New types of nicotine and tobacco products like electronic cigarettes (ECs), heated tobacco products or nicotine pouches have been discussed as less harmful alternatives to combustible cigarettes and other toxic forms of tobacco products. Their harm reduction potential lay in the efficient transition away from smoking to those new products. Numerous studies addressing the cessation efficacy of ECs have been published with contradictory outcomes. Yet, a comprehensive Cochrane review concluded with high certainty on the cessation efficacy of ECs. This prompted us to perform a review to identify weaknesses in common study designs and to summarize best practices for the study design on the potential of new nicotine products as cessation aids. 120 articles retrieved from Medline were found to be eligible. Most of the studies in the field were interventional trials while observational studies played a minor role in the evaluation of smoking cessation. Efficacy was predominantly assessed for ECs in 77% of the reports while heated tobacco (17%) and non-combustible products (11%) were less frequently investigated up to now. Measures to determine the efficacy were questionnaire-based assessments as well as use documentation/prevalence and abstinence rates. Studies varied largely in their duration and sample size with medians of 3 months and 156.5 participants, respectively.With the help of this review, we identified several weaknesses in the common study designs. One major limitation in longitudinal trials was the lack of compliance measures suited to verify the use status over longer time periods, relying solely on self-reports. Moreover, the motivation of the participants to quit was rarely defined and a profound familiarization period was not taken into account for the majority of the studies. To what extent such weaknesses influence the outcome of the studies was beyond the scope of this review. We encourage researchers to consider the recommendations which resulted from this review in order to determine the abuse liability and cessation efficacy of the products in a more robust manner. Finally, we like to call attention to the missing data for low- and middle-income countries which would require quitting strategies most urgently to combat the tobacco smoking epidemic.

BACKGROUND: Cigarette smoking is a leading cause of morbidity and mortality. For adults who smoke cigarettes and cannot or will not quit smoking, smoke-free products, such as nicotine pouches, have been recognized as a potential alternative to smoking combusted cigarettes to reduce harm due to cigarette smoking. The role of flavors in these smoke-free products in tobacco harm reduction has not been fully understood.
OBJECTIVE: This study evaluates the effect of flavors in on! nicotine pouch products (research products) in the reduction of cigarette smoking among adults who smoke cigarettes in their natural environment.
METHODS: This study uses a sequential, multiple assignment, randomized trial design. Approximately 400 eligible adults who smoke cigarettes will be enrolled and randomized to have access to either the Original (unflavored) on! nicotine pouch product only or a complete flavor profile (ie, Berry, Cinnamon, Citrus, Coffee, Mint, Original, and Wintergreen) of on! nicotine pouch products. After 3 weeks, participants in the Original-only arm will be randomized again, with half remaining in the Original-only arm and half having access to the complete flavor profile for another 3 weeks. Primary outcomes are expired-air carbon monoxide (CO) levels. Secondary outcomes are self-reported cigarette consumption and CO-verified cigarette abstinence.
RESULTS: Recruitment and data collection started in September 2023 and is projected to last until March 2025. We anticipate completing the data analysis in 2025. As of May 2024, we have enrolled 314 participants.
CONCLUSIONS: This study will provide empirical evidence about the effect that flavor availability in smoke-free products may have in reducing cigarette smoking.
BACKGROUND: ClinicalTrials.gov NCT06072547; https://clinicaltrials.gov/study/NCT06072547.
UNASSIGNED: DERR1-10.2196/56565.

Tobacco-free nicotine pouches are new nicotine products for oral consumption. They can contain very high nicotine amounts that have not been addressed with clinical studies yet. Thus, nicotine delivery, effects on craving, and side effects were assessed using pouches with up to 30 mg nicotine. In this single-center, five-arm, crossover study, 15 regular cigarette smokers consumed tobacco-free nicotine pouches from different brands with 6, 20, and 30 mg for 20 min. Comparators were nicotine-free pouches and tobacco cigarettes. At baseline and predefined time points over a study period of 240 min, plasma nicotine concentrations, effects on cigarette craving, and side effects were assessed. Cardiovascular parameters including arterial stiffness were measured using a MobilOGraph. Consumption of 30 mg nicotine pouches has led to a higher nicotine uptake compared with the cigarette (Cmax: 29.4 vs 15.2 ng/mL; AUC: 45.7 vs 22.1 ng/mL × h). Nicotine uptake in the acute phase was rapid during use of the 30 mg pouch and cigarette. Extraction rate of nicotine differed between pouches. Use of all products has reduced acute cigarette craving, even the nicotine-free pouch. During consumption of the cigarette and the pouches with 20 and 30 mg, heart rate increased about 27, 12, and 25 bpm, respectively. Parameters for arterial stiffness were elevated and all pouches have induced mouth irritations. The pouches with 30 mg nicotine had overall the strongest side effects and may induce addiction. As craving was also reduced by products with less nicotine, it is questionable whether such high nicotine contents should be allowed on the market. A limit of nicotine content is warranted. The nicotine release rate varies across products and needs to be known to estimate the nicotine delivery.

BACKGROUND: Alternative Nicotine Delivery Systems (ANDS) such as e-cigarettes (EC) and oral nicotine pouches (ONP) may facilitate the substitution of smoking for those unwilling to quit. This pilot study assesses the harm reduction potential of EC and ONP among smokers with low socioeconomic status (SES).
METHODS: Adults who smoked daily in the past 6 months, had a household income < 250% federal poverty level and had no intention of quitting smoking in the next 30 days were randomized 2:2:1 to 8 Weeks of 5% nicotine EC; 4mg ONP or assessment-only control (CC). The primary outcome was a within-group change in cigarettes per day (CPD) from Baseline to Week 8.
RESULTS: 45 individuals were randomized (EC: N=18; ONP: N=18; CC: N=9). Analyses included 33 participants who completed the Week 8 visit. Mean age was 50.2 years (SD:10.7) and average CPD at baseline was 13.9 (SD: 10.1). For those randomized to EC, average CPD decreased from 14.7 (95%CI: 10.3; 19.1) at Baseline to 2.9 (95%CI: 0.09; 5.79) at Week 8 (p-value <0.001). For those randomized to ONP, average CPD decreased from 15.0 (95%CI: 5.02; 24.93) to 8.3 (95%CI: 1.34; 15.18) by Week 8 (p-value =0.01). In the EC and ONP groups, respectively, 4 (28.6%) and 1 (8.3%) participant fully switched from smoking to the ANDS product by Week 8.
CONCLUSIONS: Individuals with low SES who smoke had lower CPD after switching to EC or ONP. These findings show the potential of ANDS in helping smokers switch to less harmful devices.
CONCLUSIONS: This study provides novel evidence that e-cigarettes and nicotine pouches can be a harm reduction tool for individuals with lower SES who smoke and are not willing to quit smoking, contributing to reducing tobacco-related disparities in this population.

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Nicotine pouches contain fewer characteristic toxicants than conventional tobacco products. However, the associated risks in terms of toxicity and addiction potential are still unclear. Therefore, endpoints of toxicity and contents of flavoring substances were investigated in this study. The in vitro toxicity of five different nicotine pouches and the reference snus CRP1.1 were studied in human gingival fibroblasts (HGF-1). Cells were exposed to product extracts (nicotine contents: 0.03-1.34 mg/mL) and sampled at different time points. Cytotoxicity, total cellular reactive oxygen species (ROS) levels, and changes in the expression levels of inflammatory and oxidative stress genes were assessed. Flavor compounds used in the nicotine pouches were identified by GC-MS. Cytotoxicity was observed in two nicotine pouches. Gene expression of interleukin 6 (IL6) and heme oxygenase 1 (HMOX1) was upregulated by one and three pouches, respectively. ROS production was either increased or decreased, by one pouch each. CRP1.1 caused an upregulation of IL6 and elevated ROS production. Toxicity was not directly dependent on nicotine concentration and osmolarity. A total of 56 flavorings were detected in the five nicotine pouches. Seven flavorings were classified according to the harmonized hazard classification system as laid down in the European Classification, Labelling and Packaging regulation. Nine flavorings are known cytotoxins. Cytotoxicity, inflammation, and oxidative stress responses indicate that adverse effects such as local lesions in the buccal mucosa may occur after chronic product use. In conclusion, flavorings used in nicotine pouches likely contribute to the toxicity of nicotine pouches.

Nicotine pouches are oral products that deliver nicotine without containing tobacco. Previous studies mainly focused on the determination of known tobacco toxicants, while yet no untargeted analysis has been published on unknown constituents, possibly contributing to toxicity. Furthermore, additives might enhance product attractiveness. We therefore performed an aroma screening with 48 different nicotine-containing and two nicotine-free pouches using gas chromatography coupled to mass spectrometry, following acidic and basic liquid-liquid extraction. For toxicological assessment of identified substances, European and international classifications for chemical and food safety were consulted. Further, ingredients listed on product packages were counted and grouped by function. Most abundant ingredients comprised sweeteners, aroma substances, humectants, fillers, and acidity regulators. 186 substances were identified. For some substances, acceptable daily intake limits set by European Food Safety Agency (EFSA) and Joint FAO/WHO Expert Committee on Food Additives are likely exceeded by moderate pouch consumption. Eight hazardous substances are classified according to the European CLP regulation. Thirteen substances were not authorized as food flavorings by EFSA, among them impurities such as myosmine and ledol. Three substances were classified by International Agency for Research on Cancer as possibly carcinogenic to humans. The two nicotine-free pouches contain pharmacologically active ingredients such as ashwagandha extract and caffeine. The presence of potentially harmful substances may point to the need for regulation of additives in nicotine-containing and nicotine-free pouches that could be based on provisions for food additives. For sure, additives may not pretend positive health effects in case the product is used.

BACKGROUND: Nicotine pouches, which emerged in the US in 2016 and are marketed as \'tobacco-free\', may appeal to young adults. This study examined young adults\' nicotine pouch awareness, use, use intentions, and related factors.
METHODS: We analyzed Spring 2022 survey data from 942 young adults recruited via social media from six US cities (mean age=27.61 years, 34.3% men, 33.1% racial/ethnic minority) to characterize nicotine pouch awareness, ever use, use intentions, exposure, and perceptions.
RESULTS: Nicotine pouch awareness and ever use were reported by 34.6% and 9.8%, respectively. Males (AOR=1.79; 95% CI: 1.33-2.38), non-White participants (vs White; AOR=1.64; 95% CI: 1.04-2.61), and those using cigarettes (AOR=2.67; 95% CI: 1.63-4.38), e-cigarettes (AOR=2.28; 95% CI: 1.57-3.31), and smokeless tobacco (SLT) (AOR=14.46; 95% CI: 1.81-115.61) had greater odds of awareness. Among those aware of nicotine pouches, males (AOR=2.27; 95% CI: 1.33-3.85), White participants (vs Asian; AOR=0.40; 95% CI: 0.17-0.94), and SLT users (AOR=4.90; 95% CI: 1.26-18.98) had greater odds of ever use; being male (B=0.39; 95% CI: -0.67 - -0.12) and using SLT (B=1.73; 95% CI: 1.10-2.36) predicted greater use intentions. Overall, 31.4% reported past-month advertising exposure, most often via tobacco retailers (67.3%). Ever users most commonly purchased them at gas stations (46.7%). The most frequently reported use motives were to quit combusted tobacco (16.8%) and reduce tobacco smell (15.4%). Nicotine pouches were perceived as less harmful and less addictive than cigarettes, e-cigarettes, and SLT, and more socially acceptable than cigarettes and SLT.
CONCLUSIONS: Young adults were exposed to advertising, accessed nicotine pouches via various sources, and perceived these products favorably. Marketing and use surveillance is needed to monitor their impact on those likely to use them (e.g. males, SLT users).

The use of alternative nicotine products by middle and high school students is a growing concern due to industry marketing techniques, availability, and popularity of new products, and ambiguous nicotine concentrations. The 2021 National Youth Tobacco Survey (NYTS) provides information about the frequency, and characteristics of middle, and high school students who have used nicotine pouches.
The National Youth Tobacco Surveys provide important information about the frequency of use of tobacco and alternative nicotine products by a representative sample of students in schools in the United States. The 2021 survey included questions about the use of nicotine pouches/dissolvable tobacco products. The results from the survey were analysis using descriptive statistics, and logistic regression to model the association between the use of these alternative nicotine products, and the use of electronic cigarettes or the use of conventional cigarettes.
A total of 20 413 students participated in the survey year 2021; 17 842 were included in the final data analysis. Their ages ranged from 9 to 18+. Identified risk factors for the use of alternative nicotine products included race, and age. The adjusted odds ratio (OR) was lower in non-Hispanic Black and Hispanic students, as compared to non-Hispanic White students. Older students had a substantially higher risk of using nicotine/dissolvable tobacco products, specifically, compared to students less than or equal to 13 years old. The OR increased 174% (OR: 2.74; 1.70-4.41) in 17-year-old students. The perception of harm associated with electronic cigarettes increased the likelihood of using alternative nicotine products. Students who did not smoke cigarettes (OR: 0.39; 0.27-0.56) or did not smoke electronic cigarettes (OR: 0.20; 0.18-0.40) had significantly lower OR for using alternative nicotine products.
The 2021 National Youth Tobacco Survey indicates that a relatively small percentage of middle school and high school student have used nicotine pouches. However, with the increase in new, alternative tobacco products, understanding adolescent use in comparison to other tobacco products is an important trend to monitor.

Background: National surveillance assessing use of novel oral tobacco products (OTPs; nicotine pouches, lozenges, and gums not approved for tobacco cessation) among adolescents and young adults is limited. Objectives: To assess OTP behaviors in a sample of adolescent and young adult e-cigarette users, including use prevalence, dual/poly use with other products, and associated demographics. Methods: A national (United States) cross-sectional survey was conducted from March to April 2021 among 2253 participants (ages 14-20; 65% female) who ever used e-cigarettes ≥3 times. Demographics, lifetime use, and past 30-day use of 10 tobacco and cannabis products, including novel and conventional (chew, moist snuff, or snus) OTPs was assessed. Analysis was descriptive, examining use prevalence (lifetime and past 30-day) of each product, including by demographics and other product use. Results: Nearly 44% reported ever using any OTP, with nicotine pouches being the most commonly ever used (29%) and used in the past month (11%). Novel OTP use was more common among older participants (18-20 years), male participants, and past 30-day users of e-cigarettes, combustible tobacco, and conventional oral tobacco. However, female participants and combustible tobacco non-users were over twice and 4-times as likely, respectively, to use novel OTPs than conventional OTPs. Nearly 73% of past 30-day conventional OTP users were past 30-day novel OTP users. Conclusion: Novel OTP use was prevalent among adolescent and young adult e-cigarette users. Compared to conventional OTPs, novel OTPs likely have greater appeal to females and combustible tobacco non-users. Action to restrict access and reduce interest in OTPs is needed to prevent use among this population.