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Background: Theoretical and empirical contributions have identified insula as key in addiction. However, anatomical modifications of the insula in addictive states, and their variations across substance use disorders (SUDs), remain to be specifically explored. We therefore explored the specificities and commonalities of insula gray matter (GM) alterations in severe alcohol use disorder (sAUD) and severe cocaine use disorder (sCUD)., Methods: We explored insula GM volume through a refined parcellation in 12 subregions (six bilateral): anterior inferior cortex (AIC), anterior short gyrus, middle short gyrus, posterior short gyrus, anterior long gyrus (ALG), and posterior long gyrus (PLG). Using a linear mixed model analysis, we explored the insula volume profiles of 50 patients with sAUD, 61 patients with sCUD, and 36 healthy controls (HCs)., Results: In both sAUD and sCUD, we showed overall insular lower volume with a right-sided lateralization effect, and a major volume deficit in bilateral ALG. Moreover, differences emerged across groups, with higher left AIC and PLG volume deficits in sCUD compared to sAUD and HC., Conclusions: We offered the first joint exploration of GM insular volumes in two SUD through refined parcellation, thus unveiling the similarities and dissimilarities in volume deficit profiles. Our results bring evidence complementing prior ones suggesting the core role of the right and posterior insula in craving and interoception, two crucial processes in addiction. Left AIC and PLG group differences also show that, while insula is a region of interest in SUD, sCUD and sAUD generate distinct insular profiles, which might parallel clinical differences across SUD.

Benzodiazepines (BZDs) are the first-line treatment of alcohol withdrawal. Comorbidity between benzodiazepine use disorder (BUD) and alcohol use disorders (AUD) is common. However, the risk factors are poorly characterized due to the paucity of available BUD screening tools. The present study aimed to rectify this by conducting an observational screening investigation for BUD in patients hospitalized for alcohol detoxification in a specialized unit. During a face-to-face interview, a short BUD screening tool, Echelle Cognitive d'Attachement aux benzodiazépines (ECAB), was administered to record recent patterns of BZD use, thereby allowing categorization of AUD patients as follows: non-BZD users, BZD users without BUD, and BUD (ECAB ≥6). Clinical and sociodemographic risk factors were identified and recorded during clinical assessment and were analyzed using nonparametric bivariate tests and multinomial regression for association with BUD, with p < 0.05 for significance. Of the 150 AUD patients, 23 (15%) had comorbid BUD. Several variables were associated with ECAB score, with their independence being verified using multinomial regression, with lower risk of BUD versus BZD use, when the initial prescriber was an addiction specialist compared with a psychiatrist or a general practitioner [odds ratio (OR) = 0.12, 95% confidence interval (CI) = 0.14-0.75]. A higher risk of BZD use versus no use was evident when comorbid psychiatric disorders were present (OR = 9.2, 95%CI = 1.3-65). Our findings raise clinicians' awareness that in patients hospitalized for alcohol detoxification, BUD is highly prevalent but not specifically related to psychiatric disorders. BUD can be effectively screened by utilization of the ECAB., (© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10 -3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10 -3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal., (© 2022 Society for the Study of Addiction.)

Background: The prevalence of cognitive impairment is high among alcohol-dependent patients. Although the clinical presentation of alcohol-related cognitive disorder (ARCD) may resemble that of Alzheimer's disease (AD), the prognosis and treatment of the 2 diseases are different. Cerebrospinal fluid (CSF) biomarkers (tau, phosphorylated tau, and amyloid β) have high diagnostic accuracy in AD and are currently being used to discriminate between psychiatric disorders and AD, but are not used to diagnose ARCD. The aim of this study was to characterize CSF biomarkers in a homogeneous, cognitively impaired alcohol-dependent population., Methods: This single-center study was conducted in an addiction medicine department of a Parisian Hospital. We selected patients with documented persistent cognitive impairment whose MoCA (Montreal Cognitive Assessment) score was below 24/30 after at least 1 month of documented inpatient abstinence from alcohol. We measured the CSF biomarkers (tau, phosphorylated tau, and amyloid β 1-42 and 1-40) in 73 highly impaired alcohol-dependent patients (Alcohol Use Disorders Identification Test score over 11 for women and 12 for men) with., Results: Patients' average age was 60 ± 9.1 years and 45 (61.6%) had a normal CSF profile, 8 (11.0%) had a typical CSF AD profile, and 20 (27.4%) had an intermediate CSF profile., Conclusions: This study revealed a high prevalence of AD in alcohol-dependent patients with persistent cognitive deficits and several anomalies in their CSF profiles. Thus, it is important to consider AD in the differential diagnosis of persistent cognitive deficits in patients with alcohol dependence and to use CSF biomarkers in addition to imaging and neuropsychological testing to evaluate alcohol-related cognitive impairment., (© 2021 by the Research Society on Alcoholism.)

For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake., (© 2020 Society for the Study of Addiction.)

Subjects with alcohol use disorder (AUD) display a high prevalence of cardiovascular risk factors (CRFs), and a high incidence of cardiovascular diseases associated with an earlier mortality. Abstinence has long-term cardiovascular and global health benefits. However, few studies have examined the short-term effect of alcohol cessation on cardiac function and key CRFs. The aim of the study was to assess brain natriuretic peptide (BNP) and other CRFs on admission for alcohol cessation and 12 days later, in inpatients with AUD. A retrospective chart review of inpatients hospitalized for alcohol cessation was conducted. Patients who did not relapse at day 12 were included. We compared, at entry and at day 12, BNP and other CRFs: hemodynamic and electromyographic variables, lipid, homocysteine level, and liver enzymes at entry and at day 12. Wilcoxon, Student tests, and repeated-measures ANOVA were conducted. Fifty-five patients were included (38 males, mean age 50.5 years, alcohol per day 60 g-750 g, 44 current tobacco smokers). BNP was significantly increased (11.8 pg/mL [±16.2] to 35.5 pg/mL [±47.6], p < 0.001). Repeated-measure ANOVA showed a significant between-subject effect (p = 0.024), but no significant interaction between BNP variation and having a BNP at entry >10 pg/mL (p = 0.092). In contrast, a significant improvement on 8 of 13 other CRFs and liver enzymes measures was observed (p ≤ 0.05). A rapid improvement of several CRFs was confirmed. However, the increase of BNP at day 12 supports its investigation as a possible relevant biomarker of cardiac function in alcohol withdrawal., Competing Interests: Declaration of competing interest In the last three years, Florence Vorspan has had congress fees paid by pharmaceutical companies (RECORDATI, CAMURUS AB). She was also briefly involved in an advisory board for CAMURUS, but donated her salary to a non-profit NGO for hospitalized patients’ welfare. Julien Azuar reports grants from Fondation Pour la Recherche en Alcoologie. Frank Bellivier has received honoraria or research or educational conference grants from Bristol-Myers Squibb, Otsuka, Eli Lilly & Co., Servier, Takeda, Sanofi Aventis, Lundbeck, AstraZeneca, and the European Space Agency, and has received peer-review research funding from the Ministry of Research, Assistance Publique – Hôpitaux de Paris, the National Institute for Research (INSERM) and the NARSAD. The other authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Repetitive negative thinking (RNT), the most studied forms of which are depressive ruminations and anxious worry, is a unique transdiagnostic process responsible for the development and maintenance of many mental disorders. Over the past decade, studies have shown that RNT could be involved in the development and maintenance of alcohol use disorder (AUD). However, to date, little is known about the factors that can influence this relationship, even though some theoretical and empirical arguments suggest that variables such as gender or metacognitive beliefs may determine the role of RNT in the onset of symptoms. The aim of the present study was to test the moderation effect of metacognitive beliefs and gender in the relationship between RNT and AUD. Eighty-one AUD patients were administered measures of AUD severity, RNT, metacognitive beliefs about thinking and alcohol use, anxiety, and depression. Results indicated that the 'capture mental resources' factor of RNT is a significant predictor of AUD severity, independent from anxiety and depression, and that this effect is moderated by metacognitive beliefs and gender. RNT is a significant predictor of AUD severity only for people with high negative beliefs about thoughts regarding uncontrollability and danger. Furthermore, RNT was found to predict AUD severity only for men with high beliefs about the need to control thoughts and for men with high positive beliefs about emotional self-regulation. Treatments that reduce attentional impairments caused by RNT and modify dysfunctional metacognitive beliefs could be promising for some patients with AUD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Providing an on-site immediate diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and lung age in tobacco smokers could be a motivational tool for smoking cessation. Our aim was to investigate the effects of an abnormal spirometry results on motivational change and subsequent smoking cessation. We conducted a retrospective analysis of smoking status after 3 months of tobacco counseling. Patients were recruited in an addiction outpatient center. Spirometry results were obtained with a portable device during the first visit. The sample was thus divided in 3 groups: COPD, subthreshold-group (no COPD but abnormal lung age) and normal spirometry. Among the three groups, we compared the immediate motivation change, difference in Q-MAT motivation scale score after minus before spirometry (Kruskal-Wallis test) and the smoking status after 3 months (Fisher test). We included 48 patients (37 males, median age 44 years, median cigarette-per-day 20). Spirometry results divided the sample in COPD ( N  = 13), subthreshold ( N  = 11) and normal group ( N  = 24). Mean Q-MAT score change after spirometry was different between groups ( p  = 0.019), greater in COPD (4.62 ± 3.38) than normal group (1.46 ± 3.11), and lower in patient with a co-occuring hazardous alcohol use ( p  = 7.6 × 10 -3 ). Three-months smoking status was different between spirometry results groups ( p  = 0.0021). COPD (5/13, 38.5%) and subthreshold patients (6/10, 60.0%) had stopped more frequently than patients from the normal-group (2/22, 9.1%). The effect of immediate spirometry results on motivation to quit varies according to the screened pulmonary damages and hazardous alcohol use. It could be a useful tool in addiction treatment centers.

High-dose baclofen is prescribed as a maintenance treatment to reduce alcohol use in patients with alcohol use disorder. Nevertheless, some patients still have massive alcohol intakes and require inpatient alcohol withdrawal. To compare the oral dose of benzodiazepine prescribed to manage alcohol withdrawal symptoms in patients with vs. without steady-state pretreatment with high-dose baclofen. Retrospective chart review study. Prescribed benzodiazepine dose expressed in diazepam-equivalent was compared between groups. Thirty-one patients were assessed in the high-dose maintenance baclofen group and compared to 31 matched patients not receiving baclofen. No statistically significant difference was evident between groups regarding levels of benzodiazepines prescribed. The mean diazepam-equivalent dose during the first 7 days was 294 ± 149 mg in the baclofen group vs. 310 ± 133 mg (t-test = 0.440, P = 0.661) in matched controls. Steady-state high-dose baclofen before an inpatient alcohol cessation hospitalization does not lower the needed benzodiazepine dose in the management of alcohol withdrawal symptoms., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m 2 , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h -1 , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Aims: As low rates of thiamine are thought to be implicated in alcohol-related cognitive disorders, we wanted to assess patients with alcohol use disorders (AUD) during detoxification for their nutritional status and test if vitamins blood levels were associated with a surrogate of cognitive impairment., Methods: We performed a retrospective chart review of medical records of 94 consecutive patients hospitalized for alcohol detoxification in a specialized addiction medicine department. Nutritional status was assessed with Body Mass Index (BMI). Vitamins blood levels were available for 80 patients, but thiamine only for 52 patients. The Montreal Cognitive Assessment (MoCA) score was used to screen for cognitive impairment at Day 10 of entry and was available in 59 patients. A binary logistic regression was performed to identify factors associated with MoCA scores below the threshold (26 points)., Results: The mean BMI was 23.28 ± 3.78 kg/m2 and 8.79% of weighted patients qualified for malnutrition. The mean MoCA score was 22.75 ± 4.88 points, and 66% of tested patients were below the threshold of suspected cognitive impairment. No low blood thiamine level was found. In multivariate analysis, BMI, but not vitamins blood rates, was significantly associated with a pathological MoCA screening test., Conclusion: Clinical examination is more sensitive than biomarkers to determine malnourished AUD patients who are at-risk for cognitive impairment. Malnourished patients with AUD should receive a full neuropsychological testing., Summary: This retrospective chart review study screened for cognitive disorders during alcohol inpatient detoxification with the MoCA test. Body mass index, but not vitamins blood rates, was associated with a pathological MoCA. Clinical examination is more sensitive than biomarkers to determine malnourished AUD patients who are at-risk for cognitive impairment., (© The Author 2017. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Inpatient alcohol detoxifications are only proposed after motivational outpatient encounters because detoxification directly from the emergency department (ED) is believed to be associated with early dropout and poor adherence to outpatient follow-up. The aim of this prospective follow-up study was to test the feasibility of unscheduled (UP) alcohol detoxification directly from the ED and to compare the 1-year follow-up of these patients to that of scheduled (SP) patients., Methods: A quasi-naturalistic prospective follow-up study of 120 patients: 60 consecutively admitted patients referred directly by the ED for alcohol detoxification (UP) were compared to 60 consecutively admitted patients who had undergone the usual preparation for an inpatient detoxification program (SP). The length of hospitalization (in days) and attendance to postdischarge outpatient visits during the first year was compared., Results: UP patients were older, less frequently employed, and had more somatic comorbidities compared with SP patients. The UP length of stay was significantly longer (20 ± 16 vs. 14 ± 6, p = 0.04). No difference in their postdischarge attendance was observed; the number of patients attending 1 session (57% UP vs. 65% SP, p = 0.227) and 5 sessions (22% UP vs. 32% SP, p = 0.151) and the mean number of postdischarge visits attended were comparable between the UP and SP groups (2.7 ± 6 vs. 4.5 ± 6; Mann-Whitney U = 1,517, p = 0.124)., Conclusions: We did not find that UP patients who had been admitted for alcohol detoxification had a significantly higher dropout rate or lower postdischarge addiction treatment attendance. Because they may have several advantages, detoxification programs directly linked with EDs should be further evaluated., (Copyright © 2016 by the Research Society on Alcoholism.)