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Electronic nicotine delivery systems (ENDS) use one of two formulations of nicotine—freebase or nicotine salt. This study examines whether maintenance or switching between nicotine formulations is associated with ENDS dependence using longitudinal survey data. 543 U.S. adults (21+) using ENDS frequently (5+ days/week) self-reported and uploaded photos of their most used ENDS liquids in wave 3–5 online surveys from September 2021 to April 2023. Nicotine formulation from photo data was used if available; otherwise, self-reported data were used. ENDS dependence was measured in each wave by a 4-item E-cigarette Dependence Scale (EDS: range 0–4, 4 being most dependent). Data were analyzed using ANCOVA. Participants using nicotine salt liquids in three waves reported the highest EDS in wave 5 (49.3%, EDS = 2.59), followed by participants switching from salt to freebase (3.2%, EDS = 2.58), participants switching from freebase to salt (10.1%, EDS = 2.52), participants using freebase in three waves (34.9%, EDS = 2.18), and participants changing back and forth (2.4%, EDS = 2.11). After controlling for smoking status, participants stably using nicotine salt and participants switching from freebase to salt reported significantly higher EDS than those stably using freebase (p < 0.01). Over an 18-month period, people consistently using nicotine salt liquids and participants switching from freebase to nicotine salt were more likely to have a higher ENDS dependence than those consistently using freebase liquids. Understanding how switching between nicotine formulations relates to ENDS dependence can inform nicotine formulation and concentration regulations that may impact addiction. [ABSTRACT FROM AUTHOR]

Background: New fourth generation electronic nicotine delivery system (ENDS) devices contain high levels of nicotine salt (up to 60 mg/mL), whose cellular and molecular effects on immune cells are currently unknown. Here, we used a physiologically-relevant in vitro air-liquid interface (ALI) exposure model to assess the toxicity of distinct ENDS, a 3rd-generation electronic-cigarette (e-cig) and two 4th-generation ENDS devices (JUUL and Posh Plus). Methods: Murine macrophages (RAW 264.7) were exposed at the ALI to either air, Menthol or Crème Brûlée-flavored ENDS aerosols generated from those devices for 1-hour per day for 1 or 3 consecutive days. Cellular and molecular toxicity was evaluated 24 h post-exposure. Results: 1-day of Menthol-flavored JUUL aerosol exposure significantly decreased cell viability and significantly increased lactate dehydrogenase (LDH) levels compared to air controls. Further, JUUL Menthol elicited significantly increased reactive oxygen species (ROS) and nitric oxide (NO) production compared to air controls. Posh Crème Brûlée-flavored aerosols displayed significant cytotoxicity – decreased cell viability and increased LDH levels –after 1- and 3-day exposures, while the Crème Brûlée-flavored aerosol produced by the 3rd-generation e-cig device only displayed significant cytotoxicity after 3 days compared to air controls. Further, both Posh and third-generation e-cig Crème Brûlée flavored-aerosols elicited significantly increased ROS plus high levels of 8-isoprostane after 1 and 3 days compared to air controls, indicating increased oxidative stress. Posh and third-generation e-cig Crème Brûlée flavored-aerosols elicited reduction in NO levels after one day, but elicited increase in NO after 3 days. Genes in common dysregulated by both devices after 1 day included α7nAChR, Cyp1a1, Ahr, Mmp12, and iNos. Conclusion: Our results suggest that ENDS Menthol and Crème Brûlée-flavored aerosol exposures from both 3rd- and 4th-generation ENDS devices are cytotoxic to macrophages and cause oxidative stress. This can translate into macrophage dysfunction. Although 4th-generation disposable ENDS devices have no adjustable operational settings and are considered low-powered ENDS devices, their aerosols can induce cellular toxicity compared to air-exposed control cells. This study provides scientific evidence for regulation of nicotine salt-based disposable ENDS products.

Abstract Background Combining short-acting nicotine replacement therapy with varenicline increases smoking cessation rates compared with varenicline alone, but not all people tolerate these medications or find them helpful. We aim to investigate the therapeutic potential of an analogous combination, by evaluating the effectiveness, safety, and acceptability of combining nicotine salt e-cigarettes with cytisine, compared to nicotine salt e-cigarettes or cytisine only, on smoking abstinence at six months. Methods A pragmatic, community-based, investigator-blinded, randomised superiority trial design will be utilised. Eligible participants will be people who smoke daily (N = 800, 90% power) from throughout New Zealand, who are: aged ≥ 18 years, motivated to quit in the next two weeks, able to provide online consent, willing to use e-cigarettes and/or cytisine, and have daily access to a mobile phone. Recruitment will utilise multi-media advertising. Participants will be randomised (3:3:2 ratio) to 12 weeks of: 1) e-cigarettes (closed pod system, 3% nicotine salt, tobacco flavour) plus cytisine; 2) e-cigarettes alone, or 3) cytisine alone. All groups will receive a six-month, text-message-based behavioural support programme. The primary outcome is self-reported, biochemically verified, continuous abstinence at six months post-quit date. Secondary outcomes, measured at quit date, then one, three, six, and 12 months post-quit date, include self-reported continuous abstinence, 7-day point prevalence abstinence, cigarettes smoked per day, withdrawal and urge to smoke, time to (re)lapse, treatment use and compliance, treatment crossover, dual-use, use of other cessation products, change in e-cigarette products, continuation of product use, acceptability, change in health state, health-related quality of life, change in body mass index, adverse events, and cost per quitter. Discussion Pragmatic trials are of particular value as they reflect the ‘real world’ impact of interventions. The trial will provide some of the first evidence on the effectiveness of combining nicotine salt e-cigarettes with cytisine for smoking cessation, in a country with strong tobacco control policy. Findings will be incorporated into relevant systematic reviews, informing practice and policy. Trial registration NCT05311085 ClinicalTrials.gov. Registered 5th April, 2022.

AbstractObjectiveParticipantsMethodsResultsConclusionsThis study examined the relationship between use patterns of a popular e-cigarette brand using nicotine salts, JUUL, and symptoms of nicotine dependence in a college cohort.Data for this study came from a prospective cohort of undergraduate students at a large Midwestern university from 2018 to 2019.Among participants who had ever tried a JUUL (N = 411), univariate and multivariable logistic regression were used to test the associations between use frequency (past 30-day use) and quantity (time to finish a pod) and nicotine dependence at follow up.In the multivariable models, both frequency of use and quantity of use were associated with subsequent nicotine dependence, based on most indicators of dependence.As salt-based nicotine is now present in the most popular e-cigarette brands used by young people, such findings inform our contemporary understanding of e-cigarettes’ addictive potential and can help inform campus-based interventions. [ABSTRACT FROM AUTHOR]

Background: The electronic nicotine delivery systems (ENDS) market is heterogeneous with a wide variety of devices and liquids available to consumers. People with distinct sociodemographic characteristics may have different ENDS device and liquid preferences. Methods: 1290 U.S. adults (21 + ) using ENDS 5 + days/week completed the Wave 5 (February-April 2023) VAPER study survey and submitted photos of their most used ENDS device and liquid. Latent class analysis (LCA) was performed based on sociodemographic characteristics and cigarette smoking status to identify groups among respondents. We examined the association between identified groups and the device (disposable device/disposable pod/refillable pod/tank, power/airflow/coil modifiability)/liquid (nicotine salt/freebase) groupings found by exploratory factor analysis. Results: Among our sample, there were three groups of adults frequently using ENDS: (1) group of women who are older, heterosexual, and have smoked cigarettes (62 % of the sample); (2) group of men who are higher-income and heterosexual (23 % of the sample); and (3) group of women who are younger and LGBTQ+ (16 % of the sample). The third group was more likely to use non-adjustable disposable devices with a nicotine salt liquid and less likely to use adjustable tanks with a freebase liquid than the other two groups (p

Background: Combining short-acting nicotine replacement therapy with varenicline increases smoking cessation rates compared with varenicline alone, but not all people tolerate these medications or find them helpful. We aim to investigate the therapeutic potential of an analogous combination, by evaluating the effectiveness, safety, and acceptability of combining nicotine salt e-cigarettes with cytisine, compared to nicotine salt e-cigarettes or cytisine only, on smoking abstinence at six months. Methods: A pragmatic, community-based, investigator-blinded, randomised superiority trial design will be utilised. Eligible participants will be people who smoke daily (N = 800, 90% power) from throughout New Zealand, who are: aged ≥ 18 years, motivated to quit in the next two weeks, able to provide online consent, willing to use e-cigarettes and/or cytisine, and have daily access to a mobile phone. Recruitment will utilise multi-media advertising. Participants will be randomised (3:3:2 ratio) to 12 weeks of: 1) e-cigarettes (closed pod system, 3% nicotine salt, tobacco flavour) plus cytisine; 2) e-cigarettes alone, or 3) cytisine alone. All groups will receive a six-month, text-message-based behavioural support programme. The primary outcome is self-reported, biochemically verified, continuous abstinence at six months post-quit date. Secondary outcomes, measured at quit date, then one, three, six, and 12 months post-quit date, include self-reported continuous abstinence, 7-day point prevalence abstinence, cigarettes smoked per day, withdrawal and urge to smoke, time to (re)lapse, treatment use and compliance, treatment crossover, dual-use, use of other cessation products, change in e-cigarette products, continuation of product use, acceptability, change in health state, health-related quality of life, change in body mass index, adverse events, and cost per quitter. Discussion: Pragmatic trials are of particular value as they reflect the 'real world' impact of interventions. The trial will provide some of the first evidence on the effectiveness of combining nicotine salt e-cigarettes with cytisine for smoking cessation, in a country with strong tobacco control policy. Findings will be incorporated into relevant systematic reviews, informing practice and policy. Trial registration: NCT05311085 ClinicalTrials.gov. Registered 5th April, 2022. [ABSTRACT FROM AUTHOR]

The use of crystal engineering to convert liquids into crystalline solids remains a powerful method for inhibiting undesired degradation pathways. When nicotine, a liquid sensitive to both light and air, is combined with the GRAS-listed compound, gentisic acid, the resulting crystalline solid, exhibits enhanced photo and thermal stability. Despite a modest ΔTm of 42.7 °C, the melting point of 155.9 °C for the nicotinium gentisate salt is the highest reported for nicotine-containing crystalline solids. An analysis of the crystal packing and thermodynamic properties provides context for the observed properties. [ABSTRACT FROM AUTHOR]

"Pod‐based" e‐cigarettes such as JUUL are currently the most prevalent electronic nicotine delivery systems (ENDS) in the United States. JUUL‐type ENDS utilize nicotine salts protonated with benzoic acid rather than freebase nicotine. However, limited information is available on the cellular effects of these products. Cytoplasmic Ca2+ is a universal second messenger that controls many cellular functions including cell growth and cell death. Of note, dysregulation of cell Ca2+ homeostasis has been linked with several disease processes including autoimmune disease and several types of cancer. We exposed HEK293T cells and THP‐1 macrophage‐like cells to different JUUL e‐liquids. We evaluated their effects on cellular viability and Ca2+ signaling by measuring fluorescence from calcein‐AM/propidium iodide and Fluo‐4, respectively. E‐liquid autofluorescence was used to look for e‐liquid permeation into cells. To identify the mechanisms behind the Ca2+ responses, different inhibitors of Ca2+ channels and phospholipase C signaling were used. JUUL e‐liquids caused significant cytotoxic effects, with "Mint" flavor being the most cytotoxic. The Mint flavored e‐liquid also caused a significant elevation in cytoplasmic Ca2+. Using autofluorescence, the permeation of JUUL e‐liquids into live cells was confirmed, indicating that intracellular organelles are directly exposed to e‐liquids. Further studies identified the endoplasmic reticulum as being the source of e‐liquid‐induced changes in cytoplasmic Ca2+. Nicotine salt‐based e‐liquids cause cytotoxicity and elevate cytoplasmic Ca2+, indicating that they can exert biological effects beyond what would be expected with nicotine alone. These effects are flavor‐dependent, and we propose that flavored e‐liquids be reassessed for potential lung toxicity. This study was designed to evaluate the effects of the most popular nicotine salt e‐liquid formulations (JUUL) on human HEK293T cells and THP‐1 macrophages‐like cells. JUUL e‐liquids rapidly permeated into cells. Although all e‐liquids induced some dose‐dependent effects, Mint was the most potent in terms of both cellular toxicity and inducing Ca2+ responses. Collectively, these observations indicate that JUUL e‐liquids cause cytotoxicity and alter cell Ca2+, which may be detrimental to pulmonary health. [ABSTRACT FROM AUTHOR]

The popularity and the high nicotine content of the American pod e-cigarette JUUL have raised many concerns. To comply with European law, the nicotine concentration in the liquids of the European version, which has been recently released on the market, is limited to below 20 mg/mL. This limit can possibly be circumvented by technological adjustments that increase vaporization and consequently, elevate nicotine delivery. In this study, we compare vapor generation and nicotine delivery of the initial European version, a modified European version, and the original American high-nicotine variant using a machine vaping set-up. Additionally, benzoic acid and carbonyl compounds are quantified in the aerosol. Further, concentrations of nicotine, benzoic acid, propylene glycol, and glycerol, along with the density and pH value of JUUL e-liquids have been assessed. Whereas the initial European version did not compensate for the low nicotine content in the liquid, we provide evidence for an increased vaporization by the modified European version. As a consequence, nicotine delivery per puff approximates the American original. Notably, this is not associated with an increased generation of carbonyl compounds. Our data suggest a similar addictiveness of the enhanced European version and the original American product. [ABSTRACT FROM AUTHOR]

E-cigarettes containing 'nicotine salts' aim to increase smoker's satisfaction by improving blood nicotine delivery and other sensory properties. Here, we evaluated the pharmacokinetic profiles and subjective effects of nicotine from two e-cigarette device platforms with varying concentrations of nicotine lactate (nicotine salt) e-liquid relative to conventional cigarettes. A randomised, open-label, cross-over clinical study was conducted in 15 healthy US adult smokers. Five different e-cigarette products were evaluated consecutively on different days after use of own brand conventional cigarette. Plasma nicotine pharmacokinetics, subjective effects, and tolerability were assessed following controlled use of the products. The rate of nicotine absorption into the bloodstream was comparable from all e-cigarettes tested and was as rapid as that for conventional cigarette. However, in all cases, nicotine delivery did not exceed that of the conventional cigarette. The pharmacokinetic profiles of nicotine salt emissions were also dependent upon the properties of the e-cigarette device. Subjective scores were numerically highest after smoking a conventional cigarette followed by the myblu 40-mg nicotine salt formulation. The rise in nicotine blood levels following use of all the tested e-cigarettes was quantified as 'a little' to 'modestly' satisfying at relieving the desire to smoke. All products were well tolerated with no notable adverse events reported. These results demonstrate that, while delivering less nicotine than a conventional cigarette, the use of nicotine salts in e-cigarettes enables cigarette-like pulmonary delivery of nicotine that reduces desire to smoke. [ABSTRACT FROM AUTHOR]

Nicotine and its salts adsorbed on silica gel are employed to simulate the nicotine release behaviors of reconstituted tobacco particles (RTPs). Thermogravimetric analysis (TGA) was applied to provide an overview of the thermal behaviors of the nicotine, its salts and the RTPs. Diffuse reflectance infrared spectroscopy (DRIFTS) measurements of pyrolysis processes were performed on a FTIR spectrometer equipped with an in-situ DRIFTS reaction cell and a MCT/A detector. Firstly, the amine groups of nicotine and its salts are mainly adsorbed on the isolated hydroxyl groups of silica gel. Secondly, three adsorption modes of nicotine have been established. Finally, smoking machine was applied to study the release behavior of nicotine from the reconstituted tobacco particles (RTPs). The interaction between nicotine and the adsorbent is identified. Our results show interesting observations on thermal release of nicotine from the different substrates, proving the adsorption and thermal release of nicotine and it salts from RTPs, which have a guiding significance for the development of heat-not-burn cigarettes. [ABSTRACT FROM AUTHOR]

Currently it is not fully understood how the device settings and electronic liquid (e-liquid) composition, including their form of nicotine content, impact mouth and throat losses, and potentially lead to the variations in total nicotine delivery to the human lungs. An in situ size assessment method was developed for real-time measurements at the mouthpiece and outlet of a biorelevant mouth-throat to account for the dynamic nature of the aerosol. The aerosol size, temperature, and delivery through the mouth-throat replica and the exhaled aerosol between the puff intervals were measured at different wattages using various e-liquid compositions. The effects of body temperature and humidity on aerosol size and nicotine delivery were also explored to evaluate the importance of considering realistic in vivo conditions in in vitro measurements. Notably, in vitro tests with body temperature and humidity in mouth-throat model vs room conditions, resulted in larger aerosol size at the end of the throat (Dv 50 = 5.83 ± 0.33 μm vs 3.05 ± 0.15 μm), significantly higher thoracic nicotine delivery (>90% vs 50–85%) potentially due to the lower exhaled amount (<10% vs 15–50%). Besides, higher VG/PG ratios resulted in significantly lower exhaled amount and higher mouth-throat nicotine deposition. One of the main outcomes of the study was finding significantly lower exhaled amount and higher thoracic nicotine delivery with nicotine salt form vs free-base. Considering body temperature and humidity also showed significant enhancement in nicotine delivery, so it is essential to account for biorelevant experimental conditions in benchtop testing. • Nicotine form, device settings, and composition of nicotine carriers in e-liquids affect respiratory nicotine delivery. • Biorelevant conditions are critical in in vitro evaluation of nicotine delivery with electronic nicotine delivery systems. • Biorelevant mouth-throat replicas, enabling in vitro measurement of regional deposition of nicotine, are practical tools. [ABSTRACT FROM AUTHOR]

Predicting the transport and deposition of e-cigarette aerosols in human respiratory systems is essential to understand how e-liquid compositions, especially different nicotine forms, can influence the absorption of nicotine in the human lung. Using a newly developed computational fluid-particle dynamics (CFPD) method based on the species transport and discrete phase models, this study simulated and compared the transport dynamics of multi-component e-cigarette aerosols in a subject-specific human respiratory system. Specifically, the experimentally calibrated and validated CFPD model can predict the gas-liquid phase change dynamics of water, propylene glycol (PG), vegetable glycerin (VG), and nicotine in the aerosols during their transport through the pulmonary route. Results indicate that acidity levels in e-liquid can affect nicotine evaporation and that higher levels of acidity can reduce evaporation rates and increase the delivery of nicotine vapor to small airways. The study also found that benzoic acid was more effective in reducing nicotine evaporation compared to lactic acid. Furthermore, increasing the PG/VG ratio in the initial e-liquid composition can potentially lead to a reduction in nicotine evaporation rate, and therefore an increase in the amount of nicotine vapor absorbed in small airways beyond generation 10 (G10). Additionally, droplet size dynamics are influenced more by larger mass components such as PG evaporation and water condensation from the humid air, rather than nicotine. However, the impact of initial e-liquid composition on droplet transport and deposition is relatively insignificant compared to its impact on vapor phase transport and absorption. Lastly, increasing the follow-up inhalation flow rate after puffing increases liquid phase deposition and nicotine vapor absorption from the mouth to G10, but does not significantly affect evaporation and condensation. A decrease in droplet size results in an increase in the nicotine evaporation rate and subsequent absorption by the airways from the mouth to G10. • A CFPD model was created to predict nicotine form effect on e-cig aerosol dynamics. • A subject-specific mouth-to-Generation 10 human respiratory system is employed. • More protonated nicotine → Nicotine evaporation ↓→ Nicotine to deep lung↑ • PG/VG↑→PG and nicotine evaporation↓ and H 2 O condensation↑ → Nicotine to deep lung↑ • Initial droplet diameter between 0.5 and 1 μm influence nicotine lung absorption [ABSTRACT FROM AUTHOR]

• Single-crystal of nicotine γ-rezocine formic acid salt was obtained. • DBN interacted with PEP via the static quenching mechanism. • DBN had a considerable effect on the conformation of PEP. • MD simulation verified DBN could be stably combined with PEP. Nicotine salt is a new form of nicotine introduced in tobacco products, and its interaction with biological macromolecules may be different from free nicotine, thereby affecting the absorption, metabolism, and physiological activity of nicotine in vivo. To explore the transport mechanism of nicotine salt into the gastrointestinal tract, this work firstly prepared a single crystal of nicotine γ-rezocine formic acid salt (named DBN) and then analyzed the interaction of DBN with pepsin (PEP) via multispectral methods and simulation technology. The results of single-crystal diffraction showed that the chemical formula of DBN was C 17 H 20 N 2 O 4 , and the crystal was closely bound by electrostatic interaction (ionic bond). DBN quenched the endogenous fluorescence of PEP by static quenching, and the binding strength between them was moderate (K a = 8006 L·mol−1, 310 K). Thermodynamic parameters implied that the binding was a spontaneous process driven by hydrophobic forces. Investigations on the PEP conformation showed that DBN had a considerable effect on the amino acid microenvironment of PEP and reduced the hydrophobicity of PEP. Molecular docking and MD simulation results further supplemented and verified that DBN could stably combine in the hydrophobic cavity of PEP. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • DBN spontaneously binds to HSA site I by hydrophobic force, and the endogenous fluorescence of HSA was dynamic quenching. • Molecular docking and molecular dynamics (MD) simulation verified that DBN could be stably combined with HSA. • DBN decreased the surface hydrophobicity and weaken the esterase-like activity of HSA. As a new form of nicotine introduction for novel tobacco products, the interaction of nicotine salt with biological macromolecules may differ from that of free nicotine and thus affect its transport and distribution in vivo. Hence, the mechanism underlying the interaction between 2,6-dihydroxybenzoic acid nicotine salt (DBN) and human serum albumin (HSA) was investigated by multi-spectroscopy, molecular docking, and dynamic simulation. Experiments on steady-state fluorescence and fluorescence lifetime revealed that the quenching mechanism of DBN and HSA was dynamic quenching, and binding constant was in the order of 10^4 L mol−1. Thermodynamic parameters exhibited that the binding was a spontaneous process with hydrophobic forces as the main driving force. Fluorescence competition experiments revealed that DBN bound to site I of HSA IIA subdomain. According to the results of synchronous fluorescence, 3D fluorescence, FT-IR spectroscopy, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulation, DBN did not affect the basic skeleton structure of HSA but changed the microenvironment around the amino acid residues. Computer simulations positively corroborated the experimental results. Moreover, DBN decreased the surface hydrophobicity and weakened the esterase-like activity of HSA, leading to the impaired function of the latter. This work provides important information for studying the interaction between DBN as a nicotine substitute and biological macromolecules and contributes to the further development and application of DBN. [ABSTRACT FROM AUTHOR]

Introduction: Unregulated e-cigarette devices and their nicotine content have amplified the potential of e-cigarettes as addictive agents. Several e-cigarette-related parameters have been identified altering nicotine's absorption profile, so their potential effects on addiction should be considered. Of these factors, nicotine forms (protonated and free base) play a significant role in the addiction potential yet their impact on nicotine's absorption has been studied with limited research., Areas Covered: Current review aims to emphasize on the possible mechanism behind different absorption profiles of nicotine forms considering their physical states (droplet and vapor phase) and the aerosol particle size, their analysis in e-cigarette research and the regulatory attention warranted by them to combat nicotine addiction in the population due to e-cigarettes., Expert Opinion: The protonated form of nicotine is being correlated with the smooth sensory effects and high nicotine absorption as compared to free base nicotine. With the introduction of nicotine salts, which yield mostly the protonated form, the youth popularity of e-cigarettes has spiked exponentially. While it is important to control nicotine levels in e-cigarette products, attention should also be given to the nicotine forms present in these products in order to address nicotine addiction in the population.