that has significant potential to interact with study drug (e.g., antidepressants, antipsychotics, psychostimulants, treatments for addictions, other dopaminergic or serotonergic agents, lithium, anticonvulsants, or benzodiazepines).
• Psychiatric assessment that yields:1) history of severe suicide attempt, 2) current suicidality 3) first degree relative with schizophrenia or schizoaffective disorder, 4) comorbid substance use including cocaine, psychostimulant, or opioid use disorder within past 12 months and/or any use within past 30 days, 5) history of co-occurring psychotic episode/diagnosis including schizophrenia, schizoaffective disorder, schizophreniform, substance-induced psychosis, delusional disorder, or psychosis not otherwise specified, 6) high risk of adverse emotional or behavioral reaction based on the medical monitor's clinical evaluation that may also yield evidence of serious current stressors, a lack of meaningful social support, antisocial behavior, and/or serious personality disorders amongst other conditions.
• Medical assessment that yields: serious ECG abnormalities (evidence of ischemia, myocardial infarction, QTc prolongation [QTc > .045]), serious abnormalities of complete blood count or chemistries, medical conditions that would preclude safe participation (significantly impaired liver function).
• MRI contraindication (pacemaker, etc.)