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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.

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 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.

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 my blu 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.

Awareness and usage of electronic cigarettes has exponentially increased during the last few years, especially among young people and women in some countries. The rapid acceptance of electronic cigarettes may be attributed in part to the perception created by marketing and the popular press that they are safer than combustible cigarettes. To alert and advise policy makers about electronic cigarettes and their potential hazards. Using The Union's position paper on electronic cigarettes as the starting template, the document was written using an iterative process. Portions of the manuscript have been taken directly from the position papers of participating societies. Because electronic cigarettes generate less tar and carcinogens than combustible cigarettes, use of electronic cigarettes may reduce disease caused by those components. However, the health risks of electronic cigarettes have not been adequately studied. Studies looking at whether electronic cigarettes can aid smoking cessation have had inconsistent results. Moreover, the availability of electronic cigarettes may have an overall adverse health impact by increasing initiation and reducing cessation of combustible nicotine delivery products. The health and safety claims regarding electronic nicotine delivery devices should be subject to evidentiary review. The potential benefits of electronic cigarettes to an individual smoker should be weighed against potential harm to the population of increased social acceptability of smoking and use of nicotine, the latter of which has addictive power and untoward effects. As a precaution, electronic nicotine delivery devices should be restricted or banned until more information about their safety is available. If they are allowed, they should be closely regulated as medicines or tobacco products.

BackgroundThe use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells.MethodsMice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot.ResultsInhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion.ConclusionsExposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use.

Objective To review the available literature evaluating electronic cigarette (e-cigarette) nicotine clinical pharmacology in order to understand the potential impact of e-cigarettes on individual users, nicotine dependence and public health. Methods Literature searches were conducted between 1 October 2012 and 30 September 2013 using key terms in five electronic databases. Studies were included in the review if they were in English and publicly available; non-clinical studies, conference abstracts and studies exclusively measuring nicotine content in e-cigarette cartridges were excluded from the review. Results Nicotine yields from automated smoking machines suggest that e-cigarettes deliver less nicotine per puff than traditional cigarettes, and clinical studies indicate that e-cigarettes deliver only modest nicotine concentrations to the inexperienced e-cigarette user. However, current e-cigarette smokers are able to achieve systemic nicotine and/or cotinine concentrations similar to those produced from traditional cigarettes. Therefore, user experience is critically important for nicotine exposure, and may contribute to the products’ ability to support and maintain nicotine dependence. Conclusions Knowledge about e-cigarette nicotine pharmacology remains limited. Because a user's e-cigarette experience may significantly impact nicotine delivery, future nicotine pharmacokinetic and pharmacodynamic studies should be conducted in experienced users to accurately assess the products’ impact on public health.

Nicotine, the signature alkaloid of Nicotiana species responsible for the addictive properties of human tobacco smoking, functions as a defensive neurotoxin against attacking herbivores. However, the evolution of the genetic features that contributed to the assembly of the nicotine biosynthetic pathway remains unknown. We sequenced and assembled genomes of two wild tobaccos, Nicotiana attenuata (2.5 Gb) and Nicotiana obtusifolia (1.5 Gb), two ecological models for investigating adaptive traits in nature. We show that after the Solanaceae whole-genome triplication event, a repertoire of rapidly expanding transposable elements (TEs) bloated these Nicotiana genomes, promoted expression divergences among duplicated genes, and contributed to the evolution of herbivoryinduced signaling and defenses, including nicotine biosynthesis. The biosynthetic machinery that allows for nicotine synthesis in the roots evolved from the stepwise duplications of two ancient primary metabolic pathways: the polyamine and nicotinamide adenine dinucleotide (NAD) pathways. In contrast to the duplication of the polyamine pathway that is shared among several solanaceous genera producing polyamine-derived tropane alkaloids, we found that lineage-specific duplications within the NAD pathway and the evolution of rootspecific expression of the duplicated Solanaceae-specific ethylene response factor that activates the expression of all nicotine biosynthetic genes resulted in the innovative and efficient production of nicotine in the genus Nicotiana. Transcription factor binding motifs derived from TEs may have contributed to the coexpression of nicotine biosynthetic pathway genes and coordinated the metabolic flux. Together, these results provide evidence that TEs and gene duplications facilitated the emergence of a key metabolic innovation relevant to plant fitness.