Stephen T. Higgins - US grants

Most drug abusers use alcohol in addition to their primary drug of abuse, yet little is known about the behavioral pharmacology of such combinations. The specific purpose of this project is to experimentally analyze in human volunteers the behavioral and physiological effects of prototypical stimulant drugs of abuse in combination with alcohol. The acute effects of varying doses of cocaine, damphetamine nicotine and caffeine will be examined in combination with alcohol under controlled laboratory conditions. The following routes of drug administration will be used: cocaine, intranasal and oral; d-amphetamine, oral; nicotine, oral; caffeine, oral; alcohol, oral. Two experiments using withinsubject repeated-measures designs are proposed for each of the stimulantalcohol combinations. First, the direct effects of each stimulant and alcohol will be determined alone and in combination on behavioral measures (repeated acquisition of behavioral chains, digit symbol substitution task, circular lights) selfreport (Addiction Research Center Inventory, visualanalogue scales) and physiological measures (pupil diameter, cardiovascular measures). Second, the effects of pretreatment with varying doses of the stimulant compounds on alcohol selfadministration will be examined. The studies proposed in this application will provide the first experimental investigations of stimulant-alcohol combinations in humans where (a) doses of both compounds are varied alone and in combination, (b) behavioral, selfreport, and physiological measures are obtained, and (c) effects on drug selfadministration are examined. Results from these studies will contribute to our basic understanding of the human behavioral pharmacology of acute stimulantalcohol interactions and provide important practical information concerning the behavioral and physiological toxicity of such combinations.

Many abused drugs share a common, acute effect of increasing rates of social interaction, especially conversation. This capacity to facilitate social interaction could be an important component of the widespread appeal of abused drugs (i.e., reinforcing effects). To date, little is known about how or why this effect occurs. The present project will investigate the following hypothesis: Abused drugs facilitate social behavior by increasing the reinforcing efficacy of social interaction. To test this, acute doses of cocaine, d-amphetamine, alcohol, secobarbital and marijuana will be administered to volunteers using two experimental procedures: The first procedure is a two- component multiple schedule. In one component of the schedule, the opportunity to earn money will be available via a fixed-ratio schedule. In the other component of the schedule, the opportunity to socialize will be available via the same schedule. If our hypothesis is correct, response rates in the social component should increase as a function of drug. The selectivity of drug effects on social interaction will be assessed by comparing the effects of the drug on responding in the social and monetary components. The second procedure will be a discretetrial choice procedure. Subjects will make a series of mutually exclusive choices between the monetary and social conditions described above. If our hypothesis is correct, preference for the social option should increase as a function of drug. This grant will 1) provide new and important information on the mechanisms involved in the interaction of abused drugs and social behavior, 2) compare and contrast the effects of abused drugs on the reinforcing function of two important aspects of human behavior (socializing & earning money) and 3) improve our understanding of the relationship between behavioral and reinforcing effects of drugs.

Intravenous (IV) drug users comprise the second largest risk group for AIDS. Recent evidence indicates that IV cocaine use may present a greater risk for AIDS that IV opioid use. Although several treatments for cocaine dependence look promising, controlled studies documenting effective treatments are rare. The proposed studies will develop and validate a behavioral intervention for IV cocaine dependence. All of the studies will involve parallel-group comparisons with random assignment. The behavioral intervention consists of contingency contracting and community reinforcement of abstinence and prosocial behavior. In Study 1 this behavioral treatment will be compared to a standard psychotherapy for cocaine dependence. If the behavioral treatment is more effective than the standard treatment, a component analysis of the behavioral intervention will be conducted comparing the complete behavior intervention vs contingency contracting alone vs community reinforcement alone (Study 2a). If the behavioral treatment is not more effective than standard treatment, it will be revised to include more potent consequences in the contingency contract and compared again to the standard treatment (Study 2b). Finally, we will assess whether the efficacy of our behavioral intervention is enhanced via the addition of desipramine (Study 3). Patients will receive either the behavioral intervention plus desipramine or behavioral intervention plus placebo. All studies will be conducted in an outpatient clinic, although brief inpatient detoxifications will be conducted as needed. Duration for all treatments will be 3 months. Outcome will be measured by (1) urinalysis to validate abstinence during treatment and longer-term abstinence (6 months), (2) patient acceptability of treatment, (3) improvement in marital, family, occupational, and legal status, and (4) changes in AIDS risk behaviors. These studies will provide new information on the efficacy of behavioral interventions with cocaine dependence, demonstrate whether the efficacy of such interventions is enhanced by adding pharmacotherapy, and provide new, sorely needed treatment opportunities for IV cocaine addicts in Vermont.

The vast majority of cocaine abusers, including those enrolled in drug abuse treatment, regularly use and abuse other drugs. Unfortunately, little scientific information is available indicating how such other drug use and abuse may influence the probability of cocaine use. This absence of information prevents clinicians from making empirically-based recommendations regarding the likely influence of other drug use on the course of cocaine abuse. The purpose of the research proposed in this application is to begin to address this important issue by experimentally analyzing the influence of other drug use on cocaine self-administration in humans under controlled laboratory conditions. Study 1 will be devoted to establishing an effective laboratory model for assessing the influence of drug pretreatment on cocaine self- administration. Intranasal doses of cocaine and varying amounts of money will be available under concurrent fixed-ratio schedules of reinforcement. The influence of the amount of money available via the alternate option on cocaine self-administration will be assessed. Using the parametric information obtained in Study 1, cocaine availability in Studies 2-5 will be scheduled under conditions supporting relatively high, intermediate, and near-zero levels of cocaine self-administration. Respectively, those studies will assess the acute effects of pretreatment with varying doses of alcohol (0, 0.5, & 1.0 g/kg), marijuana (0, 1.3, & 2.7% delta9-THC/cigarette), caffeine (0, 150, 300 mg/70 kg) and nicotine (0.14, 1.14, & 2.20 mg/cigarette) on cocaine self-administration occurring at each of those three different levels. By systematically varying both the baseline level of cocaine self-administration and dose of the pretreatment drugs, a comprehensive analysis will be provided. Detection of drug-produced increases or decreases in cocaine use should be discernible. These studies will provide novel and important information that should be useful (1) in understanding drug interactions, (2) in understanding how other drug use may alter the relative control exerted by cocaine versus an alternative, non-drug reinforcer, and, most importantly, (3) in developing effective, empirically-based treatment strategies for achieving and maintaining cocaine abstinence.

Cocaine dependence is likely to remain a serious U.S. public-health problem throughout the 1990's. In an effort to address that problem, we have been researching the efficacy of a multicomponent, outpatient treatment for cocaine dependence that is based on the principles of behavior analysis and behavioral pharmacology. This treatment effectively retains cocaine-dependent adults in outpatient treatment and engenders clinically-significant periods of continuous cocaine abstinence. The purpose of the studies proposed in this application is to analyze further which components of this multicomponent treatment contribute to the positive outcomes observed with it. Such dismantling studies are essential to the development of empirically-based and effective treatments for drug dependence, and are consistent with the research objectives outlined in RFA #DA-94-02 "Behavioral Therapies Development Program", which is the RFA to which we are responding. One of our prior trials demonstrated that an incentive program wherein patients earned vouchers exchangeable for retail items contingent on submitting cocaine-free urine specimens was an active component of this treatment. However, that study did not determine whether the incentives directly increased cocaine abstinence via reinforcement or acted indirectly by increasing treatment retention and the amount of services received and in that manner improved outcome. Study 1 of this application will systematically replicate our prior findings and extend them by dissociating effects on retention and cocaine abstinence. Study 2 will assess whether a disulfiram-therapy component used to treat alcohol abuse in this multiple-drug abusing population contributes to positive outcomes, and, if so, whether the medication-compliance procedures we use in implementing this therapy are an effective feature. Preliminary results from our clinic and others indicate that treating alcohol abuse in this cocaine-dependent population via disulfiram therapy and medication- compliance procedures significantly reduces drinking and cocaine use. Study 3 will assess whether including significant others in the treatment process improves outcome, and , if so, whether the behavioral-contracting procedures we use in this component are an effective feature. Preliminary results from our clinic indicate that including significant others in treatment and teaching them to use behavioral contracts significantly increases the probability of patients achieving clinically-significant periods of continuous cocaine abstinence. Each of the proposed trials will contribute important new information on the efficacy of specific components of this promising behavioral treatment for cocaine dependence. This information will permit us to empirically streamline this intervention down to its necessary components. Moreover, these studies will contribute to our longer-term goal of producing both a comprehensive treatment package and specific treatment components for dissemination as manual-guided and effective interventions for outpatient treatment of cocaine dependence.

Our research focuses on characterizing in humans the effects of drugs and abuse when taken in combination. We worked on two projects during 1997. First, we completed an experiment examining the effects of acutely administered caffeine on preference between cocaine use versus varying amounts of money. Preference for cocaine decreased significantly as the value of the monetary alternative increased and caffeine did not alter that relationship. These results suggest that caffeine at commonly used doses is not likely to increase relapse among cocaine abusers. Evidence from our treatment clinic are consistent with that conclusion.

The vast majority of cocaine abusers, including those enrolled in drug abuse treatment, regularly use and abuse other drugs. Unfortunately, little scientific information is available indicating how such other drug use and abuse may influence the probability of cocaine use. This absence of information prevents clinicians from making empirically-based recommendations regarding the likely influence of other drug use on the course of cocaine abuse. The purpose of the research proposed in this application is to begin to address this important issue by experimentally analyzing the influence of other drug use on cocaine self-administration in humans under controlled laboratory conditions. Study 1 will be devoted to establishing an effective laboratory model for assessing the influence of drug pretreatment on cocaine self- administration. Intranasal doses of cocaine and varying amounts of money will be available under concurrent fixed-ratio schedules of reinforcement. The influence of the amount of money available via the alternate option on cocaine self-administration will be assessed. Using the parametric information obtained in Study 1, cocaine availability in Studies 2-5 will be scheduled under conditions supporting relatively high, intermediate, and near-zero levels of cocaine self-administration. Respectively, those studies will assess the acute effects of pretreatment with varying doses of alcohol (0, 0.5, & 1.0 g/kg), marijuana (0, 1.3, & 2.7% delta9-THC/cigarette), caffeine (0, 150, 300 mg/70 kg) and nicotine (0.14, 1.14, & 2.20 mg/cigarette) on cocaine self-administration occurring at each of those three different levels. By systematically varying both the baseline level of cocaine self-administration and dose of the pretreatment drugs, a comprehensive analysis will be provided. Detection of drug-produced increases or decreases in cocaine use should be discernible. These studies will provide novel and important information that should be useful (1) in understanding drug interactions, (2) in understanding how other drug use may alter the relative control exerted by cocaine versus an alternative, non-drug reinforcer, and, most importantly, (3) in developing effective, empirically-based treatment strategies for achieving and maintaining cocaine abstinence.

This retrospective project is being conducted to further our understanding of the relationship between cigarette smoking and cocaine use. Our group has shown that there is a relationship between cocaine use and cigarette smoking such that cocaine abusers who smoke cigarettes use cocaine more frequently and in greater amounts than nonsmokers. We have also produced experimental evidence that cocaine use increases the rate of cigarette smoking. In addition, we recently reported that cocaine-dependent cigarette smokers report smoking more when under the influence of cocaine than when sober. In light of these findings, we will attempt to objectively document the self-reported increases in cigarette smoking associated with cocaine use in our cocaine-dependent clients. Towards this end, we wish to make use of data and urine samples we have collected at our cocaine-dependence treatment clinic over the past few years. The samples were analyzed for cotinine levels in the GCRC Biochemistry Core Laboratory. Results confimed patient self-reports that they smoke more when using cocaine. These observations combined with experimental results from our lab study provide compelling evidence that cocaine use increases cigarette smoking. Results were recently accepeted for publication.

This is a continuation application for a project examining the influence of other drug use on human cocaine use using a laboratory model. The prior project focused on the influence of non-prescription drug use (i.e., alcohol, caffeine, marijuana, and nicotine) and the proposed project will focus on the influence of prescription drug use (i.e., psychomotor stimulants, sedative hypnotics, and opioid analgesics). Understanding the influence of such other drug use on the probability of cocaine use is essential to the development of effective clinical strategies for managing polydrug abuse in cocaine treatment clinics, and could also prove useful to the development of effective pharmacotherapies for cocaine abuse. Laboratory models are important due to the rigorous experimental control they afford and their lower costs compared to clinical trials. In our laboratory model, volunteers participate in a series of experimental sessions in which they make exclusive choices between doses of intranasal cocaine and varying amounts of money. In studies completed to date (l) cocaine use varied as an orderly function of monetary value, demonstrating experimental control over drug use; (2) acute alcohol, but not caffeine, pretreatment increased preference for cocaine over the alternative monetary option, suggesting the model has pharmacological sensitivity and selectivity; and (3) these laboratory findings were concordant with evidence from clinic studies with cocaine-dependent patients, supporting the generalizability of these observations to treatment settings. Six studies are proposed for the next funding period. All examine the acute effects of prescription drugs that are commonly used and abused by cocaine abusers. The specific drugs proposed for study are damphetamine, methylphenidate, pentobarbital, triazolam, codeine, and buprenorphine. These studies wTh provide important new information on (l) how use of these drugs alters preference for cocaine versus alternative, non-drug reinforcers, (2) possible differences between drugs in how they affect cocaine use, and (3) the utility of laboratory models for addressing clinically important issues. Additionally, by examining non-prescription (prior application) and prescription (this application) drugs, this project will contribute a comprehensive experimental analysis of the influence of commonly used drugs on human cocaine use.

smoking; psychomotor function; central nervous system stimulants; drug interactions; amphetamines; nicotine; psychological reinforcement; psychopharmacology; drug abuse; human subject;

Cocaine dependence remains a major U.S. public health problem for which effective treatments are sorely needed. Towards that end, our group has been researching a multicomponent, outpatient treatment for cocaine dependence. The treatment integrates two key components: a voucher-based incentive program and Community Reinforcement Approach therapy. This treatment is one of the few reliably efficacious interventions for retaining cocaine-dependent adults in outpatient treatment and for engendering cocaine abstinence. The studies proposed in this competing continuation programmatically extend this treatment approach. Our current focus is on understanding how to increase post-treatment cocaine abstinence. Interestingly, evidence from us and others indicates that increasing during-treatment abstinence may be the most effective strategy for improving longer-term abstinence in cocaine-dependent outpatients. Experimental and correlational data from our clinic, for example, indicate that sustaining three or months of continuous cocaine abstinence during treatment increases greater than 3-fold the odds of cocaine abstinence at follow-up. Our prior trials also indicate clearly that the voucher-based incentive program is the most effective element in this multicomponent treatment for increasing during-treatment abstinence. Hence, the proposed studies will experimentally analyze how changes in the value of the voucher-based incentive program as well as length of treatment with it affects during-treatment and post-treatment cocaine abstinence. Additionally, while strong evidence exists supporting the efficacy of this voucher program, there is a striking dearth of information available on how alterations in its basic parameters affect outcome. Thus, the proposed trials also will provide practically important new parametric information on this intervention. We have proposed two trials. Trial 1 will use a randomized, parallel-groups design to examine the during- and post-treatment effects of this multicomponent treatment with the vouchers set at one-half, full, and twice their usual monetary value. Trial 2 will use the same design, but instead of manipulating the value of the vouchers, the length of time that patients receive them will be set at one-half, full, and twice the usual duration. Overall, these clinical trials will further understanding of cocaine-dependence treatment in at least two ways: First, they will rigorously evaluate the hypothesis that increasing during-treatment abstinence increases longer-term cocaine abstinence. If that hypothesis is supported, it will provide a concrete target for facilitating longer-term cocaine abstinence in future treatment efforts. Secondly, the trials will provide rigorous, experimental analyses of the relationships between the value of voucher-based incentives and length of treatment with them and treatment outcome. Such information is essential to a thorough evaluation of this emerging treatment technology.

Maternal cigarette smoking is the most important preventable cause of poor pregnancy outcomes in the U.S. and a leading cause of pediatric morbidity and mortality. Approximately 30% of women in the U.S. are cigarette smokers when they become pregnant and the prevalence is greater still among less educated women. About 80% of these women smoke throughout their pregnancy. Even among those who quit, 25-30% relapse during the pregnancy and 70% within 6 months of delivery. Efficacious interventions have been developed for promoting smoking cessation during pregnancy, but cessation rates are low, especially among low-income and highly nicotine-dependent women (< 15%). Efficacious interventions to prevent relapse during the postpartum period remain to be developed. . We propose to examine the efficacy of a voucher-based incentive program for promoting smoking cessation and preventing relapse during pregnancy and postpartum. This incentive program is efficacious in promoting and sustaining abstinence in cocaine and other illicit drug abusers. A recent trial suggested that vouchers may be efficacious for increasing smoking cessation among pregnant smokers. The proposed studies are designed to rigorously evaluate the efficacy of voucher-based incentives for promoting cessation and extend them to preventing relapse among pregnant women and new mothers. Two randomized trials are proposed. First, we will examine the efficacy of vouchers delivered contingent on smoking abstinence for increasing cessation rates during pregnancy and postpartum among 226 women who are still smoking at their first prenatal visit. Second, we will examine the efficacy of contingent vouchers for preventing relapse during pregnancy and postpartum among 96 women who have already quit smoking prior to the first prenatal visit. Women for both trials will be recruited from Vermont's largest obstetrical practice, which serves a large population of uninsured, low-income women. In both trials, the voucher-based intervention will be added to brief smoking advice delivered by physicians/midwives and compared against control conditions wherein brief advice is combined with vouchers delivered independent of smoking status. Overall, the proposed studies have the potential to contribute important new scientific and practical information on effective treatment for one of our nation's most daunting drug abuse problems.

DESCRIPTION: (provided by applicant)Each year millions of cigarette smokers in the U.S. try to quit, only to fail within the initial days or weeks of the effort. Sustaining abstinence through the initial weeks of a cessation effort is associated with a precipitous decline in relapse risk. Indeed, there is substantial evidence in the literature on smoking and other drug abuse supporting strong associations between the duration of prior abstinence and relapse risk. What is missing and is the focus of this competing continuation are rigorous experimental studies examining how a period of early abstinence might protect against relapse risk. Such information has the potential to facilitate development of more focused and effective behavioral and pharmacological treatments. We are proposing 4 experiments involving three different experimental models of cigarette smoking to systematically analyze the relationship between initial abstinence and relapse risk. Primary among the models is a contingency-management arrangement that allows for experimental control over the amount of initial smoking abstinence achieved. Subjects will be daily cigarette smokers not currently trying to quit, but willing to abstain as part of a study. Subjects will earn payment by sustaining abstinence that is verified via 3 x/day CO monitoring. Nicotine withdrawal, craving, abstinence self-efficacy, mood, and related measures will be assessed daily. In Studies 1 and 2, subjects will be randomized to achieve 1-14 days of abstinence prior to undergoing a 3-hr relapse-risk challenge session assessing sensitivity to the relative reinforcing effects of smoking. In Study 1, the challenge session will involve a discrete-trial choice model in which subjects choose between cigarette smoking vs. monetary reinforcement. In Study 2, the challenge session will involve a progressive ratio (PR) model in which the number of operant responses necessary to earn smoking opportunities increases progressively throughout the session to estimate the maximal price that subjects will incur in order to smoke. In Study 3, we will use these same models to experimentally analyze the clinically important and related question of how brief "lapses" back to smoking alter the profile of withdrawal and related self-report measures as well as the relative reinforcing effects of smoking. Finally, in Study 4 we will use these same models to experimentally analyze how transdermal nicotine alters the relationships between initial abstinence, withdrawal and related measures, and the relative reinforcing effects of smoking. Overall, the proposed studies have the potential to efficiently and effectively contribute new, detailed information on how initial abstinence decreases relapse risk. Such information is essential to the development of more focused and effective smoking-cessation interventions.

DESCRIPTION (provided by applicant): The purpose of this application is to obtain NIDA support to hold a small scientific meeting on the use of contingency management (CM) for treatment of substance use disorders and associated problems. The meeting will take place on Oct. 7-8, 2004, in Burlington, Vermont. The meeting presenters, who are diverse in terms of their formal training and professional rank, were selected because of their involvement in important scientific research on CM and drug abuse. The overarching aim of the proposed meeting is to bring together these experts in CM and related areas of substance abuse research to discuss the future of CM research. More specifically, we will discuss current knowledge and future directions with regard to: 1) lowering the cost of CM and testing the efficacy of such lower-cost CM interventions in community substance abuse treatment centers; 2) the integration of CM and vocational training in addressing the co-occurring problems of drug dependence and chronic unemployment; 3) the integration of CM into treatment of special populations and settings other than substance abuse treatment clinics; and 4) the rigorous and quantitative characterization of relapse rates following treatment with CM interventions, including examining whether rates differ across populations and substances, and how they compare with other substance abuse treatment interventions (e.g., cognitive behavior therapy). Critical discussion of these issues is important to the future of CM and to the research agenda of NIDA.

DESCRIPTION (provided by applicant): This is a first revision of a competing renewal to continue research on the use of voucher-based incentives to promote cigarette smoking cessation and relapse prevention among pregnant and recently postpartum women. Maternal cigarette smoking is the leading preventable cause of poor pregnancy outcomes and pediatric morbidity and mortality in the U.S. Efficacious interventions have been developed for smoking cessation during pregnancy, but cessation rates are low, typically under 20%. Efficacious interventions to prevent postpartum relapse remain to be developed. This application seeks support for a Stage II behavioral therapies development project to continue examining interventions to increase smoking cessation above the low levels noted above and to decrease postpartum relapse. With regard to cessation, we conducted studies during the prior funding period showing that voucher-based incentives delivered contingent on biochemically-verified abstinence promote smoking cessation in approximately 40% of women who were still smoking at their 1st prenatal visit compared to only 9% in a control condition. Comparable studies on decreasing postpartum relapse among women who were smokers upon learning of their pregnancy but quit by their 1 prenatal visit (spontaneous quitters) supported the efficacy of abstinence-contingent vouchers for preventing antepartum but not postpartum relapse. We also completed secondary studies on appropriate cutpoints for biochemically verifying smoking status in pregnant women, characterizing the quantitative relationship between smoking exposure and fetal growth, the time-course of depressive symptoms during pregnancy in smokers and abstainers, and the incidence and severity of nicotine withdrawal. While the treatment effect on smoking cessation during pregnancy noted above is at least two-fold greater than usual outcomes, the majority of women, especially heavier smokers (= or >10 cigs/day), failed to quit. In Study 1 of this application we propose to experimentally examine whether a revised voucher program designed to increase initial abstinence and encourage additional quit attempts among those who initially fail can promote cessation at the end-of-pregnancy assessment in the majority of women treated (= or >60%). Considering that nobody has succeeded in decreasing postpartum relapse among spontaneous quitters, we are not surprised that our first effort was unsuccessful. In Study 2 of this application we propose to experimentally test whether a revised voucher-based incentive program designed to more effectively reinforce sustained abstinence will decrease postpartum relapse. We are also proposing to continue secondary studies on biochemical verification of smoking status, fetal growth, and predictors of postpartum relapse. Overall, the proposed studies have the potential to contribute important new information on effective treatments for one of our nation's most daunting drug abuse problems.

? DESCRIPTION (provided by applicant): The purpose of this application is to continue the University of Vermont's highly successful 25-year T32 training program in the human behavioral pharmacology of drug dependence. During the past ten years, we trained 14 predoctoral and 16 postdoctoral fellows. Among those 30 fellows, all but one remains involved in research careers. Fourteen have completed the training phase of their careers. Among those 14, 7 (50%) have primary university faculty positions, 5 (33%) are principal investigators (PI) on one or more NIH research awards, and they have published more than 250 journal articles and book chapters on addiction. Collectively, the 30 fellows have published more than 350 journal articles and book chapters on addiction. In addition to being a productive training program, the training our fellows receive in human behavioral pharmacology fills a unique niche in addiction research. Our fellows learn to identify basic behavioral and pharmacological processes underpinning addiction and to translate that knowledge into effective clinical interventions and policy. We propose to continue our emphasis on human behavioral pharmacology in the next funding period, with an expansion into tobacco regulatory science and the impact of addictive behavior on health outcomes. Since last renewal, we received a P50 Tobacco Centers of Regulatory Science award and a P20 Center of Biomedical Research Excellence (COBRE) award in behavior and health, which has brought added value to our training program via access to new seminars, interactions with new fellows, and new research and career opportunities. We are proposing to continue supporting 4-predoctoral and 4-postdoctoral training slots with this T32 award. The seven members of the proposed training faculty consist of five Ph.D.s, one M.D., and one M.D. /Ph.D. This faculty is PIs on two NIH center grants, 8 R01s, 3 R01-equivalent program projects, an R34, an R21, and two R21-equivalent program projects, creating a rich range of research training opportunities in addiction research. All of our faculty and fellows are located at a singl, on-campus site composed of 8000 sq ft of newly renovated laboratory, clinic, and office space. Fellows are selected based on scholastic excellence and commitment to a career in addiction research. Predoctoral fellows are enrolled in the Department of Psychological Science PhD programs in experimental or clinical psychology where they complete required coursework including those developed for this training program, and complete master's and doctoral theses. Postdoctoral fellows primarily focus on conducting and supervising independent research, with additional opportunities to further their education via course-work. Each fellow has a primary mentor from the training faculty. Fellows attend weekly seminars in addiction research and ethics. Additionally, they present their research at two or more national scientific meetings annually. The training period is generally 4-5 years for predoctoral and 2-3 years for postdoctoral fellows. The overarching goal of the proposed training program is to continue developing productive, independent, state-of-the-art addiction researchers.

[unreadable] DESCRIPTION (reflected from application): Health disparities among disadvantaged women is a concern shared throughout the NIH, including NIDA and NCI. As was noted above, 170,000 deaths per year among women in the U.S. are attributable to smoking-related causes. The proportion of those women who are socioeconomically disadvantaged is growing (e.g., U.S. Department of Health and Human Services, 2004). These women on average are least likely to respond to prevention and treatment interventions. Greater scientific understanding of the important social, behavioral, pharmacological, and biological controlling variables involved in this problem are needed if more effective interventions and policies are to be developed. Researchers from a number of different disciplines are studying the problem, but interdisciplinary efforts are lacking. This conference has the potential to enhance recognition of the urgency of the problem, embed the problem in a broader context with regard to other types of substance abuse as well as other non-substance-related public health problems, and perhaps most importantly foster interdisciplinary research efforts. For example, how the strong socioeconomic influences on smoking are to be reconciled with the strong heritability estimates coming out of genetics studies on smoking is unclear and investigators from the relevant disciplines need to be discussing those challenges (e.g., Graham et al., 2007; Uhl et al., 2007). As another example, sociological and epidemiological research documents an important potential moderating effect of education on the risk of smoking, but says little about how education would produce those effects (e.g., Graham et al., 2007). Research being conducted on executive function and risky choice among smokers by behavioral neuroscientists has the potential to advance understanding in that area (e.g., Johnson et al., 2007). There are many other examples where research on this general problem could be advanced through interdisciplinary efforts. To our knowledge, those interdisciplinary efforts are not occurring to any great extent currently. By inviting leaders from these different disciplines to participate in a single-track conference where they will listen to each other's presentations and have ample opportunity to ask each other questions has the potential to significantly improve upon that situation. By publishing the proceedings in a peer-reviewed journal that opportunity is enhanced even further because now interested professionals who did and did not attend the conference have the opportunity to examine each other's work in careful detail. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is the first revision of an application to continue researching the CRA + Vouchers treatment for cocaine dependence. Cocaine dependence is an entrenched U.S. public-health problem. While excellent progress has been made in developing efficacious behavioral therapies for this disorder, there is considerable room for improvement. One promising area for improvement is in matching treatment parameters to patient characteristics so that lower-severity patients not receive more treatment or higher-severity patients less treatment than necessary for a positive treatment outcome. Treatment development for cocaine dependence is often biased towards optimizing efficacy without appropriate attention to constraining costs or reducing costs without sufficient attention to undermining efficacy. Matching the dose of treatment to characteristics that moderate treatment response has the potential to strike a balance between those two biases. We are proposing two matching studies. Study 1 will examine the efficacy of a 6-week contingent voucher intervention with and without voucher values matched to patient severity. We will use marital status (currently married vs. other) and route of cocaine administration (intranasal vs. smoked/intravenous) to classify severity. This severity measure moderates response to the voucher component of the CRA + Vouchers treatment. Cocaine-dependent outpatients will be randomly assigned to CRA plus one of three 6-week voucher conditions: non-contingent vouchers, contingent vouchers set at usual values for all patients, or contingent vouchers set at usual values for low-severity and twice-usual value for high-severity users. We hypothesize a significant interaction between treatment condition and severity, with the efficacy of the 6-week contingent voucher condition being dependent on patient severity when vouchers are set at the usual values, but not when values are matched to patient severity. Study 2 will examine the efficacy of combining 6 weeks of vouchers with CRA delivered as a brief intervention (2 weeks), a moderate-duration intervention (6 weeks), or an intervention wherein duration is matched to two moderators of response to CRA therapy, marital status (currently married vs. other) and alcohol dependence (with vs. without). We hypothesize a significant interaction between treatment condition and severity, with the efficacy of CRA being dependent on marital status and alcohol dependence in the uniform-duration conditions, but not in the condition where CRA duration is matched to patient characteristics. We also are proposing two secondary aims to (a) examine the role played by the behavioral-economic concept of delayed discounting as a potential moderator of treatment response and (b) further understanding of how patient drug-use severity moderates treatment response. Overall, the proposed studies have the potential to advance understanding of how to better match treatment parameters to patient severity in the treatment of cocaine dependence with the goal of streamlining the costs of the interventions without compromising the quality of care offered to more severe patients.

DESCRIPTION (provided by applicant): The purpose of this application is to continue a highly successful 20-year training program in the human behavioral pharmacology of drug dependence. During the past ten years, we have trained 13 predoctoral students of whom all (100%) remain involved in research or academics (teaching) and 16 postdoctoral students of whom 14 (88%) remain involved in research or academics. Among the 17 who have completed their training, 15 (88%) have obtained a faculty appointment, 9 (53%) have obtained an NIH research or career-development award, and 5 (29%) have already obtained one or more R01 awards. Collectively, these 29 trainees have authored more than 300 publications. Trainees from the 1st ten years of the program did equally well. In addition to being a productive training program, we feel that training students in human behavioral pharmacology fills a unique niche in addiction research. Our students are trained to identify basic behavioral and pharmacological processes underpinning addiction and to translate that knowledge into effective clinical interventions. We propose to continue our emphasis on human behavioral pharmacology in the next funding period but in response to scientific advances in addiction research to also include training in behavioral genetics and neuroscience/neuroimaging. We have added two members to our training faculty who are experts in these respective areas. We are proposing 5 predoctoral and 5 postdoctoral (M.D. or Ph.D.) training slots and a team of six training faculty. The six members of the training faculty consist of four Ph.D.s, one M.D., and one M.D./Ph.D. who are PIs on 14 NIH grants (13 from NIDA), one NIH contract, and one pharmaceutical company grant. Research opportunities range from laboratory studies examining behavioral, genetic, and neural factors influencing human drug self-administration to outpatient trials of behavioral and pharmacological treatments for a wide range of addictions. To enhance interaction, training is conducted at a single, on-campus site composed of 8000 sq ft of newly renovated laboratory, clinic, and office space. Trainees are selected on the basis of excellence in their scholastic record and by their commitment to a career in addiction research. Predoctoral trainees are enrolled in the Department of Psychology's doctoral programs in general-experimental or clinical psychology where they complete required coursework in psychology, including those developed specifically for this training program, and complete master's and doctoral theses. Postdoctoral students have the opportunity to further enhance their education via course-work but are mostly mentored in conducting independent research. Each trainee has a primary mentor from the training faculty. Trainees attend weekly seminars in addiction research and research ethics. Additionally, they present their research findings at one or more national scientific meetings annually. The training period is generally 4 to 5 years for predoctoral fellows and 2 to 3 years for postdoctoral fellows. The overarching goal of the proposed training program is to continue to develop productive, independent, state-of-the-art addiction researchers.

This Integrative Graduate Education and Research Traineeship (IGERT) award supports the interdisciplinary training of Ph.D. scientists and engineers working in the development of modern, smart-grid power systems that operate with extensive interaction and data exchange between the utility company and the consumer. The educational program integrates technology, human behavior and policy within a complex systems framework in order to understand the coupled dynamics of the integrated power system.

Intellectual Merit: This training program integrates education and research in complex systems modeling, human behavior, engineering, and policy at the University of Vermont (UVM) with expertise in modern electric power systems, renewable energy and high-performance computing at Sandia National Laboratories to train students to effectively deal with integrated technological-human-policy systems typical of the smart grid. Trainees will complete a summer internship at Sandia National Laboratories, engage in outreach activities with public museums and energy festivals in Vermont, work collaboratively with undergraduate students in game design at Champlain College, and visit the consortium of Vermont utility companies involved in developing the first state-wide smart grid in the nation.

Broader Impacts: Development of the smart grid entails a transformation from the current centralized control structure for power delivery to a decentralized structure in which the consumer plays an integral role. Design, control and optimization of smart grids to provide reliable, inexpensive power will require utility companies to understand, model and shape human behavioral responses and governments to design policies to enhance energy efficiency and smart grid adoption. This training program lays the educational foundations for a workforce trained in an integrated approach to complex human-technical-policy systems.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to establish new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries, and to engage students in understanding the processes by which research is translated to innovations for societal benefit.

The primary educational mission of the Vermont Center on Tobacco Regulatory Science (VCTRS) is to develop an exemplary predoctoral and postdoctoral training program in tobacco regulatory science. The training program will be primarily located at the University of Vermont (UVM), but will also include postdoctoral training positions at our collaborating institutions. Brown University and Johns Hopkins University. Consistent with the overarching focus of the VCTRS, this training program will focus on regulatory science related to premarketing studies on the addictiveness and adverse health effects of new tobacco products among vulnerable populations. Training slots at each of the participating sites will be dedicated to tobacco regulatory science, but will be integrated within the already existing and highly-regarded training programs in addictions at these three institutions. Such a model will serve to assure that fellows receive thorough training in regulatory science and addictions research while also creating the opportunity to introduce other fellows within these larger training programs to the fundamentals of tobacco regulatory science.

Unhealthy behavioral choices to smoke, overeat and lead sedentary lifestyles underlie the preponderance of chronic disease in the U.S. Greater understanding of the mechanisms underpinning vulnerability to such unhealthy decision making and developing more effective interventions to change behavior is vitally important to improving the U.S. public health. The overarching goal of the Administrative Core of the Vermont Center on Behavior and Health (VCBH) is to organize and grow existing strengths at the University of Vermont (UVM) while engaging in local and national collaborations in this important area of health research. This core will provide the administrative and intellectual infrastructure necessary to (a) strengthen and further collaboration among an interdisciplinary group of UVM faculty who share research and clinical expertise in this area, (b) mentor junior faculty in conducting thematically related research and preparing competitive research grant applications, (c) establish productive collaborations with community healthcare organizations and other universities located in IDeA states, (d) recruit new members into the center, and (e) secure the necessary financial support to sustain the VCBH tDeyond COBRE support. Stephen T. Higgins, PhD, will direct the core with assistance from Philip A. Ades, MD. UVM senior faculty will participate as primary and secondary mentors for junior faculty who will conduct COBRE-supported and thematically related research projects. We will collaborate with Vermont community healthcare leaders and investigators from Brown University and the University of Kentucky in pursuing the VCBH mission. Program oversight will be guided by an External Advisory Committee of distinguished scientific leaders in the area of behavior and health. An Internal Advisory Committee composed of accomplished senior UVM investigators will advise the VCBH on scientific and organizational matters. A Community Advisory Committee of experts in Vermont health care delivery and policy will help assure that the VCBH is responsive to community needs. This interdisciplinary team will work closely together to make the VCBH a nationally and internationally recognized center of research excellence.

DESCRIPTION (provided by applicant): The overarching goal of this application is to establish a Vermont Center on Tobacco Regulatory Science (VCTRS). This multidisciplinary center will be located at the University of Vermont but w/ill work closely with collaborators and consultants from Brown University, Johns Hopkins University, University of Minnesota, and University of Pittsburgh. The VCTRS will address one of the crosscutting and two of the specific research priorities of the Food and Drug Administration (FDA) Center for Tobacco Products. The crosscutting priority will be researching tobacco products in vulnerable populations, including women of childbearing age/pregnant women, individuals with comorbid other substance use disorders, and individuals with comorbid serious mental illness. Each of these populations is at increased risk for tobacco use and dependence or tobacco-related adverse health outcomes. Yet despite these serious vulnerabilities, these populations are typically excluded from tobacco regulatory studies. For the FDA to effectively execute its tobacco regulatory responsibilities, having sound scientific evidence on how new tobacco products impact vulnerable populations is critically important. Our goal is for the VCTRS to assist in providing the FDA with that evidence. Regarding specific priorities, the VCTRS will research (a) reducing the addiction potential of cigarettes and other tobacco products by reducing their nicotine content and (b) examining the impact of new products on biomarkers of exposure and health outcomes in vulnerable populations. Regulating the nicotine content of cigarettes and other products is an important responsibility of the FDA that has tremendous potential to reduce smoking prevalence and improve the U.S. public health. The VCTRS will be organized around four primary aims. First, we will establish an Administrative Core that will provide the leadership, administrative and intellectual infrastructure, and organizational oversight necessary to develop and sustain a multidisciplinary center of research and training excellence. Second, we will complete three multi-site research projects evaluating the effects of very low nicotine content (VLNC) cigarettes in vulnerable populations. Third, we will establish a program to support developmental studies in tobacco regulatory science and respond to time-sensitive research priorities. Fourth, we will develop an exemplary predoctoral and postdoctoral training program in tobacco regulatory science. Overall, this proposal has the potential to establish a multidisciplinary center capable o providing the FDA with critically important empirical evidence relevant to its regulatory responsibilities, while also contributing new scientific knowledge on reducing the addictiveness of tobacco products and associated adverse health consequences in vulnerable populations. RELEVANCE: Those individuals who are most vulnerable to the addictive properties and adverse health outcomes of tobacco use are also frequently the least studied, often specifically excluded from tobacco research studies. The proposed Vermont Center of Tobacco Regulatory Science would specifically investigate the health and behavioral impacts of the use of new tobacco products in these vulnerable populations.

This is a Phase 2 Center of Biomedical Research Excellence (COBRE) application to further develop the Vermont Center on Behavior and Health (VCBH) at the University of Vermont (UVM). This multidisciplinary research center focuses on investigating relationships between unhealthy behavior patterns (e.g., substance abuse, physical inactivity, unhealthy food choices, non-adherence with recommended medical regimens) and risk for chronic disease and premature death. The overarching scientific priorities are (a) increasing understanding of the mechanisms underpinning vulnerability to unhealthy behavior patterns and (b) developing more effective behavior-change interventions. Advances in each of these areas are essential to improving U.S. population health, reducing health disparities, and curtailing spiraling health care costs. VCBH has made considerable progress in Phase 1 towards establishing a productive center of research excellence in this important area of biomedical research. VCBH currently consists of 20 UVM faculty members, highly accomplished external, internal, and community advisors, and collaborators from other IDeA states and beyond. The current faculty is multidisciplinary, evenly distributed across academic ranks, and highly productive, having published 118 articles in peer-reviewed journals and obtained $59,135,320 in additional external grant support during the initial four years of Phase 1 funding. We propose to continue prioritizing the mentoring of promising early-career faculty in Phase 2. We provided nine early-career faculty members with funded research projects and career-development support during Phase 1, using a multi-element mentoring plan that we will continue evaluating and refining during the proposed funding period. We propose continuing an Administrative Core that promotes effective communication, fiscal planning and oversight, supports a vibrant intellectual infrastructure, and directs and supports efforts to obtain external grant support. We have established two additional VCBH cores that we propose to continue, a Behavioral Economics and Intervention Sciences (BEIS) Core and a Collaboration, Dissemination, and Education (CDE) Core. The BEIS assists investigators with a decision-making and neuroimaging component to examine processes underpinning vulnerability to unhealthy behavior patterns, development of behavior-change interventions, and economic modeling of intervention cost-effectiveness. The CDE supports local, national, and international research collaborations, dissemination of new knowledge through a monthly lecture series, annual national conferences, annual Special Issues of the peer-reviewed journal Preventive Medicine, other publications, and educational efforts including seminars and workshops in behavior and health that are offered on the UVM campus and streamed live to collaborators and interested others. We are confident that continuing to develop and grow VCBH following this overall management plan will succeed in establishing a multidisciplinary center of research excellence in behavior and health with sustainable local, national, and international impact.

The Developmental/Pilot component of the proposed VCTRS will be led by VCTRS co-director, John Hughes, MD. Dr. Hughes, Professor of Psychiatry, Psychology, and Family Practice, has received numerous national and international awards for his research and scholarship, including the Society for Research on Nicotine and Tobacco's prestigious ,Ovid Ferno Award, and is among the most cited investigators in tobacco control research. He was a seminal investigator on smoking cessation among individuals with comorbid other substance use disorders and has directed 18 NIH awards on this and other areas in tobacco and addictions research. He currently is PI on 5 NJH research awards. He is a founding member and former president of the Society for Research on Nicotine and Tobacco and currently co-directs their Training Network for graduate students, postdoctoral fellows, and Junior faculty. His research interests include all aspects of tobacco and nicotine dependence as well as other forms of drug dependence. His position at the forefront of tobacco research makes him well positioned to provide leadership in the identification of innovative developmental projects in areas of emerging interest to the NIH and the FDA Center for Tobacco Products. He will be assisted by VCTRS director Dr. Higgins, who holds the rank of Professor in UVM's Departments of Psychiatry and Psychology, and for the past 8 years has served as Vice Chair of Research within the Department of Psychiatry. He also currently directs the UVM Department of Psychiatry's Center for Substance Abuse Research and Treatment and for the past 26 years has co-directed with Dr. Hughes the Human Behavioral Pharmacology Laboratory (HBPL). For more than 22 years Dr. Higgins has served as director or co-director with Dr. Hughes of an NIH T32 training grant in the behavioral pharmacology of drug dependence awarded by the National Institute on Drug Abuse (NIDA). Together they are well prepared to lead this effort.

Nearly half of the tobacco consumed in the United States is smoked by people with psychiatric illness. Reducing the nicotine content of cigarettes to a non-addictive level {i.e., < 0.2 mg nicotine) is an innovative regulatory strategy that could significantly reduce tobacco-related morbidity and mortality. However, an expert panel that evaluated the potential impact of this policy identified the possibility of unintended consequences for smokers with comorbid psychiatric illness as a key area of concern, as these smokers could also respond to reductions in the nicotine content of cigarettes with increases in psychiatric symptoms and with compensatory smoking. One important comorbid population to consider is smokers with current major depressive disorder (MDD), who comprise 20-30% of people with current nicotine dependence. Little is known about the effects a nicotine reduction policy might have on smokers with MDD, as to our knowledge no studies have reported the effects of very low nicotine content cigarettes on smoking rate, toxicant exposure, cigarette tolerability or depression severity in these smokers. This substantial gap in the literature will be addressed in the proposed project. In Study 1, participants will assess acute effects of four cigarette conditions of varying nicotine yield (0.83, 0.28, 0.10, 0.03 mg) on craving, nicotine withdrawal, and the degree to which the reduced-nicotine cigarettes substitute for normal-nicotine cigarettes when availability of the latter is constrained. In Study 2, after a 1-week, 2-session baseline assessment period, smokers with current MDD will be randomized to one of these same four cigarette conditions for a 12-week extended exposure phase. Over the baseline and extended-exposure phases, patterns of tobacco use, biomarkers of toxicant exposure, psychiatric symptoms, cognitive performance and smoking topography will be assessed. By examining both the potential positive and negative consequences of very low nicotine cigarette use in smokers with MDD, this study will examine whether a regulatory approach of reducing the nicotine content of cigarettes to a non-addictive level is a viable method of reducing smoking in this population. RELEVANCE (See instructions): There is an unusually high rate of cigarette smoking and correspondingly high rates of smoking-related morbidity and mortality in smokers with major depressive disorder. This project will investigate the acute and extended effects of very low nicotine content cigarettes on smoking, toxicants, psychiatric symptoms, cognitive functioning and other measures in smokers with major depressive disorder. This information will help to determine whether a public health policy of limiting the nicotine content of cigarettes to very low levels would be effective and safe for these smokers.

Prevalence of smoking among opioid-dependent individuals is four-fold that of the general US adult population and is associated with increased risk for smoking-related morbidity and mortality. The 2009 passage of the Family Smoking Prevention and Tobacco Control Act gave the FDA regulatory junsdiction over tobacco products, and a public policy mandating a reduction in cigarette nicotine content is currently being considered. Such a policy could dramatically reduce smoking rates and smoking-related adverse health effects in the general population. Unfortunately, little is known scientifically about the effects of reduced-nicotine cigarettes in populations that are especially vulnerable to smoking and adverse health outcomes, including smokers with comorbid other drug dependence. Whether this more dependent group might respond with compensatory increases in smoking rate or inhalation patterns, potentially increasing exposure and adverse health effects, is unknown. The overarching objective of this project is to conduct a thorough experimental evaluation ofthe abuse liability and health effects of very low nicotine content (VLNC) cigarettes in opioid-dependent smokers. We will compare cigarettes varying in nicotine content across a range of doses starting from levels approximating those in usual brand cigarettes to very low nicotine levels (0.83, 0.28, 0.10, 0.03mg) using brief- and extended-exposure protocols. This project will represent the first investigation of VLNC cigarettes in smokers with opioid dependence or other substance use disorders and stands to contribute new scientific knowledge with the potential to inform FDA policy decisions. As Primary Aims, we will evaluate whether VLNC substitute for usual-nicotine cigarettes during bnef exposure, without producing compensatory increases in smoking, and we will compare VLNC and usual-nicotine cigarettes, under conditions of extended (12-week) exposure, on smoking rates, toxin exposure levels, and nicotine dependence. As Secondary Aims, we will assess adherence, withdrawal, cigarette demand, biomarkers of exposure to carcinogens, markers of pulmonary, cardiovascular and neurocognitive function and use of other non-prescribed drugs. Understanding how opioid-dependent smokers respond to reduced-nicotine cigarettes is essential for evaluating the potential impact of a nicotine reduction policy. We propose to provide the first experimental analysis of the effects of VLNC cigarettes in opioid-dependent smokers using measures that are relevant to the abuse liability and potential health impact of these products. Taken together, these data have the potential to directly inform FDA policv decisions regarding reduced-nicotine tobacco products.

We are proposing to establish a Vermont Center on Tobacco Regulatory Science (VCTRS) at the University of Vermont (UVM) in collaboration with colleagues from Brown University, Johns Hopkins University, University of Minnesota, and University of Pittsburgh. The VCTRS will focus on researching the effects of new tobacco products in vulnerable populations, with special emphasis on reducing the addiction potential of cigarettes and other tobacco products by reducing their nicotine content and examining the impact of these products on biomarkers of exposure and health outcomes. Each of these foci was selected to address crosscutting and specific priorities of the FDA outlined in RFA-DA-13-003. We will establish an administrative core at UVM that will provide the senior scientific and administrative leadership and support that is essential to a vibrant and successful multidisciplinary center of research excellence. We are proposing three primary research projects that will be complemented by a program of developmental research. In addition to this research mission, the VCTRS will also establish a predoctoral and postdoctoral training program in tobacco regulatory science that will be primarily located at UVM but will also include training at Brown University and Johns Hopkins University. The research and training missions will be led by experts in addictions research in collaboration with accomplished experts in biomarkers and health outcomes from the disciplines of biochemistry, family practice, internal medicine, and obstetrics and gynecology. There is strong institutional support for establishing the VCTRS at UVM that runs from the departmental level through the highest administrative offices and extending out into key Vermont state offices that are involved in establishing and implementing the state's tobacco control policies (see Letters of Support). Below we expound on each of these key aspects of establishing the VCTRS. One other point that we want to mention now, and expound upon below, is our plan to study the potential of very low nicotine content (VLNC) cigarettes for reducing the abuse liability of cigarettes. This should not be confused with earlier failed efforts to develop light cigarettes for the same purpose. VLNC cigarettes actually have lower nicotine content as opposed to the earlier ineffective strategy of keeping nicotine content the same and attempting to lower nicotine yield through ventilation, which smokers often circumvented with compensatory smoking. These are different strategies and, while still limited, the evidence on VLNC cigarettes lowering the abuse liability of cigarettes is quite promising.

DESCRIPTION (provided by applicant): Smoking during pregnancy is the leading preventable cause of poor pregnancy outcomes in the U.S. Most pregnant smokers continue smoking through pregnancy producing serious immediate and longer-term adverse health consequences for the infant. Smoking during pregnancy is highly associated with economic disadvantage and a substantive contributor to health disparities. Efficacious interventions are available but cessation rates are low (<20 percent) and improvements in birth outcomes often modest or absent. Current treatments usually entail relatively brief, low-cost interventions (e.g. pregnancy-specific quit lines). There is broad consensus that more effective interventions are sorely needed. We have developed a novel behavioral-economic intervention in which women earn financial incentives contingent on smoking abstinence. In a meta-analysis of treatments for smoking during pregnancy, effect sizes achieved with financial incentives were several-fold larger than those achieved with lower-intensity approaches or medications. The intervention also appears to improve birth outcomes and increase breastfeeding duration. While highly promising, further research is needed in at least three areas. (1) The evidence on birth outcomes and breastfeeding is from studies that combined data across trials rather than a single prospective trial, (2) whether the intervention produces other postpartum improvements in health has not been investigated, and (3) the overall cost-effectiveness of this approach has not been examined. To examine these unanswered questions, we are proposing a randomized, controlled clinical trial comparing the efficacy and cost effectiveness throuh one-year postpartum of current best practices for smoking-cessation during pregnancy vs. best practices plus financial incentives among 230 pregnant, Medicaid recipients. We will also include a third condition of 115 pregnant non-smokers matched to the smokers on socio-demographic and health conditions to compare the extent to which the treatments reduce the burden of smoking and to estimate how much more might be accomplished by further improvements in this incentives intervention without exceeding cost-effectiveness. We hypothesize that best practices plus financial incentives will be more effective than best practices alone, that the incentives intervention will be cost effective, and that while adding the incentives reduces a greater proportion of the health and economic burden of smoking than best practices alone, more can be done while remaining cost effective. Overall, the proposed study has the potential to substantially advance knowledge on cost-effective smoking cessation for pregnant women. Importantly, because of the strong association between smoking during pregnancy and economic disadvantage, the proposed study also has the potential to contribute new knowledge relevant to reducing the serious challenges of health disparities.

An effective and responsive Administrative Core will be essential to the success of the Vermont Center on Tobacco Regulatory Science (VCTRS). We propose an Administrative Core that will provide centralized services for organizational management and program development. The proposed Core will have the administrative, fiscal, and support staffing necessary to establish and maintain a vibrant, multidisciplinary research center that is focused on examining the abuse liability and health effects of new tobacco products in vulnerable populations. We propose an organizational structure that will ensure fiscal responsibility, attention to oversight responsibilities, promote open communication, collaboration, and conflict management, and include careful formative evaluation and planning. Intellectually, the Core is committed to building an infrastructure that facilitates the growth and development of established and new investigators in tobacco regulatory science with specific expertise in tobacco use in vulnerable populations. The Core will encourage local, national, and international collaboration with the VCTRS, make effective use of the knowledge and wisdom of its outstanding consultants and advisors, and nurture interest in the importance of tobacco regulatory science for reducing smoking prevalence and tobacco-related morbidity and mortality in vulnerable populations.

DESCRIPTION (provided by applicant): Smoking among women is a substantial U.S. public health problem that is highly associated with socioeconomic status, especially low educational attainment. It is also a direct contributor to health disparities. For example, smoking prevalence in the U.S. exceeds 30 percent among women with < 12 years of education compared to less than 6 percent for women with graduate degrees. Smoking prevalence among disadvantaged mothers is at strikingly high levels (40-60 percent). Disadvantaged women begin smoking at an earlier age, are heavier smokers, and are more likely to be nicotine dependent and to fail at smoking cessation. Not surprisingly, disadvantaged women are also at increased risk for smoking-related adverse health outcomes, including adversely impacting the health of their children through in-utero and second-hand smoke exposure (SHSe). Despite widespread awareness of the adverse health consequences of SHSe, almost 85 percent of U.S. children from low-income families are chronically exposed. SHSe, especially from maternal smoking, increases risk for infant death, chronic respiratory infections, asthma, and other longer-term medical problems, and is estimated to increase direct medical and life-lost costs in the U.S. by > $5 billion annually. Efficacious interventions to increase maternal smoking cessation and reduce childhood SHSe are sorely needed. In this application we are proposing to test the efficacy and cost-effectiveness of an intervention for promoting smoking-cessation among economically disadvantaged mothers of young children (< 11 yrs) that is based in the conceptual framework of behavioral economics and uses financial incentives to motivate behavior change. We are proposing to conduct a randomized controlled clinical trial comparing (1) usual care for smoking cessation and reducing SHSe among children, (2) usual care combined with financial incentives for objectively verified smoking abstinence and (3) usual care combined with financial incentives and also with nicotine replacement therapy (NRT) using innovative procedures to enhance medication efficacy. We hypothesize that both interventions involving financial incentives will increase biochemically-verified smoking abstinence in mothers and decrease SHSe in their children, but that the largest and most cost-effective treatment effects will be achieved by combining financial incentives with NRT. Behavioral-economic measures of decision-making biases and cigarette-price sensitivity will be examined as predictors of treatment response. Overall, the proposed study has the potential to advance knowledge on efficacious, cost-effective smoking cessation for maternal smokers and protection against SHSe in children. The study also has the potential to impact policies and clinical practices regarding recommended care for combating chronic SHSe in disadvantaged children.

DESCRIPTION (provided by applicant): Smoking during pregnancy is the leading preventable cause of poor pregnancy outcomes in the U.S. Most pregnant smokers continue smoking through pregnancy producing serious immediate and longer-term adverse health consequences for the infant. Smoking during pregnancy is highly associated with economic disadvantage and a substantive contributor to health disparities. Efficacious interventions are available but cessation rates are low (<20 percent) and improvements in birth outcomes often modest or absent. Current treatments usually entail relatively brief, low-cost interventions (e.g. pregnancy-specific quit lines). There is broad consensus that more effective interventions are sorely needed. We have developed a novel behavioral-economic intervention in which women earn financial incentives contingent on smoking abstinence. In a meta-analysis of treatments for smoking during pregnancy, effect sizes achieved with financial incentives were several-fold larger than those achieved with lower-intensity approaches or medications. The intervention also appears to improve birth outcomes and increase breastfeeding duration. While highly promising, further research is needed in at least three areas. (1) The evidence on birth outcomes and breastfeeding is from studies that combined data across trials rather than a single prospective trial, (2) whether the intervention produces other postpartum improvements in health has not been investigated, and (3) the overall cost-effectiveness of this approach has not been examined. To examine these unanswered questions, we are proposing a randomized, controlled clinical trial comparing the efficacy and cost effectiveness throuh one-year postpartum of current best practices for smoking-cessation during pregnancy vs. best practices plus financial incentives among 230 pregnant, Medicaid recipients. We will also include a third condition of 115 pregnant non-smokers matched to the smokers on socio-demographic and health conditions to compare the extent to which the treatments reduce the burden of smoking and to estimate how much more might be accomplished by further improvements in this incentives intervention without exceeding cost-effectiveness. We hypothesize that best practices plus financial incentives will be more effective than best practices alone, that the incentives intervention will be cost effective, and that while adding the incentives reduces a greater proportion of the health and economic burden of smoking than best practices alone, more can be done while remaining cost effective. Overall, the proposed study has the potential to substantially advance knowledge on cost-effective smoking cessation for pregnant women. Importantly, because of the strong association between smoking during pregnancy and economic disadvantage, the proposed study also has the potential to contribute new knowledge relevant to reducing the serious challenges of health disparities.

We propose to renew a Career Enhancement Core that focuses on providing predoctoral and postdoctoral fellows with high-quality research mentoring that will prepare them for careers in tobacco regulatory science research. The Core is primarily located at the University of Vermont (UVM), but also has postdoctoral fellows placed at our two collaborating sites, Brown University and Johns Hopkins University. All three institutions also have highly regarded T32 training programs in addictions research, which allows for rich cross-fertilization between tobacco regulatory science and addictions research. Consistent with the overarching focus of the UVM TCORS, this Core focuses on career enhancement around investigating use of tobacco and nicotine delivery products among vulnerable populations. The leaders of the Career Enhancement Core (Drs. Higgins and Heil) have a long history of effective collaborative mentoring in their roles as Director and Associate Director of the UVM T32 training program in addictions research. Eight additional primary mentoring faculty provide a wide range of expertise in the areas of vulnerable populations, addictions, behavioral science, and tobacco regulatory science research. Dr. Villanti bolsters our mentoring team's expertise in tobacco regulatory science. The Career Enhancement Core provides fellows with (a) hands-on research training in tobacco regulatory science in which they directly assist faculty with implementing the primary UVM TCORS studies while simultaneously leading pilot studies, (b) opportunities to participate in an ongoing, rotating seminar series on behavioral science, behavioral economics and behavioral pharmacology, research ethics, and tobacco regulatory science, and (c) abundant opportunities to present their research at national scientific meetings and prepare articles for publication in peer-reviewed journals. During the almost 4 years of the current funding period, we have mentored 14 predoctoral and postdoctoral fellows (4 predocs and 10 postdocs). Our fellows published 29 peer-reviewed articles supported by the UVM TCORS during the current funding period, including 15 as 1st author. In the current funding period, we have used pilot projects and developmental studies to ensure that fellows gain experience with independent research, collaboration, and grant writing in tobacco regulatory science. Going forward, the Core will leverage that experience and our growing expertise in tobacco regulatory science to establish the necessary infrastructure to prepare our fellows for successful careers in tobacco regulatory science, respond effectively to FDA rapid response and other initiatives, and to nurture partnerships and collaborations within the TCORS network. Overall, we feel that this Core is well positioned to continue and enhance its mission of preparing the next generation of tobacco regulatory scientists.

Despite marked reductions in cigarette smoking in the general population, smoking rates among economically disadvantaged women have increased. Smoking among women of reproductive age is a particular concern because in addition to the usual health risks, there are additional risks should they become pregnant. A national nicotine reduction policy for cigarettes has considerable potential to reduce tobacco use, dependence, and improve health in these smokers. Controlled trials in general population samples have demonstrated that switching smokers to very low nicotine content cigarettes (VLNCCs) reduces cigarettes per day (CPD), dependence severity, and tobacco toxicant exposure. Our research during the current funding period indicates that disadvantaged women respond to VLNCCs with reductions in smoking rates, cigarette demand, dependence severity, and other measures of addiction. However, tobacco market conditions are likely to exert a considerable moderating influence over the effectiveness of a nicotine reduction policy. During the next funding period, we will utilize principles and methods of behavioral economics and behavioral pharmacology to model effects of a reduced nicotine policy among disadvantaged women when implemented alone or while providing a readily available substitute, non-combusted source of nicotine (e-cigarettes). To model the potential influence of flavors, e-cigarettes will be examined in tobacco flavors only or appealing personalized flavors. This study will be a multi-site trial using a between-subject, four parallel groups, pragmatic design. Disadvantaged female smokers (18-44 yrs) will be randomized to 16 weeks of: (1) normal nicotine content cigarettes (NNCCs) alone, the control condition; (2) VLNCCs alone; (3) VLNCCs + nicotinized, tobacco-flavored e-cigarettes (TF e-cigs); or (4) VLNCCs + nicotinized, preferred-flavor e-cigarettes (PF e- cigs). Outcome measures include CPD, product demand, craving, appeal, toxicant exposure, brain function, and airway inflammation. In Week 17, participants will undergo an abstinence assessment to test whether the experimental conditions affect the ability to abstain from cigarettes. The integrative theme of this TCORS is vulnerable populations. The proposed research is highly relevant to CTP's scientific domains of Addiction and Behavior because it will test whether reducing the nicotine content of cigarettes reduces cigarette use, dependence, and product appeal, and whether these effects are enhanced by the availability of an appealing alternative source of non-combusted nicotine. It addresses the Health Effects domain by assessing effects on important biomarkers. It is significant and innovative because it will model how availability and appeal of e- cigarettes may moderate the effectiveness of a national reduced-nicotine policy in an understudied, vulnerable population. Finally, it is programmatic as it will build upon work accomplished during the current funding period. Overall, this proposal has the potential to continue a productive, multidisciplinary program of research that will provide FDA with critically important evidence relevant to its regulatory responsibilities.

The overarching goal of this application is to renew the University of Vermont Tobacco Center of Regulatory Science (UVM TCORS). This multidisciplinary center is located at UVM but leverages close collaborations with Brown University, Johns Hopkins University, University of Pittsburgh, and University of Minnesota. The UVM TCORS focuses on a crosscutting integrative theme (vulnerable populations) and two of the scientific domains (addiction, behavior) of the Food and Drug Administration Center for Tobacco Products (FDA CTP). Building programmatically on research in the current funding period, we propose to focus our primary studies on three vulnerable populations, socioeconomically disadvantaged women of reproductive age/pregnant, individuals with comorbid opioid use disorders, and individuals with comorbid affective disorders. Each of these populations is at increased risk for tobacco use, dependence, and tobacco-related adverse health outcomes. Despite their increased risk, these populations are often excluded from tobacco regulatory studies, leaving a significant knowledge gap. The overall goal of the UVM TCORS is to provide FDA CTP with sound scientific evidence on the impacts of tobacco products in vulnerable populations, a topic that is critically important to FDA CTP effectively executing its tobacco regulatory responsibilities. Regarding specific regulatory priorities, we will continue to focus on reduced nicotine standards in combusted tobacco products. We have designed our studies in vulnerable populations to align with those conducted in healthier populations by the University of Pittsburgh/University of Minnesota TCORS. The primary trials proposed in this application will examine the extent to which the availability and appeal of alternative non-combusted sources of nicotine (i.e., e-cigarettes) may moderate the impact of reduced nicotine standards on reducing cigarette smoking. That topic will be investigated in each of the primary vulnerable populations of interest using common protocols to the extent possible, and also protocols that facilitate comparisons with studies in healthier populations as noted above. We propose to continue our Administrative and Career Enhancement Cores. The Administrative Core supported completion of three multisite studies, with three others underway, during the past 4 years, along with numerous pilot/developmental studies. Cumulatively, those projects resulted in 58 publications in peer- reviewed journals and many more presentations at national scientific meetings. We are proposing a plan to effectively recruit and implement pilot and rapid-response studies. We propose to continue a highly effective predoctoral and postdoctoral mentoring program comprising 10 fellow slots that have been continuously filled during the current funding period. We will continue contributing to FDA CTP conferences and other scholarly initiatives, and plan to continue leading the Vulnerable Populations TCORS Workgroup and to participate in others. Overall, UVM TCORS is well positioned to be a valuable asset to FDA CTP and others with interests in tobacco regulatory science especially as it applies to vulnerable populations.

The University of Vermont Tobacco Center of Regulatory Science (UVM TCORS) Administrative Core was established during the current funding period with the administrative, fiscal, and technical support staffing necessary to support a vibrant, multidisciplinary research center focused on examining the addiction potential, underpinning behavioral processes, and health impacts of using new and existing tobacco products. The Core provides fiscal management, monitors adherence to regulatory oversight, and promotes open communication and collaboration. The Core provides the intellectual infrastructure necessary to support senior and early- career investigators in tobacco regulatory science, with a particular focus on investigating the potential impact of reduced nicotine standards on cigarette smoking in vulnerable populations. The Core also encourages and facilitates local, national, and international collaboration, makes effective use of the knowledge of its accomplished consultants and advisors, and nurtures interest in the importance of tobacco regulatory science for reducing smoking prevalence and tobacco-related morbidity and mortality in vulnerable populations. In the proposed funding period, the Administrative Core services will be augmented to include solicitation, review, administration and reporting for the UVM TCORS Rapid Response Projects program. Core leadership is provided by Stephen T. Higgins, PhD (Director), John R. Hughes, MD (Senior Associate Director), and Andrea C. Villanti, PhD, MPH (Associate Director of Operations). Together this Core has overseen the management of six multi-site studies and almost 30 developmental and pilot projects during the current funding period; organized and hosted 4 national conferences, with dedicated content on tobacco regulatory science; planned a 5th national conference exclusively focused on tobacco regulatory science scheduled for October of this year; edited 4 Special Issues of the peer-reviewed journal Preventive Medicine based on conference proceedings; and supported publication of 58 articles in peer-reviewed journals. The Core also provides administrative support for our successful mentoring program, which includes four predoctoral and six postdoctoral slots that were continuously filled during the current funding period. The team is well positioned to continue to provide strong management in this renewal proposal, building on the existing infrastructure for communication, coordination, and collaboration across the four proposed research projects and two cores. This infrastructure will also be leveraged to sustain and enhance existing collaboration with NIH, FDA, and other TCORS colleagues through our annual conferences, leadership in FDA workgroups, and Rapid Response Projects. Overall, we are confident that the proposed Administrative Core will allow us to sustain and enhance this center of research and mentoring excellence in tobacco regulatory science. !

PROJECT SUMMARY CORE C: Collaboration, Dissemination, and Education (CDE) Core The Vermont Center on Behavior and Health (VCBH) is an interdisciplinary research center that investigates relationships between personal behavior and risk for chronic disease and premature death. The overarching aim of the VCBH Collaboration, Dissemination, and Education (CDE) Core is to nurture and coordinate relationships between the VCBH and leaders in Vermont health care policy and delivery as well as with collaborating university partners located in other IDeA states and beyond. We propose that Stephen T. Higgins, PhD, and Richard Rawson, PhD, continue as Co-directors, and Diann E. Gaalema, PhD, as Associate Director. Locally, we have established multiple collaborations with Vermont healthcare policy makers including the University of Vermont (UVM) Medical Center, Vermont Department of Health, and public and private health insurers that we propose to continue and develop further. Nationally, we have established collaborations with colleagues at universities in other IDeA states (Brown University, University of Kentucky), and plan to expand them to include universities located in other IDeA states (Dartmouth College, University of Maine, University of Nebraska), non-IDeA states (Johns Hopkins University, State University of New York at Buffalo, Wayne State, Laureate Institute), and internationally (University of Glasgow, Oviedo University, Makerere University). These collaborations have already fostered substantive new research and funding opportunities and we are confident that they will continue to do so. To facilitate dissemination of advances in this research area we have established a UVM lecture series in behavior and health that is live streamed to collaborators and others, and also recorded and stored on the VCBH website, an annual national conference on behavior change, health, and health disparities, and a series of Special Issues of the peer-reviewed journal Preventive Medicine based on conference proceedings. VCBH scientists regularly participate in other national and international conferences and publish in peer-reviewed journals, a practice that in the past four years has resulted in 118 peer-reviewed publications. Overall, we are confident that continuation and further development of these practices will firmly establish the VCBH as a vibrant, interdisciplinary center of biomedical research excellence with local, national, and international impact, while also providing important career development opportunities for VCBH early-career faculty and predoctoral and postdoctoral fellows.

PROJECT SUMMARY The purpose of this application is to continue the University of Vermont?s highly successful 30-year T32 training program in the human behavioral pharmacology of drug use disorders. During the past 15 years, we trained 16 predoctoral and 22 postdoctoral fellows. Among those 38 fellows, all but two remain involved in research-related careers. Twenty-five have completed the training phase of their careers. Among those 25, 14 (58%) have primary university faculty/research-institute positions, six (24%) have been principal investigators (PI) on one or more NIH research awards, seven (28%) are employed by government agencies, two (8%) work in industry, and collectively they have more than 500 peer-reviewed publications on addiction. In addition to being a productive training program, the training our fellows receive in human behavioral pharmacology fills a unique niche in addiction research. Our fellows learn to identify basic behavioral and pharmacological processes underpinning addiction and to translate that knowledge into effective clinical interventions and policy. We propose to continue our emphasis on human behavioral pharmacology in the next funding period, continuing our expansion into tobacco regulatory science and the impact of addictive behavior on health outcomes. Since the last T32 renewal, we renewed our U54 Tobacco Centers of Regulatory Science (TCORS) and P20 Center of Biomedical Research Excellence (COBRE) awards in behavior and health, and obtained a new UD9 Center Award in Rural Addiction. These Centers add value to our training program via access to additional seminars, guest lectures, interactions with additional fellows and guests, and new research and career opportunities. Indeed, three of our T32 fellows have taken research scientist positions with FDA?s division on tobacco regulation. We propose to continue supporting four predoctoral and four postdoctoral training slots with this T32 award. The eight members of the proposed training faculty consist of seven PhDs and one MD. These faculty members are PIs on three NIH/HRSA center grants, five R01s, two R33/34s, two R21s, and one private- foundation award creating a rich range of training opportunities in addiction research. All faculty and fellows are located at a single, on-campus site composed of 8000 sq. ft of newly renovated space. Fellows are selected based on scholastic excellence and commitment to a career in addiction research. Predoctoral fellows are enrolled in the Department of Psychological Science PhD programs in experimental or clinical psychology where they complete required coursework including those developed for this training program, and complete master?s and doctoral theses. Postdoctoral fellows primarily focus on conducting and supervising independent research, with additional opportunities to further their education via coursework. Each fellow has a primary mentor from the training faculty. Fellows attend weekly seminars in addiction research and ethics. Additionally, they present their research at two or more national scientific meetings annually. The training period is generally 4-5 years for predoctoral and 2-3 years for postdoctoral fellows. The overarching goal of the proposed training program is to continue developing productive, independent, state-of-the-art addiction researchers.