Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial.
- Compared to a gradual nicotine reduction, an immediate nicotine reduction was associated with: lower toxicant exposure, fewer cigarettes smoked per day, greater reduction in nicotine dependence, and more smoke-free days.
- Funded by the National Institute on Drug Abuse (NIDA).
- Importance The optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined.
- Objectives To determine the effects of immediate vs gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure.
- Design, Setting, and Participants A double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017.
- Interventions (1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes.
- Main Outcomes and Measures Between-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention.
- Results Among 1250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, −4.06 parts per million [ppm] [95% CI, −4.89 to −3.23]; P < .0055), 3-HPMA (ratio of geometric means, 0.83 [95% CI, 0.77 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.88 [95% CI, 0.83 to 0.93]; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, −3.38 [95% CI, −4.40 to −2.36]; P < .0055), 3-HPMA (ratio of geometric means, 0.81 [95% CI, 0.75 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.86 [95% CI, 0.81 to 0.92]; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 [95% CI, −0.31 to 1.67]; P = .18), 3-HPMA (ratio of geometric means, 0.98 [95% CI, 0.91 to 1.06]; P = .64), and PheT (ratio of geometric means, 0.98 [95% CI, 0.92 to 1.04]; P = .52).
- Conclusions and Relevance Among smokers, immediate reduction of nicotine in cigarettes led to significantly greater decreases in biomarkers of smoke exposure across time compared with gradual reduction or a control group, with no significant differences between gradual reduction and control.
- Trial Registration clinicaltrials.gov Identifier: NCT02139930
Reducing nicotine exposure results in weight gain in smokers randomized to very low nicotine content cigarettes.
- Weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions
- The study indicates that weight gain is a likely consequence of reduced exposure to nicotine
- Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products (grant id: U54DA031659)
- Background: The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain.
- Methods: Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored.
- Findings: There were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups.
- Conclusions: The effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine.
Trial registration number: NCT01681875, Post-results.
Reduced Nicotine Content Cigarettes and Use of Alternative Nicotine Products: Exploratory Trial.
- There were higher rates of abstinence when smoking VLNC cigarettes compared with the normal nicotine condition
- The offer of, and instructions to use, reduced nicotine content cigarettes over an 8 week period led to greater reductions in smoking rates
- Funded by National Cancer Institute, and U.S. Food and Drug Administration (grant id: U19CA157345)
- Aims: To compare the use of alternative nicotine products, smoking behavior and tobacco biomarker exposure in smokers unwilling to quit who were assigned randomly to normal nicotine content (NNC) cigarettes or very low nicotine content (VLNC) cigarettes.
- Design: Randomized, parallel-arm 8-week study with assignment to VLNC (VLNC 1, n = 53) or NNC (NNC, n = 27) with access to non-cigarette combusted and non-combusted tobacco/nicotine products or to VLNC with access to only non-combusted products (VLNC2, n = 56).
- Setting: Clinics in Minnesota, USA.
- Participants: Smokers uninterested in quitting smoking with a mean [± standard deviation (SD)] age of 44 (± 14) years and smoking 16 (± seven) cigarettes/day; 51% female, 72% white.
- Measurements: During the experimental period, the measures taken included: rate of alternative products used, amount of and abstinence from combusted tobacco used and tobacco exposure biomarkers.
- Findings: There were higher rates of non-combusted alternative tobacco/nicotine product use in both VLNC conditions versus the NNC condition [rate ratio (RR) = 2.18, 95% confidence interval (CI) = 1.94, 2.46 and RR = 1.64, 95% CI = 1.46, 1.85, respectively] and in VLNC1 versus VLNC2 condition (RR = 1.33, 95% CI = 1.23, 1.44), accompanied by reduced biomarkers of exposure primarily in VLNC2 condition compared to NNC condition (Ps < 0.05). Fewer combusted products were smoked at almost all visits (Ps ≤ 0.02) and there were higher rates of abstinence for both VLNC conditions compared with the NNC condition (VLNC1 versus NNC: RR = 9.96, 95% CI = 5.01, 19.81; VLNC2 versus NNC: RR = 11.23, 95% CI = 5.74, 21.97).
- Conclusion: The offer of, and instructions to use, reduced nicotine content cigarettes during an 8-week period led to greater use of alternative tobacco/nicotine products compared with continued use of normal nicotine cigarettes and also reductions in smoking rates.
Response to varying the nicotine content of cigarettes in vulnerable populations: an initial experimental examination of acute effects
- There was no evidence of compensatory smoking with VLNC cigarettes in these vulnerable populations and there were significant reductions in nicotine withdrawal and cravings with VLNC cigarettes
- These initial results in more vulnerable populations of smokers are encouraging regarding the feasibility of a national policy to reduce the nicotine content of cigarettes to very low levels without substantial adverse effects
- Funded by a Tobacco Centers of Regulatory Science (TCORS) award (P50DA036114) from the National Institute on Drug Abuse and Food and Drug Administration
- Rationale: The purpose of this study was to begin researching the effects of very low nicotine content cigarettes in smokers especially vulnerable to dependence to assess their potential as a less dependence-producing alternative to current commercial cigarettes.
- Methods: Participants were 26 adult, daily cigarette smokers from one of three populations: economically disadvantaged women of reproductive age (n = 9), opioid-dependent individuals (n = 11), and individuals with affective disorders (n = 6). Participants completed fourteen 2-4-h experimental sessions in a within-subjects research design. Sessions were conducted following brief smoking abstinence. Four research cigarettes varying in nicotine content (0.4, 2.4, 5.2, and 15.8 mg/g) were studied under double-blind conditions, assessing smoking topography, subjective effects, and relative reinforcing effects of varying doses in concurrent choice tests. Results were collapsed across vulnerable populations and analyzed using repeated measures ANOVA.
- Results: No significant differences between doses were discernible in smoking topography. All doses were equi-effective at reducing nicotine withdrawal. Ratings of satisfaction from smoking were lower at the 0.4 compared to 15.8 mg/g dose. Participants preferred the 15.8 mg/g dose over the 0.4 and 2.4 but not the 5.2 mg/g doses in concurrent choice testing; no differences between the two lowest doses were noted.
- Conclusions: All cigarettes effectively reduced nicotine withdrawal with no differences in smoking topography, suggesting minimal compensatory smoking. Dependence potential was lowest at the 0.4 mg/g dose. These initial results are promising regarding the feasibility of lowering nicotine content in cigarettes to very low levels in vulnerable populations without untoward effects.
Evaluation of a reduced nicotine product standard: Moderating effects of and impact on cannabis use.
- Nicotine reduction in cigarettes could have beneficial effects on cigarette smoking regardless of cannabis use
- Among cannabis users and non-users, smokers randomized to VLNC cigarettes reported lower nicotine dependence, cigarettes per day, biomarkers of nicotine exposure, and craving compared to smokers randomized to normal nicotine content cigarettes
- Funded by the National Institute on Drug Abuse and FDA Center for Tobacco Products (grant id: U54 DA031659)
- Introduction: The Family Smoking Prevention and Tobacco Control Act authorized the FDA to reduce the nicotine content in cigarettes. Research is needed to guide proposed regulations, including evaluation of consequences to public health. This study evaluated how a reduced nicotine product standard might be moderated by and impact cannabis use.
- Methods: Secondary analysis of a controlled clinical trial examining the effects of nicotine content in cigarettes in adult daily smokers. Linear regression assessed whether baseline cannabis use moderated behavioral, subjective, or physiological effects of smoking very low nicotine content (VLNC) versus normal nicotine content (NNC) cigarettes. Repeated measures analysis of associations between nicotine condition and prevalence and frequency of cannabis use was completed using generalized estimating equations (GEE).
- Results: Cannabis use did not moderate most of the following effects of VLNC cigarettes: Among cannabis users and non-users, smokers randomized to VLNC cigarettes reported lower nicotine dependence, cigarettes per day, biomarkers of nicotine exposure, and craving compared to smokers randomized to NNC cigarettes. Non-cannabis using smokers randomized to VLNC cigarettes also reported lower smoking dependence motives and had lower tobacco-specific nitrosamine exposure and total puff volume versus smokers randomized to NNC cigarettes. For cannabis users, smokers randomized to VLNC cigarettes reported decreased positive affect. VLNC cigarette use did not impact the prevalence or frequency of cannabis use.
- Discussion: Findings provide evidence that nicotine reduction in cigarettes could have beneficial effects on cigarette smoking regardless of cannabis use. Results suggest that transitioning to VLNC cigarettes is unlikely to alter current rates of cannabis use.
Effects of 6-Week Use of Reduced-Nicotine Content Cigarettes in Smokers With and Without Elevated Depressive Symptoms.
- Relative to normal nicotine level cigarettes, VLNC cigarettes reduced smoking rates, nicotine dependence and cigarette craving.
- These findings provide initial evidence that a reduced-nicotine standard for cigarettes may reduce smoking, without worsening depressive symptoms, among smokers with elevated depressive symptoms.
- Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products (grant id: U54DA031659)
- Background: The FDA recently acquired regulatory authority over tobacco products, leading to renewed interest in whether reducing the nicotine content of cigarettes would reduce tobacco dependence in the United States. Given the association between depressive symptoms and cigarette smoking, it is important to consider whether smokers with elevated depressive symptoms experience unique benefits or negative consequences of nicotine reduction.
- Methods: In this secondary analysis of a randomized clinical trial that examined the effects of cigarettes varying in nicotine content over a 6-week period in non-treatment-seeking smokers, we used linear regression to examine whether baseline depressive symptom severity (scores on the Center for Epidemiologic Studies Depression Scale [CES-D]) moderated the effects of reduced-nicotine content (RNC) cigarettes, relative to normal-nicotine content (NNC) cigarettes, on smoking rates, depressive symptom severity, and related subjective and physiological measures.
- Results: Of the 717 participants included in this analysis, 109 (15.2%) had CES-D scores ≥ 16, indicative of possible clinical depression. Relative to NNC cigarettes, RNC cigarettes reduced smoking rates, nicotine dependence, and cigarette craving, and these effects were not significantly moderated by baseline CES-D score. A significant interaction between baseline CES-D score and cigarette condition on week 6 CES-D score was observed (p < .05); among those with CES-D scores ≥ 16 at baseline, those assigned to RNC cigarettes had lower week 6 CES-D scores than those assigned to NNC cigarettes. Among those in the lowest nicotine content conditions, biochemically confirmed compliance with the RNC cigarettes was associated with an increase in CES-D score for those with baseline CES-D scores < 16 and no change in CES-D score for those with baseline CES-D scores ≥ 16.
- Conclusions: These findings provide initial evidence that a reduced-nicotine standard for cigarettes may reduce smoking, without worsening depressive symptoms, among smokers with elevated depressive symptoms.
Estimations and predictors of non-compliance in switchers to reduced nicotine content cigarettes
- Despite high levels of non-compliance, smokers reduced their intake of nicotine by an average of 60% after smoking only VLNC cigarettes for six weeks
- After six weeks of smoking VLNC cigarettes, self-reported dependence and daily nicotine intake were lower at the end of the trial compared to the control condition
- Funded by the National Institute on Drug Abuse (NIDA) and FDA Center for Tobacco Products (CTP) (grant id: U54 DA031659) and the National Cancer Institute (NLB) (grant id: R01 CA78603)
Background and Aims
Clinical trials on the impact and safety of reduced nicotine content cigarettes (RNCs) are ongoing, and an important methodological concern is participant compliance with smoking only RNCs. Our aims were to measure non-compliance biochemically with urine cotinine (COT) and total nicotine equivalents (TNEs), compare with self-reported non-compliance and identify associated covariates.
Secondary analysis of a double-blind, parallel, randomized clinical trial.
Research centers from the United States, enrolling participants from June 2013 to July 2014.
Volunteer sample of 242 participants (55% Caucasian), average age of 41.2 years, smoking at least five cigarettes per day (CPD).
Smoking very low nicotine cigarettes (VLNCs; 0.4 mg nicotine/g tobacco) for 6 weeks.
The primary outcome was biochemically verified non-compliance, measured as thresholds of COT/CPD and TNE/CPD ratios, considering changes in nicotine content from conventional levels to VLNCs, and as an absolute threshold of week 6 TNEs. Self-reported non-compliance was measured via daily phone calls. Key predictors included age, sex, race, menthol preference, nicotine metabolite ratio, time to first cigarette, dependence, CPD, TNEs, tar level and cigarette evaluation.
Estimates of non-compliance with smoking the VLNCs exclusively include: the biochemical ratios (both 78%), the week 6 TNE threshold (76%) and self-report (39%). Of the key covariates, age, dependence and cigarette evaluations of satisfaction were significant; for age, younger participants more likely to be non-compliant [P = 0.01; odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96–0.99]. Dependence was associated significantly with self-reported non-compliance (P = 0.01; OR = 1.28, 95% CI = 1.06–1.55). Cigarette evaluations of satisfaction were associated significantly with non-compliance (P = 0.001; OR = 0.71, 95% CI = 0.61–0.82).
Among smokers volunteering to smoke only very low nicotine cigarettes for 6 weeks, non-compliance was common and biochemical assessments detected more cases of non-compliance than self-report. Despite high levels of non-compliance, smokers reduced their intake of nicotine by an average of 60%.
A Randomized Controlled Trial of Progressively Reduced Nicotine Content Cigarettes on Smoking Behaviors, Biomarkers of Exposure, and Subjective Ratings
- The lowest reduced nicotine level cigarette tested (0.05 mg nicotine yield) may reduce harm exposure
- Use of VLNC cigarettes decreased daily consumption, as well as nicotine and toxicant exposure, relative to use of moderate nicotine content cigarettes
- Funded by the National Institutes of Health
- Background: The U.S. FDA has the authority to reduce cigarette nicotine content if found to benefit public health. Reduced nicotine content (RNC) cigarette use does not appear to increase harm exposure, but studies have not rigorously assessed smoking behavior or used a comprehensive panel of biomarkers. This study examined the effects of progressively decreasing RNC cigarettes on smoking behaviors, biomarkers of exposure, and subjective ratings.
- Methods: One hundred and fifty-eight daily, non–treatment-seeking smokers participated in a 35-day randomized, unblinded, parallel study. After a 5-day baseline period, participants were randomly assigned to an experimental group (n = 80) that smoked progressively decreasing RNC cigarettes during three 10-day periods, or control group (n = 78) that smoked their own brand throughout the study.
- Results: Daily cigarette consumption significantly increased for the intermediate RNCs (P‘s < 0.001) but approached baseline rate for the lowest RNC (P = 0.686); in contrast, puffing behavior significantly decreased at intermediate levels and increased for the lowest RNC (P‘s < 0.001). Cotinine and NNAL significantly decreased by RNC period (P‘s ≤ 0.001–0.02), whereas CO boost initially increased (P‘s = 0.001–0.005). 1-HOP did not change by period (P = 0.109).
- Conclusions: Smoking behaviors changed by RNC period via CPD and puffing behavior. Biomarkers of exposure generally decreased with nicotine content.
Smoking Topography Characteristics of Very Low Nicotine Content Cigarettes, With and Without Nicotine Replacement, in Smokers With Schizophrenia and Controls
- Acute use of VLNC cigarettes does not increase intensity of smoking in schizophrenics and this supports the feasibility of a nicotine reduction policy
- During VLN cigarette sessions, puff duration increased and time between puffs decreased, but participants smoked fewer puffs, resulting in a net decrease in cigarette and total session volume
- Funded by the National Institute on Drug Abuse (NIDA)
- Introduction: Reducing the nicotine content of cigarettes to a minimally addictive level has been proposed as a regulatory strategy for reducing tobacco dependence. However, smokers with schizophrenia (SS) may be prone to changing their smoking topography in efforts to compensate for the reduction in nicotine content. The aims of this study were to compare smoking topography characteristics of usual-brand and very low nicotine content (VLNC) cigarettes in SS and control smokers without psychiatric illness (CS), and to determine whether nicotine replacement reversed any changes in topography produced by VLNC cigarettes.
- Methods: Using a within-subjects, counter-balanced design, SS ( n = 27) and CS ( n = 23) smoked usual brand cigarettes, VLNC cigarettes while wearing placebo patches (VLNC + PLA), or VLNC cigarettes while wearing transdermal nicotine patches totaling 42mg (VLNC + NIC) during 5-hour ad libitum smoking sessions. Cigarettes were smoked through topography measurement devices.
- Results: Across conditions, SS smoked more puffs per session and per cigarette, had higher cigarette volumes, and had shorter inter-puff intervals than CS ( P s < .01). During VLNC cigarette sessions, puff duration increased and time between puffs decreased, but participants smoked fewer puffs, resulting in a net decrease in cigarette and total session volume ( P s < .001). There were no significant interactions between group and condition.
- Conclusions: These findings indicate that acute use of VLNC cigarettes does not increase intensity of smoking in SS, and support the feasibility of a nicotine reduction policy.
- Implications: Reducing the nicotine in cigarettes to a minimally addictive level has been proposed as a means of reducing tobacco dependence. However, smokers, particularly those with schizophrenia (SS) may alter their puffing in an attempt to extract more nicotine from VLNC cigarettes. This study compared smoking topography of usual brand versus VLNC cigarettes, combined with placebo or transdermal nicotine patches, in SS and controls. Although some changes in topography were indicative of compensatory smoking, total puffs and total cigarette volume were reduced with VLNC cigarettes, indicating that acute VLNC cigarette use does not increase smoking in SS.
The Impact of Smoking Very Low Nicotine Content Cigarettes on Alcohol Use.
- A reduced nicotine product standard could positively impact related health risk behaviors like drinking
- Compensatory drinking is unlikely to occur in response to switching to VLNC cigarettes and reducing the nicotine content of cigarettes may reduce alcohol consumption
- Funded by the National Institute on Drug Abuse and FDA Center for Tobacco Products (CTP) (grant id: U54 DA031659) and National Institute on Alcohol Abuse and Alcoholism (grant id: F31AA022291)
- Background: Reducing the nicotine content in cigarettes could improve public health by reducing smoking and toxicant exposure, but may also have unintended consequences on alcohol use. The primary objective of this study was to examine the effect of reducing the nicotine content in cigarettes on alcohol outcomes. The secondary aim was to examine whether the effects of these cigarettes on alcohol outcomes were mediated by changes in nicotine exposure, smoking behavior, or withdrawal.
- Methods: Between June 2013 and July 2014, we conducted a 7-arm, double-blind, randomized clinical trial at 10 U.S.-based sites. Daily smokers not currently interested in quitting (n = 839) were assigned to equally sized groups to smoke for 6 weeks cigarettes containing either normal nicotine content (NNC; 15.8 mg/g, 9 mg tar), moderate nicotine content (5.2 mg/g nicotine, 9 mg tar), or very low nicotine content (VLNC; 0.4 to 2.4 mg/g, 9 to 13 mg tar). This investigation focused on a subsample of current drinkers (n = 403). Each reduced nicotine content cigarette condition was compared to the NNC control condition with respect to trajectories over the 6-week period of average daily alcohol use and occurrence of binge drinking. Moderating variables were considered. Mediation analyses tested potential explanatory processes including changes in nicotine exposure, cigarettes per day, and withdrawal.
- Results: Over time, reduced nicotine exposure and smoking rate mediated effects of VLNC cigarette use on reduced alcohol use. There was no evidence of compensatory drinking in response to nicotine reduction or nicotine withdrawal, even among subgroups expected to be at greater risk (e.g., relatively heavier drinkers, highly nicotine-dependent individuals).
- Conclusions: The findings suggest that compensatory drinking is unlikely to occur in response to switching to VLNC cigarettes. In contrast, reducing the nicotine content of cigarettes may reduce alcohol use (clinicalTrials.gov number, NCT01681875).