This study will randomize 64 non-treatment seeking individuals who smoke cigarettes daily in a double-blind, placebo-controlled laboratory study testing the effects of cytisinicline on the 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:

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

Exclusion Criteria:

1. current use of other smoking cessation aid (bupropion, varenicline, nortriptyline, NRT);

2. more than 3 months of smoking abstinence in past year;

3. 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;

4. current use of psychoactive drug (excluding cannabis), as determined by urine toxicology;

5. 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;

6. lifetime history of psychotic disorders, bipolar disorders, or major depression with suicidal ideation;

7. current suicidal ideation or lifetime history of suicide attempt;

8. 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;

9. medical condition that may interfere with safe study participation;

10. renal impairment defined as a creatinine clearance (CrCl) greater than 60 mL/min (estimated with the Cockroft-Gault equation);

11. 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";

12. uncontrolled hypertension (blood pressure ≥160/100 mmHg);

13. abnormal electrocardiogram;

14. non-removable ferromagnetic object in body;

15. claustrophobia;

16. serious head injury or period of unconsciousness (more than 30 minutes);

17. more than 250lbs;

18. 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;

19. have experienced adverse effects to varenicline;

20. have an intense fear of needles or have had an adverse reaction to needle puncture.