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Background: Cigarette smoking is a leading cause of morbidity and mortality. For adults who smoke cigarettes and cannot or will not quit smoking, smoke-free products, such as nicotine pouches, have been recognized as a potential alternative to smoking combusted cigarettes to reduce harm due to cigarette smoking. The role of flavors in these smoke-free products in tobacco harm reduction has not been fully understood., Objective: This study evaluates the effect of flavors in on! nicotine pouch products (research products) in the reduction of cigarette smoking among adults who smoke cigarettes in their natural environment., Methods: This study uses a sequential, multiple assignment, randomized trial design. Approximately 400 eligible adults who smoke cigarettes will be enrolled and randomized to have access to either the Original (unflavored) on! nicotine pouch product only or a complete flavor profile (ie, Berry, Cinnamon, Citrus, Coffee, Mint, Original, and Wintergreen) of on! nicotine pouch products. After 3 weeks, participants in the Original-only arm will be randomized again, with half remaining in the Original-only arm and half having access to the complete flavor profile for another 3 weeks. Primary outcomes are expired-air carbon monoxide (CO) levels. Secondary outcomes are self-reported cigarette consumption and CO-verified cigarette abstinence., Results: Recruitment and data collection started in September 2023 and is projected to last until March 2025. We anticipate completing the data analysis in 2025. As of May 2024, we have enrolled 314 participants., Conclusions: This study will provide empirical evidence about the effect that flavor availability in smoke-free products may have in reducing cigarette smoking., Trial Registration: ClinicalTrials.gov NCT06072547; https://clinicaltrials.gov/study/NCT06072547., International Registered Report Identifier (irrid): DERR1-10.2196/56565., (©Hui G Cheng, Jed E Rose, Joshua L Karelitz, David R Botts, Tanaia L Botts, Perry N Willette, Gal Cohen. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.06.2024.)

Introduction: Smoking is believed partially reinforcing via immediate sensory perceptions. Yet, unknown is whether a cigarette's relative reinforcing efficacy can be predicted by these perceptions and whether this relationship may vary due to constituents known to alter those perceptions., Methods: Sensory perceptions of acute smoking were examined as predictors of subsequent cigarette choice behavior. Also tested was whether nicotine content or menthol affected this relationship. Adult dependent smokers (N = 37) participated in five sessions comparing cigarettes varying in nicotine contents (NIC; 1.3, 2.3, 5.5, 11.2, and 17.4 mg/g), relative to the very lowest nicotine content, 0.4 mg/g (VLNC). Non-menthol (n = 17) and menthol (n = 20) cigarettes-matched on nicotine-were provided based on participant preference. One NIC was compared versus VLNC per session (single-blinded); NIC content order was randomized across sessions on separate days. Perceptions (e.g., "liking", "satisfying") were measured immediately after initial sampling of NIC or VLNC, followed by a validated puff-by-puff choice procedure to determine preference for each NIC versus VLNC., Results: NIC perceptions (difference from VLNC) and puff choices increased with nicotine. Menthol moderated associations between perceptions and nicotine; and between puff choices and nicotine. Perceptions were predictive of puff choice-greater magnitude of difference in perceptions between VLNC and NIC led to more NIC puff choices. When testing perceptions' prediction of puff choices, neither the main effect of menthol or interaction of Perceptions X Nicotine Condition were significant., Conclusions: Consistent with assumed-but rarely tested-causes of smoking reinforcement, sensory perceptions from a cigarette predict its relative reinforcing efficacy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Smoking topography, or puffing behavior, is an important measure of how consumers may use tobacco products. However, numerous issues may prevent collection of this data via in-person, electronic topography device (e.g., CReSS). This study compared cigarette topography measures collected by video observation and electronic device., Methods: Laboratory smoking sessions were video recorded and scored for 96 cigarettes collected from 34 daily, adult non-treatment-seeking smokers (73.5 % male, 82.4 % White). Participants smoked three of their preferred brand cigarettes using an electronic topography device, providing carbon monoxide (CO) samples before and after each cigarette. Analyses compared measures from both assessment methods and examined associations with device-obtained total puff volume and CO boost., Results: Agreement analyses indicated robust similarity between methods for measures of puff count and total interpuff interval (Intraclass Correlation Coefficient [ICC]'s > 0.96,p's < 0.001; Bland-Altman [B-A] plotted differences within a priori limit of clinical significance) but diverged on total duration (ICC's > .93, p's < .001, yet B-A plots outside a priori limits). Regardless of assessment method, total duration and puff count (but not total interpuff interval) predicted total puff volume (p's < .001). None predicted CO boost (p's = .07-.90).", Conclusions: Although some topography outcomes (e.g., total puff volume) cannot be assessed via video observation, video-observed measures of puff count, total duration, and total interpuff interval are generally interchangeable with their topography device-obtained counterparts. Thus, video observation is likely a sufficient substitute method for assessing cigarette topography when using an electronic device is not possible., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Expired-air carbon monoxide (CO) is commonly used to biochemically verify smoking status. The CO cutoff and CO monitor brand may affect the probability of classifying smokers as abstinent, thus influencing conclusions about the efficacy of cessation trials. No systematic reviews have tested this hypothesis. Therefore, we performed a meta-analysis examining whether the likelihood of smoking cessation classification varied due to CO cutoff and monitor brand., Methods: Eligible studies (k = 122) longitudinally assessed CO-verified cessation in adult smokers in randomized trials. Primary meta-regressions separately assessed differences in quit classification likelihood due to continuous and categorical CO cutoffs (Low, 3-4 parts per million [ppm]; [SRNT] Recommended, 5-6 ppm; Moderate, 7-8 ppm; and High, 9-10 ppm); exploratory analyses compared likelihood outcomes between monitor brands: Bedfont and Vitalograph., Results: The likelihood of quit classification increased 18% with each 1 ppm increase above the lowest cutoff (3 ppm). Odds of classification as quit significantly increased between each cutoff category and High: 261% increase from Low; 162% increase from Recommended; and 150% increase from Moderate. There were no differences in cessation classification between monitor brands., Conclusions: As expected, higher CO cutoffs were associated with greater likelihood of cessation classification. The lack of CO monitor brand differences may have been due to model-level variance not able to be followed up in the present dataset. Researchers are advised to report outcomes using a range of cutoffs-including the recommended range (5-6 ppm)-and the CO monitor brand/model used. Using higher CO cutoffs significantly increases likelihood of quit classification, possibly artificially elevating treatment strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Newly available, smartphone-enabled carbon monoxide (CO) monitors are lower in cost than traditional stand-alone monitors and represent a marked advancement for smoking research. New products are promising, but data are needed to compare breath CO readings between smartphone-enabled and stand-alone monitors. The purpose of this study was to (1) determine the agreement between the mobile iCO (Bedfont Scientific Ltd) with two other monitors from the same manufacturer (Micro+ pro and Micro+ basic) and (2) determine optimal, monitor-specific, cotinine-confirmed abstinence cutoff values., Methods: Adult (≥18) smokers (n = 26) and nonsmokers (n = 21) provided three breath CO samples (using three different monitors) in each of 10 sessions, and urine cotinine was measured for gold standard determination of abstinence. CO comparisons (N = 437) were analyzed using regression-based Bland-Altman Analysis of Agreement; receiver operating characteristics curves were used to determine optimal abstinence cutoffs., Results: Bland-Altman analyses indicated that the iCO monitor provided higher CO results than both Micro+ monitors. Sensitivity and specificity analyses showed that the optimal CO cutoff for determining abstinence was <3 ppm for the Micro+ pro (88% sensitivity, 93% specificity) and Micro+ basic (83% sensitivity, 98% specificity), but was higher for the iCO (<6 ppm; 73% sensitivity, 100% specificity)., Conclusions: Relative to both Micro+ monitors, the smartphone-enabled iCO provided systematically higher CO values and required a higher cutoff to reliably determine smoking abstinence. This does not indicate that CO values obtained using the iCO are not valid; instead, these results suggest that monitor-specific abstinence cutoffs are needed to ensure accurate bioverification of smoking status., Implications: Results from this study indicate that CO values from the smartphone-enabled iCO should not be used interchangeably with the stand-alone Micro+ pro and Micro+ basic, particularly when lower CO values (<10 ppm) are critical (ie, determination of abstinence vs confirming smoking status for study inclusion). Optimal CO cutoffs recommended for determining abstinence on Micro+ and iCO monitors are at <3 and <6 ppm, respectively., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cue-elicited craving may vary due to duration of smoking history, increasing as more years of smoking strengthen associations between nicotine intake and cues. However, research on this relationship is virtually absent. This project assessed the relationship between cue reactivity and years of smoking., Methods: Data from 53 studies (68 effect sizes) were analyzed. Eligible studies were those measuring self-reported craving following cue exposure in nontreatment seeking smokers and reporting mean years smoking. Preliminary subgroup analyses identified methodological factors influencing cue-reactivity effect sizes; primary meta-regression analysis assessed differences across years smoking; exploratory analyses assessed potential for ceiling effects., Results: Effect sizes varied due to abstinence requirement and cue presentation modality, but not dependence severity. Unexpectedly, meta-regression analysis revealed a decline in effect sizes across years smoking. Exploratory analyses suggested declines may have been due to a ceiling effect in craving measurement for those with longer smoking histories-more experienced smokers reported higher levels of craving at baseline or following neutral cue exposure, but all reported similar levels of craving after smoking cue exposure., Conclusions: Methodological factors and duration of smoking history influenced measurement of cue reactivity. Highlighted were important relationships between years smoking and magnitude of cue reactivity, depending on use of baseline or neutral cue comparisons. Further research is needed to assess differences in cue reactivity due to duration of smoking history using participant-level data, directly testing for ceiling effects. In addition, cue-reactivity studies are needed across young adults to assess onset of associations between nicotine intake and cues., Implications: This meta-analysis project contributes to the cue-reactivity literature by reporting on the previously ignored relationship between duration of smoking history and magnitude of cue-elicited craving. Results suggest that declines in cue-reactivity effect sizes across years of smoking may have been due to study-level methodological factors, but not due to differences in sample-level dependence severity. Cue-reactivity effect sizes were stable across years of smoking in studies using a neutral cue comparison but declined sharply in studies when baseline assessment (typically coupled with an abstinence requirement) was used., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: The smallest difference in nicotine that can change a smoker's cigarette preference is not clearly known., Objective: A procedure to efficiently identify the difference in nicotine needed to change cigarette preference could help inform research to gauge effects of a nicotine reduction policy., Methods: Using a within-subject design, we assessed preference for research cigarettes varying in nicotine contents (NIC; 18.7, 10.8, 5.3, 2.3, and 1.3 mg/g of tobacco), relative to a very low nicotine cigarette (VLNC; 0.4 mg/g), in 17 adult-dependent non-menthol smokers abstinent overnight. Only one NIC was compared vs. the VLNC per session, with order of the five NIC contents randomized across sessions on five separate days. Preference for each NIC vs. VLNC was determined by validated forced choice procedure, with those NIC chosen more than VLNC indicating greater reinforcement due to greater nicotine per se. Secondarily, less preference for lower NIC (vs. VLNC), relative to choice for the highest NIC, 18.7 mg/g (vs. VLNC), indexed reduced reinforcement., Results: Overall, NIC choices increased as their nicotine increased, as anticipated. Relative to the 0.4 mg/g VLNC, choice was greater for NIC ≥ 5.3 mg/g but not ≤ 2.3 mg/g. Correspondingly, relative to choice for 18.7 mg/g, choice was less for NIC ≤ 2.3 mg/g but not ≥ 5.3 mg/g., Conclusions: Although replication with larger samples and longer access is needed, results indicate that nicotine reduction to ≤ 2.3 mg/g in cigarettes would attenuate reinforcement. This choice procedure may efficiently inform future clinical trials to assess relative reinforcing effects of smoking reduced nicotine cigarettes.

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., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding variability in smoking patterns may inform smoking cessation interventions. Retrospective reports of cigarettes smoked per day may be biased and typically do not provide temporal precision regarding when cigarettes are smoked. However, real-time, user-initiated tracking, such as logging each time a cigarette is smoked, can be burdensome over long time frames. In this study, adult, non-treatment seeking daily smokers (N = 22) used an electronic, smart lighter to light and timestamp cigarettes for 14 days. Participants reported number of cigarettes smoked per day (CPD) via a mobile device (daily diary) and retrospectively reported CPD at the end of the study using the Timeline Followback (TLFB). Self-reported lighter satisfaction and adherence varied with 68% of participants reporting that they liked using the lighter and participants reporting using the lighter for 92% of cigarettes smoked, on average. Lighter-estimated CPD did not differ from daily diary-estimated CPD, but was significantly lower than TLFB estimates. The lighter resulted in greater day-to-day variability relative to other methods and fewer rounded cigarette counts (digit bias) relative to the TLFB. The lighter appears to be feasible for capturing data on smoking patterns in daily smokers. Though false positive cigarettes are likely low, additional technologies that augment data captured from the lighter may be necessary to reduce false negatives (missed cigarettes) and alternative lighter designs may appeal more to certain smokers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Marketing claims often have promoted specific perceptions that users should expect from acutely smoking that cigarette brand. Yet, little controlled study has determined the degree to which actual perceptions are based on the cigarette's tobacco constituents in the absence of knowledge about the brand's identity., Methods: 194 adult dependent smokers rated their perceptions on 'liking', 'satisfying', 'strong' and perceived amount of 'nicotine' after smoking ad lib one of their preferred brands of cigarettes. All did so either when blinded (n=118) or unblinded (n=76) to the brand they were given, with the blinding conditions from separate studies. These between-groups secondary analyses determined differences in perceptions based on blinding to brand, controlling for age and cigarettes/day., Results: All perceptions were lower for those smoking own brand under blinded versus unblinded conditions, as hypothesised. Consistent with lowered perceptions for smoking one's own brand obtained from the 118 blinded to brand, their 'somewhat' ratings for a 'how similar to own brand' item indicated uncertainty, just mid-way between 'not at all' and 'very much' on the 0-100 visual analogue scale. (The 76 unblinded were already informed it was their own brand.) CONCLUSIONS: Acute perceptions of one's own cigarette are substantially lower when smokers are simply unaware of brand, relative to those aware it is their preferred brand. Results support the notion that perceptions of smoking own brand are enhanced by marketing efforts to associate brands with expectations of pleasurable subjective effects, beyond the impact due solely to the cigarette's manufactured product constituents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Behavioral discrimination of nicotine has only recently been assessed in humans, administered mostly by nasal spray before the newly available Spectrum research cigarettes differing in nicotine content. Here we wanted to explore applicability of these procedures to assess discrimination of nicotine administered by e-cigarettes., Methods: In this feasibility study, 16 adult smokers were tested on ability to discriminate e-cigarettes with nicotine concentrations of 36, 24, and 12 mg/ml, one per session (in that order), from a placebo (0 mg/ml), each identified only by letter code. Reliable discrimination was defined by accurately identifying which was which (i.e. nicotine vs placebo) on >85% of trials (i.e. ≥7 of 8; p < .05). Subjective perceptions were also assessed., Results: Discrimination from placebo was shown with 36 mg/ml and with 24 mg/ml nicotine in 15 of 16 subjects, but only 10 discriminated placebo from 12 mg/ml nicotine. Subjective items previously related to acute nicotine exposure ("how much nicotine", "head rush/buzzed" on 0-100 VAS) generally showed nicotine concentration-dependent effects, as expected, but so did "throat irritation"., Conclusions: Preliminary results confirm feasibility of using our behavioral procedure to assess ability to discriminate nicotine administered via these e-cigarettes, broadening generalizability of this procedure beyond nicotine via nasal spray and smoked tobacco cigarettes. Findings also suggest its applicability with testing discrimination of nicotine via other methods of rapid dosing (e.g., hookah, novel products), including the newer e-cigarette products. Further study with larger samples may identify individual difference and other factors influencing nicotine discrimination administered via e-cigarettes and other products., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

Background: The effectiveness of nonconsummatory reinforcers habituate, as their ability to maintain reinforced responding declines over repeated presentations. Preclinical research has shown that nicotine can delay habituation of reinforcer effectiveness, but this effect has not been directly demonstrated in humans., Objective: In preliminary translational research, we assessed effects of nicotine from tobacco smoking (vs. a no smoking control) on within-session patterns of responding for a brief visual reinforcer., Methods: Using a within-subjects design, 32 adult dependent smokers participated in two experimental sessions, varying by smoking condition: no smoking following overnight abstinence (verified by CO ≤ 10 ppm), or smoking of own cigarette without overnight abstinence. Adapted from preclinical studies, habituation of reinforcer effectiveness was assessed by determining the rate of decline in responding on a simple operant computer task for a visual reinforcer, available on a fixed ratio schedule., Results: Reinforced responding and duration of responding were each significantly higher in the smoking vs. no smoking condition. The within-session rate of responding declined significantly more slowly during the smoking vs. no smoking condition, consistent with delayed habituation of reinforcer effectiveness. Follow-up analyses indicated that withdrawal relief did not influence the difference in responding between conditions, suggesting the patterns of responding reflected positive, but not negative, reinforcement., Conclusions: These results are a preliminary demonstration in humans that smoked nicotine may attenuate habituation, thereby maintaining the effectiveness of a reinforcer over a longer period of access. Further research is needed to confirm habituation and rule out alternative causes of declines in within-session responding.

Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject cross-over design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases. Treatments were the α7 nicotinic receptor PAM JNJ-39393406 (100 mg b.i.d.) or placebo (double-blind, counter-balanced). In each phase, all smoked ad lib with no drug on week 1 or during dose run-up on week 2, and then tried to quit every day during week 3. Abstinence (confirmed by CO <5 p.p.m.) and smoking reduction (CO <8), as well as cigarettes/day (in Study 1), were assessed daily (Monday-Friday) each quit week and compared between conditions. Secondary outcomes included abstinence symptoms (withdrawal and craving) and cognitive test responding (N-back; continuous performance task). In both studies, compared with placebo, active JNJ-39393406 did not increase the number of abstinent days nor reduce total smoking exposure. We also found no significant improvements in craving, withdrawal, or cognitive function. With this dose and study duration, our findings do not support further testing of this α7 nAChR PAM compound for possible efficacy in smoking cessation, in smokers with or without schizophrenia.

Subjective perceptions and self-administration of cigarettes are each influenced by nicotine. Yet, differences specifically due to menthol in perceptions and choice of cigarettes varying in nicotine, and the association between these responses, have not been directly tested. Using a mixed between- and within-subjects design, acute responses to each of two menthol or non-menthol Spectrum research cigarettes, moderate (16-17 mg/g) versus very low (0.4 mg/g) in nicotine contents, were compared following brief abstinence in adult smokers preferring menthol ( n=44) or non-menthol ( n=29) brands. To ensure reliable perceptions, they experienced five exposures to each cigarette, then chose between them. All perceptions and choices were greater for moderate vs very low nicotine, as expected, and the magnitude of difference in four of six perceptions was associated with subsequently greater choice of the moderate nicotine cigarette. Importantly, virtually no differences were found between menthol and non-menthol, as nearly all perceptions, cigarette choices, and the association between perceptions and choice were not moderated by menthol or the interaction of nicotine by menthol. Our results indicate perceptions and reinforcement from cigarettes do not differ due to menthol when nicotine content and smoking topography are carefully controlled. Thus, regardless of menthol, smoking perceptions directly predict self-administration behavior.

Because electronic cigarettes (e-cigs) containing nicotine may relieve smoking abstinence symptoms similar to nicotine replacement therapy medication, we used within-subjects designs to test these effects with a first-generation e-cig in nonquitting and quitting smokers. In Study 1, 28 nontreatment-seeking smokers abstained overnight prior to each of 3 sessions. Minnesota Nicotine Withdrawal Scale (MNWS) withdrawal (and craving item) relief was assessed following 4 exposures (each 10 puffs) over 2 hr to e-cigs that either did (36 mg/ml) or did not (i.e., placebo, 0 mg/ml) contain nicotine or after no e-cig. Relief was greater after nicotine versus placebo e-cig (p < .05) but not after placebo versus no e-cig, showing relief was due to nicotine per se and not simple e-cig use behavior. Using a crossover design in Study 2, smokers preparing to quit soon engaged in 2 experimental 4-day quit periods on separate weeks. In weeks 1 and 3, all received a nicotine or placebo e-cig on Monday to use ad libitum while trying to abstain from smoking on Tuesday through Friday. (Week 2 involved resumption of ad libitum smoking.) MNWS and Questionnaire of Smoking Urges (QSU) craving were assessed at daily visits following 24-hr abstinence. Of 17 enrolled, 12 quit for ≥24 hr at least once, allowing test of relief because of e-cig use on quit days. Withdrawal and craving were reduced because of nicotine versus placebo e-cig use (both p < .05). In sum, compared with placebo e-cigs, nicotine e-cigs can relieve smoking abstinence symptoms, perhaps in a manner similar to Food and Drug Administration-approved nicotine replacement therapy products, although much more research with larger samples is needed. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

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., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The current study examined the level of agreement in expired-air carbon monoxide (CO) values, focusing especially on those confirming abstinence, between the two most commonly used CO monitors, the Vitalograph BreathCO and the Bedfont piCO+ Smokerlyzer., Methods: Expired-air samples were collected via both monitors from adult dependent smokers (44 M, 34 F) participating in studies using CO values to confirm abstinence durations of: 24 hours, 12 hours, or no abstinence. All met DSM-IV nicotine dependence criteria and had a mean (SD) Fagerström Test of Cigarette Dependence score of 5.1 (1.8). Paired data collected across multiple visits were analyzed by regression-based Bland-Altman method of Limits of Agreement., Findings: Analysis indicated a lack of agreement in CO measurement between monitors. Overall, the Bedfont monitor gave mean (±SEM) readings 3.83 (±.23) ppm higher than the Vitalograph monitor. Mean differences between monitors were larger for those ad lib smoking (5.65±.38 ppm) than those abstaining 12-24 hours (1.71±.13 ppm). Yet, there also was not consistent agreement in classification of 24 hour abstinence between monitors., Conclusions: Systematic differences in CO readings demonstrate these two very common monitors may not result in interchangeable values, and reported outcomes in smoking research based on CO values may depend on the monitor used., Competing Interests: CONFLICT OF INTERESTS The authors do not have any financial interests in either of the CO monitor companies discussed in this paper. None of the authors have any other potential conflicts of interest to report.

Background: Despite its potential for understanding tobacco dependence, behavioral discrimination of nicotine via smoking has not been formally examined as a function of nicotine dependence level., Methods: Spectrum research cigarettes were used to compare non-dependent with dependent smokers on the lowest content of nicotine they could discriminate (i.e., "threshold"). Dependent (n=21; 16M, 5F) or non-dependent (n=7; 4M, 3F) smokers were tested on ability to discriminate between cigarettes with nicotine contents of 17, 11, 5, 2, and 1mg/g, one per session, from an "ultra-low" cigarette with 0.4mg/g (all had 9-10mg "tar"). All abstained from smoking overnight prior to sessions, and number of sessions was determined by the lowest nicotine content they could reliably discriminate from the ultra-low on >80% of trials (i.e., ≥5 of 6). Subjective perceptions and cigarette choice behavior were also assessed and related to discrimination behavior., Results: Discrimination thresholds (and most perceptions) did not differ between dependent and non-dependent smokers, with median thresholds of 11mg/g for both subgroups. Yet, "liking" and puff choice for threshold cigarettes were greater in dependent but not non-dependent smokers, while cigarettes with nicotine contents below threshold did not support "liking" or choice in both groups., Conclusions: In sum, this preliminary study suggests threshold for discriminating nicotine via smoking may not vary by dependence level, and further study is needed to confirm that cigarettes unable to be discriminated are also not reinforcing., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Preclinical research documents that, aside from the primary and secondary reinforcing effects of nicotine intake itself, nicotine also acutely enhances the reinforcing efficacy of non-drug reinforcers ("rewards"). Study of these effects in humans has largely been overlooked, but very recent findings suggest they may have clinical implications for more fully understanding the persistence of tobacco dependence. This overview first outlines the topic and notes some recent human studies indirectly addressing nicotine effects on related responses (e.g., subjective ratings), explaining why those findings do not directly confirm enhancement of behavioral reinforcement per se due to nicotine. Then, the methodology used in the subsequently presented studies is described, demonstrating how those studies specifically did demonstrate enhancement of reinforced responding for non-drug rewards. The main section focuses on the limited controlled research to date directly assessing nicotine's acute reinforcement-enhancing effects in humans, particularly as it relates to reinforced behavioral responding for non-drug rewards in non-human animal models. After detailing those few existing human studies, we address potential consequences of these effects for dependence and tobacco cessation efforts and then suggest directions for future research. This research indicates that nicotine per se increases responding in humans that is reinforced by some rewards (auditory stimuli via music, visual stimuli via video), but perhaps not by others (e.g., money). These reinforcement-enhancing effects in smokers are not due to dependence or withdrawal relief and can be restored by a small amount of nicotine (similar to a smoking lapse), including from e-cigarettes, a non-tobacco nicotine product. Future clinical research should examine factors determining which types of rewards are (or are not) enhanced by nicotine, consequences of the loss of these nicotine effects after quitting smoking, potential individual differences in these effects, and the possibility that nicotine via nicotine replacement therapy and non-nicotine quit medications may attenuate loss of these effects upon quitting. Further study with humans of nicotine's reinforcement-enhancing effects may provide a more complete understanding of smoking persistence and added mechanisms of cessation medication efficacy.

Rationale: The lowest threshold content (or "dose") of nicotine discriminated in cigarettes may differ due to menthol preference., Objectives: Menthol and non-menthol Spectrum research cigarettes differing in nicotine content were used to determine discrimination thresholds., Methods: Dependent smokers preferring menthol (n = 40) or non-menthol (n = 21) brands were tested on ability to discriminate cigarettes (matched for their menthol preference) with nicotine contents of 16-17, 11-12, 5, 2, and 1 mg/g, one per session, from an "ultra-low" cigarette with 0.4 mg/g. Controlled exposure to each cigarette was four puffs/trial, and the number of sessions was determined by the lowest nicotine content they could discriminate on >80% of trials (i.e., ≥5 of 6). We also assessed subjective perceptions and behavioral choice between cigarettes to relate them to discrimination responses., Results: Controlling for Fagerstrom Test of Nicotine Dependence score, discrimination thresholds were more likely to be at higher nicotine content cigarettes for menthol vs. non-menthol smokers (p < .005), with medians of 16 vs. 11 mg/g, respectively. Compared to the ultra-low, threshold and subthreshold (next lowest) cigarettes differed on most perceptions and puff choice, but menthol preference did not alter these associations. Notably, threshold cigarettes did, but subthreshold did not, increase choice over the ultra-low., Conclusions: Threshold for discriminating nicotine via smoking may be generally higher for menthol vs. non-menthol smokers. More research is needed to identify why menthol smoking is related to higher nicotine thresholds and to verify that cigarettes unable to be discriminated do not support reinforcement.

Introduction: Nicotine's interoceptive stimulus effects likely help explain smoking's reinforcing efficacy, but human studies have been limited by difficulties controlling dosing via tobacco inhalation. Our objective was to describe a procedure to study nicotine discrimination via smoking., Methods: Dependent smokers abstinent overnight (>12 hours) were first "trained" to discriminate between two cigarettes differing in nicotine content, based on four puffs of exposure, and then tested on whether they successfully acquired that discrimination. After piloting with Quest brand commercial cigarettes, 29 subjects engaged in the main study with cigarettes available through NIDA (Spectrum; 16mg vs. 0.4mg nicotine content). Discrimination training first involved two trials, one with each cigarette, prior to six testing trials. Due to results with the first 20 subjects, the remaining nine received two training trials with each cigarette (four total). Subjective perceptions were also assessed during each testing trial, and puff choice between the two cigarettes available concurrently was assessed after testing, on the last two trials., Results: All five pilot subjects successfully discriminated Quest 1 versus Quest 3 (defined by at least five out of six trials correct, ie, >80%). Yet, only 10 of 20 subjects (50%) were able to discriminate the two Spectrum cigarettes based on two training trials. After changing to four training trials, eight of nine subjects were able to discriminate (89%). Subjective perceptions and puff choice differed between cigarettes more in those able versus unable to discriminate them., Conclusions: With sufficient training exposures, smokers can discriminate nicotine between cigarettes differing in nicotine contents., Implications: The interoceptive stimulus effects of nicotine are critical to understanding reinforcement from cigarette smoking behavior. Because of the very recent availability of Spectrum research cigarettes from NIDA, with specific known amounts of nicotine content, the study of nicotine discrimination in humans via cigarette smoking may now be feasible. Our results demonstrate that, with sufficient training, smokers can behaviorally discriminate nicotine from four puffs' exposure between cigarettes differing in nicotine contents. Future research should evaluate human discrimination of nicotine from greater amounts of cigarette smoke exposure, as well as in response to other procedural variations., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Along with its primary and secondary reinforcing effects, nicotine acutely enhances reinforcement from rewards not directly related to nicotine, particularly those consisting of "sensory" stimuli. Less certain is the magnitude of these effects across types of sensory reinforcers commonly available in the natural environment, especially under different smoking exposure conditions of clinical relevance. This study compared reinforced responding for immediate auditory (music) or visual (video) sensory rewards, or no reward (nonspecific control), due to nicotine via ad lib smoking versus no nicotine (overnight abstinence), in a within-subjects design. Dependent smokers (N = 48; 21 male, 27 female) responded on an operant computer task for small units of the designated rewards during 2 sessions, following overnight abstinence (>12 hr; CO ≤ 10 ppm) or no abstinence (i.e., ad lib smoking). Preferred music and video rewards were each selected by participants to ensure their equal initial reinforcing efficacy. Responding reinforced by music and by video rewards, but not by no reward, was similarly enhanced by ad lib smoking in the entire sample. Yet, in post hoc follow-ups, the smoking-induced increase in responding for music was greater in women versus men, while the increase in responding for video was greater in men versus women. Results confirm the comparability of the reinforcement enhancing effects of nicotine via smoking on both auditory and visual rewards, consistent with the notion that enhanced sensory reinforcement may contribute to persistence of smoking behavior. However, findings also suggest the specific pattern of sensory reinforcers enhanced by nicotine may differ between men and women. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Rationale: The lowest nicotine threshold "dose" in cigarettes discriminated from a cigarette containing virtually no nicotine may help inform the minimum dose maintaining dependence., Objectives: Spectrum research cigarettes (from NIDA) differing in nicotine content were used to evaluate a procedure to determine discrimination thresholds., Methods: Dependent smokers (n = 18; 13 M, 5 F) were tested on ability to discriminate cigarettes with nicotine contents of 11, 5, 2.4, and 1.3 mg/g, one per session, from the "ultralow" cigarette with 0.4 mg/g, after having discriminated 16 mg/g from 0.4 mg/g (all had 9-10 mg "tar"). Exposure to each was limited to 4 puffs/trial. All subjects were abstinent from smoking overnight prior to each session, and the number of sessions was determined by the participant's success in discrimination behavior on >80 % of trials. Subjective perceptions and behavioral choice between cigarettes were also assessed and related to discrimination behavior., Results: The median threshold was 11 mg/g, but the range was 2.4 to 16 mg/g, suggesting wide variability in discrimination threshold. Compared to the ultralow, puff choice was greater for the subject's threshold dose but only marginal for the subthreshold (next lowest nicotine) cigarette. Threshold and subthreshold also differed on subjective perceptions but not withdrawal relief., Conclusions: Under these testing conditions, threshold content for discriminating nicotine via cigarettes may be 11 mg/g or greater for most smokers, but some can discriminate nicotine contents one-half or one-quarter this amount. Further study with other procedures and cigarette exposure amounts may identify systematic differences in nicotine discrimination thresholds.

Introduction: Primate and rodent models show that peroxisome proliferator-activated receptor-alpha (PPAR-α) ligands, including fibrate medications, reduce nicotine reinforcement, reward, and related effects. We tested fenofibrate, the most common U.S. Food and Drug Administration-approved fibrate for lipid control versus placebo for initial evidence of efficacy in smoking cessation using a validated cross-over procedure for early Phase 2 evaluations., Methods: Adult dependent smokers (N = 38) in this 4-week within-subjects study were those already intending to try to quit in the next 2 months. All smoked ad libitum during weeks 1 (baseline) and 3 (washout) and began fenofibrate (160 mg/d; dosing approved for lipid control) or placebo near the end of weeks 1 and 3. Following each 4-day dose run-up, they were then instructed to try to quit for 4 days (Tuesday-Friday) during weeks 2 and 4, with the order of medication conditions counter-balanced and administered double-blind. Abstinence was verified daily in each 4-day quit period by self-report of no smoking in the prior 24 hours and carbon monoxide < 5 ppm. Secondary measures of acute smoking reinforcement and cue reactivity prior to quitting, and smoking reduction when trying to quit, were also assessed., Results: No differences between fenofibrate versus placebo were found on days quit (means ± SEM of 1.8±0.3 vs. 1.9±0.3, respectively). Similarly, there were no differences in any of the secondary measures (all P > .20)., Conclusions: Although higher dosing or other proliferator-activated receptor-alpha agonists may show efficacy, this study indicates that fenofibrate does not aid ability to stop smoking during a brief practice quit period in dependent smokers high in current quit interest., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Recent human studies confirm animal research showing that nicotine enhances reinforcement from rewards unrelated to nicotine. These effects of acute nicotine via tobacco smoking may also occur when consumed from non-tobacco products., Methods: We assessed acute effects of nicotine via electronic cigarettes ("e-cigarettes") on responding reinforced by music, video, or monetary rewards, or for no reward (control). In a fully within-subjects design, adult dependent smokers (N=28) participated in three similar experimental sessions, each following overnight abstinence (verified by CO≤10ppm). Varying only in e-cigarette condition, sessions involved controlled exposure to a nicotine (labeled "36mg/ml") or placebo ("0″) e-cigarette, or no e-cigarette use. A fourth session involved smoking one's own tobacco cigarette brand after no abstinence, specifically to compare responses under typical nicotine satiation with these acute e-cigarette conditions after abstinence., Results: Reinforced responding for video reward, but not the other rewards, was greater due to use of the nicotine versus placebo e-cigarette (i.e., nicotine per se), while no differences were found between the placebo e-cigarette and no e-cigarette conditions (i.e., e-cigarette use per se). For nicotine via tobacco smoking, responding compared to the nicotine e-cigarette was similar for video but greater for music, while both video and music reward were enhanced relative to the non-nicotine conditions (placebo and no e-cigarette)., Conclusions: Acute nicotine from a non-tobacco product has some reinforcement enhancing effects in humans, in a manner partly consistent with nicotine via tobacco smoking and perhaps contributing to the rising popularity of nicotine e-cigarette use., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

As has been found in nicotine research on animals, research on humans has shown that acute nicotine enhances reinforcement from rewards unrelated to nicotine intake, but this effect may be specific to rewards from stimuli that are "sensory" in nature. We assessed acute effects of nicotine via smoking on responding for music or video rewards (sensory), for monetary reward (nonsensory), or for no reward (control), to gauge the generalizability of nicotine's reinforcement-enhancing effects. Using a fully within-subjects design, dependent smokers (N = 20) participated in 3 similar experimental sessions, each following overnight abstinence (verified by carbon monoxide <10 ppm) and varying only in the smoking condition. Sessions involved no smoking or smoking "denicotinized" ("denic;" 0.05 mg) or nicotine (0.6 mg) Quest brand cigarettes in controlled fashion prior to responding on a simple operant computer task for each reward separately using a progressive ratio schedule. The reinforcing effects of music and video rewards, but not money, were significantly greater due to the nicotine versus denic cigarette (i.e., nicotine per se), whereas there were no differences between denic cigarette smoking and no smoking (i.e., smoking behavior per se), except for no reward. These effects were not influenced by withdrawal relief from either cigarette. Results that generalize from an auditory to a visual reward confirm that acute nicotine intake per se enhances the reinforcing value of sensory rewards, but its effects on the value of other (perhaps nonsensory) types of rewards may be more modest., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Background: Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse., Methods: Smokers (N=24) with high quit interest were recruited for within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO<10 ppm) on the first day of each quit attempt, while on bupropion and on placebo., Results: Compared to placebo, bupropion after abstinence improved correct response times for working memory (p=.01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p<.05)., Discussion: Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim: It is important to find economical methods in early Phase 2 studies to screen drugs potentially useful to aid smoking cessation. A method has been developed that detects efficacy of varenicline and nicotine patch. This study aimed to evaluate whether the method would detect the efficacy of bupropion and identify correctly the lack of efficacy of modafinil., Design: Using a within-subject double cross-over design, smokers attempted to quit during each treatment, with bupropion (150 mg b.i.d.), modafinil [100 mg twice daily (b.i.d.)] or placebo (double-blind, counterbalanced order). In each of three medication periods, all smoked with no drug on week 1 (baseline or washout), began dose run-up on week 2, and tried to quit every day during week 3., Setting: A university research center in the United States., Participants: Forty-five adult smokers high in quit interest., Measurements: Abstinence was verified daily each quit week by self-report of no smoking over the prior 24 hours and carbon monoxide (CO) < 5 parts per million., Findings: Compared with placebo, bupropion did (F(1,44)  = 6.98, P = 0.01), but modafinil did not (F(1,44)  = 0.29, P = 0.60), increase the number of abstinent days. Also, bupropion (versus placebo) significantly increased the number of those able to maintain continuous abstinence on all 5 days throughout the quit week (11 versus four), Z = 2.11, P < 0.05, while modafinil did not (six)., Conclusions: Assessing days abstinent during 1 week of use of medication versus placebo in a cross-over design could be a useful early Phase 2 study design for discriminating between medications useful versus not useful in aiding smoking cessation., (© 2013 Society for the Study of Addiction.)

Background: Nicotine's acute effects on enhancing reinforcement from sensory rewards, shown in animal models, appear to occur with smoking in humans. These effects may vary due to reinforcer magnitude and amount of acute smoke intake (dose)., Methods: In a fully within-subjects design, dependent smokers (n=23) participated in 3 sessions. Each session followed overnight abstinence and involved 4 trials to assess responding via progressive ratio (PR 50%) for sensory reinforcement from high, moderate, or low preference music, or no reward (counter-balanced, 30-s/reinforcer). Sessions differed in smoking prior to each trial: 8 puffs on arrival and 2 puffs/trial ("8+2″), 2 puffs/trial only ("0+2″), or no smoking. Puffs were consumed via CReSS (Clinical Research Support System) to control topography, and smoking involved own brand to ensure palatability and increase generalizability of results., Results: Reinforced responding was influenced by main effects of smoking condition (p<.05) and music reward type (p<.001). Compared to no smoking, responding for music was increased after smoking 8+2/trial puffs (p<.005), but not after 0+2/trial puffs. Smoking condition significantly increased reinforced responding only for the high preference music (p=.01), and not for moderate or low preference music, or for no reward. Withdrawal did not differ between the two smoking sessions, ruling out withdrawal relief as an explanation for differential reinforcement enhancement., Conclusions: Our findings confirm that just one cigarette after abstinence is sufficient for reinforcement enhancing effects and suggest that such enhancement is greater as magnitude of a reward's reinforcing efficacy increases., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Self-reported cigarettes per day (CPD) is a very common screening as well as dependent or independent measure in clinical and nonclinical research on smoking, but the consistency of CPD across days in dependent smokers is uncertain. Adult dependent smokers (N = 357; 170 men, 187 women) retrospectively reported "usual" CPD at screening and then prospectively self-monitored CPD on 3 consecutive days of 1 week during an ad libitum baseline period. Participants were those recruited for later tests of brief medication effects in those with high (n = 170) versus low (n = 187) interest in quitting smoking soon (within 3 months). Consistency was determined by intraclass correlation (ICC). Prospective daily CPD was generally consistent (ICC = 0.78, 95% CI of 0.74-0.81), but CPD changed (increased or decreased) by 5 cigarettes/day or more in 40% of participants and by at least 10/day in 10%. Consistency in CPD was greater in higher dependent smokers and in women with low (vs. high) quit interest, but consistency tended to be greater in men with high (vs. low) quit interest. Although retrospectively reported CPD at screening was consistent with the overall mean for prospectively monitored daily CPD, 15% of participants differed by at least 5/day between methods, and digit bias was twice as likely with retrospective versus prospective CPD, which was at chance levels. Understanding variability in CPD may improve knowledge of dependence and factors that foster or discourage daily smoking amount, but precise assessment of daily CPD likely requires prospective monitoring., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Rationale: In animals, nicotine enhances reinforcement from stimuli unrelated to nicotine intake. Human research is suggestive but has not clearly shown a similar influence of nicotine., Objectives: We assessed acute effects of nicotine via smoking on enhancement of positive (money, music) or negative (termination of noise) reinforcers, or no "reward" (control). These different rewards determined the generalizability of nicotine effects., Materials and Methods: Dependent (n = 25) and nondependent (n = 27) smokers participated in three sessions, each after overnight abstinence. Using a within-subjects design, sessions involved no smoking or smoking denicotinized (0.05 mg) or nicotine (0.6 mg) Quest(R) brand cigarettes. For comparison, a fourth session involved no abstinence prior to smoking one's own brand to gauge responses under typical nicotine satiation. Reinforcement was assessed by responses on a simple operant computer task for the rewards, each available singly on a progressive ratio schedule during separate trials., Results: The reinforcing effect of music, but not other rewards, was greater due to the nicotine cigarette, compared to the denicotinized cigarette or no smoking. Reinforcement enhancing effects of nicotine did not differ between dependent and nondependent groups, indicating no influence of withdrawal relief. Responding due to acute nicotine after abstinence was very similar to responding to one's own brand after no abstinence., Conclusions: Acute nicotine intake per se from smoking after abstinence enhances the reinforcing value of rewards unassociated with smoking, perhaps in a manner comparable to ad lib smoking after no abstinence. Nicotine's reinforcement enhancing effects may be specific to certain rewards, perhaps those sensory in nature.

Introduction: Due to a drop in nicotine, smoking cessation may attenuate reinforcement from sensory stimuli unrelated to nicotine intake. Recent rodent research suggests that bupropion may reverse this attenuation, perhaps helping explain its efficacy in aiding cessation., Methods: In a within-subjects, crossover study, smokers responded on a simple computer task for brief music reward available on a progressive ratio 50% schedule. Testing was done on three separate occasions: after ad lib smoking during prequit baseline and on the first day of two brief quit attempts while taking bupropion or placebo, in counter-balanced order. Number of operant responses was the measure of reinforcement. To more clearly assess abstinence and medication effects, those meeting 24-hr abstinence criteria (CO < 5 ppm; n = 5) or clearly failing to abstain (CO > 10 ppm; n = 5) during both medication conditions were compared., Results: Among abstainers, repeated measures ANOVA showed that reinforced responding decreased by nearly 50% from baseline after quitting on placebo (p = .03), while responding after quitting on bupropion was similar to that during baseline (-17%; p = .20). In contrast, those unable to abstain showed virtually identical reinforced responding due to either medication or baseline., Conclusions: These exploratory findings confirm that responding for a reward unrelated to smoking decreases after abstinence and are consistent with animal research showing bupropion effects on enhancing reinforced responding.

Introduction: Smoking cessation is typically verified biochemically by expired-air carbon monoxide (CO) levels below 9 ppm (i.e., ≤8 ppm), but this CO criterion may lead many who have smoked within 24hr to be misclassified as abstinent., Methods: Adult dependent smokers (N = 261; 124 men, 137 women) prospectively recorded each cigarette smoked and provided CO on five consecutive days during each of two short-term attempts to quit smoking. Participants were those recruited for crossover tests of the effects of placebo versus medication (nicotine patch or varenicline) on the ability to initiate 24-hr abstinence. All had either a high or low interest in permanently quitting smoking soon (within 3 months) and were randomized to the presence or absence of daily ($12) monetary reinforcement of abstinence., Results: Total accuracy of sensitivity to detect smoking (83%) plus specificity to verify abstinence (87%) was optimal at a CO criterion for abstinence below 5 ppm (≤4 ppm), compared with below 9 ppm (sensitivity of 60%, specificity of 97%). Overall CO detection of sensitivity and specificity was higher in those with high versus low quit interest, but reinforcement of abstinence made no difference., Conclusions: Results indicate a CO criterion half that used in most clinical research may optimally validate 24-hr cessation and reduce misclassification of smokers as "abstinent."

Negative mood situations increase craving to smoke, even in the absence of any tobacco deprivation (e.g. "stressors"). Individual differences in effects of negative mood situations on craving have received relatively little attention but may include variability between men and women. Across two separate within-subjects studies, we examined sex differences in craving (via the QSU-brief) as functions of brief smoking abstinence (versus satiation; Study 1) and acute induction of negative mood (versus neutral mood; Study 2). Subjective ratings of negative affect (via the Mood Form) were also assessed. In Study 1, we compared the effects of overnight (>12h) abstinence versus non-abstinence on craving and affect in adult male (n=63) and female (n=42) smokers. In Study 2, these responses to negative versus neutral mood induction (via pictorial slides and music) were examined in male (n=85) and female (n=78) satiated smokers. Results from each study were similar in showing that craving during the abstinence and negative mood induction conditions was greater in women than men, as hypothesized, although the sex difference in craving due to abstinence was only marginal after controlling for dependence. Craving was strongly associated with negative affect in both studies. These results suggest that very acute negative mood situations (e.g. just a few minutes in Study 2), and perhaps overnight abstinence, may increase craving to smoke to a greater extent in women relative to men., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Negative mood situations often increase smoking behavior and reward, effects that may be greater among women and smokers low in tolerance for distress., Methods: Adult dependent smokers (N = 164; 86 men, 78 women) first completed measures of distress tolerance via self-report and by mirror-tracing and breath-holding tasks. They then participated in 2 virtually identical laboratory sessions, involving induction of negative versus neutral mood (control) via pictorial slides and music. They rated negative affect (NA) before and during mood induction and smoked their preferred brand ad libitum during the last 14 min of mood induction. Our aim was to examine mood effects on NA, smoking reward ("liking"), and smoking intake (puff volume and number) as a function of sex and distress tolerance., Results: Negative mood induction increased NA, as planned, and smoking reward and intake compared with neutral mood. Increases in NA and puff volume due to negative mood were greater in women compared with men, as hypothesized, but no main effects of the self-report or behavioral distress tolerance measures were seen in responses to mood induction. However, unexpectedly, lower self-reported distress tolerance was associated with greater smoking intake due to negative (but not neutral) mood in men and generally due to neutral (but not negative) mood in women., Conclusions: Negative mood may increase smoking intake more in women compared with men. Yet, low distress tolerance may enhance smoking intake due to negative versus neutral mood differentially between women and men, suggesting that sex and distress tolerance may interact to influence smoking responses to negative mood.

Smoking behavior may be more persistent among those who expect that smoking will relieve negative affect (NA). Assessing smoking expectancies temporally close to mood situations could enhance the predictive value of that assessment. Dependent smokers (n = 71; 43 male, 28 female) participated in five laboratory sessions, each involving mood induction. The NA relief scale of the Smoking Consequences Questionnaire-Adult (SCQ-A), a very common measure of smoking expectancies during hypothetical situations, was assessed during initial screening. The SCQ-A was compared with a modified acute version administered each session, in which items asked about immediate expectancy for NA relief by smoking "right now" (termed Immediate Negative Affect Relief, or INAR). Actual NA relief due to smoking was measured each session by change on the NA scale of the Diener & Emmons Mood Form. The five sessions (counterbalanced) involved three different negative mood tasks, the negative mood condition of overnight smoking abstinence, and neutral mood (control). Generalized estimating equations showed that temporal proximity to the mood situation slightly enhanced the ability of expectancy to predict actual change in NA due to smoking, as the interaction with condition was significant for the INAR but marginal for the SCQ-A. However, the acute INAR predicted NA relief due to smoking only after overnight smoking abstinence and not during the other specific mood induction conditions, contrary to expectations, while the SCQ-A was not significant during any of the individual conditions. In sum, assessment of expectancy for NA relief may be of limited use in predicting actual NA relief from smoking during a current mood situation, aside from NA due to overnight abstinence.

Introduction: Acute smoking behavior (i.e., puff topography) and subjective responses during the ad lib smoking of a single cigarette in the laboratory may provide useful measures of smoking reinforcement and reward, respectively. However, the reliability of such measures is not clear, leaving uncertain the utility of a single assessment of smoking behavior as an individual difference measure., Methods: Dependent smokers (N = 94) smoked normally prior to each of 4 laboratory sessions during which they were instructed to smoke 1 cigarette of their preferred brand in ad libitum and unblinded fashion and then rate it for subjective effects. Puff topography (puff number, total volume, and maximum volume) was assessed via portable Clinical Research Support System device. Subjective reward and perception were assessed by visual analog scales of "liking" and "how strong," respectively. The reliability of puff topography and subjective measures was determined across days by intra-class correlations (ICCs). Differences due to sex and nicotine dependence (high and low Fagerström Test for Nicotine Dependence score) were also examined., Results: Reliability was highly significant for each measure. ICCs were .70 for total puff volume, .60 for maximum puff volume, .73 for puff number, .64 for liking, and .78 for how strong. Reliability generally did not differ by sex or dependence, but absolute values for total volume and maximum puff volume were greater in men and in high dependent smokers. Liking was also greater in high dependent smokers., Conclusions: Puff topography and subjective measures during the ad lib smoking of a single cigarette are highly reliable. Smoking responses during a single ad lib smoking session may be useful in identifying stable individual differences in smoking reinforcement and reward.

Rationale: Negative mood increases smoking reinforcement and may do so to a greater degree in smokers vulnerable to negative mood dysregulation., Methods: Adult smokers (N = 71) without current depression were randomly assigned to one of two smoking conditions (nicotine or denic cigarettes, presented blind) maintained across all sessions. Subjects completed one neutral mood session and four negative mood induction sessions. Negative mood inductions included one each of the following: 1) overnight smoking abstinence, 2) challenging computer task, 3) public speech preparation, 4) watching negative mood slides. In each session, subjects took 4 puffs on their assigned cigarette, rated it for "liking" (reward), and then smoked those cigarettes ad libitum (reinforcement) during continued mood induction. Affect was assessed intermittently before and after smoking. Differences in responses were examined as functions of self-reported history of major depression and levels of distress tolerance and anxiety sensitivity., Results: Smoking reinforcement, but not reward or negative affect relief, was greater in all sessions in those with a history of depression and greater after overnight abstinence in those with lower distress tolerance. Reward and affect relief, but not reinforcement, were greater during speech preparation among those high in anxiety sensitivity., Conclusions: Low distress tolerance may enhance acute smoking reinforcement due to abstinence, while depression history may broadly increase acute smoking reinforcement regardless of mood. Neither smoking reward nor affect help explain these individual differences in smoking reinforcement.

Background: Smoking acutely relieves negative affect (NA) due to smoking abstinence but may not relieve NA from other sources, such as stressors., Methods: Dependent smokers (n = 104) randomly assigned to one of three smoking conditions (nicotine or denicotinized cigarettes, or no smoking) completed four negative mood induction procedures (one per session): 1) overnight smoking abstinence, 2) challenging computer task, 3) public speech preparation, and 4) watching negative mood slides. A fifth session involved a neutral mood control. The two smoking groups took four puffs on their assigned cigarette and then smoked those same cigarettes ad libitum during continued mood induction. All subjects rated their level of NA and positive affect on several measures (Mood Form, Positive and Negative Affect Scale, Stress-Arousal Checklist, and State-Trait Anxiety Inventory-state). They also rated craving and withdrawal., Results: Negative affect relief from smoking depended on the NA source (i.e., mood induction procedure) and the affect measure. Smoking robustly relieved NA due to abstinence on all four measures but only modestly relieved NA due to the other sources and typically on only some measures. Smoking's effects on positive affect and withdrawal were similar to effects on NA, but relief of craving depended less on NA source. Smoking reinforcement only partly matched the pattern of NA relief. Few responses differed between the nicotine and denicotinized smoking groups., Conclusions: Acute NA relief from smoking depends on the situation and the affect measure used but may not depend on nicotine intake. These results challenge the common assumption that smoking, and nicotine in particular, broadly alleviates NA., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Initial sensitivity to nicotine's effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 microg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.

Rationale: Impulsivity is related to greater risk of nicotine dependence, perhaps by enhancing sensitivity to nicotine's reinforcing and rewarding effects during initial smoking experiences., Objective: We examined the influence of impulsivity characteristics on acute sensitivity to nicotine reward, reinforcement, and other effects in 131 young adult nonsmokers., Materials and Methods: Participants engaged in four sessions: the first three to assess dose-response effects of nasal spray nicotine (0, 5, 10 microg/kg) on reward, as well as mood, physiological, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Five impulsivity factors, derived from factor analysis of self-report (e.g., Barratt Impulsivity Scale, Sensation-Seeking Scale, Novelty seeking) and computer (stop-go, delay discounting, probability discounting) measures of impulsivity, were labeled "novelty seeking", "response disinhibition", "extraversion", "inhibition", and "probability/delay discounting"., Results: The associations of novelty seeking with nicotine reinforcement and reward tended to move in opposite directions by sex, generally being directly related in men but inversely or unrelated in women. Similarly, response disinhibition was associated with reward and some mood responses to nicotine that differed by sex. Extraversion was inversely associated with nicotine reinforcement. Characteristics loading on to the other impulsivity factors had little association with nicotine sensitivity., Conclusions: These results are preliminary, but they suggest that characteristics broadly related to impulsivity, especially novelty seeking and response disinhibition, are associated with initial sensitivity to some effects of acute nicotine, including reinforcement and reward, and may do so differentially between men and women.

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.

Greater sensitivity to early exposure to tobacco smoking may predict higher risk of becoming nicotine dependent. The most common measure of this sensitivity is the retrospective self-report Early Smoking Experiences (ESE) questionnaire. We examined the relationship between responses to the retrospective ESE and prospectively assessed sensitivity to nicotine via nasal spray in young adult nonsmokers (N = 58) with modest lifetime smoking experience (>0 but < or =10 lifetime uses). Nicotine spray (0 vs 10 microg/kg) was used due to ethical and practical concerns with administering tobacco smoke to nonsmokers. Responses to cigarette smoking on the retrospective ESE items of pleasant, unpleasant, nausea, relaxed, dizzy, and buzzed were compared with prospectively assessed nicotine spray effects (NSE) on the same responses. ESE responses were also compared with subjective spray ratings of nicotine reward (e.g., "liking") and perception (e.g., "feel the effects"), cardiovascular activity, and nicotine reinforcement via a nicotine spray choice procedure. Results showed that the retrospective ESE items of dizzy and buzzed were each associated with greater prospective NSE dizzy and buzzed responses to nasal spray nicotine. However, the other four ESE items were unrelated to the corresponding NSE items. Responses to some ESE items were also related to prospective nicotine spray reward and perception, but no ESE item was related to the cardiovascular or reinforcing effects of nicotine spray. These findings show that two of six retrospective ESE items, dizzy and buzzed, predicted the same prospectively assessed responses to acute nicotine via spray in young adult nonsmokers and may reflect a stable and reliable response to nicotine intake.