Examining the Effects of Cytisinicline on Neural Substrates of Cigarette Cue-reactivity

The objective of this study is to examine the effects of cytisinicline on neural substrates of cigarette cue-reactivity. We will randomize 64 adults who smoke cigarettes daily (N=32 cytisinicline, N=32 placebo; 50% female) into a double-blind, placebo-controlled laboratory study of cytisinicline. Specifically, participants will complete a 2- to 3-week outpatient protocol that includes taking cytisinicline (3 mg, 3 times daily) or matched placebo (0 mg, 3 times daily) and completing a brief daily diary assessment of cigarette use and craving. Following 2- to 3-weeks of cytisinicline (or placebo) treatment, participants will complete a cigarette cue-exposure task during fMRI. Total study participation will be approximately 4 weeks.

Inclusion criteria

• be between the ages of 18 and 65 and provide informed consent;
• smoke 5 or more combustible cigarettes per day;
• not seeking treatment for smoking;

Exclusion criteria

• current use of other smoking cessation aid (bupropion, varenicline, nortriptyline, NRT);
• more than 3 months of smoking abstinence in past year;
• use of non-cigarette tobacco product (pipe tobacco, cigars, smokeless tobacco, hookah) or electronic cigarettes more than 5 times in the 28-days prior to enrollment;
• current use of psychoactive drug (excluding cannabis), as determined by urine toxicology;
• current (past 12-month) DSM-5 diagnosis of substance use disorder for any substances other than tobacco and mild cannabis or mild-to-moderate alcohol use disorders;
• lifetime history of psychotic disorders, bipolar disorders, or major depression with suicidal ideation;
• current suicidal ideation or lifetime history of suicide attempt;
• serious medical illness within past 3 months, including recent history of acute myocardial infarction, unstable angina, stroke, cerebrovascular incident, or hospitalization for congestive heart failure;
• medical condition that may interfere with safe study participation;
• renal impairment defined as a creatinine clearance (CrCl) greater than 60 mL/min (estimated with the Cockroft-Gault equation);
• exceed Grade 2 laboratory abnormalities, based on FDA Guidance Document "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials";
• uncontrolled hypertension (blood pressure ≥160/100 mmHg);
• abnormal electrocardiogram;
• non-removable ferromagnetic object in body;
• claustrophobia;
• serious head injury or period of unconsciousness (more than 30 minutes);
• more than 250lbs;
• Be pregnant, nursing, or planning to become pregnant while taking part in the study; and must agree to one of the following methods of birth control (if female), unless she or partner are surgically sterile:

• Oral contraceptives
• Contraceptive sponge
• Patch
• Double barrier
• Intrauterine contraceptive device
• Etonogestrel implant
• Medroxyprogesterone acetate contraceptive injection
• Hormonal vaginal contraceptive ring
• Complete abstinence from sexual intercourse;
• have experienced adverse effects to varenicline;
• have an intense fear of needles or have had an adverse reaction to needle puncture.