ABSTRACT Arkansas ranks third in the nation for cigarette smoking prevalence (25% of the population) and ranks second for smoking-attributed cancer mortality (33.5% mortality). More effective interventions for tobacco addiction are needed, and there is an ongoing need for non-nicotine based interventions in particular. For example, nicotine itself may potentially increase the risk of post-surgical complications. The reinforcing effects of nicotine may be due to its effects on glutamatergic transmission, and the use of glutamatergic medications for tobacco addiction has been proposed. A glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, has shown preclinical efficacy in reducing nicotine self-administration, similar to other NMDA antagonists. Furthermore, ketamine has shown promise in reducing craving, withdrawal symptoms, and use of other addictive drugs in humans. However, ketamine’s effects on tobacco use disorder are not yet known and an investigation of its impact on the neuropsychological substrates of tobacco addiction is warranted. While the effects of ketamine on tobacco addiction have not been tested in humans, there is indirect evidence of its potential efficacy to reduce tobacco use. To fill this gap in knowledge, we have begun collecting preliminary data supporting the feasibility and tolerability of ketamine in smokers who complete lab measures of cigarette craving and smoking latency before, and 24 hours after, an infusion of ketamine or placebo. To advance this line of research, we propose a within-subject, cross-over trial of smokers who will receive an infusion of ketamine and an active control drug in counter-balanced order, at least 2 weeks apart. In Aim 1, we will measure changes in craving, tobacco withdrawal, and tobacco use behavior. In Aim 2, we will determine the effects of ketamine on brain function using functional magnetic resonance imaging. The safety, tolerability, and acceptability of ketamine will be assessed using physiological, drug effect, and side-effect measures. This proposal is significant because it will be the first to translate preclinical research on a novel pharmacotherapy for tobacco addiction. This information is valuable because knowing precisely how ketamine disrupts tobacco addiction will help guide future therapeutic use of ketamine or the development of other pharmacotherapies with similar mechanisms of action.