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PubMed2025

Differential Expression of Erythrocyte Proteins in Patients with Alcohol Use Disorder.

Alcohol Use Disorder (AUD) poses global health challenges, and causes hematological alterations such as macrocytosis and oxidative stress. Disruption of protein structures by alcohol and/or its metabolites may exacerbate AUDs; proteomics can elucidate the underlying biological mechanisms. This study examined the proteins differentially expressed in the cytosol and membrane fractions of erythrocytes obtained from 30 male patients with AUD, comparing them to samples from 15 age- and BMI-matched social drinkers (SDs) and 15 non-drinkers (control). The analysis aimed to identify the molecular differences related to alcohol consumption. The AUD patient subgrouping was based on mean corpuscular volume (MCV), with 16 individuals classified as having a normal MCV and 14 having a high MCV. Proteins were separated via two-dimensional(2D)-gel electrophoresis, digested with trypsin, and identified via Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (TOF) mass spectrometry (MALDI-TOF/TOF). Additionally, levels of malondialdehyde and 4-hydroxyalkenals (MDA + HAE), reduced glutathione (GSH), oxidized glutathione (GSSG), serum carbohydrate-deficient transferrin (%CDT), disialotransferrin (%DST), and sialic acid (SA) were analyzed. The results showed increased MDA + HAE and decreased total thiols in AUD patients, with GSSG elevated and the GSH/GSSG ratio reduced in the AUD MCV-high subgroup. Serum %CDT, %DST, and SA were significantly higher in AUD. Compared to the control profiles, the AUD group exhibited differential protein expression. Few proteins, such as bisphosphoglycerate mutase, were downregulated in AUD versus control and SD, as well as in the MCV-high AUD subgroup. Conversely, endoplasmin and gelsolin were upregulated in AUD relative to control. Cytoskeletal proteins, including spectrin-alpha chain, actin cytoplasmic 2, were overexpressed in the AUD group and MCV-high AUD subgroup. Several proteins, such as 14-3-3 isoforms, alpha-synuclein, translation initiation factors, heat shock proteins, and others, were upregulated in the MCV-high AUD subgroup. Under-expressed proteins in this subgroup include band 3 anion transport protein, bisphosphoglycerate mutase, tropomyosin alpha-3 chain, uroporphyrinogen decarboxylase, and WD repeat-containing protein 1. Our findings highlight the specific changes in protein expression associated with oxidative stress, cytoskeletal alterations, and metabolic dysregulation, specifically in AUD patients with an elevated MCV. Understanding these mechanisms is crucial for developing targeted interventions and identifying biomarkers of alcohol-induced cellular damage. The complex interplay between oxidative stress, membrane composition, and cellular function illustrates how chronic alcohol exposure affects cellular physiology.

Humans↗

PubMed2026

Elevated intron retention implicates neuroinflammation in brains of individuals with alcohol use disorder.

Intron retention, a form of alternative RNA splicing, can occur as part of normal gene regulation or result from disruption of the splicing machinery. Retained introns can potentially form double-stranded RNA, activating innate immune sensors and inflammation. This mechanism has been implicated in cancer but has not been studied in neuropsychiatric diseases like alcohol use disorder. We systematically analysed transcriptome-wide intron retention events in post-mortem brain tissue from 142 individuals (66 with alcohol use disorder and 76 controls), encompassing 320 region-specific samples from the superior frontal cortex, nucleus accumbens, central nucleus and basolateral amygdala. Analyses were adjusted for demographic, technical and biological covariates. Validation was performed in alcohol-preferring (P) rats using long-read sequencing. In complementary experiments, immunofluorescent staining was used to detect double-stranded RNA in rat brain tissue, while single-cell RNA-sequencing was performed to test activation of double-stranded RNA-sensing pathways in human brains. Brains from individuals with alcohol use disorder showed significantly higher total intron retention compared with controls, independent of age, with females showing greater increases than males. A total of 368 introns were positively associated with alcohol use disorder, and these introns were significantly longer and had weaker splice acceptor sites compared with non-associated introns. Genes harbouring these intron retention events were enriched in Purkinje neurons, visual cortex neurons and oligodendrocytes. Computational predictions indicated these long introns could form duplex RNA structures. Increased double-stranded RNA was confirmed experimentally in multiple brain regions of alcohol-consuming rats, where it co-localized primarily with neuronal nuclei and dendrites. In individuals with alcohol use disorder, we found that multiple pathways including double-stranded RNA responses, neuroinflammation, interferon and NF-κB signalling, adaptive immunity and apoptosis were activated. In addition, NeuN-positive neuronal counts significantly decreased in both the prefrontal and visual cortices. Furthermore, single-cell analysis demonstrated upregulation of TICAM1, the target of double-stranded RNA sensor TLR3, in oligodendrocytes, as well as widespread activation of downstream inflammatory pathways across glial and neuronal cell types. These findings provide the first evidence that chronic alcohol consumption promotes an overall increase of intron retention in the brain and is associated with the presence of double-stranded RNA. Furthermore, the double-stranded RNA may contribute to neuronal loss and brain pathology by activating a neuroinflammatory response.

alcohol use disorder↗

PubMed2026

Experiences and Behavior During a Virtual Reality Buffet Simulation: A Secondary Analysis of a Ghrelin-Related Pharmacology Randomized Controlled Trial in People with Alcohol Use Disorder.

BACKGROUND: Virtual reality (VR) can deliver standardized, ecologically valid assessments while capturing nuanced psychological and behavioral outcomes. Sensitivity of VR assessments to pharmacological interventions, however, has seldom been tested. METHODS: We conducted a secondary analysis of a randomized, double-blind, placebo-controlled, crossover study evaluating a growth hormone secretagogue receptor (GHSR, the ghrelin receptor) blocker (PF-5190457) in people (N = 29) with alcohol use disorder. The previously reported primary study results demonstrated that the GHSR blocker did not reduce alcohol cue-elicited craving but did reduce the number of calories selected in a VR buffet food choice assessment. Here, we investigated the impact of the drug on experiences and behavior in the VR buffet. RESULTS: Participants reported higher levels of liking the VR, more typicality, and more satisfaction with their food choices under the GHSR blocker than the placebo. We also found that participants who were given the placebo first took longer to make a decision about the food they should eat and were also more likely to go up for a second serving of food when on the placebo. This was significantly less likely for participants who were given the GHSR blocker. CONCLUSIONS: The present results suggest that the GHSR blocker influenced experiences and behavior in the VR buffet in ways that are conceptually consistent with the known real-world effects of blocking the ghrelin system. These findings support the validity of using VR buffets as proxies for real-world measurements in pharmacology contexts.

alcohol use disorder↗

PubMed2026

Alcohol use disorder and childhood adversity in the association between polygenic risk and suicidality.

OBJECTIVE: Suicidal ideation (SI) and suicide attempt (SA) are both influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate the effects of genetic liability for suicidality. METHODS: Using data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime suicidality outcomes. We evaluated whether AUD partially accounted for these associations and ACEs moderated the direct and indirect associations. RESULTS: The SA PGS was significantly associated with SA (AFR: b = 0.36, SE = 0.01; EUR: b = 0.17, SE = 0.01; both ps < 2e-16), but the SI PGS was not associated with SI (p > 0.55). AUD statistically mediated the association between the SA PGS and SA, accounting for approximately 2% of the total association in AFR individuals and 10% in EUR individuals (both ps < 2e-16). Notably, the proportion of the association that was accounted for by AUD decreased as ACEs exposure increased, from 4.30% to 0.54% in AFR individuals and from 13.31% to 3.44% in EUR individuals. In contrast, there was only very modest mediation and no moderated mediation for SI. CONCLUSIONS: Particularly among individuals with lower ACEs exposure, AUD accounted for a meaningful proportion of the association between genetic liability to SA and lifetime SA. These findings highlight different correlates across suicidality phenotypes and suggest potential clinical relevance for AUD in the association between genetic liability and SA.

Adult↗

PubMed2026

Executive function in alcohol use disorder with low psychiatric comorbidity: Comparison with a non-clinical sample and predictive value for treatment outcome.

BACKGROUND: Executive functions (EF) encompass abilities such as planning, decision-making, and inhibitory control, critical for learning, establishing and maintaining behavioral change. The association between alcohol use disorder (AUD) and impairments in EF are well established. However, prior research is dominated by studies on convenience samples including individuals with severe AUD with high levels of psychiatric comorbidity, which limits generalizability. The present study therefore aimed to investigate the degree of impairment and predictive ability of EF, on alcohol consumption, among individuals with moderate AUD with low levels of psychiatric comorbidity. METHODS: Adults with moderate AUD (n = 147) were recruited at three specialized addiction outpatient clinics in Stockholm, to a randomized controlled trial investigating the efficacy of two psychological treatments. Participants underwent neuropsychological testing before treatment. Eight tests from the CANTAB® battery were administered at baseline, assessing mental flexibility, sustained attention, visuospatial working memory, response inhibition, and delay discounting. Assessments of alcohol use and related symptoms were conducted at baseline, the 12- and 26-weeks follow-up. A non-clinical reference sample (n = 72) completed corresponding CANTAB® tests. The two groups were compared regarding EF using descriptive statistics and t-tests, and the predictive value of EF for reduction in alcohol consumption, was investigated using multiple regression models. RESULTS: Individuals with AUD did not perform worse on any of the tests on executive function (CANTAB®) as compared to the non-clinical reference sample. Measures of EF were not significant predictors for reduction in alcohol use for the 12-week, or the 26-week follow-up. CONCLUSIONS: EFs were not impaired and were not a clinically relevant predictor of treatment outcomes in this population with AUD. Future research on EF as a predictor in AUD treatment, needs to corroborate the present findings, and include other populations, e.g., with different socio-economic backgrounds and by including other methodologies for measuring EF.

Humans↗

PubMed2026

GLP-1 Receptor Agonist and GIP/GLP-1 Receptor Dual Agonist Therapeutics at the Intersection of Alcohol Use Disorder, Obesity, and Cardiometabolic Dysfunction.

The co-occurrence of metabolic dysfunction and heavy alcohol consumption contributes substantially to global morbidity, particularly through its impact on liver disease progression. Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP1R dual agonists, currently approved for the treatment of diabetes and obesity and under investigation for metabolic dysfunction-associated steatohepatitis, are considered for repurposing to reduce alcohol consumption and stabilize metabolic health in heavy-drinking populations. This review summarizes existing evidence, highlights ongoing research, and outlines key unanswered questions regarding this therapeutic potential and the paradigm shift toward metabolic circuit-based interventions in addiction treatment. The dual-target GIPR/GLP1R approach could fill a critical gap for individuals struggling with both heavy alcohol consumption and metabolic dysfunction.

Alcohol use disorder↗

PubMed2025

Genome-wide analysis of screen behaviors among adolescents identifies novel loci and overlap with educational attainment and mental disorders.

Technological devices play a central role in adolescents' life. Despite concerns about negative effects of excessive screen time, there is little knowledge of screen behaviors' genetic architecture. Using self-reports from adolescents in the Norwegian Mother, Father, and Child Cohort Study (n = 18,490), we performed genome-wide association analysis for four screen behaviors: time spent (1) watching television; (2) gaming; (3) sitting/lying down with a screen device; and (4) using social media. The resulting summary statistics were analysed using the conditional false discovery rate (condFDR) approach to increase genetic discovery. We also estimated SNP-heritabilities of the screen behaviors and genetic correlations with eight psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, anorexia nervosa, cannabis use disorder and alcohol use disorder), and educational attainment. Screen behaviors displayed significant SNP-heritabilities (0.048-0.12). We observed significant genetic correlations between screen behaviors and psychiatric disorders (rg range: 0.21-0.42). Educational attainment demonstrated negative genetic correlation with screen behaviors, most strongly with social media use (rg = - 0.69). CondFDR analysis identified three novel loci associated with social media use. Thus, we show that screen behaviors are heritable, polygenic traits that partly share genetic signal with mental disorders and educational attainment.

Humans↗

PubMed2026

Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders.

Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg = 0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX. These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively. Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus. We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.

Journal Article↗

PubMed2026

Frequent readmissions after hospitalization for alcohol withdrawal: a systematic review and meta-analysis.

BACKGROUND: Alcohol use disorder and alcohol withdrawal syndrome impose substantial clinical and economic burdens, with repeated hospitalizations being common. We aimed to systematically review readmission rates following inpatient detoxification, assess variation across study designs and hospital settings, and identify key risk and protective factors. METHODS: We performed a literature search in Embase and Pubmed on 10/04/2026 focusing on studies assessing in hospital alcohol detoxification. Exclusion criteria included studies on substance use other than alcohol and outpatient or residential treatment. Main outcome was rehospitalization, and meta-analysis was performed to estimate pooled readmission proportions. Secondary outcomes were risk factors and protective factors influencing the rate of rehospitalization. RESULTS: Twenty-five studies were included. The pooled proportion of readmissions following alcohol detoxification was estimated at 17% (95% CI: 14%-21%; 13 studies, n = 287,896) within 1 month, increasing to 44% (95% CI: 36%-52%; 8 studies, n = 2,877) at 1 year. Substantial between-study heterogeneity was observed. Subgroup analyses found no significant differences by hospital setting or time period. Findings for study aim and study design were mixed and based on limited data A small number of studies suggested associations with housing stability, employment, and treatment engagement. CONCLUSIONS: This meta-analysis suggests that approximately one in six patients are readmitted within 1 month and nearly half within 1 year after inpatient alcohol detoxification. However, readmission rates varied considerably across settings and populations. Future research should evaluate targeted interventions to reduce readmissions among high-risk patient groups.

Humans↗

PubMed2026

Subcellular interactions of neuropeptide Y and corticotropin-releasing factor in the central nucleus of the amygdala in the mouse.

Neuropeptide Y (NPY) is ubiquitously distributed throughout the central nervous system. Recognized as a mediator of stress resilience, NPY has been shown to counteract the excitatory effects of the neuropeptide corticotropin-releasing factor (CRF), that orchestrates the stress response. In the mouse, while NPY and CRF exhibit a high degree of neuroanatomical association in the central nucleus of the amygdala (CeA) indicating potential significant interactions, the synaptic organizations of these neuropeptides have not been elucidated. In the present study, we determined the anatomical interactions between NPY and CRF in the CeA. Immunofluorescence microscopy presented that NPY-immunoreactive varicose processes were distributed throughout the CeA and appeared to be closely apposed to CRF-containing neurons. Using electron microscopy, immunoperoxidase labeling for NPY and gold-silver labeling for CRF showed that NPY-labeled axon terminals (NPY-t) form synapses with CRF-labeled dendrites (CRF-d). Semi-quantitative analysis revealed that 247 of NPY-t directly target CRF-d. In addition, approximately 80% of NPY-t form symmetric synapses with CRF-d while approximately 1% form asymmetric synapses. These findings provide the first ultrastructural evidence that NPY-containing axon terminals make direct contact with CRF-containing dendrites in the CeA. This suggests that the CRF-containing neurons in the CeA may be a key site for NPY action, potentially influencing brain regions involved in stress responses and stress-related psychiatric disorders, and alcohol use disorders.

Animals↗

PubMed2025

Global Changes in Gene Expression and Splicing in Alcoholic Liver Disease.

Alcohol use disorder is a widespread illness commonly leading to alcoholic liver disease (ALD) and cirrhosis with an increased incidence of hepatocellular carcinoma (HCC), but the mechanisms of alcohol-related oncogenesis in the liver are incompletely understood. We tested the hypothesis that ALD predisposes to HCC via dysregulation of splicing. RNA sequencing was performed on liver biopsies from patients with different stages of ALD: early alcoholic steatohepatitis (eASH), non-severe alcoholic hepatitis (nsAH), and severe alcoholic hepatitis (sAH); furthermore, explants were collected from patients who underwent liver transplantation due to sAH (exAH). We found that alcohol caused widespread changes in transcriptome in all stages of ALD: among ~ 58,000 analyzed genomic features, ~ 4,900 were altered in eASH, ~ 9,100 - in nsAH, 14,100 - in sAH, and ~ 14,300 - in exAH. We observed thousands of missplicing events in all hepatic conditions, with mutually exclusive exons (MEE) being the most common event and exon skipping (ES) - second most common event. Analysis of ~ 600,000 exons revealed that ALD is associated with a genome-wide effect on exon expression, with ~ 50,000 exons being differentially expressed in eASH, ~ 130,000 - in nsAH, ~ 150,000 - in sAH, and ~ 120,000 - in exAH. To determine whether alcohol directly perturbs splicing, we subjected rats to alcohol vapor for 7 weeks and found that the expression of multiple snRNAs was drastically decreased, while expression of splicing factors was not affected. Screening of oncogenes and tumor suppressors, commonly involved in HCC pathogenesis, revealed that ALD affected the hepatic expression and/or splicing of most of these cancer-related genes. In summary, it appears that alcohol causes profound genome-wide changes in gene expression and splicing in the liver, likely via affecting the spliceosome. This results in altered expression and missplicing of key oncogenes and tumor suppressors involved in HCC, suggesting a novel mechanism of oncogenesis in the liver of patients with ALD.

alcohol use disorder↗

PubMed2026

Polygenic risk factors for comorbid diagnoses in individuals with substance use disorders: A phenome-wide survival analysis.

OBJECTIVE: Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome-wide association studies (PheWASs). However, PheWASs are largely cross-sectional, limiting our understanding of whether diagnoses predate the development of an SUD. We characterize whether polygenic scores (PGSs) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis. METHODS: Using data from All of Us (N = 393,596), we explored: (1) whether social determinants of health (SDoHs) are associated with lifetime risk of SUD (N cases = 42,568) and (2) within a subset those with a diagnosed SUD and available genetic data SUD (N = 21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, posttraumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis. RESULTS: Multiple SDoHs were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g. <$10 K annually vs $100 K-$150 K annually: OR = 4.18; 95% CI = 3.92, 4.45). There were 86 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, posttraumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses. CONCLUSIONS: Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGSs for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.

Humans↗

PubMed2025

Polygenic Risk Factors for Comorbid Diagnoses in Individuals with Substance Use Disorders: A Phenome-Wide Survival Analysis.

OBJECTIVE: Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome wide association studies (PheWAS). However, PheWAS are largely cross-sectional, limiting our understanding of whether diagnoses predate development of an SUD. We characterize whether polygenic scores (PGS) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis. METHODS: Using data from All of Us (N = 393,596), we explored: 1) whether social determinants of health (SDoH) are associated with lifetime risk of SUD (N cases = 42,568) and 2) within a subset those with a diagnosed SUD and available genetic data SUD (N = 21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, post-traumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis. RESULTS: Multiple SDoH were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g., <$10K annually vs $100K-$150K annually: OR = 3.89, 95% CI = 3.66, 4.13). There were 101 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, post-traumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses. CONCLUSIONS: Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGS for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.

Journal Article↗

PubMed2026

Naltrexone Is Superior to Placebo for Abstinence and Craving Reduction in Alcohol-Associated Cirrhosis: NAL-CI Trial.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) coexisting with cirrhosis carries high morbidity and mortality, with no approved pharmacotherapy for AUD. We evaluated the safety and efficacy of naltrexone, an opioid receptor antagonist, in patients with compensated alcohol-associated cirrhosis (AaC) and AUD. METHODS: One hundred patients with compensated AaC and DSM-5 AUD were randomised 1:1 to naltrexone (50 mg/day) or placebo for 12 weeks. The primary endpoint was point-prevalence abstinence at 12 weeks, defined as no alcohol use in the four preceding weeks. Secondary endpoints included craving (Obsessive Compulsive Drinking Scale [OCDS]-Obsessive and Compulsive subscales), lapses, relapses, and hepatic safety. Standardised psychosocial support was provided to both arms. RESULTS: Baseline characteristics were well matched between groups (mean MELD 12.6 vs. 12.7; CTP score 5.9 vs. 6.2; age 42.9 vs. 44.3 years). AUDIT and OCDS scores were comparable between groups. Abstinence at 12 weeks was significantly higher with naltrexone: 64% (32/50) versus 22% (11/50), p < 0.001; OR 10.86 (95% CI: 1.89-62.2). Naltrexone significantly reduced lapses at 3 months (28% vs. 54%, p = 0.008) and showed a trend toward fewer heavy-drinking relapses (12% vs. 28%, p = 0.07). Maintenance of abstinence at 6 months favoured naltrexone (22% vs. 8%, p = 0.09). No patient developed hepatic decompensation attributable to study medication, and no AST/ALT elevation exceeding 5× ULN was observed in either group. Mean craving scores were lower with naltrexone by week 12 than with placebo: OCDS-O score (6.63 ± 1.16 vs. 9.29 ± 1.78, p < 0.01) and OCDS-C score (6.35 ± 1.23 vs. 9.02 ± 1.86, p < 0.01). Adverse events were comparable between the groups. CONCLUSION: Naltrexone is safe and effective in patients with compensated alcohol-associated cirrhosis, achieving a threefold higher abstinence rate and significantly reducing craving compared with placebo. These findings support the use of naltrexone as a pharmacological option in patients with compensated AaC and AUD. TRIAL REGISTRATION: NCT04391764.

Humans↗

PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p = 1 × 10-18, colocalisation posterior probability = 0.90), problematic alcohol use (association p = 0.02, posterior probability = 0.64), and AUD (association p = 9 × 10-8, posterior probability = 0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗

PubMed2026

Empathic Accuracy and Behavioral Empathy After a Moderate Dose of Beer.

OBJECTIVES: Empathic accuracy (EA) represents a person's ability to correctly infer the emotions of another person. One past study in men found lower EA for positive emotions after a moderate dose of hard liquor compared to after placebo, particularly among non-hazardous drinkers. The present study aimed to replicate this finding, using a moderate dose of beer and a mixed design. Moreover, we added a novel measure of behavioral empathy. METHODS: Participants (62% men) completed the Alcohol Use Disorders Identification Test, Empathy Quotient, and Revised Drinking Motives Questionnaire. Before and after drinking either beer (6.6% alcohol, n = 28) or its 0.0% equivalent (placebo, n = 38), they watched videoclips of targets talking about emotional autobiographical events and rated how targets felt while talking. Behavioral empathy was assessed by presenting participants with painful scenarios and asking whether they would help the people in pain. RESULTS: The previous finding of lower EA for positive emotions after alcohol was not replicated. Nonetheless, after alcohol non-hazardous drinkers were less willing to help people in pain. Trait affective empathy (i.e., a person's long-term disposition to experience emotional responses congruent to another's feelings) and the drinking to cope motive did not significantly moderate the findings. CONCLUSIONS: Although alcohol may alter empathy, its effects are not consistent and may depend on the dose and type of alcohol consumed. The moderating roles of trait empathy and trait aggressivity deserves further study.

Humans↗

PubMed2025

GSK3B inhibition partially reverses brain ethanol-induced transcriptomic changes in C57BL/6J mice: Expression network co-analysis with human genome-wide association studies.

Alcohol use disorder (AUD) is a chronic behavioral disease with greater than 50% of its risk due to complex genetic contributions. Existing pharmacological and behavioral treatments for AUD are minimally effective and underutilized. Animal model behavioral genetics and human genome-wide association studies have begun to identify individual genes contributing to the progressive compulsive consumption of ethanol that occurs with AUD, promising possible new therapeutic targets. Our laboratory has previously identified Gsk3b as a central member in a network of ethanol-responsive genes in mouse prefrontal cortex, which altered ethanol consumption with genetic manipulation and was also significantly associated with risk for alcohol dependence in human genome-wide association studies. Here we perform detailed brain RNA sequencing transcriptomic studies to characterize a highly specific and clinically available GSK3B pharmacological inhibitor, tideglusib, as a possible therapeutic for clinical trials on treatment of AUD. A model of chronic intermittent ethanol consumption was used to study gene expression changes in prefrontal cortex and nucleus accumbens in the presence or absence of tideglusib treatment. Multivariate analysis of differentially expressed genes showed that tideglusib largely reversed ethanol- induced expression changes for two prominent clusters of genes in both prefrontal cortex and nucleus accumbens. Bioinformatic analysis showed these genes to have prominent roles in neuronal functioning and synaptic activity. Additionally, mouse brain differential gene expression data was analyzed together with human protein-protein interaction and genome-wide association studies on AUD to derive networks responding to tideglusib and relevant to human genetic risk for alcohol dependence. These studies identified discrete networks significantly enriched with genes provisionally associated with AUD, and provide key information on central hubs of such networks. Together these studies document tideglusib as a major modulator of chronic ethanol consumption-evoked brain gene expression signatures, and identify possible new targets for therapeutic modulation of AUD.

Journal Article↗

PubMed2026

Astrocyte reactivity by alcohol dependence in the central amygdala.

Astrocytes play essential roles in maintaining brain homeostasis and in contributing to synaptic functions, but, in response to injury, infection, or disease, astrocytes can downregulate their homeostatic and physiological functions while increasing neuroinflammatory responses. The central amygdala (CeA) is important for stress responsivity and the development of alcohol (ethanol) dependence. Using a multi-omics approach in Aldh1l1-EGFP/Rpl10a mice and the chronic intermittent ethanol two-bottle choice (CIE-2BC) model, we have characterized the translational response of CeA astrocytes, as well as the proteomic and phosphoproteomic changes in ethanol dependent, non-dependent, and naïve mice. We identified astrocyte-specific alterations in neuroimmune functions and antioxidant/oxidative stress pathways in ethanol dependent mice as well as cytoskeletal plasticity related pathways in non-dependent mice. Proteomic analysis showed down-regulation of astrocyte physiological functions in dependent animals while phosphoproteomic analysis identified pathways associated with cytoskeleton remodeling in both dependent and non-dependent mice. Reconstructions of astrocyte morphologies demonstrated increased CeA astrocyte complexity in dependent and non-dependent groups compared to naïve mice. The astrocyte-specific activation of neuroimmune and antioxidant pathways, down-regulation of homeostatic functions, alteration in protein phosphorylation-mediated cytoskeleton remodeling, and increased astrocyte morphological complexity demonstrate that ethanol dependence induces astrocyte reactivity in the CeA consistent with both adaptive and maladaptive changes. These findings highlight the role of CeA astrocytes in the progression from alcohol intake to dependence and represent a first step toward identifying astrocyte-specific therapeutic strategies to treat Alcohol Use Disorder (AUD) aimed at potentiating reactive astrocyte adaptive changes and inhibiting maladaptive responses.

Animals↗