Addiction

Background: Alcohol use disorder (AUD) is marked by high relapse rates often driven by craving, yet less is known about whether in vivo, social, and place-based alcohol cues are differentially associated with craving across affective states. This study examined independent and affect-contingent associations of these cues with momentary craving in adults with AUD enrolled in an alcohol intervention study. Methods: Thirty-three adults with AUD completed up to four daily ecological momentary assessments (EMA) for 28 days. EMA prompts assessed craving, in vivo alcohol exposure, being around usual drinking partners, being in usual drinking places, and high-arousal positive affect (PA) and negative affect (NA). Multilevel mixed-effects models adjusted for demographics, intervention phase (1 = post, 0 = pre), AUD severity, and temporal and contextual covariates. Results: EMA compliance was high (median per-participant = 86.6%). Within-person elevations in in vivo alcohol exposure and being around usual drinking partners were independently associated with greater momentary craving, whereas being in usual drinking places was not. In vivo alcohol exposure was more strongly associated with craving during higher-than-usual PA ({beta} = 0.08, p = .032), whereas being in usual drinking places was more strongly associated with craving during higher-than-usual NA ({beta} = 0.06, p = .036), adjusting for intervention phase, which was associated with lower craving. Conclusions: Findings support the need for personalized just-in-time adaptive interventions tailored to high-risk, momentary cue-affect contexts in AUD, beyond low-frequency clinician-delivered feedback that may reduce average craving but not fully address real-time risk. ClinicalTrials.gov registration: NCT05135767.

BackgroundFetal alcohol spectrum disorders (FASD) arising from prenatal alcohol exposure (PAE) are the leading preventable cause of neurobehavioral disorders. Early pregnancy is particularly vulnerable to ethanol toxicity, yet alcohol use often continues until pregnancy recognition. In Finland, national incidence estimates of PAE and FASD remain limited. ObjectiveTo estimate the incidence of any PAE and heavy PAE in Finland between 1990 and 2025, and to model the annual number of children with FASD born in or immigrating to Finland. MethodsWe developed a mathematical modelling framework integrating studies on alcohol use during pregnancy in Finland, biomarker-based estimates of heavy PAE, national population statistics, and international active case ascertainment studies on FASD prevalence. Incidence of any PAE was estimated from self-reported alcohol use, including pre-recognition exposure. Heavy PAE was estimated by combining binge-drinking prevalence, delayed pregnancy recognition, biomarker data and anonymous self-reports. FASD incidence was modelled using two approaches: 1) an international multiplier linking FASD prevalence to heavy episodic drinking prevalence among women, and 2) a conventional epidemiological ratio between any PAE and FASD. Immigration and international adoption were incorporated. ResultsSelf-reported alcohol use during pregnancy declined following abstinence recommendations in the early 2000s, while pre-recognition use remained relatively stable. Heavy PAE decreased from 9% (uncertainty range 7-11%) in the 1990s to 6% (4-8%) in the early 2020s. Any PAE declined from 75% (60-85%) to 32% (26-38%). Modelled FASD incidence showed similar decreasing trends, ranging from 6.8% to 5.6% (multiplier model), and from 6% to 3% (any PAE-based model). ConclusionPAE remains common in Finland, and the burden of FASD is substantial despite declining trends. Additional biomarker-based studies of PAE and active case ascertainment of FASD are needed to refine current estimates. Strengthened public health efforts to reduce PAE, including the efforts before recognition of pregnancy, are essential.

Abstract Aims To examine which demographic groups nicotine pouch advertisers chose to target on social media, and which groups Meta's algorithms actually delivered the adverts to. Design Cross-sectional analysis of advert-level data from the Meta Ad Library. Setting Meta social media platforms (including Facebook and Instagram) in the UK. Cases A random sample of 741 nicotine pouch adverts shown in the 12 months up to December 2025, and a comparison sample of 1,125 general adverts. Analyses of reach were restricted to adverts eligible for all genders and adult ages (444 pouch adverts; 674 general). Measurements Outcomes were advertiser-set gender and age-group targeting criteria (i.e., groups eligible to be shown each advert) and estimated advert reach to each group (i.e., number of people who saw each advert). Male-to-female reach ratios within age groups, and reach ratios comparing age groups, were calculated per advert and summarised using geometric means. To assess whether patterns were pouch-specific, comparisons with general adverts were made using ratios of reach ratios (RRR). Findings Advertisers of nicotine pouches targeted a broad sample; most adverts (79.1%; 586/741) were eligible to be shown to all genders, the remainder were restricted to men only. All were restricted to adults (minimum age 18 years) and most (95.6%; 708/741) had no upper age limit. Despite this, of pouch adverts eligible to be shown to all adults, adverts were more likely to reach men, particularly among younger men. Among 18-24-year-olds, pouch adverts reached around ten times as many men as women (RR 10.0, 95% CI 8.7-11.5), compared with a slight skew towards women for general adverts (RR 0.81, 95% CI 0.71-0.94), corresponding to an RRR of 12.3 (95% CI 10.0-15.1). Pouch adverts also showed a skew in reach towards younger age groups. Relative to those aged 35-44 years, reach was higher among 18-24-year-olds for nicotine pouch adverts (RR 1.33, 95% CI 1.17-1.51) but much lower for general adverts (RR 0.19, 95% CI 0.17-0.21), corresponding to an RRR of 7.0 (95% CI 6.0-8.2). Conclusions Nicotine pouch adverts on social media are often eligible to be shown broadly to all demographic groups but are disproportionately delivered to young men.

Background: Xylazine and medetomidine are veterinary sedatives increasingly detected as adulterants in the U.S. illicit drug supply. In response, several states have scheduled xylazine. Whether these policies are associated with subsequent changes in xylazine and medetomidine detections remains unclear. Methods: We conducted a state-level, semiannual, serial cross-sectional study using National Forensic Laboratory Information System (NFLIS) data from 1999 to 2025. The primary outcomes were xylazine and medetomidine reports per 100,000 NFLIS drug reports. We used staggered difference-in-differences event-study models to estimate changes in report rates after xylazine scheduling. Sensitivity analyses excluded Florida and expanded the treatment definition to include states that criminalized xylazine without formal scheduling. Falsification analyses examined steroid and antidepressant reports as negative-control outcomes. Results: NFLIS recorded 101,987 xylazine reports and 12,085 medetomidine reports. Xylazine scheduling was not associated with a significant change in xylazine report rates (ATT, 2,872.29 per 100,000; 95% CI, -2,024.63 to 7,769.21; p=.250). In contrast, xylazine scheduling was associated with a significant increase in medetomidine report rates (ATT, 1,536.51 per 100,000; 95% CI, 211.14 to 2,861.88; p=.023). Sensitivity analyses produced similar findings. Negative-control outcomes showed no significant changes. Conclusions: State xylazine scheduling was associated with increases in medetomidine reports but no significant change in xylazine reports. These findings suggest that scheduling may be followed by changes in adulterant composition rather than reductions in overall 2-adrenergic agonist involvement. Our study highlights the importance of monitoring the unintended effects of xylazine scheduling and supporting continued investment in public health surveillance, drug checking, and harm reduction services.

Tobacco control treaties were written for billboards and television, not for the people now selling lifestyles to young Africans. As mobile internet saturates East African cities, social media influencers have become an unmeasured channel, especially when it comes to tobacco promotion. We assessed the prevalence of tobacco use, its association with influencer exposure, and how urban youth interpret that exposure in two capitals with different tobacco laws. We conducted a comparative mixed-methods study among youth aged 18-29 years in Kampala, Uganda, and Nairobi, Kenya (January-August 2025), combining (i) a cross-sectional survey using systematic sampling at youth-dense venues (n=772), (ii) four online focus group discussions (FGDs; n=40), and (iii) content analysis of 30 tobacco-related posts from high-reach influencers (greater than 50,000 followers). We used chi-square tests and multivariable logistic regression, thematic analysis (Braun and Clarke), and descriptive engagement metrics. Ever tobacco use among urban youth in East Africa was 29.3% (226/772), similar in Kampala (30.7%) and Nairobi (28.0%; p=0.409). After adjustment, exposure to influencers promoting tobacco independently predicted ever use (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.29-2.82; p=0.001), alongside male sex (aOR 2.35) and age 26-29 years (aOR 1.99). Tertiary education (aOR 0.45) and never seeing tobacco content (aOR 0.26) were protective. Posts framed tobacco as aspirational lifestyle; 77% of sampled comments were positive and 47.5% expressed interest in trying the product. Influencer exposure behaved as a modifiable risk factor of a magnitude comparable to established demographic drivers. Tobacco control in the region must move from print-era advertising bans to platform governance, mandatory disclosure of paid promotion, and youth-led counter-marketing.

Background: Prenatal substance exposure (PSE) occurs when an individual is exposed to substances in utero. PSEs may have lasting effects on mental health. We tested whether PSEs show threshold, cumulative, or individual substance associations with childhood psychiatric diagnoses. Methods: Clinical variables (demographics, ICD-9/10 diagnoses, PSE history) were extracted from electronic health records from the University of Minnesota Adoption Medicine Clinic. PSEs were identified from caregiver and child-protective-services narratives and/or toxicology (cord tissue/blood, meconium). For each ICD-9/10 diagnostic category, we fit logistic regression models comparing (1) exposure thresholds (0, 1, 2, 3, 4+ exposures), (2) a cumulative exposure count, and (3) individual substances to estimate marginal odds ratios (ORs) with 95% Confidence Intervals (CIs). Results: Psychiatric diagnoses increased with the number of PSEs. Relative to no exposure, odds of an Anxiety Disorder rose from OR 1.47 (95% CI 1.16-1.87) with one exposure to OR 2.03 (1.64-2.52) with >=4 exposures. Higher cumulative exposure scores were associated with Anxiety Disorders (OR 1.28, 1.18-1.38), Behavioral and Emotional Disorders (OR 1.42, 1.31-1.54), Substance Use Disorders (OR 1.52, 1.29-1.79), and Mood Disorders (OR 1.16, 1.04-1.30). Alcohol, tobacco, and marijuana exposures were associated with increased odds of at least one psychiatric diagnosis, and each substance showed at least one significant diagnostic cluster when modeled independently. Conclusion: Increasing numbers of PSEs were associated with higher odds of psychiatric diagnoses, with patterns varying by substance and outcome. These findings motivate research on exposure timing and combinations to support earlier identification and intervention for at-risk children.

Background and Aims: The North American overdose crisis is increasingly characterized by complex polysubstance use alongside a transition from injecting to smoking unregulated opioids. However, transitions involving multiple substances remain understudied. We characterized longitudinal transitions in the route of administration and frequency of heroin, fentanyl, and methamphetamine use and examined whether these transitions differed by multilevel factors hypothesized to influence patterns of polysubstance use and routes of administration over time. Design: People who inject drugs (PWID) enrolled in a cohort study completed baseline surveys (October 2020-2021) and three biannual follow-up visits (through April 2023). Setting: San Diego, California, and Tijuana, Baja California. Participants: Among 612 PWID, median age was 43 years; most were male (74%), Hispanic, Latino, or Mexican (72%), and San Diego residents (67%). Measurements: Based on past six-month substance use behaviors reported at each visit, we categorized participants according to six indicators over time: low- (< weekly) and high-frequency ([&ge;] weekly) smoking and injecting of heroin, fentanyl, and methamphetamine. We then used latent transition analysis (LTA) to identify distinct subgroups of participants with respect to these indicators at baseline and examine transitions between them over 18 months. We fit models with 2-5 subgroups, selecting the final model based on fit and interpretability and used multiple-groups LTA to examine differences in subgroup transitions by multilevel factors. Findings: We identified four subgroups: Subgroup 1 (Heroin-Methamphetamine Polyroute), characterized by high-frequency heroin and methamphetamine smoking and injection, included 22% of participants at baseline but 0% at 18 months. Subgroup 2 (Methamphetamine-dominant Smoking), characterized by high-frequency methamphetamine smoking, accounted for 14% of participants at baseline and 18 months. Subgroup 3 (Fentanyl-Methamphetamine Smoking), characterized by high-frequency fentanyl and methamphetamine smoking, included 4% of participants at baseline and 21% at 18 months. Subgroup 4 (Heroin-dominant Injecting), characterized by high-frequency heroin injection, included 61% of participants at baseline and 65% at 18 months. Participants in Subgroup 1 primarily transitioned to Subgroups 3 and 4 over time. Larger increases in Subgroup 3 prevalence occurred for participants who, at baseline, experienced homelessness, resided in San Diego (vs. Tijuana), received syringes from a syringe services program, and overdosed in the past six months. Conclusions: PWID in this region increasingly transitioned from high-frequency heroin and methamphetamine injection toward fentanyl and methamphetamine smoking, likely reflecting shifts in drug availability. Results highlight the need for multilevel interventions that address health harms resulting from polysubstance smoking alongside continued injection.

Background and Aims: Synthetic opioids cause tens of thousands of deaths each year in North America, and there are indications that synthetic opioids are also becoming increasingly prevalent in the European drug market. This study aimed to examine high-risk substance use in the German drug-using community with a particular focus on the synthetic opioids fentanyl and nitazenes and related awareness, concerns, overdose experiences, and harm-reduction behavior. Design: Cross-sectional, observational online survey. Setting: Open drug-use scenes, addiction clinics, and substitution practices at numerous geographic locations throughout Germany, August to September 2025. Participants: 235 individuals aged 14+ from the drug using community (mean age 43.4 years; 57.9% male), 79.6% recruited by peers in open drug-use scenes. Measurements: The primary outcome was substances used within the past 12 months. In addition, sources, forms, routes of administration, and perceived changes in availability and price of (synthetic) opioids were assessed as well as risk perceptions, fears, harm-reduction behavior, and overdose-related experiences. Findings: 227 respondents reported substance use with an average of 6.2 substances, and 73.1% (95% confidence interval [CI] = 67.0-78.5%) had used at least one opioid in the past year. Synthetic opioids were consumed in many parts of Germany and across all age and gender groups. Among participants who experienced a shortage of their primary opioid in the past year, 25% (95% CI = 15.8-37.2%) reported having used fentanyl instead. 56.5% (95% CI = 36.8-74.3%) of individuals using synthetic opioids reported having experienced an overdose in the past twelve months. Most of the respondents perceived synthetic opioids as posing a high risk, and a substantial proportion expressed fear that they could be mixed into their own substances. However, only 9.9% (95% CI = 6.6-14.7%) use drug checking, although the vast majority stated they would use it if it were available to them. Conclusions: Synthetic opioids, including fentanyl and nitazenes, have entered the German drug scene, with users reporting high rates of overdose and limited access to harm reduction measures. Germany may be in an early phase of a synthetic opioid transition, warranting urgent expansion of surveillance, naloxone distribution, and drug checking services.

Importance: Problematic use of the internet (PUI) behaviors, including problematic gaming, social media use, smartphone use, and general internet use, have been increasingly studied worldwide. So far, it is unclear what the global prevalence of PUI is. Objective: To critically appraise existing systematic reviews and meta-analyses on the prevalence of PUI behaviors and generate aggregated global prevalence estimates across different manifestations and definitions. Data Sources: MEDLINE (Ovid), Embase (Ovid), Scopus, Web of Science, CINAHL, and the Cochrane Review Library were searched for relevant articles from database inception to the most recent available search prior to manuscript preparation. Searches targeted systematic reviews and meta-analyses reporting prevalence for PUI-related behaviors. Study Selection: Systematic reviews and meta-analyses of observational studies reporting prevalence estimates for problematic gaming, problematic internet use, problematic smartphone use, problematic social media use, or sexting were included. Scoping reviews were retained for descriptive synthesis only. Data Extraction and Synthesis: An umbrella review methodology was used. Data extraction and methodological appraisal were conducted using AMSTAR-2 to assess the quality of included systematic reviews up to February 2026. Primary studies included in each review were extracted and pooled using random-effects meta-analysis. Analyses were conducted to estimate pooled prevalence with 95% confidence intervals (CIs) and heterogeneity across non-overlapping primary studies. Small-study effects were examined. Main Outcomes and Measures: Global pooled prevalence estimates for PUI behaviors, including problematic gaming, problematic internet use, problematic smartphone use, problematic social media use, and sexting. Results: Eleven reviews, including 10 systematic reviews and 1 scoping review, met inclusion criteria, representing data from 3,145,428 individuals, of whom 3,030,023 were included in pooled prevalence analyses. Across regions, pooled prevalence estimates were 6% (95% CI, 5%-7%) for problematic gaming, 16% (95% CI, 15%-17%) for problematic internet use, 32% (95% CI, 28%-35%) for problematic smartphone use, and 23% (95% CI, 19%-28%) for problematic social media use. Substantial heterogeneity (I2 > 99%) was observed across primary studies, reflecting variation in study methodologies, sampled populations, and definitions of PUI behaviors. Conclusions and Relevance: PUI behaviors appear to affect a substantial proportion of the global population. However, methodological concerns were common, with 9 of 10 systematic reviews rated as having low or critically low confidence according to AMSTAR-2. Evidence remains concentrated in East Asia and Europe, and many reviews combine heterogeneous populations and sampling strategies. Additional high-quality epidemiological research, including studies in underrepresented regions, is needed to refine prevalence estimates, clarify risk factors, and support the development of standardized criteria for PUI behaviors.

Objectives: To examine COVID19 vaccine uptake among people diagnosed with sexually transmitted and bloodborne infections (STBBI) and reported methamphetamine users in Manitoba, Canada, during the acute phase of the COVID19 pandemic. Methods: We conducted a retrospective matched cohort study using linked population based administrative healthcare, laboratory, and vaccination databases in Manitoba. Individuals aged 16+ years with laboratory confirmed chlamydia/gonorrhea (CT/NG), syphilis, HIV, and/or documented methamphetamine use during the four years prior to March 1, 2020 were included in eight exposed cohorts. Each cohort was matched to unexposed comparators on age, sex, geographic region, and income quintile. The primary outcome was receipt of 2+ COVID19 vaccine doses between December 1, 2020 and March 31, 2022. Poisson regression models estimated adjusted rate ratios (aRRs) and 95% confidence intervals (95% CIs) for vaccine uptake. Results: Compared with matched comparators, most exposed cohorts were less likely to complete the COVID19 primary vaccine series. Individuals in the Syphilis Only (aRR: 0.87, 95% CI: 0.85 0.90), Syphilis Plus (aRR: 0.84, 95% CI: 0.81 0.86), CT/NG Only (aRR: 0.95, 95% CI: 0.94 0.96), CT/NG Plus (aRR: 0.82, 95% CI: 0.80 0.85), Methamphetamine Only (aRR: 0.78, 95% CI: 0.76 0.80), and Methamphetamine + STBBI cohorts (aRR: 0.74, 95% CI: 0.72 0.77) had significantly lower vaccine uptake. The HIV Only cohort did not differ significantly from matched comparators (aRR: 0.98, 95% CI: 0.95 1.01). Lower uptake was concentrated among individuals living in lower-income areas. Conclusions: People diagnosed with STBBI and methamphetamine users in Manitoba experienced significant inequities in COVID19 vaccine uptake, particularly those with STBBI coinfections and concurrent substance use. Integrated vaccination approaches linked with HIV, harm reduction, and addiction services may improve vaccine equity during future public health emergencies.

PurposeOpioid overdose deaths disproportionately affect racial and ethnic minority populations in the United States, yet claims-based evidence characterizing the multi-dimensional structure of these disparities across incidence, treatment access, costs, and insurance coverage remains limited. MethodsWe conducted a retrospective cross-sectional and longitudinal cohort analysis using the HealthVerity Launch Sample, a large administrative claims database. The study population comprised 3,675,823 patients across 5 racial groups enrolled between 2020 and 2024. Eight primary analyses were conducted, including age-sex standardized overdose rates, temporal disparity trends, medication-assisted treatment (MAT) receipt, naloxone access, pharmacy costs, insurance payer type, care setting, and multivariable logistic regression for overdose risk. ResultsBlack patients had the highest age-sex standardized overdose rate (363.4 per 100,000; rate ratio [RR] = 1.27 vs. White), and those with opioid use disorder (OUD) received MAT at a rate 35% lower than White patients (19.8% vs. 30.7%; RR = 0.645), driven primarily by a buprenorphine access deficit. AIAN patients demonstrated consistent multi-dimensional disadvantage across naloxone access, MAT engagement, and pharmacy costs. After adjustment for payer type, age, and sex, all non-White groups showed lower adjusted odds of overdose than White patients (Black OR = 0.87; AIAN OR = 0.25), with Medicaid enrollment carrying 7.06 times the overdose odds of commercial insurance. ConclusionInsurance type is the dominant predictor of overdose risk, and the disproportionate Medicaid enrollment of Black patients is both a consequence of structural disadvantage and access disparities. Targeted interventions such as buprenorphine expansion in Medicaid and enhanced naloxone distribution are recommended.

Aims and SettingIn the U.S., the emergence of new adulterants and novel psychoactive substances continues to complicate approaches to overdose, treatment, and public safety. Information about this changing drug supply is often gleaned from police drug seizures, but community drug checking services, which test the contents of a persons drug supply and share that data, provide another means to understand local drug supplies. However, it is unclear how seized drugs differ from those collected in the community, whether one approach is potentially more instructive, and what can be learned about local drug supplies from each source. We therefore compared drug samples tested from police departments (PDs) and community partner (CP) drug checking programs to examine what, if any, differences existed in sample content, form, submitter characteristics, and emerging substance presence. DesignWe conducted a retrospective cohort analysis of drug samples collected and tested between April 2018 and December 2025 by the Massachusetts Drug Supply DataStream derived from CPs and PDs operating in the same geographic area across eight locations. Bivariate analyses (Chi-square, Fishers exact) tested for differences in sample and submitter characteristics by source. FindingsThere were 2,430 unique samples submitted by CPs (68.1%) and PDs (31.9%) from the same location. Compared to CP samples, proportionally more PD samples showed fentanyl as primary substance (74.2% PD vs. 64% CP, p<.001) and less often contained additives (xylazine 15.0% PD vs. 27.4% CP; medetomidine 0.6% PD vs. 2.2% CP, both p<.001). PD samples were typically powders (73.2% vs. 37.9%) and pills (13.6% vs. 3.6%) while CP samples were more often residue (51.9% vs. 2.1%, p<.001). Submitter characteristics, when reported, differed by source: gender (n=528, male: 78.6% PD vs. 50.1% CP, p<.001), race/ethnicity (n=468, Black: 15.8% PD vs. 7.8% CP; Hispanic: 6.7% PD vs. 13.2% CP, p<.05), and associated overdose (n=242, fatal: 62.9% vs. 10.9%, p<.001). Emergent substances were detected a median of 249 days sooner in CP than co-located PD samples, though drugs exhibiting concerning patterns (e.g., unexpected fentanyl in stimulants) had similar, swift detection times. ConclusionDrug samples differ based on PD vs. CP source in significant ways that may introduce bias when drawing conclusions about drug supply trends but also offer unique insights for public health and responses to emerging drugs. Modern drug monitoring should include a broad range of sources to best prepare for changes the illicit supply may bring to overdose prevention, public safety, and health systems.

Problematic Sexual Behaviour (PSB) is defined as difficult to control recurrent sexual behaviours that continue despite adverse consequences, leading to social and functional impairment. There is debate whether PSB is a disorder of compulsion or addiction; PSB often co-occurs with neuropsychiatric disorders, but further elucidation regarding underlying biology is required. A deficiency in reward neurotransmitter systems (reward deficiency syndrome: RDS) may underlie a shared vulnerability to addiction. We conducted the first case-control genome wide association study (GWAS) of PSB in patients (n=448), and comparison participants with (n=196) and without PSB (n=1488). We used polygenic risk scores (PRS) to test genetic overlap with related psychiatric, behavioural and personality phenotypes. Three models were used: 1) All-PSB (patient + comparison) vs. controls, 2) Patient-PSB vs controls, and 3) RDS (yes/no). Results suggested genetic overlap of PSB with psychiatric conditions, with PRS for major depression, substance use, and others predicting PSB status. PRS for related behavioural phenotypes (e.g., externalizing, age at first sex, number of lifetime sexual partners) and personality traits also predicted PSB. The patient model showed stronger associations than the All-PSB model, and RDS had both shared and distinct genetics with PSB. As expected with the sample size, only suggestive hits were observed with single variant and gene-based tests. PSB may share genetic mechanisms with various conditions. Further research in larger cohorts is needed to better understand the underlying genetics and environmental factors involved, and to improve diagnostic classification, intervention and treatment prospects.

Background Early onset obesity in children, almost always accompanied by significant health complications, may be driven by rare genetic variants that influence appetite, metabolism, and nutrient absorption. Traditional treatment approaches are usually insufficient for those with monogenic obesity of this type. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, and related drugs such as melanocortin 4 receptor agonists, have emerged as promising first-line treatments for severe obesity. There is no established protocol or pathway in England for identifying children with monogenic obesity who could benefit from these and similar treatments Methods We undertook early economic modelling to examine the cost-effectiveness, from a health service perspective, of implementing a new pharmacotherapeutic care pathway for the identification and treatment of monogenic obesity in children. We modelled a hypothetical population of children with hyperphagia and body mass index (BMI) three standard deviations above mean values for age and sex. We evaluated the clinical decision to initiate the pathway using a decision tree model with patient quality-adjusted life years (QALYs) and NHS healthcare costs 12 months from an initial clinic visit as outcomes, and calculated incremental cost effectiveness ratios and a cost-effectiveness acceptability curve. Results Both costs and QALYs were higher under further investigation (GBP3,247 and 0.47 QALYs) compared to no further investigation (GBP1,589 and 0.24 QALYs). The incremental cost-effectiveness ratio in the base case was GBP7,133 per QALY. Further examination of these children was therefore likely to be cost effective in this model. Conclusion A decision-tree model suggested that further investigation of severely obese children potentially eligible for treatment with semaglutide is likely to be cost-effective for the NHS. However, this result is associated with uncertainty arising from a lack of evidence for many key model parameters.

Background: Alcohol use disorder (AUD) is associated with altered gene expression across diverse cell types in reward-related brain regions, including the ventral tegmental area (VTA), which is rich in dopaminergic neurons. The VTA plays a central role in reward processing, learning, and memory; however, cell type-specific gene expression changes within the VTA remain uncharacterized. Methods: We applied single-nucleus RNA sequencing (snRNA-seq) to profile transcriptomic alterations associated with AUD in the VTA. Postmortem VTA samples from four individuals of European ancestry [two with AUD (one male, one female) and two matched controls (one male, one female)] were analyzed using the 10X Genomics Chromium Fixed RNA Profiling protocol. Differentially expressed genes (DEGs) were identified using Seurat, and enriched KEGG pathways was assessed by gene set enrichment analysis. Results: Nuclei were classified into six major cell types: astrocytes, endothelial cells, mature neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). At thresholds of P < 0.05 and |fold change| > 2.0, we identified 547 DEGs in astrocytes, 727 DEGs in endothelial cells, 715 DEGs in mature neurons, 421 DEGs in microglia, 263 DEGs in oligodendrocytes, and 432 DEGs in OPCs. DEGs across VTA cell types were enriched for pathways related to mitochondrial function, neurodegeneration, and synaptic signaling. Notably, DEGs in mature neurons were enriched for addiction-related pathways. Further subdivision of mature neurons into dopaminergic, GABAergic, glutamatergic, and unclassified subtypes revealed 526, 930, 896, and 569 DEGs, respectively. Neuronal DEGs indicate a convergence on mitochondrial/oxidative phosphorylation and neurodegeneration-related pathways across subtypes, whereas addiction- and synapse-related pathways show dopaminergic neuron-specific enrichment. Conclusions: This study provides the first cell type-resolved transcriptomic profiling of the human VTA, revealing AUD-associated gene expression alterations across neuronal, glial, and endothelial cells. The observed cell type-specific changes in synaptic plasticity and addiction-related genes offer new insights into molecular mechanisms underlying AUD pathophysiology.

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment across addictive disorders including Cannabis Use Disorder (CUD). Stimulation of two rTMS-targets, the ventromedial prefrontal cortex (vmPFC) and the left dorsolateral prefrontal cortex (LDLPFC), limbic and executive control network hubs respectively, may yield differential effects. In this pilot trial, we explored the differential effects of 36-sessions of rTMS applied to either the vmPFC or LDLPFC. Methods: Treatment-seeking participants with moderate or severe CUD (n=20, 10F, age=33.3+9.8SD) were randomized to 36-sessions of open-label rTMS (two sessions-per-visit, two or three visits-per-week) to either the LDLPFC (3000-pulses; 10Hz) or vmPFC (900-pulses; 1Hz) using personalized functional Magnetic Resonance Imaging (fMRI) targets along with three-sessions of Motivational Enhancement Therapy. At baseline and following rTMS, the Time-Line Follow-Back was used to measure Days-per-week of cannabis use and the fMRI Regulation of Craving (ROC) task was used to measure network activation to cues associated with long-term negative ('Later') and short-term positive ('Now') consequences of cannabis use. Results: Eighty percent of participants completed study-rTMS. There was a significant decrease in days-per-week of cannabis use in both groups (vmPFC: d=7.9; DLPFC, d=3.1) between the four-weeks of baseline and seven-weeks of follow-up. LDPFC-rTMS reduced fMRI BOLD signal magnitude and increased LDLPFC functional connectivity in response to cues, while vmPFC-TMS reduced functional connectivity. Conclusions: Treatment-seeking participants with CUD reduced the number of days-per-week they used cannabis when receiving rTMS applied to either the LDPFC or vmPFC, while fMRI effects differed by treatment target. Future larger sham-controlled trials are needed for efficacy and biomarker determination.

AimsTo examine the longitudinal dynamic interactions of craving and drug use in the course of treatment of stimulant use disorders. DesignCross-lagged residual dynamic structural equation modeling (R-DSEM) was used to examine the reciprocal (bidirectional) longitudinal associations between craving and drug use. SettingPooled data from 11 randomized controlled trials of pharmacotherapies for methamphetamine and cocaine use disorders in the United States sponsored by the National Institute on Drug Abuse. Participants1,936 adults with cocaine or methamphetamine use disorder. MeasurementsCraving was measured using Brief Substance Craving Scale (BSCS), drug use was measured using Timeline Followback and urine drug screen (UDS). FindingsCraving and stimulant drug use were dynamically associated over time (within-person association). Daily craving significantly predicted drug use in subsequent days (estimate=0.092, 95% credible interval [CrI]=0.081, 0.103 for self-reported drug use and estimate=0.081, 95% CrI=0.069, 0.095 for UDS-ascertained drug use). In turn, drug use predicted subsequent craving (estimate=0.361, 95% CrI=0.325, 0.398 and estimate=0.060, 95% CrI=0.028, 0.094, respectively). There was substantial between-person heterogeneity in these cross-lagged effects, as reflected in the coefficients of variation ranging from 0.78 to 2.88. ConclusionsThere is a bidirectional interaction between stimulant drug craving and drug use. The heterogeneity in the interaction of craving with stimulant drug use may partly explain between-person variability in responses to anti-craving medications in treatment of stimulant use disorders.

Background: In-laboratory polysomnography (PSG) remains the diagnostic reference standard for sleep disorders but is resource-intensive and capacity-constrained. Limited-channel home sleep apnea testing (HSAT) improves access and reduces costs compared to in-laboratory polysomnography, but underestimates disease severity due to its inability to measure true sleep time and cannot identify non-respiratory sleep disorders including periodic limb movement disorder and parasomnias.1-5 Comprehensive home polysomnography (hPSG) may preserve diagnostic fidelity while reducing system costs, improving access for patients unable to attend laboratory-based studies, and shortening time to diagnosis and therapy initiation. Objective: To estimate the short-term budget impact to a U.S. commercial health plan of substituting an appropriately selected proportion of in-laboratory PSG with comprehensive hPSG using the Onera Sleep Test System (STS). Methods: We developed a transparent budget impact model following ISPOR good practice guidelines for a hypothetical 1-million-member commercial plan. The model estimates the annual diagnostic population (top-of-funnel) using age- and sex-stratified prevalence, an undiagnosed fraction of 85%, symptom prevalence among undiagnosed individuals (30%), and an annual testing rate (12%).2-3 Baseline costs reflect current diagnostic pathways using HSAT (50% first-line) and in-laboratory PSG (50% first-line), including HSAT-to-PSG escalations (20%) and PSG repeats (4%). The intervention scenario substitutes a defined share of in-laboratory PSG and selected HSAT with Onera hPSG. Scenario and sensitivity analyses explore parameter uncertainty. Results: In the base case, approximately 4,364 individuals entered the OSA diagnostic workflow annually. Baseline diagnostic costs were estimated at $6.23 PMPM, comprising $5.45 million in PSG costs and $0.79 million in HSAT costs. Introducing Onera hPSG (30% PSG replacement, 5% HSAT replacement in Year 1) reduced per member costs to $5.66 PMPM, yielding net savings of $0.57 PMPM ($567,262 annually). In Year 3 scenarios (60% PSG, 10% HSAT replacement), savings increased to $1.64 PMPM (approximately $1.64 million annually). Sensitivity analyses demonstrated net savings ranging from $0.03 to $8.05 PMPM, depending on adoption levels. Conclusions: Partial substitution of in-laboratory PSG with Onera hPSG may yield incremental budget savings for U.S. commercial payers while maintaining access to full polysomnographic assessment. Results support further payer-specific analyses incorporating real-world utilization and downstream outcomes. Keywords: obstructive sleep apnea; polysomnography; home sleep testing; budget impact analysis; health economics

ObjectivesTo examine the extent to which heat-related causes of death are recorded in fatal drug overdoses, how these patterns vary across states and over time, and how overdose characteristics differ between deaths with, versus without, heat involvement recorded. MethodsDeath certificate data for all drug overdose deaths in US residents from 2001 to 2024 (from the National Center for Health Statistics) were analyzed to identify whether a heat-related cause of death was also listed on the death certificate. Joinpoint regression, descriptive statistics, and nonparametric tests were used to examine temporal trends and compare overdose deaths with versus without recorded heat involvement. ResultsIn 2001, fewer than 10 drug overdose deaths with recorded heat involvement were identified, but this number increased to 558 in 2024. From 2013 to 2024, mortality rates increased significantly, with an estimated annual percent change of 30.1 (95% Confidence Interval, 26.5-47.1). The highest mortality rates and numbers of deaths were observed in residents of Arizona and Nevada. American Indian/Alaska Native, Mexican-heritage, and foreign-born populations accounted for larger shares of overdose deaths with, compared to without, heat involvement recorded. A street or highway was more frequently identified as the place of injury in overdose deaths with (18.9%), versus without (2.2%) heat involvement reported. Psychostimulants such as methamphetamine were involved in 85.9% of overdose deaths with, compared to 28.9% without, recorded heat involvement. ConclusionsAlthough representing only a fraction of all overdose deaths, fatal overdoses involving heat exposure have increased markedly over time and disproportionately impact certain states and demographic groups.

Background: Cannabis use is highly prevalent among emerging adults (18-25 years), a developmental period marked by ongoing neurodevelopment and heightened risk for cannabis use disorder (CUD). Structural alterations in the orbitofrontal cortex (OFC) and medial prefrontal/anterior cingulate cortex (mPFC/ACC) have been linked to cannabis use, though findings remain inconsistent in directionality. To address this, we examined cortical thickness and surface area of the OFC and mPFC/ACC subregions using the high-resolution Glasser atlas, allowing for more granular characterization of associations with CUD severity. Method: One hundred eleven emerging adults (41% male, aged=20.6{+/-}1.1 years) reporting significant alcohol and/or cannabis use completed clinical assessments and structural MRI. The OFC and mPFC/ACC were segmented into seven and six subregions per hemisphere, respectively. Multiple linear regressions tested associations between cortical thickness or surface area and DSM-5 CUD symptom count, controlling for alcohol use and intracranial volume. Subregions surviving false discovery rate correction were examined in relation to depression, trauma-related symptoms, impulsivity, and cannabis use motives. Results: Greater CUD severity was associated with lower cortical surface area and greater cortical thickness in OFC and mPFC/ACC subregions. Lower OFC surface area was correlated with coping- and enhancement-related cannabis use motives. Lower mPFC/ACC surface area and greater thickness were associated with more severe depression, trauma-related symptoms, and impulsivity. Conclusion: In high-risk emerging adults, greater CUD symptom burden is associated with lower surface area and greater thickness in OFC and mPFC/ACC subregions. Using the high-resolution Glasser atlas, these findings provide a more precise characterization of structural correlates of CUD and highlight potential neurobiological markers linked to affective and motivational processes underlying cannabis use.