IntroductionAdolescence is a period associated with increased risk of gambling problems. Although strict age limits should apply in modern digital gambling platforms, gambling in minors remains a challenge. The present study aimed to study high school students’ gambling both before and after the legal gambling age, and to study associations between gambling-related attitudes and screening positive for problem gambling.Materials and methodsThe study is based on a digital survey which was distributed by teachers to high school students in Lund, Sweden, in April/May, 2025 (n = 528). Self-reported history of gambling was reported for each form of gambling, and problem gambling was screened for using the three-item NODS-CLiP and combined with demographic data and gambling attitudes. Risk factors for screening positive for problem gambling were studied in multivariate logistic regression analyses, including gender and age, measures of gambling-related attitudes, and each separate gambling form.ResultsA positive screen for problem gambling (NODS-CLiP >0) was seen in 16% at age 16, 15% at age 17, and 27% at age 18–19, in total among 31% of boys and 4% of girls. Gambling on online casino was reported by 41% if 18 + years and by 20% if below 18 years of age, and sports betting by 32 and 21% before and after 18 years of age, respectively. Screening positive for problem gambling was more common in case of parental acceptance of gambling, hiding gambling from parents, and liberal attitudes towards gambling policy, and in the multivariate analysis, problem gambling was significantly associated with online casino, sports betting, and gambling within videogames.ConclusionIn the present high school survey, gambling was very common, even before legal gambling age. Participants commonly screened positive for problem gambling, with a large risk increase in boys, and most strongly associated with online casino, sports betting, and gambling within videogames. Society-level policy interventions, as well as individual prevention targeting gambling attitudes, are called for.

IntroductionViolence is common in psychiatric settings. Routine violence risk screening in acute psychiatric settings may be used to identify needs for preventive measures. However, introducing general screening for violence risk in acute psychiatric care may evoke ethical controversy among professionals which in turn will influence implementation. This study aimed to assess professionals’ ethical acceptability of an intervention introducing routine use of Violence risk screening-10 (V-RISK-10) in two psychiatric emergency units in Malmö, Sweden.MethodsSemi-structured interviews with developers and staff (n=6) based on the theoretical framework of acceptability were analyzed using content analysis, with focus on ethics and ethicality.ResultsAlthough respondents were positive towards the use of V-RISK-10, in terms of its potential to promote uniform and fair assessments, they also expressed concerns. Respondents described ethical risks, tied to the accuracy and interpretation of results and their operationalization as an element in risk management. The perceived ethical acceptability of the intervention rested on a balance between different individual and collective interests.DiscussionBased on authentic clinical realities findings indicate an ethical complexity of routine violence risk screening. In the studied local implementation context, violence risk screening may fit with the ethical values of psychiatric staff in an emergency care setting. Care needs to be taken in the implementation process to ensure that necessary knowledge is disseminated throughout the healthcare organization, and clear guidelines are in place for the use of screening results.

Dopaminergic medication used in disorders like Parkinson's disease (PD) and restless legs syndrome can cause impulsive-compulsive behaviour (ICB), often with strong negative effects on patients' quality of life. This narrative review presents translational evidence on iatrogenic ICB, taking findings from epidemiological, clinical, neuroimaging and preclinical studies into consideration. Epidemiological and clinical studies find dopamine agonists with high D2/3-selectivity to be most strongly linked to ICB. Their effect on ICB has often been shown to be dose-dependent, but the impact of combining different dopaminergic drugs or applying extended-release formulations is less clear. Intervention studies support tapering or replacing dopamine agonists for ICB reduction, whereas no efficacious pharmacotherapy has been identified for ICB treatment specifically. Adequate animal models for mimicking different types of ICB are available, and point, in line with human neuroimaging studies, towards an involvement of striatum and prefrontal cortex in iatrogenic ICB. Overall, complementary research designs have led to profound evidence regarding the occurrence of ICB in PD and establishing methods transferable to other, less-studied patient populations. A combined approach integrating insights from human studies and animal models could contribute to developing dopaminergic drugs with lower ICB risk but also specific pharmacotherapies for impulsivity or compulsivity in the future.

Background:Gaming disorder has recently been recognized as a psychiatric condition, yet the clinical characteristics of treatment-seeking individuals remain understudied. This study examined youth and adults seeking treatment at a specialized outpatient clinic in southern Sweden. Methods:A total of 107 individuals aged 12-49 years (M = 22.1, SD = 7.2) underwent comprehensive clinical interviews, psychosocial assessments, MINI diagnostic interview, and standardized self-report measures. Results:Most participants were male (94%), and 80% met diagnostic criteria for gaming disorder. The average age of symptom onset was 16.0 years (SD = 4.6), with a mean duration of 5.5 years (SD = 4.6). Weekly gaming time averaged 50 hours (SD = 12.0, range 0-126). Although participants reported low levels of gaming disorder symptoms (measured by GDT) and psychological distress (measured by CORE-OM and RCADS), but 69% showed significant functional impairments based on clinician ratings using GAF and CGAS. ADHD symptoms were uniquely positively associated with both gaming disorder severity (β=0.39, p < 0.001) and psychological distress (β=0.34, p < 0.001). Psychological distress also increased with age (β=0.38, p=0.002). Discussion:Although many received a clinical diagnosis, the sample reported low levels of gaming disorder symptoms. They reported relatively low psychological distress but demonstrated substantial functional impairment. This may reflect gaming's role as both an avoidance strategy and a way to meet psychological needs. Conclusion:These findings suggest that impaired everyday functioning is a defining clinical feature of this group. Treatment should not only address gaming behavior but also support patients in improving functioning across important areas of life, such as school, work, and relationships.

Background: Klebsiella pneumoniae infections pose a great burden worldwide, causing high morbidity and mortality, which are worsened by the increase in multidrug-resistant strains. New therapeutic/prophylactic strategies are urgently needed to overcome antibiotic resistance and reduce the health and economic impacts of diseases caused by this pathogen. Fimbriae are important virulence factors involved in biofilm formation and adhesion to host cells. Their exposed location, conservation among clinical isolates and adjuvant properties make them interesting candidates for inclusion in protein-based vaccines. Therefore, the present work investigated the immunological potential of type 1 and 3 fimbriae subunits in a murine model of K. pneumoniae lung infection. Methods: MrkA and FimA were produced as recombinant proteins in E. coli, purified and used to immunize mice subcutaneously. The immune responses were characterized and protection against pneumonia was evaluated after intranasal challenge. Results: Subcutaneous immunization with recombinant FimA and MrkA induced high IgG1 production; the antibodies efficiently recognized the native proteins at the bacterial surface, promoted C3 deposition and reduced biofilm formation by K. pneumoniae in vitro. Mice vaccinated with the co-administered proteins reduced the bacterial loads in the lungs after intranasal challenge, less inflammation and reduced tissue damage. Conclusion: The results suggest that both type 1 and type 3 fimbriae contribute to protection against K. pneumoniae lung infection, inducing antibodies that bind to the bacteria and favoring Complement deposition and clearance by the host, while inhibiting biofilm formation.

IntroductionAmphetamine use is an increasing problem, and studies suggest a connection between amphetamine use and cardiovascular and cerebrovascular pathology. However, few long-term studies examine amphetamine users' risk of cardiovascular and cerebrovascular pathology, in comparison to users of other drugs. In addition, in a criminal justice system, illicit drug use and psychiatric comorbidity is common, whereas structured treatment and follow-up is uncommon, and stimulant use is common in this setting. The aim of this study was to investigate the risk of cardiovascular and cerebrovascular morbidity and mortality for intravenous drug users with different drugs as the primary drug, using data from the criminal justice system.MethodsA cohort of injecting substance users (N = 2,422) was identified in the Swedish criminal justice system through interviews with the Addiction Severity Index (ASI) between January 2001 and August 2006. Data on age, sex, self-reported injection drug, tobacco use, and time in prison or custody were retrieved from the ASI database. The clients were followed in national registers up to 2014 with respect to cardiovascular and cerebrovascular morbidity and mortality. Potential predictors of cardiovascular and cerebrovascular events were investigated.ResultSelf-reported main drug was amphetamine in 51.5% (n = 1,247), polysubstance use in 33% (n = 799), and heroin in 15.5% (n = 376) of the cohort. Total observational time for the entire cohort was 23,911 person-years [median 10.3 years (IQR 9.3–11.2 years)]. The highest incidence rates of both cardiovascular and cerebrovascular events were found among amphetamine users. Bivariate analyses showed a significantly higher percentage of cardiovascular events in amphetamine users compared to other substance users (p < 0.044). Amphetamine was not significantly associated with cardiovascular or cerebrovascular events, compared to the main drug heroin or polysubstance use.ConclusionIn this study on substance-using criminal justice clients, while the highest incidence rates of both cardiovascular and cerebrovascular events were found among amphetamine-using individuals, the study did not provide evidence of an independent association. The study highlights the need to take co-factors into account, such as comorbidities and socio-economic factors. More studies are needed to distinguish substance-specific pathology from the impact of other unhealthy lifestyle factors among substance-using individuals.

BackgroundCertain species from the normal respiratory tract microbiota have recently been proposed to positively influence human health. Corynebacterium propinquum and C. pseudodiphtheriticum (Corynebacteria) are two Gram-positive species that frequently colonize the upper respiratory tract and strongly associate with a reduced incidence of respiratory tract infections. The specific role of Corynebacteria during respiratory health and disease is, however, largely uncharacterized.MethodRespiratory tract epithelial cells NCI-H292 and BALB/cByJ mice were inoculated with Corynebacteria (C. propinquum 2018M3 and 2019M4, and C. pseudodiphtheriticum 2019M8 and 2020M12) alone or with subsequent challenge with Streptococcus pneumoniae (pneumococci). The inflammatory response and the bacterial burden of both species over time were determined by Western blot, luciferase assay, cytokine bead array, flow cytometry and viable plate counts on blood agar plates.ResultsClinical isolates of Corynebacteria were well tolerated by human cells and mice. Corynebacteria induced a transient inflammatory response during healthy conditions in the absence of known pathogens. Pre-exposure or nasal priming with Corynebacteria did not affect subsequent acquisition of pneumococci but were associated with a modulated inflammatory response in vitro and in vivo as well as with a reduced pneumococcal burden in the respiratory tract of mice. This indicates that the presence of C. propinquum or C. pseudodiphtheriticum may protect against severe pneumococcal infections.ConclusionsIn this study, we delineate the role of Corynebacteria from the normal microbiota that epidemiologically associate with respiratory health. We show that the presence of Corynebacteria modulates the inflammatory response to pneumococci and associate with faster decrease in pneumococcal burden, primarily in the lower respiratory tract. Our data indicate that Corynebacteria has potential to protect against severe pneumococcal infections.

Opioid use disorder is a chronic disorder with a high risk of overdose-related morbidity and mortality where a large proportion of these can be averted by timely administration of the antidote naloxone. For naloxone to be present when and where overdoses occur, broad-scale overdose education and naloxone distribution (OEND) must be established. A regional naloxone program was implemented in 2018, in Skåne County, Sweden. This five-year follow-up aims to describe all naloxone-related lay-person events, whether recommendations previously described in the literature were met, and to further investigate events conducted by individuals reporting overdose reversals with naloxone on three or more occasions (‘Supersavers’). Between June 2018 and June 2023, data was collected in six-month intervals from 52 participating units, containing information on trained individuals, gender, year of birth and distributed naloxone kits. Upon naloxone replenishment, patients were asked whether previous naloxone had been used for overdose reversals on someone else, or themselves, had been lost, stolen, or given to someone else. Targets for naloxone distribution and program enrolment were set to a minimum of 20 kits per annual opioid overdose death, and 100 individuals at-risk per 100,000 inhabitants, respectively. Training and initial kits were provided to 2685 individuals at risk of own opioid overdose. Upon refill (n = 2,364), naloxone had been used for overdose reversal in 39

Background Impulsive-compulsive disorders (ICDs) are commonly acknowledged as side effects of dopaminergic therapy in Parkinson’s disease (PD). While many large-scale studies have focused on prevalences and high-risk treatments, little is known about practical management of ICDs in clinical care and patients’ experiences. Objective To investigate how ICDs are recognized in clinical PD care, clinical features of patients with ICDs, and how patients are impacted by their ICD. Methods Questionnaires were sent to all patients who reported ICD symptoms in the Swedish quality register for PD in Skåne County (n = 170) and patients’ medical records were screened for mention of ICDs. Core subjects were communication between clinician and patient, course and management of ICDs, and impact on different life domains. Results Despite sufficient awareness of the ICD risk during PD treatment, there was limited communication between clinical care staff and patients regarding ICDs. Only 49% of patients had reported their ICD as part of clinical care, and only 14% had been asked about it. Additionally, collaboration with psychiatry was rare (12%). ICD severity increased over time with ongoing PD treatment, and most patients reported a mild to moderate impact of their ICD on close relationships, family, mental and physical health. Conclusions This study identified insufficient communication about ICDs as part of clinical care in PD and a very limited involvement of mental health services. Thus, to improve prevention and treatment, ICDs should be recognized, monitored and treated more systematically in routine clinical care, and collaboration with mental health services should be increased.

[This corrects the article DOI: 10.3389/fcimb.2022.877995.].

This study examined the prevalence, stability, and fluidity of sexual orientation as well as the prevalence of gender discontent. From a community sample (i.e., all adolescents of the age cohort were invited), this study analyzed data from 1513 adolescents (50.5% females), who replied to questions about sexual attraction on at least one of three occasions (age 14: n = 623; age 15: n = 1322; and age 17: n = 949). Sexual orientation was operationalized from the attraction pattern and shifts in that pattern were analyzed longitudinally. Gender discontent was measured only once, at 17 years. Various types of sexual orientation were found, including homo-, bi-, a/non-, and heterosexual (on all three occasions) alongside gender discontent (at age 17). The results revealed the fluidity of sexual orientation during adolescence, including the decrease of nonsexuality from 14 to 17 years in both girls (from 10.2 to 2.1%) and boys (from 9.4 to 3.4%) shifting to stronger sexual attractions, primarily heterosexuality (girls from 69.4 to 74.8%; boys from 83.1 to 88.5%). Bisexuality emerged as more prevalent among girls than boys (18.2 vs. 4.5%). Notably, stability in a homosexual pattern was lower than other sexual orientations, since few remained in that same group from 15 to 17 years old (girls 17.6%, boys 29.4%), suggesting frequent shifts to and from other groups. Gender discontent was endorsed by 1.7% with about the same number of both genders and an array of sexual orientations was shown. These findings emphasize the nuanced developmental trajectories that adolescents navigate while forming their sexual identities.

In elite sport, athletes and staff may face unique personal- and sports-related stressors that can both bolster and undermine their mental health. Meanwhile, toughness, perfectionism, stigma, and unwanted attention can serve as exacerbating factors and help-seeking deterrents. Two outpatient psychiatric clinics specializing in elite sport and health have been established in Sweden, including one in Malmö, to provide tailored-clinical care, narrow the patient-clinician gap, and foster greater acceptance for mental health care in sport. This population's full journey from first developing symptoms to seeking and receiving treatment in this unique context has not been previously described. This study aimed to characterize this population through a retrospective medical record review (n = 96, Study 1) and explore patient experiences with mental health, help-seeking, and the quality of care at the Malmö clinic through semi-structured interviews (n = 15 athletes and staff, Study 2). The majority of Study 1's sample were female (71 %) and identified as actively competing athletes at admission (87 %). Stress-related and somatoform disorders (53 %) were most common, followed by affective (18 %) and behavioral disorders (16 %). Participants described how their mental health was shaped and expressed through internal, external, and sport-culture-specific causes, factors, and outcomes, while barriers and facilitators to seeking treatment included perceptions of mental health, logistical aspects, and the role of support networks. Overall, participants were satisfied with the care they received, identifying strengths and limitations related to treatment approach, access, and availability. Implications and future directions are discussed.

The placement of gambling problems within the Hierarchical Taxonomy of Psychopathology (HiTOP) framework, which organizes psychopathology alongside broad overarching symptom spectra, is unclear. With the objective to identify associations between gambling problems and the internalizing, externalizing, and thought disorder spectra of the HiTOP, we distributed an online survey to a sample of 1005 Swedish gamblers (52.4% men, aged 18 to 60 and older). Gambling problems were measured using the Problem Gambling Severity Index, and the main HiTOP spectra were assessed with brief versions of the Inventory of Depression and Anxiety Symptoms II, the Externalizing Spectrum Inventory, and the Thought Disorder Scale. Exploratory and confirmatory factor analysis showed that the brief HiTOP scales adequately captured the internalizing, externalizing, and thought disorder spectra. Within this structure, gambling problems emerged as a distinct factor significantly correlated with all three spectra and with unique associations with each: externalizing (β = 0.33, p < .001), thought disorder (β = 0.30, p = .001) and internalizing (β = 0.22, p = .022). In men, gambling problems were significantly associated with the thought disorder (β = 0.54, p < .001) and externalizing (β = 0.31, p < .001) spectra. In women, gambling problems were significantly associated with the externalizing (β = 0.39, p < .001) and internalizing (β = 0.35, p = .013) spectra. Our study is a first attempt to link gambling problems to the three main spectra of the HiTOP. Our findings show that gambling problems are associated with all three spectra and that there may be potential gender differences in the associations between gambling problems and co-occurring psychopathology.

Few population studies have assessed the prevalence of various psychiatric disorders separately for sexual and gender minority groups, and none in an adolescent population. Given the increased mental health problems in sexual and gender minority groups combined, the present study aimed to estimate prevalence of mental disorders in separate sexual minority groups as well as gender discontent persons in community-recruited adolescents in Sweden. The present study is based on two waves (at 17 and 18 years of age) of a longitudinal cohort study (N = 949; 56

Background Gambling disorder is an important problem around the world and is linked to self-harm and suicides which are more common in people with gambling disorders than in people without. Economic hardship is believed to be a risk factor for self-harm in people with gambling disorder and is also common among people with gambling disorder. Therefore, the aim of this study was to investigate economic hardship, defined here as social welfare payments, as a possible risk factor for suicide in people with a gambling disorder. Methods This case-control study contained data from registers including 3592 people with gambling disorder, compared to a total of 7184 age- and gender-matched controls, all with an age of 18 or older. These groups were used to analyze the association between suicide/suicide attempts and social welfare payments and adjust this risk to other possible risk factors. Lastly, a comparison was made between potential suicides/suicides attempts in regard to when in time the individuals received social welfare payments and compare the prevalence of psychiatric disorders, age and gender with the different outcomes. Results The OR for suicide or suicide attempts when receiving social welfare payments, in the group with a gambling disorder, was 1.94 (CI 95%, 1.64–2.30). However, this risk was even greater among the control group with an OR of 3.14 (CI 95%, 2.34–4.20). Adjusted to other risk factors, both psychiatric disorders and being diagnosed with gambling disorder seemed to be a greater risk for suicide/suicide attempts. Conclusions In conclusion, even though social welfare payments seemed to be a risk factor for suicide in the gambling disorder group, the risk was greater within the control group and other risk factors than social welfare payments appeared to play a bigger part when it comes to suicides/suicide attempts. The generally increased risk of suicidal behaviour in people with over-indebtedness is confirmed.

Background: Gambling disorder severely impacts the affected individual's daily life and is considered to be a major public health issue. Gambling disorder may be a risk factor for suicidal behavior, but matched case-control studies are few. This study aims to explore suicidal behavior, and risk factors for it, among patients with GD in comparison with age- and gender-matched controls. Methods: This is a nationwide age- and gender-matched case-control study, based on all cases of gambling disorder diagnosed in Swedish specialist health care between 2005-2019. Suicidal behavior was defined as either fatal suicides or suicide attempts. Comparative statistics and multiple logistic regressions on risk factors for suicidal behavior were performed. Results: The population consisted of 10,782 individuals (78 % were men), including 3594 with gambling disorder, with an average follow-up of 4.6 years. In the gambling disorder group, 17.7 % displayed suicidal behavior, in comparison to 1.6 % of controls. Multiple logistic regression indicated a risk increase for suicidal behavior if diagnosed with gambling disorder, substance use disorders, depressive disorders, anxiety disorders, and female gender. Psychiatric comorbidity in the gambling disorder group consisted of anxiety disorders (44 %), depressive disorders (38 %) and substance use disorders (33 %). Conclusions: Suicidal behavior is elevated among individuals with gambling disorder, compared to matched controls. Findings call for further research in order to explore mechanisms and prevent suicidal behavior among patients with gambling disorder.

This study aimed to investigate suicide and general mortality in individuals with gambling disorder and to evaluate the effect of gambling disorder on mortality and death from suicide. This is a Swedish nationwide case-control, register based study with a ratio of 1:2. Controls were matched on gender, age and municipality. Cases were defined as all adults with a diagnosis of gambling disorder in Swedish in-patient and/or specialized out-patient health care 2005-2019. The total population included 10,782 individuals. Multifactor Cox regression stratified for sex was used to analyze risk factors for suicide mortality and general mortality. Suicide mortality was higher amongst cases, with 41 (1.2%) individuals passing away due to suicide vs. 22 (0.3%) of the controls (p < 0.001). In the regression model, gambling disorder was not significantly associated with suicide mortality, which was associated with substance use disorder and low education in men and for women the model could not draw conclusions on predicting factors. Mortality was also elevated in cases; 94 of the deceased were controls (1.3%) and 132 were cases (3.8%, p < 0.001). In the regression model gambling disorder was not significantly associated with mortality, this was predicted by socioeconomic status, increasing age, low education level, somatic comorbidity, substance use disorder and previous intentional self-harm in men and for women by increasing age and somatic comorbidity. In conclusion, gambling disorder is associated with increased mortality and suicide death. Comorbid disorders and socioeconomic status appear to be important reasons for the increased mortality.

BackgroundImpulse control disorders (ICDs) are known psychiatric conditions in Parkinson’s disease (PD), especially as a side effect of antiparkinsonian therapy. Screening for vulnerable patients and avoiding high-risk treatments can be an effective approach to reduce the ICD burden in patients with PD. Thus, our goal was to identify risk factors for ICDs in PD in the Swedish total population.MethodsOur longitudinal study was based on records of all patients with PD in the Swedish National Patient Registries and the Prescribed Drug Register (n=55 235). Patients with incident gambling disorder and other ICDs were compared with a control group on demographic factors, psychiatric comorbidity, antiparkinsonian dopaminergic treatment and therapies for advanced disease. Potential risk factors were analysed using logistic regressions and relative frequency comparisons (Fisher’s exact test).ResultsMain predictors for incident gambling disorder were treatment with dopamine agonists (Frequency ratio 1.4, p=0.058), monoamine oxidase B (MAO-B) inhibitors (Frequency ratio 1.8, p=0.006) and a prescription for drugs used in addictive disorders (OR 5.85, 95% CI 2.00 to 17.10). Main predictors for other ICDs were dopamine agonist treatment (frequency ratio 1.6, p=0.003), anxiety disorders (OR 7.04, 95% CI 2.96 to 16.71) and substance use disorders other than alcohol (OR 5.66, 95% CI 1.75 to 18.23).ConclusionsOur results support possible risk factors for incident ICDs that had previously been identified, like dopamine agonist treatment and raise additional attention for risk factors like MAO-B inhibitor treatment and specific psychiatric comorbidities. These findings enable tailoring antiparkinsonian therapy to individual patient-specific risk profiles.

Background:Alcohol use disorder (AUD) is associated with an enormous burden of disease and cost to society. The dopamine deficiency hypothesis posits that negative reinforcement generated by a low brain dopamine state drives ethanol intake. Here, we evaluated the efficacy and safety of combined administration of two dopamine-enhancing drugs, varenicline (a partial nicotinic acetylcholine receptor agonist) and bupropion (a weak dopamine-reuptake inhibitor) on alcohol intake in AUD. Methods:Participants aged 25-70 years with moderate-to-severe AUD (defined as ≥4/11 Diagnostic and Statistical Manual of Mental Disorders [DSM]-5 criteria) were enrolled in this randomized, double-blind, placebo-controlled trial, done at four outpatient clinics in Sweden. Participants were randomly assigned (block size 8) 1:1:1:1 to Placebo + Placebo, Varenicline + Bupropion, Varenicline + Placebo, or Placebo + Bupropion. After a 1-week titration period, Varenicline was taken as 1 mg orally twice per day and bupropion as 150 mg orally twice per day for 12 weeks. Participants, investigators, and all study personnel were unaware of treatment allocation. The two primary outcomes were phosphatidylethanol in blood (B-PEth) and self-reported percentage heavy drinking days (%HDD), assessed over a steady state 10-week-period (from start of week 2 to end of week 11). Modified intention-to-treat (mITT) and per protocol analyses (PP) were performed using a sequential hierarchical statistical method. This registered study (EudraCT 2018-000048-24; clinicaltrials.govNCT04167306) is completed. Findings:Between March 4, 2019, and December 14, 2022, 384 participants were randomly assigned: Placebo + Placebo = 97, Varenicline + Bupropion = 100, Varenicline + Placebo = 96, Placebo + Bupropion = 91. 72% participants were male (277/384) and 28% female (107/384), median age 57 (13) years. In the mITT analyses, Varenicline + Bupropion reduced B-PEth (Cohen's d [d] = 0·39, p = 0·004) and %HDD (d = 0·31, p = 0·008) vs Placebo + Placebo. Varenicline + Placebo also reduced B-PEth (d = 0·30, p = 0·005) and %HDD (d = 0·36, p = 0·023) vs Placebo + Placebo. For both primary endpoints, differences between the Varenicline + Bupropion and Varenicline + Placebo groups were not statistically significant (B-PEth: d = 0·022, p = 0·97, %HDD: d = 0·027, p = 0·76), precluding further comparisons according to the statistical hierarchy. In PP analyses, both primary outcomes were reduced with Varenicline + Bupropion (d = 0·43 [B-PEth]; d = 0·41 [%HDD]) and Varenicline + Placebo (d = 0·29 [B-PEth]; d = 0·34 [%HDD]) compared with Placebo + Placebo. Nausea, the only safety concern, was more common in the Varenicline + Placebo group than in the Placebo + Placebo group (49/96 vs 11/97, p < 0·0001) and of longer median duration (45 (70) vs 10 (14·5) days, p = 0·001). Nausea incidence was lower in the Varenicline + Bupropion group vs Varenicline + Placebo (36/100 vs 49/96, p = 0·048) and of shorter median duration (16·5 (39·3) vs 45 (70) days, p = 0·010). Interpretation:Two brain dopamine elevating treatments (Varenicline + Bupropion; Varenicline + Placebo) reduce alcohol consumption compared with placebo alone. Effect sizes were largest when Varenicline and Bupropion were combined and compliance was high (PP-population). Bupropion reduced Varenicline-induced nausea. Varenicline + Bupropion or other mild dopamine enhancers should be further explored for treatment of AUD. Funding:This study was funded primarily by the Swedish Research Council.

Introduction:Use of amphetamine-type stimulants (ATS) contributes substantially to the global burden of disease. Large-scale follow-up studies of morbidity and mortality in ATS users are few. This study analysed morbidity, mortality, and potential predictors of all-cause mortality in a nationwide cohort of patients with ATS use disorder. Methods:Data was acquired from national Swedish registers. All Swedish residents 18 years or older, with a registered ATS use diagnosis in 2013-2014 were included (N = 5,018) and followed until December 31, 2017. Comorbid diagnoses and causes of death were assessed and potential predictors of all-cause mortality were examined through Cox regression. Results:Median age at inclusion was 36.6 years (interquartile range 27.4---48.1) and 70.5 % were men. The crude mortality rate was 24.6 per 1,000 person-years. The adjusted all-cause standardized mortality ratio was 12.4 (95 % CI [11.34-13.55]). The most common cause of death was overdose (28.9 %). Multiple drug use (hazard ratio 1.39, 95 % CI [1.14-1.70], p = 0.004), anxiety (hazard ratio 1.39, 95 % CI [1.11-1.72], p = 0.014), viral hepatitis (hazard ratio 1.85, 95 % CI [1.50-2.29], p = 0.004), and liver disease (hazard ratio 2.41, 95 % CI [1.55-3.74], p = 0.004) were predictors of all-cause mortality. Conclusions:Multiple drug use, anxiety disorders, viral hepatitis and liver diseases were identified as risk factors for death. Our findings call for better screening, prevention, and treatment of somatic and psychiatric comorbidity among ATS users to reduce mortality.