Alcohol use disorder (AUD) treatment can help improve clinical outcomes among patients with alcohol-associated cirrhosis but is underutilized. Among socioeconomically disadvantaged patients with alcohol-associated cirrhosis, we examined rates of lifetime and past 12-month AUD treatment utilization and associated demographic and clinical characteristics.
Racial/ethnically diverse patients with alcohol-associated cirrhosis who had at least one hepatology clinic visit in the prior 6 months were recruited from three Northern California medical centers serving veterans and safety-net populations. Participants self-reported their AUD treatment utilization, liver disease quality of life (LDQoL), history and current symptoms of anxiety and depression, and problematic drinking as measured by the Alcohol Use Disorders Identification Test (AUDIT). Clinical measures including liver disease severity were captured from medical records.
Among 196 participants, the majority were male (88%) with a mean age of 62 years. Two-thirds of participants (67%) reported ever utilizing AUD treatment and 32% reported utilizing AUD treatment in the past 12 months. Compared with those who did not utilize AUD treatment, participants who utilized lifetime or past 12-month AUD treatment were younger, had lower LDQoL scores, and had higher scores on current symptoms of anxiety, depression, and problematic drinking. In multivariable analyses, the odds of ever utilizing pharmacological treatment alone or both behavioral and pharmacological treatment (vs. none) were lower with older age or higher LDQoL, and higher among those with a history of anxiety/depressive disorder. For past 12-month treatment utilization, odds were lower with older age, and higher among those with current clinically significant anxiety/depression or problematic drinking.
Patients with alcohol-associated cirrhosis who were younger or had anxiety/depression and problematic drinking were more likely to utilize AUD treatment. To improve AUD treatment utilization, targeted outreach to patients less likely to receive care and the provision of integrated ALD and AUD treatment is warranted.
The γ-aminobutyric acid-B (GABAB) receptor is a promising target for the development of new medications to treat alcohol use disorder (AUD). The GABAB agonist baclofen has been reported to reduce alcohol consumption but is associated with some undesirable side effects, including sedation. ASP8062 is a novel compound that acts as a positive allosteric modulator at the GABAB receptor and may be more tolerable than baclofen. This proof-of-concept human laboratory clinical trial evaluated the safety profile of ASP8062 and tested its effects on cue-elicited alcohol craving and alcohol use among treatment-seeking individuals with AUD.
This double-blind, randomized, multisite trial tested the effect of ASP8062 (25 mg once daily), relative to placebo, on alcohol cue-elicited craving in a laboratory setting and alcohol consumption, craving, mood, sleep, cigarette smoking, and alcohol-related consequences in the natural environment over a 6-week treatment period. Participants were 60 individuals (26 females and 34 males) with moderate or severe AUD.
ASP8062, relative to placebo, was well tolerated, and there were no adverse events (AEs) that significantly differed between treatment groups. Most AEs were mild/moderate, and there were no serious AEs among individuals treated with ASP8062. However, ASP8062 did not attenuate alcohol cue-elicited craving compared with placebo. Moreover, exploratory analyses indicated that ASP8062, relative to placebo, did not significantly affect alcohol consumption, naturalistic alcohol craving, mood, sleep, cigarette smoking, or alcohol-related negative consequences during the 6-week treatment period.
Although ASP8062 was well tolerated with no serious AEs, the novel compound did not significantly dampen alcohol cue-elicited craving or improve other AUD-related outcome measures. These data indicate positive allosteric modulation of the GABAB receptor at the dose evaluated here may not blunt alcohol cue-elicited craving, and preliminary drinking outcome data suggest it may not be an efficacious treatment strategy for AUD.
Impaired driving behaviors among young adults who are under the influence of simultaneous alcohol and marijuana/cannabis (SAM) use are associated with increased risks of motor vehicle accidents and resulting increased injury and mortality. Exploration of associations with descriptive and injunctive norms may have prevention implications.
Young adults (aged 18–25; N = 1941) in the 2019 cohort of the Washington Young Adult Health Survey comprised study participants. Associations between descriptive norms (estimates of other's frequency of driving under the influence of SAM [DUI-SAM] and riding with a SAM impaired driver [RWI-SAM]), injunctive norms (perceived approval or disapproval of DUI-SAM and RWI-SAM for young adults in their community), and past month DUI and RWI behaviors were assessed with logistic regression models, adjusting for covariates and applying post-stratification weights.
DUI-SAM was reported by 2.7% and almost double (5.3%) reported RWI-SAM at least once in the past month. Almost half of the participants believed the average young adults in Washington State engaged in DUI-SAM (49.8%) and RWI-SAM (48.7%) at least once a month in the past year (i.e., descriptive norms). The majority reported DUI-SAM (68.8%) and RWI-SAM (67.6%) to be totally unacceptable for young adults in their community (i.e., injunctive norms). In models adjusting for covariates including SAM use frequency and corresponding injunctive norms, descriptive norms were not associated with DUI, but were positively associated with RWI-SAM. However, after controlling for SAM use frequency and descriptive norms, higher perceived approval (i.e., injunctive norms) was significantly associated with increased odds of all DUI and RWI behaviors.
Injunctive norms for SAM impaired driving behaviors may be a promising intervention focus for DUI and RWI behaviors. Future research is needed to replicate these findings to determine if development and evaluation of individual and community-based interventions focused on changing normative beliefs are warranted.
Adenosine monophosphate-activated protein kinase (AMPK) signaling plays a vital role in regulating cellular metabolism and energy throughout the body. Ethanol and cocaine both reduce AMPK activity in addiction-related brain regions. Though AMPK activation has been found to reduce cocaine seeking, its role in harmful drinking and alcohol use disorder (AUD) progression remains unclear. We asked whether metformin, a first-line type 2 diabetes medication that targets AMPK, can reduce binge-like ethanol intake in inbred High Drinking in the Dark Line-1 (iHDID-1) mice, a genetic risk model for drinking to intoxication. We then determined whether metformin altered ethanol clearance in iHDID-1 mice. Next, we tested whether metformin and/or ethanol altered AMPK signaling in the nucleus accumbens (NAc), a brain region critically important for harmful drinking.
We measured the effects of metformin [0 or 250 mg/kg; intraperitoneal injection (i.p.)] on binge-like ethanol intake in separate acute (Experiment 1) and chronic (Experiment 3A) drinking studies (n = 6–8 iHDID-1 mice/sex/treatment/experiment). The effect of metformin (0 or 250 mg/kg) on ethanol (2.0 g/kg, i.p.) clearance was tested in iHDID-1 mice (Experiment 2; n = 7–9/sex/treatment). Lastly, we measured NAc AMPK and phosphorylated AMPK (pAMPK) levels in response to chronic ethanol (or water) drinking (n = 6 iHDID-1 mice/sex/treatment/fluid type; Experiment 3B) and an intoxicating dose of ethanol (2.0 g/kg; i.p.; Experiment 4).
Metformin reduced binge-like ethanol drinking intake in acute and chronic studies in both male and female iHDID-1 mice (p's < 0.05). We found no significant changes in ethanol clearance in response to metformin. Moreover, no differences in AMPK or pAMPK levels in the NAc were observed with either ethanol or metformin.
These findings provide early support for the repurposing of metformin, an affordable and safe diabetes medication, to reduce harmful ethanol intake and lay a foundation for testing its efficacy to treat individuals with AUD.
Clinical trials in patients with COVID-19 have exclusively used self- or proxy-reporting to characterize alcohol consumption. The aim of this study was to measure an objective biomarker of recent alcohol use in patients hospitalized with severe COVID-19-associated respiratory failure who were enrolled in an investigational clinical trial to determine the prevalence of alcohol misuse, and to explore the relationship of alcohol use with outcomes.
We conducted a substudy of patients enrolled in the multicenter, phase 2, adaptive platform design, Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And molecular Analysis in COVID-19 trial (ClinicalTrials.gov: NCT04488081), conducted at 20 hospital systems across the United States. Three hundred and fifty-five patients with available red blood cell (RBC) samples and 60-day follow-up assessments were included. RBCs were utilized to measure phosphatidylethanol (PEth). Prespecified thresholds of PEth were utilized to stratify patients into groups: low/no alcohol use (PEth < 20 ng/mL), significant alcohol use (PEth 20–200 ng/mL), and heavy alcohol use (PEth ≥ 200 ng/mL).
In this cohort, 17% of patients met criteria for significant alcohol use, while 4% met criteria for heavy alcohol use. Alcohol misuse was associated with diminished odds for home discharge, though this finding did not achieve statistical significance.
In a cohort of patients with severe COVID-19 enrolled in a clinical trial, alcohol consumption of two or more standard drinks per day was present among 21%, approximating the proportion of patients with diabetes, and raising the possibility that alcohol consumption alters risk for severe viral pneumonia. Undetected alcohol misuse among clinical trial participants has the potential to influence study outcomes or contribute to adverse events.
Alcohol-associated hepatitis (AH) is the clinical manifestation of alcohol-associated liver disease (ALD). AH is a complex disease encompassing the dysregulation of many cells and cell subpopulations. This study used a hepatic spatial transcriptomic and proteomic approach (10X Genomics Visium) to identify hepatic cell populations and their associated transcriptomic and proteomic alterations in human AH.
Formalin-fixed paraffin-embedded liver tissue from AH patients (n = 2) and non-ALD controls (donors) (n = 2) were used for Visium spatial transcriptomic and proteomic analysis.
AH cell clusters and cell markers were drastically different in regard to tissue pattern and number of cell types compared to non-ALD controls. Cholangiocytes, endothelial cells, macrophages, and stellate cells were more profuse in AH relative to non-ALD controls. Transcriptionally, proliferating cell nuclear antigen-positive (PCNA+) hepatocytes in AH more closely resembled cholangiocytes suggesting they were non-functional hepatocytes derived from cholangiocytes. Furthermore, mitochondria protein-coding genes were reduced in AH versus non-ALD control hepatocytes, suggesting reduced functionality and loss of regenerative mechanisms. Macrophages in AH exhibited elevated gene expression involved in exosomes as compared to non-ALD controls. The most upregulated macrophage genes observed in AH were those involved in exosome trafficking. Gene and protein signatures of disease-associated hepatocytes (ANXA2+/CXCL1+/CEACAM8+) were elevated in AH and could visually identify a pre-malignant lesion.
This study identified global cell type alterations in AH and distinct transcriptomic changes between AH and non-ALD controls. These findings characterize cellular plasticity and profuse transcriptomic and proteomic changes that are apparent in AH and contribute to the identification of novel therapeutics.
Alcohol consumption is an established cause of female breast cancer. This systematic review examines in detail the association between alcohol and female breast cancer overall and among the described subgroups, using all of the evidence to date. A systematic review of PubMed and Embase was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search included articles published up to November 15, 2023. Meta-analyses and regressions were performed for alcohol consumption of less than 1 standard drink (10 g of ethanol) per day and for a range of alcohol consumption categories in relation to breast cancer. Analyses by menopausal status, hormone receptor status, human epidermal growth factor receptor 2 status, and molecular subtype were performed. The search yielded 5645 publications, of which 23 publications of individual and pooled studies examined the association between overall alcohol consumption and breast cancer incidence. The meta-regression showed a positive association; relative risks (RR) of breast cancer were 1.05 (95% CI: 1.04, 1.06), 1.10 (95% CI: 1.08, 1.12), 1.18 (95% CI: 1.15, 1.21), and 1.22 (95% CI: 1.19, 1.25) for 0.5, 1, 2, and 3 standard drinks per day compared with nondrinking, respectively. A meta-analysis of nine studies indicated that for consumption of less than one standard drink per day, the RR estimate of breast cancer was 1.04 (95% CI: 1.01, 1.07) compared with nondrinking. Consumption of an additional 1 standard drink per day was associated with a higher risk of premenopausal (RR: 1.03 (95% CI: 1.01, 1.06)) and postmenopausal (RR: 1.10 (95% CI: 1.08, 1.12)) breast cancer. Alcohol consumption increases female breast cancer risk, even for women who consume one drink per day. Furthermore, alcohol consumption is associated with both pre- and postmenopausal breast cancer risk. These findings support evidence-based cancer prevention guidelines to reduce alcohol-related risks.
Observational studies link moderate alcohol consumption to reduced risk of cardiometabolic diseases, including coronary heart disease (CHD) and type 2 diabetes mellitus (T2D). Mendelian randomization (MR) studies suggest that these associations are due to confounding. We present observed and genetically proxied associations between alcohol consumption and the incidence of CHD and T2D among African Americans (AA), European Americans (EA), and Hispanic Americans (HA) from the Million Veteran Program.
We conducted two retrospective, nested case–control studies of 33,053 CHD and 28,278 T2D cases matched to five controls each at the time of the event (index date). We used the Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) score closest in time prior to the index date to estimate alcohol exposure. Models were adjusted for smoking, body mass index (BMI), chronic kidney disease, rheumatoid arthritis, and the use of statins or antihypertensive medications. MR analyses used either a single variant in ADH1B or a genetic score (GS) as instrumental variables.
Observational analysis showed a U-shaped association of alcohol consumption with CHD and T2D risk. However, in MR analyses, neither ADH1B genotype-predicted (in 36,465 AAs, 146,464 EAs, and 11,342 HAs) nor GS-predicted (in EAs) alcohol consumption was associated with CHD risk. Similarly, T2D was not associated with alcohol consumption predicted either by ADH1B genotype (in 42,008 AAs, 109,351 EAs, and 13,538 HAs) or GS (in EAs). Multivariable MR analyses that adjusted for the effects of blood pressure and smoking also showed no association between alcohol consumption and cardiometabolic diseases.
We replicate prior observational studies that show a U-shaped association between alcohol consumption and cardiometabolic diseases, but MR findings show no causal association between these traits. This is largely consistent with previous MR analyses in EAs and expands the literature by providing similar findings in AA and HA populations.
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