Hispidol Regulates Behavioral Responses to Ethanol through Modulation of BK Channels: A Novel Candidate for the Treatment of Alcohol Use Disorder.

Alcohol use disorder (AUD) is the most common substance use disorder and poses a significant global health challenge. Despite pharmacological advances, no single drug effectively treats all AUD patients. This study explores the protective potential of hispidol, a 6,4'-dihydroxyaurone, for AUD using the Caenorhabditis elegans model system. Our findings demonstrate that hispidol-fed worms exhibited more pronounced impairments in thrashes, locomotory speed, and bending amplitude, indicating that hispidol exacerbated the detrimental effects of acute ethanol exposure. However, hispidol significantly improved ethanol withdrawal behaviors, such as locomotory speed and chemotaxis performance. These beneficial effects were absent in slo-1 worms (the ortholog of mammalian α-subunit of BK channel) but were restored with the slo-1(+) or hslo(+) transgene, suggesting the involvement of BK channel activity. Additionally, hispidol increased fluorescence intensity and puncta in the motor neurons of slo-1::mCherry-tagged worms, indicating enhanced BK channel expression and clustering. Notably, hispidol did not alter internal ethanol concentrations, suggesting that its action is independent of ethanol metabolism. In the mouse models, hispidol treatment also demonstrated anxiolytic activity against ethanol withdrawal. Overall, these findings suggest hispidol as a promising candidate for targeting the BK channel in AUD treatment.

The pharmacological management of alcohol-related cirrhosis: what's new?

INTRODUCTION: Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED: This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION: Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.

Interest in the Use of Herbal Supplements to Close the Treatment Gap for Hazardous Alcohol Use Among Men Who Have Sex With Men: Secondary Analysis of a Cross-Sectional Study.

BACKGROUND: Hazardous alcohol consumption is highly prevalent for men who have sex with men (MSM). The 4 treatments currently approved by the Food and Drug Administration for alcohol use are reaching an alarmingly low percentage of people who would benefit from a reduction in their alcohol use. There is increasing interest in alternative methods of treatment, such as herbal supplements, to address hazardous drinking. However, research on the acceptability of alternative pharmacotherapies among MSM remains limited. OBJECTIVE: We examined the prevalence and correlates of expressing interest in using herbal supplements for alcohol treatment among MSM with hazardous alcohol consumption. METHODS: We conducted a secondary data analysis from a cross-sectional study of MSM who use alcohol, conducted from March 2015 to July 2017 in San Francisco, California, to assess the overall prevalence of interest in using herbal supplements to help reduce alcohol consumption. Associations between expressing interest in herbal supplements and demographic, social, and clinical characteristics were examined using bivariate and multivariable logistic regression models. RESULTS: One-third (66/200, 33%) of the participants expressed interest in an herbal supplement for reducing alcohol consumption. In the multivariable analyses, weekly binge drinking (adjusted odds ratio [aOR] 2.85, 95% CI 1.17-6.93), interest in abstaining from alcohol use (aOR 5.04, 95% CI 1.46-17.40), higher severity of alcohol dependence score (aOR 1.22, 95% CI 1.04-1.41), and interest in naltrexone (aOR 3.22, 95% CI 2.12-4.91) were independently associated with higher odds of being interested in using an herbal supplement to reduce alcohol consumption, adjusting for age, race or ethnicity, and education. CONCLUSIONS: We found that MSM who have hazardous drinking habits, more severe alcohol dependence, and interest in pharmacotherapy were more likely to express interest in using an herbal supplement for reducing alcohol consumption. To our knowledge, this is the first study that has evaluated correlates of interest in herbal supplements for alcohol use among MSM. As researchers implement novel alcohol treatment studies, they should focus on recruitment efforts among MSM with a motivation to reduce their alcohol use patterns.

Influence of inpatient withdrawal treatment on drug safety in alcohol use disorder - a quasi-experimental pre-post study.

OBJECTIVE: Most patients with alcohol use disorder (AUD) regularly take medication. Alcohol interacts negatively with many commonly prescribed medications. Little is known about whether the risk of potential alcohol-medication and drug-drug interactions increases or decreases in patients with AUD during inpatient withdrawal treatment. The aim of our study was to determine the prevalence and characteristics of potential alcohol-medication and drug-drug interactions in patients with AUD before and after withdrawal treatment in an addiction unit. DESIGN: Prospective monocentric quasi-experimental pre-post study. METHODS: Medication records before and after withdrawal treatment were analyzed and screened for potential alcohol-medication (pAMI) and drug-drug interactions (pDDI) using the drugs.com classification and the AiDKlinik® electronic interaction program, respectively. RESULTS: We enrolled 153 patients with AUD who were treated in an addiction unit of a university hospital in Germany. Of these, 67.3% experienced at least one pAMI before and 91.5% after withdrawal treatment. In total, there were 278 pAMIs classified as "mild," "moderate," or "severe" before and 370 pAMIs after withdrawal treatment. Additionally, there were 76 pDDIs classified as "moderate," "severe," or "contraindicated combinations" both before and after withdrawal treatment. CONCLUSION: The risk of exposure to pAMIs and pDDIs increases during inpatient withdrawal treatment in patients with AUD. Improvements in the quality of prescribing should particularly focus on the use of antihypertensives and opioids.

Advances in research on medications for the treatment of alcohol use disorders: A review.

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.

Is Phenobarbital an Effective Treatment for Alcohol Withdrawal Syndrome?

BACKGROUND: Alcohol use disorder is associated with a variety of complications, including alcohol withdrawal syndrome (AWS), which may occur in those who decrease or stop alcohol consumption suddenly. AWS is associated with a range of signs and symptoms, which are most commonly treated with GABAergic medications. CLINICAL QUESTION: Is phenobarbital an effective treatment for AWS? EVIDENCE REVIEW: Studies retrieved included two prospective, randomized, double-blind studies and three systematic reviews. These studies provided estimates of the effectiveness and safety of phenobarbital for treatment of AWS. CONCLUSIONS: Based on the available literature, phenobarbital is reasonable to consider for treatment of AWS. Clinicians must consider the individual patient, clinical situation, and comorbidities when selecting a medication for treatment of AWS.

Topiramate-induced acute eosinophilic pneumonia.

A man in his 40s with a known history of alcohol dependence syndrome was admitted with presenting symptoms of alcohol withdrawal. During his admission, he developed breathlessness, cough and wheezing. Investigations revealed raised absolute eosinophil count and serum IgE levels. Chest imaging showed ill-defined opacities and fibreoptic bronchoscopy with bronchoalveolar lavage confirmed eosinophilic pneumonia. Extensive workup for the cause of eosinophilia was negative. The patient's medicines were reviewed, and it was realised that the onset of eosinophilia occurred after starting topiramate for an alcohol withdrawal seizure. The drug was stopped, leading to the complete resolution of symptoms and radiological abnormalities. This case highlights the importance of considering drug-induced causes of eosinophilic pneumonia.

Naltrexone augmented with prazosin for alcohol use disorder: results from a randomized controlled proof-of-concept trial.

AIMS: We conducted a proof-of-concept randomized controlled trial of the mu-opioid receptor antagonist, naltrexone, augmented with the alpha-1 adrenergic receptor antagonist, prazosin, for alcohol use disorder in veterans. We sought a signal that the naltrexone plus prazosin combination regimen would be superior to naltrexone alone. METHODS: Thirty-one actively drinking veterans with alcohol use disorder were randomized 1:1:1:1 to naltrexone plus prazosin (NAL-PRAZ [n = 8]), naltrexone plus placebo (NAL-PLAC [n = 7]), prazosin plus placebo (PRAZ-PLAC [n = 7]), or placebo plus placebo (PLAC-PLAC [n = 9]) for 6 weeks. Prazosin was titrated over 2 weeks to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS. Naltrexone was administered at 50 mg QD. Primary outcomes were the Penn Alcohol Craving Scale (PACS), % drinking days (PDD), and % heavy drinking days (PHDD). RESULTS: In the NAL-PRAZ condition, % reductions from baseline for all three primary outcome measures exceeded 50% and were at least twice as large as % reductions in the NAL-PLAC condition (PACS: 57% vs. 26%; PDD: 51% vs. 22%; PHDD: 69% vs. 15%) and in the other two comparator conditions. Standardized effect sizes between NAL-PRAZ and NAL-PLAC for each primary outcome measure were >0.8. All but one participant assigned to the two prazosin containing conditions achieved the target prazosin dose of 16 mg/day and maintained that dose for the duration of the trial. CONCLUSION: These results suggest that prazosin augmentation of naltrexone enhances naltrexone benefit for alcohol use disorder. These results strengthen rationale for an adequately powered definitive randomized controlled trial.

Supporting alcohol brief interventions and pharmacotherapy provision in Australian First Nations primary care: exploratory analysis of a cluster randomised trial.

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).

Loss of Consciousness After Naltrexone Implantation: A Case Report. / Naltrekson Implant Uygulamasi Sonrasinda Gelisen Bilinç Kaybi: Olgu Sunumu.

Naltrexone is an µ opioid receptor antagonist that is used in alcohol and opiate use disorder. Naltrexone does not constitute tolerance and dependence, and cessation of the drug does not cause withdrawal symptoms. Sustained release form of naltrexone has been developed due to patient compliance issues. There is currently only one sustainedrelease form available in Turkey, which is inserted subcutaneously. In this case report, we present, a probable serious side effect of sustained release naltrexone implant. A 36 years old male with alcohol use disorder, developed a sudden clouding of consciousness one hour after the naltrexone implant application followed by anterograde amnesia in the next 8-10 hours. We were not able to detect any medical or neurological reasons for the altered mental status but after the removal of the naltrexone implant, the symptoms improved. To the best of our knowledge, this is the first case to report clouding of consciousness and anterograde amnesia after naltrexone implantation. Keywords: Naltrexone Implant, Side Effect, Alcohol Use Disorder, Lethargy, Consciousness.

Telemedicine for Initiation of Alcohol Use Disorder Medications.

This case-control study examines the initiation of treatment with medications for alcohol use disorder (MAUD) among US adults and compares the characteristics of adults who initiate MAUD treatment via telemedicine vs in-person care.

Alcohol pharmacotherapy dispensing trends in Australia between 2006 and 2023.

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 effect of intranasal (R,S)-ketamine on symptoms of fatigue in severe major depressive disorder or bipolar depression with and without comorbid alcohol use disorder: Results from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fatigue is a multidimensional condition that may overlap with depression. Initial studies found that fatigue responds in only a limited way to standard monoaminergic antidepressants and mood stabilizers but does respond positively to intravenous (IV) racemic (R,S)-ketamine (ketamine). However, IV ketamine's use is limited by cost and access barriers. To date, no study has evaluated intranasal (IN) ketamine in individuals with fatigue. This study sought to evaluate the anti-fatigue effects of a single 50 mg dose of IN ketamine in individuals with major depressive disorder (MDD) or bipolar depression (BDep), both with and without comorbid alcohol use disorder (AUD). METHODS: Twenty-eight individuals with primary diagnoses of MDD or BDep I/II currently experiencing a depressive episode with active suicidality were enrolled; approximately 60 % had comorbid AUD. Changes in the NIH-Brief Fatigue Inventory (NIH-BFI) were assessed at baseline and at 4, 24, and 48 h post-treatment. RESULTS: The group x time interaction for NIH-BFI score was significant (F = 3.44, p = 0.022), favoring IN ketamine over placebo. IN ketamine was well-tolerated with minimal adverse effects. LIMITATIONS: Limitations include the limited sample size, short duration, and single, fixed dose. CONCLUSIONS: IN ketamine appears to induce rapid anti-fatigue effects in individuals with severe MDD and BDep both with and without comorbid AUD. This suggests that IN ketamine holds potential as an alternative, rapid-acting, anti-fatigue option for different medical conditions.

The combination of donepezil and cognitive training for improving treatment outcomes for alcohol use disorder: Design of a randomized controlled trial.

BACKGROUND: The development of alcohol use disorder (AUD) is a major concern in public health, and cognitive impairments caused by alcohol are involved in this process. Emerging neurobiological evidence suggests that donepezil, an anticholinesterase agent, may improve AUD treatment outcomes by enhancing neurocognitive functioning. Previous research has also suggested that cognitive remediation therapy (CRT) could potentially improve cognitive function and AUD treatment outcomes. We present the rationale and design of a trial to evaluate the combination of donepezil and cognitive remediation therapy (donepezil + CRT) as an intervention for AUD. METHODS: We propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as an intervention for AUD. The main goal of the study is to evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking days and improving neurocognitive functioning. A total of 160 patients (4 groups, 40 per each group) with AUD between the ages of 18-80 years will be recruited at Yale University and the VA Connecticut Healthcare System. Primary outcome measures include 1) heavy drinking by Timeline Follow Back (TLFB) over 13 weeks and 2) global neurocognitive functioning by a global index of neurocognitive function score at 7 and 13 weeks. DISCUSSION: This protocol paper describes the rationale and proposed methods for the randomized controlled trial for improving AUD treatment outcomes. This project has significant clinical potential to help patients suffering from AUD by improving their cognition and reducing alcohol consumption. TRIAL REGISTRATION: NCT05042102.

Improving thiamine prescribing in alcohol use disorder using electronic decision support in a large urban academic medical center: A pre-post intervention study.

INTRODUCTION: Thiamine is the only therapy for prevention and treatment of Wernicke Encephalopathy among patients with Alcohol Use Disorder (AUD). Despite this fact, up to 75 % of inpatients with AUD are not prescribed thiamine during hospitalization. Even fewer patients are prescribed high-dose thiamine which many experts recommend should be standard of care. Previous attempts to improve thiamine prescribing for inpatients have had limited success. METHODS: We conducted an evaluation of thiamine prescribing in the year before and year after an intervention to increase high-dose thiamine prescribing. Pre-post study analysis occurred on two distinct study cohorts: those with alcohol-related diagnoses and those with elevated alcohol levels. The intervention was new electronic health record-based decision support which encouraged high-dose thiamine when any thiamine order was sought. No educational support was provided. The primary outcome was prescription of high-dose thiamine before versus after intervention. Of those with alcohol-related diagnoses, the monthly percentage of thiamine treatment courses including high-dose thiamine were graphed on a control chart. RESULTS: We examined 5307 admissions with alcohol-related diagnoses (2285 pre- and 3022 post-intervention) and 698 admissions with elevated alcohol levels (319 pre- and 379 post-intervention). Among admissions with alcohol-related diagnoses, the intervention was associated with a higher proportion of admissions receiving high-dose thiamine prescriptions in the first 24 h (4.7 % vs. 1.1 %, adjusted odds ratio 4.50, CI 2.93 to 6.89, p < 0.001). A similar difference in high-dose thiamine was seen post-intervention among admissions with elevated alcohol levels (14.3 % vs. 2.5 %, adjusted odds ratio 6.43, CI 3.05 to 13.53, p < 0.001). The control chart among those with an alcohol-related diagnosis demonstrated special cause variation: the median percentage of thiamine treatment courses including high-dose thiamine improved from 8.2 % to 13.0 %. CONCLUSIONS: Electronic decision support without educational interventions increased the use of high-dose thiamine among patients with alcohol-related diagnoses and with elevated alcohol levels during hospitalization. This increase occurred immediately in the month after the intervention and was sustained in the year-long study period after.

The Effect of Antidepressants on Withdrawal in Patients with Alcohol Dependence: A Retrospective Study.

The use of electronic health records has expanded in the past decades, with healthcare entities storing terabytes of patient health data. In this study, we investigated how these databases can be utilized to generate clinically relevant information. We used the Office of Addiction Services and Supports Client Data Systems data merged with the NYS Medicaid Data Warehouse to study the relationship of certain antidepressants on alcohol withdrawal (AW) rates in patients with alcohol dependence (AD). We found that in patients with AD, bupropion was associated with a significantly reduced rate of AW compared to selective serotonin reuptake inhibitors (SSRIs). This may be due to the ability of bupropion to inhibit dopaminergic reuptake. This retrospective study provides the advantage of being faster and less expensive than randomized controlled trials (RCTs).

Kappa-opioid receptor antagonism in the nucleus accumbens shell distinguishes escalated alcohol consumption and negative affective-like behavior from physiological withdrawal in alcohol-dependence.

Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol's reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics.