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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.

Rationale Pain and nicotine use are co-occurring conditions with a significant impact on health. Experimental evidence supports an acute analgesic effect of nicotine which may reinforce nicotine use among those with chronic pain. Evidence for nicotine analgesia have primarily been gathered in combustible cigarette users and have not been extended to electronic nicotine delivery systems (ENDS or vaping). Furthermore, the mechanisms of nicotine analgesia in humans are not well understood. Objectives Assess the effect of acute vaped nicotine on subjective and behavioral indices of pain sensitivity using three tasks designed to probe distinct mechanisms of analgesia. Methods This study recruited ENDS users ( N  = 86) to undergo a paced vaping protocol followed by pain tasks in counterbalanced order. Across four sessions, participants vaped e-liquid containing nicotine or placebo, and flavor or no-flavor in a 2 × 2 within-subject design. Assessments included cold pressor, submaximal effort tourniquet to induce ischemic pain, and temporal summation of heat pain, an index of central sensitization. Results Compared to placebo, nicotine increased cold pressor pain tolerance (η p 2  = 0.031), ischemic pain threshold (η p 2  = 0.073) and tolerance (η p 2  = 0.056) but had no effect on temporal summation of pain. Flavor did not affect pain sensitivity. Females reported greater ischemic pain sensitivity (η p 2  = 0.027) and greater reductions in craving (η p 2  = 0.086). Conclusions Consistent with research from tobacco smoking, analgesia may be reinforcing and contribute to nicotine dependence among ENDS users. More research on sex differences is warranted.

BackgroundE-liquid flavour restrictions may discourage electronic cigarette (e-cigarette) uptake among youth. However, possible unintended consequences may include reduced appeal and effectiveness of e-cigarettes for smoking cessation. Non-tobacco flavours appear to be important for smoking cessation, but how and why are currently unclear.MethodsWe conducted an experimental study in a UK sample of adult daily smokers using an independent groups design (N=84). Participants were randomised to use an e-cigarette with nicotine-containing fruit/sweet-flavoured e-liquid (blackcurrant, strawberry, vanilla, caramel) or unflavoured e-liquid for 1 week. The primary outcomes were average, peak and cue-elicited cigarette craving (the latter was assessed using a cue exposure task). The secondary outcomes were smoking lapse occurrence, enjoyment of the e-cigarette, ease of transitioning from smoking to using an e-cigarette, intentions to continue using an e-cigarette, intentions and motivation to quit smoking, return to smoking, and continuation of e-cigarette use.ResultsE-liquid flavouring did not appear to have an effect on average cigarette craving (b 0.18, 95% CI −0.44 to 0.79, p=0.57), peak cigarette craving (b −0.12, 95% CI −0.59 to 0.35, p=0.62) or cue-elicited cigarette craving (b −0.21, 95% CI −3.86 to 3.43, p=0.91). We did not find evidence of a difference in secondary outcomes.ConclusionsWe did not find evidence to suggest that nicotine-containing fruit/sweet-flavoured and unflavoured e-liquids have different effects on cigarette cravings after 1 week of use. Further research is needed to establish if differences emerge over longer periods of exposure and extend to smoking cessation outcomes.

Nicotine dependence and major depressive disorder (MDD) are highly comorbid, yet causal links between these prevalent disorders are unclear. One possible mechanism is that nicotine ameliorates MDD-related neurobiological dysfunction in specific networks. For instance, cortico-striatal circuitry is enhanced by nicotine, and such paths are disrupted in individuals with MDD. Specifically, MDD has been associated with reduced connectivity between the nucleus accumbens (NAc) and rostral anterior cingulate cortex (rACC) but enhanced connectivity between the dorsal striatum (DS) and dorsolateral prefrontal cortex (DLPFC). Determining whether nicotine normalizes these circuits in non-smokers with MDD may elucidate mechanisms underlying links between disorders. This was tested by administering placebo and a 2-mg dose of nicotine to unmedicated non-smokers with and without MDD prior to collecting resting-state functional magnetic imaging data using a cross-over design. On placebo, individuals with MDD showed significantly reduced NAc–rACC and a trend for enhanced DS–DLPFC functional connectivity relative to healthy controls. In MDD, acute nicotine administration normalized both pathways to the level of healthy controls, while having no impact on healthy controls. Nicotine’s effects on NAc–rACC connectivity was influenced by anhedonia, consistent with the role of this network in reward and nicotine’s ability to enhance reward deficiencies in MDD. These results indicate that nicotine normalizes dysfunctional cortico-striatal communication in unmedicated non-smokers with MDD. Nicotine’s influence on these circuitries highlights a possible mechanism whereby individuals with MDD are more vulnerable to develop nicotine dependence. Findings suggest that nicotinic agents may have therapeutic effects on disrupted cortico-striatal connectivity.

RationaleCognitive benefits of nicotinic acetylcholine receptor (nAChR) agonists are well established but have generally been of small magnitude and uncertain clinical significance. A way of raising the effect size may be to facilitate agonist-induced responses by co-administering a nAChR positive allosteric modulator (PAM).ObjectiveThe aim was to test whether galantamine, a PAM at several nAChR subtypes, can potentiate the cognitive-enhancing effects of nicotine.MethodsTwenty-six adult never-smokers were treated, in a double-blind counterbalanced sequence, with nicotine (7 mg/24 h, transdermally) and galantamine (4 mg, p.o.) combined, nicotine alone, galantamine alone, and double placebo. A low dose of galantamine was chosen to minimize acetylcholinesterase inhibition, which was verified in blood assays. In each condition, participants were tested with three cognitive tasks.ResultsNicotine significantly improved reaction time (RT) and signal detection in a visuospatial attention task and the Rapid Visual Information Processing Task. Galantamine did not modulate these effects. A trend toward RT reduction by galantamine correlated with acetylcholinesterase inhibition. In a change detection task, there were no effects of nicotine or galantamine alone on accuracy or RT. However, both drugs combined acted synergistically to reduce RT. This effect was not associated with acetylcholinesterase inhibition.ConclusionsA pattern consistent with allosteric potentiation of nicotine effects by galantamine was observed on one of six performance measures. This may reflect specific nAChR subtype involvement, or additional pharmacological actions of galantamine may have overshadowed similar interactions on other measures. The finding suggests that allosteric potentiation of nAChR agonist-induced cognitive benefits is possible in principle.

Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N  = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia ( n =28) and healthy controls ( n =32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebo-controlled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia.

Nicotine has been shown to affect cortical excitability measured using transcranial magnetic stimulation in smoking and non-smoking subjects in different ways. In tobacco-deprived smokers, administration of nicotine restores compromised cortical facilitation while in non-smokers, it enhances cortical inhibition. As cortical excitability and activity are closely linked to cognitive processes, we aimed to explore whether nicotine-induced physiological alterations in non-smokers and smokers are associated with cognitive changes. Specifically, we assessed the impact of nicotine on working memory performance (n-back letter task) and on attentional processes (Stroop interference test) in healthy smokers and non-smokers. Both tasks have been shown to rely on prefrontal areas, and nicotinic receptors are relevantly involved in prefrontal function. Sixteen smoking and 16 non-smoking subjects participated in the 3-back letter task and 21 smoking and 21 non-smoking subjects in the Stroop test after the respective application of placebo or nicotine patches. The results show that working memory and attentional processes are compromised in nicotine-deprived smokers compared to non-smoking individuals. After administration of nicotine, working memory performance in smokers improved, while non-smoking subjects displayed decreased accuracy with increased number of errors. The effects have been shown to be more apparent for working memory performance than attentional processes. In summary, cognitive functions can be restored by nicotine in deprived smokers, whereas non-smokers do not gain additional benefit. The respective changes are in accordance with related effects of nicotine on cortical excitability in both groups.