Christopher A. Arger

Addiction Potential of Cigarettes With Reduced Nicotine Content in Populations With Psychiatric Disorders and Other Vulnerabilities to Tobacco Addiction.

Importance A national policy is under consideration to reduce the nicotine content of cigarettes to lower nicotine addiction potential in the United States. Objective To examine how smokers with psychiatric disorders and other vulnerabilities to tobacco addiction respond to cigarettes with reduced nicotine content. Design, Setting, and Participants A multisite, double-blind, within-participant assessment of acute response to research cigarettes with nicotine content ranging from levels below a hypothesized addiction threshold to those representative of commercial cigarettes (0.4, 2.3, 5.2, and 15.8 mg/g of tobacco) at 3 academic sites included 169 daily smokers from the following 3 vulnerable populations: individuals with affective disorders (n = 56) or opioid dependence (n = 60) and socioeconomically disadvantaged women (n = 53). Data were collected from March 23, 2015, through April 25, 2016. Interventions After a brief smoking abstinence, participants were exposed to the cigarettes with varying nicotine doses across fourteen 2- to 4-hour outpatient sessions. Main Outcomes and Measures Addiction potential of the cigarettes was assessed using concurrent choice testing, the Cigarette Purchase Task (CPT), and validated measures of subjective effects, such as the Minnesota Nicotine Withdrawal Scale. Results Among the 169 daily smokers included in the analysis (120 women [71.0%] and 49 men [29.0%]; mean [SD] age, 35.6 [11.4] years), reducing the nicotine content of cigarettes decreased the relative reinforcing effects of smoking in all 3 populations. Across populations, the 0.4-mg/g dose was chosen significantly less than the 15.8-mg/g dose in concurrent choice testing (mean [SEM] 30% [0.04%] vs 70% [0.04%]; Cohen d = 0.40; P < .001) and generated lower demand in the CPT (&agr; = .027 [95% CI, 0.023-0.031] vs &agr; = .019 [95% CI, 0.016-0.022]; Cohen d = 1.17; P < .001). Preference for higher over lower nicotine content cigarettes could be reversed by increasing the response cost necessary to obtain the higher dose (mean [SEM], 61% [0.02%] vs 39% [0.02%]; Cohen d = 0.40; P < .001). All doses reduced Minnesota Nicotine Withdrawal Scale total scores (range of mean decreases, 0.10-0.50; Cohen d range, 0.21-1.05; P < .001 for all), although duration of withdrawal symptoms was greater at higher doses (&eegr;2 = 0.008; dose-by-time interaction, P = .002). Conclusions and Relevance Reducing the nicotine content of cigarettes may decrease their addiction potential in populations that are highly vulnerable to tobacco addiction. Smokers with psychiatric conditions and socioeconomic disadvantage are more addicted and less likely to quit and experience greater adverse health impacts. Policies to reduce these disparities are needed; reducing the nicotine content in cigarettes should be a policy focus.

Effectiveness of Motivational Incentives for Adolescent Marijuana Users in a School-Based Intervention

PURPOSE This study examined whether adolescents receiving Motivational Interviewing (MI) intervention have different outcomes compared to those receiving Motivational Incentives (Motivational Interviewing combined with Contingency Management; MI+CM). METHOD A total of 136 adolescents (from a parent study of 220 adolescents) with problematic substance use were recruited from 8 high schools in Washington State, where they completed either 8-weeks of MI or MI+CM. Frequency of marijuana use was assessed at baseline, at the end-of-treatment, and at 16-week follow-up. RESULTS A balanced and matched sample was created using propensity scores, then analyzed using Hierarchical Linear Modeling (HLM). Multilevel regression analyses revealed that adolescents who received MI+CM exhibited a greater reduction in use across time (p<.05). Reductions at the end-of-treatment were greater for the MI+CM condition (Cohens d=-.82) compared to MI alone (Cohens d=-.33), but did not differ at 16-week follow-up. Adolescents receiving MI+CM showed significantly fewer negative consequences of marijuana use at the end-of-treatment (t1, 124=2.26, p<.05), higher use of coping strategies (t1, 124=3.01, p<.01), and increased likelihood to attend additional treatment for substance use (χ2 1, 124=4.12 p<.05), though hypothesized improvements in motivation and school attendance were not found. Use of coping strategies at the end-of-treatment had a significant indirect effect on the relationship between the intervention condition and marijuana use at the end-of-treatment (F3, 121=10.20, R2=.20, p<.01). CONCLUSION These results suggest that the inclusion of contingencies into adolescent marijuana treatment decreases the end-of-treatment frequency of marijuana use and related consequences while increasing the use of coping strategies and the pursuit of additional treatment.

Use of higher-nicotine/tar-yield (regular full-flavor) cigarettes is associated with nicotine dependence and smoking during pregnancy among U.S. women.

The present study examined full-flavor cigarette use among women of reproductive age to assess whether use is associated with greater nicotine dependence and smoking during pregnancy. We used data from the National Survey on Drug Use and Health (2005-2014). Consecutive years were combined to assure sufficient numbers of pregnant women. We examined whether use of full-flavor cigarettes was associated with greater odds of nicotine dependence using the Fagerstrom Test for Nicotine Dependence and Nicotine Dependence Syndrome Scale (NDSS), controlling for other smoking characteristics. We next compared prevalence of smoking and use of full-flavor versus lower-yield cigarettes among non-pregnant versus pregnant women and across trimesters. Lastly, we examined whether pregnancy was associated with greater odds of using full-flavor cigarettes after controlling for potential confounders. Use of full-flavor cigarettes was associated with greater adjusted odds of nicotine dependence compared to lower yields among non-pregnant (Fagerstrom: 2.50, 95% CI: 2.32,2.70; NDSS: 1.75, 95% CI: 1.62,1.88) and pregnant (Fagerstrom: 1.53, 95% CI: 1.13,2.05; NDSS: 1.53, 95% CI: 1.12,2.10) smokers. As smoking prevalence decreased among pregnant compared to non-pregnant women (14.31±0.55% versus 22.73±0.17%), prevalence of using full-flavor cigarettes increased (54.82±1.63% versus 38.86±0.35%). Similarly, as smoking prevalence decreased from 1st to 3rd trimester (19.65±1.2%, 12.50±0.84%, 11.3±0.83%), prevalence of using full-flavor cigarettes increased (53.12±2.53%, 50.57+2.92%, 63.63±3.19%). Overall, pregnancy was associated with 1.43 (95% CI: 1.22, 1.68) greater adjusted odds of full-flavor cigarette use. These results indicate that users of full-flavor cigarettes have greater nicotine-dependence risk and lower likelihood of quitting smoking during pregnancy, relationships with potential for serious adverse maternal-infant health impacts.

Preliminary validity of the modified cigarette evaluation questionnaire in predicting the reinforcing effects of cigarettes that vary in nicotine content

Validity studies evaluating self-report measures in relation to behavioral preference of cigarettes varying in nicotine content are needed. The current study examined the relationship between ratings on the modified Cigarette Evaluation Questionnaire (mCEQ) and the relative reinforcing effects of Spectrum research cigarettes (15.8, 5.2, 2.4, 0.4 mg per gram of tobacco). Data for this secondary analysis were obtained from a double-blind study (Higgins et al., 2017) evaluating the subjective and reinforcing effects of Spectrum cigarettes under acute smoking abstinence. Current smokers (N = 26) were recruited from three vulnerable smoking populations (economically disadvantaged women of reproductive age, opioid-maintained individuals, individuals with affective disorders). In Phase 1 (five sessions), the mCEQ (Satisfaction, Psychological Reward, Enjoyment of Respiratory Tract Sensations, Craving Reduction, Aversion subscales) was administered following ad lib smoking of Spectrum cigarettes and subscale differences scores were calculated by subtracting ratings of the 15.8 mg/g cigarette from ratings of the reduced nicotine content cigarettes. In Phase 2 (six sessions), participants completed six 2-dose concurrent choice tests. The relationship between mCEQ subscale difference scores from Phase 1 and nicotine dose choice from Phase 2 was examined using mixed-model repeated-measures analyses of variance. Higher Satisfaction and lower Aversion subscale difference scores were associated with choosing the 15.8 mg/g cigarette more than the 5.2, 2.4, and 0.4 mg/g cigarettes. Scores on the other mCEQ subscales were not associated with nicotine choice. These results provide support for validity of the mCEQ Satisfaction and Aversion subscales predicting the relative reinforcing effects and abuse liability of varying nicotine content cigarettes.

Response to reduced nicotine content cigarettes among smokers differing in tobacco dependence severity

This study examines whether tobacco dependence severity moderates the acute effects of reducing nicotine content in cigarettes on the addiction potential of smoking, craving/withdrawal, or smoking topography. Participants (N = 169) were daily smokers with mild, moderate, or high tobacco-dependence severity using the Heaviness of Smoking Index. Following brief abstinence, participants smoked research cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg nicotine/g tobacco) in a within-subject design. Results were analyzed using repeated measures analysis of co-variance. No main effects of dependence severity or interactions with nicotine dose were noted in relative reinforcing effects in concurrent choice testing or subjective effects on the modified Cigarette Evaluation Questionnaire. Demand for smoking in the Cigarette Purchase Task was greater among more dependent smokers, but reducing nicotine content decreased demand independent of dependence severity. Dependence severity did not significantly alter response to reduced nicotine content cigarettes on the Minnesota Tobacco Withdrawal Scale nor Questionnaire of Smoking Urges-brief (QSU) Factor-2 scale; dependence severity and dose interacted significantly on the QSU-brief Factor-1 scale, with reductions dependent on dose among highly but not mildly or moderately dependent smokers. Dependence severity and dose interacted significantly on only one of six measures of smoking topography (i.e., maximum flow rate), which increased as dose increased among mildly and moderately but not highly dependent smokers. These results suggest that dependence severity has no moderating influence on the ability of reduced nicotine content cigarettes to lower the addiction potential of smoking, and minimal effects on relief from craving/withdrawal or smoking topography.

Pregnancy-Induced Increases in the Nicotine Metabolite Ratio: Examining Changes During Antepartum and Postpartum

Introduction Pregnancy-induced increases in nicotine metabolism may contribute to difficulties in quitting smoking during pregnancy. However, the time-course of changes in nicotine metabolism during early and late pregnancy are unclear. The present study investigated how pregnancy alters the nicotine metabolite ratio (NMR), a common biomarker of nicotine metabolism among non-pregnant smokers. Methods Urinary NMR (3-hydroxycotinine (3HC)/cotinine (COT)) was assessed using total (free + glucuronide) and free compounds among women (N=47) from a randomized controlled trial for smoking cessation who self-reported smoking and provided a urine sample during early pregnancy (M ± SD = 12.5 ± 4.5 weeks gestation), late pregnancy (28.9 ± 2.0 weeks gestation) and six months postpartum (24.7 ± 1.2 weeks since childbirth). Urine samples were analyzed using LC-MS/MS and NMR was calculated as Total 3HC/Free COT, Free 3HC/Free COT, and Total 3HC/Total COT. Results NMR was significantly higher during early and late pregnancy compared to postpartum and significantly increased from early to late pregnancy measured by Total 3HC/Free COT (0.76, 0.89, 0.60; all ps < .05) and Free 3HC/Free COT (0.68, 0.80, 0.51; all ps < .05). Total 3HC/Total COT did not vary over time (p = .81). Conclusions Total 3HC/Free COT and Free 3HC/Free COT increased in the first trimester and continued to increase throughout pregnancy suggesting a considerable increase in nicotine metabolism over gestation. Future analyses are needed to interpret the changes in NMR in the context of nicotine pharmacokinetics, as well its impact on changes in smoking behavior and cessation outcomes.

Longitudinal Influence of Pregnancy on Nicotine Metabolic Pathways

Nicotine metabolism increases in pregnancy, which may contribute to the difficulties that pregnant women have in quitting smoking. We aimed to determine the extent and timing of changes in nicotine metabolic pathways, including C-oxidation, N-glucuronidation, and the pregnancy-induced influences on the activity of enzymes mediating these pathways (CYP2A6 and UGT2B10, respectively). Current smoking pregnant women (n = 47) provided a urine sample during early pregnancy (12.5 weeks), late pregnancy (28.9 weeks), and 6 months postpartum. Concentrations of urinary nicotine and metabolites were analyzed using liquid chromatography tandem mass spectrometry and compared using general linear repeated measures analyses. Nicotine C-oxidation was 1.07-fold (P = 0.12) and 1.11-fold (P < 0.001) higher at early and late pregnancy, respectively, compared with postpartum. Nicotine N-glucuronidation was 1.33-fold (P = 0.06) and 1.67-fold (P = 0.003) higher at early and late pregnancy, respectively, compared with postpartum. The CYP2A6 phenotype ratio (total 3′-hydroxycotinine/cotinine) was significantly higher at early and late pregnancy compared with postpartum (all P < 0.05) and correlated with nicotine C-oxidation (all P < 0.001), suggesting CYP2A6 activity is induced during pregnancy. The UGT2B10 phenotype ratio (nicotine glucuronide/nicotine) was higher at early and late pregnancy compared with postpartum (P = 0.07 and P < 0.05, respectively) and correlated with a second UGT2B10 phenotype ratio (cotinine glucuronide/cotinine) (all P < 0.001), suggesting UGT2B10 activity is induced during pregnancy. In conclusion, pregnancy-induced increases in nicotine metabolism start by 12 weeks gestation and continue as pregnancy progresses most likely due to induction of CYP2A6 and UGT2B10, resulting in potential reductions in the effectiveness of nicotine replacement therapies and an increase in metabolism of other CYP2A6 and UGT2B10 substrates during pregnancy.

Correspondence between self-reported and biochemical measures of smoking in opioid-dependent pregnant women

Aims: Smoking exacerbates adverse outcomes among opioiddependent pregnant women (e.g., a more severe neonatal abstinence syndrome in exposed neonates). Vermont birth certificate data for opioid-dependent pregnant women indicates a significant decrease in their self-reported smoking rate over the course of pregnancy, from a mean of 17.9 cigarettes per day (CPD) prior to pregnancy to 13.8, 10.9, and 9.7 in the first, second and third trimesters, respectively. This study examined self-reported smoking rate andbiochemicalmeasures of smoking to testwhether self-reported decreases in smokingwere paralleled by decreases in biochemical measures. Methods: Participants were 18 opioid-dependent pregnant women enrolled in clinical trials for smoking cessation. All women continued to smoke throughout their pregnancies. Self-reported CPD prior to pregnancy were collected at the Intake Assessment. CPD, breathCO, andurine cotininewere collected at intake, at a second assessment 1 month later (Early Pregnancy Assessment), and againat theendofpregnancy (≥28weeksgestation; LatePregnancy Assessment). Results: Like birth certificate data, self-reported smoking rates decreased from amean of 22.6 prior to pregnancy to 15.5 at intake. During pregnancy, self-reported CPD decreased significantly from 15.5, 7.5, and 9.0 at Intake and Early and Late Pregnancy Assessments, respectively (p< .001). However, parallel changes were not evident in biochemical measures of smoking. Mean CO was 13.3, 10.0, and 12.3ppm (p= .11) and mean urine cotinine was 1422.8, 1387.8, and 1294.1ng/ml (p= .71) at the three assessments. Conclusions: Discrepancies between self-report and biochemical measures may be explained by misrepresentation of self-reported smoking or reductions in CPD offset by changes in smoking topography (i.e., compensatory smoking). Further research is needed to understand changes in smoking among opioid-dependent pregnant women. Financial support:NICHDR01HD075669, NIDAR01DA014028 and R01 DA031928, and FDA/NIDA P50 DA036114.