Characterizing reward and relief/habit drinking profiles in a study of naltrexone, varenicline, and placebo.

INTRODUCTION: This study aims to clarify differences in mood, craving, and treatment response between reward and relief/habit individuals in a study of naltrexone, varenicline, and placebo. We hypothesized that relief/habit individuals would have a poorer mood during early abstinence and higher levels of alcohol craving than reward individuals. We hypothesized that reward individuals would demonstrate better drinking outcomes on naltrexone versus placebo. METHODS: Data were culled from a randomized, double-blind, placebo-controlled human trial of 53 individuals (18F/16M) with alcohol use disorder randomized to varenicline (n = 19), naltrexone (n = 15), or matched placebo (n = 19). In this 6-day practice quit trial, participants attempted to abstain from drinking and completed daily diaries. Participants were classified into reward or relief/habit subgroups based on self-reported motivation for drinking. Multilinear models tested differences in mood and alcohol craving between reward and relief/habit individuals. General linear models tested differences between reward and relief/habit individuals' drinking outcomes on each medication versus placebo. RESULTS: Relief/habit individuals showed decreases in positive mood and increases in negative mood over the quit attempt across medications, compared to reward individuals (P's < .05). Reward individuals' tension decreased on naltrexone, while relief/habit individuals' tension remained stable (F = 3.64, P = .03). Reward individuals in the placebo group had higher percent days abstinent than relief individuals in the placebo group (P < .001). DISCUSSION: This study suggests relief/habit individuals' mood worsens during early abstinence. Our finding that reward individuals' tension decreased on naltrexone and increased on placebo may suggest a clinical response to the medication.

The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms.

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.

Effects of novel GLT-1 modulator, MC-100093, on neuroinflammatory and neurotrophic biomarkers in mesocorticolimbic brain regions of male alcohol preferring rats exposed chronically to ethanol.

Chronic ethanol consumption can lead to increased extracellular glutamate concentrations in key reward brain regions, such as medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and consequently leading to oxidative stress and neuroinflammation. Previous studies from our lab tested ß-lactam antibiotics and novel beta-lactam non-antibiotic, MC-100093, and showed these ß-lactam upregulated the major astrocytic glutamate transporter, GLT-1, and consequently reduced ethanol intake and normalized glutamate homeostasis. This present study tested the effects of novel synthetic ß-lactam non-antibiotic drug, MC-100093, in chronic ethanol intake and neuroinflammatory and trophic factors in subregions of the NAc (NAc core and shell) and mPFC (Prelimbic, PL; and Infralimbic, IL) of male P rats. MC-100093 treatment reduced ethanol intake after 5-week drinking regimen. Importantly, MC-100093 attenuated ethanol-induced downregulation of brain derived neurotrophic factor (BDNF) expression in these brain regions. In addition, MC-100093 attenuated ethanol-induced upregulation of pro-inflammatory cytokines such as TNF-a and HMGB1 in all these brain regions. Furthermore, MC-100093 treatment attenuated ethanol-induced increase in RAGE in these brain regions. MC-100093 prevented neuroinflammation caused by ethanol intake as well as increased neurotrophic factor in mesocorticolimbic brain regions. MC-100093 treatment reduced ethanol intake and this behavioral effect was associated with attenuation of reduced trophic factors and increased pro-inflammatory factors. MC-100093 is considered a small molecule that may have potential therapeutic effects for the treatment of the effects of chronic exposure to ethanol.

Randomized Placebo-Controlled Clinical Trial of Dutasteride for Reducing Heavy Drinking in Men.

BACKGROUND: Prior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of 5-alpha reductase enzymes, which play a central role in the production of 5α-reduced neuroactive steroids. The purpose of this study was to test dutasteride's tolerability and efficacy for reducing drinking. METHODS: Men (n = 142) with heavy drinking (>24 drinks per week) and a goal to either stop or reduce drinking to nonhazardous levels were randomized to placebo or 1 mg dutasteride daily for 12 weeks. We hypothesized that dutasteride-treated patients would be more successful in reducing drinking. RESULTS: Generalized linear mixed models that included baseline drinking, treatment, time and their 2-way interaction identified significant interactions of treatment-time, such that dutasteride treatment reduced drinking more than placebo. During the last month of treatment, 25% of dutasteride-treated participants had no hazardous drinking (no heavy drinking days and not more than 14 drinks per week) compared with 6% of placebo-treated participants (P = 0.006; NNT = 6). Sensitivity analysis identified baseline drinking to cope as a factor associated with larger reductions in drinking for dutasteride compared with placebo-treated participants. Dutasteride was well tolerated. Adverse events more common in the dutasteride group were stomach discomfort and reduced libido. CONCLUSION: Dutasteride 1 mg daily was efficacious in reducing the number of heavy drinking days and drinks per week in treatment-seeking men. The benefit of dutasteride compared with placebo was greatest for participants with elevated baseline drinking to cope motives.

Positive allosteric modulators of the GABAB receptor: a new class of ligands with therapeutic potential for alcohol use disorder.

BACKGROUND: Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. AIMS: This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. RESULTS: Acute or repeated treatment with CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. CONCLUSIONS: These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients.

Acute taurine reduced alcohol intake and preference in alcohol-experienced, but not in alcohol-näive rats by central mechanisms.

Taurine is a non-essential ß sulfonated amino acid involved in a plethora of biological functions in the mammalian central nervous system. Taurine is easily accessible in energy drinks for human consumption. Previous preclinical and clinical reports suggest that acute systemic administration of taurine could inhibit some of the behavioral and metabolic effects of alcohol use disorder. Overall, both in rodent and human studies, acute taurine administration reduced voluntary alcohol intake. This study aimed to assess the pharmacological effects of taurine (intracerebroventricular; i.c.v.) on ethanol intake/preference of rats either control (i.e., alcohol naïve) or forced ethanol intake (since juvenile age with a chronic intermittent access model). In addition, to explore anxiety-like behavior (through defensive burying behavior test) as pharmacological control of taurine. We found that acute (i.c.v.) taurine reduced alcohol consumption, i.e., taurine significantly decreased both alcohol intake and preference in adult male Wistar rats. Moreover, taurine elicits an anxiolytic-like effect in all administered groups independently of previous alcohol exposure.

Influence of sleep quality on lapse to alcohol use during a quit attempt.

AIMS: Sleep problems are common among individuals with alcohol use disorder (AUD) and is often associated with a heightened relapse risk. The present study examines the relationship between sleep and alcohol use among individuals with current AUD during a 6-day quit attempt as part of a medication study. METHODS: The current study is a secondary analysis of a medication trial for individuals with AUD. Individuals with AUD (N = 53, 26 females) were randomized to active medication or matched placebo. Randomized participants completed a week-long medication titration (Days 1-7). Following the titration period, participants attended an in-person visit (Day 8) to begin a 6-day quit attempt. During the quit attempt, participants completed daily diary assessments to report on previous day alcohol consumption, sleep quality, and alcohol craving. In the present study, medication condition was controlled for in all models. RESULTS: Baseline global sleep quality was not a significant predictor of drinks per drinking day (P = 0.72) or percent days abstinent (P = 0.16) during the 6-day practice quit attempt. Daily diary analyses found that greater sleep quality was associated with higher next-day drinks per drinking day (b = 0.198, P = 0.029). In contrast, participants reported worse sleep quality following nights of greater alcohol intake, albeit at a trend-level (b = -0.12, P = 0.053). CONCLUSIONS: These results suggest that better sleep quality was a risk factor for drinking during the 6-day quit period, such that better sleep may be associated with increased craving for alcohol and alcohol use the next day. These findings are limited to the early abstinence period and should be considered in studies exploring longer periods of abstinence.

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

A randomized, double-blind, placebo-controlled, multicentre trial on the efficacy of varenicline and bupropion in combination and alone for treatment of alcohol use disorder: Protocol for the COMB study.

BACKGROUND: Alcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies. METHODS: Consenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022. DISCUSSION: The COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018-000048-24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306.

The neutral CB1 antagonist AM6527 reduces ethanol seeking, binge-like consumption, reinforcing, and withdrawal effects in male and female mice.

RATIONALE: Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population. OBJECTIVE: We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice. METHODS: Independent groups of male and female mice were subjected to repeated cycles of drinking in the dark (DID), or intermittent access to alcohol (IAA) procedures. Twenty minutes prior to ethanol access in each procedure, animals were treated with intraperitoneal injections of either 1, 3, and 10 mg/kg of AM6527 or its respective vehicle. Acamprosate (100, 200, 300, and 400 mg/kg) or its respective vehicle was used as a positive control. Separate groups of male mice were subjected to a chain schedule of ethanol reinforcement to gain access to ethanol wherein completion of a fixed interval (FI; 5 min) schedule (link 1: "Seeking") was reinforced with continuous access to ethanol (fixed ratio; FR1) for up to 1.8 g/kg (link 2: "consumption"). All the animals were treated with 1, 3, and 10 mg/kg of AM6527 or its respective vehicle 20 mins prior to the start of the FI chain of the procedure. Separately, AM6527 was also evaluated in male and female mice undergoing acute ethanol withdrawal following 8 weeks of intermittent or continuous access to 20% ethanol drinking. RESULTS: In both DID and IAA procedures, AM6527 reduced ethanol consumption in a dose-related manner in both male and female mice. AM6527 produced no tolerance in the DID procedure; mice treated with 3 mg/kg of AM6527 for 3 weeks continuously drank significantly smaller amounts of ethanol as compared to vehicle-treated mice over a period of three DID cycles. Moreover, in the IAA procedure, AM6527 caused an increase in water intake over the 24-h period. Acamprosate transiently reduced ethanol intake in male mice in both the DID and the IAA procedures but failed to produce any significant effect in female mice. AM6527 also produced a decrease in the FI responding ("ethanol seeking") in animals trained to self-administer ethanol. Lastly, AM6527 mitigated neurological withdrawal signs, i.e., handling induced convulsions (HIC) in mice undergoing acute ethanol withdrawal. CONCLUSIONS: Current findings support previous studies with CB1R neutral antagonist in reducing voluntary ethanol intake and seeking behavior. Based on results shown in this work, AM6527 can be developed as a first in class CB1R neutral antagonist to treat AUD in both males and females.

A practice quit model to test early efficacy of medications for alcohol use disorder in a randomized clinical trial.

RATIONALE: Screening novel medications for alcohol use disorder (AUD) requires models that are both efficient and ecologically-valid. Ideally, such models would be associated with the outcomes of a given medication in clinical trials. OBJECTIVES: To test a novel human laboratory model in which individuals with intrinsic motivation to change their drinking engage in a "practice quit" attempt consisting of 6 days of complete abstinence from alcohol. METHOD: Individuals with current AUD completed a randomized, double-blind, placebo-controlled study of naltrexone (50 mg), varenicline (2 mg bid), or matched placebo. Participants were titrated onto the study medication for 1 week prior to starting the 6-day practice quit attempt. During the practice quit attempt, participants completed daily interviews with research staff. All participants completed an alcohol cue-exposure paradigm before starting the study medication and after 2 weeks of study medication. RESULTS: There were no significant medication effect on drinks per drinking day (F(2,49) = 0.66, p = 0.52) or percent days abstinent (F(2,49) = 0.14, p = 0.87) during the 6-day practice quit period. There were no medication effects on alcohol cue-reactivity (F(2,44) = 0.80, p = 0.46). Notably, participants sharply reduced their drinking during the entire 13-day medication treatment period, as compared to reducing only during the 6-day practice quit period. During the total medication period, higher levels of motivation to change was associated with higher percent days abstinent (F(1,49) = 8.12, p < 0.01). CONCLUSIONS: This study reports mostly null findings, which challenges us to decompose its nuanced design to consider model refinements. Possible changes to the model include considering the requirement for intrinsic motivation for change, including a longer practice quit period, encompassing the medication administration timeframe in the practice quit period, increasing the required sample size for signal detection, and examining a post COVID-19 pandemic cohort.

Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol.

The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and reward-related behavior, and their distribution can be altered by long-term heavy drinking. Therefore, AChRs are promising pharmacotherapeutic targets for treating the cognitive symptoms of AUD. In the present study, the procognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than 1 year. The muscarinic AChR antagonist scopolamine was used to disrupt performance of a serial stimulus discrimination and reversal (SDR) task designed to probe cognitive flexibility, defined as the ability to modify a previously learned behavior in response to a change in reinforcement contingencies. The ability of xanomeline and varenicline to remediate the disruptive effects of scopolamine was compared between socially dominant and subordinate monkeys, with lighter and heavier drinking histories, respectively. We hypothesized that subordinate monkeys would be more sensitive to all three drugs. Scopolamine dose-dependently impaired performance on the serial SDR task in all monkeys at doses lower than those that produced nonspecific impairments (e.g., sedation); its potency did not differ between dominant and subordinate monkeys. However, both AChR agonists were effective in remediating the scopolamine-induced deficit in subordinate monkeys but not in dominant monkeys. These findings suggest xanomeline and varenicline may be effective for enhancing cognitive flexibility in individuals with a history of heavy drinking. SIGNIFICANCE STATEMENT: Procognitive effects of two acetylcholine (ACh) receptor agonists were assessed in group-housed monkeys who had several years' experience drinking ethanol. The muscarinic ACh receptor agonist xanomeline and the nicotinic ACh receptor agonist varenicline reversed a cognitive deficit induced by the muscarinic ACh receptor antagonist scopolamine. However, this effect was observed only in lower-ranking (subordinate) monkeys and not higher-ranking (dominant monkeys). Results suggest that ACh agonists may effectively remediate alcohol-induced cognitive deficits in a subpopulation of those with alcohol use disorder.

Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity.

Alcohol Use Disorder (AUD) contributes significantly to global mortality. GLP-1 (Glucagon-like peptide-1) and GLP-1/GIP (Glucose-dependent Insulinotropic Polypeptide) agonists, FDA-approved for managing type 2 diabetes and obesity, where the former has shown to effectively reduce the consumption of alcohol in animal models but no reports exist on the latter. In this report, we conducted two studies. In the first study, we conducted an analysis of abundant social media texts. Specifically, a machine-learning based attribution mapping of ~ 68,250 posts related to GLP-1 or GLP-1/GIP agonists on the Reddit platform. Secondly, we recruited participants (n = 153; current alcohol drinkers; BMI ≥ 30) who self-reported either taking Semaglutide (GLP-1 agonist), Tirzepatide (the GLP-1/GIP combination) for ≥ 30 days or, as a control group; no medication to manage diabetes or weight loss for a within and between subject remote study. In the social media study, we report 8 major themes including effects of medications (30%); diabetes (21%); and Weight loss and obesity (19%). Among the alcohol-related posts (n = 1580), 71% were identified as craving reduction, decreased desire to drink, and other negative effects. In the remote study, we observe a significantly lower self-reported intake of alcohol, drinks per drinking episode, binge drinking odds, Alcohol Use Disorders Identification Test (AUDIT) scores, and stimulating, and sedative effects in the Semaglutide or Tirzepatide group when compared to prior to starting medication timepoint (within-subjects) and the control group (between-subjects). In summary, we provide initial real-world evidence of reduced alcohol consumption in people with obesity taking Semaglutide or Tirzepatide medications, suggesting potential efficacy for treatment in AUD comorbid with obesity.

Effects of dulaglutide on alcohol consumption during smoking cessation.

BACKGROUNDAlcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODSThis is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTSIn the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33-53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52-0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSIONThese results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov NCT03204396.FUNDINGSwiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.

Extrahepatic Health Effects of Alcohol Use and Alcohol-associated Liver Disease.

PURPOSE: Alcohol use disorder (AUD) is a growing public health concern and an important contributor to global morbidity and mortality. While the hepatotoxic effects of alcohol are well known, the adverse effects of alcohol are manifested in almost every organ system. With the growing public health impact of AUD, the aim of this narrative review is to highlight the epidemiology and burden of AUD and its association with extrahepatic diseases including malignancy and disorders of the gastrointestinal (GI), cardiovascular, immunologic, neurologic, endocrine, and hematologic systems. METHODS: A narrative review of the literature was performed to identify studies addressing the epidemiology, pathophysiology, clinical manifestations, and therapy of extrahepatic health manifestations of alcohol use. FINDINGS: In the United States, an estimated 14.5 million people have AUD and approximately 88,000 adults die yearly due to alcohol-related causes. The consumption of alcohol and AUD is associated with injuries, violence, cancers, nonmalignant conditions of the GI system, infections, effects on the cardiovascular system, and neurodegenerative diseases. These conditions contribute to the increased mortality associated with AUD and are burdensome to patients and caregivers. IMPLICATIONS: Increased awareness of the extrahepatic manifestations of AUD, screening for AUD using validated screening tools, such as the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) score, and offering evidence-based interventions to patients with AUD is imperative to reduce the public health burden of AUD. Although historically controversial, recent evidence suggests that any level of alcohol consumption can have negative health consequences. Further research is warranted to determine if any amount of alcohol is safe for consumption. Public health efforts are warranted to help curtail the growing burden of AUD.

Stress and gonadal steroid influences on alcohol drinking and withdrawal, with focus on animal models in females.

Sexually dimorphic effects of alcohol, following binge drinking, chronic intoxication, and withdrawal, are documented at the level of the transcriptome and in behavioral and physiological responses. The purpose of the current review is to update and to expand upon contributions of the endocrine system to alcohol drinking and withdrawal in females, with a focus on animal models. Steroids important in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, the reciprocal interactions between these axes, the effects of chronic alcohol use on steroid levels, and the genomic and rapid membrane-associated effects of steroids and neurosteroids in models of alcohol drinking and withdrawal are described. Importantly, comparison between males and females highlight some divergent effects of sex- and stress-steroids on alcohol drinking- and withdrawal-related behaviors, and the distinct differences in response emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of alcohol use disorder.

Alcohol Cue Processing in Co-Occurring Bipolar Disorder and Alcohol Use Disorder.

Importance: Reward circuitry dysfunction is a candidate mechanism of co-occurring bipolar disorder and alcohol use disorder (BD + AUD) that remains understudied. This functional magnetic resonance imaging (fMRI) research represents the first evaluation of alcohol cue reward processing in BD + AUD. Objective: To determine how alcohol cue processing in individuals with BD + AUD may be distinct from that of individuals with AUD or BD alone. Design, Setting, and Participants: This cross-sectional case-control study (April 2013-June 2018) followed a 2 × 2 factorial design and included individuals with BD + AUD, AUD alone, BD alone, and healthy controls. A well-validated visual alcohol cue reactivity fMRI paradigm was administered to eligible participants following their demonstration of 1 week or more of abstinence from alcohol and drugs assessed via serial biomarker testing. Study procedures were completed at the Medical University of South Carolina. Analysis took place between June and August 2022. Main Outcomes and Measures: Past-week mood symptoms were rated by clinicians using the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. The Alcohol Dependence Scale, Obsessive-Compulsive Drinking Scale, and Barratt Impulsiveness Scale were included questionnaires. Functional MRI whole-brain data were analyzed along with percent signal change within a priori regions of interest located in the ventral striatum, dorsal striatum, and ventromedial prefrontal cortex. Exploratory analyses of associations between cue reactivity and select behavioral correlates (alcohol craving, impulsivity, maximum number of alcohol drinks on a single occasion, and days since last alcohol drink) were also performed. Results: Of 112 participants, 28 (25.0%) had BD + AUD, 26 (23.2%) had AUD alone, 31 (27.7%) had BD alone, and 27 (24.1%) were healthy controls. The mean (SD) age was 38.7 (11.6) years, 50 (45.5%) were female, 33 (30%) were smokers, and 37 (34.9%) reported recent alcohol consumption. Whole-brain analyses revealed a BD × AUD interaction (F = 10.64; P = .001; η2 = 0.09) within a cluster spanning portions of the right inferior frontal gyrus and insula. Region of interest analyses revealed a main association of BD (F = 8.02; P = .006; η2 = 0.07) within the dorsal striatum. In each instance, individuals with BD + AUD exhibited reduced activation compared with all other groups who did not significantly differ from one another. These hypoactivations were associated with increased impulsivity and obsessive-compulsive alcohol craving exclusively among individuals with BD + AUD. Conclusion and Relevance: The findings of this study suggest conceptualizing reward dysfunction in BD + AUD by the potential interaction between blunted reward responsivity and deficient inhibitory control may help guide treatment development strategies. To this end, reduced right inferior frontal gyrus and insula alcohol cue reactivity represents a novel candidate biomarker of BD + AUD that may respond to pharmacological interventions targeting impulsivity-related neural mechanisms for improved executive control.