Smoking reduction using an electronic nicotine delivery system (ENDS) with nicotine delivery similar to combustible cigarettes.

BACKGROUND: Electronic nicotine delivery systems (ENDS) offer a promising approach to tobacco harm reduction, but many people use both ENDS and combustible cigarettes ("dual use"), which undermines potential risk reduction. To explore the role of ENDS nicotine delivery in promoting switching to ENDS, we conducted a study in which people who smoked cigarettes were offered an ENDS that had previously been shown to replicate the rapid nicotine pharmacokinetics of combustible cigarettes (BIDI® Stick). METHODS: Twenty-five cigarette smoking adults, not seeking smoking cessation treatment, but open to using ENDS as a cigarette substitute, were provided with a 12-week supply of BIDI® Stick in tobacco or menthol flavors, during a study that included seven biweekly sessions and a 6-month follow-up. Daily diaries assessed ENDS and cigarette use, and exhaled carbon monoxide (eCO) served as an objective marker of smoke intake. Subjective ratings were collected to assess the rewarding properties of ENDS and combustible cigarettes, and indices of nicotine dependence. RESULTS: Over 12 weeks, ENDS use increased to an average of 15.8 occasions per day (SD = 20.2) and self-reported cigarette consumption decreased by 82% from 16.7 cigarettes/day (SD = 6.0) at baseline to 3.0 cigarettes/day (SD = 4.1) at week 12. The eCO level decreased by 27% from an average of 20.0 ppm (SD = 9.8) at baseline to 14.5 ppm (SD = 9.9) at week 12. Four of 25 participants completely switched to ENDS and were smoking abstinent during weeks 9-12. At 6 months one participant was confirmed to be abstinent. Ratings of subjective reward for the ENDS were very similar to those of participants' usual brands of cigarettes. Dependence level was lower for the ENDS than for combustible cigarettes. CONCLUSIONS: In this study, the ENDS effectively replicated the subjective rewarding effects of participants' usual brands of cigarettes and led to a substantial reduction in reported cigarettes/day. Exhaled CO showed less of a decrease, possibly due to compensatory smoking behavior and/or the timing of eCO measurements that might not have reflected smoke intake throughout the day. The relatively low rate of sustained smoking abstinence at 6 months suggests that additional approaches continue to be needed for achieving higher rates of complete switching. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05855343.

Using varenicline in combination with electronic nicotine delivery systems (ENDS).

BACKGROUND: Varenicline is efficacious for smoking cessation, but a return to smokingusually occurs after treatment ends. Electronic nicotine delivery systems (ENDS) may enhance smoking reduction and cessation by providing a behavioral substitute for smoking and may deter smoking in the long term if an individual's nicotine dependence can be transferred to ENDS. The goal of this study was to evaluate varenicline in conjunction with ENDS to promote switching to ENDS. METHODS: Twenty-five individuals who smoked cigarettes, interested in switching but not seeking cessation treatment, received ENDS for 13 weeks; during weeks 2-13 they received varenicline. Assessments included self-reported cigarette and ENDS use, expired air carbon monoxide (CO), reward ratings, tolerability/side effects, and dependence measures. RESULTS: Cigarette smoking decreased from 15.6 cigarettes/day (SD=5.6) at baseline to 2.8 cigarettes/day (SD=5.1) at week 13 (paired t(22)=10.24, p<0.0001). 28% of participants were confirmed to be abstinent in the last 4 weeks of treatment. ENDS use remained relatively constant, averaging 11.8 occasions per day (SD=10.6). Cigarette dependence (assessed by time to first use of the day) decreased after introduction of ENDS (paired t(23) = -3.27, p=0.003), and again after the first week of full-dose varenicline (paired t(23) = -4.27, p=0.0003). Dependence on ENDS did not change, starting out lower than cigarettes (paired t(21) = 5.52, p<0.0001), but ending higher (paired t(22) = 2.94, p=0.008). Smoking satisfaction declined markedly, while satisfaction for ENDS remained relatively constant. Treatment tolerability and adherence were high. CONCLUSIONS: ENDS in combination with varenicline shows promise as a means to reduce dependence on cigarettes and facilitate switching from cigarettes to ENDS.

Novel rapid-acting sublingual nicotine tablet as a cigarette substitution strategy.

RATIONALE: Current nicotine replacement products provide a much slower onset of nicotine delivery than cigarettes, and hence are only marginally effective at supplanting cigarette smoking. Therefore, more effective forms of nicotine replacement are needed. OBJECTIVES: This initial investigation characterized the pharmacokinetic (PK) and subjective effects of a novel sublingual (SL) nicotine tablet designed to deliver nicotine more rapidly to the bloodstream of smokers. METHODS: Study 1 (N = 6) characterized the pharmacokinetics of a 2 mg nicotine SL tablet in comparison to an FDA-approved, marketed 2 mg nicotine lozenge. Study 2 (N = 24) assessed subjective responses of smokers to a single use of a 1 mg and 2 mg SL tablet. RESULTS: Study 1 found that the time to maximum blood nicotine concentrations was significantly shorter for the SL tablet (14 min) than for the lozenge (82 min), and the initial rate of nicotine absorption was higher (0.4 ng/mL*min vs. 0.0 ng/mL*min), supporting the hypothesis that the SL tablet delivered nicotine more rapidly. Study 2 found that participants reported immediate relief of nicotine withdrawal symptoms after tablet administration, and craving reduction after the 2 mg tablet approached the degree reported for their usual brands of cigarettes (4.2 vs. 4.6 on a 7-point scale). Other subjective responses showed the tablet to be an appealing alternative to smoking. CONCLUSIONS: The novel SL tablet studied shows promise as a nicotine substitution strategy for tobacco harm reduction and smoking cessation treatment. Additional studies are warranted to further investigate the potential of this new approach.

Bupropion/zonisamide combination to assist smokers to switch from combustible cigarettes to electronic nicotine delivery systems (ENDS).

INTRODUCTION: Electronic nicotine delivery systems (ENDS) may offer a much less harmful alternative to combustible cigarettes (CC) for adult smokers unwilling or unable to relinquish nicotine. However, dual use of CC and ENDS undermines potential harm reduction, and progress needs to be made to assist smokers to switch to ENDS. This study explored the promise of a novel treatment combination of the smoking cessation medication bupropion and an FDA-approved anti-seizure medication, zonisamide, to facilitate switching from CC to ENDS. Both medications have been found to reduce craving for CC and possibly offset each other's side effects. METHODS: Twenty-four smokers participated in a 13-week treatment during which they were provided with ENDS, bupropion and zonisamide. Assessments included CC and ENDS use, expired air carbon monoxide (CO), smoking withdrawal symptoms, reward ratings and tolerability/side effects. RESULTS: 33% of participants achieved biochemically confirmed, complete CC abstinence by the end of treatment. Those who did not achieve complete abstinence nonetheless showed a 44% reduction in expired air CO. Craving and other withdrawal symptoms were minimal, and CC smoking satisfaction declined markedly, while satisfaction ratings for ENDS increased over time to overtake those of CC. Side effects were generally mild, and adherence to the medication use was excellent. CONCLUSIONS: The use of combination bupropion/zonisamide to facilitate switching from CC to ENDS is a promising approach that merits follow-up randomized controlled trials. Combining short-term medication approaches with long-term nicotine substitution using ENDS may be a promising strategy to help smokers sustain smoking abstinence in the long term.

Combination Varenicline/Bupropion Treatment Benefits Highly Dependent Smokers in an Adaptive Smoking Cessation Paradigm.

INTRODUCTION: This study replicated and extended results of a previous trial, which found that combination varenicline/bupropion treatment increased smoking abstinence in smokers who were male, highly dependent, and who did not respond to prequit nicotine patch treatment with a >50% reduction in expired-air carbon monoxide in the first week. METHODS: One hundred and twenty-two male nicotine patch nonresponders and 52 responders were identified. Smokers in each group were randomized to receive 12 weeks of varenicline plus bupropion treatment versus varenicline plus placebo. The primary outcome was continuous smoking abstinence at weeks 8-11 after the target quit date. RESULTS: For smokers with a high level of dependence, judged by having a baseline Fagerstrom Test for Nicotine Dependence (FTND) score ≥ 6 and cigarette consumption ≥ 20/d, combination varenicline/bupropion treatment increased the abstinence rate relative to varenicline alone: 71.0% versus 43.8% (odds ratio = 3.14; 95% confidence interval = 1.11-8.92, p [one tailed] = .016). In contrast, less dependent smokers did not show a benefit of combination treatment relative to varenicline (abstinence rates of 32.1% vs. 45.6%, respectively); there was a significant interaction of treatment and dependence level. Patch nonresponders tended to benefit the most from combination treatment, which was well tolerated overall. CONCLUSIONS: Combination varenicline/bupropion treatment proved significantly more efficacious than varenicline alone among highly dependent male smokers. These results, together with prior studies, support an adaptive treatment paradigm that assigns smoking cessation treatment according to baseline smoker characteristics and initial response to nicotine patch treatment. IMPLICATIONS: This study replicated, in a prospective manner, an important and surprising retrospective finding from a previous clinical trial, which showed that a specific subpopulation of smokers benefited substantially from receiving a combination treatment of varenicline plus bupropion, relative to varenicline plus placebo. Specifically, male smokers having high baseline nicotine dependence (FTND score ≥ 6 and cigarette consumption ≥ 20/d), showed a marked increase in smoking abstinence rate on combination pharmacotherapy. The present study likewise found an enhancement in end-of-treatment abstinence rate in this subgroup, from 43.8% to 71.0%. The adaptive treatment paradigm, which classifies smokers based on initial dependence level and response to prequit nicotine patch treatment, may be used to identify target populations of smokers whose success can be enhanced by intervening with combination pharmacotherapy before the quit-smoking date. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01806779.

Sex-specific effects of cigarette mentholation on brain nicotine accumulation and smoking behavior.

Menthol cigarettes are likely associated with greater risks of smoking dependence than non-menthol cigarettes. We sought to test the hypothesis that menthol increases the rate of brain nicotine accumulation (BNA) during smoking and thereby enhances its addictive effects. In a counter-balanced cross-over design, 10 menthol and 9 non-menthol smokers (10 females and 9 males; mean age 44.3) underwent two study phases. In each phase, the participant smoked exclusively either menthol or non-menthol research cigarettes for approximately 1 week prior to a positron emission tomography (PET) scan session, during which the subject's head was scanned following inhalation of a single puff of smoke from a cigarette containing (11)C-nicotine. No differences in initial slope, Cmax, area under curve (AUC), and T1/2 of BNA were found between menthol and non-menthol cigarettes across all subjects; however, menthol relative to non-menthol cigarettes were associated with steeper initial slopes in men (p=0.008). Unexpectedly, women had faster BNA as indicated by greater values of the initial slope, Cmax, AUC, and shorter T1/2 than men (all ps<0.04). The rates of BNA were significantly correlated with ratings of smoking motivations of getting a 'rush', getting relaxing effects and marginally with alleviation of craving. These results do not provide strong support for the putative role of menthol in enhancing BNA, although further studies should explore the apparent effect of menthol on BNA in men. Fast BNA during smoking and preference of sensory properties of menthol cigarettes may independently or jointly contribute to smoking dependence among women.

Combination treatment with varenicline and bupropion in an adaptive smoking cessation paradigm.

OBJECTIVE: The authors assessed the efficacy and safety of combination treatment with varenicline and sustained-release bupropion for smokers who, based on an assessment of initial smoking reduction prior to the quit date, were deemed unlikely to achieve abstinence using nicotine patch treatment. METHOD: In a randomized, double-blind, parallel-group adaptive treatment trial, the authors identified 222 cigarette smokers who failed to show a reduction of more than 50% in smoking after 1 week of nicotine patch treatment. Smokers were randomly assigned to receive 12 weeks of varenicline plus bupropion or varenicline plus placebo. The primary outcome measure was continuous smoking abstinence at weeks 8-11 after the target quit date. RESULTS: Both treatments were well tolerated. Participants who received the combination treatment had a significantly higher abstinence rate than those who received varenicline plus placebo (39.8% compared with 25.9%; odds ratio=1.89; 95% CI=1.07, 3.35). Combination treatment had a significantly greater effect on abstinence rate in male smokers (odds ratio=4.26; 95% CI=1.73, 10.49) than in female smokers (odds ratio=0.94; 95% CI=0.43, 2.05). It also had a significantly greater effect in highly nicotine-dependent smokers (odds ratio=3.51, 95% CI=1.64, 7.51) than in smokers with lower levels of dependence (odds ratio=0.71, 95% CI=0.28, 1.80). CONCLUSIONS: Among smokers who did not show a sufficient initial response to prequit nicotine patch treatment, combination treatment with varenicline and bupropion proved more efficacious than varenicline alone for male smokers and for smokers with a high degree of nicotine dependence.

Adapting smoking cessation treatment according to initial response to precessation nicotine patch.

OBJECTIVE The authors evaluated an adaptive smoking cessation treatment strategy in which nicotine patch treatment was initiated before a quit date, and then, depending on initial therapeutic response, either the nicotine patch was continued or alternative pharmacotherapies were provided. METHOD The study was a double-blind, parallel-arm adaptive treatment trial. A total of 606 cigarette smokers started open-label nicotine patch treatment 2 weeks before the quit date. Those whose ad lib smoking did not decrease by >50% after 1 week were randomly assigned to one of three double-blind treatments: nicotine patch alone (control condition); "rescue" treatment with bupropion augmentation of the patch; or rescue treatment with varenicline alone. Participants whose precessation smoking decreased >50% but who lapsed after the quit date were also randomly assigned to the two rescue treatments or to nicotine patch alone. Logistic regression analyses compared each rescue treatment against the control condition in terms of abstinence at the end of treatment (weeks 8-11) and at 6 months. RESULTS Smokers who did not respond adequately to precessation nicotine patch benefited from bupropion augmentation; abstinence rates at end of treatment were 16% with nicotine patch alone and 28% with bupropion augmentation (odds ratio=2.04, 95% CI=1.03-4.01). Switching to varenicline produced less robust effects, but point abstinence at 6 months was 6.6% with the patch alone and 16.5% with a switch to varenicline (odds ratio=2.80, 95% CI=1.11-7.06). Postquit adaptive changes in treatment had no significant effects on any abstinence outcome. CONCLUSIONS It is possible to rescue a significant portion of smokers who would have failed to achieve abstinence if left on nicotine patch alone by identifying these smokers before their quit date and implementing adaptive changes in treatment.

Menthol preference among smokers: association with TRPA1 variants.

INTRODUCTION: Preference for smoking menthol cigarettes differs from individual to individual and population to population in ways that may provide higher levels of nicotine intake and contribute to smoking's morbidity and mortality. Menthol acts at sites that include the transient receptor potential (TRP) A1 channel that is expressed by nociceptors in the lung and airways, suggesting that individual and population differences in TRPA1 sequences might contribute to observed differences in menthol preference among smokers. METHODS: We have thus sought association between menthol preference and common variants in the TRPA1 gene in heavier and lighter European-American smokers. Smokers were recruited for studies of smoking cessation in North Carolina and of substance abuse genetics in Maryland. RESULTS: A common TRPA1 haplotype is defined by 1 missense and 10 intronic single nucleotide polymorphisms that display significant (.006 < p < .05; χ(2)) association with preference for mentholated cigarettes in heavy smokers (odds ratio ca. 1.3). There are smaller trends in the same direction in lighter smokers. CONCLUSIONS: This TRPA1 haplotype provides a novel biological basis for individual differences in menthol preference and possibly for actions of other agents that act at TRPA1.

Repetitive transcranial magnetic stimulation of the superior frontal gyrus modulates craving for cigarettes.

BACKGROUND: Previous functional magnetic resonance imaging studies have shown strong correlations between cue-elicited craving for cigarettes and activation of the superior frontal gyrus (SFG). Repetitive transcranial magnetic stimulation (rTMS) offers a noninvasive means to reversibly affect brain cortical activity, which can be applied to testing hypotheses about the causal role of SFG in modulating craving. METHODS: Fifteen volunteer smokers were recruited to investigate the effects of rTMS on subjective responses to smoking versus neutral cues and to controlled presentations of cigarette smoke. On different days, participants were exposed to three conditions: 1) high-frequency (10 Hz) rTMS directed at the SFG; 2) low-frequency (1 Hz) rTMS directed at the SFG; and 3) low-frequency (1 Hz) rTMS directed at the motor cortex (control condition). RESULTS: Craving ratings in response to smoking versus neutral cues were differentially affected by the 10-Hz versus 1-Hz SFG condition. Craving after smoking cue presentations was elevated in the 10-Hz SFG condition, whereas craving after neutral cue presentations was reduced. Upon smoking in the 10-Hz SFG condition, ratings of immediate craving reduction as well as the intensity of interoceptive airway sensations were also attenuated. CONCLUSIONS: These results support the view that the SFG plays a role in modulating craving reactivity; moreover, the results suggest that the SFG plays a role in both excitatory and inhibitory influences on craving, consistent with prior research demonstrating the role of the prefrontal cortex in the elicitation as well as inhibition of drug-seeking behaviors.

Silver acetate interactions with nicotine and non-nicotine smoke components.

Oral topical silver-containing formulations were marketed in the 1970s and 1980s as smoking deterrents, based on the finding that when using such formulations, an unpleasant taste occurs upon smoking. This approach has not been widely adopted, however, in part because of a lack of efficacy data. The advent of new pharmacologic treatments for smoking cessation renews the possibility that such a taste aversion approach may be a useful adjunct to smoking cessation treatment. This study explored the basic mechanistic question of whether topical oral silver acetate solution interacts with nicotine as opposed to non-nicotine smoke constituents. We recruited 20 smoking volunteers to rate nicotine-containing or denicotinized cigarettes, as well as the Nicotrol nicotine vapor inhaler and sham (air) puffs. In two sessions, subjects rated the sensory and hedonic qualities of puffs after rinsing their mouths with either silver acetate solution or deionized water (placebo). Silver acetate relative to placebo solution substantially reduced liking and satisfaction ratings for the usual brand and denicotinized cigarettes; in contrast, for the nicotine inhaler these ratings were unaffected by the silver-based treatment. These results support the conclusion that silver acetate not only renders the taste of cigarette smoke less appealing, but also that the compound appears to interact selectively with non-nicotine smoke constituents. Moreover, these data suggest silver acetate would be compatible with buccal nicotine delivery systems (e.g., nicotine lozenge or gum). Combined use of taste aversion with nicotine replacement therapy could provide the smoker with additional assistance to resist relapse. Further exploration is warranted of the use of silver-based preparations as a short-term adjunct to smoking cessation treatment.

Pulmonary delivery of nicotine pyruvate: sensory and pharmacokinetic characteristics.

The aim of this study was to evaluate pharmacokinetic and subjective responses to a prototype nicotine pyruvate (NP) aerosol generation system. In nine healthy adult daily cigarette smokers, plasma nicotine levels and subjective responses were assessed after double-blind administration of 10 inhalations of: NP (10 µg/puff, 20 µg/puff, and 30 µg/puff); Nicotrol/Nicorette nicotine vapor inhaler (NV) cartridge; and placebo (room air). Plasma nicotine concentrations increased to a significantly greater extent after inhalations of 20 µg/puff or 30 µg/puff NP (by 5.0 ± 3.4 ng/ml and 8.3 ± 3.1 ng/ml) than after placebo and NV conditions. Satisfaction ratings were higher for all NP conditions than for placebo, and harshness/irritation was lower for the NP 20 condition than for the NV control condition. Pulmonary function showed no adverse changes. These results demonstrate that NP inhalations produce rapid increases in plasma nicotine concentrations, provide satisfaction and are well tolerated. At the 20 µg/puff dose, peak nicotine concentrations were higher than with the Nicotrol/Nicorette nicotine vapor inhaler cartridge. Further trials of this promising nicotine inhalation technology are warranted to assess its safety and efficacy in smoking cessation treatment or harm reduction approaches.

Genome-wide association for smoking cessation success in a trial of precessation nicotine replacement.

Abilities to successfully quit smoking display substantial evidence for heritability in classic and molecular genetic studies. Genome-wide association (GWA) studies have demonstrated single-nucleotide polymorphisms (SNPs) and haplotypes that distinguish successful quitters from individuals who were unable to quit smoking in clinical trial participants and in community samples. Many of the subjects in these clinical trial samples were aided by nicotine replacement therapy (NRT). We now report novel GWA results from participants in a clinical trial that sought dose/response relationships for "precessation" NRT. In this trial, 369 European-American smokers were randomized to 21 or 42 mg NRT, initiated 2 wks before target quit dates. Ten-week continuous smoking abstinence was assessed on the basis of self-reports and carbon monoxide levels. SNP genotyping used Affymetrix 6.0 arrays. GWA results for smoking cessation success provided no P value that reached "genome-wide" significance. Compared with chance, these results do identify (a) more clustering of nominally positive results within small genomic regions, (b) more overlap between these genomic regions and those identified in six prior successful smoking cessation GWA studies and (c) sets of genes that fall into gene ontology categories that appear to be biologically relevant. The 1,000 SNPs with the strongest associations form a plausible Bayesian network; no such network is formed by randomly selected sets of SNPs. The data provide independent support, based on individual genotyping, for many loci previously nominated on the basis of data from genotyping in pooled DNA samples. These results provide further support for the idea that aid for smoking cessation may be personalized on the basis of genetic predictors of outcome.

Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.

Improving and targeting nicotine replacement therapy (NRT) are cost-effective strategies for reducing adverse health consequences for smokers. Treatment studies document the efficacy of precessation NRT and support important roles for level of nicotine dependence and precessation smoking reduction in successful quitting. However, prior work has not identified the optimal precessation dose or means for personalizing NRT. Genome-wide association has identified groups of genomic markers associated with successful quitting, allowing us to develop a v1.0 "quit-success" genotype score. We now report influences of v1.0 quit-success genotype score, level of dependence and precessation smoking reduction in a smoking cessation trial that examined effects of 21 versus 42 mg/24 h precessation NRT. Four hundred seventy-nine smokers were randomized to 21 or 42 mg NRT, initiated 2 wks prior to target quit dates. We monitored self-reported abstinence and end-expired air carbon monoxide (CO). Genotyping used Affymetrix arrays (Santa Clara, CA, USA). The primary outcome was 10-wk continuous smoking abstinence. NRT dose, level of nicotine dependence and genotype scores displayed significant interactive effects on successful quitting. Successful abstinence also was predicted by CO reductions during precessation NRT. These results document ways in which smoking cessation strategies can be personalized based on levels of nicotine dependence, genotype scores and CO monitoring. These assessments, taken together, can help match most smokers with optimal NRT doses and help rapidly identify some who may be better treated using other methods.

Hippocampal and striatal gray matter volume are associated with a smoking cessation treatment outcome: results of an exploratory voxel-based morphometric analysis.

RATIONALE: Compared to nonsmokers, smokers exhibit a number of potentially important differences in regional brain structure including reduced gray matter (GM) volume and/or density in areas including frontal and cingulate cortices, thalamus, and insula. However, associations between brain structure and smoking cessation treatment outcomes have not been reported. OBJECTIVES: In the present analysis we sought to identify associations between regional GM volume--as measured by voxel-based morphometry (VBM)--and a smoking cessation treatment outcome (point prevalence abstinence at 4 weeks). METHODS: Adult smokers underwent high-resolution anatomical MRI scanning prior to an open label smoking cessation treatment trial. VBM was conducted in SPM5 using the DARTEL algorithm and relapser vs. quitter groups were compared using independent sample t tests (p < 0.001, uncorrected). Analyses controlled for potentially confounding factors including years smoked, cigarettes per day, total intracranial volume (TIV), and sex. RESULTS: Of 18 smokers, 8 achieved a 4-week point prevalence abstinence, confirmed by CO level (

Reinforcing effects of nicotine and non-nicotine components of cigarette smoke.

RATIONALE: Nicotine and non-nicotine components of cigarette smoke contribute to its reinforcing effects; however, the specific role of each component in maintaining behavior has not yet been elucidated. OBJECTIVES: To assess the reinforcing effects of nicotine and non-nicotine components of cigarette smoke by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized ("denic") cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component. METHODS: Sixteen smokers participated in seven sessions: 1) a baseline smoking assessment, used to tailor the nicotine dose per infusion; 2) two sessions for training discrimination of IV nicotine vs. saline infusions and denic smoke vs. sham puffs; and 3) four sessions assessing choice behavior after different satiation conditions. RESULTS: Denic smoke was self-administered more than any other alternative, including IV nicotine. IV nicotine, however, was preferred over IV saline and sham puffs. Preference for denic smoke vs. IV nicotine was inversely correlated with subjective ratings of "comfort" associated with nicotine. Smoke satiation reduced the number of denic puffs taken during choice periods, while prior nicotine administration did not affect puffing behavior. Smoking withdrawal symptoms were alleviated both by nicotine administration and by denic smoke. CONCLUSIONS: In established smokers, non-nicotine aspects of cigarette smoking have potent reinforcing effects. While current smoking cessation pharmacotherapies primarily address the nicotine component of cigarette addiction, future cessation strategies should also be designed to target non-nicotine factors.

Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine.

Tobacco smoking is a chronic, relapsing disorder that constitutes one of the primary preventable causes of death in developed countries. Two of the popular hypotheses to explain the development and maintenance of strong nicotine dependence in cigarette smokers posit (i) a rapid brain nicotine accumulation during cigarette smoking and/or (ii) puff-associated spikes in brain nicotine concentration. To address these hypotheses, we investigated the dynamics of nicotine accumulation in the smoker's brain during actual cigarette smoking using PET with 3-s temporal resolution and (11)C-nicotine loaded into cigarettes. The results of the study, performed in 13 dependent smokers (DS) and 10 nondependent smokers (NDS), suggest that puff-associated spikes in the brain nicotine concentration do not occur during habitual cigarette smoking. Despite the presence of a puff-associated oscillation in the rate of nicotine accumulation, brain nicotine concentration gradually increases during cigarette smoking. The results further suggest that DS have a slower process of brain nicotine accumulation than NDS because they have slower nicotine washout from the lungs and that DS have a tendency to compensate for their slower rate of brain nicotine accumulation compared with NDS by inhaling a larger volume of smoke. For these reasons, smokers' dependence on cigarette smoking, or the resistance of NDS to becoming dependent, cannot be explained solely by a faster brain nicotine accumulation.

Precessation treatment with nicotine patch significantly increases abstinence rates relative to conventional treatment.

INTRODUCTION: Previous studies have reported that smoking abstinence rates are increased when nicotine skin patch treatment is initiated prior to the target quit smoking date, as compared with conventional treatment beginning on the quit date. We hypothesized that smoking in the presence of continuous levels of nicotine would attenuate the reinforcing effects of cigarette smoking and lead to a decline in dependence on inhaled nicotine, thus facilitating cessation. METHODS: This study involved four groups of smokers (n = 100 per group) who received either nicotine patch (21 mg/24 hr) or placebo patch treatment for 2 weeks before the quit smoking date, and during this period, smoked their usual brands of cigarettes or switched to low-tar and nicotine cigarettes: a 2 (nicotine patch) x 2 (cigarette type) factorial design. From the quit date on, all groups received standard nicotine patch treatment, consisting of 6 weeks of 21 mg/24 hr, 2 weeks of 14 mg/24 hr, and 2 weeks of 7 mg/24 hr. Abstinence was defined as self-report of no smoking from the quit date on, confirmed by expired-air carbon monoxide. RESULTS: Continuous abstinence rates were approximately doubled by precessation nicotine patch treatment. The treatment mainly benefited smokers with lower levels of dependence, based on Fagerström Test for Nicotine Dependence score. All treatments were well tolerated. DISCUSSION: In view of these findings and similar results from previous studies, current labeling of the nicotine patch, which recommends using nicotine replacement therapy only after the quit date, should be reexamined.

Selectively reduced responses to smoking cues in amygdala following extinction-based smoking cessation: results of a preliminary functional magnetic resonance imaging study.

Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment. The aims of this study was to evaluate the effect of an extinction-based smoking cessation treatment on brain responses to smoking cues using blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Sixteen (n = 16) dependent smokers were scanned using BOLD fMRI at baseline, following 2-4 weeks of smoking RNC cigarettes while wearing a 21-mg nicotine patch, and 2-4 weeks following quitting smoking. During scanning, participants viewed smoking-related pictures (e.g. lit cigarette) and pictures of people engaged in everyday activities (e.g. using a stapler). Event-related BOLD responses to smoking and control cues were analyzed in regions of interest (ROIs) known to subserve reward, attention, motivation and emotion. The extinction-based treatment simultaneously attenuated responses to smoking cues in amygdala while potentiating responses to control cues. Exploratory analysis indicated that this pattern was also observed in the thalamus of future abstinent but not relapsing smokers. The results of this preliminary study suggest that an extinction-based treatment for smoking cessation alters brain responses to smoking and control cues in amygdala--a region previously associated with drug cue reactivity and extinction.