Nicotine and Tobacco Research

Introduction The Tobacco and Vapes Act 2026 provides the UK government powers to ban vaping in public places. Proposals include extending existing indoor smoke-free legislation to also being vape-free and making public children's playgrounds and outdoor areas of education settings vape-free. We examined adults' and adolescents' views on vape-free places. Methods Two UK-wide cross-sectional online surveys were conducted in 2026, one with adult (18+) current and former nicotine users (n=2,851), and one with adolescents aged 11-17 years (n=2,123). We measured (1) perceived acceptability of vaping in public places, (2) views on whether vapes should/should not be allowed in public places, and (3) perceived likelihood of public compliance with vaping bans. Results Adults considered it unacceptable to vape on public transport (85.9%), on school grounds (outdoors) (83.6%), outside hospital entrances (59.2%), and inside pubs (57.8%) and nightclubs (52.5%). A minority considered it unacceptable to vape at open air playparks (40.6%). Most adolescents viewed vaping as unacceptable in all locations. Perceived acceptability of vaping in each place was associated with current vaping and/or smoking. Adults and adolescents believed vaping should not be allowed on public transport (88.9%; 93.8%) or outdoors on school grounds (85.8%; 93.5%). Adults and adolescents perceived likely compliance on public transport, school grounds and in pubs, but not in nightclubs, outside hospital entrances and at open air playparks. Conclusion The findings indicate public support for some vape-free places among adults and adolescents, particularly on public transport and school grounds, and less so for a ban at open air playparks.

Objectives To compare hospital claims and costs for major tobacco associated diseases with ICD 10 F17 tobacco dependence coding in Indonesian national health insurance claims and to assess whether the insurer records tobacco addiction or mainly pays for its complications. Design Retrospective claims based observational study using routinely collected administrative claims reported according to STROBE and the RECORD extension. Setting Indonesian national health insurance scheme Jaminan Kesehatan Nasional including referral hospital and primary care claims from 2015 to 2023. Participants A national mental health claims sample of 54820 members with at least one ICD 10 mental or behavioral F code diagnosis weighted to 1032022 members and 2074277 referral hospital visits. Primary and secondary outcome measures The primary outcome was verified claim costs in USD for hospital visits with a primary diagnosis of chronic obstructive pulmonary disease J44 or tracheal bronchial or lung cancer C33 to C34 or ischemic heart disease I20 to I25 or stroke I60 to I69. Secondary outcomes were counts of ICD 10 F17 tobacco dependence coding and the disease to F17 coding ratio. Results The four tobacco associated disease groups accounted for 13946 visits among 5223 patients and USD 4.20 million in verified costs representing 6.0 percent of hospital spending in the sample. Weighted costs were USD 74.7 million of which cardiovascular and cerebrovascular disease accounted for 95 percent. F17 appeared in only 51 referral hospital encounters and 26 primary care encounters. Only 2 of 5223 patients with these tobacco associated diseases or 0.04 percent were ever coded with F17. Conclusions The Indonesian national insurer paid substantially for tobacco associated morbidity while tobacco dependence was almost never coded. Smoking related diseases were reimbursed but tobacco dependence treatment was not captured as a financed care target. Embedding brief cessation care reimbursable pharmacotherapy and routine F17 coding into primary care could help shift tobacco related expenditure from downstream complications toward addiction care. Keywords tobacco dependence smoking cessation F17 coding health expenditure administrative claims Indonesia

Objective To estimate the potential health and equity impacts of a tobacco free generation (TFG) and T21 policy (increasing the legal age of sale to 21) in Australia, in the context of a complex market including widespread illicit tobacco and e-cigarette product availability. Design A Markov macrosimulation model, parameterised with yearly net movements between legal smoking, illicit smoking, vaping, and dual use states, combined with a proportional multi-state lifetable. Setting The Australian population, modelled as an open cohort for 40-years. Intervention A 'business-as-usual' (BAU) scenario was compared to TFG and T21 policies, with both starting in 2026. Variations to policy impacts were tested under increasing background illicit market enforcement. Main outcome measures The model estimates the health-adjusted life years (HALYs) and deaths over 40 years, under each scenario, with differences across age and socioeconomic status (SES) presented. Results The TFG policy reduced daily smoking prevalence among 15-24-year-olds to 4.6% (95% uncertainty interval [UI] 3.8-5.7%) in 20 years' time, compared to 7.2% under the T21 policy and 7.9% under BAU trends. Vaping was minimally impacted by either policy. The TFG policy resulted in 178,000 (95% UI 87,800-314,000) HALYs being gained over 40 years. The policy impact was largest when accompanied by increased illicit market enforcement, reducing daily smoking among 15-24-year-olds to 1.4% within 20 years. Both policies had greater prevalence and health impacts on more disadvantaged compared to advantaged SES groups. Conclusion A TFG policy is expected to produce long-term benefits for the Australian population but would be most effective in combination with increased enforcement of illicit tobacco and e-cigarette markets. Novel strategies to increase quitting in addition to reducing uptake are needed to improve tobacco-related outcomes in the short to medium term.

Adolescent use of alcohol, nicotine, and marijuana remains a major public health concern in the United States. Early identification of youth at elevated risk is critical for prevention before use begins or escalates. We developed and evaluated a longitudinal machine learning framework to predict alcohol, nicotine, and marijuana use at the next observed assessment wave. Data came from the Adolescent Brain Cognitive Development (ABCD) Study Release 6.0. The models incorporated predictors from multiple domains, including demographics, friends, family and community context, mental health, physical health, and prior substance-related behaviors. To reduce information leakage across individuals, we implemented a leakage-aware stacked ensemble. This ensemble combined diverse base learners through out-of-fold predictions and an elastic-net meta-learner. Across all three substances, the lagged stacked ensemble outperformed the cross-sectional stack and all single base learners. Adolescents identified as highest risk showed substantially higher observed rates of substance use than would be expected under random screening. Feature-importance analyses showed that the full longitudinal models were strongly influenced by developmental timing and prior-use history. Analyses restricted to current-wave features revealed distinct substance-specific risk patterns beyond prior-use history and developmental timing. Bootstrap stability analyses identified top-ranked features showing consistent positive predictive relevance across resampled adolescents. These findings suggest that longitudinal, leakage-aware machine learning can generate substance-specific risk estimates to support targeted prevention and screening in adolescent populations.

Introduction: Pediatric nicotine exposures remain an important and preventable public health issue, particularly with the rapid expansion of electronic nicotine delivery systems. This study compared demographic characteristics, exposure circumstances, and clinical outcomes between pediatric cases involving nicotine devices and bottled liquids reported to U.S. poison centers. Method: This retrospective cohort study analyzed National Poison Data System cases from 2011-2022 involving children aged less than 6 years exposed to nicotine devices or bottled liquids. Analyses were limited to cases with definitive medical outcomes. The primary outcome was defined as a moderate or major clinical effect or death. Odds ratios with 95% confidence intervals were calculated, with a secondary analysis restricted to route-concordant exposures. Results: The final cohort included 15,497 cases: 10,168 device exposures and 5,329 liquid exposures. Demographic characteristics were similar between groups. Device exposures more frequently involved inhalation, while ingestion predominated overall. Clinical effects were typically mild and transient, with vomiting and coughing most commonly reported. The primary outcome occurred in 1.9% of device cases and 2.0% of liquid cases (OR = 1.05; 95% CI 0.82-1.34). A secondary analysis restricted to inhalation-only device exposures and ingestion-only liquid exposures similarly found no significant difference in clinically important outcomes (OR = 1.38; 95% CI 0.92-2.12). Two deaths occurred, one in each group. Conclusion: These findings suggest that, despite differences in formulation and route of exposure, nicotine devices and bottled liquids produce broadly similar clinical toxicity profiles in young children. Prevention strategies should address all household nicotine products rather than focusing on specific delivery systems.

Short-form video platforms increasingly shape how young audiences encounter health information. Generative artificial intelligence can produce standardized avatar-based messages at scale, but randomized evidence for tobacco prevention is scarce. In this three-arm randomized online intervention study with pre-post assessment, participants aged 16 years or older were assigned to an AI avatar video emphasizing short-term smoking consequences, an AI avatar video presenting long-term cancer-related information matched to an American Cancer Society fact sheet, or the same fact sheet in written form. The primary outcome was post-intervention intention to avoid smoking and secondhand smoke exposure, adjusted for baseline intention. Among 400 randomized participants, 272 had complete data for the primary baseline-adjusted analysis. Intention increased from baseline to post-intervention in all conditions, with no statistically significant between-group differences. These findings support AI avatar videos as a scalable, social-media-compatible format for digital tobacco prevention, while not establishing superiority or equivalence.

Background: The UK Government aims to reduce smoking rates by implementing new, and investing in existing, tobacco control strategies including increased funding for Stop Smoking Services (SSS) in England. This study examined whether the additional funding starting in April 2024 was associated with a detectable increase in quit attempts supported by SSS and whether it was cost-effective. Methods: We used data from the Smoking Toolkit Study, a repeat cross-sectional survey conducted in 2021 to 2025. Adults aged [≥]18 years who smoked cigarettes and had made a quit attempt in the past year were included (weighted n=5,076). The outcome was monthly prevalence of past-year quit attempts supported by SSS. We fitted general additive models with a step change in April 2024 to represent the start of the increased funding. We adjusted for tobacco tax increases, the Swap-to-Stop scheme, age, gender, and a measure of socioeconomic position. In an unplanned analysis, we extended the time series back to 2006. For the cost-effectiveness, we estimated incremental cost-effectiveness ratios for the total population and age groups, accounting for future lifetime cessation. Results: In the primary model, the April 2024 step change was not statistically significant (adjusted odds ratio: 1.13; 95% CI: 0.52, 2.49). The cost-effectiveness analysis ranged from cost-effective to extremely ineffective (incremental cost-effectiveness ratio (ICER): GBP 104,126, 95% CI: 939,398 to 8,293). When using the extended time series, the adjusted odds ratio for the step change was 2.70 (95% CI: 2.03, 3.60) and the intervention was cost-effective (ICER: GBP 13,857; 21,393 to 9,620). Conclusions: Compared with the long-term trend, increased funding to SSS in England in 2024 appeared to lead to an increase in quit attempts supported by SSS at the population level. This result is somewhat uncertain because our primary pre-planned analyses assessing the impact relative to a more recent trend were insensitive.

Although cannabinoids such as delta-9-tetrahydrocannabinol (THC) are generally immunosuppressive in preclinical models, chronic cannabis use in humans is paradoxically associated with increased infection risk and systemic inflammation. In this study, we demonstrate that THC directly strengthens intestinal epithelial barrier function in vitro by increasing trans-epithelial electrical resistance in a concentration-dependent manner in Caco-2 monolayers. In a cross-sectional study of chronic cannabis users via smoking or snorting compared with non-using controls, plasma lipopolysaccharide (LPS), and microbial translocation-driven inflammatory cytokines (IL-23, MCP-1, IL-8) were significantly reduced, while some cytokines (IL-6, IL-1{beta}, TNF-, IL-10) remained unchanged. Concurrently, users exhibited elevated macrophage-derived chemokine (MDC) and homeostatic cytokines IL-15 and IL-21, markedly suppressed IL-7 and IL-4. Plasma IL-15 and MDC levels correlated with consumption intensity, and IL-23, IL-7, and IP-10 correlated with age of first use or during heaviest use. These findings suggest that habitual cannabis use may protect gut barrier integrity and reduce microbial translocation and associated inflammation, while simultaneously disrupting systemic immune homeostasis through selective cytokine dysregulation. This dual, dose-dependent immunomodulatory profile highlights the complex balance between potential benefits and risks in both recreational and therapeutic cannabis use.

Background: Sexual health vending machines have emerged as a promising approach to expanding access to contraception and other sexual health products on college campuses. This study evaluated patterns of use, perceived accessibility, and student attitudes towards the sexual health vending machine at Tufts University. Methods: This mixed-methods evaluation combined an online survey with vending machine refill data. Analyses included descriptive analysis, chi-square tests, and thematic analysis of open-ended responses. Results: The survey was open from October to December 2025 and included 118 respondents. Self-reported use suggests students engage with the vending machine on an as-needed basis. Users were significantly more likely to agree that it increased their likelihood of using a condom, compared with non-users. However, both groups expressed strong support for the vending machine, reporting that it improved access to sexual health resources, offered satisfactory product variety, and should be provided by the university. Although many students appreciated its visibility and role in reducing stigma, concerns about privacy and discretion were the most commonly reported reasons for non-use. Restock data indicated sustained year-round utilization, with expected decreases during vacation periods. Conclusion: Overall, these findings suggest that sexual health vending machines represent a scalable strategy for expanding access to sexual health resources in university settings. Offering a unique combination of immediacy, affordability, and convenience, this low-barrier resource may also promote preventive sexual health behaviors across campus, even among non-users, and support broader efforts to prevent sexually transmitted infections and unintended pregnancy among young adults.

Trimethylamine n-oxide (TMAO) is a plasma metabolite linked to adverse cardiometabolic health with complex regulation involving diet, sex, and host genetics. We explored the role of these factors in the genetic regulation of TMAO by performing a primary-level meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five distinct studies conducted in various regions of the United States. We identified a quantitative trait locus (QTL) associated with TMAO concentration at [~]86 megabase pairs on mouse chromosome 12 with a highly significant LOD score of 67.67. Alleles at the chromosome 12 QTL inherited from the Cast/EiJ (CAST) and PWK/PhJ (PWK) mouse strains primarily drove the association with reduced TMAO concentrations. The chromosome 12 QTL remained significant in sex-stratified analyses and the mode of inheritance appeared additive; furthermore, the QTL was regulated by sex-by-genotype and sex-by-diet interactions. Using a CAST/EiJ X C57BL/6J F2 cross, positional candidates were prioritized by eQTL analysis. Further analysis in a study utilizing the eight DO founding strains identified that Acyp1 was differentially expressed in hepatic tissue from CAST mice, prompting investigation into its genetic regulation. Acyp1 demonstrated relevant cis- and trans-regulation and was significantly correlated with TMAO and hepatic Fmo3. However, no significant relationships between Acyp1 and TMAO were identified in mice inactivated for Acyp1 or with AAV overexpression of Acyp1 in the liver. Genes within the chromosome 12 QTL have synteny with humans and may translate to the genetic regulation of human plasma TMAO concentrations and atherosclerosis. Author SummaryWe explored the roles of diet, sex, and genetics on the regulation of fasting plasma trimethylamine n-oxide (TMAO) concentration by performing a meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five unique studies. We identified a QTL associated with TMAO concentration on chromosome 12 at [~]86 mega base pair (Mb) with a highly significant LOD score of 67.67. The locus is modified by both sex and diet.

Alcohol demand is commonly assessed using hypothetical alcohol purchase tasks (APTs), from which individual demand curves are constructed and yield multiple indices of reinforcing value. Procedurally, APTs can confer participant burden, and existing brief alternatives cannot produce demand curves or derived indices. Thus, we evaluated a novel, adjusting APT that efficiently and idiographically assesses alcohol demand while preserving the benefits of a full task. Adults reporting past-six-month alcohol use (n=897) completed either the adjusting or full APT, the former utilizing a binary-search-style algorithm to administer six prices from the full APT's price set based on level of alcohol demand. The adjusting APT reduced item burden by 49% and produced well-fitting individual demand curves. Average demand intensity and elasticity estimates did not differ significantly by modality, whereas Omax and breakpoint estimates were significantly higher on the adjusting APT, though only by $3 each. All demand indices from both APTs were positively associated with alcohol use and problems, with similar magnitude by modality. Results provide support for the adjusting APT as a brief measure of alcohol demand that retains demand-curve-based indices of reinforcing value.

Background Childhood adversity can affect propensity to risk-taking behaviors. We aim to investigate the relation between childhood adversity and risk-taking behaviors in youth using emergency room (ER) admissions and survey data. Method Using the DANLIFE study, we included 1.2 million Danes. Individuals were assigned into five groups based on childhood adversity exposure from ages 0 to 15 years. We applied survival analyses on repeated outcomes to model ER-admissions due to substances, violence and unintentional injury in the full cohort between ages 16 and 24. We applied logistic regression models to weighted survey data on frequent binge drinking, cannabis use, drug use, and unsafe sex in a nested subsample of 34,064 18 year olds from the Danish National Birth Cohort. Results The high adversity group was at highest risk of ER-admissions due to substances (HR=3.27, 95% CI [3.10, 3.46]), violence (HR=2.67, 95% CI [2.58, 2.76]) and unintentional injuries (HR=1.30, 95% CI [1.28, 1.33]). In the nested subsample, the high adversity was at highest risk of cannabis use (OR=1.59, 95% CI [1.21, 2.09]), drug use (OR=2.44, 95% CI [1.71, 3.49]) and unsafe sex (OR=1.72, 95% CI [1.34, 2.22]), but at lower risk of frequent binge drinking (OR=0.57, 95% CI [0.37, 0.87]). Conclusion These findings highlight how childhood adversity is associated with increased engagement in and harm from risk-taking behaviors. To prevent inequalities in health in youth, there is a need for interventions and policies that promote child welfare, as well as targeted support for youth with harmful behavioral patterns.

BackgroundPrenatal cannabis use is becoming increasingly more commonplace. However, cannabis exposure is linked to adverse pregnancy outcomes, including gestational hypertension, preeclampsia, and preterm birth. The aim of this study was to determine the morphological and molecular effects of prenatal cannabinoid exposure on the placenta. MethodsPregnant Sprague-Dawley rats were exposed daily to vaporized THC (100 mg/mL) starting at gestational day (GD)5 until GD19 when dams were sacrificed and fetuses and placentas collected. Fetuses were genotyped for genetic sex and transcriptomic analysis was performed on male and female THC-exposed and control placentas. ResultsOn GD19, both the fetuses and placentas from the THC group were significantly larger than the control. When separated by sex, both male and female THC fetuses were significantly larger; however, only male THC placentas were significantly larger than male control placentas with no significant difference in placental weight between female control and THC placentas. RNA-sequencing revealed enriched biological processes related to nutrient transport and lipid catabolism, protein-lipid complex formation, and lipoprotein particle remodeling and organization. Further transcriptomic analysis determined that the differentially expressed genes and enriched biological processes related to lipid metabolism were preferentially enriched in the female THC placentas compared to the male, suggesting a sex-specific effect. DiscussionCollectively, these data present sex-specific effects of prenatal cannabinoid exposure on placental growth and global gene expression. These data also suggest that sex influences gene expression of genes related to lipid metabolism in the THC-exposed placentas.

Psychoactive and psychotoxic drugs are particularly harmful, if their use coincides with critical developmental windows of brain maturation. Methamphetamine is one such stimulant with developmental exposure increasing seizure susceptibility and long-term neuronal maladaptation in children. Nevertheless, the extent at which infant and adult vulnerability to methamphetamine could differ in time-course and severity remains incompletely understood. Here, we developed a method to monitor methamphetamine-induced hyperactivity in infant mice at high temporal resolution, differentiate it from a biphasic response in adults, and link it to activity changes in cortical areas executing goal-directed (escape) behaviors in infant subjects when using Fos expression as a molecular surrogate. Subsequently, we hypothesized that methamphetamine could alter the expression and cellular distribution of inhibitory neuropeptides, which, when co-released with fast neurotransmitters, could protect circuit plasticity by counteracting methamphetamine-induced hyperexcitability. Methamphetamine differentially altered somatostatin, cholecystokinin, and galanin expression in corticolimbic areas. These data suggest that methamphetamine can evoke age-specific neurocircuit modifications, at least in mice.

ObjectiveReliable animal models of tracheal stenosis are necessary for the development and translational testing of anti-fibrotic and regenerative therapies, but existing rabbit models frequently demonstrate substantial variability in stenosis severity, which limits their translational utility. The objective of our study was to determine whether airway diameter-matched mechanical injury improves the severity and reproducibility of experimental tracheal stenosis in a rabbit model, and to evaluate whether rabbit body weight is a reliable surrogate for tracheal luminal diameter during model creation. MethodsFourteen male New Zealand White rabbits (weight range, 2.7-3.5 kg) underwent tracheal injury using steel-bristle brushes introduced through a tracheotomy. Animals were assigned to receive either airway diameter-matched injury, in which brush size was selected to closely approximate the directly measured tracheal lumen diameter, or non-matched injury, in which brush size was selected without regard to measured lumen diameter. At postoperative day 21 (POD21), the injured tracheal segment and a native uninjured segment from the same animal were harvested and compared. Stenosis degree was quantified grossly, and lamina propria-to-cartilage (LP:C) ratio was quantified histologically by three blinded reviewers. The relationship between rabbit weight and airway diameter was assessed, and inter-rater reliability was calculated using the intraclass correlation coefficient (ICC). ResultsTwelve of fourteen rabbits reached the POD21 endpoint; two were euthanized early for severe airway compromise meeting humane endpoint criteria, both with approximately 80% stenosis. Injured tracheas demonstrated significantly greater stenosis than native controls (66.0 {+/-} 13.0% vs 16.0 {+/-} 2.7%; p = 0.00012), with a corresponding increase in LP:C ratio (p = 0.031). Airway diameter-matched injury produced significantly greater stenosis than non-matched injury (74.6 {+/-} 6.1% vs 50.6 {+/-} 4.0%; p = 0.001), while LP:C ratio did not differ between injury techniques (p = 1.0). Rabbit weight did not correlate with airway diameter (r = 0.176, p = 0.515; R2 = 0.031). Inter-rater reliability was excellent for both stenosis degree (ICC = 0.989) and LP:C ratio (ICC = 0.992). ConclusionsDirect measurement and matching of injury instrument diameter to native airway diameter substantially improves both the severity and the reproducibility of stenosis in a rabbit tracheal injury model, whereas body weight is an unreliable surrogate for airway size. This optimized, standardized protocol offers a reproducible platform for future translational studies of airway fibrosis and anti-fibrotic or regenerative therapies.

Background: Retrieval of adverse event reports based on coded drug-event co-occurrence enables large-scale pharmacovigilance analyses, but yields candidate reports rather than validated cases, risking misinterpretation if used alone. Aim: To develop and apply a framework for identification and characterization of clinically meaningful case series in pharmacovigilance. Methods: We conducted two case studies. The first developed and refined the framework in an information-rich setting, focusing on drug-induced impulsivity across selected drugs; the second tested its applicability in a more routine, information-poor setting, focusing on drug-induced suicidality. Results: In Case 1, non-relevant reports were frequent for drugs with uncertain evidence and negative controls ({approx}20-40%) compared to drugs with established causal roles (4%). The emerging framework assessed relevance based on exposure, event, drug-event relationship, and population. For suspected adverse drug reactions, relevant reports were further characterized by reporter suspicion and evidentiary qualifiers supporting or refuting causality; higher suspicion was associated with more supportive qualifiers. Applied to Case 2, the framework ruled out 69% of reports as non-relevant but highlighted substantial non-assessability (17%). Conclusions: In pharmacovigilance, retrieval is not equivalent to case identification. Relevance is question-specific and shaped by how reports are captured, processed, and retrieved. This can be especially critical for emerging or bias-prone safety questions. Transparent and reproducible case definition and adjudication are essential for interpretable analyses.

Background: Cannabis is one of the most widely used psychoactive substances worldwide. {Delta}-tetrahydrocannabinol ({Delta}-THC) is the main contributor to cannabis-induced effects such as euphoria, anxiety, and psychotomimetic effects, and is metabolized by several hepatic enzymes, including CYP3A4. There are interindividual differences in how cannabis affects users, which have substantial genetic contributors. Methods: We examined how real-time effects of {Delta}-THC on psychotomimetic measures and on subjective effects of "high", sadness and anxiety in 188 healthy volunteers in a laboratory infusion paradigm, relate to polygenic risk scores (PRS) for cannabis lifetime use (CanLU), cannabis use disorder (CanUD), and CYP3A4 expression. Results: CYP3A4 expression PRS was significantly associated with {Delta}-THC-induced psychotomimetic effects. Genetic liability to use and misuse cannabis is potentially associated with lower {Delta}-THC-induced psychotomimetic symptoms. CanLU PRS nominally predicted enhanced {Delta}-THC-induced "high", while CanUD PRS predicted it to be lower. Conclusions: Our findings suggest that genetic liability to produce more CYP3A4 enzyme may be associated with faster {Delta}-THC degradation and the consequential diminution of the latter's effects. Nominal effects suggest that aversive outcomes may reduce cannabis use and use disorder genetic liability, and that CanUD subjects may need higher {Delta}-THC doses to experience euphoria ("high"). In total, this study provides novel insights regarding some of the specific genetic factors that influence interindividual variability in {Delta}-THC effects, mainly via {Delta}-THC metabolism.

Background: Chronic and non-healing wounds remain a major clinical challenge with limited therapeutic options. Angiogenesis and inflammation are central to tissue repair, and mesenchymal stem cells (MSC) contribute to these processes through their trophic and immunomodulatory secretome. Cannabidiol (CBD) exhibits antioxidant and immunomodulatory properties. However, whether CBD-rich Cannabis sativa extract stimulate MSC toward a pro-angiogenic secretome remains unclear. Purpose: This study aims to determine whether purified CBD or a phytochemically CBD-rich full spectrum extract stimulate umbilical cord-derived human MSC (UC-hMSC) to secrete pro-angiogenic factors and enhance endothelial responses relevant to wound healing. Methods: UC-hMSC were preconditioned with either purified CBD or a CBD-rich full-spectrum extract. Transcriptional changes were assessed by qPCR. The functional impact of the resulting secretome was evaluated in vitro using HUVEC-based proliferation and tube formation assays, and in vivo through the chick chorioallantoic membrane assay. To explore underlying mechanisms, we examined HIF-1 stabilization and VEGFA release in UC-hMSC, and VEGFR-2/ERK signaling in HUVEC. Results: Purified CBD and full-spectrum CBD extract preconditioned UC-hMSC secretomes, increased HUVEC proliferation, tube formation, and enhanced vascular branching in the CAM assay. Mechanistic analyses indicated activation of the HIF-1/VEGF axis in UC-hMSC, and ERK1/2 activation in HUVEC that was sensitive to VEGFR-2 blockade. Conclusion: Purified CBD and CBD-rich full-spectrum extract prime UC-hMSC toward a pro-angiogenic secretome that promotes endothelial activation and neovascularization. These findings suggest that cannabinoid-based preconditioning of UC-hMSC involves the HIF-1/VEGF axis and VEGFR-2/ERK signaling pathways in endothelial cells, supporting further investigation of this approach in wound healing and regenerative therapies.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment for tobacco use disorder (TUD). Although at a group level, active stimulation outperforms sham, at an individual level, variability exists in clinical response. The behavioral and neurobiological factors that differentiate those who respond to rTMS from those who do not remain unclear. To explore individual factors that influence acute responses to rTMS, N = 60 human participants received one session of rTMS to the dorsolateral prefrontal cortex (DLPFC) and to a control region (visual cortex; V5) in a randomized order. They completed behavioral assessments and neuroimaging before and after rTMS sessions. Hypotheses involving behavioral and neuroimaging predictors of response were pre-registered prior to completion of data collection. rTMS to the DLPFC led to significant reductions in self-reported cigarette craving compared with rTMS to a control brain region (p = 0.0006) and participants were classified as n = 38 responders and n = 22 nonresponders. Responders used significantly more cigarettes per day (M = 11.441) compared to nonresponders (M = 7.952), reported higher levels of cigarette craving (d = 1.059), and more severe nicotine withdrawal (d = 0.803) prior to rTMS. Neuroimaging analyses based on preregistered hypotheses indicated that DLPFC-frontoparietal and insula whole-brain functional connectivity did not differ significantly between responders and nonresponders. However, exploratory analyses revealed that responders had reduced pre-rTMS functional connectivity between the insula and nucleus accumbens, precuneus, and occipital pole. These findings suggest that response to rTMS for TUD is associated with greater baseline cigarette consumption, craving, and withdrawal, in addition to distinct functional connectivity patterns related to salience, reward, and self-referential processes, providing candidate behavioral and neural markers for personalized rTMS interventions for TUD.

Evidence suggests that insomnia disorder is associated with pathophysiological alterations that may contribute to long-term physical, mental and inflammatory-related health risks. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment for insomnia disorder, yet its effects on physiological outcomes remain unclear. This randomized-controlled trial examined the effects of CBTi on cardiovascular and immunological biomarkers. Sixty-two participants with insomnia disorder were randomized to group-CBTi (N = 33, 75.8% female, Mage = 48.8 + 17.1 years) or Waitlist (WL) control (N = 29, 75.9% female, Mage = 52.2 + 15.6 years). Cardiovascular parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and nocturnal heart rate variability (HRV). Inflammatory markers from blood samples included C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF). All outcomes were assessed at baseline (T1), post-treatment assessment (T2, following completion of CBTi or WL period), and 6-months for the WL group (T3, after CBTi for the WL participants). No significant Group-by-time effects were observed for SBP, DBP, HR, HRV and any inflammatory markers (ps > .05) from T1 to T2. When pooling treatment effects following CBTi exposure across both groups (T1 to T2 in CBTi group and T1 to T3 in WL group), no significant biomarker changes were observed. Overall, results indicate that CBTi did not produce detectable changes in cardiovascular or inflammatory markers among healthy individuals with insomnia disorder. These findings suggest physiological responses to CBTi are complex and may reflect dynamic and context-dependent processes (https://www.isrctn.com/ISRCTN13983243).