Pharmacokinetics and Pharmacodynamics of Ethanol in Healthy Volunteers: Effects of Input-Rate and Degree of Ethanol Exposure on Subjective and Objective Measures of Impairment

The goal of this project was to investigate the effect of input-rate (oral and intravenous) and degree of exposure on the pharmacokinetics of ethanol and on subjective and objective measures of impairment, as well as on the development of acute tolerance to the effects of ethanol in young, healthy volunteers. The primary objective of this research was to test the following hypotheses: 1) the rate and degree of ethanol exposure (oral and intravenous) in normal healthy males and females affect the pharrnacokinetics (PK) and pharmacodynarnics (PD) of ethanol in a non-linear fashion; 2) the EEG changes after ethanol administration correlate with changes in psychometric performance and subject-rated impairment, as well as serum ethanol concentrations; and 3) acute tolerance develops to the subjective effects of ethanol which is not reflected in changes in electroencephalographic (EEG) activity or psychometric performance. This study was conducted in two parts. Part I was a five-way crossover pilot study in six healthy male volunteers to evaluate the effect of dose and dose-rate on the PK and PD of ethanol. This study evaluated changes in EEG activity, psychometric performance and subjective impairment to evaluate the relationship between these subjective and objective measures, and the relationship between these measures and serum ethanol concentrations. Part II was a 4-way crossover study in 16 healthy male and female subjects to study the PK-PD relationship for intravenous (IV) ethanol and acute tolerance development to the effects of ethanol. In this study, subjects were administered individualized intravenous ethanol infusions, to achieve a target concentration of 1000 mg/L after different durations of exposure. This study was designed to i:nvestigate the PK of ethanol, as well as to assess changes in EEG activity, psychometric performance and subjective impairment. This study evaluated the relationship between these measures, and the relationship between these measures and serum ethanol concentrations, as well as the development of acute tolerance to the effects of ethanol. Results from both studies showed that: 1) Ethanol, after oral and intravenous administration, follows capacity-limited pharmacokinetics. Intrinsic PK parameters, V max• Km and Vd were independent of dose and input-rate, but were associated with fairly high inter-individual variability. 2) Ethanol, after oral and intravenous administration, induced a transient slowing of the EEG and impairment in psychometric performance. The magnitude of the changes in these measures appeared to be dose-related as well as inputrate- related (observed in the IV study), however there was a fairly large degree of variability in response between individuals. 3) Ethanol, after oral and intravenous administration, induced transient subjective impairment, which was dose-related and input-rate-related, and correlated with serum ethanol concentrations across treatments. 4) A subset of subjects (2/6 males in the oral ethanol study, and 2/8 males and 4/8 female subjects in the IV study) were classified as non-responders based on their lack of subjective response to ethanol, despite serum ethanol concentrations, psychometric impairment and EEG changes that were consistent with the other subjects. 5) There was significant exposure-related acute tolerance development to the subjective effects of ethanol observed in both studies. This acute tolerance development could be characterized by a PK-PD model incorporating tolerance as a compensatory feedback mechanism to counter-regulate the direct subjective impairment effect of the drug. Acute tolerance was not observed for the psychometric impairment or changes in EEG activity, indicating that there was a temporal disparity be~een objective and subjective impairment following ethanol administration. 6) The EEG changes were not correlated with the psychometric or subjective impairment. 7) There was a significant gender difference observed in the Cmax and Vdss for ethanol, probably due to gender differences in body weight and body water content. There was also a significant gender difference observed in the magnitude of ethanol-induced subjective impairment, with females showing a lower degree of subjective impairment, despite achieving similar concentrations and demonstrating similar psychometric impairment and EEG changes. This gender difference may be partly confounded by the larger proportion of female non-responders compared to the male non-responders in the study

Stress Vulnerability And Alcohol Use And Consequences: From Human Laboratory Studies To Clinical Outcomes

It is well known that vulnerability to stress is a risk factor for alcohol use disorder (AUD). Chronic alcohol use can result in neuroadaptations in cortico-striatal pathways and hypothalamic pituitary adrenal (HPA) axis function that are manifested in altered behavioral and cognitive control functions contributing to alcohol craving, compulsive motivation, consumption and consequences. This symposium brings together studies utilizing novel approaches to help improve our understanding of stress – past, acute and chronic - on alcohol seeking and consumption and related outcomes using a combination of human laboratory models, neuroimaging and clinical measures. Examining factors that determine vulnerability as well as resilience to stress are of particular interest in the study of AUD because, in addition to increasing our understanding of the risk factors for AUD, such knowledge can be used to develop more effective treatments. Dr. Stangl presented a novel human experimental model that demonstrates, for the first time, stress-induced increases in alcohol self-administration in binge drinkers using a guided imagery paradigm combined with intravenous alcohol self-administration (IV-ASA). Dr. Blaine presented data demonstrating that glucocorticoid response to stress drives compulsive alcohol motivation and intake in binge/heavy drinkers. Dr. Plawecki presented data examining sex differences in the effect of two distinct stress paradigms – mood induction and abstinence – on IV-ASA in moderate drinkers. Dr. Schwandt presented clinical data providing a new perspective on the relationship between childhood trauma and AUD by suggesting possible underlying mechanisms that confer resilience, rather than vulnerability, to severe early life stress exposure

Genome-wide association studies of the self-rating of effects of ethanol (SRE).

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders

To Infuse or Ingest in Human Laboratory Alcohol Research

Human alcohol laboratory studies use two routes of alcohol administration: ingestion and infusion. The goal of this paper is to compare and contrast these alcohol administration methods. The work summarized in this report was the basis of a 2019 Research Society on Alcoholism Roundtable, “To Ingest or Infuse: A Comparison of Oral and Intravenous Alcohol Administration Methods for Human Alcohol Laboratory Designs.” We review the methodological approaches of each and highlight strengths and weaknesses pertaining to different research questions. We summarize methodological considerations to aid researchers in choosing the most appropriate method for their inquiry, considering exposure variability, alcohol expectancy effects, safety, bandwidth, technical skills, documentation of alcohol exposure, experimental variety, ecological validity, and cost. Ingestion of alcohol remains a common, and often a preferable, methodological practice in alcohol research. Nonetheless, the main problem with ingestion is that even the most careful calculation of dose and control of dosing procedures yields substantial and uncontrollable variability in the participants’ brain exposures to alcohol. Infusion methodologies provide precise exposure control but are technically complex and may be limited in ecological validity. We suggest that alcohol ingestion research may not be the same thing as alcohol exposure research; investigators should be aware of the advantages and disadvantages that the choice between ingestion and infusion of alcohol invokes

Novel paradigms for the gut–brain axis during alcohol withdrawal, withdrawal-associated depression, and craving in patients with alcohol use disorder

Introduction: Patients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms. Methods: Forty-eight AUD patients [men (n = 34) and women (n = 14)] aged 23–63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score > 10] [n = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [n = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS). Results: CS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-1β and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R2 = 0.955, p = 0.006) in the AUD patients, who had higher ratings for cravings (PACS > 5). Discussion: The interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut–brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut–brain axis response to heavy drinking. Trial registration: ClinicalTrials.gov, identifier: NCT# 00106106

Binge and High-Intensity Drinking – Associations with Intravenous Alcohol Self-Administration and Underlying Risk Factors

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders

Genome wide association studies of the Self-Rating of Effects of Ethanol (SRE)

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders

Novel paradigms for the gut–brain axis during alcohol withdrawal, withdrawal-associated depression, and craving in patients with alcohol use disorder

IntroductionPatients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms.MethodsForty-eight AUD patients [men (n = 34) and women (n = 14)] aged 23–63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score > 10] [n = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [n = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS).ResultsCS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-1β and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R2 = 0.955, p = 0.006) in the AUD patients, who had higher ratings for cravings (PACS > 5).DiscussionThe interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut–brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut–brain axis response to heavy drinking.Trial registrationClinicalTrials.gov, identifier: NCT# 00106106

Pharmacological manipulation of the ghrelin system and alcohol hangover symptoms in heavy drinking individuals: Is there a link?

Ghrelin, an orexigenic peptide synthesized in the stomach, is a key player in the gut-brain axis. In addition to its role in regulating food intake and energy homeostasis, ghrelin has been shown to modulate alcohol-related behaviors. Alcohol consumption frequently results in hangover, an underexplored phenomenon with considerable medical, psychological, and socioeconomic consequences. While the pathophysiology of hangover is not clear, contributions of mechanisms such as alcohol-induced metabolic/endocrine changes, inflammatory/immune response, oxidative stress, and gut dysbiosis have been reported. Interestingly, these mechanisms considerably overlap with ghrelin\u27s physiological functions. Here, we investigated whether pharmacological manipulation of the ghrelin system may affect alcohol hangover symptoms. Data were obtained from two placebo-controlled laboratory studies. The first study tested the effects of intravenous (IV) ghrelin and consisted of two experiments: a progressive-ratio IV alcohol self-administration (IV-ASA) and a fixed-dose IV alcohol clamp. The second study tested the effects of an oral ghrelin receptor inverse agonist (PF-5190457) and included a fixed-dose oral alcohol administration experiment. Alcohol hangover data were collected the morning after each alcohol administration experiment using the Acute Hangover Scale (AHS). IV ghrelin, compared to placebo, significantly reduced alcohol hangover after IV-ASA (p = 0.04) and alcohol clamp (p = 0.04); PF-5190457 had no significant effect on AHS scores. Females reported significantly higher hangover symptoms than males following the IV-ASA experiment (p = 0.04), but no gender × drug condition (ghrelin vs. placebo) effect was found. AHS total scores were positively correlated with peak subjective responses, including ‘stimulation’ (p = 0.08), ‘sedation’ (p = 0.009), ‘feel high’ (p = 0.05), and ‘feel intoxicated’ (p = 0.03) during the IV-ASA. IV ghrelin blunted the positive association between alcohol sedation and hangover as shown by trend-level drug × sedation effect (p = 0.08). This is the first study showing that exogenous ghrelin administration, but not ghrelin receptor inverse agonism, affects hangover symptoms. Future research should investigate the potential mechanism(s) underlying this effect