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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.

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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.

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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.

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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.

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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.

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BACKGROUND: Wearable technology for objective, continuous, and reliable alcohol monitoring has been developed. These are known as transdermal alcohol sensors (TASs). They can be worn on the wrist or ankle with the sensor pressed against the skin and can measure sweat vapors being emitted from the skin, to record transdermal alcohol concentration (TAC). Previous studies have investigated the accuracy and acceptability of the available TAS brands, but there has been little research into their use in people with alcohol use disorders (AUD). OBJECTIVE: This feasibility randomized controlled trial aims to explore the feasibility, strengths, and limitations of using a TAS to monitor alcohol consumption in individuals in treatment for AUD with or without contingency management (CM) to promote abstinence or low-level alcohol consumption. METHODS: The target sample size is 30 (15 randomized to each group). Participants will be recruited through poster adverts at alcohol services. Both groups (control and CM) will wear the TAS (BACtrack Skyn) for 2 weeks in the context of their usual treatment, meeting with the researcher every other weekday. In the last meeting, the participants will complete a postwear survey on their experience of wearing the TAS. The CM group will also receive small financial incentives for low or no alcohol consumption, as measured by the TAS. On days where the TAC peak is below a set threshold (<115.660 g/L), CM group participants will be rewarded with a £5 (US $6.38) voucher. There are financial bonuses if this target is achieved on consecutive days. The researcher will monitor TAC for each day of the study at each research visit and allocate financial incentives to participants according to a set reinforcement schedule. RESULTS: The first participant was enrolled in June 2023, and the last in December 2023. Data analysis is underway and is estimated to be completed by June 2024. A total of 32 participants were enrolled. CONCLUSIONS: Most TAS brands have had limited application in clinical settings, and most studies have included healthy adults rather than people with AUD. TAS has the potential to enhance treatment outcomes in clinical alcohol treatment. The accuracy, acceptability, and feasibility of TAS for people with AUD in clinical settings need to be investigated. This is the first study to use TAS in specialized alcohol services with diagnosed AUD individuals currently receiving treatment from a south London alcohol service. TRIAL REGISTRATION: ISRCTN Registry ISRCTN46845361; https://www.isrctn.com/ISRCTN46845361. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57653.

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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?

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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.

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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.

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This case report presents the complex analgesia management of a 52-year-old male with a significant medical history including atrial fibrillation treated with apixaban, essential trigeminal neuralgia, non-ischemic cardiomyopathy, and chronic systolic heart failure. The patient experienced a loss of control while riding a motorized bicycle, resulting in a fall and head injury with no loss of consciousness. Upon admission, he tested positive for ethanol, cannabinoids, and oxycodone. The physical exam was significant for right cephalohematoma and right elbow hematoma. Imaging revealed multiple injuries, including right rib fractures (T3-12) with hemothorax. Right paravertebral catheters were placed in the intensive care unit (ICU).

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The use of animal models continues to be essential for carrying out research into clinical phenomena, including addiction. However, the complexity of the clinical condition inevitably means that even the best animal models are inadequate, and this may go some way to account for the apparent failures of discoveries from animal models, including the identification of potential novel therapies, to translate to the clinic. We argue here that it is overambitious and misguided in the first place to attempt to model complex, multifacetted human disorders such as addiction in animals, and especially in rodents, and that all too frequently "validity" of such models is limited to superficial similarities, referred to as "face validity", that reflect quite different underlying phenomena and biological processes from the clinical situation. Instead, a more profitable approach is to identify (a) well-defined intermediate human behavioural phenotypes that reflect defined, limited aspects of, or contributors to, the human clinical disorder, and (b) to develop animal models that are homologous with those discrete human behavioural phenotypes in terms of psychological processes, and underlying neurobiological mechanisms. Examples of past and continuing weaknesses and suggestions for more limited approaches that may allow better homology between the test animal and human condition are made.

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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.

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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.

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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.

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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.

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Associations between the fat mass and obesity-associated (FTO) gene and obesity are well-established. However, recent studies have linked FTO to addiction phenotypes and dopaminergic signaling, thus suggesting broader psychiatric implications. We explored this assumption by conducting a phenome-wide association study across 4756 genome-wide association studies, identifying 23-26 psychiatric traits associated with FTO at the multiple-corrected significance level. These traits clustered into four categories: substance use, chronotype/sleep, well-being, and neuroticism. To validate these findings, we analyzed a functionally suggestive FTO variant (rs1421085) in a separate cohort, examining its impact on (i) alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), (ii) subjective well-being based on the WHO (Ten) Well-Being Index, and (iii) neuroticism based on Schafer's Five Factor Model or the Karolinska Scales of Personality. Our results confirmed a direct association between rs1421085 and neuroticism that was independent of age, sex, alcohol use, body mass index (BMI), and childhood adversities. Interestingly, while no direct association with alcohol intake was observed, both cross-sectional and lagged longitudinal mediation analyses uncovered indirect relationships between rs1421085 and problematic alcohol use (AUDIT-P), with increased neuroticism acting as the intermediary. Mediation analyses also supported an indirect effect of rs1421085 on lower well-being through the pathways of increased neuroticism and BMI. Our study is the first to validate a direct association between FTO and neuroticism. However, additional studies are warranted to affirm the causal pathways linking FTO to well-being and alcohol use through neuroticism.

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CONTEXT: According to the World Health Organization, alcohol is a major global public health problem, leading to a significant increase in illness and death. To treat alcohol use disorders, new therapeutic tools are being promoted, among which virtual reality (VR) shows promise. Previous research has demonstrated the efficacy of VR in reducing alcohol cravings in patients, but there is a lack of data on its effectiveness in maintaining abstinence or reducing consumption in recently abstinent individuals. The E-Reva study aims to compare the efficacy of a treatment strategy combining virtual reality cue exposure therapy (VR-CET) and cognitive behavioral therapy (CBT) with conventional CBT in reducing alcohol consumption and craving in patients with alcohol use disorder (AUD). In addition to this primary objective, the study will compare the effects of VR-CET combined with CBT on anxiety, depression, rumination, and feelings of self-efficacy versus conventional CBT. METHODS: This prospective randomized controlled trial will be conducted over 8 months in four addiction departments in France. It includes two parallel groups: i) the VR-CET + CBT group, and ii) the CBT-only group, which serves as a control group. Participants will be recruited by the investigating doctor in the addiction centers. The sample will consist of 156 patients diagnosed with AUD and abstinent for at least 15 days. Both treatment groups will participate in four group CBT sessions followed by four individual sessions: i) the VR-CET group will be exposed to virtual environments associated with alcohol-related stimuli, ii) the CBT-only group will receive traditional CBT sessions. After completion of the 8 sessions, patients will be followed up for 6 months. The primary outcome is the cumulative number of standard drinks consumed at 8 months, assessed using the TLFB method. DISCUSSION: Despite the promise of VR-CET to reduce the desire to drink, the effect on alcohol consumption remains uncertain in the existing literature. Our protocol aims to address the limitations of previous research by increasing sample size, targeting consumption reduction, and incorporating neutral environments. E-Reva aims to enrich the literature on the use of VR in the treatment of AUD and open new perspectives for future interventions. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06104176, Registered 2023/11/13 ( https://clinicaltrials.gov/study/NCT06104176?id=NCT06104176&rank=1 ). N° IDRCB: 2022-A02797-36. Protocol version 1.0, 12/05/2023.

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Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

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RATIONALE: Glucagon-like peptide-1 (GLP-1) receptor agonists reduce alcohol consumption in rodents and non-human primates. Semaglutide is a new long-acting GLP-1 receptor agonist, widely used in the clinic against type 2 diabetes and obesity. It is also reported to reduce alcohol intake in rodents. OBJECTIVES: This study investigates the possible inhibitory effect of semaglutide on alcohol intake in alcohol-preferring African green monkeys. METHODS: We performed a vehicle-controlled study on male monkeys that had demonstrated a preference for alcohol. In the monkeys selected for voluntary alcohol drinking, alcohol consumption was measured for ten days at baseline (Monday to Friday for two weeks). During this period, the monkeys had access to alcohol 4 h per day and free access to water 24 h per day. After two weeks of baseline measurements, the monkeys were randomized to semaglutide or vehicle. Each group consisted of ten monkeys, and the two groups were balanced with respect to baseline alcohol intake. Following the baseline period, the monkeys were treated with escalating doses of semaglutide (up to 0.05 mg/kg) or vehicle subcutaneously twice weekly for two weeks during which period alcohol was not available. After uptitration, the monkeys had access to alcohol 4 h daily for 20 days (Monday to Friday for 4 weeks), and alcohol consumption was measured. During this alcohol exposure period, treatment with semaglutide (0.05 mg/kg twice weekly) or vehicle continued for three weeks followed by a one-week washout period. RESULTS: Compared to the vehicle, semaglutide significantly reduced alcohol intake. There were no signs of emetic events or changes in water intake. CONCLUSIONS: These data demonstrate for the first time the potent effect of semaglutide in reducing voluntary alcohol intake in non-human primates and further substantiate the need for clinical trials investigating the effect of semaglutide in patients with alcohol-use disorder.

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BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

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