Psilocybin Treatment of Major Depressive Disorder With Co-occurring Alcohol Use Disorder

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 currentlyexperiencing 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 notinterested in initiating standard pharmacotherapies for major depressive disorder oralcohol 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 lessthan 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 isallowed if the type and frequency of the therapy has been stable for at least twomonths prior to screening and is expected to remain stable during participation inthe study

• Be medically stable as determined by screening for medical problems via a personalinterview, 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 theresearch unit on the mornings of drug session days. If the participant does notroutinely consume caffeinated beverages, he/she must agree not to do so on sessiondays

• Agree to refrain from using any psychoactive drugs, including nicotine, within 24hours 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 72hours 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 takingany nonprescription medication, nutritional supplement, or herbal supplement exceptwhen approved by the study investigators. Exceptions will be evaluated by the studyinvestigators 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: nouse 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 atintake and before each drug session) or nursing; women who are of child-bearingpotential and sexually active who are not practicing an effective means ofcontraception.

• Blood liver tests assessed at screening that are outside of 3x the normal range

• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolledhypertension, a clinically significant ECG abnormality (e.g., atrial fibrilation),prolonged corrected QT (QTc) interval (i.e., QTc > 450 msec), artificial heartvalve, 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 complicatedwithdrawal from alcohol

• Any history of seizures, including alcohol withdrawal seizures

• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history ofhypoglycemia

• Currently taking psychoactive prescription medication on a regular (e.g., daily)basis

• Currently taking on a regular (e.g., daily) basis any antidepressant medicationsother than SSRIs, SNRIs, or bupropion, or any other medications that have a primarycentrally-acting serotonergic effect, including mono-amine oxidase inhibitors (MAOIs). For individuals who have intermittent or "as-needed" use of suchmedications, psilocybin sessions will not be conducted until at least 5 half-livesof 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 orother psychotic disorders (except substance/medication-induced or due to anothermedical condition), or Bipolar I or II Disorder

• Current or history within one year of meeting DSM-5 criteria for a moderate orsevere substance use disorder (excluding caffeine, nicotine, and alcohol)

• If a smoker or nicotine user, consuming the equivalent of more than 10 cigarettesper day.

• Have a first or second-degree relative with schizophrenia spectrum or otherpsychotic disorders (except substance/medication-induced or due to another medicalcondition)

• Has a psychiatric condition judged to be incompatible with establishment of rapportor safe exposure to psilocybin

• History of a medically significant suicide attempt (e.g. an attempt characterized bystrong intent and/or high lethality)

• Has failed to respond to electroconvulsive therapy during the current majordepressive episode