The American Journal on Addictions, 23: 211–217, 2014 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/j.1521-0391.2014.12094.x
Sex Differences in Smoking Cue Reactivity: Craving, Negative Affect, and Preference for Immediate Smoking Neal Doran, PhD Department of Psychiatry, University of California, San Diego, California
Background and Objectives: Female smokers have greater difficulty quitting, possibly due to increased reactivity to smoking‐related cues. This study assessed sex differences in craving, affect, and preference for immediate smoking after cue exposure. Methods: Regular smokers (n ¼ 60; 50% female) were exposed to smoking and neutral cues in separate, counterbalanced sessions. Outcomes included changes in craving and affect and preference for immediate smoking following cue exposure. Results: Findings indicated that women exhibited greater preference for immediate smoking (p ¼ .004), and reported greater cue‐induced increases in cigarette craving (p ¼ .046) and negative affect (p ¼ .025). Discussion and Conclusions: These data suggest that women may have greater difficulty inhibiting smoking after cue exposure, possibly as a consequence of greater increases in craving and negative affect. Scientific Significance and Future Directions: Findings suggest a mechanism that may contribute to greater cessation failure among female smokers. (Am J Addict 2014;23:211–217)
BACKGROUND AND OBJECTIVES One of the most consistent predictors of smoking cessation outcome is sex, with women experiencing greater difficulty quitting relative to men across treatment modalities.1–4 While the prevalence of smoking has declined for both sexes over the past 50 years, this decrease has been substantially larger in men.5 Understanding this discrepancy is particularly important given that women are more vulnerable than men to smoking‐ related illnesses, including lung cancer,6 myocardial infarction,7 and pulmonary dysfunction.8 Differences in nicotine sensitivity9,10 and menstrual cycle effects11,12 are thought to contribute to sex differences in cessation success.
Received November 16, 2012; revised April 5, 2013; accepted May 10, 2013. Address correspondence to Doran, Assistant Professor, Department of Psychiatry, University of California, San Diego, 3350 La Jolla Village Drive, VMRF 317, 151B, San Diego, CA 92161. E‐mail: [email protected].
A number of laboratory studies have been conducted to further explain these sex differences. These studies suggest no variation between men and women on most effects of nicotine (eg, physiological, cognitive, psychomotor), but that one important area of difference is in the rewarding and reinforcing aspects of smoking.13,14 Specifically, women appear to be less sensitive to acute reward and reinforcement from nicotine.13 For example, studies by Perkins et al. indicate that men will self‐administer nicotine to a greater extent compared with placebo nasal spray or low nicotine cigarettes, whereas women do not.9,10 Decreased sensitivity to nicotine reinforcement and reward among women is inconsistent with the fact that smoking prevalence has declined to a lesser extent compared with men. However, it has been suggested that this reduced sensitivity is made up for by increased sensitivity among women to aspects of smoking not directly related to nicotine, including conditioned reinforcement from smoking‐related environmental cues.13 Consistent with this conceptualization, studies suggest that smoking is less reinforcing for women but not for men when smoking‐related sensory cues (taste, smell) are blocked.15,16 The cue reactivity (CR) paradigm is a common method for assessing responses to environmental cues. The CR paradigm typically involves assessing smokers’ responses to exposure to objects or experiences usually associated with smoking, such as a lit cigarette. Responses to cue exposure are thought to result from associative learning processes due to frequent pairing of the cue and the rewarding effects of nicotine.17,18 Several previous studies have assessed sex differences in reactivity to smoking‐related cues. Findings have generally indicated that women report a stronger craving response than men to smoking cues,19–21 although one found no differences,22 possibly because they were masked by medication effects. Additionally, these studies indicate that women tend to report greater increases in craving and negative affect after exposure to negative affect cues.23,24 One potential gap in this literature is that, while cue‐induced craving and negative affect are presumed to trigger smoking behavior, most CR studies have not evaluated the effect of reactivity on smoking behavior, 211
and fewer have tested whether sex moderates this effect. Those studies that have done so have found that exposure to smoking cues is associated with a preference for immediate smoking relative to delayed smoking,25 and that craving after smoking cue exposure predicts 7‐day cigarette consumption26; however, neither study directly tested whether these effects were moderated by sex. The purpose of the present study was to test the hypothesis that the effect of smoking cue exposure on preference for immediate versus delayed smoking would be moderated by sex. More specifically, it was expected that preference for immediate smoking would be heightened after exposure to a smoking cue compared with a neutral cue, and that this effect would be stronger for women than for men. Secondarily, we tested whether women reporting stronger craving and affective reactions to smoking cue exposure. We have previously reported CR outcomes from this dataset without testing for sex differences, which were not hypothesized at the beginning of the parent study. The parent study was designed to examine associations between personality and CR outcomes; findings indicated that more impulsive smokers had stronger responses to a cigarette cue compared with a neutral cue in terms of preference for immediate smoking, craving, and negative affect.25,27
METHODS Participants Adult smokers (n ¼ 60, 50% female) were recruited from the community and paid $60 for participation. Data were collected in 2003–2004. Inclusion criteria included current regular smoking (15 cigarettes per day for 1 year) and being 18–65 years old (M ¼ 30.8, SD ¼ 10.8). Candidates meeting criteria for Axis I disorders other than nicotine dependence and those currently trying to quit smoking were excluded. The sample was diverse, with 51% identifying as Caucasian, 33% as African American, 9% as Asian American, 4% as Hispanic or Latino, and 2% as multi‐racial. Participants were recruited via flyers posted on campus at a large, public, Midwestern university and in the surrounding community. They smoked an average of 19.1 (5.2) cigarettes per day and were moderately nicotine dependent as evidenced by an average score of 5.4 (1.9) on the Fagerström Test for Nicotine Dependence.28 Measures Cigarette craving was measured using the Questionnaire of Smoking Urges—brief, or QSU‐brief,29 a 10‐item self‐report measure with subscales reflecting cravings associated with pleasure and with relief from negative affect. For the present study, we combined subscale scores to yield a single craving score at each assessment point. The QSU‐brief has been shown to have good internal consistency and construct validity29; in the present study, internal consistency for the two subscales ranged from a ¼ .84–.93. 212
Affect was assessed using the Positive and Negative Affect Scale, or PANAS,30 a 20‐item scale on which participants indicated the extent to which 20 words accurately described their current mood. The 10‐item negative affect subscale includes items such as irritable, distressed, and hostile, while the 10 positive affect items include excited, inspired, and enthusiastic. Across assessments, internal consistency in the present sample ranged from a ¼ .75–.87 for the negative affect subscale and .82–.88 for the positive affect subscale. Smoking behavior was assessed via a cigarette choice task. Each participant completed the task twice: once after exposure to a smoking cue and once after exposure to a neutral cue. After the cue exposure procedure, participants were informed that they would be required to spend the next hour in the laboratory before leaving. Before the hour began, they were given the choice between one immediate cigarette, which they could smoke during the hour, and eight cigarettes that they would receive at the end of the hour. Participants who chose eight delayed cigarettes were not permitted to smoke during the next hour. Procedure Screening Candidates were initially screened via telephone to assess demographic and smoking eligibility criteria. Interested and eligible individuals came to the laboratory for an in‐person screening interview using the Structured Clinical Interview for DSM‐IIIR, non‐patient version.31 Those who remained eligible were then scheduled for two experimental sessions. Experimental Sessions Participants smoked as usual prior to experimental sessions. Each 2‐hour session began between 8 and 10 am. Upon arriving for each session, participants reported the number of minutes since their last cigarette, and provided a breath sample which was assessed for carbon monoxide (CO) to assess smoking recency (ie, >5 parts per million). At the beginning of each session, participants completed a series of questionnaires, including the QSU‐brief and PANAS. This was followed by a 20‐min rest period to minimize the possibility of CR being dampened for participants who had smoked just before the session. They then completed the cue exposure procedure, described below. The QSU‐brief and PANAS were used to re‐assess craving and affect following the cue exposure. Participants then completed the cigarette choice task. In the smoking cue condition, participants sat at a table with a pack of their usual brand of cigarettes, a lighter, and an ashtray in front of them. They were instructed to light a cigarette and hold it in their hand without smoking it for 5 minutes. The neutral cue condition was similar except that the table held a roll of tape rather than smoking paraphernalia, and participants held the tape for 5 minutes. Sessions occurred at least 48 hours apart and in counterbalanced order. The cue exposure procedure has been described in greater detail elsewhere.27
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Analytic Plan We hypothesized that, relative to males, female smokers would exhibit greater reactivity to smoking versus neutral cues in terms of preference for immediate smoking, cigarette craving, and affect. The cigarette choice outcome (one immediate vs. eight delayed cigarettes) was assessed once per experimental session and was binary (coded as 0 ¼ 1 immediate, 1 ¼ 8 delayed cigarettes), and thus was modeled using a longitudinal logistic regression model for correlated dichotomous outcomes estimated via the generalized estimating equations method (GEE32), using the xtgee module in Stata 12.0 (StataCorp LLP, College Station, TX). GEE first estimates within‐subject covariance (ie, within‐subjects correlation between repeated assessments), and then estimates a separate equation for covariate effects, accounting for within‐subjects covariance effects.33,34 Consequently, the GEE approach is thought to more accurately assess prediction and model fit.35 In this case, an unstructured covariance structure was specified. The GEE model included main effects of sex (0 ¼ male, 1 ¼ female), condition (0 ¼ neutral cue, 1 ¼ smoking cue), and their interaction. Craving and affect outcomes were measured continuously and were repeated over time (baseline vs. post‐exposure) as well as over condition (neutral vs. smoking cue), yielding four total assessments per construct. These outcomes were modeled via linear mixed models (LMM) via Stata’s xtmixed module, using maximum likelihood estimation. Each model included fixed effects of sex, condition (0 ¼ neutral cue, 1 ¼ smoking cue) and time (0 ¼ baseline, 1 ¼ post‐exposure), as well as all two‐ and three‐way interactions between them. Each model also included subject as a random effect. Significant interactions between sex and the condition and time variables were followed by simple effects analyses, in which the sample was stratified by sex to examine the effects of condition and/or time separately for male and female participants.
RESULTS Preliminary Analyses First, we tested for sex differences in demographic and study variables (Table 1). Bivariate analyses showed that men and women did not differ in terms of age or nicotine dependence, or in variables measured at baseline of both experimental sessions, including time since last cigarette, CO, craving, and negative affect. There were no order effects in terms of cigarette choice, craving, or positive or negative affect responses to cue exposure, suggesting that counterbalancing was effective. Finally, we assessed the effect of the cue exposure procedure generally, via LMM and GEE models as described above but excluding sex. We found significant time condition interactions for craving (z ¼ 3.76, p < .001) and negative affect (z ¼ 2.51, p ¼ .012), but not for positive affect (z ¼ 1.14, p ¼ .254). We also found a greater preference for one immediate cigarette following smoking cue exposure compared with neutral cue exposure Doran
TABLE 1. Sex differences in baseline variables
Variable Age CO Last cigarette Nicotine dependence Craving Negative affect
Males M (SD) 41.8 14.4 30.4 5.6 4.3 13.8
(3.9) (3.2) (12.3) (.6) (.3) (1.1)
Females M (SD) 37.4 12.9 28.7 5.8 4.0 14.6
t‐test p‐value
(4.4) .72 (5.8) .43 (10.1) .28 (.5) .32 (.3) .66 (1.1) .52
.484 .646 .610 .754 .569 .604
CO, carbon monoxide. Last cigarette was defined as self‐reported minutes since participants last smoked upon arrival at the session. Sex differences in last cigarette, CO, craving, and negative affect were examined across the two experimental sessions.
(odds ratio [OR] ¼ .63 [95% confidence interval .52, .74], p < .001). Together these data indicate that the cue manipulation was effective in terms of inducing craving, worsening negative affect, and increasing preference for immediate smoking. Primary Analyses The GEE model of cigarette choice is shown in Table 2. As expected, there was a significant sex condition interaction (OR ¼ .75 [.55, .91], p ¼ .004). To interpret the interaction, we stratified by sex and assessed the effect of condition within each group. For male participants, there was no difference in cigarette choice following smoking versus neutral cue exposure (OR ¼ .98 [.89, 1.06], p ¼ .462). Seventeen men (57%) chose one immediate cigarette in the neutral condition, compared with 18 (60%) in the smoking cue condition. However, women were 28% less likely to choose eight delayed cigarettes after being exposed to a smoking cue compared to a neutral cue (OR ¼ .72 [.62, .83], p < .001). In the neutral cue condition, 14 women (47%) chose one immediate cigarette, whereas 24 (80%) did so in the smoking cue condition. In the model of craving, the sex condition time interaction was significant (z ¼ 2.00, p ¼ .046; Table 3) as hypothesized, indicating that the effect of cue type on exposure‐induced change in craving varied by sex. To interpret this interaction we again stratified by sex and tested the condition time interaction for each group. For men, the time condition interaction was not significant (z ¼ 1.87, p ¼ .061). In comparison, for women the time condition interaction was significant (z ¼ 3.32, p ¼ .001), indicating that they reported greater increases in craving following smoking cue exposure than they did after neutral cue exposure. The analysis of negative affect produced similar results. First, as shown in Table 4, there was a significant sex condition time interaction (z ¼ 2.26, p ¼ .025). We stratified the sample by sex to interpret this interaction. Among men only, the effect of cue condition on negative affect was not significant (z ¼ 1.67, p ¼ .095). Among women, this effect was significant (z ¼ 4.33, p < .001), indicating larger May–June 2014
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TABLE 2. Effects of sex and cue exposure on cigarette choice
Effect
Coefficient
Std. err.
z‐score
OR (95% CI)
.03 .36 .28
.07 .11 .09
.53 3.10 3.06
.97 (.81, 1.15) 1.37 (1.13, 1.60) .75 (.55, .91)
Condition Sex Sex condition
Std. err., standard error; OR, odds ratio; CI, confidence interval. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female). p < .01.
The purpose of this study was to test the hypotheses that female smokers tend to be more responsive to environmental smoking cues compared with male smokers, and to have greater difficulty inhibiting smoking after cue exposure. Findings were mostly supportive of this hypothesis. Sex moderated the effects of cue exposure on preference for immediate smoking, such that men and women did not differ after exposure to a neutral cue, but women were more likely to choose immediate smoking after exposure to a smoking cue. Sex also moderated the effect of cue condition on cigarette craving, and negative affect. In both cases the effect of exposure to a smoking cue relative to a neutral cue was larger for women than it was for men. Contrary to our expectations, sex did not moderate the effect of cue exposure on positive affect. These data are consistent with previous reports that smoking‐related cues produce stronger subjective19–21,23,24 and physiological (eg, skin conductance, EEG, brain activi-
ty)19,20,36 responses in women than in men. Findings are also similar to reports that women may be more reactive to non‐ tobacco drug cues,37 suggesting heightened reactivity to environmental cues for women across drug classes. Results of the present study also extend previous work by suggesting that the heightened effect of smoking cues on women applies to smoking‐related behavior as well as to affect and cognitions. Taken as a whole, these findings suggest that when confronted with environmental stimuli that are associated with either smoking or with negative affect, female smokers tend to experience craving, negative affect, stress, and physiological arousal to a greater extent than male smokers. The present data imply that at least in the former case, female smokers may also experience greater difficulty not smoking immediately. This is consistent with the idea that women’s increased difficulty with smoking cessation is at least partly derived from decreased ability to inhibit smoking after an environmental trigger leads to craving and/or distress. An initial lapse may then lead to increased negative affect, increasing the likelihood that lapse will lead to relapse. This supposition is consistent with reports that distress is a more important predictor of smoking behavior for females than it is for males.38 The finding that women were more likely to choose to smoke immediately is potentially important to the understanding of the impact of sex differences in CR on smoking cessation. As others have noted, CR research has typically relied upon immediate physiological or self‐reported outcomes thought to be associated with smoking behavior, rather than
TABLE 3. Effects of sex, cue exposure, and time on cigarette craving
TABLE 4. Effects of sex, cue exposure, and time on negative affect
Effect
increases in negative affect following smoking cue exposure compared with neutral cue exposure. Finally, we examined whether the effects of smoking versus neutral cue exposure on positive affect varied by sex (Table 5). Contrary to our hypotheses, the sex time condition interaction was not significant (z ¼ .51, p ¼ .604). In other words, sex did not moderate the effects of cue exposure on positive affect.
DISCUSSION AND CONCLUSIONS
Condition Time Condition time Sex Sex time Sex condition Sex condition time
Coefficient
Std. err.
z‐score
Effect
.06 .25 .31 .47 .06 1.15 1.07
1.07 .26 .38 1.34 .38 1.49 .54
.06 .94 .83 .35 .16 .77 2.00
Condition Time Condition time Sex Sex time Sex condition Sex condition time
Std. err., standard error. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female), time coded as (0 ¼ pre‐exposure, 1 ¼ post‐exposure). p < .05.
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Coefficient
Std. err.
z‐score
6.07 .72 2.72 3.73 .96 3.00 6.14
5.23 1.35 1.91 6.70 1.93 7.38 2.72
1.16 .53 1.42 .56 .50 .41 2.26
Std. err., standard error. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female), time coded as (0 ¼ pre‐exposure, 1 ¼ post‐exposure). p < .01, p < .05.
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TABLE 5. Effects of sex, cue exposure, and time on positive affect
Effect Condition Time Condition time Sex Sex time Sex condition Sex condition time
Coefficient
Std. err.
z‐score
.47 .09 .84 .40 .90 1.59 .03
3.78 1.91 2.71 1.93 2.67 2.68 .05
.12 .05 .31 .21 .34 .60 .51
Std. err., standard error. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female), time coded as (0 ¼ pre‐exposure, 1 ¼ post‐exposure). p < .01, p < .05.
behavior itself; these outcomes have at best been inconsistently associated with cessation failure.39 If CR outcomes are ultimately unrelated to cessation outcomes, their clinical usefulness would be substantially diminished. This study may contribute to the resolution of this question through the use of a behavioral outcome that may be more strongly associated with behavior during a quit attempt. Thus, the current data suggesting a sex effect on behavioral choice following cue exposure add weight to the hypothesis that women’s increased difficulty with cessation may be partly associated with a heightened tendency to smoke immediately after cue exposure. It is important to note that this study was not a smoking cessation trial, nor was it designed to simulate cessation in the laboratory. All participants were aware that they would be able to smoke at will after leaving the laboratory. Thus, it is possible that these findings are not representative of how male and female smokers respond to cue exposure during a quit attempt. One alternative explanation is that there are sex differences in reward‐related decision‐making under certain conditions. Studies examining sex differences in preference for immediate versus larger, delayed have been inconsistent, but a meta‐ analysis found a small effect such that women showed a greater preference for larger, delayed rewards,40 in contrast to the current findings. However, a recent review suggests that women may be less focused than men on long term gains, particularly when experiencing negative affect,41 as they did after exposure to the smoking cue in this study. In other words, in the neutral cue condition, the context was not particularly aversive, and thus men and women made similar reward‐related decisions. When negative affect was induced by exposure to a smoking cue, women may have been more prone than men to focus on the perceived short‐term gains associated with one immediate cigarette (ie, craving and negative affect reduction42). The present study has several limitations that are important to note. First, participants were current, relatively heavy smokers who were not trying to quit; such individuals may respond differently to cues relative to those currently trying to quit, or to those who smoke intermittently or at lower rates. Another potential limitation is the use of a lit but unsmoked Doran
cigarette as the smoking cue. Such proximal and prolonged exposure to a lit cigarette is likely less common among quitting smokers than other smoking‐related cues such as stress or negative affect. By the time an individual attempting to quit smoking has lit a cigarette, avoiding relapse may be very unlikely. The fact that this cue did induce craving and negative affect suggests that similar responses to more typical environmental cues may have been observed, but this discrepancy may limit the extent to which these findings reflect cessation processes in general and sex differences in cessation in particular. Finally, participants completed only a single trial of each cue exposure condition, raising the possibility that subsequent exposures could elicit different response patterns. However, previous studies suggest that both subjective and physiological responses to smoking versus neutral cues are stable across repeated exposures.43,44 In sum, this study adds to the evidence that female smokers experience greater increases in smoking urges and in negative affect when exposed to smoking cues than male smokers do. It also extends previous findings by suggesting that smoking cue exposure inhibits the ability to refrain from immediate smoking in women but not in men, consistent with previous evidence that pharmacological aspects of smoking are most important for men, and non‐pharmacological aspects are most important for women. The possibility that women are more likely to smoke immediately after cue exposure may help to explain why they are at greater risk for cessation failure. Findings also have implications for women’s smoking cessation efforts. For example, given their heightened CR, women trying to quit smoking may be more successful if they quit abruptly, rather than gradually reducing cigarette consumption.45 Additionally, nicotine replacement therapies are likely to be less useful to women. Instead, female smokers may benefit from treatment that is designed to dampen subjective reactivity and/or develop adaptive behavioral strategies when exposed to smoking cues. In light of the limitations noted above, additional research is needed to assess the impact of sex differences in CR on smoking maintenance and relapse. Future laboratory studies should utilize measures of smoking behavior that may better generalize to cessation and to cues in smokers’ natural environments. Additionally, research is needed to determine whether CR effects on cessation success46 are moderated by sex. Finally, this study suggests that sex differences in CR may be related to increased cue‐induced distress. Given that smokers who are vulnerable to mood disorders exhibit greater CR,47,48 additional research is needed to assess for sex differences in CR among smokers with mood disorders or related symptoms and whether any such differences predict cessation success. This research was supported by American Heart Association grant 0410025Z. Conflicts of Interest The author reports no conflicts of interest. The author alone is responsible for the content and writing of this article. May–June 2014
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43. Miranda R, Rohsenow D, Monti P, et al. Effects of repeated days of smoking cue exposure on urge to smoke and physiological reactivity. Addict Behav. 2008;33:347–353. 44. LaRowe S, Saladin M, Carpenter M, et al. Reactivity to nicotine cues over repeated cue reactivity sessions. Addict Behav. 2007;32: 2888–2899. 45. Payne T, Smith P, Adams S, et al. Pretreatment cue reactivity predicts end‐ of‐treatment smoking. Addict Behav. 2006;31:702–710. doi: 10.1016/j. addbeh.2005.05.053
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46. Conklin C, Parzynski C, Salkeld R, et al. Cue reactivity as a predictor of successful abstinence initiation among adult smokers. Exp Clin Psychopharmacol. 2012;20:473–478. doi: 10.1037/a0029599 47. Weinberger A, McKee S, George T. Smoking cue reactivity in adult smokers with and without depression: A pilot study. Am J Addict. 2012;21:136–144. doi: 10.1111/j.521‐0391.2011.00203.x 48. Herrera M, McChargue D. Mood and cue reactivity among smokers with a history of major depression: The role of rumination and impulsivity. Am J Addict. 2011;20:161–165. doi: 10.1111/j.521‐0391.2010.0012.x
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Sex Differences in Smoking Cue Reactivity: Craving, Negative Affect, and Preference for Immediate Smoking Neal Doran, PhD Department of Psychiatry, University of California, San Diego, California
Background and Objectives: Female smokers have greater difficulty quitting, possibly due to increased reactivity to smoking‐related cues. This study assessed sex differences in craving, affect, and preference for immediate smoking after cue exposure. Methods: Regular smokers (n ¼ 60; 50% female) were exposed to smoking and neutral cues in separate, counterbalanced sessions. Outcomes included changes in craving and affect and preference for immediate smoking following cue exposure. Results: Findings indicated that women exhibited greater preference for immediate smoking (p ¼ .004), and reported greater cue‐induced increases in cigarette craving (p ¼ .046) and negative affect (p ¼ .025). Discussion and Conclusions: These data suggest that women may have greater difficulty inhibiting smoking after cue exposure, possibly as a consequence of greater increases in craving and negative affect. Scientific Significance and Future Directions: Findings suggest a mechanism that may contribute to greater cessation failure among female smokers. (Am J Addict 2014;23:211–217)
BACKGROUND AND OBJECTIVES One of the most consistent predictors of smoking cessation outcome is sex, with women experiencing greater difficulty quitting relative to men across treatment modalities.1–4 While the prevalence of smoking has declined for both sexes over the past 50 years, this decrease has been substantially larger in men.5 Understanding this discrepancy is particularly important given that women are more vulnerable than men to smoking‐ related illnesses, including lung cancer,6 myocardial infarction,7 and pulmonary dysfunction.8 Differences in nicotine sensitivity9,10 and menstrual cycle effects11,12 are thought to contribute to sex differences in cessation success.
Received November 16, 2012; revised April 5, 2013; accepted May 10, 2013. Address correspondence to Doran, Assistant Professor, Department of Psychiatry, University of California, San Diego, 3350 La Jolla Village Drive, VMRF 317, 151B, San Diego, CA 92161. E‐mail: [email protected].
A number of laboratory studies have been conducted to further explain these sex differences. These studies suggest no variation between men and women on most effects of nicotine (eg, physiological, cognitive, psychomotor), but that one important area of difference is in the rewarding and reinforcing aspects of smoking.13,14 Specifically, women appear to be less sensitive to acute reward and reinforcement from nicotine.13 For example, studies by Perkins et al. indicate that men will self‐administer nicotine to a greater extent compared with placebo nasal spray or low nicotine cigarettes, whereas women do not.9,10 Decreased sensitivity to nicotine reinforcement and reward among women is inconsistent with the fact that smoking prevalence has declined to a lesser extent compared with men. However, it has been suggested that this reduced sensitivity is made up for by increased sensitivity among women to aspects of smoking not directly related to nicotine, including conditioned reinforcement from smoking‐related environmental cues.13 Consistent with this conceptualization, studies suggest that smoking is less reinforcing for women but not for men when smoking‐related sensory cues (taste, smell) are blocked.15,16 The cue reactivity (CR) paradigm is a common method for assessing responses to environmental cues. The CR paradigm typically involves assessing smokers’ responses to exposure to objects or experiences usually associated with smoking, such as a lit cigarette. Responses to cue exposure are thought to result from associative learning processes due to frequent pairing of the cue and the rewarding effects of nicotine.17,18 Several previous studies have assessed sex differences in reactivity to smoking‐related cues. Findings have generally indicated that women report a stronger craving response than men to smoking cues,19–21 although one found no differences,22 possibly because they were masked by medication effects. Additionally, these studies indicate that women tend to report greater increases in craving and negative affect after exposure to negative affect cues.23,24 One potential gap in this literature is that, while cue‐induced craving and negative affect are presumed to trigger smoking behavior, most CR studies have not evaluated the effect of reactivity on smoking behavior, 211
and fewer have tested whether sex moderates this effect. Those studies that have done so have found that exposure to smoking cues is associated with a preference for immediate smoking relative to delayed smoking,25 and that craving after smoking cue exposure predicts 7‐day cigarette consumption26; however, neither study directly tested whether these effects were moderated by sex. The purpose of the present study was to test the hypothesis that the effect of smoking cue exposure on preference for immediate versus delayed smoking would be moderated by sex. More specifically, it was expected that preference for immediate smoking would be heightened after exposure to a smoking cue compared with a neutral cue, and that this effect would be stronger for women than for men. Secondarily, we tested whether women reporting stronger craving and affective reactions to smoking cue exposure. We have previously reported CR outcomes from this dataset without testing for sex differences, which were not hypothesized at the beginning of the parent study. The parent study was designed to examine associations between personality and CR outcomes; findings indicated that more impulsive smokers had stronger responses to a cigarette cue compared with a neutral cue in terms of preference for immediate smoking, craving, and negative affect.25,27
METHODS Participants Adult smokers (n ¼ 60, 50% female) were recruited from the community and paid $60 for participation. Data were collected in 2003–2004. Inclusion criteria included current regular smoking (15 cigarettes per day for 1 year) and being 18–65 years old (M ¼ 30.8, SD ¼ 10.8). Candidates meeting criteria for Axis I disorders other than nicotine dependence and those currently trying to quit smoking were excluded. The sample was diverse, with 51% identifying as Caucasian, 33% as African American, 9% as Asian American, 4% as Hispanic or Latino, and 2% as multi‐racial. Participants were recruited via flyers posted on campus at a large, public, Midwestern university and in the surrounding community. They smoked an average of 19.1 (5.2) cigarettes per day and were moderately nicotine dependent as evidenced by an average score of 5.4 (1.9) on the Fagerström Test for Nicotine Dependence.28 Measures Cigarette craving was measured using the Questionnaire of Smoking Urges—brief, or QSU‐brief,29 a 10‐item self‐report measure with subscales reflecting cravings associated with pleasure and with relief from negative affect. For the present study, we combined subscale scores to yield a single craving score at each assessment point. The QSU‐brief has been shown to have good internal consistency and construct validity29; in the present study, internal consistency for the two subscales ranged from a ¼ .84–.93. 212
Affect was assessed using the Positive and Negative Affect Scale, or PANAS,30 a 20‐item scale on which participants indicated the extent to which 20 words accurately described their current mood. The 10‐item negative affect subscale includes items such as irritable, distressed, and hostile, while the 10 positive affect items include excited, inspired, and enthusiastic. Across assessments, internal consistency in the present sample ranged from a ¼ .75–.87 for the negative affect subscale and .82–.88 for the positive affect subscale. Smoking behavior was assessed via a cigarette choice task. Each participant completed the task twice: once after exposure to a smoking cue and once after exposure to a neutral cue. After the cue exposure procedure, participants were informed that they would be required to spend the next hour in the laboratory before leaving. Before the hour began, they were given the choice between one immediate cigarette, which they could smoke during the hour, and eight cigarettes that they would receive at the end of the hour. Participants who chose eight delayed cigarettes were not permitted to smoke during the next hour. Procedure Screening Candidates were initially screened via telephone to assess demographic and smoking eligibility criteria. Interested and eligible individuals came to the laboratory for an in‐person screening interview using the Structured Clinical Interview for DSM‐IIIR, non‐patient version.31 Those who remained eligible were then scheduled for two experimental sessions. Experimental Sessions Participants smoked as usual prior to experimental sessions. Each 2‐hour session began between 8 and 10 am. Upon arriving for each session, participants reported the number of minutes since their last cigarette, and provided a breath sample which was assessed for carbon monoxide (CO) to assess smoking recency (ie, >5 parts per million). At the beginning of each session, participants completed a series of questionnaires, including the QSU‐brief and PANAS. This was followed by a 20‐min rest period to minimize the possibility of CR being dampened for participants who had smoked just before the session. They then completed the cue exposure procedure, described below. The QSU‐brief and PANAS were used to re‐assess craving and affect following the cue exposure. Participants then completed the cigarette choice task. In the smoking cue condition, participants sat at a table with a pack of their usual brand of cigarettes, a lighter, and an ashtray in front of them. They were instructed to light a cigarette and hold it in their hand without smoking it for 5 minutes. The neutral cue condition was similar except that the table held a roll of tape rather than smoking paraphernalia, and participants held the tape for 5 minutes. Sessions occurred at least 48 hours apart and in counterbalanced order. The cue exposure procedure has been described in greater detail elsewhere.27
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Analytic Plan We hypothesized that, relative to males, female smokers would exhibit greater reactivity to smoking versus neutral cues in terms of preference for immediate smoking, cigarette craving, and affect. The cigarette choice outcome (one immediate vs. eight delayed cigarettes) was assessed once per experimental session and was binary (coded as 0 ¼ 1 immediate, 1 ¼ 8 delayed cigarettes), and thus was modeled using a longitudinal logistic regression model for correlated dichotomous outcomes estimated via the generalized estimating equations method (GEE32), using the xtgee module in Stata 12.0 (StataCorp LLP, College Station, TX). GEE first estimates within‐subject covariance (ie, within‐subjects correlation between repeated assessments), and then estimates a separate equation for covariate effects, accounting for within‐subjects covariance effects.33,34 Consequently, the GEE approach is thought to more accurately assess prediction and model fit.35 In this case, an unstructured covariance structure was specified. The GEE model included main effects of sex (0 ¼ male, 1 ¼ female), condition (0 ¼ neutral cue, 1 ¼ smoking cue), and their interaction. Craving and affect outcomes were measured continuously and were repeated over time (baseline vs. post‐exposure) as well as over condition (neutral vs. smoking cue), yielding four total assessments per construct. These outcomes were modeled via linear mixed models (LMM) via Stata’s xtmixed module, using maximum likelihood estimation. Each model included fixed effects of sex, condition (0 ¼ neutral cue, 1 ¼ smoking cue) and time (0 ¼ baseline, 1 ¼ post‐exposure), as well as all two‐ and three‐way interactions between them. Each model also included subject as a random effect. Significant interactions between sex and the condition and time variables were followed by simple effects analyses, in which the sample was stratified by sex to examine the effects of condition and/or time separately for male and female participants.
RESULTS Preliminary Analyses First, we tested for sex differences in demographic and study variables (Table 1). Bivariate analyses showed that men and women did not differ in terms of age or nicotine dependence, or in variables measured at baseline of both experimental sessions, including time since last cigarette, CO, craving, and negative affect. There were no order effects in terms of cigarette choice, craving, or positive or negative affect responses to cue exposure, suggesting that counterbalancing was effective. Finally, we assessed the effect of the cue exposure procedure generally, via LMM and GEE models as described above but excluding sex. We found significant time condition interactions for craving (z ¼ 3.76, p < .001) and negative affect (z ¼ 2.51, p ¼ .012), but not for positive affect (z ¼ 1.14, p ¼ .254). We also found a greater preference for one immediate cigarette following smoking cue exposure compared with neutral cue exposure Doran
TABLE 1. Sex differences in baseline variables
Variable Age CO Last cigarette Nicotine dependence Craving Negative affect
Males M (SD) 41.8 14.4 30.4 5.6 4.3 13.8
(3.9) (3.2) (12.3) (.6) (.3) (1.1)
Females M (SD) 37.4 12.9 28.7 5.8 4.0 14.6
t‐test p‐value
(4.4) .72 (5.8) .43 (10.1) .28 (.5) .32 (.3) .66 (1.1) .52
.484 .646 .610 .754 .569 .604
CO, carbon monoxide. Last cigarette was defined as self‐reported minutes since participants last smoked upon arrival at the session. Sex differences in last cigarette, CO, craving, and negative affect were examined across the two experimental sessions.
(odds ratio [OR] ¼ .63 [95% confidence interval .52, .74], p < .001). Together these data indicate that the cue manipulation was effective in terms of inducing craving, worsening negative affect, and increasing preference for immediate smoking. Primary Analyses The GEE model of cigarette choice is shown in Table 2. As expected, there was a significant sex condition interaction (OR ¼ .75 [.55, .91], p ¼ .004). To interpret the interaction, we stratified by sex and assessed the effect of condition within each group. For male participants, there was no difference in cigarette choice following smoking versus neutral cue exposure (OR ¼ .98 [.89, 1.06], p ¼ .462). Seventeen men (57%) chose one immediate cigarette in the neutral condition, compared with 18 (60%) in the smoking cue condition. However, women were 28% less likely to choose eight delayed cigarettes after being exposed to a smoking cue compared to a neutral cue (OR ¼ .72 [.62, .83], p < .001). In the neutral cue condition, 14 women (47%) chose one immediate cigarette, whereas 24 (80%) did so in the smoking cue condition. In the model of craving, the sex condition time interaction was significant (z ¼ 2.00, p ¼ .046; Table 3) as hypothesized, indicating that the effect of cue type on exposure‐induced change in craving varied by sex. To interpret this interaction we again stratified by sex and tested the condition time interaction for each group. For men, the time condition interaction was not significant (z ¼ 1.87, p ¼ .061). In comparison, for women the time condition interaction was significant (z ¼ 3.32, p ¼ .001), indicating that they reported greater increases in craving following smoking cue exposure than they did after neutral cue exposure. The analysis of negative affect produced similar results. First, as shown in Table 4, there was a significant sex condition time interaction (z ¼ 2.26, p ¼ .025). We stratified the sample by sex to interpret this interaction. Among men only, the effect of cue condition on negative affect was not significant (z ¼ 1.67, p ¼ .095). Among women, this effect was significant (z ¼ 4.33, p < .001), indicating larger May–June 2014
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TABLE 2. Effects of sex and cue exposure on cigarette choice
Effect
Coefficient
Std. err.
z‐score
OR (95% CI)
.03 .36 .28
.07 .11 .09
.53 3.10 3.06
.97 (.81, 1.15) 1.37 (1.13, 1.60) .75 (.55, .91)
Condition Sex Sex condition
Std. err., standard error; OR, odds ratio; CI, confidence interval. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female). p < .01.
The purpose of this study was to test the hypotheses that female smokers tend to be more responsive to environmental smoking cues compared with male smokers, and to have greater difficulty inhibiting smoking after cue exposure. Findings were mostly supportive of this hypothesis. Sex moderated the effects of cue exposure on preference for immediate smoking, such that men and women did not differ after exposure to a neutral cue, but women were more likely to choose immediate smoking after exposure to a smoking cue. Sex also moderated the effect of cue condition on cigarette craving, and negative affect. In both cases the effect of exposure to a smoking cue relative to a neutral cue was larger for women than it was for men. Contrary to our expectations, sex did not moderate the effect of cue exposure on positive affect. These data are consistent with previous reports that smoking‐related cues produce stronger subjective19–21,23,24 and physiological (eg, skin conductance, EEG, brain activi-
ty)19,20,36 responses in women than in men. Findings are also similar to reports that women may be more reactive to non‐ tobacco drug cues,37 suggesting heightened reactivity to environmental cues for women across drug classes. Results of the present study also extend previous work by suggesting that the heightened effect of smoking cues on women applies to smoking‐related behavior as well as to affect and cognitions. Taken as a whole, these findings suggest that when confronted with environmental stimuli that are associated with either smoking or with negative affect, female smokers tend to experience craving, negative affect, stress, and physiological arousal to a greater extent than male smokers. The present data imply that at least in the former case, female smokers may also experience greater difficulty not smoking immediately. This is consistent with the idea that women’s increased difficulty with smoking cessation is at least partly derived from decreased ability to inhibit smoking after an environmental trigger leads to craving and/or distress. An initial lapse may then lead to increased negative affect, increasing the likelihood that lapse will lead to relapse. This supposition is consistent with reports that distress is a more important predictor of smoking behavior for females than it is for males.38 The finding that women were more likely to choose to smoke immediately is potentially important to the understanding of the impact of sex differences in CR on smoking cessation. As others have noted, CR research has typically relied upon immediate physiological or self‐reported outcomes thought to be associated with smoking behavior, rather than
TABLE 3. Effects of sex, cue exposure, and time on cigarette craving
TABLE 4. Effects of sex, cue exposure, and time on negative affect
Effect
increases in negative affect following smoking cue exposure compared with neutral cue exposure. Finally, we examined whether the effects of smoking versus neutral cue exposure on positive affect varied by sex (Table 5). Contrary to our hypotheses, the sex time condition interaction was not significant (z ¼ .51, p ¼ .604). In other words, sex did not moderate the effects of cue exposure on positive affect.
DISCUSSION AND CONCLUSIONS
Condition Time Condition time Sex Sex time Sex condition Sex condition time
Coefficient
Std. err.
z‐score
Effect
.06 .25 .31 .47 .06 1.15 1.07
1.07 .26 .38 1.34 .38 1.49 .54
.06 .94 .83 .35 .16 .77 2.00
Condition Time Condition time Sex Sex time Sex condition Sex condition time
Std. err., standard error. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female), time coded as (0 ¼ pre‐exposure, 1 ¼ post‐exposure). p < .05.
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Coefficient
Std. err.
z‐score
6.07 .72 2.72 3.73 .96 3.00 6.14
5.23 1.35 1.91 6.70 1.93 7.38 2.72
1.16 .53 1.42 .56 .50 .41 2.26
Std. err., standard error. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female), time coded as (0 ¼ pre‐exposure, 1 ¼ post‐exposure). p < .01, p < .05.
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TABLE 5. Effects of sex, cue exposure, and time on positive affect
Effect Condition Time Condition time Sex Sex time Sex condition Sex condition time
Coefficient
Std. err.
z‐score
.47 .09 .84 .40 .90 1.59 .03
3.78 1.91 2.71 1.93 2.67 2.68 .05
.12 .05 .31 .21 .34 .60 .51
Std. err., standard error. Condition coded as (0 ¼ neutral, 1 ¼ smoking cue), sex coded as (0 ¼ male, 1 ¼ female), time coded as (0 ¼ pre‐exposure, 1 ¼ post‐exposure). p < .01, p < .05.
behavior itself; these outcomes have at best been inconsistently associated with cessation failure.39 If CR outcomes are ultimately unrelated to cessation outcomes, their clinical usefulness would be substantially diminished. This study may contribute to the resolution of this question through the use of a behavioral outcome that may be more strongly associated with behavior during a quit attempt. Thus, the current data suggesting a sex effect on behavioral choice following cue exposure add weight to the hypothesis that women’s increased difficulty with cessation may be partly associated with a heightened tendency to smoke immediately after cue exposure. It is important to note that this study was not a smoking cessation trial, nor was it designed to simulate cessation in the laboratory. All participants were aware that they would be able to smoke at will after leaving the laboratory. Thus, it is possible that these findings are not representative of how male and female smokers respond to cue exposure during a quit attempt. One alternative explanation is that there are sex differences in reward‐related decision‐making under certain conditions. Studies examining sex differences in preference for immediate versus larger, delayed have been inconsistent, but a meta‐ analysis found a small effect such that women showed a greater preference for larger, delayed rewards,40 in contrast to the current findings. However, a recent review suggests that women may be less focused than men on long term gains, particularly when experiencing negative affect,41 as they did after exposure to the smoking cue in this study. In other words, in the neutral cue condition, the context was not particularly aversive, and thus men and women made similar reward‐related decisions. When negative affect was induced by exposure to a smoking cue, women may have been more prone than men to focus on the perceived short‐term gains associated with one immediate cigarette (ie, craving and negative affect reduction42). The present study has several limitations that are important to note. First, participants were current, relatively heavy smokers who were not trying to quit; such individuals may respond differently to cues relative to those currently trying to quit, or to those who smoke intermittently or at lower rates. Another potential limitation is the use of a lit but unsmoked Doran
cigarette as the smoking cue. Such proximal and prolonged exposure to a lit cigarette is likely less common among quitting smokers than other smoking‐related cues such as stress or negative affect. By the time an individual attempting to quit smoking has lit a cigarette, avoiding relapse may be very unlikely. The fact that this cue did induce craving and negative affect suggests that similar responses to more typical environmental cues may have been observed, but this discrepancy may limit the extent to which these findings reflect cessation processes in general and sex differences in cessation in particular. Finally, participants completed only a single trial of each cue exposure condition, raising the possibility that subsequent exposures could elicit different response patterns. However, previous studies suggest that both subjective and physiological responses to smoking versus neutral cues are stable across repeated exposures.43,44 In sum, this study adds to the evidence that female smokers experience greater increases in smoking urges and in negative affect when exposed to smoking cues than male smokers do. It also extends previous findings by suggesting that smoking cue exposure inhibits the ability to refrain from immediate smoking in women but not in men, consistent with previous evidence that pharmacological aspects of smoking are most important for men, and non‐pharmacological aspects are most important for women. The possibility that women are more likely to smoke immediately after cue exposure may help to explain why they are at greater risk for cessation failure. Findings also have implications for women’s smoking cessation efforts. For example, given their heightened CR, women trying to quit smoking may be more successful if they quit abruptly, rather than gradually reducing cigarette consumption.45 Additionally, nicotine replacement therapies are likely to be less useful to women. Instead, female smokers may benefit from treatment that is designed to dampen subjective reactivity and/or develop adaptive behavioral strategies when exposed to smoking cues. In light of the limitations noted above, additional research is needed to assess the impact of sex differences in CR on smoking maintenance and relapse. Future laboratory studies should utilize measures of smoking behavior that may better generalize to cessation and to cues in smokers’ natural environments. Additionally, research is needed to determine whether CR effects on cessation success46 are moderated by sex. Finally, this study suggests that sex differences in CR may be related to increased cue‐induced distress. Given that smokers who are vulnerable to mood disorders exhibit greater CR,47,48 additional research is needed to assess for sex differences in CR among smokers with mood disorders or related symptoms and whether any such differences predict cessation success. This research was supported by American Heart Association grant 0410025Z. Conflicts of Interest The author reports no conflicts of interest. The author alone is responsible for the content and writing of this article. May–June 2014
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