Drug and Alcohol Dependence

BackgroundLong-acting injectable buprenorphine (LAIB) has been positioned as a potentially transformative option for opioid use disorder (OUD), in part because patient experiences reported in qualitative studies emphasize reduced daily burden, increased "freedom," reduced stigma, and fewer pressures related to diversion--while also noting barriers such as insufficient information, early adverse experiences, and concerns about coercion. MethodsWe conducted a cross-sectional online survey of adults recruited from the Behavioral Health Research Panel (BHRP). Eligibility included age [≥]18, English literacy, and OUD diagnosis or problematic opioid use within the past 5 years. Survey content assessed buprenorphine experience, knowledge and attitudes toward LAIB, attribute preferences, and open-text feedback. Descriptive statistics were generated; analyses were stratified by buprenorphine experience (experienced vs naive). ResultsAmong 105 participants, 82.9% reported prior buprenorphine use, and 17.1% were buprenorphine-naive. Overall, 53.3% preferred a long-acting injection regimen (weekly/monthly/3-monthly) versus 46.7% preferring a daily oral tablet/film. Convenience and adherence-related themes (e.g., not missing doses, fewer visits) drove LAIB preference, while oral-route preference and concerns about side effects and safety were prominent among those favoring oral formulations. ConclusionsIn this national convenience sample, preferences were nearly evenly split between daily oral and long-acting injectable buprenorphine regimens, with a slight overall preference for LAIB. Findings align with the qualitative literature, emphasizing the practical and psychosocial benefits of LAIB, alongside persistent needs for improved education, shared decision-making, and attention to tolerability, safety perceptions, and cost/coverage barriers.

BackgroundCannabis use is highly prevalent among people who use unregulated drugs. While daily cannabis use has been hypothesized to provide protective effects through substitution or tolerance mechanisms, the relationship between cannabis use frequency and overdose risk remains poorly understood, particularly for infrequent users. MethodsWe conducted a secondary analysis of cross-sectional interview data from people who use unregulated drugs in Vancouver, British Columbia, collected during the fentanyl crisis (November 2019-July 2021; n=657). Binary logistic regression examined associations between self-reported cannabis use frequency (five categories: less than monthly, 1-3 times per month, weekly, more than weekly and daily) and non-fatal overdose in the preceding six months. Daily use served as the reference category. Models adjusted for age, gender, ethnicity, homelessness, mental health, HIV status, incarceration and daily use of alcohol, opioids, fentanyl, cocaine and stimulants. ResultsAmong 657 participants, 95 (14.5%) reported non-fatal overdose in the past six months. In adjusted models with daily cannabis use as the reference, infrequent cannabis use was associated with significantly increased odds of overdose: use 1-3 times per month (aOR=3.17, 95% CI: 1.50-6.69, p=.002) and more than weekly use (aOR=3.13, 95% CI: 1.70-5.76, p<.001) showed approximately three-fold increased odds compared to daily use. Less frequent use showed non-significant trends in the same direction (less than monthly: aOR=1.73, 95% CI: 0.89-3.37, p=.109; weekly: aOR=1.44, 95% CI: 0.59-3.51, p=.421). Sensitivity analysis restricted to participants with daily stimulant or fentanyl use (n=148) revealed even stronger associations. ConclusionsInfrequent cannabis use was associated with substantially increased overdose risk compared to daily use. This frequency-dependent relationship, with infrequent users at highest risk, likely reflects tolerance differences: infrequent users lack tolerance to synergistic cannabis-opioid effects. These findings were completely obscured in preliminary analyses that dichotomized cannabis use as daily versus less-than-daily, demonstrating how analytical choices can mask critical public health insights. Current harm reduction approaches, including cannabis distribution programs, should incorporate frequency-dependent risk communication and develop strategies to protect infrequent users who may be at heightened overdose risk.

BackgroundIntravenous self-administration (IVSA) of opioids by rats has been shown frequently to exhibit no sex differences, in many cases a higher intake of females, and only rarely higher rates in males. A diversity of methodological parameters (opioid identity, training doses, rat strain, session duration) makes it difficult to identify consistent contributions to these outcomes. ObjectiveTo determine if Heterogeneous Stock (HS) rats derived from 8 founder strains differ by sex in the IVSA of opioids. MethodsMale and female Heterogeneous Stock (N=7-8 per sex) rats were permitted to self-administer heroin (20 {micro}g/kg/infusion) in 2 hour sessions under a Fixed Ratio 1 schedule of reinforcement. After acquisition, animals completed sessions in which different infusion doses of heroin (0, 15, 30, 60, 120 {micro}g/kg/infusion), oxycodone (0, 30, 60, 150, 300 {micro}g/kg/infusion) and fentanyl (0, 0.625, 1.25, 2.5, 5.0 {micro}g/kg/infusion) were assessed. Next, animals were evaluated on doses of heroin (15, 30, 60, 120 {micro}g/kg/infusion), oxycodone (30, 60, 150, 300 {micro}g/kg/infusion) and fentanyl (0.625, 1.25, 2.5, 5.0 {micro}g/kg/infusion) under a Progressive Ratio schedule. Anti-nociceptive effects of heroin (0.56-2.4 mg/kg, s.c.) were examined with a warm water tail-withdrawal assay. ResultsFemale HS rats consistently self-administered more infusions of opioids, including heroin during acquisition, all three opioids during FR-1 dose substitution and of oxycodone and fentanyl in the PR procedure. Male rats were moderately more sensitive to the anti-nociceptive effects of heroin. ConclusionsFemale rats drawn at random from a genetically diverse population self-administer opioids at higher rates than their male counterparts.

Background and AimsAlcohol use disorder (AUD) remains a major public health concern, with persistent disparities in access to evidence-based treatment. This study aimed to examine associations between perceived discrimination in healthcare settings (PDHS), patient-clinician communication (PCC), and receipt of treatment for AUD, and compared these with sociodemographic and insurance-related factors. DesignCross-sectional analysis using structural equation modeling (SEM), logistic and multinomial logistic regression, and machine learning approaches including SHapley Additive exPlanations (SHAP). SettingUnited States, using data from the National Institutes of Health All of Us Research Program. ParticipantsA total of 5,287 adults with AUD (mean age 61 years; 57% men), including 71.6% non-Hispanic White, 12.2% Black, and 8.6% Hispanic participants. Insurance coverage included 52% government (Medicaid/Medicare), 37% private, and 21% military with 19% reporting more than one type. MeasurementsPrimary outcomes were receipt of Food and Drug Administration-approved pharmacotherapy and/or psychotherapy for AUD, examined as binary and multinomial outcomes. The primary exposure was PDHS, measured using a 7-item scale (range 7-35), with higher scores indicating more frequent discrimination. PCC, assessed using a 2-item scale (range 2-8) with higher scores indicating poorer communication, was examined as a potential mediator. Models were adjusted for age group, sex at birth, race/ethnicity, insurance type (government, private, military), household income, and Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores (range 0-12). FindingsPDHS was associated with poorer PCC ({beta} = 0.209, p < 0.001), although communication was not independently associated with treatment receipt. The indirect pathway from discrimination to treatment via communication was not supported. Military insurance was the strongest predictor of treatment receipt, with 6-7 times higher odds compared with other insurance types. Higher AUDIT-C scores and greater PDHS were also associated with increased likelihood of treatment. In analyses restricted to civilian participants, PDHS showed a stronger association with treatment receipt, while PCC demonstrated more modest effects. Machine learning models identified PDHS, AUDIT-C, and PCC as strong contributors, with the impact of poor communication most pronounced among individuals with lower income. ConclusionsAccess to treatment for alcohol use disorder is most strongly associated with insurance coverage, particularly military insurance. PDHS and PCC also contribute to treatment engagement, with differential effects across socioeconomic groups. These findings highlight the importance of addressing structural and interpersonal barriers to improve equitable access to evidence-based AUD treatment.

BackgroundLong-acting injectable buprenorphine (LAI-BUP) is safe and effective, however is dramatically underutilized in comparison to oral formulations. Little is known regarding how buprenorphine prescribers view LAI-BUP, and which medication attributes they prioritize when selecting treatment for opioid use disorder (OUD). MethodsA secondary analysis of a national, cross-sectional online survey of U.S. physicians who prescribe buprenorphine for OUD was conducted. Respondents reported OUD caseload, LAI-BUP use, and the importance of medication attributes relevant to treatment selection (e.g., efficacy, safety, ease of administration, ease of prescribing, and administrative requirements). Providers were categorized as no LAI-BUP use or, among LAI-BUP prescribers, Low vs High use based on a median split. Group comparisons used chi-square (or Fishers exact) tests for categorical variables and Jonckheere-Terpstra tests for ordinal responses. ResultsAmong 125 respondents, 39 (31.2%) reported no patients receiving LAI-BUP. The remaining 86 (68.8%) were LAI-BUP prescribers, split evenly into Low and High (ns=43; 34.4%) groups using a median cut of 23.2%. LAI-BUP use did not differ meaningfully by specialty, region, or practice setting. Greater LAI-BUP use was reported by providers with larger OUD panels. Ratings of key medication attributes were uniformly high. ConclusionsLAI-BUP remains underused, with uptake highest among clinicians managing larger OUD caseloads. Measured attitudes toward medication attributes did not explain these differences. Future work should assess clinic workflow, staffing, reimbursement, and REMS burden, testing targeted implementation strategies using mixed-methods trials. Identifying what shifts clinicians from no use to low and high use may guide scalable implementation interventions.

AimsTo characterize decreases in overdose mortality in the United States between 2023 and 2024 by substance involvement, geography, race/ethnicity, demographic, and other key dimensions. DesignPopulation-based study of national death records. SettingUnited States. Participants/casesAll individuals who died from drug overdose between January 1999 and December 2024. MeasurementsAnnual or monthly (annualized) overdose deaths per 100,000 population. Year and month of occurrence of overdose death; substance involvement; census region and division; state; county; race/ethnicity, age, and sex. FindingsAfter over two decades of mostly exponential increases, monthly data show consistent decreases in overdose deaths between June 2023 and December 2024. Decreases reflected declining illicit fentanyl-involved deaths (with and without stimulants); however, increasing trends through 2024 were still seen in deaths involving stimulants without fentanyl, and those involving xylazine. Death rates in the Northeast, South and Midwest fell to 19.5, 19.4 and 17.3 per 100,000, respectively, in December 2024, but remained elevated in the West, compared with other regions, at 27.2 per 100,000. Non-Hispanic Black and African Americans had the largest decrease in death rates in 2023-2024 falling 29.3%, but remained elevated at 36.0 per 100,000, compared to the national average of 23.7 per 100,000. Non-Hispanic American Indian and Alaska Native individuals had the highest overdose mortality rate in 2024, at 50.8 per 100,000. ConclusionsRecent decreases in overdose deaths are encouraging and unprecedented. Racial gaps remained large but shrunk by a modest margin. The geography of the overdose crisis has shifted, with the West now the most affected region, which may have implications for the targeting of funding. The nature of the crisis is also shifting, as stimulants and xylazine continue to represent increasingly important public health challenges, and renewed attention to nonfatal aspects of addiction in the US is needed.

BACKGROUNDThis study evaluates the reach, scalability, and implementation of a large-scale, multi-site tele-buprenorphine program designed to treat opioid use disorder (OUD) within rural carceral settings. Given that individuals transition frequently between jails and the community, these facilities represent a critical window for OUD intervention, yet they often face significant provider shortages and logistical barriers. We conducted a retrospective chart review of 842 unique patients (1,321 treatment episodes) enrolled in the University of Marylands tele-buprenorphine program across six rural county jails between June 2020 and May 2025. Data extracted from jail records and electronic health records were used to analyze patient demographics, prescribing patterns, and program retention. RESULTSThe patient population was primarily male (71.1%) and White (75.7%), with a mean age of 35.4 years. Participants reported high-severity OUD, with an average of 12.6 years of opioid use. Reflecting broad admission criteria, 55.2% of participants were new treatment initiates not receiving MOUD prior to booking. Patients spent a mean of 35.6 days incarcerated before initiation and were retained in the program for an average of 66 days. Buprenorphine doses were titrated from a mean initiation dose of 8.8 mg to 16.2 mg at discharge. The program demonstrated a 99.5% adherence rate among retained patients. Only 3% of the total sample were discharged for medication diversion or hoarding. CONCLUSIONSTelemedicine is a highly feasible and scalable model for delivering evidence-based MOUD in rural jails. By utilizing a "liberal admission policy" that prioritizes both treatment initiation and maintenance, programs can successfully reach high-risk individuals who lack access to community-based care. These findings suggest that tele-buprenorphine can effectively bridge the treatment gap in underserved jurisdictions, potentially reducing the risk of overdose during the high-risk post-release period.

IntroductionMaternal mental health conditions, comprising maternal suicide and drug overdose, are currently the leading cause of maternal mortality in the United States. However, the relationship between suicidality and drug use behavior in the perinatal period is not well understood. We examined the association between suicidality and drug use behavior among perinatal individuals. Given the racial disparities in both drug use and suicide rates in the U.S., we also examined any differences in suicidality and drug use behavior by race. MethodsParticipants were recruited from a High-Risk Obstetric & Gynecological Clinic in the Midwestern U.S that specializes in providing obstetric care to perinatal individuals who have histories or current use of opioids and other illicit drugs. Participants (N = 66) were a sub-sample of a larger cohort enrolled in an mHealth intervention to support recovery from opioid and stimulant use disorders. We performed chi-square tests and t-tests to examine any significant associations between lifetime suicidality and drug use behavior during the perinatal period. ResultsThe final analytic sample included participants who had responded to the suicidality survey questions (n=43). Nearly 40% (n=16) of our sample endorsed a lifetime history of suicidal thoughts and behaviors (SITB). Of those, 87% (n=15) reported a previous suicide attempt. SITB was significantly associated with cravings for opioids during the perinatal period (p = .01) as well as comorbidities with perinatal anxiety symptoms? ( p < .05), depression symptoms? (p < .05), and bipolar disorder (p < .05). A higher proportion of recent cannabis use was found among mothers with SITB, compared to those without SITB (p=0.04). Mothers with SITB also had a strong positive correlation between preconception and postnatal nicotine use compared to mothers without SITB (p < .01). Finally, while white mothers endorsed more lifetime overdoses (p= 0.01), Black mothers endorsed higher cravings for opioids during pregnancy (p = 0.03). ConclusionsA history of SITB is a distinct risk factor for both illicit and recreational drug use behavior in the perinatal period, and frequently co-occurs with other perinatal mental health conditions. Further research is needed to better understand the directionality of this relationship and the complex interplay between high risk drug use behavior and suicidality.

Pregnant and postpartum people who use drugs in the United States are trying to survive at the intersection of two of the gravest public health crises of the 21st century US: epidemics of (1) maternal mortality and (2) the overdose epidemic. Although extensive evidence documents racial/ethnic disparities in each of these epidemics separately, comparatively little research has characterized racial/ethnic patterns in their collision, that is, in maternal overdose mortality. We analyzed individual-level mortality records from the National Vital Statistics System (NVSS) for 2016-2022 to describe racial/ethnic disparities in pregnancy-associated overdose deaths (PA-OD) and pregnancy-associated substance use disorder-related deaths (PA-SUD). Racial/ethnic-specific mortality rates were calculated per 100,000 live births with exact Poisson confidence intervals. Temporal trends were summarized using annual percent change (APC), and disparities were quantified using rate ratios and differences relative to non-Hispanic White individuals. Overdose-related maternal mortality increased substantially during the study period across multiple racial and ethnic groups. Rates increased nearly threefold among non-Hispanic White individuals and rose more steeply among non-Hispanic Black individuals, producing a Black-White disparity that emerged over time. Rates among Hispanic individuals remained lower but increased rapidly, while estimates among American Indian and Alaska Native individuals were often high but unstable because of small counts. Substance use disorder-related maternal mortality exhibited a pronounced surge during 2019-2021 across several racial and ethnic groups. These findings highlight rapidly evolving racial/ethnic patterns in maternal overdose mortality and underscore the need for targeted prevention and harm-reduction strategies to reduce overdose-related deaths during pregnancy and the postpartum period. FundingWe are grateful to the following NIH grants for supporting this research: U54HD113292 and R01DA059182.

Alcohol Use Disorder (AUD) is a multifactorial condition with severe individual and societal impacts. Extending our 2024 study, this work examines lifestyle, background, and family history determinants of AUD using an expanded dataset from the All of Us Research Program. The updated analysis includes approximately 2.5 times more participants than the prior study, enabling improved statistical power and evaluation of result stability over time. Using interpretable machine learning models and statistical analyses, we identified annual income, residential stability, recreational drug use, sex/gender, marital status, education, and family history as key contributors to AUD risk. Annual income remained the most influential predictor across both datasets, while other feature rankings showed modest shifts. Family history factors continued to demonstrate non-linear effects, with close relatives AUD status remaining influential despite differences between statistical association and predictive importance. In predicting AUD versus non-AUD status, Random forest models achieved the highest classification accuracy (81%), consistent with 2024 results but with improved precision for identifying AUD cases. Overall, the findings confirm the robustness of previously identified AUD determinants and underscore the need for coordinated, multi-level prevention strategies addressing behavioral, familial, and structural factors contributing to AUD.

BackgroundEarly low-level alcohol use predicts subsequent alcohol use and problems. Impulsivity and poor inhibitory control also predict later problematic alcohol use. However, few studies prospectively examine early sipping in combination with modeling impulsivity and inhibitory control change over time as predictors of adolescent alcohol use. MethodsData Release 6.0 from the Adolescent Brain Cognitive Development (ABCD) Study was used (n=11,866; 48% Female). A series of linear mixed-effect models examined trajectories of non-religious sipping at baseline (ages 9-10) and self-reported impulsivity (UPPS-P) and task-based inhibitory control (Flanker task) over time as predictors of past year drinks and problematic alcohol use by ages 15-16. Predictors were run as separate models and a full model with all predictors together. Models were nested within the participant and study site. Interactions with age (to measure change over time from Baseline to Year 6) were included. Corrections for multiple comparisons were employed. ResultsIn individual models, four impulsivity interactions were significant: (1) negative urgency*age ({beta}=.04, FDR-p<.001), (2) positive urgency*age ({beta}=.04, FDR-p<.001), (3) lack of planning*age ({beta}=.04, FDR-p<.001), and (4) sensation seeking*age ({beta}=.04, FDR-p<.001), suggesting that as age increases, the relationship between impulsivity and alcohol use strengthens. Sipping*age ({beta}=.02, FDR-p<.001) interactions also predicted standard drinks. Regarding problematic use, there was a significant interaction in the full model: negative urgency*age ({beta}=-.07, p=.05), indicating that this relationship is more pronounced at earlier ages. ConclusionsTrait impulsivity and sipping in late childhood relate to future alcohol use, and the relationship strengthens with age. Our results found a negative interaction between negative urgency and age on problematic use, potentially indicating negative urgency as a phenotype of vulnerability to experiencing alcohol related problems at younger ages. Findings indicate the importance of understanding facets of impulsivity in the context of adolescent alcohol use for prevention and intervention efforts.

Background: The Adolescent Brain Cognitive Development (ABCD) Study provides rich longitudinal data on environmental, genetic, and behavioral factors related to substance use initiation. Classical marginal structural models (MSMs) require selecting covariates for propensity models, which is challenging when there are many correlated predictors. Methods: We analyzed longitudinal panel data from 11,868 ABCD participants with repeated observations over time. Interval-level binary outcomes were defined for initiation of alcohol, nicotine, cannabis, and any substance, including only participants at risk before initiation. All predictors were constructed as lagged variables to preserve temporal ordering. We used a two-stage machine learning-based causal framework. First, we performed graph discovery using a Granger-inspired lagged predictive modeling approach with elastic-net logistic regression to identify relationships between past predictors and future outcomes. Stable candidate edges were selected using subject-level bootstrap stability selection. Second, we estimated adjusted effects for stable predictors using double machine learning (DML) with partialling-out and cross-fitting. For each predictor, the lagged variable was treated as the exposure and adjusted for high-dimensional lagged covariates. Cross-fitting with group-based splitting accounted for within-subject dependence. Nuisance functions were estimated using random forests, and cluster-robust standard errors were used for inference. Results: We identified stable predictors across multiple domains, including sleep patterns, family environment, peer relationships, behavioral traits, and genetic risk. Many predictors were shared across substance outcomes, while some were outcome-specific. Effect sizes were modest, typically ranging from -0.01 to 0.02 per standard deviation increase in the predictor. Both risk-increasing and protective associations were observed. Risk factors included sleep disturbance and behavioral risk indicators, while protective factors included parental monitoring and structured environments. Conclusions: This study presents a practical framework for analyzing high-dimensional longitudinal data and identifying time-varying predictors of substance use initiation. The approach combines machine learning for variable selection with causal inference for effect estimation. The results highlight both shared and outcome-specific risk factors and identify modifiable targets, such as family environment and sleep, that may inform prevention strategies.

Background: Drug checking services (DCS) promote drug supply awareness among people who use drugs (PWUD) by detecting adulterants such as fentanyl and xylazine that are associated with overdose morbidity and mortality. However, there is limited research on DCS implementation in Latin America (LA). Methods: We conducted a survey of 38 DCS across LA (n=10) and the US (n=28) and compared program characteristics and barriers between these two regions. We also conducted a focus group discussion (FGD) with staff representing six organizations implementing DCS in LA. FGD themes were mapped to constructs quantitatively assessed in the survey. Results: Compared to US DCS, LA DCS more frequently reported funding gaps as a major implementation barrier (80% vs. 54%), law enforcement confiscating DCS supplies (38% vs. 11%), as well as offering supervised drug consumption (30% vs. 4%) and mental health/counseling (40% vs. 18%), but less frequently reported that DCS equipment was legal (44% vs. 75%). DCS on the Mexico-US border focused on people who inject drugs and offered syringe services, supervised consumption, and rapid sexually transmitted infection testing. DCS in central Mexico, Colombia, Peru, and Chile primarily provided DCS for the nightlife community (e.g., attendees of concerts/raves). Barriers to DCS implementation cited by FGD discussants included inadequate funding, DCS legal ambiguities, lack of government support, and cartel violence. Conclusion: DCS in LA would benefit from increased funding, government support, and a more permissive legal environment, thereby strengthening harm reduction efforts and improving safety for PWUD. Keywords: drug checking services; harm reduction; overdose; people who use drugs; Latin America; fentanyl; tusi

BackgroundPsychotherapy is proven efficacious for the treatment of alcohol use disorder (AUD). However, the patient-perceived importance of its effect is not fully appreciated in the evidence base. The smallest worthwhile difference (SWD) represents the smallest beneficial effect of an intervention that patients deem worthwhile in exchange for the harms, expenses, and inconveniences associated with the intervention, and facilitates the interpretation of patient perceived worthiness of an intervention. MethodsThe proposed study will estimate the SWD of NIAAA recommended psychotherapies for AUD treatment with English-speaking American respondents aged 18 and older. Primary participants will be recruited using the Prolific research crowdsourcing site. The SWD will be estimated using the Benefit-Harm Trade-off Method, presenting survey respondents with variable, hypothetical magnitudes of psychotherapy outcomes to find the smallest acceptable effect over a natural remission alternative. The overall average SWD, and subgroup distributions by participant AUD treatment experiences and AUD symptomology will be described. Secondary findings will estimate the smallest recommendable risk difference for AUD psychotherapy from providers and criminal justice professionals. Expected ResultsWe expect to find an estimate of the SWD for AUD psychotherapy. Further, we expect that the SWD will vary between clinical subgroups based on AUD symptomology and treatment experiences. We expect differences in SWDs between the general population and those of providers and criminal justice professionals. Findings from this project will inform the treatment decision process about psychotherapy during the clinical consultation for people with AUD.

Background and AimsOn April 1st, 2024, Germany implemented the Act on the Handling of Cannabis for Non-Medical Use (KCanG), allowing adults to cultivate and possess recreational cannabis. We assessed whether this policy shift was associated with a change in the prevalence of cannabis use in the general population and in daily or almost daily cannabis use. DesignA series of 21 repeated cross-sectional surveys conducted between April/May 2022 and October/November 2025 (covering the period approximately two years before and one and a half years after the KCanG). SettingPopulation of Germany. ParticipantsA total of 32,991 people aged 14-64 years, including 2,092 (6.3%) people who used cannabis in the past 12 months. MeasurementsPast 12-month cannabis use (at least once). In past 12-month users: daily or almost daily use. To test a potential change in prevalence following the KCanG, we used piecewise binomial logistic regression models using the exact date of each wave as the predictor variable, allowing for a change in the slope at the first full wave after implementation of the KCanG in April 2024, with a random effect for wave. We conducted this analysis for the total sample as well as stratified by gender (male vs. female), age (14-24 vs. 25-64 years), and for daily or almost daily cannabis use in the subgroup of people who used cannabis in the past 12 months. Sensitivity analyses used alternate intervention dates (in-time placebo tests). FindingsThe prevalence of cannabis use and the share of (almost) daily users among 12-month users remained largely stable before and after the law reform. None of the slope coefficients before the introduction of the KCanG were statistically significant (all p [&ge;] .08), and none of the coefficients for the change in the slope were statistically significant (all p [&ge;] .31). Results of sensitivity analyses confirmed the stable trends for both outcomes. ConclusionsThe legislation of cannabis introduced in Germany in April 2024 was not associated with a change in trends of 12-month cannabis use prevalence early (1.5 years) after implementation, and also not with a change in the proportion of heavy users among past-12-month users. We recommend continued close monitoring of trends using multiple data sources and over a longer post-implementation period, as the effects of the legislation may not have fully unfolded yet.

BackgroundCannabinoid hyperemesis syndrome (CHS) is characterized by episodes of severe nausea, vomiting, and abdominal pain among those with heavy cannabis use. We estimated differences between those reporting CHS symptoms and other daily and less frequent cannabis users on drug use, psychiatric problems, other health problems, antisocial behavior, and personality. MethodsThe National Firearms, Alcohol, Cannabis, and Suicide survey was administered to 7034 US adults in 2025. Survey items assessed substance use, common psychiatric symptoms, personality traits, and symptoms of CHS. ResultsThose with CHS symptoms reported the highest rates and greatest variety of drug use compared to others who used cannabis. Those with CHS symptoms reported higher rates of other drug use than those who used cannabis daily without CHS symptoms across a variety of drug classes, including opioids, hallucinogens, and sedatives, higher rates of drug overdoses, and greater use of all drug classes than those with less-than-daily cannabis use. Those with CHS symptoms also reported more depression, anxiety, sleep problems, chronic pain, antisocial behavior, intimate partner violence, and disinhibited personality traits than those who used daily (mean d = 0.58) and less frequently (mean d = 0.69) and those with no cannabis use in the past 12 months (mean d = 0.99). ConclusionsThose with CHS symptoms exhibit a variety of psychological and behavioral problems including higher rates of other drug use, psychiatric symptoms, antisocial behavior, and dysfunctional personality traits. Results highlight the importance of understanding and addressing the broader psychosocial challenges faced by people experiencing CHS symptoms. Highlights O_LICHS symptoms are linked to greater polysubstance use and overdose risk C_LIO_LICHS symptoms are associated with depression, anxiety, sleep, and pain problems C_LIO_LICHS tied to antisocial behavior and intimate partner violence C_LIO_LICHS shows disinhibited personality traits and low well-being C_LIO_LINational survey identifies high-risk psychosocial CHS profile C_LI

Introduction. Current best practice is for primary care physicians (PCPs) to screen patients for problematic substance use at checkups. However, this practice is not routine, is done in an unstandardized manner, and contributes to the overburdening of PCPs. Screening practices also target current, potentially problematic use behaviors, thus limiting their capacity to help patients prevent problems before they start. Recent scientific advances in identifying people at high risk for substance use problems as a means of facilitating prevention efforts have not yet been integrated into medical practice. To address these issues, our research team developed a freestanding platform called the Comprehensive Addiction Risk Evaluation System (CARES). CARES provides personalized information about genetic and behavioral/environmental risk for substance use disorder (SUD) and connects individuals to resources based on their risk profile. The present study evaluated the potential for adoption and implementation of CARES within a health care system through qualitative interviews with key stakeholders. Methods. Semi-structured interviews were developed using the Consolidated Framework for Implementation Research (CFIR) and conducted with N=15 interviewees. Transcripts were analyzed using rapid qualitative analysis. Results. Key themes included perceived need for new SUD screening tools, current SUD screening procedures and their pros/cons, openness to new ideas and clinical tools, fit of CARES with organizational goals and priorities, considerations for use of CARES with adolescent populations, anticipated patient response to CARES, barriers to implementation and uptake of CARES, changes required for implementation, and possibility for medical record integration. Interviewees generally expressed need for new screening tools and openness to using new tools, but expressed concern that existing provider burden, lack of SUD knowledge, and discomfort/stigma could stymie efforts to implement CARES. Conclusions. There is a clear need for a low-burden, easy-to-use tool for substance use screening. CARES appears to be an acceptable and feasible approach to fill this gap. These findings will be used to inform pilot implementation of CARES in a clinical care setting.

Tobacco use disorder is a chronic condition characterized by compulsive nicotine use, withdrawal, and relapse following abstinence. Impulsivity contributes to persistent nicotine use and poor cessation outcomes. This study examined whether nicotinic acetylcholine receptor (nAChR) modulators alter impulsive action in a nicotine self-administration Go/No-Go task in male and female rats. Rats acquired intravenous nicotine self-administration and were then trained in a Go/No-Go procedure in which active lever presses were reinforced during Go periods but not during No-Go periods. We then assessed the effects of varenicline (0.1-3 mg/kg), nicotine (0.1-0.6 mg/kg), and the nAChR antagonist mecamylamine (0.5-2 mg/kg) in the Go/No-Go procedure. Varenicline and nicotine pretreatment reduced active responding during both Go and No-Go periods, whereas mecamylamine selectively reduced responding during No-Go periods. Mecamylamine decreased the percentage of active responses during No-Go trials, indicating reduced bias toward the nicotine-associated lever. In contrast, nicotine and varenicline did not alter response allocation, suggesting that their effects reflected nonspecific reductions in responding rather than changes in impulsive action. No sex differences were observed. Substituting saline for nicotine during self-administration did not alter active responding during Go periods, but rats in the saline group had fewer active responses during No-Go periods than rats in the nicotine group. These results show that chronic nicotine self-administration increases impulsive action and that nAChR antagonism, but not agonism or partial agonism, reduces nicotine-related impulsive action. This work supports the utility of the Go/No-Go self-administration task for investigating nAChR-dependent mechanisms underlying nicotine-induced impulsivity.

BackgroundExternalizing liability is a strong risk factor for early substance initiation, but the neurobiological pathways linking polygenic risk to initiation remain incompletely characterized. MethodsUsing the ABCD Study, we implemented a four-stage framework linking an externalizing polygenic risk score (extPRS) to baseline multimodal neuroimaging-derived phenotypes (IDPs) and longitudinal substance initiation (alcohol [primary], nicotine, cannabis, and any substance). First, we screened extPRS-IDP associations using covariate-adjusted linear models (age, sex, ancestry principal components, site/scanner variables; modality-specific covariates where applicable) and controlled multiple testing using false discovery rate (FDR) procedures. Second, we estimated direct extPRS associations with time-to-initiation using Cox proportional hazards models. Third, we fit joint Cox models including extPRS and each discovery-significant IDP, retaining outcome-IDP associations after within-outcome FDR correction. Fourth, we conducted mediation analyses for prioritized outcome-IDP pairs using an extPRS [-&gt;] IDP mediator model and an initiation model including both extPRS and IDP, estimating indirect (ACME) and direct (ADE) effects via bootstrap with multiple-testing control. ResultsAmong 10,608 participants, higher extPRS was associated with earlier initiation across outcomes, with the largest effects observed for nicotine and cannabis and a modest but significant effect for alcohol. Stage 1 identified thousands of extPRS-associated IDPs that were highly concordant across robustness specifications. Stage 3 prioritized outcome-specific IDPs associated with initiation beyond extPRS, with the number of retained IDPs varying across sensitivity settings (site-clustered vs. HC3 standard errors; SES covariates on/off) but showing a replicated core set across models. In Stage 4, mediation analyses showed that indirect effects of extPRS through IDPs were small in magnitude (ACME {approx} 10-4) and accounted for less than 2% of the total effect, while direct effects (ADE {approx} 0.02-0.05) remained strong across outcomes. FDR-significant mediation signals were observed only for alcohol and any-substance initiation, whereas no mediation effects survived multiple testing correction for cannabis or nicotine. Across outcomes, direct genetic effects were substantially larger than mediated effects, indicating that genetic liability operates primarily through direct pathways rather than through baseline brain measures. ConclusionsExternalizing polygenic liability is broadly associated with substance initiation, with robust and consistent direct effects across substances. Although specific frontal structural and microstructural phenotypes show statistically significant mediation signals, their contribution is small, suggesting that baseline brain measures explain only a limited proportion of genetic risk. This framework provides a scalable approach to prioritize neurobiological pathways linking genetic liability to early substance initiation while highlighting the dominant role of direct genetic effects.

IntroductionNeural cue reactivity is increasingly being investigated as a biomarker of treatment response and relapse prediction in addiction disorders. Whilst aberrant brain responses to salient cues (e.g. drugs) have been widely reported in addiction, it is unclear whether these brain responses persist during longer-term abstinence, how they compare between substance use disorder and obesity, and relate to potential differences in eating behaviours. As part of the Gut Hormones in ADDiction (GHADD) neuroimaging study, we investigated how salient cue reactivity to drugs or food, craving and eating behaviours compare in three clinical populations where alterations have been previously observed: abstinent nicotine use disorder (NUD) and alcohol use disorder (AUD), and obesity. MethodsThis study compared group differences in salient cue reactivity and eating behaviours between ex-smokers (n=25, ExS), adults with alcohol dependence who are abstinent (n=26, AAD), adults with obesity who were actively dieting (n=26, OB). Participants completed a high-energy food, preferred alcohol and cigarette functional magnetic resonance imaging (fMRI) cue reactivity task, along with eating behaviour questionnaires, appetite visual analogues scales and an ad libitum test meal. ResultsExS exhibited greater blood oxygen level dependent (BOLD) signal to high-energy food pictures in several reward processing regions in both whole brain and region of interest (ROI) analyses, compared with the OB and AAD groups, with no difference in their appeal rating. Compared with the OB group, ExS exhibited greater BOLD signal to cigarette pictures in the frontal gyrus, orbitofrontal cortex, frontal pole and insula, with no difference in their appeal rating. There were no group differences in preferred alcohol cue reactivity. The AAD group rated sweet taste as more pleasant, and consumed more calories from sweet dishes in the ad libitum meal than the OB and ExS groups. ConclusionsThe presence of heightened cue reactivity to high-energy foods in ex-smokers could contribute to post-quitting weight gain after smoking cessation. Neuroimaging findings were consistent with persistence of some salient drug cue reactivity, despite absence of craving, after medium term abstinence in ExS, but not in AAD. This study also adds to the body of evidence supporting a sweet taste preference endophenotype predisposing individuals to AUD. These changes in eating behaviour in NUD and AUD may provide targets for treatments to reduce substance misuse and facilitate abstinence.