PROJECT SUMMARY / ABSTRACT Smoking is the leading cause of preventable disease and death in the U.S. As of 2021, over 30 million U.S. adults reported that they currently smoked cigarettes, and over 16 million Americans suffered from diseases attributed to smoking. Alarmingly, the rise of youth “vaping” is creating a new generation of nicotine-addicted individuals. Indeed, as of 2023, the U.S. Centers for Disease Control and Prevention reported that more than 11% of young adults used e-cigarettes daily. Given the relative success of anti-Tobacco public health policies over the last several decades, the rise of youth vaping is a troubling statistic that could sustain inhaled forms of nicotine dependence for decades to come. Despite the unprecedented and ongoing havoc that cigarette smoking wreaks on U.S. and global public health, our arsenal of FDA-approved smoking cessation therapies is woefully inadequate. It is estimated that over 80% of smokers report a desire to quit smoking, with at least 40% attempting to do so each year. Despite this, there are only three FDA-approved smoking cessation pharmacotherapies. The “gold-standard” treatment – varenicline (Chantix) – is effective in less than 25% of individuals, and ongoing perceptions of severe neuropsychiatric side effects have further limited its acceptance among both healthcare providers and patients. Because of this, it is estimated that a smoker will attempt to quit up to 30 times on average before achieving success. There is a clear and unmet clinical need for more effective smoking cessation therapies. In response to recent calls to action from Key Opinion Leaders and the Biden Administration, including a draft framework from the U.S. Department of Health and Human Services to “promote ongoing and innovative research to support and accelerate smoking cessation,” our goal is to develop a highly structured, multimodal nicotine cessation program with dramatically higher efficacy than the current standard of care. This Phase I proposal is intended to support the development of the novel FDA-regulated pharmacotherapy at the core of our platform.