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.

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), individuals with affective disorders (n = 6). Participants completed fourteen 2–4 hrs 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, 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.

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 ( = 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 ( = 0.12) and 1.11-fold ( < 0.001) higher at early and late pregnancy, respectively, compared with postpartum. Nicotine N-glucuronidation was 1.33-fold ( = 0.06) and 1.67-fold ( = 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 < 0.05) and correlated with nicotine C-oxidation (all < 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 ( = 0.07 and < 0.05, respectively) and correlated with a second UGT2B10 phenotype ratio (cotinine glucuronide/cotinine) (all < 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.