Cytisinicline Reduces Cravings and Nicotine Intake in People Who Smoke and Don't Quit Completely

Abstract Rationale: Tobacco smoking remains the leading cause of preventable mortality. Cytisinicline, a partial agonist/antagonist of the nicotinic acetylcholine receptor, has demonstrated strong efficacy for smoking cessation, attributed to a dual mechanism of action (MOA) in which it reduces cravings and reward from smoking. To further validate the proposed MOA, this analysis explored the impact of cytisinicline on craving and cotinine levels in people who didn't quit completely on cytisinicline. Methods: Adults smoking >10 cigarettes daily were enrolled in a double-blind, placebo-controlled randomized trial comparing cytisinicline treatment to placebo. Participants were randomized (1:1:1) to receive 12 weeks of placebo (Arm A, n=265), cytisinicline 3 mg TID for 6 weeks followed by placebo for 6 weeks (Arm B, n=263) or cytisinicline 3 mg TID for all 12 weeks (Arm C, n=264). All groups had behavioral support. The analyses here focused on the 519 participants who did not quit completely as defined by self-report and a confirmatory breath CO>=10 ppm. Craving was measured with the Brief Questionnaire of Smoking Urges (QSU-brief) at Week 6 and assessed using a GLM. Nicotine exposure was measured with serum cotinine at baseline and week 6 for Arm B & week 12 for Arm C. Results: Among participants who continued smoking during treatment, those on cytisinicline had significantly lower mean QSU-Brief craving scores at week 6 compared to placebo (15.9 vs 18.9, p=0.0001) and significantly greater reduction in cotinine levels from baseline to end of treatment at 6 and 12 weeks compared to placebo. The mean cotinine reduction for those who continued smoking in the 6-week cytisinicline arm (n=193) was -150.21 ng/ml (95% CI, -168.00 to -132.61) vs -38.26 ng/ml (95% CI, -55.11 to -21.42) for placebo (p<0.0001). In the 12-week cytisinicline arm (n=138), cotinine reduction was -125.87 ng/ml (95% CI, -146.51 to -105.23) vs -31.03 ng/ml (95% CI, -48.72 to -13.35) for placebo (p<0.0001). Conclusions: Among participants randomized to cytisinicline treatment who did not achieve complete abstinence, we observed significant reductions in cotinine (i.e., nicotine intake) and lower cravings to smoke. The findings suggest that cytisinicline makes smoking less rewarding and support the hypothesis that cytisinicline functions as both a partial agonist and antagonist at the nicotine acetylcholine receptor. This mechanism underscores cytisinicline's effectiveness as an aid for quitting smoking and highlights the medication's potential role for helping people reduce or quit nicotine vaping and use of other tobacco products that activate the nicotine acetylcholine receptor.