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Background: Phenibut (β-phenyl-γ-aminobutyric acid) is an analog of the neurotransmitter gamma-aminobutyric acid (GABA). Like abapentin and pregabalin, it inhibits α2-δsubunits of voltage-dependent presynaptic calcium channels. The potential harm resulting from the use of these gabapentinoids is currently a matter of debate. Methods: This review is based on pertinent publications retrieved by a selective literature search and on cases reported to the Giftinformationszentrum-Nord (GIZ-Nord), a poison information center at the University of Gttingen, Germany. Results: Phenibut is a prescription drug in Russia but its production, possession, use, trafficking, or administration is illegal in Germany. The phenibut toxicity syndrome resembles that of gabapentinoids and GABA mimetics: benzodiazepine-like withdrawal symptoms including epileptic seizures, delirium and paradoxical activation have been described, as have cases of abuse and dependence. A few cases of use in the setting of multidrug abuse, and of phenibut-related death, have been described to date in the USA. The GIZ-Nord received 17 inquiries about phenibut, 55 about gabapentin, and 126 about pregabalin over the period 20082022. Over the same period, the GIZ-Nord was informed of 1207 cases involving Z substances and 4324 involving benzodiazepines. In the majority of the registered intoxications, including those with phenibut, the symptoms were mild. Overdoses of phenibut (2100 g) were reported in 15 of the 17 cases; 8 of the persons who had taken an overdose were somnolent. In such cases, observation in intensive care was recommended. Respiratory depression or coma was not encountered in any case, not even in the patient who had taken 100 g of phenibut. Conclusion: Phenibut causes symptoms resembling those of gabapentinoid and benzodiazepine use. There have been reports of phenibut use in combination with other psychotropic drugs; in particular, its use together with opiates could increase the risk of coma and respiratory depression. No deaths due to phenibut intoxication have been published in Germany or elsewhere in Western Europe, although such cases may have been overlooked, as this drug is still largely unknown to Western medicine. [ABSTRACT FROM AUTHOR]

This review discusses major developments in chronic rhinosinusitis. The latest papers on prevalence of the disease, the burden for patients and society, the lack of awareness, the development of patient classifications and the consequences for the management of the disease. Our discussion includes major developments in the treatment of the disease with biologics but also their limitations. Recent developments also include evolution in the goals of care, where until recently we were content with control of disease but now start to aim for remission and maybe even cure. To reach that aim we need better definitions of disease, outcomes and biomarkers to predict the optimal moment of intervention in the development of the disease. Time will tell whether earlier intervention can prevent development of the disease and later sequelae.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently leads to olfactory dysfunction. This study aimed to assess the impact of dupilumab on CRSwNP patients, focusing on olfactory outcomes and potential correlations with other clinical factors., Methods: CRSwNP patients eligible for dupilumab therapy received subcutaneous Dupixent® injections every two weeks (300mg/2ml dupilumab). The 12-item Sniffin' Sticks Test (SST-12), fractional exhaled nitric oxide (FeNO) and Nasal Polyp Score (NPS) were assessed at baseline and after one, three, and six months. Patients also completed the Sino-Nasal Outcome Test (SNOT-22) weekly., Results: 26 CRSwNP patients were included. After one month, dupilumab led to substantial reductions in FeNO, SNOT scores, andNPS, whereas SST-12 scores improved significantly only after three months. A shift toward normosmia occurred, with 81% achieving normosmia after six months, and a drop in anosmia prevalence to 9.5%. Significant negative correlations between olfaction (SST-12) and polyp severity (NPS) at baseline and after six months were found, while no significant correlations were observed between SST-12 and FeNO or SNOT scores. Age did not correlate with olfaction., Conclusions: Dupilumab demonstrated efficacy in restoring olfaction in CRSwNP patients. Reaching normosmia in over 80% ofpatients after six months of treatment underscores the drug's effectiveness in managing this challenging symptom.

Sexual health has been recognized as an essential component of the overall health and wellbeing. The current article aims, first, to review the current state of sexual health education in undergraduate medical curricula, identifying gaps, needs and challenges. The main part of this paper describes the development and content of an undergraduate sexual medicine curriculum based on a clear concept of the competencies students should learn regarding knowledge, skills and attitudes. The content is based on a biopsychosocial understanding of human sexuality elaborated by international experts from different European countries integrating basic knowledge in biology, psychology, sociocultural and political sciences, preventive medicine, and the various therapeutic approaches to help women, men and couples with sexual health problems on a primary care level. In order to enable students to learn the basic skills of sexual history taking and sexual basic counselling two educational videos were produced. The material presented is part of the European Collaboration in Science and Technology (COST) supported project European Sexual Medicine Network (ESMN). The material provided can serve universities to give the training as a 25-30 hours course equivalent to 1 ECTS., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Di Dionisio CM et al.)

Aims: Alcohol cravings are considered a major factor in relapse among individuals with alcohol use disorder (AUD). This study aims to investigate the frequency and triggers of cravings in the daily lives of people with alcohol-related issues. Large amounts of data are analyzed with Artificial Intelligence (AI) methods to identify possible groupings and patterns., Methods: For the analysis, posts from the online forum "stopdrinking" on the Reddit platform were used as the dataset from April 2017 to April 2022. The posts were filtered for craving content and processed using the word2vec method to map them into a multi-dimensional vector space. Statistical analyses were conducted to calculate the nature and frequency of craving contexts and triggers (location, time, social environment, and emotions) using word similarity scores. Additionally, the themes of the craving-related posts were semantically grouped using a Latent Dirichlet Allocation (LDA) topic model. The accuracy of the results was evaluated using two manually created test datasets., Results: Approximately 16% of the forum posts discuss cravings. The number of craving-related posts decreases exponentially with the number of days since the author's last alcoholic drink. The topic model confirms that the majority of posts involve individual factors and triggers of cravings. The context analysis aligns with previous craving trigger findings related to the social environment, locations and emotions. Strong semantic craving similarities were found for the emotions boredom, stress and the location airport. The results for each method were successfully validated on test datasets., Conclusions: This exploratory approach is the first to analyze alcohol cravings in the daily lives of over 24,000 individuals, providing a foundation for further AI-based craving analyses. The analysis confirms commonly known craving triggers and even discovers new important craving contexts., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kramer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis., Methods: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239)., Results: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis., Conclusions: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Phenibut (β-phenyl-γ-aminobutyric acid) is an analog of the neurotransmitter gamma-aminobutyric acid (GABA). Like abapentin and pregabalin, it inhibits α2-δ-subunits of voltagedependent presynaptic calcium channels. The potential harm resulting from the use of these gabapentinoids is currently a matter of debate., Methods: This review is based on pertinent publications retrieved by a selective literature search and on cases reported to the Giftinformationszentrum-Nord (GIZ-Nord), a poison information center at the University of Göttingen, Germany., Results: Phenibut is a prescription drug in Russia but its production, possession, use, trafficking, or administration is illegal in Germany. The phenibut toxicity syndrome resembles that of gabapentinoids and GABA mimetics: benzodiazepine-like with - drawal symptoms including epileptic seizures, delirium and paradoxical activation have been described, as have cases of abuse and dependence. A few cases of use in the setting of multidrug abuse, and of phenibut-related death, have been described to date in the USA. The GIZ-Nord received 17 inquiries about phenibut, 55 about gabapentin, and 126 about pregabalin over the period 2008-2022. Over the same period, the GIZ-Nord was informed of 1207 cases involving Z substances and 4324 involving benzodiazepines. In the majority of the registered intoxications, including those with phenibut, the symptoms were mild. Overdoses of phenibut (2-100 g) were reported in 15 of the 17 cases; 8 of the persons who had taken an overdose were somnolent. In such cases, observation in intensive care was recommended. Respiratory depression or coma was not encountered in any case, not even in the patient who had taken 100 g of phenibut., Conclusion: Phenibut causes symptoms resembling those of gabapentinoid and benzodiazepine use. There have been reports of phenibut use in combination with other psychotropic drugs; in particular, its use together with opiates could increase the risk of coma and respiratory depression. No deaths due to phenibut intoxication have been published in Germany or elsewhere in Western Europe, although such cases may have been overlooked, as this drug is still largely unknown to Western medicine.

In Germany, only about 10% of patients with alcohol use disorder (AUD) are treated by the professional help system. "The First 30 Days without Alcohol", an interactive e-health intervention, was developed to support people with "alcohol problems" to abstain from alcohol. The aim of this study was to examine the feasibility of the approach, the program's target group, if and why it is effective. In March 2022 an email was sent to all users who had completed the program. A link to a web-based survey regarding the target group's characteristics, its alcohol-use patterns, former attempts to change the problematic drinking behavior and experience with the program was introduced. The Alcohol Use Disorders Identification Test (AUDIT) was used prior and post intervention. A total of 718 participants completed the questionnaire. Of these, 99.2% suffered from AUD; 81.6% of participants were females, and about one third reported some form of psychiatric comorbidity; 46.6% did not use any additional help or assistance apart from the program; 78.3% reported to be abstinent after participation in the 30-day program, and the data show a significant AUDIT score reduction. Primary e-health interventions may contribute to the established addiction-help system. The intervention seems to reach predominantly highly educated and high-functioning females because of their characteristics.

Chronic insomnia occurs in ~10% of the general population and has numerous negative health effects. The recommended first line treatment of cognitive behavior therapy for insomnia is not widely available for patients in Europe, so pharmacotherapies such as benzodiazepine receptor agonist agents (benzodiazepines and Z-drugs) are commonly used. However, their use is only recommended for ≤4 weeks due to unproven long-term efficacy in treatment of chronic insomnia, and the risk of tolerance, and the potential for dependence and misuse. In Europe, recommendations limiting the use of benzodiazepines (lowest dose and shortest duration) in chronic insomnia are not always followed, likely due to the lack of approved effective alternative therapies. Here we present a recent pilot survey of the pharmacological treatment landscape in chronic insomnia in five European countries (France, Germany, Italy, Spain, and the United Kingdom) and physicians' attitude toward treatment. The results suggest that benzodiazepines and Z-drugs are the most widely used treatments in chronic insomnia and are being used for longer than their recommended duration. Country variations in prescription rates were observed. Due to the known association between long-term benzodiazepine use and potential for developing dependence, further analysis of the literature was performed on the use and misuse of benzodiazepines. The results show that long-term use of benzodiazepines is associated with multiple consequences of treatment, including dependence, but also that previous use of benzodiazepines may increase the risk of opioid use disorder., Competing Interests: BC and CL are employees of Idorsia Pharmaceuticals Ltd. IW was an employee of Idorsia Pharmaceuticals Ltd. at the time of preparation of the manuscript. FL has received payment for consultations, presentations, speaker bureaus, and educational events from Molteni Farmaceutici. GH has received payment for honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Bristol-Meyers Squibb, FEO, Gedeon Richter, Georg Thieme, Heel, Hexal, Hikma, Idorsia, Janssen-Cilag, Jazz, Lundbeck, Medfora, Medice, Medical Tribune, MedScape, MedTrix, Neuraxpharm, Pfizer, Prosomno, Recordati, Repha, Rovi, Sanofi-Aventis, and Schwabe. MS has received consultancy fees from Camurus. The reviewer TW declared a shared affiliation with the author GH to the handling editor at the time of review., (Copyright © 2023 Soyka, Wild, Caulet, Leontiou, Lugoboni and Hajak.)

Background & Aims: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD., Methods: Patients with alcohol-associated cirrhosis, with (n = 385) and without hepatocellular carcinoma (HCC) (n = 656), with HCC attributable to viral hepatitis C (n = 280), controls with alcohol abuse without liver damage (n = 366), and healthy controls (n = 277) were genotyped regarding the LPL rs13702 polymorphism. Furthermore, the UK Biobank cohort was analysed. LPL expression was investigated in human liver specimens and in liver cell lines., Results: Frequency of the LPL rs13702 CC genotype was lower in ALD with HCC in comparison to ALD without HCC both in the initial (3.9% vs. 9.3%) and the validation cohort (4.7% vs . 9.5%; p <0.05 each) and compared with patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%), or healthy controls (9.0%). This protective effect (odds ratio [OR] = 0.5) was confirmed in multivariate analysis including age (OR = 1.1/year), male sex (OR = 3.0), diabetes (OR = 1.8), and carriage of the PNPLA3 I148M risk variant (OR = 2.0). In the UK Biobank cohort, the LPL rs13702 C allele was replicated as a risk factor for HCC. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with ALD cirrhosis compared with controls and alcohol-associated HCC. Although hepatocyte cell lines showed negligible LPL protein expression, hepatic stellate cells and liver sinusoidal endothelial cells expressed LPL., Conclusions: LPL is upregulated in the liver of patients with alcohol-associated cirrhosis. The LPL rs13702 high producer variant confers protection against HCC in ALD, which might help to stratify people for HCC risk., Impact and Implications: Hepatocellular carcinoma is a severe complication of liver cirrhosis influenced by genetic predisposition. We found that a genetic variant in the gene encoding lipoprotein lipase reduces the risk for hepatocellular carcinoma in alcohol-associated cirrhosis. This genetic variation may directly affect the liver, because, unlike in healthy adult liver, lipoprotein lipase is produced from liver cells in alcohol-associated cirrhosis., Competing Interests: None of the authors has any conflict of interest in relation to the contents of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Introduction: In Germany, the prevalence rates for alcohol use disorders amount to approx. 6%, while about 3% are diagnosed as being alcohol dependent. Only 10% of the patients are undergoing treatment. There are apparent deficits with respect to early interventions. The internet presence of "Ohne Alkohol mit Nathalie" (OAmN) (Abstinence with Nathalie) ameliorates options for early treatment interventions using a web-based design; however, this intervention has not been evaluated to date, especially with respect to previous treatments., Methods: Over a 4-week period, 4 different channels of OAmN posted announcements for a survey participation introducing a link leading to a web-based survey questionnaire on the domain oamn.jetzt. The questionnaire offered open and closed as well as multiple choice questions regarding alcohol use patterns and attempts to change the problematic drinking behavior., Results: Out of 2022 participants 84.3% (n = 1705) stated to have or have had a problem with alcohol use, 17.7% (n = 302) had a diagnosis of alcohol dependence by a physician or psychologist and only 21% (n = 529) had been in therapy before. The majority of responders (85.5%, n = 1457) had stopped alcohol use before participating in the survey. Most of them (48.5%, n = 705) were assisted by OAmN, 97.5% (n = 1662) had been employed while having the abovementioned problem use of alcohol, 34.3% (n = 570) rated their job performance as "very good" and 43.2% (n = 718) as "good"., Discussion: This pilot study revealed that OAmN can reach people affected by problematic drinking behavior who had not been in contact with the professional medical system for addiction treatment despite having a problematic alcohol use combined with the willingness to quit., (© 2022. The Author(s).)

Introduction: Concomitant drug use is common among opioid-dependent patients in maintenance therapy. Attention deficit hyperactivity disorder (ADHD), a common comorbidity among opioid users, is associated with a higher risk of concomitant drug use. Earlier studies showed that methylphenidate (MPH) can reduce cocaine consumption among patients with ADHD. The use of MPH as an agonist-replacement or maintenance therapy in cocaine-dependent patients without ADHD is also common in Switzerland, despite a lack of supporting evidence. The aim of this study was to assess concomitant cocaine, amphetamine, MDMA, MPH, and heroin use among patients in opioid maintenance therapy either with or without comorbid ADHD. We expected stimulant consumption to be higher in patients with cocaine dependence and comorbid ADHD and that use of MPH would not lead to a reduction in cocaine consumption in patients without ADHD. We therefore evaluated correlations between use of MPH and cocaine consumption and between MPH consumption and cocaine craving within the two groups., Methods: This cross-sectional study included 94 opioid-dependent patients in maintenance therapy in an outpatient department of the Psychiatric Hospital of Zurich. The patients were divided into two groups based on comorbid ADHD; a group with ADHD (N = 27) and a group without ADHD (N = 67). Drug use was assessed using 3-month hair analysis., Results: We did not find significant differences in the number of patients using cocaine, amphetamine, MDMA, or heroin between groups with or without ADHD. With respect to cocaine use, 85.2 percent of patients in the ADHD group and 73.1 percent in the non-ADHD group were users. The non-ADHD group showed a significant positive correlation between the concentration of MPH and cocaine in hair samples (p &lt; 0.05), and a positive correlation between cocaine craving and the concentration of MPH in hair samples (p = 0.065). These two trends were not evident in the ADHD group., Conclusion: Among patients without ADHD, use of MPH correlates with higher cocaine consumption and craving. Conversely, no significant correlation was found between MPH and cocaine use in patients with ADHD. Our study adds to the evidence that MPH confers negative effects in cocaine users without ADHD and should thus have no place in the treatment of these patients., (© 2023 S. Karger AG, Basel.)

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort of patients with advanced alcoholic liver disease (ALD). A large, well-characterised cohort of patients with alcoholic cirrhosis without (n = 674) and with (n = 386) HCC, as well as controls with HCC due to viral hepatitis (n = 134), controls with heavy alcohol abuse without liver disease (n = 266) and healthy subjects (n = 237), were genotyped for SAMM50 rs3827385 and rs3761472 and for PNPLA3 rs738409. Genotype frequencies were compared between patients with alcohol-associated cirrhosis with and without HCC by uni- and multivariate analysis. Minor variants in both SAMM50 rs3827385 and rs3761472 were significantly more frequent in patients with alcoholic HCC versus alcoholic cirrhosis and versus the control cohorts. An even stronger association was noted for PNPLA3 rs738409. The univariate analysis resulted in an odds ratio (OR) of 1.8 for carriers of at least one minor variant of SAMM50 rs3827385 and rs3761472 (each p < 0.001), but this association was lost in multivariate analysis with age (OR 1.1/year), male sex (OR 3.2), diabetes (OR 1.9) and carriage of PNPLA3 148M (OR 2.1) remaining in the final model. Although minor variants of both SAMM50 loci are strongly associated with alcoholic HCC, this association is not independent of carriage of the well-known risk variant PNPLA3 148M.

Opiate addiction is common among offenders, and many opiate-dependent lawbreakers are treated in the correctional system according to § 64 STGB. While substitution treatment in prisons has become common practice, substitution treatment in forensic hospitals in the traditionally abstinence-oriented prison system is controversial and also varies from region to region. Basic data on this are lacking so far. The problem is discussed against the background of a current expert opinion case. Current figures from a large forensic hospital in Munich-East show that almost 30% of the patients are treated with substitutes (n=186). The problem of substitution treatment in the prison system is discussed., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fischler, Soyka, Seifritz and Mutschler.)

Background: The rising number of people using methamphetamine leads to an increasing need for treatment options for this patient group. Evidence-based research on the efficacy of treatment programs for methamphetamine users is limited. Due to specific characteristics of methamphetamine users, the question arises whether established treatment methods for individuals using other substances can be effective for the treatment of methamphetamine dependence as well. We hypothesize that there are significant differences between the two groups that may affect the effectiveness of treatment and worsen the prognosis of treatment outcomes for methamphetamine users compared to consumers of other substances., Aim: To investigate potential differences in cognitive functioning and psychopathology between methamphetamine users and other substance users and possible correlations with treatment outcomes., Methods: A total of 110 subjects were recruited for an observational, longitudinal study from a German inpatient addiction treatment center: 55 patients with methamphetamine dependence and 55 patients with dependence of other substances ("OS group"). Both groups were examined at beginning (baseline) and end of treatment (after 6 mo) with regard to treatment retention, craving, cognitive functioning, psychosocial resources, personality traits, depression, and other psychiatric symptoms. Instruments used were Raven's IQ test, Mannheimer craving scale, cognitrone cognitive test battery, NEO personality factors inventory, Hamilton depression scale, Becks depression inventory, and a symptom checklist. The statistical methods used were χ 2 -test, t -test and multiple mixed ANOVAs., Results: A total drop-out rate of 40% (methamphetamine-group: 36.4%; OS-group: 43.6%) was observed without significant differences between groups. At baseline, methamphetamine-group subjects significantly differed from OS-group individuals in terms of a lower intelligence quotient, fewer years of education, slower working speed, and decreased working accuracy, as well as less cannabinoid and cocaine use. Methamphetamine-group subjects further showed a significantly lower score of conscientiousness, depressive, and psychiatric symptoms than subjects from the OS-group. In both groups, a reduction of craving and depressive symptoms and an improvement of working speed and working accuracy was noted after treatment., Conclusion: There are differences between methamphetamine users and users of other drugs, but not with regard to the effectiveness of treatment in this inpatient setting. There are differences in cognitive function and psychopathology between methamphetamine and other drugs users. The existing treatment options seem to be an effective approach in treating methamphetamine dependence., Competing Interests: Conflict-of-interest statement: All authors declare no conflict of interests for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Comorbidity of bipolar disorder (BD) and alcohol use disorder (AUD) is very frequent resulting in detrimental outcomes, including increased mortality. Diagnosis of AUD in BD and vice versa is often delayed as symptoms of one disorder mimic and obscure the other one. Evidence for pharmacotherapies for people with comorbid BD and AUD remains limited, and further proof-of-concept studies are urgently needed., Areas Covered: This paper explores the currently available pharmacotherapies for AUD, BD and their usefulness for comorbid BD and AUD. It also covers to some degree the epidemiology, diagnosis, and potential common neurobiological traits of comorbid BD and AUD., Expert Opinion: The authors conclude that more controlled studies are needed before evidence-based guidance can be drawn up for clinician's use. Since there are no relevant pharmacological interactions, approved medications for AUD can also be used safely in BD. For mood stabilization, lithium should be considered first in adherent persons with BD and comorbid AUD. Alternatives include valproate, lamotrigine, and some atypical antipsychotics, with partial D2/D3 receptor agonism possibly being beneficial in AUD, too.

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., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk., Methods: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC)., Results: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption., Conclusions: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions., Lay Summary: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients., Competing Interests: Conflict of interest NPC has a number of consulting agreements with and research grants from the pharmaceutical industry but they are not significantly or directly related to this paper. MP receives research funding from various organisations including the MRC and NIHR. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is part of the IMI Consortium ARDAT (www.ardat.org). None of these funding sources were deployed in the undertaking of this study. TRM has conducted clinical research with AbbVie, Genfit, Gilead, and Merck but none of these are related to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. All rights reserved.)

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., Competing Interests: Prof. Dr. med. Scherbaum erhielt Honorare für verschiedene Aktivitäten (z. B. Mitgliedschaft im Beirat, Vorträge, Manuskripte) von AbbVie, Camurus, Hexal, Janssen-Cilag, MSD, Medice, Mundipharma, Reckitt-Benckiser/Indivior und Sanofi-Aventis. In den letzten drei Jahren hat er an klinischen Studien teilgenommen, die von der Pharmaindustrie finanziert wurden.Dr. med. Thomas Alberti erhielt Honorare (z. B. Mitgliedschaft im Beirat) und / oder Ausbildungsstipendien von Janssen-Cilag, Medice und Otsuka-Lundbeck.Prof. Dr. med. Norbert Wodarz erhielt Honorare für (nicht produktbezogene) Vorträge (Janssen-Cilag, Mundipharma und Reckitt-Benckiser/Indivior). Er erhielt öffentliche Mittel (BayStMGP) zur Bewertung von „Naloxon zum Mitnehmen“.Prof. Dr. med. Thomas Hillemacher hat Honorare für verschiedene Aktivitäten (z. B. Mitgliedschaft im Beirat, Vorträge) von Janssen-Cilag, Amomed, Shire, Takeda, Servier erhalten.Prof. Dr. med. Michael Soyka arbeitet seit drei Jahren als Berater oder hält Vorträge für Ammomed, Indivior, Camurus.Prof. Dr. med. Jens Reimer erhielt Honorare für die Teilnahme an Beiräten, Beratungen und Vorträgen von AbbVie, Amomed, Camurus, Gilead, Indivior und Sanofi-Aventis.Prof. Dr. med. Jens Kuhn erhielt Honorare von Bayer, Janssen, Lundbeck, Neuraxpharm, Otsuka Pharma, Schwabe und Servier für Vorträge auf Konferenzen und für die Reisen dorthin. Von der Medtronic GmbH hat er finanzielle Unterstützungen für Investigator-initiierte Studien erhalten. Die übrigen Autoren gaben an, keine Interessenskonflikte bezüglich dieser Studie zu haben., (Thieme. All rights reserved.)

Background: Pharmacological neuroenhancement (PN) is a common healthcare problem at least among students. PN seems to be associated with stressful situations. There is a lack of data about personal characteristics, comorbidities, and coping strategies regarding stress and factors of resilience in students and medical staff. Methods: A web-based survey about the non-medical use of PN drugs with a focus on neuroenhancement was developed and distributed among medical students throughout Germany; the questionnaire was open in April and May of 2020. The survey contained questions about the use of well-known PN drugs, frequency, special purposes, reasons for the use, psychiatric disorders, use of psychotropic drugs apart from PN purposes, and factors of resilience using the brief resilience scale. Results: Data of 1,159 students of medicine were analyzed. The most frequently used substances for PN were coffee (78.8% lifetime prevalence rate), energy drinks (45.7%), caffeine tablets (24.3%), methylphenidate (5.2%), illicit amphetamines (2.0%), and cocaine (1.7%). 98.4% suspected that PN drug use could lead to addiction. PN drug use specifically for PN was significantly associated with the use of (a) any psychotropic drug (other than neuroenhancers), (b) any psychiatric disorder, and (c) higher values of feeling pressure to perform in professional/students' life and in private life as well as (d) the subjective feeling of pressure to perform to be burdening and (e) harmful to one's own health. PN drug use in general was significantly associated with being less resilient. The use of illicit PN drugs, over the counter drugs and prescription drugs was associated with being less resilient. Conclusion: This study indicates that PN with legal and illegal drugs is a widespread phenomenon among German medical students. Users seem to be more often burdened by psychiatric disorders, especially addictive disorders, the perception of stress, pressure to perform and low levels of resilience. These aspects should be considered in further investigation of PN drug use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jebrini, Manz, Koller, Krause, Soyka and Franke.)

Methadone, a full opioid agonist at the mu-, kappa-, and delta-receptor, and buprenorphine, a partial agonist at the mu receptor, are first-line medications in opioid maintenance treatment. Transition from methadone to buprenorphine may precipitate withdrawal, and no accepted algorithm for this procedure has been developed. Current treatment strategies recommend transfer from methadone to buprenorphine predominantly in patients at low doses of methadone (30-40 mg/day). There are some reports indicating that transition from higher doses of methadone may be possible. A number of dosing strategies have been proposed to soften withdrawal symptoms and facilitate transfer including use of other opioids or medications and especially microdosing techniques for buprenorphine. The case series and studies available thus far are reviewed., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Soyka.)