Associations of history of alcohol use disorder with loneliness, social support, and mental health during the COVID-19 pandemic.

This study examined the effects of alcohol use disorder (AUD) and treatment history on changes in loneliness, social support, and mental health symptoms from before to during the pandemic, and tested loneliness and social support as mediators of the AUD-mental health associations. Participants (n = 427) enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol Study were categorized into three groups: healthy control (62.3%), nontreatment AUD (14.1%), and treatment AUD (23.7%). Multilevel generalized linear models were conducted to examine changes in loneliness, social support, and mental health symptoms by group. Path analyses tested the mediating roles of loneliness and social support. Loneliness increased during the pandemic, especially in the nontreatment AUD group. Social support decreased in the healthy control and AUD treatment group. Anxiety and depressive symptoms increased in the nontreatment AUD group. Individuals with a history of AUD regardless of treatment history reported greater loneliness, which was linked to higher anxiety and depressive symptoms. Loneliness, but not social support, mediated the AUD-mental health associations. Psychosocial interventions aimed at increasing positive social engagement among individuals with AUD may help alleviate feelings of loneliness and mitigate mental health symptoms. Study findings can also help improve preparedness for future public health crises.

Exercising healthy behaviors: A latent class analysis of positive coping during the COVID-19 pandemic and associations with alcohol-related and mental health outcomes.

OBJECTIVE: To identify latent classes of positive coping behaviors during the COVID-19 pandemic and examine associations with alcohol-related and mental health outcomes across participants with and without a history of alcohol use disorder (AUD). METHODS: Baseline data from 463 participants who were enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol (C19-PIA) Study were analyzed. Latent class analysis (LCA) was applied to five positive coping behaviors during COVID-19: taking media breaks, taking care of their body, engaging in healthy behaviors, making time to relax, and connecting with others. Latent class differences and the moderating role of history of AUD on six alcohol-related and mental health outcomes were examined using multiple regression models. RESULTS: LCA revealed two latent classes: 83.4% High Positive Coping and 16.6% Low Positive Coping. Low Positive Coping was associated with higher levels of perceived stress, anxiety symptoms, and loneliness. A history of AUD was consistently associated with higher levels of alcohol-related and mental health outcomes. Significant interactions between Coping Latent Classes and history of AUD indicated that the associations of Low Positive Coping with problematic alcohol use, depressive symptoms, and drinking to cope motives were either stronger or only significant among individuals with a history of AUD. CONCLUSIONS: Individuals with a history of AUD may be particularly vulnerable to depressive symptoms and alcohol-related outcomes, especially when they do not utilize positive coping strategies. The promotion of positive coping strategies is a promising avenue to address alcohol-related and mental health problems during a public health crisis and warrants future research.

Stress and alcohol-related coping mechanisms linking lifetime suicide ideation and attempt to multidimensional quality of life.

BACKGROUND: Suicide ideation and attempt are linked to adverse mental health outcomes, but few studies have examined their associations with quality of life (QoL). This study examined the impact of lifetime history of suicidal ideation and attempt on four QoL domains via perceived stress and problematic drinking. METHODS: Participants were drawn from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol (N = 1055), including those with no history of suicidality (78.6 %), suicidal ideation only (15.3 %), and a history of suicide attempt (6.2 %). Structural equation modeling (SEM) was utilized to test perceived stress and drinking as mediational pathways to multidimensional QoL. RESULTS: Individuals with a history of suicide ideation and/or attempt reported higher perceived stress in the past month, more problematic drinking in the past year, and lower QoL domains in the past two weeks. SEM showed significant mediation effects through dimensions of perceived stress (helplessness, lack of self-efficacy) and alcohol problems. When these mediators were considered simultaneously, the mediation effects through alcohol problems were attenuated, while several direct effects of suicidality on physical, psychological, and social QoL were weakened but remained significant. LIMITATIONS: Cross-sectional data with retrospective report of suicidality history. CONCLUSIONS: A lifetime history of suicidality was associated with lower multidimensional QoL. These associations were partially explained by stress and alcohol-related coping mechanisms such as feeling helpless or inadequate when encountering stressors and problematic drinking. Perceived stress and drinking to cope may be important intervention targets to improve QoL among those with a history of suicidality.

Early life stress and body-mass-index modulate brain connectivity in alcohol use disorder.

Early life stress (ELS) significantly increases susceptibility to alcohol use disorder (AUD) by affecting the interplay between the executive and the salience networks (SNs). The link between AUD and higher body-mass index (BMI) is known, but we lack understanding of how BMI impacts the relationship between ELS and brain connectivity in individuals with AUD. To bridge this gap, we investigated the main and interaction effects of ELS and BMI on brain connectivity in individuals with AUD compared to non-AUD participants (n = 77 sex-matched individuals per group). All participants underwent resting-state functional magnetic resonance imaging, revealing intriguing positive functional connectivity between SN seeds and brain regions involved in somatosensory processing, motor coordination and executive control. Examining the relationship of brain connectivity with ELS and BMI, we observed positive associations with the correlations of SN seeds, right anterior insula (RAIns) and supramarginal gyrus (SMG) with clusters in motor [occipital cortex, supplementary motor cortex]; anterior cingulate cortex (ACC) with clusters in frontal, or executive, control regions (middle frontal gyrus; MFG, precentral gyrus) that reportedly are involved in processing of emotionally salient stimuli (all |ß | > 0.001, |p | < 0.05). Interestingly, a negative association of the interaction effect of ELS events and BMI measures with the functional connectivity of SN seeds ACC with decision-making (MFG, precentral gyrus), RAIns and RSMG with visuo-motor control regions (occipital cortex and supplementary motor cortex) (all |ß | = -0.001, |p | < 0.05). These findings emphasize the moderating effect of BMI on ELS-associated SN seed brain connectivity in AUD. Understanding the neural mechanisms linking BMI, ELS and AUD can guide targeted interventions for this population.

Social media addiction as a mediator of the associations between fear of COVID-19, mental health symptoms, and problematic alcohol use.

Background: Fear of COVID-19 is a risk factor for anxiety and depressive symptoms. During the COVID-19 pandemic, drinking to cope with psychological distress has been proposed as a key mechanism leading to problematic drinking. The goal of this study was to test social media addiction as a mediator linking fear of COVID-19 to mental health symptoms and problematic alcohol use. Methods: In between April 6 and July 2 of 2022, 250 participants completed an online survey as part of the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study. Path analyses were conducted to test the mediational pathways. Results: Using the polythetic classification scheme, 13.2% (n = 33) of participants were classified as having social media addiction. Compared with participants without social media addiction, participants with social media addiction spent significantly more time on social media platforms and on digital communications with a family member or friend. They also reported greater fear of COVID-19, higher anxiety symptoms, and higher depressive symptoms. Path analyses indicated that social media addiction mediated the associations of fear of COVID-19 with anxiety and depressive symptoms. Furthermore, there were indirect pathways linking fear of COVID-19 to problematic alcohol use through higher social media addiction and higher anxiety and depressive symptoms. Conclusion: Social media addiction may be a maladaptive coping mechanism that individuals with high fear of COVID-19 utilized to deal with uncertainty and perceived risks during the pandemic. Findings underscore the need to examine cognitions related to fear of COVID-19 and address excessive social media use in the context of mental health and alcohol interventions.

Novel paradigms for the gut-brain axis during alcohol withdrawal, withdrawal-associated depression, and craving in patients with alcohol use disorder.

Introduction: Patients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms. Methods: Forty-eight AUD patients [men (n = 34) and women (n = 14)] aged 23-63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score > 10] [n = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [n = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS). Results: CS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-1ß and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R2 = 0.955, p = 0.006) in the AUD patients, who had higher ratings for cravings (PACS > 5). Discussion: The interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut-brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut-brain axis response to heavy drinking. Trial registration: ClinicalTrials.gov, identifier: NCT# 00106106.

Effects of clustering and timing of early life stress exposure on mood problems, ADHD symptoms, and problematic drinking.

OBJECTIVE: Exposure to early life stress (ELS) may lead to long-term health consequences. The Early Life Stress Questionnaire (ELSQ) is a retrospective measure of multiple ELS and their timing. Latent class analysis (LCA) has not been applied to the ELSQ and questions regarding timing are rarely explored. This study examined the effects of clustering and timing of ELS exposure on internalizing and externalizing symptoms. METHOD: Data from 1095 participants in the NIAAA Natural History Protocol were analyzed. LCA was conducted on 18 ELS items. Regression and correlational analyses examined associations of latent classes with sociodemographic variables and clinical outcomes. RESULTS: LCA revealed three classes: Class 1: Minimal ELS (54.2%), Class 2: Moderate ELS (33.2%), and Class 3: Multiple and High ELS (12.6%). Black/African American participants were more likely to be in Class 2, and participants with low household income were more likely to be in Classes 2 and 3. Family history of problematic alcohol use and individual alcohol use disorder diagnosis were linked to Classes with higher ELS exposure. Compared with Class 1, Class 2 reported higher anxiety symptoms, depressive symptoms, ADHD symptoms, and problematic drinking, and Class 3 reported the highest levels across all these outcomes. Regarding timing, earlier exposure to ELS (e.g., sustained family conflict and witnessed domestic violence) was associated with higher psychopathological symptoms. CONCLUSIONS: The ELSQ can effectively capture clustering and timing of exposure to multiple ELS. Greater and earlier exposure to ELS were positively associated with internalizing and externalizing symptoms, underscoring the need for early and well-timed intervention.

Investigating the relationship between early life adversity, inflammation and alcohol use.

Early life adversity (ELA) has long-lasting and potentially harmful effects on adult mental and physical health, including a higher likelihood of developing psychiatric conditions such as depression, anxiety and alcohol use disorder (AUD). It has been suggested that inflammation may play a role in linking ELA to the development of AUD. Here, we evaluated a number of predictive factors of high sensitivity C-reactive protein (hsCRP), a key inflammatory marker, and the potential mediating role of hsCRP in the relationship between ELA and alcohol misuse in adulthood. Data was collected from participants who participated in NIAAA screening protocols between January 2013 and December 2019. In this secondary analysis, we first tested, via multiple linear regression, potential predictors of hsCRP levels among adults with AUD (N = 781) and non-AUD (N = 440) individuals. We subsequently conducted mediation analyses to evaluate the potential role of hsCRP in the relationship between early life stress and alcohol use. Regression analysis showed that stress in early life, but not childhood trauma, significantly predicted increased hsCRP levels in adulthood (p < 0.05). Additionally, a greater amount of alcohol drinking, but not a diagnosis of AUD, significantly predicted increased hsCRP levels (p < 0.05). Furthermore, hsCRP mediated the relationship between early life stress and alcohol consumption. Early life stress and heavier alcohol drinking both predicted increased hsCRP levels; however, an AUD diagnosis did not. Elevated inflammation, due to and/or predicted by greater early life stress, may contribute to the development of unhealthy alcohol use in adulthood.

A person-centered approach to capture health disparities and multidimensional impact of COVID-related stressors.

The COVID-19 pandemic has influenced people's lives in diverse ways. The authors utilized latent class analysis (LCA), a person-centered approach, to examine distinct patterns of COVID-related stressors and their associations with alcohol-related, mental health, and quality of life outcomes. Participants were 463 adults who completed the baseline assessment of the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study from June 2020 to January 2022. Using cross-sectional data, three analytic methods (continuous sum score, categorical grouping, and LCA) were applied to model 17 COVID-related stressors. Regression analyses indicated higher COVID-related stress and endorsement of four or more COVID-related stressors were generally associated with worse health-related outcomes. LCA revealed four classes: Class 1: Minimal COVID-Related Impact (51.6%); Class 2: Work Interruptions (24.8%); Class 3: Family/Friends Affected by COVID (14.5%); and Class 4: Serious Financial Stress (9.1%). Racial/ethnic minorities were more likely to be in Class 3, whereas individuals with more years of education and higher income were less likely to be in Class 4. Individuals with a history of alcohol use disorder were more likely to be in Classes 2 and 4. Compared with Class 1, Class 4 reported highest levels of perceived stress, problematic alcohol use, anxiety symptoms, depressive symptoms, alcohol craving, loneliness, drinking to cope, and lowest levels of physical, psychological, social, and environment quality of life. COVID-related stressors disproportionately affected minority and vulnerable groups. Individuals who experienced multiple financial stressors had the greatest risk for negative health-related outcomes and may benefit from holistic interventions and community outreach. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Chemosensory Alterations and Impact on Quality of Life in Persistent Alcohol Drinkers.

BACKGROUND: Heavy alcohol consumption-associated chemosensory dysfunction is understudied, and early detection can help predict disease-associated comorbidities, especially those related to four quality of life (QOL) domains (physical, psychological, social and environment). We examined self-reports of chemosensory ability of individuals with different alcohol drinking behaviors and their association with changes in QOL domains. METHODS: Participants (n = 466) were recruited between June 2020 and September 2021 into the NIAAA COVID-19 Pandemic Impact on Alcohol study. Group-based trajectory modeling was used to categorize participants without any known COVID-19 infection into three groups (non-drinkers, moderate drinkers and heavy drinkers) based on their Alcohol Use Disorders Identification Test consumption scores at four different time points (at enrollment, week 4, week 8 and week 12). Linear mixed models were used to examine chemosensory differences between these groups. The associations between chemosensory abilities and QOL were determined in each group. RESULTS: We observed significant impairment in self-reported smell ability of heavy drinking individuals compared to non-drinkers. In contrast, taste ability showed marginal impairment between these groups. There were no significant differences in smell and taste abilities between the moderate and non-drinking groups. Heavy drinkers' impairment in smell and taste abilities was significantly associated with deterioration in their physical, psychological, social and environmental QOL. CONCLUSION: Persistent heavy drinking was associated with lower chemosensory ability. Heavy drinkers' reduced smell and taste function and association with poorer QOL indicate that early assessment of chemosensory changes may be crucial in identifying poorer well-being outcomes in heavy drinkers at risk for alcohol use disorder.

One-month assessment of Th-cell axis related inflammatory cytokines, IL-17 and IL-22 and their role in alcohol-associated liver disease.

Introduction: Changes in the expression of cyto- and chemokines due to alcohol-associated liver disease (ALD) have been reported to be both protective and pathogenic. This study examined plasma levels of two key cytokines, Il-17 and Il-22, which construct the proinflammatory vs. anti-inflammatory axes across the spectrum of alcohol use disorder (AUD) and ALD including alcohol-associated hepatitis (AH) to determine the underlying status of the inflammation. Methods: Forty-two males and females aged 25-63 yrs. were grouped as healthy controls (HV[n=8]), AUD with no liver injury (AUDNLI [n=8]), AUD with liver injury (AUDLI [n=8]), non-severe alcohol-associated hepatitis (NSAH [n=9]), and severe alcohol-associated hepatitis (SAH [n=9]). Demographic, drinking, and clinical data were collected. Blood samples were collected at baseline (BL, all subjects) and during week 4 (W4, only patients) for IL-17 and IL-22; and statistically analyzed. Results: IL-17 was highly elevated in the SAH group both at BL and post-SOC. LTDH and BL IL-22 in non-severe AH patients were associated significantly. LTDH significantly predicted W4 IL-22 levels, positively (increasing) in NSAH and inversely (lowering) in SAH patients. BL and W4 IL-22 levels were significantly higher (4-fold, p≤0.001) in all AH patients compared to all AUD patients (AUROC=0.988, p≤0.001). IL-22 showed significant affinity with AST, AST: ALT ratio, total bilirubin, INR, and PT both at BL and W4. IL-22 was inversely associated with IL-1ß; and positively with TNF-α and IL-8 both at BL, and W4. BL IL-17 showed a positive correlation with MELD (p=0.017) in all AH patients. In SAH, > 2-fold W4 IL-17 level compared to BL showed significant within subjects' effects, p=0.006. In AUD patients without AH, the drop in IL-17 at W4 vs. BL showed a significant within subjects' effect, p=0.031. Discussion: Drinking chronicity predicted opposite effects in IL-22 levels in NSAH (antiinflammatory) and SAH (pro-inflammatory) patients at post-SOC. BL IL-22 levels differentiated AH patients robustly from the AUD patients (with or without liver injury); and showed corresponding increases stepwise with the stages of ALD. IL-22 was closely associated with progression and injury markers of the liver; and response to the cytokines of pro-inflammatory nature. Pro-inflammatory indicator of IL-17 cell axis, IL-17 showed a strong positive association with MELD, a severity indicator of AH.

Multidimensional Quality of Life Across the Spectrum of Alcohol Use Behavior.

Objective: Quality of life (QoL) is inversely associated with alcohol misuse and is a key measure by which recovery from alcohol use disorder (AUD) might be assessed. Yet, the determinants of QoL are scarcely known. The authors examined three ways through which demographic characteristics, familial and early life factors, and psychopathology conferred risks for QoL, including unique direct effects, developmental pathways, and clinical risk Profiles. Methods: Cross-sectional data from 1095 adults (50.4% without AUD; 49.6% with AUD) who participated in the NIAAA Natural History Protocol from January 2015 to March 2022 were analyzed. Multivariable regressions, path analysis, and latent Profile analysis were conducted. Results: AUD was uniquely associated with lower QoL, and adverse effects of child maltreatment history and psychopathology symptoms on QoL were of similar or larger magnitudes. Mediation analysis indicated family history of AUD and child maltreatment history were indirectly associated with lower QoL through higher attention-deficit/hyperactivity disorder symptoms, higher depressive symptoms, and positive AUD diagnosis. Latent Profile analysis of an enriched set of clinical characteristics identified four latent Profiles capturing the full range of alcohol use behavior. Latent Profiles with greater severity of familial and early life factors, psychopathology, and problematic drinking showed dose-response associations with lower levels of physical, psychological, social, and environment QoL. Conclusions: A constellation of developmental and clinical characteristics disproportionately affects individuals with AUD and is negatively associated with QoL domains. To improve QoL, prevention and intervention need to target multiple factors, including history of child maltreatment, comorbid psychopathology, and problematic drinking itself.

Association of Hypomagnesemia and Liver Injury, Role of Gut-Barrier Dysfunction and Inflammation: Efficacy of Abstinence, and 2-Week Medical Management in Alcohol Use Disorder Patients.

(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients were sub-divided within each group into patients with normal magnesium (0.85 and more mmol/L) and deficient magnesium (less than 0.85 mmol/L) levels. All participants were assessed at baseline (BL) and received standard medical management for 2 weeks with reassessment at the treatment end (2w). (3) Female participants of this study showed a significantly lower baseline level of magnesium than their male counterparts. Gr.2 patients showed a greater propensity in the necrotic type of liver cell death, who reported higher chronic and recent heavy drinking. Magnesium level improved to the normal range in Gr.2 post-treatment, especially in the hypomagnesemia sub-group (0.77 ± 0.06 mmol/L (BL) vs. 0.85 ± 0.05 mmol/L (2w), p = 0.02). In Gr.2, both apoptotic (K18M30) and necrotic (K18M65) responses were significantly and independently associated with inflammasome activity comprising of LBP (Lipopolysaccharide binding-protein) and TNFα (Tumor necrosis factor -α), along with serum magnesium. (4) In AUD patients with liver injury, 2-week medical management seems to improve magnesium to a normal level. This group exhibited inflammatory activity (LBP and TNFα) contributing to clinically significant hypomagnesemia. In this group, the level of magnesium, along with the unique inflammatory activity, seems to significantly predict apoptotic and necrotic types of hepatocyte death.

Illustration of Gut-Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.

(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1ß, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 ß, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut-immune-thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut-thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut-brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD.

An exploratory study of pro-inflammatory cytokines in individuals with alcohol use disorder: MCP-1 and IL-8 associated with alcohol consumption, sleep quality, anxiety, depression, and liver biomarkers.

Background: High levels of sleep disturbances reported among individuals with alcohol use disorder (AUD) can stimulate inflammatory gene expression, and in turn, may alter pro-inflammatory cytokines levels. We aimed to investigate associations between pro-inflammatory cytokine markers with subjective measures of sleep quality, psychological variables and alcohol consumption among individuals with AUD. Methods: This exploratory study is comprised of individuals with AUD (n = 50) and healthy volunteers (n = 14). Spearman correlation was used to investigate correlations between plasma cytokine levels and clinical variables of interest (liver and inflammatory markers, sleep quality, patient reported anxiety/depression scores, and presence of mood and/or anxiety disorders (DSM IV/5); and history of alcohol use variables. Results: The AUD group was significantly older, with poorer sleep quality, higher anxiety/depression scores, and higher average drinks per day as compared to controls. Within the AUD group, IL-8 and MCP-1 had positive significant correlations with sleep, anxiety, depression and drinking variables. Specifically, higher levels of MCP-1 were associated with poorer sleep (p = 0.004), higher scores of anxiety (p = 0.006) and depression (p < 0.001), and higher number of drinking days (p = 0.002), average drinks per day (p < 0.001), heavy drinking days (p < 0.001) and total number of drinks (p < 0.001). The multiple linear regression model for MCP-1 showed that after controlling for sleep status and heavy drinking days, older participants (p = 0.003) with more drinks per day (p = 0.016), and higher alkaline phosphatase level (p = 0.001) had higher MCP-1 level. Conclusion: This exploratory analysis revealed associations with cytokines MCP-1 and IL-8 and drinking consumption, sleep quality, and anxiety and depression in the AUD group. Furthermore, inflammatory and liver markers were highly correlated with certain pro-inflammatory cytokines in the AUD group suggesting a possible relationship between chronic alcohol use and inflammation. These associations may contribute to prolonged inflammatory responses and potentially higher risk of co-morbid chronic diseases.

Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use.

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system is involved in mechanisms underlying alcohol seeking and consumption. Accordingly, the GLP-1 receptor (GLP-1R) has begun to be studied as a potential pharmacotherapeutic target for alcohol use disorder (AUD). The aim of this study was to investigate the association between genetic variation at the GLP-1R and brain functional connectivity, according to the severity of alcohol use. Participants were 181 individuals categorized as high-risk (n = 96) and low-risk (n = 85) alcohol use, according to their AUD identification test (AUDIT) score. Two uncommon single nucleotide polymorphisms (SNPs), rs6923761 and rs1042044, were selected a priori for this study because they encode amino-acid substitutions with putative functional consequences on GLP-1R activity. Genotype groups were based on the presence of the variant allele for each of the two GLP-1R SNPs of interest [rs6923761: AA + AG (n = 65), GG (n = 116); rs1042044: AA + AC (n = 114), CC (n = 67)]. Resting-state functional MRI data were acquired for 10 min and independent component (IC) analysis was conducted. Multivariate analyses of covariance (MANCOVA) examined the interaction between GLP-1R genotype group and AUDIT group on within- and between-network connectivity. For rs6923761, three ICs showed significant genotype × AUDIT interaction effects on within-network connectivity: two were mapped onto the anterior salience network and one was mapped onto the visuospatial network. For rs1042044, four ICs showed significant interaction effects on within-network connectivity: three were mapped onto the dorsal default mode network and one was mapped onto the basal ganglia network. For both SNPs, post-hoc analyses showed that in the group carrying the variant allele, high versus low AUDIT was associated with stronger within-network connectivity. No significant effects on between-network connectivity were found. In conclusion, genetic variation at the GLP-1R was differentially associated with brain functional connectivity in individuals with low versus high severity of alcohol use. Significant findings in the salience and default mode networks are particularly relevant, given their role in the neurobiology of AUD and addictive behaviors.

Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis.

(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21−65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.

Central nervous system monoamine metabolite response to alcohol exposure is associated with future alcohol intake in a nonhuman primate model (Macaca mulatta).

It is widely held that the central monoamine neurotransmitters modulate alcohol intake. Few studies, however, directly assess the relationship between baseline and alcohol-induced monoamine turnover, as well as the change from baseline, as predictors of alcohol intake. Using a nonhuman primate model, this study investigates baseline, alcohol-induced and alcohol-induced change in monoamine activity and their relationship with alcohol intake. Alcohol-naïve, adolescent rhesus macaques (Macaca mulatta, N = 114) were administered a standardized intravenous bolus of alcohol solution (16.8%, v/v) on two occasions, approximately 1 month apart. One month prior to and 1 h following each alcohol infusion, cisternal cerebrospinal fluid (CSF) was obtained and assayed for monoamine metabolite concentrations. Approximately 6-7 months later, subjects were allowed unfettered access to an aspartame-sweetened alcohol solution (8.4%, v/v) for 1 h/day, 5 days/week, over 5-7 weeks. Results showed strong positive correlations between baseline and post-infusion CSF monoamine metabolite concentrations, indicating a trait-like response. Low baseline and post-infusion serotonin and dopamine metabolite concentrations and a smaller change in serotonin and dopamine metabolites from one infusion to the next were associated with higher alcohol intake. Low baseline and post-infusion norepinephrine metabolite concentrations predicted high alcohol intake, but unlike the other monoamines, a greater change in norepinephrine metabolite concentrations from one infusion to the next was associated with higher alcohol intake. These findings suggest that individual differences in naturally occurring and alcohol-induced monoamine activity, as well as the change between exposures, are important modulators of initial alcohol consumption and may play a role in the risk for excessive alcohol intake.

Variation in the Mu-Opioid Receptor (OPRM1) and Offspring Sex Are Associated With Maternal Behavior in Rhesus Macaques (Macaca mulatta).

A µ-opioid receptor (OPRM1) single-nucleotide-polymorphism, found in both humans and rhesus macaques mediates the mother-infant attachment bond. Because mothers treat their sons and daughters differently, it is somewhat surprising that the role of infant sex has not been assessed in the context of a maternal-OPRM1-genotype-by-infant-sex interaction. The present study investigates the effect of maternal-OPRM1-genotype and infant sex on mother-infant behaviors. Over the first 6 months of offspring life, mother-infant behavioral data assessing attachment quality was collected twice weekly from a large number of rhesus monkey mother-infant pairs (N = 161 dyads; n = 64 female infants, n = 97 male infants). Mothers were genotyped for OPRM1 variation. Factor analysis of the observed behaviors showed two factors: Attachment (maternal-infant cradling, rejections, and infant approaches and leaves), and Maternal Restraints (mother restrains infant, preventing exploration). Further analyses showed a two-way, maternal-genotype-by-infant-sex interaction for both factors. For Attachment, mothers with the CC genotype cradled and restrained (Maternal Restraints) their female infants more and rejected them less, when compared to female infants of CG mothers. Perhaps as a consequence, female infants of CC genotype mothers approached and left their mothers less often, when compared to female infants of CG mothers, likely an indication that female infants from mothers with CG genotype play a greater role in maintaining the mother-infant bond than do female infants from CC genotype mothers. This finding may also indicate a more secure attachment in infants from CC genotype mothers. Unlike female infants, on average, the mother-infant relationship of dyads with a male infant was largely undifferentiated by maternal genotype. These findings suggest that, in contrast to female infants from CG mothers, CC mothers and their female infants appear to have a closer mother-infant relationship which may portend close life-long bonds, as mothers and female offspring remain together throughout life. Male offspring appear to have a more aloof mother-infant bond regardless of OPRM1-genotype. The results of this study indicate that maternal-OPRM1 variation mediates mother-infant attachment behaviors for female infants and has less effect for male infants. This suggests that offspring sex should be included in studies investigating the effect of maternal-OPRM1 genotype on the mother-infant attachment relationship.