[First Aid Training for Drug Overdose in Opioid Addicts and Provision of Take-Home Naloxone on Release from Prison: Feasibility Study from the Bavarian Model Project]. / Drogennotfallschulung Opioidabhängiger in Haft und Versorgung mit Take-Home Naloxon bei Haftentlassung: Machbarkeitsstudie aus dem bayerischen Modellprojekt.

INTRODUCTION: Between 22 and 30% of prisoners in Germany are reported to be intravenous drug users. There is a 12-fold increase in mortality, mostly as a result of opioid overdose in the first weeks after release from prison. We evaluated the feasibility of first aid training for drug overdose, including take-home naloxone in incarcerated opioid addicts. METHODOLOGY: Within the Bavarian Take-Home Naloxone Model Project (BayTHN), a subsample of imprisoned opioid addicts was recruited in 5 Bavarian correctional facilities. Manualized first aid training for drug overdose, including take-home naloxone was provided. All surveys were conducted with standardized questionnaires or semi-structured interviews. RESULTS: Sixty-two long-term opioid addicts were included (age: 36 years (22-53 years); 53.2% women; age at first opioid use: 19.2 years (10-31 years). On average, 3.9 (1-10) opioid addicts participated per training session. At the time of training, the opioid addicts had been in prison on average for 42 (1-228) weeks and expected their release from prison in about 10 (1-64) weeks. 68% of participants reported having experienced a drug overdose by themselves. 84% had already experienced at least one drug emergency with another person, 36% more than once. Nearly one-third had not offered helped in the last emergency they had experienced, mostly out of fear of doing something wrong. Only 50% of participants had called emergency services. 25% tried to help, however, by not very effective means. 75% often consumed in the presence of other persons, such as partners and/or friends. The incarcerated opioid addicts were well motivated to participate and showed a significant increase in knowledge and skills for effective first aid in an opioid overdose situation. CONCLUSION: The feasibility study carried out among imprisoned opioid addicts shows that manualized first aid training in handling opioid overdose, including take-home naloxone can be successfully implemented. A best-practice model for reducing initial caveats, organization, and prescribing take-home naloxone at release from prison was established. The high rate of drug overdoses and drug use in the presence of others (potential first responders) proves that the target group for successful use of first aid training along with take-home naloxone could be reached. However, a broad roll-out is needed to achieve a relevant reduction in mortality in opioid addicts after release from prison.

German Guidelines on Screening, Diagnosis, and Treatment of Alcohol Use Disorders: Update 2021.

INTRODUCTION: Alcohol consumption in Germany is associated with considerable health and economic consequences. In addition to prevention, the early detection and differential treatment of those affected play an important role. The guideline "Screening, Diagnosis, and Treatment of Alcohol Use Disorders" forms the basis of this care for people suffering from alcohol use disorders. Regular updates integrate the current state of research evidence and clinical expertise. METHODS: Under the auspices of the German Society for Psychiatry, Psychotherapy, Psychosomatics, and Neurology and the German Society for Addiction Research and Addiction Therapy e.V. (DG-Sucht), the 2019-2020 S3 guideline on alcohol was revised by eight working groups. Thirty-five professional societies participated in a structured consensus process to deliberate the recommendations. Potential conflicts of interest were examined in advance, documented, and taken into account during the voting on the recommendations. RESULTS: The guideline provides recommendations on screening and brief interventions for different groups of people, as well as on treatment of individuals in the acute and post-acute phases of withdrawal. Special emphasis was placed on the treatment of comorbid somatic and psychological disorders. In addition, recommendations for specific groups of people (e.g., children and adolescents, pregnant women) have been made and adapted to the German care landscape.

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

BACKGROUND: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. METHODS: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. RESULTS: Variants at the CTRC (p = 1.22 × 10-21) and SPINK1 (p = 6.59 × 10-47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. CONCLUSIONS: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.

[Weighing the benefits and harms of psychotropic and analgesic substances - A perspective of German addiction medicine experts]. / Abwägung von Nutzen und Schädlichkeit von berauschenden und schmerzlindernden Substanzen aus der Perspektive von deutschen Suchtmedizinern.

BACKGROUND: In Europe, there have been several addiction-expert rankings of harms related to the use of psychotropic substances in the last 15 years. Among them, only one expert ranking took into account the potential benefits of these drugs. Non-Opioidergic Analgesics (NOAs), such as gabapentinoids and NSAIDs, which have been increasingly the subject of abuse / misuse reports, have not been considered in such expert rankings. Likewise, there is currently no multi-substance comparison as to whether the valuation rank of the harmfulness of an illegal drug may change along with an imagined change in legal status in Germany. OBJECTIVES AND METHODS: Using a questionnaire, 101 experienced addiction physicians (first cohort) evaluated 33 psychoactive substances including analgesics with regard to their health and social harms as well as potential usefulness for the consumer and their environment / society ('others'). In addition, this cohort investigated whether the harmfulness assessment of an illegal substance changes if it would be legalized. In order to obtain the average overall harmfulness (overall risk) of a substance, the percentage contribution of each dimension to the overall harmfulness was determined in a second survey (second cohort, 36 experienced addiction medicine experts). Finally, the average benefit and overall risk ratings of each substance were related to each other. RESULTS: Prescription psychoactive substances such as analgesics, NOAs (including gabapentinoids) and opioidergic maintenance medications to treat opiate dependence were judged to have a favorable benefit-harm profile. Cannabis and ketamine were placed in the midfield of both, the harm and benefit rankings. Together with most illicit narcotic drugs, alcohol and nicotine, have been ranked among the most harmful and least useful substances, whereby alcohol was judged on average to be more harmful but also more useful than nicotine. In the event of potential legalization, the overall harm of the traditional illegal drugs methamphetamine, heroin, cocaine and cannabis was estimated to be reduced. This was mainly due to a more favorable valuation of the harm to others under these virtual conditions. CONCLUSION: Prescription substances including opioidergic and non-opioidergic analgesics as well as opioid maintenance therapy medications (methadone and buprenorphine) were assigned a favorable benefit-harm profile. Alcohol, nicotine and traditional illicit drugs (with the exception of cannabis and ketamine) were determined to have an unfavorable profile. The overall harm of traditional illicit drugs was assessed to decrease along with legalization, mainly by decreasing the harm to others in this virtual event.

[Treatment of Opioid-dependent Inmates - Attitudes and Treatment Practice of medical Staff in Bavarian Prisons]. / Behandlung opioidabhängiger Inhaftierter ­ Einstellungen und Behandlungspraxis des medizinischen Personals in bayerischen Justizvollzugsanstalten.

BACKGROUND: The present study examines the treatment practice and attitudes of medical staff towards opioid-dependent inmates in Bavarian prisons. METHOD: We interviewed medical staff (n=20) from 18 Bavarian prisons about substitution practice and attitudes by semi-structured interviews. RESULTS: With regard to the treatment routines and the attitudes of the medical staff, we found mixed results. From the perspective of the medical staff, the treatment decision depends on the patients' wishes, the severity and duration of the dependence, the length of sentence and organizational factors. Problems were discussed in particular with regard to the care situation inside and outside the prisons and difficulties in transition management. CONCLUSIONS: Substitution therapy is considered a standard treatment method in prisons today. However, our respondents highlighted some disadvantages (e. g. passing on the substitution drug). Although the treatment goal of complete abstinence was generally viewed positively by a part of the medical staff, it was not considered very realistic. From the point of view of the respondents, special attention should be paid to the continuity of the chosen treatment strategy in the context of discharge management.

[Kratom - a short review for pain medicine]. / Kratom ­ eine kurze Übersicht für die Schmerzmedizin.

BACKGROUND: Consumption of the psychotropic plant kratom (botanical name: Mitragyna speciosa) is sometimes used for the self-medication of chronic or acute pain. An increase in the use is possible in Germany in the future. OBJECTIVE: This review provides an overview on kratom for pain specialists. The topics of the review are the pharmacological aspects, the mental effects, the effects on pain and the risks of kratom including possible addiction. MATERIAL AND METHODS: We conducted a review of literature in PubMed published until 15 January 2021 resulting in 426 publications of which 8 were specifically concerned with the topic of kratom and pain. RESULTS: In addition to other alkaloids, kratom also contains 7­hydroxymitragynine, which is active on opioid receptors. The use of kratom is not without risks, e.g. because there is no standardized form of administration as well as the possibility of direct damage to health and of addiction. DISCUSSION: There are currently no evidence-based reasons to recommend the use of kratom as an analgesic. It is important for pain specialists to ask patients about a possible abuse of kratom and to be able to inform the patients about the potential risks of kratom.

Ranking the Harm of Psychoactive Drugs Including Prescription Analgesics to Users and Others-A Perspective of German Addiction Medicine Experts.

Background: Over the past 15 years, comparative assessments of psychoactive substance harms to both users and others have been compiled by addiction experts. None of these rankings however have included synthetic cannabinoids or non-opioid prescription analgesics (NOAs, e.g., gabapentinoids) despite evidence of increasing recreational use. We present here an updated assessment by German addiction medicine experts, considering changing Western consumption trends-including those of NOAs. Methods: In an initial survey, 101 German addiction medicine physicians evaluated both physical and psychosocial harms (in 5 dimensions) of 33 psychoactive substances including opioids and NOAs, to both users and others. In a second survey, 36 addiction medicine physicians estimated the relative weight of each health and social harm dimension to determine the overall harm rank of an individual substance. We compared our ranking with the most recent European assessment from 2014. Results: Illicit drugs such as methamphetamine, heroin, cocaine and also alcohol were judged particularly harmful, and new psychoactive drugs (cathinones, synthetic cannabinoids) were ranked among the most harmful substances. Cannabis was ranked in the midrange, on par with benzodiazepines and ketamine-somewhat more favorable compared to the last European survey. Prescribed drugs including opioids (in contrast to the USA, Canada, and Australia) were judged less harmful. NOAs were at the bottom end of the ranking. Conclusion: In Germany, alcohol and illicit drugs (including new psychoactive substances) continue to rank among the most harmful addictive substances in contrast to prescribed agents including opioid analgesics and NOAs. Current laws are incongruent with these harm rankings. This study is the first of its kind to include comparative harm rankings of several novel abused substances, both licit/prescribed and illicit.

[Scientific Rationale for the Directive on Opioid Substitution Treatment of the German Medical Association: A Summary]. / Zusammenfassende Darstellung der wissenschaftlichen Grundlagen der Richtlinie der Bundesärztekammer zur Durchführung der substitutionsgestützten Behandlung Opioidabhängiger.

BACKGROUND: According to the Narcotic Drugs Prescription Ordinance (BtMVV), the German Medical Association was commissioned to issue a directive on opioid substitution treatment (OST) based on the current state of scientific medical knowledge. METHOD: For the publication of the initial version of the German Medical Association's directive in 2002, an extensive literature research had been conducted, categorizing the results by levels of evidence. Subsequent revisions in 2010 and 2017 included recent systematic reviews, studies of evidence levels I-III and international guidelines. RESULTS: OST showed its potential in the pursuit of health- and addiction-related as well as psychological and social goals. There was a decline in the rate of mortality, and high risk consumption of illegally acquired opioids was eliminated in 70 to 80% of patients in OST. Psycho-social assistance was found to enhance treatment outcome. Scientific evidence was lacking for the identification of patient groups suitable for different duration of take-home prescription. CONCLUSIONS: With its 2017 amendment, the guideline of the German Medical Association was revised on the basis of the current state of science on substitution treatment. This creates more legal certainty for doctors, and treatment can be delivered in accordance with the existing scientific knowledge. Whether the effects of OST observed in this study have an impact on the care of opioid addicts by attracting more doctors to participate in their treatment needs further evaluation.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Shared genetic etiology between alcohol dependence and major depressive disorder.

The clinical comorbidity of alcohol dependence (AD) and major depressive disorder (MDD) is well established, whereas genetic factors influencing co-occurrence remain unclear. A recent study using polygenic risk scores (PRS) calculated based on the first-wave Psychiatric Genomics Consortium MDD meta-analysis (PGC-MDD1) suggests a modest shared genetic contribution to MDD and AD. Using a (~10 fold) larger discovery sample, we calculated PRS based on the second wave (PGC-MDD2) of results, in a severe AD case­control target sample. We found significant associations between AD disease status and MDD-PRS derived from both PGC-MDD2 (most informative P-threshold=1.0, P=0.00063, R2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R2=0.663%) meta-analyses; the larger discovery sample did not yield additional predictive power. In contrast, calculating PRS in a MDD target sample yielded increased power when using PGC-MDD2 (P-threshold=1.0, P=0.000038, R2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R2=0.81%). Furthermore, when calculating PGC-MDD2 PRS in a subsample of patients with AD recruited explicitly excluding comorbid MDD, significant associations were still found (n=331; P-threshold=1.0, P=0.042, R2=0.398%). Meanwhile, in the subset of patients in which MDD was not the explicit exclusion criteria, PRS predicted more variance (n=999; P-threshold=1.0, P=0.0003, R2=0.693%). Our findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors. Larger target samples are needed to reduce noise and take advantage of increasing discovery sample size.

Methamphetamine-Related Disorders.

BACKGROUND: Methamphetamine is considered more dangerous than other stimulants because of its acute complications, long-term neurotoxicity, and potential for drug dependence. Until now, there have been no evidence-based guidelines for the treatment of methamphetamine-related disorders, either in Germany or abroad. METHODS: A systematic literature search was performed on the treatment of methamphetamine-related disorders. Based on this literature review, a multidisciplinary expert panel developed recommendations using the nominal group technique. RESULTS: The evidence base for the treatment of methamphetamine-related disorders is sparse. The efficacy of psychotherapeutic techniques such as cognitive behavioral therapy and contingency management and the efficacy of complex, disorder-specific treatment programs have been proven in ran - domized controlled trials, but it remains unclear which method is best. Persons carrying a diagnosis of substance abuse should be offered psychotherapy. Structured exercise programs, whether self-directed or professionally led, can improve addiction-specific endpoints as well as comorbid disorders and should, therefore, be offered as well. Pharmacotherapy has shown little to no effect in relatively low-quality clinical trials with low case numbers and high dropout rates, and therefore only a few weak recommendations were made. These include tranquilizers for the short-term treatment of agitation and atypical antipsychotics if necessary. Attempts to substitute other substances, such as methylphenidate or dexamphetamine, for methamphetamine have not yielded any robust evidence to date. Sertraline should not be administered due to serious adverse events. CONCLUSION: Many of the recommendations in the guideline are made with a weak grade of recommendation because of the poor evidence base and the modest size of the reported therapeutic effects. In acute situations, symptomoriented treatment is recommended. Psychotherapy and exercise should be offered as well.

Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis.

The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10-6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed.

Recovery from alcohol dependence: Do smoking indicators predict abstinence?

BACKGROUND AND OBJECTIVES: There is inconsistent evidence about the potential influence of smoking on recovery from alcohol dependence. Our study aimed at assessing the impact of smoking-behavior on relapse during a 12 months follow-up period following a detoxification in patients with Alcohol Use Disorder (AUD). METHODS: Three hundred Patients with AUD (74.9% smoking) were recruited from two inpatient detoxification units in psychiatric hospitals in Germany and their alcohol consumption was prospectively followed for 1 year. Data on different indicators of smoking behavior was gathered. Cox regression model was used to evaluate potential risk factors on time to relapse of alcohol consumption. Two hundred seventy-nine participants (n = 279) were included in the final analysis. RESULTS: Smoking increased the risk for alcohol relapse (hazard ratio = 3.962, 95% CI 1.582-9.921). However, this increased risk is slightly reduced with higher numbers of daily consumed cigarettes (hazard ratio per cigarette = .986, 95% CI .976-.995). CONCLUSION: Smoking reduced the probability of maintaining alcohol abstinence significantly, whereas higher number of cigarettes smoked daily diminished the increased risk of alcohol relapse in alcohol-dependent patients. SCIENTIFIC SIGNIFICANCE: Coordinated psychiatric and substance abuse interventions for different subgroups of patients with AUD in the post-acute treatment phase are necessary. Individualized treatment planning is especially important in smoking patients with AUD who are vulnerable for a relapse to alcohol drinking and for somatic complications. Our findings might support individualized treatment plans. (Am J Addict 2017;26:366-373).

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.

BACKGROUND: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. METHODS: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. RESULTS: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). CONCLUSIONS: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

[Psychometric Evaluation of the German Version of the Short Questionnaire for Family Members-Affected by Addiction SQFM-AA (Gambling)]. / Psychometrische Evaluation des deutschen Kurzfragebogens für suchtbelastete Familienmitglieder SQFM-AA (Version Glücksspiel).

INTRODUCTION: Affected others of disordered gamblers are often heavily impacted because of the illness. Up till now, there is no standardized German instrument to assess this impact. Internationally, the Short Questionnaire for Family Members-affected by addiction (SQFM-AA) is often used which is based on the Stress-Strain-Coping-Support-Modell. That is why we translated this questionnaire into the German Kurzfragebogen für suchtbelastete Familienmitglieder SQFM-AA (Version Glücksspiel) to be able to assess the impact on affected others and to compare our results internationally. METHODS: The SQFM-AA was translated and retranslated and tested in an online convenience sample of affected others. Essential psychometric properties, discriminatory power, and internal consistency were calculated. Factor structure was analysed using an exploratory factor analysis (principal axis analysis, varimax rotation). RESULTS: Data collected from 122 affected others (87% female; 67% partners; 61% joint household) were analysed. Discriminatory power ranges between 0.30-0.94, Cronbach's alpha between 0.61-0.95. Factor analysis shows that 69% of variance can be explained in a solution with 9 factors. DISCUSSION: Due to the methods used when translating and back-translating the SQFM-AA, it can be assumed that both versions are comparable. Internal consistency of all scales is in an acceptable to good range. In our sample, the postulated 11 sub-scales cannot be reproduced. The 9 factors found here can be derived based on theoretical preliminary considerations. 4 of the scales are reflected well in the analysis, 3 more factors show a relevant load on other scales. Furthermore, one item each does not load on the proposed factor for the 2 remaining scales. All in all, the factors can be interpreted well regarding their content. A modification of the questionnaire would improve some of the statistical values, but the international comparability would no longer be possible. CONCLUSION: With the adaptation presented here, impact on affected others of disordered gamblers can be assessed and relevant areas for therapy and counselling can be identified.

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Inpatient treatment for pathological gamblers in Germany: setting, utilization, and structure.

In Germany, there are two different approaches to inpatient treatment of pathological gambling (PG): Facilities focusing on addiction or on psychosomatic illness. However, little is known about how these differences influence utilization and structure of treatment. Therefore, in our study, we analyzed all known German gambling inpatient treatment centers concerning patients' sex, age and number of comorbid disorders and evaluated an expert assessment of the treatment system, access to treatment, and structure characteristics of inpatient treatment facilities. In 2011, 2,229 pathological gamblers were treated. This amounts to 1 % of all past-year pathological gamblers. 90 % of the patients were men, 93 % had at least one comorbid disorder. Access to treatment was mostly gained via psychosocial counseling centers, but was not readily available. Facilities with addiction departments treated less pathological gamblers per year (29.3 gamblers) than facilities with psychosomatic departments (53.3 gamblers) or with both departments (76.4 gamblers). Treatment duration was significantly longer in addiction departments treating PG as secondary diagnosis only, with a low rate of gamblers on all patients, or treating few gamblers. Some facilities specialized on PG and treated more gamblers, had a higher rate of gamblers on all patients, and offered specific treatment programs. The impact of this specialization on treatment outcome is still unclear. Although treatment numbers have risen steadily for the past years, only a small fraction of affected gamblers seek inpatient treatment. Therefore, awareness to the disease and access to treatment needs to be improved.

XRCC5 as a risk gene for alcohol dependence: evidence from a genome-wide gene-set-based analysis and follow-up studies in Drosophila and humans.

Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.

αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior.

The α-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in αCaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that αCaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in αCaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.