Inclusion Criteria:
1. Are able to provide voluntary informed consent
2. Have a breath alcohol concentration (BrAC) ≤ 0.01% at screening, as determined by a breath alcohol reading from a calibrated breath alcohol sensor. (Note: this criterion may be re-evaluated within the 30-day screening period.
3. Are able to read, speak, and understand English, as documented during the informed consent process.
a. Non-English speaking subjects will be excluded because the study is using only validated English-language versions of assessment instruments.
4. Are 18 to 65 years old, inclusive, at Screening visit.
5. Have DSM-5 diagnosis of moderate or severe AUD (using MINI)
6. Eligible participants must either (a) not currently receiving treatment for alcohol use disorder (AUD), or (b) have been in continuous treatment for AUD for at least 3 months and plan to continue. (Any medications used to treat AUD would need to be discontinued no less than 5 half lives or 14 days (whichever is greater) prior to the IP administration session. Patients who who are completing detoxification from alcohol and do not have plans for follow-up treatment would be eligible to participate in the study after completion of the detoxification program).
7. Are able and willing to adhere to all study requirements, including attending all study visits and therapy sessions, and completing all assessments.
8. Have least 4 heavy drinking days (4 or more drinks per day for a woman, 5 or more drinks per day for a man) in the 30 days prior to admission to the screening visit.
9. Agree to refrain from alcohol use as well as any non-prescribed psychotropic substance or illicit drug use for at least 24 hours prior to investigational product (IP) administration and before each fMRI assessment visit, with the exceptions of nicotine and caffeine. Regarding nicotine, they must agree not to use nicotine for at least 1 hour before and 6 hours following IP administration, and for at least 1 hour before fMRI scans. Regarding caffeine, they must agree to consume approximately their usual amount of caffeine on the morning of Day 0 (prior to IP administration).
10. Agree to refrain from taking all non-prescription medications and supplements (nutritional and herbal) for at least 1 week prior to the IP administration session unless approved by the Investigator.
11. Are able to swallow capsules.
12. If able to become pregnant, have a negative serum pregnancy test at screening.
13. If able to become pregnant or produce viable sperm (male or female), are willing to use approved contraception for duration of the trial
14. Able to provide at least 2 locators.
15. Participants must be able to commit to being sober at the time all treatment sessions and the two fMRI sessions, and to stay sober from the time of the drug administration until the second fMRI session.
Exclusion Criteria:
1. Pregnancy or lactation
2. Any medical condition that would preclude safe participation in the study, including the following, as determined by medical history review, physical examination, electrocardiogram (ECG), and clinical laboratory tests:
1. Seizure disorder
2. Significantly impaired liver function, defined as 1) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 5 × upper limit of normal (ULN); 2) ALT or AST \> 3 × ULN with concomitant total bilirubin \> 2.0 × ULN; or 3) ALT or AST ≥ 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia.
3. Cardiovascular disease including coronary artery disease, angina, history of arrhythmia (unless a successful ablation has been performed), heart failure, history of heart valve replacement, and history of cerebrovascular accident or transient ischemic attack.
4. Uncontrolled hypertension with systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg. (Note: participants who otherwise meet all eligibility criteria during the screening visit will have 3 opportunities to produce 1 blood pressure reading ≤ 140/90 mmHg (each reading will be collected at least 15 minutes apart). If blood pressure at Screening is consistently elevated (\> 140/90 mmHg across all 3 attempts), participants may be referred to their medical provider for management of hypertension. Participants may continue study participation if they are able to provide documentation of adequate control (BP \> 140/90 mmHg) prior to the IP administration session.)
5. Resting heart rate \> 100 bpm (Note: participants will have an opportunity to return once within the 30 day screening window to make 3 additional attempts at a resting heart rate ≤ 100 bpm.).
6. Serious ECG abnormalities present on the ECG obtained at the screening visit (e.g., evidence of ischemia, myocardial infarction, QT interval corrected for heart rate \[QTc\] prolongation (QTc \> 0.450 seconds), arrhythmia, or conduction abnormalities that increase the risk of arrhythmia.
7. Hyperthyroidism
8. Insulin-dependent diabetes
9. Any other medical condition which precludes safe participation in the study in the medical opinion of the Investigator. (Note: medical history will be updated on Day 0. Those not meeting the criterion will not be randomized but may be rescheduled once within 14 days if the criterion is likely to resolve within 14 days in the judgement of the Investigator.)
3. Have any of the following DSM-5 psychiatric disorders, as determined by the MINI and Psychiatric History at the Screening Visit: (Note: psychiatric history will be re-evaluated on Day 0, but the MINI will not be re-administered on Day 0)
1. Lifetime history of schizophrenia spectrum or other psychotic disorder (including substance or medication-induced psychosis or psychosis due to a co-occurring medical condition).
2. Current alcohol withdrawal (CIWA-Ar score \>7)
3. History of mania
4. Have active suicidal ideation with intent, based on Columbia-Suicide Severity Rating Scale (C-SSRS) (past week severity score \>3) at the Screening visit, confirmed by the Investigator. (Note: this criterion will be reassessed at each visit that occurs prior to Day 0, and on Day 0 prior to randomization. Participants will be withdrawn if actively suicidal, and appropriate follow-up will be arranged.
5. Have made a medically significant suicide attempt (i.e., one that had a significant possibility of causing death or permanent harm in the absence of intervention) within the past 12 months, based on Screening C-SSRS assessment and confirmation by the Investigator. (Note: this criterion will be reassessed at each visit that occurs prior to Day 0, and on Day 0 prior to randomization. Participants will be withdrawn if actively suicidal, and appropriate follow-up will be arranged.)
6. Have a family history (first degree relatives) of schizophrenia, schizoaffective disorder, or bipolar disorder type 1.
7. Have a history of hallucinogen use disorder.
8. Have a history of hallucinogen persisting perceptual disorder (HPPD).
9. Have any use of classic psychedelics in the past 1 year.
10. Have \> 25 lifetime uses of classic psychedelics.
11. Incarcerated or have pending legal action that could prevent participation in study activities.
12. Are court-mandated to complete treatment or are a prisoner.
13. Are unable or unwilling to discontinue taking any protocol-prohibited medications and supplements. (A detailed list of exclusionary medications is found in Section 6.5 of the protocol). Current SSRI use is allowed only if the dose has been stable for at least one month at the time of Screening visit. Prohibited medications and supplements must have been stopped for at least 5 elimination half-lives or 14 days, whichever is longer, prior to Day 0 (Note: Psychiatric medications will not be discontinued or changed in order to allow study participation unless such change does not cause any increase in risk to the study participant, in the judgement of the study physician and the prescribing provider. For example, a change in a medication for sleep might be appropriate if a non-exclusionary alternative is available. Any such study-related changes in medication will be documented in a progress note which will include explanation for why the change does not increase overall clinical risk and documentation of the prescribers concurrence with the treatment plan.)
a. Note that any medication prescribed to the participant for AUD is exclusionary, including FDA-approved medications as well those prescribed off-label, such as topiramate, ondansetron, gabapentin, and varenicline.
14. Have a known allergy or hypersensitivity to psilocybin or any of the materials contained in the IP used in the study.
15. Have an allergy, hypersensitivity, or other contraindication that would preclude safe treatment of acute hypertension, anxiety, or psychotic symptoms if necessary during or immediately after the IP Administration Session, using the adjunctive medications used in this study to treat these symptoms (i.e., unable to take captopril and unable to take clonidine; unable to take diazepam; or unable to take olanzapine).
16. Have any other medical, psychiatric, or psychosocial disorder, symptom, condition, or situation that is likely to interfere with the establishment of rapport, adherence to study requirements, or safe administration of psilocybin or fMRI scanning, based on the judgement of the Investigator.
17. Inability to safely complete fMRI sessions (MRI screening form), including presence of metallic implants or devices that contraindicate MRI or claustrophobia.
18. Any history of severe traumatic brain injury (assessed using OSU TBI-ID modified). (Note: If current (past 12 months) mild/moderate TBI and CSI score \>/=12 (for either lifetime month or current month), the PI will determine eligibility.)