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Alcohol hangover refers to the combination of negative mental and physical symptoms that can be experienced after an episode of alcohol consumption, typically emerging as blood alcohol concentration (BAC) approaches zero. Hangover has been associated with heavy drinking and may be relevant in the transition to alcohol use disorder (AUD). Our aim was to examine hangover prevalence and associated symptoms following intravenous alcohol self-administration (IV-ASA), and to identify possible predictors of hangover in non-dependent drinkers. Ninety-five drinkers without AUD completed an IV-ASA session. Pharmacodynamic measures of alcohol consumption included peak and average breath alcohol concentrations. Subjective measures of alcohol response included the Drug Effects Questionnaire and Biphasic Effects of Alcohol Scale. The Alcohol Hangover Scale assessed hangover symptoms from the end of the session until the following morning. 78% of participants endorsed at least one hangover symptom following IV-ASA. There was no association between hangover scores and IV-ASA measures of alcohol consumption. Additional mediation and moderation analysis revealed that self-reported intoxication was a significant mediator of the relationship between recent drinking and hangover symptoms. Hangover symptoms may be an early marker of the relationship between subjective response to alcohol and heavy drinking for those with no prior history of AUD. In particular, the effects of hangover go beyond exposure to alcohol and the individual's subjective response to this exposure is associated with their experience of hangover. Future studies should further characterize the determinants of hangover across different populations of drinkers to better understand the risk for AUD and inform prevention methods.

Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested.In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory.During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups.Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders.

Alcohol hangover is one of the most commonly experienced consequences of alcohol consumption. An alcohol hangover develops as the blood alcohol concentrations (BAC) approaches zero, and is characterized by a general feeling of misery. More insight into the pathology of an alcohol hangover needs to be gained, in order to enhance the understanding of the area, and as a potential contribution to the innovation of a preventative or hangover curing treatment. The Alcohol Hangover Research Group (AHRG) was founded to support the area of alcohol hangover. This proceeding describes the latest findings in the area of alcohol hangovers, and future research plans, discussed at the 8th Alcohol Hangover Research Group meeting, held on June 25, 2016, New Orleans, USA. Novel insight in potential causes, consequences, and treatment of alcohol hangover were revealed during the meeting, as well as further research plans to examine biomarkers of recent alcohol consumption, immune functioning, alcohol metabolism, and potential treatments.

There are substantial inter-individual variations in alcohol metabolism and response that are likely due to sex and age; however, these are not well understood. We investigated age and sex influences on alcohol elimination rate (AER) and subjective responses following intravenous (IV) administration in non-dependent drinkers. Participants underwent a 2-session study where they received IV alcohol (target breath alcohol level: 0.05 g%) and placebo in counter-balanced order. AER was higher in males than in females across age groups. These differences were partly explained by sex differences in lean body mass and liver volume. Alcohol significantly increased peak feelings of high, intoxication, drug-effects, liking-effects, and wanting-more, with no major sex differences. There were no age-related differences in feelings of high and intoxication; however, the older group reported significantly lower peak liking-effects and stimulation responses than the younger group. These findings highlight the significant impact of sex and age as sources of variability in the clinical pharmacology of alcohol.

Pharmacotherapies for alcohol use disorder have been shown to reduce hazardous drinking and improve overall health. The effect sizes for the effectiveness of these medications, however, are small, underscoring the need to expand the range of therapeutics and develop personalized treatment approaches. Recent studies have suggested that varenicline, an α4β2-nicotinic partial agonist widely used for smoking cessation, can help alcoholics reduce drinking, but the neurocognitive underpinnings of its effectiveness remain largely unexplored.In this double-blind study, 32 heavy drinkers were randomized to receive varenicline (2 mg/d) or placebo. After 2 weeks of dosing, participants underwent functional MRI scans, during which they viewed images of faces with either neutral or fearful expressions at baseline and following an intravenous alcohol infusion to a target breath alcohol concentration of 80 mg%. Blood oxygen level-dependent (BOLD) response was analyzed with Analysis of Functional Neuroimaging software. Linear mixed-effects models were used to examine the effects of facial expression (fearful vs. neutral) and medication (placebo vs. varenicline) on BOLD response. The effect of medication on measures of subjective response to alcohol was also examined.Results indicated a significant facial expression-by-medication interaction in the left amygdala. The groups showed equivalent activation to neutral faces, but, whereas the placebo group showed increased activation to fearful faces, the varenicline group showed no change in activation. Amygdala activation to fearful faces correlated with number of drinks in the previous 90 days and Obsessive Compulsive Drinking Scale scores. There was no effect of varenicline on subjective response to alcohol.Our results indicate that varenicline may disrupt amygdala response to fearful faces in heavy drinkers. Further, amygdala activation correlated with alcohol consumption, suggesting that the effects of varenicline may be related to aspects of drinking behavior. These results suggest that amygdala response to fearful faces may be developed as a biomarker of the effectiveness of medications being developed for the treatment of alcohol use disorder.

Background and Aims Chronic alcohol consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to the pathogenesis of alcohol‐associated liver disease (ALD). Approach and Results We used wild‐type mice, retinoid‐related orphan receptor gamma t (RORγt)‐deficient mice, sphingosine kinase–deficient mice, and local gut anti‐inflammatory, 5‐aminosalicyclic acid–treated mice in a chronic‐binge ethanol feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. Alcohol intake induces a pro‐inflammatory shift in immune cell populations in the gut, including an increase in Th17 cells. Using RORγt‐deficient mice, we found that Th17 cells are required for alcohol‐associated gut inflammation and the development of ALD. Treatment with 5‐aminosalicyclic acid decreases alcohol‐induced liver injury and reverses gut inflammation by the suppression of CD4+/RORγt+/interleukin‐17A+ cells. Increased Th17 cells were due to up‐regulation of sphingosine kinase 1 activity and RORγt activation. We found that S1P/S1PR1 signaling is required for the development of Th17 cell–mediated ALD. Importantly, in vivo intervention blocking of S1P/S1PR1 signaling markedly attenuated alcohol‐induced liver inflammation, steatosis, and damage. Conclusions Gut inflammation is a functional alteration of immune cells in ALD. Reducing gut Th17 cells leads to reduced liver damage. S1P signaling was crucial in the pathogenesis of ALD in a Th17 cell–dependent manner. Furthermore, our findings suggest that compounds that reduce gut inflammation locally may represent a unique targeted approach in the treatment of ALD.

AbstractHangover refers to the cluster of physiological and behavioral symptoms that occur following the end of a drinking episode. While hangover has been studied after the typical oral consumption of alcohol, the occurrence of hangover following intravenous (IV) alcohol administration in human laboratory studies has not been previously reported. This study characterizes hangover symptoms and post‐infusion drinking behavior following acute IV alcohol administration in social drinkers. Twenty‐one to thirty‐year‐old healthy social drinkers (n = 24) underwent an alcohol clamp session at breath alcohol concentration of 0.06 percent. Hangover symptoms as well as any post‐infusion drinking that occurred between the end of the session and the following morning were assessed using the Acute Hangover Scale, and examined for influences of recent drinking history, family history of alcoholism and Sex. Results indicated a 79 percent prevalence of hangover symptoms, with the most common symptoms being ‘tired’, ‘thirsty’ and ‘headache’. Recent drinking measures showed significant effects on Average Hangover Scale scores, with heavier drinkers showing greater hangover symptoms. There was a significant sex difference in average hangover scores, with females reporting higher scores than males. Subjective measures of stimulation and intoxication were also associated with Average Hangover Scale scores. The probability of post‐infusion drinking was not predicted by hangover scores, but was related to recent drinking history; subjective response to alcohol was a significant mediator of this relationship. These findings demonstrate that hangover symptoms are experienced following IV alcohol administration, and extend previous studies of influences of risk factors for alcohol use disorders including recent drinking on hangover.

BackgroundThe objective of this study was to determine the effect of acute intravenous (IV) alcohol infusion on skin blood flow (SBF) response, measured at fingertip and earlobe, and subjective responses associated with SBF in social drinkers.MethodsTwenty‐four social drinkers underwent a computer‐assisted alcohol self‐infusion study. SBF was measured continuously using laser Doppler flow meter, with the probe placed on the fingertip or earlobe. Perfusion recordings were collected at baseline, and at 0‐minute (0 to 5 minutes), 10‐minute (10 to 15 minutes), and 20‐minute (20 to 25 minutes) time points during the priming phase of IV alcohol self‐administration paradigm at low breath alcohol levels of approximately 30 mg%. Subjective response was measured using the Drug Effects Questionnaire (DEQ) and Biphasic Alcohol Effects Scale.ResultsOverall SBF (collective data from both fingertip and earlobe) and SBF by each site showed significant drop at 0 minutes and then subsequent significant elevation with alcohol self‐administration. Males showed higher overall SBF at baseline and 0 minutes than the females. At fingertip site, lowering in 0‐minute SBF compared to baseline, and subsequent significant increase at the 10‐ and 20‐minute SBF recordings were observed. DEQ measures of “like” and “want more” alcohol were significantly associated with 10‐ and 20‐minute SBF recordings collected at fingertip site.ConclusionsThe changes in SBF following acute IV alcohol exposure are consistent with the sympathetic response of alcohol on the cardiovascular system. This acute hemodynamic effect characterizes differences in blood flow that are sensitive to relatively low levels of acute alcohol exposure. The association of subjective perceptions with the SBF response provides evidence of the psychophysiological effects of alcohol at low levels of exposure.