Scott E. Lukas, Ph.D. - US grants

We propose to conduct a series of experiments designed to extend our original findings from the first year of this grant concerning the relationship between polydrug abuse and euphoria in human subjects. Specific drug combinations planned for study include: cocaine and marihuana, marihuana and ethanol, and alprazolam and ethanol. Drug- induced alterations in electroencephalographic (EEG) activity, evoked potentials, physiological responses, behavioral states, and cognitive function after both acute drug administration and during drug self- administration will be studied. Regional changes in brain electrical activity during intoxication will be quantified using topographic mapping procedures to determine if neurophysiologic changes precede cocaine-and marihuana-seeking behavior and if cocaine-induced euphoria is qualitatively different from marihuana-induced euphoria. EEG topographic mapping procedures will also be used to determine the extent to which prior exposure to marihuana affects the acute cocaine response and subsequent cocaine self-administration. Potentially new pharmacological therapies for cocaine abuse will be explored by evaluating the effects of acute administration of amantadine, benztropine, or trazodone on cocaine- induced EEG and behavioral responses. Studies will be conducted using multiple drug combinations and within-subject designs under double-blind conditions. Plasma drug levels will also be measured to determine if drug-induced euphoria is directly correlated with specific plasma drug levels and to determine if the nature of the observed drug interactions is due to alterations in pharmacokinetic profiles. We will also address the issue of whether acute tolerance or sensitization to cocaine's effects on brainstem auditory and visual evoked potentials, P300 evoked potentials, and performance on a divided attention task. A more detailed analysis of P300 activity will be accomplished by acquiring single sweep data to determine whether latency shifts or amplitude reductions occur after cocaine administration. Finally, to complete the spectrum of our interest in polydrug abuse, we propose to evaluate inpatients undergoing detoxification from polydrug dependence using the above series of neurophysiological and cognitive tasks to determine if such measures can be used to monitor progress and predict treatment outcome. Data obtained from these experiments will enhance our basic understanding of the nature of the interactions between two drugs of abuse and how this relationship alters drug reinforcement and drug-seeking behavior. In addition, the issue of vulnerability to drug abuse will be explored by correlating pre-drug control measures of EEG and evoked potential responses with the subsequent cocaine- marihuana- and alprazolam-induced responses. Results from the drug self-administration and the detoxification experiments will have direct applications in the management and treatment of drug abuse.

We propose to conduct a series of experiments designed to extend our original findings from the first 5 years of this grant concerning the relationship between polydrug abuse and euphoria in men and women. Specific drug combinations planned for study in women include: cocaine and marihuana and marihuana and ethanol. Drug-induced alterations in electroencephalographic (EEG) activity, evoked potentials, physiological responses, behavioral states, and cognitive function will be studied during acute intoxication. Regional changes in brain electrical activity during intoxication will be quantified using topographic mapping techniques to determine if neurophysiologic changes are correlated with drug-induced euphoria. EEG topographic, mapping procedures will also be used to determine the extent to which prior exposure to marihuana affects the acute cocaine response and if such alterations are modified by pretreatment with potential pharmacotherapeutic agents for cocaine abuse. The effects of short-term maintenance on fluoxetine, amantadine and benztropine on cocaine-induced EEG and behavioral responses will be studied. Studies will be conducted using multiple drug combinations and within-subject designs under double-blind conditions. Plasma drug levels will also be measured to determine if drug-induced euphoria is directly correlated with specific plasma drug levels and to determine if the nature of the observed drug interactions is due to alterations in pharmacokinetic profiles. A second major aim of this proposal is to use EEG and ERP topographic mapping procedures to compare the effects of chronic buprenorphine or methadone on men who are dully dependent on opiates and cocaine. We will monitor cognitive performance of these individuals during various stages of their treatment and after discharge into either a buprenorphine or naltrexone outpatient program. Measures will include auditory and visual P300 evoked potentials, and performance on psycholinguistic tasks. A more detailed analysis of P300 activity will be accomplished by acquiring single sweep data to determine whether latency shifts or amplitude reductions occur. We will address the issue of whether buprenorphine or methadone maintenance alters the EEG and behavioral effects of acute i.v. challenges with morphine and cocaine. The results of these studies should provide new information on polydrug abuse and will assess whether the above series of neurophysiological and cognitive tasks can be used to monitor progress and predict treatment outcome. Data obtained from these experiments will enhance our basic understanding of the nature of the interactions between two drugs of abuse and how this relationship alters drug reinforcement. In addition, the issue of vulnerability to drug abuse will be explored by correlating pre-drug control measures of EEG and event-related potentials with the subsequent cocaine-and marihuana-induced responses. Results from the buprenorphine and methadone maintenance experiments will have direct applications in the management and treatment of individuals who are dully dependent on opiates and cocaine.

In this competing renewal application currently in its 9th year of funding we propose to expand our findings of the last funding period to explore new dimensions of polydrug abuse using both electrophysiological and behavioral instruments. Seven specific experiments are planned to address the following: 1) Whether pretreatment with ethanol or marihuana alters the electrophysiological and behavioral components of cocaine-seeking behavior. 2) Whether the presentation of cocaine-related cues to cocaine-dependent subjects elicits changes in brain electrical activity and behavior that are similar to those observed during cocaine-seeking behavior. A related experiment will measure whether tobacco-related cues elicit conditioned responses in cocaine freebase smokers. 3) Whether tobacco-related cues elicit electrophysiological and behavioral responses in tobacco-dependent subjects that are similar to those observed in cocaine-dependent subjects who are exposed to cocaine-related cues. 4) Whether cocaine alone, ethanol alone or cocaine/ethanol combinations disrupt sleep architecture and continuity. A related study will evaluate chronic cocaine freebase smokers for primary sleep disorders. 5) Whether the acute effects of cocaine are different in heavy tobacco smokers as compared to non smokers. Whether pretreatment with a nicotine transdermal patch alters cocaine's acute effects and cocaine self-administration using a choice procedure. 6) Whether ethanol, cocaine or ethano/cocaine combinations increase aggressive behavior and whether estrogen or marihuana pretreatment attenuates the resultant aggressive behavior. 7) What are the neuroanatomical profiles of the alterations in EEG alpha activity and P3 event-related potentials (ERP) associated with drug-seeking behavioral and drug-related cue exposure? Both male and female healthy volunteers will serve as subjects; cocaine- dependent subjects will be recruited from our outpatient treatment program for the cocaine cue studies. The major dependent variables will be brain electrical activity, P3 ERPs, heart rate, skin temperature, subjective reports of intoxication, Addiction Research Inventory scales, visual analog scales, instrumental joystick responding, Point Subtraction Aggression Paradigm for aggressive behavior and reaction time performance. Frequent blood samples will be collected to quantify potential changes in pharmacokinetic parameters. These studies will expand the scope of our understanding of the dynamics of polydrug abuse by examining the factors that contribute to multiple drug use with tools that are sensitive to the subtle but reproducible changes in brain activity and behavior associated with drug reinforcement. Our observations that tobacco and cocaine share many common features helped to shape our current strategy of evaluating pharmacotherapies that is a departure from the currently popular theme of studying drugs that alter dopamine and/or serotonin systems. It is anticipated that information obtained in the present series of experiments will be useful in understanding the mechanism of polydrug abuse, identifying factors that support polydrug abuse and to designing completely new strategies for treating polydrug abuse and dependence.

This is a new application designed to study ethnic, gender and hormonal status as factors in the response to acute cocaine intoxication. Specific attention will be paid to subjective reports of intoxication, Addiction Research Inventory scales, Profile of Mood State Scales, visual analog scales, instrumental joystick responding and reaction time performance. Frequent blood samples will be collected to quantify possible pharmacokinetic alterations in cocaine bioavailability. In addition, three of cocaine's metabolites (norcocaine, ecgonine methyl ester and benzoylecgonine) will be measured to determine if metabolic profiles are affected by the above factors. These data should help quantify the contribution of pharmacodynamic or pharmacokinetic factors in cocaine's response. Both the intranasal and intravenous cocaine will be studied to determine the importance of route of administration. The first experiment will measure ethnic factors by giving acute cocaine challenges to subjects belonging to the following groups: African American, Asian American, Caucasian and Latino. If no group differences are found, then the remainder of the studies will be conducted using a balanced proportion of subjects from these ethnic backgrounds. If significant differences in cocaine responses or kinetic profiles are found, then these findings will be incorporated into the design of the subsequent experiments and a scientific basis for not grouping subjects from various ethnic groups together will have been made. The second experiment will evaluate the degree to which various hormones play a role in an individuals response to cocaine. Embedded in this experiment is an assessment of gender differences to cocaine response and whether route of cocaine administration (intranasal or intravenous) is an important factor in the efficacy of these hormone treatments. We propose to study gonadotrophic hormones, spironolactone and thyroid hormone as they have proven to be the most effective agents in altering cocaine response in our pilot studies. Women will be studied during various phases of their menstrual cycle. The third experiment will evaluate whether women who take a combination of estrogen and progesterone (e.g., oral contraceptives) have different responses to cocaine. The fourth experiment will use the information gained in the prior experiments to select the most promising hormone to be tested in a cocaine self- administration study. After a training session, subjects will be given the opportunity to select between two different doses of cocaine or placebo in a controlled laboratory setting both with and without pretreatment medication. All behavioral, physiological and subjective report data will be collected as before and compared with the number of times cocaine is selected. These studies should reveal new and interesting data on the nature of the interactions among ethnic background, gender and hormonal status on cocaine response. This strategy represents a departure from the currently popular theme of studying pharmacotherapies that affect dopamine and/or serotonin systems. It is anticipated that information obtained in the present series of experiments will be useful in designing completely new strategies for treating cocaine abuse and dependence.

We propose to continue our studies of the Chinese herb, kudzu (Puerariae lobata), as a potential treatment for alcohol abuse/dependence. We are extremely encouraged by the results obtained during the first 2.75 years of this project as we have demonstrated that a two-day treatment regimen with raw kudzu root attenuates ethanol-induced subjective reports of intoxication in light, but not heavy drinkers. Our safety data indicate that the isoflavones are devoid of any physiologic, behavioral or medical side effects, and subjects cannot detect the active preparation from the placebo. A Supplement to this grant was awarded to develop an isoflavone extract and a matched placebo under GMP. They are both ready for testing and we now propose to explore the consumption-related and sex-related differences in alcohol effects using this isoflavone extract. Using a multidisciplinary battery of subjective, physiologic and behavioral measures as well as plasma ethanol levels, we propose new studies to systematically evaluate the efficacy of this extract in treating alcohol-related problems. We will first determine the dose that is effective in reducing the subjective and physiologic effects of acute ethanol challenges in male and female non-dependent heavy drinkers. The second experiment will determine if the isoflavone extract attenuates alcohol-related cue-induced craving. Third, the effects of isoflavone extract on ethanol self-administration will be measured in a natural environment to simulate realistic drinking conditions. Fourth, the extract's amethystic properties will be assessed in acutely intoxicated subjects under controlled laboratory conditions. Finally, using brain imaging techniques, we will explore the possible mechanism of action of this isoflavone preparation using proton magnetic resonance spectroscopy (MRS) to determine whether isoflavone pretreatment alters the amount of ethanol that actually enters the brain. We plan to continue and expand this experiment and, in addition, will measure changes in cerebral blood flow and cerebral vasculature using functional MR imaging (fMRI). The results of these studies will help define the role that isoflavones may have in treating alcohol-related problems. Because of its complete lack of toxicity this isoflavone preparation may be a useful addition to treating alcohol-related problems in special populations such as adolescents and pregnant women. Further, its anti-inebriating effects may make it useful in keeping "slips" from becoming full relapses.

DESCRIPTION (provided by applicant): This is a request to continue a K05 Senior Scientist Award to permit the candidate to continue his career development in drug abuse research. During the past 15 years as a K02/K05 awardee the candidate has spent 80-85% of his time engaged in drug abuse research. His overall research goals employ multidisciplinary approaches to study the neurobiological bases of reinforcement, polydrug abuse, sex-related differences and novel pharmacotherapies for drug and alcohol abuse. The research plan is based on three currently funded R01 grants and a likely T32 Training grant on which the candidate is the Principal Investigator. The Career Development plan for the next five years will include 1) conducting research and acquiring new skills (80%), 2) mentoring (10%), 3) CPDD (5%), 4) Responsible Conduct of Research (5%). Currently funded projects are well stocked with a variety of brain imaging protocols to enhance the value of the information learned from the studies. Such ventures require a great deal of collaboration with other scientists at McLean. Mentoring the next generation of scientists is aimed primarily at the K23/K25 level but if the candidate's T32 is awarded he will take on postdoctoral trainees as well. The College on Problems of Drug Dependence (CPDD) is the major scientific organization dedicated to the study of drug abuse and as Chair of the Program Committee (and now candidate for president-elect) the candidate will continue to play a major role in the future development of the field. As Chair of McLean's IRB the candidate is responsible for monitoring the ethical conduct of all human research protocols at the hospital. Further, the candidate directs a monthly seminar series on the Responsible Conduct of Research for postdoctoral fellows, K-awardees, junior scientists and senior scientists. The candidate has made a strong commitment to drug abuse research and actively collaborates with junior and senior scientists to conduct the variety of protocols. Over the next five years he will study the effects of drug-related cues on brain function of adolescents and adults using brain electrical activity and fMRI, evaluate nicotine patches and citicoline as novel pharmacotherapies for cocaine abuse, and evaluate the utility of a Chinese herbal medicine, kudzu, as a possible treatment for alcohol abuse. The present application is being sought to provide the candidate with continued stability of support essential for his sustained commitment to research in the field of drug abuse and to ensure his continued level of productivity not only as a senior scientist, but as a mentor for the next generation of drug abuse scientists.

DESCRIPTION: (Applicant's Abstract) This is a revised application that focuses on the development of a novel medication for cocaine dependence--CDP-choline. This naturally occurring nucleotide is a major component in phospholipid metabolism and is an integral ingredient in membrane synthesis. It is approved for use in Europe to treat head trauma and a variety of neurological degenerative disorders. Interestingly, it also enhances dopamine activity. Thus, CDP-choline's efficacy as a treatment for cocaine dependence may be high because it repairs two putative consequences of chronic cocaine abuse: 1) membrane damage, and 2) depleted dopamine levels. Two experiments are proposed in this three year study. The first is a challenge study designed to assess the acute effects of cocaine administration in CDP-choline treated non-dependent, casual cocaine users. A multidisciplinary assessment battery including EEG, physiologic, subjective responses and plasma cocaine and metabolite levels will be conducted after cocaine or placebo challenge. This experiment will be conducted in the first six months of the project and will provide basic information on how cocaine's effects are altered by this medication. Study 2 is a 6-week placebo-controlled clinical trial of CDP-choline in cocaine dependent men and women. Follow-up assessments will be made at 8, 12 and 26 weeks. In an attempt to gain insight into the possible mechanism of CDP- choline's effects, two different assessments of CNS function will be conducted at baseline, after 6 weeks of treatment and at the 12 week follow-up visit. The first is a cue reactivity challenge using subjective reports of craving, physiologic and EEG activity after neutral, emotionally laden and cocaine-related stimuli. The second assessment is Magnetic Resonance Spectroscopy (MRS), which will be used to measure changes in brain chemistry that reflect neuronal damage. One of the major appeals of CDP-choline is its low inherent toxicity. Large doses have been given for relatively long periods of time with no adverse effects. The implication of this is that CDP-choline may be safe enough to treat cocaine dependence in pregnant women and adolescents and may even be useful for treating infants who are born to cocaine-dependent mothers. Although we have collected very encouraging preliminary data on CDP-choline's effects in cocaine-dependent male and female subjects, we recognize that it is not a "magic bullet" and that CDP-choline may serve as an important adjunct to other psychotherapy or pharmacotherapy programs.

DESCRIPTION (provided by applicant): In this competing renewal application (currently in its 14th year) we propose to explore the behavioral correlates of polydrug abuse in male and female adult and adolescent subjects by expanding upon our findings during the previous four years of funding. Further, we will continue to focus on changing trends in polydrug abuse, the most recent of which involves the club drug MDMA. The proposed series of experiments are connected via three major inter related themes: I) The neurobiological bases of polydrug abuse will be explored using cue-induced craving and functional magnetic resonance imaging (fMRI). Regional brain activation after exposure to cues from different modalities and drug classes will be assessed using a 4 Tesla magnet that improves spatial resolution and reveals individual differences. The activation profile of exposure to different cues in polydrug abusers will help determine whether there is significant cross-generalization among cues. II) Differences between adolescent and adult polydrug use will be measured using EEG mapping, physiology and behavioral indices during cue-induced craving procedures. As the rate of both tobacco and marihuana smoking among adolescents continues to rise, we will explore the relationship between these two drugs and the generalizability of drug-related cues in adolescents. III) Novel pharmacotherapies for polydrug abuse will be tested as traditional medication trials have focused on testing a single treatment drug. We will use new strategy of combining two medications (polypharmacy) to address the multi-faceted nature of polydrug abuse. Nicotine and selegilinepatches for combined cocaine/tobacco abuse and gabapentin for combined cocaine/alcohol abuse will be studied. A new direction for our laboratory is to study drug-taking behavior in the natural fieldenvironment using a unique wrist actigraphy and data input device to monitor sleep/wake activity, MDMA craving and actual polydrug use while subjects continue with their usual daily routines. Finally, we will explore the impact that the availability of MDMA has on alcohol and marihuana use in a Natural Setting Laboratory. The proposed studies will fill important gaps in our understanding of polydrug abuse including: cue-induced craving in adolescents, actual polydrug patterns, sex-related differences, brain sites associated with craving, similarities among cues, and how best to design effective pharmacotherapies for polydrug abuse. Results of these studies may also reveal why cue-induced craving has not been a good predictor of relapse as there may be significant cross generalization among the cues that can trigger relapse in successfully treated patients.

[unreadable] DESCRIPTION (provided by applicant): This is a proposal to continue a postdoctoral research-training program in brain imaging and drug abuse. We have at our disposal a variety of brain imaging tools that have yielded valuable information about brain reward systems and addiction. The need for such a dedicated program is dictated by the emergence of new and innovative techniques to view both the anatomical and functional aspects of the brain under a variety of conditions related to substance abuse such as: acute intoxicating effects, tracking cue-induced craving, measuring cognitive effects, detecting persistent neurological and cognitive defects, monitoring withdrawal, sleep disturbances, medication compliance, tracking treatment progress and medication development. Because the nature and spectrum of the disciplines involved in imaging are complex, a new breed of scientists with backgrounds in imaging technology, neuroscience, pharmacology, addiction medicine and treatment will be needed to more fully explore the neurobiological bases of drug abuse and fill the anticipated vacancies in research centers in the United States-this Training Program is designed to fill this void. Over the past 4 years we established an integrated, multidisciplinary Drug Abuse and Brain Imaging Training Program (DABITP) that was jointly supported by the McLean Hospital/Harvard Medical School and Boston University School of Medicine. In the past year we have engaged in translational research and will be installing a 9.4T magnet in November 2006. In anticipation of NIDA's mission to enhance the integration of preclinical with clinical research, we have added a new track to our training program. In addition, we also have teamed with the Center for Drug Discovery at Northeastern University in a joint P20 application and have begun to tap into each other's resources to enhance training in translational research. Our 2-3 year postdoctoral training program is structured to provide the trainees with the basics of MR and EEC techniques, which is followed by placement in one of four distinct research tracks that meets the trainees' specific career goals: 1) MR Technology and Instrumentation; 2) Basic Clinical; 3) Clinical Treatment; and 4) Translational. The combination of didactic training in brain imaging and psychopharmacology with practical applications in a variety of highly successful research laboratories will provide our trainees with the skills to employ brain imaging techniques as they embark on the next decade of research on the addicted brain. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): In this competing renewal application (currently in its 14th year) we propose to explore the behavioral correlates of polydrug abuse in male and female adult and adolescent subjects by expanding upon our findings during the previous four years of funding. Further, we will continue to focus on changing trends in polydrug abuse, the most recent of which involves the club drug MDMA. The proposed series of experiments are connected via three major inter related themes: I) The neurobiological bases of polydrug abuse will be explored using cue-induced craving and functional magnetic resonance imaging (fMRI). Regional brain activation after exposure to cues from different modalities and drug classes will be assessed using a 4 Tesla magnet that improves spatial resolution and reveals individual differences. The activation profile of exposure to different cues in polydrug abusers will help determine whether there is significant cross-generalization among cues. II) Differences between adolescent and adult polydrug use will be measured using EEG mapping, physiology and behavioral indices during cue-induced craving procedures. As the rate of both tobacco and marihuana smoking among adolescents continues to rise, we will explore the relationship between these two drugs and the generalizability of drug-related cues in adolescents. III) Novel pharmacotherapies for polydrug abuse will be tested as traditional medication trials have focused on testing a single treatment drug. We will use new strategy of combining two medications (polypharmacy) to address the multi-faceted nature of polydrug abuse. Nicotine and selegilinepatches for combined cocaine/tobacco abuse and gabapentin for combined cocaine/alcohol abuse will be studied. A new direction for our laboratory is to study drug-taking behavior in the natural fieldenvironment using a unique wrist actigraphy and data input device to monitor sleep/wake activity, MDMA craving and actual polydrug use while subjects continue with their usual daily routines. Finally, we will explore the impact that the availability of MDMA has on alcohol and marihuana use in a Natural Setting Laboratory. The proposed studies will fill important gaps in our understanding of polydrug abuse including: cue-induced craving in adolescents, actual polydrug patterns, sex-related differences, brain sites associated with craving, similarities among cues, and how best to design effective pharmacotherapies for polydrug abuse. Results of these studies may also reveal why cue-induced craving has not been a good predictor of relapse as there may be significant cross generalization among the cues that can trigger relapse in successfully treated patients.

This Project is focused on both Phase I and Phase II level clinical studies to evaluate the efficacy of selected herbal medicines to alter acute effects of alcohol or drugs of abuse, to modify alcohol- or drug-seeking behavior and to begin to explore the central mechanism of action of these products. In brief, a novel herbal preparation will be initially standardized, purified and characterized in Project 1 using cell based kappa receptor binding and functional assays and tested in a sequential animal model for efficacy in reducing drug or alcohol intake and discriminative stimulus properties in Project 2 and then a herbal remedy (or fractions) that remains efficacious through Project 1, and 2 will be studied clinically. However, as we have already identified two candidate products based on strong preclinical data, the first two years of this project will focus on studying the effects of the Chinese herbal remedy (NPI-028) on alcohol intoxication and drinking behavior. In subsequent years, we will either study the second Chinese herbal remedy (NPI-025) or if the drug discovery process in Projects 1 and 2 uncover a more promising candidate, the focus may shift to that product instead. Regardless of which products are selected, the protocols described in this project are easily adaptable and could be used to study any number of likely candidates. Using a multidisciplinary battery of subjective, physiologic and behavioral measures as well as plasma ethanol levels, we propose three main studies to systematically evaluate the efficacy of NPI-028 in altering alcohol's acute intoxicating effects and pharmacokinetic profile in adult male and female heavy drinkers. The effects of NPI-028 on ethanol drinking will be measured in a natural environment to simulate realistic drinking conditions. Finally, using brain imaging techniques, we will explore the possible mechanism of action of this herbal preparation using proton magnetic resonance spectroscopy (MRS) to determine whether pretreatment alters the amount of ethanol that actually enters the brain. We plan to continue and expand this experiment and, in addition, will measure changes in cerebral blood flow and cerebral vasculature using functional MR imaging (fMRI). The results of these studies will help define the role that herbal medicines may have in treating alcohol-related problems.

DESCRIPTION (provided by applicant): This application, in response to RFA-DA-04-014 Medication Development for Cannabis-Related Disorders, addresses cannabis dependence from two perspectives: 1) quantifying the acute, chronic and withdrawal effects of cannabis using brain imaging (EEG/ERP, fMRI and MRS) and 2) using these data to serve as a foundation for exploring new strategies for cannabis medication development. It is unclear how cannabis affects brain function, either acutely or after chronic use so knowledge of the changes in brain function during cannabis dependence and withdrawal will aid greatly in our understanding of the neurobiological bases of cannabis abuse and will thus serve as an important foundation for developing new medications to treat this disorder. New and improved brain imaging techniques such as fMRI and MRS offer us a unique opportunity to view these subtle, yet important changes in brain function. As a first step in devising a medication to treat cannabis dependence we propose to carefully document the effects of acutely administered cannabis on regional cerebral blood flow and brain chemistry. These effects will be compared to the acutely withdrawn brain and thus will serve as baselines to assess the efficacy of a novel medication, cytidine-5'- diphosphate choline (CDP-choline, citicoline) in reducing cannabis use, and reversing the psychomotor performance deficits, memory loss and sleep disorders that occur during cannabis intoxication and withdrawal. We chose citicoline based on our serendipitous findings that it reduces not only cocaine use in our ongoing clinical trial, but appears to reduce marihuana smoking as well. Our experiments capitalize on the results obtained in our ongoing clinical studies of cocaine-dependent subjects along with pilot MR data. If positive, these results could have important implications for the pharmacotherapy of cannabis dependence as well as primary and secondary prevention of neurobiological damage associated with chronic cannabis use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of cannabis dependence (and potentially on other drug dependence disorders). As multidisciplinary approaches to treating drug abuse have been the most successful, we will use a 2 x 2 design to test the combination of citicoline and cognitive behavioral therapy (CBT) for insomnia as an effective treatment for cannabis dependence. Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug dependent mothers, and adolescents.

DESCRIPTION (provided by applicant): Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. As a significant public health problem because of its known association with the Gateway theory of drug abuse, NIDA's mission over the past few years has been aimed at identifying safe and effective candidate therapies for marihuana abuse and dependence, particularly those that can be given to vulnerable populations. The overall objectives of this proposal are to test a nutritional supplement of the natural brain chemical, cytidine-5'-diphosphate choline (citicoline) for its effects on marihuana-induced intoxication and abuse patterns. This supplement was recently shown to reduce marihuana use in an open label trial of a grant that was awarded under RFA-DA-04-014 (Medication Development for Cannabis-Related Disorders). Because citicoline is a natural chemical in mammalian brain, it is relatively safe and has been very useful in treating stroke and other neurological disorders. It is still unclear how marihuana affects brain function, either acutely or after chronic use, so the proposed studies are designed to collect data that will serve as a foundation for exploring new strategies for treating marihuana abuse. These goals will be accomplished by using brain imaging techniques such as electroencephalography, magnetic resonance imaging and studies will be conducted to identify the mechanism of action of citicoline's effects on marihuana use and its intoxicating effects. As a first step in devising a medication to treat marihuana dependence we propose to conduct a double-blind, placebo-controlled assessment of citicoline on marihuana use patterns in a natural setting. We will then document the effects of acutely administered marihuana on regional cerebral blood flow using BOLD signal detection. Finally, we will study whether citicoline alters marihuana-induced cue-induced craving. Collectively, these studies should yield important information on how supplementation with a natural brain chemical alters marihuana's effects such that its use is decreased. The results of the present series of studies could have important implications for the pharmacotherapy of marihuana dependence as well as primary and secondary prevention of the neurobiological damage associated with chronic use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of marihuana dependence (and potentially on other drug dependence disorders). Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug-dependent mothers and adolescents. PUBLIC HEALTH RELEVANCE: Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. Citicoline, a naturally occurring chemical in the brain, has been shown to reduce marihuana use in a pilot clinical trial. Using magnetic resonance brain imaging and EEG techniques, this application will explore the mechanism of action and develop new treatment strategies for marihuana dependence.

6. Project Summary Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. As a significant public health problem because of its known association with the Gateway theory of drug abuse, NIDA's mission over the past few years has been aimed at identifying safe and effective candidate therapies for marihuana abuse and dependence, particularly those that can be given to vulnerable populations. The overall objectives of this proposal are to test a nutritional supplement of the natural brain chemical, cytidine-5'-diphosphate choline (citicoline) for its effects on marihuana-induced intoxication and abuse patterns. This supplement was recently shown to reduce marihuana use in an open label trial of a grant that was awarded under RFA-DA-04-014 (Medication Development for Cannabis-Related Disorders). Because citicoline is a natural chemical in mammalian brain, it is relatively safe and has been very useful in treating stroke and other neurological disorders. It is still unclear how marihuana affects brain function, either acutely or after chronic use, so the proposed studies are designed to collect data that will serve as a foundation for exploring new strategies for treating marihuana abuse. These goals will be accomplished by using brain imaging techniques such as electroencephalography, magnetic resonance imaging and studies will be conducted to identify the mechanism of action of citicoline's effects on marihuana use and its intoxicating effects. As a first step in devising a medication to treat marihuana dependence we propose to conduct a double-blind, placebo-controlled assessment of citicoline on marihuana use patterns in a natural setting. We will then document the effects of acutely administered marihuana on regional cerebral blood flow using BOLD signal detection. Finally, we will study whether citicoline alters marihuana-induced cue-induced craving. Collectively, these studies should yield important information on how supplementation with a natural brain chemical alters marihuana's effects such that its use is decreased. The results of the present series of studies could have important implications for the pharmacotherapy of marihuana dependence as well as primary and secondary prevention of the neurobiological damage associated with chronic use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of marihuana dependence (and potentially on other drug dependence disorders). Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug-dependent mothers and adolescents.

DESCRIPTION (provided by applicant): This application seeks to challenge current approaches to treating drug dependence by investigating the idea of neurobiological readiness for treatment. This notion is analogous to the behavioral stages of change conceptualized in the field of psychotherapy and already applied to substance abuse treatment, but here it refers to objective indicators of the brain's ability to respond to medication at a specific point during recovery. The proposed project will focus on the cocaine-GABA relationship as an exemplar because no FDA-approved pharmacotherapeutics exist for treating cocaine dependence, but a number of candidate medications targeting the GABA system are under investigation. While the strategy of boosting GABA activity pharmacologically is supported by a significant body of evidence implicating GABAergic dysfunction in the etiology of cocaine dependence, we believe its modest success to date is due to the one-size-fits-all approach that assumes cocaine-related GABAergic impairment is stable over the stages of recovery. We challenge this by asking, how do GABA levels change when the brain has an opportunity to readjust after drug exposure ceases? Also, how does the GABA baseline affect the brain's ability to respond to treatment with GABAergic medications? The primary goal of this project is to address these gaps in our knowledge that we believe represent barriers to treatment. To accomplish this goal, we will assess proton magnetic resonance spectroscopy (1H MRS) and blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) correlates of GABAergic function longitudinally during an incentivized abstinence period in non-treatment-seeking cocaine-dependent volunteers. The first aim will establish the timeline of cocaine abstinence-related changes in GABA levels by tracking GABA during active exposure and through both early and prolonged abstinence. The second aim will demonstrate the dynamic nature of GABAergic responsivity over the same time course by probing the system with a GABAergic drug challenge. Together, these aims will use neuroimaging as a tool to establish the cross- over point to readiness for treatment. These objective indicators will improve our ability to plan treatment by permitting the clinician to predict the points at which an individual will be receptiv to a specific medication. Thus, one medication may be employed for abstinence initiation, and then once the brain has re-established GABAergic homeostasis, another medication can be used for relapse prevention. However, because not every treatment center has access to an imaging facility, a secondary goal is to evaluate the relationship between recovering GABA activity and cocaine-related cognitive impairments to determine the extent to which timed administration of a neuropsychological performance battery can predict GABAergic function. Our results will have the potential for high impact because the conceptual framework of brain readiness for treatment can be applied to drug dependence and psychiatry in general in order to provide a foundation for individualizing medicine.

DESCRIPTION (provided by applicant): This is a revised application (A2) for interdisciplinary behavioral, neuroendocrine and neuroimaging studies of sex differences in response to nicotine submitted in response to NIDA PA-07-329. Among the addictive disorders, nicotine addiction is one of the most pervasive, and is associated with a number of potentially lethal diseases (lung cancer, cardiovascular and respiratory disease) that result in an estimated 448,000 deaths each year. Improved treatments for nicotine addiction are urgently needed, and will be facilitated by advances in our understanding of the basic neurobiology of nicotine. We propose clinical studies to examine the covariance between the hormonal, behavioral and neuroimaging effects of nicotine in nicotine- dependent men and women to determine if there are significant sex differences. Women will be studied during the mid-follicular and the mid-luteal phase of the menstrual cycle to determine if the effects of nicotine are influenced by changes in the neuroactive gonadal steroid hormones that define phases of the menstrual cycle. Functional magnetic resonance imaging (fMRI) will be used to study regional changes in brain activity. The effects of IV nicotine and placebo nicotine on neuronal activity in brain areas with a high density of nicotinic receptors, and also in regions that may be important drug reward pathways will be measured over time, and correlated with subjective and hormonal responses. Nicotine (0, 1.0 or 2.0 mg/70 kg, IV) will be administered under double-blind conditions. Samples for analysis of hypothalamic-pituitary-adrenal and gonadal hormones will be collected every 2 min to examine the temporal covariance with neuroimaging activation patterns and reports of subjective effects. We hypothesize that neuronal and hormonal activation and positive subjective responses to IV nicotine administration will be greater in men than in women. We also hypothesize that women will have greater neuronal and hormonal activation and positive responses to nicotine during the follicular phase of the menstrual cycle (when neuroactive steroid hormone levels are low) than during the luteal phase of the menstrual cycle (when neuroactive steroid hormone levels are high). Because the neuroactive steroid hormones are being used to treat a number of psychiatric disorders including drug abuse, this could lead to novel treatments for nicotine addiction. The results of these translational studies will increase our understanding of the interaction between sex, hormones, and the abuse-related effects of nicotine. These interdisciplinary studies will integrate behavioral, hormonal and neuroimaging measures to provide a comprehensive analysis of how sex differences and phases of the menstrual cycle may affect the abuse- related effects of nicotine. Advances in understanding the basic neurobiology of nicotine will inform efforts to develop better pharmacologic interventions to treat nicotine addiction.

Project Summary This proposal seeks to expand upon breath analysis technology that is being actively studied as the focus of NIH grant #6R42DA049655-02 and leverage this technology for rapid COVID-19 diagnostics. There is a dire need for sensitive and specific diagnostic tests for COVID-19 that can be performed quickly. The differential mobility spectrometry (DMS) breath analysis technology currently under investigation for drug detection may be adapted to fill this void. During this supplement we will perform a biomarker discovery effort to determine the exhaled breath molecular species most suitable for use as a COVID-19 biomarker. Once a target species has been identified, methods of capture that can be implemented within the safety paradigm governing COVID-19 testing will be investigated. We will also initiate conversation with the FDA and develop an FDA approval strategy to expedite the deployment of a future breath based COVID-19 diagnostic instrument based upon the technology being studied under this administrative supplement?s parent grant.