Lara a. Ray, PhD - US grants

DESCRIPTION (provided by applicant): The objective of this Support Opportunity for Addiction Researchers (SOAR) R03 proposal is to integrate laboratory and imaging phenotypes for alcoholism by adding a neuroimaging component to a larger ongoing laboratory-based study of the genetics of subjective responses to alcohol and alcohol craving among alcohol dependent individuals. Specifically, we propose to enroll a subset of participants who complete our laboratory- based study in an imaging component which will characterize the neural bases of alcohol-induced craving. The within-subjects nature of the design will allow us to more directly examine the overlap between laboratory and imaging phenotypes. Importantly, the parent study seeks to further characterize the role of the Asn40Asp allele of the mu-opioid receptor (OPRM1) gene in these laboratory-based controlled phenotypes (i.e., subjective responses to alcohol and alcohol craving), therefore equal numbers of participants with and without the minor allele (Asp40) of the OPRM1 gene will be enrolled (Asn40, n = 10;Asp40, n = 10). As a result, this study will also clarify the role of this important genetic polymorphism by examining it on a neural level of analysis. The long-term objective of this research is to integrate findings across different levels of analysis in order to more fully characterize the neural and genetic bases of important alcoholism phenotypes, which in turn will be used to inform and refine intervention strategies. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to integrate laboratory and imaging phenotypes for alcoholism by adding a neuroimaging component to a larger ongoing laboratory-based study of the genetics of subjective responses to alcohol and alcohol craving among alcohol dependent individuals. The completion of this project will more fully characterize the neural and genetic bases of important alcoholism phenotypes, which in turn will be used to refine intervention strategies.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research seeks to characterize the biobehavioral effects of alcohol by integrating two human laboratory paradigms, namely intravenous (IV) alcohol administration and alcohol cue exposure. Initial reactions to moderate amounts of alcohol (i.e., priming) have been demonstrated to largely determine subsequent drinking and represent a critical decision point between moderate and excessive drinking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cigarette smoking is the leading preventable cause of disease and death in the United States, responsible for approximately 438,000 deaths annually (2005). The federal government s health goal is to reduce the smoking prevalence among adults to less than 12% by the year 2010, although currently 23% of the US adult population continues to smoke (Trosclair et al., 2005).

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To test whether naltrexone reduces sensitivity to the effects of alcohol and alcohol craving among Asian Americans using a controlled alcohol challenge design

DESCRIPTION (provided by applicant): Heavy drinking smokers constitute an important group of treatment resistant individuals. The study proposed herein seeks to add a neuroimaging component to the ongoing pharmacotherapy project in order to elucidate the neural basis of response to promising pharmacotherapies for smoking cessation in heavy drinkers. We propose to enroll a subset (n = 40;10 participants from each medication condition) of heavy drinking smokers randomized to one of the following four medication conditions: (1) varenicline (1 mg twice per day) alone;(2) naltrexone (25 mg once per day) alone;(3) varenicline + naltrexone;and (4) placebo. Participants will be matched on gender, alcohol use, and nicotine dependence severity. The proposed neuroimaging session will assess brain activity in response to smoking and alcohol cues. Based on previous research in this area, we propose to examine the following regions of interest (ROI): striatum, ventral tegmental area / substantia nigra (VTA / SN), orbitofrontal cortex (OFC), medial prefrontal cortex (MPFC), and insula. The neuroimaging paradigms proposed herein will allow us to elucidate the pathways and functional neuroanatomy underlying the effects of a promising combination of pharmacotherapies for smoking cessation. The objective of this program of research is to optimize smoking cessation for heavy drinking smokers, a sizeable and treatment resistant subgroup of smokers. PUBLIC HEALTH RELEVANCE: Heavy drinking smokers constitute an important group of treatment resistant individuals. The proposed study seeks to add a neuroimaging component to an ongoing study of combined medications for heavy drinking smokers in order to elucidate the neural basis of medication response. The proposed work aims to optimize smoking cessation for heavy drinking smokers, a sizeable and treatment resistant subgroup of smokers.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed study seeks to gather pilot data for a grant proposal (R01) seeking to study the mechanisms of action of quetiapine for the treatment of alcoholism

DESCRIPTION (provided by applicant): Methamphetamine (MA) misuse has increased dramatically in the United States during the past decade. Nevertheless, efficacious pharmacotherapies for MA dependence remain elusive despite extensive research on the neurobiology of the effects of amphetamines. Naltrexone (NTX) is an opioid receptor antagonist with empirically supported efficacy and FDA-approval for the treatment of alcoholism. A recent placebo-controlled study has suggested that NTX may be promising for the treatment of amphetamine dependence as it significantly increased abstinence, measured by amphetamine-negative urine samples, compared to placebo. This New Investigator R21 seeks to (a) examine the biobehavioral mechanisms of action of NTX for MA use disorders; and (b) test the pharmacogenetics of NTX for these disorders. We propose to recruit 50 non- treatment seeking individuals who meet criteria for MA dependence. Participant will complete two double- blinded, within-subjects MA administration laboratory sessions, one after taking NTX (50 mg/day) and one after taking placebo for four days. It is hypothesized that NTX will blunt MA-induced reward and craving and will improve response inhibition. In addition, we hypothesize that genetic polymorphisms of the mu, kappa, and delta opioid receptors will be useful in identifying responders to NTX and individual differences in MA-induced reward. The successful completion of this application will provide an initial characterization of the mechanisms of action of NTX among MA abusers and its pharmacogenetics. The long-term objective of this research is to develop and optimize pharmacotherapies for MA dependence by combining behavioral pharmacology and pharmacogenetics to elucidate the mechanisms of action of NTX for MA use disorders and their genetic bases.

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a chronic and relapsing condition affecting 10 million Americans. To date, only four pharmacotherapies are approved by the FDA for the treatment of alcoholism and their efficacy is modest. Therefore, medication development for AD represents a high priority area. Ibudilast (IBUD) is a glial cell modulator that inhibits phosphodiesterases (PDE) -4 and -10 and macrophage migration inhibitory factor (MIF). Preclinical data suggest that neuroimmune modulation is critical to the rewarding properties of drugs of abuse, including alcohol. Further, IBUD has been shown to enhance GDNF release in vivo and GDNF modulation has been implicated in alcohol reinstatement in animals, while PDE inhibition has been shown to reduce alcohol intake in mice. Together, these findings suggest that neuroimmune modulation constitutes a novel target for the treatment of alcoholism. The objective of this Developmental/Exploratory (R21) application is to advance medication development for alcoholism by conducting an initial Phase II study of IBUD for AD. Consistent with our ongoing program of research, human laboratory models are proposed to obtain initial efficacy data and to translate promising preclinical findings. Specifically, the proposed study consists of a randomized, double- blind, placebo-controlled within-subject crossover design to determine the safety, tolerability, and initial human laboratory efficacy of IBUD in a sample of 24 non-treatment seeking individuals with either alcohol abuse or dependence treated with IBUD (50mg BID) and placebo. Participants will complete two separate 7-day inpatient stays at the UCLA CTRC during which they will take the study medication, complete an IV alcohol challenge, and take part in a stress-exposure and cue-exposure paradigms. Specific aims are to test whether IBUD (a) is safe in the context of alcohol administration, (b) attenuates alcohol-induced reinforcement, and (c) dampens stress-induced and cue-induced alcohol craving. In sum, this study will efficiently evaluate safety and initial efficacy of IBUD thereby screening novel medications for AD and elucidating potential mechanisms by which IBUD may be clinically efficacious. Results from this study will inform a subsequent R01 application to conduct a randomized controlled trial of IBUD for alcoholism.

DESCRIPTION (provided by applicant): Recent pharmacogenetic studies have advanced the gene coding for ¿-opioid receptors (OPRM1) gene as a potential moderator of responses to naltrexone. The most widely studied polymorphism of the OPRM1 gene is the Asn40Asp single nucleotide polymorphism (SNP), a functional mutation thought to affect receptor activity such that the Asp40 variant binds ¿-endorphin three times stronger than the Asn40 allele. Recent studies have found that Asp40 carriers have a stronger striatal dopamine response to intravenous alcohol administration and report stronger feelings of alcohol reward. Findings from the COMBINE Study demonstrated that if treated with Medication Management alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of Asn40 homozygotes. While these findings are promising, studies have also highlighted allele frequency imbalance as a function of ethnicity such that the Asp40 allele frequency is approximately 20% in Caucasians, 5% in individuals of African Ancestry, and as high as 50% among individuals of East Asian descent. Therefore, to the extent to which this SNP moderates behavioral and clinical responses to NTX, ethnicity must be carefully considered in order to extend the findings from primarily Caucasian samples to ethnic minorities, such as Asian Americans. Preliminary work by our team has found that among individuals of East Asian descent, Asp40 carriers show greater NTX-induced blunting of alcohol craving as well as potentiation of the aversive effects of alcohol. This pilot study also found support for a gene dose-response, such that Asp40Asp individuals showed greater NTX responsivity than those with the Asn40Asp genotype. The proposed New Investigator R01 seeks to build upon these preliminary findings by testing heavy drinkers of East Asian descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n = 30). Participants will complete two double-blinded, counterbalanced alcohol infusion and self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched placebo for five days. In each medication condition, participants will complete a functional neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural markers of response to naltrexone in individuals of Asian descent, an ethnic group most likely to express the positive predictive allele (Asp40). The long-term objective of this research is to optimize alcoholism pharmacotherapy and to address health disparities by advancing pharmacogenetic studies in ethnic minority groups.

DESCRIPTION (provided by applicant): Both animal and human models of alcoholism etiology have focused on biobehavioral response to alcohol as a potential marker of alcoholism risk vulnerability and disease progression. Alcoholism has been conceptualized in neurobiological models as a transition from positive reinforcement (i.e., drinking to feel good) to negative reinforcement (i.e., drinking not to feel bad or to feel normal), representing a cycl of progressive neurobiological dysregulation. Alcohol administration studies in the human laboratory allow for the translation of preclinical theory to clinical populations through examination of the subjective response to alcohol (comprising stimulation, sedation and tension relieving dimensions) at different levels of drinking status (i.e. heavy drinking or alcohol dependent groups). To date, no studies have used alcohol administration paradigms to translate neurobiological models of alcoholism etiology to clinical populations. The objective of this application is to examine well-established neurobiological theories of alcoholism etiology in the human laboratory. To do so this study combines traditional alcohol challenge and progressive ratio self-administration methodologies to elucidate the relationship between subjective response to alcohol and one's willingness to work for alcohol. In order to model the transition from positively to negatively reinforced alcohol use two groups (n total = 82) will be recruited, a group of non- dependent heavy drinkers and a group of alcohol dependent individuals. An exploratory aim will examine candidate genes subserving the positive and negative reinforcing effects of alcohol. The proposed study extends the alcoholism literature through testing neurobiologically informed hypotheses about the moderating role of drinking status on subjective response to alcohol in the lab and the relationship between subjective response and self-administration of additional alcohol ad lib.

? DESCRIPTION (provided by applicant): There is a strong positive association between cigarette smoking and alcohol use. It is estimated that approximately 20-25% of current smokers are also heavy drinkers. Greater alcohol use is associated with decreased odds of smoking cessation and it is estimated that smokers are 4 times more likely to experience a smoking lapse during drinking episodes. Despite these data, there are no available treatments tailored to heavy drinking smokers, a sizeable and treatment-resistant sub-group. This proposal seeks to address this gap in the literature by conducting a double-blind, randomized clinical trial using three group medication design consisting of VAR alone (1 mg twice daily), NTX alone ( 50 mg once daily), and the combination of VAR (1 mg twice daily) + NTX (50 mg once daily) for smoking cessation and alcohol use reduction in a sample of heavy drinking daily smokers (i.e., individuals who smoke = 10 cigarettes/day and who meet NIAAA guidelines for heavy drinking).The PI has recently completed a laboratory trial with non-treatment seeking heavy drinking which found that the combination of VAR + NTX was superior to monotherapy and to placebo in attenuating nicotine- and alcohol-induced reward during alcohol and cigarette administration in the lab. Further, the combination group significantly reduced cigarette and alcohol consumption during the active medication period, as compared to placebo. Based on the preliminary evidence from our human laboratory trial, this proposal extends these findings to treatment seeking populations by testing the combination of VAR and NTX for smoking cessation among heavy drinking smokers. A total of 411 treatment-seeking heavy drinking smokers will be randomized to (1) VAR only, (2) NTX only, or (3) VAR + NTX. Medication will be titrated over a 14-day period and all participants will receive individual counseling for smoking and drinking and will complete the laboratory testing session prior to the quit day. Smoking abstinence, verified by carbon monoxide (CO) levels and alcohol consumption will be measured at 2, 8, 12, 16, and 26 weeks after quit date. This study will test whether VAR + NTX result in higher rates of point prevalence smoking abstinence at 2, 8, 12, 16, and 26 weeks compared to monotherapy. It will also examine the effects of medication on alcohol use. The secondary aims are to test mechanisms of pharmacotherapy response by examining laboratory markers of nicotine and alcohol response as predictors of treatment outcome. Building upon our previous work, these aims will elucidate the combination of VAR + NTX is superior to monotherapy for alcohol use and smoking cessation in heavy drinking smokers.

DESCRIPTION (provided by applicant): Research on alcohol misuse has provided little definitive evidence about the mechanisms that influence positive behavior change. The difficulty of identifying how people change applies not only to the narrow segment of the population who are treatment seekers, but also to the vast majority of heavy alcohol users who do not seek treatment. Recently, increased attention has been given to the need for cross-disciplinary research that views behavior change as the result of a complex interplay between one's environment, thoughts and behaviors, and brain function. Such research provides new opportunities to identify how people change their alcohol use behavior. This application proposes a multidisciplinary research approach to identify the role of alcohol-related cognitions in positive behavior change among non-treatment seeking heavy alcohol users. The proposed study will attempt to characterize the effects of a behavioral intervention that incorporates components of alcohol screening and a motivation-based brief therapy on perceptions of alcohol-related reward and risk. These interventions are among the most robustly supported by empirical research and a putative mechanism is reduction of the perceived value of alcohol, although this has not been directly investigated. In addition, reward value will be examined using both behavioral and neural indices via functional magnetic resonance imaging (fMRI). No studies to date have used fMRI to characterize alcohol-related mechanisms of behavior change. Participants (n=60) will be randomized to either a single-session behavioral intervention or to an attention-matched health education condition that will not address alcohol use. Alcohol reward value will be characterized using two fMRI paradigms, alcohol cue reactivity and an alcohol purchase task, for a multidimensional assessment. Additional behavioral measures will be used to assess reward and perceived risk. Alcohol reward value and perceived risks will be assessed at baseline and 2 weeks later (immediately after the intervention) using a 2 (baseline/post-intervention) x 2 (active behavioral intervention/control) mixed design. Compared to the control condition, we hypothesize that the active intervention will significantly reduce the value of alcohol, both in behavioral performance and neural activity on both fMRI paradigms. We also hypothesize that the active intervention will significantly increase the perceived risk of drinking It is further hypothesized that decreases in perceived alcohol rewards and increases in perceived alcohol risks will mediate an intervention effect on reducing quantity of alcohol use at 1-month follow-up. Brain regions of interest will include those associated with learning and memory, reward sensitivity and executive function. Findings from this research may significantly further our understanding of the behavioral and neural mechanisms of behavior change in brief alcohol interventions. In turn, the proposed study may inform future efforts to promote positive behavior change among heavy drinkers in the general population.

? DESCRIPTION (provided by applicant): There is a strong positive association between cigarette smoking and alcohol use. It is estimated that approximately 20-25% of current smokers are also heavy drinkers. Greater alcohol use is associated with decreased odds of smoking cessation and it is estimated that smokers are 4 times more likely to experience a smoking lapse during drinking episodes. Despite these data, there are no available treatments tailored to heavy drinking smokers, a sizeable and treatment-resistant sub-group. This proposal seeks to address this gap in the literature by conducting a double-blind, randomized clinical trial using three group medication design consisting of VAR alone (1 mg twice daily), NTX alone ( 50 mg once daily), and the combination of VAR (1 mg twice daily) + NTX (50 mg once daily) for smoking cessation and alcohol use reduction in a sample of heavy drinking daily smokers (i.e., individuals who smoke = 10 cigarettes/day and who meet NIAAA guidelines for heavy drinking).The PI has recently completed a laboratory trial with non-treatment seeking heavy drinking which found that the combination of VAR + NTX was superior to monotherapy and to placebo in attenuating nicotine- and alcohol-induced reward during alcohol and cigarette administration in the lab. Further, the combination group significantly reduced cigarette and alcohol consumption during the active medication period, as compared to placebo. Based on the preliminary evidence from our human laboratory trial, this proposal extends these findings to treatment seeking populations by testing the combination of VAR and NTX for smoking cessation among heavy drinking smokers. A total of 411 treatment-seeking heavy drinking smokers will be randomized to (1) VAR only, (2) NTX only, or (3) VAR + NTX. Medication will be titrated over a 14-day period and all participants will receive individual counseling for smoking and drinking and will complete the laboratory testing session prior to the quit day. Smoking abstinence, verified by carbon monoxide (CO) levels and alcohol consumption will be measured at 2, 8, 12, 16, and 26 weeks after quit date. This study will test whether VAR + NTX result in higher rates of point prevalence smoking abstinence at 2, 8, 12, 16, and 26 weeks compared to monotherapy. It will also examine the effects of medication on alcohol use. The secondary aims are to test mechanisms of pharmacotherapy response by examining laboratory markers of nicotine and alcohol response as predictors of treatment outcome. Building upon our previous work, these aims will elucidate the combination of VAR + NTX is superior to monotherapy for alcohol use and smoking cessation in heavy drinking smokers.

PROJECT SUMMARY/ABSTRACT This application for a Mid-Career Investigator Award (K24) will provide Dr. Ray with the opportunity to continue her career development, mentorship of clinical investigators, and research in medications development for alcoholism. Consistent with the goal of supporting Dr. Ray?s career trajectory in AUD treatment development, the research aims are comprised of projects that will allow her to extend the impact of her research program in the areas of (a) neuroscience, (b) clinical trials, and (c) advanced quantitative methods. The ultimate research goal of the proposal is to integrate basic neuroscience and clinical trials methods to medications development for AUD. The mentoring plan will focus on continued training of undergraduate students, graduate students in clinical psychology, psychiatric residents, postdoctoral fellows, and junior faculty to conduct patient-oriented alcohol research. Dr. Ray will provide training in areas of clinical research methods, data analysis, data interpretation, manuscript preparation, grantsmanship, research ethics, and professional development. Mentoring occurs through Dr. Ray?s active research laboratory, which includes weekly individual and group meetings with trainees. Dr. Ray is active in providing lectures and seminars through multiple training programs at UCLA. In particular, Dr. Ray is committed to mentoring students from underrepresented backgrounds and as a Latina scientist, is sensitive to the issues of diversity in science. Through active participation in multiple programs aimed at diversifying the pool of alcohol scientists, Dr. Ray will broaden her impact in this arena. The training plan consists of coursework and training experiences in areas that are important to her career development as an investigator and mentor, particularly in the topics of basic neuroscience, clinical trials, and advanced quantitative methods. An outstanding group of collaborators has agreed to support Dr. Ray in her training goals. These areas of training and professional development have been selected in synergy with the research aims and ongoing funded-projects in Dr. Ray?s laboratory with the overarching goal of broadening the impact of her research program as well as that of her mentees. In summary, the support of the Mid-Career Investigator Award (K24) will allow Dr. Ray to devote her effort to patient-oriented alcohol research and research mentoring. She will also develop her own skill set through proposed training in basic neuroscience of AUD, clinical trials, and advanced quantitative methods while continuing to actively disseminate research findings along with her mentees through scientific presentations and publications. Through her mentoring, Dr. Ray is committed to training the new generation of patient-oriented alcohol researchers and will prioritize efforts to diversify the pool of junior scientists in the field of alcohol research.

ABSTRACT Alcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function. IBUD inhibits phosphodiesterases -4 (PDE4) and -10 (PDE10) and macrophage migration inhibitory factor. To advance medications development for AUD, our laboratory has recently completed a randomized, double-blind, placebo-controlled crossover laboratory study of IBUD in non-treatment seeking individuals with current AUD (R21 AA022214; NCT02025998). This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50mg BID). Results indicated that IBUD was well tolerated and associated with mood improvements during stress- and alcohol-cue exposures as well as reductions in tonic levels of alcohol craving. Building upon the strong rationale and preclinical findings for IBUD, along with safety data and early efficacy in human testing conducted in our laboratory, this proposal seeks to conduct a 12-week, double-blind, placebo controlled randomized clinical trial of IBUD (50mg BID). We propose to randomize 132 treatment-seeking men and women with current AUD. The primary aims are (a) to test whether IBUD (50mg BID) will decrease percent heavy drinking days (PHDD; HDD defined as 5+ drinks for men and 4+ for women), as compared to placebo, over the course of the 12-week trial; and (b) to test the efficacy of IBUD (50mg BID) on secondary alcohol consumption endpoints, namely (a) drinks per day, (b) drinks per drinking day, (c) percent days abstinent, (d) percent subjects with no heavy drinking days, and (e) percent subjects abstinent, as well as measures of alcohol craving and negative mood, over the course of the 12-week trial. The successful completion of the proposed study will further develop IBUD, a safe and promising novel compound with strong preclinical and safety data for AUD. If IBUD proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.

ABSTRACT This administrative supplement application is intended to support the timely and full completion of the proposed study and to offset delays caused by the COVID-19 Pandemic. As detailed in the application, we have dealt with a host of COVID-19 related delays, while also maintaining the laboratory open and conducting ongoing recruitment to the maximum degree allowed by the UCLA COVID-19 Response and Recovery Task Force. In this administrative supplement, we carefully justify the request for additional resources to effectively complete the original project and mitigate COVID-19 delays in recruitment. Despite the challenges of the COVID-19 pandemic our team has been resilient and hard-working. We have maintained recruitment efforts to the best of our ability and completed 19 randomizations during a full year of COVID-19 disruption. Further, we have kept the protocol integrity and have conducted daily telephone and zoom-based sessions, which enable close contact between participants and study staff. This allowed us to stay consistent with regard to the proposed protocol, provide careful medication management, verify medication compliance, and obtain all necessary clinical safety labs at the beginning of study participation. This administrative supplement will provide much-needed support a high-fidelity protocol that has been kept intact and operational despite substantial challenges associated with the pandemic.

ABSTRACT Alcohol use disorder (AUD), as defined in DSM-5, represents a highly prevalent, costly, and often untreated condition in the United States. Pharmacotherapy offers a promising avenue for treating AUD and for improving clinical outcomes for this debilitating disorder. While developing novel medications to treat AUD remains a high priority research area, there remain major opportunities to further elucidate clinical response in completed medication trials. To that end, a key question in randomized clinical trials (RCTs) is which patients respond to a given pharmacotherapy. Identifying treatment responders provides major opportunities to advance clinical care for AUD by personalizing medication practices on the bases of variables/predictors of good clinical response. For example, while the effect size for medications such as naltrexone is deemed small-to-moderate, a host of studies over the past decade have shown that its effect size may be considerably larger for certain subgroups of patients. Towards advancing precision medicine for AUD and leveraging data from a host of carefully conducted RCTs for AUD, this R03 application seeks to conduct secondary data analysis. Specifically, we propose to analyze data from four RCTs conducted by the NIAAA Clinical Investigations Group (NCIG). These state-of-the-art RCTs for AUD have tested the following pharmacotherapies: (a) quetiapine, (b) Levetiracetam XR (Keppra XR®), (c) Varenicline (Chantix®), and (d) HORIZANT® (Gabapentin Enacarbil) Extended-Release. In this R03 application, we propose to use a machine learning approach to identify treatment responders in the NCIG RCTs. Machine learning represents a highly promising and underutilized data analytic strategy in the field of AUD treatment response. Machine learning models prioritize the ability to predict future outcomes over creating perfectly fitting models for the data at hand. This results in models which are more generalizable to future observations, which fits well with our goal of identifying responders in RCTs. Leveraging data from these pivotal RCTs through secondary data analysis and using novel analytic methods, namely machine learning, provides a cost-effective approach to identifying AUD pharmacotherapy responders.