Nicotine Formulations Research Articles

Effect of packaging with versus without candy-oriented marketing themes on the appeal and sensory attributes of flavoured e-cigarettes

SignificanceE-cigarettes with candy-themed marketing are implicated in decisions to first try e-cigarettes but have unknown effects on the experience of vaping. We compared adults’ perceived appeal and sensory attributes after...

Electronic Cigarette Device and Liquid Characteristics: Comparison of Self-Reports to User-Provided Pictures

Introduction: Self-reports of electronic cigarette (ECIG) device and liquid characteristics are not always accurate or consistent with characteristics as measured by researchers. Two methods for measuring ECIG characteristics were compared: user self-reports and rater-coded pictures. Methods: Exclusive ECIG users (N = 321) reported on device (disposable, refillable, adjustable power, brand) and liquid (nicotine concentration, formulation, flavor) characteristics. To measure device type, they chose the term that best described their device (“cig-alike,” “vape pen,” “mod,” “pod,” “don’t know”) and the picture that best resembled their device (cig-alike, vape pen, box mod, USB-shaped pod, teardrop-shaped pod, none). Respondents uploaded device and liquid pictures, and independent raters coded these same features. Agreement between methods was examined with Cohen’s kappa and intra-class correlations, including with “don’t know” responses included and excluded from analyses. Results: Regardless of how “don’t know” responses were treated, agreement was highest for disposable (95.3–97.7%), refillable (96.3%), adjustable power (83.6–88.7%), and brand (77.9–80.4%), and lower for nicotine concentration (72.7%), nicotine formulation (58.6–79.4%), and flavor (66.2%). For device type, agreement was moderate using both term-based (67.9–78.8%) and picture resemblance-based (71.7%) items. For terms, the greatest discrepancy was for devices classified as “vape pens” by self-reports; of these, 70.6% were classified as “pods” by raters. For picture resemblance, ∼13% of users reported that their device resembled none of the pictures; raters classified these devices as USB-shaped pods (50.0%) and mods (23.8%). Conclusions: Self-reports may be sufficient for measuring some characteristics (brand, disposable, refillable, adjustable power), but not others (nicotine concentration and formulation, and some flavor).

Physical and Chemical Characterization of Aerosols Produced from Experimentally Designed Nicotine Salt-Based E-Liquids.

Nicotine salt-based e-liquids deliver nicotine more rapidly and efficiently to electronic nicotine delivery system (ENDS) users than freebase nicotine formulations. Nicotine salt-based products represent a substantial majority of the United States ENDS market. Despite the popularity of nicotine salt formulations, the chemical and physical characteristics of aerosols produced by nicotine salt e-liquids are still not well understood. To address this, this study reports the harmful and potentially harmful constituents (HPHCs) and particle sizes of aerosols produced by laboratory-made freebase nicotine and nicotine salt e-liquids. The nicotine salt e-liquids were formulated with benzoic acid, citric acid, lactic acid, malic acid, or oxalic acid. The nicotine salt aerosols had different HPHC profiles than the freebase nicotine aerosols, indicating that the carboxylic acids were not innocent bystanders. The polycarboxylic acid e-liquids containing citric acid, malic acid, or oxalic acid produced higher acrolein yields than the monocarboxylic acid e-liquids containing benzoic acid or lactic acid. Across most PG:VG ratios, nicotine benzoate or nicotine lactate aerosols contained the highest nicotine quantities (in %) and the highest nicotine yields (per milligram of aerosol). Additionally, the nicotine benzoate and nicotine lactate e-liquids produced the highest carboxylic acid yields under all tested conditions. The lower acid yields of the citric, malic, and oxalic acid formulations are potentially due to a combination of factors such as lower transfer efficiencies, lower thermostabilities, and greater susceptibility to side reactions because of their additional carboxyl groups serving as new sites for reactivity. For all nicotine formulations, the particle size characteristics were primarily controlled by the e-liquid solvent ratios, and there were no clear trends between nicotine salt and freebase nicotine aerosols that indicated nicotine protonation affected particle size. The carboxylic acids impacted aerosol output, nicotine delivery, and HPHC yields in distinct ways such that interchanging them in ENDS can potentially cause downstream effects.

Dose–response effects of two nicotine salt formulations on electronic cigarette appeal and sensory attributes

ObjectivesVarious organic acids are used to create nicotine salt formulations, which may improve the appeal and sensory experience of vaping electronic cigarettes (e-cigarettes). This clinical experiment examined the effects of...

Is Maintenance or Switching Between Freebase and Nicotine Salt Liquid Associated with Electronic Nicotine Delivery Systems Dependence?

Background 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. Methods 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. Results 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). Conclusions 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.

Pharmacokinetics and Pharmacodynamics of Inhaled Nicotine Salt and Free-Base Using an E-cigarette: A Randomized Crossover Study.

Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. This study investigated the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes. In this randomized, double-blind, within-subject crossover study, 20 non-nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20 mg/mL, nicotine salt 20 mg/mL, nicotine salt 40 mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed. Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0 ng/mL (1.6-27.3), 5.4 ng/mL (1.9-18.7), and 3.0 ng/mL (1.3-8.8) for nicotine salt 40 mg/mL, nicotine salt 20 mg/mL and free-base 20 mg/mL, respectively). All groups reached Cmax 2.0-2.5 minutes (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed. Free-base 20 mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20 mg/mL, while 40 mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation. Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine-free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40 mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and nonsmokers.

Comparison of brain nicotine accumulation from traditional combustible cigarettes and electronic cigarettes with different formulations.

Rapid brain accumulation is critical for the acute reinforcing effects of nicotine. Although nicotine formulation (free-base vs. protonated or salt) in electronic cigarette (E-cig) liquid affects user satisfaction, its impact on brain nicotine accumulation (BNA) from E-cig use has not been evaluated in comparison with traditional combustible cigarettes (C-cigs) using a within-subjects design. BNA was directly assessed with 29 adult dual users (13 females) of E-cigs and C-cigs, using [11C]nicotine and positron emission tomography (PET). Participants underwent two 15-min upper body (from chest to head) scanning sessions during which they inhaled a single puff of [11C]nicotine-labeled vapor from E-cigs with free-base nicotine or C-cig smoke in a randomized order. Seventeen of them also went through another session during which they inhaled from E-cigs with nicotine salt. A full-body scan was also conducted at each session to measure total absorbed dose of [11C]nicotine. Mean maximum nicotine concentration (Cmax) in brain following inhalation of free-base nicotine E-cig vapor was 19% and 15% lower relative to C-cig smoke and nicotine salt E-cig vapor (ps = 0.014 and 0.043, respectively). The Cmax values did not differ significantly between the C-cig and nicotine salt E-cig. Mean values of time to the maximum concentration (Tmax) were not significantly different between the two types of E-cig, but they were 64% and 40% longer than that for C-cig smoking (ps = 0.0005 and 0.004, respectively). Mean Cmax with C-cigs and free-base nicotine E-cigs were greater in females relative to males and correlated with T1/2 of lung nicotine clearance and participants' pack-years. These results suggest that while E-cigs with free-base nicotine formulation can deliver nicotine rapidly to the brain, those with nicotine salt formulation are capable of even more efficient brain nicotine delivery closely resembling combustible cigarettes. Therefore, nicotine formulation or pH in E-liquid should be considered in evaluation of E-cigs in terms of abuse liability and potential in substituting for combustible cigarettes.

Electronic Vaporization of Nicotine Salt or Freebase produces differential effects on metabolism, neuronal activity and behavior in male and female C57BL/6J mice

The use of Electronic Nicotine Delivery Systems (ENDS) is increasing in prevalence and popularity. ENDS are a rapidly evolving technology as devices and e-liquid formulations adapt to policy restrictions and market demand. To identify the impacts of nicotine formulation and concentration, we exposed female and male C57BL/6J mice to passive electronic vaporization of different nicotine formulations (freebase or salt) and concentrations (1% or 3%) and measured serum nicotine metabolite levels, brain activity by cFos expression, and anxiety-like and motivated behavior using the novelty suppressed feeding test. We found that the 3% freebase nicotine vapor group displayed significantly higher serum nicotine levels than either 1% or 3% nicotine salt formulations, and female mice displayed higher serum nicotine and cotinine levels compared to males. Central amygdala (CeA) activity was significantly elevated in male mice following nicotine vapor exposure, but the increase was not significantly different between nicotine vapor groups. CeA activity in female mice was unaffected. In contrast, increased activity in the ventral tegmental area (VTA) was only observed in female mice exposed to 3% nicotine freebase and specifically in the dopaminergic population. Anxiety-like behavior in female mice was relatively unaffected by nicotine vapor exposure, however male mice displayed increased anxiety-like behavior and reduced motivation to feed after vapor exposure, specifically in the 3% freebase group. These results identify important sex differences in the impact of nicotine formulation and concentration on nicotine metabolism, brain region-specific activity and anxiety-like behavior, which may have significant relevance for different consequences of vaping in men and women.

Design and Preclinical Evaluation of Nicotine-Stearic Acid Conjugate-Loaded Solid Lipid Nanoparticles for Transdermal Delivery: A Technical Note.

This study aimed to develop and evaluate nicotine--stearic acid conjugate-loaded solid lipid nanoparticles (NSA-SLNs) for transdermal delivery in nicotine replacement therapy (NRT). Nicotine conjugation to stearic acid prior to SLN formulation greatly increased drug loading. SLNs loaded with a nicotine-stearic acid conjugate were characterized for size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and morphology. Pilot in vivo testing was carried out in New Zealand Albino rabbits. The size, PDI, and ZP of nicotine-stearic acid conjugate-loaded SLNs were 113.5 ± 0.91 nm, 0.211 ± 0.01, and -48.1 ± 5.75 mV, respectively. The entrapment efficiency of nicotine-stearic acid conjugate in SLNs was 46.45 ± 1.53%. TEM images revealed that optimized nicotine-stearic acid conjugate-loaded SLNs were uniform and roughly spherical in shape. Nicotine-stearic acid conjugate-loaded SLNs showed enhanced and sustained drug levels for up to 96 h in rabbits when compared with the control nicotine formulation in 2% HPMC gel. To conclude, the reported NSA-SLNs could be further explored as an alternative for treating smoking cessation.

Agreement Between Self-reports and Photos to Assess e-Cigarette Device and Liquid Characteristics in Wave 1 of the Vaping and Patterns of e-Cigarette Use Research Study: Web-Based Longitudinal Cohort Study.

Backgrounde-Cigarette device and liquid characteristics are highly customizable; these characteristics impact nicotine delivery and exposure to toxic constituents. It is critical to understand optimal methods for measuring these characteristics to accurately assess their impacts on user behavior and health.ObjectiveTo inform future survey development, we assessed the agreement between responses from survey participants (self-reports) and photos uploaded by participants and the quantity of usable data derived from each approach.MethodsAdult regular e-cigarette users (≥5 days per week) aged ≥21 years (N=1209) were asked questions about and submitted photos of their most used e-cigarette device (1209/1209, 100%) and liquid (1132/1209, 93.63%). Device variables assessed included brand, model, reusability, refillability, display, and adjustable power. Liquid variables included brand, flavor, nicotine concentration, nicotine formulation, and bottle size. For each variable, percentage agreement was calculated where self-report and photo data were available. Krippendorff α and intraclass correlation coefficient (ICC) were calculated for categorical and continuous variables, respectively. Results were stratified by device (disposable, reusable with disposable pods or cartridges, and reusable with refillable pods, cartridges, or tanks) and liquid (customized and noncustomized) type. The sample size for each calculation ranged from 3.89% (47/1209; model of disposable devices) to 95.12% (1150/1209; device reusability).ResultsPercentage agreement between photos and self-reports was substantial to very high across device and liquid types for all variables except nicotine concentration. These results are consistent with Krippendorff α calculations, except where prevalence bias was suspected. ICC results for nicotine concentration and bottle size were lower than percentage agreement, likely because ICC accounts for the level of disagreement between values. Agreement varied by device and liquid type. For example, percentage agreement for device brand was higher among users of reusable devices (94%) than among users of disposable devices (75%). Low percentage agreement may result from poor participant knowledge of characteristics, user modifications of devices inconsistent with manufacturer-intended use, inaccurate or incomplete information on websites, or photo submissions that are not a participant’s most used device or liquid. The number of excluded values (eg, self-report was “don’t know” or no photo submitted) differed between self-reports and photos; for questions asked to participants, self-reports had more usable data than photos for all variables except device model and nicotine formulation.ConclusionsPhotos and self-reports yield data of similar accuracy for most variables assessed in this study: device brand, device model, reusability, adjustable power, display, refillability, liquid brand, flavor, and bottle size. Self-reports provided more data for all variables except device model and nicotine formulation. Using these approaches simultaneously may optimize data quantity and quality. Future research should examine how to assess nicotine concentration and variables not included in this study (eg, wattage and resistance) and the resource requirements of these approaches.

E-Cigarette Aerosol Deposition and Disposition of [11C]Nicotine Using Positron Emission Tomography: A Comparison of Nicotine Uptake in Lungs and Brain Using Two Different Nicotine Formulations.

Smoking is a cause of serious disease in smokers. Electronic cigarettes, delivering aerosolized nicotine, offer adult smokers a potentially less harmful alternative to combustible cigarettes. This explorative PET/CT study investigated the distribution and deposition of inhaled [11C]nicotine using the mybluTM e-cigarette with two nicotine formulations, freebase and lactate salt. Fifteen healthy adult smokers participated in the two-part study to assess the distribution and accumulation of [11C]nicotine in the respiratory pathways and brain. Time-activity data for the respiratory pathways, lungs, oesophagus and brain were derived. 31–36% of both inhaled tracer formulations accumulated in the lung within 15–35 s. [11C]Nicotinefreebase exhibited higher uptake and deposition in the upper respiratory pathways. For [11C]nicotinelactate, brain deposition peaked at 4–5%, with an earlier peak and a steeper decline. A different kinetic profile was obtained for [11C]nicotinelactate with lower tracer uptake and accumulation in the upper respiratory pathways and an earlier peak and a steeper decline in lung and brain. Using nicotine lactate formulations in e-cigarettes may thus contribute to greater adult smoker acceptance and satisfaction compared to freebase formulations, potentially aiding a transition from combustible cigarettes and an acceleration of tobacco harm reduction initiatives.

Parsing Intra- and Inter-Individual Covariation Between the Sensory Attributes and Appeal of E-Cigarettes: Associations and Gender Differences.

Perceived sensory attributes of e-cigarettes may associate with their appeal. However, limited studies have accounted for individuals' variability in sensory attributes or have addressed how associations of sensory attributes with appeal may differ by gender. Individuals (n = 119, 32.8% female) who currently used combustible cigarettes and/or e-cigarettes attended one laboratory session in which they completed a standardized e-cigarette puffing procedure according to a 10 Flavor (green apple, strawberry, chocolate, vanilla, menthol, koolada, peppermint, spearmint, subtle tobacco, and full-flavored tobacco) × 2 Nicotine Formulation (free-base, salt) double-blind factorial design. The mean nicotine concentration was 23.4 (SD = 0.9) mg/mL in the nicotine salt formulations and 23.8 (SD = 1.7) mg/mL in the free-base formulations. Following each trial, participants completed ratings of sensory attributes (sweet, smooth, cool, bitter, harsh) and appeal (mean of liking, disliking [reverse-scored], and willingness-to-use-again ratings). Sensory attributes were partitioned into between-person and within-person variables. Gender was tested as a moderator of associations of sensory attributes with appeal. Sweet, smooth, and cool sensory attributes positively associated with appeal at the between- and within-person level (ps < .001). Bitter and harsh negatively associated with appeal at the between- and within-person level (ps < .001). The associations of between-person sweet, smooth, and cool ratings with appeal was larger in males compared to females. The associations of within-person smooth, bitter, and harsh with appeal was larger in females compared to males. This study showed important gender differences in associations of sensory attributes and appeal. While evidence suggests that sensory attributes may contribute to the appeal of e-cigarettes, there is little experimental evidence accounting for individual variability in sensory attributes and whether sensory attribute-appeal associations differ by gender. The current study provides evidence that average sweet, cool, and smooth ratings positively associated with appeal and that these associations were larger in males. Within-person bitter, harsh, and smooth ratings significantly associated with appeal in both genders, but these associations were larger in females compared to males. Data from the current report reinforces the need for researchers to study gender stratified effects in tobacco regulatory science.

Nicotine formulations impact reinforcement-related behaviors in a mouse model of vapor self-administration

BackgroundElectronic nicotine delivery systems (ENDS) differ from combustible cigarettes given that nicotine-salt or nicotine-freebase may be used depending on the product. We have investigated how nicotine-salt and freebase formulations alter e-Vape® self-administration (EVSA) behavior and plasma cotinine levels in male and female mice. MethodsAdult C57/BL6 J mice were used in EVSA and assigned vaping e-liquids (50:50 PGVG, 6 mg/mL nicotine-freebase, or 6 mg/mL nicotine-salt). Mice were escalated on a fixed ratio 1 (FR1) schedule in daily 2 h sessions and then transitioned to a FR3 to examine reinforcement-related behaviors. ResultsHere we observed that mice assigned nicotine-salt exhibited increased EVSA on a FR3 schedule compared to nicotine-freebase. Additionally, mice assigned nicotine-salt exhibited higher plasma cotinine concentrations following delivery-controlled passive-inhalation sessions. ConclusionsThese data provide evidence nicotine-salt formulations may contribute to greater reinforcement-related behavior and highlight the need for further investigations regarding nicotine formulation in ENDS.

Effect of Exposure to e-Cigarettes With Salt vs Free-Base Nicotine on the Appeal and Sensory Experience of Vaping

Alkaline free-base nicotine is bitter and a respiratory irritant. High-nicotine electronic cigarette (e-cigarette) products contain acid additives that change nicotine from a free-base to a protonated salt chemical form, which could improve the sensory experience of vaping, particularly among never smokers unaccustomed to inhaling free-base nicotine. To determine whether exposure to e-cigarettes with salt vs free-base nicotine formulations improves the appeal and sensory experience of vaping e-cigarettes and whether nicotine formulation effects differ by e-cigarette flavor and ever combustible cigarette smoking status. Single-visit double-blind within-participant randomized clinical trial was conducted in an academic medical center outpatient clinical research facility in Southern California. Participants were 119 individuals with past 30-day e-cigarette or combustible cigarette use aged 21 years or older recruited from November 2019 to March 2020. Participants self-administered standardized puffs of each 10 differently flavored e-cigarette solutions using a pod-style device. Each flavor was administered in salt (benzoic acid added) and free-base (no benzoic acid) nicotine formulations with commensurate nicotine concentrations (mean, 23.6 mg/mL). The 20 solutions were administered in randomly assigned sequences. Immediately after puffing each solution, participants rated appeal and sensory attributes. Self-reported appeal (mean of like, dislike [reverse-scored], and willingness to use again ratings) and 4 sensory attributes (sweetness, smoothness, bitterness, and harshness; analyzed individually) on visual analog scales with not at all and extremely anchors (range, 0-100). Of the 119 participants; 39 (32.8%) were female. The mean (SD) age was 42.1 (14.4) years; 105 (88.2%) were ever combustible cigarette smokers, and 66 (55.5%) were current e-cigarette users. Salt vs free-base nicotine formulations produced higher ratings of appeal (salt vs free-base mean difference effect estimate: b = 12.0; 95% CI, 9.9-14.1; P < .001), sweetness (b = 9.3; 95% CI, 7.1-11.4; P < .001), and smoothness (b = 17.4; 95% CI, 15.2-19.6; P < .001) and lower ratings of bitterness (b = -13.3; 95% CI, -15.4 to -11.2; P < .001) and harshness (b = -21.0; 95% CI, -23.2 to -18.7; P < .001). Nicotine formulation effects largely generalized across different flavors and the smoothness-enhancing and harshness-reducing effects of nicotine salt were stronger in never vs ever cigarette smokers. In this randomized clinical trial of adult current nicotine or tobacco product users, controlled exposure to e-cigarette puffs with salt vs free-base nicotine formulations appeared to increase product appeal and improve the sensory experience of vaping, particularly among never smokers. Regulatory policies limiting acid additives in e-cigarettes might reduce the appeal of high-nicotine e-cigarettes among populations deterred from vaping e-cigarettes that emit harsh aerosol. ClinicalTrials.gov Identifier: NCT04399031.

Critical research gaps in electronic cigarette devices and nicotine aerosols.

Electronic cigarettes (e-cigs) are devices that aerosolize nicotine-containing liquids for delivery as an inhaled vapor. E-cigs are currently marketed as smoking cessation devices, though the emergence and rapid adoption of these devices in recent years has sparked a great deal of concern over their safety. Given the plethora of devices and nicotine solutions available on the market and the lack of regulation and quality control, it is imperative that these devices and nicotine formulations are studied to assess critical operating parameters, the pharmacokinetic profiles of the inhaled nicotine, and the toxicity profiles of the e-cig aerosols. This review aims to deliver an overview of current research regarding electronic cigarette devices, nicotine-containing liquid formulations, pharmacokinetics of nicotine, and toxicology studies in order to highlight areas lacking in research or requiring greater standardization and regulation.

Pod-mod vs. conventional e-cigarettes: nicotine chemistry, pH, and health effects.

A new type of electronic cigarettes, the “pod-mod” e-cigarette, has raised public health concerns in the press, the e-cigarette research community, and among regulatory agencies. A recent US FDA statement regarding safety issues of e-cigarette use, particularly in youth and young adults, states “we’re looking at the potential for direct effects of harm from e-cigarettes on the lungs as well as other health factors that these products could negatively impact. In particular, we have concerns about the direct effects of e-cigarettes on the airways. This includes the potential for the use of such products to cause changes to airways that could be a precursor to cancer” (11). In addition, a series of CDC and FDA announcements reported over 2,000 cases of respiratory illnesses associated with e-cigarette/vaping product use (11a). Patients develop shortness of breath, fatigue, chest pain, cough, anorexia, nausea, diarrhea, and weight loss, with symptoms worsening over days or weeks with some dying from this condition. More research is urgently needed to understand the causes and pathophysiology of the respiratory toxicity. Traditional e-cigarette products use E-liquid with free-base nicotine while JUUL and other pod-mods use protonated nicotine formulations derived from the nicotine salts in loose-leaf tobacco. JUUL contains 0.7 ml E-liquid per pod with concentration of 50 mg/ mL (5%), which is 2 to 10 times those found in most free-base nicotine e-cigarette products—equivalent to ~20 combustible cigarettes (2). Goniewicz et al. (10) confirmed the concentration of nicotine in a JUUL pod to be 56.2 mg/mL. The JUUL website further states that the salt-based nicotine E-liquid formula is intended to help satisfy smokers when transitioning from cigarettes. Here we focus on discussions on the potential health effects of E-liquid pH, nicotine salt versus free-base nicotine, and protonated versus unprotonated nicotine, as well as an important distinction of pH effects on the lungs and other organ systems.

Respirable aerosol exposures of nicotine dry powder formulations to in vitro, ex vivo, and in vivo pre-clinical models demonstrate consistency of pharmacokinetic profiles

Background: Nicotine, because of its volatility, has a complex dosimetry following inhalation as a vapor/aerosol mix. To better control the dosimetry, nicotine could be formulated with a suitable dry powder excipient for use in a clinical inhaler.Aim and Methods: The aim of this study was to investigate the pharmacokinetic PK profile of two dry powder formulations containing 2.5% or 5% nicotine using three experimental models associated to the PreciseInhale™ aerosolization system: the in vitro DissolvIt dissolution system; the ex vivo isolated, ventilated, and perfused lung (IPL) of the rat; and the in vivo intratracheally intubated rat. Results and Discussion: Following exposure, both nicotine formulations had very rapid and similar dissolution and absorption kinetics in both the DissolvIt and IPL exposure models, with an initial half-time of absorption to the single-pass perfusate of 34 and 72 seconds, respectively. In the intratracheally intubated rat, following a rapid initial equilibration between the lungs and systemic compartments, nicotine had a systemic elimination half-time of 2.3–2.4 hours for both formulations. The rapid pulmonary PK of nicotine was likely close to the theoretical equilibration of a low-binding substance with a tissue-blood partition coefficient close to 1. Conclusions: The data generated with the three experimental models provided a comprehensive picture of the inhalation PK of the two nicotine formulations. In particular, the results showed a very rapid dissolution and absorption of the two nicotine formulations and these results could be highly useful for improving the design and calibration of physiologically based PK models to produce more robust predictions. Abbreviations: AED: animal equivalent dose; BW: body weight; HPLC: high-performance liquid chromatography; IPL: isolated, ventilated, and perfused lung; PK: pharmacokinetics; SEM: scanning electron microscopy; USP: United States Pharmacopeia.

Substitutability of nicotine alone and an electronic cigarette liquid using a concurrent choice assay in rats: A behavioral economic analysis

BackgroundFor the Food and Drug Administration to effectively regulate tobacco products, the contribution of non-nicotine tobacco constituents to the abuse liability of tobacco must be well understood. Our previous work compared the abuse liability of electronic cigarette refill liquids (EC liquids) and nicotine (Nic) alone when each was available in isolation and found no difference in abuse liability (i.e., demand elasticity). Another, and potentially more sensitive measure, would be to examine abuse liability in a choice context, which also provides a better model of the tobacco marketplace. MethodsDemand elasticity for Nic alone and an EC liquid were measured when only one formulation was available (alone-price demand) and when both formulations were concurrently available (own-price demand), allowing an assessment of the degree to which each formulation served as a substitute (cross-price demand) when available at a low fixed-price. ResultsOwn-price demand for both formulations were more elastic compared to alone-price demand, indicating that availability of a substitute increased demand elasticity. During concurrent access, consumption of the fixed-price formulation increased as the unit-price of the other formulation increased. The rate of increase was similar between formulations, indicating that they served as symmetrical substitutes. ConclusionThe cross-price model reliably quantified the substitutability of both nicotine formulations and indicated that the direct CNS effects of non-nicotine constituents in EC liquid did not alter its abuse liability compared to Nic. These data highlight the sensitivity of this model and its potential utility for examining the relative abuse liability and substitutability of tobacco products.

Self-Administration of Smokeless Tobacco Products in Rats.

Preclinical abuse liability assessment is an essential component of tobacco regulatory science. The goal of this project was to evaluate the relative abuse liability of smokeless tobacco products in rats using aqueous extracts of those products. These extracts provide exposure to an extensive range of nicotine and non-nicotine tobacco constituents as occurs in humans. Rats were trained to self-administer either nicotine alone or extracts of Camel Snus or Kodiak smokeless tobacco at an equivalent nicotine unit dose. In Experiment 1, the relative reinforcing efficacy of these formulations was assessed in adults and adolescents using a progressive ratio schedule under limited-access conditions. In Experiment 2, relative reinforcing efficacy was assessed in adolescents under unlimited-access conditions using behavioral economic demand curve analysis. The reinforcing efficacy of nicotine formulations was higher in adolescents than adults, but no difference was observed between formulations in either age group. Similarly, there was no difference in elasticity of demand between formulations in adolescents. The present findings suggest that the abuse liability of these smokeless tobacco products is similar to nicotine alone, and that nicotine dose is the primary determinant of the reinforcing efficacy of systemic exposure to these products.

Promoting smoking cessation in pharmacy practice: Tips for busy pharmacists

Community pharmacists are a largely untapped resource, with huge potential to promote smoking cessation because they interface with patients daily, according to Robin Corelli, PharmD, Professor of Clinical Pharmacy at the University of California, San Francisco (UCSF) School of Pharmacy. At APhA2015, she presented on tobacco cessation in pharmacy practice.