Alcohol's Impact on the Gut and Liver.

Alcohol is inextricably linked with the digestive system. It is absorbed through the gut and metabolised by hepatocytes within the liver. Excessive alcohol use results in alterations to the gut microbiome and gut epithelial integrity. It contributes to important micronutrient deficiencies including short-chain fatty acids and trace elements that can influence immune function and lead to liver damage. In some people, long-term alcohol misuse results in liver disease progressing from fatty liver to cirrhosis and hepatocellular carcinoma, and results in over half of all deaths from chronic liver disease, over half a million globally per year. In this review, we will describe the effect of alcohol on the gut, the gut microbiome and liver function and structure, with a specific focus on micronutrients and areas for future research.

Effects of alcohol sensitivity on alcohol-induced blackouts and passing out: An examination of the alcohol sensitivity questionnaire among underage drinkers.

BACKGROUND: The role of alcohol sensitivity in the experience of blacking out and passing out has not been well established. Here, we examined the relation between individual differences in alcohol sensitivity (i.e., numbers of drinks required to experience various effects of alcohol) and reports of blacking out and passing out in the past year. METHODS: Participants (925 healthy, underage college student drinkers) completed the Alcohol Sensitivity Questionnaire (ASQ) and reported on their past year blacking out and passing out experiences. RESULTS: The fit of the ASQ's 2-factor structure was fair (CFI = 0.90, RMSEA = 0.09) in this sample of underage drinkers. In unadjusted models, higher ASQ scores (i.e., requiring more drinks to experience effects, indicating lower alcohol sensitivity) were associated with experiencing more blackouts (IRR = 1.68 [1.31-2.15]) and passing out (IRR = 2.25 [1.59-3.18]) in the past year. After controlling for typical consumption, however, higher ASQ scores were associated with fewer past-year blackouts (IRR = 0.76 [0.60-0.98]). Total ASQ scores moderated the relationship between typical alcohol consumption and blackout occurrence (interaction IRR = 0.96 [0.93-0.98]), but not passing out occurrence (interaction IRR = 0.95 [0.89-1.01]), with the quantity of alcohol consumed more strongly associated with blackout occurrence among higher-sensitivity than lower-sensitivity drinkers. CONCLUSIONS: These findings are consistent with prior work suggesting that low sensitivity may act as a paradoxical risk factor for certain heavy drinking effects, contributing to higher levels of alcohol consumption and more frequent negative consequences while also conferring protection (relative to high-sensitivity peers) at a given level of alcohol exposure.

Depolarization of the Rat Atria in Experimental Simulation of the Holiday Heart Syndrome.

In the study of the sequence of depolarization of the atrial subepicardium of rats in the short-term alcohol consumption model (the "Holiday heart" syndrome), the localization of the sources of atrial arrhythmias was determined for the first time. The difference in the excitation of the right and left atria was discovered: the right atrium is activated anterogradely from the sinoatrial node, whereas the left atrium is activated retrogradely from the ectopic focus located in the left auricular appendage.

Alcohol Cue-Induced Ventral Striatum Activity Predicts Subsequent Alcohol Self-Administration.

BACKGROUND: Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory. METHODS: Non-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm. RESULTS: Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2  = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes. CONCLUSIONS: Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Heart Rate Variability Reactivity Moderates the Indirect Link Between Child Maltreatment and Young Adult Alcohol Use Problems Via Depressive Symptoms.

BACKGROUND AND OBJECTIVES: Young adults with childhood maltreatment (CM) histories are particularly vulnerable to depressive symptoms and alcohol use problems. Research suggests that maltreated youth may misuse alcohol in part to alleviate depressive symptoms. However, many youths with depressive symptoms exercise self-control and abstain from heavy alcohol use. The present study aimed to examine the influence of heart rate variability reactivity (HRV-R), a psychophysiological biomarker of self-regulation, in the indirect link between CM and alcohol-use problems via depressive symptoms among low socioeconomic-status rural young adults. METHODS: Two waves of data were collected from a community sample of 225 low socioeconomic-status nonmetropolitan young adults (Mage = 21.56, 52.9% female). HRV data were obtained with an electrocardiogram during a social stress task. CM was assessed through the Childhood Trauma Questionnaire. Alcohol use problems were measured using the Alcohol Use Disorders Identification Test. RESULTS: The indirect effect of CM on alcohol use problems via elevated depressive symptoms was positive and significant (α × ß = .159, P < .001). Self-regulation, indicated by high HRV-R (ie, vagal withdrawal), was found to significantly buffer the link between depressive symptoms and alcohol use problems (ß = .193, P = .022). DISCUSSION AND CONCLUSIONS: Adequate self-regulation capacities can protect maltreated youths from self-medicating alcohol use problems. SCIENTIFIC SIGNIFICANCE: This study will advance researchers' understanding of the development of alcohol use problems through unwrapping the risk and protective mechanisms underlying the association between young adults' early life stress and alcohol use behaviors. (Am J Addict 2020;29:141-150).

Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse striatum by chronic ethanol exposure.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu2) is a Gi/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu2-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu2-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu2-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu2 fully rescues mGlu2-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu2-LTD. We did not observe a reduction of mGlu2 mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Stress vulnerability promotes an alcohol-prone phenotype in a preclinical model of sustained depression.

Major depression and alcohol-related disorders frequently co-occur. Depression severity weighs on the magnitude and persistence of comorbid alcohol use disorder (AUD), with severe implications for disease prognosis. Here, we investigated whether depression vulnerability drives propensity to AUD at the preclinical level. We used the social defeat-induced persistent stress (SDPS) model of chronic depression in combination with operant alcohol self-administration (SA). Male Wistar rats were subjected to social defeat (five episodes) and prolonged social isolation (~12 weeks) and subsequently classified as SDPS-prone or SDPS-resilient based on their affective and cognitive performance. Using an operant alcohol SA paradigm, acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking were examined in the two subpopulations. SDPS-prone animals showed increased alcohol SA, heightened motivation to acquire alcohol, persistent alcohol seeking despite alcohol unavailability, signs of extinction resistance, and increased cue-induced relapse; the latter could be blocked by the α2 adrenoreceptor agonist guanfacine. In SDPS-resilient rats, prior exposure to social defeat increased alcohol SA without affecting any other measures of alcohol seeking and alcohol taking. Our data revealed that depression proneness confers vulnerability to alcohol, emulating patterns of alcohol dependence seen in human addicts, and that depression resilience to a large extent protects from the development of AUD-like phenotypes. Furthermore, our data suggest that stress exposure alone, independently of depressive symptoms, alters alcohol intake in the long-term.

Contributing Roles of CYP2E1 and Other Cytochrome P450 Isoforms in Alcohol-Related Tissue Injury and Carcinogenesis.

The purpose of this review is to briefly summarize the roles of alcohol (ethanol) and related compounds in promoting cancer and inflammatory injury in many tissues. Long-term chronic heavy alcohol exposure is known to increase the chances of inflammation, oxidative DNA damage, and cancer development in many organs. The rates of alcohol-mediated organ damage and cancer risks are significantly elevated in the presence of co-morbidity factors such as poor nutrition, unhealthy diets, smoking, infection with bacteria or viruses, and exposure to pro-carcinogens. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. In this chapter, we summarize the important roles of ethanol/acetaldehyde in promoting inflammatory injury and carcinogenesis in several tissues. We also review the updated roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and other cytochrome P450 isozymes in the metabolism of various potentially toxic substrates, and consequent toxicities, including carcinogenesis in different tissues. We also briefly describe the potential implications of endogenous ethanol produced by gut bacteria, as frequently observed in the experimental models and patients of nonalcoholic fatty liver disease, in promoting DNA mutation and cancer development in the liver and other tissues, including the gastrointestinal tract.

Within- and between-person associations from mood to alcohol consequences: The mediating role of enhancement and coping drinking motives.

Between-subjects literature has established that trait-like negative mood predicts coping motives, which predict alcohol-related problems and that trait-like positive mood predicts mood enhancement motives, which then predict alcohol consumption. However, there is considerable within-person variation in drinking motives, and the relationship between mood, motives, and alcohol outcomes must be more closely examined at a daily level. The current study used ecological momentary assessment (EMA) to measure mood, motives, alcohol use, and alcohol consequences in 101 college drinkers over a 15-day period. At the between-subjects level, positive mood predicted enhancement motives, which in turn predicted alcohol consumption and consequences. Negative mood predicted coping motives, which were associated with only alcohol-related consequences. At the within-subjects level, daily anxious and depressed mood were associated with endorsing coping motives, but coping motives were not associated with alcohol consumption or problems. Positive mood was associated with enhancement motives, which was associated with both daily alcohol consumption and problems. These results corroborate previous findings that enhancement motives are most predictive of outcomes in the college population and highlight the importance of considering within-subject variance in drinking motives. The relationships between mood, motives, and alcohol outcomes differ when examined as between-subjects versus within-subject constructs. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Predictors of aging out of heavy episodic drinking in emerging adults: a systematic review protocol.

BACKGROUND: Heavy episodic drinking (HED) refers to alcohol consumption that exceeds the recommended threshold for a given episode and increases risk for diverse negative alcohol-related consequences. A pattern of weekly HED is most prevalent in emerging adults (i.e., age 18-25). However, rates of HED consistently decline in the mid to late twenties, referred to as 'aging out' or 'maturing out' of HED. Although many individual studies have followed changes in drinking behaviour over the transition to adulthood, there has yet to be a systematic review to identify consistent factors contributing to risk (i.e. failure to age out) and protection (i.e. successful aging out). The objective of this review will be to summarize and critically appraise the literature on factors contributing to aging out of HED among emerging adults. METHODS: A systematic search of observational cohort studies following drinking behaviours in age cohorts overlapping with the emerging adulthood period will be conducted in MEDLINE, EMBASE, PsychInfo, and CINAHL. Two independent reviewers will evaluate identified studies for inclusion eligibility, extract study data, and assess the quality of included studies. Primary outcomes will be quantity/frequency of alcohol use (e.g. drinks/week) and severity of alcohol-related problems. Predictors of maturing out of HED will be reported narratively, and where appropriate, random effects meta-analyses will be conducted to provide pooled effect sizes. An evidence map will be created to characterize the overall pattern of findings. DISCUSSION: This systematic review will provide a timely and warranted summary of published work contributing to understanding aging out of heavy episodic drinking. Our findings will provide critical commentary on the developmental course of HED during the transition from adolescence to adulthood and will be the first review to consider both protective and risk factors for maturing out of frequent binge drinking. By highlighting factors identifying those at-risk for prolonged heavy episodic drinking, our conclusions will have important treatment implications for primary, secondary, and tertiary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017078436 .

Alcohol and Hypertension-New Insights and Lingering Controversies.

PURPOSE OF REVIEW: To examine outstanding issues in the relationship of alcohol to hypertension. These include whether the increase in BP with alcohol is causally related, the nature of the relationship in women, the contribution of alcohol-related increases in BP to cardiovascular disease and the aetiology of alcohol-related hypertension. RECENT FINDINGS: Intervention studies and Mendelian randomisation analyses confirm the alcohol-BP relationship is causal. The concept that low-level alcohol intake reduces BP in women is increasingly unsustainable. Alcohol-related hypertension is in the causal pathway between alcohol use and increased risk for several cardiovascular outcomes. The aetiology of alcohol-related hypertension is multifactorial with recent data highlighting the effects of alcohol on the vasoconstrictor 20-HETE and oxidative stress. The high prevalence of both alcohol use and hypertension mandates a careful alcohol history in every patient with elevated BP. Early intervention for excessive alcohol use offers the promise of lower levels of BP and reduced risk of adverse cardiovascular outcomes.

Attention deficit hyperactivity disorder and future alcohol outcomes: Examining the roles of coping and enhancement drinking motives among young men.

OBJECTIVE: Although there is evidence that Attention Deficit Hyperactivity Disorder (ADHD) symptoms are positively related to alcohol use and related problems among young adults, little research has examined the mechanisms that might explain this association. In response, this study examined the mediating effects of coping and enhancement drinking motives on the prospective associations between ADHD symptoms and alcohol outcomes. METHOD: Participants (N = 4,536) were young men from the Cohort Study on Substance Use Risk Factors. Measures of ADHD symptoms and those of drinking motives, heavy episodic drinking (HED) and alcohol use disorder symptoms were used from the baseline and 15-month follow-up assessments. RESULTS: Findings indicated that the associations of ADHD-inattention symptoms with alcohol use disorder (AUD) symptoms and with HED were partially and completely mediated through drinking motives, respectively, whereas drinking motives did not mediate the ADHD-hyperactivity/impulsivity-symptoms-alcohol outcomes associations. CONCLUSION: Results indicated that coping and enhancement motives partially explained the ADHD-inattention symptoms-subsequent alcohol outcomes association. These findings suggest that interventions targeting enhancement and coping motives may help prevent problematic drinking among young men with elevated ADHD-inattention symptoms.

Acute alcohol and cognition: Remembering what it causes us to forget.

Addiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders, it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry. In general, exposure to ethanol doses that produce intoxicating effects causes consistent impairments in learning and memory processes mediated by specific brain circuitry, whereas lower doses either have no effect or produce a facilitation of memory under certain task conditions. Therefore, acute ethanol does not produce a global impairment of learning and memory, and can actually facilitate particular types of memory, perhaps particular types of memory that facilitate the development of excessive alcohol use. In addition, the effects on cognition are dependent on brain region, task demands, dose received, pharmacokinetics, and tolerance. Additionally, we explore the underlying alterations in neurophysiology produced by acute alcohol exposure that help to explain these changes in cognition and highlight future directions for research. Through understanding the impact that acute alcohol intoxication has on cognition, the preliminary changes potentially causing a problematic addiction memory can better be identified.

Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment.

Relapse remains the most prominent hurdle to successful rehabilitation from alcoholism. The neural mechanisms underlying relapse are complex, but our understanding of the brain regions involved, the anatomical circuitry and the modulation of specific nuclei in the context of stress and cue-induced relapse have improved significantly in recent years. In particular, stress is now recognised as a significant trigger for relapse, adding to the well-established impact of chronic stress to escalate alcohol consumption. It is therefore unsurprising that the stress-responsive regions of the brain have also been implicated in alcohol relapse, such as the nucleus accumbens, amygdala and the hypothalamus. Environmental enrichment is a robust experimental paradigm which provides a non-pharmacological tool to alter stress response and, separately, alcohol-seeking behaviour and symptoms of withdrawal. In this review, we examine and consolidate the preclinical evidence that alcohol seeking behaviour and stress-induced relapse are modulated by environmental enrichment, and these are primarily mediated by modification of neural activity within the key nodes of the addiction circuitry. Finally, we discuss the limited clinical evidence that stress-reducing approaches such as mindfulness could potentially serve as adjunctive therapy in the treatment of alcoholism. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Problematic alcohol use and acute intoxication predict anger-related attentional biases: A test of the alcohol myopia theory.

Previous research has demonstrated a significant association between alcohol and aggression. However, the precise mechanisms underlying this relationship have yet to be fully elucidated. In the present study, we examined alcohol's effects on an attentional bias toward aggressogenic cues as the first step in a possible mediation model of alcohol-facilitated intimate partner aggression. More specifically, we tested an interactive effect of problematic alcohol use and acute alcohol intoxication on an attentional bias toward anger words. Participants in this study were 249 male and female heavy drinkers from the community with a history of past-year intimate partner aggression perpetration who participated in an alcohol-administration laboratory study assessing the effect of alcohol intoxication on cognitive biases. Multiple linear regression was used to test the proposed moderation model. Acute alcohol intoxication moderated the effect of problematic alcohol use on an attentional bias toward anger, with this effect being stronger for individuals in the alcohol compared to no-alcohol control condition. These findings suggest that problematic drinkers may be more likely to attend to aggressogenic stimuli while acutely intoxicated, relative to when they are sober. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Chronic Intermittent Ethanol Exposure Selectively Increases Synaptic Excitability in the Ventral Domain of the Rat Hippocampus.

Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety- and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long-Evans rats were exposed to CIE or AIR for 10 days (12 h/day; targeting blood ethanol levels of 175-225 mg%) and recordings were made 24 h into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze and successive alleys test. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, were dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal.

Test-retest reliability and clinical correlates of the Eurofit test battery in people with alcohol use disorders.

People with alcohol use disorder (AUD) are at an increased risk for cardiovascular diseases (CVD). Physical fitness is a predictor of CVD and premature mortality. Currently, no existing measures of physical fitness used in the general population have been tested for validity and reliability in this vulnerable population. Therefore, we examined the reproducibility, feasibility and correlates of the Eurofit test battery in this population. From 32 men (age = 40.8 ±â€¯13.8years; illness duration = 10.2 ±â€¯10.3years; body mass index, BMI = 24.8 ±â€¯3.8) and 13 women (age = 41.9 ±â€¯12.1years; illness duration = 13.7 ±â€¯13.1years; BMI = 26.3 ±â€¯4.9) with AUD two trials of the Eurofit test, administered within one week, were analyzed. All patients also completed the International Physical Activity Questionnaire, the Positive Affect and Negative Affect Scale and Alcohol Use Disorders Identification Test. All Eurofit items showed good reproducibility with intraclass correlation coefficients ranging from 0.82 for the flamingo balance test to 0.97 for the standing broad jump and handgrip strength tests. Better performance on Eurofit test items was associated with younger age, a shorter illness duration, a lower BMI and higher physical activity levels. The current study demonstrates that the Eurofit test can be recommended as a reliable test for evaluating the physical fitness of inpatients with alcohol use disorder.

Chronic Neurologic Effects of Alcohol.

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.

Evaluating the Validity of the DSM-5 Alcohol Use Disorder Diagnostic Criteria in a Sample of Treatment-seeking Native Americans.

OBJECTIVE: Despite high rates of alcohol use disorder (AUD) and alcohol-induced deaths among Native Americans, there has been limited study of the construct validity of the AUD diagnostic criteria. The purpose of the current study was to examine the validity of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) AUD criteria in a treatment-seeking group of Native Americans. METHODS: As part of a larger study, 79 Native Americans concerned about their alcohol or drug use were recruited from a substance use treatment agency located on a reservation in the southwestern United States. Participants were administered the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID for DSM-IV-TR) reworded to assess 11 DSM-5 criteria for AUD. Confirmatory factor analysis (CFA) was used to test the validity of the AUD diagnostic criteria, and item response theory (IRT) was used to examine the item characteristics of the AUD diagnostic criteria in this Native American sample. RESULTS: CFA indicated that a 1-factor model of the 11 items provided a good fit of the data. IRT parameter estimates suggested that "withdrawal," "social/interpersonal problems," and "activities given up to use" had the highest magnitude of discrimination. "Much time spent using" and "activities given up to use" were associated with the greatest severity. CONCLUSIONS: The current study provided support for the validity of the AUD DSM-5 criteria and a unidimensional latent construct of AUD in this sample of treatment-seeking Native Americans. IRT analyses replicate findings from previous studies. To our knowledge, this is the first study to examine the validity of the DSM-5 AUD criteria in a treatment-seeking sample of Native Americans. Continued research in other Native American samples is needed.