This is a double-blind, randomized, placebo-controlled Phase 2 mechanistic clinical trial designed to evaluate the therapeutic neural mechanisms of psilocybin in patients with alcohol use disorder (AUD), and to determine whether further studies are warranted to study the relationship of any such effects to clinical improvement in AUD symptoms. The primary aims are to evaluate the effects of psilocybin on AUD; measures will include 1) fMRI neural activation and functional connectivity, using a well-validated task to characterize neural and subjective response to negative affective and alcohol visual stimuli; 2) alcohol use data (self-report and blood biomarkers); and 3) self-report measures related the NE, IS, and EF domains.

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. This criterion will also be reassessed at Baseline, on Day 0, and on Day 2. Those not meeting the criterion may be rescheduled once within 14 days if the criterion is likely to resolve within 14 days in the judgement of the Investigator).

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 Alcohol Use Disorder (AUD) (using MINI)

6. Are in treatment at Silver Hill Hospital (either in Residential Treatment program, or Inpatient with plan to enter Residential Treatment 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 SHH

9. Agree to refrain from any non-prescribed psychotropic substance or illicit drug use for at least 72 hours prior to investigational product (IP) administration, and for at least 24 hours 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. Have a negative pregnancy test at screening, Baseline, Day 0 (pre-IP administration); and Day 2.

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.

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:

   a. Seizure disorder ii. 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.

   iii. 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.

   iv. Uncontrolled hypertension with systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg. (Note: participants who otherwise qualify at 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 the Screening visit is consistently elevated > 140/90 mmHg across all 3 attempts, participants may be referred to their primary care provider for management of hypertension. Upon management of blood pressure, participants will have an opportunity to return once within the 30 day screening window to make 3 additional attempts at a blood pressure reading ≤ 140/90 mmHg. Participants will be considered eligible upon registering 1 blood pressure reading ≤ 140/90 mmHg during the Screening period.) v. 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.).

   vi. Serious ECG abnormalities present on the ECG obtained on Day -65 (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.

   vii. Hyperthyroidism viii. Insulin-dependent diabetes ix. 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 assessment (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 discharged 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 discharged 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 residential treatment at SHH

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) 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. Concomitant medications will be reassessed on Day 0. Any patient who has started prohibited medications will be discharged from the study.)

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 and unable to take lorazepam; 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. (Note: This criterion will be reassessed 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.)

17. Inability to safely complete fMRI sessions (MRI screening form)

18. Any history of severe traumatic brain injury (assessed using the Ohio State University Traumatic Brain Injury (TBI) Identification [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.)

The de-identified participant data from the final research dataset used in the published manuscript will be shared upon request and approval by the NIH Data Access Committee immediately following article publication or as required by a condition of awards and agreements supporting the research. The NIH will provide access to scientific investigators for research purposes. Investigators requesting shared data must be affiliated with an NIH-recognized research institution (in the NIH's eRA Commons) that maintains an active FWA, and complete and submit a Data Use Certification approved by an authorized institutional business official with signature authority. Once approved, researchers will be granted access to the entire collection of shared data in the NDA research clusters requested. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

The NIH will provide access to scientific investigators for research purposes. Investigators requesting shared data must be affiliated with an NIH-recognized research institution (in the NIH's eRA Commons) that maintains an active FWA, and complete and submit a Data Use Certification approved by an authorized institutional business official with signature authority. This request will then be reviewed by the Data Access Committee (DAC). Once approved, researchers will be granted access to the entire collection of shared data in the NDA research clusters requested.