Varenicline Significantly Enhances Nicotine Vaping Cessation in Youth: Insights from a Landmark Randomized Clinical Trial

Highlight

• Varenicline significantly increased biochemically verified continuous vaping abstinence rates in youth who vape nicotine daily but do not regularly smoke tobacco.
• During weeks 9-12, 51% of youth on varenicline achieved continuous abstinence compared to 14% on placebo, and 6% in enhanced usual care.
• Varenicline was well tolerated with no drug-related serious adverse events; adverse events were comparable across groups.
• Behavioral counseling combined with pharmacotherapy is an effective strategy to address nicotine vaping, an emerging public health concern in adolescents and young adults.

Study Background and Disease Burden

The ongoing rise in electronic cigarette use (vaping) among adolescents and young adults presents a significant public health challenge. Vaping is highly prevalent in this demographic, often involving daily or near-daily nicotine consumption. Unlike traditional tobacco smoking, vaping presents unique behavioral and physiological dependencies, and, importantly, there is a paucity of evidence-based treatments tailored for youth focused on nicotine vaping cessation. Existing cessation programs primarily target combustible tobacco smokers and are less effective or untested in youth who vape exclusively. This gap in clinical therapeutics necessitates robust research into efficacious pharmacologic and behavioral interventions for youth nicotine vaping cessation.

Study Design

This randomized clinical trial was conducted in a single US state from June 2022 to May 2024, enrolling 261 participants aged 16 to 25 years who vaped nicotine daily or near daily but did not regularly smoke tobacco. Inclusion criteria required motivation to reduce or quit vaping. The trial design included three groups randomized in equal proportions (1:1:1): 1) double-blind varenicline group receiving 12 weeks of varenicline titrated to 1 mg twice daily, weekly remotely delivered behavioral counseling, and referral to the “This is Quitting” (TIQ) text messaging support program; 2) double-blind placebo group receiving identical counseling and TIQ referral; and 3) single-blind enhanced usual care group receiving only referral to TIQ.

Primary endpoint was biochemically verified continuous vaping abstinence during the last 4 weeks of treatment (weeks 9-12). Secondary endpoints included continuous vaping abstinence through weeks 9 to 24. Monthly follow-ups extended to 24 weeks to assess sustained cessation.

Key Findings

Among the 261 randomized participants (mean age 21.4 years, 53% female), retention was high at 97.3% completing the trial.

The varenicline group demonstrated significantly higher biochemically verified continuous abstinence rates compared to placebo: 51% vs 14% at weeks 9-12 (adjusted odds ratio [aOR] 6.5; 95% confidence interval [CI], 3.0-14.1; P < .001) and 28% vs 7% at weeks 9-24 (aOR 6.0; 95% CI, 2.1-16.9; P < .001).

Similarly, compared with enhanced usual care, varenicline yielded continuous abstinence rates of 51% vs 6% at weeks 9-12 (aOR 16.9; 95% CI, 6.2-46.3) and 28% vs 4% at weeks 9-24 (aOR 11.0; 95% CI, 3.1-38.8). No significant difference in abstinence was observed between placebo and enhanced usual care.

Safety analyses demonstrated that the medication was generally well tolerated. Treatment-emergent adverse events occurred in 86% of varenicline recipients, 79% in placebo, and 79% in enhanced usual care groups. Discontinuation due to adverse events was low (2% varenicline, 1% placebo), and no drug-related serious adverse events were reported.

These results robustly support the efficacy and safety of varenicline combined with behavioral counseling as an intervention to increase vaping cessation rates among youth.

Expert Commentary

The study addresses a critical unmet need in adolescent and young adult health. Varenicline’s mechanism as a selective nicotinic receptor partial agonist is biologically plausible to attenuate withdrawal symptoms and reduce nicotine cravings, thereby facilitating abstinence. The inclusion of remote behavioral counseling and TIQ support integrates behavioral reinforcement with pharmacotherapy, reflecting contemporary, scalable models of cessation support.

While promising, limitations include restriction to a single US state, which may limit generalizability to other regions or populations with different vaping patterns or social determinants. The reliance on self-selection for willingness to quit may also limit applicability to less motivated vapers. Long-term abstinence beyond 24 weeks remains unexplored.

These findings expand the armamentarium for youth vaping cessation, warranting incorporation into treatment guidelines and further research on optimizing integrated behavioral and pharmacologic approaches.

Conclusion

This randomized clinical trial establishes that varenicline, when combined with behavioral counseling and text support, significantly improves nicotine vaping cessation among youth who vape daily and do not regularly smoke tobacco. The intervention was safe and well tolerated. Given the increasing health concerns associated with adolescent vaping, varenicline offers a valuable therapeutic option that fills a critical gap in cessation services for this population. Implementation of such evidence-based cessation programs could help mitigate the burgeoning public health impact of youth nicotine vaping.

References

Evins AE, Cather C, Reeder HT, Evohr B, Potter K, Pachas GN, Gray KM, Levy S, Rigotti NA, Iroegbulem V, Dufour J, Casottana K, Costello MA, Gilman JM, Schuster RM. Varenicline for Youth Nicotine Vaping Cessation: A Randomized Clinical Trial. JAMA. 2025 Jun 3;333(21):1876-1886. doi:10.1001/jama.2025.3810. PMID: 40266580; PMCID: PMC12019676.

National Academies of Sciences, Engineering, and Medicine. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press; 2018.

U.S. Department of Health and Human Services. Smoking Cessation: A Report of the Surgeon General. Atlanta, GA: CDC; 2020.