Electronic Nicotine-Delivery Systems for Smoking Cessation.

BACKGROUND: Electronic nicotine-delivery systems - also called e-cigarettes - are used by some tobacco smokers to assist with quitting. Evidence regarding the efficacy and safety of these systems is needed. METHODS: In this open-label, controlled trial, we randomly assigned adults who were smoking at least five tobacco cigarettes per day and who wanted to set a quit date to an intervention group, which received free e-cigarettes and e-liquids, standard-of-care smoking-cessation counseling, and optional (not free) nicotine-replacement therapy, or to a control group, which received standard counseling and a voucher, which they could use for any purpose, including nicotine-replacement therapy. The primary outcome was biochemically validated, continuous abstinence from smoking at 6 months. Secondary outcomes included participant-reported abstinence from tobacco and from any nicotine (including smoking, e-cigarettes, and nicotine-replacement therapy) at 6 months, respiratory symptoms, and serious adverse events. RESULTS: A total of 1246 participants underwent randomization; 622 participants were assigned to the intervention group, and 624 to the control group. The percentage of participants with validated continuous abstinence from tobacco smoking was 28.9% in the intervention group and 16.3% in the control group (relative risk, 1.77; 95% confidence interval, 1.43 to 2.20). The percentage of participants who abstained from smoking in the 7 days before the 6-month visit was 59.6% in the intervention group and 38.5% in the control group, but the percentage who abstained from any nicotine use was 20.1% in the intervention group and 33.7% in the control group. Serious adverse events occurred in 25 participants (4.0%) in the intervention group and in 31 (5.0%) in the control group; adverse events occurred in 272 participants (43.7%) and 229 participants (36.7%), respectively. CONCLUSIONS: The addition of e-cigarettes to standard smoking-cessation counseling resulted in greater abstinence from tobacco use among smokers than smoking-cessation counseling alone. (Funded by the Swiss National Science Foundation and others; ESTxENDS ClinicalTrials.gov number, NCT03589989.).

Electronic cigarettes and cardiovascular disease: epidemiological and biological links.

Electronic cigarettes (e-cigarettes), as alternative nicotine delivery methods, has rapidly increased among youth and adults in recent years. However, cardiovascular safety is an important consideration regarding e-cigarettes usage. e-cigarette emissions, including nicotine, propylene glycol, flavorings, nitrosamine, and metals, might have adverse effects on cardiovascular health. A large body of epidemiological evidence has indicated that e-cigarettes are considered an independent risk factor for increased rates of cardiovascular disease occurrence and death. The incidence and mortality of various types of cardiovascular disease, such as cardiac arrhythmia, hypertension, acute coronary syndromes, and heart failure, have a modest growth in vapers (users of e-cigarettes). Although the underlying biological mechanisms have not been fully understood, studies have validated that oxidative stress, inflammation, endothelial dysfunction, atherosclerosis, hemodynamic effects, and platelet function play important roles in which e-cigarettes work in the human body. This minireview consolidates and discusses the epidemiological and biological links between e-cigarettes and various types of cardiovascular disease.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Notes from the Field: E-Cigarette and Nicotine Pouch Use Among Middle and High School Students - United States, 2024.

Current e-cigarette use among U.S. youth has declined considerably since 2019*; however, approximately 2.13 million youths used e-cigarettes in 2023 (1). As sales of nicotine pouches (small, dissolvable, flavored pouches containing nicotine derived from tobacco that users place in the mouth between the lip and gum)† have continued to rise nationally since 2016, their use among U.S. youths has become concerning (2,3). All pouches and most e-cigarettes contain nicotine,§ which is highly addictive and can harm the developing adolescent brain (4,5).

Key issues surrounding the health impacts of electronic nicotine delivery systems (ENDS) and other sources of nicotine.

Answer questions and earn CME/CNE Over the last decade, the use of electronic nicotine delivery systems (ENDS), including the electronic cigarette or e-cigarette, has grown rapidly. More youth now use ENDS than any tobacco product. This extensive research review shows that there are scientifically sound, sometimes competing arguments about ENDS that are not immediately and/or completely resolvable. However, the preponderance of the scientific evidence to date suggests that current-generation ENDS products are demonstrably less harmful than combustible tobacco products such as conventional cigarettes in several key ways, including by generating far lower levels of carcinogens and other toxic compounds than combustible products or those that contain tobacco. To place ENDS in context, the authors begin by reviewing the trends in use of major nicotine-containing products. Because nicotine is the common core-and highly addictive-constituent across all tobacco products, its toxicology is examined. With its long history as the only nicotine product widely accepted as being relatively safe, nicotine-replacement therapy (NRT) is also examined. A section is also included that examines snus, the most debated potential harm-reduction product before ENDS. Between discussions of NRT and snus, ENDS are extensively examined: what they are, knowledge about their level of "harm," their relationship to smoking cessation, the so-called gateway effect, and dual use/poly-use. CA Cancer J Clin 2017;67:449-471. © 2017 American Cancer Society.

Perceptions of a reduced nicotine policy and predictors of policy support: A nationally representative U.S. survey.

BACKGROUND: The U.S. Food and Drug Administration is considering a policy to reduce nicotine in cigarettes to non-addictive levels. Although current evidence supports the public-health benefits of a reduced-nicotine policy, almost half of people who smoke (∼ 40%) do not support the policy. This study estimates the factors most strongly associated with support or opposition toward the policy, including tobacco use status, perceived effects of a reduced nicotine policy, trust in the FDA, and psychological distress. The study aims to inform messaging campaigns and policy makers. METHODS: Data were collected in 2021 with nationally representative samples of U.S. adults (n = 1763). After receiving information about the reduced nicotine policy, participants indicated their beliefs and support for or opposition to the policy, along with other individual difference characteristics. Univariate population parameters and multinomial logistic regression coefficients were estimated. RESULTS: In adjusted models, people who formerly or never smoked were less likely to oppose the policy compared to those who currently smoke; people with higher psychological distress and those who believe the policy will promote switching to e-cigarettes were more likely to oppose the policy. In addition, people were more likely to support the policy if they believed it would make quitting easier or that the FDA is trustworthy. CONCLUSIONS: Educational campaigns about reduced nicotine policy should expect higher impact by targeting prevalent perceptions and those more strongly associated with policy sentiment. In anticipation of the policy rollout, there may be a critical window to shape public opinion.

Non-tobacco nicotine E-cigarette use and flavored E-cigarette use among young adults in the United States.

BACKGROUND: E-cigarette flavors can create sensations of sweetness and coolness while masking the aversiveness of nicotine. Recently, non-tobacco nicotine (NTN) products were introduced to the market, but little is known about flavors in NTN e-cigarette use. We examined associations between flavors (i.e., sweet, mint/menthol) and susceptibility to and use of NTN e-cigarettes. METHODS: 1239 US young adults (18-25 years) completed an anonymous, online survey in Fall 2021. The analytic sample included 520 participants who had used e-cigarettes and heard of NTN. Multinomial logistic regression models analyzed associations of flavored e-cigarette use (sweet and mint/menthol) with NTN e-cigarette use status (i.e., current [past-month] use, past [ever but not current] use, susceptible to use, and non-susceptible to use [reference]). RESULTS: Overall, 46.2% of participants reported current NTN use, 14.8% reported past use, 16.7% were susceptible to use, and 22.3% reported no susceptibility. Participants reported dual-use of sweet and mint/menthol NTN e-cigarette flavors (56.5%), sweet flavors use (24.8%), and mint/menthol flavor use (1.7%). Ever dual use of sweet and mint/menthol flavors was associated with current (OR = 9.64, 95%CI: 3.21-28.98) and past NTN e-cigarette use (8.30, [2.10-32.80]). Ever sweet flavor use was associated with current NTN use (3.80, 95%CI: 1.44-10.03) and susceptibility to future use (4.25, [1.53-11.81]). Similar findings were observed for mint/menthol flavors (current: 5.03, [1.41-17.99]; susceptible: 5.65, [1.64-19.51]). CONCLUSION: The use of sweet and mint/menthol flavors was significantly associated with NTN e-cigarette use among US young adults, highlighting the need for ongoing surveillance of flavored NTN e-cigarettes and appropriate regulations to discourage use.

Associations of educational and marketing messages with beliefs about nicotine and reduced nicotine cigarettes.

INTRODUCTION: Widespread misperceptions about nicotine may have unintended effects on public health. We examined associations between existing messages about nicotine or tobacco and beliefs about nicotine and reduced nicotine cigarettes (RNC). METHODS: 2962 U.S. 18-45-year-olds were randomized in a May 2022 web-based survey to view one of 26 text-based messages about tobacco or nicotine from three sources: ongoing research (n = 8), messages authorized by FDA for VLN cigarettes (n = 6), and FDA's "From Plant to Product to Puff" campaign (n = 12); six messages from FDA's campaign did not reference nicotine and were treated as the reference source. Analyses examined associations between messages, grouped by source and individually, with beliefs about nicotine and RNC addictiveness and harms. RESULTS: Relative to FDA messages that did not reference nicotine, all message sources were associated with greater odds of a correct belief about nicotine (Odds Ratios [ORs] = 1.40-1.87, p's < 0.01); VLN messages were associated with greater correct beliefs about RNC addictiveness (b = 0.23, p < .05). No campaign produced greater correct beliefs about RNC harms. At the individual level, only five messages were associated with a correct belief about nicotine (ORs = 2.12-2.56, p-values < .01), and one with correct beliefs about RNC harms (b = 1.09, p < .05), vs. the reference message. CONCLUSIONS: Few existing messages improved understanding of the risks of nicotine separately from the risks of combustible products. Communication research is needed to promote greater public understanding of nicotine while minimizing unintended effects on nicotine and tobacco use.

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

INTRODUCTION: 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. AIMS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPLICATIONS: 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.

Nicotinic Receptor Alpha-5 Subunit Gene Polymorphism is Associated With Heavy Smoking Under a Range of Nicotine Dosing Conditions.

INTRODUCTION: This study aimed to assess the role of the rs16969968 variant of nicotinic receptor alpha-5 subunit in regulating smoking behavior and nicotine intake in response to nicotine manipulations among dependent smokers in a naturalistic environment. AIMS AND METHODS: Sixty-nine adults (19 females) smoking 10 or more cigarettes per day (CPD) were asked to complete four 2-week study phases during which they smoked exclusively one of two types of Spectrum nicotine research cigarettes (FTC nicotine yield 0.8 and 1.6 mg, respectively), their usual brand of cigarettes, or their usual brand of cigarettes while wearing a 21-mg nicotine patch. Measurements included rs16969968 genotype, number of CPD, smoking topography, and plasma cotinine. RESULTS: Compared to controls (G/G carriers), A allele carriers reported smoking 4 to 5 more CPD across all conditions (all ps < .05). Mean total smoke volume per day and cotinine were greater in A allele carriers than in controls (ps = .05, .046, respectively). No significant genotype differences were found in smoking compensation indices for the switch from medium to high-nicotine-yield cigarettes. Nicotine patch-induced reductions in cigarettes smoked per day and total smoke volume per day showed significant interactions between genotype and pre-patch levels, with heavier smokers showing greater effects of genotype (p = .052 and p = .006, respectively). CONCLUSIONS: Results suggest that the rs16969968 variants regulate the heaviness of smoking primarily by their impact on daily numbers of cigarettes smoked, but no genotype differences were found in smoking compensation after switching from medium to high-nicotine cigarettes. IMPLICATIONS: The differences in daily cigarette consumption between rs16969968 risk-allele carriers and controls are shown to be consistent regardless of manipulations of cigarette nicotine content and transdermal nicotine supplementation and markedly greater among dependent smokers than those observed in the general smoker populations. G/G allele carriers, relative to A allele carriers, appeared to be more sensitive to the nicotine patch manipulation, reducing their smoking to a greater extent. These findings support continued efforts in the development of personalized intervention strategies to reduce the rs16969968-conveyed genetic propensity for heavy smoking.

Methoxsalen Inhibits the Acquisition of Nicotine Self-Administration: Attenuation by Cotinine Replacement in Male Rats.

INTRODUCTION: Cigarette smoking remains the leading preventable cause of disease and death. Nicotine is the primary reinforcing ingredient in cigarettes sustaining addiction. Cotinine is the major metabolite of nicotine that produces a myriad of neurobehavioral effects. Previous studies showed that cotinine-supported self-administration in rats and rats with a history of cotinine self-administration exhibited relapse-like drug-seeking behavior, suggesting that cotinine may also be reinforcing. To date, whether cotinine may contribute to nicotine reinforcement remains unknown. Nicotine metabolism is mainly catalyzed by hepatic CYP2B1/2 enzymes in rats and methoxsalen is a potent CYP2B1/2 inhibitor. AIMS AND METHODS: The study examined nicotine metabolism, self-administration, and locomotor activity. The hypothesis is that methoxsalen inhibits nicotine self-administration and cotinine replacement attenuates the inhibitory effects of methoxsalen in male rats. RESULTS: Methoxsalen decreased plasma cotinine levels following a subcutaneous nicotine injection. Repeated daily methoxsalen treatments reduced the acquisition of nicotine self-administration, leading to fewer nicotine infusions, lower nicotine intake, and lower plasma cotinine levels. However, methoxsalen did not alter the maintenance of nicotine self-administration despite a significant reduction of plasma cotinine levels. Cotinine replacement by mixing cotinine with nicotine for self-administration dose-dependently increased plasma cotinine levels and enhanced the acquisition of self-administration. Neither basal nor nicotine-induced locomotor activity was altered by methoxsalen. CONCLUSIONS: These results indicate that methoxsalen inhibition of cotinine formation impaired the acquisition of nicotine self-administration, and cotinine replacement attenuated the inhibitory effects of methoxsalen on the acquisition of self-administration, suggesting that cotinine may contribute to the initial development of nicotine reinforcement. IMPLICATIONS: Smoking cessation medications targeting nicotine's effects are only moderately effective, making it imperative to better understand the mechanisms of nicotine misuse. Methoxsalen inhibited nicotine metabolism to cotinine and impaired the acquisition of nicotine self-administration. Cotinine replacement restored plasma cotinine and attenuated the methoxsalen inhibition of nicotine self-administration in rats. These results suggest that (1) the inhibition of nicotine metabolism may be a viable strategy in reducing the development of nicotine reinforcement, (2) methoxsalen may be translationally valuable, and (3) cotinine may be a potential pharmacological target for therapeutic development given its important role in the initial development of nicotine reinforcement.

Using Pod Based e-Cigarettes and Nicotine Pouches to Reduce Harm for Adults With Low Socioeconomic Status Who Smoke: A Pilot Randomized Controlled Trial.

INTRODUCTION: Alternative Nicotine Delivery Systems (ANDS) such as e-cigarettes (EC) and oral nicotine pouches (ONP) may facilitate the substitution of smoking for those unwilling to quit. This pilot study assesses the harm-reduction potential of EC and ONP among smokers with low socioeconomic status (SES). AIMS AND METHODS: Adults who smoked daily in the past 6 months, had a household income < 250% federal poverty level and had no intention of quitting smoking in the next 30 days were randomized 2:2:1 to 8 weeks of 5% nicotine EC; 4 mg ONP or assessment-only control (CC). The primary outcome was a within-group change in cigarettes per day (CPD) from Baseline to week 8. RESULTS: Forty-five individuals were randomized (EC: N = 18; ONP: N = 18; CC: N = 9). Analyses included 33 participants who completed the week 8 visit. The mean age was 50.1 years (SD: 10.7) and the average CPD at baseline was 13.9 (SD: 10.1). For those randomized to EC, the average CPD decreased from 14.7 (95% CI: 10.3 to 19.1) at the Baseline to 2.9 (95% CI: .1 to 5.8) at week 8 (p-value < .001). For those randomized to ONP, average CPD decreased from 15.0 (95% CI: 5.0 to 24.9) to 8.3 (95% CI: 1.3 to 15.2) by week 8 (p-value = .01). In the EC and ONP groups, respectively, 4 (28.6%) and 1 (8.3%) participant fully switched from smoking to the ANDS product by week 8. CONCLUSIONS: Individuals with low SES who smoke had lower CPD after switching to EC or ONP. These findings show the potential of ANDS in helping smokers switch to less harmful devices. IMPLICATIONS: This study provides novel evidence that e-cigarettes and nicotine pouches can be a harm-reduction tool for individuals with lower SES who smoke and are not willing to quit smoking, contributing to reducing tobacco-related disparities in this population.Clinical Trials Identifier: NCT05327439.

Dual-Vaping of Nicotine and Cannabis Among Adults Who Currently Use Tobacco Products in Five New England States.

INTRODUCTION: Current measures of vaping behaviors in the U.S. do not distinguish what substances participants are vaping and to what extent they are dual-vaping nicotine and cannabis. This study describes the use of new survey questions that more specifically ask whether participants who vape are vaping nicotine, cannabis, cannabidiol (CBD), or another substance. AIMS AND METHODS: Adults, who reported any past 30-day tobacco use, from five New England states participated in an online survey from April 2021 to July 2022. Participants who vaped were asked, "Have you used any of the following vape substances in the past 30 days?" with the possible responses of nicotine, cannabis, CBD, other, and "don't know." Dual use of both nicotine and cannabis was defined as the vaping of both nicotine and cannabis and/or CBD in the past 30 days, operationalized as a dichotomous outcome. Data were collected in monthly, repeated cross-sectional waves. Multinomial logistic regression was used to examine correlates of dual-vaping. RESULTS: The analytic sample included 1547 adults who reported past 30-day tobacco use (mean age 42.9 years, 62.8% female, 85.4% White, 48.5% income of less than $50 000). Over one-quarter (26.1%) reported dual-vaping in the past 30 days. Identifying as male (p = .002) and self-rated anxiety (p = .043) were associated with a higher odds of dual-vaping. CONCLUSIONS: Our findings show that a sizable proportion of a sample of New England adults who have used tobacco in the past 30 days are dual-vaping nicotine and cannabis. Adequate survey measures for assessing the vaping of multiple substances can help in better screening and characterization of health behaviors around dual-use. IMPLICATIONS: This study addresses a key gap in adequate survey measures for assessing vaping of multiple substances. We found that among adults with past 30-day tobacco use, dual-vaping was prevalent and associated with different correlates, such as self-reported anxiety and education level, compared to sole-vaping of nicotine or cannabis. Our findings may help in characterizing and targeting future population-level surveillance and intervention efforts for multiple substance use behaviors.

Nicotine Delivery and Changes in Withdrawal and Craving During Acute Electronic Cigarette, Heated Tobacco Product, and Cigarette Use Among a Sample of Black and White People Who Smoke.

INTRODUCTION: E-cigarettes and heated tobacco products (HTPs) may serve as potential options for harm reduction for smokers if they possess reward profiles similar to cigarettes. Little is known about the abuse liability of HTPs and e-cigarettes versus cigarettes in racial/ethnic minority smokers. AIMS AND METHODS: Twenty-two nicotine-deprived people who smoke (black [n = 12] and white [n = 10]) completed three visits that included a standardized 10-puff bout followed by a 50-minute ad libitum use assessment with their usual brand cigarette (UBC), an e-cigarette, and HTP. Visits were completed in a randomized crossover design and were separated by a minimum 48-hour washout period. Assessments included plasma nicotine, Cmax, and reductions in craving and withdrawal. RESULTS: UBC delivered significantly greater levels of nicotine compared to the e-cigarette (p < .001) and HTP (p < .01) during both the standardized and ad libitum sessions. HTP delivered more nicotine than the e-cigarette during the standardized puffing session (p = .047) but not the ad libitum session. Only craving during the standardized puffing session and not the ad libitum session showed significant differences across products (p < .001) such that UBC resulted in the greatest reduction followed by HTP and e-cigarette. CONCLUSIONS: Despite greater nicotine delivery from the UBC compared to e-cigarette and HTP, participants reported reductions in craving and withdrawal across products, particularly following ad libitum use. IMPLICATIONS: Use of participant's UBCs (UBC) resulted in greater nicotine delivery compared to both the e-cigarette and HTP. Despite this relative difference in nicotine delivery, participants reported reductions in craving and withdrawal across products, particularly following ad libitum use. These findings suggest that in this sample of black and white people who smoke, HTPs and e-cigarettes provided significant relief from negative symptoms that maintain smoking.

The fate of an inhaled cigarette puff in the human respiratory tract.

OBJECTIVE: Cigarette smoking can lead to a host of adverse health effects such as lung and heart disease. Increased lung cancer risk is associated with inhalation of carcinogens present in a puff of smoke. These carcinogenic compounds deposit in the lung at different sites and trigger a cascade of events leading to adverse outcomes. Understanding the site-specific deposition of various smoke constituents will inform the study of respiratory diseases from cigarette smoking. We previously developed a deposition model for inhalation of aerosol from electronic nicotine delivery systems. In this study, the model was modified to simulate inhalation of cigarette smoke consisting of soluble and insoluble tar, nicotine, and cigarette-specific constituents that are known or possible human carcinogens. MATERIALS AND METHODS: The deposition model was further modified to account for nicotine protonation and other cigarette-specific physics-based mechanisms that affect smoke deposition. Model predictions showed a total respiratory tract uptake in the lung for formaldehyde (99%), nicotine (80%), and benzo[a]pyrene (60%). RESULTS: The site of deposition and uptake depended primarily on the constituent's saturation vapor pressure. High vapor pressure constituents such as formaldehyde were preferentially absorbed in the oral cavity and proximal lung regions, while low vapor pressure constituents such as benzo[a]pyrene were deposited in the deep lung regions. Model predictions of exhaled droplet size, droplet retention, nicotine retention, and uptake of aldehydes compared favorably with experimental data. CONCLUSION: The deposition model can be integrated into exposure assessments and other studies that evaluate potential adverse health effects from cigarette smoking.

Smoking reduction using an electronic nicotine delivery system (ENDS) with nicotine delivery similar to combustible cigarettes.

BACKGROUND: Electronic nicotine delivery systems (ENDS) offer a promising approach to tobacco harm reduction, but many people use both ENDS and combustible cigarettes ("dual use"), which undermines potential risk reduction. To explore the role of ENDS nicotine delivery in promoting switching to ENDS, we conducted a study in which people who smoked cigarettes were offered an ENDS that had previously been shown to replicate the rapid nicotine pharmacokinetics of combustible cigarettes (BIDI® Stick). METHODS: Twenty-five cigarette smoking adults, not seeking smoking cessation treatment, but open to using ENDS as a cigarette substitute, were provided with a 12-week supply of BIDI® Stick in tobacco or menthol flavors, during a study that included seven biweekly sessions and a 6-month follow-up. Daily diaries assessed ENDS and cigarette use, and exhaled carbon monoxide (eCO) served as an objective marker of smoke intake. Subjective ratings were collected to assess the rewarding properties of ENDS and combustible cigarettes, and indices of nicotine dependence. RESULTS: Over 12 weeks, ENDS use increased to an average of 15.8 occasions per day (SD = 20.2) and self-reported cigarette consumption decreased by 82% from 16.7 cigarettes/day (SD = 6.0) at baseline to 3.0 cigarettes/day (SD = 4.1) at week 12. The eCO level decreased by 27% from an average of 20.0 ppm (SD = 9.8) at baseline to 14.5 ppm (SD = 9.9) at week 12. Four of 25 participants completely switched to ENDS and were smoking abstinent during weeks 9-12. At 6 months one participant was confirmed to be abstinent. Ratings of subjective reward for the ENDS were very similar to those of participants' usual brands of cigarettes. Dependence level was lower for the ENDS than for combustible cigarettes. CONCLUSIONS: In this study, the ENDS effectively replicated the subjective rewarding effects of participants' usual brands of cigarettes and led to a substantial reduction in reported cigarettes/day. Exhaled CO showed less of a decrease, possibly due to compensatory smoking behavior and/or the timing of eCO measurements that might not have reflected smoke intake throughout the day. The relatively low rate of sustained smoking abstinence at 6 months suggests that additional approaches continue to be needed for achieving higher rates of complete switching. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05855343.

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.

Smoking Cessation After Initial Treatment Failure With Varenicline or Nicotine Replacement: A Randomized Clinical Trial.

Importance: Most people who smoke do not quit on their initial attempt. Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT). Design, Setting, and Participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic. Interventions: The initial treatment was 2 mg/d of varenicline or the combined replacement therapy of a 21-mg patch plus 2-mg lozenge. The rerandomized participants either continued with their initial therapies, switched between varenicline and CNRT, or increased dosages either to 3-mg or more of varenicline or to a 42-mg patch and lozenges. All received weekly brief counseling. Main Outcomes and Measures: Biochemically verified 7-day point prevalence abstinence at the end of treatment at 12 weeks. Results: The 490 randomized participants (210 female [43%], 287 non-Hispanic White [58%], mean age, 48.1 years) smoked an average of 20 cigarettes per day. After the first phase, 54 participants in the CNRT group were abstinent and continued their therapy; of the 191 who were not abstinent, 151 were rerandomized, and the 40 who did not return for rerandomization were assigned to continue their initial CNRT condition in phase 2. The end-of-treatment abstinence rate for the 191 phase 1 nonabstainers was 8% (95% credible interval [CrI], 6% to 10%) for the 90 (47%) who continued at the dosage condition, 14% (CrI, 10% to 18%) for the 50 (33%) who increased their dosage, and 14% (95% CrI, 10% to 18%) for the 51 (34%) who switched to varenicline (absolute risk difference [RD], 6%; 95% CrI, 6% to 11%) with more than 99% posterior probability that either strategy conferred benefit over continuing the initial dosage. After the first phase, 88 participants in the varenicline group were abstinent and continued their therapy; of the 157 who were not abstinent, 122 were rerandomized and 35 who did not return for rerandomization were assigned to continue with the varenicline condition. The end-of-treatment abstinence rate for the 157 phase 1 nonabstainers was 20% (95% CrI, 16% to 26%) for the 39 (32%) who increased their varenicline dosage, 0 (95% CrI, 0 to 0) for the 41 (34%) who switched CNRT, and 3% (95% CrI, 1% to 4%) for the 77 (49%) who were assigned to the continued varenicline condition (absolute RD, -3%; 95% CrI, -4% to -1%) with more than 99% posterior probability that continuing varenicline at the initial dosage was worse than switching to a higher dosage. Furthermore, increasing the varenicline dosage had an absolute RD of 18% (95% CrI, 13% to 24%) and a more than 99% posterior probability of conferring benefit. The secondary outcome of continuous abstinence at 6 months indicated that only increased dosages of the CNRT and varenicline provided benefit over continuation of the initial treatment dosages. Conclusions and Relevance: For individuals who smoked but did not achieve abstinence after treatment with varenicline, increasing the dosage enhanced abstinence vs continuing, whereas for nonabstainers initially treated with CNRT, a dosage increase or switch to varenicline enhanced abstinence and may be viable rescue strategies. Trial Registration: ClinicalTrials.gov Identifier: NCT02271919.

Development and In vivo Evaluation of Atomoxetine Hydrochloride ODMTs in a Nicotine-induced Attention Deficit Hyperactivity Disorder (ADHD) Model in Rats.

The current study aimed to evaluate the efficacy of orally administered rapid mini-tablets containing atomoxetine hydrochloride (ODMT) relative to the conventional capsule formulation of atomoxetine hydrochloride (ATO). To mask the bitter taste of ATO and render it more palatable for pediatric administration in individuals with Attention Deficit Hyperactivity Disorder (ADHD), an inclusion complex of ATO with ß-cyclodextrin (ß-CD) was synthesized. The ODMT and conventional capsule ATO formulations were administered orally to a cohort of ADHD rat pups born to nicotine-exposed dams, facilitating an in vivo efficacy assessment. Behavioral assays, including the open field test, novel object recognition test, and Barnes maze test, were conducted pre- and post-administration of the therapeutics. The outcomes suggested that the ODMT formulation, incorporating ATO-ß-CD inclusion complexes, shows promise as a viable alternative to the capsule form of ATO. Conclusively, the preparation of the ATO-ß-CD complexes and ODMTs leveraged a factorial experimental design, with the animal model being subjected to nicotine-induced hyperactivity to provide a unique evaluative framework for the ODMT formulation under development.

Systemic allopurinol administration reduces malondialdehyde, interleukin 6, tumor necrosis factor α, and increases vascular endothelial growth factor in random flap Wistar rats exposed to nicotine.

INTRODUCTION: Smoking poses a risk to flap viability, with nicotine being a major contributor to the formation of free radicals. Allopurinol, known for its antioxidant properties, has been shown to enhance tissue survival in ischemic conditions by reducing the production of reactive oxygen species (ROS). This study aims to assess the impact of allopurinol on the viability and success of skin flaps in Wistar rats exposed to nicotine. METHODS: This study examined skin flap survival in nicotine-exposed rats treated with allopurinol. Twenty-eight rats were separated into two groups. During 1 month of nicotine exposure, the treatment group received systemic allopurinol 7 days before and 2 days after the flap procedure, while the control group received no allopurinol. Pro-angiogenic factors, proinflammatory factors, anti-inflammatory factors, and oxidative markers were assessed on the 7th day after the flap procedure using enzyme-linked immunosorbent assay method. Macroscopic flap viability was evaluated on the 7th day using Image J photos. RESULTS: As an oxidative marker, malondialdehyde levels were significantly lower in rats given allopurinol than in controls (P < 0.001). The levels of interleukin 6 and tumor necrosis factor α, as markers of inflammatory factors, were significantly lower in the group of rats given allopurinol compared to controls (P < 0.001). The level of angiogenesis in rats given allopurinol, measured by vascular endothelial growth factor levels, was also higher in the treatment group compared to controls (P < 0.001). Macroscopically, the percentage of distal flap necrosis in Wistar rats given allopurinol was lower and statistically significant compared to controls (P < 0.001). CONCLUSIONS: Xanthine oxidoreductase is part of a group of enzymes involved in reactions that produce ROS. Allopurinol, as an effective inhibitor of the xanthine oxidase enzyme, can reduce oxidative stress by decreasing the formation of ROS. This reduction in oxidative stress mitigates the risk of ischemic-reperfusion injury effects and significantly increases the viability of Wistar rat flaps exposed to nicotine.