Reactions to a Nicotine Reduction Policy Among Adolescents Who Smoke: A Qualitative Study.

INTRODUCTION: The Biden administration is pursuing a nicotine reduction policy in the U.S. to render cigarettes less addictive. In this study, we qualitatively investigated adolescents' subjective responses to very low nicotine content (VLNC) cigarettes, reasons for incomplete adherence to using them, and their expected responses to a nicotine reduction policy. METHODS: Adolescents who smoke cigarettes daily (ages 15-19; N=60) were enrolled in a three-week double-blind randomized clinical trial and assigned to smoke either normal nicotine content (NNC) or VLNC research cigarettes. Following the trial, 52 participants completed qualitative interviews about their reactions to the cigarettes and to the idea of a nicotine reduction policy. We utilized a template style approach to thematic analysis involving immersion in the data, codebook development with both inductive and deductive codes, and iterative refinement of themes. RESULTS: Reasons for incomplete adherence to smoking only research cigarettes focused on dislike for cigarette taste and lower satisfaction compared to usual brand cigarettes. Negative evaluations of research cigarettes were common across both groups. Many participants in both groups reported that they would decrease their smoking or quit entirely if the research cigarettes were the only ones legally available for purchase in the U.S. CONCLUSIONS: Adolescents may respond to a cigarette nicotine reduction policy by decreasing their cigarette smoking and eventually quitting. These findings suggest a need for public health strategies to reduce smoking initiation and progression in young people and to encourage cessation in the context of a nicotine reduction policy. IMPLICATIONS: Participants' negative subjective responses and challenges with research cigarette adherence offer insight into factors that might influence young people's reactions to a real-world nicotine reduction policy. Adolescents who smoke may increase their use of alternative tobacco products, especially e-cigarettes, if this policy were implemented. Specifically, themes identified across participant responses highlight important considerations for how such a policy might be implemented with specific attention to the unique smoking behaviors and needs of this vulnerable population.

Examining the Predictive Utility of Behavioral Economic Demand Indices and Subjective Effects on the Actualized Reinforcing Value of Menthol Cigarettes and Potential Alternatives.

INTRODUCTION: Considering recent and proposed bans on menthol cigarettes, methods are needed to understand the substitutability of potential menthol cigarette alternatives (MCAs) for menthol cigarettes. This study examined the prospective relationship between behavioral economic demand indices and subjective effects of usual brand menthol cigarettes (UBMC) and preferred MCAs with subsequent performance on a laboratory-based concurrent-choice task comparing UBMC and MCAs. METHODS: Eighty participants who typically smoked menthol cigarettes completed this clinical laboratory study. After sampling each product, participants completed the cigarette purchase task (CPT) and modified cigarette evaluation questionnaire (mCEQ). Following 1 week of substituting their preferred MCA for their UBMC, participants completed a 90-minute concurrent-choice self-administration (SA) task comparing their UBMC and preferred MCA. Linear regression models explored associations between CPT demand indices and mCEQ subjective effects in the laboratory with subsequent response effort for UBMCs on the concurrent-choice task. RESULTS: Three demand indices for UBMC were positively associated with UBMC response effort: essential value (EV; p = .02), Omax (p = .02), and breakpoint (p = .04). Four CPT demand indices for the preferred MCA significantly corresponded with UBMC response effort: EV (p = .03), price associated with maximal expenditure (Pmax) (p = .04), maximal expenditure (Omax) (p = .03), and breakpoint (p = .03). Subjective effects captured by the mCEQ were not associated with response effort. CONCLUSIONS: Demand indices reflecting Persistence (ie, sensitivity to escalating price) predicted effort to obtain UBMC puffs on the concurrent-choice task. Among this sample, the CPT captured information on the relative reinforcing value (ie, addiction potential) of combustible tobacco products similar to the longer SA task. IMPLICATIONS: In an ever-changing product market, assessing the reinforcing efficacy of menthol cigarettes and putative substitutes quickly and with validity is an important methodological tool for understanding abuse liability. Results suggest that behavioral economic demand indices of CPT efficiently capture information on the relative reinforcing value of UBMC and plausible alternative tobacco products, similar to a 90-minute in-laboratory SA task.

Examining Demand and Substitutability of Usual Brand Little Cigars/Cigarillos and Cigarettes in Young Adults Who Dual Use.

INTRODUCTION: Cigarette and little cigar/cigarillo (LCC) dual use is popular among young people and poses a substantial health risk. What remains unclear is the abuse liability of LCCs vs. cigarettes, LCCs' substitutability for cigarettes, and the influence of flavors on the abuse liability and substitutability of LCCs. METHODS: Sixty-five young adults (18-34 years) who dual use completed hypothetical purchase tasks to measure consumption of usual brand cigarettes and LCCs in 24 hours at increasing prices (demand), and LCC consumption at increasing cigarette prices (substitution). Three demand indices were calculated from raw data: breakpoint (price after which consumption reaches 0), Omax (maximum daily expenditure), and Pmax (price at maximum expenditure). Two indices were estimated using nonlinear mixed-effects modeling: intensity (consumption when free) and price-sensitivity (rate of decline in consumption as price increases). Substitution, and associations of flavored use with demand and substitution, were estimated using linear mixed models. RESULTS: Results indicated similar abuse liability for LCCs and cigarettes. Intensity was greater for cigarettes, but price-sensitivity was similar. Flavored LCC use was associated with lower price-sensitivity and greater intensity than unflavored. LCCs were significant substitutes for cigarettes, but the effect was small. Flavored use was not associated with substitution. CONCLUSIONS: Among young adults who dual use, LCCs and cigarettes had similar abuse liability, and those who used flavored had higher demand for their LCCs. A flavored cigar ban, as well as targeted prevention and cessation services for those who smoke flavored LCCs, may be important for reducing dual use in young adults. IMPLICATIONS: Cigarette and LCC dual use remains high among young adults. Using hypothetical purchase tasks with young adults who dual use, LCCs had abuse liability similar to cigarettes, but were only modest substitutes for cigarettes. Participants who used flavored LCCs reported greater abuse liability than those who used unflavored, but not greater substitution for cigarettes. Prevention and cessation services are needed to target LCCs in young people, particularly those smoking flavored products. A flavored cigar ban may help to reduce their demand.

Effects of Very Low Nicotine Content Cigarettes and Nicotine Vaping Device Characteristics on Choices to Smoke, Vape, or Abstain in Early Young Adults.

INTRODUCTION: A national nicotine reduction policy could reduce the public health toll of smoking. However, reducing nicotine in cigarettes may lead to changes in the use of other tobacco products such as nicotine vaping devices, particularly among young people. Product use outcomes may depend on characteristics of available nicotine vaping devices. We aimed to determine the impact of cigarette nicotine content, vaping device nicotine concentration, and vaping device flavors on choices to smoke, vape, or abstain. METHODS: Early young adults (ages 18-20 inclusive, N=80) who reported smoking daily and vaping nicotine at least twice in their lifetime participated in a laboratory study. Participants received either Very Low Nicotine Content (VLNC; 0.4 mg nicotine/g of tobacco) or Normal Nicotine Content (NNC; 15.8 mg/g) cigarettes. First, participants chose between their assigned cigarette or abstaining. Subsequently, participants chose between 2 cigarette puffs, 2 vape puffs, or abstaining. Vaping device nicotine concentration (3mg vs. 18mg/ml) and flavor (tobacco vs. non-tobacco) were manipulated within-subjects. RESULTS: When only cigarettes were available, there were no differences between the VLNC and NNC groups on cigarette choices. When the nicotine vaping device was concurrently available, the VLNC group made fewer choices to smoke than the NNC group. Non-tobacco flavors and lower vaping device nicotine concentration were associated with fewer choices to smoke. CONCLUSIONS: Nicotine vaping device availability reduced choices to smoke VLNC cigarettes, and vaping devices with lower nicotine and non-tobacco flavors led to the fewest choices to smoke. Regulators should consider that the availability and characteristics of alternative tobacco products can moderate the product standard's impact. IMPLICATIONS: The U.S. Food and Drug Administration may enact a reduced nicotine product standard that would affect all commercially-available cigarettes. One important population affected by this policy would be early young adults who smoke. We aimed to determine the impact of cigarette nicotine content, vaping device nicotine concentration, and vaping device flavors on choices to smoke, vape, or abstain. Lower nicotine in cigarettes, along with non-tobacco flavors and lower nicotine concentration in the vaping device, were associated with the fewest choices to smoke. Regulators should consider that the availability and characteristics of alternative tobacco products can moderate the product standard's impact.

The Impact of Reducing Nicotine Content on Adolescent Cigarette Smoking and Nicotine Exposure: Results From a Randomized Controlled Trial.

INTRODUCTION: As the science base around the potential benefits of a reduced-nicotine standard for cigarettes grows, information on the potential effects on adolescent smokers is a high priority. The aim of this randomized trial was to test the influence of 3-week exposure to reduced nicotine cigarettes in a sample of adolescent daily smokers. AIMS AND METHODS: In this double-blind, two-arm, randomized controlled trial (NCT0258731), following a 1-week baseline, adolescent daily smokers not currently intending to quit (ages 15-19 years, n = 66 randomized) were urn randomized to use either very low nicotine content (VLNC; 0.4 mg/g; n = 33) or normal nicotine content (NNC, 15.8 mg/g; n = 33) research cigarettes for 3 weeks. Participants attended five study sessions at our clinical laboratory. The primary outcome was average total cigarettes smoked per day (CPD; including both study and non-study cigarettes) at week 3. RESULTS: Stepwise regression results demonstrated that compared with NNC cigarettes (n = 31), assignment to VLNC cigarettes (n = 29), was associated with 2.4 fewer CPD on average than NNC assignment (p < .05) week 3 when controlling for covariates (p < .01, Cohen's d = 0.52 n = 60 completed all procedures). VLNC cigarettes were also associated with lower levels of craving reduction than NNC cigarettes (Questionnaire on Smoking Urges Factor 2, p < .05). No group differences were found for secondary outcomes. CONCLUSIONS: Adolescent participants assigned to VLNC use for 3 weeks smoked fewer total CPD relative to the NNC group. Overall, data suggest that a VLNC policy would reduce cigarette smoking in adolescents who smoke, but high rates of incomplete adherence suggest that youth may seek alternative sources of nicotine in this scenario. IMPLICATIONS: The US Food and Drug Administration may enact a reduced-nicotine product standard that would affect all commercially available cigarettes. One important population affected by this policy would be adolescents who smoke. This study, the first clinical trial of VLNC cigarettes in adolescents, demonstrates that adolescents switched to VLNC cigarettes for 3 weeks reduced their CPD relative to the normal-nicotine cigarette control group, without leading to increased respiratory symptoms or increased withdrawal. Biomarkers indicated the use of other sources of nicotine, suggesting that such a policy will need to consider approaches to assist in transitioning away from smoking.

The Impact of the Covid-19 Pandemic on Smoking Among Vulnerable Populations.

AIM: While accumulating evidence suggests that people modified their smoking during the ongoing COVID-19 pandemic, it remains unclear whether those most at risk for tobacco-related health disparities did so. The current study examined changes in smoking among several vulnerable smoker populations during the COVID-19 pandemic. METHODS: A web-based survey was distributed in 2020 to 709 adults with socioeconomic disadvantage, affective disorders, or opioid use disorder who participated in a previous study investigating the effects of very low nicotine content (VLNC) cigarettes on smoking. Current smoking status and rate, and adoption of protective health behaviors in response to the pandemic (eg social distancing, mask wearing) were examined. RESULTS: Among 332 survey respondents (46.8% response rate), 84.6% were current smokers. Repeated measures ANOVA showed that current cigarettes/day (CPD) was higher during COVID than pre-COVID (12.9 ± 1.0 versus 11.6 ± 1.0; p < .001). Most respondents had adopted protective health behaviors to prevent infection (>79% for all behaviors). More than half indicated that they were still leaving their homes specifically to buy cigarettes (64.6%) and were buying more packs per visit to the store (54.5%) than pre-COVID. Individuals unemployed at the time of the survey experienced greater increases in CPD (from 11.4 ± 1.4 to 13.3 ± 1.4, p = .024) as did those with higher levels of anxiety (from 11.5 ± 1.1 to 13.6 ± 1.1, p < .001). CONCLUSIONS: Smoking increased during the COVID-19 pandemic in this sample of adults from vulnerable populations, even while most adopted protective health measures to prevent infection. Unemployment and anxiety might identify those at greatest risk for increases in tobacco use. IMPLICATIONS: Individuals from populations especially vulnerable to smoking might be at risk for greater harm from cigarette smoking during times of pandemic-related stress. Public health interventions are warranted to ameliorate increases in smoking among these populations. Special attention should be paid to those experiencing unemployment and high anxiety.

Immediate Switching to Reduced Nicotine Cigarettes in a U.S.-Based Sample: The Impact on Cannabis Use and Related Variables at 20 Weeks.

INTRODUCTION: The FDA proposed rule-making to reduce nicotine in cigarettes to minimally addictive levels. Research suggests decreasing nicotine levels (i.e. very low nicotine content cigarettes [VLNCs]) produced greater quit attempts, reduced smoking, and reduced exposure to harmful constituents among smokers. The impact of long-term VLNC use among people who co-use cigarettes and cannabis on non-tobacco-specific toxicant and carcinogen exposure has not been investigated. AIMS AND METHODS: This study presents secondary analyses of a controlled clinical trial examining switching to VLNC (versus a normal nicotine cigarettes control group [NNCs]) between people who co-use cigarettes and cannabis (n = 174) versus smoked cigarettes (n = 555). Linear mixed-effects models compared changes in smoking behavior, and tobacco-specific (i.e. total nicotine equivalents [TNE], 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK; total NNAL]) and non-tobacco-specific (i.e. carbon monoxide (CO), 2-cyanoethylmercapturic acid [CEMA], phenanthrene tetraol [PheT]) toxicant and carcinogen exposure at week 20 (with random intercept for participants). Cannabis use was measured among co-use groups. RESULTS: CO was significantly lower only among the cigarette-only group assigned VLNCs (interaction: p = .015). Although both VLNC groups demonstrated decreased CEMA, greater decreases emerged among the cigarette-only group (interaction: p = .016). No significant interactions emerged for TNE, cigarettes per day (CPD), NNAL, and PheT (ps > .05); both VLNC groups decreased in TNE, CPD, and NNAL. Only the cigarette-only group assigned VLNCs demonstrated decreased PheT (p < .001). The VLNC co-use group showed increased cannabis use over time (p = .012; 0.5 more days per week by week 20). CONCLUSIONS: Those who co-use cannabis and cigarettes may still be at risk for greater exposure to non-tobacco-specific toxicants and carcinogens compared to those who only smoke cigarettes. IMPLICATIONS: The present study is the longest longitudinal, prospective comparison study of smoking behavior and exposure to harmful constituents among those who co-use cigarettes and cannabis versus cigarette-only after immediately switching to very low nicotine content cigarettes (VLNC). Those who co-use experienced similar reductions in CPD and tobacco-specific exposure, compared to those who only use cigarettes. However, co-use groups experienced smaller reductions in non-tobacco-specific toxicants and carcinogens compared to the cigarette-only group, potentially because of combustible cannabis use. Additionally, those who co-use and switched to VLNC may be susceptible to slight increases in cannabis use (approximately two more days per year).

Effects of very low nicotine content cigarettes on smoking across vulnerable populations.

There has been long-standing interest in a reduced-nicotine product standard for combusted tobacco, which is within the regulatory purview of the Food and Drug Administration (FDA). In weighing whether to establish this standard, it is important to consider potential responses among people who are at elevated risk for tobacco-related health harms. In this narrative review, we summarize studies of very low nicotine content (VLNC) cigarettes conducted between 2010 and 2021 in groups that the FDA has identified as vulnerable populations. Studies conducted to date in adults with mental health conditions, adults with opioid use disorder, socioeconomically-disadvantaged adults, and youth or young adults indicate that immediate switching to VLNC cigarettes decreases smoking, with minimal or no unintended negative consequences. Few studies have investigated the effects of VLNC cigarettes in racial or ethnic minorities, people who smoke menthol cigarettes, and pregnant women, but initial findings suggest that responses of these individuals are similar to responses observed in other vulnerable populations. We are not aware of studies that have investigated VLNC cigarettes in military/veteran populations, sexual or gender minority individuals, or people living in underserved rural environments. Future research directions include understanding how to promote cessation in the context of a reduced-nicotine standard, and how to correct VLNC misperceptions in vulnerable populations. Nevertheless, the evidence to date indicates that a reduced-nicotine standard is likely to have the same beneficial effects on smoking reductions as it does in less vulnerable populations, which should provide some confidence in pursuing this regulatory approach.

Leveraging the cigarette purchase task to understand relationships between cumulative vulnerabilities, the relative reinforcing effects of smoking, and response to reduced nicotine content cigarettes.

We examined if the relative-reinforcing effects of smoking increase with greater cumulative vulnerability and whether cumulative vulnerability moderates response to reduced nicotine content cigarettes. Participants were 775 adults from randomized clinical trials evaluating research cigarettes differing in nicotine content (0.4, 2.4, 15.8 mg/g). Participants were categorized as having low (0-1), moderate (2-3), or high (≥4) cumulative vulnerability. Vulnerabilities included rural residence, opioid use disorder, affective disorder, low educational attainment, poverty, unemployment, and physical disability. We used the cigarette purchase task (CPT) to assess the relative-reinforcing effects of participants' usual-brand cigarettes at baseline and study cigarettes during the 12-week trial. The CPT is a behavioral-economic task wherein participants estimate likely smoking (demand) over 24 h under escalating cigarette price. Demand is characterized by two factors: Amplitude (demand volume at zero/minimal price) and Persistence (demand sensitivity to price). Greater cumulative vulnerability was associated with greater demand Amplitude (F[2709] = 16.04,p < .0001) and Persistence (F[2709] = 8.35,p = .0003) for usual-brand cigarettes. Demand Amplitude for study cigarettes increased with increasing cumulative vulnerability (F[2619] = 19.59, p < .001) and decreased with decreasing nicotine content ([4879] = 5.45, p < .001). The only evidence of moderation was on demand Persistence (F[8867] = 2.00,p = .04), with larger reductions at the 0.4 mg/g compared to 15.8 mg/g doses among participants with low compared to moderate or high cumulative vulnerability. The relative-reinforcing effects of smoking clearly increase with greater cumulative vulnerability. Reducing nicotine content would likely reduce demand Amplitude across cumulative-vulnerability levels but reductions in demand Persistence may be more limited among those with greater cumulative vulnerability.

Potential effects of nicotine content in cigarettes on use of other substances.

A national nicotine reduction policy has the potential to reduce cigarette smoking and associated adverse health impacts among vulnerable populations. However, possible unanticipated adverse effects of reducing nicotine content in cigarettes, such as increasing the use of alcohol or other abused substances, must be examined. The purpose of this study was to evaluate the effects of exposure to varying doses of nicotine in cigarettes on use of other substances. This was a secondary analysis (n = 753) of three simultaneous, multisite, double-blind, randomized-controlled trials examining 12 weeks of exposure to study cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco) among daily smokers from three vulnerable populations: individuals with affective disorders (n = 251), individuals with opioid use disorder (n = 256), and socioeconomically-disadvantaged women of reproductive age (n = 246). Effect of study cigarette assignment on urine toxicology screens (performed weekly) and responses to drug and alcohol use questionnaires (completed at study weeks 6 and 12) were examined using negative binomial regression, logistic regression, or repeated measures analysis of variance, controlling for sex, age, and menthol status. The most common substances identified using urine toxicology included tetrahydrocannabinol (THC; 44.8%), cocaine (9.2%), benzodiazepine (8.6%), and amphetamines (8.0%), with 57.2% of participants testing positive at least once for substance use (27.3% if excluding THC). No significant main effects of nicotine dose were found on any of the examined outcomes. These results suggest that reducing nicotine content does not systematically increase use of other substances, even among individuals at increased risk of substance use. ClinicalTrials.gov Identifiers: NCT02232737, NCT2250664, NCT2250534.

Relating individual differences in the reinforcing value of smoking and dependence severity to nicotine exposure levels in vulnerable populations.

Cigarette smoking is overrepresented in populations with psychiatric conditions and socioeconomic disadvantage. Greater understanding of the role of reinforcement and nicotine dependence in smoking among vulnerable populations may facilitate development of better targeted interventions to reduce smoking. Prior research demonstrated that individual differences in the reinforcing value of smoking and nicotine-dependence severity predicted total nicotine-exposure in vulnerable populations. The present study uses multivariate regression to address two aims: (1) Quantify the degree to which the reinforcing value of smoking, assessed using the Cigarette Purchase Task (CPT), and dependence severity assessed using the Fagerström Test of Nicotine Dependence and Brief Wisconsin Inventory of Smoking Dependence Motives (B-WISDM) each account for individual differences in cotinine-plus-3'-hydroxycotinine (COT+3HC) levels. (2) Explore whether there is overlap in the variance accounted for by the CTP, FTND, and B-WISDM. Participants were 628 adults with co-morbid psychiatric conditions or socioeconomic disadvantage who smoked daily. The CPT, FTND, and B-WISDM models accounted for 23.76%, 32.45%, and 29.61% of the variance in COT+3HC levels, respectively. Adding CPT to the FTND model failed to increase the variance accounted for and adding it to the B-WISDM model did so by only 1.2% demonstrating considerable overlap in the variance in nicotine exposure levels accounted for by these three instruments. These results provide new knowledge on the relationship between individual differences in the reinforcing value of smoking and nicotine-exposure levels and suggest differences in reinforcing value may underpin a considerable portion of the variance in nicotine exposure accounted for by dependence severity.

Predicting Non-Adherence With Very Low Nicotine Content Cigarettes Among Adults With Serious Mental Illness Who Smoke.

INTRODUCTION: Reducing the nicotine content of cigarettes is a promising policy intervention to decrease cigarette dependence among people who smoke. Randomized trials support the potential efficacy of a reduced nicotine product standard for cigarettes. However, interpretation of such trials is challenged by incomplete adherence to the randomized treatment assignment, as some participants may continue to use commercial cigarettes not provided by the trial. The current study examined prevalence and predictors of non-adherence among trial participants with serious mental illness (SMI). AIMS AND METHODS: Adults with SMI who smoke daily and were not trying to quit (N = 58) were randomized to receive very low nicotine content (VLNC) or normal nicotine content cigarettes over 6 weeks. We investigated predictors of biologically assessed non-adherence in participants assigned to VLNC cigarettes (n = 30). Predictors included subjective responses to VLNC cigarettes, baseline nicotine dependence and dependence motives, and psychiatric symptom severity. We fit a series of linear models regressing non-adherence metrics onto covariates (gender; menthol preference) and focal predictors. RESULTS: Nearly all participants (96%) were estimated to be less than completely adherent to VLNC cigarettes. Lower enjoyment ratings of respiratory tract sensations of VLNC cigarettes predicted a greater degree of non-adherence (b = -.40, SE = .14, 95% CI: -0.71, -0.10). CONCLUSIONS: Less positive subjective response to smoking VLNC cigarettes was the only significant predictor of incomplete adherence among individuals with SMI, consistent with prior research in a general population sample. This suggests the potential for shared strategies to help different smoking populations adjust to a reduced nicotine product standard. IMPLICATIONS: Results offer preliminary insight into potential barriers to adherence in SMI populations. Adherence might be enhanced by supplementing VLNC cigarettes with alternative sources of non-combusted nicotine, paired with educational campaigns to encourage quitting or switching to less harmful products. Future studies should replicate these analyses in a larger sample of individuals with SMI who smoke.

Effects of Reduced Nicotine Content Cigarettes on Fractional Exhaled Nitric Oxide and Self-Reported Respiratory Health Outcomes Among Smokers With Psychiatric Conditions or Socioeconomic Disadvantage.

INTRODUCTION: This study examined whether exposure to reduced-nicotine-content cigarettes (RNCCs) for 12 weeks alters respiratory health using Fractional Exhaled Nitric Oxide (FeNO), a validated biomarker of respiratory epithelial health, and the Respiratory Health Questionnaire (RHQ), a subject-rated questionnaire on respiratory symptoms. Participants were 747 adult daily smokers enrolled in three double-blind, randomized clinical trials evaluating effects of cigarette nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco) in people with affective disorders, opioid use disorder (OUD), or socioeconomic disadvantage. AIMS AND METHODS: FeNO levels and RHQ ratings were collected at baseline and Weeks 6 and 12 following randomization. Multiple regression was used to assess associations of FeNO and RHQ with smoking characteristics. Mixed-model repeated-measures ANOVA was used to evaluate the effects of nicotine content on FeNO and RHQ outcomes over the 12-week study period. RESULTS: FeNO levels but not RHQ ratings varied inversely with smoking characteristics at baseline (Ps < 0.0001) in smokers with affective disorders and socioeconomic disadvantage but less so in those with OUD. Participants with affective disorders and socioeconomic disadvantage, but not those with OUD, who were assigned to RNCCs had higher FeNO levels at Week 12 than those assigned to the 15.8 mg/g dose [F(2,423) = 4.51, p = .01, Cohen's d = 0.21]. No significant dose-related changes in RHQ scores were identified. CONCLUSIONS: Use of RNCCs across a 12-week period attenuates smoking-related reductions in FeNO levels in smokers with affective disorders and socioeconomic disadvantage although not those with OUD. FeNO changes were not accompanied by changes in respiratory-health ratings. TRIAL REGISTRATION: Inclusion and exclusion criteria for the sample and experimental manipulation of the nicotine content of assigned cigarettes are registered: NCT02232737, NCT02250664, NCT02250534. The FeNO measure reported in this manuscript is an exploratory outcome that was not registered. IMPLICATIONS: Should a reduced nicotine content standard be implemented; these results suggest that reduced nicotine content in cigarettes will not exacerbate and instead may attenuate smoking-related decreases in FeNO. This is significant as NO is an important component in maintaining a healthy respiratory system and necessary to defend against infection. Furthermore, the results of the current study demonstrate that the adoption of the reduced nicotine content standard may result in beneficial impacts on respiratory epithelial health among vulnerable populations that are disproportionally affected by the adverse health outcomes precipitated by combustible tobacco use.

Cumulative vulnerabilities as a potential moderator of response to reduced nicotine content cigarettes.

Risk for smoking increases in a summative manner corresponding to the number of co-occurring vulnerabilities present (cumulative vulnerability). We examined whether cumulative vulnerabilities moderate response to reduced nicotine content cigarettes in a secondary analysis of results from 775 participants in three 12-week randomized clinical trials examining research cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco). Participants were categorized as having 0-1, 2-3, or ≥ 4 cumulative vulnerabilities. Vulnerabilities included: rural residence, current substance use disorder, current affective disorder, low educational attainment, poverty, unemployment, physical disability. The primary outcome was total cigarettes per day (CPD) during Week 12; secondary outcomes included CPD across weeks, toxin exposure, dependence severity, craving/withdrawal (17 dependent measures). Results were analyzed using repeated measures analysis of covariance and growth-curve modeling. Total CPD during Week 12 increased as cumulative-vulnerability increased (P = 0.004), and decreased as nicotine content decreased (P < 0.001), with no significant interaction of cumulative vulnerability and dose (P = 0.67). Effects on other outcomes generally followed that same pattern. The only exception across the other outcomes was on Questionnaire-on-Smoking-Urges Factor-2 ratings for usual-brand cigarettes where cumulative vulnerability, dose, and time interacted (P = 0.007), with craving at the 0.4 and 2.4 mg/g doses decreasing over time, but inconsistently across vulnerability categories. Overall, we saw little evidence that cumulative vulnerabilities moderate response to reduced nicotine content cigarettes suggesting that a policy reducing nicotine content in cigarettes to minimally addictive levels could benefit even highly vulnerable smokers including those residing in rural or other regions with overrepresentation of co-occurring vulnerabilities. Clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

Responses to Gradual and Immediate Reduction of Nicotine in Cigarettes in Young Versus Older Adult Smokers.

INTRODUCTION: As the FDA works to determine whether a nicotine reduction policy would benefit public health, one key question is whether to mandate an immediate or gradual reduction in nicotine levels in cigarettes. The aim of this study was to determine whether the effects of gradual versus immediate nicotine reduction on cigarettes per day (CPD), total nicotine equivalents, and subjective responses differed in younger adults versus older adults. METHODS: Using data from a recent randomized trial conducted in the United States (N = 1250) that switched smokers over a 20-week period to very low nicotine content (VLNC) cigarettes either immediately, gradually (via monthly reductions in nicotine content), or not at all (control condition, normal nicotine content research cigarette), we analyzed the moderating effect of age (age 18-24 or 25+). RESULTS: For both age groups, CPD in the immediate condition was significantly lower relative to gradual condition (estimated mean difference of 6.3 CPD in young adults, 5.2 CPD in older adults; p's < .05). Younger and older adults in the immediate and gradual reduction conditions had lower total nicotine equivalents at Week 20 (all p's < .05) than those in the control condition; age group did not moderate this effect. Positive subjective responses to cigarettes were lower among young adults relative to older adults in the immediate condition. CONCLUSIONS: These results indicate that an immediate reduction in nicotine would result in beneficial effects in both young and older adults. Young adults show less positive subjective effects of smoking following switching to VLNC cigarettes relative to older adults. IMPLICATIONS: As researchers work to understand how a potential reduced-nicotine product standard for cigarettes may affect public health, one question is whether nicotine should be reduced immediately or gradually. This study demonstrates that both young and older adults who were switched immediately to the lowest content of nicotine smoked fewer CPD and had lower nicotine intake than those in the gradual condition. Furthermore, young adults appear to show lower positive subjective effects following switching to VLNC cigarettes relative to older adults. This is consistent with previous work demonstrating that young people appear to show lower abuse liability for VLNC cigarettes.

An Evaluation of Potential Unintended Consequences of a Nicotine Product Standard: A Focus on Drinking History and Outcomes.

INTRODUCTION: A nicotine product standard reducing the nicotine content in cigarettes could improve public health by reducing smoking. This study evaluated the potential unintended consequences of a reduced nicotine product standard by examining its effects on (1) smoking behaviors based on drinking history; (2) drinking behavior; and (3) daily associations between smoking and drinking. METHODS: Adults who smoke daily (n = 752) in the United States were randomly assigned to smoke very low nicotine content (VLNC) cigarettes versus normal nicotine content (NNC; control) cigarettes for 20 weeks. Linear mixed models determined if baseline drinking moderated the effects of VLNC versus NNC cigarettes on Week 20 smoking outcomes. Time-varying effect models estimated the daily association between smoking VLNC cigarettes and drinking outcomes. RESULTS: Higher baseline alcohol use (vs no use or lower use) was associated with a smaller effect of VLNC on Week 20 urinary total nicotine equivalents (ps < .05). No additional moderation was supported (ps > .05). In the subsample who drank (n = 415), in the VLNC versus NNC condition, daily alcohol use was significantly reduced from Weeks 17 to 20 and odds of binge drinking were significantly reduced from Weeks 9 to 17. By Week 7, in the VLNC cigarette condition (n = 272), smoking no longer predicted alcohol use but remained associated with binge drinking. CONCLUSIONS: We did not support negative unintended consequences of a nicotine product standard. Nicotine reduction in cigarettes generally affected smoking behavior for individuals who do not drink or drink light-to-moderate amounts in similar ways. Extended VLNC cigarette use may improve public health by reducing drinking behavior. IMPLICATIONS: There was no evidence that a VLNC product standard would result in unintended consequences based on drinking history or when considering alcohol outcomes. Specifically, we found that a very low nicotine standard in cigarettes generally reduces smoking outcomes for those who do not drink and those who drink light-to-moderate amounts. Furthermore, an added public health benefit of a very low nicotine standard for cigarettes could be a reduction in alcohol use and binge drinking over time. Finally, smoking VLNC cigarettes may result in a decoupling of the daily associations between smoking and drinking.

Biopsychosocial mechanisms associated with tobacco use in smokers with and without serious mental illness.

Smokers with serious mental illness (SMI) are less responsive to cessation treatments than those without SMI. In this study, we compared smokers with and without SMI on validated measures of biological and psychosocial factors associated with tobacco use. Smokers with (n = 58) and without SMI (n = 83) who were enrolled in parallel clinical trials were compared on measures of carbon monoxide (CO) exposure, nicotine exposure, tobacco-specific nitrosamine exposure, craving, smoking motives, affect, perceived stress, environmental exposure to smoke/smokers, respiratory symptoms, tobacco-related health risk perceptions, and whether they had received recent advice to quit smoking from a health care provider. Data were collected between 2013 and 2017 in Providence, Rhode Island, USA. Samples were compared using independent-sample t-tests and chi-squared tests. Smokers with SMI had higher CO, nicotine, and tobacco-specific nitrosamine exposure levels, greater cigarette dependence, higher craving, and higher scores on eight out of eleven smoking motives (p's < 0.05). Smokers with SMI reported more severe respiratory symptoms but lower perceived health risks of tobacco (p's < 0.05). These smokers were more likely to report having received advice to quit from a medical provider in the past 6 weeks (p < 0.05). Affect, stress, and exposure to smoke/smokers did not differ across samples. Our findings advance the understanding of the elevated smoking rates of people with SMI by comparing smokers with and without SMI on validated biopsychosocial measures. There is a need for interventions that reduce craving, reduce smoking motives, and increase risk awareness among smokers with SMI.

Relating individual differences in nicotine dependence severity to underpinning motivational and pharmacological processes among smokers from vulnerable populations.

We examined whether elucidating underpinning smoking motivation and related pharmacological processes enhances understanding of nicotine dependence among smokers from vulnerable populations. Data were obtained between Oct, 2016 and Sept, 2019 from 745 adult smokers with co-morbid psychiatric conditions or socioeconomic disadvantage at University of Vermont, Brown University, Johns Hopkins University. Smoking motivation was assessed using the Cigarette Purchase Task (CPT), a behavioral-economic task that models the relative reinforcing value of smoking under varying monetary constraint. Dependence severity was measured using the Heaviness of Smoking Index (HSI), Fagerström Test for Nicotine Dependence total scores (FTND), and FTND total scores minus items 1 and 4 (FTND2,3,5,6). We also assessed associations between dependence severity and smoking motivation with nicotine levels and metabolism rate. Principal Component Analysis was used to examine the latent structure of the conventional five CPT indices; bivariate and multivariable modeling was used to test associations. Factor analysis resulted in a two-factor solution, Amplitude (demand unconstrained by price) and Persistence (price sensitivity). CPT latent factors were associated with each dependence-severity measure (ps ≤ 0.0001), with associations stronger for Amplitude than Persistence across each, especially HSI which was exclusively associated with Amplitude. Amplitude and each dependence measure were associated with nicotine intake (ps ≤ 0.0002); Persistence was not (p = .19). Demand Amplitude more than Persistence appears key to understanding individual differences in dependence severity. Regarding potential application, the results suggest a need for interventions that more effectively target demand Amplitude to make greater headway in reducing smoking in vulnerable populations. Trial Registration:clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

Exclusive E-Cigarette Users Report Lower Levels of Respiratory Symptoms Relative to Dual E-Cigarette and Cigarette Users.

INTRODUCTION: Exclusive e-cigarette use has been shown to be associated with reduced levels of respiratory symptoms relative to smoking combustible cigarettes; this association has been less frequently studied in smokers using advanced-generation e-cigarette devices. Advanced-generation devices generate denser vapor than either early generation or pod-style devices, and engender longer inhalations; these vaping topography patterns may contribute to respiratory symptoms. METHODS: In a single-session, cross-sectional study of exclusive e-cigarette users (N = 59) and dual users of e-cigarettes and cigarettes (N = 54), participants completed questionnaires, including the American Thoracic Society Questionnaire (ATSQ) and were videotaped vaping their own device in the lab for 1 hour. Using a hierarchical regression method, we examined whether topography variables, level of nicotine concentration used in their e-cigarette device in the past month, e-cigarette dependence, amount of e-cigarette use in the past month, and smoking status (any smoking in the last month vs. none) predicted ATSQ score severity. RESULTS: There was a significant mean difference in ATSQ score across smoking status, with greater ATSQ scores for vapers who also smoked cigarettes (19.0, SD = 6.7) than for exclusive vapers (13.4, SD = 5.3). In the final model, of the predictors of interest, only cigarette smoking status predicted significantly greater ATSQ scores (overall F = 2.51, p = .006; R2 = .26; smoking status ß = 0.39, p < .0001). CONCLUSIONS: Findings suggest that differences in respiratory symptoms between dual and exclusive e-cigarette users appear to be attributable to combustible cigarette smoking, rather than more intense or frequent e-cigarette use across groups. IMPLICATIONS: In this comparison of exclusive advanced-generation vape device users (N = 59) versus dual users of these devices and combustible cigarettes (N = 54), we set out to determine the extent to which smoking status and e-cigarette use variables predicted self-reported respiratory symptom severity. We found that dual users showed greater respiratory symptom severity (ATSQ scores) than exclusive vapers. Despite examining vaping topography and other variables, smoking status and race were the only significant predictor of respiratory symptoms. We conclude that combustible cigarette use, not individual vaping topography, likely accounts for differences in respiratory symptoms between dual users and exclusive vapers.

Validation of an E-cigarette Purchase Task in Advanced Generation Device Users.

INTRODUCTION: Behavioral economic purchase tasks are used to estimate the reinforcing value of drugs by asking participants how much they would purchase across a range of increasing prices. We sought to validate such a task for e-cigarettes in experienced users of advanced generation, tank-style devices. METHODS: Dual users of cigarettes and e-cigarettes (N = 54) and exclusive e-cigarette users (N = 59) attended one session during which they completed assessments including two versions of the E-cigarette Purchase Task: one that asked how many puffs of their e-cigarette they would purchase in 24 hours at varying prices and one that asked how many mLs of e-liquid they would purchase. We correlated purchase task outcomes with other measures of e-cigarette use. We also compared the tasks across dual and exclusive users. RESULTS: Indices derived from the mLs-based task were more likely to be correlated with self-reported use rates, e-cigarette dependence, and cotinine levels than the puffs-based task. Exclusive users showed greater demand on than dual users only on the mLs version when using an F-test comparison method, while multivariate analysis of variance (MANOVA) results showed that dual users showed greater demand only on the puffs task. CONCLUSIONS: Results indicate that the mLs version had greater validity than the puffs version in terms of clinical indices. Dual users may still be on a trajectory to fully switching to e-cigarettes; thus, puffs as a measure may be more intuitive, as this measure is shared by cigarettes and e-cigarettes. For exclusive users, the unit they purchase their e-liquid in may be the most relevant unit and better capture their demand for that product. IMPLICATIONS: Behavioral economic purchase tasks have been widely used to understand nicotine use. We have developed two versions of a purchase task for e-cigarette use and compared the two versions in users of advanced generation e-cigarette devices. We found that the mLs version of the task better-reflected use patterns relative to a puffs version, which suggests that participants struggle to place monetary value on a unit of consumption (ie, puffs). Validated measures of e-cigarette reinforcement will be important as researchers and regulators determine which features of these products contribute to reinforcing efficacy.