Upregulation of cannabinoid type 1 receptors in dopamine D2 receptor knockout mice is reversed by chronic forced ethanol consumption

Background: The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R–DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol’s reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. Methods: We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2?/? mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [³H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. Results: We found that the lack of DRD2 leads to a marked upregulation (approximately 2‐fold increase) of CB1R in the cerebral cortex, the caudate‐putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. Conclusions: The results suggest that DRD2‐mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.     

Loss of dopamine D2 receptors induces atrophy in the temporal and parietal cortices and the caudal thalamus of ethanol-consuming mice

Background: The need of an animal model of alcoholism becomes apparent when we consider the genetic diversity of the human populations, an example being dopamine D2 receptor (DRD2) expression levels. Research suggests that low DRD2 availability is associated with alcohol abuse, while higher DRD2 levels may be protective against alcoholism. This study aims to establish whether (i) the ethanol‐consuming mouse is a suitable model of alcohol‐induced brain atrophy and (ii) DRD2 protect the brain against alcohol toxicity. Methods: Adult Drd2+/+ and Drd2?/? mice drank either water or 20% ethanol solution for 6 months. At the end of the treatment period, the mice underwent magnetic resonance (MR) imaging under anesthesia. MR images were registered to a common space, and regions of interest were manually segmented. Results: We found that chronic ethanol intake induced a decrease in the volume of the temporal and parietal cortices as well as the caudal thalamus in Drd2?/? mice. Conclusions: The result suggests that (i) normal DRD2 expression has a protective role against alcohol‐induced brain atrophy and (ii) in the absence of Drd2 expression, prolonged ethanol intake reproduces a distinct feature of human brain pathology in alcoholism, the atrophy of the temporal and parietal cortices.     

Longitudinal assessment of drinking changes during the pandemic: The 2021 COVID-19 follow-up study to the 2019 to 2020 National Alcohol Survey

Background

Surveys of changes in drinking during the COVID-19 pandemic have primarily relied on retrospective self-report. Further, most such surveys have not included detailed measures of alcohol use patterns, such as beverage-specific consumption, nor measures of alcohol use disorder (AUD) symptoms that would allow a comprehensive understanding of changes in alcohol use.

Methods

Data from 1819 completed interviews from the N14C follow-up survey to the 2019 to 2020 National Alcohol Survey (N14) were conducted between January 30 and March 28, 2021. Questions on alcohol use from the Graduated Frequency series, beverage-specific quantity and frequency, and DSM-5 AUD items were asked in both surveys and used to estimate changes from pre-pandemic drinking to drinking during the pandemic. Analyses focus on changes in these measures over time and comparisons between key subgroups defined by gender, race/ethnicity, and age.

Results

Key findings include particularly large increases in drinking and AUD for African Americans and women, reduced drinking and heavy drinking prevalence among men and White respondents, and a concentration of increased drinking and AUD among respondents aged 35 to 49. Increases in alcohol use were found to be driven particularly by increases in drinking frequency and the consumption of spirits.

Conclusions

Results confirm prior findings of overall increases and subgroup-specific changes, and importantly, provide detailed information on the patterns of change across major socio-demographic subgroups. Substantial increases in the prevalence of DSM-5 moderate to severe AUDs are a novel finding that is of particular concern.

     

Reducing the standard serving size of alcoholic beverages prompts reductions in alcohol consumption

Aims

To test whether reducing the standard serving size of alcoholic beverages would reduce voluntary alcohol consumption in a laboratory (study 1) and a real‐world drinking environment (study 2). Additionally, we modelled the potential public health benefit of reducing the standard serving size of on‐trade alcoholic beverages in the United Kingdom.

Design

Studies 1 and 2 were cluster‐randomized experiments. In the additional study, we used the Sheffield Alcohol Policy Model to estimate the number of deaths and hospital admissions that would be averted per year in the United Kingdom if a policy that reduces alcohol serving sizes in the on‐trade was introduced.

Setting

A semi‐naturalistic laboratory (study 1), a bar in Liverpool, UK (study 2).

Participants

Students and university staff members (study 1: n = 114, mean age = 24.8 years, 74.6% female), residents from local community (study 2: n = 164, mean age = 34.9 years, 57.3% female).

Interventions and comparators

In study 1, participants were assigned randomly to receive standard or reduced serving sizes (by 25%) of alcohol during a laboratory drinking session. In study 2, customers at a bar were served alcohol in either standard or reduced serving sizes (by 28.6–33.3%).

Measurements

Outcome measures were units of alcohol consumed within 1 hour (study 1) and up to 3 hours (study 2). Serving size condition was the primary predictor.

Findings

In study 1, a 25% reduction in alcohol serving size led to a 20.7–22.3% reduction in alcohol consumption. In study 2, a 28.6–33.3% reduction in alcohol serving size led to a 32.4–39.6% reduction in alcohol consumption. Modelling results indicated that decreasing the serving size of on‐trade alcoholic beverages by 25% could reduce the number of alcohol‐related hospital admissions and deaths per year in the United Kingdom by 4.4–10.5% and 5.6–13.2%, respectively.

Conclusions

Reducing the serving size of alcoholic beverages in the United Kingdom appears to lead to a reduction in alcohol consumption within a single drinking occasion.     

Genes regulating levels of ω-3 long-chain polyunsaturated fatty acids are associated with alcohol use disorder and consumption,and broader externalizing behavior in humans

Background

Individual variation in the physiological response to alcohol is predictive of an individual's likelihood to develop alcohol use disorder (AUD). Evidence from diverse model organisms indicates that the levels of long-chain polyunsaturated omega-3 fatty acids (ω-3 LC-PUFAs) can modulate the behavioral response to ethanol and therefore may impact the propensity to develop AUD. While most ω-3 LC-PUFAs come from diet, humans can produce these fatty acids from shorter chain precursors through a series of enzymatic steps. Natural variation in the genes encoding these enzymes has been shown to affect ω-3 LC-PUFA levels. We hypothesized that variation in these genes could contribute to the susceptibility to develop AUD.

Methods

We identified nine genes (FADS1, FADS2, FADS3, ELOVL2, GCKR, ELOVL1, ACOX1, APOE, and PPARA) that are required to generate ω-3 LC-PUFAs and/or have been shown or predicted to affect ω-3 LC-PUFA levels. Using both set-based and gene-based analyses we examined their association with AUD and two AUD-related phenotypes, alcohol consumption, and an externalizing phenotype.

Results

We found that the set of nine genes is associated with all three phenotypes. When examined individually, GCKR, FADS2, and ACOX1 showed significant association signals with alcohol consumption. GCKR was significantly associated with AUD. ELOVL1 and APOE were associated with externalizing.

Conclusions

Taken together with observations that dietary ω-3 LC-PUFAs can affect ethanol-related phenotypes, this work suggests that these fatty acids provide a link between the environmental and genetic influences on the risk of developing AUD.

     

Emotion differentiation in early recovery from alcohol use disorder: Associations with in-the-moment affect and 3-month drinking outcomes

Background

Early recovery from alcohol use disorder (AUD) is commonly associated with high levels of negative affect, stress, and emotional vulnerability, which confer significant relapse risk. Emotion differentiation—the ability to distinguish between discrete emotions—has been shown to predict relapse after treatment for a drug use disorder, but this relationship has not been explored in individuals recovering from AUD.

Methods

The current study used thrice daily random and up to thrice daily self-initiated ecological momentary assessment surveys (N = 42, observations = 915) to examine whether 1) moments of high affective arousal are characterized by momentary differences in emotion differentiation among individuals in the first year of a current AUD recovery attempt, and 2) individuals’ average emotion differentiation would predict subsequent alcohol use measured by the timeline follow-back over a 3-month follow-up period.

Results

Multilevel models showed that moments (Level 1) of higher-than-average negative affect (p < 0.001) and/or stress (p = 0.033) were characterized by less negative emotion differentiation, while moments of higher-than-average positive affect were characterized by greater positive emotion differentiation (p < 0.001). At the between-person level (Level 2), participants with higher stress overall had lower negative emotion differentiation (p = 0.009). Linear regression showed that average negative, but not positive, emotion differentiation was inversely associated with percent drinking days over the subsequent 3-month follow-up period (p = 0.042). Neither form of average emotion differentiation was associated with drinking quantity.

Conclusions

We found that for individuals in early AUD recovery, affective states are associated with acute shifts in the capacity for emotion differentiation. Further, we found that average negative emotion differentiation prospectively predicts subsequent alcohol use.

     

A latent class analysis of DSM-IV alcohol use disorder criteria and binge drinking in undergraduates

Background: Adolescent and adult samples have shown that the Diagnostic and Statistical Manual of Mental Disorders‐IV (DSM‐IV) abuse and dependence criteria lie on a continuum of alcohol problem severity, but information on criteria functioning in college students is lacking. Prior factor analyses in a college sample ( Beseler et al., 2010 ) indicated that a 2‐factor solution fit the data better than a single‐factor solution after a binge drinking criterion was included. The second dimension may indicate a clustering of criteria related to excessive alcohol use in this college sample. Methods: The present study was an analysis of data from an anonymous, online survey of undergraduates (N = 361) that included items pertaining to the DSM‐IV alcohol use disorder (AUD) diagnostic criteria and binge drinking. Latent class analysis (LCA) was used to determine whether the criteria best fit a categorical model, with and without a binge drinking criterion. Results: In an LCA including the AUD criteria only, a 3‐class solution was the best fit. Binge drinking worsened the fit of the models. The largest class (class 1, n = 217) primarily endorsed tolerance (18.4%); none were alcohol dependent. The middle class (class 2, n = 114) endorsed primarily tolerance (81.6%) and drinking more than intended (74.6%); 34.2% met criteria for dependence. The smallest class (class 3, n = 30) endorsed all criteria with high probabilities (30 to 100%); all met criteria for dependence. Alcohol consumption patterns did not differ significantly between classes 2 and 3. Class 3 was characterized by higher levels on several variables thought to predict risk of alcohol‐related problems (e.g., enhancement motives for drinking, impulsivity, and aggression). Conclusions: Two classes of heavy‐drinking college students were identified, one of which appeared to be at higher risk than the other. The highest risk group may be less likely to “mature out” of high‐risk drinking after college.     

Major life events and risk of alcohol use disorders: a prospective cohort study

Aims

To estimate associations of individual major life events as well as accumulated major life events in childhood, adult private life and adult work life with risk of alcohol use disorders (AUD).

Design

Prospective cohort study with baseline examination in 1991–93 and linkage to national registers to identify AUD at follow‐up.

Setting

Copenhagen, Denmark.

Participants

Individuals (aged 21–93 years) who participated in the Copenhagen City Heart Study in 1991–93 (n = 8758).

Measurements

The primary outcome was first registration with AUD during follow‐up (n = 249). AUD was identified in the Danish National Patient Register, in the Danish Psychiatric Central Register and in an outpatient treatment register. Major life events were assessed by a questionnaire in the Copenhagen City Heart study. Data were analysed by Cox proportional hazards models adjusted for age, sex, educational level, household income, cohabitation status and psychiatric comorbidity.

Findings

Serious family conflicts in childhood [hazard ratio (HR) = 1.35; 95% confidence interval (CI) = 1.00, 1.83] and serious economic problems in adult life (HR = 2.22; 95% CI = 1.64, 3.01) were associated significantly with increased risk of AUD. Prospective analyses did not show consistent effects of accumulation of major life events in childhood or adult life, but an additional analysis based on all AUD registrations suggested an association between accumulated childhood events and risk of AUD.

Conclusions

Serious economic problems in adult life are associated strongly with risk of alcohol use disorders, and there may be an influence of accumulated childhood events on risk of alcohol use disorders.     

Affective circuitry and risk for alcoholism in late adolescence: differences in frontostriatal responses between vulnerable and resilient children of alcoholic parents

Background: Children of alcoholics (COAs) are at elevated risk for alcohol use disorders (AUD), yet not all COAs will develop AUD. The 2 primary aims of this study were to identify neural activation mechanisms that may mark protection or vulnerability to AUD in COAs and to map the same activation patterns in relation to risk behavior (externalizing or internalizing behavior). Methods: Twenty‐two adolescent COAs were recruited from an ongoing community longitudinal study of alcoholic and matched control families. They were categorized as either vulnerable (n = 11) or resilient (n = 11) based on the level of problem drinking over the course of adolescence. Six other adolescents with no parental history of alcoholism, and no evidence of their own problem drinking were recruited from the same study and labeled as low‐risk controls. Valenced words were presented to the participants in a passive viewing task during functional magnetic resonance imaging. Activation to negative versus neutral words and positive versus neutral words were compared between groups. Behavior problems were assessed with the Youth Self‐Report (YSR). Results: The resilient COA group had more activation of the orbital frontal gyrus (OFG), bilaterally, and left insula/putamen than the control and vulnerable groups, in response to emotional stimuli. In contrast, the vulnerable group had more activation of the dorsomedial prefrontal cortex and less activation of the ventral striatum and extended amygdala, bilaterally, to emotional stimuli than the control and resilient groups. The vulnerable group had more externalizing behaviors which correlated with increased dorsomedial prefrontal activation and decreased ventral striatal and extended amygdala activation. Conclusions: These results are consistent with dissociable patterns of neural activation underlying risk and resiliency in COAs. We propose that the pattern observed in the resilient COAs represents an active emotional monitoring function, which may be a protective factor in this group. On the other hand, the vulnerable group displayed a pattern consistent with active suppression of affective responses, perhaps resulting in the inability to engage adaptively with emotional stimuli.     

Should symptom frequency be factored into scalar measures of alcohol use disorder severity?

Aims To evaluate whether weighting counts of alcohol use disorder (AUD) criteria or symptoms by their frequency of occurrence improves their association with correlates of AUD. Design and participants Data were collected in personal interviews with a representative sample of US adults interviewed in 1991–92. Analyses were conducted among past‐year drinkers (12+ drinks, n = 18 352) and individuals with past‐year DSM‐IV AUD (n = 2770). Measurements Thirty‐one symptom item indicators, whose frequency of occurrence was measured in eight categories, were used to create unweighted and frequency‐weighted counts of DSM‐IV past‐year AUD symptoms and criteria. Correlates included density of familial alcoholism and past‐year volume of ethanol intake, frequency of intoxication and utilization of alcohol treatment. Findings Although the AUD correlates were associated strongly and positively with the frequency of AUD symptom occurrence, weighting for symptom frequency did not strengthen their association consistently with AUD severity scores. Improved performance of the weighted scores was observed primarily among AUD correlates linked closely with the frequency of heavy drinking and among individuals with AUD. Criterion counts were correlated nearly as strongly as symptom counts with the AUD correlates. Conclusions Frequency weighting may add somewhat to the validity of AUD severity measures, especially those that are intended for use among individuals with AUD, e.g. in clinical settings. For studying the etiology and course of AUD in the general population, an equally effective and less time‐consuming alternative to obtaining symptom frequency may be the use of unweighted criterion counts accompanied by independent measures of frequency of heavy drinking.     

Stimulation of nicotinic acetylcholine receptors attenuates collagen‐induced arthritis in mice

Objective

The parasympathetic nervous system, through the vagus nerve, can down‐regulate inflammation in vivo by decreasing the release of cytokines, including tumor necrosis factor α (TNFα), by activated macrophages. The vagus nerve may exert antiinflammatory actions via a specific effect of its principal neurotransmitter, acetylcholine, on the α7 subunit of nicotinic acetylcholine receptors (α7nAChR) on macrophages. The present study was undertaken to obtain insight into the role of the cholinergic antiinflammatory pathway in arthritis.

Methods

To inhibit the cholinergic antiinflammatory pathway, mice were subjected to unilateral cervical vagotomy or sham surgery, after which arthritis was induced with type II collagen. In a separate study, nicotine was added to the drinking water of mice with collagen‐induced arthritis (CIA). In addition, we investigated the effects of intraperitoneally (IP)–injected nicotine and the specific α7nAChR agonist AR‐R17779.

Results

Clinical arthritis was exacerbated by vagotomy and ameliorated by oral nicotine administration. Moreover, oral nicotine inhibited bone degradation and reduced TNFα expression in synovial tissue. Both IP‐injected nicotine and AR‐R17779 ameliorated clinical arthritis and reduced synovial inflammation. This was accompanied by a reduction of TNFα levels in both plasma and synovial tissue. The effect of AR‐R17779 was more potent compared with that of nicotine and was associated with delayed onset of the disease as well as with protection against joint destruction.

Conclusion

These data provide the first evidence of a role of the cholinergic antiinflammatory pathway in the murine CIA model of rheumatoid arthritis.

     

Effect of a Comprehensive Lifestyle Modification Program on the Bone Density of Male Heavy Drinkers

Background: Heavy alcohol drinking is implicated in osteoporosis. Although abstinence is rapidly followed by a restoration of osteoblastic activity, little is known about the contributions of alcohol‐related factors or the effectiveness of a lifestyle modification program (LMP) on bone density. Methods: We conducted a study of 138 male alcoholic patients to investigate whether drinking history and concurrent factors were associated with the bone density of the calcaneus. A 2.5‐months LMP in an institutionalized setting was completed by 20 of them, and its effect on bone density, serum parathyroid hormone (PTH), and 1.25‐(OH)₂ vitamin D levels were assessed. Results: The patients had a high prevalence of daytime drinking (93.5%), continuous drinking (84.1%), and current smoking (82.0%) with mean duration of alcohol abuse of 30.0 ± 12.8 years. The patients had lower bone density than a reference control group (Z‐scores: ?0.45 ± 1.02). Multiple stepwise regression analysis identified age, poor activities of daily living (ADL), continuous drinking, absence of liver cirrhosis, depression, and dementia as determinants of low bone density. The bone density of the 20 participants in the LMP improved 2.3% (p = 0.0003) with a more ameliorating effect on bone density than a conventional abstinence therapy (p = 0.014 for interventional effect). The upper normal range of PTH levels at baseline were significantly decreased, and 1.25‐(OH)₂ vitamin D levels also had a trend toward decrease during the abstinence. Conclusions: Alcoholic patients may have many complications such as poor ADL and dementia, which are independently associated with decreased bone density. The results of this study support the idea that comprehensive approach to lifestyle factors to minimize risk of osteoporosis is the best way to improve bone density.     

Tryptophan-kynurenine metabolism during acute alcohol withdrawal in patients with alcohol use disorder: The role of immune activation

Background

Recent research has suggested that excessive alcohol consumption in patients with alcohol use disorder (AUD) is associated with chronic immune activation, which affects the metabolism of the neurotransmitter precursor amino acid tryptophan (TRP) and contributes to the complex pathophysiology of AUD. Our study investigated possible immune-associated alterations of TRP to kynurenine (KYN) metabolism in patients with AUD during acute alcohol withdrawal.

Methods

We measured serum concentrations of TRP, KYN, quinolinic (QUIN), kynurenic acid (KYNA), and the immune activation marker neopterin (NEO) at the first, fifth and 10th day of alcohol withdrawal in patients with AUD, who attended a standardized in-patient treatment program and underwent a detailed clinical assessment.

Results

Data from these individuals were compared to data from a reference control group (RCG). The primary outcome measures were the differences in serum concentrations of metabolites between AUD patients and RCG and correlations between NEO and metabolites of the tryptophan-kynurenine pathway. r = 0.695, p < 0.001) in the AUD group. Mixed models analysis showed that NEO concentrations were positively associated with QUIN but not with KYNA concentrations. Several behavioral symptoms correlated positively with QUIN concentrations and negatively with the KYNA/QUIN ratio.

Conclusions

Our findings demonstrate that the changes in TRP catabolism in acute alcohol withdrawal resulting in increased KYN production could reflect the involvement of immune-associated activation of the enzyme indoleamine 2,3-dioxygenase, as NEO concentrations correlated with the KYN/TRP ratio. In addition, our data show that this low-grade immune activation may cause an imbalance in the production of neurotoxic and neuroprotective kynurenine metabolites in AUD.     

Strain differences in alcohol-induced neurochemical plasticity: a role for accumbens glutamate in alcohol intake

Background: Repeated alcohol administration alters nucleus accumbens (NAC) basal glutamate content and sensitizes the capacity of alcohol to increase NAC extracellular glutamate levels. However, the relevance of alcohol‐induced changes in NAC glutamate for alcohol drinking behavior is under‐investigated. Methods: To examine the relationship between genetic variance in alcohol consumption and alcohol‐induced neuroadaptations within the NAC, in vivo microdialysis was conducted in the alcohol‐preferring C57BL/6J (B6) and alcohol‐avoiding DBA2/J (D2) mouse strains on injections 1 and 8 of repeated alcohol treatment (8 × 2 g/kg, IP). To confirm an active role for NAC glutamate in regulating alcohol drinking behavior, the glutamate reuptake inhibitor dl ‐threo‐β‐benzyloxyaspartic acid (TBOA) (300 μM) and the Group 2 metabotropic glutamate autoreceptor agonist (2R,4R)‐4‐aminopyrrolidine‐2,4‐dicarboxylate (APDC) (50 μM) were infused into the NAC of B6 and D2 mice prior to alcohol consumption in a 4 bottle‐choice test. Results: While strain differences were not apparent for NAC basal levels of dopamine, serotonin or γ‐amino butyric acid (GABA), repeated alcohol treatment elevated NAC basal glutamate content only in B6 mice. Strain differences in both the acute and the sensitized neurochemical responses to 2 g/kg alcohol were observed for all neurotransmitters examined. While the alcohol‐induced rise in NAC dopamine and glutamate levels sensitized in B6 mice, a sensitization was not observed in D2 animals. Moreover, B6 mice exhibited a sensitized serotonin and GABA response to alcohol followed repeated treatment, whereas neither tolerance nor sensitization was observed in D2 animals. An intra‐NAC APDC infusion reduced alcohol intake in both B6 and D2 mice by approximately 50%. In contrast, TBOA infusion elevated alcohol intake selectively in B6 mice. Conclusions: These data indicate an active role for NAC glutamate in regulating alcohol consumption in mice and support the hypothesis that predisposition to high alcohol intake involves genetic factors that facilitate alcohol‐induced adaptations in glutamate release within the NAC.     

Lifetime alcohol intake and pattern of alcohol consumption in patients with alcohol-induced pancreatitis in comparison with patients with alcohol use disorder

Objective: To examine lifetime drinking patterns in men and women with alcohol-induced pancreatitis (AIP) in comparison with patients with alcoholic use disorder (AUD) without pancreatic disease.

Methods: Alcohol consumption patterns were assessed using a validated questionnaire, the Lifetime Drinking History (LDH), during an outpatient visit. Patients diagnosed with AIP were matched for gender and age (+/? 5 years) with patients with AUD in addiction treatment.

Results: A total of 45 patients with AIP (35 males, 10 females) and 45 AUD patients were included. Alcohol consumption patterns were not significantly different between males and females with AIP and those with history of acute AIP and chronic pancreatitis (CP). Alcohol consumption patterns of AIP and AUD patients were similar in terms of onset age and duration of alcohol consumption, lifetime alcohol intake and drinks per drinking day. A higher proportion of binge drinking was found among patients with AUD than those with AIP (median 1.00 vs. 0.94, p?=?.01). Males with AUD had lower onset age (15 vs. 16 years, p?=?.03), higher total amount of spirits (35520 vs. 10450 drinks, p?=?.04) and higher proportion of binge drinking (1.00 vs. 0.97, p?=?.01) than males with AIP, whereas females with AIP and AUD had similar drinking patterns.

Conclusions: Alcohol drinking patterns and lifetime drinking history was similar in patients with AIP and patients with AUD. Males with AIP had lower total amount of spirits and lower proportion of binge drinking than those with AUD, suggesting the idiosyncratic etiology of AIP.     

Lifetime drinking history in patients with alcoholic liver disease and patients with alcohol use disorder without liver disease

Objective: To determine the differences in lifetime alcohol intake (LAI) and drinking patterns between patients with alcoholic liver disease (ALD) and alcohol use disorder (AUD) without notable liver injury and between males and females with ALD.

Methods: Alcohol drinking patterns were assessed using the Lifetime Drinking History (LDH) a validated questionnaire, during an outpatient visit. Patients with AUD, currently in addiction treatment, were matched for gender and age (±5 years) with the ALD group.

Results: A total of 39 patients with ALD (26 males and 13 females; median age 58) and equal number of AUD patients were included (median age 56 years). The onset age for alcohol drinking and duration of alcohol consumption was similar in ALD and AUD. The number of drinking days was higher in women with ALD than in women with AUD: 4075 [(3224–6504) versus 2092 (1296–3661), p?=?.0253]. The LAI and drinks per drinking day (DDD) were not significantly different between patients with ALD and AUD. Females with ALD had lower LAI than males with ALD: 32,934 (3224–6504) versus 50,923 (30,360–82,195), p?=?.0385, fewer DDD (p?=?.0112), and lower proportion of binge drinking as compared to males with ALD (p?=?.0274).

Conclusions: The total LAI was similar in patients with ALD and AUD. The number of drinking days over the lifetime was associated with the development of ALD in females. Females with ALD had significantly lower alcohol consumption than men with ALD despite similar duration in years of alcohol intake which supports the concept of female propensity of ALD.     

Age at first drink and the first incidence of adult-onset DSM-IV alcohol use disorders

Background: Existing studies of the association between age at first drink (AFD) and the risk of alcohol use disorders (AUD) suffer from inconsistent levels of control and designs that may inflate associations by failure to control for duration of exposure to risk. Methods: This study examined associations between AFD (ages <15 and 15–17 vs. 18+ years) and first incidence of DSM‐IV alcohol dependence, abuse, and specific AUD criteria over a 3‐year follow‐up in a longitudinal study of U.S. drinkers 18 years of age and older at baseline (n = 22,316), controlling for duration of exposure, family history, and a wide range of baseline and childhood risk factors. Results: After adjusting for all risk factors, the incidence of dependence was increased for AFD < 15 years (OR = 1.38) and for women only with AFD at ages 15 to 17 (OR = 1.54). The incidence of abuse was increased at AFD <15 and 15 to 17 years (OR = 1.52 and 1.30, respectively). Most dependence criteria showed significant associations with AFD, but hazardous drinking and continued drinking despite interpersonal problems were the only abuse criteria to do so. All associations were nonsignificant after controlling for volume of consumption, except that AFD at all ages <18 combined was associated with a reduced likelihood of impaired control, and AFD at ages 15 to 17 was associated with lower odds of drinking more/longer than intended among heavy‐volume drinkers. In a population of low‐risk drinkers that excluded those with positive family histories, personality disorders, and childhood risk factors, there were strong associations between early AFD (<18) and the incidence of dependence (OR = 3.79) and continued drinking despite physical/psychological problems (OR = 2.71), but no association with incidence of abuse. Conclusions: There is a robust association between AFD and the risk of AUD that appears to reflect willful rather than uncontrolled heavy drinking, consistent with misuse governed by poor decision‐making and/or reward‐processing skills associated with impaired executive cognitive function (ECF). Additional research is needed to determine causality in the role of impaired ECF, including longitudinal studies with samples of low‐risk adolescents.     

Impact of Long-Term Alcohol Consumption and Relapse on Genome-Wide DNA Methylation Changes in Alcohol-Dependent Subjects: A Longitudinal Study

Background

Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks.

Methods

Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent.

Results

Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample.

Conclusion

Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders.

     

Age and ethnic differences in the onset, persistence and recurrence of alcohol use disorder

Aims To estimate ethnic differences in three components of alcohol use disorder and alcohol dependence course (onset, persistence and recurrence) in a developmental framework. Design Longitudinal data from The National Epidemiologic Survey of Alcohol and Related Conditions (NESARC), collected using face‐to‐face interviews. Setting Civilian non‐institutionalized US population aged 18 years and older, with oversampling of Hispanics, blacks and those aged 18–24 years. Participants Individuals who completed both NESARC assessments, were not life‐long abstainers and were either white (n = 17 458), black (n = 4995), US‐born Hispanic (n = 2810) or Hispanic‐born outside the United States (n = 2389). Measurements Alcohol dependence (AD) and alcohol use disorder (AUD; abuse or dependence) onset, persistence and recurrence were examined using the Alcohol Use Disorders and Associated Disabilities Interview Schedule, DSM‐IV version. Findings Among men: relative to whites aged 18–29, AUD onset and persistence were elevated only in US‐born Hispanics aged 40 years and older; odds were reduced for all non‐US‐born Hispanics, older whites, most blacks and US‐born Hispanics aged 30–39. For AD, onset risk was elevated for all younger minority men and only reduced among non‐US‐born aged Hispanics 40 or older. For women: compared to young whites, non‐US‐born Hispanics were at decreased AUD and AD onset risk; AUD and AD onset and persistence were increased for older blacks and US‐born Hispanics. Conclusions In the United States, ethnic differences in alcohol disorder transitions (onset, persistence, and recurrence) vary across age, gender and whether a broad (alcohol use disorder) or narrow (alcohol dependence) alcohol definition is used. Evidence of increased risk for some transitions in minority groups suggests that attention should be paid to the course of alcohol use disorders, and that differences in prevalence should not be assumed to reflect differences in specific transitions.