Nicotine and Tobacco Research

Introduction: Nicotine Pouches are increasingly used as a smokeless alternative to cigarettes and other nicotine products, yet their acute cardiovascular effects remain poorly documented. While nicotine's impact on heart rate and electrocardiogram (ECG) parameters is well-documented in smoking, no trials have evaluated these effects specifically for nicotine pouches. Methods: This study is a single-center, double-blind, placebo-controlled, crossover trial which will include 20 healthy adult nicotine users. Participants will undergo three sessions, receiving either a placebo, 6 mg, or 14 mg nicotine pouch in random order. Heart rate obtained by an ECG and various other ECG parameters, vital signs, and subjective symptoms will be measured at baseline, and multiple time points over 30 minutes. Conclusions: This study aims to determine whether nicotine pouches cause acute changes in heart rate, ECG parameters, vital signs, and self-reported symptoms. We hypothesize that higher nicotine pouch does will lead to measurable increases in heart rate and other autonomic effects compared to placebo.

Background: In the United States, several states have restricted sales of flavoured tobacco products, including popular menthol- and mint-flavoured Oral Nicotine Pouches (ONP). In response, tobacco companies introduced "unflavoured" ONP containing odorless synthetic cooling agents. Since these, in turn, have become targets of legislative bans, the tobacco industry may seek out flavourants with other sensory effects to increase the appeal of "unflavoured" ONP. Methods: Online merchants were searched for "unflavored" ONP marketed to consumers in jurisdictions with flavour bans. Sensory effects of aqueous extracts from identified "heat", "spicy" and "unflavoured" ONP were analyzed by Ca2+ microfluorimetry in HEK293 cells expressing the human heat/chili pepper flavourant (capsaicinoid) receptor, hTRPV1. ONP were analyzed for capsaicinoids and sweeteners by Liquid Chromatography/Mass Spectrometry (LC/MS). Results: A new category of "heat" or "spicy" ONP was identified, including products marketed as "unflavoured". Extracts from all these ONP robustly activated TRPV1, with "unflavoured" Lucy Heat the most potent. Chemical analysis demonstrated that Lucy Heat contained the synthetic capsaicinoid nonivamide at high levels (~675 microgram/pouch), while others contained mixtures of capsaicinoids (5-25 microgram/pouch) combined with other characterizing flavours (tropical, fruit). All tested ONP contained sweeteners. Conclusions: The tobacco industry continues to probe regulatory loopholes by claiming that newly introduced capsaicinoid flavourants and sweeteners in ONP do not represent characterizing flavours. This is contradicted by industry and regulatory determinations assigning characterizing flavour properties to these additives. The toxicological health risks of repeated capsaicinoid exposures due to ONP use, in combination with nicotine and other constituents, need to be assessed.

BackgroundObservational comparisons of former smokers who use non-combusted nicotine products with former smokers who quit without them require that two quantities be measured precisely: which product is being used, and how long ago cigarette smoking stopped. Neither quantity is recorded by the National Health Insurance Service (NHIS) screening instrument used in a recent Korean cohort study of post-cessation e-cigarette use and lung cancer risk. We characterized both quantities in a contemporaneous, nationally representative survey of the same population. MethodsWe analyzed the public-release microdata of the Korea National Health and Nutrition Examination Survey (KNHANES), 2018 to 2023, restricted to adults aged 19 years and older. Former smokers were identified by smoking status, and cessation duration was taken from the item recording months since the last cigarette. Former smokers currently using a heated tobacco product (HTP) or an e-cigarette (EC) were compared with former smokers using neither. KNHANES 2018 asked a generic e-cigarette question and, separately, a checklist naming HTP brands, allowing the two product classes to be separated. Distributions were compared with rank-based methods, the age-duration relationship with Theil-Sen regression, and residual imbalance by restricting the comparison group to respondents age-matched to within two years. ResultsThe 2018 analytic sample comprised 1,348 former smokers, of whom 43 currently used HTP or EC and 1,305 used neither. Among the product-using former smokers, 58% reported HTP use without e-cigarette use, 21% reported both, and 21% reported e-cigarette use without HTP use; 79% reported any HTP use. Median cessation duration was 0.7 years (IQR 0.25 to 1.5) among product users and 12.0 years (IQR 5.0 to 20.0) among those using neither (Kolmogorov- Smirnov D = 0.76, P < 0.001), with the product user having quit more recently in 92% of cross-group pairs. The separation persisted within the short-term (<5 year) stratum (D = 0.34, P < 0.001; 73% of pairs) and after age matching, where the residual gap was 9.3 years. Cessation duration rose with age among those using no product (Theil-Sen slope +0.30 years per year) but was flat among product users (-0.01). Restricting to the screening-eligible stratum used in the cohorts high-risk analysis did not attenuate the imbalance: among those aged 50 to 80, median cessation among no-product quitters rose to 15.5 years (n = 858), and adding a 20 pack-year criterion left 421 no-product quitters with a median of 11.0 years against three HTP/EC users who had quit 0.25, 1.0 and 2.0 years earlier, despite closely matched cumulative exposure (mean 37.6 vs 37.7 pack-years). The overall contrast reproduced in every wave from 2018 to 2023, with an age-matched residual of 9 to 11 years. ConclusionsIn a nationally representative survey of the same population and the same calendar year as the NHIS screening cohort analyzed by Kim et al., Korean former smokers using non-combusted nicotine products differed from other former smokers in two respects that bear directly on how such comparisons should be read. First, they were predominantly HTP users: 79% reported any HTP use, and only 21% reported e-cigarette use without HTP use. Second, they had stopped smoking approximately a decade more recently, a difference that survived stratification at five years and exact age matching. Neither quantity is recorded in the NHIS screening instrument. Cohort estimates comparing post-cessation product users with other quitters should therefore be interpreted with caution if they do not precisely characterize product composition and to time since cessation, and future studies should measure both directly.

Introduction Smoking prevalence remains higher in rural than in urban populations in the United States. To examine recent trends, we assessed state-level differences in cigarette smoking between urban and rural areas from 2018 to 2024. Methods Using repeated cross-sectional data from the Behavioral Risk Factor Surveillance System, we estimated state-specific logistic regression models to examine the relationship between urban-rural county residence and cigarette smoking. Unadjusted models (model 1) included urban-rural county status and year. Subsequent models (model 2) added age, sex, and race/ethnicity. A final model (model 3) included education and an interaction term between urban-rural county status and year to examine whether gaps in urban-rural smoking changed over time. In states with significant interactions, simple effects tests compared trends for urban-rural groups separately. Results Compared to urban adults, rural adults had higher unadjusted odds of cigarette smoking (odds ratio [OR] range:1.07-1.88) in 88.4% (38/43) of states. Adjusting for demographic covariates (model 2) increased the proportion of states with significant marginal effects of rurality to 90.7% (ORs:1.09-1.87). A final model that also controlled for education (model 3) decreased the proportion of states with significant marginal effects of rurality to 60.5% (ORs:1.10-1.54). Among the 14 states with significant interaction terms, the odds of smoking declined faster among urban than rural residents. Conclusion Urban-rural differences in smoking persist across most states. No state showed a reduction in urban-rural disparities over time, and the urban-rural gap widened in 14 states. Demographic variation accounted for some, but not the majority, of observed urban-rural differences.

Aims To estimate the prevalence of past-year smoking quit attempts in Great Britain and examine variation by sociodemographic and socioeconomic characteristics, mental health, alcohol use, smoking-related characteristics, and geographic area. Design Cross-sectional analysis of data from a nationally representative household survey (the Smoking Toolkit Study) conducted October 2020 to May 2026. Setting Great Britain. Participants 24,786 adults ([&ge;]18y) who reported past-year tobacco smoking. Measurements The outcome was self-reporting having made at least one serious attempt to stop smoking in the previous 12 months. Associations with age, gender, ethnicity, social grade, health-related economic inactivity, mental health conditions, psychological distress, alcohol consumption, use of non-combustible nicotine, cigarette type and consumption, strength of urges to smoke, and motivation to stop smoking were assessed. We calculated weighted prevalence estimates and odds ratios (ORs) adjusted for survey year. Findings Overall, 36.7% [95%CI=36.0-37.4] of adults who had smoked in the past year self-reported making at least one quit attempt. Annual prevalence was relatively stable over the study period (range: 35.5% [33.9-37.1] to 37.6% [35.9-39.3]). Making a past-year quit attempt was more common among younger adults (48.0% among 18-24-year-olds) and declined progressively with age (24.6% among [&ge;]65-year-olds; OR=0.35, 95%CI=0.31-0.39). Compared with White adults, making a past-year quit attempt was more common among Black (OR=1.31, 1.11-1.55) and Asian (OR=1.40, 1.21-1.62) adults. Adults with a history of diagnosed mental health conditions (OR=1.27, 1.17-1.38) and moderate (OR=1.31, 1.20-1.43) or severe psychological distress in the past month (OR=1.39, 1.25-1.56) had greater odds of reporting a past-year quit attempt than those without. Those reporting increasing/higher risk alcohol consumption had lower odds than non-drinkers (OR=0.88, 0.82-0.95). Current use of nicotine replacement therapy (OR=2.59, 2.36-2.83) and vapes (OR=2.15, 2.02-2.30) were positively associated with reporting a past-year quit attempt. Odds were lower among those with greater cigarette consumption (OR range 0.79-0.86 among those smoking >10 vs. [&le;]5 cigarettes per day). Motivation to stop smoking showed the strongest gradient (OR range 2.95-29.09). Geographic differences were modest, with prevalence ranging from 32.1% [29.9-34.3] in Wales to 39.4% [35.9-43.1] in North East England. Conclusions Between 2020 and 2026, around one in three adults in Great Britain who smoked in the past year reported making a serious attempt to quit, corresponding to approximately 3.5 million people annually. Making a past-year quit attempt was more strongly associated with smoking-related factors than sociodemographic characteristics.

Background: The nicotine analog 6-methyl nicotine (6-MN) has appeared in commercial e-cigarette liquids, and other products, spurring interest in determining the extent to which it conveys similar effects to those of nicotine. Objective: To determine if 6-MN acts like nicotine to decrease body temperature, decrease nociception, suppress wheel activity and reinforce operant behavior when delivered by vapor inhalation using an Electronic Nicotine Delivery System (ENDS; "e-cigarette") approach in a rat model. Methods: Male and female (N=8 per sex) young adult Sprague-Dawley rats were evaluated for rectal temperature and nociceptive responses (warm water tail-withdrawal) to the inhalation of vapor from (-)-6-MN or (-)-nicotine in concentrations ranging from 5-30 mg/mL in the propylene glycol vehicle. Rats were then assessed for the reinforcing effects of nicotine and 6-MN using a vapor self-administration procedure and the rate suppressing effects of nicotine and 6-MN on wheel activity following injection. Results: Inhalation of nicotine or 6-MN for 30 minutes decreased the rectal temperature and increased tail-withdrawal latency of female and male rats in a concentration-dependent manner. The magnitude of the effects of 6-MN and nicotine were similar at similar vapor concentrations. Operant responding for 6-MN vapor was increased by pre-treatment with the antagonist mecamylamine. 6-MN was more potent than nicotine at suppressing wheel activity after injection. Conclusions: 6-MN induces effects very similar to those of nicotine, at a similar potency when inhaled and at a slightly increased potency when injected.

Tobacco use is the leading preventable cause of death worldwide. Anxiety increases the risk for smoking, and smoking in turn increases the risk for anxiety disorders. There is therefore a need to identify interventions that reduce anxiety, in general and in the context of smoking, without producing sedation. Kava (Piper methysticum), a natural product with a long history of indigenous use, has been shown to have anxiolytic and calming effects and reduce nicotine withdrawal. The current study examined whether kava without the hepatotoxic flavokavains A and B (AB-free) could reduce anxiety-like behavior in mice repeatedly treated with nicotine. Male and female C57BL/6NCrl mice received either a control diet or an AB-free kava-supplemented diet and underwent two blocks of nicotine treatments. Mice underwent a first block of five every-other-day injections of nicotine (0.5 mg/kg) or saline, with open field testing after each injection, followed one week later by a nicotine challenge. A second block of injections was given using the same injection schedule, followed by a second challenge one week later, and two weeks afterward mice received a final challenge in a novel open field. During the first treatment block, AB-free kava significantly increased center time overall, an effect most pronounced in saline-treated animals, and increased locomotor activity, while nicotine decreased both measures. During the second challenge, nicotine reduced center time but not locomotor activity, and AB-free kava increased center time in saline-treated animals only. During the final challenge, nicotine reduced both measures, whereas AB-free kava increased center time regardless of nicotine treatment, and kava-treated animals also showed a near-significant increase in center entries. These results suggest that AB-free kava reduces anxiety-like behavior without inducing sedation but does not prevent nicotine-induced suppression of exploratory behavior.

Introduction: Childrens exposure to second hand tobacco smoke is a preventable global public health issue, yet there is no consensus on how best to support families to create a smoke free home. This pilot randomised controlled trial tested the feasibility of use of free nicotine replacement therapy combined with telephone delivered support to reduce childrens exposure to second hand smoke in the home, and inform a future full scale trial. Methods: Parents and carers aged 18 and over, who smoke in the home and care for one or more children aged 0 to 16 years were recruited through existing initiatives and social media. Participants were randomised to either the intervention or control arm. Group A received free posted to home nicotine replacement therapy, alongside fortnightly telephone calls to support smoking abstinence in the home. Group B were signposted to the Scottish Government Take it Right Outside website which provides interactive advice on creating a smoke free home. To measure second-hand smoke levels, participants installed an air quality monitor in their living room for 7 days to measure fine particulate matter at baseline and 12 week follow-up. Results: Approximately one-quarter (27 of 100) of the intended sample size was recruited. Median fine particulate matter concentrations reduced in both the intervention (by 36mg per cubic metre) and control (by 16mg per cubic metre) groups. Retention rates and adherence rates to nicotine replacement therapy were 70 percent and above, with no risks and or safety concerns reported, suggesting this approach is feasible and acceptable to participants. The estimated cost of delivering this 12 week intervention was two hundred and forty four pounds per individual. Conclusions: Although recruitment rates were insufficient to recommend progression to a larger trial to test effectiveness of this approach in Scotland, this study could inform trial development in other countries where smoking in the home is commonplace. Insights regarding the alignment of smoke free home interventions with broader smoking cessation initiatives could inform future policy and public health approaches.

Background and Aims: Anxiety remains prevalent among adolescents while tobacco and nicotine product use, especially the recent increases of novel product use such as e-cigarettes and nicotine pouches, raises further public health concerns. The associations between novel tobacco and nicotine product use and anxiety remains understudied. This study aims to determine whether tobacco and nicotine product use is associated with generalised anxiety and whether this association differs by used product. Design: Cross-sectional survey, School Health Promotion study in 2025. Setting: A school-based nationwide survey conducted in all Finnish lower and upper secondary schools. Participants: Students aged 13-20 years in three school levels: 8.-9. grade students in lower secondary schools (N= 94 743, 73% of the students), 1st and 2nd-year students in general upper secondary schools (n=47 248, 70% of the students) and of vocational institutions (n=24 998, 38% of the students). Measurements: Exclusive (single product) and non-exclusive ([&ge;]1 products) daily or weekly use of tobacco and nicotine products, including nicotine pouches, e-cigarettes, cigarettes, and smokeless tobacco (snus). Generalised anxiety was measured using the Generalised Anxiety Disorder Scale (GAD-7). The cut-off of >10 points indicated participants with moderate to severe self-reported generalised anxiety symptoms. Background variables included sociodemographic variables and heavy drinking. Results: Of the 166,989 participants 51.4% were females, mean age was 15.7 (SD 1.27), 21.2% reported generalised anxiety. Prevalence of generalised anxiety increased gradient-wise in accordance with both non-exclusive and exclusive use frequency of different tobacco and nicotine products, as well as with number of products used. Daily use of nicotine pouches was associated with higher odds of anxiety compared with never use (boys: adjusted odds ratios (aOR) 1.19, 95% CI, 1.05 to 1.34; girls: aOR 1.74, 95% CI, 1.58 to 1.91), yet the association between daily e-cigarette use seemed to be stronger (boys aOR 1.96, 95% CI, 1.54 to 2.49; girls: aOR 2.29, 95% CI, 2.09 to 2.51). Summary: Any use of tobacco and nicotine products, including new products, is associated with generalised anxiety among adolescents, with some differences between products. Measures to prevent the initiation of tobacco and nicotine product use and to promote mental health among adolescents should be enacted.

Introduction: Self-rated health is an important patient-centred measure of health. The relationship between cannabis use and self-rated health has been previously studied, although with methodologic concerns which we aimed to address in this investigation. Methods: Propensity score weighted analyses of the National Health and Nutrition Examination Survey (NHANES) 2009-2018 were conducted. The primary exposure was self-reported cannabis use in the 30 days prior to survey response. The primary outcome was self-rated health measured on a five-level ordinal scale. Secondary outcomes included the number of days in the past months with: i) poor physical health, ii) poor mental health, and iii) activity limitations related to poor health. A weighted proportional odds regression model was used for the primary analysis and weighted zero-inflated negative binomial regression models were used for each secondary analysis. Results: Among 22,055 adults aged 20-59 responding to the NHANES cannabis questionnaire, 14.4% endorsed use in the past 30 days. After reweighting the sample to balance cannabis users and non-users across sociodemographic, medical, and lifestyle characteristics, there was no statistically significant association between recent cannabis use and higher levels of self-rated health (OR 0.90, 95% CI 0.80-1.01). Cannabis use was associated with poor mental health and activity limitations in the past month, but not poor physical health. Conclusions: Recent cannabis use was not associated with self-rated health but was associated with poor mental health and activity limitations in the past month. Cannabis users at risk of poor mental health should be connected with clinicians to help guide therapy.

Background: As cannabis policy changes in the United States, secondhand cannabis smoke (SCS) is increasingly common, including within families. However, prevalence of exposure and clinical correlates over time in adolescents are not fully understood. Objectives: (1) To estimate the prevalence of SCS and personal cannabis use in US-based teens exposed to SCS, and (2) examine the cognitive trajectories of adolescents exposed to SCS compared to non-exposed peers. Methods: Data from the Adolescent Brain Cognitive Development (ABCD) Study was used. Participants (n=11,316 of full cohort with follow-up data; n=776 with self-reported family SCS exposure) attended yearly visits from ages 11-17, completing substance use interviews, toxicological testing, and the NIH Toolbox Cognitive battery. Youth with SCS but no personal cannabis use (n=419; 47% female) were matched on prenatal substance exposure, family substance use history, and sociodemographics to non-SCS exposed and non-cannabis-using youth with a 1:2 ratio (Controls n=838). Linear mixed-effects models assessed cognitive performance by SCS*age interactions, accounting for random effects of subject and family. Covariates included sex and alcohol, nicotine, and other substance use. Secondary models analyzed performance by cumulative waves of reported SCS exposure interacting with age. Results: Of the full cohort, 6.9% (n=776) reported exposure to SCS. Of these individuals, 46% endorsed lifetime personal cannabis use by age 17, relative to 20% of non-SCS exposed youth (OR=3.83[95%CI:3.29,4.44]). Within matched participants, SCS*age demonstrated a significant interaction on attention and inhibitory control ({beta}=-0.32, p=.028), with SCS demonstrating reduced improvement over time. More waves of exposure were also associated with worse performance over time ({beta}=-0.39, p=.057). Discussion: Almost half of those who had been exposed to SCS endorsed personal cannabis use. Cognitive findings were domain specific, similar to findings in secondhand tobacco: SCS exposed youth showed restricted improvement in attention and inhibitory control by age 17. Public health and policymakers should make efforts to curb youth SCS exposure, given the potential for risk which has not been fully explored to date.

Background: Loneliness and social isolation may contribute to tobacco and nicotine use, but existing studies have been inconsistent. This systematic review and meta-analysis examined these associations among adults amid the evolving nicotine product landscape. Methods: A systematic search of PubMed, MEDLINE, PsycINFO, and CINAHL identified peer-reviewed quantitative studies published between 2014 and 2025 searched in February-April 2026. Eligible studies included adults aged [&ge;]18 years examining loneliness and/or social isolation in relation to smoking or nicotine use. Two reviewers independently screened studies, extracted data, and assessed risk of bias (using the National Heart, Lung, and Blood Institute risk of bias tool). Random effects meta-analyses were conducted to estimate pooled odds ratio (OR) with 95% confidence intervals (CIs). Results: 22 studies involving 273,954 participants met inclusion criteria, and 14 studies were included in the meta-analysis. A majority of the studies had low risk of bias. Meta-analysis findings showed that social isolation or loneliness was associated with significantly higher odds of nicotine product use (OR 1.84, 95% CI 1.48-2.29). Although no statistically significant association of nicotine product use and social isolation or loneliness (OR 1.35, 95% CI 0.72-2.53), some studies suggested bidirectional relationships, with smoking contributing to reduced social support and greater isolation over time. Sensitivity analysis showed the robustness of the meta-analysis findings. Subgroup analysis found no statistically significant differences were seen between subgroups defined by type of nicotine product, age groups, social isolation vs loneliness, measures of nicotine use behaviours and pre- vs post- COVID-19 pandemic period in the meta-regression. Limitations of included studies and analysis are discussed. Conclusions: Loneliness and social isolation are significant psychosocial correlates of nicotine product use. Cessation interventions may benefit from integrating social support and mental health strategies alongside traditional nicotine dependence treatment.

Volatile organic compounds (VOCs) define the distinctive aroma of cannabis and critically influence consumer preference, cultivar authentication, and breeding programs. However, systematic characterization of VOC diversity across commercial drug-type cultivars remains limited. This study presents a comprehensive volatilomics-based phenotypic characterization of 165 commercial drug-type cannabis accessions using gas chromatography with flame ionization detection and mass spectrometry (GC-FID/MS). We identified 61 high-confidence VOCs assigned to three biosynthetic classes: terpenoids (n = 45), fatty acid-derived volatiles (n = 12) and amino acid-derived volatiles (n = 4), resolved into 12 subclasses. Analysis of variance revealed highly significant among-accession differences for all compounds (p < 0.001; 2 = 0.67-0.97), with repeatability estimates averaging 0.81 (range 0.50-0.95). Unsupervised clustering partitioned accessions into three distinct chemotypes (n = 90, 53, and 22), supported by principal component and t-SNE analyses. Machine learning-based feature selection identified a consensus panel of 12 discriminative compounds (camphene, -fenchene, sabinene, -terpinene, ({+/-})-limonene, -humulene, linalool, endo-fenchol, {Delta}3-carene, -thujene, {gamma}-terpinene and -phellandrene) that recovered the chemotype assignment of 32 of 33 held-out accessions. Estimated odor-activity screening ranked prenylthiol, -pinene, ({+/-})-limonene, linalool and myrcene highest among the odor-active compounds. All three chemotypes shared a prenylthiol-dominated core (67-77% of summed OAV) and were distinguished by the extent and nature of terpenoid modulation of that core: minimally modulated (Cluster ZERO), citrus-floral modulated (Cluster ONE) and pine-terpenic modulated (Cluster TWO). These findings indicate that volatile diversity in this panel can be summarized by three reproducible chemotypes, providing a quantitative basis for accession characterization and a foundation for future breeding and quality-assessment studies.

Background: Adverse drug withdrawal events (ADWEs) are a key safety concern during deprescribing but remain poorly explored in pharmacovigilance systems. Objectives: To identify and compare ADWE signals across drug classes, different drugs within drug classes, and across patient characteristics, countries, and over time. Methods: A case/non-case disproportionality analysis was conducted in FDA-FAERS and EMA-EudraVigilance pharmacovigilance databases, with stratification by age (adults: 18-64, older adults: [&ge;]65), sex (male/female), reporting time (2004-2023 in 5-year intervals), and country (for EMA data). Disproportionality analysis (quantitative signal detection) was used to detect signals between ADWEs and drugs using the proportional reporting rate (PRR[&ge;]2), reporting odds ratio (ROR>1), and information component (IC>0) with case count [&ge;]5. Results: Overall, 158,501 reports (FDA-FAERS 145,514; EMA-EudraVigilance 12,987) included drug-event pairs related to ADWEs. In FDA-FAERS, clobetasone (IC=5.58; PRR=79.18; ROR=176.90) showed the strongest ADWE signals, followed by hydromorphone (4.85; 29.94; 37.37), hydrocodone, and paroxetine. In EMA-EudraVigilance, ethyl loflazepate (IC=6.01; PRR=119.80; ROR=197.53), clobetasone (5.39; 102.73; 155.10), veralipride, and levomethadone had the strongest signals. Most drugs maintained positive ADWE signals in analysis stratified into adults and older adults. However, among the top 10 drugs (based on highest IC values), buprenorphine/naloxone, desvenlafaxine, and baclofen in FDA-FAERS (ICs 4.95-6.05) showed stronger signals in older adults. A sex-based difference was observed, with paroxetine, venlafaxine, and buprenorphine/naloxone showing a stronger positive signal in females in both databases, whereas several opioids had stronger signals in males versus females across both databases. Conclusion: This study suggests ADWE signals for some medications differ by age and sex, potentially indicating different risks for withdrawal effects.

Background YouTube highlights packages are a major and growing route to football consumption, particularly among children and young people, but brand exposure within them has not been quantified. We measured unhealthy commodity brand exposure in English Premier League (EPL) and FIFA World Cup (WC) highlights. Methods We coded brand appearances lasting two or more seconds in 10 Sky Sports EPL highlights (final 10 games of the 2025/26 season) and 19 official FIFA 2026 WC highlights, recording commodity category, placement, and match moment, alongside pre-roll YouTube adverts. Data were collected between 4 June and 27 July 2026. Five highlights were double-coded (Cohen's kappa 0.85). Results Overall brand density was similar across competitions (13.1 vs 13.9 references per minute), but composition differed markedly. Unhealthy commodity branding occupied 38.0% of EPL screen time versus 18.7% at the WC, a difference driven almost entirely by gambling (32.6% vs 1.5%). Gambling appeared in every EPL package, mainly on pitchside boards and LED screens (50.4%), with front-of-shirt accounting for 27.1%. WC exposure was more evenly spread across HFSS food (13%), alcohol (4%) and trading/crypto/prediction markets (3.7%), and appeared almost exclusively pitchside. Gambling brands accounted for ten of twelve pre-roll EPL adverts (123 of 153 seconds); no gambling adverts preceded WC highlights. Conclusions Gambling dominates unhealthy commodity exposure in EPL highlights, both in-video and in pre-roll advertising. Because most appearances occur away from the front of shirt, the voluntary front-of-shirt sponsorship withdrawal will leave the majority of this exposure intact. The WC comparison shows that tighter central control of the advertising environment produces lower and more diffuse exposure, and that governments and governing bodies with such control could restrict unhealthy categories altogether.

Understanding the neurobiological systems that regulate alcohol cue-induced craving is of utmost importance for the development of novel intervention strategies for alcohol use disorders (AUDs). However, although a human experimenter is required to conduct alcohol self-administration studies in the lab, the cues associated with the experimenter are seldom if ever factored into the experimental design. Thus, although we have learned much to date about alcohol cue-induced behavior and neurobiology, and in particular about discrete cues presented many times throughout a single daily alcohol self-administration session, we know relatively little about how responses to alcohol availability cues might predict subsequent alcohol consumption. For the current experiment, mice were exposed daily to auditory cues that preceded 2 hours of alcohol or water access using drinking-in-the-dark (DID) methods. An additional control group experienced cues but were not otherwise manipulated. Importantly, cues were initiated remotely from outside the animal facility, avoiding the experimenter being the first cue predicting ethanol availability. Head direction, location in the home cage, and movement velocity were the primary variables on interest. Surprisingly, during the cue period, there were no significant differences between groups in any of these measures, despite meaningful alterations over days. However, we observed many significant correlations between behaviors and drinking variables. First, we observed significant positive associations between ambulatory velocity during cues and subsequent total alcohol (R2=0.14; p<0.0001) and total water (R2=0.12; p=0.0002) consumption, but only in females. We also observed a significant positive relationship (R2=0.25; p<0.0001) between the amount of time oriented toward the sipper port during the auditory cues and the average rate of subsequent alcohol consumption (i.e. front-loading), but only in females. In males, head direction was found to be positively associated with subsequent total water consumption (R2=-0.21; p<0.0001), but not alcohol (R2=-0.01; p=0.2267). We also observed a significant negative relationship (R2=-0.15; p<0.0001) between proximity to the sipper during the cue period and subsequent total 2-hour alcohol intake in males. Although these associations were modest in strength, they suggest potential sex-specific behavioral predictors of alcohol consumption that are regulated by different neural dynamics.

Background Treatment of Raynaud phenomenon(RP) with oral vasodilators(calcium channel block-ers and phosphodiesterase type 5 inhibitors) has shown moderate efficacy, may not benefit to all patients, and adverse effects often compromise long-term treatment. In addition, a large placebo effect may jeopardize the assessment of treatment benefits. Pharmaconutritional strategies aiming at increasing nitric oxide bioavailability (beet-root juice and L-citrulline) may be promising alternatives, and we further hypothesized that patient preference for a treatment could be a driver of the response. Methods This study consisted of a series of randomized, double-blind, N-of-1 trials conducted in outpa-tients with primary or secondary RP. Each patient underwent a multiple crossover design with repeated blocks of randomized treatments periods: 2 weeks of placebo, 2 weeks of active treat-ments, and 1 week of washout. Outcomes included the Raynaud Condition Score(RCS), fre-quency and daily duration of attacks. Each patient prespecified its preferred primary outcome, efficacy threshold and preferred treatment, which was used for stratified randomization. Gener-alized linear mixed-effects models were used to determine individual and aggregated efficacy. Results Twenty-one patients completed 2 to 8 treatment blocks. Seventeen patients tested L-citrulline, 17 beetroot juice and 13 both treatments. Ten patients selected RCS as a primary outcome, 6 patients the number of attacks and 5 the duration of attacks. Me-dian threshold for considering treatment efficacy chosen by patients was 50% (min-max 20% to 75%) reduction of symptoms. Using individual criteria to define efficacy neither L-citrulline nor beetroot juice showed significant efficacy compared to baseline. Based on the aggregated data, our results show no significant difference between L-citrulline and the L-citrulline-based placebo, nor between beetroot juice and nitrate-depleted beetroot juice, with the exception of the daily duration of RP attacks with beetroot juice (p=0.002). Finally, there was a marked placebo response, notably when patients received their preferred treatment. Conclusions: Our study did not show significant beetroot juice or L-citrulline efficacy in RP. However, we found that individual preference for one treatment over another maximizes responses to both placebo and active treatments, particularly with regard to the frequency and duration of RP attacks, thus suggesting that a real and modifiable placebo effect exists in RP.

Unhealthy retail outlets, including liquor stores, bars, convenience stores, and fast food, are concentrated in lower-income neighbourhoods. This is a well-documented cross-sectional fact; the process that sustains it is not. A neighbourhood can hold more because more open there or because those already there survive longer, and these point to different responses. We assembled an establishment-level panel of every business in Rhode Island from 2016 to 2025 (480,923 geocoded establishment-years across nine annual cross-sections), following the same outlets year to year, and classified and counted unhealthy outlets by census tract. We estimated the tract income gradient three ways (negative binomial regression, a concentration index, and a Bayesian spatial model), tested its stability, and decomposed it into openings and closures. The gradient was strong, stable, and robust: about 30 percent fewer unhealthy outlets per resident per standard deviation of higher income, with racial composition and poverty no longer associated once income was included. It was reproduced through entry, not survival: closures were even-handed across income, while new unhealthy outlets opened about 2.2 times as often per resident in the lowest-income tracts as in the highest. This entry was not unhealthy-specific: new healthy food retail tilted toward lower-income tracts at least as strongly, and the unhealthy share of openings did not rise as income fell. The standing burden was nonetheless dominated by convenience stores and off-premise alcohol. Efforts to reshape the retail environment will have more leverage on new openings than on the existing stock, through instruments defined by outlet type.

Background: Adolescent and youth substance use is an important public health concern in rapidly urbanizing low- and middle-income countries; however, evidence on how social networks and community substance-use environments jointly shape recent use remains limited, particularly in African megacities. Methods: We conducted a cross-sectional, community-based, convergent mixed-methods study of adolescents and young adults aged 12-24 years in the Yaba Local Council Development Area, Lagos, Nigeria. Quantitative data were collected using a structured questionnaire adapted from established, international survey instruments. The primary outcome was self-reported substance use within the past 30 days. Key exposures included a Social Exposure Score incorporating substance use among friends and family members, membership in a substance-using peer group, and perceived easy community availability of substances. Multivariable logistic regression was used to examine factors associated with past-30-day substance use, followed by an interaction model to assess whether perceived availability modified the association between social exposure and recent use. Open-ended responses on community approaches to reducing substance use were thematically analyzed and integrated with quantitative findings through a joint display. Results: Among 285 participants (mean age 18.9 years; 52.6% male), 66 (23.2%) reported past-30-day substance use and 84 (29.5%) reported lifetime polysubstance use. A Higher Social Exposure Score was associated with increased odds of past-30-day substance use (adjusted odds ratio [aOR]=2.18; 95% CI: 1.59-2.99; p<0.001), while perceived easy community availability was independently associated with recent use (aOR=3.22; 95% CI: 1.42-7.30; p=0.005). The interaction between social exposure and perceived availability was statistically significant (aOR=1.51; 95% CI: 1.01-2.27; p=0.047), indicating that the association between social exposure and recent use varied according to perceived availability. The marginal effect of a one-unit increase in the Social Exposure Score on the predicted probability of past-30-day use was +0.08 when easy availability was not reported and +0.18 when it was reported. Among lifetime substance users, past-30-day use was more common among polysubstance users than single substance users (50.0% vs. 22.0%; chi-square[1]=16.51; p<0.001). Qualitative findings identified supply side law enforcement (43.5%), population awareness campaigns (24.6%), regulatory and legislative control (16.1%), enhanced parental supervision (14.7%), and economic and youth empowerment (13.3%) as prominent community-proposed solutions. Integrated analysis demonstrated complementarity between the quantitatively identified social and environmental correlates and community-proposed intervention priorities. Conclusions: In this urban Nigerian setting, past-30-day substance use was independently associated with social exposure and perceived community availability, with evidence that the association between social exposure and recent use varied according to perceived availability. The findings support multilevel prevention approaches that address environmental access alongside peer, family, community, and broader socioeconomic influences.

Background: Young people who are Not in Education, Employment, or Training (NEET) represent a major public health and societal challenge. Existing evidence has linked adolescent mental health problems and health risk behaviours to NEET but has largely treated NEET as a static, rather than longitudinal outcome and overlooked the combined effects of multiple health conditions. Methods: Using data from 5,262 participants born between 1993 and 2000 in the UK Household Longitudinal Study, this study examined the independent and combined associations of adolescent mental health problems (emotional symptoms, conduct problems, hyperactivity) and health risk behaviours (regular smoking, drug use, alcohol use, and high social media use) with ever-NEET status, NEET chronicity, and NEET trajectories from ages 16 to 24, using modified Poisson, proportional odds, and multilevel logistic regression models, respectively. Findings: All mental health problems were associated with ever-NEET status (RRs 1.24-1.27) and NEET chronicity (ORs 1.41-1.98); emotional symptoms showed a widening disadvantage with age, while the disadvantages associated with conduct problems and hyperactivity remained stable. Among health risk behaviours, regular smoking showed the strongest and most persistent relationships with NEET (ever-NEET RR 1.54; chronicity OR 1.64); drug use was related to ever-NEET status (RR 1.37) and an increasing disadvantage after age 21-22, while alcohol use and social media use showed limited associations. NEET risk generally increased with the number of co-occurring conditions, but for recurrent NEET (three or more occasions), risk was only elevated at three or more co-occurring conditions. Interpretation: Adolescent health exposures were associated with NEET risk during ages 16-24, but the strength and pattern varied by exposure and outcome, offering potential insights into the timing and emphasis of any interventions.