Examining the moderating role of cannabis use on the relationship between alcohol consumption and inflammation in individuals with alcohol use disorder.

Inflammation appears to be a critical mechanism in the development of alcohol use disorder (AUD) and a consequence of chronic alcohol use. The potential anti-inflammatory properties of cannabis may modulate the proinflammatory effects of alcohol. This study sought to extend previous work investigating the relationship between alcohol consumption, cannabis use and circulating interleukin (IL)-6 levels in a sample with AUD. One hundred and thirty-three individuals with an AUD provided blood samples to assess IL-6 and answered questions regarding alcohol and cannabis use. An ordinary least squares multiple regression analysis was conducted to assess the effect of alcohol and cannabis use on IL-6. A moderation analysis examined cannabis use as a potential moderator of the relationship between alcohol use and circulating IL-6 levels. Alcohol use was predictive of higher log IL-6 levels (standardized ß = 0.16, p = 0.03), while cannabis use was not predictive of log IL-6 levels (p = 0.36). Days of cannabis use moderated the relationship between alcohol use and IL-6 levels, such that the relationship between alcohol use and IL-6 levels was only significant in individuals with AUD without recent cannabis use. This study extends previous work to a clinical sample with an AUD and underscores the importance of considering cannabis use in studies on alcohol use and inflammation. This study also indicates the need for in-depth analyses on cannabinoids and inflammation and the interaction between cannabinoids and alcohol use on inflammation.

Characterizing reward and relief/habit drinking profiles in a study of naltrexone, varenicline, and placebo.

INTRODUCTION: This study aims to clarify differences in mood, craving, and treatment response between reward and relief/habit individuals in a study of naltrexone, varenicline, and placebo. We hypothesized that relief/habit individuals would have a poorer mood during early abstinence and higher levels of alcohol craving than reward individuals. We hypothesized that reward individuals would demonstrate better drinking outcomes on naltrexone versus placebo. METHODS: Data were culled from a randomized, double-blind, placebo-controlled human trial of 53 individuals (18F/16M) with alcohol use disorder randomized to varenicline (n = 19), naltrexone (n = 15), or matched placebo (n = 19). In this 6-day practice quit trial, participants attempted to abstain from drinking and completed daily diaries. Participants were classified into reward or relief/habit subgroups based on self-reported motivation for drinking. Multilinear models tested differences in mood and alcohol craving between reward and relief/habit individuals. General linear models tested differences between reward and relief/habit individuals' drinking outcomes on each medication versus placebo. RESULTS: Relief/habit individuals showed decreases in positive mood and increases in negative mood over the quit attempt across medications, compared to reward individuals (P's < .05). Reward individuals' tension decreased on naltrexone, while relief/habit individuals' tension remained stable (F = 3.64, P = .03). Reward individuals in the placebo group had higher percent days abstinent than relief individuals in the placebo group (P < .001). DISCUSSION: This study suggests relief/habit individuals' mood worsens during early abstinence. Our finding that reward individuals' tension decreased on naltrexone and increased on placebo may suggest a clinical response to the medication.

Endpoints for Pharmacotherapy Trials for Alcohol Use Disorder.

Alcohol use disorder (AUD) is a debilitating disorder, yet currently approved pharmacotherapies to treat AUD are under-utilized. The three medications approved by the US Food and Drug Administration (FDA) for the indication of AUD are disulfiram, acamprosate, and naltrexone. The current landscape of pharmacotherapies for AUD suggests opportunities for improvement. Clinical trials investigating novel pharmacotherapies for AUD traditionally use abstinence-based drinking outcomes or no heavy drinking days as trial endpoints to determine the efficacy of pharmacotherapies. These outcomes are typically measured through patient self-report endorsements of their drinking. Apart from these traditional outcomes, there have been recent developments in novel endpoints for AUD pharmacotherapies. These novel endpoints include utilizing the World Health Organization (WHO) risk drinking level reductions to promote a harm-reduction endpoint rather than an abstinence-based endpoint. Additionally, in contrast to patient self-report measurements, biological markers of alcohol use may serve as objective endpoints in AUD pharmacotherapy trials. Lastly, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from AUD and patient-oriented outcomes offer new frameworks to consider endpoints associated with more than alcohol consumption itself, such as the provider-patient experiences with novel pharmacotherapies. These recent developments in new endpoints for AUD pharmacotherapies offer promising future opportunities for pharmacotherapy development, so long as validity and reliability measures are demonstrated for the endpoints. A greater breadth of endpoint utilization may better capture the complexity of AUD symptomatology.

Novel medications for problematic alcohol use.

Alcohol-related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral pathology, low-intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol-related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.

Early life stress is associated with greater negative emotionality and peripheral inflammation in alcohol use disorder.

Early life stress (ELS) increases risk for psychiatric illness, including alcohol use disorder (AUD). Researchers have hypothesized that individuals with and without a history of ELS who have the same primary DSM-5 diagnosis are clinically and biologically distinct. While there is strong support for this hypothesis in the context of mood disorders, the hypothesis remains largely untested in the context of AUD. This study investigated the impact of ELS on the neuroclinical phenomenology and inflammatory profile of individuals with AUD. Treatment-seeking adults with AUD (N = 163) completed the Adverse Childhood Experiences (ACE) Questionnaire and phenotypic battery as part of a pharmacotherapy trial for AUD (NCT03594435). Participants were classified as having "no-ELS," (ACE = 0) "moderate-ELS," (ACE = 1, 2 or 3) or "high-ELS" (ACE = 4 + ). The Addictions Neuroclinical Assessment domains incentive salience and negative emotionality were derived and used to assess the neuroclinical phenomenology of AUD. We tested (1) cumulative ELS as a predictor of ANA domains and (2) ELS group differences in ANA domains. A subset of participants (N = 98) provided blood samples for a biomarker of peripheral inflammation (C-reactive protein; CRP); analyses were repeated with CRP as the outcome variable. Greater ELS predicted higher negative emotionality and elevated CRP, but not incentive salience. The high-ELS group exhibited greater negative emotionality compared with the no-ELS and moderate-ELS groups, with no difference between the latter two groups. The high-ELS group exhibited elevated CRP compared with the no/moderate-ELS group. Findings suggest that high-ELS exposure is associated with a unique AUD neuroclinical presentation marked by greater negative emotionality, and inflammatory profile characterized by elevated peripheral CRP.

The gut microbiome in alcohol use disorder and alcohol-associated liver disease: A systematic review of clinical studies.

Evidence suggests that a relationship exists between the gut microbiome and the pathogenesis of alcohol use disorder (AUD) and alcohol-associated liver disease (AALD). This systematic review identified studies that investigated the gut microbiome in individuals with an AUD or an AALD. A search was conducted on October 27, 2022, in PubMed, Web of Science, and Embase databases. Fifty studies satisfied eligibility criteria. Most studies found evidence for gut dysbiosis in individuals with AUD and AALD. Microbiome intervention studies have mostly been conducted in AALD patients; fecal microbial transplant interventions show the most promise. Because most studies were conducted cross-sectionally, the causal relationship between the gut microbiome and alcohol use is unknown. Furthermore, almost all studies have been conducted in predominantly male populations, leaving critical questions regarding sex differences and generalizability of the findings. The study summaries and recommendations provided in this review seek to identify areas for further research and to highlight potential gut microbial interventions for treating AUD and AALD.

Reward, relief, and habit drinking profiles in treatment seeking individuals with an AUD.

AIMS: This study aimed to compare reward, relief, and habit treatment-seeking individuals on recent drinking, alcohol use disorder (AUD) phenomenology, and mood. The second aim of the study was to evaluate the predictive validity of reward, relief, and habit profiles. METHOD: Treatment-seeking individuals with an AUD (n = 169) were recruited to participate in a medication trial for AUD (NCT03594435). Reward, relief, and habit drinking groups were assessed using the UCLA Reward Relief Habit Drinking Scale. Group differences at baseline were evaluated using univariate analyses of variance. A subset of participants were enrolled in a 12-week, double-blind, placebo-controlled medication trial (n = 102), and provided longitudinal drinking and phenomenology data. The predictive validity of group membership was assessed using linear regression analyses. RESULTS: At baseline, individuals who drink primarily for relief had higher craving and negative mood than those who drink for reward and habit. Prospectively, membership in the relief drinking group predicted greater alcohol use, greater heavy drinking, and fewer days abstinent compared to those in the reward drinking group. Membership in the relief drinking group also predicted greater alcohol craving, more alcohol-related consequences, and more anxiety symptoms over 12 weeks compared to those in the reward drinking group. CONCLUSIONS: This study provides support for reward and relief drinking motive profiles in treatment-seeking individuals with an AUD. Membership in the relief drinking motive group was predictive of poorer drinking outcomes and more negative symptomology over 12 weeks, indicating that individuals who drink for relief may be a particularly vulnerable sub-population of individuals with AUD.

Sex differences in neural response to an acute stressor in individuals with an alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) and stress influence overlapping neural circuits in the brain. The literature is mixed regarding the presence of sex differences in the neural response to acute stressors, and this issue has not been examined in individuals with AUD. We validated a stress functional magnetic resonance imaging (fMRI) paradigm in individuals with AUD and tested for sex differences. METHODS: Twenty-five treatment-seeking individuals with AUD (15M/10F) were recruited to participate in the neuroimaging study linked to a clinical trial of ibudilast (NCT03594435). To assess social-evaluative stress, participants completed the Montreal Imaging Stress Task (MIST). Whole brain and amygdala region-of-interest analyses were conducted. Subjective ratings of anxiety and distress were collected. Repeated measures ANCOVAs were performed to evaluate the effect of stress on anxiety and distress and to evaluate sex differences. RESULTS: There were trend-level effects of stress on anxiety ratings and amygdala activation (p's = 0.06). There was a significant effect of stress in the bilateral thalamus, ventral tegmental area, and paracingulate (Z's > 4.09, p's < 0.03). There was a trend-level effect of sex on subjective ratings of stress (p's = 0.07). Females had higher amygdala activation in response to stress (p = 0.02). Females also had greater activation than males in the precuneus, posterior cingulate cortex, and right inferior frontal gyrus during acute stress (Z's > 3.56, p's < 0.03). CONCLUSIONS: This study provides an initial validation of the MIST in a sample of individuals with AUD. It also provides preliminary evidence of sex differences in the response to social-evaluative stress, which is important, given the relevance of stress and negative emotionality as motivators for alcohol use in females.

Leveraging meta-regression to test if medication effects on cue-induced craving are associated with clinical efficacy.

RATIONALE: The alcohol cue exposure paradigm is a common method for evaluating new treatments for alcohol use disorder (AUD); however, it is unclear if medication-related reductions in cue-induced craving in the human laboratory can predict the clinical success of those medications in reducing alcohol consumption during clinical trials. OBJECTIVES: To use a novel meta-analytic approach to test whether medication effect sizes on cue-induced alcohol craving are associated with clinical efficacy in clinical trials. METHOD: We searched the literature for medications tested for AUD treatment using both the alcohol cue-reactivity paradigm and randomized clinical trials (RCTs). For alcohol cue-reactivity studies, we computed medication effect sizes for cue-induced alcohol craving (k = 36 studies, 15 medications). For RCTs, we calculated medication effect sizes for heavy drinking and abstinence (k = 139 studies, 19 medications). Using medication as the unit of analysis, we applied the Williamson-York bivariate weighted least squares estimation to account for errors in both independent and dependent variables. We also conducted leave-one-out cross validation simulations to examine the predictive utility of cue-craving medication effect sizes on RCT heavy drinking and abstinence endpoints. RESULTS: There was no significant relationship between medication effects on cue-induced alcohol craving in the human laboratory and medication effects on heavy drinking ( ß ^ = 0.253, SE = 0.189, p = 0.090) and abstinence ( ß ^ = 0.829, SE = 0.747, p = 0.133) in RCTs. CONCLUSIONS: The preliminary results of the current study challenge the assumption that alcohol cue-reactivity alone can be used as an early efficacy indicator for AUD pharmacotherapy development. These findings suggest that a wider range of early efficacy indicators and experimental paradigms be considered for Phase II testing of novel compounds.

Characterizing alcohol cue reactive and non-reactive individuals with alcohol use disorder.

PURPOSE: Exposure to alcohol-related cues is thought to elicit a conditional response characterized by increased craving in individuals with alcohol use disorder (AUD). In the context of AUD research, it is important to consider that not all individuals with an AUD are alcohol cue reactive. This study systematically examined subjective alcohol cue reactivity and its clinical and drinking correlates in individuals with an AUD enrolled in a human laboratory pharmacotherapy trial. METHODS: Individuals with current moderate-to-severe AUD (N = 52) completed a standard alcohol cue exposure paradigm and individual difference assessments as part of a human laboratory pharmacotherapy trial (NCT04249882). We classified participants as cue reactive (CR+) and cue non-reactive (CR-), as indicated by self-reported, subjective alcohol urge, and examined group differences in baseline clinical characteristics and drinking outcomes over the course of the trial. RESULTS: Twenty participants (38%) were identified as CR+, while 32 participants (62%) were identified as CR-. The CR+ and CR- groups did not differ in baseline drinking and AUD clinical characteristics, but the groups differed in race composition (p = 0.02) and smoking prevalence (p = 0.04) such that the CR+ group had lower prevalence of smokers. The CR+, compared with the CR-, group drank more during the trial titration period (p = 0.03). Both groups reduced drinking across the trial (p's < 0.001), but the CR+ group exhibited a smaller reduction in drinking, compared with the CR- group (time x group, p = 0.029; CR-, p < 0.0001; CR+: p = 0.01). CONCLUSION: Results indicate that cue reactivity is a heterogenous construct. Recognizing this heterogeneity, and the clinical factors associated with it, is critical to advancing this paradigm as an early efficacy marker in AUD research.

Neural correlates of the addictions neuroclinical assessment (ANA) incentive salience factor among individuals with alcohol use disorder.

The Addictions Neuroclinical Assessment (ANA) is a recently-developed framework offering a more holistic understanding of three neurofunctional and behavioral domains that reflect the neurobiological dysfunction seen in alcohol use disorder (AUD). While the ANA domains have been well-validated across independent laboratories, there is a critical need to identify neural markers that subserve the proposed neurofunctional domains. The current study involves secondary data analysis of a two-week experimental medication trial of ibudilast (50 mg BID). Forty-five non-treatment-seeking participants with AUD (17F / 28 M) completed a battery of validated behavioral assessments forming the basis of their incentive salience factor score, computed via factor analysis, as well as a functional neuroimaging (fMRI) task assessing their neural reactivity to visual alcohol cues after being on placebo or ibudilast for 7 days. General linear models were conducted to examine the relationship between incentive salience and neural alcohol cue-reactivity in the ventral and dorsal stratum. Whole-brain generalized linear model analyses were conducted to examine associations between neural alcohol cue-reactivity and incentive salience. Age, sex, medication, and smoking status were included as covariates. Incentive salience was not associated with cue-elicited activation in the dorsal or ventral striatum. Incentive salience was significantly positively correlated (p < 0.05) with alcohol cue-elicited brain activation in reward-learning and affective regions including the insula and posterior cingulate cortices, bilateral precuneus, and bilateral precentral gyri. The ANA incentive salience factor is reflected in brain circuitry important for reward learning and emotion processing. Identifying a sub-phenotype of AUD characterized by increased incentive salience to alcohol cues allows for precision medicine approaches, i.e. treatments specifically targeting craving and reward from alcohol use. This study serves as a preliminary bio-behavioral validation for the incentive salience factor of the ANA. Further studies validating the neural correlates of other ANA factors, as well as replication in larger samples, appear warranted.

Influence of sleep quality on lapse to alcohol use during a quit attempt.

AIMS: Sleep problems are common among individuals with alcohol use disorder (AUD) and is often associated with a heightened relapse risk. The present study examines the relationship between sleep and alcohol use among individuals with current AUD during a 6-day quit attempt as part of a medication study. METHODS: The current study is a secondary analysis of a medication trial for individuals with AUD. Individuals with AUD (N = 53, 26 females) were randomized to active medication or matched placebo. Randomized participants completed a week-long medication titration (Days 1-7). Following the titration period, participants attended an in-person visit (Day 8) to begin a 6-day quit attempt. During the quit attempt, participants completed daily diary assessments to report on previous day alcohol consumption, sleep quality, and alcohol craving. In the present study, medication condition was controlled for in all models. RESULTS: Baseline global sleep quality was not a significant predictor of drinks per drinking day (P = 0.72) or percent days abstinent (P = 0.16) during the 6-day practice quit attempt. Daily diary analyses found that greater sleep quality was associated with higher next-day drinks per drinking day (b = 0.198, P = 0.029). In contrast, participants reported worse sleep quality following nights of greater alcohol intake, albeit at a trend-level (b = -0.12, P = 0.053). CONCLUSIONS: These results suggest that better sleep quality was a risk factor for drinking during the 6-day quit period, such that better sleep may be associated with increased craving for alcohol and alcohol use the next day. These findings are limited to the early abstinence period and should be considered in studies exploring longer periods of abstinence.

Anterior cingulate and medial prefrontal cortex alcohol cue reactivity varies as a function of drink preference in alcohol use disorder.

BACKGROUND: Functional MRI visual cue reactivity studies have not considered that brain responses to various alcohol-containing beverage types may vary as a function of an individual's drinking patterns and preferences. This study tested whether the brain's reward system responds differently to visual cues associated with an individuals' most commonly consumed ("preferred") alcohol beverage compared with less commonly consumed ("non-preferred") alcohol beverages in individuals with alcohol use disorder (AUD). METHODS: Participants (N=70) with current AUD completed a standard visual alcohol cue reactivity procedure during fMRI and reported recent alcohol use through the Timeline Followback interview. Alcohol use patterns were used to infer drink preference. Repeated measure ANCOVAs were used to evaluate differences in subjective craving (alcohol urge) and neural reactivity to cues of individual's "preferred" versus "non-preferred" alcohol beverages. RESULTS: Fifty-four (77%) participants were determined to have a "preferred" alcohol beverage, as defined by their pattern of alcohol use. These participants reported greater subjective alcohol urge (p=0.02) and activation in the anterior cingulate cortex (ACC) (p=0.005) and medial prefrontal cortex (mPFC) (p=0.001)) in response to visual cues associated with their "preferred" versus "non-preferred" alcohol beverage. Individuals with an alcohol preference did not differ from those with no alcohol preference on subjective or neural responses to their "preferred" and "non-preferred" alcohol cues. DISCUSSION: Results suggest alcohol cue-elicited subjective and neural responses vary as a function of alcohol beverage preference in individuals with AUD and a behaviorally defined alcohol preference. Stronger ACC and mPFC activation may reflect greater subjective value of an individual's "preferred" alcohol beverage cue.

A practice quit model to test early efficacy of medications for alcohol use disorder in a randomized clinical trial.

RATIONALE: Screening novel medications for alcohol use disorder (AUD) requires models that are both efficient and ecologically-valid. Ideally, such models would be associated with the outcomes of a given medication in clinical trials. OBJECTIVES: To test a novel human laboratory model in which individuals with intrinsic motivation to change their drinking engage in a "practice quit" attempt consisting of 6 days of complete abstinence from alcohol. METHOD: Individuals with current AUD completed a randomized, double-blind, placebo-controlled study of naltrexone (50 mg), varenicline (2 mg bid), or matched placebo. Participants were titrated onto the study medication for 1 week prior to starting the 6-day practice quit attempt. During the practice quit attempt, participants completed daily interviews with research staff. All participants completed an alcohol cue-exposure paradigm before starting the study medication and after 2 weeks of study medication. RESULTS: There were no significant medication effect on drinks per drinking day (F(2,49) = 0.66, p = 0.52) or percent days abstinent (F(2,49) = 0.14, p = 0.87) during the 6-day practice quit period. There were no medication effects on alcohol cue-reactivity (F(2,44) = 0.80, p = 0.46). Notably, participants sharply reduced their drinking during the entire 13-day medication treatment period, as compared to reducing only during the 6-day practice quit period. During the total medication period, higher levels of motivation to change was associated with higher percent days abstinent (F(1,49) = 8.12, p < 0.01). CONCLUSIONS: This study reports mostly null findings, which challenges us to decompose its nuanced design to consider model refinements. Possible changes to the model include considering the requirement for intrinsic motivation for change, including a longer practice quit period, encompassing the medication administration timeframe in the practice quit period, increasing the required sample size for signal detection, and examining a post COVID-19 pandemic cohort.

Implementation of Specialty Tobacco Use Disorder Services in a Community Health Setting: Support for Enhanced Prescription Practices.

OBJECTIVES: Although public efforts to reduce tobacco use have been successful, millions of US adults currently smoke tobacco. Reducing the public health burden of tobacco use disorder (TUD) and eliminating disparities experienced by underresourced communities requires increased accessibility to services. The goal of this study was to assess whether prescriptions for evidence-based medications for tobacco treatment showed steeper growth rates among community health clinics providing specialty TUD services as compared with treatment as usual. METHODS: Clinic-wide data on prescriptions for smoking cessation pharmacotherapy at 18 primary care or mental health community clinics operated by Los Angeles County were retrieved for 4 years of an ongoing implementation trial. Specialty services included behavioral counseling and medications for tobacco treatment. Descriptive statistics characterized prescriptions rates across clinics and time. Analyses compared the slopes of the changes between intervention groups across time for primary care and mental health sites. RESULTS: Within primary care clinics, the most commonly prescribed smoking cessation medications were nicotine patches, nicotine gum, and varenicline. Throughout the trial, all clinics displayed increased rates of prescribing smoking cessation medications. Analytic results supported overall steeper increases in prescription rates for these medications among clinics randomized to specialty services versus treatment as usual within primary care ( P = 0.020) and mental health sites ( P = 0.004). CONCLUSIONS: This work provides support for the effectiveness of community-based implementation interventions that promote prescribing smoking cessation medications with the potential to reduce health disparities among communities at greater risk for TUD and its consequences.

Neurobiology and the Treatment of Alcohol Use Disorder: A Review of the Evidence Base.

Alcohol use disorder (AUD) is a significant public health concern, accounting for a majority of substance use disorder cases in the United States. Treatment for AUD is complex, with multiple intervention points that may be further complicated by genotype and phenotype, resulting in diverse outcomes. In order to better understand the current landscape of AUD treatment, the present review considers different etiological models of AUD and assesses the evidence base of current treatment options. The first section of this review summarizes various etiological models of AUD and presents different approaches to classifying the disorder. Various theories, including neurobiological models, are discussed. The second section presents a comprehensive analysis of available treatment options for AUD, encompassing behavioral and pharmacological interventions and their current evidence base. Finally, this review discusses the ongoing treatment gap and significant factors contributing to low treatment utilization. Together, this review provides an overview of different etiological processes and mechanisms of AUD, as well as summarizes the literature on key treatment approaches. By integrating historical, theoretical, and empirical data, this review aims to inform both researchers and providers with valuable insights to advance AUD treatment approaches and narrow the treatment gap.

Alcohol use disorder (AUD) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge.

BACKGROUND: Inflammation has been associated with alcohol use disorder (AUD). A novel method to characterize AUD-related immune signaling involves probing Toll-like receptor (TLR)-4 stimulated monocyte production of intracellular cytokines (ICCs) via lipopolysaccharide (LPS). We evaluated relationships between AUD and ICC production at rest and after LPS stimulation. METHODS: We analyzed blood samples from 36 participants (AUD N = 14; Controls N = 22), collected across time, with ICC expression assessed at rest (i.e., unstimulated) and following stimulation with LPS (i.e., a total of 5 repeated unstimulated or stimulated measures/participant). Markers assessed included tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), TNF-α and IL-6 co-expression, and interferon (IFN). For each marker, we constructed linear mixed models with AUD, LPS, and timepoint as fixed effects (BMI as covariate), allowing for random slope and intercept. AUD × LPS was included as an interaction. RESULTS: For TLR4-stimulated monocyte production of TNF-α, there were effects of AUD (p < 0.01), LPS (p < 0.001), and AUD × LPS interaction (p < 0.05), indicating that individuals with AUD showed greater unstimulated- and stimulated monocyte expression of TNF-α. Similarly, for TLR4-stimulated monocyte co-expression of TNF-α and IL-6, there were effects of AUD (p < 0.01), LPS (p < 0.001), and AUD × LPS interaction (p < 0.05). No AUD or LPS effects were found for IL-6. Timepoint effects were observed on IL-6 and TNF-α/IL-6 co-expression (p < 0.001). Finally, for IFN there were also effects of AUD (p < 0.05), LPS (p < 0.001), and AUD × LPS (p < 0.001). CONCLUSIONS: Individuals with AUD showed greater resting or unstimulated levels of intracellular monocyte expression of TNF-α and IL-6/TNF-α co-expression than controls. AUD was associated with increases in TLR4-stimulated monocyte production of TNF-α and co-production of IL-6 and TNF-α. This is, to our knowledge, the first study to investigate relationships between AUD and monocyte production of proinflammatory cytokines, at rest and in response to TLR4 stimulation with LPS. The study extends previous findings on the roles of proinflammatory cytokines in AUD and serves as a critical proof of concept for the use of this method to probe neuroimmune mechanisms underlying AUD.

Testing pharmacotherapies for alcohol use disorder with cue exposure paradigms: A systematic review and quantitative synthesis of human laboratory trial methodology.

Alcohol cue exposure is a widely used experimental paradigm for screening pharmacotherapies for alcohol use disorder (AUD). Medication-related reductions in cue-reactivity signal early efficacy and inform medications development. Yet, across trials, the design of cue exposure, parameter testing, and outcome reporting is heterogeneous. This systematic review is a quantitative synthesis of trial methodologies and effect size estimation for AUD medication-related craving and psychophysiological outcomes under the cue exposure paradigm. A PubMed search was conducted on January 3, 2022 based on identified pharmacotherapies for peer-reviewed articles reported in English. Study-level characteristics, including sample descriptors, paradigm design, analytic approach, and Cochrane Risk of Bias, along with descriptive statistics for cue-exposure outcomes, were coded by two independent raters. Study-level effect sizes were estimated for craving and psychophysiological outcomes separately and sample-level effect sizes were calculated for each medication. Thirty-six trials, comprising 1640 participants and testing 19 different medications satisfied eligibility criteria. All studies reported on biological sex (71% male participants on average). The exposure paradigms implemented used in vivo (n = 26), visual (n = 8), and audio script (n = 2) cues. Some trials included means for craving by medication condition in text (k = 7) or figures (k = 18). The quantitative synthesis included 63 effect sizes (craving kes = 47; psychophysiological kes = 16) from 28 unique randomized trials testing 15 medications for effects on cue reactivity. For cue-induced craving, eight medications (kes range: 1-12) demonstrated small-to-medium effects (Cohen's d range: |0.24-0.64|) compared to placebo, with individuals randomized to receive medication reporting lower craving following cue exposure. Recommendations are provided to promote further consilience, so that the utility of cue exposure paradigms can be maximized in the development of effective AUD pharmacotherapies. Future work should explore the predictive utility of medication-related reductions in cue-reactivity on clinical outcomes.