Nicotine and Tobacco Research

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: Non-communicable diseases (NCDs) account for approximately 75% of global deaths, with 79% occurring in low- and middle-income countries. Tobacco use remains a major modifiable risk factor, contributing to more than 8 million deaths annually. In Zambia, evidence on tobacco use among individuals with hypertension, diabetes mellitus, and cardiovascular disease remains limited. This study assessed the prevalence and determinants of tobacco use among adults with NCDs in Zambia. Methods: We conducted a secondary analysis of the 2017 Zambia STEPS survey. The analytic sample included 716 adults aged 18-69 years with self-reported hypertension, diabetes, and/or cardiovascular disease. Tobacco use was defined as current smoking or smokeless tobacco use. Multivariable logistic regression was used to estimate adjusted odds ratios (AORs), accounting for the complex survey design. Results: Among 716 participants, 65.5% had hypertension, 7.7% diabetes, and 26.8% cardiovascular disease; 89.5% had multimorbidity. The overall prevalence of tobacco use was 12.2%. Prevalence was 12.2% among those with hypertension, 5.5% among those with diabetes, and 14.1% among those with cardiovascular disease. Tobacco use was significantly higher among males. Female sex was associated with lower odds of tobacco use (AOR = 0.16, 95% CI: 0.05-0.54, p = 0.004). Secondary education (AOR = 0.15, 95% CI: 0.03-0.66) and higher education (AOR = 0.04, 95% CI: 0.01-0.44) were protective. Alcohol consumption increased the odds of tobacco use (AOR = 5.23, 95% CI: 1.17-23.28). Conclusion: Tobacco use remains common among adults with NCDs in Zambia. Integration of tobacco cessation interventions into routine NCD care is urgently needed.

Primary human bronchial epithelial cells (pHBECs) of the airways of smokers are chronically exposed to cigarette smoke, which may induce chronic obstructive pulmonary disease (COPD) ranked fourth among the most common global causes of death. Using an established protocol for differentiation of pHBECs to a pseudostratified epithelium at an air liquid interface (ALI), we analyzed functional expression of transient receptor potential vanilloid 4 (TRPV4) proteins after application of cigarette smoke extract (CSE), which upregulated seven smoke exposure regulated genes (SERGs). TRPV4 protein expression in the plasma membrane and localization next to the cilia of ciliated cells was reduced, while cell barrier function was not altered after chronic exposure to CSE for 28 days compared to untreated control cells. Accordingly, TRPV4-mediated Ca2+ influx was blocked in pHBECs after CSE exposure. Moreover, Os-9 protein, which after binding mediates protection from degradation of TRPV4 protein by polyubiquitination, was significantly less expressed in pHBECs upon CSE exposure. Most interestingly, overexpression of OS-9 in pHBECs rescued reduced TRPV4 protein levels induced by CSE. Our study identifies a novel molecular mechanism of toxicity by CSE interfering with TRPV4 and OS-9 expression in pHBECs, which may blaze the trail for new therapeutic options in COPD.

Background: Despite the significant risks associated with online substance procurement (SP), few researchers have examined this practice in U.S. youth. The studies that do exist are cross-sectional and cannot temporally connect specific digital behaviors to online SP. This longitudinal cohort study examined youth SP and digital media habits to determine whether use of certain smartphone applications correlated with increased odds of online SP or being contacted online about procuring drugs or alcohol. Methods: A cohort of U.S. youth (aged 15-20) with a history of non-daily substance use in the 3 months prior to enrollment was recruited to use the digital phenotyping smartphone application EARS for 90 days. On a nightly basis, participants were asked to complete surveys about online experiences related to SP and instances of substance use. Smartphone-generated screen use data were also collected passively each day. Results: Out of 112 enrolled participants, 106 were able to be included in analyses. Over approximately 3 months, 28.3% of participants (n=30) reported a collective 91 instances where they used social media to acquire drugs or alcohol. Screen use data demonstrated temporal relationships between social media SP and applications previously connected to the social media drug-purchasing process (e.g., TikTok, encrypted apps), as well as other school-specific social media. Discussion: Our results provide critically needed research evidence to support a body of literature composed predominantly of anecdotal reports. Despite measures taken by social media companies to prevent use of their platforms for drug procurement, underage youth continue to engage in this practice.

In some countries, melatonin is sold without a physician prescription and dosage is unregulated. Transdermal products have become popular including those marketed for children. We measured consumer assumptions about these products among adult residents of the United States, analyzed lot-to-lot variability, and compared the pharmacokinetics of melatonin administered in oral, lotion, and bath product forms. Survey respondents (n=199) believed oral melatonin was more effective than transdermal products and that all melatonin products were relatively safe. Melatonin lotion products analyzed by HPLC displayed lot-to-lot variability as well as changes in formulation and product claims. To determine pharmacokinetics, three different treatments (oral tablets, lotion, and bath immersion) were administered to twelve undergraduate participants in a randomized, crossover design. Five additional participants completed bath product treatment only. Participants collected saliva samples up to 48 hours after administration, which were analyzed for melatonin by enzyme-linked immunosorbent assay. Oral (n=11) and lotion formulations (n=12) caused maximum salivary melatonin levels within 30 minutes after administration, but bath immersion did not cause increases in saliva melatonin (n=17). The half-life of oral melatonin was 1.17 [0.69 -- 1.65] hours versus 5.72 [3.75 -- 7.68] hours for lotion treatment (p = 0.011, effect size r = 0.770). Melatonin lotion may pose a risk to consumers who assume it is safe and less effective than oral tablets, when in fact it may be very potent and remain at high physiological levels into the following day. This study is registered on clinicaltrials.gov (NCT06382610) and was funded by the Sleep Research Society.

E-cigarettes have attracted significant attention as a safer substitute for conventional tobacco smoking. However, they have introduced new inhalable toxicants, including benzaldehyde-propylene glycol acetal (BPGA)--a chemical adduct produced by cherry-flavoured e-cigarettes. The health risks associated with such flavour-derived acetals remain insufficiently elucidated at the cellular level. This study investigated the role of BPGA in the progression of epithelial-to-mesenchymal transition (EMT)-like changes in alveolar epithelial cells (A549 cells). A549 cells exposed to various concentrations of BPGA were analysed for cell viability, morphology, mitochondrial function, lysosomal health, and cytoskeletal integrity using viability assays and fluorescence imaging. Intracellular reactive oxygen species (ROS) production was quantified using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Antioxidant enzyme expression, inflammatory responses, and EMT-associated phenotypic alterations were evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence (IF) assays. Exposure of alveolar epithelial cells to BPGA caused a concentration-dependent decrease in cell viability. BPGA exposure resulted in mitochondrial membrane depolarisation, lysosomal damage, cytoskeletal changes, and stress fibre formation, which altered cell morphology. It significantly increased intracellular ROS production. As a result, antioxidant enzyme levels were upregulated as a protective response. However, during severe oxidative stress, this response was overwhelmed. Excess ROS disrupted cellular homeostasis and initiated apoptosis, though not completely. ROS also acted as a signalling molecule, promoting the upregulation of inflammatory mediators. These changes were associated with altered EMT marker expression, suggesting that BPGA might drive EMT-like remodelling. In conclusion, BPGA, a chemical adduct from e-cigarette vapour, induces alveolar injury by promoting oxidative stress, inflammation, and EMT-related changes, which may explain a mechanism by which e-cigarette exposure could lead to lung injury and pulmonary fibrosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/724520v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@f7739dorg.highwire.dtl.DTLVardef@1c74f11org.highwire.dtl.DTLVardef@180aeeorg.highwire.dtl.DTLVardef@75ae14_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

BackgroundThe initiation of tobacco and nicotine product use often occurs in adolescents. This necessitates monitoring of this behaviour in this population, particularly in countries such as the Democratic Republic of the Congo (DRC) where approximately 58% of the population is under 19 years of age. Our study assessed the prevalence of, and factors associated with use in the DRC. MethodsWe conducted a nationally representative, cross-sectional, household survey between March and May 2024 among adolescents aged 10 to 17 years. We estimated the prevalence of use of smoked and smokeless tobacco products, heated tobacco products, and nicotine products (i.e., electronic cigarettes and nicotine pouches). We used logistic regression to identify factors associated with current use of any tobacco product, smoked tobacco, and smokeless tobacco using adjusted odd ratios. All analyses included 95% confidence intervals (CI). ResultsOf the 4,675 adolescents who completed the survey, the prevalence of current use of any tobacco or nicotine product was 11.87% (95% CI: 6.93-19.58). This was 7.98% (95% CI: 4.23-14.55) for smoked tobacco products, 5.86% (95% CI: 3.42-9.87) for smokeless tobacco products, 0.11% (95% CI: 0.11-0.11) for heated tobacco products and 0.60% (95% CI: 0.10-3.40) for nicotine products. Boys were more likely to use tobacco than girls. Being enrolled in school and having both parents alive were protective from tobacco use. Having a male household head, a household head education level of at least secondary school, and exposure to tobacco smoking in public places increased the odds of being a tobacco user. ConclusionsThe DRC should strengthen policies that make tobacco and nicotine products less accessible or appealing to adolescents. This includes raising excise taxes; banning the sale of single cigarette sticks, small packets and flavoured products; and comprehensive smoke-free laws. Policies should account for factors that make adolescents more vulnerable product use. Key messagesO_ST_ABSWhat is already known on the topicC_ST_ABSO_LIThe last survey on tobacco use among adolescents in the DRC was a school-based survey among 13-15-year-olds conducted in 2008, and only covered Kinshasa and Lubumbashi. C_LI What this study addsO_LIThis survey provided national-level estimates that cover adolescents aged 10-17years, includes out-of-school adolescents, and covers both tobacco and nicotine products. C_LIO_LIIt also identifies individual-, household-, and environmental-level factors that are associated with tobacco and nicotine product use among adolescents in the DRC. C_LI How this study might affect research, practice or policyO_LIBy providing current and more comprehensive data, our study enhances policymakers ability to design evidence-based tobacco control interventions that are aimed at preventing the initiation and use of tobacco and nicotine products among adolescents in the DRC and other similar settings. C_LI

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.

RationaleThe progression of psychostimulant abuse is associated with a shift from recreational to habitual use (R2H-shift). Because this R2H-shift can be modeled using behavioral economics, we developed a novel Behavioral Economic model for the Analysis of Self-administration Time-curve (BEAST) to obtain R2H-shift variable(s). The relationship(s) between R2H-shift variables and drug intake (under normal and/or punishment conditions) is/are unknown. Our goal was to determine if the R2H-shift variable and intake variables obtained during the initial self-administration training phase were related to 1) drug intake at that time, and subsequent drug intake under 2) normal, 3) punishment, 4) post-punishment, and 5) price-constrained conditions. MethodLong Evans rats self-administered methamphetamine (METH, males n = 16, females n = 14), sucrose (males n = 22, females n = 22) and/or saline (males n = 3, females n = 10) under FR1 for 6 h per day for 20 days to obtain 1) followed by the assessment of subsequent drug intake under different conditions (2-5 above). We obtained all variables referenced above. We determined the relationships between all variables (multivariate analysis). ResultsThere were no sex differences detected in the METH and sucrose studies. For METH and sucrose, prior drug intake levels could predict drug intake under normal/punishment but not under price-constrained conditions. The R2H-shift variable could predict drug intake under a consumption-price curve but could not predict intake under normal/punishment conditions. ConclusionsWhile related to economic demand, the recreational-to-habitual shift rate was unrelated to drug intake levels (under normal and punishment conditions).

BackgroundThis study aimed to investigate whether retinal fractal dimension (Df), a measure of microvascular branching complexity from fundus images, together with plasma metabolites, can help identify pathways linking microvascular changes to cardiovascular disease (CVD) events. MethodsWe analyzed longitudinal data from a subset of 4,781 participants from the Comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA), free of CVD at baseline (mean age 58.74 {+/-} 8.39; 47% male), and with 811 plasma metabolites measured at baseline and retinal imaging. Total, arterial and venular Df were derived from fundus photographs using the Vessel Assessment and Measurement Platform for Images of the Retina. Incident CVD was defined as one or more of self-reported physician-diagnosed myocardial infarction, angina, coronary heart disease, stroke, transient ischemic attack, or peripheral vascular disease during follow-up. Regression models tested associations among Df, plasma metabolites and incident CVD. ResultsOver a median follow-up of 5.75 years (IQR 5.48-6.04), 546 participants (11.42%) developed CVD. Higher total, arterial and venular Df were associated with lower CVD risk in unadjusted analyses (Odds Ratio (OR)=0.62, 95% CI:0.53-0.72 for total Df; OR=0.78, 95% CI:0.70-0.86 for arterial Df; OR=0.74, 95% CI:0.67-0.82 for venular Df). Total Df demonstrated the strongest predictive value for incident CVD but not independently of established CVD risk factors. Nine plasma metabolites, including amino acids, lipids, and xenobiotics, were associated with both incident CVD and one Df measure (p < 0.05), with cotinine and hydroxycotinine satisfying a false discovery rate adjustment (q < 0.05). Consistent with these findings the Total Nicotine Equivalent (TNE-3) was also associated with both lower arterial Df and increased CVD risk. ConclusionsRetinal microvascular complexity is associated with incident CVD. Nicotine metabolism from tobacco smoking exposures emerged as the strongest association linking microvascular changes and CVD events. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LILower retinal branching complexity, as measured through Df, is significantly associated with incident cardiovascular disease (CVD) in unadjusted analyses. C_LIO_LIIn a population-based sample, we found nine plasma metabolites associated with both retinal vascular complexity and incident CVD, but only nicotine metabolites were significant after multiple testing correction. C_LIO_LINicotine metabolites, particularly cotinine and hydroxycotinine, remained significantly associated with incident CVD even after adjustment for self-reported smoking status. C_LI What Are the Clinical Implications?O_LIRetinal Df measures could be used as a predictor of CVD event, although not independently of age and traditional cardiovascular risk factors. C_LIO_LIMicrovascular changes may lie on the pathway linking nicotine metabolites to CVD events. C_LIO_LIPlasma nicotine metabolites may provide additional cardiovascular risk information beyond self-reported smoking, reflecting individual exposure, metabolism and passive smoke exposure. C_LI

ABSTRACT Background: Self medication with analgesics and non steroidal anti inflammatory drugs (NSAIDs) is common in low- and middle income countries and may expose users to preventable adverse outcomes. Evidence from Guinea remains scarce. This study aimed to estimate the prevalence of self medication with analgesics and NSAIDs among pharmacy clients in urban Conakry, identify associated factors, and describe clinical risk situations. Methods: We conducted a pharmacy based analytical cross sectional study in 30 private pharmacies across Conakry, Guinea. A total of 1,032 participants seeking analgesics or NSAIDs were enrolled between November 3, 2012, and April 5, 2013. Self-medication was defined as acquisition or use without a valid medical prescription. Factors associated with self-medication were analysed using multivariable logistic regression. Results: Among 1,032 participants, 603 reported self medication (prevalence 58.4%). Previous unsupervised use was reported by 78.7%. The most frequently used medicines were paracetamol (56.9%, n=587), diclofenac (21.3%, n=220), ibuprofen (17.9%, n=185), and aspirin (3.9%, n=40). Overall, 68.0% (n=702) reported no knowledge of potential adverse effects. Clinical risk situations were frequent: gastrointestinal disorders (41.3%, n=426), hypertension (9.2%, n=95), and pregnancy exposure among reproductive age women (26.0%). In multivariable analysis, self medication was independently associated with previous analgesic/NSAID use (aOR = 2.8, 95% CI: 2.1 to 3.6), lack of knowledge of adverse effects (aOR = 1.9, 95% CI: 1.4 to 2.5), informal occupation (aOR = 1.6, 95% CI: 1.2 to 2.2), and age 18 to 59 years (aOR = 1.5, 95% CI: 1.1 to 2.1). Conclusions: In this pharmacy based study conducted in urban Conakry, self medication with analgesics and NSAIDs was common and frequently associated with limited awareness of potential adverse effects. These findings support the need for strengthened pharmaceutical regulation, pharmacist-led counselling, health literacy interventions, and improved access to primary care. Keywords: self medication; analgesics; NSAIDs; paracetamol; diclofenac; ibuprofen; pharmacy; Guinea; Conakry; drug safety; public health.

BackgroundWildland firefighters experience repeated occupational exposure to wildfire smoke at high particulate matter (PM) concentrations, leading to elevated cardiovascular disease risk and hypertension prevalence. However, the pathophysiological processes linking cumulative smoke inhalation to vascular damage and blood pressure elevation remain poorly characterized. To evaluate these effects under controlled exposure conditions, we used a preclinical exposure model calibrated to match the cumulative PM burden deposited in wildland firefighter airways over 7-14 years of service. Male apolipoprotein E knockout (Apoe-/-) mice underwent whole-body inhalation of Douglas fir smoke or filtered air for 2 hours/day, 5 days/week, for 8 or 16 weeks at target PM concentrations of 40 mg/m3. ResultsProlonged smoke exposure induced sustained elevation of circulating tumor necrosis factor-alpha (TNF-), interleukin-1 beta (IL-1{beta}), and interleukin-6 (IL-6), coupled with diffused nuclear factor kappa B (NF-{kappa}B) activation throughout the aortic wall. Smoke inhalation disrupted endothelial adherens junctions, upregulated intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and promoted monocyte recruitment to aortic tissues, concurrent with enhanced monocyte chemoattractant protein-1 (MCP-1) expression. Oxidative stress was evidenced by increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 2 (NOX2) expression, elevated superoxide levels, and endothelial nitric oxide synthase (eNOS) uncoupling in the aorta, leading to lipid peroxidation and accompanied by intimal apoptosis. These inflammatory and oxidative perturbations occurred alongside a pro-fibrotic phenotypic shift characterized by transforming growth factor beta 1 (TGF-{beta}1) upregulation, myofibroblast differentiation, and progressive collagen accumulation in medial and adventitial compartments of the aortic wall. Functionally, smoke exposure progressively impaired aortic cyclic distensibility through combined wall thickening and circumferential tissue stiffening, while severely attenuating endothelium-dependent and nitric oxide (NO)-mediated vasodilation. These functional and structural shifts culminated in elevated systolic and diastolic blood pressures. While endothelial dysfunction reached maximal impairment by 8 weeks, aortic stiffening continued to worsen through 16 weeks of exposure, demonstrating differential temporal progression of vascular damage. ConclusionsThese findings demonstrate that occupationally relevant wildfire smoke exposure produces convergent inflammatory, oxidative, and profibrotic vascular remodeling with progressive loss of arterial compliance and impaired endothelium-dependent vasodilation, underscoring potential vascular targets for cardiovascular health surveillance and risk mitigation in wildland firefighters.

Excessive alcohol consumption remains a major public health challenge with limited therapeutic options. Both glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) independently regulate alcohol intake through complementary metabolic and reward pathways, but their combined potential has not been explored. Here, we report that a long-acting dual agonist, GLP1-ELP-FGF21 modulates behavioural, neurophysiological, and cognitive components of alcohol seeking in mice. A single GLP1-ELP-FGF21 dose reversibly reduces voluntary alcohol intake for at least 72 hours in male mice, has sustained effects in female mice, and markedly blunts nucleus accumbens dopamine transients aligned to the initiation and termination of lick bouts during alcohol consumption. To assess its effects on decision-making, we used a novel two-choice (alcohol versus food) decision task modelled with evidence-accumulation frameworks. Alcohol choice behaviour conformed to evidence accumulation decision models: Linear Ballistic Accumulator (LBM) and Racing diffusion models (RDM). Critically, GLP1-ELP-FGF21 selectively reduces choices for alcohol and slows the latent accumulation rate for alcohol options, without affecting food-directed choice or non-decision processes. Sensory-specific satiety devaluation confirms that reductions in reward value are explained by reductions in accumulation rates. Together, these results highlight GLP1-ELP-FGF21 as a therapeutic strategy for alcohol use disorder via modulation of central reward pathways and decision-making when confronted with alcohol rewards.

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.

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.

RationalePrenatal alcohol exposure (PAE) can result in Fetal Alcohol Spectrum Disorder (FASD), which consists of a group of diagnosable medical conditions that can include an increased risk for anxiety disorders and/or alcohol misuse, and sensory issues, such as increased mechanical sensitivity. ObjectiveThis study investigated how a single moderate PAE on gestational day 12 (G12) alters anxiety-like behavior, ethanol (EtOH) intake, and mechanical sensitivity across the lifespan of Sprague Dawley rats. MethodsPregnant dams were exposed to vaporized EtOH or room air (control) for 6 hours (BECs [~]108 mg/dL). Testing in male and female offspring began at three different ages: juveniles ([~]postnatal day (P) 25), adolescents ([~]P45) and adults ([~]P80). ResultsThe greatest PAE effects were observed in adolescent animals, with alterations in anxiety-like behaviors demonstrated in the light-dark box and elevated plus maze. Additionally, adolescent female animals consumed more sweetened EtOH compared to males. However, PAE adolescent animals consuming less sweetened EtOH compared to their counterparts, which was also observed in adult PAE females. Interestingly, this effect is reversed in juvenile and adolescent males when tested with unsweetened EtOH, with juvenile females consuming more EtOH also. Finally, PAE and air animals exhibited increased mechanical sensitivity following post-natal EtOH consumption across all ages. ConclusionThese data demonstrate that there are age- and sex-specific effects of PAE on anxiety-like behaviors, EtOH intake, and mechanical sensitivity that are more distinct in adolescent animals.

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.

BackgroundAlcohol use disorder is a chronic relapsing condition characterized by excessive drinking and withdrawal symptoms. Alcohol dependence disrupts function across multiple brain regions, and recent evidence implicates the cortical amygdala (CoA) as a critical node in alcohol-related circuits. However, how CoA activity influences alcohol intake and brain-wide network function during withdrawal remains unclear. MethodsAlcohol dependence was induced using chronic intermittent ethanol vapor (CIE). In one cohort, electrophysiological activity of CoA neurons was assessed during withdrawal. In a second cohort, mice underwent CIE paired with two-bottle choice drinking, and inhibitory DREADDs (hM4Di) were used to suppress CoA activity during drinking and withdrawal while behavioral outcomes were measured. Brains were then collected for Fos immunolabeling and iDISCO+ based whole-brain activity mapping to determine how CoA inhibition during withdrawal altered network organization. ResultsRepeated CIE increased alcohol sensitivity in CoA neurons during withdrawal. Chemogenetic inhibition of the CoA reduced alcohol intake in dependent mice without affecting withdrawal-related behaviors. Whole-brain Fos mapping showed that CoA inhibition reduced activity within the CoA while enhancing functional connectivity across multiple brain regions, particularly in the isocortex, thalamus, and anterior hypothalamic nucleus. During withdrawal without CoA inhibition, thalamic regions exhibited negative connectivity, consistent with disrupted network function; CoA inhibition reversed this pattern, producing strongly positive thalamic and medial prefrontal cortex connectivity. ConclusionsThese findings demonstrate that alcohol dependence alters CoA sensitivity, alcohol dependence-induced drinking and brain-wide network organization during withdrawal. The CoA appears to selectively regulate withdrawal-associated alcohol drinking, and its inhibition may reduce intake by restoring thalamic and cortical connectivity. HighlightsO_LIThis study identifies the cortical amygdala as a previously underexplored brain region involved in alcohol-related behaviors. C_LIO_LIBy integrating chemogenetic inhibition with brain-wide network analysis, the study reveals candidate circuit connections through which the CoA may regulate alcohol dependence-related brain activity. C_LIO_LIThis study establishes the CoA as a potential driver of excessive alcohol drinking and alcohol-related network dysfunction. C_LI