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. Author manuscript; available in PMC: 2020 Nov 1.
Published in final edited form as: Addict Behav. 2019 Jul 3;98:106043. doi: 10.1016/j.addbeh.2019.106043

Subjective Response to Intranasal Nicotine Administration in Oral Contraceptive Users and Naturally-Cycling Women

Alicia M Allen 1, Samantha C Friedrichsen 2, Nicole Petersen 3, Sharon S Allen 4
PMCID: PMC6708721  NIHMSID: NIHMS1534637  PMID: 31310925

Abstract

Introduction:

Approximately half of premenopausal women who smoke cigarettes also use hormonal contraceptives, with most using oral contraceptives (OCs). While research on the effects of endogenous hormones on smoking-related outcomes continues to expand, little is known about the influence of OCs on similar outcomes. We sought to explore differences in the subjective response to nicotine by OC use after stratifying by testing condition (e.g., smoking status).

Methods:

Participants were regular (≥5 cigarettes/day) smokers, classified into OC and naturally cycling (NC) groups. All participants completed four total lab sessions by smoking status (ad libitum smoking, acute smoking abstinence) and anticipated progesterone level (low progesterone week (LPW), high progesterone week (HPW)). Each lab session included self-administration of intranasal nicotine (Time 0 minutes), assessment of subjective response via the Subjective State Scale (−30 and +5 minutes).

Results:

Compared to the NC group (n=28), the OC group (n=14) was younger (26.2±1.1 versus 24.2±1.1; p <0.001) and had a lower Fagerstrom Test for Nicotine Dependence score (3.4±0.5 versus 2.6±0.5; p=0.011). Progesterone-to-estradiol ratios varied significantly by group at three of the four time points (p<0.05). During ad libitum smoking, the OC group had significantly lower craving after nicotine administration than the NC group (1.93±0.33 versus 2.89±0.23; p=0.024). No other significant differences in subjective response were identified.

Conclusions:

Despite significantly different hormone levels, group differences in subjective response to nicotine were relatively few. Additional research is needed to elucidate the mechanisms involved in these observations, as well as explore how they may influence cessation in women.

1. Introduction

Although smoking poses a substantial threat to the health and longevity of both women and men, women experience additional risk factors that do not affect men, such as pregnancy-related complications and early menopause.1 Moreover, women are also more likely to relapse to smoking from a quit attempt (for meta-analysis, see Smith et al2). Therefore, developing smoking cessation interventions that are designed to address the unique needs of women is of great public health importance.

An expanding literature has related sex hormones to smoking-related outcomes, specifically the neuroactive ovarian hormones progesterone and estradiol, often measured by proxy via the menstrual phase.3 For example, consistent with the preclinical literature – which indicates that estradiol is associated with heightened drug reward 4 whereas progesterone is associated with suppressed drug reward 5 – a series of manuscripts by Sofuoglu and colleagues demonstrated that favorable subjective effects of nicotine (via intravenous administration or cigarette smoking) were significantly lower during the luteal phase (i.e., a high progesterone to estradiol ratio) and during exogenous progesterone administration compared to placebo.6–9 These observations suggest that the luteal phase (or higher progesterone) may be favorable for smoking cessation, and indeed quit attempts that did not use nicotine replacement therapy (NRT) have indicated that the risk of relapse is lower among women who set their quit date during the luteal phase.10,11 However, during NRT-aided quit attempts, risk of relapse was lower among women who set their quit date in the follicular phase,12–14 despite evidence that higher progesterone levels are associated with greater reductions in negative affect and urges to smoke.15 Overall, these observations indicate that menstrual phase and/or sex hormones have a complicated effect on smoking-related outcomes.

The majority (85%) of premenopausal women who smoke report using hormonal contraceptives at some point in their life, with approximately half (48%) reporting current use and oral contraceptive use was the most common type currently in use (29%).16 Hormonal contraceptives, in general, work by replacing endogenous ovarian hormones with synthetic analogues with high binding affinities, thereby cutting off the hypothalamic-pituitary-gonadal feedback loop that regulates ovulation and ultimately reduces endogenous sex hormone levels and variability.17 Despite the popularity of hormonal contraceptives among premenopausal women who smoke and their known significant effect on sex hormones, relatively little is known about the effect of hormonal contraceptives on smoking-related outcomes.18 We previously demonstrated in a cross-sectional sample that smoking motives (e.g., smoking satisfaction, craving) significantly varied between hormonal contraceptive users and nonusers such that the women who did not use hormonal contraceptives and were in the follicular phase had the highest levels of smoking motives, followed by hormonal contraceptive users, and then women who did not use hormonal contraceptives and were in the luteal phase having the lowest levels.16 However, this work was limited by our inclusion of a heterogeneous group of long-acting hormonal contraceptives (e.g., hormonal intrauterine device) and cyclical hormonal contraceptives (e.g., oral contraceptives). Future work would benefit from the standardization of type of hormonal contraceptive. We also demonstrated that greater variability in craving over the menstrual cycle is related to a higher risk of smoking relapse.19 Therefore, if the subjective response to nicotine is less variable with the exogenous hormone stability of hormonal contraceptives compared to nonusers, this may indicate that hormonal contraceptive users have decreased risk of smoking relapse.

This secondary data analysis utilized data from a controlled cross-over study with a sample of naturally cycling (NC) women and a sample of oral contraceptive (OC) users on a standardized tri-phasic combination OC to address three aims. Our first aim was to compare the smoking-related symptoms (such as craving) both prior to nicotine nasal spray administration (i.e., the participants’ natural state) and after nicotine nasal spray administration (i.e., the participants’ response to nicotine) while participants were smoking ad libitum during anticipated low and high progesterone levels. Our second aim was to compare the same subjective response items before and after nicotine nasal spray during biochemically-verified smoking abstinence also during both high and low progesterone levels. Lastly, our third aim was to assess the overall effect of oral contraceptive use on subjective response to nicotine regardless of smoking status and anticipated progesterone levels. We expected to see differences in the subjective response to nicotine nasal spray by study group (OC versus NC) overall and after stratifying by testing condition (e.g., smoking status and anticipated progesterone level).

2. Methods

2.1. Study Sample.

As previously reported,20,21 we recruited a convenience sample primarily via social and mass media advertisements. Participants were women who smoked at least five cigarettes per day for at least the past six months and did not plan to quit smoking within the next three months. The NC participants had to be between the ages of 18 and 40 with regular menstrual cycles (defined as every 24 to 36 days per self-report) and no recent (<3 months) use of exogenous hormones. The OC participants had to be on a combination OC for at least three months without any complications, be willing to switch to a study-supplied OC for the duration of the study and be between the ages of 18 and 35 (given the clinical recommendation to limit combination OC use to those who smoke to under the age of 35 22). Exclusion criteria for both groups included recent (<3 months) or planned pregnancy or breastfeeding, use of illicit drugs, use of psychotropic medications, and unstable physical or mental health.

2.2. Study Protocol.

All study procedures were approved by the University of Minnesota’s Human Research Protection Program. In brief, potential participants were screened via telephone followed by an in-person screening visit, which was scheduled during the early follicular phase for the NC group and during the week of placebo pills for the OC group. At the in-person screening visit, participants provided informed consent and completed standardized forms to provide demographic and baseline smoking-related information including the Fagerstrom Nicotine Dependence (FTND).23 All OC participants were supplied with Tri-Sprintec, which contains ethinyl estradiol and norgestimate, at this visit and instructed to commence use the next day. Ethinyl estradiol inhibits folliculogenesis, which prevents ovulation.24 Norgestimate is a synthetic form of progestin that inhibits ovulation and is an agonist of the progesterone receptor.25 As a result of these medications, endogenous production progesterone and estradiol level are suppressed and relatively stable over time.17,26

Once enrolled all participants were randomized to testing order - either anticipated low progesterone week (LPW) followed by anticipated high progesterone week (HPW) or vice versa. Specifically, LPW in the NC group was during the follicular phase (2 to 7 days post the onset of menses, per self-report as recommended with retrospective confirmation via progesterone levels with < 2 ng/ml indicative of follicular phase27) and in the OC group it was during the first week of Tri-Sprintec (ethinyl estradiol 35 mcg and norgestimate 0.18 mcg). HPW in the NC group was during the luteal phase (2 to 7 days post luteinizing hormone surge, per results of urinary luteinizing tests with retrospective confirmation via progesterone levels with > 2 ng/ml indicative of luteal phase as recommended27) and in the OC group it was during the third week of Tri-Sprintec (ethinyl estradiol 35 mcg and norgestimate 0.25 mcg).

Each testing week consisted of the following identical study procedures. On Day 1, while participants were ad libitum smoking, they attended a one-hour in-person clinic visit to practice all study procedures. On Day 2, while participants were ad libitum smoking, they attended a two-hour in-person clinic visit to complete their first nicotine exposure session. Daily on Day 3 (quit day), Day 4 and Day 5, participants attended a clinic visit to verify smoking status via expired carbon monoxide breathalyzer. On Day 6, while participants were abstinent, they attended a four-hour in-person clinic visit to complete their second nicotine exposure session. Upon completion of the second nicotine exposure session, all participants then resumed ad libitum smoking for approximately 6 weeks until their second testing week.

2.3. Nicotine Exposure Lab Session.

The two nicotine exposure lab sessions included identical procedures. In brief, upon arrival at the clinic, participants had their expired carbon monoxide measured to confirm smoking status (< 5 ppm indicating smoking abstinence). After a 30 minute rest period (during which participants could not smoke), at Time 0 minutes participants self-administered nicotine nasal spray (Nicotrol 2mg). We opted to use nicotine nasal spray rather than alternate forms of nicotine given the absorption is more similar to the absorption of nicotine from combustible cigarettes (as opposed to transdermal, gum, lozenge forms of nicotine) and less invasive than intravenously delivered nicotine. Participants also completed a subjective assessment of the response to nicotine at Time −30 and Time +5 minutes using the Subjective State Scale (SSS),28,29 which included subscales for craving, withdrawal, negative affect, positive affect, and physical symptoms. Subjective response, as well as other effects (e.g., cognitive effects) were monitored for 90 minutes post nicotine administration (data not shown). On Day 6, the abstinent session, also contained a second dose of nicotine administration that was monitored for an additional 90 minutes (data not shown). Additional details on this protocol can be found elsewhere.20

2.4. Statistical Analyses.

SAS version 9.4 was used for analysis (SAS Institute Inc., Cary, NC). In this secondary data analysis, OC participants (n=14) were matched 1:2 with non-OC participants (n=28) on education (exact match: no college versus at least some college), age (± 5 years), and FTND score (± 2 points).30 The distributions of all outcome variables (SSS subscales) were assessed using histograms and quantile-quantile plots, and all were assumed to be normally distributed. Demographics and baseline characteristics were summarized by study group (OC and NC) using descriptive statistics (counts and proportions for categorical variables and adjusted means and standard deviations for continuous variables). Differences at baseline were assessed using linear or generalized linear mixed regression models (in SAS GLIMMIX) with a random intercept for matched set.

All models were adjusted for FTND given there was a statistically significant (and potentially clinically meaningful) difference between the two groups even after matching. For all analyses, correlated data analysis methods (i.e., random intercept) were used to account for the matching in the study design, and given the crossover study design, the order was also adjusted for (i.e., HPW followed by LPW or vice versa) to account for any potential order effects. Due to small sample size and limited model stability, the mixed models were not adjusted for additional covariates, and results for each testing conditions were examined separately (HPW and LPW, ad libitum smoking and acute abstinence days). When examining differences in the SSS level after nicotine administration, we adjusted for the pre-nasal-spray SSS levels. There were some models where the variance of the random effect was 0. However, to be consistent with the matching in our study design, the random intercepts were not removed for these models.31 We used linear mixed regression models (one model per outcome and time-point) with a random intercept for matched set to test for differences in the SSS levels by OC use at the following time-points (repeated for HPW and LPW): (1) ad libitum smoking, prior to nasal spray administration, (2) ad libitum smoking, five minutes after nicotine nasal spray administration adjusted for pre-nasal spray SSS level, (3) acute abstinence, prior to nasal spray administration, (4) acute abstinence, five minutes after nicotine nasal spray administration adjusted for prenasal spray SSS level. In addition to the stratified models, for the SSS outcomes with significant findings in the post-nasal spray stratified models, repeated measures models were run using linear mixed regression models for all timepoints, with a random intercept for matched set and a random intercept for subject nested within matched set. The purpose of these models was to test for the main effect of study group on post-nasal spray SSS level, after adjusting for prenasal spray SSS level, and subsequently to test if this effect varies by progesterone level. These models included the following predictors: study group, progesterone level, smoking status, pre-nasal spray SSS level, FTND score, and order of testing week (HPW followed by LPW or vice versa) , progesterone level*order of testing week and smoking status*order of testing week. Additional models were run with a study group*progesterone level interaction term to test if the group effect on post-nasal-spray SSS differed by progesterone level. Given the exploratory nature of the study and small sample size, we did not adjust for multiple comparisons. This should be considered in the interpretation of the results. P-values <0.05 were considered statistically significant.

3. Results

3.1. Study Sample.

A total of 42 participants were included (OC group n=14; NC group n=28). Participants were, on average, in their mid-20s (OC group: [mean ± standard error] 24.2±1.1 [range 19 to 34] years old versus NC group: 26.2±1.1 [range 21 to 36] years old, p-value<0.001) and smoked slightly more than 10 cigarettes per day (OC group: 10.5±1.3 versus NC group: 11.6±1.0, p-value=0.468). The progesterone level during the LPW abstinence session was comparable between the two study groups (OC group: 0.56±0.08 ng/ml versus NC group: 0.72±0.06 ng/ml, p-value=0.154). As displayed in Table 1, all other hormone values were significantly higher (p-values<0.01) in the NC group compared to the OC group at each time point. Within the NC group, all hormone values were significantly greater during HPW as compared to LPW (p-value<0.001). In contrast, in the OC group, none of the hormone values differed significantly by testing week (p-value>0.05). The amount of time between enrollment (and, for the OC group, start of study-supplied OC) and the first testing week was (mean ± standard deviation) 13.79 ± 8.15 days for the OC group and 32.29 ± 23.57 days for the NC group.

Table 1.

Demographics, Smoking-Related Characteristics and Hormone Levels by Study Group

Oral Contraceptives Users (OC) (n=14) Naturally Cycling Participants (NC) (n=28) p-value
Age, Mean ± SE 24.2 ± 1.1 26.2 ± 1.1 <.001
Education, n (%) at least some college 13 (92.9%) 26 (92.9%) 1.00
White, n (%) Non-Hispanic race 12 (85.7%) 21 (75.0%) .437
Cigarettes per day, Mean ± SE 10.5 ± 1.3 11.6 ± 1.0 .468
Nicotine dependence (FTND score), Mean ± SE 2.6 ± 0.5 3.4 ± 0.5 .011
Time to first cigarette in the morning, n (%)
  5 minutes or less 2 (14.3%) 2 (7.1%) .024
  6-30 minutes 4 (28.6%) 14 (50.0%)
  31-60 minutes 1 (7.1%) 10 (35.7%)
  More than 60 minutes 7 (50.0%) 2 (7.1%)
Study week order
  Anticipated low progesterone week first 8 (57.1%) 13 (46.4%) .513
  Anticipated high progesterone week first 6 (42.9%) 15 (53.6%)
Hormones, Mean ± SE
Anticipated Low Progesterone Week
Ad Libitum Smoking
 Progesterone (ng/ml) 0.51 ± 0.12 0.94 ± 0.09 a 0.009
 Estradiol (pg/ml) 21.41 ± 7.82 54.28 ± 5.42 a 0.002
 Progesterone/Estradiol ratio 25.68 ± 6.87 26.47 ± 4.76 a 0.926
Smoking Abstinence
 Progesterone (ng/ml) 0.56 ± 0.08 0.72 ± 0.06 a 0.154
 Estradiol (pg/ml) 26.00 ± 11.87 68.21 ± 8.58 a 0.006
 Progesterone/Estradiol ratio 30.43 ± 4.63 16.86 ± 3.45 a 0.017
Anticipated High Progesterone Week
Ad Libitum Smoking
 Progesterone (ng/ml) 0.45 ± 1.34 7.91 ± 0.87 b <.001
 Estradiol (pg/ml) 21.36 ± 14.85 122.38 ± 9.66 b <.001
 Progesterone/Estradiol ratio 32.86 ± 13.12 71.92 ± 8.54 b 0.021
Smoking Abstinence
 Progesterone (ng/ml) 0.45 ± 1.24 11.44 ± 0.88 b <.001
 Estradiol (pg/ml) 13.81 ± 18.61 148.01 ± 14.15 b <.001
 Progesterone/Estradiol ratio 44.06 ± 14.60 86.69 ± 10.33 b 0.025
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Notes. p-values are from linear/generalized linear mixed models with a random intercept for matched set, FTND = Fagerstrom test for nicotine dependence

a

Value significantly (p<0.001) different from corresponding hormone values during the Anticipated High Progesterone Week.

b

Value significantly (p<0.001) different from corresponding hormone values during the Anticipated Low Progesterone Week.

3.2. Subjective Nicotine Response during Ad Libitum Smoking by Oral Contraceptive Use.

After nicotine nasal spray administration (Table 2, Figure 1) during HPW, craving was significantly lower in the OC group compared to the NC group during (OC group: [adjusted mean ± standard error] 1.93±0.33 versus NC group: 2.89±0.23, p-value=0.024) after adjusting for pre-nasal spray craving levels. A similar, though not statistically significant, difference was noticed during the LPW such that craving was lower in the OC group compared to NC group (OC group: 1.91 ± 0.29 versus NC group: 2.62 ± 0.20, p-value=0.061). In contrast, an opposite, though not statistically significant, difference was noticed prior to nicotine nasal spray during LPW such that craving was higher in the OC group compared to the NC group (OC group: 3.56 ± 0.45 versus NC group: 2.70 ± 0.36, p-value=0.061).

Table 2.

Ad libitum smoking: Subjective response (adjusted mean ± standard error) to nicotine nasal spray by oral contraceptive use and testing week

Oral Contraceptive Users (n=14) Naturally Cycling Participants (n=28) Mean Difference* p-value**
Anticipated Low Progesterone Week
 Prior to Nicotine Nasal Spray
       Positive Affect 2.82 ± 0.40 3.18 ± 0.29 −0.36 ± 0.49 0.475
       Negative Affect† 1.34 ± 0.34 1.70 ± 0.23 −0.36 ± 0.41 0.395
       Craving 3.56 ± 0.45 2.70 ± 0.36 0.90 ± 0.46 0.061
       Withdrawal† 1.04 ± 0.27 1.29 ± 0.19 −0.25 ± 0.34 0.473
       Physical Symptoms 0.80 ± 0.23 0.72 ± 0.17 0.08 ± 0.25 0.741
 After Nicotine Nasal Spray, Adjusted for Pre-Nasal-Spray Level
       Positive Affect 3.12 ± 0.21 3.01 ± 0.17 0.11 ± 0.23 0.638
       Negative Affect† 1.18 ± 0.19 1.59 ± 0.13 −0.41 ± 0.23 0.091
       Craving 1.91 ± 0.29 2.62 ± 0.20 −0.71 ± 0.36 0.061
       Withdrawal† 1.13 ± 0.13 1.12 ± 0.09 0.01 ± 0.16 0.940
       Physical Symptoms 0.82 ± 0.08 0.68 ± 0.06 0.14 ± 0.10 0.145
Anticipated High Progesterone Week
 Prior to Nicotine Nasal Spray
       Positive Affect 2.59 ± 0.36 3.32 ± 0.25 −0.73 ± 0.44 0.110
       Negative Affect 1.08 ± 0.27 1.33 ± 0.19 −0.25 ± 0.34 0.458
       Craving 3.02 ± 0.51 2.88 ± 0.37 0.14 ± 0.61 0.825
       Withdrawal† 0.80 ± 0.24 1.21 ± 0.17 −0.41 ± 0.29 0.174
       Physical Symptoms 0.69 ± 0.12 0.53 ± 0.09 0.17 ± 0.14 0.243
 After Nicotine Nasal Spray, Adjusted for Pre-Nasal-Spray Level
       Positive Affect† 2.79 ± 0.24 3.05 ± 0.16 −0.26 ± 0.30 0.381
       Negative Affect 1.16 ± 0.16 1.26 ± 0.12 −0.10 ± 0.20 0.615
       Craving 1.93 ± 0.33 2.89 ± 0.23 −0.96 ± 0.40 0.024
       Withdrawal† 0.91 ± 0.11 1.04 ± 0.08 −0.13 ± 0.13 0.336
       Physical Symptoms 0.71 ± 0.11 0.62 ± 0.09 0.10 ± 0.13 0.446
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*

(β ± Standard Error),

**

P-values are from linear mixed models with a random intercept for matched set and adjusted for FTND, and study week order (post-nasal-spray models also adjusted for pre-nasal-spray SSS level), each row is its own model,

†

Random effect variance of 0 in linear mixed model.

Figure 1. Craving Before and After Use of Nicotine Nasal Spray by Oral Contraceptive Use during Ad Libitum Smoking in anticipated low progesterone week (LPW) and anticipated high progesterone week (HPW).

Figure 1.

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Nicotine nasal spray reduced self-reported craving by 36-46% in OC users regardless of progesterone levels, but had almost no effect (0-3% change) in naturally-cycling women, again irrespective of progesterone levels. Craving levels are adjusted for FTND and order effects, and after-nasal-spray craving is adjusted for before-nasal-spray craving.

3.2. Subjective Nicotine Response during Smoking Abstinence by Oral Contraceptive Use.

There were no statistically significant differences by study group during smoking abstinence either prior to or after nicotine nasal spray during either testing week (Table 3). However, prior to nicotine nasal spray administration, positive affect was lower in the OC group compared to the NC group during both LPW (OC group: 2.48 ± 0.36 versus NC group: 3.24 ± 0.28, p-value=0.072) and HPW (OC group: 2.25 ± 0.36 versus NC group: 3.10 ± 0.27, p-value=0.056). Physical symptoms also trended towards being higher in the OC group (0.93±0.15) than the NC group (0.59±0.11, p-value=0.057) prior to nicotine nasal spray administration during HPW only. Though none of these differences were statistically significant.

Table 3.

Smoking abstinence: Subjective response (adjusted mean ± standard error) to nicotine nasal spray by oral contraceptive use and testing week

Oral Contraceptive Users (n=14) Naturally Cycling Participants (n=28) Mean Difference* p-value**
Anticipated Low Progesterone Week
 Prior to Nicotine Nasal Spray
      Positive Affect 2.48 ± 0.36 3.24 ± 0.28 −0.76 ± 0.40 0.072
      Negative Affect† 1.70 ± 0.35 1.79 ± 0.25 −0.09 ± 0.44 0.835
      Craving† 3.73 ± 0.58 3.89 ± 0.42 −0.16 ± 0.70 0.820
      Withdrawal† 1.38 ± 0.26 1.28 ± 0.18 0.11 ± 0.32 0.743
      Physical Symptoms 0.78 ± 0.17 0.60 ± 0.12 0.18 ± 0.21 0.389
 After Nicotine Nasal Spray, Adjusted for Pre-Nasal Spray Level
      Positive Affect† 3.02 ± 0.20 3.14 ± 0.14 −0.12 ± 0.25 0.637
      Negative Affect 1.43 ± 0.18 1.39 ± 0.13 0.04 ± 0.22 0.853
      Craving 3.12 ± 0.45 3.58 ± 0.35 −0.46 ± 0.50 0.365
      Withdrawal 0.93 ± 0.12 1.05 ± 0.08 −0.13 ± 0.14 0.366
      Physical Symptoms† 0.76 ± 0.12 0.73 ± 0.08 0.03 ± 0.15 0.847
Anticipated High Progesterone Week
 Prior to Nicotine Nasal Spray
      Positive Affect 2.25 ± 0.36 3.10 ± 0.27 −0.85 ± 0.42 0.056
      Negative Affect† 1.63 ± 0.29 1.88 ± 0.20 −0.26 ± 0.36 0.482
      Craving 3.49 ± 0.61 4.00 ± 0.49 −0.51 ± 0.65 0.436
      Withdrawal† 1.17 ± 0.19 1.24 ± 0.13 −0.07 ± 0.24 0.766
      Physical Symptoms 0.93 ± 0.15 0.59 ± 0.11 0.34 ± 0.17 0.057
 After Nicotine Nasal Spray, Adjusted for Pre-Nasal Spray Level
      Positive Affect† 2.84 ± 0.25 2.92 ± 0.17 −0.09 ± 0.31 0.787
      Negative Affect 1.37 ± 0.19 1.32 ± 0.13 0.05 ± 0.24 0.844
      Craving 3.00 ± 0.39 3.25 ± 0.29 −0.25 ± 0.45 0.588
      Withdrawal 0.83 ± 0.12 1.03 ± 0.09 −0.20 ± 0.15 0.181
      Physical Symptoms 0.59 ± 0.09 0.71 ± 0.07 −0.13 ± 0.10 0.234
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*

(β ± Standard Error),

**

P-values are from linear mixed models with a random intercept for matched set and adjusted for FTND and study week order (post-nasal-spray models also adjusted for pre-nasal-spray SSS level), each row is its own model,

†

Random effect variance of 0 in linear mixed model.

3.3. Overall Effect of Oral Contraceptive Use on Subjective Nicotine Response.

Regardless of smoking status and testing week, though not statistically significant (Table 4), craving was higher in the NC group compared to the OC group (OC Group: 2.51 ± 0.29 versus NC Group: 3.07 ± 0.23, p-value: 0.062). A similar differences was observed during HPW (OC Group: 2.44 ± 0.33 versus NC Group: 3.10 ± 0.25, p-value: 0.061) but not during LPW (OC Group: 2.57 ± 0.33 versus NC Group: 3.05 ± 0.25, p-value: 0.174), regardless of smoking status.

Table 4.

Subjective craving response (adjusted mean ± standard error) to nicotine nasal spray by oral contraceptive use

Oral Contraceptive Users (n=14) Naturally Cycling Participants (n=28) Mean Difference* Group difference p-value** Phase difference in group difference p-value**
Craving after nicotine nasal spray, adjusted for Pre-Nasal-Spray level
 Model 1
   All testing sessions together 2.51 ± 0.29 3.07 ± 0.23 −0.57 ± 0.30 0.062
 Model 2 0.605
   Anticipated low progesterone week 2.57 ± 0.33 3.05 ± 0.25 −0.48 ± 0.35 0.174
   Anticipated high progesterone week 2.44 ± 0.33 3.10 ± 0.25 −0.66 ± 0.35 0.061
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*

(β ± Standard Error),

**

P-values are from linear mixed models with a random intercept for matched set, a random intercept for subject nested within matched set, and adjusted for progesterone level (model 1), FTND, study week order, smoking status, and pre-nasal-spray SSS level; each row is its own model.

4. Discussion

This study is the first to examine acute subjective effects to nicotine by OC use after stratifying by testing condition (e.g., smoking status and anticipated progesterone level). In brief, we observed that, regardless of testing week but only during ad libitum smoking, nicotine reduced the adjusted average craving level by 36-46% as compared to only 0-3% in the NC group. In other words, the nicotine nasal spray satiated craving for cigarettes more in the OC group compared to the NC group. We have previously reported higher craving in hormonal contraceptive users in cessation trials that used standard doses of nicotine replacement therapy (transdermal patch, lozenge).32,33 OC use has also been linked to faster nicotine metabolism.34–36 These observations suggest that the OC users may need a higher dose of nicotine replacement therapy to be an effective aid for smoking cessation. While this has yet to be examined in OC users specifically, higher doses of nicotine replacement therapy have been shown to be effective in those with faster nicotine metabolism, in general. 37,38 Further, the lack of an effect of nicotine on craving within the NC group was surprising given our previous observations from the same study that demonstrated a significant increase in blood pressure, heart rate and maximum concentrations of nicotine after nicotine nasal spray administration, especially during the luteal phase.39 Additional research is needed to elucidate the mechanisms responsible for these observations.

We also observed that OC users had lower, though not statistically significant, positive affect during smoking abstinence prior to nicotine nasal spray administration during both LPW and HPW. After nicotine nasal spray administration, there were no differences in positive affect between the OC and NC groups. In another analysis with the same sample of OC users in the current study, we also observed significantly lower positive affect levels in OC users compared to NC outside of the nicotine exposure lab and during both anticipated low and high progesterone week.21 Previous investigations have documented abstinence-induced increases in negative affect40,41 and reductions in positive affect and in female but not male smokers.42 This finding highlights the need to investigate the potential that OC use may be driving these sex differences, at least in part.

One of the most interesting aspects of this project is the number of null findings between the OC and NC groups despite the significant differences in most hormone levels. Specifically, the estradiol values significantly varied by group at all four time points (difference ranging from 60% to 90% lower in OC group than NC group) and the progesterone values significantly varied by group at three of the four time points (difference ranging from 46% to 96% lower in the OC group than the NC group). At one time point - during the smoking abstinence session during the anticipated low progesterone week - the progesterone levels were statistically equivalent between the two groups This is expected as the progesterone value in the natural menstrual cycle is the lowest during the mid-follicular phase (i.e., approximately menstrual cycle day 7).27 One explanation for this observation is that we had a relatively small sample size and limited power. Indeed, the results from the liner mixed regression models for craving trended towards significance during the HPW but not the LPW. This suggests that differences between the groups may be more pronounced when hormonal differences are more extreme. However, these observations did not reach statistical significance. These null findings may also suggest that more exploration into the mechanisms of action is warranted. In general, based primarily on observations from the preclinical literature, progesterone is thought to be protective against drug use behaviors (e.g., lower self-administration) whereas estradiol is thought to facilitate these same behaviors.45 In the clinical research, it is theorized that the neurobiological reward response to nicotine varies by menstrual phase as a result of the variation of progesterone and estradiol across the menstrual cycle.43 However, in the current study, the progesterone and estradiol levels varied between the NC and OC groups by up to ten-fold and the group differences in subjective response to nicotine were relatively sparse. This suggests that there may be other variables responsible for the drug reward response observed here and elsewhere. For example, the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are blunted with hormonal contraceptive use and, therefore, likely differ between our NC and OC groups. The direct relationship between FSH and LH with drug reward response variables has not been examined in clinical samples. Similarly, allopregnanolone is also blunted with hormonal contraceptive use 44 and has been recently implicated as playing a role in smoking-related behaviors in women.45,46 Because OCs both reduce endogenous hormone levels but also replace these with potent, neuroactive steroids it is challenging to disentangle effects that are produced by decreasing endogenous hormone levels versus those produced by the synthetic hormones themselves - a problem compounded by the paucity of existing literature describing endogenous hormone decreases vs. synthetic hormone effects. One investigation of endogenous ovarian hormone suppression via a gonadotropin-releasing hormone agonist (not via OC use) showed reduced amygdala reactivity to monetary rewards, indicating that endogenous hormones play a role in normal reward processing.47 This is consistent with literature from both human and preclinical work pointing to a relationship between estrogen and dopamine.48,49 Because OC users show similar results to each other in low vs. high progesterone conditions, and also differ somewhat from NC women during those conditions, these findings suggest that the OCs themselves rather than the reduction in endogenous hormones may be affecting craving and positive affect in smokers. However, a great deal of further research is needed to identify the mechanisms of action involved in these observations.

Despite the strengths of the methodologies used in this study - including the controlled cross-over design, biochemical confirmation of smoking status, measurement of sex hormones, and use of a standardized OC - there are several limitations to consider. First, the study sample was a convenience sample of participants who were not interested in quitting smoking and were able to comply with an intensive study protocol. Thus, it is unknown how these observations may translate to those trying to quit. Second, we did not standardize the initiation of the study-supplied OC with the timing of their own brand of OCs, nor did we include a period of time to allow for hormonal stabilization within the OC group. Thus, the hormonal changes and subsequent stabilizing may be variable within the OC group. Third, we examined the response to nicotine nasal spray. Nicotine nasal spray can be aversive, which may have influenced the response in this study. This also limits the generalizability of these observations to response to cigarette smoking which contains other reinforcing effects (such as respiratory tract sensations, which may be especially reinforcing to women50). Further, we did not include statistical adjustments for multiple tests. The small sample size and the large number of tests conducted suggest an exploratory study with low power to detect significant differences. With the high number of tests run, there is a risk of reporting spurious findings that may have occurred by chance (Type I error), and thus the results of this study need to be replicated and should be interpreted with this in mind.

In summary, this study provides some additional evidence for differences in smoking-related outcomes by OC use; however, the number of significant differences was relatively few. Future research should examine how these observations may play a role in smoking cessation efforts made by women who use OCs as well as examine the biological mechanisms responsible for these observations.

Highlights.

  • We compared subjective response (5 items) to nicotine by oral contraceptive (OC) use.

  • OC users had lower progesterone and estradiol levels at 7/8 time points.

  • Nicotine nasal spray reduced craving by 36-46% in OC users but 0-3% in non-users.

  • Despite differences in hormones, few differences in subjective response were noted.

Acknowledgements

We extend our thanks to Lindsay Jarvis, Kathryn Resner, Sara Paradise, Nicole Tosun, Jennifer Vanvliet, Jennifer Widenmier, and Danielle Young for their participation in data management and collection. We also thank Evelyn Rens for her editorial assistance and Sara Richter for her statistical analysis advice.

Funding

This project was funded by National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) Grant R01-DA08075.

Footnotes

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Conflict of Interest

All authors declare that they have no conflict of interest.

Contributor Information

Alicia M. Allen, Department of Family & Community Medicine, College of Medicine, University of Arizona, 3950 South Country Club Drive, Suite 330, Tucson, Arizona 85714-2238.

Samantha C. Friedrichsen, Professional Data Analysts, Inc., 219 Main Street SE, Suite 302, Minneapolis, MN 55414.

Nicole Petersen, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90024, USA.

Sharon S. Allen, Department of Family Medicine & Community Health, Medical School, University of Minnesota 420 Delaware Street SE, Room A682, Minneapolis, Minnesota 55455.

References

  • 1.CDC. Smoking and Tobacco Use; Surgeon General’s Reports; 2001.; 2001. [Google Scholar]
  • 2.Smith PH, Bessette AJ, Weinberger AH, Sheffer CE, McKee SA. Sex/gender differences in smoking cessation: A review. Prev Med (Baltim). 2016. doi: 10.1016/j.ypmed.2016.07.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Weinberger AH, Smith PH, Allen SS, et al. Systematic and Meta-Analytic Review of Research Examining the Impact of Menstrual Cycle Phase and Ovarian Hormones on Smoking and Cessation. Nicotine Tob Res. 2015;17(4):407–421. doi: 10.1093/ntr/ntu249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP. Sex and estrogen influence drug abuse. Trends Pharmacol Sci. 2004;25(5):273–279. doi: 10.1016/J.TIPS.2004.03.011. [DOI] [PubMed] [Google Scholar]
  • 5.Lynch WJ, Sofuoglu M. Role of progesterone in nicotine addiction: evidence from initiation to relapse. Exp Clin Psychopharmacol. 2010;18(6):451–461. doi: 10.1037/a0021265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.DeVito EE, Herman AI, Waters AJ, Valentine GW, Sofuoglu M. Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. Neuropsychopharmacology. 2014;39(6):1431–1440. doi: 10.1038/npp.2013.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Sofuoglu M, Babb DA, Hatsukami DK. Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Pharmacol Biochem Behav. 69(1-2):299–304. http://www.ncbi.nlm.nih.gov/pubmed/11420098. Accessed March 5, 2018. [DOI] [PubMed] [Google Scholar]
  • 8.Sofuoglu M, Mitchell E, Mooney M. Progesterone effects on subjective and physiological responses to intravenous nicotine in male and female smokers. Hum Psychopharmacol. 2009;24(7):559–564. doi: 10.1002/hup.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Sofuoglu M, Mouratidis M, Mooney M. Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers. Psychoneuroendocrinology. 2011;36(1):123–132. doi: 10.1016/j.psyneuen.2010.07.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Allen SS, Bade T, Center B, Finstad D, Hatsukami D. Menstrual phase effects on smoking relapse. Addiction. 2008;103(5):809–821. doi: 10.1111/j.1360-0443.2008.02146.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Mazure CM, Toll B, McKee S a, Wu R, O’Malley SS. Menstrual cycle phase at quit date and smoking abstinence at 6 weeks in an open label trial of bupropion. Drug Alcohol Depend. 2011;114(1):68–72. doi: 10.1016/j.drugalcdep.2010.07.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Carpenter MJ, Saladin ME, Leinbach AS, Larowe SD, Upadhyaya HP. Menstrual phase effects on smoking cessation: a pilot feasibility study. J Womens Health (Larchmt). 2008;17(2):293–301. doi: 10.1089/jwh.2007.0415. [DOI] [PubMed] [Google Scholar]
  • 13.Franklin TR, Ehrman R, Lynch KG, et al. Menstrual cycle phase at quit date predicts smoking status in an NRT treatment trial: a retrospective analysis. J Womens Health (Larchmt). 2008;17(2):287–292. doi: 10.1089/jwh.2007.0423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Saladin ME, Gray KM, Carpenter MJ, Baker NL, McClure EA. Increasing progesterone levels in free cycling women smokers are associated with abstinence during a medication-assisted quit attempt In: Society for Research on Nicotine and Tobacco. ; 2014:228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Pang RD, Liautaud MM, Kirkpatrick MG, Huh J, Monterosso J, Leventhal AM. Ovarian Hormones and Transdermal Nicotine Administration Independently and Synergistically Suppress Tobacco Withdrawal Symptoms and Smoking Reinstatement in the Human Laboratory. Neuropsychopharmacology. 2018;43(4):828–837. doi: 10.1038/npp.2017.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Allen AM, Lundeen K, Eberly LE, et al. Hormonal contraceptive use in smokers: Prevalence of use and associations with smoking motives. Addict Behav. 2018;77. doi: 10.1016/j.addbeh.2017.10.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Fleischman DS, Navarrete CD, Fessler DMT. Oral Contraceptives Suppress Ovarian Hormone Production. Psychol Sci. 2010;21(5):750–752. doi: 10.1177/0956797610368062. [DOI] [PubMed] [Google Scholar]
  • 18.Allen AM, Weinberger AH, Wetherill RR, Howe CL, McKee SA. Oral Contraceptives and Cigarette Smoking: A Review of the Literature and Future Directions. Nicotine Tob Res. November 2017. doi: 10.1093/ntr/ntx258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Allen SS, Allen AM, Pomerleau CS. Influence of phase-related variability in premenstrual symptomatology, mood, smoking withdrawal, and smoking behavior during ad libitum smoking, on smoking cessation outcome. Addict Behav. 2009;34(1):107–111. doi: 10.1016/j.addbeh.2008.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Allen AM, Lunos S, Heishman SJ, al’Absi M, Hatsukami D, Allen SS. Subjective response to nicotine by menstrual phase. Addict Behav. 2015;43(1). doi: 10.1016/j.addbeh.2014.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hinderaker K, Allen AM, Tosun N, al’Absi M, Hatsukami D, Allen SS. The effect of combination oral contraceptives on smoking-related symptomatology during short-term smoking abstinence. Addict Behav. 2015;41:148–151. doi: 10.1016/j.addbeh.2014.10.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Frieden TR, Harold Jaffe DW, Director for Science James Stephens AW, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2013 Adapted from the World Health Organization Selected Practice Recommendations for Contraceptive Use, 2nd Edition Morbidity and Mortality Weekly Report Centers for Disease Control and Preven. Early Release MMWR. 2013;6262. [Google Scholar]
  • 23.Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119–1127. [DOI] [PubMed] [Google Scholar]
  • 24.Craig CR, Stitzel RE. Modern Pharmacology with Clinical Applications - Google Books. Lippincott Williams & Wilkins; 2004. https://books.google.com/books?id=KqA29hQm3AC&pg=PA708#v=onepage&q&f=false. Accessed March 26, 2019.
  • 25.Kuhl H Pharmacology of estrogens and progestogens: influence of different routes of administration. doi: 10.1080/13697130500148875. [DOI] [PubMed] [Google Scholar]
  • 26.Montoya ER, Bos PA. How Oral Contraceptives Impact Social-Emotional Behavior and Brain Function. Trends Cogn Sci. 2017;21(2):125–136. doi: 10.1016/j.tics.2016.11.005. [DOI] [PubMed] [Google Scholar]
  • 27.Allen AM, McRae-Clark AL, Carlson S, et al. Determining Menstrual Phase in Human Biobehavioral Research: A Review With Recommendations. Exp Clin Psychopharmacol. November 2015. doi: 10.1037/pha0000057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.al’Absi M, Wittmers LE, Erickson J, Hatsukami D, Crouse B. Attenuated adrenocortical and blood pressure responses to psychological stress in ad libitum and abstinent smokers. Pharmacol Biochem Behav. 2003;74(2):401–410. http://www.ncbi.nlm.nih.gov/pubmed/12479961. Accessed November 28, 2017. [DOI] [PubMed] [Google Scholar]
  • 29.al’Absi M Hypothalamic-pituitary-adrenocortical responses to psychological stress and risk for smoking relapse. Int J Psychophysiol. 2006;59(3):218–227. doi: 10.1016/j.ijpsycho.2005.10.010. [DOI] [PubMed] [Google Scholar]
  • 30.Grandits G, Neuhaus J. Using SAS ® to Perform Individual Matching in Design of Case Control Studies.; 2010. http://support.sas.com/resources/papers/proceedings10/061-2010.pdf. Accessed October 16, 2018.
  • 31.Kiernan K, Tao J, Gibbs P. Tips and Strategies for Mixed Modeling with SAS/STAT ® Procedures. http://support.sas.com/resources/papers/proceedings12/332-2012.pdf. Accessed October 16, 2018.
  • 32.Dickmann PJ, Mooney ME, Allen SS, Hanson K, Hatsukami DK. Nicotine withdrawal and craving in adolescents: effects of sex and hormonal contraceptive use. Addict Behav. 34(6-7):620–623. doi: 10.1016/j.addbeh.2009.03.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Allen AM, Carlson S, Eberly LE, Hatsukami D, Piper ME. Use of hormonal contraceptives and smoking cessation: A preliminary report. Addict Behav. 2018;76. doi: 10.1016/j.addbeh.2017.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P. Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther. 2006;79(5):480–488. doi: 10.1016/j.clpt.2006.01.008. [DOI] [PubMed] [Google Scholar]
  • 35.Berlin I, Gasior MJ, Moolchan ET. Sex-based and hormonal contraception effects on the metabolism of nicotine among adolescent tobacco-dependent smokers. Nicotine Tob Res. 2007;9(4):493–498. doi: 10.1080/14622200701243193. [DOI] [PubMed] [Google Scholar]
  • 36.Chenoweth MJ, Novalen M, Hawk LW, et al. Known and Novel Sources of Variability in the Nicotine Metabolite Ratio in a Large Sample of Treatment-Seeking Smokers. Cancer Epidemiol Prev Biomarkers. 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Carpenter MJ, Jardin BF, Burris JL, et al. Clinical Strategies to Enhance the Efficacy of Nicotine Replacement Therapy for Smoking Cessation: A Review of the Literature. Drugs. 2013;73(5):407–426. doi: 10.1007/s40265-013-0038-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Schnoll RA, Wileyto EP, Leone FT, Tyndale RF, Benowitz NL. High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine: A Proof of Concept Placebo-Controlled Trial. Nicotine Tob Res. 2013;15(2):348–354. doi: 10.1093/ntr/nts129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Allen SS, Allen AM, Kotlyar M, Lunos S, al’Absi M, Hatsukami D. Menstrual Phase and Depressive Symptoms Differences in Physiological Response to Nicotine Following Acute Smoking Abstinence. Nicotine Tob Res. 2013;15(6):1091–1098. doi: 10.1093/ntr/nts236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Pang RD, Leventhal AM. Sex differences in negative affect and lapse behavior during acute tobacco abstinence: A laboratory study. Exp Clin Psychopharmacol. 2013;21(4):269–276. doi: 10.1037/a0033429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Xu J, Azizian A, Monterosso J, et al. Gender effects on mood and cigarette craving during early abstinence and resumption of smoking. Nicotine Tob Res. 2008;10(11):1653–1661. doi: 10.1080/14622200802412929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Faulkner P, Petersen N, Ghahremani DG, et al. Sex differences in tobacco withdrawal and responses to smoking reduced-nicotine cigarettes in young smokers. Psychopharmacology (Berl). 2018;235(1):193–202. doi: 10.1007/s00213-017-4755-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Franklin TR, Allen SS. Influence of menstrual cycle phase on smoking cessation treatment outcome: a hypothesis regarding the discordant findings in the literature. Addiction. 2009;104(11):1941–1942. doi: 10.1111/j.1360-0443.2009.02758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Santoru F, Berretti R, Locci A, Porcu P, Concas A. Decreased allopregnanolone induced by hormonal contraceptives is associated with a reduction in social behavior and sexual motivation in female rats. Psychopharmacology (Berl). 2014;231(17):3351–3364. doi: 10.1007/s00213-014-3539-9. [DOI] [PubMed] [Google Scholar]
  • 45.Allen AM, al’Absi M, Lando H, Hatsukami D, Allen SS. Menstrual phase, depressive symptoms, and allopregnanolone during short-term smoking cessation. Exp Clin Psychopharmacol. 2013;21(6). doi: 10.1037/a0034075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Allen AM, Al’Absi M, Lando H, Allen SS. Allopregnanolone association with psychophysiological and cognitive functions during acute smoking abstinence in premenopausal women. Exp Clin Psychopharmacol. 2015;23(1). doi: 10.1037/a0038747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Macoveanu J, Henningsson S, Pinborg A, et al. Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward. Neuropsychopharmacology. 2016;41(4):1057–1065. doi: 10.1038/npp.2015.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Petersen N, London ED. Addiction and dopamine: sex differences and insights from studies of smoking. Curr Opin Behav Sci. 2018;23:150–159. doi: 10.1016/j.cobeha.2018.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Meitzen J, Meisel RL, Mermelstein PG. Sex Differences and the Effects of Estradiol on Striatal Function. Curr Opin Behav Sci. 2018;23:42–48. doi: 10.1016/j.cobeha.2018.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Perkins KA. Smoking Cessation in Women: Special Considerations. CNS Drugs. 2001;15(5):391–411. [DOI] [PubMed] [Google Scholar]

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