The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis.

AIMS: This study aimed to estimate the strength of association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP-1 RA and substance use-outcome association among patients with comorbid type 2 diabetes and obesity. DESIGN: A retrospective cohort study analyzing de-identified electronic health record data from the Oracle Cerner Real-World Data. SETTING: About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022. PARTICIPANTS: The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older. MEASUREMENTS: The exposure indicated the presence (one or more) or absence of GIP/GLP-1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors. FINDINGS: Patients with GIP/GLP-1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43-0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40-0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP-1 RA among patients with OUD and AUD. CONCLUSIONS: Prescriptions of glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity.

Triglyceride-glucose index is associated with all-cause mortality in critically ill patients with alcohol use disorder: a retrospective cohort study.

BACKGROUND: The relationship between Triglyceride-glucose (TyG) index and clinical outcomes in patients with alcohol use disorder (AUD) is unclear. The aim of this study was to evaluate the association between TyG index and all-cause mortality in critically ill patients with AUD. METHODS: We used data from the multi-parameter intelligent monitoring in intensive care IV (MIMIC-IV) database. The patients were equally divided into quartiles. Kaplan-Meier curves were used for survival analysis. The primary endpoint of the study was 28-day mortality, followed by 1-year mortality. We used Cox proportional hazard models to assess the relationship between TyG index and all-cause mortality at different endpoints. RESULTS: A total of 537 AUD patients were included. Using TyG value as a continuous variable (HR 1.460, 95% CI 1.121-1.903, p = 0.005) and categorical variable (HR 1.447-3.477 from Q2 to Q4, with Q1 as reference), elevated TyG value was significantly associated with increased 28-day mortality. TyG was positively associated with 1-year mortality in AUD patients with an HR of 1.295 (95% CI 1.011-1.659, p = 0.041). CONCLUSION: TyG index is positively associated with different clinical outcomes of critically ill AUD patients.

Assessment of reduction in stimulus generalization of ethanol-seeking during recovery: A rapid procedure.

Previously, we developed a procedure which showed that longer histories of reinforced alternative behavior decrease the risk of relapse caused by a range of stimuli which had previously occasioned drinking. The decrease in relapse risk was likely due to a decrease in attention to the stimuli over the course of repeated engagement in the alternative behavior. However, this previous procedure was time consuming and did not mirror the procedure we used to observe changes in relapse risk. This study aimed at replicating the previous relationship between the duration of engaging in an alternative behavior and shift in stimulus generalization for drinking using a procedure that allows longitudinal analysis over time and is consistent with other procedures we have developed. Rats were trained to respond for ethanol in the presence of one stimulus (16 kHz tone; food Fixed Ratio (FR)150 and ethanol FR5), and for food in the under another stimulus (8 kHz tone; food and ethanol FR5). Then, recovery-like sessions with food predominant responding occurred in the presence of only the low-cost food stimulus. During these sessions, rats were exposed to non-reinforced graded stimuli alternation from 8 to 16 kHz alternating with the reinforced low-cost food stimulus. The number of responses on each (food and ethanol) lever before completing 5 responses on either lever was the main measure. Consistent with the earlier procedure, the current procedure showed that graded variation of tone from 8 to 16 kHz produced a graded increase in responding for ethanol compared to responding for food. In addition, longer periods of engaging in recovery-like responding shift the generalization function downwards. This procedure confirms the earlier pattern of stimulus generalization over longer periods of behavior consistent with recovery. This strengthens our hypothesis that shifts in attention to alcohol-related stimuli are important to the development of relapse resistance during recovery.

The TMEM132B-GABAA receptor complex controls alcohol actions in the brain.

Alcohol is the most consumed and abused psychoactive drug globally, but the molecular mechanisms driving alcohol action and its associated behaviors in the brain remain enigmatic. Here, we have discovered a transmembrane protein TMEM132B that is a GABAA receptor (GABAAR) auxiliary subunit. Functionally, TMEM132B promotes GABAAR expression at the cell surface, slows receptor deactivation, and enhances the allosteric effects of alcohol on the receptor. In TMEM132B knockout (KO) mice or TMEM132B I499A knockin (KI) mice in which the TMEM132B-GABAAR interaction is specifically abolished, GABAergic transmission is decreased and alcohol-induced potentiation of GABAAR-mediated currents is diminished in hippocampal neurons. Behaviorally, the anxiolytic and sedative/hypnotic effects of alcohol are markedly reduced, and compulsive, binge-like alcohol consumption is significantly increased. Taken together, these data reveal a GABAAR auxiliary subunit, identify the TMEM132B-GABAAR complex as a major alcohol target in the brain, and provide mechanistic insights into alcohol-related behaviors.

Was receipt of any specialty alcohol treatment during the pandemic effective at reducing drinking for patients with or at risk of AUD?

INTRODUCTION: The COVID-19 pandemic changed the way healthcare providers delivered most health services, including treatment for alcohol use disorder (AUD). Specialty alcohol treatment remained available through the pandemic, and within some systems treatment use increased likely due to telehealth availability. However, the field knows little about the relationship between the pandemic's expanded access to specialty alcohol treatment and alcohol use outcomes. METHODS: The sample included 14,712 patients from Kaiser Permanente Northern California who screened positive for unhealthy alcohol use in primary care and had an AUD diagnosis or risked developing an AUD by reporting 5 or more heavy drinking days in a 3-month period between 1/1/2019 and 2/29/2020 (pre-pandemic). The study examined the receipt of any specialty alcohol treatment (including at least one outpatient, inpatient, or telehealth specialty treatment encounter, or pharmacotherapy prescription) from 3/1/2020 (pandemic start) to either the first completed follow-up alcohol screening or 6/20/2022 (study period end). The outcomes of alcohol use included changes in heavy drinking days, drinks per week, drinking days per week, and drinks per drinking day between the pre- and post-pandemic periods. RESULTS: On average patients significantly decreased alcohol use across all four alcohol use measures examined, regardless of whether they received treatment. However, those who received any treatment compared to those who did not had greater reductions in alcohol use, with an additional decrease of -3.55 heavy drinking days (95 % CI = -5.93, -1.17), -3.80 drinks per week (95 % CI = -5.18, -2.42), -0.72 drinks per drinking day (95 % CI = -1.14, -0.30), and - 1.01 drinking days per week (95 % CI = -1.30, -0.72). Treatment effects were greatest among patients who exceeded both daily and weekly limits pre-pandemic, with an additional decrease of -10.75 heavy drinking days (95 % CI = -15.28, -6.21), -12.83 drinks per week (95 % CI = -16.31, -9.35), -1.67 drinks per drinking day (95 % CI = -2.19, -1.14), and -2.02 drinking days per week (95 % CI = -2.41, -1.63). CONCLUSIONS: On average, patients decreased alcohol use during the onset of the pandemic, however, those who had any specialty alcohol treatment had significantly greater decreases, suggesting that the hybrid in-person and telehealth treatment approach was effective during the pandemic.

Efficacy of medications for the treatment of alcohol use disorder (AUD): A systematic review and meta-analysis considering baseline AUD severity.

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.

The Relationship Between Early Maladaptive Schemas and Coping Styles, Reasons for Drinking, Craving and Remission in Patients with Alcohol Use Disorder. / Alkol Kullanim Bozuklugu Hastalarinda Erken Dönem Uyumsuz Semalar ve Basa Çikma Biçimlerinin, Içme Nedenleri, Aserme ve Remisyon Öyküsü ile Iliskisi.

OBJECTIVE: Alcohol Use Disorder (AUD) is a serious mental disorder that affects the individual, family, environment and society as a whole. In this study, we aimed to analyze the relationship between early maladaptive schemas and coping styles, with craving, reasons for consumption and finally remission history. METHOD: This is a cross sectional study. We included 90 Erenköy Mental Health and Neurological Diseases Training and Research Hospital AMATEM patients with AUD according to DSM-5. AUD diagnosis is confirmed by SCID-5 CV. Subjects with additional psychiatric conditions are excluded. Subjects without withdrawal symptoms by CIWA-Ar are included. Sociodemographic data form, Young Schema Questionnaire Short form-3, Young Rygh Avoidance Inventory, Young Compensation Inventory, Drinking Motives Questionnaire-Revised, Obsessive Compulsive Drinking Scale was applied. RESULTS: Our findings show that male subjects who have early maladaptive schemas, especially in Impaired autonomy and performance; Failure, Disconnection and rejection; Social Isolation/alienation, Impaired Limits; Insufficient Self-Control/Self-Discipline domains, experience more cravings. Individuals coping with the Psychosomatism, Activity and Distraction, and Rebellion schemes experienced more craving. Those who coped with 'schema avoidance' tended towards alcohol consumption with Coping Motivation, and those who coped with 'schema compensation' with Impact Enhancement and Social motivations. There was no significant difference between the scores of the scales and the craving levels between the groups with and without a history of permanent remission. CONCLUSION: The data in our study showed that early maladaptive schemas and ways of coping with schemas are associated with craving. In the early stages of treatment, it is important to consider cognitive intervention focused on schemas and coping styles.

Alcohol use disorder disrupts BDNF maturation via the PAI-1 pathway which could be reversible with abstinence.

The plasminogen activator inhibitor-1 (PAI-1)→mature brain-derived neurotrophic factor (mBDNF) pathway plays a pivotal role in the conversion of probrain-BDNF (ProBDNF) to mBDNF, but its clinical relevance in patients with alcohol use disorder (AUD) remains unknown. Enzyme-linked immunosorbent assays were used to examine the relevant protein levels of components of the PAI-1→mBDNF pathway in plasma samples from three groups of subjects, and statistical analysis was performed using analysis of variance (ANOVA) and one-way repeated-measures ANOVA. Our findings revealed significant alterations induced by alcohol. (1) AUD was associated with significant decreases in tissue plasminogen activator (tPA), mBDNF, and tropomyosin receptor kinase B (TrkB); significant increases in PAI-1, ProBDNF, and P75 neurotrophin receptor (P75NTR); and inhibited conversion of ProBDNF to mBDNF. (2) Following abstinence, the levels of tPA, mBDNF, and TrkB in the AUD group significantly increased, whereas the levels of PAI-1, ProBDNF, and P75NTR significantly decreased, promoting the conversion of ProBDNF to mBDNF. These clinical outcomes collectively suggest that AUD inhibits the conversion of ProBDNF to mBDNF and that abstinence reverses this process. The PAI-1→mBDNF cleavage pathway is hypothesized to be associated with AUD and abstinence treatment.

Antimicrobial Stewardship of Oral Third-Generation Cephalosporins in Community Pharmacy: A Single-Center Quasi-Experimental Study.

Proper use of antimicrobials in hospital and outpatient settings is critical for minimizing the occurrence of antimicrobial resistance. Some hospitals have intervened in the inappropriate use of third-generation oral cephalosporins. However, there have been no such studies in community pharmacy settings. This study aimed to investigate how the use of oral third-generation cephalosporins in community pharmacies affects the amount of antimicrobials used. Patients who visited Nakanomaru Pharmacy after being prescribed antimicrobials at target medical institutions between February 2021 and January 2023 were identified. The number of oral antimicrobials used, duration of use, number of prescriptions, patient age and sex, and infectious diseases in the target patients before and after the intervention for the proper use of oral third-generation cephalosporins were retrospectively investigated based on the patients' medication history and prescription receipts. Through efforts to ensure the proper use of oral third-generation cephalosporins, the amount of oral third-generation cephalosporins used has decreased, and the use of penicillins and oral first-generation cephalosporins has increased. There was no increase in the antimicrobial change or relapse rates associated with treatment failure before and after the initiation of appropriate antimicrobial use. By working toward the proper use of oral third-generation cephalosporins in community pharmacies, we were able to reduce the doses of oral third-generation cephalosporins without compromising their therapeutic efficacy. We believe that recommending the selection of narrow-spectrum antimicrobials based on these guidelines will contribute to their proper use.

Driving Under the Influence of Alcohol in People With Major Depressive Episodes and Alcohol Use Disorder.

OBJECTIVES: Alcohol use disorder (AUD) and depression are the most commonly reported psychiatric comorbid conditions. We examined trends in the past-year prevalence of driving under the influence of alcohol (DUIA) among people with major depressive episodes (MDE), AUD, or both in the United States. METHODS: We analyzed 543,573 individuals aged 18 years or older from the 2005 to 2019 National Surveys on Drug Use and Health (NSDUH). Multivariate logistic regression models were applied to examine the adjusted past-year prevalence of DUIA. To assess trends in DUIA over time, average annual percent change (AAPC) was calculated. RESULTS: From 2005 to 2019, DUIA prevalence among US adults with MDE declined significantly from 18.1% to 9.4% (AAPC = -4.9). Decreasing trends in DUIA were also observed among those with AUD (from 55.4% to 37.8%, AAPC = -3.0) and among those with co-occurring MDE and AUD (from 58.3% to 38.8%, AAPC = -3.1). Compared to those with no MDE or AUD, individuals with AUD and those with co-occurring MDE and AUD had significantly lower AAPCs across all examined sociodemographic subgroups except Non-Hispanic Other and those without a high school diploma. CONCLUSIONS: From 2005 to 2019, DUIA prevalence declined significantly with varying rates of decrease across different diagnostic and sociodemographic groups. Focused public health efforts are needed to engage high-risk groups that have shown a tendency toward less expedient reductions in DUIA.

A Case of Prolonged Wernicke's Encephalopathy After Treatment With IV Thiamine Due to the Subsequent Development of Refeeding Syndrome.

Wernicke's encephalopathy (WE) is a rare, life-threatening condition in which thiamine deficiency causes dysfunction of the Kreb's cycle, accumulation of lactic acid in the brain tissues, and irreversible cognitive impairment. Prompt treatment with IV thiamine can reverse the process. The classic Wernicke's triad of ataxia, memory issues, and ocular abnormalities is not often present. Caine's criteria, which requires two of the following: dietary deficiencies, ocular abnormalities, altered cognition or mental status, and cerebellar dysfunction, is highly sensitive and specific for Wernicke's diagnosis, especially in patients with alcohol use disorder. Refeeding syndrome (RS) has similar risk factors to WE, including disease states that lead to malnutrition. Patients with RS develop WE due to thiamine depletion that occurs when oral nutrition is reinitiated after a period of poor oral intake. We present a patient with initially undetected WE who developed RS after the initiation of treatment with IV thiamine. RS prolonged the neurologic symptoms of WE and led to an extended hospital stay and significant physical debility. In our patient, WE preceded RS instead of occurring as a consequence of it. The case highlights that if one of these disorders is present, the other may not be far behind. When WE precedes RS, prolonged treatment with IV thiamine may be warranted until the symptoms of both disorders resolve.

Trend of alcohol use disorder as a percentage of all-cause mortality in North America.

OBJECTIVE: To evaluate the trend of alcohol use disorder (AUD) mortality as a percentage of all-cause mortality in Canada and the United States (US) between 2000 and 2019, by age group. RESULTS: Joinpoint regression showed that AUD mortality as a percentage of all-cause mortality significantly increased between 2000 and 2019 in both countries, and across all age groups (i.e., young adults (20-34 years), middle-aged adults (35-49 years), and older adults (50 + years)). The trend has been levelling off, and even reversing in some cases, in recent years. The average annual percentage change differed across countries and between age groups, with a greater increase among Canadian adults aged 35-49 years and among adults aged 50 + years in the US. Over the past two decades, AUD mortality as a percentage of all-cause mortality has been increasing among all adults in both Canada and the US.

Web-Based Coping Skills Training and Coach Support for Women Living With a Partner With an Alcohol Use Disorder: Randomized Controlled Trial.

BACKGROUND: Individuals living with a partner with an alcohol use disorder (AUD) can experience significant psychological distress and use health care more than those without a partner with an AUD. However, the prevailing treatment system's focus on the partner and personal barriers limit these individuals from getting help for themselves. Preliminary work on a self-directed, web-based coping skills training program, Stop Spinning My Wheels (SSMW), shows promise in broadening available treatments for this population. In this study, we conducted a robust evaluation of SSMW primary outcomes. OBJECTIVE: The study aims to test whether women with a partner with an AUD assigned to SSMW experienced a greater reduction in negative affect (depression and anger) (1) than a usual web care (UWC) control and (2) with brief phone coach support (SSMW+coach) rather than without (SSMW only) and (3) whether baseline negative affect moderated treatment effects. METHODS: Women (mean age 45.7, SD 10.8 years; Black: 17/456, 3.7%; White: 408/456, 89.5%) were randomized to SSMW only, SSMW+coach, or UWC. Depression (Beck Depression Inventory-II) and anger (State-Trait Anger Expression Inventory 2-State Anger) were assessed at baseline, 12-week posttest, and 6- and 12-month follow-ups. RESULTS: Participants in all conditions decreased in depression from baseline to posttest and from baseline to follow-up; SSMW-only and SSMW+coach participants decreased in anger, but UWC participants did not. Compared to UWC participants, SSMW-only participants experienced greater anger reduction (P=.03), and SSMW+coach participants experienced a greater reduction in depression (P<.001) from baseline to posttest. However, from baseline to follow-up, only a greater, but not statistically significant (P=.052), reduction in anger occurred in SSMW+coach compared to UWC. Although the SSMW conditions did not differ from each other in negative affect outcomes (P=.06-.57), SSMW+coach had higher program engagement and satisfaction (all P<.004). Baseline negative affect did not moderate effects, although remission from baseline clinically relevant depressive symptoms (Beck Depression Inventory≥14) was higher in SSMW only (33/67, 49%; odds ratio 2.13, 95% CI 1.05-4.30; P=.03) and SSMW+coach (46/74, 62%; odds ratio 3.60, 95% CI 1.79-7.23; P<.001) than in UWC (21/67, 31%); remission rates did not differ between the SSMW conditions (P=.12). CONCLUSIONS: The results partially supported the hypotheses. The SSMW conditions had earlier effects than UWC, but positive change in UWC mitigated the hypothesized long-term SSMW-UWC differences. The results highlight the importance of incorporating active controls in web-based clinical trials. Although SSMW+coach showed benefits over SSMW only on engagement and satisfaction measures and in the number needed to treat (5.6 for SSMW only; 3.2 for SSMW+coach), the SSMW conditions were comparable and superior to UWC on depressive symptom remission levels. Overall, SSMW with or without a coach can reduce clinically meaningful distress and add to available treatment options for this large, underserved group. TRIAL REGISTRATION: ClinicalTrials.gov NCT02984241; https://www.clinicaltrials.gov/study/NCT02984241.

Modulation of Alcohol Use Disorder by Brain Stimulation.

Currently available therapeutic modalities for alcohol use disorder (AUD) produce limited effect sizes or long-term compliance. Recent methods that were developed to modulate brain activity represent potential novel treatment options. Various methods of brain stimulation, when applied repeatedly, can induce long-term neurobiological, behavioral, and cognitive modifications. Recent studies in alcoholic subjects indicate the potential of brain stimulation methods to reduce alcohol craving, consumption, and relapse. Specifically, deep brain stimulation (DBS) of the nucleus accumbens or non-surgical stimulation of the dorsolateral prefrontal cortex (PFC) or medial PFC and anterior cingulate cortex using transcranial magnetic stimulation (TMS) has shown clinical benefit. However, further preclinical and clinical research is needed to establish understanding of mechanisms and the treatment protocols of brain stimulation for AUD. While efforts to design comparable apparatus in rodents continue, preclinical studies can be used to examine targets for DBS protocols, or to administer temporal patterns of pulsus similar to those used for TMS, to more superficial targets through implanted electrodes. The clinical field will benefit from studies with larger sample sizes, higher numbers of stimulation sessions, maintenance sessions, and long follow-up periods. The effect of symptoms provocation before and during stimulation should be further studied. Larger studies may have the power to explore predictive factors for the clinical outcome and thereby to optimize patient selection and eventually even develop personalization of the stimulation parameters.

Sex differences in dorsolateral prefrontal cortical and superior colliculus activities support the impact of alcohol use severity and sleep deficiency on two-back memory.

Background: Working memory refers to a process of temporary storage and manipulation of information to support planning, decision-making, and action. Frequently comorbid alcohol misuse and sleep deficiency have both been associated with working memory deficits. However, how alcohol misuse and sleep deficiency interact to impact working memory remains unclear. In this study, we aim to investigate the neural processes inter-relating alcohol misuse, sleep deficiency and working memory. Methods: We curated the Human Connectome Project (HCP) dataset and investigated the neural correlation of working memory in link with alcohol use severity and sleep deficiency in 991 young adults (521 women). The two were indexed by the first principal component (PC1) of principal component analysis of all drinking metrics and Pittsburgh Sleep Quality Index (PSQI) score, respectively. We processed the imaging data with published routines and evaluated the results with a corrected threshold. We used path model to characterize the inter-relationship between the clinical, behavioral, and neural measures, and explored sex differences in the findings. Results: In whole-brain regression, we identified ß estimates of dorsolateral prefrontal cortex response (DLPFC ß) to 2- vs. 0-back in correlation with PC1. The DLPFC showed higher activation in positive correlation with PC1 across men and women (r=0.16, P<0.001). Path analyses showed the model PC1 → DLPFC ß â†’ differences in reaction time (2- minus 0-back; RT2-0) of correct trials → differences in critical success index (2- minus 0-back; CSI2-0) with the best fit. In women alone, in addition to the DLPFC, a cluster in the superior colliculus (SC) showed a significant negative correlation with the PSQI score (r=-0.23, P<0.001), and the path model showed the inter-relationship of PC1, PSQI score, DLPFC and SC ß's, and CSI2-0 in women. Conclusions: Alcohol misuse may involve higher DLPFC activation in functional compensation, whereas, in women only, sleep deficiency affects 2-back memory by depressing SC activity. In women only, path model suggests inter-related impact of drinking severity and sleep deficiency on 2-back memory. These findings suggest potential sex differences in the impact of drinking and sleep problems on working memory that need to be further investigated.

Group based metacognitive therapy for alcohol use disorder: a pilot study.

Introduction: Alcohol use disorder (AUD) is a severe clinical disorder, which has been associated with 5.3% of death worldwide. Although several treatments have been developed to improve AUD symptomatology, treatment effects were moderate, with a certain amount of patients displaying symptom deterioration after treatment termination. Moreover, outpatient treatment placements become increasingly scarce, thus necessitating more efficient treatment options. Therefore, the aim of the present study was to investigate the efficacy, feasibility, and acceptability of a newly invented, short, group based metacognitive therapy (MCT) for patients diagnosed with AUD. Method: Seven patients were treated with eight sessions of group based MCT using a single case series design with an A-B replication across patients. Patients were assessed one month and one week before treatment, as well as one week and three months after treatment termination. Results: Patients improved significantly and with large effect sizes regarding dysfunctional metacognitive beliefs, desire thinking/craving and depressive symptoms up to three months after treatment termination. AUD symptomatology as well as positive and negative metacognitive beliefs improved at post-treatment, but improvements could not be maintained at follow-up. All included patients completed the treatment and were highly satisfied. Conclusion: The presented findings show preliminary evidence for the efficacy, feasibility, and acceptability of the implemented group based MCT treatment. Large scale randomized controlled trials (RCTs) are needed to confirm the effectiveness of the developed program for patients diagnosed with AUD.

Voluntary Exercise Ameliorates Chronic Ethanol Withdrawal-Induced Adaptations of Opioid Receptor Expression in the Nucleus Accumbens, Dopamine Release, and Ethanol Consumption.

Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors. In this study, we investigated the impact of voluntary exercise in EtOH-dependent mice on EtOH consumption, KOR and delta opioid receptor (DOR) expression in the NAc and VTA, and functional effects on EtOH-induced alterations in DA release in the NAc. Our findings reveal that voluntary exercise reduces EtOH consumption, reduces KOR and enhances DOR expression in the NAc, and modifies EtOH-induced adaptations in DA release, suggesting a competitive interaction between exercise-induced and EtOH-induced alterations in KOR expression. We also found changes to DOR expression in the NAc and VTA with voluntary exercise but no significant changes to DA release. These findings elucidate the complex interplay of AUD-related neurobiological processes, highlighting the potential for exercise as a therapeutic intervention for AUD.

Changes of attentional bias in patients with alcohol use disorder during abstinence: A longitudinal study.

BACKGROUND: Alcohol Use Disorder (AUD) is linked to an attentional bias towards alcohol-related cues (e.g. images, smells), which acquire incentive properties and promote continued consumption. METHOD: We investigated how the general and alcohol attentional bias evolved longitudinally in AUD patients along two periods of abstinence: t = 0 (baseline, 1-3 months of abstinence) and t = 1 (follow-up; 6 months of abstinence), as well as their relationship with alcohol-related variables. General and alcohol-specific attentional bias were evaluated by the Classic and the Alcohol Stroop tests (neutral and alcohol conditions) in abstinent AUD patients and controls. RESULTS: At t = 0, the AUD group exhibited both general and alcohol-specific attentional biases, with greater effect in the general bias. At t = 1, alcohol-specific attentional bias decreased specifically in the AUD group and reached control levels (with interference index levels increasing from 1-3 months to 6 months). However, general attentional bias showed a trend toward improvement but it did not significantly change through abstinence process (linear mixed models, controlling for age, BMI, sex and education). CONCLUSIONS: In AUD patients, general and alcohol attentional biases exhibit different trajectories during abstinence, with the attentional bias toward alcohol improving significantly throughout this process whereas general attentional bias is maintained.

Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models.

Alcohol tolerance is a neuroadaptive response that leads to a reduction in the effects of alcohol caused by previous exposure. Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.

AA, Bill Wilson, Carl Jung and LSD.

Alcoholics Anonymous (AA) is an established resource for people suffering from alcohol use disorder (AUD). However, Bill Wilson, the co-founder of AA, in his second letter to Jung referred to its low success rate. One evidence-based alternative, dating back to the 1950s, is the clinical use of lysergic acid diethylamide (LSD) for treating AUD. Bill Wilson was a strong advocate of using LSD as a preparation for alcoholics who had difficulty grasping the spiritual aspect of the 12-step programme. Bill Wilson wrote a "secret" four-page letter to Carl Jung detailing his own use of LSD and the success two psychiatrists in Canada had in treating alcoholics and asked for his advice on using LSD to help alcoholics. Aniela Jaffé, a Jungian analyst and co-worker of Jung, replied to Wilson on May 29, 1961, "… as soon as Dr. Jung feels better and has enough strength to begin again his mail, I will show it to him." Jung died a week later. This article quotes Jung's previous hostile opinions on psychedelics and asks: Just as Jung overcame his negative views on groups when giving "complete instructions" on extending the 12-step programme of AA to "general neurotics", might he similarly have changed his mind when he saw the documented success of using LSD with recalcitrant alcoholics?

Alcooliques Anonymes (A.A.) est une ressource reconnue pour les personnes souffrant du Trouble de l'Usage de l'Alcool (TUA). Bill Wilson, co­fondateur des AA, dans sa deuxième lettre à Jung, a fait référence à son faible taux de réussite. Une alternative fondée sur des preuves, et qui remonte aux années 1950, est l'utilisation médicale de l'acide lysergique diéthylamide (LSD) pour le traitement du TUA. Bill Wilson a fortement préconisé l'utilisation du LSD pour la préparation des alcooliques qui avaient des difficultés à saisir l'aspect spirituel du programme en douze étapes. Bill Wilson écrivit à Carl Jung une lettre de quatre pages, « secrète ¼, exposant en détails sa propre utilisation du LSD et le succès de deux psychiatres canadiens dans le traitement de personnes alcooliques avec le LSD. Il demandait conseil à Jung sur l'utilisation du LSD pour aider les alcooliques. Aniela Jaffé, une analyste jungienne et collaboratrice de Jung répondit à Wilson le 29 mai 1961 : « … dès que le Dr Jung se sentira mieux et aura suffisamment de force pour recommencer à s'occuper de son courrier, je lui montrerai. ¼ Jung est mort une semaine plus tard. Cet article cite les opinions antérieures négatives de Jung concernant les drogues psychédéliques et pose la question suivante: tout comme Jung avait dépassé ses perspectives négatives sur les groupes en donnant des « instructions complète ¼ sur l'extension du programme en douze étapes pour les « névrosés de base ¼, aurait­il de la même manière changé d'avis s'il avait vu les résultats probants de l'utilisation du LSD avec les alcooliques récalcitrants?

Alcohólicos Anónimos (A.A.) es un recurso establecido para las personas que padecen Trastorno por Consumo de Alcohol (AUD). Sin embargo, Bill Wilson, cofundador de AA, en su segunda carta a Jung se refirió a su baja tasa de éxito. Una alternativa basada en la evidencia, que se remonta a la década de 1950, es el uso clínico de la dietilamida del ácido lisérgico (LSD) para tratar el AUD. Bill Wilson era un firme defensor del uso del LSD como preparación para los alcohólicos que tenían dificultades para captar el aspecto espiritual del programa de 12 pasos. Bill Wilson escribió una carta "secreta" de cuatro páginas a Carl Jung en la que detallaba su propio uso del LSD y el éxito que habían tenido dos psiquiatras en Canadá en el tratamiento de alcohólicos con LSD y le pedía consejo a Jung sobre el uso del LSD para ayudar a los alcohólicos. Aniela Jaffé, analista Junguiana y compañera de trabajo de Jung, respondió a Wilson el 29 de mayo de 1961: "…tan pronto como el Dr. Jung se sienta mejor y tenga fuerzas suficientes para mirar de nuevo su correo, se lo mostraré". Jung murió una semana después. Este artículo cita las anteriores opiniones hostiles de Jung sobre los psicodélicos y pregunta: Del mismo modo que Jung superó sus opiniones negativas sobre los grupos al dar "instrucciones completas" sobre la extensión del programa de 12 pasos de A.A. a los "neuróticos en general", ¿podría haber cambiado de opinión de forma similar cuando vio el éxito documentado del uso del LSD con alcohólicos recalcitrantes?