Punishment of ethanol choice in group-housed male cynomolgus monkeys.

Alcohol use disorder treatment delivered outside hepatology clinic.

Culture, stigma, and inequities creating barriers in alcohol use disorder management in alcohol-associated liver disease.

Alcohol is among the leading contributors to the global burden of morbidity and mortality. Alcohol Use Disorders (AUD) account for the majority of this burden. Numerous interventions have demonstrated effectiveness in the treatment of AUD, but treatment response is modest and relapse rates remain high. No one treatment approach has demonstrated unequivocal superiority, prompting calls for individualised intervention strategies. Insufficient understanding of the mechanisms involved in AUD maintenance and treatment response impair the design and implementation of such approaches. The aim of this thesis was to progress understanding of potential treatment targets within personalised treatments for AUD. Alcohol craving, alcohol outcome expectancies, and rash impulsivity comprise the focus of this thesis, as each has been implicated in AUD maintenance and treatment response. A series of studies examining clinical applications of alcohol craving, outcome expectancies, and rash impulsivity within personalised AUD interventions were conducted.Study 1 (Chapter Two) examined the clinical utility of alcohol craving, focusing on issues of measurement. Highlighting the absence of a theoretically and psychometrically robust measure of craving which is also brief enough to be routinely administered within busy clinical settings, the study aimed to develop a new measure. Using data from 747 treatment seeking AUD patients the 22-item Alcohol Craving Experience Questionnaire (ACE) was reduced to 5-items while preserving its key theoretical elements, psychometric integrity, and clinical implications. The shortened ‘Mini ACE’ (MACE) is ideal for use with AUD populations in time-limited settings, such as weekly assessment in treatment contexts. An extended review of common issues in craving measurement is provided in the following chapter (Chapter Three). The chapter is intended to assist researchers and treatment providers in the selection, effective application, interpretation of the scales comprising the Alcohol Craving Experience Questionnaire.Study 2 (Chapter Four) highlights an absence of research on targeting alcohol outcome expectancies within Cognitive Behavioural Therapy (CBT) for AUD. Alcohol expectancies of 175 patients who completed a 12-week CBT program for AUD were assessed pre-and post-treatment. Several positive expectancies were predictive of drinking behaviour during treatment, and most reduced toward community norms post-treatment. However, positive expectancy change was not related to drinking behaviour during treatment, challenging cognitive theory emphasising the importance of this process. Increase in negative expectations of alcohols effect on mood was associated with fewer drinking days, supporting emphasis on modification of negative alcohol expectations within treatment. Further implications of both positive and negative alcohol outcome expectancies regarding AUD treatment are discussed.Study 3 (Chapter Five) is a large clinical randomised controlled trial (RCT; n = 379) examining the effectiveness of personalising AUD treatment based on individual differences in a) alcohol craving, b) alcohol outcome expectancies, and c) rash impulsivity. Patients were randomly assigned to Treatment as Usual (TAU, 8 sessions of standard CBT for AUD) or Targeted Treatment (TT). TT manualised content for 4 of 8-sessions sessions to address the risk-factor most elevated for each patient based on measures standardised by AUD norms (either Craving, Expectancy or Impulsivity). No significant differences in treatment outcome were observed between overall TT and standard, CBT (TAU) conditions. Craving and impulsivity, though not positive outcome expectancies, were found to reduce more for patients within their respective target modules. Only reduction in craving was associated with reduced drinking, supporting an indirect effect for personalised interventions targeting craving. The effectiveness of targeting rash impulsivity and outcome expectancies within personalised AUD could not be confirmed. Alcohol craving stands out as useful construct for consideration within future research of personalised interventions.Study 4 (Chapter Six) examined the association between alcohol craving and rash impulsivity in the prediction of treatment response. Craving and rash impulsivity were positively associated among 470 AUD patients. Both were found to predict lapse-risk during treatment, though impulsivity was mediated by craving. Patients with higher craving pre-treatment, were found to have more persistent craving as treatment progressed, which increased risk of lapse. These findings have clinical implications for the assessment and treatment of AUD, as well as theoretical implications for cognitive models of craving and impulsivity. The mediating role of craving is further considered in the context of the RCT findings (Chapter Three, Study 4).These four studies progress understanding of key mechanisms implicated within AUD maintenance and treatment response. Support was found for the utility of alcohol craving, outcome expectancies, and rash impulsivity as prognostic markers for AUD treatment. The novel contributions of this thesis pertain to understanding their utility as treatment targets. The processes which determine treatment response are complex, requiring equally sophisticated procedures to effectively adapt treatment to individuals. The findings of this program of research can inform the progression of such approaches.

In the United States there are approximately 14.4 million adults diagnosed with alcohol use disorder (AUD). Despite this, there is an incomplete understanding of how chronic stress influences the development of AUD. Previous studies have shown that long‐term alcohol drinking negatively impacts cognitive flexibility (the ability to alter behavior in response to changing contingencies) and impulsive choice (the tendency to overvalue smaller, immediate rewards compared to larger, delayed rewards). However, the timing and extent of deficits that result from specific drinking patterns have not been well‐characterized. A better understanding of the progression of cognitive dysfunction is critical because deficits in these processes can perpetuate problematic alcohol use. In the present study, group‐housed adult male cynomolgus monkeys formed social hierarchies, which represent a continuum from environmental enrichment in high‐ranking (dominant; DOM; n=6) monkeys to chronic social stress in low‐ranking (subordinate; SUB; n=6) monkeys. Monkeys were trained to drink an unflavored 4% ethanol (EtOH) solution via schedule induction, then had access to self‐administer EtOH 22 hours/day, 4 days/week in the home cage (“free access”) while concurrently pressing a lever to deliver food pellets. To assess the effects of EtOH consumption on cognitive flexibility, monkeys performed a stimulus discrimination and reversal task (SD/SDR) on non‐drinking days using home cage touchscreen technology. Three stimuli appeared on the screen and the task ended when the monkey chose the correct stimulus on 18 of 20 consecutive trials. The task was administered just after induction and again after 6 months of free access. At this point, two modifications were made to increase task difficulty. First, two stimuli were added as additional distractors. In addition, the session was extended to 90 minutes and the total number of reversals was measured. We also characterized impulsive choice using a mean adjusted delay discounting task just after induction and after 4 months of free access. We hypothesized that subordinate monkeys would have greater EtOH intakes versus dominant monkeys and, as a result, would show greater cognitive dysfunction. As hypothesized, subordinate monkeys maintained greater (1.77 ± 0.95 g/kg) mean daily EtOH intakes compared to dominant monkeys (0.85 ± 0.91 g/kg) during 6 months of free access. However, there were no significant differences between dominant and subordinate monkeys in discrimination or reversal trials to criterion, or number of errors at baseline or after 6 months of free access using the 3‐stimuli SD/SDR task. There were also no rank‐related differences in these dependent variables (or number of reversals completed) when the task was modified to include 5 stimuli. Regarding the delay discounting task, both groups showed decreased impulsive choice from baseline to 4 months of free access, however the effect was lesser in subordinates. Although there are rank‐related differences in mean EtOH intake, monkeys do not appear to have significant EtOH‐induced deficits in these two domains of cognitive function in the present study. This study is ongoing and results following one year of access to EtOH will be assessed.

Despite the significant medical and economic consequences of coexisting alcohol use disorder (AUD) in patients with cirrhosis, little is known about AUD treatment patterns and their impact on clinical outcomes in this population. We aimed to characterize the use of and outcomes associated with AUD treatment in patients with cirrhosis. This retrospective cohort study included Veterans with cirrhosis who received Veterans Health Administration care and had an index diagnosis of AUD between 2011 and 2015. We assessed the baseline factors associated with AUD treatment (pharmacotherapy or behavioral therapy) and clinical outcomes for 180 days following the first AUD diagnosis code within the study time frame. Among 93,612 Veterans with cirrhosis, we identified 35,682 with AUD, after excluding 2,671 who had prior diagnoses of AUD and recent treatment. Over 180 days following the index diagnosis of AUD, 5,088 (14%) received AUD treatment, including 4,461 (12%) who received behavioral therapy alone, 159 (0.4%) who received pharmacotherapy alone, and 468 (1%) who received both behavioral therapy and pharmacotherapy. In adjusted analyses, behavioral and/or pharmacotherapy-based AUD treatment was associated with a significant reduction in incident hepatic decompensation (6.5% vs. 11.6%, adjusted odds ratio [AOR], 0.63; 95% confidence interval [CI], 0.52, 0.76), a nonsignificant decrease in short-term all-cause mortality (2.6% vs. 3.9%, AOR, 0.79; 95% CI, 0.57, 1.08), and a significant decrease in long-term all-cause mortality (51% vs. 58%, AOR, 0.87; 95% CI, 0.80, 0.96). Most Veterans with cirrhosis and coexisting AUD did not receive behavioral therapy or pharmacotherapy treatment for AUD over a 6-month follow-up. The reductions in hepatic decompensation and mortality suggest that future studies should focus on delivering evidence-based AUD treatments to patients with coexisting AUD and cirrhosis.

Pharmacotherapy of Alcohol Use Disorders in the Veterans Health Administration

More than 3 million individuals receive treatment for alcohol use disorder (AUD) and/or substance use disorder each year, yet there exists no standardized method for measuring patient success in treatment. Quantifying a more comprehensive assessment of treatment outcomes could identify the relative efficacy of different treatment strategies for individuals with AUD/substance use disorders, and help patients to identify, in advance, appropriate treatment options. This study developed and embedded patient-reported outcome measures into the routine clinical operations of a residential treatment program. Surveys assessed demographics, drug use history, physical and mental health, and quality of life. Outcomes were assessed among participants at admission (n = 961) and in patients who completed the survey at time of discharge (n = 633). Past 30-day alcohol and/or opioid use at admission were correlated with worse self-reported physical and mental health, sleep, and quality of life, and greater negative affect and craving ( P s < 0.05). Previous history of treatment and/or withdrawal management were associated with worse self-reported physical and mental health, quality of life, and increased craving ( P s < 0.05). Physical and mental health improved across timepoints and was most pronounced when comparing persons receiving treatment for opioid use disorder versus AUD, wherein persons with opioid use disorder had worse physical health at all time points, and greater sleep disturbance and negative affect at discharge ( P s < 0.05). It is feasible to embed patient outcome monitoring into routine clinic operations, which could be used in the future to tailor treatment plans.

Introduction: Individuals with alcohol-associated liver disease (ALD) have low engagement in alcohol use disorder (AUD) treatment. This study aimed to identify barriers and facilitators to AUD treatment in ALD patients and provide recommendations to improve recognition of need, treatment initiation, and care continuation. Methods: We conducted a mixed-methods systematic review to identify barriers and facilitators of AUD treatment. We combined quantitative and qualitative studies following the convergent integrated approach and performed directed content analysis based on the Capability, Opportunity, and Motivation–Behavior (COM-B) model. Results: Twenty-three eligible studies were analyzed. Discordance between patients and providers in the need recognition stage led to missed opportunities; patients recognized the need for AUD treatment during symptomatic ALD, but providers focused on it after immediate liver-related symptoms subsided. Liver transplant (LT) status influenced motivations for concealing alcohol use that hindered treatment initiation; LT candidates were confident in self-managing their alcohol use and feared reprimand or disqualification, while LT recipients felt shame in disclosing alcohol use. Low prescription and uptake of medications for AUD (MAUD) were linked to limited training and provider discomfort, along with patients’ misconceptions about MAUD. Care coordination and patient experience were key to care continuation. Conclusions: To increase AUD treatment in ALD, we suggest to: (1) Deepen patient and provider insights on AUD treatment during asymptomatic and symptomatic ALD, (2) Normalize AUD treatment for LT candidates and recipients, (3) Apply choice architecture and address misunderstandings about MAUD, (4) Improve collaborative care models accounting for patient preferences.

Alcohol use disorder (AUD) treatment can help improve clinical outcomes among patients with alcohol-associated cirrhosis but is underutilized. Among socioeconomically disadvantaged patients with alcohol-associated cirrhosis, we examined rates of lifetime and past 12-month AUD treatment utilization and associated demographic and clinical characteristics. Racial/ethnically diverse patients with alcohol-associated cirrhosis who had at least one hepatology clinic visit in the prior 6 months were recruited from three Northern California medical centers serving veterans and safety-net populations. Participants self-reported their AUD treatment utilization, liver disease quality of life (LDQoL), history and current symptoms of anxiety and depression, and problematic drinking as measured by the Alcohol Use Disorders Identification Test (AUDIT). Clinical measures including liver disease severity were captured from medical records. Among 196 participants, the majority were male (88%) with a mean age of 62 years. Two-thirds of participants (67%) reported ever utilizing AUD treatment and 32% reported utilizing AUD treatment in the past 12 months. Compared with those who did not utilize AUD treatment, participants who utilized lifetime or past 12-month AUD treatment were younger, had lower LDQoL scores, and had higher scores on current symptoms of anxiety, depression, and problematic drinking. In multivariable analyses, the odds of ever utilizing pharmacological treatment alone or both behavioral and pharmacological treatment (vs. none) were lower with older age or higher LDQoL, and higher among those with a history of anxiety/depressive disorder. For past 12-month treatment utilization, odds were lower with older age, and higher among those with current clinically significant anxiety/depression or problematic drinking. Patients with alcohol-associated cirrhosis who were younger or had anxiety/depression and problematic drinking were more likely to utilize AUD treatment. To improve AUD treatment utilization, targeted outreach to patients less likely to receive care and the provision of integrated ALD and AUD treatment is warranted.

Alcohol-associated liver disease (ALD) is the most common indication for liver transplantation in the United States. Alcohol use disorder (AUD) treatment is recommended in all patients with ALD and AUD, but it remains underutilized. To identify predictors of AUD treatment and to assess 30-day readmission, return to drinking, and 1-year transplant-free survival. Retrospective single-center cohort study of consecutive patients hospitalized with ALD and AUD between 2018 and 2020. Patients who died or were lost to follow-up at 90 days after hospitalization were excluded. AUD treatment was defined as receiving medication or participating in residential, outpatient, or support groups within 90 days of discharge. One hundred nine patients were included. Mean age was 51.7 years, and 63% were male. Fifty-six (51%) patients received AUD treatment, and 23 (21%) patients received more than one treatment. Predictors of AUD treatment were younger age (OR, 1.07 [95% CI, 1.04-1.12]; P < 0.001), gastroenterology/hepatology consult (AOR, 8.54 [95% CI, 2.55-39.50]; P = 0.0002), addiction psychiatry consult (AOR, 2.77 [95% CI, 1.16-6.84]; P = 0.02), and a brief AUD intervention (AOR, 18.19 [95% CI, 3.36-339.07]; P = 0.0001). Cirrhosis decompensation, MELD-Na score, and insurance status were not associated with treatment. Thirty-one patients (28.4%) were readmitted, and 29 (26.6%) remained abstinent 30 days from discharge. Patients who received treatment had improved transplant-free survival (HR, 0.44, P = 0.04). A brief intervention on AUD had the strongest association with receiving AUD treatment in our cohort. Further efforts to incorporate brief interventions when offering AUD treatment to patients with ALD may be beneficial.

This is the first systematic review of the extant literature on all major psychedelic-assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic-assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for research. This was a prospectively registered narrative systematic review of open-label, randomised controlled trials (RCT), and observational studies of d-lysergic acid diethylamide (LSD), mescaline, psilocybin, ayahuasca, ketamine, ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Eligible studies had SUD outcome measures including craving, substance use, relapse, and remission. Study quality was evaluated using the Cochrane Collaboration Risk of Bias (RoB), and Cochrane Collaboration RoB in Non-randomised Studies of Interventions tool. Certainty of evidence for RCTs was judged using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. 37 studies (2035 participants) were reviewed: LSD (14; n = 1047); mescaline (1; n = 7); psilocybin (4; n = 135); ayahuasca (3; n = 101); ketamine (10; n = 579); ibogaine (5; n = 166); and MDMA (1; n = 14). There were no serious adverse events reported in any study. A two-centre, placebo-controlled, phase 2 superiority RCT of psilocybin for AUD, and a two-centre, double-blind, four-arm, placebo-controlled phase 2 RCT of ketamine for AUD yielded the best evidence of efficacy. Progression support to a phase 3 trials was secured from an open-label phase 2 study of psilocybin for TUD and nine phase 2 RCTs of ketamine for AUD, cannabis use disorder, cocaine use disorder, and opioid use disorder (all nine with high-RoB and low-GRADE evidence certainty). Psilocybin-assisted treatment for alcohol use disorder appears to have the best evidence of efficacy among all major psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders. Future research of psychedelic-assisted treatment should report all safety events; screen for person-level characteristics indicating that psychedelic-assisted substance use disorders treatment is contraindicated; strive to mitigate blinding of participants to interventions; use factorial designs for drug and psychotherapy randomised controlled trials; and build consensus for a field-specific Core Outcome Set.

Alcohol-associated liver disease (ALD) is a leading cause of liver-related deaths in the United States and worldwide, occurring in persons with alcohol use disorder (AUD). Effective treatment of AUD is essential to curtail the progression of ALD and/or reverse the disease course, yet there is a paucity of information on care models for the concomitant treatment of AUD in persons with ALD, particularly when liver transplant is not imminent or warranted. Here, we reviewed existing literature on care models for the concomitant treatment of ALD and AUD among individuals not undergoing liver transplant evaluation or consideration. A comprehensive search of electronic databases including Cochrane Library, CINAHL, Ovid MEDLINE, Ovid Embase, Scopus, Google Scholar, PubMed, and Web of Science Core Collection from inception to July 2024 was conducted to identify original studies reporting care for both ALD and AUD in persons not undergoing liver transplant evaluation or consideration. From the 1146 publications identified, 43 studies were selected for further review, of which three articles were selected for data charting and inclusion in the review. Concomitant treatment of ALD and AUD were implemented both within inpatient and outpatient settings, with multidisciplinary care teams typically involving hepatology and addiction medicine and/or addiction psychiatry. One study showed that attention and care for AUD led to improvement in liver disease and a decrease in emergency department visits and frequency of hospitalization. The studies reviewed suggest that concomitant care for ALD and AUD in the nontransplant setting may improve outcomes for some patients. The limited number of studies highlights the need for more prospective and longitudinal studies evaluating concomitant treatment, especially in persons for whom liver transplant may not be an option or a consideration.

The COVID-19 pandemic disrupted health-care provision in the United States and prompted increases in telehealth-delivery of care. This study measured alcohol use disorder (AUD) treatment trends across visit modalities before and during COVID-19. We conducted a national, retrospective cohort study with interrupted time-series models to estimate the impact of COVID-19 on AUD treatment in the Veterans Health Administration (VHA) in the United States during pre-COVID-19 (March 2019 to February 2020) and COVID-19 (March 2020 to February 2021) periods. We analyzed monthly trends in telephone, video and in-person visits for AUD treatment and compared patient and treatment characteristics of patients receiving AUD treatment between the pre-COVID-19 and COVID-19 periods. AUD was defined using International Classification of Diseases, 10th revision (ICD-10) codes for alcohol abuse (F10.1) and alcohol dependence (F10.2), which have previously been used to study AUD in VHA. The predicted percentage of VHA patients with an AUD diagnosis receiving any AUD treatment at the beginning of the pre-COVID period was 13.8% (n = 49 494). The predicted percentage decreased by 4.3% (P = 0.001) immediately at the start of the COVID-19 period due to a decline in AUD psychotherapy. Despite an increase of 0.3% per month (P = 0.026) following the start of COVID-19, the predicted percentage of VHA patients with an AUD diagnosis receiving any AUD treatment at the end of the study period remained below the pre-COVID-19 period. In February 2021, AUD psychotherapy visits were primarily delivered by video (50%, 58 748), followed by in-person (36.6%, 43 251) and telephone (13.8%, 16 299), while AUD pharmacotherapy visits were delivered by telephone (38.9%, 3623) followed by in-person (34.3%, 3193) and video (26.8%, 2498) modalities. Characteristics of VHA patients receiving AUD treatment were largely similar between pre-COVID-19 and COVID-19 periods. Despite increased telehealth use, the percentage of United States Veterans Health Administration patients with an alcohol use disorder (AUD) diagnosis receiving AUD treatment declined during COVID-19 (March 2020 to February 2021) mainly due to a decrease in psychotherapy.

Excessive alcohol use is a leading cause of preventable death in the United States. Despite the availability of effective alcohol use disorder (AUD) treatments, usage remain low. This quality improvement project explored the use of direct-to-consumer (DTC) patient education across multiple US Department of Veterans Affairs (VA) facilities to increase AUD treatment. Patients with AUD or at high risk for AUD at 5 Veterans Integrated Service Network (VISN) 21 sites who were not receiving AUD pharmacotherapy were identified. Veterans were eligible for inclusion if they had an Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score ≥ 6 with an AUD diagnosis, or ≥ 8 without diagnosis, and a scheduled appointment with primary care, mental health, or a substance use disorder (SUD) health care practitioner between October 1, 2023, and January 31, 2024. The final cohort was mailed education materials about 2 weeks prior to their appointment. A comparator group from the previous year was identified using propensity score matching, and findings were assessed using logistic regression. The outcomes were assessed within 30 days of the scheduled visit, with the primary outcome being the initiation of pharmacotherapy and the secondary outcome being the placement of a consultation for mental health or SUD services. DTC education was mailed to 1260 veterans. Primary and secondary outcomes did not find statistically significant differences between patients that received DTC education and the comparator group (P > .59). Although the results of this study were not statistically significant, this project initiated conversations at the VISN around AUD and available treatments. Future research should focus on addressing primary care involvement in AUD treatment, assessing different methods for delivering DTC education, and its potential long-term impact in the treatment of AUD.

Compulsive ethanol intake, characterized by persistent consumption despite negative consequences, is an addictive behavior identified by the DSM-5 as a central criterion in diagnosing alcohol use disorders (AUD). Epidemiological data suggest that females transition from recreational alcohol use to AUD more rapidly than males. Because of this potential sex difference in the etiology of AUD, it is critical to assess addictive behaviors such as compulsive intake in both males and females in preclinical studies. We used the model of aversion-resistant ethanol consumption to assess compulsive-like ethanol intake. In these experiments, C57BL6/J mice were first provided with continuous access two-bottle choice between water and ethanol to establish baseline intake. Ethanol solution was then adulterated with increasing concentrations of the bitter tastant quinine hydrochloride. Animals that consume ethanol solution despite its pairing with this negative stimulus are thought to be exhibiting compulsive-like behavior. We found that higher concentrations of quinine were required to suppress ethanol consumption in female mice relative to males. We found no effect of estrous cycle phase on baseline ethanol intake or on quinine-adulterated ethanol intake in females. Collectively, these data suggest that females exhibit a higher degree of aversion-resistance than male mice. Because we observed no effect of estrous cycle phase, it is likely that the presence of threshold levels of estradiol or progesterone, as opposed to their natural fluctuation across the estrous cycle, mediates increased aversion-resistance in females. Alternatively, or in combination, developmental effects of sex hormones could contribute to aversion-resistant ethanol intake.