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 6 or greater at screening) with multiple unsuccessful previous quit attempts, and report a continued desire to quit smoking * Read, write, and speak English * Agree to abstain from smoking for the psilocybin/niacin session from 1 hour before psilocybin/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), and routine medical blood and urinalysis lab tests. See Exclusion Criteria below for specific ECG and specific blood test criteria Exclusion Criteria: * The use of e-cigarettes or tobacco products other than machine-manufactured combustible 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 practicing an 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 be rescheduled * For blood samples, the following lab values will be exclusionary: transaminases greater 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 will be excluded from participation: Systolic blood pressure (SBP) \> 139 mmHG, diastolic blood pressure (DBP)\> 89 mmHG, and heart rate of \<=95 beats per minute (BPM). The investigators will perform serial heart rate monitoring with 3 total attempts. That is, heart rate must be \<=95 bpm on one of these attempts to be included in the study. * Currently taking on a regular basis (e.g., daily) antidepressants of any drug class, antipsychotics, or monoamine oxidase inhibitors (MAOIs), or serotonin-acting dietary supplements (e.g., 5-hydroxy- tryptophan, St. John's wort). Currently taking efavirenz, 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 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 * Current use of medications for smoking cessation (i.e., varenicline, nicotine replacement 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 central nervous system (CNS) tumor * Recent (within the past 12 months) or an extensive history of psychedelic use (\>20 lifetime uses) * Current or past history of meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Schizophrenia, Psychotic Disorder (unless substance-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 for alcohol or drug use disorder (excluding caffeine and nicotine) or severe major depression * Recent (past year) history of suicidal behavior or attempt or high-level current suicidal 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 II disorder * Currently meets DSM-5 criteria for Dissociative Disorder, Anorexia Nervosa, Bulimia Nervosa, Major Depression, or Post-traumatic Stress Disorder