Showing papers in "Alcoholism: Clinical and Experimental Research in 2019"

Fetal Alcohol Spectrum Disorders: A Review of the Neurobehavioral Deficits Associated With Prenatal Alcohol Exposure

Abstract: In utero alcohol exposure can disrupt the development of the fetal brain and result in a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). This paper provides a comprehensive review of the cognitive and behavioral outcomes of prenatal alcohol exposure, including domains of general intelligence, executive functioning, language development, learning and memory, adaptive functioning, academic performance, and concurrent psychopathology. In addition, the current status of the neurobehavioral profile of FASD and its potential as a diagnostic tool will be discussed.

Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings.

Abstract: The Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms. Using adolescent intermittent ethanol (AIE) exposure models, NADIA investigators identified long-lasting AIE-induced changes in adult behavior that are consistent with observations in humans, such as increased alcohol drinking, increased anxiety (particularly social anxiety), increased impulsivity, reduced behavioral flexibility, impaired memory, disrupted sleep, and altered responses to alcohol. These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the molecular level, AIE results in long-lasting changes in neuroimmune/trophic factor balance and epigenetic-microRNA (miRNA) signaling across glia and neurons. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology. This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. Many of these AIE-induced brain changes replicate findings seen in postmortem brains of humans with alcohol use disorder (AUD). NADIA researchers are now elucidating mechanisms of these adaptations. Emerging data demonstrate that exercise, antiinflammatory drugs, anticholinesterases, histone deacetylase inhibitors, and other pharmacological compounds are able to prevent (administered during AIE) and/or reverse (given after AIE) AIE-induced pathology in adulthood. These studies support hypotheses that adolescent binge drinking increases risk of adult hazardous drinking and influences brain development, and may provide insight into novel therapeutic targets for AIE-induced neuropathology and AUDs.

Is There a Recent Epidemic of Women's Drinking? A Critical Review of National Studies.

Abstract: Alcohol consumption is increasing in the United States, as is alcohol-attributable mortality. Historically, men have had higher rates of alcohol consumption than women, though evidence for birth cohort effects on gender differences in alcohol consumption and alcohol-related harm suggests that gender differences may be diminishing. We review studies using U.S. national data that examined time trends in alcohol consumption and alcohol-related harm since 2008. Utilizing a historical-developmental perspective, here we synthesize and integrate the literature on birth cohort effects from varying developmental periods (i.e., adolescence, young adulthood, middle adulthood, and late adulthood), with a focus on gender differences in alcohol consumption. Findings suggest that recent trends in gender differences in alcohol outcomes are heterogeneous by developmental stage. Among adolescents and young adults, both males and females are rapidly decreasing alcohol consumption, binge and high-intensity drinking, and alcohol-related outcomes, with gender rates converging because males are decreasing consumption faster than females. This pattern does not hold among adults, however. In middle adulthood, consumption, binge drinking, and alcohol-related harms are increasing, driven largely by increases among women in their 30s and 40s. The trend of increases in consumption that are faster for women than for men appears to continue into older adult years (60 and older) across several studies. We conclude by addressing remaining gaps in the literature and offering directions for future research.

Alcohol Use Disorders in ICD-11: Past, Present, and Future.

Abstract: The Eleventh Revision of the International Classification of Diseases (ICD-11) was formally published in May 2019. Alcohol use disorders form a key part of the section of Disorders due to Substance Use and Addictive Behaviours. This review describes and discusses the alcohol diagnoses within this section of ICD-11, including Alcohol Dependence, Harmful Pattern of Use of Alcohol, and entities such as Alcohol Intoxication, Alcohol Withdrawal, and several alcohol-induced mental disorders, and briefly covers Hazardous Alcohol Use, which is listed separately as a health risk factor. We summarize the historical background to the development of these diagnoses, including work within the World Health Organization since the 1970s, and the corresponding diagnoses in the current ICD-10. The process by which ICD-11 diagnoses have been made is described and may be summarized as a conceptual-pragmatic-confirmatory one. The available empirical data supporting the ICD-11 diagnoses are presented, particularly in relation to the diagnostic guidelines for Alcohol Dependence. Comparison is made with the corresponding diagnoses in ICD-10 and their nearest counterparts in the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders. Field testing of the ICD-11 diagnoses is currently in progress. A plea is made for matching of diagnoses, diagnostic guidelines/criteria, and the assessment tools intended to capture these diagnoses.

Simultaneous Alcohol and Marijuana Use Among College Students: Patterns, Correlates, Norms, and Consequences

Abstract: Background Alcohol and marijuana users often engage in simultaneous alcohol and marijuana (SAM) use (i.e., using the 2 substances together so that their effects overlap), which can result in more negative consequences than using either substance alone. Nevertheless, little is known about SAM use among contemporary college students to aid in the development of preventive interventions. This study examined SAM use patterns, demographic correlates of SAM use, and normative influences on SAM use and related negative consequences among college students. Methods Students who had used alcohol and marijuana in the past year were recruited from 3 state universities in states with different laws regarding recreational marijuana use (N = 1,389). They completed an online survey, which assessed their own alcohol, marijuana, and SAM use and related consequences, their perceptions of the proportion of same-gender peers and close friends who engaged in SAM use, marijuana access, and demographic characteristics. Results About three-fourths of participants reported at least 1 occasion of SAM use in the past year with an average frequency of twice per month among SAM users. There were significant differences in SAM use prevalence and frequency by sociodemographic characteristics controlling for past-year alcohol and marijuana frequency. Students in a state with decriminalized recreational marijuana use reported higher frequency of past-year SAM use than students in states with legalized or criminalized use. There were significant demographic differences in perceived norms regarding SAM use among close friends and same-gender peers. SAM users endorsed significantly higher perceived peer and friend norms than nonusers. Also, higher perceived norms predicted more frequent SAM use and more negative consequences of use. Conclusions Results indicate a need for prevention programs on college campuses that address SAM use. Interventions that use personalized normative feedback may be effective.

Shifting Age of Peak Binge Drinking Prevalence: Historical Changes in Normative Trajectories Among Young Adults Aged 18 to 30.

Abstract: Background This study examined the extent to which the developmental pattern of prevalence of binge drinking in the past 2 weeks from ages 18 through 30 has changed across 29 cohorts of U.S. young adults, and whether the changes differed by gender. Methods Analyses used national longitudinal data from 58,019 12th-grade students (from graduating high school classes 1976 to 2004) participating in the Monitoring the Future study followed through modal age 30 (with age 29/30 data collected from 1987 to 2016). Weighted time-varying effect modeling was used to model cohort group differences in age-related patterns of binge drinking. Results The age of peak binge drinking prevalence increased across cohorts (from age 20 in 1976 to 1985 to 22 in 1996 to 2004 for women, and from 21 in 1976 to 1985 to 23 in 1996 to 2004 for men). Historical change in the developmental pattern of binge drinking across all ages of young adulthood differed for men and women. Even after controlling for key covariates, women in the more recent cohort group reported significantly higher binge drinking prevalence than women in earlier cohorts from ages 21 through 30. Men in the more recent cohort group reported higher binge drinking prevalence at ages 25 to 26, but prevalence levels then converged to those seen in earlier cohort groups by age 30. Conclusions An older age of peak binge drinking and a decreased rate of decline in the prevalence of binge drinking in later young adulthood among more recent cohorts have resulted in an extension of individual and societal risks associated with binge drinking, particularly for women, across young adulthood. High-risk alcohol use prevention efforts are needed throughout at least the third decade of life.

Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review.

Abstract: There is substantial interest in the therapeutic potential of cannabidiol (CBD), a nonpsychoactive cannabinoid found in plants of the genus Cannabis. The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). Using a comprehensive search strategy, 303 unique potential articles were identified and 12 ultimately met criteria for inclusion (8 using rodent models, 3 using healthy adult volunteers, and 1 using cell culture). In both rodent and cell culture models, CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus. In rodent models, CBD was found to attenuate alcohol-induced hepatotoxicity, specifically, alcohol-induced steatosis. Finally, findings from preclinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking, alcohol self-administration, withdrawal-induced convulsions, and impulsive discounting of delayed rewards. In human studies, CBD was well tolerated and did not interact with the subjective effects of alcohol. Collectively, given its favorable effects on alcohol-related harms and addiction phenotypes in preclinical models, CBD appears to have promise as a candidate AUD pharmacotherapy. This is further bolstered by the absence of abuse liability and its general tolerability. A clear limitation to the literature is the paucity of human investigations. Human preclinical and clinical studies are needed to determine whether these positive effects in model systems substantively translate into clinically relevant outcomes.

Alcohol and Women: A Brief Overview.

Abstract: This paper provides a brief overview of research on women and alcohol and introduces a virtual issue of Alcoholism: Clinical and Experimental Research devoted to this important subject. Women-focused topics include the epidemiology of alcohol use among women, health and behavioral consequences of drinking, prenatal alcohol use and interventions, and enhanced alcohol treatment services. The introduction and selected papers highlight: temporal trends that are narrowing the gender gap in alcohol use; mounting evidence of the more rapid progression and greater severity of harmful physiological and behavioral effects of alcohol in women; impact of targeted public health campaigns and public policies on prenatal drinking; and finally intervention strategies to improve detection and care of women who misuse alcohol. Finally, future research directions to address continuing knowledge gaps are identified. This article is protected by copyright. All rights reserved.

Inulin Ameliorates Alcoholic Liver Disease via Suppressing LPS-TLR4-Mψ Axis and Modulating Gut Microbiota in Mice.

Abstract: Background Alcoholic liver disease (ALD) represents a chronic liver disorder caused by alcohol abuse. Numerous studies have demonstrated that gut microbiota dysbiosis plays a critical role in ALD pathogenesis. Application of prebiotic, probiotic, and dietary supplementation to the modulation of gut microbiota contributes to a novel approach to the management of ALD. Inulin, a natural prebiotic found in plants, can restore gut dysbiosis in ALD. However, the exact mechanism of dietary inulin in ALD remains largely unknown. Methods Sixty female C57BL/6J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON); alcohol-fed (AF) group (AF/CON); PF with inulin (INU) group (PF/INU); and AF with INU group (AF/INU). All mice were fed with isocaloric modified Lieber-DeCarli liquid diets with or without alcohol. Results After 6 weeks of feeding, mice were euthanized and associated indications were investigated. The results showed that chronic ethanol (EtOH) intake led to the loss of body weights, abnormal levels of transaminases, and inflammatory indicators (lipopolysaccharide [LPS], interleukin [IL]-6, IL-10, tumor necrosis factor-α, IL-17A), while inulin administration ameliorated these effects. To further understand the underlying mechanism, we investigated macrophages (Mψs) and gut microbiota in diverse groups. The number of Mψs was reduced after dietary inulin treatment in chronic EtOH exposure. Hepatic Toll-like receptor 4 (TLR4+ ) Mψs in AF/INU group were lower than AF/CON group. 16S rRNA sequencing and analysis of gut microbiota indicated the reduction of Allobaculum, Lactobacillus, and Lactococcus, as well as the increase of Parasutterella in AF group compared with PF control. Increased Allobaculum, Lactobacillus, and Lactococcus but reduced Parasutterella in AF/INU group were confirmed that dietary inulin rectified gut dysbiosis to attenuate ALD. Conclusions Dietary inulin ameliorates ALD via suppressing LPS-TLR4-Mψ axis and modulating gut microbiota in mice, thus potentially provides theoretical foundation for inulin intervention in the prevention and treatment of ALD.

Gender Disparities in Alcohol Use Disorder Treatment Among Privately Insured Patients with Alcohol-Associated Cirrhosis.

Abstract: BACKGROUND The burden of alcohol-associated cirrhosis (AC) is high, and though alcohol cessation improves mortality, many patients fail to engage in alcohol use disorder (AUD) treatment and continue drinking. Our aim was to determine rates, predictors, and outcomes of AUD treatment utilization in AC patients with private insurance. METHODS We collected data from persons with AC (diagnosed by ICD-9/ICD-10 codes), aged 18 to 64 years, enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009 to 2016). We determined rates and predictors of substance abuse treatment visits as well as rates of alcohol relapse prevention medication prescriptions, weighted to the national employer-sponsored insured population. Effects of AUD treatment utilization on decompensation rates were calculated using proportional hazards regression with propensity score adjustment. RESULTS A total of 66,053 AC patients were identified, 32% were female, and mean age at diagnosis was 54.5 years. About 72% had insurance coverage for substance abuse treatment. Overall, AUD treatment utilization rates were low, with only 10% receiving a face-to-face mental health or substance abuse visit and only 0.8% receiving a Food and Drug Administration (FDA)-approved relapse prevention medication within 1 year of index diagnosis. Women were less likely to receive a face-to-face visit (hazard ratio [HR] 0.84, p < 0.001) or an FDA-approved relapse prevention medication (0.89, p = 0.05) than men. AC patients who had a clinic visit for AUD treatment or used FDA-approved relapse medication showed decreased risk of decompensation at 1 year (HR 0.85, p < 0.001 for either). CONCLUSIONS AUD treatment utilization is associated with lower decompensation rates among privately insured patients with AC. Women were less likely to utilize AUD treatment visits. Efforts to reduce gender-specific barriers to treatment are urgently needed to improve outcomes.

Prevalence and Correlates of Past-Year Recovery From DSM-5 Alcohol Use Disorder: Results From National Epidemiologic Survey on Alcohol and Related Conditions-III.

Abstract: Background Little is known about remission, recovery, and other outcomes of alcohol use disorder (AUD) as defined by the DSM-5. Methods Data from a large representative sample of the United States was used to examine correlates of past-year AUD status among individuals with prior-to-past-year AUD: persistent AUD, symptomatic high-risk drinking, asymptomatic high-risk drinking, symptomatic low-risk drinking, asymptomatic low-risk drinking (nonabstinent recovery, NAR), and abstainer (abstinent recovery, AR). Multiple logistic regression analyses were conducted to compare: (i) AR and NAR with persistent AUD, (ii) AR with NAR, and (iii) asymptomatic and symptomatic high-risk drinking with AR and NAR. Results Among individuals with AUD prior to past year (n = 7,785), 34.2% were classified with persistent AUD, 8.8 and 1.6% were symptomatic high-risk and symptomatic low-risk drinkers, respectively, 21.5% were asymptomatic high-risk drinkers, 17.9% were asymptomatic low-risk drinkers, and 16.0% were abstainers. One-quarter of individuals with AUD prior to past year achieved AR or NAR without the benefit of treatment, while a much greater percentage of individuals achieving AR (43.2%) reported receiving treatment relative to those with NAR (12.3%). The number of lifetime AUD symptoms was greater among those achieving AR (among the treated) and lower among those achieving NAR relative to persistent AUD. The number of AUD symptoms was also greater among those achieving AR than NAR and lower among asymptomatic and symptomatic risk drinkers relative to those achieving AR and NAR. Consumption was greater among those achieving AR relative to those achieving NAR and greater among asymptomatic and symptomatic risk drinkers relative to AR and NAR. Odds of achieving AR or NAR relative to persistent AUD were generally lower among non-Hispanic Blacks and those with higher education, greater among women and married individuals, and lower among illicit drug users and individuals with histories of a personality disorder or mood/anxiety disorder. Conclusions There appears to be a substantial level of recovery from AUD. Information on specific factors associated with AUD outcomes can be useful in targeting appropriate treatment efforts.

Alcohol Use in Pregnancy and Miscarriage: A Systematic Review and Meta-Analysis

Abstract: To systematically review and critically evaluate studies reporting alcohol exposure during pregnancy and miscarriage. We searched PubMed, EMBASE, PsycINFO, and ProQuest Theses for publications from January 1970 to January 2019. We identified studies about alcohol exposure during pregnancy and miscarriage. Information about study population, alcohol exposure assessment, outcome definition, covariates, and measures of association was collected. We assessed study quality using an adapted Newcastle-Ottawa Scale. Data were abstracted by 2 investigators independently. We conducted a random-effects meta-analysis to calculate the association between alcohol exposure and miscarriage risk and performed subgroup analyses to determine robustness of results to study differences. For studies reporting dose-specific effects, a pooled dose-response association was estimated using generalized least squares regression with and without restricted cubic spline terms for number of drinks consumed per week. Of 2,164 articles identified, 24 were eligible for inclusion. Meta-analysis of data from 231,808 pregnant women finds those exposed to alcohol during pregnancy have a greater risk of miscarriage compared to those who abstained (odds ratio [OR] 1.19, 95% confidence intervals [CI] 1.12, 1.28). Estimates did not vary by study design, study country, or method of alcohol ascertainment. For alcohol use of 5 or fewer drinks per week, each additional drink per week was associated with a 6% increase in miscarriage risk (OR 1.06, 95% CI 1.01, 1.10). Common study limitations reflect challenges inherent to this research, including difficulty recruiting participants early enough in pregnancy to observe miscarriage and collecting and quantifying information about alcohol consumption during pregnancy that accurately reflects use. This review provides evidence that alcohol consumption during pregnancy is associated with a dose-mediated increase in miscarriage risk. Future studies evaluating change in alcohol use in pregnancy are needed to provide insight into how alcohol consumption prior to pregnancy recognition impacts risk.

Assessment of Alcohol Use in the Natural Environment.

Abstract: The current article critically reviews 3 methodological options for assessing drinking episodes in the natural environment. Ecological momentary assessment (EMA) typically involves using mobile devices to collect self-report data from participants in daily life. This technique is now widely used in alcohol research, but investigators have implemented diverse assessment strategies. This article focuses on "high-resolution" EMA protocols that oversample experiences and behaviors within individual drinking episodes. A number of approaches have been used to accomplish this, including using signaled follow-ups tied to drinking initiation, asking participants to log entries before and after individual drinks or drinking episodes, and delivering frequent signaled assessments during periods of the day when alcohol use is most common. Transdermal alcohol sensors (TAS) are devices that are worn continuously and are capable of detecting alcohol eliminated through the skin. These methods are appealing because they do not rely upon drinkers' self-report. Studies using TAS have been appearing with greater frequency over the past several years. New methods are making the use of TAS more tractable by permitting back-translation of transdermal alcohol concentration data to more familiar estimates of blood alcohol concentration or breath alcohol concentration. However, the current generation of devices can have problems with missing data and tend to be relatively insensitive to low-level drinking. An emerging area of research investigates the possibility of using mobile device data and machine learning to passively detect the user's drinking, with promising early findings. EMA, TAS, and sensor-based approaches are all valid, and tend to produce convergent information when used in conjunction with one another. Each has a unique profile of advantages, disadvantages, and threats to validity. Therefore, the nature of the underlying research question must dictate the method(s) investigators select.

Temporal Dynamics of Transdermal Alcohol Concentration Measured via New-Generation Wrist-Worn Biosensor.

Abstract: BACKGROUND The development of a transdermal alcohol biosensor could represent a tremendous advance toward curbing problematic drinking. But several factors limit the usefulness of extant transdermal technology, including relatively lengthy delays between blood alcohol concentration (BAC) and transdermal alcohol concentration (TAC), as well as the large/bulky designs of currently available transdermal sensors (e.g., ankle monitors). The current research examined the lag time between BAC and TAC using a prototype of BACtrack Skyn-a new-generation wrist-worn transdermal sensor featuring a compact design and smartphone integration. METHODS Participants (N = 30) received either a dose of alcohol (target BAC 0.08%) or a nonalcoholic beverage in the laboratory while wearing both the AMS SCRAM ankle monitor and a Skyn prototype. Participants were monitored in the laboratory until breath alcohol concentration (BrAC) dropped below 0.025%. RESULTS Device failure rates for Skyn prototypes were relatively high (18 to 38%) compared with nonprototype SCRAM devices (2%). Among participants with usable data, both Skyn- and SCRAM-measured TAC showed strong correlations with BrAC, and both Skyn and SCRAM devices detected alcohol within 30 minutes of first alcohol administration. Skyn-measured TAC peaked over 1 hour earlier than SCRAM-measured TAC (54 versus 120 minutes after peak BrAC, respectively), and time-series models suggested that, on average across all measured portions of the BrAC curve, Skyn TAC lagged behind BrAC by 24 minutes, whereas SCRAM TAC lagged behind BrAC by 69 minutes-all differences statistically significant at p < 0.001. CONCLUSIONS Results provide preliminary evidence for the validity of a new-generation wrist-worn transdermal sensor under controlled laboratory conditions and further suggest favorable properties of this sensor as they pertain to the latency of transdermal alcohol detection. The prototype version of Skyn employed here displayed a higher failure rate compared with SCRAM, and, in future, more reliable and robust Skyn prototypes will be required suitable to field testing across diverse environmental conditions.

Working Memory Training in Alcohol Use Disorder: A Randomized Controlled Trial

Abstract: Background Alcohol use disorder (AUD) is associated with cognitive deficits such as impaired executive functions, which are hypothesized to contribute to the progression of the disease and worsen treatment outcome. Training of working memory (WM) to improve cognitive functions and thereby reduce alcohol use has been proposed as a novel treatment strategy. Methods Patients with AUD (n = 50) who were recruited to an outpatient addiction clinic were randomized to receive 5 weeks of active WM training or control training. Participants had weekly follow-up visits, and all cognitive training sessions were done online at home. Primary outcomes were WM function and change in self-reported heavy drinking. Secondary outcomes were craving, other drinking outcomes, and performance on a range of neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery. Results The active training group demonstrated a significantly greater improvement in verbal WM compared with the control group. No statistically significant effect of training was found on the primary drinking outcome, but a trend was observed indicating that WM training reduces the number of drinks per drinking occasion. WM training had no statistically significant effect on any of the other neuropsychological tasks. Conclusions Cognitive training can improve WM function in individuals with AUD, suggesting that such interventions are feasible to administer in this patient population. The results do not support an effect of WM training on heavy drinking or transfer effects to other cognitive domains. Future studies should evaluate WM training as an adjunct to evidence-based treatments for AUD to assess potential synergistic effects.

Cognitive Behavioral Therapy for Insomnia in Alcohol-Dependent Veterans: A Randomized, Controlled Pilot Study.

Abstract: Background Insomnia is highly prevalent in individuals recovering from alcohol dependence (AD) and increases their risk of relapse. Two studies evaluating cognitive behavior therapy for insomnia (CBT-I) have demonstrated its efficacy in non-Veterans recovering from AD. The aim of this study was to extend these findings in an 8-week trial of CBT-I in Veterans. Methods Veterans recovering from AD were randomly assigned to 8 weeks of treatment with CBT-I (N = 11) or a Monitor-Only (MO; N = 11) condition and were evaluated 3 (N = 21/22) and 6 months posttreatment (N = 18/22). The primary outcome measure was the Insomnia Severity Index (ISI) score. Secondary outcome measures were sleep diary measures, percent days abstinent (PDA), and scores on the Dysfunctional Beliefs and Attitudes About Sleep Scale (DBAS), Sleep Hygiene Index (SHI), Penn Alcohol Craving Scale (PACS), Quick Inventory of Depressive Symptoms (QIDS), State-Trait Anxiety Inventory-Trait (STAI-T) scale, and Short Form 12-item (SF-12). Mixed-effects regression models, adjusted for race, evaluated differences in outcomes between the groups over a 6-month period (clinicaltrials.gov identifier = NCT01603381). Results Subjects were male, aged 54.5 (SD = 6.9) years, and had 26.4 (SD = 26.3) days of abstinence before their baseline evaluation. CBT-I produced a significantly greater improvement in model-based estimates than MO (mean change at 6 months compared to their baseline) for ISI, sleep latency from a daily sleep diary, DBAS mean score, and SHI total score. PDA and QIDS improved over time, but there was no difference between the groups. PACS, STAI-T, or SF-12 scale did not show any improvement from their baseline scores. Conclusions CBT-I treatment demonstrated substantial efficacy in reducing insomnia, associated negative cognitions, and improving sleep hygiene in Veterans during early recovery, though it did not reduce drinking behavior.

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline.

Abstract: While alcohol use disorder (AUD) is a highly heritable psychiatric disease, efforts to elucidate that heritability by examining genetic variation (e.g., single nucleotide polymorphisms) have been insufficient to fully account for familial AUD risk. Perhaps not coincidently, there has been a burgeoning interest in novel nongenomic mechanisms of inheritance (i.e., epigenetics) that are shaped in the male or female germ cells by significant lifetime experiences such as exposure to chronic stress, malnutrition, or drugs of abuse. While many epidemiological and preclinical studies have long pointed to a role for the parental preconception environment in offspring behavior, over the last decade many studies have implicated a causal relationship between the environmentally sensitive sperm epigenome and intergenerational phenotypes. This critical review will detail the heritable effects of alcohol and the potential role for epigenetics.

How Many Recovery Attempts Does it Take to Successfully Resolve an Alcohol or Drug Problem? Estimates and Correlates From a National Study of Recovering U.S. Adults.

Abstract: Background Alcohol and other drug (AOD) problems are commonly depicted as chronically relapsing, implying multiple recovery attempts are needed prior to remission. Yet, although a robust literature exists on quit attempts in the tobacco field, little is known regarding patterns of cessation attempts related to alcohol, opioid, stimulant, or cannabis problems. Greater knowledge of such estimates and the factors associated with needing fewer or greater attempts may have utility for health policy and clinical communication efforts and approaches. Methods Cross-sectional, nationally representative survey of U.S. adults (N = 39,809) who reported resolving a significant AOD problem (n = 2,002) and assessed on number of prior serious recovery attempts, demographic variables, primary substance, clinical histories, and indices of psychological distress and well-being. Results The statistical distribution of serious recovery attempts was highly skewed with a mean of 5.35 (SD = 13.41) and median of 2 (interquartile range [IQR] = 1 to 4). Black race, prior use of treatment and mutual-help groups, and history of psychiatric comorbidity were associated with higher number of attempts, and more attempts were associated independently with greater current distress. Number of recovery attempts did not differ by primary substance (e.g., opioids vs. alcohol). Conclusions Estimates of recovery attempts differed substantially depending on whether the mean (5.35 recovery attempts) or median (2 recovery attempts) was used as the estimator. Implications of this are that the average may be substantially lower than anticipated because cultural expectations are often based on AOD problems being "chronically relapsing" disorders implicating seemingly endless tries. Depending on which one of these estimates is reported in policy documents or communicated in public health announcements or clinical settings, each may elicit varying degrees of help-seeking, hope, motivation, and the use of more assertive clinical approaches. The more fitting, median estimate of attempts should be used in clinical and policy communications given the distribution.

A Prospective Study of Health Conditions Related to Alcohol Consumption Cessation Among 97,852 Drinkers Aged 45 and Over in Australia.

Abstract: Background Evidence suggests that people who develop serious health conditions are likely to cease drinking alcohol (sometimes known as "sick-quitters"). We quantified the likelihood of quitting drinking in relation to the onset of a variety of health conditions. Methods Odds ratios (ORs) and 95% confidence intervals (CIs) of ceasing alcohol consumption after diagnosis of 28 health conditions and 4 general indicators of health were derived from logistic regression among 97,852 drinkers aged ≥ 45 years between baseline (2006 to 2009) and median 5.3 years of follow-up in the New South Wales 45 and Up Study. Incident health conditions at follow-up were self-reported. Results At follow-up, 9.6% (n = 9,438) of drinkers had ceased drinking. Drinking cessation was significantly associated with 24 of 32 health conditions examined: 15.4% of participants with newly diagnosed diabetes quit drinking (OR for quitting vs. continuing 1.77, 95% CI: 1.60 to 1.96), 16.4% with Parkinson's disease (1.71, 1.35 to 2.17), 17.8% with poor memory (1.68, 1.43 to 1.97), 19.2% with hip fracture (1.64, 1.30 to 2.06), 14.7% with stroke (1.45, 1.27 to 1.66), 12.5% with depression (1.40, 1.26 to 1.55), 15.0% with breast cancer (1.38, 1.18 to 1.61), 12.3% with heart disease (1.34, 1.25 to 1.44), and 13.3% with osteoarthritis (1.22, 1.12 to 1.33). Strong associations with quitting were observed in those with a decline in self-rated overall health (2.93, 2.53 to 3.40) and quality of life (2.68, 2.24 to 3.21). Some health conditions not significantly associated with quitting were prostate cancer, melanoma, nonmelanoma skin cancer, hay fever, and hearing loss. Findings were generally consistent for men and women, by age group and by smoking status. Conclusions Diagnosis with a variety of health conditions appears to prompt drinking cessation in older adults.

Maintenance of World Health Organization Risk Drinking Level Reductions and Posttreatment Functioning Following a Large Alcohol Use Disorder Clinical Trial.

Abstract: BACKGROUND Reductions in the World Health Organization (WHO) risk drinking levels have been proposed as an alternative primary outcome for alcohol clinical trials. Yet, little is known about whether reductions in WHO risk drinking levels can be maintained over time. The current study examined whether reductions in WHO risk drinking levels were maintained for up to 1 year following treatment, and whether reductions over time were associated with improvements in functioning. METHODS Secondary data analysis of individuals with alcohol dependence (n = 1,226) enrolled in the COMBINE study, a multisite, randomized, placebo-controlled clinical trial. Logistic regression was used to examine the maintenance of end-of-treatment WHO risk level reductions and WHO risk level reductions at the 1-year follow-up. Repeated-measures mixed models were used to examine the association between WHO risk level reductions and functional outcomes over time. RESULTS Achieving at least a 1- or 2-level reduction in risk by the end of treatment was significantly associated with WHO risk level reductions at the 1-year follow-up assessment (p < 0.001). Among individuals who achieved at least a 1-level reduction by the end of treatment, 85.5% reported at least a 1-level reduction at the 1-year follow-up. Among individuals who achieved at least a 2-level reduction by the end of treatment, 77.8% reported at least a 2-level reduction at the 1-year follow-up. WHO risk level reductions were associated with significantly lower alcohol consumption, better physical health (p < 0.01), and fewer alcohol-related consequences (p < 0.001) up to 1 year following treatment. CONCLUSIONS One- and 2-level reductions in WHO risk levels during alcohol treatment were maintained after treatment and associated with better functioning over time. These findings support the use of the WHO risk level reductions as an outcome measure that reflects clinically significant improvement in how individuals seeking treatment for alcohol use disorder feel and function.

Hunting for What Works: Adolescents in Addiction Treatment.

Abstract: Although adolescents are developmentally distinct from adults, they often receive addiction treatment based on adult models. This is problematic because adolescents face significantly different conditions in addiction treatment, including distinct basic biological and neurodevelopmental stages, unique sociodevelopmental concerns, distinctive addiction trajectories, and, in turn, disparate treatment goals and outcomes. In sum, it can be difficult for even savvy clinicians to know how to approach addiction treatment with this important age group. In an effort to help clinicians and researchers consider substance use via a neurodevelopmental lens, we approached this review with 4 goals: (i) characterize the prevalence, and related health and safety implications of substance use within this age group; (ii) identify the nature of the adolescent brain, including characteristic features of this phase of neurodevelopment relevant to adolescent substance use treatment; (iii) provide an overview of current adolescent addiction interventions and avenues to improve clinical treatment and clinical research efforts for adolescents; and (iv) examine the intersection between the nature of the developing brain and adolescent substance use, and utilize that information to inform alternative routes and directions for substance use treatment in this critical age group. This review concludes by offering a novel neurodevelopmental model and framework to examine substance use interventions, along with a series of recommendations to optimize adolescent substance use treatment and clinical research.

Gender Differences in Use of Alcohol Treatment Services and Reasons for Nonuse in a National Sample.

Abstract: BACKGROUND The majority of adults with alcohol use disorders do not obtain help, and women are less likely to utilize alcohol services than men. We sought to quantify gender differences in alcohol services utilization, overall and by type, using national longitudinal data and to explore potential gender differences in perceived need for help and reasons for not seeking help. METHODS We analyzed data from the National Epidemiologic Survey on Alcohol and Related Conditions from White, African American, and Hispanic adults (n = 2,592) who met DSM-IV criteria for alcohol abuse or dependence at Wave 1 (2000 to 2001). We tested gender differences in Wave 2 (2004 to 2005) services utilization, perceived need for help, and treatment barriers using Rao-Scott chi-square tests and assessed predictors of outcomes in multivariable logistic regression, adjusting for problem severity, co-occurring disorders, and demographics. RESULTS Women had much lower odds than men of utilizing any alcohol service (adjusted odds ratio [aOR] 0.53; 95% confidence interval [95% CI]: 0.33, 0.86), specialty services (aOR 0.41; 95% CI 0.19, 0.87), and 12-step groups (aOR 0.39; 95% CI 0.21, 0.71). Perceived need for help among those who had not used any services was very low (5%), with no gender difference. Further, men and women reported equivalent numbers of treatment barriers and the same rank order for the most frequently endorsed barriers. However, women were twice as likely as men to think a problem would get better by itself-the most frequent reason for not seeking help (47% vs. 24%, p < 0.001), and men were more likely than women to report unsuccessful past help-seeking and not thinking anyone could help (19% vs. 3%, p < 0.001 and 17% vs. 5%, p = 0.001, respectively). CONCLUSIONS Consistent with previous studies, women were less likely to utilize alcohol services than men. Future interventions should address low problem recognition, and tailoring to gender-specific barriers may help close the disparity in services utilization.

DSM-5 Alcohol Use Disorder Severity as a Function of Sexual Orientation Discrimination: A National Study

Abstract: Background Sexual minorities are more likely than their heterosexual counterparts to develop alcohol use disorder (AUD), and understanding the underlying reasons for this heightened risk is a public health priority. This study examined relationships between sexual orientation discrimination and DSM-5 AUD severity. Methods The 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions III conducted in-person interviews with a nationally representative sample of U.S. adults (N = 36,309). Approximately 2.8% of the target population self-identified as lesbian, gay, or bisexual, 3.1% had at least 1 past-year same-sex sexual partner, and 8.3% reported same-sex sexual attraction. Results Adults who identified as lesbian, gay, bisexual, heterosexual with same-sex attraction and/or current same-sex sexual partners, and those not sure of their sexual identity, had higher rates of individual DSM-5 AUD criteria than heterosexual-identified adults with only opposite-sex attraction and sexual partners. Respondents who were bisexual or unsure of their sexual identity consistently had the highest probabilities of endorsing each of these AUD criteria relative to the other subgroups. Differences in AUD severity across sexual orientation subgroups were much larger among women than among men. Sexual minorities who experienced higher levels of sexual orientation discrimination had significantly higher levels of AUD severity than sexual minorities who experienced lower levels or no discrimination. In particular, greater levels of sexual orientation discrimination increased the odds of impaired control criteria and pharmacologic criteria. Associations between prior-to-past-year sexual orientation discrimination and AUD severity were not as robust as those involving past-year discrimination. Conclusions Sexual minorities are at substantially greater risk of severe DSM-5 AUD, and this is particularly true among those who experience high levels of sexual orientation discrimination. Findings indicate that proximal experiences of discrimination are more salient than distal experiences. AUD treatment should address recent sexual orientation discrimination given that such experiences are associated with more severe AUD.

Advancing Precision Medicine for Alcohol Use Disorder: Replication and Extension of Reward Drinking as a Predictor of Naltrexone Response.

Abstract: Background Precision medicine aims to identify those patients who will benefit the most from specific treatments. Recent work found large effects of naltrexone among "reward drinkers," defined as individuals who drink primarily for the rewarding effects of alcohol. This study sought to replicate and extend these recent findings by examining whether the desire to drink mediated the effect of naltrexone among reward drinkers. Methods We conducted a secondary analysis of a 12-week randomized clinical trial of daily or targeted naltrexone among problem drinkers (n = 163), with a focus on 86 individuals (n = 45 naltrexone and n = 41 placebo) who received daily medication. Interactive voice response technology was used to collect daily reports of drinking and desire to drink. Factor mixture models were used to derive reward and relief phenotypes. Moderation analyses were used to evaluate naltrexone effects, with phenotype as a moderator variable. Multilevel mediation tested average desire to drink as a mediator. Results Results indicated 4 phenotypes: low reward/low relief; low reward/high relief; high reward/low relief; and high reward/high relief. There was an interaction between the high reward/low relief subgroup (n = 10) and daily naltrexone versus placebo on drinks per drinking day (DPDD; p = 0.03), percent heavy drinking days (p = 0.004), and daily drinking (p = 0.02). As compared to placebo, individuals in the high reward/low relief phenotype who received daily naltrexone had significantly fewer DPDD (Cohen's d = 2.05) and had a lower proportion of heavy drinking days (Cohen's d = 1.75). As hypothesized, reductions in average desire to drink mediated the effect of naltrexone on average daily drinking among the high reward/low relief drinkers (moderated mediation effect: p = 0.029). Conclusions This theory-driven study replicates the empirical finding that naltrexone is particularly efficacious among high reward/low relief drinkers. Our study brings the field a step closer to the potential of using a precision medicine approach to treating alcohol use disorder.

Event-Level Correlates of Drinking Events Characterized by Alcohol-Induced Blackouts.

Abstract: Background Prior research identifies a range of potential predictors of blackouts and suggests that blackouts increase risk for additional negative consequences. However, these studies are based on epidemiological work that allows us to draw conclusions about groups of people but not within-person processes. The present study examined within-person, event-level correlates of blackouts. Methods Ninety-six heavy drinking college students (52% female) completed 28 days of daily reports of alcohol use and consequences, including blackouts. Thirty-three participants reported 56 blackouts. Hierarchical linear modeling compared morning reports of drinking events on which participants did versus did not report a blackout, controlling for total drinks at the event. Results Blackout likelihood increased as a function of total drinks consumed and of crossing thresholds for heavy episodic drinking (4+/5+ drinks for women/men) and high-intensity drinking (8+/10+). Participants reported a higher total number of additional negative consequences on blackout events. Specific consequences that were more likely included embarrassing oneself and hangover. Blackouts were associated with morning ratings of less positive mood and a less favorable drinking event. Motives for drinking and simultaneous use of marijuana were not associated with blackouts. Conclusions Event-level findings of this study document that events leading to alcohol-induced memory loss are associated with other adverse experiences relative to drinking events that do not result in blackout, and offer potentially motivational levers for preventive interventions.

Technology-Delivered Cognitive-Behavioral Interventions for Alcohol Use: A Meta-Analysis.

Abstract: Background Cognitive-behavioral therapy (CBT) has long-standing evidence for efficacy in the treatment of alcohol use, yet implementation in clinical practice has been challenging. Delivery of CBT through technology-based platforms, such as web-based programs and mobile applications, has the potential to provide widespread access to this evidence-based intervention. While there have been reviews indicating the efficacy of technology-based delivery of CBT for various psychiatric conditions, none have focused on efficacy for alcohol use. The current meta-analysis was conducted to fill this research gap. Methods Descriptive data were used to characterize the nature of the literature on technology-delivered, CBT-based interventions for alcohol use ("CBT Tech"). Inverse-variance-weighted effect sizes were calculated, and random effects, effect sizes were pooled in 4 subgroups. Results Fifteen published trials conducted primarily with at-risk or heavy drinkers were identified. Of these studies, 60% explicitly targeted alcohol use moderation. The content of CBT Tech programs varied, ranging from 4 to 62 sessions/exercises, with many programs combining elements of motivational interviewing (47%). With respect to efficacy, CBT Tech as a stand-alone treatment in contrast to a minimal treatment control showed a positive and statistically significant, albeit small effect (g = 0.20: 95% CI = 0.22, 0.38, kes = 5). When CBT Tech was compared to treatment as usual (TAU), effects were nonsignificant. However, when CBT Tech was tested as an addition to TAU, in contrast to TAU only, the effect size was positive, significant (g = 0.30: 95% CI = 0.10, 0.50, kes = 7), and stable over 12-month follow-up. Only 2 studies compared CBT Tech to in-person CBT, and this pooled effect size did not suggest superior efficacy. Conclusions These results show a benefit for technology-delivered, CBT-based interventions as a stand-alone therapy for heavy drinking or as an addition to usual care in specialty substance use settings.

Ethanol Exposure Increases miR-140 in Extracellular Vesicles: Implications for Fetal Neural Stem Cell Proliferation and Maturation.

Abstract: Background Neural stem cells (NSCs) generate most of the neurons of the adult brain in humans, during the mid-first through second-trimester period. This critical neurogenic window is particularly vulnerable to prenatal alcohol exposure, which can result in diminished brain growth. Previous studies showed that ethanol (EtOH) exposure does not kill NSCs, but, rather, results in their depletion by influencing cell cycle kinetics and promoting aberrant maturation, in part, by altering NSC expression of key neurogenic miRNAs. NSCs reside in a complex microenvironment rich in extracellular vesicles, shown to traffic miRNA cargo between cells. Methods We profiled the miRNA content of extracellular vesicles from control and EtOH-exposed ex vivo neurosphere cultures of fetal NSCs. We subsequently examined the effects of one EtOH-sensitive miRNA, miR-140-3p, on NSC growth, survival, and maturation. Results EtOH exposure significantly elevates levels of a subset of miRNAs in secreted extracellular vesicles. Overexpression of one of these elevated miRNAs, miR-140-3p, and its passenger strand relative, miR-140-5p, significantly increased the proportion of S-phase cells while decreasing the proportion of G0 /G1 cells compared to controls. In contrast, while miR-140-3p knockdown had minimal effects on the proportion of cells in each phase of the cell cycle, knockdown of miR-140-5p significantly decreased the proportion of cells in G2 /M phase. Furthermore, miR-140-3p overexpression, during mitogen-withdrawal-induced NSC differentiation, favors astroglial maturation at the expense of neural and oligodendrocyte differentiation. Conclusions Collectively, the dysregulated miRNA content of extracellular vesicles following EtOH exposure may result in aberrant neural progenitor cell growth and maturation, explaining brain growth deficits associated with prenatal alcohol exposure.

Driving the Downward Spiral: Alcohol-Induced Dysregulation of Extended Amygdala Circuits and Negative Affect.

Abstract: Alcohol use disorder (AUD) afflicts a large number of individuals, families, and communities globally. Affective disturbances, including stress, depression, and anxiety, are highly comorbid with AUD, contributing in some cases to initial alcohol use and continued use. Negative affect has a particularly strong influence on the withdrawal/abstinence stage of addiction as individuals with AUD frequently report stressful events, depression, and anxiety as key factors for relapse. Treatment options for negative affect associated with AUD are limited and often ineffective, highlighting the pressing need for preclinical studies examining the underlying neural circuitry driving AUD-associated negative affect. The extended amygdala (EA) is a set of brain areas collectively involved in generating and regulating affect, and extensive research has defined a critical role for the EA in all facets of substance use disorder. Here, we review the expansive historical literature examining the effects of ethanol exposure on the EA, with an emphasis on the complex EA neural circuitry driving negative affect in all phases of the alcohol addiction cycle. Specifically, this review focuses on the effects of alcohol exposure on the neural circuitry in 2 key components of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Additionally, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and neural circuitry in the EA, with the long-term goal of developing better diagnostic tools and new pharmacological targets aimed at treating negative affect in AUD. The concepts detailed here will serve as the foundation for a companion review focusing on the potential for the endogenous cannabinoid system in the EA as a novel target for treating the stress, anxiety, and negative emotional state driving AUD.

Sex Differences in Ethanol Reward Seeking Under Conflict in Mice

Abstract: Background Alcohol use disorders are characterized by inflexible alcohol seeking that occurs despite adverse consequences. Males and females are differentially sensitive to ethanol (EtOH) reward, but it is unclear whether sex differences in EtOH seeking under reward-aversion conflict are present. Methods To investigate sex differences in EtOH seeking under conflict, adult male and female C57BL/6J mice underwent chronic intermittent EtOH (CIE) exposure by vapor inhalation or served as air-exposed controls. After CIE, mice were trained in a modified EtOH conditioned place preference paradigm. During 3 conditioning sessions, 2 g/kg EtOH was administered prior to confinement in the "EtOH-paired" chamber. On alternating days, saline was injected prior to confinement in the "saline-paired" chamber. After conditioning, mice experienced a footshock in the EtOH-paired chamber. EtOH-seeking behavior was assessed before and after footshock. Results Control and CIE-exposed males reduced the time spent in and increased latency to enter the reward-paired chamber following footshock. Control females did not alter EtOH-seeking behavior following footshock. CIE-exposed females spent more time in the EtOH-paired chamber at baseline. However, following a footshock, CIE-exposed females significantly reduced the time spent in and increased latency to enter the EtOH-paired chamber. Conclusions Nondependent female mice exhibited aversion-resistant alcohol seeking to a greater degree than males. Chronic EtOH exposure did not impact EtOH seeking in males. In females, CIE enhanced EtOH seeking in the absence of conflict, but reduced EtOH seeking after an aversive experience. While these sex-specific effects of CIE are not present when reward seeking is assessed in the absence of an aversive experience, multiple factors may underlie the differences in reward seeking despite adverse consequences, including reward- and aversion-related learning and decision making under conflict. These data highlight the importance of considering sex as a variable influencing EtOH seeking and provide a greater understanding of how sex interacts with EtOH exposure to alter behavior.

Microsomal Ethanol-Oxidizing System: Success Over 50 Years and an Encouraging Future.

Abstract: Fifty years ago, in 1968, the pioneering scientists Charles S. Lieber and Leonore M. DeCarli discovered the capacity for liver microsomes to oxidize ethanol (EtOH) and named it the microsomal ethanol-oxidizing system (MEOS), which revolutionized clinical and experimental alcohol research. The last 50 years of MEOS are now reviewed and highlighted. Since its discovery and as outlined in a plethora of studies, significant insight was gained regarding the fascinating nature of MEOS: (i) MEOS is distinct from alcohol dehydrogenase and catalase, representing a multienzyme complex with cytochrome P450 (CYP) and its preferred isoenzyme CYP 2E1, NADPH-cytochrome P450 reductase, and phospholipids; (ii) it plays a significant role in alcohol metabolism at high alcohol concentrations and after induction due to prolonged alcohol use; (iii) hydroxyl radicals and superoxide radicals promote microsomal EtOH oxidation, assisted by phospholipid peroxides; (iv) new aspects focus on microsomal oxidative stress through generation of reactive oxygen species (ROS), with intermediates such as hydroxyethyl radical, ethoxy radical, acetyl radical, singlet radical, hydroxyl radical, alkoxyl radical, and peroxyl radical; (v) triggered by CYP 2E1, ROS are involved in the initiation and perpetuation of alcoholic liver injury, consequently shifting the previous nutrition-based concept to a clear molecular-based disease; (vi) intestinal CYP 2E1 induction and ROS are involved in endotoxemia, leaky gut, and intestinal microbiome modifications, together with hepatic CYP 2E1 and liver injury; (vii) circulating blood CYP 2E1 exosomes may be of diagnostic value; (viii) circadian rhythms provide high MEOS activities associated with significant alcohol metabolism and potential toxicity risks as a largely neglected topic; and (ix) a variety of genetic animal models are useful and have been applied elucidating mechanistic aspects of MEOS. In essence, MEOS along with its CYP 2E1 component currently explains several mechanistic steps leading to alcoholic liver injury and has a promising future in alcohol research.