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) The IV-ASA paradigm models the trajectory of an individual’s preferred alcohol exposure in the lab, and is a unique approach to assess binge consumption, i.e., consuming alcohol to breath alcohol concentrations (BrACs) >0.08%, under highly controlled conditions. Binge drinking is associated with a greater risk of negative 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 alcohol use disorder (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 behavior across the spectrum of use. II. Understanding neurobiological domains underlying AUD In collaboration with the Office of the Clinical Director, (PI: Nancy Diazgranados), we have been conducting a deep phenotyping study titled Addictions Neuroclinical Assessment (ANA), to characterize the primary neurofunctional domains of incentive salience, negative emotionality and executive function, using a prospective battery of tasks and questionnaires along with ancillary measures. These domains map onto the 3 stages of the so-called Koobian cycle of addiction: binge-intoxication, preoccupation-anticipation, and withdrawal-negative affect. We recently published findings demonstrating a multi-level factor structure of the domains, with unique features and additional dimensionality that demonstrated cross-correlations among factors such as alcohol motivation, internalizing behaviors, and impulsivity, as well as differentially sensitivity in classifying individuals with and without AUD. With our IV-ASA paradigms, we have been working on characterizing the pharmacodynamics of alcohol across the neurobiological domains in the ANA framework. Alcohol response phenotypes span a wide and heterogeneous range from subjective effects to objective psychophysiological impairment, and these measures can be broadly categorized into the 3 ANA domains, specifically reward/incentive salience (stimulation, liking, wanting, craving), negative valence (subjective and psychophysiological reactivity to stress-cues), and executive control (loss of control, ability to resist, compulsivity). 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 pharmacological targets for treatment of AUD. We have recently expanded our interest to examine associations of AUD with common co-occurring conditions, and their impact on AUD risk and outcomes. We examine the impact of obesity (BMI) on level of response to alcohol, and the role of total body water and other factors. We also evaluated impulsivity traits and behaviors in individuals with AUD and history of suicidality. We are currently examining the impact of comorbid depression and anxiety as well as PTSD on biobehavioral phenotypes of AUD using the ANA framework. III. 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, as reported previously, 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. We recently published initial results from the fMRI changes during an fMRI task of reward activation, which showed a significant effect of reward cue type on activation in the nucleus accumbens, but no significant difference between nalmefene and placebo on this response. 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. IV. 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. We have previously reported findings on latent classes of COVID-related stressors and health disparities, role of social media addiction as a mediator of the associations between fear of COVID-19, mental health and alcohol use problems, impact of AUD history on loneliness and links to higher anxiety and depressive symptoms, characterization of latent classes of positive and negative coping behaviors during the pandemic that were associated with disparate mood symptoms and alcohol-related outcomes, and reports of parosmia and phantosmia that were associated with greater problematic alcohol use and depression, suggesting olfactory deficits in these groups. In the past year, we have reported results of analyses examining financial well-being and relationships with alcohol and mental health outcomes, disparities in group-based medical mistrust and associations with mental health symptoms, and AUD history and housing instability as predictors of fatigue and mental health problems during the pandemic. We also conducted an analysis examining gaps in treatment for chronic conditions during the pandemic, and impact on problematic alcohol use as well as the moderating roles of perceived stress and resilience. Additional analyses are underway to examine the trajectory of changes in alcohol use and related consequences in individuals in the post-pandemic phase, as well as examination of novel measures related to stress mindset, flourishing, and resilience and recovery. V. Collaborative Studies: Translational imaging genetics project to examine the role of nicotine receptor gene variation and alcohol reward (Co-PI: Mariella De Biasi, UPenn). Translational imaging genetics project to examine the role of ZIP8 gene variation and alcohol reward (Co-PI: Mariella De Biasi, UPenn). Using ecological momentary assessment (EMA) to examine real-world alcohol consumption, human lab consumption, and related perceptions and behaviors (Andrew Waters, USUHS) Pharmacokinetics and subjective responses to alcohol after bariatric surgery (Marta Yanina Pepino de Gruev, UIUC). Ketone supplements and alcohol response (Corinde Wiers, UPenn). Transcriptomic response to alcohol and determinants (Robert Messing, UT Austin, Laura Ferguson UNC).