Imaging the brain's immune response to alcohol with [11C]PBR28 TSPO Positron Emission Tomography.

In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [11C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Participants (n = 12; 5 F; 25-45 years) who reported consuming binge levels of alcohol (>3 drinks for females; >4 drinks for males) 1-3 months before scan day were enrolled. Imaging featured a baseline [11C]PBR28 scan followed by an oral laboratory alcohol challenge over 90 min. An hour later, a second [11C]PBR28 scan was acquired. Dynamic PET data were acquired for at least 90 min with arterial blood sampling to measure the metabolite-corrected input function. [11C]PBR28 volume of distributions (VT) was estimated in the brain using multilinear analysis 1. Subjective effects, blood alcohol levels (BAL), and plasma cytokines were measured during the paradigm. Full completion of the alcohol challenge and data acquisition occurred for n = 8 (2 F) participants. Mean peak BAL was 101 ± 15 mg/dL. Alcohol significantly increased brain [11C]PBR28 VT (n = 8; F(1,49) = 34.72, p > 0.0001; Cohen's d'=0.8-1.7) throughout brain by 9-16%. Alcohol significantly altered plasma cytokines TNF-α (F(2,22) = 17.49, p < 0.0001), IL-6 (F(2,22) = 18.00, p > 0.0001), and MCP-1 (F(2,22) = 7.02, p = 0.004). Exploratory analyses identified a negative association between the subjective degree of alcohol intoxication and changes in [11C]PBR28 VT. These findings provide, to our knowledge, the first in vivo human evidence for an acute brain immune response to alcohol.

Words matter: descriptors for nicotine that comes from tobacco and descriptors for synthetic nicotine that is created in a laboratory differentially impact understanding of nicotine source and risk perceptions.

BACKGROUND: Nicotine products increasingly contain synthetic nicotine made in a lab (NML), not from tobacco. 'Tobacco-free nicotine' is most often used to describe NML commercially, but other descriptors are emerging (eg, 'non-tobacco,' 'zero-tobacco'). We examined whether terms for NML differentially impact public understanding of nicotine source or risk perceptions relative to each other and to terms for describing nicotine from tobacco (NFT) as 'tobacco-derived.' METHODS: From December 2022 to April 2023, 1000 participants aged 13 and older completed an online survey (mean age: 33.02 (SD=18.15) years, 50.5% female, 16.6% Hispanic, 67.4% White and 79.8% with current tobacco use). Participants read 11 terms describing nicotine and reported on perceived nicotine source (ie, NML, NFT) and addictiveness. Rank-ordered harm was included as a sensitivity analysis. RESULTS: Significant differences were observed among terms (eg, 'zero tobacco nicotine' and 'no tobacco nicotine' were rated as least addictive overall). 'NML' and 'NFT' adequately conveyed nicotine source and were rated as conveying comparable, yet high addictiveness, making them the optimal terms. CONCLUSIONS: Many terms for NML and NFT are differentially related to understanding nicotine source and risk perceptions even though no existing research indicates that NML and NFT differ meaningfully from each other on characteristics like addictiveness. In the absence of prohibiting product differentiation by nicotine source, regulatory agencies should promote using the terms 'Nicotine from Tobacco' and 'Nicotine Made in a Lab' and investigate whether products using descriptors conveying reduced harm (eg, 'zero-tobacco,' 'no-tobacco,' 'non-tobacco') should require review as Modified Risk Tobacco Products.

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder.

AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

The Scientific Basis for the Regulation of Flavors in Tobacco Products.

Effective tobacco policies are important for reducing the harm of tobacco use and can have a broad impact at the population level. This review provides an overview of how clinical science can inform tobacco policies with a focus on policies related to flavored tobacco products, using menthol cigarettes as an illustrative example. Specifically, this review summarizes the role of flavors in tobacco use and the history of regulation of flavored tobacco products by the US Food and Drug Administration (FDA), provides an overview of clinical research methods used to contribute to the scientific evidence to inform FDA tobacco policies, discusses key findings related to menthol tobacco products using these methods, and proposes future directions for clinical research. As the tobacco marketplace continues to evolve with new products and flavor chemicals, ongoing clinical science will be essential for establishing evidence-based policies to protect public health and reduce tobacco-related health disparities.

Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving.

The efficacy of naltrexone to treat alcohol use disorder (AUD) is modest. A better understanding of the neurobiology underlying naltrexone effects could optimize treatments. We evaluated the occupancy of the kappa opioid receptor (KOR) by naltrexone measured with [11C]-LY2795050 positron emission tomography (PET) as a predictor of response to naltrexone. Response to naltrexone was defined as the difference in craving and the difference between the number of drinks consumed during an alcohol drinking paradigm (ADP) before and after 1 week of supervised 100 mg daily oral naltrexone. Forty-four (14 F) nontreatment seeking heavy drinkers meeting criteria for AUD were enrolled. Participants drank 47 ± 16 drinks per week and were balanced in family history of alcoholism (FH, 26 positive). High KOR occupancy (92 ± 1%) was achieved. Occupancy was negatively associated with number of years drinking (YOD) in FH positive, but not FH negative, participants (t3,42 = 4.00, p = 0.0003). Higher KOR occupancy by naltrexone was associated with higher alcohol craving during the ADP (F1,81 = 4.88, p = 0.030). The reduction in drinking after naltrexone was negatively associated with KOR occupancy, with significant effects of FH status (t1,43 = -2.08, p = 0.044). A logistic regression model including KOR occupancy, YOD, and FH variables achieved an 84% prediction accuracy for ≥50% reduction in drinking. These results confirm that naltrexone binds at the KOR site and suggest that KOR occupancy by naltrexone may be related to clinical response. Based on our results, we propose that differential affinities for the mu and KOR could explain why lower doses of naltrexone can have greater clinical efficacy.

Differences in the association between kappa opioid receptors and pain among Black and White adults with alcohol use disorders.

BACKGROUND: The relationship between alcohol and pain is complex. Associations between pain and alcohol use disorder (AUD) vary by race, but the underlying biological basis is not understood. We examined the association of the kappa opioid receptor (KOR) with responses to the cold-pressor test (CPT), before and after treatment with the opioid antagonist naltrexone, among individuals with AUD who self-identified as Black or White. METHODS: Thirty-seven individuals (12 Black, 24 White, and 1 Multiracial) with AUD participated in two CPTs, separated by 1 week during which they received naltrexone 100 mg daily. During each CPT, pain reporting threshold (PRT), average pain increase rate (APIR), relative pain recovery (RPR), and alcohol craving were recorded. KOR availability was measured using [11 C]-LY2795050 positron emission tomography (PET) prior to treatment with naltrexone. RESULTS: Black participants reported higher PRT and APIR than White participants during the CPT before, but not after, naltrexone treatment. Among Black participants, KOR availability was positively associated with PRT and APIR before, but not after naltrexone. Greater KOR availability was associated with faster RPR for White, but not Black, participants. The CPT induced more alcohol craving in Black than White participants, particularly in individuals with low KOR availability, an effect that was not attenuated by naltrexone. CONCLUSIONS: KOR involvement and naltrexone effects on responses to the CPT were different between Black and White participants. These preliminary findings suggest that further exploration of the differences in the opioid system and pain among Black and White individuals with AUD and their relationship with naltrexone's effects is warranted.

Combination treatment with varenicline and naltrexone reduces World Health Organization risk drinking levels.

BACKGROUND: The U.S. Food and Drug Administration identifies abstinence and the absence of heavy drinking days as outcomes for pharmacotherapy trials for alcohol use disorder (AUD). However, many individuals with AUD struggle to achieve these outcomes, which may discourage them from seeking treatment. World Health Organization (WHO) risk drinking levels have garnered attention in the alcohol field as potential non-abstinent outcomes for AUD medication trials. Further, testing combination pharmacotherapy for AUD represents an important direction in the field, particularly using medications such as naltrexone and varenicline, which are approved for treating AUD and smoking, respectively. The objective of the current study was to test the utility of the WHO risk drinking levels as a drinking outcome in a randomized clinical trial of combined varenicline and naltrexone for smoking cessation and drinking reduction. These analyses provide additional tests of the efficacy of this combination treatment. METHODS: The current study is a secondary analysis of a phase 2, randomized, double-blind clinical trial, wherein participants (N = 165) who were daily smokers and heavy drinkers were randomly assigned to receive either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus placebo for 12 weeks. Medication effects on 1- and 2-level reductions in WHO risk drinking levels were assessed at 4, 8, and 12 weeks into the active medication period. RESULTS: In logistic growth curve models individuals receiving the combined treatment had greater reductions in WHO risk drinking levels than individuals taking varenicline alone when assessed at 4 weeks into the active medication period. Among individuals who were WHO high and very high risk drinkers at baseline, the largest effect sizes favoring combination treatment were at Week 4 for the WHO 2-level reduction outcome (Cohen's h = 0.202) and Week 12 for the WHO 1-level reduction outcome (Cohen's h = 0.244), although these effects did not reach statistical significance. CONCLUSIONS: These findings provide evidence that combined varenicline plus naltrexone treatment is effective at reducing WHO risk drinking levels, particularly among individuals who smoke cigarettes daily and drink heavily. These results add to a growing body of literature validating reductions in WHO risk drinking levels as outcomes of alcohol medication trials.

Predictors of abstinence, no heavy drinking days, and a 2-level reduction in World Health Organization drinking levels during treatment for alcohol use disorder in the COMBINE study.

BACKGROUND: Data from trials of medications for alcohol use disorder (AUD) can be used to identify predictors of drinking outcomes regardless of treatment, which can inform the design of future trials with heterogeneous populations. Here, we identified predictors of abstinence, no heavy drinking days, and a 2-level reduction in World Health Organization (WHO) drinking levels during treatment for AUD in the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study. METHODS: We utilized data from the COMBINE Study, a randomized placebo-controlled trial evaluating the efficacy of naltrexone and acamprosate, both alone and in combination, for AUD (n = 1168). A tree-based machine learning algorithm was used to construct classification trees predicting abstinence, no heavy drinking days, and a 2-level reduction in WHO drinking levels in the last 4 weeks of treatment, based on 89 baseline variables. RESULTS: The final tree for predicting abstinence had one split based on consecutive days abstinent prior to randomization, with a higher proportion of subjects achieving abstinence among those classified as abstinent for >2 versus ≤2 consecutive weeks prior to randomization (66% vs. 29%). The final tree for predicting no heavy drinking days in the last 4 weeks of treatment had three splits based on consecutive days abstinent, age, and total Alcohol Dependence Scale score at baseline. Seventy-three percent of the subjects classified as abstinent for >2 consecutive weeks prior to randomization had no heavy drinking days in the last 4 weeks of treatment. Among those classified as abstinent ≤2 consecutive weeks prior, three additional splits showed that younger subjects (age ≤44 years; 37%), and older subjects (age >44) with a total Alcohol Dependence Scale score >13 and complete abstinence (56%) or other drinking goals (35%), were less likely to have no heavy drinking days than older subjects with a total Alcohol Dependence Scale score ≤13 (67%). The final tree for predicting a 2-level reduction in WHO levels had no splits. CONCLUSIONS: Consecutive days abstinent prior to randomization may predict abstinence and no heavy drinking days and total Alcohol Dependence Scale score and age may predict no heavy drinking days. The 2-level reduction in WHO levels outcome may be less likely to discriminate based on multiple patient characteristics.

Within- and between-person effects of naltrexone on the subjective response to alcohol and craving: A daily diary investigation.

OBJECTIVE: Naltrexone is an effective treatment for heavy drinking among young adults. Laboratory-based studies have shown that naltrexone dampens the subjective response to alcohol and craving. However, few studies have tested naltrexone's dynamic, within-person effects on subjective response and craving among young adults in natural drinking environments. METHODS: Using daily diary data from a randomized, placebo-controlled study of naltrexone's efficacy in young adults, we examined the between-person effects of treatment condition (i.e., naltrexone vs. placebo) and medication dosage (i.e., daily, targeted, and daily + targeted) on the subjective response to alcohol and craving on drinking days. Multilevel mediation models predicted subjective response and craving from treatment condition (between-person) and medication dosage (within-person), accounting for drinking levels. All effects were disaggregated within and between persons. RESULTS: At the between-person level, naltrexone directly blunted intense subjective effects (i.e., "impaired", "drunk") and indirectly blunted subjective effects through reduced drinking. Naltrexone was not associated with craving. Between-person effects were not significant after alpha correction, but their effect sizes (bs = 0.14 to 0.17) exceeded the smallest effect size of interest. At the within-person level, taking two (vs. 1) pills was associated with heavier drinking, and taking one (vs. 0) pill was associated with lighter drinking, and lighter drinking was associated with a lower subjective response and craving. Treatment condition did not moderate the within-person effects of dosing on outcomes. CONCLUSIONS: Our findings suggest that the direct between-person effect of naltrexone was largest on intense subjective responses, blunting feelings of being "drunk" and "impaired". Future research using momentary (rather than daily) assessments could confirm and extend these findings.

Sensitivity, specificity, and tolerability of the BACTrack Skyn compared to other alcohol monitoring approaches among young adults in a field-based setting.

BACKGROUND: There is a need for novel alcohol biosensors that are accurate, able to detect alcohol concentration close in time to consumption, and feasible and acceptable for many clinical and research applications. We evaluated the field accuracy and tolerability of novel (BACTrack Skyn) and established (Alcohol Monitoring Systems SCRAM CAM) alcohol biosensors. METHODS: The sensor and diary data were collected in a larger study of a biofeedback intervention and compared observationally in the present sub-study. Participants (high-risk drinkers, 40% female; median age 21) wore both Skyn and SCRAM CAM sensors for 1-6 days and were instructed to drink as usual. Data from the first cohort of participants (N = 27; 101 person-days) were used to find threshold values of transdermal alcohol that classified each day as meeting or not meeting defined levels of drinking (heavy, above-moderate, any). These values were used to develop scoring metrics that were subsequently tested using the second cohort (N = 20; 57 person-days). Data from both biosensors were compared to mobile diary self-report to evaluate sensitivity and specificity in relation to a priori standards established in the literature. RESULTS: Skyn classification rules for Cohort #1 within 3 months of device shipment showed excellent sensitivity for heavy drinking (94%) and exceeded expectations for above-moderate and any drinking (78% and 69%, respectively), while specificity met expectations (91%). However, classification worsened when Cohort #1 devices ≥3 months from shipment were tested (area under curve for receiver operator characteristic 0.87 vs. 0.79) and the derived classification threshold when applied to Cohort #2 was inadequately specific (70%). Skyn tolerability metrics were excellent and exceeded the SCRAM CAM (p ≤ 0.001). CONCLUSIONS: Skyn tolerability was favorable and accuracy rules were internally derivable but did not yield useful scoring metrics going forward across device lots and months of usage.

Multimodal neuroimaging of metabotropic glutamate 5 receptors and functional connectivity in alcohol use disorder.

BACKGROUND: People recovering from alcohol use disorder (AUD) show altered resting brain connectivity. The metabotropic glutamate 5 (mGlu5) receptor is an important regulator of synaptic plasticity potentially linked with synchronized brain activity and a target of interest in treating AUD. The goal of this work was to assess potential relationships of brain connectivity at rest with mGlu5 receptor availability in people with AUD at two time points early in abstinence. METHODS: Forty-eight image data sets were acquired with a multimodal neuroimaging battery that included resting-state functional magnetic resonance imaging (fMRI) and mGlu5 receptor positron emission tomography (PET) with the radiotracer [18 F]FPEB. Participants with AUD (n = 14) were scanned twice, at approximately 1 and 4 weeks after beginning supervised abstinence. [18 F]FPEB PET results were published previously. Primary comparisons of fMRI outcomes were performed between the AUD group and healthy controls (HCs; n = 23) and assessed changes over time within the AUD group. Relationships between resting-state connectivity measures and mGlu5 receptor availability were explored within groups. RESULTS: Compared to HCs, global functional connectivity of the orbitofrontal cortex was higher in the AUD group at 4 weeks of abstinence (p = 0.003), while network-level functional connectivity within the default mode network (DMN) was lower (p < 0.04). Exploratory multimodal analyses showed that mGlu5 receptor availability was correlated with global connectivity across all brain regions (HCs, r = 0.41; AUD group at 1 week of abstinence, r = 0.50 and at 4 weeks, r = 0.46; all p < 0.0001). Furthermore, a component of cortical and striatal mGlu5 availability was correlated with connectivity between the DMN and salience networks in HCs (r = 0.60, p = 0.003) but not in the AUD group (p > 0.3). CONCLUSIONS: These preliminary findings of altered global and network connectivity during the first month of abstinence from drinking may reflect the loss of efficient network function, while exploratory relationships with mGlu5 receptor availability suggest a potential glutamatergic relationship with network coherence.

Stability of Drinking Reductions and Long-term Functioning Among Patients with Alcohol Use Disorder.

BACKGROUND: The World Health Organization (WHO) categorizes alcohol consumption according to grams consumed into low-, medium-, high-, and very-high-risk drinking levels (RDLs). Although abstinence has been considered the ideal outcome of alcohol treatment, reductions in WHO RDLs have been proposed as primary outcomes for alcohol use disorder (AUD) trials. OBJECTIVE: The current study examines the stability of WHO RDL reductions and the association between RDL reductions and long-term functioning for up to 3 years following treatment. DESIGN AND PARTICIPANTS: Secondary data analysis of patients with AUD enrolled in the COMBINE Study and Project MATCH, two multi-site, randomized AUD clinical trials, who were followed for up to 3 years post-treatment (COMBINE: n = 694; MATCH: n = 806). MEASURES: Alcohol use was measured via calendar-based methods. We estimated all models in the total sample and among participants who did not achieve abstinence during treatment. KEY RESULTS: One-level RDL reductions were achieved by 84% of patients at the end of treatment, with 84.9% of those individuals maintaining that reduction at a 3-year follow-up. Two-level RDL reductions were achieved by 68% of patients at the end of treatment, with 77.7% of those individuals maintaining that reduction at a 3-year follow-up. One- and two-level RDL reductions at the end of treatment were associated with significantly better mental health, quality of life (including physical quality of life), and fewer drinking consequences 3 years after treatment (p < 0.05), as compared to no change or increased drinking. CONCLUSION: AUD patients can maintain WHO RDL reductions for up to 3 years after treatment. Patients who had WHO RDL reductions functioned significantly better than those who did not reduce their drinking. These findings are consistent with prior reports suggesting that drinking reductions, short of abstinence, yield meaningful improvements in patient health, well-being, and functioning.

Mapping data-driven individualized neurobehavioral phenotypes in heavy alcohol drinkers.

OBJECTIVE: Recent studies have examined the factor structure and associated correlates of three neurofunctional domains, executive function, incentive salience, and negative emotionality in the development and maintenance of alcohol use disorders in clinical samples. The current study sought to replicate and extend prior work by testing this 3-factor model, utilizing both exact and similar phenotypic measures, as well as novel measures, in a non-treatment-seeking sample. METHODS: Self-report measures of alcohol addiction, impulsivity, behavior, and exposure to early-life stress were collected as part of baseline assessments for alcohol imaging and pharmacotherapy studies in 335 individuals. Confirmatory factor analysis (CFA) was used to examine model structure and fit. A multiple indicators, multiple causes (MIMIC) model identified predictors of latent factors identified by CFA. RESULTS: Results supported an intercorrelated model with three factors: executive function, incentive salience, and emotionality. All factors were associated with current AUD, and incentive salience was uniquely associated with past 30-day drinking frequency. MIMIC results identified multiple significant predictors of these latent factors, including history of alcohol use disorder, positive family history of alcohol dependence, earlier age of first drink, and a history of childhood emotional abuse and physical neglect. CONCLUSIONS: Our results support an intercorrelated 3-factor model of neurofunctional domains in alcohol use models, consistent with published findings. Because childhood physical neglect was a significant predictor of all latent factors, these results also highlight the significant negative impact of childhood neglect on later addiction development.

Quantification of Flavorants and Nicotine in Waterpipe Tobacco and Mainstream Smoke and Comparison to E-cigarette Aerosol.

INTRODUCTION: Waterpipe use remains popular among youth with the availability of flavored shisha tobacco being one of the main drivers of waterpipe use. Although waterpipe mainstream toxicant emissions are well understood, less is known about the carryover of flavorants such as vanillin, benzaldehyde, and eugenol. In this study, flavored waterpipe tobacco was analyzed for flavorants and nicotine, and subsequent carryover to mainstream smoke. METHODS: Flavorants vanillin, benzaldehyde, and eugenol, and nicotine were quantified in vanilla-, cherry-, and cinnamon-flavored shisha tobacco by gas chromatography/flame ionization detector and subsequently in waterpipe mainstream smoke generated by a smoking machine. The setup allowed for sampling before and after the water-filtration step. RESULTS: Flavorant and nicotine content in smoke was reduced 3- to 10-fold and 1.4- to 3.1-fold, respectively, due to water filtration. Per-puff content of filtered waterpipe mainstream smoke ranged from 13 to 46 µg/puff for nicotine and from 6 to 55 µg/puff for flavorants. CONCLUSIONS: Although water filtration reduced flavor and nicotine content in waterpipe mainstream smoke, the detected flavorant concentrations were similar or higher to those previously reported in e-cigarette aerosol. Therefore, users could be drawn to waterpipes due to similar flavor appeal as popular e-cigarette products. Absolute nicotine content of waterpipe smoke was lower than in e-cigarette aerosol, but the differential use patterns of waterpipe (>100 puffs/session) and e-cigarette (mostly <10 puffs/session, multiple session throughout the day) probably result in higher flavorant and nicotine exposure during a waterpipe session. Strategies to reduce youth introduction and exposure to nicotine via waterpipe use may consider similar flavor restrictions as those for e-cigarettes. IMPLICATIONS: Although waterpipe mainstream smoke is well characterized for toxicants content, little is known about carryover of molecules relevant for appeal and addiction: flavorants and nicotine. This study shows that flavorant content of waterpipe mainstream smoke is comparable or higher than e-cigarette aerosol flavorant content. Regulatory action to address tobacco use behaviors targeting the availability of flavors should also include other tobacco products such as flavored shisha tobacco.

Drinking and responses to antidrinking messages among young adults: An fMRI study.

Young adults consume most of their alcohol by binge drinking, and more than one-third report binge drinking in the past month. Some will transition out of excessive drinking, while others will maintain or increase alcohol use into adulthood. Public health campaigns depicting negative consequences of drinking have shown some efficacy at reducing this behavior. However, substance use in dependent individuals is governed in part by automatic or habitual responses to drug cues rather than the consequences. This study used functional magnetic resonance imaging to measure neural responses to drinking cues and drinking cues paired with antidrinking messages among young adults who binge drink (N = 30). This study also explored responses to smoking cues and antismoking messages. Neural responses were also compared between drinking/smoking and neutral cues. Self-reported drinking and smoking were collected at baseline, postscan, and 1 month. Results indicate that activity in the ventral striatum-implicated in reward processing-was lower for drinking cues paired with antidrinking messages than drinking cues. This difference was less pronounced in young adults who reported greater baseline past month drinking quantity. Past month drinking quantity decreased from baseline to 1 month. Further, young adults who showed higher activity during antidrinking messages in the medial prefrontal cortex-implicated in processing message self-relevance- reported a greater decrease in past month drinking frequency from baseline to 1 month. Findings may help to identify young adults who are at risk for continued heavy drinking in adulthood and inform interventions aimed to reduce drinking and reward in young adults.

Multiple Psychiatric Morbidity and Continued Use of Naltrexone for Alcohol Use Disorder.

BACKGROUND AND OBJECTIVES: Despite substantial evidence of the efficacy of naltrexone in treating alcohol use disorder (AUD), naltrexone is used infrequently and often for short durations. Understanding factors related to the initiation and continued use of naltrexone could identify targets for improving its use in clinical practice. METHODS: We used the Fiscal year 2012 national data from the Veterans Health Administration to identify the proportion of veterans diagnosed with AUD who initiated and then continued to receive naltrexone for AUD over a 6-month period (N = 67,788). We further examined correlates of any use and continued use, and patterns of use in inpatient and outpatient mental health services and psychotropic prescription fills. Comparisons were made using bivariate analyses and multinomial logistic regression. RESULTS: Among the veterans diagnosed with AUD, 2.02% initiated treatment with naltrexone. Naltrexone initiation was associated with recent homelessness, concurrent psychiatric disorders, receipt of psychiatric outpatient services, psychotropic prescription fills, residential treatment, and psychiatric and medical-surgical hospitalization. Of the 1,366 patients initiating naltrexone, 43.2% (590) received 2 to 5 prescriptions and 16.3% (223) received more than 5 prescriptions for naltrexone. Use of naltrexone beyond one prescription was associated with homelessness, major depressive disorder, schizophrenia, psychotropic medication use, and psychiatric hospitalization. CONCLUSION: Veterans with AUD who used and continued naltrexone were primarily those with multimorbidity and extensive involvement in psychiatric treatment. SCIENTIFIC SIGNIFICANCE: Prior studies examined the correlates of initiation of naltrexone but retention in treatment has received less attention. This study identified the frequency and important patient and service correlates of continued use of naltrexone. (Am J Addict 2021;30:55-64).

Examining the Relationship Between Self-Reported Drinking and In-Laboratory Drinking and Craving: Is There Concordance?

BACKGROUND: In-laboratory drinking sessions that allow direct assessment of drinking and craving are an emerging method for testing novel pharmacotherapy compounds and behavioral interventions for alcohol use disorders. Despite wide implementation, limited evidence supports the concordance between drinking in the laboratory and in a natural setting. This study examined the relationship between self-reports of drinking prior to and drinking and craving during an alcohol drinking paradigm (ADP). METHODS: Participants were adult heavy drinkers (N = 64) who participated in a pharmacotherapy study. Participants completed self-report alcohol assessments and a baseline ADP session prior to any medication administration. Alcohol craving was assessed during priming and ad lib ADP phases. Outcomes were the associations of total drinks consumed in-laboratory and summary drinking measures for the 30 days prior to the ADP and reports of maximum drinks (past year and lifetime). Additional outcomes were the association of self-reported drinking and alcohol craving during the ADP and the concordance between self-report and ADP World Health Organization (WHO) drinking classifications. RESULTS: Number of drinking days, average drinks per drinking occasion, and lifetime and past-year maximum drinks were all related to drinking in the laboratory. Heavy drinking days were not related to drinking in the laboratory but were associated with ADP craving. Alcohol craving was also associated with other measures of self-reported drinking. There was also a significant association between WHO drinking risk classification and in-laboratory drinking. CONCLUSIONS: The observed relationships between self-reported drinking and drinking in-laboratory across drinking indices suggest that in-laboratory alcohol consumption may reflect participants' real-world alcohol consumption, supporting the value of laboratory-based drinking paradigms. The demonstrated relationship with self-reported drinking and ADP alcohol craving further supports the value of such paradigms to model key drinking predictors. These results provide support for the validity of laboratory-based paradigms to accurately reflect participants' recent drinking levels.

Interaction of Ethanol and Oral ANS-6637, a Selective ALDH2 Inhibitor in Males: A Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Cohort Study.

BACKGROUND: ANS-6637, an orally bioavailable selective and reversible aldehyde dehydrogenase-2 (ALDH2) inhibitor, is under development for drug and alcohol use disorders. During the elimination of alcohol, ALDH2 metabolizes acetaldehyde to acetate; inhibiting this enzyme can lead to aversive reactions due to the accumulation of acetaldehyde. Thus, understanding the safety and tolerability of ANS-6637 in combination with alcohol is essential. TRIAL DESIGN AND METHODS: Forty eight healthy males participated in a randomized, double-blind, placebo-controlled, single-ascending dose cohort study of oral ANS-6637. Eligible participants were randomized to ANS-6637 (n = 36) or placebo (n = 12) in a 3:1 fashion in each of 6 dose cohorts (8 per cohort; ANS-6637 dose levels were 25, 50, 100, 200, 400, and 600 mg). Two hours after receiving study drug, participants drank up to 5 standard drinks, 1 every 30 minutes. Safety assessments, pharmacodynamic measures, and pharmacokinetic blood samples were obtained. RESULTS: Flushing was the most common adverse event (AE) associated with ANS-6637 (24 of 36 participants) compared with placebo (3 of 12). Statistically significant, but modest, increases in heart rate (HR) occurred (+10.5 bpm after 2 drinks; +16.9 to + 20.5 bpm after 3rd through 5th drink). No participant met HR or systolic blood pressure criteria for stopping ethanol administration. There were no clinically significant QTc interval prolongations. Individuals receiving ANS-6637 reported lower ratings of liking, alcohol effects, and feeling drunk. CONCLUSIONS: A single oral dose of ANS-6637 with up to 5 standards drinks over 2.5 hours was generally well tolerated in healthy males. The most common pharmacological response was flushing and an increase in HR, which are known effects of acetaldehyde accumulation and consistent with inhibition of ALDH2 with oral ANS-6637 in combination with alcohol. The results of this alcohol interaction study support further testing of ANS-6637 in individuals who consume alcohol heavily.

Reduction in World Health Organization Risk Drinking Levels and Cardiovascular Disease.

BACKGROUND: Reductions in World Health Organization (WHO) risk drinking levels have recently been shown to lower the risk of multiple adverse health outcomes, but prior work has not examined reductions in WHO risk drinking levels in relation to cardiovascular disease (CVD), the leading cause of death for men and women in the United States and of global mortality. This study examined associations between reductions in WHO risk drinking levels and subsequent risk for CVD. METHODS: In a US national survey, 1,058 very-high-risk and high-risk drinkers participated in Wave 1 interviews (2001 to 2002) and Wave 2 follow-ups (2004 to 2005). Self-reported CVD history that was communicated to the participant by a doctor or other healthcare professionals included arteriosclerosis, hypertension, angina, tachycardia, or myocardial infarction. We used logistic regression to estimate adjusted odds ratios (aOR) evaluating relationships between ≥2-level reductions in WHO risk drinking levels from Wave 1 to Wave 2 and the risk of Wave 2 CVD, controlling for baseline characteristics. RESULTS: Reductions of ≥2 WHO risk drinking levels were associated with significantly lower odds of CVD in individuals who at Wave 1 were very-high-risk (aOR = 0.58 [0.41 to 0.80]) or high-risk drinkers (aOR = 0.81 [0.70 to 0.94]). Interaction terms showed that this relationship varied by age. Among individuals >40 years old at Wave 1, reductions of ≥2 WHO risk drinking levels were associated with significantly lower odds of CVD among very-high-risk drinkers (aOR = 0.42 [0.28 to 0.63]) but not high-risk drinkers (p = 0.50). Among individuals ≤40 years old at Wave 1, reductions of ≥2 WHO risk drinking levels were associated with significantly lower odds of CVD among high-risk drinkers (aOR = 0.50 [0.37 to 0.69]) but not very-high-risk drinkers (p = 0.27). CONCLUSIONS: These results show that reductions in WHO risk drinking levels are associated with reduced CVD risk among very-high-risk and high-risk drinkers in the US general population, and provide further evidence that reducing high levels of drinking provides important benefit across multiple clinical domains.

The Association of Impulsivity and Family History of Alcohol Use Disorder on Alcohol Use and Consequences.

BACKGROUND: Extensive research indicates that having a positive family history of alcohol use disorder (FHP) and impulsivity are 2 risk factors for problem drinking. To our knowledge, no study has investigated which facets of impulsivity interact with family history to increase risk for problem drinking. The goal of this study was to: (i) examine whether FHP individuals with higher levels of impulsivity are more likely to engage in problematic drinking, and (ii) identify which facets of impulsivity interact with FHP to increase risk for problems. METHODS: The data consisted of a combined sample of 757 participants (50% female, 73% White, mean age = 32.85, SD = 11.31) drawn from the Transdisciplinary Tobacco Use Research Center and the Center for the Translational Neuroscience of Alcohol. Analyses of covariance and cumulative logistic regression models investigated the association of family history and impulsivity-related traits with drinking quantity, frequency, and alcohol-related problems. Models were adjusted for age, sex, race, ethnic group, education level, and data source. RESULTS: Significant interactions between impulsivity and family history were found for measures of alcohol-related problems. Specifically, there was a stronger positive association of Barratt Impulsiveness Scale (BIS) poor self-regulation with interpersonal, F(1, 504) = 6.27, p = 0.01, and impulse control alcohol-related problems, F(1, 504) = 6.00, p = 0.01, among FHP compared to FHN individuals. Main effects of family history and impulsivity on alcohol quantity and frequency of use and problems were also found. CONCLUSIONS: These findings suggest that having both a family history of AUD and high BIS poor self-regulation is more strongly associated with alcohol-related consequences in the interpersonal and impulse control domains. Given the heterogeneity of impulsivity, these findings highlight the need for additional research to examine which facets of impulsivity are associated with which alcohol outcomes to narrow phenotypic risk for alcohol misuse.