Aimee McRae-Clark - US grants

DESCRIPTION (provided by applicant): This application for a Mentored-Patient Oriented Research Career Development Award is designed to prepare the candidate for a career in clinical research in drug use disorders with a special emphasis on marijuana use, abuse, and dependence. The training plan involves course work, supervised readings, and "hands on" experience with leading experts in the pharmacology of cannabinoids and the treatment of marijuana dependence. There is a disconnect between the advances in the pharmacology and basic science of cannabinoids and clinical research in this area. By studying both basic science and clinical aspects, the candidate will be well-positioned to design and carry out methodologically sound patient-oriented research with a strong theoretical background. Developing this well-rounded perspective and expertise in the area of cannabinoids and marijuana abuse and dependence is the aim of the training plan outlined. The proposed research project integrates the candidate's experience in conducting pharmacotherapeutic trials with newly developed skills in motivational interviewing. The clinical research that has been conducted in the area of marijuana use and dependence has almost exclusively focused on psychotherapeutic interventions, including motivational interviewing. However, recent neuroscientific advances, such as the discovery of the cannabinoid receptors, suggest that pharmacotherapeutic strategies for treating marijuana dependence should be explored in conjunction with psychotherapeutic interventions. As anxiety may play a key role in marijuana abuse anxiolytic medications in particular may prove useful in reducing marijuana use. The hypothesis to be tested in the proposed research project is whether buspirone, an anxiolytic medication, will increase efficacy in reducing marijuana use in marijuana-dependent patients when delivered with motivational interviewing. The study will be a 12-week, randomized, double-blind, placebo-controlled trial evaluating a flexible dose of buspirone or placebo in combination with motivational interviewing. The primary outcome measure will be marijuana use as assessed by self-report and weekly urine drug screens. The results of this study will help guide future directions for research in the area of marijuana dependence.

[unreadable] DESCRIPTION (provided by applicant): Marijuana dependence is a significant problem in the United States today. It is critical to expand the investigation of treatment options for patients with marijuana use disorders. Attention deficit hyperactivity disorder (ADHD) commonly co-occurs in patients with marijuana use disorders, and comorbid substance use disorders have been shown to worsen treatment outcomes. Dopamine dysfunction is a hypothesized link between ADHD and substance use disorders, and it has been postulated that illicit substances may be used by individuals with ADHD to overcome a relative lack of dopamine transmission. Preliminary studies suggest that the use of medications that increase dopaminergic levels may improve substance use outcomes in these patients. The first-line treatment of ADHD is stimulant medications. However, there has been concern about the use of stimulants in individuals with substance use disorders because of the abuse potential of these agents. This R21 application proposes to explore the treatment of adult patients with comorbid marijuana dependence and ADHD with atomoxetine, a recently approved non-stimulant ADHD medication. Subjects will receive treatment with either atomoxetine or placebo for 12 weeks combined with brief motivational enhancement therapy. Measures of marijuana use and craving and ADHD symptomatology will be collected. The specific aims of this project are to gather preliminary data on the safety and efficacy of atomoxetine in reducing marijuana use in adult patients with comorbid ADHD and marijuana dependence, and to preliminarily evaluate the efficacy of atomoxetine in reducing ADHD symptoms in this population. The proposed work is novel in that little clinical research has focused on marijuana-dependent patients with ADHD, and no work has been published examining the safety, tolerability, or efficacy of atomoxetine inpatients with this comorbidity. The project is designed to increase our knowledge of treatment options for patients with marijuana dependence, an area which has been under investigated. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Marijuana is the most commonly used illicit drug in the United States. Although its use and potential health consequences are widespread and the basic science research on cannabinoids is well developed, little research has focused on the clinical treatment of marijuana use disorders. One area of importance in the study of substance use disorders is relapse. Several risk factors have been recognized as critical in the elicitation of craving and drug-seeking, such as exposure to drug-related cues or experiencing negative emotional stimuli. Although these factors have been explored in other substance use disorders, little research has focused on drug cue-related or stress- induced relapse in marijuana dependent individuals. The proposed R-21 project will investigate the effects of marijuana cues, stress and their interaction in a clinical laboratory paradigm. Specifically, HPA axis (ACTH, cortisol), physiologic (heart rate, blood pressure, skin conductance) and subjective responses to an acute stress (Trier Social Stress Test) or no stress condition followed by the presentation of marijuana- related cues will be investigated in marijuana-dependent individuals. It is predicted that stress exposure will potentiate the response to drug-related cues. This project is designed to extend our ongoing research in the area of cue- and stress-related reactivity in drug-dependent individuals to the area of marijuana dependence. Exploration of potential precipitants of relapse can have important implications for prevention and treatment of marijuana dependence. Marijuana is the most commonly used illicit drug, yet little is known about factors that may precipitate relapse to marijuana use. The interaction of stress and cues has not been systematically investigated although this paradigm closely mirrors real-life situations. Results from this novel study will address how stress impacts other relapse risk factors, and may help direct future treatment studies in which therapies are directed to reduce stress-potentiated craving to cues in marijuana-dependent individuals. [unreadable] [unreadable] [unreadable]

3beta-Hydroxyandrost-5-en-17-one; 5-Androsten-3-beta-hydroxy-17-one; 8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; Acute; Addiction, Cocaine; Aeroseb-HC; Androst-5-en-17-one, 3-hydroxy-, (3beta)-; Androstenolone; Arousal; Blood Serum; CRISP; Cetacort; Clinical Research; Clinical Study; Cocaine; Cocaine Dependences; Computer Retrieval of Information on Scientific Projects Database; Condition; Corpus Luteum Hormone; Cort-Dome; Cortef; Cortenema; Cortisol; Cortispray; Cortril; Cues; DHEA; Dehydroisoandrosterone; Delta4-pregnene-3,20-dione; Dependences, Cocaine; Dermacort; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Eldecort; Equilibrium; Estrogenic Agents; Estrogenic Compounds; Estrogens; Funding; Grant; Hydrocortisone; Hydrocortone; Hytone; Institution; Investigators; Measurement; Measures; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nutracort; PBO; Participant; Physiologic; Physiological; Placebos; Prasterone; Pregn-4-ene-3,20-dione; Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11beta)-; Pregnenedione; Proctocort; Progesterone; Research; Research Personnel; Research Resources; Researchers; Resources; SCHED; Salivary; Schedule; Serum; Sham Treatment; Source; Testing; Therapeutic Dehydroepiandrosterone; Therapeutic Estrogen; Therapeutic Hydrocortisone; Therapeutic Progesterone; United States National Institutes of Health; Woman; Yohimban-16-carboxylic acid, 17-hydroxy-, methyl ester, (16alpha,17alpha)-; Yohimbine; balance; balance function; corynine; craving; day; dehydroepiandrosterone; men; men's; quebrachine; response; sham therapy

DESCRIPTION (provided by applicant): Marijuana is the most commonly used illicit drug in the United States. Although its use and potential health consequences are widespread and basic science research on cannabinoids is well developed, little research has focused on the clinical treatment of marijuana use disorders. Buspirone, a partial serotonin 1-A (5-HT1A [5-hydroxytryptamine1A]) receptor agonist, has shown promise for reducing marijuana use in preliminary trials. Accordingly, we propose a double-blind randomized trial of buspirone in marijuana-dependent individuals. A contingency management (CM) intervention coupled with motivational enhancement therapy (MET) will be incorporated to encourage study engagement and retention. We hypothesize that individuals who receive buspirone treatment combined with MET and CM will have improved marijuana use outcomes compared to individuals receiving a placebo treatment combined with MET and CM. Further, as genetic variations in 5-HT1A receptors have been identified, and may alter the response to buspirone, we propose to extract genomic DNA to characterize subjects according to polymorphisms of genes relevant to 5-HT1A receptor activity. We hypothesize that individuals with functionally deficient 5-HT1A receptors will have poorer treatment outcomes than individuals without functional deficiency at the 5-HT1A receptor. Finally, as a reliable assessment of compliance is critical to interpretation of outcome measures, we propose as a secondary aim to develop and validate an assay of a major metabolite of buspirone (6-hydroxy-buspirone) to measure compliance with treatment. Results from this study could lead to the development of a new pharmacotherapy for marijuana dependence, increase our knowledge of a potential genetic biomarker for prediction of outcomes, and improve clinical trial methodology in the investigation of marijuana dependence. . PUBLIC HEALTH RELEVANCE: Marijuana is the most commonly used illicit drug, yet few clinical trials have evaluated pharmacotherapy treatments for marijuana dependence. This study will evaluate the efficacy of buspirone for reducing marijuana use in marijuana-dependent adults. A contingency management intervention and motivational enhancement therapy will be incorporated to encourage study engagement and retention. An assay determining serum levels of a major metabolite of buspirone will be employed to measure compliance, and genomic DNA will be extracted to characterize subjects according to polymorphisms of genes potentially relevant to the activity of buspirone.

DESCRIPTION (provided by applicant): Marijuana is the most commonly used illicit drug in the United States. Although its use and potential health consequences are widespread and basic science research on cannabinoids is well developed, little research has focused on the clinical treatment of marijuana use disorders. Preclinical and clinical studies implicate cannabinoid interactions with the serotonin system. Vilazodone, a compound combining serotonin reuptake inhibition and 5-HT1A partial agonism, has recently become available. Given its dual serotonergic mechanism of action, vilazodone may have promise as a treatment for marijuana dependence. Therefore, we propose to conduct a randomized, placebo-controlled trial of vilazodone in marijuana-dependent adults. A contingency management intervention coupled with motivational enhancement therapy will be incorporated to encourage study engagement and retention. Further, genomic DNA will be extracted to characterize subjects according to polymorphisms of genes relevant to the 5-HT1A receptor activity, specifically the C-(1019) G variant. We hypothesize that individuals who receive vilazodone treatment combined with MET and CM will have improved marijuana use outcomes compared to individuals receiving a placebo treatment combined with MET and CM. Further, as genetic variations in 5-HT1A receptors have been identified, and may alter the response to vilazodone, we propose to extract genomic DNA to characterize subjects according to polymorphisms of genes relevant to 5-HT1A receptor activity. We hypothesize that individuals with functionally deficient 5-HT1A receptors will have poorer treatment outcomes than individuals without functional deficiency at the 5-HT1A receptor. Results from this study could lead to the development of a new pharmacotherapy for marijuana dependence and increase our knowledge of a potential genetic biomarker for prediction of outcomes. . PUBLIC HEALTH RELEVANCE: Marijuana is the most commonly used illicit drug, yet few clinical trials have evaluated pharmacotherapy treatments for marijuana dependence. This study will evaluate the efficacy of vilazodone for reducing marijuana use in marijuana-dependent adults. A contingency management intervention and motivational enhancement therapy will be incorporated to encourage study engagement and retention, and genomic DNA will be extracted to characterize subjects according to polymorphisms of genes potentially relevant to the activity of vilazodone.

DESCRIPTION (provided by applicant): Drug abuse and addiction are devastating and chronic conditions that place a significant medical, financial, legal and social burden on our country. Interdisciplinary collaboration combined with technical advances has resulted in unprecedented opportunities to enhance addiction treatment efficacy and durability, and reduce vulnerability to addiction. Continued progress is vital to improving existing evidenced-based treatments and developing new treatments. It is therefore critical to attract and train clinical researchers in order to ensure that a diverse pool of highly skilled scientists will be available t address these urgent health care needs. Dr. Aimee McRae-Clark is a productive mid-career investigator who has maintained consistent NIH funding for her innovative work in the area of medications development and gender differences in addictions. In addition, she has a strong track-record of attracting and successfully mentoring medical, graduate and post-doctoral students as well as junior faculty in clinical research focused on substance use disorders. The objective of this Midcareer Investigator Award in Patient-Oriented Research is to provide support for protected time so that Dr. McRae-Clark can develop a more formal, intensive program of mentored clinical research training and career development activities to promote junior scholars in the area of drug abuse and addiction. Particular emphasis will also be placed on increasing the participation of underrepresented minorities conducting patient-oriented research. In addition, she will build on her existing program of research by incorporating new proficiencies and research directions, including advanced biostatistical methods and exploration of the role the endogenous cannabinoid system plays in stress response. This award will enable her to increase the time she is able to devote to mentorship, to consolidate her training activities, and take her research activities in new and exciting directions.

ABSTRACT Cannabis is the most commonly used illicit drug in the United States. Although cannabis use is widespread and basic science research on cannabinoids is well-developed, advancements in medication development for cannabis use disorder (CUD) have been limited. Varenicline, a selective nicotinic nACH receptor partial agonist of the ?4?2 subtype and a full agonist of the ?7 subtype, is arguably the most effective pharmacotherapy for promoting tobacco abstinence, and has also shown promise for the treatment of alcohol use disorder. Varenicline may improve cannabis use outcomes through multiple mechanisms, including interaction with the mesolimbic dopamine system, enhancement of cognitive functioning, and restoration of inhibitory control. To date, however, varenicline has not been evaluated in individuals specifically seeking treatment for CUD. In this UG3/UH3 application, we propose to rapidly yet thoroughly assess the utility of varenicline for CUD to potentially advance varenicline through the FDA's drug development approval pipeline. In the UG3 component, we will conduct a six-week, placebo-controlled proof-of-concept clinical trial of varenicline for CUD, paired with pre- and post- evaluations of cognitive functioning and neural circuitry involved in cannabis cue reactivity and inhibitory control to elucidate the pharmacodynamics of varenicline as a treatment for CUD. If milestones of the UG3 component are met, the UH3 project will be an adequately powered 12-week clinical trial with follow-up to fully assess the efficacy of varenicline in this population.

? DESCRIPTION (provided by applicant): Social stress can lead to drug craving and relapse in cocaine-dependent (CD) individuals. In addition, CD individuals often favor drug use over social interactions. Moreover, social avoidance and lack of trust are significant obstacles to effective treatment. Currently, there are no FDA approved medications for the treatment of cocaine dependence and behavioral interventions have had limited success in sustaining abstinence. Data from human neuroimaging studies using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) suggest that top-down prefrontal cortical control of amygdala reactivity to social stimuli plays an important role in mediating emotion related behavior. Dysregulation in the functional connectivity between the prefrontal cortex and amygdala has been found in CD subjects at rest and attenuated corticolimbic functional connectivity was associated with a shorter time to relapse. Thus, dysregulation in corticolimbic network activity may underscore the vulnerability of CD individuals to social stress. In addition, interventions that restore functional connectivity between the prefrontal cortex and amygdala, and attenuate bottom-up amygdala drive may reduce anxiety and improve treatment outcomes for CD individuals. Oxytocin (OT) is an anxiolytic neuropeptide that reduces amygdala reactivity to aversive social cues. In addition, OT increases functional connectivity between the amygdala and prefrontal cortex in patients with generalized social anxiety disorder. The broad and long-term objectives of this proposal are to (1) to identify the neurobiologic mechanisms that control emotional responses to social stimuli in CD individuals and (2) use these data to facilitate the development of effective therapeutic treatments and preventative strategies for behavioral disorders and disease. To meet these objectives we propose two specific aims: Specific Aim 1: To determine the impact of cocaine dependence and oxytocin on functional connectivity between corticolimbic brain regions during acute social stress. Specific Aim 2: Use an implicit facial affect recognition paradigm to determine the impact of cocaine dependence and oxytocin on amygdala activity in response to fearful faces. The BOLD signal measured during neutral faces will be subtracted from the BOLD signal measured during fearful faces. To address the hypotheses associated with Specific Aims 1 and 2 we propose a we propose a double-blind placebo (PBO) controlled study using BOLD fMRI to measure (1) corticolimbic functional connectivity during the Montreal Imaging Stress Task (MIST) and (2) amygdala activity in response to an implicit facial affect recognition paradigm in groups of CD individuals (CD n=80) and healthy non-dependent controls (HC, n=80). Prior to the scanning session, participants will receive either intranasal OT (24 IU) or PBO spray (n=40 per treatment group). Psychophysiologic interaction (PPI) analysis using the amygdala as the seed region will be used to assess significant task (stress condition > control condition) x seed interactions. Subjective anxiety and craving data will be collected at baseline and after each run of the MIST. The order of the tasks will be counterbalanced.

ABSTRACT This renewal application from the Medical University of South Carolina (MUSC) requests support for the continuation of the NIDA Mentored Clinical Scientists Development Program in Drug Abuse and Addiction (NIDA K12) at MUSC. Established in 2012, the overall objective of the NIDA K12 program was to establish an intensive program of mentored clinical research training and career development activities to promote Scholars' research independence in the area of drug abuse and addiction. The substantial expertise in addictions research at MUSC ensures our ability to mentor individuals in early stages of their research careers to contribute significantly to the understanding and treatment of substance use disorders. In the initial funding period, infrastructure of a strong mentorship development program was established, and participating Scholars have had significant success in obtaining independent federal funding. This application requests support to build on these early programmatic successes by making innovative changes to strengthen the K12 program. Specifically, we will focus on providing novel training opportunities and hands-on experience to promote addiction team science among our K12 Scholars, as well as increase opportunities for training in areas such as mHealth, biomedical imaging, public health, and biomedical informatics. Additionally, in keeping with the mission of NIDA, emphasis during the renewal funding period will continue to be placed on attracting and training clinical researchers to ensure that a diverse pool of highly trained scientists will be available to address the Nation's critical health care needs in the area of drug abuse. The renewal of the NIDA K12 program would allow us to continue to meet the urgent need to extend the addictions research training potential to faculty-level trainees at MUSC, and to continue our synergistic work with existing programs on campus to attract and promote faculty development in clinical research focused on addictions throughout the educational continuum.

ABSTRACT Important sex differences exist in the behavioral, biologic, and clinical correlates of cannabis use disorder (CUD); these sex differences are critical to consider in CUD treatment development. In particular, stress may be an important intervention target for women using cannabis, as multiple studies have shown that women use cannabis for coping and tension reduction more than men and are more likely to crave cannabis following stress. Ovarian hormones have been identified as potential mechanisms of these stress-related disparities, and recent clinical trials have begun to examine progesterone's utility as a possible pharmacotherapeutic agent in addictive disorders. While progesterone has shown promise as a treatment for women with cocaine and tobacco use disorders, it has not yet been tested in cannabis users. We propose to evaluate the impact of progesterone on stress reactivity and cannabis use in 140 cannabis using individuals (70 men and 70 women). Participants will complete a 3-week protocol combining naturalistic and laboratory-based methodologies. During the first week, participants will be compensated to remain abstinent and will be randomly assigned to receive either daily progesterone (200 mg twice daily) or matching placebo; additionally, stress and neutral cues will be delivered to their mobile devices and they will also collect daily saliva samples for progesterone measurement. On the first day of the second study week, participants will be exposed to a standardized laboratory stressor (Trier Social Stress Task) to assess the effects of exogenous progesterone vs placebo on stress reactivity. At the completion of the laboratory procedures, participants will no longer be compensated for abstinence but they will use their mobile device to respond to stress and neutral cues, monitor stress/craving levels, and report cannabis use (three times daily) for the next fourteen days. Throughout these two weeks, ovarian hormone levels will continue to be collected daily (via saliva samples) to evaluate their impact on stress and cannabis use. The proposed study has significant synergies with Projects 2 and 3, utilizing similar assessment and pharmacologic interventions, respectively. Presently, little is known about sex differences in CUD; this study has the potential to expand that knowledge landscape. Importantly, this project will also assess the effects of exogenous and endogenous progesterone on the challenges posed by initial abstinence and/or daily stress, which could directly inform gender-specific treatment development for CUD.

ABSTRACT The Leadership Administrative Core (LAC) is the backbone of the MUSC SCORE operations. As it has in previous funding periods, the LAC will continue to provide the organizational framework for addressing emergent issues, budgetary concerns and daily operations within the SCORE. It will also ensure the integration of the SCORE within MUSC, with local and statewide officials and community treatment centers, and across the national consortium of SCOREs. The LAC will (1) provide fiscal and administrative management for all program components; (2) provide scientific and programmatic leadership; (3) manage the SCORE Pilot Project Program; (4) support campus-wide, regional, and national cross-SCORE collaborations; and (5) oversee the SCORE Evaluation Program. During the next funding period, the LAC will build on its previous successes to expand the MUSC SCORE's functionality as a valuable regional and national resource on sex and gender differences in addictive disorders through establishment of a Women's Health Research Consortium, expansion of MUSC's Women's Health Research Day, and strategic partnership with statewide treatment providers.

ABSTRACT The MUSC Specialized Center of Research (SCOR) on sex/gender differences in addictive disorders and the relationship between stress and relapse has been highly productive for 15 years. In addition to coalescing a multidisciplinary group of investigators across different disciplines working closely together to explore sex and gender differences in addictions and the relationship between stress and drug use, the MUSC SCOR has provided a fertile training ground for new investigators and attracted senior investigators to apply their skills to sex- and gender-specific research. During the proposed renewal period, we will transition to a Specialized Center of Research Excellence (SCORE). We will continue to reach across campus and also extend our reach to nationwide, cross-SCORE collaborations and community-based initiatives focused on dissemination of research findings to improve health outcomes. The science within our research group also will grow with three tightly integrated research projects, new investigators and innovative technologies. To address critical public health needs, the proposed research projects will investigate sex differences in cannabis and opioid use disorders and directly inform addiction treatment development. The specific aims of this SCORE are to support and enhance translational scientific collaborations among the investigators conducting primary and pilot research projects, catalyze further growth of interdisciplinary sex- and gender-based research on the MUSC campus, expand foundational research training for Early Career Investigators dedicated to sex and gender-focused translational research, and develop strategic partnerships to enhance the translation and dissemination of SCORE findings and other relevant research to improve health outcomes.

PROJECT SUMMARY Cocaine use disorder (CUD) is among the few substance use disorders without an effective pharmacotherapy. One hypothesized mechanism contributing to the intransigence of CUD is the dysregulation of brain iron homeostasis. Iron homeostasis is a critical biological mechanism that has been largely overlooked in addiction research. Corroborating a previous report, our group recently demonstrated that brain iron is significantly elevated in non-treatment seeking individuals with CUD. However, while elevated brain iron has been associated with cognitive decline in aging and disease severity in neurodegenerative diseases, the neurobiological and clinical relevance in CUD remain unknown. The goal of this project is to establish the impact of brain iron dysregulation in CUD. We propose to investigate whether elevated brain iron in CUD contributes to disease severity as defined by measures that have been associated with poor treatment outcome: aberrant neural microstructure within the executive control and limbic arousal neural networks and behavioral and cognitive deficits. We will accomplish this utilizing advanced, quantitative MRI methods that are sensitive and specific for brain iron and neural microstructure, in which our group has particular expertise, focusing on cognitive measures consistently found as aberrant in CUD. The overall hypothesis of this project is that, by increasing the risk of oxidative damage and cell death, excess buildup of brain iron in CUD contributes to compromised neural microstructure within brain networks implicated in the disorder and are associated with behavioral and cognitive deficits in executive control and reward-based decision making. Demonstrating the adverse impact of elevated brain iron in CUD would establish brain iron dysregulation as a promising therapeutic target for future studies of CUD.

PROJECT SUMMARY/ABSTRACT Cannabis use disorder (CUD) is prevalent and associated with significant clinical sequelae. Effective treatment for CUD may be complicated by gender and sex differences in the behavioral, biological, and clinical correlates of CUD. Women demonstrate more severe withdrawal, more rapid progression from first use to CUD, and greater likelihood of comorbid psychiatric disorder, while men tend to initiate use earlier and have higher lifetime prevalence rates of CUD. In other addictive disorders, such as alcohol use disorder, clinical trial endpoints are sex/gender specific. However, to date, no work has focused on whether different clinically relevant endpoints may be needed for men and women with CUD. An expert workgroup recently concluded that reduced cannabis use is a viable alternative endpoint to abstinence in CUD trials, particularly in the context of changing patient preferences and growing cannabis legalization. However, the amount of reduction necessary for remission from CUD is unknown and may differ for men and women. An emerging literature suggests that ovarian hormones play a key role in drug use. Preclinical and clinical research suggests that endogenous progesterone attenuates drug sensitivity and behavior. Recent clinical studies investigating exogenous progesterone as a potential pharmacotherapy have shown that it attenuates the subjective and physiological effects of cocaine and tobacco in drug-dependent individuals. Presently, little is known regarding the interface of progesterone and CUD, and if fluctuations in progesterone levels may impact ability to reduce cannabis use. This proposal addresses a key gap in CUD treatment research by empirically-deriving the threshold of cannabis quantity and frequency of use below which most individuals in CUD treatment can achieve CUD remission. Importantly, the roles of gender and ovarian hormones in CUD outcomes are considered and gender-specific endpoints will be derived. Treatment-seeking adults who meet criteria for CUD (N=224, ages 18+, 50% female) will receive 8 weeks of a psychosocial intervention, including computerized CBT4CBT. CUD symptoms and detailed information on cannabis use will be collected from participants during the 8-week treatment period and during a three month follow-up (1, 2, and 3 month follow-up visits). Participants will complete daily electronic diaries to enhance assessment of self-reported cannabis quantity and frequency of use, corroborated by weekly assessment of a urinary cannabis metabolite, 11-nor-9-carboxy- ??-tetrahydrocannabinol. Daily saliva samples will be collected for assessment of progesterone. Analyses will examine whether the threshold for cannabis reduction necessary to achieve remission from CUD differs by gender and the effect of variation in progesterone on successful cannabis reduction. The establishment of gender-specific reduction endpoints will have both real-world clinical treatment implications as well as enable future studies to rigorously test promising candidate treatments for CUD.

ABSTRACT The MUSC Specialized Center of Research (SCOR) on sex/gender differences in addictive disorders and the relationship between stress and relapse has been highly productive for 15 years. In addition to coalescing a multidisciplinary group of investigators across different disciplines working closely together to explore sex and gender differences in addictions and the relationship between stress and drug use, the MUSC SCOR has provided a fertile training ground for new investigators and attracted senior investigators to apply their skills to sex- and gender-specific research. During the proposed renewal period, we will transition to a Specialized Center of Research Excellence (SCORE). We will continue to reach across campus and also extend our reach to nationwide, cross-SCORE collaborations and community-based initiatives focused on dissemination of research findings to improve health outcomes. The science within our research group also will grow with three tightly integrated research projects, new investigators and innovative technologies. To address critical public health needs, the proposed research projects will investigate sex differences in cannabis and opioid use disorders and directly inform addiction treatment development. The specific aims of this SCORE are to support and enhance translational scientific collaborations among the investigators conducting primary and pilot research projects, catalyze further growth of interdisciplinary sex- and gender-based research on the MUSC campus, expand foundational research training for Early Career Investigators dedicated to sex and gender-focused translational research, and develop strategic partnerships to enhance the translation and dissemination of SCORE findings and other relevant research to improve health outcomes.