Gender differences have been noted in the neuropharmacological actions of nicotine , such that P4 and E2 have been associated with the rewarding effects of nicotine , with E2 regulating nicotine-induced release of dopamine . A recent meta-analysis by Weinberger and colleagues suggested that the luteal phase of the menstrual cycle, a time in which P4 and E2 levels are elevated, is associated with greater nicotine withdrawal and moderately higher craving than the follicular phase, a time of low P4 levels. Severity of pre-menstrual symptoms, often occurring towards the end of the luteal phase when E2 and P4 levels are elevated, is associated with smoking behavior, nicotine withdrawal, and relapse . These results suggest that sex hormone levels, as a function of menstrual cycle phase, may affect smoking related behaviors and ability to quit smoking. Sex differences have also been examined in response to opioid receptor antagonists such as naltrexone. Naltrexone has been shown to produce greater nicotine withdrawal and ACTH and cortisol levels in women than men . Menstrual cycle phase and sex hormone levels have been shown to affect responses to naltrexone . A previous study enrolled 70 subjects in a double-blind, placebo-controlled human laboratory study in which men and women completed two sessions where they received either 50 mg oral naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular or luteal phase of their menstrual cycle. Due to the change in sex hormone levels across the menstrual cycle,cannabis hydroponic set up the early follicular and luteal phases of the menstrual cycle allowed for a comparison of high and low E2 and P4 levels.

Hormone measurements of E2, P4, follicle stimulating hormone , and luteinizing hormone were used to confirm menstrual cycle phase. In luteal women, but not early follicular women or men, naltrexone increased salivary cortisol from baseline compared with placebo . Naltrexone significantly increased serum cortisol and prolactin in both early follicular and luteal women, but not men. Of note, luteal women’s serum cortisol and prolactin responses to naltrexone were significantly greater than those of both men and early follicular women. In luteal women, but not in men and early follicular women, In luteal women, but not early follicular women or men, naltrexone increased salivary cortisol from baseline compared with placebo . Naltrexone significantly increased serum cortisol and prolactin in both early follicular and luteal women, but not men. Of note, luteal women’s serum cortisol and prolactin responses to naltrexone were significantly greater than those of both men and early follicular women. In luteal women, but not in men and early follicular women,naltrexone increased the severity of adverse effects from baseline . These results suggest that women in the luteal phase of the menstrual cycle, most likely due to high P4 and E2 levels, are more sensitive to the effects of naltrexone compared to men and early follicular women with low P4 and E2 levels. The increased negative health consequences and worse smoking cessation outcomes provide clear evidence for the necessity of finding smoking cessation medications that are effective among women. Chapter 2 of the dissertation examined the effects of sex hormones on smoking and drinking outcomes among premenopausal women during a randomized controlled trial for smoking cessation and drinking reduction. This chapter is currently published in Alcohol and Alcoholism. Cigarette smoking remains a leading preventable cause of morbidity and mortality. Sex differences in cigarette smoking and smoking cessation rates have been noted. The 2019 National Health Interview Survey found 14% of U.S. adults reported current cigarette smoking; of that, 15.3% were men and 12.7% were women .

While men are more likely to smoke than women , women may be at greater risk for worse health consequences, have greater difficulty quitting, and often have less success in smoking cessation trials . It is therefore essential that sex be examined in smoking cessation treatment. While pharmacological treatments are available to aid in smoking cessation and drinking reduction, their efficacy is moderate. Varenicline is a first-line treatment for smoking cessation that has shown benefit on drinking outcomes as well . Several studies have found that the effects of varenicline on smoking outcomes may be sex dependent. A meta-analysis by McKee and colleagues found that in comparison to men, varenicline was more effective among female smokers for short and immediate smoking cessation outcomes but was equally efficacious for longer term outcomes. These findings are promising, however in contrast to the aforementioned findings of women experiencing worse outcomes in smoking cessation trials. Naltrexone has a robust literature for drinking outcomes and has also been used in a host of smoking cessation trials in heavy drinking smokers with mixed results . Studies of sex effects have also considered the role of menstrual cycle hormones on smoking and drinking behaviors. At the onset of menses and throughout the follicular phase of the menstrual cycle, progesterone remains low. After ovulation, P4 rises to its peak level by mid-luteal phase and gradually declines before the next menses. Conversely, estradiol is lowest during menses, rises throughout the follicular phase, peaks at ovulation, and then reaches a secondary peak during the luteal phase before again declining. In comparison to the luteal phase, women randomized to quit smoking in the follicular phase exhibited worse cessation outcomes as shown by fewer days to relapse from continuous abstinence and prolonged abstinence . When examining hormone values directly, P4 has been shown to be protective in reducing smoking by decreasing the rewarding aspects of smoking, while E2 may increase smoking through increasing smoking reward .

An observational study in non-treatment seeking smokers revealed that higher within-subject levels of P4 were associated with reduced cigarettes per day, however there was no effect of estradiol on cigarettes per day . Furthermore, exogenous progesterone has also been shown to promote smoking cessation among women . Specific to alcohol use, P4 and E2 have also been shown to have a distinct association with alcohol use. Alcohol consumption, both in a naturalistic environment and in a controlled experimental condition, has been associated with reductions in P4 . Greater endogenous E2 was associated with an increased likelihood of drinking and binge drinking on weekend days, and these effects were the strongest in the context of low P4 . The effect of hormone levels on alcohol consumption may also be dependent on mood: women were more likely to consume alcohol on days when their progesterone levels were low and they were experiencing greater negative mood than their typical mood state . Conversely, when women were experiencing an increase in progesterone, they were more likely to consume alcohol on days when they reported a positive mood . Relative to smoking cessation, fewer studies have examined the impact of P4 or E2 on alcohol reduction or abstinence outcomes. Collectively, these studies suggest the potential for P4 to serve as a protective factor, and E2 a risk factor, for both smoking behavior and alcohol use. In addition to examining P4 and E2 separately, past studies have examined the ratio of P4 to E2 in relation to cigarette use . Schiller and colleagues examined how ratios of P4/E2 and E2/P4 may alter smoking topography in a sample of female cigarette smokers. They found the ratio of P4/E2 was more strongly correlated with smoking behavior than the ratio of E2/P4 . Lastly,hydroponic system for cannabis there is evidence to suggest that pharmacotherapy may alter crucial hormone levels that could impact smoking behaviors. A prior examination of brief pharmacotherapy for smoking cessation found an increase in progesterone levels following treatment with varenicline and nicotine replacement therapy; of note, this effect was predominantly driven by those randomized to the nicotine replacement therapy group . Interestingly, there is also evidence that the acute effects of naltrexone may be sex-dependent with regard to menstrual cycle phase. Roche and King found that in response to an acute dose of naltrexone, women in the luteal phase exhibited greater cortisol and prolactin responses, and reported greater severity of adverse effects, in comparison to women in the follicular phase and men. Taken together, the literature suggests that both varenicline and naltrexone have sexdependent effects that may be best captured mechanistically through assessing menstrual cycle hormones. Ray and colleagues conducted a randomized controlled trial for smoking cessation and drinking reduction. Participants were assigned to receive either varenicline plus placebo or varenicline plus naltrexone for 12 weeks, with follow-up appointments conductedat week-12 and week-26. The results from this randomized clinical trial by Ray and colleagues found participants randomized to the varenicline plus placebo condition reported greater smoking cessation at week-26. For alcohol use outcomes, there was some benefit of the combined varenicline plus naltrexone for reducing drinks per drinking day however it did not meet statistical significance .

This study highlights the potential benefits of combined pharmacotherapy for predominantly alcohol use outcomes among heavy drinking smokers. The present study is an exploratory secondary analysis of Ray and colleagues , supported by an NIH supplement to investigate sex-differences. At weeks 4, 8, and 12 postrandomization and during the active medication phase, participants provided saliva samples for assays of P4 and E2. The present study examines the effects of the ratio of P4/E2 during the active medication phase as predictors of smoking and drinking behaviors. The present study was an exploratory secondary data analysis to examine the effects of menstrual cycle hormones among premenopausal women on smoking and drinking outcomes during a clinical trial testing varenicline and naltrexone for smoking cessation and drinking reduction. The parent study for this secondary analysis found a benefit of combined varenicline and naltrexone for drinking outcomes, however not for smoking outcomes . Given previous work suggesting women in the luteal phase may be more sensitive to the effects of naltrexone , we were particularly interested in examining whether there was an interaction between medication and sex hormones. For smoking abstinence, we found no interaction effect between medication and ratio of P4/E2 or lower-order simple effect of P4/E2. There was a significant effect of medication in favor of those in the varenicline plus placebo condition experiencing greater smoking abstinence. This aligns with the results of the larger clinical trial . For the drinking outcome percent days abstinent, there was a significant interaction between medication and the ratio of P4/E2. In comparison to varenicline plus placebo, greater P4/E2 ratio was associated with greater percent days abstinent for those in the varenicline plus naltrexone condition. Since we expect to see higher P4/E2 ratio during the luteal phase, our results imply that during the luteal phase, participants in the combined varenicline plus naltrexone exhibited improvements in their drinking behavior as indexed by greater percent days abstinent in the 28- days leading up to the study visit. It is also possible that women who had relatively higher P4 and/or lower E2 during their luteal phase are more likely to be responsive to naltrexone. These results align with the findings of Roche and King in which women in the luteal phase were more sensitive to the acute hormonal effects and subjective effects of naltrexone, notably with increases in cortisol and severity of adverse effects in the luteal phase. Our results suggest that during a time when the ratio of P4/E2 is high, as we would expect in the luteal phase, women may experience an added benefit of naltrexone compared to when P4/E2 ratios are low, as we would expect in the follicular phase. It may be that the luteal phase is a time when women are more responsive to both the positive and negative effects of naltrexone. However, this finding should be viewed with caution, as there were no significant interactive or lower-order simple effects for the remaining drinking outcomes. The larger study from where these data was culled showed that the largest reduction in drinks per drinking day occurred from baseline to follow-up week 4, with notably smaller changes from week 4 through week 12 .Previous studies have shown an effect of P4 and E2 on smoking outcomes, independent of each other and as a ratio of P4/E2 . However, our results did not show an effect of lower or higher P4/E2 ratios on smoking abstinence and cigarette per day during the trial. It is possible that our sample did not have large enough variation in menstrual cycle phase across the three study visits.