This study aims to determine the safety and preliminary efficacy of psilocybin-assisted psychotherapy in improving alcohol-related outcomes among adults with severe alcohol use disorder in a a double-blind, dose-comparison concurrent control, randomized trial. Participants will undergo structured psychotherapy and will be randomized to two psilocybin sessions to receive either a full dose (30mg or 40mg) or low dose (10mg or 15mg).

This study is a double-blind, dose-comparison concurrent control randomized trial designed to evaluate the effects of psilocybin-assisted psychotherapy on alcohol-related outcomes, neurocognitive processes related to craving and stress, and neural circuits involved in reward and regulation among adults with severe alcohol use disorder (AUD). Participants are recruited up to 3 months after completing inpatient alcohol withdrawal treatment to ensure medical stabilization prior to psilocybin administration. The study examines both preliminary efficacy and safety while also exploring mechanistic pathways through behavioral assessments and functional neuroimaging.

Participants (N=36) are randomized in a 1:1 ratio to receive either a full-dose psilocybin (30 mg, with option to escalate to 40 mg on the second session) or a low-dose (10 mg, with option to escalate to 15 mg on the second session). All participants complete two dosing sessions spaced four weeks apart. The psychotherapy is delivered by a dyad of trained therapists before, during, and after the dosing sessions and is based on established therapeutic frameworks used in prior psilocybin-assisted therapy trials. The aim of the therapeutic support is to prepare participants for the psilocybin experience, facilitate psychological processing during and after dosing, and support integration of insights into daily life. A peer recovery coach is integrated into the study to support relapse prevention, enhance coping skills, and encourage engagement in ongoing addiction treatment. All participants are offered follow-up services at the institution's outpatient addiction treatment program (including the BWH Bridge Clinic), regardless of study arm. This combination of medical oversight, psychotherapy, and recovery support reflects an effort to embed the intervention within real-world addiction care settings.

Alcohol-related outcomes are assessed repeatedly from baseline through 48 weeks after the second dosing session. The primary clinical outcome is the percentage of heavy drinking days during the 24-week follow-up period, measured using Timeline Follow-Back. Secondary alcohol outcomes include drinking quantity and frequency, relapse timing, direct alcohol biomarkers (phosphatidylethanol and ethylglucuronide), withdrawal symptoms, treatment expectancy, blinding integrity, and quality of life measures. Additional exploratory outcomes assess peer support engagement and 12-step attendance.

Safety is evaluated throughout the study using structured assessments of adverse events, vital signs, and mood and anxiety symptoms. Because participants have severe AUD and recent withdrawal treatment, careful medical screening is conducted prior to each dosing session. The study includes multiple follow-up assessments up to 48 weeks after the second psilocybin dose, allowing characterization of both acute and longer-term safety.

Two mechanistic components are incorporated. First, neurocognitive tasks assess cue-induced craving, attentional bias, stress reactivity, delayed discount, decision making, and distress tolerance. These measures evaluate whether psilocybin influences cognitive and affective processes known to contribute to alcohol use and relapse. Second, participants complete two fMRI scans-first within one week prior to the first dosing session and the second within one week after the second dosing session. The fMRI tasks evaluate neural response to alcohol-related cues and the ability to down-regulate craving, focusing on the nucleus accumbens (NAcc) and dorsolateral prefrontal cortex (DLPFC). Connectivity analyses examine changes in functional coupling between these regions during alcohol cue processing.

Together, these approaches allow the study to evaluate whether full-dose psilocybin, compared to low-dose, produces greater reductions in heavy drinking and craving, whether the treatment is safe and tolerable for individuals with severe AUD, and whether changes in cognitive, emotional, and neural functioning help explain clinical outcomes. By recruiting individuals immediately following inpatient detoxification, the study also examines the feasibility of incorporating psilocybin-assisted therapy into a critical window of early recovery. Results will inform whether a larger, fully powered clinical trial is justified and will contribute to the broader understanding of psilocybin's therapeutic potential in alcohol use disorder.

To be eligible, individuals must be:

• English speaking adults between ages 18 and 65
• Diagnosis of DSM5 AUD, severe
• Completion of inpatient withdrawal management (i.e. "detox") for AUD within 90 days of enrollment
• Amenable to attending all psychotherapy and study visits at BWH CCI
• Able to identify an individual who can act as points of contact during the trial
• Have a friend or family member who can bring the participant home after the psilocybin sessions and stay overnight

Individuals with any of the following will be excluded:

• • Any personal history of a psychotic disorder (schizophrenia, schizoaffective disorder, brief psychotic disorder, delusional disorder, schizophreniform disorder, substance-induced psychotic disorder or major depression with psychotic features) or any bipolar-spectrum disorder
• Participants with a family history of first-degree relatives with psychotic disorder or bipolar-spectrum disorder
• Participants who have a significant suicide risk as defined by current suicidal ideation (Columbia-Suicide Severity Rating Scale (C-SSRS) score 2 to 5) and/or recent (within the past 6 months) active suicidal ideation (C-SSRS score 4 or 5)
• Participants who have a history of significant or serious adverse reaction to classic psychedelics
• Homicidality within the last six months
• History of DSM5 hallucinogen use disorder
• Positive breath alcohol level at screening
• Need for inpatient withdrawal management for alcohol at the time of screening
• Current DSM5 opioid, cocaine, stimulant or sedative/hypnotic use disorder
• Systolic blood pressure persistently above 165mmHg during screening
• History of hypersensitivity to psilocybin
• Use of psilocybin or other psychedelics with 5-HT2B activity in the prior 12 months
• Significant EKG abnormalities including QTc prolongation defined as >450 ms for men and women, or a diagnosis or family history of Long QT syndrome.
• History of any cardiac valvulopathy that raises the risk for participation as determined by the cardiology consultant
• History of intracranial mass or bleed, seizure disorder other than alcohol withdrawal seizures, liver cirrhosis, renal failure, obstructive lung disease requiring supplemental oxygen, hyperthyroidism, narrow-angle glaucoma, uncontrolled cardiac arrythmias, heart failure
• History of head trauma, stroke, or myocardial infarction in one year prior to enrollment.
• Expected to require surgical treatment at any point during the trial
• Liver dysfunction with LFTs > 3x upper normal limit at screening and Total bilirubin > 2.5x the upper normal limit
• MRI contraindications (other ferromagnetic implants, body weight greater than 550 lbs., etc.)
• Pregnant or breastfeeding
• High risk for adverse emotional or behavioral reaction based on the opinion of the study investigators such as evidence of a personality disorder
• Currently taking medications with serotonergic activity (other than SSRIs/SNRIs); inhibitors of UGT1A9, UGT1A10, MAO, and aldehyde or alcohol dehydrogenase; antipsychotics (e.g., first and second generation); mood stabilizers (e.g., lithium, valproic acid); or significant inhibitors of UGT enzymes that metabolize psilocin
• Selective serotonergic reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors are allowed if participants have been on stable doses of the medication(s) for at least 90 days prior to enrollment.
• Currently receiving insulin for blood sugar management.

This trial uses double-blind masking. Participants, therapists, clinical staff present during dosing sessions, outcome assessors, and study investigators are all masked to treatment assignment. The psilocybin doses are prepared and dispensed by unmasked pharmacy personnel who have no contact with participants and no role in assessments or data analysis.