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The Journal of Clinical Investigation Feb 2024Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple... (Review)
Review
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
Topics: Humans; Liver Diseases, Alcoholic; Ethanol; Fatty Liver; Liver Cirrhosis; Carcinoma, Hepatocellular; Liver Neoplasms; Liver
PubMed: 38299591
DOI: 10.1172/JCI176345 -
JAMA Nov 2023Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. (Comparative Study)
Comparative Study Meta-Analysis
IMPORTANCE
Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality.
OBJECTIVE
To compare efficacy and comparative efficacy of therapies for alcohol use disorder.
DATA SOURCES
PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023.
STUDY SELECTION
For efficacy outcomes, randomized clinical trials of at least 12 weeks' duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included.
DATA EXTRACTION AND SYNTHESIS
Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate strength of evidence for benefit.
MAIN OUTCOMES AND MEASURES
The primary outcome was alcohol consumption. Secondary outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms.
RESULTS
Data from 118 clinical trials and 20 976 participants were included. The numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, -4.99 days; 95% CI, -9.49 to -0.49 days) Adverse effects included higher gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI, 1.23-1.91) compared with placebo.
CONCLUSIONS AND RELEVANCE
In conjunction with psychosocial interventions, these findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.
Topics: Humans; Acamprosate; Alcohol Drinking; Alcoholism; Drug-Related Side Effects and Adverse Reactions; Naltrexone; Prospective Studies; Quality of Life; United States; Alcohol Deterrents; Psychosocial Intervention
PubMed: 37934220
DOI: 10.1001/jama.2023.19761 -
JCI Insight Jun 2023Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for...
Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.
Topics: Rats; Mice; Male; Female; Animals; Glucagon-Like Peptide 1; Alcohol Drinking; Alcoholism; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 37192005
DOI: 10.1172/jci.insight.170671 -
Proceedings of the National Academy of... Aug 2023Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and...
Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
Topics: Animals; Mice; Disulfiram; Toll-Like Receptor 4; Lipopolysaccharides; Signal Transduction; Alcoholism; Cytokines
PubMed: 37487070
DOI: 10.1073/pnas.2306399120 -
Neuropsychopharmacology Reports Dec 2023Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment for alcohol withdrawal syndrome (AWS). Currently, existing...
AIM
Phenobarbital, a long-acting barbiturate, presents an alternative to conventional benzodiazepine treatment for alcohol withdrawal syndrome (AWS). Currently, existing research offers only modest guidance on the safety and effectiveness of phenobarbital in managing AWS in hospital settings. The study objective was to assess if a phenobarbital protocol for the treatment of AWS reduces respiratory complications when compared to a more traditionally used benzodiazepine protocol.
METHODS
A retrospective cohort study analyzing adults who received either phenobarbital or benzodiazepine-based treatment for AWS over a 4-year period, 2015-2019, in a community teaching hospital in a large academic medical system.
RESULTS
A total of 147 patient encounters were included (76 phenobarbital and 71 benzodiazepine). Phenobarbital was associated with a significantly decreased risk of respiratory complications, defined by the occurrence of intubation (15/76 phenobarbital [20%] vs. 36/71 benzodiazepine [51%]) and decreased incidence of the requirement of six or greater liters of oxygen when compared with benzodiazepines (10/76 [13%] vs. 28/71 [39%]). There was a significantly higher incidence of pneumonia in benzodiazepine patients (15/76 [20%] vs. 33/71 [47%]). Mode Richmond Agitation Sedation Scale (RASS) scores were more frequently at goal (0 to -1) between 9 and 48 h after the loading dose of study medication for phenobarbital patients. Median hospital and ICU length of stay were significantly shorter for phenobarbital patients when compared with benzodiazepine patients (5 vs. 10 days and 2 vs. 4 days, respectively).
CONCLUSION
Parenteral phenobarbital loading doses with an oral phenobarbital tapered protocol for AWS resulted in decreased risk of respiratory complications when compared to standard treatment with benzodiazepines.
Topics: Adult; Humans; Benzodiazepines; Substance Withdrawal Syndrome; Alcoholism; Hypnotics and Sedatives; Retrospective Studies; Phenobarbital
PubMed: 37368937
DOI: 10.1002/npr2.12347 -
Scientific Reports Nov 2023Alcohol Use Disorder (AUD) contributes significantly to global mortality. GLP-1 (Glucagon-like peptide-1) and GLP-1/GIP (Glucose-dependent Insulinotropic Polypeptide)...
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.
Topics: Animals; Humans; Alcoholism; Diabetes Mellitus, Type 2; Alcohol Drinking; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Obesity; Ethanol; Weight Loss; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents
PubMed: 38017205
DOI: 10.1038/s41598-023-48267-2 -
EBioMedicine Jul 2023Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However,...
BACKGROUND
Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.
METHODS
In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.
FINDINGS
In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.
INTERPRETATION
Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.
FUNDING
Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.
Topics: Female; Rats; Mice; Male; Animals; Exenatide; Dopamine; 3,4-Dihydroxyphenylacetic Acid; Overweight; Ethanol; Alcoholism; Alcohol Drinking; Recurrence
PubMed: 37295046
DOI: 10.1016/j.ebiom.2023.104642 -
CMAJ : Canadian Medical Association... Mar 2024
Topics: Humans; Alcoholism; Selective Serotonin Reuptake Inhibitors; Alcohol Drinking; Cognition
PubMed: 38467411
DOI: 10.1503/cmaj.231015-f -
CMAJ : Canadian Medical Association... Mar 2024
Topics: Humans; Alcoholism; Canada; Alcohol Drinking
PubMed: 38467412
DOI: 10.1503/cmaj.230715-f