Significance and Background For the general population of the United States, tobacco use disorder (TUD) is well-recognized to be the leading preventable cause of death1,2. What is not as well appreciated is that in people with HIV (PWH), the prevalence of tobacco use is three times higher compared to the general population, and there is corresponding enhanced morbidity and mortality: TUD has substantial consequences in PWH3,4. While there is appropriate emphasis on sophisticated approaches to enhancing the quality and duration of survival for PWH by using more potent antiretrovirals, immunomodulators, and anti-inflammatory agents, effective treatment of TUD in this population would likely have at least comparable benefit to any of these strategies. More effective use of currently available therapeutic modalities for TUD should be implemented more widely, however, the poor performance of any current approach suggests that new and more effective interventions are needed. A systematic review conducted by our group shows the rates of CVD have tripled in PWH in the last 2 decades, conferring a 2-fold risk for CVD compared to the general population5, and TUD magnifies this risk6,7. Despite the disproportionate morbidity and mortality, PWH are less likely to quit smoking compared to the general population7-9. There is a scarcity of research on effective smoking cessation strategies for PWH10,11, since these individuals were excluded from studies evaluating the efficacy of pharmacologic smoking cessation strategies7,12. One of the few randomized control trials available on PWH and smoking cessation13 demonstrated that the use of varenicline was safe and had a higher rate of smoking cessation in PWH compared to placebo, however, the continued abstinence rate of 18% was significantly lower than the rate of up to 70% in phase III clinical trials of varenicline(which enrolled non-HIV infected individuals)14. The lack of evidence-based, effective smoking cessation strategies and the low smoking cessation rates among PWH highlight the need for novel therapeutic strategies for TUD in order to reduce tobacco-related morbidity and mortality in all populations, including PWH. TUD in DC is disproportionately high compared to other areas in the U.S. According to DC Cohort data (a prospective cohort that is a part of DC PFAP, N=7160), 42.3% are current smokers15, compared to an estimated prevalence of 17.1% in the United States16,17. In 2016, of 6,329 DC cohort participants, 230 (3.6%) had an incident diagnosis of COPD. In addition, the incidence of non-AIDS defining cancers was higher than AIDS-defining cancers in the DC Cohort between 2011 and 201718. The most common cancers were breast, prostate, skin, anal, head/neck, and lung cancer18, all of which are associated with tobacco use19-28. More than 65% of current smokers in the U.S. want to quit smoking29, however, over 50% of those who attempt to quit relapse and begin smoking again within a year30. Predictors of relapse include craving31; during chronic use, craving is mediated by the persistent release of dopamine and recruitment of the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex32. Though this dopamine surge is a central part of addictions, including addiction to nicotine33, the mechanisms of the available FDA- approved pharmacologic therapies do not address the dopamine surge and subsequent craving that is associated with addiction and relapse, thus predisposing to failed quit attempts. Therefore, modulating the CNS dopamine response in order to reduce tobacco craving is an unexplored but important strategy to treat TUD. This proposal aims to assess a novel approach to managing craving for tobacco using ANS-6637, a first-in-class aldehyde dehydrogenase 2 (ALDH-2) inhibitor, which prevents dopamine surge, inhibits craving, and decreases nicotine use in animal models. While this drug is currently in early stage development for opioid use disorder and potentially for alcohol, it is important to recognize that all substance use disorders may not respond identically to one pharmacologic intervention and all patient groups are not identical (e.g. PWH and non-HIV infected), therefore, separate investigations are warranted. It might be thought that this was an obvious target for intramural funding but assiduous efforts with all logical institutes have indicated lack of interest in TUD and HIV, although OAR considers such morbidities to be a priority. We are in close contact with Amygdala Neurosciences in terms of its development plans, and we have a ready population of patients, good data about TUD in Maryland and the District of Columbia, strong links to translational issues with biologic correlates, close ties to the appropriate populations of patients in existing clinics which this group staffs, and a track record of rapid protocol implementation and completion. Our clinics in Baltimore and DC serve low-income African American patients almost exclusively, and this population in particular could derive benefit from a successful treatment strategy, given its rates of TUD and CVD. This study is a collaboration between NIH-CC CCMD, NIH CC PET, University of Maryland Infectious Diseases, District of Columbia Partnership for AIDS Progress, and the University of Maryland Department of Psychiatry.