Disulfiram's journey from rubber vulcanization to T-cell activation.

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.

Patient Perspectives on Pharmacotherapy of Alcohol Dependence.

INTRODUCTION: Pharmacotherapy with drugs like naltrexone or acamprosate is a well-evaluated element in the treatment of alcohol dependence (AD). However, in many countries, these medications are rarely administered. The objective of the present study was to identify from patients' perspective factors that prevent the initiation and compliance with pharmacological treatment of AD. METHODS: Patients from inpatient alcohol withdrawal treatment underwent a standardized interview. Questions included socio-demographic data, history of AD, treatment history, knowledge and personal experience regarding pharmacotherapy of AD, and personal views about the causes of AD. RESULTS: Three hundred patients (mean age 47.3 years, 27.7% female, mean duration of AD 8.9 years, 67% with a history of previous inpatient withdrawal treatment) were included. The majority of patients (58.7%) already knew drugs for the pharmacotherapy of AD. Thirty percent had ever used such medications, most often acamprosate. Except for disulfiram, pharmacotherapy of AD had lasted only a few weeks, on average. Medication usually had been applied without additional psychotherapy. No severe side effects were reported. Patients had often stopped pharmacotherapy on their own, when assuming they had reached stable abstinence. Openness to start pharmacotherapy for AD was currently stated by 67% of the total sample. In multiple logistic regression, openness was predicted by having a concept of AD as a medical disease and by a shorter duration of AD. DISCUSSION: To improve the administration of pharmacotherapy for AD implementation strategies should be systematically developed and evaluated with a focus on the concept of AD as a medical disease.

Psychosocial and medication interventions to stop or reduce alcohol consumption during pregnancy.

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; I2 =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; I2 = 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; I2 = 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.

Medications for Alcohol Use Disorder.

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.

[Disulfiram encephalopathy: an underrecognized complication of accidental overdose]. / Disulfiramencefalopathie: een mogelijke complicatie bij accidentele overdosering.

In this paper we discuss the case of a 52-year-old man who consulted the emergency department because of confusion. Based on anamnesis, clinical presentation, various technical investigations and recovery after discontinuation of disulfiram, the diagnosis of disulfiram encephalopathy is made. This is a less common but serious complication of a frequently used therapy and underscores the importance of early recognition and careful but also controlled prescription of disulfiram. We describe the pathophysiology behind this complication and reflect on some important numbers.

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4.

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

Pharmacotherapy for Alcohol Use Disorder: A Systematic Review and Meta-Analysis.

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.

Integration of a physiologically-based pharmacokinetic model with a whole-body, organ-resolved genome-scale model for characterization of ethanol and acetaldehyde metabolism.

Ethanol is one of the most widely used recreational substances in the world and due to its ubiquitous use, ethanol abuse has been the cause of over 3.3 million deaths each year. In addition to its effects, ethanol's primary metabolite, acetaldehyde, is a carcinogen that can cause symptoms of facial flushing, headaches, and nausea. How strongly ethanol or acetaldehyde affects an individual depends highly on the genetic polymorphisms of certain genes. In particular, the genetic polymorphisms of mitochondrial aldehyde dehydrogenase, ALDH2, play a large role in the metabolism of acetaldehyde. Thus, it is important to characterize how genetic variations can lead to different exposures and responses to ethanol and acetaldehyde. While the pharmacokinetics of ethanol metabolism through alcohol dehydrogenase have been thoroughly explored in previous studies, in this paper, we combined a base physiologically-based pharmacokinetic (PBPK) model with a whole-body genome-scale model (WBM) to gain further insight into the effect of other less explored processes and genetic variations on ethanol metabolism. This combined model was fit to clinical data and used to show the effect of alcohol concentrations, organ damage, ALDH2 enzyme polymorphisms, and ALDH2-inhibiting drug disulfiram on ethanol and acetaldehyde exposure. Through estimating the reaction rates of auxiliary processes with dynamic Flux Balance Analysis, The PBPK-WBM was able to navigate around a lack of kinetic constants traditionally associated with PK modelling and demonstrate the compensatory effects of the body in response to decreased liver enzyme expression. Additionally, the model demonstrated that acetaldehyde exposure increased with higher dosages of disulfiram and decreased ALDH2 efficiency, and that moderate consumption rates of ethanol could lead to unexpected accumulations in acetaldehyde. This modelling framework combines the comprehensive steady-state analyses from genome-scale models with the dynamics of traditional PK models to create a highly personalized form of PBPK modelling that can push the boundaries of precision medicine.

Pharmacological interventions for alcohol misuse in correctional settings: A systematic review.

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.

Naltrexone moderates the association of alcohol use and affect among adolescent drinkers in daily life.

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.

In recently detoxified alcohol-dependent adults, acamprosate increases abstinence maintenance and reduces dropout.

SOURCE CITATION: Cheng HY, McGuinness LA, Elbers RG, et al. Treatment interventions to maintain abstinence from alcohol in primary care: systematic review and network meta-analysis. BMJ. 2020;371:m3934. 33239318.

Cost-effectiveness of alcohol use treatments in patients with alcohol-related cirrhosis.

BACKGROUND & AIMS: Alcohol use treatment such as medication-assisted therapies (MATs) and counseling are available and effective in promoting alcohol abstinence. We sought to explore the cost-effectiveness of different alcohol use treatments among patients with compensated alcohol-related cirrhosis (AC). METHODS: We simulated a cohort of patients with compensated AC receiving care from a hepatology clinic over their lifetimes. We estimated costs (in 2017 US$) and benefits in terms of quality-adjusted life years (QALYs) gained from healthcare and societal perspectives. Transition probabilities, costs, and health utility weights were taken from the literature. Treatment effects of FDA-approved MATs (acamprosate and naltrexone) and non-FDA approved MATs (baclofen, gabapentin, and topiramate) and counseling were based on a study of employer-insured patients with AC. We calculated incremental cost-effectiveness ratios (ICERs) and performed one-way and probabilistic sensitivity analyses to understand the impact of parameter uncertainty. RESULTS: Compared to a do-nothing scenario, MATs and counseling were found to be cost-saving from a healthcare perspective, which means that they provide more benefits with less costs than no intervention. Compared to other interventions, acamprosate and naltrexone cost the least and provide the most QALYs. If the effectiveness of MATs and counseling decreased, these interventions would still be cost-effective based on the commonly used $100,000 per QALY gained threshold. Several sensitivity and scenario analyses showed that our main findings are robust. CONCLUSIONS: Among patients with compensated AC, MATs and counseling are extremely cost-effective, and in some cases cost-saving, interventions to prevent decompensation and improve health. Health policies (e.g. payer reimbursement) should emphasize and appropriately compensate for these interventions. LAY SUMMARY: Alcohol use treatments, including physician counseling and medication-assisted therapies (MATs), improve the outcomes of patients with compensated alcohol-related cirrhosis, though use and access have remained suboptimal. In this study, we found that counseling and MATs are extremely cost-effective, and in some cases cost-saving, interventions to help patients with alcohol-related cirrhosis abstain from alcohol and improve their health. Wider use of these interventions should be encouraged.

The interaction of disulfiram and H2S metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth.

Disulfiram (DSF), a sulfur-containing compound, has been used to treat chronic alcoholism and cancer for decades by inactivating aldehyde dehydrogenase (ALDH). Hydrogen sulfide (H2S) is a new gasotransmitter and regulates various cellular functions by S-sulfhydrating cysteine in the target proteins. H2S exhibits similar properties to DSF in the sensitization of cancer cells. The interaction of DSF and H2S on ALDH activity and liver cancer cell survival are not clear. Here it was demonstrated that DSF facilitated H2S release from thiol-containing compounds, and DSF and H2S were both capable of regulating ALDH through inhibition of gene expression and enzymatic activity. The supplement of H2S sensitized human liver cancer cells (HepG2) to DSF-inhibited cell viability. The expression of cystathionine gamma-lyase (a major H2S-generating enzyme) was lower but ALDH was higher in mouse liver cancer stem cells (Dt81Hepa1-6) in comparison with their parental cells (Hepa1-6), and H2S was able to inhibit liver cancer stem cell adhesion. In conclusion, these data point to the potential of combining DSF and H2S for inhibition of cancer cell growth and tumor development by targeting ALDH.

Tetraethylthiuram disulphide alleviates pulmonary fibrosis through modulating transforming growth factor-ß signalling.

Idiopathic pulmonary fibrosis (IPF) induces significant morbidity and mortality, for which there are limited therapeutic options available. Here, we found that tetraethylthiuram disulphide (disulfiram, DSF), a derivative of thiuram, used in the treatment of alcohol abuse, has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis via the attenuation of the fibroblast-to-myofibroblast transition, migration, and proliferation of fibroblasts. Furthermore, DSF inhibited the activation of primary pulmonary fibroblasts and fibroblast cell line under transforming growth factor-ß 1 (TGF-ß1) challenge. Mechanistically, the anti-fibrotic effect of DSF on fibroblasts depends on the inhibition of TGF-ß signalling. We further determined that DSF interrupts the interaction between SMAD3 and TGF-ß receptor Ι (TBR Ι), and identified that DSF directly binds with SMAD3, in which Trp326, Thr330, and Cys332 of SMAD3 are critical binding sites for DSF. Collectively, our results reveal a powerful anti-fibrotic function of DSF in pulmonary fibrosis through the inhibition of TGF-ß/SMAD signalling in pulmonary fibroblasts, indicating that DSF is a promising therapeutic candidate for IPF.

A Critical Review of Alcohol Administration Guidelines in Laboratory Medication Screening Research: Is It Time to Include Treatment Seekers?

Human laboratory studies play an important role in alcohol use disorder (AUD) medication development. Medications that are found to be safe and effective during human laboratory screening will then move to more expensive clinical trials in patient populations. Given the gatekeeping role of human laboratory studies in the medication development pipeline, it is critical that these studies accurately forecast how pharmacotherapies will perform under true-to-life clinical conditions. On the other hand, the design of these studies also must adhere to ethical guidelines: certain aspects of clinical reality cannot be incorporated into screening studies because doing so might place the participant at risk for harm or breach other ethical guidelines. Conventions exist that guide the resolution of these conflicting ideals. This article considers the practice of recruiting non-treatment-seeking heavy drinkers to participate in laboratory screening studies. By convention, volunteers are excluded from laboratory screening studies that involve alcohol administration if they are deemed "treatment seeking," meaning that they recently stopped drinking or are motivated to do so. Although this common practice may reduce risk to participants, findings may not accurately predict medication effects on treatment seekers. Indeed, there is empirical evidence that treatment seekers differ from nontreatment seekers in their responses to medications (Neuropsychopharmacology 2017a; 42: 1776; Am J Drug Alcohol Abuse 2017b; 43: 703; J Psychiatr Res 2006; 40: 383). Here, we argue for the importance of recruiting treatment seekers for this research due to their qualitative difference from nontreatment seekers. We argue that these individuals should be the default population in human laboratory medication screening studies. We conclude by discussing 2 case examples of medication experiments led by our research groups that involved administering medications to treatment seekers.

Secondary Analysis of a Randomized Clinical Trial of Naltrexone Among Women Living With HIV: Correlations Between Reductions in Self-Reported Alcohol Use and Changes in Phosphatidylethanol.

BACKGROUND: Direct biomarkers such as phosphatidylethanol (PEth) have the capability to detect heavy alcohol use, but it is unclear how strongly self-reported reduction in alcohol use correlates with reduction in PEth. We sought to explore the strength of correlation between reductions in self-reported alcohol use and change in PEth among a sample of women living with HIV (WLWH) who participated in a clinical trial to reduce heavy alcohol use. We also sought to determine whether this correlation was stronger in women with lower body mass index (BMI) and women without an alcohol use disorder (AUD). METHODS: 81 WLWH (mean age = 48.7, 80% Black) engaging in a randomized trial of naltrexone versus placebo with a positive baseline PEth (≥8 ng/ml), and alcohol use data at baseline, 2, and 7 months were included in this analysis. Spearman correlation coefficients were compared to measure the correlation between baseline PEth and number of drinks per week by demographic, biological, and alcohol use factors. Mini-International Neuropsychiatric Interview was used to screen for AUD. Further analyses were stratified by BMI and AUD. Spearman correlation coefficients were calculated for the change in PEth and the change in number of drinks per week over 7 months, including 3 time-points: baseline, 2, and 7 months. RESULTS: At baseline, the correlation between baseline PEth and the number of drinks per week was significantly stronger for those with a BMI ≤25 compared to those with a BMI > 25 (r = 0.66; r = 0.26, respectively). Similarly, the correlation between baseline PEth and number of drinks was stronger for those who did not screen positive for AUD compared with those who did (r = 0.66; r = 0.25, respectively). When stratifying by BMI, a low-to-moderate correlation (r = 0.32, p = 0.02) was present for persons with a BMI > 25; when stratifying by AUD, a moderate correlation (r = 0.50, p < 0.01) was present for persons without an AUD between 0 and 2 months only. CONCLUSIONS: In this sample of WLWH, BMI and AUD affected the strength of correlation between PEth and drinks per week. Future work examining changes in PEth over time in broader populations is needed, particularly to understand the sex differences in PEth levels.

Effects of 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine on alcohol consumption in Long-Evans rats.

The objectives of this study were to determine alcohol consumption after administration of (R)(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) or naltrexone in Long-Evans rats, and to assess the effectiveness of these treatments based on individual differences in alcohol consumption. Adult male Long-Evans rats (N = 16) were given opportunities to orally self-administer a 20% (v/v) ethanol (EtOH) solution using an intermittent access, two-bottle (vs. tap water) choice procedure in their home cages. EtOH consumption and preference, total fluid consumption and food intake were measured. Last, we assessed the effects of naltrexone (1 mg/kg; subcutaneous) and (R)(-)-DOI (0.1-1 mg/kg; subcutaneous) on EtOH intake and preference using a quartile analysis. Rats showed stable EtOH (20%) intake and preference after 15 EtOH access sessions. Naltrexone produced a transient decrease in EtOH intake, but an inconsistent effect on EtOH preference, whereas DOI dose-dependently reduced EtOH intake and preference for at least 24 h. Subsequent quartile analyses revealed that rats with the highest EtOH intake during the first 60 min of access to EtOH showed greater reductions in EtOH intake and preference after DOI treatment. This is the first report to show that DOI-elicited reductions in EtOH intake and preference in rats depend on baseline EtOH intake, perhaps supporting a 'baseline dependency' hypothesis of effectiveness with phenethylamine psychedelics on EtOH consumption. If so, individuals with greater potential to develop severe AUDs may be particularly responsive to the positive motivational changes produced by treatment with psychedelics that target the 5-HT2 receptor family.

Development of new disulfiram analogues as ALDH1a1-selective inhibitors.

Disulfiram is an FDA-approved drug used to treat chronic alcoholism. This drug works by blocking the second step of ethanol metabolism by inhibiting aldehyde dehydrogenase-2 (ALDH2), the enzyme responsible for acetaldehyde oxidation into acetic acid. This leads to the accumulation of acetaldehyde in the blood following alcohol ingestion and to highly unpleasant symptoms known as acetaldehyde syndrome. Disulfiram also inhibits ALDH1a1, another member of the aldehyde dehydrogenases that catalyzes the oxidation of retinal into retinoic acid. ALDH1a1 represents a key therapeutic target for the treatment of important diseases such as cancer and obesity. The substrate tunnel is larger in ALDH1a1 than in ALDH2; therefore. Thus, replacing disulfiram ethyl groups with larger groups will yield selective ALDH1a1 inhibitors. In this work, we successfully synthesized derivative 2b, in which two ethyl groups were replaced by two para fluorobenzyl groups. The 2b derivative showed a comparable activity to disulfiram against ALDH1a1; however, it was completely devoid of inhibitory activity against ALDH2.

Implementation of Oral and Extended-Release Naltrexone for the Treatment of Emergency Department Patients With Moderate to Severe Alcohol Use Disorder: Feasibility and Initial Outcomes.

STUDY OBJECTIVE: Despite evidence supporting naltrexone as an effective treatment for alcohol use disorder, its use in emergency department (ED) patients has not been described. We implemented a protocol that combined substance use navigation with either oral naltrexone or extended-release intramuscular naltrexone for patients with alcohol use disorder as a strategy to improve follow-up in addiction treatment after ED discharge. METHODS: In this descriptive study, we analyzed the results from adult patients discharged from the ED with moderate to severe alcohol use disorder who received either oral naltrexone or extended-release intramuscular naltrexone between May 1, 2020, and October 31, 2020, and assessed their engagement in formal addiction treatment within 30 days after discharge from the ED. RESULTS: Among 59 patients with moderate to severe alcohol use disorder who accepted naltrexone treatment, 41 received oral naltrexone and 18 received extended-release intramuscular naltrexone. The mean (SD) age of the patients was 45.2 (13.4) years; 22 patients (37.3%) were Latinx, 18 (30.5%) were Black, and 16 (27.1%) were White. Among all patients, 9 (15.3%) attended follow-up formal addiction treatment within 30 days after discharge; 5 patients (27.8%) who received extended-release intramuscular naltrexone and 4 patients (9.8%) who received oral naltrexone attended follow-up treatment within 30 days. CONCLUSION: We implemented a clinical protocol for ED patients with moderate to severe alcohol use disorder using oral naltrexone and extended-release intramuscular naltrexone together with substance use navigation. Identification of alcohol use disorder, a brief intervention, and initiation of naltrexone resulted in a 15% follow-up rate in formal addiction treatment. Future work should prospectively examine the effectiveness of naltrexone as well as the effect of substance use navigation for ED patients with alcohol use disorder.

The Effectiveness of Non-Benzodiazepine, Non-Barbiturate Medications for Alcohol Withdrawal Syndrome: A Rapid Systematic Review.

AIM: There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal symptoms (AWS) through telemedicine or ambulatory outpatients. A rapid systematic review to (a) qualitatively summarize the non-benzodiazepine treatment alternatives, (b) evaluate the quality of evidence for the same to effectively manage moderate to severe AWS. METHODS: We conducted searches on PubMed (January 1990 to 31 March 2020), Cochrane Central Register of Controlled Trials, and Google Scholar. We selected the English language randomized controlled trials (RCTs) assessing the efficacy and adverse effects of non-benzodiazepine and non-barbiturate medications among adults with a diagnosis of AWS. Data extraction was done in a predefined format. Risk of bias (RoB) assessment and qualitative synthesis of evidence was done with the RoB2 tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) proGDT. RESULTS: Thirty-four RCTs were included. Gabapentin (n = 6), carbamazepine (n = 5), baclofen (n = 5), valproate (n = 3), clonidine/lofexidine (n = 3) and acamprosate (n = 2) had more than one trial with a particular comparison group. Four studies were found to have a low ROB. The GRADE evidence summary showed gabapentin had a 'moderate' level of evidence against standard benzodiazepine treatments for reducing the severity of AWS. The level of certainty was 'low' for carbamazepine, baclofen and valproate and 'very low' for acamprosate and clonidine/lofexidine. Reported adverse events between these alternative medications and benzodiazepines or placebo were generally unremarkable. CONCLUSIONS: Although benzodiazepines remain the treatment of choice for AWS, during particular circumstances, gabapentin could be an alternative although like benzodiazepines is not without risk when used in the community. Future RCTs must aim to improve upon the quality of evidence.