The purpose of this study is to determine whether psilocybin, a hallucinogenic drug, is effective in reducing depressive symptoms and amount of drinking in patients with co-occurring Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD).

The objectives of this double-blind, placebo-controlled study are to test the hypotheses that a single high (25 mg) oral dose of psilocybin will lead to enduring reductions in depressive symptoms (as measured by the clinician-rated grid version of the Hamilton Depression Rating Scale, or GRID-HAMD) and amount of drinking (as measured using the Time Line Follow Back, or TLFB, procedure) compared to placebo in patients with co-occurring MDD and AUD. 90 male and female volunteers who are between the ages of 21 and 65 years old and who meet Diagnostic and Statistical Manual, Fifth Edition (DSM-5) criteria for MDD and AUD will be recruited from the community and complete all study procedures. Volunteers will be randomized to one of two study arms (psilocybin [N=45] or placebo [N=45]), and will complete a drug administration session paired with a brief Motivational Interviewing intervention for alcohol use. Volunteers will undergo assessments of depression and alcohol use before and after treatment. After primary endpoints are measured, all volunteers will receive a second, unblinded intervention with a single high dose of psilocybin (25 mg) to test a secondary hypothesis that two doses of psilocybin are more effective in treating MDD with co-occurring AUD than a single dose.

Inclusion Criteria:

• 21 to 65 years old
• Fluent in English
• Have given written informed consent
• Have at least a high-school level of education or equivalent (e.g. GED).
• Have a baseline GRID-HAMD score ≥ 16
• Have a confirmed DSM-5 diagnosis of Major Depressive Disorder and currently experiencing a major depressive episode
• Have a confirmed DSM-5 diagnosis of Alcohol Use Disorder
• Have undergone some form of therapy for MDD or AUD in the past, but are not interested in initiating standard pharmacotherapies for major depressive disorder or alcohol use disorder (e.g. selective serotonin reuptake inhibitor, disulfiram, naloxone, etc.)
• Be judged by study team clinicians to be at low risk for suicidality
• Average of at least 4 non-drinking day/month in the past 90 days, or a score of less than 4 on the PAWWS scale
• Have at least 2 heavy drinking days per month in the past 90 days
• Concurrent psychotherapy or pharmacotherapy with SSRIs, SNRIs, and/or bupropion is allowed if the type and frequency of the therapy has been stable for at least two months prior to screening and is expected to remain stable during participation in the study
• Be medically stable as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests
• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of drug session days. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days
• Agree to refrain from using any psychoactive drugs, including nicotine, within 24 hours of each drug administration. The exception is caffeine
• Agree not to take any "as needed" medications on the mornings of drug sessions
• Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of each drug administration
• Agree to use effective methods of contraception during the study (females)
• Agree that for one week before each drug session, he/she will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the study investigators. Exceptions will be evaluated by the study investigators and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals
• Have limited lifetime use of hallucinogens (the following criteria are preferred: no use in the past 5 years; total hallucinogen use less than 10 times)
• Proof of COVID-19 vaccination

Exclusion Criteria:

• Women who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing; women who are of child-bearing potential and sexually active who are not practicing an effective means of contraception.
• Blood liver tests assessed at screening that are outside of 3x the normal range
• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrilation), prolonged corrected QT (QTc) interval (i.e., QTc > 450 msec), artificial heart valve, or transient ischemic attack in the past year
• Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) score > 9, or any other indication that the volunteer may experience medically complicated withdrawal from alcohol
• Any history of seizures, including alcohol withdrawal seizures
• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia
• Currently taking psychoactive prescription medication on a regular (e.g., daily) basis
• Currently taking on a regular (e.g., daily) basis any antidepressant medications other than SSRIs, SNRIs, or bupropion, or any other medications that have a primary centrally-acting serotonergic effect, including mono-amine oxidase inhibitors (MAOIs). For individuals who have intermittent or "as-needed" use of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose.
• Currently taking more than 300mg bupropion daily
• Currently taking medications for the treatment of depression or alcohol use disorder
• Current or past history of meeting DSM-5 criteria for schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or Bipolar I or II Disorder
• Current or history within one year of meeting DSM-5 criteria for a moderate or severe substance use disorder (excluding caffeine, nicotine, and alcohol)
• If a smoker or nicotine user, consuming the equivalent of more than 10 cigarettes per day.
• Have a first or second-degree relative with schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition)
• Has a psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin
• History of a medically significant suicide attempt (e.g. an attempt characterized by strong intent and/or high lethality)
• Has failed to respond to electroconvulsive therapy during the current major depressive episode

During the first phase of the study, participants will receive either placebo or treatment and all parties will be blinded. During the second phase of the study, all participants will receive treatment (open label).