Nearly 50 million Americans smoke cigarettes, the leading preventable cause of death worldwide. Although most report wanting to quit, few are successful during a given quit attempt even with currently available therapeutics. Of dozens of drugs tested in clinical trials for cessation over the last three decades, only 3 have been approved by the FDA (nicotine replacement, varenicline, bupropion). Additional effective medications are needed to help the majority of dependent smokers succeed in quitting permanently. This application uses a streamlined two-stage approach to evaluate the efficacy of a new compound as a medication for smoking cessation. In the first stage, preclinical feasibility studies will be performed based on highly convincing preliminary data in rodent models that are validated predictors of medications for smoking cessation in humans. These will be followed by the second stage, human clinical Phase 2a studies to detect medication evidence of efficacy for smoking cessation. Abstinence due to medication versus placebo will be compared within a well-validated, innovative procedure for initial test of efficacy. We will also assess the mechanisms through which this medication reverses symptoms of abstinence. These clinical studies benefit from a within- subject crossover design as a high throughput method for predicting therapeutic efficacy of smoking cessation drugs in a highly efficient manner. Moreover, a highly innovative component of this application is to test medication efficacy for smoking cessation in both the broader population of healthy dependent smokers and in smokers with schizophrenia, who have very high rates of smoking but limited therapeutic alternatives to quit smoking. The feasibility of this research is substantial, given the investigators'extensive experience conducting very similar preclinical and clinical research. Results of this application could lead to a new medication to treat nicotine dependence, reducing enormous costs to public health and providing perhaps the first effective treatment for cessation in the most vulnerable smokers.

Public Health Relevance

Cigarette smoking is the leading preventable cause of death in the US. The majority of smokers are unsuccessful at quitting with currently approved cessation therapies, indicating an imminent need for novel therapeutics. Using a two-stage approach that includes preclinical feasibility trials followed by a Phase 2a within-subject crossover design to streamline decisions with increased accuracy, the proposed studies will test an existing industry compound as a novel therapeutic for nicotine/tobacco cessation.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
Application #
Study Section
Special Emphasis Panel (ZTR1-CI-2 (01))
Program Officer
Colvis, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Medicine
United States
Zip Code
Karelitz, Joshua L; Michael, Valerie C; Perkins, Kenneth A (2017) ANALYSIS OF AGREEMENT BETWEEN EXPIRED-AIR CARBON MONOXIDE MONITORS. J Smok Cessat 12:105-112
Perkins, Kenneth A; Roy Chengappa, K N; Karelitz, Joshua L et al. (2017) Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia. Neuropsychopharmacology :
Brunzell, Darlene H; Stafford, Alexandra M; Dixon, Claire I (2015) Nicotinic receptor contributions to smoking: insights from human studies and animal models. Curr Addict Rep 2:33-46
Stafford, Alexandra M; Anderson, Shawn M; Shelton, Keith L et al. (2015) Oral operant ethanol self-administration in the absence of explicit cues, food restriction, water restriction and ethanol fading in C57BL/6J mice. Psychopharmacology (Berl) 232:3783-95
Perkins, Kenneth A (2014) Improving efficiency of initial tests for efficacy in smoking cessation drug discovery. Expert Opin Drug Discov 9:1259-64
Brunzell, Darlene H; McIntosh, J Michael; Papke, Roger L (2014) Diverse strategies targeting ?7 homomeric and ?6?2* heteromeric nicotinic acetylcholine receptors for smoking cessation. Ann N Y Acad Sci 1327:27-45