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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Psychopharmacology (Berl). 2020 Mar 27;237(6):1885–1891. doi: 10.1007/s00213-020-05509-9

Differences in Acute Reinforcement Across Reduced Nicotine Content Cigarettes

Kenneth A Perkins 1, Joshua L Karelitz 1
PMCID: PMC7244375  NIHMSID: NIHMS1580146  PMID: 32221696

Abstract

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-subjects 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 the 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 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.

Keywords: Nicotine, Tobacco cigarette smoking, Dependence, Very low nicotine content cigarettes, Choice testing, Acute reinforcement, Preference, Abuse Liability, Nicotine reduction

Introduction

Although the steady increase in tobacco use prevalence over decades may now be leveling off at 1.3 billion globally (WHO 2019), it remains a public health crisis. Tobacco use is a cause of preventable mortality that annually accounts for over 7 million deaths worldwide (GBD 2015), including nearly a half million in the United States alone (USDHHS, 2014). Nicotine is the primary reinforcing constituent in tobacco largely responsible for initiation and maintenance of cigarette smoking behavior (Stolerman and Jarvis, 1995; USDHHS, 2014), and most popular U.S. brands have contents ranging between 15 and 20 mg/g (mg nicotine per gram of tobacco; Carmines and Gillman 2019). To accelerate the decline in smoking prevalence, regulation to reduce the maximum nicotine content in cigarettes may help prevent dependence and aid quitting in dependent smokers (Benowitz and Henningfield 2013). Such a policy has been under serious consideration by regulatory authorities (FDA 2018; WHO 2015).

Several lines of research are needed to reliably determine the addictiveness of different products, but self-administration can provide assessment of a product’s reinforcing effects, or its abuse potential (Panlilio and Goldberg, 2017). Notably, one large randomized controlled multi-site clinical trial, with 780 healthy adult smokers not trying to quit (Donny et al. 2015), assessed reductions in smoking behavior after 6 weeks of switching from own brand to one of several lower nicotine content cigarettes (15.8, 5.2, 2.4, 1.3, or 0.4 mg/g). These Spectrum investigational research cigarettes (Richter et al. 2016) were recently made available from the U.S. National Institute on Drug Abuse (see Hatsukami et al. 2013; Kamens et al. 2020). Donny et al. (2015) found the number of cigarettes smoked per day was similar between own brand and the 15.8 and 5.2 mg/g groups, but lower in groups assigned to contents ≤2.4 mg/g. In particular, this and related research showed that extended use of the very lowest nicotine content cigarettes available (0.4 mg/g, or VLNC), was associated with fewer cigarettes smoked per day, decreased dependence, increased probability of making a quit attempt for smokers not originally interested in quitting, and decreased likelihood of relapse for smokers who subsequently did make a quit attempt (Dermody et al. 2014; Donny et al., 2015; Hatsukami et al., 2018; Smith et al., 2019).

However, establishing a lower nicotine content standard for cigarettes, if enacted (FDA 2018), requires support from an extensive research base (Berman and Glasser 2019). Despite their strengths, randomized controlled trials to assess reinforcement, such as comparing ad lib consumption of single products alone as in Donny et al. (2015), are resource intensive, requiring large samples and concomitant research costs, often taking years to plan, implement, and complete (e.g., Frieden, 2017). Without prior evaluation of preferences between cigarettes differing in nicotine content, such trials could be rather impractical for initially gauging how other smoking subpopulations, or smokers tested with other types of study designs, might respond to reduced nicotine cigarettes. Needed is an efficient method to obtain preliminary estimates of differences in the reinforcing effects of cigarettes with nicotine that is greater than the lowest available, currently the 0.4 mg/g VLNC, or that is lower than that in standard commercial cigarette brands, now averaging 17.2 mg/g (Carmines and Gilman 2019).

Toward this end, initial acute testing with the same Spectrum research cigarettes as those later used in Donny et al. (2015) found lower subjective pleasurable effects after brief smoking of the VLNC vs. the highest nicotine content compared, approx. 12 mg/g (Hatsukami et al. 2013), generally consistent with reduction in daily use among Donny et al.’s VLNC group. However, an intermediate nicotine content cigarette, with 6 mg/g, differed little from the VLNC and not at all from the 12 mg/g cigarette, and actual self-administration (i.e. reinforcement; Carter et al. 2009) was not assessed. By contrast, another acute test, this one in a sample of “vulnerable” smokers with diverse psychiatric diagnoses or low SES status, found preference for all the higher vs. lower nicotine research cigarettes compared, including the VLNC (Higgins et al. 2017). Yet, between-group differences were seen in sensitivity to the relative reinforcing effects of the lower nicotine cigarettes, as those with affective disorders did, and those with opioid dependence or low SES women did not, choose 2.4 mg/g over the 0.4 mg/g. The very lowest Spectrum content above the 0.4 mg/g, 1.3 mg/g, was not tested. Other studies have assessed acute responses likely related to reductions in reinforcement due to VLNC, such as subjective effects, puff topography, or hypothetical purchase choices (e.g. Tucker et al. 2018), but not actual reinforcement behavior. Thus, acute testing of behavioral preference for nicotine content cigarettes above the VLNC up to the content typical of commercial brands in healthy dependent smokers (i.e. those without characteristics that may make them “vulnerable”) has not clearly been done to gauge the threshold for increased reinforcement.

Fortunately, a recent lab-based within-subjects choice procedure has shown validity in healthy smokers for assessing differences in the acute relative reinforcing efficacy of nicotine doses administered by cigarette smoking, as well as by non-smoked means (Perkins and Karelitz, 2019 a). As with the other acute tests above, this procedure requires a much smaller sample (and is thus more feasible) and offers potential for informing designs of larger randomized trials with different smoking populations or facilitating similar nicotine reduction research (Frieden 2017; Tunis et al., 2003). This procedure was recently used with the same research cigarettes as Donny et al. (2015) to explore choice of higher nicotine cigarettes vs. the 0.4 mg/g VLNC, finding choice was greater for those ≥ 5.3 mg/g but not at smaller nicotine content comparisons (Perkins and Karelitz, 2019 a). Yet, these results are tentative, as choice was a secondary measure following added smoking exposure trials assessing behavioral discrimination responding (see Perkins 2019). Other study limitations included presenting the different higher nicotine content cigarettes vs. the 0.4 mg/g across sessions in a fixed order (ascending or descending), a more limited number of choices per session, and sessions involving variable subsamples of roughly half the initial sample for each choice test due to other study aims.

The current study was solely focused on choice testing to compare the reinforcing effects of cigarettes differing in nicotine contents, using a valid within-subjects lab-based procedure. The primary aim was to determine how much of an increase in cigarette nicotine content beyond 0.4 mg/g, already shown to reduce indices of dependence with long-term use (Donny et al. 2015; Hatsukami et al. 2018), is needed to significantly increase the acute relative reinforcing effects of smoked nicotine. To do so, we conducted comparisons between all the higher nicotine research cigarettes vs. 0.4 mg/g VLNC with all participants, doubling the number of choices per session, and randomizing nicotine content order across sessions, thereby addressing limitations from the prior exploratory study (Perkins and Karelitz 2019 a). Notably, we also included choice between 1.3 mg/g and 0.4 mg/g to stringently test whether a threshold for relative reinforcement can be identified, which requires detection of a nicotine content (lower bound) below such a threshold (e.g. Grebenstein et al. 2015). Based on our prior tentative findings, we hypothesized that cigarettes containing >5 mg/g of nicotine would significantly increase choice (indexing reinforcement) relative to the 0.4 mg/g VLNC. In a secondary aim, we examined the reverse comparison, determining how much of a decrease in nicotine content from the cigarette most typical of commercial brands, 18.7 mg/g, would significantly decrease choice, suggesting reduced relative reinforcement. Based on the clinical trial results for “switching” from own brand to one of the research cigarette nicotine content conditions from Donny et al. (2015), we anticipated choice would decline for cigarettes <5 mg/g of nicotine.

Methods

Participants

Non-menthol preferring healthy adult smokers were recruited using online and print advertisements. Inclusion criteria were smoking ≥5 cigarettes per day for ≥12 months, not interested in quitting permanently, and meeting DSM-V criteria for tobacco dependence (APA, 2013). Exclusion criteria were current psychiatric diagnosis (other than nicotine dependence), intending to quit soon, current use of psychiatric or smoking cessation medications (including nicotine replacement), pregnancy, and currently nursing mothers. Because our prior studies to validate this within-subjects choice procedure showed significantly greater choice for the higher nicotine options administered by cigarettes with n’s of 13–20 (Perkins et al. 1996; Blendy et al. 2005), we anticipated a similar sample size would be sufficient in this study of acute choice for Spectrum cigarettes differing in nicotine content. Of the 27 initially screened, 6 were excluded for not meeting DSM-V criteria or for not abstaining overnight as instructed (see Session Procedures below), and 4 others were enrolled but dropped out after the first session, leaving 17 completing the study. These 17 dependent adult smokers (11 M, 6 F) had mean (SD) age of 36.1 (12.4) years and averaged 14.7 (4.6) cigarettes per day, with a mean nicotine content of their reported usual brand of 17.7 (2.5) mg/g (Carmines and Gillman, 2019). They were moderately nicotine dependent, with a mean Fagerström Test of Nicotine Dependence (FTND; Heatherton et al. 1991) score of 3.9 (2.1). Racial/ethnic representation was mostly non-Hispanic White (82%), with remainder African American (6%), or more than one race (12%). Sample characteristics did not vary between sex or ethnicity. These data were obtained from Sept 2017 through Sept 2019. All procedures were reviewed and approved by the University of Pittsburgh Institutional Review Board.

Cigarettes

The most recent non-menthol Spectrum brand research cigarettes (22nd Century Group, Clarence NY; http://www.xxiicentury.com) were tested. As reported by RTI International (Research Triangle Park, NC), this batch contained nicotine contents of 0.4, 1.3, 2.3, 5.3, 10.8, and 18.7 mg/g, which are generally matched on tar. Critical for assessing choice (or other responses) due specifically to cigarette nicotine content per se is to ensure the alternatives are carefully matched on constituents other than nicotine content (e.g. Perkins and Karelitz, 2019 c). Thus, cigarettes were administered without any markings on the paper, and identified only by letter code specific to the session (e.g. “A” and “B” for session 1, “C” and “D” for session 2 and so on). Menthol-preferring smokers were not included here, as in other similar acute studies with these research cigarettes (e.g. Faulkner et al. 2017), for the following reasons. Comparable menthol versions in this Spectrum batch were not as closely matched on menthol content, ranging from 0.91 to 2.08 mg/g, potentially causing choice to vary by menthol content, rather than solely by nicotine content, and complicating interpretation of results. Moreover, this menthol content, consistent with a “slight menthol sensory effect,” is less than half that of most commercial menthol brands (approx. 3–4 mg/g), which produce a “strong menthol effect” (Ai et al., 2016), perhaps explaining the lower subjective effects for menthol vs non-menthol Spectrum research cigarettes reported by Hatsukami et al. (2013).

Session Procedures

Participants completed six, 3-hour sessions, each after overnight (≥12 hrs) abstinence, confirmed by expired air CO <10 ppm (using a Vitalograph CO monitor; Lenexa KS). Following an introductory session to learn study procedures, five virtually identical experimental sessions involved the choice procedure (details below), in which cigarettes varying in moderate to low nicotine contents (18.7, 10.8, 5.3, 2.3, and 1.3 mg/g; one “NIC” dose per session) were compared with a very low nicotine content cigarette (“VLNC”; 0.4 mg/g). Sessions started with separate administration of each cigarette alone (NIC or VLNC), identified by distinct letter codes, to perceive how they differed from each other. These were followed by choice trials in which the designated NIC and VLNC cigarettes were presented concurrently. The total number of puffs self-administered from the NIC cigarette, out of the fixed total of 16 choices per session, was the measure of that NIC cigarette’s relative reinforcing effects (preference).

Choice Procedure.

The order of the NIC cigarettes compared singly with the VLNC was random across sessions. As indicated to maintain subject blinding, all cigarettes were labeled by letter code. Smoke intake from all cigarettes was standardized at 4 puffs per trial, as in the acute testing by Hatsukami et al. (2013), enough to perceive the psychoactive effects due to the cigarette’s nicotine but not cause satiation or carryover across intermittent trials of exposure (Gu et al. 2015; Hasenfratz et al. 1993; Perkins and Karelitz 2019 a). One puff was taken every 30 sec through a portable Clinical Research Support System smoking topography device (“CReSS Pocket”; Borgwaldt KC, Inc., Richmond VA), guided by instructions presented on a computer screen to control and standardize smoke intake at 60 ml per puff (Perkins and Karelitz 2019 b).

Each session began with four “exposure” trials in a fixed order (VLNC, NIC, NIC, VLNC), one or the other cigarette every 20 mins, to inform choice later in the session. Then, four forced choice trials, one every 10 minutes, followed as both cigarettes were presented concurrently in separate smoking topography devices labeled with their respective letter code from the exposure trials. All were told to smoke exactly 4 puffs from some combination of the NIC and VLNC cigarettes presented, based solely on their own preference for each (e.g. some mix of the two, or all 4 puffs from one or from the other). Out of 16 total puffs in the four choice trials per session, the number of times the NIC cigarette was chosen was the measure of that NIC cigarette’s relative reinforcement (with 8.0, or 50% of choices, being “random”). Total exposure to these cigarettes from the four exposure and the four choice trials was thus 32 puffs over nearly 3 hrs, or about 3 full cigarettes (Perkins et al. 2012). Because participants were abstinent overnight prior to each session, and most of these Spectrum cigarettes were much lower in nicotine content than commercial brands, the total smoke intake by the end of sessions was similar to, and total nicotine intake almost certainly less than, that in dependent smokers during a morning of ad lib smoking following overnight abstinence (Mooney et al. 2006). Further details on this choice procedure are described elsewhere (Perkins and Karelitz, 2019 a).

Analyses

All analyses were performed using SPSS 25.0 (IBM, Chicago, IL), with alpha set to 0.05. A preliminary analysis tested the consistency in exposure trial puff volumes (NIC – VLNC) across nicotine content conditions using a linear mixed model (LMM; SPSS MIXED command), with a random intercept and fixed effects for the intercept and nicotine content condition. Generalized linear mixed models (GLMM; SPSS GENLINMIXED command) using a Poisson probability distribution and log link were used in all analyses of choice data. Initial GLMM analysis examined influences on the difference in choice at the lower-level (i.e., between trials), upper-level (i.e., between nicotine contents), and cross-level interaction where patterns of choosing across forced choice trials may have varied as a function of nicotine content (Mathieu, et al., 2012). For the analysis of primary and secondary aims, GLMM was used to assess change in the number of NIC puff choices across nicotine content conditions. This model included a random intercept and fixed effects for the intercept and nicotine condition. An effect size (R2) was calculated for the primary analysis as per Snijders and Bosker (2012).

Results

Preliminary tests

Confirming consistent smoke exposure with each cigarette due to the standardized puffing procedure, there was no effect of nicotine content condition on the difference (NIC – VLNC) in puff volume across exposure trials, F(4,172) = 0.45, p = 0.77. Regarding choice, the number of NIC puffs per session differed by NIC nicotine content , F(4, 704) = 2.62, p = 0.03, as expected. Yet, no effects of trial or the trial by nicotine content interaction were significant, F(3, 704) = 0.64, p = 0.59 and F(12, 704) = 0.22, p = 0.99, respectively, indicating stability of choice responding over trials within sessions.

Main choice testing

Puff choice for the higher nicotine content cigarette (i.e., NIC), over the VLNC, increased significantly with nicotine content in an orderly fashion, F(4, 77) = 5.14, p = 0.001, R2 = 0.91, as shown in Figure 1. To address the primary aim, the number of NIC choices was significantly greater than eight (i.e., 95% CI’s did not overlap with 8.0, or “random”) for the 5.3, 10.8, and 18.7 mg/g nicotine cigarettes, indicating that each of those was chosen more than the 0.4 mg/g VLNC, while choice for 1.3 and 2.3 mg/g cigarettes was not greater than the VLNC. In planned comparisons, puff choices for all contents ≥5.3 mg/g were significantly greater than those for 1.3 mg/g, the lowest content tested vs. the 0.4 mg/g (Figure 1). For the secondary aim, additional planned comparisons examining the number of puffs for each nicotine content versus those for 18.7 mg/g found that the number of NIC choices for both 2.3 and 1.3 mg/g were each significantly less than that for 18.7 mg/g (also shown in Figure 1).

Figure 1.

Figure 1.

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Mean number of NIC puff choices by nicotine content condition, out of a fixed total of 16 per condition. Horizontal dashed line at 8.0 indicates no difference in choice from the 0.4 mg/g VLNC (i.e. 50% of 16). Vertical bars represent 95% confidence intervals, and those not overlapping with 8.0 indicate significantly greater choice for that NIC content vs. VLNC, addressing the primary aim. Horizontal bars indicate significant differences in the planned comparisons between choice for 1.3 mg/g vs. the higher NIC conditions and between choice for 18.7 mg/g vs the lower NIC conditions. ***p<.001, *p<.05.

Discussion

Overall, our data confirm the validity of this within-subjects forced choice procedure in assessing differences in relative reinforcement among pairs of cigarettes differing across a range of low to moderate nicotine contents. Our main objective was to efficiently obtain evidence identifying the difference in nicotine content needed to significantly increase or decrease cigarette preference, or its relative reinforcing effects (used here to index self-administration behavior). Findings indicated that relative reinforcement was sensitive in dose-dependent fashion to increases in cigarette nicotine content, at least up to 10.8 mg/g (Figure 1). With this sample size, a threshold for reinforcement must be tentative, but choice for cigarettes ≥5.3 mg/g, and not ≤ 2.3 mg/g, was significantly greater relative to the 0.4 mg/g VLNC alternative, addressing the primary aim of this study. Moreover, in the secondary aim, comparisons of decline in reinforcement from the highest content cigarette (representing standard commercial brands), 18.7 mg/g, showed choice for NIC-VLNC was less for both 1.3 and 2.3 mg/g, but not for contents ≥5.3 mg/g, similar to the findings reported by Donny et al. (2015). Thus, these data converge with the Donny et al. (2015) trial results to indicate that reducing nicotine content in cigarettes to levels ≤ 2.3 mg/g, about 15% or less than the content in most commercial brands (Carmines and Gillman 2019), may diminish reinforcement from smoking.

We viewed this testing approach as potentially offering a step toward informing future research to gauge effects of a nicotine reduction policy (FDA 2018). Use of a within-subjects design allowed for a small sample size; each participant acted as his/her own control to increase statistical power to detect differences in reinforcement due to cigarette nicotine content (Cohen, 1988). The paired Spectrum research cigarettes tested across sessions were otherwise identical, isolating their differences in nicotine content per se. Yet, it is unclear whether reductions in acute relative reinforcement observed in the lab would translate to fewer cigarettes smoked over longer periods of time by a larger and diverse sample in the real world, the ultimate aim of a nicotine reduction policy (FDA 2018; WHO 2015). Aside from Donny et al. (2015), results of a recent trial by Hatsukami et al. (2018) offer initial support for potential translation, as their 20-week long study randomized smokers to one of three groups: 1) use cigarettes gradually declining in nicotine content (15.5, 11.7, 5.2, 2.4, 0.4 mg/g; four weeks per content); 2) use only cigarettes containing 15.5 mg/g; or 3) use only cigarettes containing 0.4 mg/g. At the end of the study, participants in group 1, gradual reduction, smoked a similar number of cigarettes per day as those randomized to the 15.5 mg/g control condition but tended to reduce cigarette consumption (non-significantly) during the 2.4 and 0.4 mg/g conditions, perhaps comparable to the current study. (Those randomized to group 3, exclusive use of the 0.4 mg/g over the entire 20-week study, smoked significantly fewer cigarettes per day than those in both the gradual reduction and group 2 control conditions.)

Regarding limitations, the choice options did not include a true placebo cigarette (i.e., 0 mg/g) for comparison, requiring all the NIC cigarettes to be compared with the VLNC, containing some, if minimal (0.4 mg/g), nicotine. Legal restrictions preclude eliminating all nicotine from commercial cigarettes in the U.S. (FDA 2018), so replicating these results with a zero nicotine cigarette comparison is needed. For example, cigarettes only slightly higher in nicotine than the 0.4 mg/g might not be more reinforcing under that comparison but might be more reinforcing if compared with a no nicotine option (e.g., Perkins et al. 1996). Because of the reinforcing effects of non-nicotine smoking stimuli (Rose et al. 2010), smoking them certainly might be reinforcing if individually they were the only ones made available (as in Donny et al. 2015). Our choice procedure makes cigarettes differing in nicotine content concurrently available, explicitly to control for those non-nicotine stimuli (Perkins and Karelitz, 2019 a). A second limitation was that these results were restricted to non-menthol Spectrum research cigarettes, due to potential confounds with the current menthol version available (as noted).

Replication with larger samples is needed to confirm the pattern of choice found here, as more of a “graded effect” across the higher nicotine cigarettes vs. 0.4 mg/g could result (e.g. starting from 2.3 mg/g), rather than the ≥5.3 mg/g pattern (Figure 1). Yet, we found absolutely no evidence of choice for 1.3 mg/g vs. 0.4 mg/g in this first-ever comparison between the two lowest nicotine Spectrum cigarettes, establishing that 1.3 mg/g and 0.4 mg/g do not differ in relative reinforcing efficacy under these conditions. Future acute research on nicotine regulation may benefit from confirmation that increasing cigarette content from 0.4 mg/g to 1.3 mg/g nicotine does not increase reinforcement, perhaps setting a level below the range of differences in nicotine contents that do raise the reinforcing efficacy of smoking (Perkins 2019). This study also would benefit from replication with menthol-preferring smokers being tested with cigarettes differing in nicotine contents but with fixed menthol contents closer to those of commercial brands (Ai et al. 2015), and in a diverse sample of smokers (e.g. Drope et al. 2018) powered to detect potential between-groups differences in responding.

In conclusion, use of this acute forced choice procedure with cigarettes containing well-controlled nicotine contents (i.e. Spectrum or other) could efficiently inform the design and expected results of additional clinical trials testing differences in preference for reduced nicotine cigarettes (Berman and Glasser, 2019). Such testing could aid preparations for randomized “switching” trials similar to that of Donny et al. (2015) or Hatsukami et al. (2018), especially with various subpopulations of smokers for whom recruitment of large samples might not be feasible, placing a premium on the validity of such preliminary testing. Future research could examine dose-dependent effects of smoking these cigarettes in an effort to better understand factors responsible for acute smoking reinforcement, such as their discriminability or subjective perceptions (e.g. Perkins 2019). Similarly, future clinical trials assessing changes in self-administration behavior among other tobacco or non-tobacco products varying in nicotine content (e.g. Heat-not-Burn tobacco, electronic cigarettes; Perkins et al. 2019; Simonavicius 2018) may benefit from using this forced choice procedure in early piloting. Such testing may be able to inform selection of doses and provide effect sizes for power analyses, among other benefits in planning such research. In sum, our results validate use of this procedure as an initial test to inform design of future clinical research on changes in preference as a result of differences in cigarette nicotine contents.

Acknowledgment:

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under grant awards R21 DA035968 and R01 DA035774 (KAP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Compliance with ethical standards:

These study procedures were approved by the Univ of Pittsburgh Institutional Review Board and are in accordance with the Helsinki Declaration of 1975.

Conflict of interest/disclosure:

The authors have no potential conflicts of interest to report.

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