Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level.

Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol-dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol-dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABAB receptors and extrasynaptic GABAA receptors resulting in alcohol-mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new-as yet unpublished-large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO-defined DRLs and (d) from multiple meta-analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol-dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ-hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol-dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well-tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol-dependent patients with VH DRL.

A Randomized, Placebo-Controlled Study of High-Dose Baclofen in Alcohol-Dependent Patients-The ALPADIR Study.

AIMS: Alcohol dependence is a major public health issue with a need for new pharmacological treatments. The ALPADIR study assessed the efficacy and safety of baclofen at the target dose of 180 mg/day for the maintenance of abstinence and the reduction in alcohol consumption in alcohol-dependent patients. METHODS: Three hundred and twenty adult patients (158 baclofen and 162 placebo) were randomized after alcohol detoxification. After a 7-week titration, the maintenance dose was provided for 17 weeks, then progressively decreased over 2 weeks before stopping. RESULTS: The percentage of abstinent patients during 20 consecutive weeks (primary endpoint) was low (baclofen: 11.9%; placebo: 10.5%) and not significantly different between groups (OR 1.20; 95%CI: 0.58 to 2.50; P = 0.618). A reduction in alcohol consumption was observed from month 1 in both groups, but the difference of 10.9 g/day at month 6 between groups, in favour of baclofen, was not statistically significant (P = 0.095). In a subgroup of patients with high drinking risk level at baseline, the reduction was greater with a difference at month 6 of 15.6 g/day between groups in favour of baclofen (P = 0.089). The craving assessed with Obsessive-Compulsive Drinking Scale significantly decreased in the baclofen group (P = 0.017). No major safety concern was observed. CONCLUSIONS: This study did not demonstrate the superiority of baclofen in the maintenance of abstinence at the target dose of 180 mg/day. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. SHORT SUMMARY: Baclofen was assessed versus placebo for maintenance of abstinence and reduction in alcohol consumption in alcohol-dependent patients. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen.

The Efficacy of Three Modalities of Internet-Based Psychotherapy for Non-Treatment-Seeking Online Problem Gamblers: A Randomized Controlled Trial.

BACKGROUND: Internet-based interventions targeted at the most at-risk gamblers could reduce the treatment gap for addictive disorders. Currently, no clinical trial has included non-treatment-seeking patients who have been recruited directly in their gambling environment. This study was the first exclusively Internet-based randomized controlled trial among non-help-seeking problem gamblers with naturalistic recruitment in their gambling environment. OBJECTIVE: The aim of this study was to assess the efficacy of three modalities of Internet-based psychotherapies with or without guidance, compared to a control condition, among problem gamblers who play online poker. METHODS: All active poker gamblers on the Winamax website were systematically offered screening. All problem poker gamblers identified with a Problem Gambling Severity Index (PGSI) score of ≥ 5 were eligible to be included in the trial. Problem gamblers were randomized into four groups: (1) waiting list (control group), (2) personalized normalized feedback on their gambling status by email, (3) an email containing a self-help book to be downloaded with a Cognitive Behavioral Therapy (CBT) program without guidance, and (4) the same CBT program emailed weekly by a trained psychologist with personalized guidance. Efficacy was assessed based on the change in PGSI between baseline and 6 weeks (end of treatment) or 12 weeks (maintenance) and supported by player account-based gambling data automatically collected at the three time points. RESULTS: All groups met high attrition rates (83%), but the group with guidance had a significantly higher dropout rate than the other three groups, including the control group. Although all groups showed some improvement, with a mean decrease of 1.35 on the PGSI, no significant difference in efficacy between the groups was observed. One-third of the problem gamblers fell below the problem gambling threshold at 6 weeks. CONCLUSIONS: Guidance could have aversively affected problem gamblers who had not sought help. Despite the lack of significant difference in efficacy between groups, this naturalistic trial provides a basis for the development of future Internet-based trials in individuals with gambling disorders. Comorbidities, natural course of illness, and intrinsic motivation seem to be critical issues to consider in future designs. TRIAL REGISTRATION: ANSM 2013-A00794-41.

Smoker's identity scale: Measuring identity in tobacco dependence and its relationship with confidence in quitting.

BACKGROUND AND OBJECTIVES: Persistent smoking behaviours are associated with numerous motives, explaining the absence of a single treatment for quitting. One of these motives may include that of identification. The threat of losing their smoker's identity may represent a significant obstacle to lasting abstinence. The objective of this study is to design a specific identity questionnaire and examine correlations between the degree of smoking identity and persistent smoking. METHODS: Patients attending a smoking cessation seminar completed the Modified Reasons for Smoking Scale, Barriers to smoking cessation checklist and our 6-item Smoker's Identity Scale (SIS) (n = 170 questionnaires). RESULTS: SIS showed good internal consistency, calculated by a Chronbach test (α = .785) with no redundant questions. There was a correlation between strong tobacco dependence (measured by the Fagerström questionnaire) and strong smoking identity (p = .0001). Strong identity was associated with less confidence in quitting at both 1 and 6 months (p = .037 and p = .002, respectively). We showed that identity represents an obstacle to quitting in 32% of our patients and is associated with decreased confidence in quitting. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our study shows that measuring identity in smokers who wish to make a quit attempt may help to identify specific obstacles to abstinence. This may also help in elaborating improved quitting strategies and patient management. Further research is necessary to confirm these results.

[Acute substance-induced psychotic disorder]. / État délirant aigu induit par une substance.

An acute substance induced psychotic disorder is a cause to raise with a state of agitation in an acute delusional clinical setting. Patients are most often seen in hospital emergency rooms. Rapid diagnosis must be made. An integrated therapeutic management should be considered. Both psychiatric and addiction problems must be taken into account.

Chronic alcohol consumption and its effect on nodes of frontocerebellar and limbic circuitry: comparison of effects in France and the United States.

Alcohol use disorders present a significant public health problem in France and the United States (U.S.), but whether the untoward effect of alcohol on the brain results in similar damage in both countries remains unknown. Accordingly, we conducted a retrospective collaborative investigation between two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) with T1-weighted, structural MRI data collected on a common imaging platform (1.5T, General Electric) on 288 normal controls (NC), 165 uncomplicated alcoholics (ALC), and 26 patients with alcoholic Korsakoff's syndrome (KS) diagnosed at all sites with a common interview instrument. Data from the two countries were pooled, then preprocessed and analyzed together at the U.S. site using atlas-based parcellation. National differences indicated that thalamic volumes were smaller in ALC in France than the U.S. despite similar alcohol consumption levels in both countries. By contrast, volumes of the hippocampus, amygdala, and cerebellar vermis were smaller in KS in the U.S. than France. Estimated amount of alcohol consumed over a lifetime, duration of alcoholism, and length of sobriety were significant predictors of selective regional brain volumes in France and in the U.S. The common analysis of MRI data enabled identification of discrepancies in brain volume deficits in France and the U.S. that may reflect fundamental differences in the consequences of alcoholism on brain structure between the two countries, possibly related to genetic or environmental differences.

[Therapeutic use of cannabis derivatives]. / Usage thérapeutique des dérivés du cannabis.

The therapeutic use of cannabis has generated a lot of interest in the past years, leading to a better understanding of its mechanisms of action. Countries like the United States and Canada have modified their laws in order to make cannabinoid use legal in the medical context. It's also the case in France now, where a recent decree was issued, authorizing the prescription of medication containing "therapeutic cannabis" (decree no. 2013-473, June 5, 2013). Cannabinoids such as dronabinol, Sativex and nabilone have been tested for the treatment of acute and chronic pain. These agents are most promising to relieve chronic pain associated with cancer, with human immunodeficiency virus infection and with multiple sclerosis. However, longer-term studies are required to determine potential long-term adverse effects and risks of misuse and addiction.

[Psychiatric complications of cannabis use]. / Complications psychiatriques de la consommation de cannabis.

Cannabis is the most widely used illicit substance, especially among young people. Cannabis use is extremely commonplace and frequently comorbid with psychiatric disorders that raise questions about the etiology. The use of cannabis is an aggravating factor of all psychiatric disorders. Psychiatric complications are related to the age of onset, duration of exposure and individual risk factors of the individual (mental and social health). The panic attack is the most common complication. The link with psychosis is narrow that leads to increased prevention for vulnerable populations. Cannabis is also an indicator of increased depressive vulnerability and an aggravating factor for bipolar disorder.

Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism.

A variable (GT)(n) repeat in the 5'-regulatory region of N-methyl-D-aspartate GRIN2A subtype has recently been identified and associated with psychiatric disorders. In this study, we examined the association of this polymorphism with alcohol dependence. Subject-control analysis included 206 alcohol-dependent and 168 control subjects. Average observed repeat numbers and genotype distributions were significantly different (P-value = 0.001) in alcohol-dependent subjects versus control subjects. Short alleles were significantly less frequent among alcohol-dependent subjects (odds ratio = 0.58, P-value = 7 × 10(-4)). These results could be replicated in an independent sample of 116 alcohol-dependent subjects. For the first time, a significant association was identified between this polymorphism and alcoholism.

Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study.

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects.

Is baclofen a revolutionary medication in alcohol addiction management? Review and recent updates.

Baclofen, a γ-aminobutyric acid (GABA)-B receptor agonist, represents a promising drug in alcohol addiction management. Animal models have shown its action at various stages of the process of alcohol addiction. Moreover, initial open and randomized controlled trials have shown the efficacy of 30 mg/day baclofen on alcohol craving, intake, and relapse prevention. It may also decrease alcohol withdrawal symptoms. However, these initial studies were conducted by the same Italian team; 2 American studies, using a different methodology, did not confirm these effects. Following recent reports by an alcohol-dependent French physician who treated himself with high doses (120-270 mg/day), claiming prolonged suppression of alcohol craving and absence of dependence symptoms, baclofen has since received wide media exposure in France where it has been called "the treatment for alcoholism." An open-label French study supports these findings. In addition, baclofen seems to be particularly interesting because of its safety and tolerance, even in patients with cirrhosis. Thus, baclofen should benefit from further studies of its biobehavioral mechanisms, dose-response effect, and indications in various alcoholic patient profiles.

[Synthetic drugs: the new low-cost landscape of drugs]. / Drogues de synthèse: le nouveau cadre low-cost des drogues.

Designer drugs include, among others, synthetic cannabinoids and synthetic cathinones. These new "legal highs" drugs are sold on line for recreational public or private use. Synthetic cannabinoids are a psychoactive herbal and chemical product that, when used, mimics the effects of cannabis. Cathinone is a naturally occurring betaketone amphetamine analogue found in the leaves of the Catha edulis plant. Synthetic cathinones are phenylalkylamines derivatives, and may possess both amphetamine-like properties. They are often sold as "bath salts" or "plant food" and labeled "not for human consumption" to circumvent drug abuse legislation. The absence of legal risks, the ease of obtaining these drugs, the moderate cost, and the avaibility via Internet are the main criteria attracting the user. There is evidence that negative health and social consequences may occur in recreational and chronic users. The addictive potential of designer drugs is not weak. Furthermore, there is a lack of epidemiological, pharmacological, animal, clinical, psychological and therapeutic data concerning these new synthetic agents.

[Energy drinks: an unknown risk]. / Boissons énergisantes: un risque méconnu.

The term "energy drink" designates "any product in the form of a drink or concentrated liquid, which claims to contain a mixture of ingredients having the property to raise the level of energy and vivacity". The main brands, Red Bull, Dark Dog, Rockstar, Burn, and Monster, are present in food stores, sports venues, and bars among other soft drinks and fruit juices. Their introduction into the French market raised many reluctances, because of the presence of taurine, caffeine and glucuronolactone. These components present in high concentrations, could be responsible for adverse effects on health. The association of energy drinks and spirits is widely found among adolescents and adults who justify drinking these mixed drinks by their desire to drink more alcohol while delaying drunkenness. Given the importance of the number of incidents reported among the energy drinks consumers, it seemed appropriate to make a synthesis of available data and to establish causal links between the use of these products and the development of health complications. For a literature review, we selected scientific articles both in English and French published between 2001 and 2011 by consulting the databases Medline, Embase, PsycINFO and Google Scholar. The words used alone or in combination are "energy dinks", "caffeine", "taurine", "toxicity", "dependence". An occasional to a moderate consumption of these drinks seems to present little risk for healthy adults. However, excessive consumption associated with the use of alcohol or drugs in amounts that far exceed the manufacturers recommended amount, could be responsible for negative consequences on health, particularly among subjects with cardiovascular disease.

CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta-analysis.

The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high risk' versus 'low risk' alleles in cases with dependence versus controls. Studies were analyzed by random-effects meta-analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta-analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of ≥ 16 repeats. Our analysis showed a small effect size (OR = 1.55, P = 0.045), with strong heterogeneity (Q = 19.87, P < 0.01 with I² = 85%). In line with the polygenic model, our meta-analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well-phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms.

Association of inflammation genes with alcohol dependence/abuse: a systematic review and a meta-analysis.

The aim of the present work was to systematically review all association studies of inflammation genes with alcohol dependence/alcohol abuse (AD/AA) and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high-risk' versus 'low-risk' alleles in AD/AA cases versus controls. Data reported in at least three published studies were available for four genetic polymorphisms [TNF-α-238 (rs361525, G/A); TNF-α-308 (rs1800629, G/A); IL-1RA (VNTR [86 bp]n); IL-10-592 (rs1800896, C/A)]. In total, nine meta-analyses were performed. Of these, only the TNF-α-238 polymorphism showed a significant association with AD/AA (OR=1.36, 95% CI: 1.05-1.76). This risk remained significant and increased slightly when we considered only patients with advanced alcohol-related liver disease (AALD) (OR=1.5, 95% CI: 1.13-1.98) but not when we considered only patients without AALD (OR=1.08, 95% CI: 0.5-2.35). Sensitivity analysis showed that this genetic association is derived from the AALD phenotype rather than from AD. Our approach is limited by our phenotype definition; some studies included chronic heavy drinkers (minimal daily consumption of 80 g for a minimal duration of 10 years) but without a standardized psychiatric assessment.

[Current strategies for treatment of alcohol problems]. / Stratégies actuelles de prise en charge des troubles de l'alcoolisation.

Amongst validated psychological treatments, brief intervention appears to be the best suited for primary care. It aims at increasing motivation for change after a screening for an alcohol use disorder. The first therapeutic step for an alcohol-dependent patient aiming at abstinence is alcohol detoxification. At this stage, benzodiazepines should be briefly prescribed if the patient manifests clinically significant withdrawal symptoms. The next step is relapse prevention, for which only three medications are currently validated in France, acamprosate, naltrexone, and disulfiram.

Heavy episodic drinking and alcohol consumption in French colleges: the role of perceived social norms.

BACKGROUND: The effect of normative perceptions (social norms) on heavy episodic drinking (HED) behavior is well known in the U.S. college setting, but little work is available in other cultural contexts. The objective of this study is therefore to assess whether social norms of alcohol use are related to HED in France, taking account of other influential predictors. METHODS: A cross-sectional survey was carried out among 731 second-year university students in the Paris region to explore the role of 29 potential alcohol use risk factors. The probability of heavy episodic drinking and the frequency of HED among heavy episodic drinkers were modeled independently. Monthly alcohol consumption was also assessed. RESULTS: Of the students, 56% overestimate peer student prevalence of HED (37% for alcohol drinking prevalence). HED frequency rises with perceived peer student prevalence of HED. Other social norms associated with HED are perceived friends' approval of HED (increasing both HED probability and HED frequency) and perceived friend prevalence of alcohol drinking (increasing HED probability only). Cannabis and tobacco use, academic discipline, gender, and the number of friends are also identified as being associated with HED. CONCLUSIONS: Overestimation of peer student prevalence is not uncommon among French university students. Furthermore, perceived peer student prevalence of HED is linked to HED frequency, even after adjusting for other correlates. Interventions correcting misperceived prevalences of HED among peer students have therefore the potential to reduce the frequency of HED in this population.

Pharmacological approaches to methamphetamine dependence: a focused review.

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

Peer substance use overestimation among French university students: a cross-sectional survey.

BACKGROUND: Normative misperceptions have been widely documented for alcohol use among U.S. college students. There is less research on other substances or European cultural contexts. This study explores which factors are associated with alcohol, tobacco and cannabis use misperceptions among French college students, focusing on substance use. METHODS: 12 classes of second-year college students (n = 731) in sociology, medicine, nursing or foreign language estimated the proportion of tobacco, cannabis, alcohol use and heavy episodic drinking among their peers and reported their own use. RESULTS: Peer substance use overestimation frequency was 84% for tobacco, 55% for cannabis, 37% for alcohol and 56% for heavy episodic drinking. Cannabis users (p = 0.006), alcohol (p = 0.003) and heavy episodic drinkers (p = 0.002), are more likely to overestimate the prevalence of use of these consumptions. Tobacco users are less likely to overestimate peer prevalence of smoking (p = 0.044). Women are more likely to overestimate tobacco (p < 0.001) and heavy episodic drinking (p = 0.007) prevalence. Students having already completed another substance use questionnaire were more likely to overestimate alcohol use prevalence (p = 0.012). Students exposed to cannabis prevention campaigns were more likely to overestimate cannabis (p = 0.018) and tobacco use (p = 0.022) prevalence. Other identified factors are class-level use prevalences and academic discipline. CONCLUSIONS: Local interventions that focus on creating realistic perceptions of substance use prevalence could be considered for cannabis and alcohol prevention in French campuses.

Is love passion an addictive disorder?

AIMS: Inquiry regarding the relationship between passionate love and addiction has long been a topic of intense debate. Recent advances in neurobiology now allow for an examination between these two states. METHODS: After describing the clinical distinctions between "love passion," "love addiction," and "sex addiction," we compare clinical, neuropsychological, neurobiological, and neuroimaging data on love, passion, pathological gambling (PG) and substance dependence. RESULTS: There are no recognized definitions or diagnostic criteria for "love addiction," but its phenomenology has some similarities to substance dependence: euphoria and unrestrained desire in the presence of the love object or associated stimuli (drug intoxication); negative mood, anhedonia, and sleep disturbance when separated from the love object (drug withdrawal); focussed attention on and intrusive thoughts about the love object; and maladaptive or problematic patterns of behavior (love relation) leading to clinically significant impairment or distress, with pursuit despite knowledge of adverse consequences. Limited animal and human studies suggest that brain regions (e.g., insula, anterior cingulated [ACC], orbitofrontal [OFC]) and neurotransmitters (dopamine) that mediate substance dependence may also be involved with love addiction (as for PG). Ocytocin (OT), which is implicated in social attachment and mating behavior, may also be involved in substance dependence. There are no data on the epidemiology, genetics, co-morbidity, or treatment of love addiction. CONCLUSION: There are currently insufficient data to place some cases of "love passion" within a clinical disorder, such as "love addiction," in an official diagnostic nomenclature or to firmly classify it as a behavioral addiction or disorder of impulse control. Further clinical and scientific studies are needed to improve our understanding and treatment of this condition. For these studies, we propose new criteria for evaluating addiction to love.