Search

Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol‐associated liver disease (ALD) are the top two pathologies among alcohol‐related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual‐pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol‐seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD. [ABSTRACT FROM AUTHOR]

Background: Ghrelin may influence several alcohol‐related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD). Methods: We used serum samples from a randomized, crossover, double‐blind, placebo‐controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3 µg/kg) followed by continuous infusion (16.9 ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self‐administration (IV‐ASA) session and the second experiment included an IV alcohol clamp (IV‐AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session. Results: In both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV‐ASA q‐value = 0.0003 and IV‐AC q < 0.0001), corticosterone (IV‐ASA q = 0.0202 and IV‐AC q < 0.0001), and glycochenodeoxycholic acid (IV‐ASA q = 0.0375 and IV‐AC q = 0.0013). In the IV‐ASA experiment, ghrelin infusion increased levels of cortisone (q = 0.0352) and fatty acids 18:1 (q = 0.0406) and 18:3 (q = 0.0320). Moreover, in the IV‐AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q < 0.0001) and phenylalanine (q = 0.0458). Conclusion: IV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine‐conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol. [ABSTRACT FROM AUTHOR]

Background: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high‐severity population) than in a mild‐severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. Methods: We conducted a systematic literature review on placebo‐controlled RCTs for AD.We assigned retained RCTs to high‐ or mild‐severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta‐regression analysis. Results: Among the 19 retained RCTs (comprising 1996 placebo‐treated patients), 11 trials were high‐severity and 8 were mild‐severity RCTs. The between‐study variability in AR was lower in the high‐severity than in the mild‐severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high‐severity studies (16.8% at 3 months) than the mild‐severity studies (36.7% at 3 months). Conclusions: Pharmacological RCTs for AD should select high‐severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD. [ABSTRACT FROM AUTHOR]

Background: One of the challenges in early‐stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD. Aims: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol‐related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome. Methods: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes. Results: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part‐time or unemployed (p's < 0.05); they met fewer DSM‐IV AD criteria and had significantly lower scores on alcohol‐related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD. Conclusions: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD. [ABSTRACT FROM AUTHOR]

The article offers information on priority areas for improving medications development for alcohol use disorder and promoting. It mentions about the drug development process more efficient in terms of speed, cost, and predictability and also focuses on the U.S. Food and Drug Administration's (FDA's) approval of disulfiram.

Since its discovery, the gut hormone, ghrelin, has been implicated in diverse functional roles in the central nervous system. Central and peripheral interactions between ghrelin and other hormones, including the stress-response hormone cortisol, govern complex behavioral responses to external cues and internal states. By acting at ventral tegmental area dopaminergic projections and other areas involved in reward processing, ghrelin can induce both general and directed motivation for rewards, including craving for alcohol and other alcohol-seeking behaviors. Stress-induced increases in cortisol seem to increase ghrelin in the periphery, suggesting a pathway by which ghrelin influences how stressful life events trigger motivation for rewards. However, in some states, ghrelin may be protective against the anxiogenic effects of stressors. This critical review brings together a dynamic and growing literature, that is, at times inconsistent, on the relationships between ghrelin, central reward-motivation pathways, and central and peripheral stress responses, with a special focus on its emerging role in the context of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Background While the role of attention-deficit/hyperactivity disorder (ADHD) as a risk factor for developing alcohol use disorder (AUD) has been established, the underlying pathways connecting the two are still not fully understood. Overlapping constructs such as impulsivity may explain the increased risk for developing AUD in individuals with ADHD. Methods In this study, we assessed whether adult ADHD symptoms increase the odds of having a diagnosis of AUD. Furthermore, we tested whether facets of impulsivity explained the relationship between ADHD symptoms and alcohol dependence (AD) severity. Results In a logistic regression of 749 participants (464 = AD, 285 = controls), overall adult ADHD symptoms, and more specifically, symptoms of hyperactivity/restlessness and problems with self-concept, increased the odds of having a diagnosis of AD. Within the AD sample, we found that impulsivity mediated the relationship between adult ADHD symptoms and AD severity. In particular, negative and positive urgency meditated the relationship of overall adult ADHD symptoms, and symptoms of hyperactivity/restlessness and problems with self-concept with AD severity. Conclusions These results highlight the importance of looking at cohorts of ADHD symptoms and facets of impulsivity to assess the risk of developing AUD. They also suggest potential avenues for intervention strategies in individuals with preexisting adult ADHD symptoms who are seeking treatment for AUD. [ABSTRACT FROM AUTHOR]

Background The Montgomery-Asberg Depression Rating Scale ( MADRS) is commonly used to examine depressive symptoms in clinical settings, including facilities treating patients for alcohol addiction. No studies have examined the validity of the MADRS compared to an established clinical diagnostic tool of depression in this population. This study aimed to examine the following: (i) the validity of the MADRS compared to a clinical diagnosis of a depressive disorder (using the Structured Clinical Interview for DSM-IV-TR [SCID-IV-TR]) in patients seeking treatment for alcohol dependence ( AD); (ii) whether the validity of the MADRS differs by type of SCID-IV-TR-based diagnosis of depression; and (iii) which items contribute to the optimal predictive model of the MADRS compared to a SCID-IV-TR diagnosis of a depressive disorder. Methods Individuals seeking treatment for AD and admitted to an inpatient unit were administered the MADRS at day 2 of their detoxification program. Clinical diagnoses of AD and depression were made via the SCID-IV-TR at the beginning of treatment. Results In total, 803 participants were included in the study. The MADRS demonstrated low overall accuracy relative to the clinical diagnosis of depression with an area under the receiver operating characteristic curve of 0.68. The optimal threshold for balancing sensitivity and specificity identified by the Euclidean distance was >14. This cut-point demonstrated a sensitivity of 66%, a specificity of 60%, a positive predictive value of 50%, and a negative predictive value of 75%. The MADRS performed slightly better for major depressive disorders compared to alcohol-induced depression. Items related to lassitude, concentration, and appetite slightly decreased the accuracy of the MADRS. Conclusions The MADRS does not appear to be an appropriate substitute for a diagnostic tool among alcohol-dependent patients. The MADRS may, however, still be a useful screening tool assuming careful consideration of cut-points. [ABSTRACT FROM AUTHOR]

Background Post hoc analyses of 2 randomized controlled trials suggest naltrexone may reduce alcohol use and improve smoking cessation outcomes among heavy drinkers receiving smoking cessation treatment. However, no studies have been conducted specifically to examine naltrexone for this purpose or to test whether naltrexone has benefit when added to smoking cessation counseling that explicitly addresses heavy drinking. Methods We recruited heavy-drinking smokers from the community and randomized them to receive 10 weeks of either (i) 50 mg naltrexone ( n = 75) or (ii) placebo ( n = 75) daily. Participants received 6 weeks of transdermal nicotine patch and 6 sessions of counseling that addressed both heavy drinking and smoking. Participants were followed for 26 weeks after their target quit smoking date. Results Across medication conditions, there were substantial reductions at follow-up in percent heavy drinking days (primary outcome) and average drinks per week (secondary outcome). However, participants receiving naltrexone did not differ significantly from those receiving placebo on percent heavy drinking days (effect size d = −0.04, 95% CI [−0.30, 0.22], p = 0.76) or average drinks per week ( d = −0.09, 95% CI [−0.35, 0.18], p = 0.54) during follow-up. Naltrexone compared to placebo was not associated with a significant increase in smoking abstinence rates during follow-up, odds ratio = 0.93, 95% CI [0.46, 1.86], p = 0.83. The effect of naltrexone on these outcomes was not significantly moderated by current alcohol dependence or gender. Conclusions Results indicate that heavy-drinking smokers, including those with current alcohol dependence, can make substantial reductions in drinking in the context of smoking cessation treatment. However, this study provided no evidence that naltrexone is efficacious for enhancing reductions in drinking or improving smoking cessation in this population. Limitations of this study included lower-than-desired sample size and modest adherence to study medication. [ABSTRACT FROM AUTHOR]

Background Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. To date, attempts to characterize subgroups of alcohol-dependent (AD) individuals have largely been focused on categorical distinctions based on behaviors such as ability to abstain, age of onset, and drinking motives, but these have failed to yield predictors of treatment response and disease course. The distinction between AD individuals who are or are not interested in treatment holds significant implications for interpreting results of human laboratory studies with nontreatment seekers and clinical trials with treatment-seeking AD patients. However, despite their crucial role in alcohol-related research, these 2 groups are poorly defined. In this exploratory analysis, we attempt to better define the phenotypic differences between these 2 experimentally relevant populations. Methods We analyzed data from AD individuals who participated in screening protocols to evaluate their suitability for participation in either treatment or nontreatment research studies at NIAAA. Scores on individual measures from a battery of behavioral, neuropsychological, and blood laboratory measures were compared between those who presented seeking treatment for AD and those who were not seeking treatment. Differences in each measure were assessed between the 2 groups. In addition, we explored whether significant differences were apparent when drinking behavior was used as a covariate. Results Treatment seekers manifested more impairment compared to nontreatment seekers on a wide variety of measures in the following categories: alcohol drinking, personality, impulsivity, trauma/stress, cognition, aggression, mood, and liver enzyme tests. Treatment seekers endorsed a greater number of AD criteria. Several measures including elevations in liver enzyme tests remained significantly different between the 2 groups when average daily alcohol consumption per drinking day was used as a covariate. Conclusions Treatment-seeking, compared to nontreatment-seeking AD subjects who present for alcohol-related research studies, differ in characteristics beyond the quantity of alcohol consumption. Implications of these differences with respect to clinical research for treatments of AD are discussed. [ABSTRACT FROM AUTHOR]