A Procedure to Standardize Puff Topography During Evaluations of Acute Tobacco or Electronic Cigarette Exposure.

INTRODUCTION: Documenting factors that influence differential sensitivity to acutely inhaled nicotine products requires carefully controlling the amount of exposure (dose), and thus a procedure by which to control such exposure. METHODS: We evaluated consistency of puff volume from intermittent acute exposures to smoked tobacco cigarettes (study 1, n = 45, plus a comparison study of uninstructed use with n = 59) and to vaped electronic cigarettes (e-cigarettes; study 2, n = 27 naive to e-cigarettes) in adult-dependent smokers. All in primary studies 1 and 2 participated in research administering different nicotine levels in each product under blind conditions, one per session using within-subject designs. In both studies, participants followed an automated instructional procedure on a computer monitor standardizing the timing and amount of exposure to each product during a given trial, with four trials per session, each separated by 20 minutes. Puff volume per trial via Clinical Research Support System (CReSS) was the primary dependent measure to determine consistency across trials via intraclass correlation coefficients (ICCs). RESULTS: Control over topography with both inhaled products was demonstrated by highly significant ICCs for puff volume across trials. Instructed control with own brand was generally better in study 1 than with uninstructed smoking in the comparison sample, as expected. As intended, reliability of puff volume generally did not differ by menthol preference or sex in either study, but ICCs in study 2 tended to be lower for some men using the placebo e-cigarette. CONCLUSIONS: This instructional procedure may substantially improve control over amounts of acute exposure to tobacco or e-cigarette use. IMPLICATIONS: Control over topography in studies of acute exposure to these inhaled products can potentially aid validity of research into differential sensitivity to use, so findings can be attributed to factors of interest and not to variable exposure. Our procedure minimized variability in exposure to the same product and between moderate nicotine products, but remaining differences suggest that compensation for very low or no nicotine commercial products may be difficult to totally eliminate with these instructions alone. Further study is needed to determine this procedure's utility with other inhaled products among experienced users and when comparing different products in between-groups analyses.

A Forced-Choice Procedure to Assess the Acute Relative Reinforcing Effects of Nicotine Dose per se in Humans.

INTRODUCTION: A method to assess acute reinforcement due to nicotine may aid identification of doses needed to maintain dependence. After describing development of a forced-choice procedure, results are presented from two studies using it to determine the relative reinforcing effects of nicotine dose per se. AIMS AND METHODS: Choice between a higher versus a very low or no nicotine option, via smoking (Study 1, n = 59) and via nasal spray (Study 2, n = 42), was assessed in nontreatment-seeking dependent smokers abstinent overnight. Using a within-subject design, different nicotine levels for each product were administered under blind conditions, initially to assess their discriminability (Study 1: 1.3-17 mg/g each vs. 0.4 mg/g nicotine Spectrum cigarettes; Study 2: 2.5 µg/kg vs. 0 µg/kg nicotine per spray). At the end of sessions for each study, participants engaged in forced-choice trials to assess preference, requiring a fixed number of puffs/sprays for one and/or the other. RESULTS: Confirming the procedure's validity, the choice of the higher nicotine option was significantly greater than that for the very low or no nicotine option in both studies. In Study 1, choice relative to 0.4 mg/g was greater for cigarettes 5.3 mg/g or more but not 2.3 mg/g or less (p = .003 for the interaction of higher content vs. 0.4 mg/g comparison). In Study 2, choice was greater for the nicotine versus placebo spray (p < .005), as nicotine was preferred nearly twice as much as the placebo. CONCLUSION: This forced-choice procedure may efficiently determine the relative reinforcing value of a nicotine dose per se. IMPLICATIONS: The forced-choice procedure described here may identify nicotine doses that are acutely reinforcing in dependent smokers. A priori research of choice comparisons between small versus zero nicotine doses could inform clinical research in larger and more diverse samples to determine nicotine contents in cigarettes, and perhaps in other commercial products, that are not reinforcing and, thus, likely to reduce the risk of their addictiveness. This procedure may also be applicable to assessing changes in acute nicotine reinforcement due to different product formulations, novel drugs, or other manipulations, perhaps helping inform development of new interventions for cessation or harm reduction.

Research on Behavioral Discrimination of Nicotine May Inform FDA Policy on Setting a Maximum Nicotine Content in Cigarettes.

INTRODUCTION: The Food and Drug Administration may set a maximum nicotine content in cigarettes to minimize smoking's addictiveness. Our recent research may indirectly support setting levels applicable to the population of dependent smokers below 1 mg/g (mg nicotine/g of tobacco filler). METHODS: Using a within-subjects design in laboratory-based studies totaling 61 nontreatment seeking adult dependent smokers, Spectrum research cigarettes with nicotine contents ranging from 1.3 to 17 mg/g (just one per session) were compared with the lowest content available, 0.4 mg/g. Identified for each participant was the smallest difference in nicotine content, or "threshold," between cigarettes that still supported behavioral discrimination (ie, ability to objectively distinguish their difference). The next lower nicotine content cigarette, not discriminated (by definition), was labeled their "subthreshold." Subjective perceptions and choice behavior were also assessed. RESULTS: Thresholds varied widely among all 61 smokers but, importantly, fewer than 7% of smokers could discriminate the two lowest, 1.3 versus 0.4 mg/g nicotine, meaning more than 90% could not do so. Moreover, we found a consistent association between their nicotine discrimination threshold and their subjective perceptions and subsequent reinforcement behavior later in the session. Specifically, a participant's discrimination threshold cigarette was also more highly rated and preferred (ie, self-administered), whereas their subthreshold cigarette was rated similarly to the 0.4 mg/g and not preferred. CONCLUSIONS: Cigarette nicotine content below the threshold for perceiving nicotine's effects (ie, its discriminability) in nearly all smokers from a no nicotine comparison is likely below 1.0 mg/g, or less than or equal to 10% of that in typical commercial cigarettes. IMPLICATIONS: Cigarettes with nicotine contents able to be discriminated (threshold) are also reinforcing, and those unable to be discriminated are not reinforcing, as anticipated. Yet, research explicitly comparing cigarettes with contents below 1.0 mg/g versus no nicotine (ie, a "placebo") is needed with larger samples. Results may confirm what nicotine content lower than 1.0 mg/g is below the threshold for discrimination (and self-administration) in the vast majority (>95%) of adult dependent smokers as well as teens beginning to smoke. Identifying that content would strongly support the Food and Drug Administration policy to establish a maximum nicotine content in cigarettes that will not maintain dependence.

Reinforcement Enhancing Effects of Nicotine Via Patch and Nasal Spray.

INTRODUCTION: Confirming preclinical findings, nicotine in humans (via smoking) enhances reinforcement from nondrug rewards. Recent demonstration of similar effects with nicotine via e-cigarettes suggests they may also occur when using nicotine replacement therapies (NRT). METHODS: Effects of nicotine via NRT patch or nasal spray were assessed on responding reinforced by music, video, or monetary rewards, or for no reward (control). Nontreatment seeking smokers (N = 31) participated in three virtually identical experimental sessions, each following overnight abstinence (CO ≤ 10 ppm). In a fully within-subjects design using a double-dummy procedure, these sessions involved: (1) nicotine patch (Nicoderm 14 mg) plus placebo spray, (2) placebo patch plus nicotine spray (Nicotrol, 2 × 1 mg/trial), or (3) placebo patch plus placebo spray. Session order was counter-balanced. RESULTS: Relative to placebo, reinforced responding due to nicotine via spray or patch was greater for video reward (both p < .01) but not for music reward (both p > .10). Similar results for NRT spray and patch confirms preclinical findings indicating no difference between fast and slow nicotine delivery, respectively, on reinforcement enhancing effects. Withdrawal relief was unrelated to these effects of nicotine via NRT on nondrug reinforcement. CONCLUSIONS: Nicotine from NRT has some reinforcement enhancing effects in humans, possibly in a manner consistent with nicotine via e-cigarettes but not tobacco smoking. Our findings could suggest differential dose-dependency of available rewards to enhanced reinforcement by nicotine. Such effects may help contribute to the efficacy of NRT for aiding smoking cessation, but more research focusing on dose-dependency of these nicotine actions is needed. IMPLICATIONS: Acute nicotine from smoking enhances reinforced responding for nondrug sensory rewards. Yet, nonsmoked nicotine, including from NRT medications of patch and nasal spray, may act more selectively across rewards, perhaps due to lower dosing exposure. Our results suggest that nicotine via NRT enhances responding for visual (video) reward, but not from auditory (music) reward, just as in prior results using e-cigarettes. Withdrawal relief from NRT was unrelated to reinforced responding, consistent with positive (and not negative) reinforcement from this nicotine. Further research evaluating the dose-response effects of nicotine may clarify differences in enhanced reinforcement depending on the type of available reward.

Sex Differences in Subjective Responses To Moderate Versus Very Low Nicotine Content Cigarettes.

Introduction: Men and women may be differentially sensitive to the acute perceptual responses to smoking cigarettes that vary in nicotine content ("dose") but are matched on non-nicotine constituents. Methods: Dependent adult smokers (43 M, 31 F) took four controlled puffs from Spectrum research cigarettes that were moderate (16-17 mg/g) or very low (0.4 mg/g) in nicotine content, and matched on "tar." To ensure reliable responses, each cigarette was administered singly five times in random order under blind conditions, with one or the other provided every 15 minutes over a 2.5-hour session following overnight abstinence. Subjective perceptions (eg, "satisfying", "how much nicotine") were rated after each cigarette. Results: Subjective ratings differed due to cigarette nicotine content, as expected, and did so differentially between men and women. The interaction of nicotine content by sex was significant for most rated subjective perceptions of the cigarette, as multivariate analyses showed that differences due to nicotine content were highly significant for men (p < .001) but only marginal for women (p = .08). Conclusions: Relative to men, women's subjective responses to acute smoking are less sensitive to differences in cigarette nicotine content. To our knowledge, this is the first comparison of sex differences in response to very carefully controlled doses of smoked nicotine per se. Further research should examine possible sex differences in nicotine dosing administered by other smoked and nonsmoked methods, as well as the developmental pattern of these differences during onset and during cessation of dependent smoking. Implications: Subjective perceptions of smoking cigarettes varying in nicotine contents differ between men and women. These results with research cigarettes are similar to other studies with carefully dosed nicotine administration by other means, supporting the notion that women, relative to men, are less sensitive to pharmacological factors and more sensitive to nonpharmacological factors in acute cigarette smoking. Future studies are warranted to examine sex differences in other responses to controlled nicotine intake via smoking, and via other smoked and nonsmoked methods of administering nicotine doses.

Validating Use of Internet-Submitted Carbon Monoxide Values by Video to Determine Quit Status.

INTRODUCTION: Daily visits to biochemically verify continuous smoking abstinence via expired-air carbon monoxide (CO) may deter participation in cessation trials. One way to reduce need for daily visits while continuing to monitor abstinence success may be use of a recent procedure to verify abstinence from daily CO values via the Internet. This method requires participants submit to study staff video recordings of themselves correctly using a CO monitor. However, it has not been clearly demonstrated that those classified quit via Internet-submitted videos of CO would be reliably classified quit when assessed in lab. METHODS: Our study examined agreement in quit status from Internet-submitted CO values with quit status via CO collected in later same-day lab visits. Participants (n = 23) were from a short-term cessation study who agreed to record and submit videos of offsite CO testing, in addition to attending daily lab visits. All CO values were obtained via Bedfont pico+ Smokerlyzer monitors, with CO < 8 ppm indicating quit. During two 4-day practice quit attempts, a video was submitted before daily lab visits, up to eight videos each. RESULTS: Of the total of 150 videos submitted, 97 videos indicated "not quit" and 53 "quit." Cohen's Kappa indicated substantial agreement in quit status between assessments, 0.70, p < .001, as 85% of the videos indicating "quit" CO were also "quit" CO in lab. CONCLUSIONS: To our knowledge, these results are the first validation of daily Internet-submitted CO values to confirm daily quit status, supporting the utility of this approach for close monitoring of continuous abstinence. IMPLICATIONS: This study compared consistency between quit status from CO values submitted over the Internet and quit status via CO collected in later same-day lab visits. Findings indicate substantial agreement in quit status between these two methods of CO assessment. Our results validate the use of Internet-submitted CO values to verify daily quit status. This method can be used in future cessation trials as a means to biochemically validate continuous abstinence without the burden of daily lab visits or relying on self-report of recent smoking lapses.

Sex differences in acute relief of abstinence-induced withdrawal and negative affect due to nicotine content in cigarettes.

INTRODUCTION: Acute cigarette smoking may relieve withdrawal and negative affect due to tobacco abstinence to a greater extent in women versus men. Yet, the relative contribution of the cigarette's nicotine content to this sex difference is not clear. METHODS: Non-quitting dependent adult smokers (N = 44; 21 males, 23 females) participated in 2 virtually identical sessions, each after abstaining overnight (CO < 10 ppm) and differing only in the nicotine content of the designated cigarette. While blind to brand markings, they consumed a total of 24 puffs in controlled fashion for 2 hr in each session, either from a nicotine (Quest 1, 0.6 mg) or denicotinized (Quest 3, 0.05 mg) cigarette. Withdrawal symptoms were obtained before and after smoking, and negative affect was assessed after each period of cigarette exposure consisting of 6 puffs every 25 min. RESULTS: Men and women did not differ in baseline withdrawal and negative affect due to overnight abstinence, but reductions in each symptom were significantly influenced by the interaction of sex × nicotine/denicotinized cigarette (both p < .05). In men, but not in women, each symptom was generally decreased more by the nicotine versus denicotinized cigarette, and the nicotine cigarette reduced each to a greater degree in men versus women. CONCLUSIONS: Sex differences in relief of abstinence-induced withdrawal and negative affect due to the nicotine content in cigarettes are consistent with prior research indicating that nicotine per se, compared to non-nicotine smoke stimuli, is less rewarding in women versus men.

Do people serve as cues to smoke?

INTRODUCTION: Recent research has identified that the environments in which smoking has previously occurred can alone, in the absence of any explicit smoking stimuli (e.g., cigarettes, lighters), serve as cues that induce robust craving to smoke. The goal of the present study was to determine if people can similarly function as smoking and nonsmoking cues capable of directly affecting smokers' cue-induced craving. METHODS: Smokers (N = 72) borrowed cameras to take photos of the people in their lives around whom they do and do not smoke ("personal" smoking and nonsmoking people, PS and PN, respectively). Self-report and physiological cue reactivity to those photos were compared with smokers' reactivity to photos of people unknown to them ("standard" smoking and nonsmoking people, SS and SN, respectively). RESULTS: Results suggest that the people around whom smokers regularly smoke (PS) can alone function as cues capable of eliciting patterns of reactivity similar to that evoked by proximal and environment smoking cues, namely, increased craving to smoke, negative affect, and excitement. In contrast, the people around whom smokers do not smoke become associated with not smoking (PN) and serve a potential protective function by reducing craving and increasing calm. CONCLUSIONS: This novel investigation and its results have implications for promoting smoking cessation by developing strategies to manage a smoker's social environment.

The first 7 days of a quit attempt predicts relapse: validation of a measure for screening medications for nicotine dependence.

OBJECTIVES: There is a critical need for the development of novel treatments for nicotine dependence. Because the majority of smokers who make a quit attempt fail within 7 days, medication screening procedures that focus on this early cessation period may provide an indicator of treatment efficacy. To establish the clinical validity of this paradigm, it is critical to demonstrate the association of early abstinence with longer-term abstinence. We tested the number of days of abstinence during the first week after the target quit date (TQD) as a predictor of point prevalence abstinence in 3 independent pharmacotherapy trials for nicotine dependence. METHODS: This was a secondary data analysis of 3 randomized clinical trials: a placebo-controlled trial of transdermal nicotine (N = 545); an open-label nicotine replacement therapy (patch vs spray) trial (N = 566); and a bupropion placebo-controlled trial (N = 538). In separate logistic regression models, the maximum number of consecutive days of abstinence during the first week after the TQD was used to predict biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT) and 6 months post-TQD. RESULTS: Across the 3 trials, the number of days of abstinence significantly predicted abstinence at EOT and 6 months (odds ratios > 1.4; Ps < 0.0001). Likewise, not having any lapse during the first week predicted abstinence at EOT and 6 months (odds ratios > 4.7; Ps < 0.0001). CONCLUSIONS: The first week of abstinence was highly predictive of EOT and long-term abstinence. Medication screening procedures that focus on this early abstinence period (ie, 6 or 7 days of consecutive abstinence) represent a valid tool for assessing the presence of a signal for medication efficacy.