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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Exp Clin Psychopharmacol. 2019 Aug 29;28(3):306–316. doi: 10.1037/pha0000312

Response to nicotine following overnight smoking abstinence during short-term progesterone treatment in women

Sharon Allen 1, Ashley Petersen 2, Katherine Harrison 3, Nicole Tosun 4, Jacquelyn Cameron 5
PMCID: PMC7048655  NIHMSID: NIHMS1038266  PMID: 31464476

ABSTRACT

Preclinical and clinical literature suggest that sex hormones impact tobacco use behaviors in women. The goal of this double-blind crossover laboratory study was to examine the effect of oral exogenous progesterone (200 mg twice per day) versus placebo on nicotine response using measures of motor speed and cognitive function in women following overnight smoking abstinence. We hypothesized that increased progesterone would blunt the nicotine response whereby producing less change in motor speed and cognition in response to nicotine exposure. Female smokers, age 18–35, were randomized to participate in two 9-day crossover testing weeks. Participants completed a lab session following overnight abstinence where they were administered nicotine nasal spray and asked to complete measures of immediate memory (IMT), delayed memory (DMT), word recall (WR), and finger tapping speed (FT). After the first 9-day testing week, participants resumed smoking and returned the following month to complete the identical lab session in the crossover condition. Forty-seven women were included in this analysis (n=47). We found no differences in the magnitude of response for IMT, DMT, and WR between conditions. For FT, women had a blunted response to nicotine during the placebo condition. When examining the association between hormone levels and relative performance, we found increases in DMT, WR, and FT but decreases in IMT during the progesterone condition. We observed differences between progesterone versus placebo in relative change in some measures of nicotine response following overnight abstinence. Future studies are needed to further characterize this response.

Keywords: Sex Hormones, Nicotine Response, Impulsivity, Memory, Motor Speed

INTRODUCTION

Women face unique challenges with regards to quitting smoking compared to men. They have greater rates of relapse (Perkins, 2008; Weinberger, Pittman, Mazure, & Mckee, 2014; Torres & Odell, 2016), are less likely to achieve long term abstinence (Smith, Bessette, Weinberger, Sheffer, & Mckee, 2016), and have greater difficulty quitting (Wetter et al., 1999; McKee, Smith, Kaufman, Mazure, & Weinberger, 2015). They also do not respond as successfully to nicotine replacement therapies (Perkins, 2008; Weinberger, Pittman, Mazure, & Mckee, 2014). Further, women are more likely to be negatively influenced by stress, negative affect (McKee et al., 2010), and weight gain (Levine, Bush, Magnusson, Cheng, & Chen, 2012). Given these sex differences, it is important to elucidate factors that help explain these challenges. One factor that has gained considerable attention is neuroactive sex hormones. Progesterone and estrogen interact with neurotransmitters and receptors in the brain modulating the rewarding effect of drug use (Frye, 2007; Solis-Ortiz & Corsi-Cabrera, 2008; Stein, 2008).

Preclinical literature provides strong evidence for the influence of sex hormones on drug use behaviors. Specifically, progesterone appears to blunt drug use behaviors, whereas estradiol enhances the rewarding effects of drug use behaviors (Carroll & Anker, 2010; Jackson, Robinson, & Becker, 2005; Larson, Anker, Gliddon, Fons, & Carroll, 2007; Lynch & Sofuoglu, 2010). The clinical literature provides further evidence of the relationship between sex hormones, cessation, and the subjective experience of drug use behaviors. Sofuoglu and colleagues (2001) showed that a single dose of 200 mg exogenous progesterone in female smokers attenuated craving and subjective effects of smoking compared to placebo during a self-administration smoking paradigm. Another study by Sofuoglu and colleagues (2011) showed that giving 200 mg of progesterone was associated with lower “drug liking” than placebo and 200-and 400-mg doses of progesterone demonstrated lower ratings of “drug strength” regarding smoking. Our prior work demonstrated that naturally cycling women who began a quit attempt in the luteal phase, when progesterone levels are highest, had a greater number of days to relapse than those who began a quit attempt in the follicular phase (Allen, Bade, Center, Finstad, & Hatsukami, 2008). Additionally, increased levels of progesterone have been shown to reduce smoking-related risk factors such as cravings, stress, and urges, which are predictors of smoking relapse (Potvin, Tikàsz, Dinh-Williams, Bourque, & Mendrek, 2015). A study conducted by Saladin and colleagues (2015) identified an association between increasing progesterone levels and improved smoking cessation, with increased progesterone levels being associated with a 23% increase in the odds of being abstinent within each week of treatment with nicotine patches. Further, Schiller and colleagues (2012) found that the ratio of progesterone:estradiol may be more important to smoking behavior and subjective state than the absolute levels of either hormone.

The findings related to the impact of progesterone on cognitive functioning have been inconsistent. Frye and Walf (2008) found that in preclinical models cognitive functioning varies with hormonal transition periods and progesterone treatment. They found that male and female ovariectomized mice who received progesterone treatment had enhanced learning and memory. Naturally cycling women have also been shown to have greater inhibitory control in the luteal phase compared to the follicular phase (Phillips & Sherwin, 1992; Solis-Ortiz & Corsi-Cabrera, 2008). In contrast, other studies showed when progesterone was administered it did not affect cognitive function in males (Gron, Friess, Herpers, & Rupprecht, 1997), in cycling females (van Wingen et al., 2007), or in postmenopausal women (Rapp et al., 2003). This raises further questions about the specific effects of exogenous versus endogenous progesterone on cognitive function and how this might be moderated by variables such as nicotine and other drug use and the impact of concomitant estrogen. Cognitive functions such as attention, working memory, fine motor skills, and episodic memory are sensitive to and enhanced by stimulant use, e.g., nicotine (Valentine & Sofuoglu, 2018). However, the literature on the role of sex hormones in the relationship between cognition and drug use behavior is lacking. This study is unique in that we are assessing the effects of exogenous progesterone on nicotine response using measures of cognitive and motor function in women on oral contraceptives for precise hormonal timing.

The goal of this double-blind crossover human laboratory study was to examine the effect of oral exogenous progesterone compared to placebo on response to nicotine using a series of cognitive and motor measures following overnight smoking abstinence in women. We hypothesized that women in the progesterone condition would demonstrate a blunted response to nicotine (i.e., less change in motor speed and cognition following nicotine exposure) compared to women in the placebo condition.

METHODS

All procedures were approved by the University of Minnesota Institutional Review Board. Participants provided informed consent and were compensated for their participation.

Participants

Women ages 18–35 were recruited through mass media and postings at local women’s health clinics. Eligible participants had to meet the following criteria: (1) smoking 5 or more cigarettes per day for at least the last year and (2) current use of combination hormonal birth control pills for at least the last three months and a willingness to switch to a study-supplied pill, Tri-Sprintec (Barr Laboratories). Only women using birth control pills (as opposed to naturally cycling women) were included in this study to better standardize hormone levels during the study period across participants. Exclusionary criteria were: (1) use of psychotropic medications within the last three months, (2) current use of other forms of tobacco or nicotine including e-cigarettes, cigars, nicotine replacement therapy, or other smoking cessation products, (3) use of illicit drugs (self-report) with the exception of marijuana less than 3 times per month, (4) any condition contraindicated to progesterone use, or (5) plans to become pregnant or breastfeed during the duration of their participation study.

Randomization

At the screening visit, all participants reported demographic measures (e.g., age, race, income, education), smoking behavior (e.g., cigarettes smoked per day via Timeline Follow Back (Brown et al., 1998), and nicotine dependence via the Fagerstrom Nicotine Dependence Scale (FTND) (Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991)). Vital signs (e.g., blood pressure, heart rate, and weight) were collected at all study visits.

At the end of the screening visit, eligible participants were prescribed the study-supplied birth control Tri-Sprintec (to replace their current birth control pill) and asked to begin this new medication on day 1 of their next pill cycle. On day 21 of their pill cycle (i.e., the first day of inactive “sugar” pills), participants were randomized (1:1) to either oral exogenous progesterone (200 mg twice daily) or placebo and asked to take this medication throughout a 9-day testing week. After a three-week washout period (continuing on Tri-Sprintec), participants were assigned the crossover to their first assignment and asked to take that medication for a second 9-day testing week. Because this protocol adjusted the menstrual cycle length from the typical 28-day cycle to a 30-day cycle, participants were asked to use additional non-hormonal contraceptive methods (i.e., condoms) throughout the study and pregnancy tests were completed at all study visits.

Oral micronized exogenous progesterone (Teva Pharmaceuticals) was over-encapsulated and identical appearing placebo capsules were prepared by Investigational Drug Services at the University of Minnesota, Fairview Medical Center. Both types of capsules contained riboflavin which caused the urine to change color which was detected by a fluorescent light, allowing for a real-time objective indication of adherence. Pill counts were also done at all clinic visits. Typically, 50–60% of micronized exogenous progesterone is absorbed after oral administration; it reaches its peak plasma levels in two to three hours and has an elimination half-life of three to four hours (McAuley, Kroboth, & Kroboth, 1996). Our previous work has demonstrated that a dose of 200 mg of micronized exogenous progesterone twice daily results in serum progesterone levels comparable to those found in the mid-luteal phase of the menstrual cycle (3–25 ng/ml) (Allen, Allen, Lunos, & Tosun, 2016). Due to the relatively short half-life of micronized exogenous progesterone, we utilized the following measures to ensure that participants achieved an adequate dose of progesterone during their lab session: (1) 200 mg progesterone was administered twice daily, (2) all lab sessions began between 7:00 and 10:00 am, and (3) participants were instructed to take the study medication at least 2 hours prior to the nicotine nasal spray administration. The most common side effects of progesterone reported in this study were fatigue and breast tenderness.

Procedures

Participants completed two 9-day testing weeks. The testing periods included seven days of ad libitum smoking where cortisol and smoking-related symptomatology were collected (results forthcoming) and two days of lab sessions, each following overnight abstinence. The first lab session on day 8 measured smoking topography (results forthcoming) while the second lab session on day 9 measured nicotine response (results presented here). Participants were instructed to quit smoking at 6:00 pm on the evening of day 8 and to remain abstinent until they completed the day 9 lab session. Upon arrival at the clinic for the day 9 lab session, overnight abstinence was confirmed by expired carbon monoxide (CO). A CO cutoff of less than or equal to 5 ppm was considered abstinent (Marrone, Paulpillai, Evans, Singleton, & Heishman, 2010). Participants who were confirmed abstinent were eligible to participate in the four-hour lab session. Those who were not abstinent were not eligible to participate in the four-hour lab session but were allowed to return in one month to try again.

The day 9 lab session measuring nicotine response followed procedures outlined in our previous work (Allen, al’Absi, Lando, Hatsukami, & Allen, 2013a). Participants were asked to self-administer nicotine nasal spray (Nicotrol; Pfizer Pharmaceuticals) at two time points: time 0 and time 100 min. Measures of nicotine response were completed five times and were distributed across the following time points: −40, 10, 20, 30, 60, 110, 120, 130, and 160 minutes (see Figure 1).

Figure 1.

Figure 1.

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Timing of procedures during the day 9 laboratory session

Nicotrol is an FDA-approved product used to deliver nicotine. One metered spray delivers 0.5 mg of nicotine. Participants used one spray per nostril twice (for each nicotine exposure time point) which is equivalent to 2 mg or to the nicotine delivery from approximately two cigarettes. Nasal spray closely mimics the kinetics of smoking, is easy to administer, and delivers a consistent dose. There were no adverse events reported related to the nicotine nasal spray. Nasal spray can have irritating symptoms including itching, burning, and watering eyes; however, participants completed a nasal spray practice session 2 days prior to the day 9 lab session. Further, we have used this method successfully in the past (Allen et al., 2013b).

Measures of nicotine response included are listed below. While previous studies have used a variety of measures to assess nicotine response, we chose established and validated measures in consideration of participant burden as well as our experience with them. (1) Motor speed was measured by Finger Tapping (FT) (Hindmarch, 1981). Participants were instructed to use the index finger on the dominant hand to tap a key on a computer as quickly as possible for two 30-second periods. Scores from these two periods were averaged at each time point. (2) Episodic memory was measured by Word Recall (WR) (Phillips & Fox, 1998). Twenty-five 3 to 6 letter nouns were individually presented on a computer screen for three seconds each. Upon completion of the display, participants were given a short distractor of counting backwards from 20 to 0. They then completed a 2-minute written recall of the words. Writing the correct first 3 letters of a word was scored as correct. (3) Brief attention was measured by Immediate Memory Task (IMT) (Dougherty, Marsh, & Mathias, 2002). Participants were presented with a series of random 5-digit numbers on a computer screen at a rate of one per second. Participants were instructed to click a button when the number displayed was identical to the preceding number. (4) Sustained attention was measured by Delayed Memory Task (DMT) (Dougherty, Marsh, & Mathias, 2002). The DMT was identical to the IMT except a series of distracter sequences (i.e., 12345) were presented between target stimuli. The scores for both the IMT and the DMT were determined by the ratio of the percent of errors to percent of correct detections at each time point. Higher scores on the IMT indicated less brief attention and higher scores on the DMT indicated less sustained attention. Both the IMT and DMT measure an aspect of attention and are a proxy for impulsivity. See Figure 1 for the sequencing of these tasks.

In order to analyze progesterone and estradiol during the two testing periods, serum blood samples were collected from all eligible participants on the morning of the day 9 lab session. Samples were processed and stored, then sent for batch analysis to the University of Southern California Endocrine Research Laboratory. Results were obtained by radioimmunoassay with preceding organic solvent extraction and celite column partition chromatography. Elution of progesterone and estradiol was carried out with isooctane and 40% ethyl acetate in isooctane, respectively. The sensitivity of the progesterone assay was 10 pg/ml and the interassay coefficient of variation (CV) was 12% at 230 pg/ml. For the estradiol assay, the sensitivity was 2 pg/ml and the interassay CVs were 11%, 13%, and 12% at 15, 36, and 101 pg/ml, respectively. The ratio of progesterone to estradiol (P/E2 ratio) was calculated by dividing the level of progesterone (in ng/ml) by the level of estradiol (in ng/ml).

Statistical Methods

Using descriptive statistics, we compared the sex hormone levels and baseline measures of nicotine response between the placebo week and progesterone week, as well as described the overall characteristics of the study population. Categorical variables were summarized with counts and percentages, while continuous variables were summarized with the mean and standard deviation (SD) or median and first/third quartiles. We compared the heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) measurements at −1 min to those at 5, 10, and 20 min to confirm a response to the nicotine nasal spray.

To test whether progesterone blunts the response to nicotine, we compared the absolute value of the changes over time from baseline (i.e., 40 minutes prior to the initial nicotine nasal spray) between the progesterone vs. placebo weeks for the four measures of nicotine response: DMT, IMT, FT, and WR. We expected women to have smaller absolute changes during their progesterone weeks due to the blunting effect of progesterone on nicotine response. For DMT and IMT, we analyzed the measures on the log scale due to their distribution, and thus considered the absolute geometric mean percent change from baseline. To test for an overall difference in response between the progesterone vs. placebo weeks across all time points, we fit a linear mixed effects model with the outcome of absolute value of nicotine response measure change, the primary predictor of week (progesterone vs. placebo), adjustment for time point, and a random intercept to account for the correlation of measurements on the same subject.

In addition to testing for a difference in response between the progesterone vs. placebo weeks, we tested for associations between the women’s sex hormone levels and their absolute change in measures of nicotine response following nicotine nasal spray. To do this, we fit a linear mixed effects model with the outcome of absolute value of response change and the predictor of log hormone level with adjustment for time point. A random intercept was included to account for the correlation between measurements on the same subject. We fit a total of twelve models to investigate the relationships between the outcomes of change in DMT, IMT, FT, and WR and the predictors of progesterone, estradiol, and the progesterone/estradiol ratio (P/E2).

Our primary analyses above consider the effect of sex hormone levels on the magnitude of changes in response to nicotine. Large absolute changes correspond to either large increases or large decreases from baseline. As exploratory analyses, we also considered whether sex hormone levels are associated with the relative changes in response, which takes into account both the magnitude and direction of change (i.e., increase or decrease). Of note, analyses of absolute change and relative change answer different research questions. Figure 2 illustrates the differences between relative and absolute change for three hypothetical scenarios. To address relative changes in response, we fit analogous models to those fit for our primary analyses, but used the outcome of response change, rather than the absolute value of it.

Figure 2.

Figure 2.

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To illustrate the differences between relative and absolute change in nicotine response, we consider three hypothetical scenarios. In each plot, the dashed and solid bold lines are the mean responses for the progesterone and placebo weeks, respectively, while the remaining lines are individuals’ responses. In scenario 1, nicotine response increases relative to baseline during both the progesterone and placebo weeks, but the increase is larger during the placebo week. In this scenario, there is a significant difference between the weeks for both relative and absolute change. However, while these measures of change agree in this scenario, this is not always the case. In scenario 2, nicotine response increases relative to baseline during the placebo week and decreases during the progesterone week. In this scenario, there is a significant difference between the weeks for relative change, but no difference for absolute change since the magnitude of change was the same for the weeks. In scenario 3, response may increase or decrease during either week, but the changes from baseline are of a smaller magnitude during the progesterone week. In this scenario, there is no significant difference between the weeks in terms of relative change, while the absolute change analysis captures that those during the progesterone week tend to move further from baseline.

The primary analysis comparing differences in response between the placebo and progesterone weeks was an intent-to-treat analysis in which all women were included according to their randomization, regardless of their observed progesterone levels. We also conducted a per-protocol analysis in which we excluded women who had low levels of progesterone (<2.5 ng/ml) during the progesterone week or high levels of progesterone (>3.5 ng/ml) during the placebo week. No formal corrections for multiple testing were applied. All analyses were performed using R version 3.4.1.

RESULTS

Fifty-three women completed at least one testing period. Of these 53 women, 47 women had at least one week of data that was eligible for inclusion in the final analysis. Overall, 33 women had data from both the progesterone and placebo weeks included in the final analysis, 5 women had data from the progesterone week only included in the final analysis, and 9 women had data from the placebo week only included in the final analysis. For the progesterone week, 15 women were excluded from the final analysis: 10 were not compliant with overnight abstinence (CO > 5) and 5 did not complete the study visit due to experiencing illness and choosing not to redo the testing period or no show. For the placebo week, 11 women were excluded from the final analysis: 6 were not compliant with overnight abstinence (CO > 5) and 5 did not complete the study visit due to a change in eligibility (smoking less than 5 cigarettes per day in the interim period and non-compliance with study medication), transportation problems, or no show.

The mean age of study participants was 23 yrs (SD: 4.0). Almost all women (87%) had never been married and most had completed at least some college (72%). Yearly household income was less than $15,000 (53%), $15,001 to $20,000 (13%), $20,001 to $30,000 (16%), or greater than $30,000 (18%). Most women were White (74%) with others being Black (4.3%), American Indian or Alaskan (4.3%), Asian (2.1%), or more than one race (15%). The average self-reported number of cigarettes per day was 11 (SD: 4.2) with a mean FTND score of 3.3 (SD: 1.7). As expected, progesterone levels and P/E2 ratios were higher during the progesterone week than the placebo week (Table 1). There were no significant differences in estradiol levels between the weeks (Table 1). In terms of baseline measures of nicotine response, there were no significant differences between the weeks except for WR, which was lower at baseline during the progesterone week (Table 1).

Table 1.

Sex Hormone Levels and Baseline (−40 min) Measures of Nicotine Response During the Placebo Week and Progesterone Week

Measurement Placebo week Progesterone week p-value
Sex hormone levels
 Progesterone (ng/ml) 1.11 (0.76, 2.98) 6.73 (3.80, 13.8) <0.001
 Estradiol (pg/ml) 81.4 (63.1, 114) 72.3 (55.3, 90.4) 0.79
 P/E ratio 15.2 (9.1, 37.4) 98.2 (44.8, 179) <0.001
Baseline (−40 min) measures of nicotine response
 Delayed Memory Task 0.27 (0.18, 0.37) 0.23 (0.12, 0.36) 0.57
 Immediate Memory Task 0.22 (0.15, 0.31) 0.25 (0.20, 0.30) 0.70
 Finger Tapping 164 (19) 161 (21) 0.41
 Word Recall (First 3 letters) 12 (3.8) 9.6 (3.1) <0.001
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Summaries shown are mean (standard deviation) or median (1st quartile, 3rd quartile).

From prior to the first nicotine nasal spray (−1 minute) to 5 minutes after the spray, women’s HR increased an average of 15.7 beats per minute (95% CI: 11.8–19.7; p<0.001), women’s SBP increased an average of 8.2 mmHg (95% CI: 5.6–10.8; p<0.001), and women’s DBP increased an average of 6.2 mmHg (95% CI: 3.3–9.0; p<0.001) during the placebo week. There were also significant increases in HR, SBP, and DBP from −1 minute to 10 and 20 minutes after the spray, though the increases were of a smaller magnitude (Supplementary Table 1). Similar significant increases occurred during the progesterone week (Supplementary Table 1). During the placebo week, reported craving decreased 1.55 points (95% CI: 0.99–2.11 point decrease; p<0.001) from before to after the first nicotine nasal spray and decreased 0.50 points (95% CI: 0.04–0.96 point decrease; p=0.035) from before to after the second nicotine nasal spray. During the progesterone week, reported craving decreased 1.52 points (95% CI: 0.85–2.19 point decrease; p<0.001) from before to after the first nicotine nasal spray and decreased 1.00 point (95% CI: 0.44–1.56 point decrease; p=0.001) from before to after the second nicotine nasal spray.

Absolute Changes Following Nicotine Response

Figure 3 presents the results for testing the hypothesis of whether women had a blunted response to nicotine during their progesterone week vs. placebo week. Women during their progesterone week tended to have a larger response to nicotine than during the placebo week for the FT task, as reflected by a greater absolute change (p<0.001). During their progesterone week, women had 2.43-point larger magnitude changes from baseline for FT compared to during the placebo week (95% CI: 1.05–3.81-point larger changes). There were no differences in absolute change between the weeks for DMT (p=0.85), IMT (p=0.79), or WR (p=0.61). The findings from the per-protocol analysis were consistent with these results (see Supplementary Figure 1).

Figure 3.

Figure 3.

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The average absolute changes in measures of nicotine response over time are plotted for the progesterone and placebo weeks, as estimated from a linear mixed effect model accounting for within-subject correlation. For the Delayed Memory Task (DMT) and Immediate Memory Task (IMT), the geometric mean and 95% confidence interval (CI) for the absolute percent change since baseline (i.e., 40 minutes prior to the initial nicotine nasal spray) are shown, and the mean and 95% CI for the absolute change from baseline are shown for the Finger Tapping (FT) and Word Recall (WR). There was a statistically significant difference between the progesterone vs. placebo weeks for FT (p<0.001), but no statistically significant differences for DMT (p=0.85), IMT (p=0.79), or WR (p=0.61).

Figure 4 summarizes the associations between the sex hormone levels and absolute changes in response to nicotine. For FT, there were less extreme responses for those with lower progesterone (p<0.001) and lower P/E2 ratio (p<0.001). A doubling of progesterone levels was associated with 0.81-point larger magnitude changes from baseline for FT (95% CI: 0.41–1.20-point larger changes). Similarly, a doubling of the P/E2 ratio was associated with 0.67-point larger magnitude changes from baseline for FT (95% CI: 0.29–1.04-point larger changes). There was a marginally significant (p=0.03), in light of the number of comparisons, association between estradiol and absolute changes in WR with lower estradiol levels being associated with a blunted response. No other associations were significant.

Figure 4.

Figure 4.

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We summarize the associations between changes in sex hormone levels between the progesterone and placebo weeks and the absolute changes in the measures of Delayed Memory Task (DMT), Immediate Memory Task (IMT), Finger Tapping (FT), and Word Recall (WR) following exposure to nicotine nasal spray.

Relative Changes Following Nicotine Response

When comparing whether the women had different relative changes in nicotine response during their progesterone vs. placebo weeks, there was a significant difference between the progesterone vs. placebo weeks for all measures: DMT (p=0.02), IMT (p=0.02), FT (p=0.005), and WR (p<0.001) (Figure 5). For DMT, we found that the women had 18% higher scores (95% CI: 2–36% higher) during their progesterone weeks compared to their placebo weeks. For IMT, we found that the women had 9% lower scores (95% CI: 1–17% lower) during their progesterone weeks compared to their placebo weeks. For FT, women during their progesterone weeks had on average 2.62-point greater change from baseline (95% CI: 0.81–4.44-point greater change) compared to their placebo weeks. For WR, we found that women had on average 1.31-point greater change from baseline (95% CI: 0.72–1.90-point greater change) during their progesterone weeks than their placebo weeks. The findings from the per-protocol analysis were consistent with these results (see Supplementary Figure 2). In Figure 6, we present the results from the models that considered how the changes in sex hormone levels between the progesterone and placebo weeks correlated with the relative changes in the measures of nicotine response following exposure to nicotine nasal spray. Both progesterone and P/E2 ratio had highly significant associations with relative changes in DMT, FT, and WR. Higher levels of progesterone and P/E2 ratio were correlated with higher impulsivity (i.e., higher scores on the DMT), faster motor speed (i.e., higher scores on FT), and higher episodic memory (i.e., higher scores on WR) following nicotine exposure. A doubling of progesterone levels was associated with 9% higher scores on DMT (95% CI: 513% higher), 0.96-point higher scores on FT (95% CI: 0.41–1.50 points higher), and 0.39-point higher scores on WR (95% CI: 0.21–0.56 points higher). There were similar associations for P/E2 ratio.

Figure 5.

Figure 5.

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The average changes in measures of nicotine response over time are plotted for the progesterone and placebo weeks, as estimated from a linear mixed effect model accounting for within-subject correlation. For the Delayed Memory Task (DMT) and Immediate Memory Task (IMT), the geometric mean and 95% confidence interval (CI) for the percent change since baseline (i.e., 40 minutes prior to the initial nicotine nasal spray) are shown, and the mean and 95% CI for the change from baseline are shown for the Finger Tapping (FT) and Word Recall (WR). There were statistically significant differences between the progesterone vs. placebo weeks for all measures: DMT (p=0.02), IMT (p=0.02), FT (p=0.005), and WR (p<0.001).

Figure 6.

Figure 6.

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We summarize the associations between changes in sex hormone levels between the progesterone and placebo weeks and the changes in the measures of Delayed Memory Task (DMT), Immediate Memory Task (IMT), Finger Tapping (FT), and Word Recall (WR) following exposure to nicotine nasal spray.

DISCUSSION

We hypothesized that participant responses to nicotine measured by motor and cognitive testing would be blunted (i.e., less change in motor speed and cognition following nicotine exposure) during the progesterone week compared to the placebo week. We found no differences in the magnitude of response for sustained attention (DMT), brief attention (IMT), or episodic memory (WR). For motor speed (FT), women had a blunted response (less change in motor speed) during the placebo week, which is contrary to our hypothesis. Similarly, we found that lower levels of progesterone and P/E2 ratio were associated with a blunted motor response to nicotine (FT). When examining the association between hormone levels and relative performance following the nicotine nasal spray, we found that women had increased sustained attention (DMT), decreased brief attention (IMT), faster motor speed (FT), and increased episodic memory (WR) during their progesterone week verses placebo week, where performance was measured relative to baseline levels prior to the nicotine spray. Similar associations were found between the individual progesterone levels and P/E2 ratios and performance on DMT, FT, and WR.

Our findings suggest that progesterone may influence domains of cognition and motor speed in women who smoke. Although we found only one difference between the progesterone and placebo conditions in absolute change (blunted motor speed during the placebo condition), we did find significant differences in relative change. We found a significant increase in 3 of 4 domains examined in this study (sustained attention, motor speed, and episodic memory) following nicotine exposure during the progesterone condition relative to the placebo condition. This finding is consistent with previous studies that found naturally cycling women had enhanced verbal memory, attention, and visual memory during the luteal phase compared to the follicular phase and performance in these functions were positively correlated with endogenous progesterone levels (Phillips & Sherwin, 1992; Solis-Ortiz & Corsi-Cabrera 2008). In contrast, previous studies found that administering progesterone did not affect cognitive performance (Gron et al., 1997; van Wingen et al., 2007; Schussler et al., 2008). These conflicting results regarding the impact of sex hormones on cognitive functioning are difficult to interpret as these studies are limited by cross-sectional methodology, short-term follow-up, and small sample sizes. Thus it is important that further evaluation of progesterone consider these factors as there may be a potential clinical benefit of progesterone for treating drug abuse particularly in women. Other variables such as age and the type of progesterone endogenous verse exogenous should also be considered in future work.

Imaging studies have found an association between a higher progesterone level and lower nicotinic acetylcholine receptors (β2*-nAChRs) in the cortex and cerebellum (Cosgrove et al., 2012). This suggests that nicotinic acetylcholine receptor might be affected by progesterone. Other in vitro studies (Kudo, Tachikawa, & Kashimoto, 2002; Takashima, Kawasaki, Kimura, Fujita, & Sasaki, 2002) of adrenal chromaffin cells have also shown that progesterone interferes with nicotinic receptors. These findings suggest that pregnenolone sulfate (progesterone metabolite) inhibits nicotinic receptor-operated ion channels and may modulate nicotinic receptor-mediated responses in the brain. In contrast, estrogen enhances the rewarding effects of nicotine and other drugs of abuse by facilitating the release of dopamine in the nucleus accumbens (Odell & Torres, 2014). These data taken together strongly support a neurobiological role of both estrogen and progesterone in tobacco use behaviors in women.

Sex hormones have been shown to influence aspects of impulsivity, in turn affecting the susceptibility to relapse in people with substance use disorders (Hudson & Stamp, 2011). Estrogen has been shown to enhance dopamine release, which is important in the control and organization of goal-directed behaviors and decision-making (Cools, 2008). Our results support the role of progesterone influencing impulsivity (measured in this study as brief and sustained attention) and ultimately addictive behaviors. However, our results do not support progesterone producing a blunted response in impulsive behavior. Diekhof (2015) found that women tend to act more impulsively in the early follicular phase of the menstrual cycle, when estrogen is high and progesterone is low. Progesterone appears to inhibit dopamine by decreasing its release and promoting degradation (Demaria, Livingstone, & Freeman, 2000). Similarly, in a preclinical study by Smethells and colleagues (2016), females were found to have reduced impulsivity for cocaine following progesterone treatment. The reason for our findings are unclear. Perhaps our progesterone levels were not adequate to produce a true response to nicotine.

However, this is unlikely given participant levels were equivalent to luteal phase levels. Another possible explanation is that endogenous and exogenous progesterone act differently as a neuroactive sex steroid and therefore elicit a different response. It may also be that the measures of nicotine response that we considered are differentially affected by progesterone or that the 12-hour abstinence period was not sufficient to produce the desired response. However, we believe this is unlikely since a 12-hour abstinence period has been used in prior work and elicits a positive nicotine response (Liakoni et al., 2019; Schlienz, Hawk, & Rosch, 2013). Heishman and colleagues (2010) conducted a meta-analysis of 41 placebo-controlled studies and found that nicotine had significant positive effects on fine motor, shortterm episodic memory, and working memory performance. However, across and within performance domains, there was little consistency in dose-response functions. Linear and curvilinear effects were reported for different performance domains, but most studies reported no dose-response effects (Heishman, Kleykamp and Singleton, 2010).

This study contributes to the growing literature related to the effect of exogenous progesterone on drug use behaviors. This double-blind placebo-controlled crossover designed study is unique in that we were able to evaluate the effect of exogenous progesterone when endogenous levels of progesterone and estrogen were low due to the use of oral contraceptives. Further the rigor of the crossover design allowed for the within subject comparison which allows for consideration of variables such as age, cigarettes per day, and nicotine dependence.

Although this study is strengthened by a tightly controlled human lab study with a strong crossover design, our findings should be considered in the context of a few considerations. Participants in this study were non-treatment seeking women and therefore, may have responded differently to the progesterone treatment than treatment-seeking women. These results therefore may not be as generalizable as had we made this comparison. Exogenous and endogenous progesterone may also act differently as a neuroactive sex steroid on nicotinic receptors in the brain which could influence the response to nicotine. Further, nicotine is metabolized faster in women using oral contraceptives compared to women not using oral contraceptives (Benowitz, Jacobiii, & Herrera, 2006) affecting the pharmacokinetics of the nicotine exposure. Lastly, the nicotine nasal spray may not have produced a significant nicotine response. However, we believe this to be unlikely given the significant change in both physiological and subjective responses from the participants.

In summary, we observed a relative increase in brief attention, episodic memory, and motor speed during the progesterone condition following nicotine exposure in our sample. We also observed a relative decrease in sustained memory during the progesterone condition following nicotine exposure in our sample. Additionally, individual hormone levels (progesterone and P/E2 ratio) were similarly associated with these relative changes. This supports the role that progesterone may influence domains of cognition and motor speed in women who smoke. These findings need to be interpreted in the context of the study population: young women (18–35 years of age) who were relatively light smokers (average cigarettes per day was 11), non-treatment seeking on oral contraceptives (faster metabolism of nicotine), and receiving exogenous progesterone. Future studies would be important to further characterize this response.

Supplementary Material

Supplemental Figure 1
Supplemental Figure 2
Supplemental Table 1

PUBLIC SIGNIFICANCE STATEMENTS.

We observed differences in nicotine response among women receiving short-term exogenous progesterone treatment in comparison to those receiving placebo. This information is valuable within the context of understanding how sex hormones may play a role in developing strategies to support smoking cessation in women.

ACKNOWLEDGMENTS

Support for this project was provided by the National Institute on Drug Abuse (R01DA08075). Support was also provided by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000114). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

DISCLOSURES

All authors contributed in a significant way to the manuscript and all authors have read and approved the final manuscript. No authors have a conflict of interest to disclose. We would like to acknowledge Brittany Niesen for her assistance with recruitment and data collection. We also thank Dr. Frank Stanczyk, a Professor of Research, Obstetrics and Gynecology, and Preventive Medicine and Director of the Reproductive Endocrine Research Laboratory at the University of Southern California’s Keck School of Medicine, for his expertise in the analysis of serum hormone samples.

Contributor Information

Sharon Allen, Department of Family Medicine & Community Health, University of Minnesota 516 Delaware Street SE, Minneapolis, MN 55455.

Ashley Petersen, Division of Biostatistics, School of Public Health, University of Minnesota 420 Delaware Street SE, Minneapolis, MN 55455.

Katherine Harrison, Department of Family Medicine & Community Health, University of Minnesota 717 Delaware Street SE, Minneapolis, MN 55414.

Nicole Tosun, Department of Family Medicine & Community Health, University of Minnesota 717 Delaware Street SE, Minneapolis, MN 55414.

Jacquelyn Cameron, William Beaumont School of Medicine, Oakland University 586 Pioneer Dr, Rochester, MI 48309.

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Supplementary Materials

Supplemental Figure 1
NIHMS1038266-supplement-Supplemental_Figure_1.pdf (445.4KB, pdf)
Supplemental Figure 2
NIHMS1038266-supplement-Supplemental_Figure_2.pdf (460.1KB, pdf)
Supplemental Table 1
NIHMS1038266-supplement-Supplemental_Table_1.pdf (73.4KB, pdf)

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