Alcohol Pharmacokinetics and Pharmacodynamics in Humans

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

I. Intravenous Alcohol Self-Administration (IV-ASA) We have conducted a series of studies to characterize IV alcohol self-administration (IV-ASA) across the spectrum of alcohol use. We first tested a free-access paradigm where participants could self-administer short standardized IV alcohol infusions via single button presses. This paradigm demonstrated high test-retest reliability and face validity, with lab-based consumption measures reflecting real-life drinking history. We also found robust positive relationships between IV-ASA and subjective responses including high, liking, intoxication and stimulation. We have also developed a progressive ratio (PR) IV-ASA paradigm as an operant assessment of motivation for alcohol rewards. The PR paradigm showed robust test-retest reliability, and PR-IV-ASA measures were significantly associated with recent drinking history and reflected subjective perceptions of alcohol hedonic and rewarding effects. This paradigm has been used to examine the effect of exogenous ghrelin on alcohol salience and consumption, and to examine relationships between subjective response and motivation to consume alcohol across the AUD severity spectrum. The PR paradigm represents a novel approach toward improving our understanding of what drives alcohol seeking and consumption, and offers an attractive translational endpoint for evaluating novel therapeutics for AUD. Modeling Binge Consumption: The IV-ASA paradigm models the trajectory of an individual's preferred alcohol exposure in the laboratory, and represents a unique approach to assess binge consumption, i.e., consuming alcohol to BrACs >0.08%, under highly controlled conditions. Binge drinking is associated with a greater risk of negative acute and chronic consequences, and has a major impact on psychological and physical well-being. We have shown that faster rates of alcohol consumption to binge-levels were associated additively with risk factors for AUD, including family history of AUD, male sex, impulsivity, and low level of response to alcohol. Thus, faster binge drinking may be an early indicator of vulnerability to AUD and should be carefully assessed as part of a thorough clinical evaluation. We have also shown that social drinkers with AUD risk factors achieve rates of binge consumption akin to heavy drinkers, and have reported on neuropsychological predictors of binge drinking in young adults. Recently, we published a collaborative study on behavioral and pharmacological correlates of high intensity binge drinking using IV-ASA models and clinical data. The IV-ASA model of binge-consumption can provide unique insights into the biobehavioral mechanisms and heterogeneity of this compulsive behavior across the spectrum of use. Understanding neurobiological domains underlying AUD: IV-ASA paradigms have great utility in characterizing the pharmacodynamics of alcohol across neurobiological domains relevant to addiction. Alcohol response phenotypes span a wide and heterogeneous range from subjective effects on mood and behavior to objective functional impairment to physiological effects. These response measures can be broadly categorized into 3 domains: (1) Reward/Incentive Salience (stimulation, liking, wanting, craving), (2) Negative Valence (subjective and psychophysiological reactivity to stress cues), and (3) Executive Control (loss of control and ability to resist, as well as impulsivity and compulsivity). These domains are aligned with the alcohol neuroclinical assessment (ANA) domains within the alcohol addiction framework, and map onto the 3 stages of the so-called Koobian cycle of addiction: binge-intoxication, preoccupation-anticipation, and withdrawal-negative affect. Our work suggests that the free-access and PR IV-ASA paradigms primarily assess alcohol seeking and consumption, including binge-consumption, driven by the incentive salience and reinforcing properties of alcohol, and can therefore be useful in assessing the underpinnings of alcohol reward. We have completed a study combining IV-ASA with acute stress cues to characterize stress-induced craving and alcohol consumption. We have also developed a human laboratory model of impaired control over alcohol consumption that demonstrated lower ability to resist alcohol for an alternate monetary reward in individuals with impaired control over alcohol. These human lab models provide a unique opportunity to obtain a deeper understanding of the heterogeneity of alcohol response phenotypes across the spectrum of alcohol use and misuse. Our work provides novel and important insights into the critical and essential relationship between alcohol response and AUD risk, and supports the development of novel pharmacotherapy targets for AUD. II. Human Laboratory Models in Medication Development for AUD The laboratory is developing and utilizing human laboratory models to examine the effects of pharmacological agents for the treatment of alcohol use disorder (AUD). These translational studies can complement preclinical studies to screen novel therapeutics that are likely to succeed in clinical trials, thus facilitating future medication development for AUD. Our prior experimental medicine study examined the effect of varenicline, a (nicotinic) acetylcholine receptor partial agonist approved for smoking cessation, in non-treatment seeking heavy drinkers. This study was reported in previous annual reports and indicated that varenicline could be a targeted treatment for reward-drinking individuals with AUD. This study also exemplified the utility of human laboratory paradigms and the use of fMRI-derived brain biomarkers in medications development for AUD. Currently, we are analyzing the data from a study examining the effect of the opioid antagonist nalmefene on IV-ASA and neural response to alcohol cues in heavy drinkers. This study could provide important information about the underlying mechanisms of opioid receptor modulation in alcohol response, and could provide novel data to develop personalized medicine approaches to optimize the therapeutic benefit of nalmefene and other opioid antagonists in the treatment of AUD. III. COVID-19 Pandemic Impact on Alcohol and Related Outcomes Together with the Office of the Clinical Director, we are conducting a longitudinal survey study examining the impact of the COVID-19 pandemic on alcohol use and consequences and related outcomes. This study is being conducting in individuals enrolled in the NIAAA natural history study, leveraging the deep phenotyping assessment and genomic data collected on these individuals prior to the pandemic. Initial publications from this study have identified latent classes of COVID-related stressors that had disproportionate effects on racial/ethnic minority groups and individuals with AUD, with increased perceived stress, problem drinking and greater drinking to cope suggesting a shift to greater negative emotionality. There were bidirectional changes in drinking, with increased drinking being related to increased alcohol salience, greater negative affect and stress, and greater impaired control. Additional analyses are underway to examine the trajectory of changes in alcohol use and related consequences including quality of life. IV. Collaborative Studies: Translational imaging genetics project on the role of nicotine receptor gene variation and alcohol reward (U01 Co-PI: Mariella De Biasi, UPenn). Translational imaging genetics project on the role of ZIP8 gene variation and alcohol reward (BtB Co-PI: Mariella De Biasi, UPenn). Pharmacokinetics and subjective responses to alcohol after bariatric surgery (PI: Marta Yanina Pepino de Gruev, UIUC). Ketone supplements and alcohol response (PI: Corinde Wiers, UPenn). Transcriptomic response to alcohol and determinants (PI: Robert Messing, UT Austin).