Nicotine & Tobacco Research

BackgroundSince late 2022, the sale of most flavoured tobacco products has been prohibited in California, including menthol cigarettes. Tobacco companies responded by introducing "non-menthol" cigarettes in which menthol was replaced with WS-3, an odorless synthetic cooling agent to elicit cooling sensations similar to menthol. Legislation enacted in 2024 banned the addition of cooling characterizing flavours in tobacco products in California. However, the industry continues to market "non-menthol" cigarettes in the state, with very similar package designs. It is unknown whether these cigarettes contain a cooling agent. MethodsAvailable Newport-branded "non-menthol" cigarettes were purchased in California in 2025, extracted and tested for sensory cooling activity by Ca2+ microfluorimetry of HEK293T cells expressing the human TRPM8 cold/menthol receptor. Chemical analysis was performed by gas chromatography - mass spectrometry (GCMS). "Non-menthol" and menthol cigarettes marketed in 2023-24 served as controls. ResultsExtracts from Newport-branded "non-menthol" cigarettes marketed in California in 2025 did not elicit sensory cooling activity. Chemical analysis confirmed the absence of menthol and any of the major commercial synthetic cooling agents. ConclusionsThe tobacco industry removed sensory cooling agents from "non-menthol" cigarettes marketed in California. However, this did not result in the market withdrawal of "non-menthol" cigarettes in the state. "Non-menthol" cigarettes in California continue to be marketed with package designs resembling those of former menthol cigarettes, signaling the potential presence of a characterising flavour.

The debate about electronic cigarettes has divided healthcare professionals, policymakers, and communities. Central points of disagreement are whether vaping electronic cigarettes are addictive and whether they produce major pulmonary complications. We developed a novel model of nicotine vapor self-administration in rats and found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans, exhibiting both addiction-like behaviors and cardiopulmonary abnormalities. The smoking cessation drug varenicline decreased electronic cigarette self-administration. These findings confirm the addictive properties and harmful effects of nicotine vapor and identify a potential medication for the treatment of electronic cigarette addiction.\n\nOne Sentence SummaryVaping nicotine-containing electronic cigarettes produces cardiopulmonary abnormalities, nicotine dependence and addiction-like behaviors, which are reduced by the smoking cessation drug varenicline.

RATIONALEThe ban of menthol cigarettes is one of the key strategies to promote smoking cessation in the United States. Menthol cigarettes are preferred by young beginning smokers for smoking initiation. Almost 90% of African American smokers use menthol cigarettes, a result of decades-long targeted industry marketing. Several states and municipalities already banned menthol cigarettes, most recently California, effective on December 21, 2022. In the weeks before Californias ban took effect, the tobacco industry introduced several "non-menthol" cigarette products in California, replacing previously mentholated brands. Here, we hypothesize that tobacco companies replaced menthol with synthetic cooling agents to create a cooling effect without using menthol. Similar to menthol, these agents activate the TRPM8 cold-menthol receptor in sensory neurons innervating the upper and lower airways. METHODSCalcium microfluorimetry in HEK293t cells expressing the TRPM8 cold/menthol receptors was used to determine sensory cooling activity of extracts prepared from these "non-menthol" cigarette brands, and compared to standard menthol cigarette extracts of the same brands. Specificity of receptor activity was validated using TRPM8-selective inhibitor, AMTB. Gas chromatography mass spectrometry (GCMS) was used to determine presence and amounts of any flavoring chemicals, including synthetic cooling agents, in the tobacco rods, wrapping paper, filters and crushable capsule (if present) of these "non-menthol" cigarettes. RESULTSCompared to equivalent menthol cigarette extracts, several California-marketed "non-menthol" cigarette extracts activated cold/menthol receptor TRPM8 at higher dilutions and with stronger efficacies, indicating substantial pharmacological activity to elicit robust cooling sensations. Synthetic cooling agent, WS-3, was detected in tobacco rods of several of these "non-menthol" cigarette brands. Crushable capsules added to certain "non-menthol" crush varieties contained neither WS-3 nor menthol but included several "sweet" flavorant chemicals, including vanillin, ethyl vanillin and anethole. CONCLUSIONTobacco companies have replaced menthol with the synthetic cooling agent, WS-3, in California-marketed "non-menthol" cigarettes. WS-3 creates a cooling sensation similar to menthol, but lacks menthols characteristic "minty" odor. The measured WS-3 content is sufficient to elicit cooling sensations in smokers, similar to menthol, that facilitate smoking initiation and act as a reinforcing cue. Regulators need to act quickly to prevent the tobacco industry from bypassing menthol bans by substituting menthol with synthetic cooling agents, and thereby thwarting smoking cessation efforts.

Genome-wide association studies have identified associations between variation at rs16969968/rs1051730 in the CHRNA5-A3-B4 gene cluster and smoking related outcomes. Experiments in rodents have described the nicotinic acetylcholine receptors (nAChRs) subunits encoded by this gene cluster and showed a lack of nicotine aversion in nAChRs deficient animal models. We conducted a nicotine challenge and a smoking topography study in humans, hypothesising that: 1. responses to a nicotine challenge would differ according to the rs16969968/rs1051730 genotype and 2. genotype may influence nicotine intake via smoking topography.\n\nWe used linear regressions to examine associations between rs16969968/rs1051730 genotype and subjective (questionnaires) and objective (physiological parameters) responses following acute nicotine exposure in never smokers (hypothesis 1) or cigarette smoking in current smokers (hypothesis 2). There was evidence to suggest nicotine exposure increases blood pressure and heart rate, and negatively affects mood, but insufficient evidence that these effects differ by genotype. Carriers of the minor allele following smoking one cigarette, exhibited reduced cravings (b=-2.46, 95% CI -4.87 to - 0.06, p=0.04) and inhaled less smoke per cigarette (b=-0.24, 95% CI - 0.43 to - 0.06, p=0.01) and per puff (b=-0.18, 95% CI -0.32 to -0.01, p=0.02). These results suggest that we need to carefully consider the translational value of the findings of aversion behaviour in nAChRs rodent models, and that deeper inhalation does not explain the strong association between rs16969968/rs1051730 genotype and objective biomarkers of tobacco exposure.

IntroductionThe FDA announced its intention to issue proposed product standards banning menthol as a characterizing flavor in cigarettes and cigars. The public health benefits of these product standards may be attenuated by the role of plausible substitutes in the marketplace. Therefore, the present study examined the addiction potential of plausible combustible menthol alternatives compared to usual brand menthol cigarettes (UBMC). MethodsEighty adult menthol cigarette smokers completed four visits, smoking their UBMC at the first session and 3 menthol cigarette alternatives in random order at the subsequent visits: 1) a pre-assembled menthol roll-your-own cigarette using menthol pipe tobacco and mentholated cigarette tube (mRYO), 2) a menthol filtered little cigar (mFLC), and 3) a non-menthol cigarette (NMC). Measures of smoking topography, exhaled carbon monoxide (CO), craving and withdrawal, subjective effects, and behavioral economic demand indices were assessed. ResultsCompared to UBMC, menthol cigarette alternatives resulted in similar topography and CO exposure but significantly lower levels of positive subjective experience and behavioral economic demand indices. Among the alternative products, participants reported the highest level of positive subjective experience and higher demand for mRYO, compared with mFLC and NMC. Similarly, participants were significantly more likely to want to try again, purchase, and use the mRYO product regularly compared with mFLC and NMC. Conclusions and RelevancemRYO cigarettes were the most highly rated cigarette alternative among study products, suggesting their potential appeal as a menthol cigarette substitute and needed inclusion of menthol pipe tobacco and cigarette tubes in FDAs proposed ban. What is already known on this topicMenthol cigarettes are associated with increased smoking initiation, higher nicotine dependence, and decreased adult cessation, particularly among vulnerable populations. To address this public health issue, the FDA announced in April 2021 its intention to issue product standards banning menthol as a characterizing flavor in both cigarettes and cigars within a year. However, the public health benefits of these product standards may be attenuated by the role of plausible substitutes available in the marketplace What this study addsIn this randomized cross-over design study that included 80 adult menthol cigarette smokers, each of the alternative products demonstrated the ability to significantly reduce nicotine craving and withdrawal symptoms, but the combination of mentholated pipe tobacco and tubes in a menthol roll-your-own cigarette, resulted in the highest behavioral economic demand and positive subjective experience. How this study may affect policyTo maximize the benefits of a menthol cigarette ban, restrictions should extend to plausible substitutes, particularly menthol pipe tobacco and cigarette tubes.

BackgroundUS sales of oral nicotine pouches (ONPs) have rapidly increased, with cool/mint-flavored ONPs the most popular. Restrictions on sales of flavored tobacco products have either been implemented or proposed by several US states and localities. Zyn, the most popular ONP brand, is marketing Zyn-"Chill" and Zyn-"Smooth" as "Flavor-Ban Approved", probably to evade flavor bans. At present it is unclear whether these ONPs are indeed free of flavor additives that can impart pleasant sensations such as cooling. MethodsSensory cooling and irritant activities of "Flavor-Ban Approved" ONPs, Zyn-"Chill" and "Smooth", along with "minty" varieties (Cool Mint, Peppermint, Spearmint, Menthol), were analyzed by Ca2+ microfluorimetry in HEK293 cells expressing the cold/menthol (TRPM8) or menthol/irritant receptor (TRPA1). Flavor chemical content of these ONPs was analyzed by GC/MS. ResultsZyn-"Chill" ONP extracts robustly activated TRPM8, with much higher efficacy (39-53%) than the mint-flavored ONPs. In contrast, mint-flavored ONP extracts elicited stronger TRPA1 irritant receptor responses than Zyn-"Chill" extracts. Chemical analysis demonstrated the presence of WS-3, an odorless synthetic cooling agent, in Zyn-"Chill" and several other mint-flavored Zyn-ONPs ConclusionsSynthetic cooling agents such as WS-3 found in Flavor-Ban Approved Zyn-"Chill" can provide a robust cooling sensation with reduced sensory irritancy, thereby increasing product appeal and use. The label "Flavor-Ban Approved" is misleading and may implicate health benefits. Regulators need to develop effective strategies for the control of odorless sensory additives used by the industry to bypass flavor bans.

BackgroundThere are challenges that require collaboration among researchers to ensure that tobacco harm reduction strategies are evidence-based. One key challenge is evaluating the safety of flavors used in electronic cigarettes (e-cigarettes). While many flavorings are approved as food additives or deemed "generally recognized as safe" (GRAS) for ingestion, this does not guarantee their safety when inhaled. In this context, the international research group Replica replicated a study conducted by Fetterman and colleagues in 2018, investigating the effects of aerosolized vanillin - one of the most popular flavors in vaping - on vascular endothelium when vaporized by an electronic cigarette. MethodsWe used Aspire Zelos 3 e-cigarette and prepared e-liquids containing propylene glycol, vegetable glycerin and vanillin. The e-liquids were vaporized under two settings - regular (1 ohm coil using wattage control mode at 14 watts) and sub-ohm (0.3 ohm coil using temperature control mode at 200 {degrees}C) - using a vaping machine, following the standardized puffing regime, ISO20768:2018. The vapor was then collected into a trapping solution to prepare aqueous extracts for the treatment of human aortic endothelial cells. We evaluated cytotoxicity, oxidative stress, nitric oxide bioavailability, and inflammation addressing some gaps reported in the original study. ResultsWe observed some harmful effects, mostly attributable to ethanol, used to dilute vanillin in the original work by Fetterman, but no harmful effects on cell viability, their ability to produce nitric oxide, or oxidative stress from vanillin. Furthermore, no pro-inflammatory effects of vanillin were observed in terms of ICAM-1 and IL-6 gene expression. ConclusionsOur results confirm the endothelial cell dysfunction observed in the original paper, but clarify that these effects are mainly attributable to ethanol and not to vaporized vanillin. These findings suggest that vanillin could be a safer flavoring agent for e-cigarette, without causing adverse effects on the cardiovascular system.

BackgroundVaping cessation is virtually unexplored. The efficacy and safety of varenicline for vaping cessation has not been studied and rigorous research is required to advance best practice and outcomes for e-cigarettes users who want to quit. MethodsEligible patients were randomized to either varenicline (1 mg, administered twice daily for 12 weeks) or placebo treatment (administered twice daily, for 12 weeks) combined with vaping cessation counseling. The trial consisted of a 12-week treatment phase followed by a 12-week follow-up, nontreatment phase. The primary efficacy endpoint of the study was biochemically validated continuous abstinence rate (CAR) at weeks 4 to 12. Secondary efficacy end points were the CAR at weeks 4 to 24 and 7-day point prevalence of vaping abstinence at weeks 12 and 24. ResultsCAR was significantly higher for varenicline vs placebo at each interval: weeks 4-12, 40.0% and 20.0%, respectively (OR = 2.67, 95% CI = [1.25 - 5.68], P = 0.011); weeks 4-24, 34.3% for varenicline and 17.2% for placebo (OR = 2.52, 95% CI = [1.14 - 5.58], P = 0.0224). The 7-day point prevalence of vaping abstinence was also higher for the varenicline than placebo at each time point. Serious adverse events were infrequent in both groups and not treatment-related. ConclusionsInclusion of varenicline and counseling in a vaping cessation program for EC users intending to quit may result in prolonged abstinence. These positive findings may also help guiding future recommendations for vaping cessation by health authorities and healthcare providers.

ObjectiveTo systematically review and meta-analyse evidence regarding the efficacy of electronic nicotine delivery systems (ENDS) as smoking cessation aids. Data SourcesPubMed, Scopus, Web of Science, PsycINFO, MEDLINE and Cochrane Library were searched up to February-March 2020 (PROSPERO registration CRD42020170692). Study selectionPublished peer-reviewed randomised controlled trials (RCTs) of the efficacy of ENDS for sustained cessation of combustible tobacco smoking and/or nicotine use, compared with no intervention, placebo or nicotine replacement therapy (NRT) by intention-to-treat, with a minimum of four months follow-up. Data ExtractionData were extracted independently into a pre-specified template. Risk of bias was assessed with the Cochrane Collaborations tool and evidence quality rated using GRADE. Data SynthesisFrom 3,973 titles identified, nine RCTs were identified; 330 of 5,445 smokers randomised quit. Smoking cessation did notPublic health consequences differ significantly for randomisation to ENDS versus: no intervention (three studies, random-effects meta-analysis RR 1.95; 95%CI 0.90-4.22); placebo (three studies, 1.61; 0.93-2.78) or NRT (three studies; 1.25; 0.74-2.11). Fixed-effects sensitivity analyses showed significant results for ENDS vs NRT (1.43; 1.10-1.86). Smokers randomised to ENDS were substantially more likely than control to use nicotine at follow-up. Overall evidence quality was low. Considering only studies without potential competing interests further limited evidence but did not materially change conclusions. ConclusionsThere is insufficient evidence that ENDS are efficacious for smoking cessation compared to no intervention, placebo or NRT. Results are promising, particularly for therapeutic use, but vary according to analytic method. ENDS may lead to greater ongoing nicotine exposure than other smoking cessation methods. ImplicationsThis systematic review and meta-analysis consolidates current evidence on the efficacy of ENDS as an aid to sustained smoking and nicotine cessation and considers these findings in the context of potential competing interests. While findings are promising more research - preferably independent of industry funding - is needed to provide robust evidence of the efficacy of ENDS for smoking cessation. Future research should investigate nicotine cessation in addition to smoking cessation.

ImportanceThe tobacco industry exploits legislative loopholes by introducing products with novel constituents, sensory features, and/or branding to bypass flavor restrictions and maintain appeal, particularly among young populations. Post Californias 2022 flavor ban, leading oral nicotine pouch (ONP) brand (ZYN) started marketing two new "unflavored" products, Classic and Original, but it is unknown if they differed from pre-ban products marketed as "flavor-ban approved" (Chill and Smooth) in their chemical composition, sensory characteristics and human appeal. MethodsNicotine, menthol, and synthetic coolants, WS-3 and WS-23, were quantified using gas chromatography-mass spectrometry. Menthol receptors (TRPM8 and TRPA1) activity was measured by calcium-microfluorimetry to assess cooling-and irritation-potential. ONP sensory attributes and appeal were assessed in young-adults (21-25Yr old) after 5-minute standardized use in a double-blind, randomized remote trial. Results"Chill" and "Classic" ONPs contained WS-3 exclusively (0.24{+/-}0.02 mg/pouch), with consistent levels across nicotine strengths; "Smooth" and "Original" contained neither menthol nor WS-3. Extracts of "Chill" and "Classic" robustly activated the cold/menthol TRPM8-receptor with similar potency and efficacy, while weakly activating the sensory irritant TRPA1 receptor. Human participants rated "Chill" and "Classic" as having stronger cooling sensations (p<0.05), while "Classic" was rated as more minty flavored when compared to unflavored "Smooth" and "Original" (p<0.005) ONPs. Conclusions and RelevancePre- and post-ban ONPs showed similar chemical, sensory, and appeal profiles based on WS-3 presence. By using concept names and sensory cues to disguise flavors, industry exploits regulatory loopholes to sustain marketing of banned products. What is already known on this topicOral nicotine pouches (ONPs) have gained popularity among young adults, and manufacturers have introduced products and marketed as "ban-compliant" with concept names and sensory additives that may mimic flavors despite flavor bans. What this study addsChemical, receptor, and sensory analyses of pre- and post-ban ZYN ONPs showed both contained the synthetic coolant WS-3, producing flavor-like cooling sensations even without menthol or other flavor compounds. How this study might affect research, practice, or policyFindings indicate that post-ban ONPs retain the same sensory and chemical properties as pre-ban products, highlighting enforcement challenges when odorless sensory additives and branding strategies allow products to retain flavor-like effects despite legislative restrictions.

AimsTo examine the association between household members and their tobacco smoking behaviour on patterns of smoking cessation and relapse. Design and participantsData was sourced from 19 waves (years 2001 to 2019) of the nationally representative Household Income and Labour Dynamics in Australia (HILDA) survey, with all household members 15 years or older completing the survey annually. The final sample included, on average, 3,056 ex-smokers and 2,612 smokers per wave. MeasurementsSelf-reported annual smoking status was used to construct measures of smoking cessation and relapse. Information on household structure and relationships was then used to develop variables describing the presence of household members and their smoking status by relationship to the individual (i.e., child, parent, spouse, sibling, or other). Multivariate regression analyses were then used to predict the likelihood of smoking cessation and relapse controlling for the presence of other household members and their smoking status, sociodemographic characteristics, number of cigarettes smoked per day, previous quit attempts, and years abstained from smoking. FindingsIndividuals that lived with non-smokers were more likely to quit [OR1.22 (95%CI 1.11;1.34)] relative to those living alone. However, this favourable association was negated if living with another smoker, which was associated with a reduced likelihood of smoking cessation [OR0.77 (95%CI 0.72;0.83)] and a higher likelihood of relapse [1.37 (95%CI 1.22;1.53)]. In particular, living with a spouse or parent that smoked reduced the likelihood of smoking cessation [OR0.71 (95%CI 0.65;0.78) and OR0.71 (95%CI 0.59;0.84), respectively] and increased the likelihood of relapse [OR1.47 (95%CI 1.28;1.69) and OR1.39 (95%CI 1.00;1.94) respectively] relative to living with their non-smoking counterparts. ConclusionsHousehold composition and intrahousehold smoking behaviour should be considered when delivering, or estimating the benefits of, smoking cessation interventions. Interventions which encourage smoking cessation at the household level may assist individuals to quit and abstain from smoking.

IntroductionTobacco smoking remains a leading cause of preventable death in the UK. Although e-cigarettes are promoted as a harm-reduction option, longitudinal evidence on short-term health outcomes across different smoking transition pathways is limited. This study examined short-term associations between transitions to exclusive e-cigarette use, dual use, or cessation and physical health, mental health, and health-related quality of life, compared with continued smoking. MethodsA target trial emulation framework was applied to Waves 7-14 (2015-2024) of the UK Household Longitudinal Study, including 18,011 participant-wave observations from baseline smokers. Propensity score matching (1:3) was used to create comparable exposure groups. A doubly robust analysis-combining matching with Ordinary Least Squares regression-estimated outcomes using the SF-12 Physical (PCS) and Mental (MCS) Component Summary scores and a mapped EuroQol 5-Dimensions 3-Level version (EQ-5D-3L) index. The SF-12 is a validated generic health measure, where PCS and MCS are norm-based scores (mean = 50, SD = 10). The EQ-5D-3L index (range: 0 to 1) reflects overall health utility. ResultsCompared with continued smokers, exclusive e-cigarette users had higher short-term mental health scores (SF-12 MCS {beta} = 1.042; 95% CI: 0.229 to 1.855). In contrast, dual users had lower mental health scores ({beta} = -1.023; 95% CI: -1.574 to -0.472). Short-term physical health scores (SF-12 PCS) were lower among both exclusive switchers ({beta} = -0.670; 95% CI: - 1.287 to -0.053) and quitters ({beta} = -0.486; 95% CI: -0.853 to -0.119), with no evidence of short-term physical health improvement for any transition group. Dual users also had lower health-related quality of life (EQ-5D-3L {beta} = -0.016; 95% CI: -0.025 to -0.008). Subgroup analyses suggested heterogeneity by age and socioeconomic position, with poorer outcomes among older and more disadvantaged smokers. Sensitivity analyses produced directionally consistent findings. ConclusionExclusive switching to e-cigarettes was associated with higher short-term mental health scores, whereas dual use was associated with poorer mental health and health-related quality of life. These findings underscore the importance of distinguishing complete switching from dual use when designing harm-reduction policies and smoking cessation support.

BackgroundMenthol and tobacco-flavored nicotine delivery systems (ENDS) are widely used as safer alternatives to combustible cigarettes. These flavored products include constituents such as propylene glycol/vegetable glycerin (PG/VG), benzoic acid, acetoin, L-menthone, 98% menthone, 2-isopropyl-N,2,3-trimethylbutanamide (WS-23), vanillin, and carvone. However, little is known about the potential adverse effects of the constituents in these flavored products. Rationale and hypothesisWe hypothesized that exposure to common constituents in tobacco- and menthol-flavored ENDS constituents could elicit a lung-injurious response mediated by nicotinic acetylcholine receptor (-nAChR or CHRNA) modulation. MethodsHuman bronchial epithelial cells, BEAS-2B, cells were treated with commonly used menthol and tobacco constituents on trans well inserts. Transepithelial barrier resistance (TEER) and millivolts (mV) across epithelial cells were measured over a 24-hour time. To assess the elicited inflammatory response, cytokines IL8 and IL6 were quantified in the conditioned media. Cytotoxicity caused by these constituents was evaluated by acridine orange/propidium iodide (AO/PI) staining of the cells after 24 hrs. alpha nicotinic receptor protein abundance (1, 4, 5, and 7) was quantified by immunoblotting. ResultsEpithelial integrity was decreased over time with a significant decrease in TEER and voltage by ENDS constituents. A significant increase in IL6 in conditioned media was observed in PG/VG, carvone, and WS-23 treated cells. Carvone-treated cells also elicited significantly elevated IL8 in conditioned media. Further, increased 1, 4, 5, and 7 nAChR were seen in cells treated with PG/VG, Acetoin, Carvone, and WS-23. ConclusionThese findings suggested that common constituents in menthol- and tobacco-flavored ENDS induce lung inflammation, epithelial barrier dysfunction, and lung injury. Further, our data implicate potential lung disease pathogenesis via nAChR modulation-mediated inflammation by exposure to these ENDS constituents, even in the absence of nicotine.

BackgroundRegulating features of tobacco products can reduce the appeal and addictiveness of smoking. We examined predicted behavioural responses to bans on i) filter ventilation (FV), ii) regular nicotine content (RNC), and iii) menthol and flavour crushballs (MFC), as well as perceived rationales for these bans. MethodsAustralian adults who smoked at least weekly were recruited from an online research panel to participate in a cross-sectional survey and were allocated to either the FV (n=301), RNC (n=335), or MFC (n=298) study arm, depending on current product use. Respondents viewed a basic description of each ban before completing measures of predicted behavioural responses and perceived rationale. ResultsThe proportion of respondents who reported being likely to try to quit smoking in response to the product regulations was 25.9% in the FV arm, 18.5% in the RNC arm, and 13.4% in the MFC arm. However, in each study arm, respondents more commonly predicted that they would switch to tobacco products that would remain available after the ban (FV: 33.6%; RNC: 37.0%; MFC: 51.3%), and some reported being likely to switch to e-cigarettes (FV: 14.6%; RNC: 11.6%; MFC: 23.2%). The majority of respondents reported either misperceptions or uncertainty about the rationale for the bans (FV: 69.8%; RNC: 81.5%; MFC: 62.4%). ConclusionA higher proportion of people who smoke anticipate that they would respond to tobacco product bans by switching to a different product, rather than using the ban as an opportunity to quit. Future studies should experimentally investigate whether public health messaging about these product regulation measures can be used to encourage greater rates of quitting by minimising switching to available products, including e-cigarettes, and to minimise misperceptions by increasing awareness of the rationale for each product regulation measure.

ObjectivesUptake of evidence-based smoking cessation support remains limited. Digital interventions offer the prospect of scalable and highly accessible support. Smoke Free, a digital mobile application using established behaviour change techniques, has shown promise, but no large-scale randomised controlled efficacy trial has yet been conducted. We assessed its effectiveness for smoking cessation. DesignIn this prospective, randomised, controlled, two-arm, parallel clinical trial with 6-month follow-up, study personnel and patients were blinded. SettingThe trial was conducted nationwide in Germany, utilising a decentralised, fully remote trial design. Enrolment took place digitally after receiving brief advice from a healthcare professional, following guidelines for primary care. ParticipantsOut of a volunteer sample of 1850 patients assessed for eligibility, 1466 adult cigarette smokers who had at least moderate cigarette dependence (F17.2, FTCD[&ge;]3) were recruited between August 2023 and February 2024; 84.1% (1233 participants) completed the primary outcome measure. InterventionsThe intervention group (IG) received the Smoke Free app including behaviour-change missions and gamification elements, while the control group (CG) received a text-only cessation information app. Both groups received brief advice from a healthcare professional. Main outcome measuresThe prespecified primary outcome was self-reported 7-day point-prevalence abstinence from combustible tobacco at 6 months post-randomisation; secondary outcomes included biochemical validation of abstinence in participants providing a saliva sample (59% of eligible participants). ResultsSelf-reported abstinence (primary outcome) was significantly higher in the IG compared with the CG (283 [39.3%] vs. 182 [24.4%], OR=2.01, 95% CI 1.60 to 2.50, p<0.0001). The NNT was 6.7 (5.1 to 9.8). The effect was consistent with biochemical validation (OR=1.76, 95% CI 1.27 to 2.44, p<0.0001) and across secondary outcomes and sensitivity analyses. The 6-month follow-up rates for the primary outcome did not differ between groups (IG: 601 [83.5%]; CG: 632 [84.7%]; p=0.52). Eighty-four serious adverse events were reported by 75 participants (IG: 31, 4.3%; CG: 44, 5.9%; p=0.53); none were treatment-related. ConclusionsThe Smoke Free app is effective for aiding smoking cessation in at least moderately dependent cigarette smokers compared with an informational app when provided as an adjunct to brief advice from a healthcare professional. Trial registrationThe trial was registered with the German Clinical Trials Register (DRKS00031140). FundingSmoke Free 23 GmbH (for-profit company).

BackgroundPictorial health warnings on tobacco packs can stimulate short-term cognitive and emotional responses that lead to quit attempts. We tested novel product attribute health warnings (PAHWs) that corrected misperceptions about harm created by the use of filter-venting, menthol and roll-your-own tobacco. PAHWs uniquely influenced outcomes assessing knowledge of industry manipulation of cigarettes, industry-centric negative emotional responses, and product-specific smoking dissonance. In this study, we examined if these unique short-term responses predicted subsequent quitting-related behaviours. MethodWe analysed follow-up data from a between-subjects online experiment that assessed effects of new PAHWs. Participants were randomised to view PAHWs alone (PAHW condition) or with a complementary video (PAHW+Video), and exposure occurred during a baseline session and then repeatedly each day for 7 days. Short-term PAHW responses were measured at 8-day follow-up (N=712). Quitting-related behaviours were measured at 4-week follow-up (N=301). Covariate-adjusted logistic regression models examined associations between short-term PAHW responses and subsequent quitting-related behaviours. ResultsTwo of the short-term responses - knowledge of industry manipulation of cigarettes, and product-specific smoking dissonance - significantly and positively predicted all three quitting-related outcomes: smoke-limiting micro-behaviours (e.g., foregoing cigarettes), quit attempts, and 7-day sustained abstinence. Additionally, industry-centric negative emotional responses significantly and positively predicted smoke-limiting micro-behaviours and 7-day sustained abstinence, but not quit attempts. ConclusionPAHWs featuring corrective information about the tobacco industrys manipulation of tobacco products elicited short-term responses that predicted subsequent engagement in smoke-limiting micro-behaviours, quit attempts, and sustained quit attempts. PAHWs can complement other health warnings featuring the health risks of smoking and may help motivate people who smoke to quit and stay quit.

Electronic cigarette liquids (e-liquids) often contain flavors and solvents that may influence nicotine addiction. In this study, we characterized the dose-response relationship of commercial unflavored nicotine e-liquids and investigated the impact of vanilla-flavored e-liquids on nicotine vapor self-administration (VSA) and withdrawal in rats. Male adolescent Sprague Dawley rats self-administered aerosols generated from commercial e-liquids containing 0, 3, 6, or 12 mg/ml nicotine in a propylene glycol (PG) and glycerol (G) vehicle. The vehicle (0 mg/ml nicotine) supported robust VSA, indicating the reinforcing effects of PG/G vapor. 3 mg/ml nicotine did not support VSA, while both 6 and 12 mg/ml nicotine concentrations produced significant reinforcement, with 6 mg/ml yielding the most stable responding. The 6 mg/ml concentration was selected for subsequent comparisons with vanilla-flavored e-liquids. Vanilla flavor (0 mg/ml nicotine) led to maintained VSA behavior, confirming its reinforcing effects. However, the combination of vanilla and nicotine (6 mg/ml) did not alter nicotine intake or withdrawal severity, as assessed by mecamylamine-precipitated somatic signs. Blood nicotine and cotinine levels were similar between nicotine and vanilla + nicotine conditions, indicating that vanilla flavor did not affect systemic nicotine metabolism. Additionally, the PG/G vehicle induced significant somatic signs, suggesting that vapor exposure itself, independent of nicotine, contributes to these physiological responses. These findings provide critical insights into the reinforcing and physiological effects of both nicotine and non-nicotine constituents in e-cigarette aerosols, underscoring the need for future studies and regulatory strategies that consider the abuse liability of flavors and solvents, such as PG/G, particularly among adolescents. Significance StatementFlavored electronic nicotine delivery systems raise concern for promoting nicotine use in youth. Using a rat vapor self-administration model, we show nicotine produces concentration-dependent reinforcement, while vanilla flavor is reinforcing but does not enhance nicotine intake or withdrawal.

IntroductionTobacco smoking is a major cause of preventable disease in Australia. Individuals receiving opiate agonist treatment (OAT) are a group who experience high tobacco-related morbidity and mortality rates. Despite reporting a desire to stop, relapse rates in OAT clients are high and cessation attempts supported by pharmacotherapy are less effective than in general populations. New and innovative ways of addressing smoking amongst this group are needed. Vaporised nicotine products (VNPs), or e-cigarettes, may reduce a persons exposure to toxicants and carcinogens when compared to tobacco cigarettes. High quality evidence indicates that VNPs can increase rates of smoking cessation compared to nicotine replacement therapy. Pilot results of VNPs as a smoking cessation aid in OAT clients suggests their use is feasible and acceptable but effectiveness in this group has not been explored. This protocol details the rationale and methodology for a randomised controlled trial to examine the effectiveness of VNPs for tobacco smoking cessation amongst OAT clients in New South Wales, Australia. Methods and AnalysisThis will be a randomised single-blinded parallel group trial comparing 12-weeks of 12mg/mL vaporised nicotine to best-practice NRT. Participants must be 18 years or older, accessing opiate treatment at a participating health site, and a current daily tobacco smoker seeking to quit or reduce their smoking. The primary outcome will be self-reported 7-day point prevalence abstinence from tobacco after 12-weeks of treatment. Secondary outcomes include biochemically verified abstinence, self-reported 30-day abstinence, number of cigarettes smoked each day, craving and withdrawal symptoms, and VNP safety. Between-group comparisons will be conducted at end of treatment, and at 12-weeks post-treatment. DiscussionThis study examines new ways of reducing tobacco related harm in individuals receiving OAT. Outcomes may be enhanced by leveraging participants interactions with health care provides who can facilitate the required support. Study findings have the potential to significantly impact tobacco smoking prevalence in priority populations. Ethics and DisseminationProtocol approval was granted by Hunter New England Human Research Ethics Committee (Reference 2020/ETH01866). Findings will be disseminated via academic conferences, peer-reviewed publications and social media. RegistrationThe study was registered in the Australian New Zealand Clinical Trials Registry (Reference ACTRN12621000148875).

BackgroundUnderstanding the relationship between electronic nicotine delivery systems (ENDS) use and chronic obstructive pulmonary disease (COPD) and other respiratory conditions is critical. However, previous studies have not adequately controlled for history of cigarette smoking. Research QuestionTo examine the prospective association between ENDS use and self-reported incident COPD after adjusting for cigarette smoking history. Study Design and MethodsUsing waves 1-5 of the US Population Assessment of Tobacco and Health (PATH) study, we examined the association between ENDS use and self-reported incident COPD among adults aged 40+ using discrete time survival models. Current ENDS use was measured as a time-varying covariate, lagged by one wave, defined as established daily or some days use. We controlled for baseline demographics (age, sex, race/ethnicity, education), health characteristics (asthma, obesity, exposure to second-hand smoke), and smoking history (smoking status and cigarette pack-years). ResultsIncident COPD was self-reported by 925 respondents during the five-year follow-up period. Prior to adjusting for other covariates, time-varying ENDS use appeared to nearly double the risk of incident COPD (HR 1.98, 95% CI 1.44-2.74). However, ENDS use was no longer significantly associated with COPD (aHR 1.10, 95% CI 0.78-1.57) after adjusting for current cigarette smoking and cigarette pack-years. The risk of self-reported incident COPD increased with cigarette pack-years and was higher for respondents who were older, female, less educated, and had baseline asthma or obesity. InterpretationENDS use did not significantly increase the risk of self-reported incident COPD over a five-year period once current smoking status and cigarette pack-years were taken into account. Cigarette pack-years, on the other hand, remained associated with a net increase in the risk of self-reported incident COPD. These findings highlight the importance of using prospective longitudinal data and properly controlling for cigarette smoking history to assess the independent health effects of ENDS.

IntroductionThe use and availability of heated tobacco products has increased globally. However, the health effects of IQOS product use remain contradictory, and the impact of IQOS product use on respiratory health and immune biomarkers is lacking. Industry sponsored studies suggest IQOS products reduce exposure to harmful chemicals compared to conventional cigarettes and show attenuated inflammatory responses compared to cigarette smoke, yet independent research studies indicate exposure to IQOS is still associated with negative health outcomes similar to conventional cigarettes. Clinical data is needed to understand the respiratory health impacts of IQOS use in people who currently smoke cigarettes. MethodsAdults located in Los Angeles, California were recruited for the Adult IQOS Respiratory Study (AIRS, N = 32; 21-65 years). Nasal epithelial lining fluid (NELF) and saliva collected from adults who were willing to incorporate IQOS into their daily habits, were analyzed by multiplex enzyme linked immunosorbent assays for 29 different inflammatory markers or cotinine, respectively. Repeated measures ANOVA were used to identify changes in immune markers across the weekly visits. Linear mixed modelling was used to identify changes in participant cigarette or IQOS HeetStick use over the study period. Day was added as a fixed effect. ResultsBetween-participants variability in IQOS or cigarette usage was identified (p < 0.0001). IQOS and cigarette use did not significantly change across time and remained stable over the course of the 4-week study period. No significant changes were identified in soluble protein mediators across each week. Cotinine concentrations remained consistent, even when disaggregated by sex and visit. ConclusionsAll together, these data highlight that dual product use may be more likely in individuals who smoke cigarettes, particularly over the first month of incorporation, rather than completely switching to IQOS products when provided. Furthermore, incorporating IQOS did not significantly change nicotine exposure or nasal inflammatory biomarkers, suggesting, at least with nicotine exposure and nasal inflammation, that addition of heated tobacco products may not substantially reduce harm. What is already known on this topicHeated tobacco products are marketed as less harmful and smoke-free alternative products compared to conventional cigarettes; however, lack of respiratory data and contradictory reports suggest they may still pose risks and use may contribute to consequential health impacts. Short-term and industry sponsored studies are available, but limited clinical data exists on the respiratory and immunological impacts of IQOS product use. What this study addsIn the follow repeated measures study, our findings provide clinical evidence there are no significant differences in nasal immune biomarkers in individuals that smoke, who incorporate IQOS into their lifestyles. While each participant varied in their IQOS and cigarette product use, no significant trends were observed over the four-week sampling period in overall IQOS or cigarette use. Additionally, when participants were provided with the IQOS option, they were more inclined to dual use both products rather than switch from cigarettes to only IQOS use in the 4 week period studied. How this study might affect research, practice or policyThe following clinical study suggests there is an increased likelihood of dual use among individuals who are provided alternative tobacco products. Additional studies should consider evaluating health differences, including immunological markers, between individuals who dual use IQOS and other tobacco products, exclusively use IQOS, people who completely switch their product use and people who quit altogether to establish whether IQOS use reduces harmful exposures resulting in differential inflammatory responses when compared to cigarette use.