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2004 March

Alcohol and Adverse Drug Reactions in a VA Population

Katharine A. Bradley, MD, MPH
Associate Professor

Medicine

Description: Many primary care patients who drink excessively take medications that could interact with alcohol. However, little is known about adverse drug reactions (ADRs) due to alcohol use. We hypothesize that many hazardous drinkers take the following commonly prescribed medications that could interact with alcohol: warfarin, acetaminophen (e.g. Tylenol), non-steroidal anti-inflammatory drugs, aspirin, and a class of cholesterol-lowering medications called statins. Further, we hypothesize that the incidence of ADRs from these medications will be increased among drinkers as self-reported alcohol consumption increases. The proposed study seeks: (1) to determine the prevalence and severity of hazardous drinking among VA patients taking commonly prescribed medications hypothesized to interact with alcohol, and (2) to determine the association between AUDIT-C scores and the annual incidence of ADRs among these patients. Using a VA regional database that contains pharmacy and laboratory data, as well as AUDIT-C scores for over 40,000 VA Puget Sound outpatients, the proposed study will evaluate the association between a validated measure of alcohol consumption, the AUDIT-C, and ADRs hypothesized to be associated with alcohol use. This would be the first clinical study, to our knowledge, to evaluation this association. After collecting this essential pilot data, we plan to submit a proposal to NIH, seeking funds for a larger, more definitive study of alcohol use and ADRs in a nationwide sample. We believe this research will lead to the development of important clinical interventions, such as computerized systems that alert providers to potential interactions between prescribed medications and patients' alcohol use.

Resulting articles & projects:

  • Plans for publishing results and for expanding this research have been delayed due to barriers to obtaining proprietary lists of medication that have alcohol warning labels, however we have recently received the necessary permission, and are working on publishing preliminary results. We plan to submit a major grant within 2 years to evaluate adverse drug reactions to medications with alcohol-related warnings, including warfarin, among patients with alcohol misuse.

Does Neighborhood Context Matter? Evaluating the Impact of Local Context on Substance Abuse among Youth

Jerald R. Herting, PhD
Research Associate Professor

Sociology, Psychosocial and Community Health

Karen Snedker, PhD
(Co-investigator)

Description: This project will explore the influence of neighborhood context on drug and alcohol use among youth. The majority of research on adolescent substance use has overlooked the role of contextual factors such as neighborhood conditions. In attempt to fill this void, the goal of this study is to explore the role of neighborhood characteristics on the initiation and maintenance of adolescent substance use. Do neighborhood-level variables have a direct and/or moderating effect on adolescent drug involvement net of individual, family, and peer characteristics? To address this question, multiple data sources will need to be brought together. The base dataset comes from the Reconnecting Youth prevention research studies funded by NIDA, Department of Education, and CDC and provides a stratified (by high risk) random sample of high school aged youth in the Seattle metropolitan area. The secondary data comes from the United States Census and the Seattle police department.

The first stage of this project will link individuals in this dataset to their census tracts. The second stage will add local characteristics at the census tract-level. Neighborhood characteristics -- poverty and income measures, unemployment, residential stability, female-headed households, racial/ethnic composition and segregation, and crime indices -- will be included in the analysis. We will explore cross-sectional associations among neighborhood characteristics and drug involvement (measured by frequency of use and scales of control and consequences of use) and change in use over a 9-month period (initiation/cessation and change in frequency of alcohol, marijuana, and hard drug use). Neighborhood effects will be examined while controlling for individual, family and peer factors; for example the effect of single female households in the neighborhood are explored net of the individuals' family composition. Multilevel techniques will be used to assess the impact of neighborhood on substance use and adjust for the natural clustering within neighborhoods. It is expected that adding neighborhood context will enhance our understanding of substance abuse patterns and change among teenagers. This project represents a preliminary exploration into the effects of context. The findings from this project will represent the foundation for a larger study to be submitted for additional funding.

Resulting articles & projects:

  • Using the pilot data and experience gained from this ADAI Small Grant project, Karen Snedker received an R03 grant from NIMH: (PI: Snedker; NIMH grant 2007-2010, 1R03MH074618-01A2)
  • Using the pilot data and experience gained from this ADAI Small Grant project, Karen Snedker received an R03 grant from NIDA: (PI: Snedker; NIDA grant 2006-2009, 5R03DA019622-02)
  • Snedker KA, Herting JR, Walton E. Contextual effects and adolescent substance use: Exploring the role of neighborhoods. Social Science Quarterly 2009;90(5):1272-1297. [doi: 10.1111/j.1540-6237.2009.00677.x]
  • Herting JR, Snedker KA, Walton EC. "Adolescent Mental Health: Neighborhood Stress Effects on Emotional Distress." Presented at the Population Association of America Annual Meeting, March 30-April 1, 2006, Los Angeles, CA.
  • Snedker KA, Herting JR "Neighborhood Conditions and Adolescent Substance Use". Symposium on Geography and Drug Addiction at the Association of American Geographer Annual Meeting, March 2006, Chicago.
  • Snedker KA, Walton EC, Herting JR. "Does neighborhood context matter? Evaluating the impact of local characteristics on substance abuse among youth." Presented at Population Association of America Annual Meeting, March 31-ApriI 2, 2005, Philadelphia, PA.

The Effects of Alcohol and Placebos on Eyewitness Memory Distortions

G. Alan Marlatt, PhD
Professor and Director

Addictive Behaviors Research Center, Psychology

Seema Clifasefi, PhD

Description: Almost a third of violent crimes committed in the United States involve alcohol or other drugs, and eyewitnesses to these crimes may also be intoxicated. Given alcohol's prevalence in crime situations, and the fact that mistaken eyewitness evidence is the leading cause of wrongful convictions in the US, it is crucial to understand alcohol's role on eyewitness memory accounts. Although we know that alcohol has separate physiological and psychological effects on various behaviors, we know nothing about the combination of these effects on eyewitness memory and susceptibility to distortion.

The overarching goal of our research proposal is to investigate the reliability of drunken eyewitness memory reports, and to evaluate the effects of misleading suggestions on intoxicated witnesses. There are three aims to the proposed study. Aim 1: Separately examine the physiological and psychological effects of alcohol, as well as any interaction between these two mechanisms, on eyewitness memory distortions using a balanced placebo design. Aim 2: Manipulate the timing of the alcohol or alcohol placebo administration throughout a three staged eyewitness task (witnessing of the crime, presentation of inaccurate witness statements, and memory test) to evaluate the various stages of cognitive processing at which alcohol affects memory and susceptibility to distortion. Aim 3: Examine the relationship between people's beliefs about alcohol's effects on memory and the extent to which one experiences memory distortions as a result of drinking, as well as obtain self-reports about cognitive functioning under the influence of alcohol or placebos. The long term goal of this research is to inform not only psychological science, but also the medical and legal communities about the physiological and psychological effects of alcohol on eyewitness memory accounts.

Resulting articles & projects:

  • Due in large part to this funding award, Dr. Clifasefi was awarded an individual National Research Service Award (F32) to continue her postdoctoral studies at the University of Washington Addictive Behaviors Research Center. [1F32AA015240-01A1]
  • Clifasefi SL, Parker S, Burlingham B, Marlatt GA. "The effects of alcohol and state dependent learning on eyewitness memory and the misinformation effect." Poster poster presented at the Association for Psychological Science, May 2008.
  • Clifasefi, S.L., Parker, S., Burlingham, B. & Marlatt, G.A. (manuscript in preparation). The effects of alcohol and state dependent learning on eyewitness memory and the misinformation effect.

2004 October

Patient Distress and Satisfaction as Predictors of Treatment Engagement: A Pilot Study

John S. Baer, PhD
Research Associate Professor

Psychology

Erik J. Hawkins, PhD

Description: A remarkably high rate of patient attrition routinely occurs in the first few weeks of outpatient substance abuse treatment. The consistency and strength of this association has led some to conclude that retention is the best intermediate measure of outcome in the treatment of substance use disorders. Patient retention and/or engagement have been recently targeted by the Veterans Affairs Office of Quality and Performance as a measure of treatment quality for addiction treatment services. Systems that can identify risk of early attrition and intervene to promote treatment retention are therefore important for the ongoing improvement of treatment outcomes. Historically, the search for predictors of treatment retention or engagement has emphasized patient pretreatment variables. Unfortunately, studies that have investigated the relationships between pretreatment variables (e.g. age, race, employment, education, addiction severity) and retention have not produced a reliable predictive profile. Other research efforts have sought to determine aspects of agencies that foster treatment engagement across all patients. These studies are helpful but may suggest organizational changes that are difficult or expensive.

This proposal is for funds to support a pilot study to develop a research program designed to both identify individual patients at risk of early attrition, and allow targeted interventions to increase patient retention, through systematic monitoring (weekly assessments) of patient treatment response as indicated by assessment of psychological distress and treatment satisfaction. This model of systematic weekly assessments of distress to predict treatment attrition has been developed and validated in research on individual psychotherapy, but has not been evaluated in addictions treatment.

Veterans (n=100) receiving specialty outpatient addiction treatment will be recruited to complete brief measures of psychological distress and treatment satisfaction on a weekly basis using interactive voice response technology (IVR) for the initial eight weeks of a treatment episode. Results of this study will be used to evaluate the feasibility of the IVR strategy of obtaining repeated assessments of psychological distress and patient satisfaction, and determine the degree to which such measures predict treatment attendance and treatment retention. Assuming positive results, the data from this study will support a larger grant application to test feedback systems for providers in several agencies as a mechanism to increase patient engagement.

Resulting articles & projects:

  • Hawkins EJ, Baer JS, Kivlahan DR. Concurrent monitoring of psychological distress and satisfaction measures as predictors of addiction treatment retention. J Subst Abuse Treat 2008;35(2):207-16. [PubMed abstract ]

Automatic Alcohol Motivation in At-Risk Drinking

G. Alan Marlatt, PhD
Professor and Director

Psychology, Addictive Behaviors Research Center

Brian D. Ostafin, PhD

Description: Alcohol researchers have begun to develop theoretical models for the role of automatically activated (i.e. without the mediation of conscious deliberation) motivational processes in at-risk drinking. However, relatively little research has examined the structure of alcohol-motivation associations in memory using implicit cognition methods such as reaction time tasks. Even less research has examined how contextual factors may influence the effect of automatic alcohol motivation on behavior. The proposed study will use a sample of 134 at-risk drinkers in a between-groups experimental design (self-regulation resources depleted vs. control group) to assess the relationship between automatic alcohol motivation and alcohol consumption in a drinking task during which participants are motivated both to consume and restrain their consumption. There are three aims for the proposed study. Aim 1: Examine the hypothesis that the automatic activation of alcohol-motivation associations in memory will predict alcohol consumption in an ad lib laboratory drinking task. Aim 2: Examine the hypothesis that resources available for the self-regulation of automatic motivation to drink are limited. Aim 3: Examine the hypothesis that the relation between ad lib drinking behavior and automatic motivational responses to alcohol cues is moderated by the contextual variable of self-regulation resource availability. The long-term goals of this research are to make theoretical and applied contributions to the field of alcohol studies. The results may provide supportive evidence for automatic process theories of alcohol use, increase the ability to predict alcohol use in high-risk situations, and serve to direct the development of intervention strategies.

Resulting articles & projects:

  • Ostafin BD, Marlatt GA. Automatic alcohol motivation and the prediction of disinhibited drinking. Paper presented at the annual meeting of the Association for Behavioral and Cognitive Therapies, Philadelphia, PA, 2007.
  • Ostafin BD, Marlatt GA, Greenwald AG. Drinking without thinking: an implicit measure of alcohol motivation predicts failure to control alcohol use. Behav Res Ther 2008 Nov;46(11):1210-9. [Pubmed abstract]
  • Ostafin BD, Marlatt GA, Troop-Gordon W. Testing the incentive-sensitization theory with at-risk drinkers: Wanting, liking, and alcohol consumption. Psychol Addict Behav 2010;24(1):157-162. [PubMed abstract]
  • Farris SR, Ostafin BD. Alcohol consumption primes automatic alcohol-approach associations. Am J Drug Alcohol Abuse. 2008;34(6):703-11. [PubMed abstract]

Subsecond Dopamine Release during Acquisition of Drug-Taking Behavior

Paul E.M. Phillips, PhD
Assistant Professor

Psychiatry & Behavioral Sciences

Description: Release of dopamine into the extracellular space has been highly implicated in motivated behavior and is thought to have a central role in drug abuse. However, the specific behavioral elements to which it is linked are less clearly understood. This is chiefly because the components that make up the behavior occur in close temporal proximity (a few seconds), whereas classic neurochemical measurements in awake animals can only resolve chemical transmission on the order of minutes. Moreover, changes in dopamine activity in response to reward-related stimuli occur on a subsecond timescale. Recently, we have used fast-scan cyclic voltammetry to detect dopamine release with subsecond resolution. During cocaine self-administration we find rapid changes in extracellular dopamine concentration that are time-locked to specific components of the behavior. There is a rise in dopamine just prior to the seeking behavior which appears to bias the animal to initiate that behavior. There is another rapid dopamine change upon completion of the task to obtain the drug. This signal appears to be invoked by environmental cues that predict the ensuing cocaine delivery.

Those studies were carried out in rats that had previously been trained to self-administer cocaine. This study will measure the development of these signals during the acquisition of drug-taking behavior -- a time analogous to human drug experimentation that can lead to more frequent recreation drug use and eventually compulsive behavior. In addition to recording these phasic dopamine changes that are time-locked to operant responses, the effect of a discriminative stimulus that signifies cocaine availability will be studied. This work should provide insight into neural substrates that promote ongoing drug use following initial drug exposure and can ultimately lead to addiction.

Resulting articles & projects:

  • The pilot data collected with support from the ADAI small grant was used to successfully apply for a 3-year R21 grant from NIDA. Subsecond dopamine release during compulsive drug taking (5R21DA021793-02 ) PI: Phillips (06/01/2007 -05/31/2010)
  • In addition, using the paradigms we set up with support from ADAI, we helped John Neumaier's lab to collect pilot data which were used as part of the preliminary studies to secure an R01 on which he is the PI. The role of 5-HT1 B receptors in brain reward circuits (R01 DA016432) PI: Neumaier (07/01/2009-07/31/2011)

A Double-Blind Placebo-Controlled Trial of Prazosin for the Treatment of Alcohol Dependence

Tracy L. Simpson, PhD
Assistant Professor

Psychiatry & Behavioral Sciences

Description: Alcohol consumption in excess causes numerous significant biopsychosocial complications. Individuals presenting for treatment of alcohol use disorders frequently return to drinking and suffer with this chronic impairment that may eventually be fatal. The three FDA approved medications for the treatment of alcohol dependence suffer from sub-optimal efficacy, significant side effects, or other limitations that have reduced the frequency with which they are used. However, medications that decrease noradrenergic activity appear to have potential in the treatment of alcohol dependence by decreasing craving in response to characteristic triggers.

Cues such as stress are thought to trigger the experience of craving, and possibly relapse, to the substance of choice in abstinent individuals. Thus, a treatment to decrease craving may decrease the risk of relapse and avert the myriad of problems associated with chronic alcohol use. A growing body of animal and human data support a mechanism of noradrenergic hyperactivity in the cascade of neurobiologic events leading to resumption of alcohol in response to stress intolerance or substance-associated cues.

Prazosin, a centrally-acting alpha-1 adrenergic antagonist, has been found to decrease trauma-related nightmares in combat veterans with post-traumatic stress disorder (PTSD). Incidentally, study participants also reported the subjective experience of a decrease in alcohol and cocaine craving. A case report also suggests the efficacy of prazosin in attenuating alcohol craving. The proposed double-blind placebo controlled pilot trial will test the hypothesis that prazosin reduces alcohol consumption and alcohol craving in alcohol dependent veterans without PTSD who are entering outpatient chemical dependency treatment. Interactive Voice Response (IVR) daily telephone monitoring will be used to assess medication adherence and any differences in day-to-day craving between the two experimental groups.

Resulting articles & projects:

  • The results from the ADAI pilot study led directly to a 5-year grant from NIAAA to Dr. Simpson: "Clinical Trials of the Adrenergic A-1 Antagonist Prazosin for Alcohol Dependence." [ 5R01AA017184 ]
  • Simpson TL, Saxon AJ, Meredith CW, Malte CA, McBride B, Ferguson LC, Gross CA, Hart KL, Raskind M. A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. Alcohol Clin Exp Res 2009;33(2):255-63. [ PubMed abstract ]
  • Dr. Saxon has used the pilot results to enhance the following lectures and courses: Grand Round lectures at University of Utah and at Uniformed Services University in Washington DC; and a course for the Washington Society of Addiction Medicine.

Genetics of Endocannabinoid Metabolism

Nephi Stella, PhD
Assistant Professor

Pharmacology

Description: Endogenous cannabinoid ligands (endocannabinoids, eCB) produced by neural cells activate cannabinoid receptors, the molecular target for marijuana's bioactive ingredient Delta-9-tetrahydrocannabinol. In order to tackle the major public health problem associated with cannabis abuse, we must increase our understanding of the molecular mechanisms underlying eCB signaling. Several enzymes have been implicated in the production and inactivation of anandamide, the first identified eCB, and 2-arachidonoylglycerol (2-AG), the most abundant eCB in the brain. Yet how many eCB actually have a signaling function and what are the enzymes controlling their metabolism is unknown. Analysis of the yeast genome showed that many potential players in eCB metabolism are conserved between yeast and higher eukaryotes. Recently, we improved the sensitivity and selectivity of our gas chromatography mass spectrometry (GC/MS) method and were able to identify and quantify eCB in Saccharomyces cerevisiae. An exciting feature of this result is that yeast provides an unbiased genetic tool to identify genes involved in controlling biological functions, in our case eCB metabolism. The aim of this grant is to use viable mutant hapolid yeast strains to identify the genes controlling eCB levels. Results obtained will provide the basis for application for federal funding aimed on understanding the genetic and molecular basis of mammalian eCB production and inactivation.