Alcohol and stress study
This study sought to better understand the role of psychological stress and cue-reactivity on urge to drink. Genetic factors underlying the association between stress exposure and urge to drink were examined. This study applied an innovative combination of two human laboratory paradigms, namely imaginal-exposure and cue exposure, and a genetics framework to study the mechanisms of psychological stress in alcohol use and abuse. Following recruitment and screening procedures eligible individuals who sign informed consent completed a two-part (or two-visit) experiment. During the first visit they provided a DNA sample (via check swabs), completed individual differences measures such as alcohol and drug use, alcohol problems, family history of alcoholism. Participants reported recent stressful and neutral events in their lives. Information on recent stressful events was used to develop a personalized imagery script for each participant, one that was neutral and one that was stressful. During visit 2 individuals completed an imaginal exposure to the neutral and stressful scripts, in randomized and counterbalanced fashion. The imaginal exposure was followed by the presentation of their favorite alcoholic beverage, following the cue-exposure paradigm.
Ray, L.A. (2011) Stress-induced and cue-induced craving for alcohol in heavy drinkers: Preliminary evidence of genetic moderation by the OPRM1 and CRH-BP Genes. Alcoholism: Clinical and Experimental Research, 35(1), 166-174.
Pharmacogenetics of naltrexone in Asian Americans
This study was designed to follow-up on my previous work with naltrexone and the moderating role of the Asn40Asp SNP of the OPRM1 gene. Population studies have shown differences in allele frequencies for this candidate gene across various ethnic groups with individuals of Asian descent being more likely to have at least one copy of the minor (i.e. Asp40 allele) than individuals of European ancestry. The study examined the role of the Asn40Asp SNP of the OPRM1 gene in subjective responses to alcohol and responses to naltrexone among Asian Americans. Additional pharmacogenetic candidate genes for naltrexone were investigated in this sample of Asian American drinkers. This project was funded by the UCLA Academic Senate.
Ray, L.A., Green, R., Roche, D.J.O., Bujarski, S.E., Hartwell, E. E., Lim, A., Rohrbaugh, T., Ghahremani, D., Hutchison, K.E., & Miotto, K. (2018). Pharmacogenetic effects of naltrexone in individuals of East Asian descent: Human laboratory findings from a randomized trial. Alcoholism: Clinical and Experimental Research, 42(3), 613-623.
Bujarski, S., MacKillop, J., & Ray, L.A. (2012). Understanding naltrexone mechanism of action and pharmacogenetics via behavioral economics: a preliminary study. Experimental and Clinical Psychopharmacology, 20(3): 181-190.
A pilot study of quetiapine on alcoholism
This study sought to gather pilot and feasibility data on the effects of quetiapine for alcoholism. Non-treatment seeking alcohol dependent individuals were assigned to either quetiapine or placebo for a total of four weeks. Participants completed weekly assessments of drinking and two placebo-controlled intravenous alcohol administration sessions. The larger study informed by this pilot seeks to characterize the mechanisms of action of quetiapine for alcoholism and genetic predictors of response to this medication.
Brief intervention to reduce harmful alcohol use among Latino day laborers
This project sought to develop a brief intervention to reduce harmful alcohol use among Latino day laborers, a large and underserved population in California. The study comprised several phases, including focus groups with health promoters, survey, and brief intervention development, pilot testing, and training of community health promoters. This project was supported by the National Institute on Aging (NIA), through the Center for Health Improvement of Minority Elderly. http://www.chime.ucla.edu/investigators/lara.html.
Integrating human laboratory paradigms to refine alcoholism phenotypes
This study sought to characterize the bio-behavioral effects of alcohol by integrating two human laboratory paradigms, intravenous alcohol administration and alcohol cue exposure. We enrolled 40 non-treatment seeking, alcohol dependent participants. All participants completed two counterbalanced intravenous placebo-controlled alcohol administration sessions (Alcohol: placebo vs. alcohol) followed by a controlled and counterbalanced cue-exposure paradigm (Cue: neutral cues vs. alcohol cues). This study represents a novel integration of two well-established laboratory paradigms in order to dissociate the effects of alcohol’s pharmacology from alcohol cues in terms of the subjective responses to alcohol and craving and to examine the underlying genetic basis of these refined laboratory phenotypes. This project was funded by ABMRF, The Foundation for Alcohol Research.
Ray, L.A., Bujarski, S., MacKillop, J., Courtney, K.E., Monti, P.M., & Miotto, K. (2013). Subjective response to alcohol among alcohol dependent individuals: the effects of the mu opioid receptor (OPRM1) gene and alcoholism severity. Alcoholism: Clinical and Experimental Research, 37(1), E116-E124.
Ray, L.A., Bujarski, S., Squeglia, L.M., Ashenhurst, J.R., & Anton, R. (2014). Interactive effects of OPRM1 and DAT1 genetic variation on subjective responses to alcohol. Alcohol & Alcoholism, 49(3), 261-270.
Integrating laboratory and neuroimaging phenotypes
This study sought to characterize neural response to alcohol cues among individuals who completed our laboratory alcohol infusion paradigm. The objective was to integrate laboratory and neuroimaging phenotypes in order to better characterize biobehavioral and neural risk markers for problematic alcohol use. This study was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Ray, L.A., Courtney, K., Hutchison, K.E., MacKillop, J., Galvan, A., & Ghahremani, D. (2013). Initial evidence that OPRM1 genotype moderates ventral and dorsal striatum functional connectivity during alcohol cues. Alcoholism: Clinical and Experimental Research, 38(1), 78-89.
Testing the effects of varenicline on stress and cue-induced cigarette craving
This study compared varenicline (1 mg/twice per day) to placebo for its effects on stress-induced cigarette craving, cue-induced cigarette craving, and the relative reinforcing value of cigarettes during stress and cue-exposure. Daily smokers were recruited and completed a randomized, double-blind, placebo-controlled medication crossover study. This study sought to help elucidate the mechanisms of action of varenicline by leveraging important human laboratory paradigms relevant to smoking behavior and relapse. This project was supported by Pfizer through the Global Research Award for Nicotine Dependence (GRAND).
Ray, L.A., Lunny, K., Bujarski, S., Moallem, N., Krull, J.L., & Miotto, K. (2013). The effects of varenicline on stress-induced and cue-induced craving for cigarettes. Drug and Alcohol Dependence, 131(1-2), 136-142.
Pharmacotherapies for heavy-drinking smokers
Heavy drinking smokers represent a treatment resistant group who are more likely to relapse into smoking during drinking episodes. This study sought to test the singular and combined effects of varenicline and naltrexone on smoking urges among heavy-drinking smokers. This project was funded by the Tobacco Related Disease Research Program (TRDRP).
Ray, L.A., Courtney, K., Ghahremani, D., Miotto, K., Brody, A., & London, E.D. (2014). Varenicline, low dose naltrexone, and their combination for heavy drinking smokers: Human laboratory findings. Psychopharmacology, 231(19):3843-53.
Neural markers of response to medications for smoking
This study examined response to combined pharmacotherapies for heavy drinking smokers by testing brain-based measures of cigarette and alcohol craving. This study sought to help elucidate the effects of pharmacotherapies at the neural level of response and combined tests of cue-induced craving for alcohol and smoking with neuroimaging methods. This project was funded by the National Institute on Drug Abuse (NIDA).
Ray, L.A., Courtney, K., Ghahremani, D., Miotto, K., Brody, A. & London, E.D. (2015). Varenicline, naltrexone, and their combination for heavy drinking smokers: Preliminary neuroimaging findings. American Journal of Drug and Alcohol Abuse, 41(1), 35-44.
Brief smoking cessation intervention
This study consisted of 2 sessions: an intervention (targeting cigarette smoking and alcohol or smoking only) and a 1-month follow up. During the intervention session, participants met with a therapist (either the PI, a licensed clinical psychologist, or a clinical psychology PhD student working under the PI’s supervision) and were provided feedback on their smoking and drinking behaviors and discussed their smoking and drinking goals with the therapist. The therapist explored individually targeted ways to achieve those goals with the participant, and additional resources were provided (e.g., http://www.tobaccofreeca.com/).
Pharmacogenetics of naltrexone for methamphetamine use disorder
Methamphetamine (MA) dependence has increased dramatically in the United States during the past decade, yet there are no medications approved for the treatment of MA dependence. This study was designed to help develop medications for MA dependence by studying naltrexone (NTX) and its mechanisms of action, while using genetic markers to predict who responded best to this medication. This study looked at non-treatment seeking individuals who met criteria for MA dependence. Participants completed two double-blinded, counterbalanced, within-subjects MA administration laboratory sessions, one after taking NTX and one after taking matched placebo for four days. This project is funded by the National Institute on Drug Abuse (NIDA).
Bujarski, S., Roche, D., Lunny, K., Moallem, N.R., Courtney, K.E., Allen, V., Hartwell, E., Leventhal, A., Rohrbaugh, T., & Ray, L.A. (2014). The relationship between methamphetamine and alcohol use in a community sample of methamphetamine users. Drug and Alcohol Dependence, 142:127-32
Alcohol prediction error study
The objective of this study was to identify disease-related changes in brain reward system activity specific to alcohol as a reinforcer. We compared age matched non-dependent social drinkers with alcohol dependent individuals during a reward prediction error task performed during a brain scan. We hypothesized that positive prediction error (receiving an alcohol reward when unexpected) will produce greater activation in reward brain regions in alcohol dependent individuals compared to social drinkers. Conversely, a negative prediction error (not receiving an alcohol reward when expected) will produce reduced activation in these regions in alcohol dependent individuals compared to social drinkers.
EMA smoking study
Smoking is the leading cause of preventable death in the United States representing a serious public health burden. Abstinence promoting interventions have largely targeted smokers as a homogenous group; however, differences may exist in the experience of early abstinence between groups of smokers based on their smoking patterns, which could impact intervention efficacy and treatment optimization. Thus, the purpose of this study was to characterize the pattern of cigarette craving and withdrawal over the first 24 hours of abstinence in two groups of daily smokers who differ in their smoking pattern. We tested whether smoking pattern predicts the time course of cigarette craving, withdrawal, and affective responses during the first 24 hours of abstinence.
Repositioning Ivermectin for the Treatment of Alcohol Use Disorders
This project sought to provide key evidence that ivermectin (IVM), which is currently used worldwide as a broad-spectrum antiparasitic avermectin, can be repositioned as a novel and effective therapeutic agent to treat alcohol use disorders. The study consisted of a randomized, double-blind, placebo-controlled within-subject crossover design to determine the safety, tolerability, and initial human laboratory efficacy of IVM in a sample of 10 individuals treated with IVM (30 mg QD) and placebo. Participants completed two separate 2-day inpatient stays at the UCLA CTRC during which they took the study medication, complete an IV alcohol challenge, and take part in cue-exposure.This project was funded by a Clinical and Translational Science Institute (CTSI) seed grant. http://www.ctsi.ucla.edu/opportunities/pages/ctrcseed
Development of Ibudilast as a Novel Treatment for Alcoholism
Alcohol dependence (AD) is a chronic and relapsing condition affecting 10 million Americans. To date, only four pharmacotherapies are approved by the FDA for the treatment of alcoholism and their efficacy is modest. Therefore, medication development for AD represents a high priority area. Ibudilast (IBUD) is a glial cell modulator that inhibits phosphodiesterases (PDE) -4 and -10 and macrophage migration inhibitory factor (MIF). Preclinical data suggest that neuroimmune modulation is critical to the rewarding properties of drugs of abuse, including alcohol. This study aimed to advance medication development for alcoholism by conducting an initial Phase II study of IBUD for AD. Specifically, the study consisted of a randomized, double-blind, placebo-controlled, within-subject crossover design to determine the safety, tolerability, and initial human laboratory efficacy of IBUD in a sample of 24 participants treated with IBUD (50mg BID) and placebo. Participants completed two separate medication conditions during which they took the study medication, completed an IV alcohol challenge, and took part in stress-exposure and cue-exposure paradigms. This project was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA; R21AA02214). http://www.niaaa.nih.gov/
Ray, L.A., Bujarski, S.E., Shoptaw, S., Roche, D.J.O., Heinzerling, K., & Miotto, K. (2017). Development of the neuroimmune modulator ibudilast for the treatment of alcoholism: A randomized, placebo-controlled, human laboratory trial. Neuropsychopharmacology, 42, 1776-1788.
HORIZANT (Gabapentin Enacarbil Extended-Release Tablets) for the Treatment of Alcohol Use Disorder
The purpose of this study is to determine whether gabapentin enacarbil is effective in the treatment of problems with alcohol. UCLA is one of 10 clinical sites in this national, multi-site trial. The 28-week trial consists of study medication, outpatient clinic visits, and compensation. This project is sponsored by the NIAAA Clinical Investigators Group (NCIG/NIAAA/NIH). http://www.niaaa.nih.gov/NCIG-NIAAA-Clinical-Investigations-Group
Optimizing Naltrexone for Individuals of East Asian Descent
Recent pharmacogenetic studies have advanced the gene coding for the µ-opioid receptor (OPRM1) gene as a potential moderator of responses to naltrexone. This study will build upon preliminary findings by testing heavy drinkers of East Asian descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n = 30). Participants will complete two double-blinded, counterbalanced alcohol infusion and self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched placebo for five days. Additionally, in each medication condition participants will complete a functional neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on bio-behavioral and neural markers of response to naltrexone in individuals of Asian descent, an ethnic group most likely to express the positive predictive allele (Asp40). The long-term objective of this research is to optimize alcoholism pharmacotherapy and to address health disparities by advancing pharmacogenetic studies in ethnic minority groups. This project is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA; R01AA021744). http://www.niaaa.nih.gov/
Modeling Alcohol Reward and Reinforcement in the Human Laboratory
Both animal and human models of alcoholism etiology have focused on bio-behavioral response to alcohol as a potential marker of alcoholism risk vulnerability and disease progression. Alcoholism has been conceptualized in neurobiological models as a transition from positive reinforcement (i.e., “drinking to feel good”) to negative reinforcement (i.e., “drinking not to feel bad or to feel normal”), representing a cycle of progressive neurobiological dysregulation. Alcohol administration studies in the human laboratory allow for the translation of preclinical theory to clinical populations through examination of the subjective response to alcohol (comprising stimulation, sedation and tension relieving dimensions) at different levels of drinking status (i.e. heavy drinking or alcohol dependent groups). To date, no studies have used alcohol administration paradigms to translate neurobiological models of alcoholism etiology to clinical populations. The objective of this study is to examine well-established neurobiological theories of alcoholism etiology in the human laboratory. To do so this study combines traditional alcohol challenge and progressive ratio self-administration methodologies to elucidate the relationship between subjective response to alcohol and one’s willingness to work for alcohol. In order to model the transition from positively to negatively reinforced alcohol use two groups (ntotal = 82) will be recruited, a group of non-dependent heavy drinkers and a group of alcohol dependent individuals. An exploratory aim will examine candidate genes subserving the positive and negative reinforcing effects of alcohol. The study extends the alcoholism literature through testing neurobiologically informed hypotheses about the moderating role of drinking status on subjective response to alcohol in the lab and the relationship between subjective response and self-administration of additional alcohol ad lib. This project is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA; R21AA022752). http://www.niaaa.nih.gov/
Perceived Alcohol Rewards and Risks Study
The identification of mechanisms that underlie how people reduce or eliminate alcohol use is a critical public health issue. Understanding these mechanisms can inform how to effectively intervene with problem drinkers. Thus far it has been a challenge for the alcohol research field to find consistent empirical evidence in support of candidate mechanisms of behavior change. Scientific advancement in this area may be aided by longitudinal transdisciplinary research on the interplay between behavioral intervention, cognition and brain activity to understand underlying processes of behavior change among heavy drinkers. The proposed study uses this general strategy by combining validated brain imaging paradigms with a randomized trial of a brief motivation-based intervention to examine changes in alcohol use among heavy drinkers. Findings from this proof-of-concept study will contribute to the understanding of behavior change processes and will inform both future research and clinical practice regarding the delivery of brief alcohol interventions.
The Effects of Naltrexone on Neural Responses to Methamphetamine Cues
Preclinical and clinical data suggest naltrexone is effective at reducing amphetamine craving; however, the neural mechanisms underlying this effect remain unknown. Thus, this study sought to investigate the neurobiological effects of naltrexone on methamphetamine cues in individuals who use methamphetamine. Participants underwent an fMRI protocol in which visual methamphetamine and control cues are presented. The participants were scanned twice, once while on the target dose of naltrexone (50mg) and once on placebo. The results of this translational project will advance medication development for methamphetamine dependence by assessing the pathways by which methamphetamine craving is instated and by testing whether naltrexone effectively targets these neural pathways. This was the dissertation project of 5th year Kelly Courtney and was funded by the National Institutes of Health (NIH) through a National Research Service Award (NRSA). http://grants.nih.gov/training/nrsa.htm
The Effects of Methamphetamine Use on Impulsivity and Executive Functioning
Cognitive therapy remains the leading treatment for MA dependence; however, abuse of psychostimulants, including MA, has been linked to cognitive deficits. As such, treatment retention and/or success rates may be impacted by patients’ cognitive impairments. In this study, individuals who use MA completed a comprehensive neuropsychological battery during early abstinence (5-7 days). This study tested a multivariate structural equation model where clinical variables of MA use (i.e., years of use, route of administration, age of first use, etc.) were used to predict executive functioning at early abstinence and examine the relationship between impulsivity, response inhibition, and delayed reward discounting and MA use severity. This is the dissertation project of 5th year Nathasha Moallem.
Black Men’s Health Study
Epidemiological data indicate Black men who have sex with men (BMSM) are the most at-risk group for HIV. Non-condom use during sex is associated with HIV transmission, and alcohol use in the context of sex may increase the likelihood of sexual risk-taking. This project examined the relationship between alcohol consumption and condom use among BMSM. Specific aims were to: 1) test the effects of alcohol consumption on condom use among BMSM at the global (lifetime), time-limited global (past 6 months), and event (most recent) levels of analyses; and 2) examine moderators of the relationship between alcohol consumption and condom use across all three levels of analysis. An exploratory aim was to investigate differences in the association between alcohol and risky sexual behavior between behaviorally homosexual vs. behaviorally bisexual men. This study was innovative in addressing unique predictors of HIV risk for BMSM that are often not examined in general studies of MSM. Results can inform HIV intervention strategies for BMSM that are culturally relevant and reflect the issues of importance to this at-risk, yet underserved, population. This was the dissertation project of 5th year Vincent Allen, Jr. and was funded by a UCLA AIDS Institute and Center for AIDS Research seed grant as well as the United Negro College Fund and Merck Foundation.