Study on the efficiency of virtual reality in the treatment of alcohol use disorder: study protocol for a randomized controlled trial : E-Reva.

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.

Virtual reality efficiency as exposure therapy for alcohol use: A systematic literature review.

Virtual reality is an immersive technology that can be used as a tool in the treatment of disorders linked to substance use disorders, such as alcohol use disorder. This systematic review of the literature examines the effectiveness of virtual reality as exposure therapy for heavy social drinkers, defined as people who regularly consume alcohol in a variety of social contexts, with or without a diagnosis of alcohol use disorder. The current review includes ten studies with a total of 377 participants. Most participants were adult men (61.03%), with an age average of 44.1 years [± 7.42] and alcohol use ranging from light to heavy. Although studies show heterogeneous results, the use of virtual reality cue exposure therapies has shown greater improvement in terms of craving reduction for patients suffering from alcohol use disorder. Studies have also shown that the realism of the virtual environment can influence levels of craving and anxiety, both in heavy social drinkers. In addition, the use of virtual reality has proven to increase feeling of self-efficacy and decrease the tendency to engage in automatic drinking behaviors. However, the review also mentions the necessity of larger research to determine the efficiency of virtual reality as a therapeutic treatment for alcohol use disorder, whilst considering comorbidities and treatment background, especially for resistant patients.

Occurrence and severity of cocaine-induced hallucinations: Two distinct phenotypes with shared clinical factors but specific genetic risk factors.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity. METHODS: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately. RESULTS: Cocaine dependence (poccurrence= 6.18 × 10-5, pseverity= 9.25 × 10-8), number of cocaine dependence DSM IV-Tr criteria (poccurrence= 1.22 × 10-7, pseverity= 5.09 × 10-6), and frequency of intake during the worst period of misuse (poccurrence= 8.51 × 10-04, pseverity= 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs. CONCLUSION: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.

Influence of Clinical Markers of Dopaminergic Behaviors on Depressive Symptoms During Withdrawal in Cocaine Users.

Background: During cocaine withdrawal, transient depressive symptoms that do not meet the criteria for depression, but promote relapse, are frequently observed. Their temporality could evoke a role of dopamine, especially since the underlying mechanism of these depressive symptoms is not well understood. We hypothesized that variation in the dopaminergic activity profile, modeled from clinical markers, could be implicated in the development of depressive symptoms during cocaine withdrawal. Methods: We compared patients reporting depressive symptoms (RDS+) or not (RDS-) during cocaine withdrawal. We evaluated dopaminergic activity through indirect clinical markers based on the known dopaminergic behaviors. A combined criterion was constructed for hyper and hypo dopaminergic models according to the O'Brien method and illustrated by the Hedges' effect-size and forest-plot graph. A multidimensional factorial analysis was carried out to determine which parameters discriminate RDS+/RDS- patients. Results: 313 patients were included, and 77% reported depressive symptoms during cocaine withdrawal. Hyperdopaminergic variables used to discriminate the two groups had a large overall effect size (-0.669) and included psychotic symptoms (-0.524), hallucinations (-0.548), and delusions (-0.528). The overall effect of the hypodopaminergic component was considerable (-0.604) with a large effect size for the severity of dependence (-0.616), withdrawal symptoms (-0.578), and anhedonia (-0.528). The combined model including hyperdopaminergic and hypodopaminergic components had the largest effect size (-0.785). Conclusion: The dopaminergic activities profile, assessed by indirect clinical markers, seems to characterize patients with depressive symptoms very well during cocaine withdrawal. RDS+ patients reported moreover higher levels of psychotic symptoms and more severe cocaine use disorder than RDS-.

Risk and Protective Factors of Lifetime Cocaine-Associated Chest Pain.

Introduction: Cocaine users often present with repetitive events of cocaine-associated chest pain (CACP), clinically resembling acute coronary syndromes. The aim of the study is to describe the specific risk factors for CACP. Method: Cocaine users (n = 316) were recruited for a multicenter cross-sectional study. Lifetime CACP history, sociodemographic factors, and lifetime use of cocaine and other substances were assessed. Thirty single nucleotide polymorphisms (SNPs) of NOS3, ROCK2, EDN1, GUCY1A3, and ALDH2 genes, suggested by the literature on coronary spasms, were selected. The associations with CACP history were tested using the chi-square test, Student's t-test and logistic regression. Results: Among the 316 subjects [78.5% men, mean age 37.5 years, (standard-deviation ±8.7)], 190 (60.1%) were daily cocaine users and 103 (32.6%) reported a lifetime CACP history. Among those with a lifetime CACP history, the median was 10 events per individual. In multivariate analysis, lifetime CACP history was associated with daily cocaine use [odds-ratio (OR) 3.24; 95% confidence intervals (1.29-9.33)], rapid route of cocaine use [OR 2.33 (1.20-4.64) vs. intranasal use], and lifetime amphetamine use [daily amphetamine use: OR 2.80 (1.25-6.32) and non-daily amphetamine use: OR 2.14 (1.15-4.04) vs. never used]. Patients with lifetime opioid maintenance treatment (OMT) reported significantly less lifetime CACP history [OR 0.35 (0.16-0.76)]. None of the selected SNPs was associated with CACP history after multiple testing corrections. Conclusions: Clinical variables describing the intensity of stimulant use were positively associated with lifetime CACP history, while OMT was negatively associated with it. Specific harm reduction strategies can target these risk factors.

Chronic exposure to cocaine is associated with persistent behavioral disturbances. A cross-sectional dimensional study in outpatients with multiple substance use disorders.

RATIONALE: Behavioral disturbances (BD) are prevalent in patients with substance use disorders (SUD). OBJECTIVES: To test the hypothesis that chronic exposure to cocaine could favor the acquisition of BD that were not present in childhood. METHODS: We used child and adult ADHD self-report screening scales (WURS-25 and ASRS-6, respectively, with their usual threshold) as assessment tools for significant BD. In a cross-sectional assessment of 382 patients with multiple SUD, we investigated BD and then "de novo" BD (i.e., by restricting the sample to patients below the threshold for childhood BD) (N = 214). We also tested for a gradient effect between patients' lifetime DSM IV cocaine and opioid dependence status and the prevalence of BD. RESULTS: BD were found in 188/382 (42.9%) subjects and in 74/214 (34.6%) subjects. Three clinical factors were associated with BD in the whole sample: the number of cocaine dependence criteria (OR = 1.36 [1.14-1.64], p = 0.001), the number of opioid dependence criteria (OR = 0.69 [0.52-0.91], p = 0.010), and a personal history of using cocaine through rapid routes of administration (OR = 0.41 [0.19-0.88], p = 0.022). The same three factors were associated with "de novo" BD in the restricted sample: OR = 1.35 ([1.11-1.63], p = 0.002), OR = 0.83 ([0.70-0.99], p = 0.046), and OR 0.37 ([0.16-0.86], p = 0.022), respectively. There were significant gradients for BD according to the cocaine exposure categories in the whole (Mantel-Haenszel, p < 0.001) and in the restricted sample (Mantel-Haenszel, p = 0.002). CONCLUSIONS: Cocaine exposure was positively associated with behavioral disturbances in a dose-dependent manner in this clinical sample, whilst opioid exposure showed a negative association.

QT length during methadone maintenance treatment: gene × dose interaction.

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (rPearson  = 0.26; P = 10-3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10-4 ; pcorrected  = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (pempirical  = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients' genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

TLR4 gene polymorphism associated with lifetime cigarette smoking in bipolar disorder.

Bipolar disorder (BD) is associated with an increased risk of tobacco dependence, the leading addictive substance worldwide. Toll-like receptor 4, a sensor of pathogens and of products of cellular stress and damage, is a major innate immune molecule and logical candidate gene for tobacco dependence in BD because (i) the involvement of TLR4 molecules in several substance use disorders has been suggested, (ii) and the association between the TLR4 gene and BD. We analysed herein the potential association between six TLR4 polymorphisms and lifetime tobacco smoking in 514 BD patients. Significant association between tobacco smoking and rs10759932 was found (genotype, Cochrane Armitage trend test, p=0.008, pcorrected=0.040 and alleles, p=0.008; pcorrected=0.040), where the C minor allele is associated with a protective effect, even after adjusting for confounding factors (OR=1.54 [1.04-2.30], p=0.03). Our results suggest that TLR4 gene polymorphism may act as an intermediate factor for the association between tobacco smoking addiction and BD.

Self-reported cue-induced physical symptoms of craving as an indicator of cocaine dependence.

BACKGROUND: The presence of cocaine dependence is under-recognized by cocaine users and requires a careful standardized interview to be ascertained by clinicians. OBJECTIVE: To test if past experiences of cue-induced physical symptoms of craving (nausea, vomiting, sweating, shaking, nervousness) before cocaine use could be a useful way to boost the diagnosis of cocaine dependence. METHODS: A cross-sectional study of 221 cocaine users from several outpatient addiction treatment services in France, addressing the most severe period of cocaine use. DSM-IV cocaine dependence was determined with the MINI International Neuropsychiatric Interview (MINI). Physical symptoms before using cocaine were retrospectively assessed with a single item rated on a 0-5 scale. RESULTS: The prevalence of DSM-IV cocaine dependence was 84.6%. The mean score on the physical symptoms item was 1.3 (SD 1.3). A cut-off score of ≥ 1 on this item alone resulted in a sensitivity of 62%, a specificity of 88.2%, a positive predictive value of 96.6% and a negative predictive value of 29.7% to detect DSM IV cocaine dependence in this sample. Adding this item to a model with the frequency of cocaine use significantly increased the predictive power: Nagelkerke's R(2) increased from .149 to .326 (p < .001). DISCUSSION AND CONCLUSION: Recalling past experiences of cue-induced physical signs of cocaine craving is associated with a clinical diagnosis of lifetime cocaine dependence and could be a simple way to improve its detection in clinical settings.

Childhood trauma are not associated with the intensity of transient cocaine induced psychotic symptoms.

A personal history of childhood trauma has been associated with the severity of psychotic symptoms in several disorders. We evaluated retrospectively cocaine-induced psychotic symptoms with the SAPS-CIP and childhood trauma with the CTQ in a clinical sample of 144 cocaine users. The SAPS-CIP score was not statistically associated with the presence or number or intensity of trauma, but was associated with rapid routes of administration (intravenous and smoked) and with frequent cocaine use.

Congenital anosmia and emotion recognition: A case-control study.

Patients with anosmia are not able to detect volatile chemicals signaling the presence of infectious and non-infectious environmental hazards, which typically elicit disgust and fear, respectively. Social animals may compensate a loss of olfaction by taking advantage of signals of threat that are produced by their conspecifics. Among humans and other primates, body postures and facial expressions are powerful cues conveying emotional information, including fear and disgust. The aim of the present study was to examine whether humans with agenesis of the olfactory bulb, a rare disorder characterized by congenital anosmia, would be more accurate in recognizing facial expressions of fear and disgust. A total of 90 participants with no history of mental disorder or traumatic brain injury were recruited, including 17 patients with congenital anosmia (10 men, mean age ± standard deviation: 36.5 ± 14.8 years), 34 patients with acquired anosmia (18 men, mean age ± standard deviation: 57.2 ± 11.8 years) and 39 healthy subjects (22 men, mean age ± standard deviation: 36.7 ± 13.2 years). For each patient with congenital anosmia, the agenesis of the olfactory bulb was ascertained through magnetic resonance imaging. Emotion recognition abilities were examined with a dynamic paradigm in which a morphing technique allowed displaying emotional facial expressions increasing in intensity over time. Adjusting for age, education, depression and anxiety, patients with congenital anosmia required similar levels of intensity to correctly recognize fear and disgust than healthy subjects while they displayed decreased error rates for both fear (mean difference [95% confidence interval] = -28.3% [-46.3%, -10.2%], P = 0.003) and disgust (mean difference [95% confidence interval] = -15.8% [-31.5%, -0.2%], P = 0.048). Furthermore, among patients with acquired anosmia, there was a negative correlation between duration of anosmia and the rate of errors for fearful (Spearman's ρ = -0.531, P= 0.001) or disgust (Spearman's ρ = -0.719, P < 0.001) faces recognition. No significant difference was observed for the other primary emotions. Overall, these results suggest that patients with congenital anosmia and long-lasting acquired anosmia may compensate their inability to detect environmental hazards through olfaction by an increased ability to detect fear or disgust as facially expressed by others.