Grant-Funded Lab Projects
A Novel Human Laboratory Model for Screening Medications for Alcohol Use Disorder (Practice Quit Study)
Alcohol use disorder (AUD), as defined in DSM-5, represents a highly prevalent, costly, and often untreated condition in the United States. Pharmacotherapy offers a promising avenue for treating AUD and for improving clinical outcomes for this debilitating disorder. While developing novel medications to treat AUD remains a high priority research area, there are major opportunities to refine the process of screening novel compounds. To that end, a key question in clinical studies of novel compounds for AUD is how to efficiently determine whether a novel medication has sufficient evidence of initial treatment efficacy to warrant proceeding to clinical trials.The process of screening novel compounds for initial efficacy, known as the early phase 2 of medications development, often consists of human laboratory studies assessing constructs of putative clinical relevance, such as alcohol craving, subjective response to alcohol, and alcohol self-administration under laboratory conditions. Nevertheless, these controlled human laboratory models lack the ecological validity of clinical trials in which medication efficacy is established via clinically meaningful endpoints in individuals motivated to change their drinking behavior. The scientific premise of this study is that screening novel AUD medications can be more efficient and clinically meaningful if early efficacy (phase 2) studies combine the internal validity of laboratory testing with the external validity of clinical trials. To that end, we propose to develop and validate a novel early efficacy paradigm informed by the smoking cessation medication development literature, to screen AUD medications in humans. Specifically, the proposed early efficacy paradigm consists of a study in which individuals with current AUD reporting intrinsic motivation to change their drinking (i.e., wanting to quit or reduce their drinking within the next 6 months) will complete a week-long “practice quit attempt” while on study medication (either varenicline, naltrexone, or placebo). The primary outcomes of the practice quit attempt are (a) percentage of days abstinent and (b) drinks per drinking day. The proposed laboratory protocol has been carefully developed and validated for screening smoking cessation pharmacotherapies. The objective of this proposal is to develop, refine, and validate this novel approach to screen pharmacotherapies for AUD.
A Randomized Controlled Clinical Trial of the Neuroimmune Modulator Ibudilast for the Treatment of Alcohol Use Disorder (Ibudilast Alcohol Study)
Alcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. To that end, modulation of neuroimmune function represents a promising novel target for AUD. Chronic alcohol consumption produces a sustained inflammatory state, such that individuals with AUD have increased neuroinflammation throughout the brain, and alcohol-induced neuroinflammation is thought to contribute to chronic alcohol seeking behavior and to the behavioral and neurotoxic effects of alcohol. Ibudilast (IBUD) has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function. IBUD inhibits phosphodiesterases -4 (PDE4) and -10 (PDE10) and macrophage migration inhibitory factor (MMIF). Additionally, IBUD enhances neurotrophin expression, reduces pro-inflammatory cytokine release, and attentuates neuronal death. Our laboratory has recently completed a randomized, double-blind, placebo-controlled crossover laboratory study of IBUD in non-treatment seeking individuals with AUD, and concluded that IBUD is well tolerated and associated with mood improvements during stress- and alcohol-cue exposures in conjunction with a reduction in tonic levels of alcohol craving. This current study seeks to advance medication development for AUD by conducting a 12-week, double-blind, placebo-controlled randomized clinical trial of IBUD. A total of 132 treatment-seeking drinkers that meet criteria for moderate or severe AUD will be randomized to either IBUD or placebo.The primary aims of this study are to (1) to test whether IBUD will decrease percent heavy drinking days, and (2) test the efficacy of IBUD on secondary alcohol consumption endpoints, alcohol craving, and negative mood, compared to placebo, and over the course of the 12-week trial.
A Randomized Controlled Clinical Trial of the Neuroimmune Modulator Ibudilast for the Treatment of Alcohol Use Disorder: A Pilot Study Examining Withdrawal-Related Dysphoria (DDA Study)
Alcohol use disorder (AUD) is a prevalent and disabling psychiatric disorder with few, and only moderately efficacious, treatment options. Consequently, the identification of novel treatment targets and the development of rigorous laboratory paradigms to screen and optimize novel therapeutics represents a research priority. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. Recently in an AUD sample, IBUD was shown to decrease reactivity to a psychological stressor. Furthermore, IBUD was effective in blunting alcohol reward among participants with greater depressive symptoms, a hallmark symptom of protracted withdrawal. It is still unknown how neuroimmune modulation impacts brain processes that underlie alcohol reward processing. Recently, preclinical research in opiates has demonstrated that drug withdrawal is necessary for microglia activation and neuroinflammation in reward networks, suggesting that IBUD may be most effective among patients who experience withdrawal-related dysphoria. Therefore, this study aims to examine withdrawal-related dysphoria as a moderator of IBUD efficacy in the natural environment measured using Daily Diary Assessment (DDA) approaches.
UCLA Psychology Cognitive Behavioral Therapy (CBT) Treatment for Alcohol Use Disorder (AUD) Clinic
Alcohol problems are highly prevalent among adults in the U.S. Specifically, twenty-five percent of adults in the U.S. report either currently having alcohol-related problems or drinking patterns that put them at risk for developing problems. Further, only 1 in 5 individuals with alcohol problems seek treatment and the available treatments are often not informed by science. In order to address the service needs of our community and to provide a training opportunity for advanced doctoral students in clinical psychology at UCLA, we propose to develop an outpatient alcoholism clinic providing evidence-based cognitive behavioral therapy for individuals with alcohol problems. In keeping with our service, training, and research missions, this clinical protocol will combine a research component with evidence-based practices. Specifically, participants will be asked to complete an alcohol cue-reactivity testing session at the end of their intake session and will discuss their reactions to alcohol cues with the therapist. Participants will be asked to repeat the alcohol cue-reactivity testing session after completing the 12-week CBT protocol. The CBT protocol will be derived from the Project MATCH Treatment Manual, which is an effective and well-disseminated evidence-based intervention for alcohol use disorder. Participants will complete a battery of assessments at the intake visit (30 minutes of assessments at intake) as well as weekly assessments immediately prior to their clinic visits (10-15 minutes of assessments each week), including a breathalyzer test, and random urine toxicology tests (one at intake and three random tests over the course of the 12-week treatment).