Rationale Electronic cigarettes are becoming increasingly popular among smokers worldwide. Commonly reported reasons for use include: to quit smoking, avoid relapse, reduce urge to smoke, or as a perceived lower risk alternative to smoking. Few studies however, have explored whether e-cigarettes deliver measurable levels of nicotine to the blood.Objective This study in experienced users explores 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 (3 female), abstinent from smoking and ecigarette use for 12 h, each completed a 3 h testing session. Blood was sampled and questionnaires 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 7 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 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.

Funding: This study was fully funded by the University of East London PhD Excellence Studentship to CK. Declaration of interests:We declare that we have received no support from any companies for this work and there are no non-financial conflicts of interest that would be considered relevant to this work. LED has previously conducted research for several independent electronic cigarette companies. These companies had no input into the design, conduct or write up of the projects. She has also acted as a consultant for the pharmaceutical industry and as an expert witness in a patent infringement case. CK and OC declare no competing interests. MD and CF have previously supported other research groups by the quantification of cotinine, 3-hydroxy cotinine and nicotine. These groups had no input into the design, conduct or write up of this project.Keywords: Nicotine, Titration, E-cigarette, Puffing topography, Compensation 2 Abstract Rationale Self-titration is well documented in the tobacco literature. The extent to which ecigarette users (vapers) self-titrate is unknown.Objective This study explored the effects of high and low nicotine strength liquid on puffing topography, nicotine delivery and subjective effects in experienced vapers.Methods Eleven experienced male vapers completed 60 minutes of ad libitum vaping under low (6 mg/mL) and high (24 mg/mL) nicotine liquid conditions in two separate sessions.Measurements included: puffing topography (puff number, puff duration, volume of liquid consumed); and changes in: plasma nicotine levels, craving, withdrawal symptoms, selfreported hit, satisfaction and adverse effects.Results Liquid consumption and puff number were higher, and puff duration longer, in the low nicotine strength condition (all ps < 0.01). The mean difference in nicotine boost from baseline in the low condition was 8.59 (7.52) ng/mL, 16.99 (11.72) ng/mL and 22.03 (16.19) ng/mL at 10, 30 and 60 minutes respectively. Corresponding values for the high condition were 33.77 (34.88) ng/mL, 35.48 (28.31) ng/mL and 43.57 (34.78) ng/mL (ps < 0.05). There were no statistically significant differences between conditions in self-reported craving, withdrawal symptoms, satisfaction, hit or adverse effects.Conclusions Vapers engaged in compensatory puffing with lower nicotine strength liquid, doubling their consumption. Whilst compensatory puffing was sufficient to reduce craving and withdrawal discomfort, self-titration was incomplete with significantly higher plasma nicotine levels in the high condition.

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Cryogenic cooling of the NMR radio frequency coils and electronics to give greatly enhanced sensitivity is arguably the most significant recent advance in NMR spectroscopy. Here we report the first cryogenic probe built in flow configuration and demonstrate the application to LC-NMR-MS studies. This probe provides superior sensitivity over conventional noncryogenic flow NMR probes, allowing the use of 100 microL of untreated urine (40% less material than previous studies that required preconcentration) and yet revealing drug metabolites hitherto undetected by LC-NMR-MS at 500 MHz. Besides the known sulfate and glucuronide metabolites, previously undetected metabolites of acetaminophen were directly observable in a 15-min on-flow experiment. Simultaneous MS data also provided knowledge on the NMR-silent functional moieties. Further, stop-flow LC-NMR-MS experiments were conducted for greater signal-to-noise ratios on minor metabolites. The cryoflow probe enables the NMR analysis of lower concentrations of metabolites than was previously possible for untreated biofluids. This strategy is generally applicable for samples containing mass-limited analytes, such as those from drug metabolism studies, biomarker and toxicity profiling, impurity analysis, and natural product analysis.

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