Development and initial validation of a new self-report measure to assess perceived dependence on tobacco and nicotine products.

How nicotine is administered has evolved from cigarettes to various delivery systems. Assessing perceived dependence on nicotine-containing products now requires accounting for product specificity while allowing comparisons across products and users. This study aims to develop a new self-report measure to assess perceived dependence on tobacco and nicotine products (TNPs) among exclusive and poly-TNP users. A draft version of the new measure, the ABOUT-Dependence, was constructed based on literature review, qualitative research, and expert opinion. Data for scale formation and psychometric assessment was obtained through a US-based web survey (n = 2334) that included additional dependence measures for convergent validity assessment. Qualitative research confirmed a preliminary conceptual framework with seven sub-concepts. Following a cognitive debriefing, 19 items were considered to best represent the different sub-concepts. Psychometric findings supported a three-domain structure [i.e., behavioral impact (five items), signs and symptoms (five items), and extent/timing of use (two items)] and an overall total composite score. The data confirmed convergent and known-group validity, as well as test-retest reliability. The ABOUT-Dependence is a 12-item, psychometrically sound, self-report measure that may be used as a tool for research and further understanding of perceived dependence across the spectrum of TNP and TNP users.

Nicotinic Receptor Alpha-5 Subunit Gene Polymorphism is Associated with Heavy Smoking Under a Range of Nicotine Dosing Conditions.

INTRODUCTION: This study aimed to assess the role of the rs16969968 variant of nicotinic receptor alpha-5 subunit in regulating smoking behavior and nicotine intake in response to nicotine manipulations among dependent smokers in a naturalistic environment. METHODS: Sixty-nine adults (19 females) smoking 10 or more cigarettes per day were asked to complete four 2-week study phases during which they smoked exclusively one of two types of Spectrum nicotine research cigarettes (FTC nicotine yield 0.8 and 1.6 mg, respectively), their usual brand of cigarettes, or their usual brand of cigarettes while wearing a 21-mg nicotine patch. Measurements included rs16969968 genotype, number of cigarettes per day, smoking topography, and plasma cotinine. RESULTS: Compared to controls (G/G carriers), A allele carriers reported smoking 4 to 5 more cigarettes per day across all conditions (all ps < .05). Mean total smoke volume per day and cotinine were greater in A allele carriers than in controls (ps = 0.05, 0.046, respectively). No significant genotype differences were found in smoking compensation indices for the switch from Medium to High nicotine yield cigarettes. Nicotine patch-induced reductions in cigarettes smoked per day and total smoke volume per day showed significant interactions between genotype and pre-patch levels, heavier smokers showing greater effects of genotype (p = .052 and p =.006, respectively). CONCLUSIONS: Results suggest that the rs16969968 variants regulate heaviness of smoking primarily by their impact on daily numbers of cigarettes smoked, but no genotype differences were found in smoking compensation after switching from Medium to High nicotine cigarettes. IMPLICATIONS: The differences in daily cigarette consumption between rs16969968 risk-allele carriers and controls are shown to be consistent regardless of manipulations of cigarette nicotine content and transdermal nicotine supplementation and markedly greater among dependent smokers than those observed in the general smoker populations. G/G allele carriers, relative to A allele carriers, appeared to be more sensitive to the nicotine patch manipulation, reducing their smoking to a greater extent. These findings support continued efforts in the development of personalized intervention strategies to reduce the rs16969968-conveyed genetic propensity for heavy smoking.

Comparison of brain nicotine accumulation from traditional combustible cigarettes and electronic cigarettes with different formulations.

Rapid brain accumulation is critical for the acute reinforcing effects of nicotine. Although nicotine formulation (free-base vs. protonated or salt) in electronic cigarette (E-cig) liquid affects user satisfaction, its impact on brain nicotine accumulation (BNA) from E-cig use has not been evaluated in comparison with traditional combustible cigarettes (C-cigs) using a within-subjects design. BNA was directly assessed with 29 adult dual users (13 females) of E-cigs and C-cigs, using [11C]nicotine and positron emission tomography (PET). Participants underwent two 15-min upper body (from chest to head) scanning sessions during which they inhaled a single puff of [11C]nicotine-labeled vapor from E-cigs with free-base nicotine or C-cig smoke in a randomized order. Seventeen of them also went through another session during which they inhaled from E-cigs with nicotine salt. A full-body scan was also conducted at each session to measure total absorbed dose of [11C]nicotine. Mean maximum nicotine concentration (Cmax) in brain following inhalation of free-base nicotine E-cig vapor was 19% and 15% lower relative to C-cig smoke and nicotine salt E-cig vapor (ps = 0.014 and 0.043, respectively). The Cmax values did not differ significantly between the C-cig and nicotine salt E-cig. Mean values of time to the maximum concentration (Tmax) were not significantly different between the two types of E-cig, but they were 64% and 40% longer than that for C-cig smoking (ps = 0.0005 and 0.004, respectively). Mean Cmax with C-cigs and free-base nicotine E-cigs were greater in females relative to males and correlated with T1/2 of lung nicotine clearance and participants' pack-years. These results suggest that while E-cigs with free-base nicotine formulation can deliver nicotine rapidly to the brain, those with nicotine salt formulation are capable of even more efficient brain nicotine delivery closely resembling combustible cigarettes. Therefore, nicotine formulation or pH in E-liquid should be considered in evaluation of E-cigs in terms of abuse liability and potential in substituting for combustible cigarettes.

Adaptive Smoking Cessation Using Precessation Varenicline or Nicotine Patch: A Randomized Clinical Trial.

Importance: Adaptive pharmacotherapy, ie, starting a medication regimen and then modifying that regimen based on patient response, is common in many medical domains but is not common in smoking cessation. Recently, studies have found that adaptive treatment using precessation nicotine patches is efficacious for smoking cessation; however, adaptive treatment using precessation varenicline and adaptive treatment in clinical practice settings have not been fully assessed. Objective: To determine whether adaptive pharmacotherapy leads to higher smoking abstinence rates than standard pharmacotherapy in a clinical practice setting. Design, Setting, and Participants: This double-blinded stratified placebo-controlled randomized clinical trial compared adaptive treatment with standard treatment for smoking cessation. The study was conducted at a university health system in Durham, North Carolina, from February 2018 to May 2020 and was stopped early due to COVID-19. Data were analyzed as intent-to-treat from May 24, 2021, to February 27, 2022. Interventions: Participants were allowed to choose varenicline or nicotine patches and were then randomized to adaptive or nonadaptive (standard) treatment. Participants started on their chosen medication (adaptive) or placebo (standard) 4 weeks before their target quit day. Two weeks later, participants were assessed for treatment response. Adaptive participants who did not decrease daily cigarettes smoked by at least 50% (nonresponders) received bupropion in addition to their chosen medication. Participants in the adaptative treatment group who did decrease daily cigarettes smoked by at least 50% (responders) and participants in the standard treatment group received additional placebo bupropion. Participants in the standard treatment group received varenicline starting 1 week before the target quit date or nicotine patches starting on the target quit day. All participants received brief behavioral support. Main Outcome and Measures: The main outcome was biochemically verified 30-day continuous smoking abstinence 12 weeks after their target quit smoking day. Other measures included demographic characteristics, smoking history, and repeated smoking assessments. Results: Of the planned 300 participants, a total of 188 participants (mean [SD] age, 49.1 [12.5] years; 102 [54%] female) were enrolled before the trial was stopped because of the COVID-19 pandemic. A total of 127 participants chose to use varenicline, including 64 randomized to adaptive treatment and 63 randomized to standard treatment, and 61 participants chose to use nicotine patches, including 31 randomized to adaptive treatment and 30 randomized to standard treatment. At baseline, participants smoked a mean (SD) of 15.4 (7.3) cigarettes per day. At 12 weeks after the target quit day, biochemically verified 30-day continuous smoking abstinence was observed in 23 of 95 participants (24%) in the adaptive treatment group and 8 of 93 participants (9%) in the standard treatment (odds ratio [OR], 3.38; 95% CI, 1.43-7.99; P = .004); among participants who used varenicline, 30-day continuous abstinence was 18 participants (28%) in the adaptive treatment group, and 5 participants (8%) in the standard treatment group (OR, 4.54; 95% CI, 1.57-13.15); among participants who used nicotine patches, 30-day continuous abstinence was 5 participants (16%) in the adaptive treatment group and 3 participants (10%) in the standard treatment group (OR, 1.73; 95% CI, 0.38-7.99). Sleep problems were more common for participants in the varenicline adaptive treatment group than in the varenicline standard treatment group (rate ratio, 1.74; 95% CI, 1.18-2.58; P = .03). Conclusions and Relevance: This randomized clinical trial found that adaptive pharmacotherapy was efficacious for smoking cessation treatment in a practice setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02501265.

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.

Smoking reduction using electronic nicotine delivery systems in combination with nicotine skin patches.

RATIONALE: Electronic nicotine delivery systems (ENDS) are used by smokers seeking to reduce combustible cigarette (CC) use, but the role of nicotine replacement vs. behavioral and sensory factors is still poorly understood. We hypothesized that providing nicotine from ENDS in addition to nicotine skin patches would promote smoking reduction relative to non-nicotine control ENDS. OBJECTIVES: To assess the effects on smoking behavior of using nicotine vs. placebo ENDS in smokers using nicotine vs. placebo patches. METHODS: Ninety-four daily smokers were enrolled in a study that randomly assigned them to receive ENDS with nicotine vs. without nicotine and skin patches with vs. without nicotine. Smoking reduction and cessation were assessed over an 8-week period by self-report and by expired air carbon monoxide (CO) measurements. The primary outcome was defined as reduction in expired air CO. RESULTS: The use of nicotine in ENDS led to significant reductions in smoking (ENDS nicotine vs. placebo difference in CO change = -9.2 ppm; 90% CI (-1.5 ppm, -16.9 ppm)) and was highly correlated with reductions in self-reported cigarettes per day (r=0.6). The effect of nicotine in nicotine patches was not statistically significant (patch nicotine vs. placebo difference in CO change = -0.1 ppm; 90% CI (-7.8 ppm, 7.6 ppm)). CONCLUSIONS: The presence of nicotine in ENDS was associated with a large reduction in smoking. Additional studies will be needed to determine whether there may be additive effects of nicotine ENDS and nicotine patches on smoking abstinence.

Effect of Electronic Cigarette Liquid pH on Retention of 11C-Nicotine in a Respiratory Tract Model.

INTRODUCTION: Based on our preliminary 11C-nicotine positron emission tomography (PET) imaging studies in humans, we speculated that greater deposition of nicotine in the respiratory tract from electronic cigarettes compared to combustible cigarettes could result from the alkaline pH of typical aerosol-producing electronic cigarette liquids (e-liquids). To address this hypothesis, we assessed the effect of e-liquid pH on the retention of nicotine in vitro using 11C-nicotine, PET, and a human respiratory tract model of nicotine deposition. AIMS AND METHODS: A single 2-second 35-mL puff was delivered to a human respiratory tract cast from a 2.8-Ohm cartomizer at 4.1 volts. Immediately after the puff, a 2-second 700-mL air wash-in volume was administered. E-liquids (glycerol and propylene glycol 50/50 vol/vol) containing 24 mg/mL nicotine were mixed with 11C-nicotine. Deposition (retention) of nicotine was assessed using a GE Discovery MI DR PET/CT scanner. Eight e-liquids with different pH values (range 5.3-9.6) were investigated. All experiments were performed at room temperature and at a relative humidity of 70%-80%. RESULTS: Retention of nicotine in the respiratory tract cast was pH dependent and the pH-sensitive component of the retention was well described by a sigmoid curve. In total, 50% of the maximal pH-dependent effect was observed at pH 8.0, which is close to the pKa2 of nicotine. CONCLUSIONS: The retention of nicotine in the respiratory tract conducting airways is dependent on the e-liquid pH. Lowering the e-liquid pH reduces retention of nicotine. Nonetheless, reduction of the pH below 7 has little effect, consistent with the pKa2 of protonated nicotine. IMPLICATIONS: Similar to combustible cigarettes, the retention of nicotine in the human respiratory tract from consumption of electronic cigarettes may have some health consequences and affect nicotine dependence. Here we demonstrated that the retention of nicotine in the respiratory tract is dependent on the e-liquid pH, and lowering pH reduces retention of nicotine in conducting airways of the respiratory tract. Therefore, e-cigarettes with low pH values would result in reduced respiratory tract nicotine exposure and faster delivery of nicotine to the central nervous system (CNS). The latter can be associated with e-cigarette abuse liability and the effectiveness of e-cigarettes as substitutes for combustible cigarettes.

Comparison of brain nicotine uptake from electronic cigarettes and combustible cigarettes.

Brain accumulation rate and magnitude are critical for the acute reinforcing effects of nicotine. Despite electronic cigarettes' (E-cigs) appeal as substitutes for traditional combustible cigarettes (C-cigs), brain nicotine accumulation (BNA) from E-cigs has not been compared with that from C-cigs using a within-subjects design. BNA was directly assessed with 16 adult dual users (10 females) of E-cigs (e-liquid pH 9.4) and C-cigs, using 11C-nicotine and positron emission tomography (PET). Participants went through two 15-min head scanning sessions during which they inhaled a single puff of E-cig vapor or C-cig smoke containing 11C-nicotine in a randomized order. A full-body scan was also conducted at each session to measure total absorbed dose of 11C-nicotine. Mean maximum concentration (Cmax) and area under curve of BNA were 22.1% and 22.7% lower, respectively, following E-cig compared with C-cig inhalation. Meanwhile, T1/2 was 2.7 times longer following inhalation of E-cig vapor relative to C-cig smoke (all ps < 0.005). Whole-body imaging indicated greater nicotine retention in the respiratory tract from vapor versus smoke inhalation (p < 0.0001). Following vapor inhalation, nicotine retention in the respiratory tract was correlated with Cmax values of BNA (rs = -0.59, p < 0.02). Our results confirm that E-cigs with alkaline pH e-liquid can deliver nicotine rapidly to the brain, albeit less efficiently than C-cigs partly due to greater airway retention of nicotine. Since brain nicotine uptake mediates reinforcement, these results help elucidate actions of E-cigs in terms of abuse liability and effectiveness in substituting for combustible cigarettes.

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.

Chronic infusions of mecamylamine into the medial habenula: Effects on nicotine self-administration in rats.

The habenula is an epithalamic structure through which descending connections go from the telencephalon to the brainstem, putting it in a key location to provide feedback control over the ascending projections from the brainstem to the telencephalon. The medial habenula has a high concentration of nicotinic receptors. We assessed the role of medial habenular nicotinic receptors for nicotine self-administration (SA) in female young adult Sprague-Dawley rats. The rats had bilateral chronic infusion cannulae placed into the medial habenula nucleus. Each cannula was connected to a slow delivery osmotic minipump to chronically infuse mecamylamine (100 µg/side/day) or vehicle for four consecutive weeks. The rats were tested for nicotine SA for the first two weeks of mecamylamine infusion. Then, they had one week of enforced abstinence, during which they had no access to the nicotine SA. Finally, they had one week of resumed nicotine SA access. There was a significantly differential mecamylamine effects in animals with lower and higher pretreatment baseline nicotine SA. Rats with lower baseline nicotine SA levels showed a nearly significant mecamylamine-induced reduction in SA while those with higher baseline levels of SA showed a significant mecamylamine-induced increase in nicotine SA. This study determined that medial habenular nicotinic receptors are important for nicotine reinforcement. Baseline level of performance makes a crucial difference for the involvement of habenular mechanisms in nicotine reinforcement with nicotinic activation being important for maintaining nicotine self-administration for those with lower levels of baseline self-administration and the opposite effect with subjects with higher levels of baseline self-administration.

Self-administration by female rats of low doses of nicotine alone vs. nicotine in tobacco smoke extract.

BACKGROUND: Nicotine has reinforcing effects, but there are thousands of other compounds in tobacco, some of which might interact with nicotine reinforcement. AIMS: This rat study was conducted to determine if nicotine self-administration is altered by co-administration of the complex mixture of compounds in tobacco smoke extract (TSE). METHODS: Female Sprague-Dawley rats were tested for self-administration of low doses of nicotine (3 or 10 µg/kg/infusion) at three different rates of reinforcement (FR1, FR3 and FR5) over three weeks either alone or together with the complex mixture of tobacco smoke extract (TSE). RESULTS: Rats self-administering 3 µg/kg/infusion of nicotine alone showed a rapid initiation on an FR1 schedule, but declined with FR5. Rats self-administering nicotine in TSE acquired self-administration more slowly, but increased responding over the course of the study. With 10 µg/kg/infusion rats self-administered significantly more nicotine alone than rats self-administering the same nicotine dose in TSE. Rats self-administering nicotine alone took significantly more infusions with the 10 than the 3 µg/kg/infusion dose, whereas rats self-administering nicotine in TSE did not. Nicotine in TSE led to a significantly greater locomotor hyperactivity at a dose of 0.1 mg/kg compared to rats that received nicotine alone. Rats self-administering nicotine alone had significantly more responding on the active vs. inactive lever, but rats self-administering the same nicotine doses in TSE did not. CONCLUSIONS: Self-administration of nicotine in a purer form appears to be more clearly discriminated and dose-related than nicotine self-administered in the complex mixture of TSE.

Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats.

Opiate addiction has risen substantially during the past decade. New treatments to combat opiate addiction are sorely needed. The current study was conducted to determine the acute individual and interactive effects of bupropion and dextromethorphan in a rat model of opiate self-administration using the short-acting synthetic opioid remifentanil. Both of these drugs have been found to reduce self-administration of nicotine. Bupropion and dextromethorphan and their combination had differential effects depending on whether the rats showed higher or lower baseline remifentanil self-administration. The rats with higher initial remifentanil self-administration showed a significant decrease in remifentanil self-administration with bupropion or dextromethorphan treatment, compared to the vehicle control condition. This decrease in self-remifentanil administration was most pronounced when combination of the higher doses of bupropion and dextromethorphan were administered. In contrast, the rats with lower baseline remifentanil self-administration showed the opposite effect of drug treatment with an increase in remifentanil self-administration with bupropion treatment compared to the vehicle control condition. Dextromethorphan had no significant effect inthis group. This study shows that combination bupropion and dextromethorphan affects remifentanil self-administration in a complex fashion with differential effects on low and high baseline responders. In subjects with high baseline remifentanil self-administration, bupropion and dextromethorphan treatment significantly reduced self-administration, whereas in subjects with low baseline remifentanil self-administration, bupropion increased remifentanil self-administration and dextromethorphan had no discernible effect. This finding suggests that combination bupropion-dextromethorphan should be tested in humans, with a focus on treating people with high-level opiate use.

Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats.

RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.

Prolonging the Reduction of Nicotine Self-Administration in Rats by Coadministering Chronic Nicotine With Amitifadine, a Triple Monoamine Reuptake Inhibitor With CYP2B6 Inhibitory Actions.

INTRODUCTION: Existing treatments can aid tobacco smoking cessation, but they have low efficacy. Because there is a network of neural systems involved in tobacco addiction, combination treatments may provide greater efficacy. Chronic nicotine and amitifadine have each been shown to significantly reduce nicotine self-administration in rats. This study was conducted to determine if the combination of chronic nicotine with amitifadine, a triple monoamine reuptake inhibitor with CYP2B inhibitory effects, would reduce nicotine self-administration to a greater extent than either alone or placebo. METHODS: This study tested the combination of nicotine plus amitifadine in young adult female Sprague-Dawley rats self-administering nicotine (0.03 mg/kg/infusion). This combination was compared with each treatment alone and the vehicle during continuing nicotine self-administration as well as during resumption of self-administration after a week of enforced abstinence, modeling a quit attempt. Finally, we studied the residual effects of these therapies after discontinuation of treatment. RESULTS: Treatment with either chronic nicotine or amitifadine alone significantly reduced nicotine self-administration relative to controls. The combination of the treatments significantly enhanced this effect. After treatment withdrawal, all of the groups showed increases in nicotine self-administration, but only the combined treatment group remained significantly below control rates of nicotine self-administration. CONCLUSIONS: This study showed the promise of amitifadine as a possible new treatment for smoking cessation and suggested that amitifadine is more effective when given with chronic nicotine. The improved efficacy of the amitifadine and nicotine combination may be potentiated by amitifadine's inhibitory effects on CYP2B, which slows nicotine metabolism. IMPLICATIONS: This study replicated the effects that chronic nicotine or chronic amitifadine, a triple reuptake inhibitor, significantly reduces nicotine self-administration in rats. It extends those findings by showing that the combination of chronic nicotine plus amitifadine causes significantly greater reduction in nicotine self-administration than either drug treatment alone. The combination of chronic amitifadine and chronic nicotine also causes a persistent significant reduction in nicotine self-administration after the end of treatment. The amitifadine and nicotine treatment should be assessed in humans to determine whether this combination provides greater efficacy in smoking cessation than transdermal nicotine treatment alone.

Combination Lorcaserin and Nicotine Patch for Smoking Cessation Without Weight Gain.

INTRODUCTION: This study explored the efficacy of combination lorcaserin and nicotine patch for smoking cessation treatment and prevention of postsmoking cessation weight gain. METHODS: We conducted a trial in which 61 adult daily smokers were asked to quit smoking using a combination of lorcaserin and nicotine patch. During the first 2 weeks of treatment prior to the quit day, participants were randomized to receive either lorcaserin (10 mg twice daily) plus nicotine patch (21 mg) or placebo plus nicotine patch (21 mg). Following this 2-week period, participants received both medications for 12 weeks. Outcomes included 4-week continuous smoking abstinence at the end of treatment (weeks 7-10 postquit attempt), weight change, ad libitum smoking, withdrawal symptoms, and ratings of cigarette reward. RESULTS: Biochemically confirmed continuous smoking abstinence from 7 to 10 weeks postquit attempt was 31.1% (90% confidence interval, 21.4%-40.8%). Participants who quit smoking showed no weight gain; in fact, mean weight change was minus 0.16 kg (SD = 3.27) over the study period. There was an unexpected but strong association (p = .006) between a decrease in sensory enjoyment of smoking and successful quit outcome on this regimen. During the prequit randomization period, lorcaserin versus placebo reduced the impact of smoking to relieve craving for cigarettes as well as the sensory enjoyment of smoking (p = .005). Adherence and tolerability to lorcaserin and nicotine patch was good. CONCLUSIONS: The combination of lorcaserin and nicotine patch was well tolerated, associated with a relatively high smoking abstinence rate, and effectively prevented weight gain associated with quitting smoking. IMPLICATIONS: This report provides an important contribution to the literature because it details evidence of a medication combination-lorcaserin and nicotine-that is effective for smoking cessation and for ameliorating weight gain associated with smoking cessation. For many smokers, postcessation weight gain is a major obstacle to quitting, and this medication combination provides a suitable treatment option for these smokers. CLINICAL TRIAL REGISTRATION: NCT02906644.

Rapid Brain Nicotine Uptake from Electronic Cigarettes.

This study sought to determine brain nicotine kinetics from use of the increasingly popular electronic cigarette (E-cig). Methods: In 17 E-cig users (9 men and 8 women), brain uptake of nicotine after inhalation from E-cigs was directly assessed using 11C-nicotine PET. The brain nicotine kinetics were compared with those from smoking combustible cigarettes (C-cigs). Results: A single puff of E-cig vapor caused the nicotine concentration in the brain to rise quickly (mean time to reach 50% of maximum brain nicotine concentration, 27 s), with a peak amplitude 25% higher in women than men, resembling previous observations with C-cigs. Nonetheless, the accumulation from E-cigs (24%) was less than that from C-cigs (32%) in both men and women. Conclusion: E-cigs can deliver nicotine to the brain with a rapidity similar to that of C-cigs. Therefore, to the extent that rapid brain uptake promotes smoking reward, E-cigs might maintain a degree of nicotine dependence and also serve as a noncombustible substitute for cigarettes.

Chronic memantine decreases nicotine self-administration in rats.

Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.