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Introduction: Electronic cigarette (EC) use has increased rapidly in the last decade, especially among youth. Regulating nicotine delivery from ECs could help curb youth uptake and leverage EC use in harm reduction yet is complicated by varying device and liquid variables that affect nicotine delivery. Nicotine flux, the nicotine emission rate, is a parameter that incorporates these variables and focuses on the performance rather than the design of an EC. Nicotine flux therefore could be a powerful regulatory tool if it is shown empirically to predict nicotine delivery and subjective effects related to dependence., Methods and Analysis: This project consists of two complementary clinical trials. In Trial I, we will examine the relationship between nicotine flux and the rate and dose of nicotine delivery from ECs, hence, impacting abuse liability. It will also examine the extent to which this relationship is mediated by nicotine form (i.e., freebase versus protonated). At Yale School of Medicine (YSM), study participants will puff EC devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. In Trial II, we will assess the relationship between nicotine flux, form, and subjective effects. At the American University of Beirut (AUB), participants will use EC devices with varying nicotine fluxes and forms, while dependency measures, such as the urge to use ECs, nicotine craving, and withdrawal symptoms, will be assessed. We will also monitor puffing intensity and real-time exposure to toxicants., Ethics and Dissemination: The protocol of Trial I and Trial II was approved by YSM and AUB IRBs, respectively. We will disseminate study results through peer-reviewed publications and conference presentations., Trial Registration: NCT05706701 for Trial I and NCT05430334 for Trial II., Competing Interests: AS and TEissenberg are paid consultants in litigation against the tobacco and EC industry and are named on a patent for a device that measures the puffing behavior of EC users and another patent application for a smoking cessation intervention. TEissenberg is also named on a patent application for a smartphone app that determines EC device and liquid characteristics. All other authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 El-Hellani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The U.S. Food and Drug Administration proposed new product standards that would ban characterizing flavors (other than tobacco) in cigars. To inform this regulatory action, we compared physiological effects, use behavior, and subjective effects of four popular cigar flavors in cigar-naïve young adult cigarette smokers. Across five laboratory visits, participants ( n = 25) used and evaluated own brand (OB) cigarettes or Black & Mild cigars (original, wine, apple, and cream flavors). Linear mixed models tested differences in saliva nicotine, exhaled carbon monoxide (CO), heart rate (HR), blood pressure (BP), puff topography, and subjective effects ( p < .05). Compared to all cigars, OB resulted in higher nicotine boost (953 vs. < 300 ng/ml) and lower CO boost (4 vs. 8-9 ppm). Nicotine boost for original cigars (283 ng/ml) was significantly higher than wine (190 ng/ml). All products significantly increased HR/BP relative to baseline, but across time wine and apple cigars were associated with significantly lower HR than OB and BP effects varied. Relative to OB, participants took approximately 0.5 s longer puffs for all cigars and took significantly larger puffs (+ 21%-24%) of original, wine, and apple cigars. OB was rated more positively than all cigars, which had similar subjective effects. Wine cigars were disliked most and were less effective in reducing tobacco abstinence symptoms than OB; cream cigars were harsher and had stronger flavor intensity than original. The consistency in toxicant exposure, use behavior, and subjective effects across cigar flavors, including original, highlights the need for product standards to interpret characterizing flavors subject to prohibition broadly. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Electronic nicotine delivery systems (ENDSs) are used by some smokers to reduce cigarette consumption, but their effectiveness is uncertain. We aimed to examine the extent to which ENDSs or a non-nicotine cigarette substitute influence tobacco-related toxicant exposure and cigarette consumption in smokers interested in smoking reduction., Methods: We did a four-arm, parallel-group, randomised controlled trial at two sites in the USA (Penn State University, Hershey, PA, and Virginia Commonwealth University, Richmond, VA). We enrolled adults aged 21-65 years who smoked more than nine cigarettes per day (for at least the past year), with exhaled CO of more than 9 parts per million at screening, who were not currently using an ENDS, and who were interested in reducing smoking but not quitting. Participants were randomised (site-specific with allocation concealment; 1:1:1:1) to receive either a cartomiser-based, pen-style ENDS (eGo-style) paired with 0, 8, or 36 mg/mL liquid nicotine (participants and researchers masked to concentration) or a non-ENDS cigarette-shaped plastic tube that delivered no nicotine or aerosol (cigarette substitute; unmasked) for 24 weeks. Conditions were chosen to reflect a range of nicotine delivery including none (cigarette substitute and 0 mg/mL ENDS), low (8 mg/mL), and cigarette-like (36 mg/mL), and all conditions were paired with smoking reduction instructions. The primary outcome was concentration of the tobacco-specific carcinogen metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; urinary total) collected at randomisation and at 4, 12, and 24 weeks. Multiple imputation with and without covariate adjustment was used in addition to sensitivity analyses. This trial is registered with ClinicalTrials.gov, NCT02342795., Findings: Between July 22, 2015, and Nov 16, 2017, 684 individuals were screened and 520 (76%) were enrolled and randomised. 188 (36%) of 520 participants were lost to follow-up by week 24; attrition did not differ by study group (39 [30%] of 130 in the cigarette substitute group, 56 [43%] of 130 in the ENDS with 0 mg/mL nicotine group, 49 [38%] of 130 in the ENDS 8 mg/mL group, and 44 [34%] of 130 in the ENDS 36 mg/mL group). Urinary total NNAL at 24 weeks in the ENDS with 36 mg/mL nicotine group was 210·80 pg/mg creatinine (95% CI 163·03-274·42) compared with 346·09 pg/mg creatinine (265·00-455·32) in the cigarette substitute group (p=0·0061). No other significant differences between groups were observed for any time point for urinary total NNAL. Serious adverse event frequency was similar across groups (12 events in 12 participants [9%] in the ENDS with 36 mg/mL nicotine group, seven events in six participants [5%] in the 8 mg/mL group, 11 events in ten participants [8%] in the 0 mg/mL group, and 13 events in 13 participants [10%] in the cigarette substitute group), and all of these were deemed unrelated or unlikely to be related to study product use. There was one death between randomisation and 24 weeks (suicide; in the ENDS with 0 mg/mL nicotine group)., Interpretation: Use of an ENDS with cigarette-like nicotine delivery can reduce exposure to a major pulmonary carcinogen, NNAL, even with concurrent smoking. Future ENDS trials should involve products with well characterised nicotine delivery, including those with nicotine delivery approaching that of a cigarette., Funding: National Institutes of Health, US Food and Drug Administration., Competing Interests: Declaration of interests COC reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. JF reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study, and grants, personal fees, and non-financial support from Pfizer, outside of the submitted work. AAL reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. JMY reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. LK reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. SV reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study. CB has previously undertaken trials of electronic cigarettes for smoking cessation (with electronic cigarettes purchased from an online retailer [NZVAPOR], electronic cigarette liquid for one trial purchased from Nicopharm, Australia, and nicotine patches supplied by the New Zealand Government via their contract with Novartis [Sydney, Australia]). Neither NZVAPOR nor Nicopharm have links with the tobacco industry. None of these parties had any role in the design, conduct, analysis, or interpretation of the trial findings, or writing of this publication. TE reports grants from National Institute on Drug Abuse and US Food and Drug Administration, during the conduct of the study, and is a paid consultant in litigation against the tobacco industry and also the electronic cigarette industry and is named on one patent for a device that measures the puffing behavior of electronic cigarette users and on another patent for a smartphone application that determines electronic cigarette device and liquid characteristics. M-SY reports grants from the National Institute on Drug Abuse and the US Food and Drug Administration, during the conduct of the study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Electronic cigarettes (ECIGs) are battery-powered devices that emit vaporized solutions for the user to inhale. ECIGs are marketed as a less harmful alternative to combustible cigarettes. The current study examined the effects of ECIG aerosol exposure on learning and memory, expression of brain derived neurotrophic factor (BDNF), and the activity of antioxidant enzymes in the hippocampus. Methods: Male Wistar rats were exposed to ECIG aerosol, by a whole-body exposure system, 1 h/day for 1 week, 4 weeks, and 12 weeks. Spatial learning and memory were tested using the Radial Arm Water Maze (RAWM). Hippocampal BDNF protein level, and oxidative stress biomarkers (GPx, SOD, GSH, GSSG, GSH/GSSG ratio) were also assessed. Results: ECIG aerosol exposure for 4 and 12 weeks impaired both short- and long- term memory and induced reductions in the hippocampus BDNF, SOD and GPx activities, and GSH/GSSG ratio ( p  < 0.05). No changes in any examined biomarkers were observed after 1-week exposure to ECIG aerosol ( p  > 0.05). Conclusions: ECIG aerosol exposure impaired functional memory and elicited changes in brain chemistry that are consistent with reduced function and oxidative stress.

Electronic cigarette (ECIG) nicotine delivery and other effects can be influenced by device and/or liquid characteristics and user puffing behavior. One class of ECIGs includes "sub-ohm" devices that incorporate heating coils with resistance less than 1 ohm (Ω), lower than that observed in conventional devices (e.g., ≥1.5 Ω). Relative to conventional ECIGs that operate at ≤10 W, low-resistance coils can be used to increase device power (e.g., 40-300 W). However, little is known about the individual and combined effects of ECIG power, manipulated by coil resistance, and liquid nicotine concentration on ECIG acute effects. Experienced ECIG users ( N = 32) completed 4 sessions that differed by ECIG power and coil resistance (40.5 W, 0.5 Ω or 13.5 W, 1.5 Ω) and liquid nicotine concentration (3 or 8 mg/ml). In each session, participants used a 4.5-V Kanger SUBOX ECIG in a 10-puff directed and 60-min ad libitum bout. Nicotine delivery, heart rate, subjective effects, puff topography, and liquid consumption were measured. Nicotine delivery was greatest in the 8mg/ml+0.5Ω condition and lowest in the 3mg/ml+1.5Ω condition. The greatest reduction in abstinence symptoms were observed in the 8mg/ml+0.5Ω condition, although the highest ratings for satisfaction and liking were reported in the 3mg/ml+0.5Ω condition. Use of ECIGs containing 3 mg/ml nicotine liquid resulted in longer and larger puffs and increased puff frequency, though high-power/low-resistance ECIGs resulted in greater consumption of ECIG liquid. ECIG device and liquid characteristics and user puff topography should be considered simultaneously when making regulatory decisions aimed at protecting public health. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Introduction: Relative to non-waterpipe (WP) smokers, WP smokers are more than twice as likely to use alcohol and frequently consume alcohol before or during smoking sessions. Co-use of alcohol and WP may result in greater toxicant exposure compared to WP smoking alone. To date, no study systematically has investigated the impact of acute alcohol intoxication on WP smoking topography, exposure to tobacco-related toxicants, or abuse liability., Methods: Dyads of current WP smokers and drinkers (N = 42; age = 21-32 years) completed two in-laboratory ad libitum smoking sessions (≤2 hours) following 12-hour nicotine abstinence in a double-blind, randomized crossover design in which they consumed a placebo versus active drink (sustained breath alcohol concentration = .08). Exhaled carbon monoxide (eCO) and plasma nicotine concentration were assessed. Questionnaires assessed smoking experience and smoking urge. Smoking topography was measured continuously throughout each smoking session., Results: The alcohol session was associated with increased inhaled volume, flow rate, and WP session duration compared to placebo. Compared to placebo, participants reported a more positive overall smoking experience following the alcohol session and greater smoking urges pre- and post-smoking session. Although both sessions resulted in significant increases in eCO and plasma nicotine, no significant differences emerged in eCO or nicotine exposure between the active and placebo sessions., Conclusions: Co-use of alcohol and WP may contribute to the maintenance of WP smoking through enhanced smoking experiences, increased urge to smoke, and significant exposure to addictive nicotine. Regulations may be necessary to limit the sale of alcohol in WP smoking lounges and reduce exposure to secondhand smoke., Implications: The findings suggest co-use of alcohol and WP tobacco likely maintain WP use and dependence by enhancing the smoking experience and increasing urges to smoke. These findings have implications for regulations aimed at limiting co-use of alcohol and WP tobacco in WP lounges and limiting exposure to secondhand smoke., Clinical Trials Registration: NCT03096860., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction : Electronic cigarettes (e-cigarettes) are a rapidly evolving class of tobacco products intended to deliver nicotine to users. There are many types of e-cigarettes available and the most popular type today in the United States are 'pod' based devices that use high nicotine concentration liquids. Understanding the nicotine delivery capabilities of e-cigarettes is imperative for understanding their addictive potential and safety profile, informing regulation, and revealing their potential use as smoking cessation aids. Areas covered : This review discusses nicotine content of e-cigarettes, effectiveness of nicotine aerosolization by devices, delivery of nicotine to users, and user and device characteristics that impact each of these. Expert opinion : Modern e-cigarettes have the potential to deliver equal or more nicotine compared to a tobacco cigarette. Future research needs to identify the nicotine delivery profiles likely to benefit public health and the means to regulate them appropriately while also identifying those that are likely to cause harm. Public health benefit accrues if e-cigarettes help smokers quit combustible cigarettes completely. Harm is possible if inadequate nicotine delivery undermines cessation attempts, e-cigarettes facilitate continued combustible cigarette use, long-term e-cigarette use is associated with substantial morbidity/mortality, and/or e-cigarettes increase the initiation of combustible cigarette use among never smokers.

Background: A rapidly evolving tobacco marketplace highlights the timeliness of the FDA's authority to regulate tobacco, specifically the role that flavorings in nicotine-containing electronic cigarette (ECIG) liquids have on public health. This study aimed to evaluate the extent to which ECIG liquid flavor and nicotine concentration influenced subjective measures of abuse liability among young adult cigarette (cig) smokers., Methods: Young adult (18-21 y.o.) smokers (M = 10.1 cig/day, no regular ECIG use history) completed 7 Latin-square ordered conditions each preceded by 12 h. nicotine/tobacco abstinence. Conditions were own brand cig (OB) and eGo-style ECIG paired with three liquid flavors (cream, tropical fruit, tobacco/menthol) varying in nicotine concentration (0 or 36 mg/ml). Products were administered in two 10-puff bouts in each condition. Heart rate/blood pressure (HR/BP) and tobacco/nicotine abstinence symptoms, nicotine/general drug effects, and acceptability measures were assessed repeatedly throughout sessions. Mixed linear models were followed-up with Tukey's HSD t-tests., Results: HR/BP indicated nicotine exposure during nicotine-containing conditions. OB and tobacco/menthol 36 mg/ml conditions produced significant decreases in ratings of cig smoking urges. Nicotine/drug effects were elevated significantly for OB and 36 mg/ml ECIG conditions with one exception noted for the tobacco/menthol 0 mg/ml condition. OB had the highest acceptability ratings, and ECIG condition results varied by acceptability item., Conclusions: Among young adult smokers, ECIG conditions containing nicotine were positively associated with several subjective measures of abuse liability but not all. Flavors did not consistently mask/enhance effects observed. Results reinforce continued examination of ECIG-delivered nicotine and liquid flavors in relationship to abuse liability., (Copyright © 2019. Published by Elsevier B.V.)

Background: The capability of electronic cigarette devices (e-cigs) to deliver nicotine is key to their potential to replace combustible cigarettes. We compared nicotine delivery and subjective effects associated with the use of two classes of e-cigarettes and cigarettes., Methods: 14 e-cigarette users were instructed to vape their own e-cigarette device every 20 seconds for 10 minutes while blood was drawn at 1, 2, 4, 6, 8, 10,12, and 15 minutes after initiating vaping. Users rated withdrawal symptoms and side effects before and after vaping. E-cigarette devices were classified as first-generation (same size as cigarette, no activation button) or advanced (larger than cigarette with an activation button). Separately, 10 cigarette smokers completed a similar protocol. Fisher's Exact Test and two-sided t-tests were used as appropriate to determine differences in outcomes between first-generation e-cigarette users, advanced e-cigarette users, and smokers., Results: Compared to first-generation devices, advanced devices were associated with greater serum nicotine Cmax (ng/ml) (11.5 v. 2.8, p = 0.0231) and greater nicotine boost (ng/ml) (10.8 v. 1.8, p = 0.0177). Overall, e-cigarettes users experienced a significant reduction in withdrawal and craving, although there were no significant differences between users of first-generation and advanced devices. Comparing e-cigarettes overall to cigarettes, cigarettes were associated with greater Cmax (25.9 v. 9.0, p = 0.0043) and greater nicotine boost (21.0 v. 8.2, p = 0.0128)., Conclusions: Advanced e-cigarettes delivered significantly more nicotine than first-generation devices but less than combustible cigarettes. Overall, e-cigarette use was associated with a reduction in withdrawal and craving with no reported side effects. The wide variation in nicotine absorption from different e-cigarette devices should be considered in studies of e-cigarettes for smoking cessation., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JF has done paid consulting for pharmaceutical companies involved in producing smoking cessation medications, including GSK, Pfizer, Novartis, J&J, and Cypress Bioscience. TE is a paid consultant in litigation against the tobacco industry and is named on a patent application for a device that measures the puffing behavior of electronic cigarette users. There are no other competing interests to report for other authors.

Background: Studies that assess waterpipe tobacco smoking behaviour and toxicant exposure generally use controlled laboratory environments with small samples that may not fully capture real-world variability in human behaviour and waterpipe products. This study aimed to conduct real-time sampling of waterpipe tobacco use in natural environments using an in situ device., Methods: We used the REALTIME sampling instrument: a validated, portable, self-powered device designed to sample automatically a fixed percentage of the aerosol flowing through the waterpipe mouthpiece during every puff. We recruited participants at café and home settings in Jordan and measured puffing behaviour in addition to inhalation exposure of total particulate matter (TPM), carbon monoxide (CO), nicotine, polycyclic aromatic hydrocarbons and volatile aldehydes. We correlated total inhaled volume with five selected toxicants and calculated the regression line of this relationship., Results: Averaged across 79 singleton sessions (52% male, mean age 27.0, 95% home sessions), sessions lasted 46.9 min and participants drew 290 puffs and inhaled 214 L per session. Mean quantities of inhaled toxicants per session were 1910 mg TPM, 259 mg CO, 5.0 mg nicotine, 117 ng benzo[a]pyrene and 198 ng formaldehyde. We found positive correlations between total inhaled volume and TPM (r=0.472; p<0.001), CO (r=0.751; p<0.001), nicotine (r=0.301, p=0.035) and formaldehyde (r=0.526; p<0.001), but a non-significant correlation for benzo[a]pyrene (r=0.289; p=0.056)., Conclusions: In the natural environment, waterpipe tobacco users inhale large quantities of toxicants that induce tobacco-related disease, including cancer. Toxicant content per waterpipe session is at least equal, but for many toxicants several magnitudes of order higher, than that of a cigarette. Health warnings based on early controlled laboratory studies were well founded; if anything our findings suggest a greater exposure risk., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Waterpipe tobacco smoking (WTS) exposes users to toxicants in much greater amounts than a cigarette. Little is known about how gender affects WTS toxicant exposure and subjective response. Data from three WTS clinical laboratory studies were combined for analysis. Participants ( N = 99; 38 women) completed a 45-min WTS session where they smoked a waterpipe ad libitum. Puff topography was measured throughout, and plasma nicotine concentration, expired air carbon monoxide (CO), and subjective responses were measured pre- and post-WTS. There was a gender effect for total puff volume with men inhaling a greater smoke volume, on average ( M = 59.9 L, SD = 40.7), compared with women ( M = 38.8 L, SD = 27.8; p < .01). Men had greater post-WTS mean plasma nicotine concentrations ( M = 10.0 ng/ml, SD = 7.1) compared with women ( M = 6.9 ng/ml, SD = 5.2; p < .05). Post-WTS expired air CO was not associated with gender (men M = 27.6 ppm, SD = 18.9; women M = 22.7 ppm, SD = 17.0, ns ). Relative to men, women had higher post-WTS scores for subjective measures of "nauseous," "dizzy," "nervous," "headache," and "heart pounding." Men and women are exposed to toxicants during WTS, and men may achieve higher nicotine exposure than women, likely resulting from differences in smoke inhaled. However, similar post-WTS expired air CO between men and women and higher ratings of negative subjective responses among women may indicate that factors beyond puff topography may impact toxicant exposure and subjective response to WTS. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Background: Electronic cigarettes (ECIGs) are a class of tobacco products that produce different effects (e.g., nicotine delivery), depending on the device, liquid, and behavioral factors. However, the influence of the two primary ECIG liquid solvents, propylene glycol (PG) and vegetable glycerin (VG), on ECIG acute effects is unknown., Methods: Thirty ECIG-experienced, ≥12-h nicotine- abstinent participants completed four conditions consisting of two ECIG-use bouts (10 puffs, 30 s interpuff-interval) differing only by liquid PG:VG ratio (2PG:98VG, 20PG:80VG, 55PG:45VG, 100PG). Device power (7.3 W) and liquid nicotine concentration (18 mg/ml) remained constant. Nicotine delivery, subjective effects, heart rate (HR), and puff topography were assessed., Results: In the 100PG condition, participants took shorter and smaller puffs but obtained significantly more nicotine relative to the two VG-based conditions. Total nicotine exposure (i.e., area under the curve) was also significantly higher during use of the two PG-based liquids. However, participants reported that the 100 PG liquid was significantly less "pleasant" and "satisfying" relative to the other liquids (all ps < .05). Increases in HR and decreases in abstinence symptoms (e.g., "craving") did not differ across conditions., Conclusions: PG:VG ratio influenced nicotine delivery, some subjective effects, and puff topography. Lower overall product satisfaction associated with the 100PG liquid suggests factors other than nicotine delivery (e.g., aerosol visibility) may play a role in maintaining ECIG use. Regulating ECIG acute effects such as nicotine delivery and subjective effects may require simultaneous attention to liquid PG:VG ratio as well as device, liquid, and behavioral factors known to influence these outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: One possible reason for the rapid proliferation of waterpipe (WP) smoking is the pervasive use of flavoured WP tobacco. To begin to understand the impact of WP tobacco flavours, the current study examined the impact of a preferred WP tobacco flavour compared with a non-preferred tobacco flavoured control on user's smoking behaviour, toxicant exposure and subjective smoking experience., Method: Thirty-six current WP smokers completed two, 45-minute ad libitum smoking sessions (preferred flavour vs non-preferred tobacco flavour control) in a randomised cross-over design. Participants completed survey questionnaires assessing subjective smoking experience, exhaled carbon monoxide (eCO) testing, and provided blood samples for monitoring plasma nicotine. WP smoking topography was measured continuously throughout the smoking session., Results: While participants reported an enhanced subjective smoking experience including greater interest in continued use, greater pleasure derived from smoking, increased liking and enjoyment, and willingness to continue use after smoking their preferred WP tobacco flavour (p values <0.05), no significant differences were observed in nicotine and carbon monoxide boost between flavour preparations. Greater average puff volume (p=0.018) was observed during the non-preferred flavour session. While not significant, measures of flow rate, interpuff interval (IPI), and total number of puffs were trending towards significance (p values <0.10), with decreased IPI and greater total number of puffs during the preferred flavour session., Discussion: The current study is the first to examine flavours in WP smoking by measuring preferred versus control preparations to understand the impact on subjective experience, smoking behaviour and toxicant exposure. The pattern of results suggests that even this relatively minor manipulation resulted in significant changes in subjective experience. These results indicate a possible need for regulations restricting flavours in WP tobacco as with combustible cigarettes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Electronic cigarettes (ECIGs) aerosolize liquids for user inhalation that usually contain nicotine. ECIG nicotine emission is determined, in part, by user behavior, liquid nicotine concentration, and electrical power. Whether users are able to report accurately nicotine concentration and device electrical power has not been evaluated. This study's purpose was to examine if ECIG users could provide data relevant to understanding ECIG nicotine emission, particularly liquid nicotine concentration (mg/ml) as well as battery voltage (V) and heater resistance (ohms, Ω) - needed to calculate power (watts, W)., Methods: Adult ECIG users (N=165) were recruited from Los Angeles, CA for research studies examining the effects of ECIG use. We asked all participants who visited the laboratory to report liquid nicotine concentration, V, and Ω., Results: Liquid nicotine concentration was reported by 89.7% (mean=9.5mg/ml, SD=7.3), and responses were consistent with the distribution of liquids available in commonly marketed products. The majority could not report voltage (51.5%) or resistance (63.6%). Of the 40 participants (24.8%) who reported voltage and resistance, there was a substantial power range (2.2-32,670W) the upper limit of which exceeds that of the highest ECIG reported by any user to our knowledge (i.e., 2512W). If 2512W is taken as the upper limit, only 30 (18.2%) reported valid results (mean 237.3W, SD=370.6; range=2.2-1705.3W)., Conclusions: Laboratory, survey, and other researchers interested in understanding ECIG effects to inform users and policymakers may need to use methods other than user self-report to obtain information regarding device power., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Electronic cigarette (ECIG) nicotine delivery and other effects may depend on liquid nicotine concentration and user experience. This study is the first to systematically examine the influence of ECIG liquid nicotine concentration and user experience on nicotine delivery, heart rate, puff topography, and subjective effects. Thirty-three ECIG-experienced individuals and 31 ECIG-naïve cigarette smokers completed 4 laboratory conditions consisting of 2, 10-puff bouts (30-sec interpuff interval) with a 3.3-V ECIG battery attached to a 1.5-Ω "cartomizer" (7.3 W) filled with 1 ml ECIG liquid. Conditions differed by liquid nicotine concentration: 0, 8, 18, or 36 mg/ml. Participants' plasma nicotine concentration was directly related to liquid nicotine concentration and dependent on user experience, with significantly higher mean plasma nicotine increases observed in ECIG-experienced individuals relative to ECIG-naïve smokers in each active nicotine condition. When using 36 mg/ml, mean plasma nicotine increase for ECIG-experienced individuals was 17.9 ng/ml (SD = 17.2) and 6.9 (SD = 7.1; p < .05) for ECIG-naïve individuals. Between-group differences were likely due to longer puffs taken by experienced ECIG users: collapsed across condition, mean puff duration was 5.6 sec (SD = 3.0) for ECIG-experienced and 2.9 (SD = 1.5) for ECIG-naïve individuals. ECIG use also suppressed nicotine/tobacco abstinence symptoms in both groups; the magnitude of abstinence symptom suppression depended on liquid nicotine concentration and user experience. These and other recent results suggest that policies intended to limit ECIG nicotine delivery will need to account for factors in addition to liquid nicotine concentration (e.g., device power and user behavior). (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Introduction: Electronic cigarettes e-cigarettes aerosolize a liquid solution often containing nicotine. e-cigarette nicotine delivery may be influenced by user puffing behaviors ("puff topography"). E-cigarette puff topography can be recorded using mouthpiece-based computerized systems. The present study sought to examine the extent to which these systems influence e-cigarette nicotine delivery and other e-cigarette associated acute effects under ad libitum use conditions., Methods: Plasma nicotine concentration, heart rate, and subjective effects were assessed in 29 experienced e-cigarette users using their preferred e-cigarette battery and liquid (≥12mg/mL nicotine) in two sessions differing only by the presence of a mouthpiece-based device. In both sessions, participants completed a directed e-cigarette use bout (10 puffs, 30-s interpuff interval) and a 90-min ad libitum bout. Puff topography was recorded in the session with the topography mouthpiece., Results: Plasma nicotine, heart rate, and subjective effects, aside from "Did the e-cigarette Taste Good?" were independent of topography measurement (higher mean taste ratings were observed in the no topography condition). Mean (SEM) plasma nicotine concentration following the ad libitum bout was 34.3ng/mL (4.9) in the no topography condition and 35.7ng/mL (4.3) in the topography condition. Longer puff durations, longer interpuff intervals, and larger puff volumes were observed in the ad libitum relative to the directed bout., Conclusions: E-cigarette use significantly increased plasma nicotine concentration and heart rate while suppressing abstinence symptoms. These effects did not differ when a topography mouthpiece was present. Future studies using ad libitum e-cigarette use bouts would facilitate understanding of e-cigarette toxicant yield., Implications: No prior study has examined whether mouthpiece-based topography recording devices influence e-cigarette associated nicotine delivery, heart rate, or subjective effects under ad libitum conditions or assessed ad libitum puff topography in experienced individuals using their preferred e-cigarette battery and liquid with a mouthpiece-based computerized device. E-cigarette use significantly increased plasma nicotine concentration and heart rate while suppressing abstinence symptoms. These effects did not differ when a topography mouthpiece was present. Ad libitum puff topography differed from puff topography recorded during directed puffing. These findings suggest that future studies using ad libitum use bouts would facilitate better understanding of e-cigarette toxicant yield., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Novel tobacco products entering the US market include electronic cigarettes (ECIGs) and products advertised to "heat, not burn" tobacco. There is a growing literature regarding the acute effects of ECIGs. Less is known about "heat, not burn" products. This study's purpose was to expand existing clinical laboratory methods to examine, in cigarette smokers, the acute effects of a "heat, not burn" "loose-leaf tobacco vaporizer" (LLTV)., Methods: Plasma nicotine and breath carbon monoxide (CO) concentration and tobacco abstinence symptom severity were measured before and after two 10-puff (30-s interpuff interval) product use bouts separated by 60min. LLTV effects were compared to participants' own brand (OB) cigarettes and an ECIG (3.3V; 1.5ohm; 18mg/ml nicotine)., Results: Relative to OB, LLTV increased plasma nicotine concentration to a lesser degree, did not increase CO, and did not appear to reduce abstinence symptoms as effectively. Relative to ECIG, LLTV nicotine and CO delivery and abstinence symptom suppression did not differ. Participants reported that both the LLTV and ECIG were significantly less satisfying than OB., Conclusions: Results demonstrate that LLTVs are capable of delivering nicotine and suppressing tobacco abstinence symptoms partially; acute effects of these products can be evaluated using existing clinical laboratory methods. Results can inform tobacco product regulation and may be predictive of the extent that these products have the potential to benefit or harm overall public health., Competing Interests: No conflict declared., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Electronic cigarettes (ECIGs) aerosolize a liquid that usually contains propylene glycol and/or vegetable glycerin, flavorants, and the dependence-producing drug nicotine in various concentrations. This study examined the extent to which ECIG liquid nicotine concentration is related to user plasma nicotine concentration in ECIG-naïve tobacco cigarette smokers., Methods: Sixteen ECIG-naïve cigarette smokers completed four laboratory sessions that differed by the nicotine concentration of the liquid (0, 8, 18, or 36 mg/ml) that was placed into a 1.5 Ohm, dual coil "cartomizer" powered by a 3.3V battery. In each session, participants completed two, 10-puff ECIG use bouts with a 30-second inter-puff interval; bouts were separated by 60 minutes. Venous blood was sampled before and after bouts for later analysis of plasma nicotine concentration; puff duration, volume, and average flow rate were measured during each bout., Results: In bout 1, relative to the 0mg/ml nicotine condition (mean = 3.8 ng/ml, SD = 3.3), plasma nicotine concentration increased significantly immediately after the bout for the 8 (mean = 8.8 ng/ml, SD = 6.3), 18 (mean = 13.2 ng/ml, SD = 13.2), and 36 mg/ml (mean = 17.0 ng/ml, SD = 17.9) liquid concentration. A similar pattern was observed after bout 2. Average puff duration in the 36 mg/ml condition was significantly shorter compared to the 0mg/ml nicotine condition. Puff volume increased during the second bout for 8 and 18 mg/ml conditions., Conclusions: For a given ECIG device, nicotine delivery may be directly related to liquid concentration. ECIG-naïve cigarette smokers can, from their first use bout, attain cigarette-like nicotine delivery profiles with some currently available ECIG products., Implications: Liquid nicotine concentration can influence plasma nicotine concentration in ECIG-naïve cigarette smokers, and, at some concentrations, the nicotine delivery profile of a 3.3V ECIG with a dual coil, 1.5-Ohm cartomizer approaches that of a combustible tobacco cigarette in this population. Finding a product that delivers nicotine as effectively as a tobacco cigarette, as we report here, may be essential for smokers who want to replace completely their combustible tobacco cigarettes with ECIGs., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Cigars remain a widely used tobacco product among adolescent and adult populations. The appeal of a certain type of cigar, the cigarillo, may be enhanced by users' beliefs that their harm potential can be reduced by removing the inner tobacco liner before use (a.k.a. "hyping"). The purpose of this within-subject study was to compare the acute effects of smoking an original cigarillo, a modified ("hyped") cigarillo, and an unlit cigarillo., Methods: Twenty smokers (19 males, 1 female; 19 non-Hispanic blacks, 1 Hispanic "other") of at least 7 Black&Mild (B&M) cigarillos/week and at most 5 cigarettes/day completed the study. All participants reported hyping their cigarillos at least occasionally. Primary outcomes, assessed over two, 30-minute smoking bouts, included plasma nicotine, expired air carbon monoxide (CO) concentration, subjective ratings (product effects, nicotine abstinence symptoms), and puff topography., Results: Mean plasma nicotine concentration increased significantly within (pre- to post-bouts), but not between, original and modified B&M conditions. Mean CO concentration was significantly lower for modified, relative to original, B&M smoking at all post-administration timepoints. Both smoked conditions significantly increased ratings of positive product effects (satisfaction, pleasant) and decreased abstinence symptom magnitude; however, ratings generally did not differ between these conditions. Overall, topography outcomes did not differ between modified and original B&M smoking., Conclusions: Results are consistent with a previous report in that "hyping" may decrease users' CO, but not nicotine, exposure. While these data collectively suggest reduced exposure to CO acutely with engagement in "hyping," longer-term assessments are needed to determine the impact on individual and public health., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Electronic cigarettes (ECIGs) aerosolise a liquid that usually contains propylene glycol and/or vegetable glycerine, flavourants and the dependence-producing drug, nicotine, in various concentrations. This laboratory study examined the relationship between liquid nicotine concentration and plasma nicotine concentration and puffing behaviour in experienced ECIG users., Methods: Sixteen ECIG-experienced participants used a 3.3-Volt ECIG battery attached to a 1.5-Ohm dual-coil 'cartomiser' loaded with 1 mL of a flavoured propylene glycol/vegetable glycerine liquid to complete four sessions, at least 2 days apart, that differed by nicotine concentration (0, 8, 18 or 36 mg/mL). In each session, participants completed two 10-puff ECIG-use bouts (30 s puff interval) separated by 60 min. Venous blood was sampled to determine plasma nicotine concentration. Puff duration, volume and average flow rate were measured., Results: Immediately after bout 1, mean plasma nicotine concentration was 5.5 ng/mL (SD=7.7) for 0 mg/mL liquid, with significantly (p<0.05) higher mean concentrations observed for the 8 (mean=17.8 ng/mL, SD=14.6), 18 (mean=25.9 ng/mL, SD=17.5) and 36 mg/mL (mean=30.2 ng/mL; SD=20.0) concentrations; a similar pattern was observed for bout 2. For bout 1, at 36 mg/mL, the mean post- minus pre-bout difference was 24.1 ng/mL (SD=18.3). Puff topography data were consistent with previous results and revealed few reliable differences across conditions., Discussion: This study demonstrates a relationship between ECIG liquid nicotine concentration and user plasma nicotine concentration in experienced ECIG users. Nicotine delivery from some ECIGs may exceed that of a combustible cigarette. The rationale for this higher level of nicotine delivery is uncertain., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Introduction: Clinical laboratory work among intermittent and daily waterpipe tobacco smokers has revealed significant risks for tobacco dependence and disease associated with waterpipe tobacco smoking (WTS). No studies have compared these groups directly. This study examined whether WTS frequency was associated with differential puff topography, toxicant exposure, and subjective response using a placebo-control design., Methods: Eighty participants reporting WTS of 2-5 episodes (LOW; n = 63) or ≥20 episodes (HIGH; n = 17) per month for ≥6 months completed 2 double-blind, counterbalanced 2-hr sessions that were preceded by ≥12hr of tobacco abstinence. Sessions differed by product smoked ad libitum for 45+ min: preferred brand/flavor of waterpipe tobacco (active) or a flavor-matched tobacco-free waterpipe product (placebo). Outcomes included puff topography, plasma nicotine, carboxyhemoglobin (COHb), and subjective response., Results: HIGH users had more puffs, shorter inter-puff-intervals, and a higher total puff volume for placebo relative to active, as well as relative to LOW users during placebo. Plasma nicotine concentrations increased when smoking active (but not placebo) with no significant differences between groups at 25min post-product administration. COHb increased significantly during all conditions; the largest increase was for HIGH users when smoking placebo. There was some evidence of higher baseline scores for nicotine/tobacco nicotine abstinence symptomology., Conclusions: Higher frequency waterpipe users may be more sensitive to the effects of waterpipe smoke nicotine content. Among HIGH users, higher baseline nicotine/tobacco abstinence symptoms may indicate greater nicotine dependence. These data support continued surveillance of WTS and development of dependence measures specific to this product., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Electronic cigarettes (ECIGs) use an electric heater to aerosolize a liquid that usually contains propylene glycol, vegetable glycerin, flavorants, and the dependence-producing drug nicotine. ECIG-induced nicotine dependence has become an important concern, as some ECIGs deliver very little nicotine while some may exceed the nicotine delivery profile of a tobacco cigarette. This variability is relevant to tobacco cigarette smokers who try to switch to ECIGs. Products with very low nicotine delivery may not substitute for tobacco cigarettes, so that ECIG use is accompanied by little reduced risk of cigarette-caused disease. Products with very high nicotine delivery may make quitting ECIGs particularly difficult should users decide to try. For non-smokers, the wide variability of ECIGs on the market is especially troublesome: low nicotine products may lead them to initiate nicotine self-administration and progress to higher dosing ECIGs or other products, and those that deliver more nicotine may produce nicotine dependence where it was not otherwise present. External regulatory action, guided by strong science, may be required to ensure that population-level nicotine dependence does not rise.

Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively), and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence.

Introduction: Electronic cigarettes (ECIGs) heat a nicotine-containing solution; the resulting aerosol is inhaled by the user. Nicotine delivery may be affected by users' puffing behavior (puff topography), and little is known about the puff topography of ECIG users. Puff topography can be measured using mouthpiece-based computerized systems. However, the extent to which a mouthpiece influences nicotine delivery and subjective effects in ECIG users is unknown., Methods: Plasma nicotine concentration, heart rate, and subjective effects were measured in 13 experienced ECIG users who used their preferred ECIG and liquid (≥ 12 mg/ml nicotine) during 2 sessions (with or without a mouthpiece). In both sessions, participants completed an ECIG use session in which they were instructed to take 10 puffs with 30-second inter-puff intervals. Puff topography was recorded in the mouthpiece condition., Results: Almost all measures of the effects of ECIG use were independent of topography measurement. Collapsed across session, mean plasma nicotine concentration increased by 16.8 ng/ml, and mean heart rate increased by 8.5 bpm (ps < .05). Withdrawal symptoms decreased significantly after ECIG use. Participants reported that the mouthpiece affected awareness and made ECIG use more difficult. Relative to previously reported data for tobacco cigarette smokers using similar topography measurement equipment, ECIG-using participants took larger and longer puffs with lower flow rates., Conclusions: In experienced ECIG users, measuring ECIG topography did not influence ECIG-associated nicotine delivery or most measures of withdrawal suppression. Topography measurement systems will need to account for the low flow rates observed for ECIG users., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Electronic cigarettes (ECIGs) comprise an aerosolized nicotine delivery product category that provides consumers with probably unprecedented control over extensive features and operating conditions, allowing a wide range of nicotine yields to be obtained. Depending on the combination of such ECIG variables as electrical power input, geometry, liquid composition, and puff behavior, ECIG users can extract in a few puffs far more or far less nicotine than with a conventional combustible cigarette. These features of ECIG design and use present challenges for public health policy, central among which is the question of how to regulate nicotine delivery. In this commentary, we propose a conceptual framework intended to provide a convenient approach for evaluating and regulating the nicotine emitted from ECIGs. This framework employs nicotine flux to account for the total dose and rate at which nicotine reaches the user, 2 key factors in drug abuse liability. The nicotine flux is the nicotine emitted per puff second (e.g., mg/s) by a given ECIG design under given use conditions, and it can be predicted accurately using physical principles. We speculate that if the flux is too low, users likely will abandon the device and maintain conventional tobacco product use. Also, we speculate that if the flux is too high, individuals may suffer toxic side effects and/or the device may have higher-than-necessary abuse liability. By considering ECIG design, operation conditions, liquid composition, and puff behavior variables in combination, we illustrate how ECIG specifications can be realistically mandated to result in a target flux range., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood., Purpose: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes., Results and Conclusions: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: To assess dependence levels in users of e-cigarettes, and compare them with dependence levels in users of nicotine gums and tobacco cigarettes., Design: Self-reports from cross-sectional Internet and mail surveys. Comparisons of: (a) 766 daily users of nicotine-containing e-cigarettes with 30 daily users of nicotine-free e-cigarettes; (b) 911 former smokers who used the e-cigarette daily with 451 former smokers who used the nicotine gum daily (but no e-cigarette); (c) 125 daily e-cigarette users who smoked daily (dual users) with two samples of daily smokers who did not use e-cigarettes (2206 enrolled on the Internet and 292 enrolled by mail from the general population of Geneva). We used the Fagerström test for nicotine dependence, the nicotine dependence syndrome scale, the cigarette dependence scale and versions of these scales adapted for e-cigarettes and nicotine gums., Results: Dependence ratings were slightly higher in users of nicotine-containing e-cigarettes than in users of nicotine-free e-cigarettes. In former smokers, long-term (>3 months) users of e-cigarettes were less dependent on e-cigarettes than long-term users of the nicotine gum were dependent on the gum. There were few differences in dependence ratings between short-term (≤3 months) users of gums or e-cigarettes. Dependence on e-cigarettes was generally lower in dual users than dependence on tobacco cigarettes in the two other samples of daily smokers., Conclusions: Some e-cigarette users were dependent on nicotine-containing e-cigarettes, but these products were less addictive than tobacco cigarettes. E-cigarettes may be as or less addictive than nicotine gums, which themselves are not very addictive., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Some electronic cigarette (ECIG) users attain tobacco cigarette-like plasma nicotine concentrations while others do not. Understanding the factors that influence ECIG aerosol nicotine delivery is relevant to regulation, including product labeling and abuse liability. These factors may include user puff topography, ECIG liquid composition, and ECIG design features. This study addresses how these factors can influence ECIG nicotine yield., Methods: Aerosols were machine generated with 1 type of ECIG cartridge (V4L CoolCart) using 5 distinct puff profiles representing a tobacco cigarette smoker (2-s puff duration, 33-ml/s puff velocity), a slow average ECIG user (4 s, 17 ml/s), a fast average user (4 s, 33 ml/s), a slow extreme user (8 s, 17 ml/s), and a fast extreme user (8 s, 33 ml/s). Output voltage (3.3-5.2 V or 3.0-7.5 W) and e-liquid nicotine concentration (18-36 mg/ml labeled concentration) were varied. A theoretical model was also developed to simulate the ECIG aerosol production process and to provide insight into the empirical observations., Results: Nicotine yields from 15 puffs varied by more than 50-fold across conditions. Experienced ECIG user profiles (longer puffs) resulted in higher nicotine yields relative to the tobacco smoker (shorter puffs). Puff velocity had no effect on nicotine yield. Higher nicotine concentration and higher voltages resulted in higher nicotine yields. These results were predicted well by the theoretical model (R (2) = 0.99)., Conclusions: Depending on puff conditions and product features, 15 puffs from an ECIG can provide far less or far more nicotine than a single tobacco cigarette. ECIG emissions can be predicted using physical principles, with knowledge of puff topography and a few ECIG device design parameters., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Electronic cigarettes (ECs) are marketed as nicotine delivery devices. Two studies with EC-naïve participants suggest that ECs deliver little or no nicotine. In those studies, standard-sized ECs were used, though experienced EC users often use larger devices that house higher voltage and/or longer lasting batteries. Whether user experience and device characteristics influence EC nicotine delivery is uncertain. The purpose of the present study was to examine the effects of ECs in experienced users who were using their preferred devices., Methods: Eight EC users (3 women) who had been using ECs for at least 3 months, completed one 5-hr session using devices they provided and the flavor/strength nicotine cartridges they selected. Sessions consisted of 4 phases: baseline, 10 puffs (30-s interpuff interval) from the device, 1-hr ad lib puffing period, and a 2-hr rest period (no puffing). Outcome measures in each phase included plasma nicotine concentration, heart rate, and subjective ratings of nicotine/product effects and abstinence symptoms., Results: Relative to baseline, plasma nicotine and heart rate increased significantly within 5 min of the first puff and remained elevated throughout the ad lib puffing period. Increases in ratings of direct effects of nicotine and product were observed as well as decreases in abstinence symptoms., Conclusions: User experience and/or device characteristics likely influence EC nicotine delivery and other effects. Systematic manipulation of these and other variables could elucidate conditions that produce intended effects.

The International Classification of Diseases and the Diagnostic and Statistical Manual for diagnosing tobacco/nicotine dependence emphasize the dependence-producing drug nicotine. These diagnostic tools have been challenged on grounds of poor predictive validity, and they do not differentiate across various forms of nicotine-containing products. In fact, nicotine-containing products (e.g., tobacco cigarettes, smokeless tobacco [ST], waterpipe, electronic cigarettes [ECIGs], and nicotine replacement [NR] products) have very different characteristics both in terms of sensory and behavioral involvement and also in pharmacokinetic and pharmacodynamic effects. For example, a cigarette and a nicotine patch are very different on almost every one of these dimensions. When ability to stop using a nicotine/tobacco product is used as a criterion for dependence, success rates vary considerably across products: Tobacco cigarette cessation is more difficult than ST cessation that in turn is more difficult than NR product cessation. Based on these results, we hypothesize that there is a continuum of dependence as much as there is a continuum of harm, with tobacco cigarettes and NR products on opposite ends of both continua and other products (waterpipe and ECIGs) somewhere in between. In order to capture more precisely the dependence produced by both nicotine and its administration forms, product-specific instruments may be required. The pros and cons of this approach are discussed.

Background: Waterpipe tobacco package labelling typically indicates "0.0% tar" and "0.05% or 0.5% nicotine"., Objective: To determine the extent to which nicotine labeling is related to nicotine delivery., Methods: 110 waterpipe smokers engaged in a 45-minute waterpipe smoking session. Puff topography and plasma nicotine were measured. Three waterpipe tobacco brands were used: Nakhla (0.5% nicotine), Starbuzz (0.05% nicotine), and Al Fakher (0.05% nicotine). Data were analyzed by one-way ANOVA., Results: Topography did not differ across brands. Peak plasma nicotine varied significantly across brands. Al Fakher had the highest nicotine delivery (11.4 ng/ml) followed by Nakhla (9.8 ng/ml) and Starbuzz (5.8 ng/ml)., Conclusions: Nicotine labelling on waterpipe tobacco products does not reflect delivery; smoking a brand with a "0.05% nicotine" label led to greater plasma nicotine levels than smoking a brand with a "0.5% nicotine" label. Waterpipe tobacco products should be labelled in a manner that does not mislead consumers.

Waterpipe (hookah, narghile, shisha) use has become a global phenomenon, with numerous product variations. One variation is a class of products marketed as "tobacco-free" alternatives for the "health conscious user". In this study toxicant yields from waterpipes smoked using conventional tobacco-based and tobacco-free preparations were compared. A human-mimic waterpipe smoking machine was used to replicate the puffing sequences of 31 human participants who completed two double-blind ad libitum smoking sessions in a controlled clinical setting: once with a tobacco-based product of their choosing and once with a flavor-matched tobacco-free product. Outcome measures included yields of carbon monoxide, nitric oxide, volatile aldehydes, nicotine, tar, and polycyclic aromatic hydrocarbons. Smoke from both waterpipe preparations contained substantial quantities of toxicants. Nicotine yield was the only outcome that differed significantly between preparations. These findings contradict advertising messages that "herbal" waterpipe products are a healthy alternative to tobacco products., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The global increase in tobacco smoking with a water pipe (hookah, narghile, or shisha) has made understanding its health consequences imperative. One key to developing this understanding is identifying and quantifying carcinogens and other toxicants present in water pipe smoke. To do so, the toxicant yield of machine-generated water pipe smoke has been measured. However, the relevance of toxicant yields of machine-generated smoke to actual human exposure has not been established., Methods: In this study, we examined whether carbon monoxide (CO) and nicotine yields measured with a smoking machine programmed to replicate the puffing behavior of 31 human participants who smoked a water pipe could reliably predict these participants' blood-level exposure. In addition to CO and nicotine, yields of polyaromatic hydrocarbons, volatile aldehydes, nitric oxide (NO), and "tar" were measured., Results: We found that when used in this puff-replicating manner, smoking machine yields are highly correlated with blood-level exposure (nicotine: r > 0.76, P < 0.001; CO: r > 0.78, P < 0.001). Total drawn smoke volume was the best predictor of toxicant yield and exposure, accounting for approximately 75% to 100% of the variability across participants in yields of NO, CO, volatile aldehydes, and tar, as well as blood-level CO and normalized nicotine., Conclusions: Machine-based methods can be devised in which smoke toxicant yields reliably track human exposure., Impact: This finding indicates the basic feasibility of valid analytic laboratory evaluation of tobacco products for regulatory purposes., (© 2011 AACR.)

Background: Waterpipe tobacco smoking usually involves heating flavored tobacco with charcoal and inhaling the resulting smoke after it has passed through water. Waterpipe tobacco smoking increases heart rate and produces subjective effects similar to those reported by cigarette smokers. These responses are thought to be nicotine-mediated, though no placebo-control studies exist. Accordingly, this double-blind, placebo-control study compared the acute physiological and subjective effects of waterpipe tobacco smoking to those produced when participants used a waterpipe to smoke a flavor-matched, tobacco-free preparation., Methods: Occasional waterpipe tobacco smokers (n = 37; 2-5 monthly smoking episodes for ≥ 6 months) completed two double-blind, counterbalanced sessions that differed by product: preferred brand/flavor of waterpipe tobacco or flavor-matched, tobacco-free preparation. For each 45-min, ad lib smoking episode blood and expired air CO were sampled, cardiovascular and respiratory response were measured, and subjective response was assessed., Results: Waterpipe tobacco smoking significantly increased mean (± SEM) plasma nicotine concentration (3.6 ± 0.7 ng/ml) and heart rate (8.6 ± 1.4 bpm) while placebo did not (0.1 ± 0.0 ng/ml; 1.3 ± 0.9b pm). For carboxyhemoglobin (COHb) and expired air CO, significant increases were observed for tobacco (3.8 ± 0.4%; 27.9 ± 2.6 ppm) and for placebo (3.9 ± 0.4%; 27.7 ± 3.3 ppm) with no differences across condition. Independent of condition, symptoms of nicotine/tobacco abstinence (e.g., "urges to smoke", "anxious") were reduced and direct effects (e.g., "dizzy", "satisfy") increased., Discussion: These results from the first placebo-control study of waterpipe tobacco smoking demonstrate that waterpipe-induced heart rate increases are almost certainly mediated by nicotine though the subjective effects observed in these occasional smokers were not., (Published by Elsevier Ireland Ltd.)

Electronic nicotine delivery systems (ENDS, also called electronic cigarettes or e-cigarettes) are marketed to deliver nicotine and sometimes other substances by inhalation. Some tobacco smokers report that they used ENDS as a smoking cessation aid. Whether sold as tobacco products or drug delivery devices, these products need to be regulated, and thus far, across countries and states, there has been a wide range of regulatory responses ranging from no regulation to complete bans. The empirical basis for these regulatory decisions is uncertain, and more research on ENDS must be conducted in order to ensure that the decisions of regulators, health care providers and consumers are based on science. However, there is a dearth of scientific research on these products, including safety, abuse liability and efficacy for smoking cessation. The authors, who cover a broad range of scientific expertise, from basic science to public health, suggest research priorities for non-clinical, clinical and public health studies. They conclude that the first priority is to characterize the safety profile of these products, including in long-term users. If these products are demonstrated to be safe, their efficacy as smoking cessation aids should then be tested in appropriately designed trials. Until these studies are conducted, continued marketing constitutes an uncontrolled experiment and the primary outcome measure, poorly assessed, is user health. Potentially, this research effort, contributing to the safety and efficacy of new smoking cessation devices and to the withdrawal of dangerous products, could save many lives.

This study's objective is to examine the relative effectiveness of cigarettes and waterpipe (WP) in reducing tobacco abstinence symptoms in dual cigarette/WP smokers. Sixty-one dual cigarette/WP smokers participated (mean age±SD 22.0±2.6 year; mean cigarettes/day 22.4±10.1; mean WPs/week 5.2±5.6). After 12-hour abstinence participants completed two smoking sessions (WP or cigarette), while they responded to subjective measures of withdrawal, craving, and nicotine effects administered before smoking and 5, 15, 30 and 45 min thereafter. For both tobacco use methods, scores on measures of withdrawal and craving were high at the beginning of session (i.e., before smoking) and were reduced significantly and comparably during smoking. Analysis of smoking and recovery (post-smoking) phases showed similarity in the way both tobacco use methods suppressed withdrawal and craving, but the recovery of some of these symptoms can be faster with cigarette use. This study is the first to show the ability of WP to suppress abstinence effects comparably to cigarettes, and its potential to thwart cigarette cessation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Waterpipe tobacco smoking is increasing in popularity worldwide and available evidence point to its addictive and harmful potential. This study is conducted to assess nicotine exposure in daily waterpipe smokers, and its correlation with puff topography parameters. Sixty-one waterpipe tobacco smokers (56 males; mean age±SD, 30.9±9.5years; mean number of weekly waterpipe smoking episodes 7.8±5.7) abstained from smoking for at least 24h, and then smoked tobacco from a waterpipe ad libitum in a laboratory setting. During the session puff topography parameters were monitored continuously, and pre- and post-smoking expired-air CO was measured. Before and after smoking, venous blood was sampled for the assessment of plasma nicotine using Gas Chromatography-Mass Spectrometry. The average pre- and post-smoking expired-air CO was 4±1.7 and 35.5±32.7ppm, respectively (i.e., a CO boost of 31.5ppm, p<.001). Mean plasma nicotine concentration increased from 3.07±3.05ng/ml pre-smoking to 15.7±8.7ng/ml post-smoking (p<.001). Plasma nicotine boost was correlated with total session time (Pearson correlation coefficient r=.31, p=.04), cumulative puff duration (r=.37, p=.01), mean puff duration (r=.34, p=.02), and total smoke inhaled in the session (r=.34, p=.02. These data show considerable nicotine exposure in daily waterpipe smokers, and that nicotine exposure is a function of waterpipe smoking patterns., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Waterpipe tobacco smoking is increasing worldwide and is believed by many users to be less harmful and addictive than cigarette smoking. In fact, waterpipe tobacco and cigarette smoke contain many of the same chemicals, and users are exposed to the dependence-producing drug nicotine as well as other smoke toxicants. The subjective effect profile of these 2 tobacco use methods has not been compared directly, though this information is relevant to understanding the risk of dependence development., Methods: Fifty-four participants who reported waterpipe and cigarette smoking completed 2, 45-min, counter-balanced sessions in which they completed a waterpipe use episode (mean smoking time = 43.3 min) or a cigarette (mean = 6.1 min). Outcome measures included plasma nicotine, carboxyhemoglobin (COHb), and subjective effects, including those relevant to predicting dependence potential., Results: Mean (±SEM) peak plasma nicotine concentration did not differ by session (waterpipe = 9.8 ± 1.0 ng/ml; cigarette = 9.4 ± 1.0 ng/ml). Mean peak COHb concentration differed significantly (waterpipe = 4.5% ± 0.3%; cigarette = 1.2% ± 0.1%). Subjective effect changes for waterpipe and cigarette were comparable in magnitude but often longer lived for waterpipe., Conclusions: Relative to a cigarette, waterpipe tobacco smoking was associated with similar peak nicotine exposure, 3.75-fold greater COHb, and 56-fold greater inhaled smoke volume. Waterpipe and cigarette influenced many of the same subjective effect measures. These findings are consistent with the conclusion that waterpipe tobacco smoking presents substantial risk of dependence, disease, and death, and they can be incorporated into prevention interventions that might help deter more adolescents and young adults from experimenting with an almost certainly lethal method of tobacco use.

Smokers experience cognitive decrements during tobacco abstinence and boosts in performance on resumption of smoking. Few studies have examined whether smoking cessation treatments such as transdermal nicotine (TN) ameliorate these decrements or attenuate the cognitive effects of smoking. Identifying the effects of nicotine on these tobacco-related changes in performance could guide the development of more efficacious treatments. The purpose of this double-blind, randomized, laboratory study was to use process-specific cognitive tasks to examine the effects of TN and tobacco smoking on attention and working memory in overnight-abstinent smokers (N = 124; 54 women). Each participant completed 4 sessions lasting 6.5 hr corresponding to 0-, 7-, 14-, or 21-mg TN doses, and smoked a single cigarette 4 hr after TN administration. Outcome measures were administered before and after smoking and included tasks measuring attention (alerting, orienting, and executive function), working memory (verbal and spatial), and psychomotor function. Analysis of variance (p < .05) revealed that TN improved verbal and spatial working memory performance, as well as psychomotor function. Smoking, independent of TN dose, improved alerting, verbal working memory, and psychomotor function. Lastly, TN partially attenuated the effects of smoking on some working memory outcomes. These findings lend evidence to the idea that TN ameliorates some abstinence-related cognitive decrements and suggest that TN does not completely attenuate the cognitive effects of a concurrently smoked cigarette. Consequently, TN's efficacy as a smoking cessation treatment might be improved if these limitations are better addressed by either modifying or supplementing existing treatments., ((c) 2011 APA, all rights reserved)

Introduction: Understanding factors that influence tobacco use often involves detailed assessment of smoking behavior (i.e., puff topography) via mouthpiece-based, computerized devices. Research suggests that the use of a mouthpiece to evaluate topography may alter natural smoking behavior. This study was designed to compare topography measurement using mouthpiece-based methods (i.e., desktop and portable computerized devices) to methods that do not use a mouthpiece (i.e., direct observation)., Methods: A total of 30 smokers (> or =15 full-flavor or light cigarettes/day) participated in six Latin square-ordered, 2.5-hr experimental sessions that were preceded by at least 8 hr of objectively verified tobacco abstinence (carbon monoxide level < or = 10 ppm). Each session consisted of participants smoking four cigarettes (own brand or Merit ultra-light) ad libitum, conventionally or using a desktop or portable device. Sessions were videotaped using a digital camcorder., Results: All three measurement methods were sensitive to oft-reported brand- and bout-induced changes. Topography measurement differed little between methods (across methods, all r values > .68), and each method was reliable (across bouts within each condition, most r values > .78). In contrast, participants perceived the use of either mouthpiece-based device to alter aspects of their smoking behavior (e.g., increased smoking difficulty, reduced enjoyment, altered cigarette taste; p < .05), relative to video recording only., Discussion: Although direct observational methods may be optimal for measuring certain smoking characteristics, logistical challenges posed by this method likely limit its usefulness. Together, these results suggest that mouthpiece-based devices offer a convenient and useful tool for researchers examining smoking topography.

Several potential reduced exposure products (PREPs) for smokeless tobacco (SLT) users are marketed in the United States, though their effects are largely unknown. These products include some that are low in tobacco-specific nitrosamines (TSNs), like Stonewall, a pressed tobacco tablet, and General snus, a moist snuff product produced in Sweden. Methodology assessing the toxicant exposure and effects of cigarette-like PREPs for smokers has been developed, and might be modified for use in evaluating PREPs for SLT users. This report describes two studies examining the toxicant exposure and effects of two PREPs for SLT users. Study 1 (n = 13) consisted of four 4.5-hr laboratory sessions where SLT products (own brand, Stonewall, General snus, and tobacco-free placebo) were used for four 30-min episodes and nicotine exposure and tobacco/nicotine abstinence symptoms were measured. Study 2 (n = 19) consisted of four 5-day ad libitum use periods when participants used own brand, Stonewall, General snus, or no SLT and urinary levels of metabolites of nicotine (cotinine) and the TSN 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNAL) and abstinence symptoms were measured. Compared with own brand, Stonewall was associated with lower levels of cotinine and NNAL, while General snus was associated with similar levels of cotinine and lower levels of NNAL. Abstinence symptoms generally did not differ across tobacco conditions. These results show that clinical laboratory methods can be used to evaluate the toxicant exposure and abstinence symptom suppression associated with PREPs for SLT users.

Transdermal nicotine (TN) is an efficacious smoking cessation pharmacotherapy thought to work, in part, by attenuating the effects of tobacco/nicotine abstinence and the effects of concurrently smoked cigarettes. Clinical trials suggest that TN may be less efficacious for women. This study explored the possibility of TN-related gender differences in > or = 8 hour abstinent smokers (54 women, 70 men) who completed four within-subject, double-blind, placebo-controlled sessions corresponding to 0, 7, 14, and 21 mg TN. In each approximately 6.5-hr long session participants smoked an own-brand cigarette 4 hours after TN administration and physiological and subjective outcomes were examined throughout each session. Results revealed that TN suppressed some signs and symptoms of tobacco abstinence and attenuated some effects of smoking, and these effects were not dependent on gender. Women were more sensitive to the direct effects of nicotine (e.g., ratings of Nauseous) and, independent of TN dose, self-administered less nicotine when smoking and rated smoking as less rewarding. Thus, although this study does not shed light on clinical observations that TN is less effective for women, results suggest that TN might need to be combined with other interventions to supplement its effects on tobacco/nicotine abstinence and concurrent smoking.

The tobacco industry markets potential reduced exposure products (PREPs) to smokers, including oral products that are intended to be used in situations where cigarettes cannot. For example, Ariva, marketed by Star Scientific, is a tablet made from compressed tobacco powder and is intended for "adult smokers in situations where they cannot or choose not to smoke." No objective data are available regarding Ariva's effects in smokers, including its nicotine delivery, cardiovascular profile, or subjective effects. In this single-session, clinical laboratory study, 10 overnight-abstinent cigarette smokers were administered one Ariva tablet, followed 90 min later by two Ariva tablets, followed 90 min later by three Ariva tablets. Participants allowed each dose to dissolve in their mouths according to package instructions. Blood was sampled, heart rate monitored, and subjective effects assessed regularly. Ariva delivered nicotine in a dose-dependent manner; mean (SD) nicotine levels increased from 2.4 ng/ml (0.9) at baseline, to 3.4 ng/ml (1.4) 45 min post-1 tablet, 7.3 ng/ml (4.0) 45 min post-2 tablets, and 9.7 ng/ml (4.4) 45 min post-3 tablets. Heart rate increased after tablet administration, independent of dose. The tablets also significantly decreased subjective ratings of craving and urge, and increased ratings of nausea. Based on this short-term laboratory evaluation, Ariva exposes users to nicotine and may suppress some symptoms of tobacco abstinence, though its nausea-inducing characteristics may limit initial acceptability.

Objective: To determine if nicotine's effects are influenced by caffeine in nonsmoking, moderate-caffeine consuming individuals (N=20)., Methods: The first 3 sessions included one of 3 randomly ordered, double-blind caffeine doses (0, 75, or 150 mg, oral [po]) and 2 single-blind nicotine gum doses (2 and 4 mg) in ascending order. The fourth session (single blind) repeated the 0 mg caffeine condition., Results: Nicotine increased heart rate and subjective ratings indicative of aversive effects, and decreased reaction times. These effects were independent of caffeine dose and reliable across sessions., Conclusions: In nonsmokers, nicotine effects are not influenced by moderate caffeine doses.

Purpose: The objective of this study was to explore the smoking topography of adolescent smokers. It is well established that the majority of adult nicotine-dependent smokers began smoking as adolescents. Whereas recent advances have been made with respect to identification of factors that predispose to nicotine dependence, very little is known about the actual smoking behavior (e.g., topography) of adolescent smokers, or its relationship to nicotine dependence. Correspondingly, the extent to which adolescent smokers smoke to obtain nicotine is also unknown., Methods: In the present study, we assessed several topographical indices of smoking (e.g., puff volume, puff number) in a sample of 35 light, adolescent smokers. Moreover, we examined whether smoking behavior is different in response to smoking a denicotinized relative to a high-yield, nicotine cigarette., Results: All participants evidenced a significant increase in expired air carbon monoxide after the smoking of a cigarette. Results of independent-sample t-tests revealed that adolescents who smoked a low-yield nicotine cigarette took significantly more puffs per cigarette than did those who smoked a high-yield cigarette., Conclusions: These findings suggest that adolescent smokers do titrate their nicotine intake in response to smoking denicotinized cigarettes, but do so not by taking larger puffs or smoking more quickly, but by simply taking more puffs per cigarette. Implications of the findings and future directions for this type of research with adolescents are discussed.