5-HT2A Agonist Psilocybin in the Treatment of Tobacco Use Disorder

Inclusion Criteria:

• 21 years old or older

• Be a daily smoker (minimum of 5 cigarettes/day on a typical day and breath CO of 6or greater at screening) with multiple unsuccessful previous quit attempts, andreport a continued desire to quit smoking

• Read, write, and speak English

• Agree to abstain from smoking for the psilocybin/niacin session from 1 hour beforepsilocybin/niacin administration until at least 8 hours afterward

• Agree to refrain from using any psychoactive drugs, including alcoholic beverages,within 24 hours of psilocybin/niacin administration

• Be healthy as determined by screening for medical problems via a personal interview,a medical questionnaire, a physical examination, an electrocardiogram (ECG), androutine medical blood and urinalysis lab tests. See Exclusion Criteria below forspecific ECG and specific blood test criteria

Exclusion Criteria:

• The use of e-cigarettes or tobacco products other than machine-manufacturedcombustible cigarettes (e.g., cigarillos) on more than 5 of the previous 30 days

• Women who are pregnant (positive pregnancy test) or nursing, or are not practicingan effective means of birth control

• Positive urine drug screen for illicit drugs (excluding cannabis)

• Positive urine breath test for alcohol. Participants with positive tests will berescheduled

• For blood samples, the following lab values will be exclusionary: transaminasesgreater than x2 the upper limit of normal lab reference range, hemoglobin less than 11 g/d, and creatinine clearance < 40 ml/min using the Cockroft-Gault equation.

• For ECG screening: The ECG will be read by a cardiologist. Corrected heart rate (QTc) greater than 450 msec will be excluded.

• Patients who have baseline vital signs that exceed the following measurements willbe excluded from participation: Systolic blood pressure (SBP) > 139 mmHG, diastolicblood pressure (DBP)> 89 mmHG, and heart rate of <=95 beats per minute (BPM). Theinvestigators will perform serial heart rate monitoring with 3 total attempts. Thatis, heart rate must be <=95 bpm on one of these attempts to be included in thestudy.

• Currently taking on a regular basis (e.g., daily) antidepressants of any drug class,antipsychotics, or monoamine oxidase inhibitors (MAOIs), or serotonin-acting dietarysupplements (e.g., 5-hydroxy- tryptophan, St. John's wort). Currently takingefavirenz, Acetaldehyde dehydrogenase inhibitors such as disulfiram (Antabuse),Alcohol dehydrogenase inhibitors, or uridine diphosphate glucuronosyltransferase 1-9 (UGT1A9) inhibitors or uridine diphosphate glucuronosyltransferase 1-10 (UGT1A10)inhibitors such as phenytoin, regorafenib, eltrombopag. For individuals who haveintermittent or "as needed" use of such medications, psilocybin sessions will not beconducted until at least 5 half-lives of the agent have elapsed after the last dose

• Current use of medications for smoking cessation (i.e., varenicline, nicotinereplacement products, bupropion)

• Current neurological illnesses including, but not limited to, seizure disorders,frequent migraines or on prophylaxis, multiple sclerosis, movement disorders,history of significant head trauma (loss of consciousness > 24 hours), or centralnervous system (CNS) tumor

• Recent (within the past 12 months) or an extensive history of psychedelic use (>20lifetime uses)

• Current or past history of meeting Diagnostic and Statistical Manual of MentalDisorders (DSM-5) criteria for Schizophrenia, Psychotic Disorder (unlesssubstance-induced or due to a medical condition), or Bipolar I or II Disorder.Current or past history within the last 5 years of meeting DSM-5 criteria foralcohol or drug use disorder (excluding caffeine and nicotine) or severe majordepression

• Recent (past year) history of suicidal behavior or attempt or high-level currentsuicidal ideation assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

• Have a first- or second-degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or bipolar I or IIdisorder

• Currently meets DSM-5 criteria for Dissociative Disorder, Anorexia Nervosa, BulimiaNervosa, Major Depression, or Post-traumatic Stress Disorder