Using Vagal Nerve Stimulation in Conjunction with NRT for Smoking Cessation - PROJECT SUMMARY This research proposal aims to evaluate vagal nerve stimulation (VNS) as a novel treatment for Tobacco Use Disorder (TUD), targeting improved smoking cessation rates. Cigarette smoking remains a major public health issue, leading to over 400,000 premature deaths annually in the U.S. and contributing to diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), and heart disease. Despite widespread awareness of the risks and a strong desire to quit, many smokers are unsuccessful in their attempts, with only a small percentage achieving long-term abstinence. Current FDA-approved treatments—nicotine replacement therapy (NRT), varenicline, bupropion, and transcranial magnetic stimulation (TMS)—offer limited success in terms of efficacy and accessibility. There is a clear need for more effective and accessible treatments to support smoking cessation in TUD. This study's innovation lies in exploring VNS as a neuromodulation technique for treating TUD. Preclinical studies suggest that the vagal nerve is involved in addiction pathways, making it a promising target for smoking cessation interventions. This study will be the first to test VNS as a treatment for TUD using a non-invasive, handheld, and portable device, addressing key barriers to existing therapies like TMS, which requires specialized centers, and surgically implanted VNS devices. By using a pragmatic, decentralized clinical trial (DCT) approach, the study will combine VNS with existing pharmacotherapies, such as NRT and varenicline, to enhance smoking abstinence rates. The proposed phase-II randomized, double- blind, parallel-group clinical trial will assess the efficacy of NRT plus active VNS versus NRT plus sham VNS in smokers. Participants will receive 12 weeks of nicotine patch treatment combined with VNS, with an additional 12 weeks of varenicline and VNS for those who do not achieve abstinence. The trial will utilize remote carbon monoxide (CO) monitoring and telehealth visits to create a fully decentralized clinical trial environment, allowing for a patient-centered approach. Recruitment will occur through the Mayo Clinic’s Nicotine Dependence Center, leveraging our extensive experience in smoking cessation research. The primary endpoint of the study is biochemically confirmed smoking abstinence at 12 weeks, with secondary outcomes including prolonged abstinence at 24 and 26 weeks. This trial aims to provide preliminary evidence for the efficacy of combining VNS with NRT and varenicline, potentially leading to large-scale trials and FDA approval of VNS as a viable treatment for TUD. If successful, this research could add a novel, effective, and accessible therapy to the limited treatment options currently available for smokers attempting to quit.
