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Smoking-related diseases kill more Americans than alcohol, illegal drugs, murder and suicide combined. The passage of the Family Smoking Prevention and Tobacco Control Act of 2009 gave the FDA authority to regulate \"modified risk tobacco products\" (MRTPs), tobacco products that are either designed or advertised to reduce harm or the risk of tobacco-related disease. MRTPs must submit to the FDA scientific evidence to demonstrate the product has the potential to reduce tobacco related harms as compared to conventional tobacco products. The IOM identifies minimum standards for scientific studies that an applicant would need to complete to obtain an order to market the product from the FDA.

This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and α3- and α4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with α3- and α4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and self-administered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, α3-nAChR, and α4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with α3- and α4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.

Modern oral nicotine delivery (MOND) offers potentially reduced harm nicotine delivery for adult smokers who do not wish to quit. Most clinical studies to date have characterised MOND with lower nicotine content, therefore, this study aimed to assess products with higher nicotine strengths. This randomised, open-label, cross-over, confinement study, conducted in Sweden, compared the nicotine pharmacokinetic and subjective effects of three MOND products, zoneX #5 slim (14 mg nicotine/pouch), zoneX #5 (16 mg) and zoneX #6 (20 mg), and a tobacco snus product (Skruf Slim Fresh #5 (16.6 mg)) in 27 adult snus or MOND users. The zoneX #6 product delivered the highest levels of nicotine; however, all products exhibited similar reductions in urge to use nicotine during and following a controlled product use session. Furthermore, the zoneX products generally scored more favourably than the snus on a 7-point Likert product evaluation scale for satisfaction, psychological reward, aversion and relief, assessed 8 h after the start of product use. There was some indication that pouch size may influence nicotine uptake, however, further characterisation is required. All study products demonstrated good short-term tolerability, with no serious adverse events observed. Overall, the findings support that MOND has tobacco harm reduction potential, providing a satisfactory alternative for adult smokers. Clinical Trial identifier: NCT05452278 https://clinicaltrials.gov/ .

Background This randomized, partially single-blinded, 6-period crossover clinical study of adult smokers compared the nicotine pharmacokinetics, impacts on smoking urge and tolerability of various formulations of one brand of e-cigarettes with that of a tobacco cigarette. Methods Five e-cigarettes with different e-liquid formulations containing 1.6 % and 2.4 % nicotine and a conventional tobacco cigarette were randomized among 24 subjects under two exposure sessions consisting of a 30-min controlled and a one-hour ad lib use period to assess plasma nicotine levels, impacts on smoking urge and adverse events. The 30-min controlled use session comprised an intensive use of the e-cigarettes with a total of 50 puffs taken every 30 s for comparison to a single conventional cigarette having a typical machine-measured nicotine yield (~0.8 mg). Ad lib product use conditions provided insight into more naturalistic product use behaviors and their accompanying smoking urge reductions. Adverse events (AEs) were assessed by the Principal Investigator. Results Significant ( p  < 0.05) increases in plasma nicotine concentrations occurred within 10 min of controlled e-cigarette use and significant ( p  < 0.001) reductions from baseline smoking urge were observed within 5 min. E-cigarette and cigarette nicotine plasma levels were comparable for up to one hour of use. After both sessions (90 min), nicotine exposure was the highest for the cigarette, with all e-cigarettes showing 23 % to 53 % lower plasma concentrations. During controlled use, peak reduction in smoking urge for e-cigs occurred later than for the cigarette. After completion of both sessions, significant smoking urge reduction persisted for most of the tested e-cigarettes, albeit at levels lower than that provided by the tobacco cigarette. Nicotine content, vehicle differences, and the presence of menthol did not significantly affect smoking urge reduction by the e-cigarettes. No subjects were discontinued due to AEs. The most frequently reported AEs events included cough, throat irritation, headache, and dizziness. Conclusions Blood plasma nicotine levels obtained from short-term use of e-cigarettes containing 1.6 % and 2.4 % nicotine were significant, but lower than those of conventional tobacco cigarettes, yet the reduction in craving symptoms were broadly comparable. The types of AEs were consistent with other research studies of longer duration that have reported that use of e-cigarettes by adult smokers is well-tolerated. Trial Registration http://ClinicalTrials.gov identifier: NCT02210754 . Registered 8 August 2014.

The introduction of a new product line of the popular disposable electronic cigarette brand Puffbar, advertised as containing synthetic nicotine, has drawn attention to the increasing use of synthetic nicotine in marketed products and its uncertain regulatory status. A search of the Truth Tobacco Industry Documents revealed that the industry considered using synthetic nicotine already in the 1960s, efforts that were abandoned due to high costs and insufficient purity. Recent patents revealed renewed efforts to develop more efficient strategies for the synthesis of nicotine. Nicotine exists as two stereoisomers, S-nicotine and R-nicotine. While S-nicotine is the prevalent (>99%) form of nicotine in tobacco, a market-leading form of synthetic nicotine contains both stereoisomers at equal amounts, raising concerns about inaccurate labelling and the poorly understood health effects of R-nicotine. Other manufacturers, including a leading vendor of pharmaceutical grade nicotine, developed stereospecific strategies to synthesise pure S-nicotine, now added to electronic cigarette products marketed in the USA and UK. While S-nicotine and R-nicotine can be differentiated by enantioselective High Performance Liquid Chromatography (HPLC), differentiation of synthetic (fossil-derived) from tobacco-derived S-nicotine will require development of methods to measure carbon isotope (14C or 13C) content. Vendors claim that the FDA has no authority to regulate synthetic nicotine as a tobacco product, allowing them to circumvent the premarket tobacco product application process. However, legal analysis suggests that FDA may have the authority to regulate synthetic nicotine as a drug. Alternatively, Congress needs to include nicotine from any source within the legal definition of tobacco products.

The single-dose pharmacokinetics (PK) of a novel, non-tobacco-based nicotine pouch, ZYN, 3 and 6 mg, were compared with 8 mg General snus (part 1) and ZYN 8 mg was compared with 18 mg Longhorn moist snuff (part 2). The present study demonstrates the characteristics of three strengths of a novel tobacco-free oral snus, ZYN, viz. the extraction of nicotine from the oral cavity and its uptake into the systemic blood circulation. Comparison is made to Swedish General snus and American Longhorn moist snuff and from literature 4 mg Nicorette gum and mean of 13 brands of e-cigarettes. A single-dose randomized crossover design was used. In vivo extraction and PK parameters were determined. Part 1. The AUCinf of ZYN 3 mg was 27% smaller than that of 8 mg General and the AUCinf of ZYN 6 mg was 34% larger than that of 8 mg General. Less nicotine was extracted from ZYN 3 mg (1.5 mg) and more from ZYN 6 mg (3.5 mg) than from 8 mg General (2.4 mg). The extracted fractions of nicotine for both ZYN products (56% and 59%) were significantly larger than for 8 mg General (32%). Part 2. Close to identical plasma nicotine curves, AUCinf and Cmax were found for ZYN 8 mg and Longhorn Natural 18 mg moist snuff. The extracted amount of nicotine from ZYN 8 mg (3.8 mg) was larger than the amount extracted from Longhorn Natural 18 mg (3.0 mg), but smaller than the extracted amount of nicotine from General 2 × 8 mg snus pouches (5.0 mg). The extracted fraction of nicotine for ZYN 8 mg (50%) was larger than for Longhorn Natural (19%) and General 2 × 8 mg snus pouches (33%). The two higher doses of ZYN (6 and 8 mg) deliver nicotine as quickly and to a similar extent as existing smokeless products, with no significant adverse effects.

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

Rationale Electronic cigarettes are becoming increasingly popular among smokers worldwide. Commonly reported reasons for use include the following: to quit smoking, to avoid relapse, to reduce urge to smoke, or as a perceived lower-risk alternative to smoking. Few studies, however, have explored whether electronic cigarettes (e-cigarettes) deliver measurable levels of nicotine to the blood. Objective This study aims to explore in experienced users the effect of using an 18-mg/ml nicotine first-generation e-cigarette on blood nicotine, tobacco withdrawal symptoms, and urge to smoke. Methods Fourteen regular e-cigarette users (three females), who are abstinent from smoking and e-cigarette use for 12 h, each completed a 2.5 h testing session. Blood was sampled, and questionnaires were completed (tobacco-related withdrawal symptoms, urge to smoke, positive and negative subjective effects) at four stages: baseline, 10 puffs, 60 min of ad lib use and a 60-min rest period. Results Complete sets of blood were obtained from seven participants. Plasma nicotine concentration rose significantly from a mean of 0.74 ng/ml at baseline to 6.77 ng/ml 10 min after 10 puffs, reaching a mean maximum of 13.91 ng/ml by the end of the ad lib puffing period. Tobacco-related withdrawal symptoms and urge to smoke were significantly reduced; direct positive effects were strongly endorsed, and there was very low reporting of adverse effects. Conclusions These findings demonstrate reliable blood nicotine delivery after the acute use of this brand/model of e-cigarette in a sample of regular users. Future studies might usefully quantify nicotine delivery in relation to inhalation technique and the relationship with successful smoking cessation/harm reduction.

The Food and Drug Administration has the authority to reduce the nicotine content of cigarettes. In this randomized trial, participants assigned to reduced-nicotine cigarettes smoked fewer cigarettes than those assigned to standard-nicotine cigarettes. Twenty years ago, Benowitz and Henningfield published a landmark commentary that coincided with initial attempts by the Food and Drug Administration (FDA) to regulate tobacco products. 1 They reasoned that if the nicotine content of cigarettes were limited to approximately 0.5 mg per cigarette (approximately 0.7 mg per gram of tobacco), cigarettes would be rendered nonaddictive. Although a reduction in nicotine content was endorsed by representatives of the medical community, 2 in 2000, the FDA lost its initial argument to regulate cigarettes in a hearing before the Supreme Court, and the proposal ultimately languished. 3 In the past 8 years, the prospect of . . .

ObjectivesTo measure the short-term effects of an electronic nicotine delivery device (“e cigarette”, ENDD) on desire to smoke, withdrawal symptoms, acceptability, pharmacokinetic properties and adverse effects.DesignSingle blind randomised repeated measures cross-over trial of the Ruyan V8 ENDD.SettingUniversity research centre in Auckland, New Zealand.Participants40 adult dependent smokers of 10 or more cigarettes per day.InterventionsParticipants were randomised to use ENDDs containing 16 mg nicotine or 0 mg capsules, Nicorette nicotine inhalator or their usual cigarette on each of four study days 3 days apart, with overnight smoking abstinence before use of each product.Main outcome measuresThe primary outcome was change in desire to smoke, measured as “area under the curve” on an 11-point visual analogue scale before and at intervals over 1 h of use. Secondary outcomes included withdrawal symptoms, acceptability and adverse events. In nine participants, serum nicotine levels were also measured.ResultsOver 60 min, participants using 16 mg ENDD recorded 0.82 units less desire to smoke than the placebo ENDD (p=0.006). No difference in desire to smoke was found between 16 mg ENDD and inhalator. ENDDs were more pleasant to use than inhalator (p=0.016) and produced less irritation of mouth and throat (p<0.001). On average, the ENDD increased serum nicotine to a peak of 1.3 mg/ml in 19.6 min, the inhalator to 2.1 ng/ml in 32 min and cigarettes to 13.4 ng/ml in 14.3 min.ConclusionsThe 16 mg Ruyan V8 ENDD alleviated desire to smoke after overnight abstinence, was well tolerated and had a pharmacokinetic profile more like the Nicorette inhalator than a tobacco cigarette. Evaluation of the ENDD for longer-term safety, potential for long-term use and efficacy as a cessation aid is needed.Trial registrationNo.12607000587404, Australia and New Zealand Clinical Trials Register