Cytisinicline for Smoking Cessation: A Randomized Clinical Trial

Shuang (Jeremy) Chen, PharmD, Minnesota Community Care East Side Family Clinic

Background: Cigarette smoking has been linked to increased health risks and decreased life expectancy. Although current FDA-approved smoking cessation medications can enhance the likelihood of successful quitting, these medications have limited long-term success and are associated with potential moderate to severe neuropsychiatric and cardiovascular side effects, necessitating the development of new alternatives since no approved smoking cessation drugs have emerged since 2006. Cytisinicline (cytisine), similar to varenicline, is a natural alkaloid derived from plants that selectively binds to α4β2 nicotinic acetylcholine receptors responsible for nicotine addiction. While it is not approved in the United States, cytisinicline 1.5 mg has been used six times daily for 25 days in certain European countries as an over-the-counter smoking cessation product. However, evidence regarding its dosing regimen and treatment duration varies.

Objective: To evaluate the smoking cessation efficacy and tolerability of cytisinicline 3 mg three times daily for six and twelve weeks vs placebo.

Study Design: This study was a multisite, three-group, double-blind, placebo-controlled, randomized Phase III clinical trial. A total of 810 participants were randomized to the cytisinicline six-week, cytisinicline twelve-week, or placebo group. Participants were included if they met the following criteria: ≥ 18 years old, smoking ≥ 10 cigarettes daily, having ≥ 10 ppm of expired carbon monoxide (CO), and being ready to set a quit date at screening. Participants were excluded if they used any noncigarette tobacco products, took other smoking cessation medications, or had the following co-morbidities: such as cardiovascular, mental, hepatic or renal disorders. Cytisinicline 3 mg or placebo was administered three times daily, and smoking cessation behavioral support was provided for all participants at every visit. Outcomes were measured by verified continuous smoking abstinence (defined as self-reported and breath CO < 10 ppm) for the last four weeks of cytisinicline treatment vs. placebo (primary) and from the end of treatment to 24 weeks (secondary). Randomized groups were compared by exact analyses 2 x 2 tables. Logistic regression explored subsets based on baseline attributes for effect modification, and longitudinal analysis employed mixed models for repeated measures, constrained for pre-randomization data.

Results: The continuous abstinence rates of six-week cytisinicline and placebo were 25.3% and 4.4% during weeks three to six (odds ratio, 8.0; 95% CI, 3.9-16.3; P<0.001) and 8.9% and 2.6% during weeks three to 24 (odds ratio, 3.7; 95% CI, 1.5-10.2; P=0.002). For the 12-week course, the continuous abstinence rates of cytisinicline and placebo were 32.6% vs 7.0% for weeks nine to twelve  (odds ratio, 6.3; 95% CI, 3.7-11.6; < 0.001) and 21.1% and 4.8% during weeks nine to twelve (odds ratio, 5.3; 95% CI, 2.8-11.1; P< 0.001). Less than 10% of participants experienced side effects such as nausea, abnormal dreams, and insomnia, but no serious adverse events were treatment-related. The difference in adverse events occurrence was insignificant between the cytisinicline and placebo group (odds ratio, 3.08; 95% CI, 0.98-13.18). If cytisinicline-treated participants achieved four weeks of tobacco abstinence by week six, extending cytisinicline treatment for an extra six weeks did not reduce the likelihood of relapse, compared to stopping treatment at week six. 

Conclusion: Both six- and twelve-week cytisinicline treatment, along with behavioral support, is effective and safe for smoking cessation and tobacco dependence treatment.

Key Point: Cytisinicline, a smoking cessation medication that is not approved in the US, significantly improved smoking abstinence in both six-week and twelve-week groups vs. placebo in phase III clinical trials with good tolerance. The group receiving cytisinicline for 12 weeks saw ongoing improvement in point-prevalence abstinence rates after week six, indicating that participants who hadn't achieved abstinence by week six and remained on cytisinicline were still able to quit smoking. This study has some limitations with its predominantly White participants and exclusion of participants with mental and/or cardiovascular co-morbidities, illicit drug use, and/or non-cigarette tobacco users (e.g., vape, marijuana), which limits the generalizability for these populations. In addition, this trial could not predict long-term effectiveness and safety as the treatment and follow-up duration were not enough to assess post-trial abstinence or detect rare adverse events.


Rigotti NA, Benowitz NL, Prochaska J, et al. Cytisinicline for smoking cessation. JAMA. 2023;330(2):152-160. doi:10.1001/jama.2023.10042