Small pouches, but high nicotine doses-nicotine delivery and acute effects after use of tobacco-free nicotine pouches.

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.

Oral nicotine pouches with an aftertaste? Part 2: in vitro toxicity in human gingival fibroblasts.

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.

Two Different Heated Tobacco Products vs. Cigarettes: Comparison of Nicotine Delivery and Subjective Effects in Experienced Users.

Heated tobacco products (HTPs) produce aerosol using a different mechanism than tobacco cigarettes, leading to lower emissions of some harmful substances, but also of nicotine as reported by some independent studies. Lower nicotine delivery could lead to compensatory puffing when product use does not sufficiently satisfy cravings. Thus, this three-arm crossover study was conducted to characterize the potential of two different HTPs to deliver nicotine and satisfy cravings compared with conventional cigarettes in users who had already switched to HTPs. Fifteen active, non-exclusive HTP users consumed the study products according to a pre-directed puffing protocol. At predetermined time points, venous blood was sampled and the subjective effects of consumption were assessed. Nicotine delivery by both HTPs was comparable, but significantly lower than that by conventional cigarettes, suggesting a lower addictive potential. Cravings were reduced by all products, with no statistically significant differences between them, despite the different nicotine deliveries. This indicated that HTPs do not necessarily need high nicotine deliveries with high addictive potential, as are characteristic of tobacco cigarettes. These results were followed up on with an ad libitum use study.

Oral nicotine pouches with an aftertaste? Part 1: screening and initial toxicological assessment of flavorings and other ingredients.

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.

Usage Pattern and Nicotine Delivery during Ad Libitum Consumption of Pod E-Cigarettes and Heated Tobacco Products.

Many different nicotine delivery products, such as e-cigarettes (e-cigs) or heated tobacco products (HTPs), are available on the market. To better understand these products, it is crucial to learn how consumers use them and how much nicotine they deliver. Therefore, a pod e-cig, an HTP, and a conventional cigarette (CC) were each used by 15 experienced users of the respective product category for 90 min without special use instructions ("ad libitum"). Sessions were video recorded to analyze usage patterns and puff topography. At defined time points, blood was sampled to determine nicotine concentrations, and subjective effects were inquired about using questionnaires. During the study period, the CC and HTP groups averaged the same number of consumption units (both 4.2 units). In the pod e-cig group, the highest number of puffs was taken (pod e-cig 71.9; HTP: 52.2; CC: 42.3 puffs) with the most extended mean puff duration (pod e-cig: 2.8 s; HTP: 1.9 s; CC: 1.8 s). Pod e-cigs were predominantly used with single puffs or in short clusters of 2-5 puffs. The maximum plasma nicotine concentration was highest for CCs, followed by HTPs, and then pod e-cigs with 24.0, 17.7, and 8.0 ng/mL, respectively. Craving was reduced by all products. The results suggest that the high nicotine delivery known for tobacco-containing products (CCs and HTPs) may not be needed for non-tobacco-containing products (pod e-cigs) to satisfy cravings in experienced users.