, 2001). In that study, the highest predicted probability of quitting was observed at the highest erythro-metabolite sellckchem concentrations. A limitation of our study is that we measured total bupropion. Bupropion as provided for medical use is a racemic mixture, and the rate of elimination and the pharmacologic activity of the different steroisomers of bupropion and its metabolisms differ from one another. Thus it is possible that finding little or no change in total bupropion and metabolite concentrations might miss stereoselective changes in concentrations that could be selective for one enantiomer but not for total analyte. Measuring the enantiomers of hydroxybupropion may also be important because animal studies show that 2S,3S-hydroxybupropion is much more active on nicotinic receptors and on behavioral models of depression and development of nicotine reward compared with the 2R,3R-hydroxybupropion isomer (Damaj et al.

, 2004, 2010). In addition, without knowing the intake dose of menthol in the smokers, we were not able to normalize our results to plasma levels of menthol or its metabolite. Also, the small sample size with resultant large SDs may have contributed to lack of statistical significance in observed changes. It could be possible for a study with a larger sample size to reach different conclusions. In addition, although participants were instructed and incentivized to quit smoking during the nonsmoking phase of the study, most participants were not abstinent, and this may have contributed to finding a lack of significant differences by menthol status.

Nevertheless, being the first to examine the effects of mentholated cigarettes on the PKs of bupropion, a Food and Drug Administration�Capproved smoking pharmacotherapy, this study provided estimates of plasma concentrations of bupropion and metabolites that would inform design of future studies assessing interactions between menthol and other drugs. In conclusion, we did not find a significant effect of menthol compared with nonmenthol cigarette smoking on the PKs of bupropion and metabolites at steady state. It is possible that the adverse effect of menthol cigarettes on bupropion-aided smoking cessation is a pharmacodynamic one, perhaps acting via addiction-related sensory or neurochemical pathways.

Given poorer smoking cessation outcomes observed among menthol smokers in some studies, research is needed to advance the understanding of mechanisms underlying disparities in smoking cessation outcomes related to smoking of menthol cigarettes. Funding This work was supported by the National Institutes of Health (R21DA018720 and M01 Brefeldin_A RR0239410). Declaration of Interests Dr Benowitz has been a consultant to several pharmaceutical companies that are developing or market smoking cessation medications and has been a paid expert witness in litigation against tobacco companies.