One possibility is that there were differences in nicotine concentrations by menstrual phase or depressive status that such were not able to be quantified and, therefore, the results underestimate the differences between groups. However, the frequency of undetectable levels did not appear to vary by menstrual phase (F: n = 13; L: n = 16) nor depressive symptoms status (NDS: n = 15; DS: n = 16) . In post-hoc analyses, excluding participants with any undetectable levels of serum nicotine, the overall results were largely unchanged (data not shown). Second, it is unknown how these observations may apply to smoking cessation efforts. It is well known that women receive less benefit from NRT (e.g., Bjornson et al., 1995; Perkins & Scott, 2008).

Our results suggest that women may receive less beneficial effects from nicotine replacement during the luteal phase because lower levels of nicotine are achieved, accounting for higher relapse in this phase in studies that have used the nicotine patch. Finally, our results are limited by our relatively small sample size, which limits our power to detect smaller differences in the physiological response to nicotine by menstrual phase and/or depressive symptoms status. Despite these limitations, this study has several strengths including its detailed measurement of menstrual phase, sex hormones, depressive symptoms status, and smoking status. Further, the randomized crossover study design is a strength of this study as this type of design limits the bias and confounding typically occurring in other study designs.

In conclusion, this study provides further evidence for the role of sex hormones and depressive symptoms on physiological response to nicotine in women. Although additional research is needed to further characterize the role of menstrual phase and depressive symptoms on risk for smoking relapse in women, these observations should be taken into consideration in the development of new smoking cessation interventions. FUNDING This project was funded by National Institute on Drug Abuse (NIDA) grant R01 DA08075. This publication was made possible by support from the National Center for Research Resources (NCRR) grant M01 RR00400, a component of the National Institutes of Health (NIH).

Additional support comes from the National Center for Research Resources (NCRR) grant 1UL1RR033183 and National Center for Advancing Translational Sciences (NCATS) grant 8UL1TR000114-02 of the NIH to the University of Minnesota Clinical and Translational Science Dacomitinib Institute (CTSI). The University of Minnesota CTSI is part of a national Clinical and Translational Science Award (CTSA) consortium created to accelerate laboratory discoveries into treatments for patients. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of CTSI, NIDA, NCRR, NCATS, or NIH.