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 (FA) paradigm where participants could self-administer short standardized IV alcohol infusions via single button presses. We have demonstrated high test-retest reliability of this paradigm, and shown that consumption measures obtained in the laboratory reflect recent drinking history, providing face validity to the paradigm. We also found robust positive relationships between IV-ASA and subjective responses including high, liking, intoxication and stimulation. We have examined the influence of factors such as impaired control and suggestibility on alcohol consumption using IV-ASA. 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 was used in studies 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 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 individuals preferred alcohol exposure during a lab session 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. This indicates that 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. More recently we have reported on neuropsychological predictors of binge drinking in young adults. We are currently evaluating 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 sources of inter-individual variability in 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 assesses 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 recently completed a study combining IV-ASA with acute stress cue exposure to characterize stress-induced craving and consumption of alcohol. In addition, we are currently developing a human laboratory model of impaired control over alcohol consumption. 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 problems. Given the critical and essential relationship between alcohol response and risk for AUD, this approach can provide novel and important insights into the etiology of AUD as well as support the development of novel pharmacological targets for treatment of AUD. II. Human Laboratory Models in Medication Development for Alcoholism 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. The first experimental medicine conducted by the laboratory 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 medication repurposing of varenicline could be targeted towards reward-drinking individuals seeking help for treatment of AUD. This study also demonstrates the utility of human laboratory paradigms and the use of fMRI-derived brain biomarkers in medications development for AUD. Currently, the laboratory is conducting a study examining the effect of opioid receptor modulation using 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 In collaboration with the Office of the Clinical Director, we have initiated 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 that have participated in NIAAA studies, leveraging the deep phenotyping assessment and genomic data collected on these individuals prior to the pandemic. The study plans to follow these individuals for upto 2 years to characterize the trajectory of changes in alcohol use, motives, response, sensitivity and problems, along with measures of nicotine and other substance sue, stress, isolation, resilience, sleep, as well as behavioral impact of the pandemic. The study was initiated in June 2020 and analysis of data collected in the first year of the pandemic are ongoing. IV. Collaborative Studies: 1) Sleep disturbance and relapse in individuals with alcohol dependence (PI: Gwenyth Wallen, NIH CC). 2) Using the alcohol clamp to examine the mechanistic relationship between ethanol and atrial fibrillation (PI: Greg Marcus, UCSF). 3) Translational imaging genetics project to examine the role of nicotine receptor gene variation and alcohol reward (Co-PI: Mariella De Biasi, UPenn). 4) Pharmacokinetics and subjective responses to alcohol after bariatric surgery (PI: Marta Yanina Pepino de Gruev, UIUC).