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Primary care physicians play an integral role in the identification and management of alcohol use disorder, which has implications for the safety and physical and mental health of patients, their families, and the public. Screening to identify risky drinking behavior is recommended by the US Preventive Services Task Force but is not always performed consistently or correctly in primary care. When alcohol use disorder is identified, collaboration with patients is essential to determine an appropriate treatment approach. Abstinence may not always be the answer. Approximately one-half of patients with alcohol use disorder experience symptoms of alcohol withdrawal syndrome when decreasing alcohol use abruptly or substantially. Physicians must be adept at recognizing and managing signs of alcohol withdrawal. They should be aware of the range of management options and recognize that pharmacotherapy has been underused., (Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.)

Objective: The authors examined racial/ethnic and socioeconomic disparities in receiving treatment for alcohol use disorder (AUD)., Methods: A retrospective cohort study was conducted that included adults (≥18 years) with AUD from the All of Us Controlled Tier database v7. Outcomes were lifetime receipt of FDA-approved medications (disulfiram, acamprosate, and naltrexone), psychotherapy (individual, family, and group-based session), and combination treatment (medication and psychotherapy). The study examined treatment receipt by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, other), insurance (private, Medicare, Medicare and Medicaid, Medicaid, Veteran Affairs [VA], none), income (<$10K, $10-<$50K, $50-$100K, >$100K), and area deprivation index (ADI) quintiles. Multivariable logistic and multinomial logistic regressions were used to assess the association between patient characteristics and treatment receipt., Results: The cohort consisted of 18,692 patients (mean age=57.1 years; 60.7% were male; 47.1% were non-Hispanic White). Almost 70% received no treatment, 11.4% received medication, 24.0% received psychotherapy, and 4.9% received combination treatment. In adjusted analysis, non-Hispanic Black (aOR=0.78, 95% CI=0.69-0.89) and Hispanic (aOR=0.75, 95% CI=0.64-0.88) individuals were less likely to receive medication than non-Hispanic White counterparts. There was no association between race/ethnicity and receipt of psychotherapy or combination treatment. Compared with private insurance, dual eligibility was associated with less use of medication, Medicare and Medicaid with less use of medication and combination treatment, and VA and no insurance with more use of psychotherapy and combination treatment. Higher income and lower ADI were positively associated with all treatment types., Conclusions: There are disparities in AUD treatment by race/ethnicity, socioeconomic status, and insurance. Systematic approaches are required to improve equitable access to effective treatment., Competing Interests: Mr. Rich is a policy analyst at the Reason Foundation. Dr. Bernstein reports receiving funding support from an Institutional National Research Service Award (T32HP32715) and personal fees from Alosa. Dr. Glass facilitated a quality improvement pilot study for which Pear Therapeutics Inc provided digital therapeutic prescriptions at no cost to Kaiser Permanente Washington. Dr. Rothberg serves as a consultant for Blue Cross Blue Shield Association. The other authors report no financial relationships with commercial interests.

Baseline severity of alcohol use disorder (AUD) is an influencing factor in the response to medications recommended for the treatment of AUD. The scarce efficacy of AUD medications partly justifies their limited uses. We were interested in evaluating the efficacy of approved and recommended AUD medications using generic inverse-variance, an analysis facilitating comparison between medications and placebo both at the end of the study and, concomitantly, to baseline values for the same participants. We conducted a systematic review to include randomized controlled trials (RCTs) comparing any medication to placebo providing, both at baseline and end of treatment, percent heavy drinking days (%HDD), percent drinking days (%DD), and/or drinks per drinking day (DDD). We searched PubMed, Embase, PMC, and three CT registers from inception to April 2023. A total of 79 RCTs (11,737 AUD participants; 30 different medications) were included: 47 RCTs (8465 participants) used AUD medications, and 32 RCTs (3272 participants) used other medications. At baseline, participants consumed on average approximately 12 DDD, and experienced 70 % DD, and 61 % HDD. Placebo halved or reduced these values to a third. Compared to placebo, AUD medications further reduced these outcomes (moderate to high certainty evidence). Other medications reduced the DDD without modifying other alcohol outcomes. AUD medications increased the risk of developing adverse events (high-certainty evidence). Despite the large placebo effects, our results support the benefits of providing AUD medications to people with AUD, helping them reduce alcohol consumption., Competing Interests: Declaration of Competing Interest On behalf of all authors, I state that: (a) each author has contributed significantly to the work and agrees to submission of the manuscript, (b) none of the original material contained in the manuscript has been submitted for consideration nor will any of it be published elsewhere, and (c) each author has no conflict of interest that is directly relevant to the content of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prevalence of alcohol use disorder (AUD) has significantly increased over the last decade, leading to an increase in alcohol-associated liver disease (ALD) rates worldwide. Despite this prominence, AUD in ALD remains undertreated and carries significant implications in the progression to end-stage ALD and increased mortality. In efforts to bridge this gap, interprofessional and integrated AUD treatment is necessary for patients with ALD to ensure early detection and an appropriately targeted level of care. Although pharmacotherapy, psychotherapy, and psychosocial interventions independently play a role in treating AUD, a combination of these evidence-based modalities often results in lasting change., Competing Interests: Disclosure None of the authors report any conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To examine the quarterly incidence and prevalence of medications for opioid use disorder (OUD) and alcohol use disorder (AUD) from 2015 to 2021., Methods: A retrospective population-wide observational study in Manitoba, Canada, was conducted using administrative claims data from the Manitoba Centre for Health Policy to examine the incidence and prevalence of OUD (methadone, buprenorphine-naloxone, buprenorphine) or AUD medications (naltrexone, acamprosate, disulfiram) per 10,000 individuals in each quarter between January 1, 2015, and December 31, 2021., Results: There were 1179 and 451 individuals who received at least one prescription for OUD and AUD, respectively, in the first quarter of 2020. The prevalence of OUD medications more than doubled from 6.3 to 14.3 per 10,000 from January 1, 2015, to December 31, 2021. Likewise, AUD medication prevalence increased almost 10-fold from 0.68 to 6.5 per 10,000 from January 1, 2015, to December 31, 2021, primarily due to naltrexone. The incidence of AUD prescription use increased 8.6-fold from 0.29 to 2.51 per 10,000 during the study period. In contrast, the incidence of opioid agonist therapy declined from 2.1 per 10,000 in the first quarter of 2015 to 0.53 per 10,000 the first quarter of 2016, primarily due to methadone. Whereas methadone incidence declined, buprenorphine-naloxone incidence increased almost 15-fold during the study period., Conclusion: An increase in both AUD medication prevalence and incidence in addition to an increase in buprenorphine-naloxone incidence was observed. These findings reflect an increase in the uptake of medications for treating AUD and OUD following changes to improve coverage and access to these medications., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

Refining clinical trial methodology has become increasingly important as study design is shown to influence treatment efficacy. To maximize the efficiency of randomized clinical trials (RCTs), researchers aim to establish standardized practices. The goal of this systematic review is to describe methodological practices of clinical trials for alcohol use disorder (AUD) over the past 40 years. To achieve this goal, a PubMed search was conducted in April 2023 for RCTs on AUD medications published between July 2018 through April 2023. Resulting studies were combined with a previous search from 1985 through 2018. Inclusion criteria for the RCT studies were: (1) a randomized controlled trial, (2) double or single blinded, (3) placebo or active control condition, (4) alcohol use as the primary endpoint, (5) 4 or more weeks of treatment, and (6) 12 or more weeks of follow-up. In total, methodological data from 139 RCTs representing 19 medications and spanning the past four decades were summarized. Results indicated that the most common medications tested were naltrexone (k = 42), acamprosate (k = 24), and baclofen (k = 11). On average, participants were 74% male and consumed 226 drinks per month pre-randomization. The median length of treatment was 12 weeks (IQR = 12-16; min = 4 max = 52) and the median follow-up duration was 12.5 weeks (IQR: 12-26; min = 7 max = 104). There were two broad domains of outcomes (i.e., abstinence and heavy drinking), with most studies featuring outcomes from both domains (k = 87; 63%). Reporting practices were summarized by decade, revealing an increased enrollment of females, better reporting of race and ethnicity data, and less studies requiring pre-trial abstinence. This review summarizes the current state of the literature on randomized clinical trials for AUD including effect sizes for individual studies and summaries of key methodological features across this representative set of clinical trials., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Alcohol use disorders (AUD) are prevalent and responsible for substantial morbidity and mortality; yet efficacious treatments are underused. Previous studies have identified demographic and clinical predictors of medication fills, yet these studies typically do not include patients who were prescribed a medication but did not fill it., Objectives: To examine rates of and factors associated with prescription order and prescription fill for medications for AUD (MAUD) among individuals diagnosed with AUD in outpatient settings., Design: In a cross-sectional analysis, we used multivariate logistic regression to identify factors associated with prescription order and fill., Patients: We used data from the Optum Labs Data Warehouse that linked 2016-2021 de-identified claims and electronic health record (EHR) data, allowing us to observe prescription orders and whether they were filled. We identified 14,674 patients aged ≥ 18 who had an index outpatient encounter with an AUD diagnosis in the EHR., Key Measures: We computed the proportion for whom a MAUD prescription was ordered within 1 year of index visit, and for whom one was filled within 30 days of the order., Key Results: 5.8% of the sample had a MAUD prescription order within 1 year of their index visit. Among those with an order, 87% filled their MAUD prescription within 30 days of receipt (i.e., 5.1% of full sample). After multivariable adjustment, receipt of a MAUD prescription order was more likely for patients who were female (adjusted odds ratio (aOR) [95%CI] = 1.44 [1.24-1.67]), or had moderate or severe AUD (1.74 [1.50-2.01]). Patients receiving an order were more likely to fill it if they had a comorbid mental disorder (1.64 [1.09-2.49])., Conclusions: The low rate of prescription orders was notable. Low use of MAUD appears to result chiefly from prescription order decisions, rather than from prescription fill decisions made by patients., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Alcohol use disorder (AUD) is responsible for a significant burden of medical, economic, and social harm globally and across the United States. Currently, only three FDA-approved medications for AUD are available, and most patients with AUD never receive pharmacotherapy. Disulfiram, the first medication that FDA approved for treatment of AUD, is recommended as a second-line treatment option by several national treatment guidelines citing safety concerns and lack of high-quality comparative studies. In this issue, Holt argues that disulfiram should be reclassified as a first-line treatment for AUD based on promising open-label randomized controlled trials (RCTs) for disulfiram as a behavioral intervention. Review of the literature suggests that disulfiram can be a useful treatment for a highly selected group of patients with no medical or psychiatric contraindications, high motivation for abstinence, and adequate family support. Unfortunately, many patients with AUD, a disorder characterized by high rates of medical and psychiatric multimorbidity and social vulnerability, fall outside of this narrow selection criteria. Prescribers should consider other FDA-approved medications as first-line treatment options for most patients with AUD, reserving disulfiram for the rare patients in whom the potential for benefit clearly outweighs risk of harm., Competing Interests: The author reports no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Abstract: Despite the prevalence of alcohol use disorder (AUD) in the United States, the armamentarium of FDA-approved medications available for AUD treatment is remarkably small. Disulfiram, 1 of only 3 approved medications, is consistently designated as a second-line option in national treatment guidelines, citing inconsistent evidence, lack of patient preference, and safety concerns. These concerns, however, stem from a misguided interpretation of the evidence that exclusively relies upon double-blind randomized controlled trials (RCT). When viewed instead as both a medication and a behavioral intervention, open-label RCTs become a more appropriate research method, yielding overwhelmingly favorable efficacy data for disulfiram, and supervised disulfiram, in particular. With these data in mind, supervised disulfiram should be redesignated as a first-line intervention in both treatment guideline creation and clinical pathway tools. The addiction medicine community can no longer afford to neglect this critical therapeutic resource., Competing Interests: The author reports neither sources of funding nor any commercial or financial conflicts of interest to disclose., (Copyright © 2024 American Society of Addiction Medicine.)

Alcohol use disorder (AUD) has become a global public health challenge, with the social and economic costs of alcohol abuse escalating, drawing widespread attention from healthcare professionals and the public worldwide. Particularly in recent years, the COVID-19 pandemic and associated lockdown measures have led to a significant increase in global alcohol consumption, further exacerbating the risk of AUD and sparking in-depth discussions on its prevention and treatment methods. Given that the current mainstay of AUD treatment relies on pharmacotherapy, the aim of this article is to review the progress of existing drug research for the treatment of AUD, and at the same time to focus on drug classes that have not yet been applied to the clinic, but have been shown in recent studies to be potentially exploitable for the treatment of AUD, in order to provide new ideas and directions for future drug research and development efforts., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Primary care provides an important opportunity to detect unhealthy alcohol use and offer assistance but many barriers to this exist. In an Australian context, Aboriginal Community Controlled Health Services (ACCHS) are community-led and run health services, which provide holistic primary care to Aboriginal and Torres Strait Islander peoples. A recent cluster randomised trial conducted with ACCHS provided a service support model which showed a small but significant difference in provision of 'any treatment' for unhealthy alcohol use. However, it was not clear which treatment modalities were increased., Aims: To test the effect of an ACCHS support model for alcohol on: (i) delivery of verbal alcohol intervention (alcohol advice or counselling); (ii) prescription of relapse prevention pharmacotherapies., Methods: Intervention: 24-month, multi-faceted service support model., Design: cluster randomised trial; equal allocation to early-support ('treatment') and waitlist control arms., Participants: 22 ACCHS., Analysis: Multilevel logistic regression to compare odds of a client receiving treatment in any two-month period as routinely recorded on practice software., Results: Support was associated with a significant increase in the odds of verbal alcohol intervention being recorded (OR = 7.60, [95% CI = 5.54, 10.42], p < 0.001) from a low baseline. The odds of pharmacotherapies being prescribed (OR = 1.61, [95% CI = 0.92, 2.80], p = 0.1) did not increase significantly. There was high heterogeneity in service outcomes., Conclusions: While a statistically significant increase in verbal alcohol intervention rates was achieved, this was not clinically significant because of the low baseline. Our data likely underestimates rates of treatment provision due to barriers documenting verbal interventions in practice software, and because different software may be used by drug and alcohol teams. The support made little impact on pharmacotherapy prescription. Changes at multiple organisational levels, including within clinical guidelines for primary care, may be needed to meaningfully improve provision of alcohol treatment in ACCHS., Trial Registration: ACTRN12618001892202 (retrospectively registered on 21/11/2018)., (© 2024. The Author(s).)

Objectives: Medications for alcohol use disorder (MAUDs) are recommended for patients with alcohol use disorder yet are underprescribed. Consistent with Minority Stress and Intersectionality theories, persons with multiple sociodemographically marginalized identities (eg, Black women) often experience greater barriers to care and have poorer health outcomes. We use data from the Veterans Health Administration to assess disparities in Federal Drug Administration (FDA)-approved MAUDs and all effective MAUDs between the following groups: racialized and ethnic identity, sex, transgender status, and their intersections., Methods: Among all Veterans Health Administration outpatients between August 1, 2015, and July 31, 2017, with documented alcohol screenings and an International Classification of Diseases diagnosis for alcohol use disorder in the 0-365 days prior (N = 308,238), we estimated the prevalence and 95% confidence intervals of receiving FDA-approved MAUDs and any MAUDs in the following year and compared them using χ2 or Fisher's exact test. Analyses are unadjusted to present true prevalence and group differences., Results: The overall prevalence for MAUDs was low (FDA-MAUDs = 8.7%, any MAUDs = 20.0%). Within sex, Black males had the lowest rate of FDA-MAUDs (7.3%, [7.1-7.5]), whereas American Indian/Alaskan Native females had the highest (18.4%, [13.8-23.0]). Among those identified as transgender, Asian and Black transgender persons had the lowest rates of FDA-MAUDs (0%; 4.3%, [1.8-8.5], respectively), whereas American Indian/Alaskan Native transgender patients had the highest (33.3%, [2.5-64.1]). Similar patterns were observed for any MAUDs, with higher rates overall., Conclusions: Substantial variation exists in MAUD prescribing, with marginalized veterans disproportionately receiving MAUDs at lower and higher rates than average. Implementation and quality improvement efforts are needed to improve MAUD prescribing practices and reduce disparities., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Introduction: Alcohol Use Disorder (AUD) poses an ongoing significant global health burden. AUD is highly prevalent and affects not only the individuals with AUD, but also their communities and society at large. Even though pharmacotherapy is an integral part of AUD treatment, the few available substances show limited efficacy and limited clinical impact. Thus, there is a need for new innovative pharmacotherapeutic approaches., Areas Covered: This paper provides a comprehensive review of drugs approved for the treatment of AUD as well as those currently in phase II and III development. Data from recent clinical trials has been reviewed and supplemented by additional literature based on a systematic search of the PubMed database and clinical trials registries. Compounds discussed include disulfiram, naltrexone, nalmefene, acamprosat, baclofen, sodium oxybate, doxazosin, varenicline, zonisamide, gabapentin, apremilast, ibudilast, ivermectin, tolcapone, mifepristone, suvorexant, ketamine, psilocybin, semaglutide, oxytocin and cannabidiol., Expert Opinion: Even though the majority of the discussed compounds lack sufficient evidence to support their efficacy, multiple promising new treatment options are currently under investigation. Future research has to consider specific phenotypes and subgroups of AUD as well as a possible enhancement of the effects of psychotherapy through combination with pharmacotherapy. Practitioners should be encouraged to use available compounds to support existing therapeutic regimens.

Purpose: Exposure to alcohol-related cues is thought to elicit a conditional response characterized by increased craving in individuals with alcohol use disorder (AUD). In the context of AUD research, it is important to consider that not all individuals with an AUD are alcohol cue reactive. This study systematically examined subjective alcohol cue reactivity and its clinical and drinking correlates in individuals with an AUD enrolled in a human laboratory pharmacotherapy trial., Methods: Individuals with current moderate-to-severe AUD (N = 52) completed a standard alcohol cue exposure paradigm and individual difference assessments as part of a human laboratory pharmacotherapy trial (NCT04249882). We classified participants as cue reactive (CR+) and cue non-reactive (CR-), as indicated by self-reported, subjective alcohol urge, and examined group differences in baseline clinical characteristics and drinking outcomes over the course of the trial., Results: Twenty participants (38%) were identified as CR+, while 32 participants (62%) were identified as CR-. The CR+ and CR- groups did not differ in baseline drinking and AUD clinical characteristics, but the groups differed in race composition (p = 0.02) and smoking prevalence (p = 0.04) such that the CR+ group had lower prevalence of smokers. The CR+, compared with the CR-, group drank more during the trial titration period (p = 0.03). Both groups reduced drinking across the trial (p's < 0.001), but the CR+ group exhibited a smaller reduction in drinking, compared with the CR- group (time x group, p = 0.029; CR-, p < 0.0001; CR+: p = 0.01)., Conclusion: Results indicate that cue reactivity is a heterogenous construct. Recognizing this heterogeneity, and the clinical factors associated with it, is critical to advancing this paradigm as an early efficacy marker in AUD research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Acamprosate is a Food and Drug Administration (FDA) approved medication for the treatment of alcohol use disorder (AUD). However, only a subset of patients achieves optimal treatment outcomes. Currently, no biological measures are utilized to predict response to acamprosate treatment. We applied our established pharmaco-omics informed genomics strategy to identify potential biomarkers associated with acamprosate treatment response. Specifically, our previous open-label acamprosate clinical trial recruited 442 patients with AUD who were treated with acamprosate for three months. We first performed proteomics using baseline plasma samples to identify potential biomarkers associated with acamprosate treatment outcomes. Next, we applied our established "proteomics-informed genome-wide association study (GWAS)" research strategy, and identified 12 proteins, including interleukin-17 receptor B (IL17RB), associated with acamprosate treatment response.​ A GWAS for IL17RB concentrations identified several genome-wide significant signals. Specifically, the top hit single nucleotide polymorphism (SNP) rs6801605 with a minor allele frequency of 38% in the European American population mapped 4 kilobase (Kb) upstream of IL17RB, and intron 1 of the choline dehydrogenase (CHDH) gene on chromosome 3 (p: 4.8E-20). The variant genotype (AA) for the SNP rs6801605 was associated with lower IL17RB protein expression. In addition, we identified a series of genetic variants in IL17RB that were associated with acamprosate treatment outcomes. Furthermore, the variantgenotypes for all of those IL17RB SNPs were protective for alcohol relapse. Finally, we demonstrated that the basal level of mRNA expression of IL17RB was inversely correlated with those of nuclear factor-κB (NF-κB) subunits, and a significantly higher expression of NF-κB subunits was observed in AUD patients who relapsed to alcohol use. In summary, this study illustrates that IL17RB genetic variants might contribute to acamprosate treatment outcomes. This series of studies represents an important step toward generating functional hypotheses that could be tested to gain insight into mechanisms underlying acamprosate treatment response phenotypes. (The ClinicalTrials.gov Identifier: NCT00662571)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Aims: This study aimed to investigate acamprosate and naltrexone dispensing patterns in Australia., Methods: A 10% representative sample of medications subsidized by the Australian Pharmaceutical Benefits Scheme (PBS) was used to identify individuals who were dispensed naltrexone or acamprosate between January 2006 and December 2023. Data were used to examine concurrent dispensing, medication switching and treatment episode length, as well as changes in prevalence and incidence over time., Results: During the study, we identified 22 745 individuals with a total of 117 548 dispensed prescriptions (45.3% naltrexone, 43.0% acamprosate, and 11.7% concurrent dispensing). Alcohol pharmacotherapy dispensing occurred in 1354 per 100 000 individuals. It is estimated that 2.9% of individuals with an alcohol use disorder in Australia are receiving a PBS-listed pharmacological treatment. For both pharmacotherapies, individuals were most likely to be male (60.0%) and 35-54 years of age (56.0%). Individuals were more likely to switch from acamprosate to naltrexone rather than the reverse. From 2006 and 2023, the number of prevalent individuals treated with an alcohol pharmacotherapy significantly increased, driven mainly the use of naltrexone, which more than doubled over the study period. Incident naltrexone-treated individuals were more likely to remain on treatment for the recommended minimum 3-month period compared to acamprosate treated individuals, although overall dispensing for at least 3 months was low (5.1%)., Conclusions: In Australia between 2006 and 2023, rates of naltrexone dispensing have substantially increased, while acamprosate dispensing showed minimal changes. However, the use of alcohol pharmacotherapies remains low compared with the likely prevalence of alcohol use disorders., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press.)

Introduction: We assessed the prevalence of prescribing of certain medications for alcohol dependence and the extent of any inequalities in receiving prescriptions for individuals with such a diagnosis. Further, we compared the effectiveness of two of the most prescribed medications (acamprosate and disulfiram) for alcohol dependence and assessed whether there is inequality in prescribing either of them., Methods: We used a nationwide dataset on prescriptions and hospitalisations in Scotland, UK (N = 19,748). We calculated the percentage of patients receiving alcohol dependence prescriptions after discharge, both overall and by socio-economic groups. Binary logistic regressions were used to assess the odds of receiving any alcohol-dependence prescription and the comparative odds of receiving acamprosate or disulfiram. Comparative effectiveness in avoiding future alcohol-related hospitalisations (N = 11,239) was assessed using Cox modelling with statistical adjustment for potential confounding., Results: Upto 7% of hospitalised individuals for alcohol use disorder received prescriptions for alcohol dependence after being discharged. Least deprived socio-economic groups had relatively more individuals receiving prescriptions. Inequalities in prescribing for alcohol dependence existed, especially across sex and comorbidities: males had 12% (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81-0.96) and those with a history of mental health hospitalisations had 10% (OR 0.90, 95% CI 0.82-0.98) lower odds of receiving prescriptions after an alcohol-related hospitalisation. Prescribing disulfiram was superior to prescribing acamprosate in preventing alcohol-related hospitalisations (hazard ratio ranged between 0.60 and 0.81 across analyses). Disulfiram was relatively less likely prescribed to those from more deprived areas., Discussion and Conclusions: Inequalities in prescribing for alcohol dependence exists in Scotland with lower prescribing to men and disulfiram prescribed more to those from least deprived areas., (© 2024 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Alcohol use disorder (AUD) is a debilitating disorder, yet currently approved pharmacotherapies to treat AUD are under-utilized. The three medications approved by the US Food and Drug Administration (FDA) for the indication of AUD are disulfiram, acamprosate, and naltrexone. The current landscape of pharmacotherapies for AUD suggests opportunities for improvement. Clinical trials investigating novel pharmacotherapies for AUD traditionally use abstinence-based drinking outcomes or no heavy drinking days as trial endpoints to determine the efficacy of pharmacotherapies. These outcomes are typically measured through patient self-report endorsements of their drinking. Apart from these traditional outcomes, there have been recent developments in novel endpoints for AUD pharmacotherapies. These novel endpoints include utilizing the World Health Organization (WHO) risk drinking level reductions to promote a harm-reduction endpoint rather than an abstinence-based endpoint. Additionally, in contrast to patient self-report measurements, biological markers of alcohol use may serve as objective endpoints in AUD pharmacotherapy trials. Lastly, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from AUD and patient-oriented outcomes offer new frameworks to consider endpoints associated with more than alcohol consumption itself, such as the provider-patient experiences with novel pharmacotherapies. These recent developments in new endpoints for AUD pharmacotherapies offer promising future opportunities for pharmacotherapy development, so long as validity and reliability measures are demonstrated for the endpoints. A greater breadth of endpoint utilization may better capture the complexity of AUD symptomatology., (© 2024. The Author(s).)

Background: The 15-method is a targeted screening and treatment approach for alcohol problems in primary care. The 15-method used in primary care has proven as effective as specialized treatment for mild to moderate alcohol dependence in Sweden. A feasibility study of the 15-method in Danish primary care found the method acceptable and feasible., Aims: To evaluate the effectiveness of the 15-method in a Danish primary care setting in (1) lowering the proportion of patients exceeding the Danish low-risk alcohol consumption limit of ten standard units per week and a maximum of four standard units on a single day for men and women, and (2) increasing the likelihood of alcohol use being addressed during a consultation in general practice. Further, the rate of prescribed pharmacological treatment for alcohol problems (Disulfiram, Naltrexone, Acamprosate, and Nalmefene) will be measured along with the use of the biomarkers Alanine Transaminase and Gamma-Glutamyl Transferase., Methods: Stepped wedge cluster randomized controlled trial in sixteen general practices in the Region of Southern Denmark. Following a three-month baseline, the practices are randomly assigned to launch dates in one of four clusters. General practitioners and nurses receive three hours of training in the 15-method before launch. Patient questionnaires will collect data on alcohol consumption levels among patients affiliated with the practices. The healthcare professionals will register consultations in which alcohol is addressed in their patient filing system. Pharmacological treatment rates and the use of biomarkers will be collected through Danish national registries. The study follows the Medical Research Council's guidelines for developing and evaluating complex interventions., Discussion: From the patient's perspective, the 15-method may help identify alcohol-related problems at an earlier stage with flexible treatment offers in a familiar setting. For healthcare professionals, it addresses a traditionally challenging topic by equipping them with concrete tools, communication training, and clear treatment directives. From a societal perspective, primary care holds a unique position to identify hazardous and harmful alcohol use across different age groups, with potential public health and economic benefits through early identification and intervention., Trial Registration: Clinicaltrials.gov NCT05916027. Retrospectively registered 22 June 2023., (© 2024. The Author(s).)

Background: Alcohol-attributable medical disorders are prevalent among individuals with alcohol use disorder (AUD). However, there is a lack of research on prescriptions of pharmacological treatment for AUD in those with comorbid conditions. This study aims to investigate the utilization of pharmacological treatment (acamprosate, disulfiram and naltrexone) in specialist care among patients with AUD and comorbid medical diagnoses., Methods: This was a descriptive register-based Swedish national cohort study including 132,728 adults diagnosed with AUD (N = 270,933) between 2007 and 2015. The exposure was alcohol-attributable categories of comorbid medical diagnoses. Odds ratios (OR) were calculated using mixed-effect logistic regression analyses for any filled prescription of acamprosate, disulfiram or oral naltrexone within 12 months post AUD diagnosis., Results: Individuals with comorbid alcohol-attributable medical diagnoses had lower odds of filling prescriptions for any type of AUD pharmacotherapy compared to those without such comorbidities. Cardiovascular (OR = 0.41 [95% CI: 0.39-0.43]), neurological (OR = 0.52 [95% CI: 0.48-0.56]) and gastrointestinal (OR = 0.57 [95% CI: 0.54-0.60]) diseases were associated with the lowest rates of prescription receipt. The presence of diagnoses which are contraindications to AUD pharmacotherapy did not fully explain the low prescription rate., Conclusion: There is a substantial underutilization of AUD pharmacotherapy in patients with AUD and comorbid medical disorders in specialist care. Increasing the provision of pharmacotherapy to this group of patients is essential and may prevent morbidity and mortality. There is a need to further understand barriers to medical treatment both from the patient and prescriber perspective., (© 2024. The Author(s).)

Objectives: Alcohol-related concerns commonly present to the emergency department (ED), with a subset of individuals experiencing the symptoms of an alcohol use disorder (AUD). As such, examining the efficacy of pharmacological anti-craving treatment for AUD in the ED is of increasing interest. The objective of this systematic review was to evaluate the direct evidence assessing the efficacy of providing anti-craving medications for AUD treatment in the ED., Methods: A systematic search was conducted according to the patient-intervention-control-outcome question: (P) adults (≥18 years old) presenting to the ED with an AUD (including suspected AUD); (I) anti-craving medications (i.e., naltrexone, acamprosate, gabapentin); (C) no prescription or placebo; (O) reduction of repeat ED visits, engagement in addiction services, reductions in heavy drinking days, reductions in any drinking and amount consumed (or abstinence), and in relapse. Two reviewers independently assessed articles for inclusion and conducted risk of bias assessments for included studies., Results: From 143 potentially relevant articles, 6 met inclusion criteria: 3 clinical trials, and 3 case studies. The clinical trials identified evaluated oral versus extended-release naltrexone, monthly extended-release naltrexone injections, and disulfiram. Both oral and extended-release naltrexone resulted in decreased alcohol consumption. Monthly extended-release naltrexone injections resulted in significant improvements in drinking and quality of life. Although out of scope, the disulfiram studies identified did not result in an improvement in drinking in comparison to no medication., Conclusions: Overall, there are few studies directly examining the efficacy of anti-craving medications for AUD in the ED, although the limited evidence that exists is supportive of naltrexone pharmacotherapy, particularly extended-release injection formulation. Additional randomized controlled trials are necessary for substantive direct evidence on anti-craving medication initiation in the ED., (© 2023 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Background and Aims: Relapse is common in alcohol dependence (AD) and alcohol use disorder (AUD), so alcohol reduction therapy should be measured over as long a period as possible; however, existing reviews do not consider the duration of treatment and therefore alcohol reduction therapy may not have been appropriately evaluated. This review evaluated the efficacy and safety of alcohol reduction pharmacotherapy in patients with AD or AUD according to the duration of treatment., Methods: We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) that assessed 15 pharmacological agents. MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov and the International Clinical Trials Registry Platform were searched for eligible trials through to May 2021. Outcomes were heavy drinking days (HDD), total alcohol consumption (TAC), any adverse event and days without drinking., Results: Fifty-five RCTs (n = 8891) were included. Nalmefene was superior to placebo for reducing HDD (standard mean difference [SMD] -0.28, 95% confidence interval [CI] -0.37, -0.18) and TAC (SMD -0.25, 95% CI -0.35, -0.16) in the long-term, but not in the short-term. Topiramate was superior to placebo for reducing HDD (SMD -0.35, 95% CI -0.59, -0.12) and days without drinking (SMD 0.46, 95% CI 0.11, 0.82), and baclofen was superior for reducing TAC (SMD -0.70, 95% CI -1.29, -0.11), in the short-term. The frequency of adverse events was higher with nalmefene and topiramate than with placebo., Conclusion: Nalmefene, topiramate and baclofen may be effective as alcohol reduction pharmacotherapy; however, only nalmefene has demonstrated long-term efficacy, and nalmefene and topiramate have a significantly higher frequency of adverse events compared with placebo., (© 2024 Society for the Study of Addiction.)

Background: Despite the known harms, alcohol consumption is common in pregnancy. Rates vary between countries, and are estimated to be 10% globally, with up to 25% in Europe., Objectives: To assess the efficacy of psychosocial interventions and medications to reduce or stop alcohol consumption during pregnancy., Search Methods: We searched the Cochrane Drugs and Alcohol Group Specialised Register (via CRSLive), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO, from inception to 8 January 2024. We also searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). All searches included non-English language literature. We handsearched references of topic-related systematic reviews and included studies., Selection Criteria: We included randomised controlled trials that compared medications or psychosocial interventions, or both, to placebo, no intervention, usual care, or other medications or psychosocial interventions used to reduce or stop alcohol use during pregnancy. Our primary outcomes of interest were abstinence from alcohol, reduction in alcohol consumption, retention in treatment, and women with any adverse event., Data Collection and Analysis: We used standard Cochrane methodological procedures., Main Results: We included eight studies (1369 participants) in which pregnant women received an intervention to stop or reduce alcohol use during pregnancy. In one study, almost half of participants had a current diagnosis of alcohol use disorder (AUD); in another study, 40% of participants had a lifetime diagnosis of AUD. Six studies took place in the USA, one in Spain, and one in the Netherlands. All included studies evaluated the efficacy of psychosocial interventions; we did not find any study that evaluated the efficacy of medications for the treatment of AUD during pregnancy. Psychosocial interventions were mainly brief interventions ranging from a single session of 10 to 60 minutes to five sessions of 10 minutes each. Pregnant women received the psychosocial intervention approximately at the end of the first trimester of pregnancy, and the outcome of alcohol use was reassessed 8 to 24 weeks after the psychosocial intervention. Women in the control group received treatment as usual (TAU) or similar treatments such as comprehensive assessment of alcohol use and advice to stop drinking during pregnancy. Globally, we found that, compared to TAU, psychosocial interventions may increase the rate of continuously abstinent participants (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.14 to 1.57; I 2 =0%; 3 studies; 378 women; low certainty evidence). Psychosocial interventions may have little to no effect on the number of drinks per day, but the evidence is very uncertain (mean difference -0.42, 95% CI -1.13 to 0.28; I 2 = 86%; 2 studies; 157 women; very low certainty evidence). Psychosocial interventions probably have little to no effect on the number of women who completed treatment (RR 0.98, 95% CI 0.94 to 1.02; I 2 = 0%; 7 studies; 1283 women; moderate certainty evidence). None of the included studies assessed adverse events of treatments. We downgraded the certainty of the evidence due to risk of bias and imprecision of the estimates., Authors' Conclusions: Brief psychosocial interventions may increase the rate of continuous abstinence among pregnant women who report alcohol use during pregnancy. Further studies should be conducted to investigate the efficacy and safety of psychosocial interventions and other treatments (e.g. medications) for women with AUD. These studies should provide detailed information on alcohol use before and during pregnancy using consistent measures such as the number of drinks per drinking day. When heterogeneous populations are recruited, more detailed information on alcohol use during pregnancy should be provided to allow future systematic reviews to be conducted. Other important information that would enhance the usefulness of these studies would be the presence of other comorbid conditions such as anxiety, mood disorders, and the use of other psychoactive substances., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Alcohol, the most widely consumed substance globally, can lead to severe adverse effects for both users and those around them. Chronic ethanol consumption may lead to alcohol use disorder (AUD), a chronic relapsing condition characterized by compulsive drinking despite negative consequences. AUD is marked by a high relapse rate among individuals attempting abstinence. Currently, only a few medications, such as disulfiram, naltrexone, nalmefene, and acamprosate, are approved to treat AUD. Moreover, genetic factors and comorbid conditions can significantly influence both the development of AUD and the efficacy of its treatment. This chapter explores the genetic underpinnings of AUD and reviews the main pharmacological treatments available for managing this disorder., (Copyright © 2024. Published by Elsevier Inc.)

Excessive alcohol use is a leading cause of preventable death in the United States, with alcohol-related deaths increasing during the pandemic. The Substance Abuse and Mental Health Services Administration recommends that physicians offer pharmacotherapy with behavioral interventions for patients diagnosed with alcohol use disorder. Several medications are available to help patients reduce drinking and maintain abstinence; however, in 2019, only 7.3% of Americans with alcohol use disorder received any treatment, and only 1.6% were prescribed medications to treat the disorder. Strong evidence shows that naltrexone and gabapentin reduce heavy-drinking days and that acamprosate prevents return-to-use in patients who are currently abstinent; moderate evidence supports the use of topiramate in decreasing heavy-drinking days. Disulfiram has been commonly prescribed, but little evidence supports its effectiveness outside of supervised settings. Other medications, including varenicline and baclofen, may be beneficial in reducing heavy alcohol use. Antidepressants do not decrease alcohol use in patients who do not have mood disorders, but they may help patients who meet criteria for depression to decrease their alcohol intake. Systematic policies are needed to expand the use of medications when treating alcohol use disorder in inpatient and outpatient populations.

Background: Patients with psychotic disorders (PD) often have comorbid alcohol use disorder (AUD), which is typically treated pharmacologically. Up till now, no systematic review has examined the effectiveness and safety of AUD treatment in PD patients., Objectives: This study aimed to systematically review the literature on (1) the effects of pharmacological treatments for AUD on drinking outcomes, (2) the side effects of the drugs, and (3) the effects of polypharmacy in patients with comorbid AUD and PD., Methods: Bibliographic searches were conducted in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PsycINFO. At least two reviewers extracted the data, assessed the risk of bias, and performed the qualitative synthesis of the collected evidence., Results: Twelve eligible studies were identified, half being randomized controlled trials (RCTs). Three studies examined disulfiram, nine naltrexone, two acamprosate, and one nalmefene by comparing the effects of treatment to placebo, baseline, or pharmacological agents. Disulfiram and naltrexone were shown to reduce alcohol intake. Regarding acamprosate, the findings were mixed. Nalmefene decreased alcohol intake. All pharmacological agents appeared safe to use as AUD monotherapy, but cardiac events were reported when combining naltrexone and disulfiram. Nine studies had a high risk of bias, and three had some other concerns., Conclusion: The studies provide tentative support for the use of naltrexone and disulfiram in this population, although combinations of pharmacological AUD treatments and other polypharmacy remain unexplored. The studies had high adherence rates that are hardly replicable in real-world settings. Thus, the findings should be confirmed in larger high quality efficacy and effectiveness RCTs with longer follow-ups., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Importance: Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality., Objective: To compare efficacy and comparative efficacy of therapies for alcohol use disorder., Data Sources: PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023., Study Selection: For efficacy outcomes, randomized clinical trials of at least 12 weeks' duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included., Data Extraction and Synthesis: Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate strength of evidence for benefit., Main Outcomes and Measures: The primary outcome was alcohol consumption. Secondary outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms., Results: Data from 118 clinical trials and 20 976 participants were included. The numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, -4.99 days; 95% CI, -9.49 to -0.49 days) Adverse effects included higher gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI, 1.23-1.91) compared with placebo., Conclusions and Relevance: In conjunction with psychosocial interventions, these findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.

Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram's anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma., (© 2023. Springer Nature Limited.)

Alcohol is regularly consumed throughout most of the world, including by nearly half the U.S. population age 12 or older. Heavy drinking, which is also common, contributes to multiple adverse medical, psychiatric, and social outcomes and more than 140,000 deaths annually in the United States. It is the major risk factor for alcohol use disorder (AUD), whose current U.S. prevalence is 11%. However, AUD is undertreated, with less than 15% of individuals with a lifetime diagnosis receiving any treatment. Risk of AUD is nearly equally genetic and environmental. AUD is responsive to psychosocial treatments, including cognitive-behavioral therapy and motivational enhancement therapy. Alcohol affects multiple neurotransmitter systems, and thus pharmacotherapy for AUD is also effective. The three medications approved in the United States to treat AUD-disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate-are underprescribed, despite being considered first-line treatments in clinical practice guidelines. Two medications not approved for treating AUD, topiramate and gabapentin, have shown efficacy in treating the disorder and are used off-label. Recent studies of novel drug candidates, including psychedelics and phosphodiesterase-4 inhibitors, are promising additions for the treatment of AUD, although they require further evaluation before being used clinically. Despite the growing availability of efficacious psychosocial and pharmacological treatments for AUD, it remains a highly stigmatized condition. Research aimed at enhancing the identification and treatment of AUD, including precision therapeutics, could broaden the acceptability of AUD treatment, benefiting affected individuals and their families and reducing the stigma associated with the disorder., Competing Interests: Dr. Kranzler has served on advisory boards for Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, and Sophrosyne Pharmaceuticals and as a consultant for Sobrera Pharmaceuticals; he has received research funding and medication supplies for an investigator-initiated study from Alkermes; he is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics; and he is a holder of U.S. patent 10,900,082 (“Genotype-guided dosing of opioid agonists”).

No single effective therapy for alcohol abuse has been found, despite it being a serious sociological and economic problem for hundreds of years. It seems difficult to find a single drug as a panacea for the alcohol problem due to the complexity of the pathophysiology of alcohol dependence. The purpose of this narrative review is to review existing and potentially future pharmaceuticals for the treatment of alcohol dependence in the most affordable way possible. Psychotherapy is the mainstay of treatment for alcoholism, while few drugs approved by legislators are available in the augmentation of this treatment, such as acamprosate, disulfiram, and naltrexone, approved by the FDA, and nalmefene by the EMA. There are recent reports in the literature on the possibility of using baclofen, topiramate, varenicline, and gabapentin in the treatment of alcohol dependence. Moreover, the results of recent clinical trials using psychoactive substances such as psilocybin and MDMA appear to be a breakthrough in the modern treatment of alcohol abuse. Despite this initial optimism, a lot of scientific effort is still needed before new pharmacological methods supporting the treatment of alcohol dependence syndrome will be widely available.

Background: Acamprosate and naltrexone, evidence-based pharmacotherapies for alcohol use disorder (AUD), are publicly covered by the Ontario Drug Benefit (ODB) programs; however, their availability has changed over time, with expanded formulary access in July 2018, followed by an acamprosate shortage in February 2019 and ending in July 2020. We evaluated the impact of these events on the use of these medications in Ontario, Canada., Methods: We conducted a time-series analysis among individuals with AUD dispensed acamprosate or naltrexone through the ODB from July 2016 to December 2020. Outcomes included monthly rates of those with AUD on therapy (primary), and rate of initiation (secondary) overall and by treatment type. We used autoregressive moving average models to evaluate the impact of expanded coverage and the acamprosate shortage on rates of use, and reported characteristics at first dispensation., Results: Over the study period, 10,637 individuals (61.0% male) initiated acamprosate or naltrexone. Expanded coverage increased monthly utilization rates of acamprosate (p = 0.0004), naltrexone (p < 0.0001), and either AUD pharmacotherapy (p < 0.0001). The acamprosate shortage led to a 98.1% reduction in acamprosate use (p = 0.0003) but did not impact naltrexone (p = 0.51). Our secondary analysis yielded consistent results with respect to the shortage; however, the expanded formulary listing did not impact the rate of new acamprosate patients (p = 0.3). By December 2020, 5.3% of ODB recipients with AUD were accessing pharmacotherapy., Conclusions: Although coverage expansion increased access to medications that treat AUD, the shortage of acamprosate led to large reductions in its use, with no responsive increase in naltrexone prescribing., Competing Interests: Conflict of Interest No conflict declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Mason's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.

Disulfiram, a drug prescribed for the treatment of alcohol use disorders for more than 60 years, has recently been repurposed for cancer treatment. New work in The EMBO Journal now describes a disulfiram role in immunotherapy of cancer, involving direct binding to Lck to mediate activation of tumor-infiltrating T cells., (© 2022 The Authors.)

As a key regulator involved in tumor development and progression, DJ-1 has been proposed as a potential therapeutic target against cancer. Also, the development of DJ-1 inhibitors holds great interests in cancer treatment. In the current study, by utilizing a small molecule covalent compounds library screening, we found that disulfiram (DSF), an FDA-approved chronic alcoholism drug, is a potent DJ-1 inhibitor. Glyoxalase assay and microscale thermophoresis analysis suggested that DSF exhibits strong inhibitory activity and high affinity to DJ-1 protein. Additionally, DSF similarly inhibited the methylglyoxal detoxification function of DJ-1 protein at the intracellular level. Notably, we discovered that DSF could significantly enhance N-(4-hydroxyphenyl) retinamide-based proliferation inhibition and apoptosis induction in different types of cancer cell lines, but not in normal tissue lines. Thus, our data suggest DSF functions as a potential inhibitor targeting DJ-1, which may provide a potential synergistic treatment option for cancer therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes., Experimental Approach: We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3-month follow-up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics., Key Results: Baseline plasma arginine, threonine, α-aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics-informed genome-wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell-derived forebrain astrocytes showed that a series of genes identified during the metabolomics-informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes., Conclusion and Implications: These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Precision medicine approaches attempt to reduce variability in alcohol use disorder (AUD) outcomes by identifying patient characteristics that predict response to a particular treatment. Recent work has examined the extent to which individuals with AUD may seek alcohol to enhance positive experiences (reward drinking) or relieve negative states (relief drinking) and shown that a high reward/low relief phenotype predicts naltrexone treatment response. Yet, limitations of reward/relief drinking measures may hamper efforts to translate findings to clinical practice. We sought to refine a brief measure of reward/relief drinking and develop cutoff scores to identify reward/relief subgroups that predict pharmacotherapy response., Methods: The Inventory of Drinking Situations (IDS), used in previous studies to measure reward/relief drinking, was administered to 426 participants (77% male; average age = 45.3) in a clinical trial examining naltrexone and acamprosate., Results: Item response theory and tests of differential item functioning across sex, age, and alcohol dependence severity were used to create a 10-item measure, titled the Reward and Relief IDS (RR-IDS). Cutoff scores on the RR-IDS for the reward/relief drinking subgroups were identified using latent profile and area under the curve analyses. The cutoff scores demonstrated good construct validity. Individuals in the high reward/low relief subgroup who received naltrexone or acamprosate had a decreased likelihood of heavy drinking (large effect sizes) versus those who received placebo., Conclusions: The RR-IDS is a practical measure for identifying reward/relief subgroups and predicting pharmacotherapy response. Pending replication of these findings, the RR-IDS could be a critical precision medicine tool for prescribing AUD medications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine the reliability of the adherence monitoring and measurement methods used in these trials., Methods: The protocol for this review was pre-registered (PROSPERO: CRD42021230011). A search of the literature was conducted using OVID MEDLINE, Embase and PsycINFO from database inception to January 2021. Randomised controlled trials with a minimum sample size of 10 per treatment arm that compared the efficacy of acamprosate with placebo or other active medication in adults with a diagnosis of alcohol dependence were included. Data on rates of adherence, methods of measurement and monitoring of adherence was extracted from eligible studies independently in duplicate by two reviewers. A weighted mean adherence rate was calculated. The reliability of adherence monitoring methods was determined by calculating an adherence-assurance score based on the adherence monitoring method used. Risk of bias was assessed using the Cochrane Risk of Bias Tool., Results: Fifteen studies met the eligibility criteria involving 4,450 participants (2,480 participants in the placebo arms). A mean adherence rate of 88% (54.2-95.0%) was reported across studies that reported the percentage of medication taken. A mean adherence rate of 84.9% (56.4-91.3%) was reported for trials that reported the percentage of participants taking more than 80% of medication prescribed. There is low confidence in the methods used to monitor adherence with all clinical trials having a low adherence-assurance rating. Risk of bias was judged to be high for all included studies., Conclusions: Adherence to acamprosate in clinical trials can be poor with low confidence in the methods used to measure it. Adherence rates therefore might not be accurate, which has implications for determining the efficacy of acamprosate., Competing Interests: The authors have declared that no competing interests exist.

Alcohol contributes to more than 5% of global mortality, and causes more than half of all liver-related deaths. The Alcohol Use Disorders Identification Test (AUDIT) can be used to detect those patients with hazardous drinking and alcohol dependence who will benefit from psychosocial and pharmacological alcohol treatment. Psychosocial treatments range from brief interventions and cognitive behavioral therapy, to experimental neuropsychological treatments. Psychosocial intervention can be combined with acamprosate or naltrexone as first line pharmacological treatments. For patients with liver disease, abstinence increases survival and is therefore an important treatment goal. Acamprosate is a good choice, as it prevents relapse to drinking with a number needed to treat of 12. There are no reports indicating high risks of liver toxicity for acamprosate or naltrexone, but evidence is scarce. We recommend vigorous screening for alcohol use disorder in liver disease patients, followed by psychosocial intervention and complemented by pharmaceutical therapy., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Naltrexone is an efficacious medication for the treatment of alcohol use disorder in adults. As an opioid receptor antagonist, naltrexone blocks activation of the endogenous opioid system, which is involved in the affectively reinforcing properties of substance use. Few studies, however, have examined the moderating effect of naltrexone on the association between affect and alcohol use. Additionally, most existing research on naltrexone has been with adults in the human laboratory., Method: We conducted a secondary analysis of ecological momentary assessment data from a randomized, double-blinded, placebo-controlled cross-over study that compared naltrexone (50 mg/daily) and placebo in 26 adolescents (15 to 19 years old) who exhibited problematic drinking patterns. Multilevel models tested whether naltrexone moderated associations of alcohol use with both positive and negative affect (PA, NA)., Results: Results indicated that, during naltrexone treatment, greater estimated blood alcohol concentration (eBAC) levels were associated with greater NA further into drinking episodes. In turn, greater NA after the first drink of an episode was associated with reduced subsequent eBAC values during naltrexone treatment. Low PA was also associated with lower subsequent eBAC levels in the naltrexone condition after the first drink., Conclusions: These findings support the idea that naltrexone can disrupt the association between affect and alcohol use, effects that emerge later in drinking episodes. Greater attention to the effects of naltrexone on affect and reinforcement may help to tailor psychotherapy to maximize the benefits of naltrexone. However, in the present study, as most drink reports were in the first 2 h of the drinking episode and participants reported affect only at the first three end-drink reports of a drinking episode (limiting the number of drinks reported), we had reduced power to detect effects in the continuation phase. Thus, replication of the findings is needed using a design that assesses the impact of naltrexone across the entire episode., (© 2022 by the Research Society on Alcoholism.)

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD., (© 2022. The Author(s).)

Background: The prevalence of alcohol use disorder (AUD) is estimated to be 10 times higher amongst individuals in the criminal justice system than the general population. Alcohol use is also one of the strongest modifiable risk factors for recidivism. One intervention that has been shown to be effective in reducing alcohol consumption in the general population is medication-assisted treatment (MAT), and this systematic review synthesized the existing evidence on MAT for AUD in correctional settings., Methods: Empirical, peer-reviewed studies on approved medications for AUD in correctional populations were searched in major databases. One hundred sixty-two articles were initially screened and 14 eligible articles were included in the final review. Four articles examined disulfiram, and 10 articles examined naltrexone., Results: The studies on disulfiram were considerably older than those on naltrexone, predating contemporary scientific standards. Disulfiram in combination with substantial contingencies in a supervised setting significantly reduced alcohol-related measures of consumption and recidivism and had acceptable safety and tolerability. All naltrexone studies showed significant reductions in alcohol-related measures, but effects on recidivism were mixed. The naltrexone studies indicated that it was highly acceptable and well tolerated. In addition, offenders receiving naltrexone had significantly greater medication adherence, treatment attendance, and treatment duration than with placebo., Conclusions: A small number of studies on pharmacological interventions for AUD in the correctional population suggest that MAT is effective in reducing alcohol consumption, although results on recidivism are mixed. On balance, the evidence was more supportive of naltrexone in reducing alcohol-related outcomes than disulfiram and it may also be a more feasible intervention in correctional settings. Further research on MAT to address AUD in correctional populations with larger sample sizes, longer duration, and in combination with behavioral interventions is warranted., (© 2021 by the Research Society on Alcoholism.)