John R. Hughes - US grants

This is an application for an ADAMHA RSDA (Level 1). While the candidate has published experimental work and obtained research funding, a full clinical load as a staff physician and little formal training in research techniques have hampered his development as a research scientist. This RSDA will help the candidate become a full-time researcher by relieving him of his clinical duties and providing research training and experience. The specific aim of the RSDA will be to provide the candidate with a working knowledge of a variety of methodologies and concepts applicable to research on smoking as a dependence process. The main site for the training and research experience will be the Departments of Psychiatry and Psychology at the University of Minnesota. Both departments have several investigators in drug dependence and have a long history of research in the area. The sponsor will be Roy W. Pickens, Ph.D., a Professor in both departments who has extensive experience in training and research in drug dependence. The training will consist of 1) didactic course work, primarily in behavioral pharmacology, drug abuse and tactics of scientific research, 2) collaboration with faculty in ongoing research projects and 3) participation in the existing NIDA training program in drug dependence. In addition, off-site training will occur at the NIDA Addiction Research Center (supervised by Jack Henningfield, Ph.D.) and the Addiction Research Unit of the Institute of Psychiatry in London (supervised by M.A.H. Russell, M.D.). The research experience will consist of participation in 17 studies in 4 areas in which the candidate has aleady begun working: 1) nicotine self-administration, 2) measurement of smoking behavior, 3) tobacco withdrawal, and 4) use of nicotine gum in smokers. With these studies, the candidate will learn a variety of research strategies (from laboratory psychophysiology to clinical studies in physicians' offices). Most of the studies (14 of 17) will be funded from 5 existing NIDA and NCI grants. Evaluation of the RSDA will be by a team of local advisors. In addition, an established investigator will visit the institution annually to review the career development of the candidate. This RSDA will provide the time, training and research experience necessary for the candidate to develop a full-time research career in smoking as a dependence process.

Nicotine gum has been recently approved as a prescription drug to help smokers stop smoking. Despite both theoretical and clinical evidence that a substantial proportion of patients will persist in chronic use of the gum, a study of the self-administration properties of the gum has not been performed. In the first study of this proposal, the patterns of self-administration of nicotine gum will be determined among smokers seen in a general medical practice who follow FDA-approved guidelines for gum use. This study will use a double-blind placebo-controlled design to determine the incidence of chronic use of gum after the prescribed period and the relationship between chronic use and behavioral factors (e.g., history of abuse of other drugs. A second set of studies will test whether factors that control the self-administration of other drugs of abuse also control self-administration of nicotine gum. The factors to be studied are (1) dose (1 vs. 2 vs. 4 mg gum), (2) response cost (free vs. half price vs. full price gum), (3) schedule of self-administration (i.e., ad-lib vs. fixed times), and (4) duration of exposure (1 vs. 2 vs. 3 mo.). The studies proposed will provide the first experimental determination of how nicotine gum is actually used, the incidence of chronic use of the gum, and factors that can be used to identify smokers at increased risk of chronic use (Study 1), as well as prescription practices that can be used to reduce chronic use of nicotine gum (Studies 2-5).

This study will test whether abstinent smokers who experience intense withdrawal are more likely to relapse to smoking than abstinent smokers who experience little withdrawal. Most smokers who quit on their own relapse in the first two weeks. Whether this is due to aversive withdrawal symptoms (e.g. irritability) is unknown because prior studies have had several major flaws; e.g., retrospective designs, nongeneralizable samples and unvalidated, self-report measures of withdrawal. We have experimentally documented several physiological signs and observable behaviors that reliably occur upon cessation of smoking and have the characteristics of classical withdrawal syndromes. We now propose to prospectively test the ability of these withdrawal variables to predict relapse in self-quitters. 1000 smokers who are about to quit on their own will name a reliable observer to rate their withdrawal behavior. These observer ratings plus weight, heart rate, and self-reported symptoms will be recorded prior to and 2, 14 and 30 days after subject quit. One year later, salivary cotinine will verify whether smokers have relapsed. We will test the hypothesis that among smokers who quit for 2 days, those with more intense withdrawal are more likely to relapse by one year follow-up. The results of this study will be a crucial, direct test of the nicotine dependence theory of smoking. The results will also encourage or discourage the development of smoking treatments designed to combat withdrawal symptoms.

Over 90% of Americans drink caffeinated beverages daily. Caffeine appears to fulfill several criteria for a drug of dependence; i.e., it can produce: 1) adverse effects (e.g. arrythymias, insomnia, etc.), 2) physical dependence (e.g. withdrawal symptoms of headache and fatigue), and 3) behavioral effects that might be rewarding (e.g. decreased fatigue and improved performance). However, whether caffeine fulfills the most crucial criteria for dependence potential - ability to serve as a reinforcer - is debatable. For example, whether coffee drinkers will consistently self-administer caffeinated coffee in preference to decaffeinated coffee has only begun to be studied. The ability of a drug to function as a reinforcer is highly dependent on pharmacological, environmental and behavioral conditions. This application proposes six parametric studies to determine conditions under which caffeine will serve as a reinforcer. We will test dose (25, 50, 100, & 150 mg), present history of drug use (heavy users, light users & abstainers), vehicle (coffee, non-coffee beverage & capsules), instructions (told beverage does or does not contain caffeine), fatigue (after normal sleep vs. after sleep deprivation) and method of testing (concurrent access vs. exclusive choice tests). These studies will help NIDA deliver rational public information about whether coffee drinking is a drug dependence. They will also help devise treatments for those who need to abstain from caffeine but have difficulty doing so. Finally, the studies will test whether commonalities across forms of substance abuse can be extended to coffee drinking.

Laboratory studies will develop methods to examine the reinforcing and discriminative effects of alcohol, caffeine and nicotine in humans, examine the effects of nicotine administration in smokers and nonsmokers, further characterize caffeine and nicotine withdrawal, describe the effects of combining stimulants (e.g. cocaine) and sedatives (e.g. alcohol) and test the effects of drugs on learning, performance and social interaction. Laboratory studies will also examine the influence of environmental, pharmacological, organismic (e.g. behavioral history and genetics) and procedural variables on the reinforcing, discriminative, and direct effects of drugs. Epidemiological studies will longitudinally study the process of smoking cessation in self-quitters, examine the prevalence of DSM-III-R defined caffeine and nicotine disorders, and test the association of nicotine dependence with past and present psychiatric disorders. Treatment studies will test new nicotine replacement and non-nicotine pharmacological treatments for nicotine dependence, as well as behavioral treatments for cocaine and nicotine dependence. Continued funding of the candidate will help develop the Human Behavioral Pharmacology Laboratory and allow the applicant to select only administrative, clinical and teaching activities that are consistent with his career goals and growth of the laboratory.

Over 85% of alcoholics smoke, most are heavy smokers and many die of smoking-related illnesses. Despite the recent interest of both patients and clinicians, experimental studies of treatment for smoking cessation among alcoholics are lacking. A post-hoc finding in an earlier study of ours suggests recovering alcoholic smokers are more dependent on and are especially benefitted by nicotine replacement therapy. We propose to prospectively test this finding by randomly assigning recovering alcoholics to group behavior therapy plus either nicotine or placebo transdermal patches in a double-blind manner. 200 Ss at two sites (VT & MN) will receive daily patches and weekly group therapy for 12 was. Biochemically verified smoking abstinence and observer- and self-ratings of nicotine withdrawal and craving will be obtained. These results with recovering alcoholics will be compared with those from smokers drawn from the general population who were tested with the exact same patch and protocol in an earlier study. We will also compare desire for alcohol and confidence in not relapsing back to drinking between our recovering alcoholics who are abstinent from smoking with a group of recovering alcoholic smokers who are not trying to stop smoking. Post-hoc analyses will be used to estimate the optimal timing pose-drinking for smoking cessation to occur. This trial will provide initial information on whether 1) transdermal nicotine plus group behavior therapy is an effective treatment for smoking cessation in recovering alcoholics, 2) recovering alcoholics are less likely to stop smoking in a smoking cessation program than smokers in the general population, 3) stopping smoking increases desire to drink alcohol or decreases confidence in not relapsing to alcohol, and 4) it is better to attempt smoking cessation soon after or long after achieving sobriety. Positive results would encourage recovering alcoholics to enter and their counselors to provide smoking cessation treatment.

APPLICANT'S ABSTRACT: This application is to renew a Research Scientist Development Award, Level 2 (K02) from NIDA. The goal of this RSDA is to free the applicant from clinical and administrative duties so he can conduct and acquire training in laboratory, treatment and epidemiological studies on nicotine and caffeine. Despite increasing public and governmental concerns around nicotine and caffeine use and dependence, to our knowledge, this is the only NIDA-funded RSDA that focuses on nicotine or caffeine. In the first 4 yrs of the prior KO2, the applicant published 108 articles, including articles in NEJM, JAMA and JPET, fostered growth of the University of Vermont, Human Behavioral Pharmacology Laboratory (HBPL), mentored several undergraduate graduate, post- graduate and medical students and several physicians served as a resource to the University of Vermont, the State of VT, NIDA and other federal agencies, the general public and the media on drug abuse matters, especially policy issues about nicotine and caffeine use. In the renewal the applicant proposes laboratory studies to test the conditions that control the reinforcing and subjective effects of nicotine and caffeine, nicotine and caffeine withdrawal, and the effect of nicotine and caffeine on the use of other drugs of abuse; treatment studies to test new nicotine and nonnicotine therapies for nicotine dependence both in the general population and in alcohol/drug abusers; and epidemiological studies to examine the utility of DSM/WHO generic criteria for drug dependence/abuse when applied to nicotine and caffeine. In addition, the applicant will continue collaboration with Drs. Bickel and Higgins in studies of alcohol, benzodiazepine, cocaine and opioid use/dependence.

The major aim of this study was to determine whether one's past history of smoking or alcoholism is associated with a different response to nicotine. We tested this by exposing never, ex and current smokers to nicotine via nicotine gum and by exposing current smokers with and without a history of alcoholism to nicotine.

The subjective effects and degree of seeking or avoiding of nicotine will be compared among neversmokers (NS), ex-smokers (ES), current smokers (CS), and current smokers with a history of alcohol dependence. During a three-day exposure period, subjects receive three doses each day of either 0 mg, 2 mg or 4 mg nicotine gum in a double-blind, randomized crossover. Subjects provide subjective ratings (euphoria, liking, etc.) after each dose. On the fourth day, subjects (Ss) choose among the three types of gum to which they were exposed previously. Saliva samples will be analyzed in the GCRC Biochemistry Core Laboratory for levels of nicotine and cotinine.

DESCRIPTION: (Applicant's Abstract) Despite many years of education, social pressure, physician advice and effective treatments, the average smoker tries to quit only once every three years; thus, interventions to prompt smoking cessation are needed. This application tests whether a behavioral instruction program plus nicotine gum will induce a large and durable reduction in smoking and whether this will serve as a success experience and thereby prompt a quit attempt. Smokers who do not plan to quit smoking in the next month will be randomly assigned to one of four groups: non-specific therapy + brief advice to quit, a behavioral instructional program to reduce smoking + brief advice to quit, behavioral instructions to reduce + advice + placebo gum, or behavioral instructions to reduce + advice + nicotine gum. To increase generalizability, treatment will be delivered via written materials and five telephone contacts. Our major hypothesis is that both behavioral instructions to reduce and nicotine gum will each increase quit attempts over the ensuing 12 months. We will also test whether increased self-efficacy or the magnitude and duration of reduced smoking mediate any increase in quit attempts. Finally, we will monitor the safety of concurrent use of gum and cigarettes. The present application is not designed to test reduced smoking as a treatment for cessation among smokers trying to quit (i.e., "gradual reduction"). It also is not a test of reduced smoking as a goal in itself (i.e., "harm reduction"). Rather, the application focuses on using reduced smoking to prompt cessation. Current public health strategies discourage reduced smoking. If we show reduced smoking prompts quit attempts, it will suggest reconsideration of reduced smoking as an intermediary step toward quitting smoking.

DESCRIPTION: (Applicant's Abstract) Cigarette substitutes (CS) have been and continue to be developed. Although advertised for smokers concerned about secondhand smoke, many smokers may see these as safer cigarettes and alternatives to cessation. We will determine a) by whom, why and how such substitutes are used, b) whether CS use undermines motivation to stop smoking, and c) whether CS use (+/- cigarette use) produces less nicotine and toxin exposure than cigarettes. One survey and two experimental studies will examine the newest CS: Eclipse. We will survey 400 Eclipse users to determine their characteristics (e.g., level of nicotine dependence), reasons for purchase (e.g., to decrease risks of smoking), pattern of use (e.g., along with vs instead of cigarettes), etc. These users will be compared to 400 smokers who have not used Eclipse to determine who is attracted to CSs. Both groups will be followed for one year to determine whether the incidence of attempts to stop smoking is less in CS users than nonusers. Study 2 will enter 60 smokers interested in using a CS to an A-B-A design of smoking their normal cigarette for 3 weeks, followed by using Eclipse for 12 weeks, followed by a return-to-baseline for 3 weeks. The major dependent variables will be CS and cigarette use, cotinine, CO, SCN, withdrawal symptoms, product ratings, adverse events and vital signs. Whether or not Eclipse itself becomes a commonly used product, CSs are very likely to be marketed in the near future. We believe it imperative to begin studying these substitutes so that, unlike low-tar/low nicotine cigarettes, we will know whether their introduction is good or bad for public health.

DESCRIPTION: (Applicant's Abstract) This Research Scientist Award (K05) will a) generate research on interventions for smokers who are and are not currently interested in quitting and b) assist professional (e.g. SRNT) and governmental (e.g. WHO) organizations interested in tobacco control. The applicant's past research contributions include description of the nicotine withdrawal syndrome, psychiatric comorbidity, the role of expectancies in nicotine effects and caffeine reinforcement and dependence in humans. In the last K02, the applicant averaged 17.2 papers/yr of which he was first author on 12.2/yr and of which 6.2/yr were empirical studies. He founded the Human Behavioral Pharmacology Laboratory (HBPL) at UVM and cofounded the Society for Research on Nicotine and Tobacco (SRNT). This K05 will examine interventions for smokers not interested in quitting: i.e., reduced smoking, using Eclipse, and offering free samples of NRT to use during smoking restrictions or during "test quits." The K05 will also investigate interventions for smokers currently interested in quitting. i.e, it will compare gradual vs abrupt, group vs individual and patient-vs expert-chosen interventions and interventions for treatment-resistant smokers. The K05 will include assisting other drug abuse researchers at UVM. The applicant will continue to mentor 4-6 students/yr and to explore new disciplines (e.g., diagnostic nosology) and methodologies (e.g. Markov models, IVR technologies). This would be the first NIDA K05 to focus on nicotine dependence.

DESCRIPTION (provided by applicant): This revised competing continuation tests whether a gradual reduction treatment we found effective for smokers not interested in quitting in our prior grant period will also be effective as a treatment for smokers who are trying to quit. Most treatment guidelines, reviews and tobacco control programs recommend abrupt cessation over gradual cessation yet many smokers prefer to quit gradually. Although recent work suggests gradual cessation may be effective, the five experimental studies of gradual vs. abrupt cessation have produced inconsistent results and had methodological problems such as small sample sizes. We hypothesize gradual cessation is more efficacious than abrupt cessation when aided by nicotine replacement. We will randomize 750 smokers to receive gradual cessation counseling (aided by pre-cessation nicotine lozenge) vs. abrupt cessation counseling vs. no counseling prior to the quit date. The first two conditions will receive 60 min of phone counseling prior to the quit date. After the quit date, all three conditions will receive nicotine lozenge for cessation and one 10 min counseling phone call. Our major outcome will be 6-month prolonged abstinence. We also hypothesize that significant adverse events are not greater when using lozenge with gradual cessation than with abrupt cessation. Prior to the trial, pilot work will include focus groups, a small survey, development of treatment manuals, recruitment strategies and mediator measures and a pilot rehearsal of the final protocol. This revision adds procedures to increase and verify treatment fidelity and decreases the number of differences between the two active treatment groups. If we find gradual cessation produces higher quit rates than abrupt cessation, this would suggest cessation services should encourage gradual cessation. If we find abrupt cessation is superior to gradual cessation, this would be the most comprehensive verification of the current practice of recommending abrupt cessation for all smokers. If we find gradual and abrupt cessation produce similar outcomes and if gradual cessation counseling is better than no counseling, this would suggest gradual cessation should be offered to those who request it. This study will be the first large, systematic test of gradual vs. abrupt cessation.

DESCRIPTION (provided by applicant): This competing continuation of a Senior Scientist Award (K05) will allow the applicant to conduct research on cessation and reduction of tobacco and marijuana use and on new methods to treat nicotine and cannabis dependence. The K05 would allow the PI to continue leadership roles in organizations interested in tobacco research and tobacco control and to continue science education activities such as mentoring and teaching. The applicant's past research contributions include description of the nicotine withdrawal syndrome, psychiatric co-morbidity with nicotine dependence, abuse liability of nicotine replacement, the role of expectancies in nicotine effects, caffeine reinforcement and dependence, and harm reduction approaches to nicotine dependence. The applicant founded the Human Behavioral Pharmacology Laboratory at the University of Vermont (UVM) and co-founded the Society for Research on Nicotine and Tobacco and the Association for the Treatment of Tobacco Use and Dependence. In the prior K05, the applicant averaged 13 published papers/yr of which he was first author on 9/yr and of which 7/yr were empirical studies. UVM has several resources to aid the applicant to learn new disciplines and methods; e.g. UVM currently has 25 NIH grants on drug abuse across 13 Pis. This continuation proposes tobacco studies to a) compare the efficacy of NRT-assisted abrupt vs gradual cessation, b) test a cannabinoid antagonist for smoking cessation, c) test a computer mediated clinical decision support system to help clinicians treat tobacco dependence, d) describe why the large majority of smokers do not seek free treatment and e) comprehensively review the world literature on the nicotine withdrawal syndrome. The continuation proposes a new line of research on marijuana to f) describe the natural history of attempts to stop or reduce marijuana use, g) determine if the marijuana withdrawal syndrome is due to THC deprivation, h) directly compare the clinical significance of marijuana and tobacco withdrawal syndromes, i) describe marijuana withdrawal in treatment seekers and j) describe marijuana withdrawal in adolescent marijuana users. The continuation will also include collaborating with other drug abuse researchers at UVM and elsewhere. The applicant will continue to mentor 4-6 students/yr and to be actively engaged in media and policy initiatives.

DESCRIPTION (provided by applicant): The purpose of this grant is to discover the most important attitudes and beliefs (i.e., internal barriers) that prevent smokers from seeking treatment; e.g., beliefs that seeking treatment is a sign of weakness or that treatments do not work. Such knowledge could be used to devise media and other interventions to increase treatment seeking among smokers. Several behavioral and pharmacological treatments for smoking cessation have been well validated; however, even when external barriers such as awareness, cost and availability are minimized, few smokers trying to quit access treatment. We hypothesize certain beliefs and attitudes of smokers are internal barriers to seeking treatment. Studies have examined internal barriers to attempting to quit smoking and to succeeding in quitting smoking; however, few have examined internal barriers to seeking treatment per se. We will focus on the use of telephone help line treatments as this is the most commonly used psychosocial treatment for smoking cessation and is free of most external barriers; e.g., high cost and low availability. Study 3 is our main validity test of whether internal barriers are important. Studies 1A and 1B will generate a list of possible internal barriers to use in Study 3. Study 1A will interview 16 smoking cessation/drug dependence experts on why smokers/drug abusers do not seek treatment even when external barriers are minimized. Study 1B will ask 80 smokers who have recently tried to stop smoking and were aware of an available phone quit line to volunteer reasons they did or did not use this treatment. Study 2 will select barriers to be used in Study 3. We will administer barrier items from Studies 1A and 1B to 400 recent quit attempters to examine understandability and response bias. We will conduct an exploratory factor analysis in 200 of these smokers to derive a set of factors that covers the breadth of internal barriers followed by a confirmatory factor analysis in the other 200 smokers. We will also conduct tests of test-retest reliability, content validity, concurrent validity and discriminant validity. Study 3 will be a test of predictive validity; i.e. a test of whether our internal barrier factors prospectively predict use of a help line. We will recruit 560 smokers who plan to quit in the next 30 days, inform them of a free phone help line and ask them our barrier items. They will be re-contacted 2 months later to determine which of our internal barrier factors best predict calling the help line. To assess generalizability, we will also determine if our factors also predict use of other smoking cessation treatments. Our results will suggest messages for media campaigns and for clinicians to use to motivate smokers to access proven treatments.

DESCRIPTION (provided by applicant): This competing continuation of a Senior Scientist Award (K05) will allow the applicant to conduct research on cessation and reduction of tobacco and marijuana use and on new methods to treat nicotine and cannabis dependence. The K05 would allow the PI to continue leadership roles in organizations interested in tobacco research and tobacco control and to continue science education activities such as mentoring and teaching. The applicant's past research contributions include description of the nicotine withdrawal syndrome, psychiatric co-morbidity with nicotine dependence, abuse liability of nicotine replacement, the role of expectancies in nicotine effects, caffeine reinforcement and dependence, and harm reduction approaches to nicotine dependence. The applicant founded the Human Behavioral Pharmacology Laboratory at the University of Vermont (UVM) and co-founded the Society for Research on Nicotine and Tobacco and the Association for the Treatment of Tobacco Use and Dependence. In the prior K05, the applicant averaged 13 published papers/yr of which he was first author on 9/yr and of which 7/yr were empirical studies. UVM has several resources to aid the applicant to learn new disciplines and methods; e.g. UVM currently has 25 NIH grants on drug abuse across 13 Pis. This continuation proposes tobacco studies to a) compare the efficacy of NRT-assisted abrupt vs gradual cessation, b) test a cannabinoid antagonist for smoking cessation, c) test a computer mediated clinical decision support system to help clinicians treat tobacco dependence, d) describe why the large majority of smokers do not seek free treatment and e) comprehensively review the world literature on the nicotine withdrawal syndrome. The continuation proposes a new line of research on marijuana to f) describe the natural history of attempts to stop or reduce marijuana use, g) determine if the marijuana withdrawal syndrome is due to THC deprivation, h) directly compare the clinical significance of marijuana and tobacco withdrawal syndromes, i) describe marijuana withdrawal in treatment seekers and j) describe marijuana withdrawal in adolescent marijuana users. The continuation will also include collaborating with other drug abuse researchers at UVM and elsewhere. The applicant will continue to mentor 4-6 students/yr and to be actively engaged in media and policy initiatives.

DESCRIPTION (provided by applicant): Smoking cessation can be enhanced either by increasing the success of quit attempts or by increasing in the number of quit attempts. Although many studies have determined the variables that influence remaining abstinent after a quit attempt, few have examined the variables that influence the onset of a quit attempt. The current application tests two facets of a model of the processes that lead to a quit attempt. First, we test whether certain environmental cues (e.g., a request from a child to quit smoking or exposure to a smoking-related health message) increase the probability of a quit attempt in the near future. We also examine whether such cues predict attempts over and above the predictive ability of cognitive factors such as self-efficacy and perceived social norms and whether these cognitive factors interact to make cues more powerful predictors. Second, we test whether planning behaviors (e.g. seeking information about treatment) and setting a quit date are common and increase the probability of a quit attempt. We also provide a more rigorous replication test of prior findings that spontaneous, unplanned quit attempts are more successful than delayed, planned quit attempts. In a pilot study, we will develop measures of external cues and planning activities. The main study is a non-treatment, prospective, natural history study. In this study, we will recruit 200 adult daily smokers who are interested in quitting in the next 6 months. They will call an Interactive Voice Recording (IVR) system daily and complete mailed or internet questionnaires weekly for 6 months. Our prior work has shown that we can obtain such daily and weekly reports for 6 months with little missing data. The daily IVR will record tobacco use/abstinence, intentions to quit, external cues and planning behaviors. The weekly questionnaires will measure cognitive variables and other outcomes (e.g. other drug use). Data analysis will use multilevel models designed to accommodate many repeated measures over time within participants. The results of this study will a) help develop a model of the causes of smoking cessation attempts, b) guide development of media and individual interventions to motivate smokers to make a quit attempt, and c) provide a more rigorous test of whether spontaneous, impulsive quit attempts should be encouraged rather than delayed, planned quit attempts. PUBLIC HEALTH RELEVANCE: Despite many public health efforts, most smokers do not try to quit in a given year and, despite significant public health efforts, the number of smokers who try to quit each year has not increased in the last 15 yrs. We propose a study to better understand how smokers decide to quit smoking;e.g., what cues prompt them to try to quit and how much they plan out their quit attempts. The study will also test a recent finding that smokers who make a spontaneous, unplanned quit attempt do better than those who delay and plan out their quit attempt. The study will have smokers call in information daily or weekly about cigs/day, exposure to cues to stop smoking, their intentions to quit, their actual quit attempts, etc for 6 months. The results of this study will a) help develop media and individual interventions to motivate smokers to make a quit attempt, and b) help decide if smokers should be encouraged to quit spontaneously or wait and plan out their quit attempts.

DESCRIPTION (provided by applicant): The major aim of this study is to provide a detailed understanding of attempts to stop or reduce marijuana use that can be used to develop better behavioral treatments for marijuana dependence. The application will provide a prospective description of attempts by dependent adult marijuana users to stop or reduce their marijuana use in a real-world setting. Although prospective, natural history studies describing attempts to stop or reduce alcohol, heroin and tobacco use have proved useful, we know of no such study among adult marijuana users. A pilot study will develop measures and assess compliance with our procedures. The main study will recruit 200 daily, adult marijuana smokers who plan to quit or reduce in the near future. Participants will call an Interactive Voice Recording (IVR) system daily for 3 months to report marijuana use, intentions to change marijuana use, quit/reduction attempts, and events that might increase or decrease the probability of initiating a quit/reduction attempt or the success of an attempt. Participants will be called weekly to obtain more detailed measures such as other drug use, self-efficacy, psychiatric/medical symptoms, and treatment seeking. Phone follow-ups at 4, 5 and 6 months will track marijuana and other drug use and dependence/abuse. PUBLIC HEALTH RELEVANCE: Knowing what motivates marijuana users to try to stop or reduce, and knowing which strategies for stopping marijuana use are successful, can help develop treatments for marijuana dependence. For example, if stopping tobacco when trying to stop marijuana decreases the chance of stopping marijuana, then smoking cessation should be done after stopping marijuana. Or if reducing marijuana often leads to cessation, then convincing those not interested in quitting marijuana to first try reducing may be helpful.

0922961
Druschel

This MRI proposal seeks funding to acquire materials characterization equipment. Requested are a wavelength-dispersive spectrometer (WDS), and energy-dispersive spectrometer (EDS), and an electron-backscatter-diffraction unit (EBSD) to be added to an existing electron microscope. In addition, the PIs are requesting an x-ray diffractometer (XRD), and x-ray fluorescence spectrometer (XRF), a Raman spectrometer, and an optical microscope with digital imaging capabilities. Instrumentation will be put to use in NSF, EPA, USDA, NOAA, DoD, DOE and other agency-funded research. Major research areas involve understanding mineralogical controls on nutrient availability and mobility in watersheds, characterizing microbial-mineral and water interactions in watersheds and the critical zone, characterizing mixed phase materials such as zeolites and other microporous mineral matrices, understanding mineral distributions at mining sites, and physicochemical condition control by mineralogical microstructure. The fundamental research to be undertaken here will advance the state of knowledge for how mineralogical surfaces impact contaminant and natural compound movement and distribution in groundwaters, watersheds and in the critical zone. The studies will server as a foundation for education and training for environmental science and engineering. Equipment will be incorporated into classes and workshops. The equipment will be placed in recently-renovated existing laboratory space within the Department of Geology. The PIs will comprise the management team and will arrange training and administer day-to-day usage. Funded researchers will be charged a small fee to use the instrumentation. Online scheduling software will be used to solicit instrument use. The EDS will upgrade an existing EM, which is administered by a full-time technician.

***

With this award, co-funded by the Division of Chemistry and the Major Research Instrumentation (MRI) program , Professor Rory Waterman and colleagues Randall Headrick and John Hughes from University of Vermont & State Agricultural College will acquire a single-crystal X-ray diffractometer with low-temperature capabilities to be used in chemistry, geology and material science projects. The proposal is aimed at enhancing research training and education at all levels, especially in areas of study such as phosphaalkane synthesis, use of phthalocyanines for organic electronics and discotic liquid crystals, apatite OH-F-Cl ternary systems in geology, as well as studies of oxidation-reduction reactions of organotransition metal complexes and polycyclic heterocycles.

An X-ray diffractometer allows accurate and precise measurements of the full three dimensional structure of a molecule, including bond distances and angles, and provides accurate information about the spatial arrangement of a molecule relative to neighboring molecules. The studies described here will impact a number of areas, including organic and inorganic chemistry, materials chemistry and geology. This instrument will be an integral part of teaching as well as research.

DESCRIPTION (provided by applicant): Recent animal research indicates acute nicotine increases the reinforcing effects of other rewards; however, chronic use of nicotine recruits an opponent process that counteracts the acute effects of nicotine and decreases sensitivity to rewards. When nicotine is discontinued in animals, this opponent process persists and the resultant decreased sensitivity to rewards may be a cause of nicotine withdrawal symptoms such as depression and a cause of relapse back to smoking. Although this animal model is widely cited, whether decreased reward sensitivity occurs when smokers stop smoking is unclear. The investigators propose an experimental test that focuses on whether abstinent smokers a) are less sensitive to monetary rewards during an operant task and/or b) report anhedonia (less pleasure from rewards) and apathy (less motivation to seek rewards). The investigators will recruit 120 current smokers who plan to quit smoking for good to smoke their usual amount for one week and then will abstain for 4 weeks. To insure an adequate number of continuously abstinent smokers and to decrease selection bias, they will use monetary contingencies to encourage abstinence. The investigators anticipate this will produce > 70 smokers who remain abstinent for all 4 weeks. To assist in interpretation of results, they will also recruit a comparison group of 70 long-abstinent former smokers to be measured on the same schedule. The investigators will measure reward sensitivity three times each week using a) progressive ratio (PR) responding for monetary rewards and b) self-report measures of anhedonia and apathy scales. If reward sensitivity changes with abstinence, secondary aims will be to determine a) its magnitude, incidence and time course; b) whether it exhibits the time course expected of a withdrawal effect, c) whether reward sensitivity becomes similar to the level among long-abstinent smokers and c) whether decreased reward sensitivity could be the basis for much of withdrawal discomfort. The results of this study will be an important translational test of the leading animal model of nicotine withdrawal. If decreased reward sensitivity is found, this would suggest revisions in clinical descriptions of nicotine withdrawal, new targets for behavioral and pharmacological interventions and new treatments for smoking cessation (e.g., increased exposure to rewarding events). If reward sensitivity does not change with abstinence, then (given the adequacy of the investigators' test) this would suggest a widely cited animal model of abstinence effects may not be generalizable to human attempts to stop smoking.

DESCRIPTION (provided by applicant): Despite tobacco control interventions, the incidence of quitting among US adult smokers has not increased in the last decade. One new method to increase quit attempts is to have smokers reduce their cigs/day. We and others have shown that reduction aided by NRT can increase quit attempts and later abstinence among smokers not ready to quit. Because half of smokers are reluctant to use NRT for a non-cessation reason, we now propose to test whether reduction not aided by NRT can be effective. Another new method to increase quit attempts is motivational counseling. Although some studies have found motivational interviewing prompts quit attempts, this treatment is intensive (median time = 1.7 hours) and thus not practical in many settings. We previously found implementation of the USPHS Guidelines 5 Rs motivational intervention via three 15 min phone calls can provide a large increase in quitting (OR = 6.3). However, that study employed a no treatment control group~ thus, we propose to test for efficacy using a more clinically-relevant usual care control condition. We will proactively call adult, daily smokers to recruit 850 smokers who do not plan to quit in the next month and randomize them to a) reduction counseling without the aid of NRT, b) counseling guided by the USPHS 5 R's, or c) usual care. The first two conditions will be delivered via brief counseling calls at study onset and then 2 and 4 weeks later (total = 35 min). The usual care condition will consist of a brief (< 5 min) 2 As intervention and three newsletters providing information on quitting sent at these same times. Our major hypothesis is that the incidence of quit attempts over the 6 months of the study will be greater in both the reduction and the 5 Rs conditions than in the usual care condition. A secondary hypothesis is that the increase in quit attempts will lead to increased abstinence. Another secondary hypothesis is that beneficial effects of both treatments will be mediated by increases in self-efficacy and intentions to quit. A final hypothesis is that decreases in cigs/day and nicotine dependence will mediate the efficacy of the reduction treatment but not the 5 Rs treatment and, conversely, that a shift in decisional balance will mediate the efficacy of the 5 Rs treatment but not of the reduction treatment. If our two interventions are effective, this would encourage quitlines, healthcare organizations and clinicians to offer these time-limited interventions to ambivalent smokers. Also, having an action-oriented intervention (reduction) and a cognitive-oriented intervention (5 Rs) could increase the acceptability of these interventions to different types of smokers. Finally, prior studies have been interpreted to indicate that reducing cigs/day will increase later quitting~ however, all prior studies that have shown this included NRT to aid reduction~ thus, it may be that pretreatment, not reduction is the cause of any increase quitting in prior studies. A study showing that reduction without the aid of NRT increases later quitting would be the first direct test to indicate reduction per se aids later quitting. PUBLIC HEALTH RELEVANCE: New methods to prompt smokers to quit could have a significant public health impact. In a prior study, we found that, helping such smokers to reduce the number of cigarettes/day by counseling plus nicotine replacement therapy (NRT), or motivating them with brief discussions over the phone, both dramatically increased later quitting compared to no treatment. We now propose to re-test these treatments for three reasons: a) because most smokers are not willing to use NRT, we wish to see if reduction without using NRT is effective, b) we wish to test if our reduction and motivational treatments are better than current usual care and c) we wished to conduct a more rigorous experimental test.

DESCRIPTION (provided by applicant): Over-the-counter nicotine replacement therapy (OTC NRT) is, by far, the most common treatment for smoking cessation in the US. Over 80% of those using NRT will lapse and return to smoking. One possible reason for this high rate of treatment failure is that smokers are instructed to stop medication when they lapse (in contrast to recommendations to increase medication dose when heroin users lapse). Recent indirect evidence suggests that, in fact, a lapse is the most important time to continue NRT. We propose a randomized controlled trial of continued NRT post-lapse vs. stopping NRT post- lapse. Smokers who want to quit will receive, counseling, stop abruptly and begin NRT. All psychosocial treatment will occur via phone and medications via mail. Instructions and rationales for continuing or stopping NRT during a lapse episode will be delivered via written material, Interactive Voice Response (IVR) phone messages and reinforced during phone counseling. We will enter 1000 smokers and anticipate observing 580 lapses while using NRT. We hypothesize our intervention to continue NRT use upon a lapse will increase 6 month point prevalent abstinence with an OR of 2.0. We will also examine compliance with instructions and possible behavioral mechanisms of efficacy (e.g. does continued NRT reduce nicotine reward from cigarettes) as well as the incidence of serious adverse events when participants are concurrently smoking and using NRT after a lapse. This study will be the first direct experimental test of whether continuing NRT after a relapse increases abstinence and is safe. Positive results would suggest the package instructions for NRT, treatment guidelines and training programs should change to explicitly encourage smokers to continue NRT treatment after a lapse.

Apatite, Ca10(PO4)6(OH,F,Cl)2, is the tenth most abundant mineral on Earth and one with fundamental importance in geology, materials science, medicine, dentistry, pollutant mitigation, and as the foundation of the Earth's phosphorus cycle; indeed, all hard tissue of the human body except small parts of the inner ear are made of apatite. All of these applications of apatite require understanding of the atomic arrangement of the mineral. Despite the extensive multidisciplinary literature on apatite crystal chemistry, the atomic arrangements of members of the (OH,F,Cl) binary and ternary systems are not well understood and our current knowledge is full of inconsistencies that must be resolved; apatite is one of the rare minerals for which the atomic arrangement of the solid solutions cannot be predicted from the end-member arrangements.

Mixing of the end-member atomic arrangements suggests, for example, that binary members of the system must undergo symmetry breaking, possess immiscibility gaps, incorporate essential vacancies with an unknown method of charge balance, and/or possess anion positions that are not currently recognized. This multi-faceted proposed study will couple mineral synthesis and detailed compositional characterization with single-crystal X-ray structure analysis and Magic-Angle-Spinning Nuclear Magnetic Resonance spectroscopic studies in order to elucidate the nature of solid solution among and between the OH, F, Cl ternary apatites, and provide a better fundamental understanding of anionic substitution and phase behavior. The results of this study will have applications in the fields of geology, materials science, medicine, and dentistry. A proof-of-concept study demonstrates that miscibility along the F-Cl join is achieved by the creation of at least four anion sites in the F-Cl anion column, and confirms the efficacy of the proposed synthesis and analysis methods.

? DESCRIPTION (provided by applicant): Electronic cigarettes (e-cigarettes) are the fastest growing harm reduction product. Many e-cigarette users obtain nicotine blood levels from e-cigarettes that are much higher than those from nicotine replacement products and, in some studies, similar to that for tobacco cigarette users. Given this, one would expect abrupt cessation of e-cigarettes to produce withdrawal symptoms but this has not been tested. We propose to recruit 120 long-term e- cigarette-only users. Participants will enter a within-participants study with random, balanced order of assignment to four conditions: a) their own e-cigarettes, b) a new nicotine e-cigarette, c) the non-nicotine (i.e. placebo) version of the new e-cigarette, and d) no use of any e-cigarettes. The use of nicotine or non-nicotine new e-cigarettes will be double-blind. Participants will be instructed to abstain from tobacco and nicotine products during the study. Each condition will last 5 days with a 2 day washout between conditions. To encourage compliance we will use an escalating payment system with bonuses that has resulted in high compliance rates in our prior studies. Participants will monitor symptoms of nicotine withdrawal daily via an Interactive Voice Response system. They will also attend 3 lab visits/week to provide carbon monoxide and cotinine samples to determine compliance payments, and to complete longer surveys, a cognitive task and a task to measure increased motivation to use e-cigarettes. We will test the effect of abstinence (own e-cigarette vs no e-cigarette) and its pharmacological specificity (new nicotine e-cigarette vs new non-nicotine e-cigarette). Our results will help determine a) the addiction potential of e-cigarettes, b) whether labeling should warn purchasers of e-cigarettes that abrupt cessation can induce withdrawal, and c) whether withdrawal problems should be included in risk/benefit assessments of e-cigarettes.