An Open-Label, Randomized, Controlled, Crossover Study to Assess Nicotine Pharmacokinetics and Subjective Effects of the JUUL System with Three Nicotine Concentrations Relative to Combustible Cigarettes in Adult Smokers.

INTRODUCTION: This randomized, open-label, crossover clinical study evaluated nicotine pharmacokinetics (PK) and subjective effects of the JUUL System (JS; Juul Labs, Inc.) with three nicotine concentrations compared to the usual brand (UB) cigarettes in 24 adult smokers. METHODS: At five study visits, subjects used either the JS in 59 mg/mL, JS 18 mg/mL (two visits), and JS 9 mg/mL (all tobacco-flavored) or smoked their UB cigarette first during a controlled puffing sequence (CPS) and then ad libitum (5 min) use sessions. Blood samples were taken at specified timepoints for 60 min in each session. The modified Product Evaluation Scale assessed subjective effects 30-min post-use in the CPS session. RESULTS: Maximum plasma nicotine concentration (Cmax-BL), total nicotine exposure (AUC0-60-BL), and rate of plasma nicotine rise were significantly lower for all JS products compared to subjects' UB cigarette in CPS and ad libitum use sessions. In both use sessions these PK parameters were significantly higher for JS 59 mg/mL compared to 18 and 9 mg/mL. Subjective measures of cigarette craving relief and "Enough Nicotine" for JS 59 mg/mL did not differ significantly from UB cigarettes, but JS 18 and 9 mg/mL were rated significantly lower than JS 59 mg/mL and UB cigarettes. CONCLUSIONS: Nicotine exposure and subjective relief were directly related to JS nicotine concentration: higher nicotine concentrations gave rise to significantly greater plasma nicotine levels and relief from craving. Heavier and more dependent smokers may require the greater nicotine delivery of JS 59 mg/mL to successfully transition away from cigarettes. IMPLICATIONS: It has been suggested that electronic nicotine delivery systems (ENDS) and other alternative nicotine delivery products that more closely mimic the nicotine pharmacokinetics (PK) of cigarettes may facilitate smokers transitioning away from cigarettes. We examined nicotine PK and subjective effects of JUUL System (JS) ENDS with three nicotine concentrations (59, 18 and 9 mg/mL) compared to combustible cigarettes. Nicotine delivery from JS ENDS was nicotine concentration dependent, with higher nicotine concentrations giving rise to higher nicotine exposure. These findings suggest that heavier and more dependent smokers may require ENDS with nicotine concentrations greater than 20 mg/mL to successfully transition away from cigarettes.

Abuse liability assessment of the JUUL system in two nicotine concentrations compared to combustible cigarette, nicotine gum and comparator electronic nicotine delivery system.

BACKGROUND: To assess the abuse liability of the JUUL System (JS) in 5.0 % (59 mg/mL) and 3.0 % (35 mg/mL) nicotine concentrations. METHODS: Adult smokers (N = 146; 45.9 % female; mean age = 41.29 years) were randomized to one of four study flavor arms and then to a within-subjects cross-over sequence for five test product categories: (1) JS 5.0 % nicotine concentration; (2) JS 3.0 % nicotine; (3) usual brand (UB) cigarette; (4) 4 mg mint nicotine gum; (5) comparator ENDS (VUSE Alto 5.0 % nicotine). Products were tested by ad libitum use (5 min for ENDS and cigarette; 30 min for gum); nicotine pharmacokinetic (PK) parameters and subjective effects were assessed following use. RESULTS: Maximum plasma nicotine concentration (Cmax-BL), rate of plasma nicotine rise and total nicotine exposure (AUC0-60-BL) of UB cigarette were significantly greater than all other test products. The comparator ENDS was significantly greater than 5.0 % and 3.0 % JS and nicotine gum on Cmax-BL, rate of plasma nicotine rise, and AUC0-60-BL; Cmax-BL of JS 5.0 % was significantly greater than JS 3.0 % and nicotine gum. Product liking and satisfying effects were significantly highest for the UB cigarette; JS products and comparator ENDS did not significantly differ and were rated higher than nicotine gum on most subjective measures. CONCLUSIONS: These results suggest that the abuse liability of both 5.0 % and 3.0 % JS is: (1) substantially lower than UB cigarette; (2) somewhat lower than comparator ENDS; and (3) higher than nicotine gum. Additionally, the abuse liability of JS 5.0 % is somewhat higher than JS 3.0 %.

Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers.

BACKGROUND: The abuse liability of the JUUL System (JS) in four flavors were evaluated compared to combustible cigarettes, nicotine gum, and a comparator electronic nicotine delivery system (ENDS) with pharmacokinetics (PK) and subjective effects. METHODS: Adult smokers (N = 66; 50.0 % female; mean age = 41.1; 63.6 % white) completed a 7-arm within-subjects cross-over product-use study while confined to a clinical laboratory. Participants used JS in four flavors (Virginia Tobacco, Mango, Mint, Creme, [5.0 % nicotine; 59 mg/mL]), their usual brand (UB) cigarette, a comparator ENDS (VUSE Solo; 4.8 % nicotine, tobacco-flavor), and mint nicotine gum (4 mg) under controlled use conditions. After each product use, nicotine PK and subjective effects were assessed. RESULTS: Maximum plasma nicotine levels (Cmax-BL), rate of plasma nicotine rise, overall nicotine exposure (AUC0-60-BL), and subjective liking and satisfaction of JS were significantly lower than UB cigarettes. These parameters were generally greater for JS than nicotine gum; the comparator ENDS was somewhat lower but within the range of JS. Nicotine PK did not differ among the Mint, Mango, and Virginia Tobacco JS flavors. Mint and Mango were rated as more satisfying than Virginia Tobacco and Creme. CONCLUSIONS: Controlled use of JS among adult smokers resulted in nicotine delivery, product liking, and satisfaction that were less than that of combustible cigarettes but generally greater than nicotine gum. These results support the conclusion that JS has lower abuse liability than combustible cigarettes, higher abuse liability than nicotine gum, and may provide sufficient nicotine delivery and satisfying effects to support substitution for combustible cigarettes among adult smokers.

Pharmacotherapy for tobacco dependence.

Pharmacotherapy can provide effective treatment of tobacco dependence and withdrawal, and thereby facilitate efforts to achieve and sustain tobacco abstinence. Currently approved medications for smoking cessation are nicotine replacement medications (NRT), including nicotine patch, gum, lozenge, sublingual tablet, inhaler and nasal spray, the antidepressant bupropion, and the nicotinic partial agonist varenicline. This review discusses the pharmacological basis for the use of these medications, and the properties that might contribute to their efficacy, safety, and abuse liability. The review also discusses how pharmacological principles can be used to improve existing medications, as well as assist in the development of new medications.

Rapid absorption of nicotine from new nicotine gum formulations.

RATIONALE: A clinically limiting feature of currently-available nicotine gum is its slow rate of nicotine delivery and consequently slow onset of therapeutic effects. Previous research suggested that a nicotine hydrogen tartrate gum (NHTG1) that delivered nicotine more rapidly provided more effective craving relief. A subsequent gum formulation (NTHG2) was developed to further increase speed of delivery. OBJECTIVE: Compare the plasma nicotine absorption and clinical tolerability of NHTG2 to NHTG1 and Nicorette FreshMint. METHODS: A single-dose, randomized, crossover study evaluated the early kinetics of nicotine absorption and tolerability of 4 mg NHTG2 compared to NHTG1 and Nicorette. RESULTS: NHTG2 gum reached higher Cmax (p=0.059 versus Nicorette; p=0.006 versus NHTG1) and delivered significantly more nicotine than Nicorette or NHTG1 within the first 10-30 min of chewing (AUCs0-10, 0-30) and overall (AUC0-180). NHT gums and Nicorette were well tolerated, with little difference in their AE profiles. CONCLUSIONS: Study results indicate that NHTG2 gum provided more rapid uptake of nicotine in blood without notable decreases in tolerability. To the extent that rate of delivery and onset of therapeutic effects are related, these gums would be expected to provide more rapid therapeutic effects.

Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status.

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease. This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an alpha4beta2 nicotine partial agonist, an alpha2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.

Nicotine delivery systems.

Over the past 20 years, medicinal nicotine has been used to aid smoking cessation, and has led to a significant increase in the number of smokers who successfully quit. This review describes currently available medicinal nicotine products, which include nicotine patch, gum, lozenge, nasal spray, inhaler and sublingual tablet, including their pharmacokinetics and recommended dosing. New developments in nicotine delivery that could further increase cessation rates include high-dose patches, rapid release gum, combined patch and acute forms, and several novel channels for nicotine delivery, such as nicotine drink, straw, lollipop and a pulmonary inhaler. New applications of existing and novel medicinal nicotine products may include relapse prevention, nicotine maintenance, temporary withdrawal management, reduced smoking and gradual quitting.

Pharmacotherapy for nicotine dependence.

Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on cancer, cardiovascular disease, lung disease, or other illness. This risk can be substantially reduced by smoking cessation, with greater benefits occurring the earlier in the smoking career that cessation occurs. However, cessation provides benefits at any stage, including after the onset of smoking-related disease, by improving the prognosis and quality of life. Clinicians can have a significant impact on reducing tobacco use by their patients by following the US Public Health Service Clinical Practice Guidelines. Proven strategies include structured methods of advising cigarette smokers to quit and guidance to facilitate their efforts, as well as the use of various pharmacotherapies. Pharmacotherapies for tobacco dependence include nicotine replacement medications in the form of gum, transdermal patch, lozenge, sublingual tablet, nasal spray, and vapor inhaler formulations. The only nonnicotine medication that has been approved by the US Food and Drug Administration is bupropion. Combination therapies, long-term medication therapies, and harm reduction strategies may further improve outcome with approved medications. Further, new medications such as varenicline and rimonabant are likely to reach tobacco users who are refractory to current treatments. Increasing the treatment options, increasing availability, and reducing the perceived cost of these medications may have an additional public health impact.

Tobacco abstinence symptom suppression: the role played by the smoking-related stimuli that are delivered by denicotinized cigarettes.

AIMS: Cigarette smoking causes cancer and disease, yet people find quitting difficult due to aversive symptoms that accompany tobacco abstinence. Understanding how to suppress these symptoms is critical in developing effective smoking cessation treatments. Pharmacologically, pure nicotine suppresses tobacco abstinence symptoms partially, and non-nicotine, smoking-related stimuli suppress these abstinence symptoms fully, at least for 24 hours. The current study was designed to clarify the impact of smoking-related stimuli on tobacco withdrawal, and to explore the duration of their ability to suppress withdrawal in smokers. DESIGN: Three double-blind, within-subjects, Latin square-ordered, 5-day conditions in which participants smoked nicotinized, denicotinized or no cigarettes. SETTING: Out-patient laboratory at Virginia Commonwealth University. PARTICIPANTS: Thirteen women and 19 men. MEASUREMENTS: Subjective, physiological and performance measures were collected daily and compliance with study conditions was verified objectively. FINDINGS: Smoking-related stimuli are sufficient for suppressing some symptoms of tobacco abstinence over a 5-day period [i.e. Questionnaire of Smoking Urges (QSU) factor 1, 'Desire for sweets', 'Hunger' and 'Urges to smoke'], while in this study a combination of nicotine and smoking-related stimuli suppressed other symptoms (i.e. 'Difficulty concentrating', 'Increased eating', 'Restlessness' and 'Impatient'). CONCLUSIONS: These results indicate that, while some tobacco abstinence symptoms may be suppressed with nicotine, suppressing others may also require strategies that address the absence of smoking-related stimuli.

Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology.

Harm reduction for tobacco smokers may involve reducing their exposure to lethal smoke constituents. Assessing smoke constituent exposure and any resulting harm reduction from a potential reduced-exposure product (PREP) will involve preclinical, clinical, and epidemiological research. The purpose of this study was to evaluate a clinical laboratory model for assessing the acute effects of PREPs for smokers. Philip Morris' Accord and R.J. Reynolds' Eclipse were used as examples. Twenty overnight-abstinent smokers (> 15 'light' or 'ultra-light' cigarettes/day) participated in 4 Latin-square ordered, 2.5-hr sessions in which they completed an 8-puff smoking bout every 30 minutes. Sessions were separated by at least 24 hours and differed by product used: own brand, denicotinized tobacco cigarettes, Accord, or Eclipse. Tobacco withdrawal and carbon monoxide (CO) were assessed before and after smoking, heart rate was assessed before and during smoking, and puff volume, duration, and interpuff interval were assessed while subjects smoked. Blood was sampled at the beginning and end of each session. Relative to normal cigarettes, Accord was less effective at suppressing withdrawal and produced minimal CO boost despite the fact that, when using Accord, subjects took bigger and longer puffs. Eclipse suppressed withdrawal fully and increased CO boost by approximately 30%. Own brand, Accord, and Eclipse, but not denicotinized cigarettes, increased plasma nicotine concentration. Taken together, these results suggest that neither Accord nor Eclipse is likely to be an effective reduced-exposure product for smokers and that this clinical laboratory model is valuable.