Menstrual cycle phase effects on nicotine withdrawal and cigarette craving: A review

Transcription

1 Nicotine & Tobacco Research Volume 8, Number 5 (October 2006) Review Menstrual cycle phase effects on nicotine withdrawal and cigarette craving: A review Matthew J. Carpenter, Himanshu P. Upadhyaya, Steven D. LaRowe, Michael E. Saladin, Kathleen T. Brady Received 6 June 2005; accepted 31 October 2005 Evidence suggests that women are less likely to quit smoking than are men. This may reflect differences in nicotine dependence and, more specifically perhaps, nicotine withdrawal and craving. However, there is conflicting research on gender differences on the experience of withdrawal and craving. Menstrual cycle effects may moderate this relationship. Given hormonal changes during the menstrual cycle, abstinence-related symptoms such as withdrawal and craving may vary as a function of menstrual phase as well. This qualitative review summarizes the modest but expanding body of research in this area. One of the challenges inherent in interpreting this literature is the difficulty in distinguishing withdrawal symptomatology from premenstrual symptomatology. Methodological variation, including limited sample size and possible selection bias, in which several studies finding null effects excluded women with severe premenstrual dysphoric disorder, may explain some of the inconsistent findings across studies. Nonetheless, some of the 13 studies included in this review found heightened experiences of withdrawal or craving within the latter days of the menstrual cycle (i.e., the luteal phase). Further research is necessary to replicate these findings, but they may suggest the need for focused cessation treatment during the luteal phase or quit attempts that are well timed relative to specific menstrual phases. Introduction Awareness of the importance of gender in smoking cessation research is growing, largely related to discrepant rates of smoking and cessation in men and women. The prevalence of smoking is lower among adult females than males (U.S. Department of Health and Human Services, 2004). However, whereas some studies have shown no gender differences in quitting or even a slight increase among women (Klesges, Haddock, Lando, & Talcott, 1999; Toneatto, Sobell, & Sobell, 1992), the growing Matthew J. Carpenter, Ph.D., Himanshu P. Upadhyaya, M.B.B.S., M.S., Steven D. LaRowe, Ph.D., Kathleen T. Brady, M.D., Ph.D., Department of Psychiatry and Behavioral Sciences; Michael E. Saladin, Ph.D., Department of Psychiatry and Behavioral Sciences and Department of Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC. Correspondence: Matthew J. Carpenter, Ph.D., Medical University of South Carolina, Institute of Psychiatry, 67 President Street, P. O. Box , Charleston, SC 29425, USA. Tel: +1 (843) ; Fax: +1 (843) ; carpente@musc.edu evidence is that women may be less likely than men to quit successfully (Perkins, 2001). This appears true for self-quitters (Fortmann & Killen, 1994; Ward, Klesges, Zbikowski, Bliss, & Garvey, 1997), smokers in large population-based intervention trials (Bjornson, Rand, Connett, & Lindgren, 1995; COMMIT Research Group, 1995), and smokers in medication trials (Bohadana, Nilsson, Rasmussen, & Martinet, 2003; Collins et al., 2004; Scharf & Shiffman, 2004; Wetter, Kenford et al., 1999). There are many gender-related influences on quitting smoking, including negative affect, social support, concerns of weight gain (see Perkins, 2001, for a discussion). It has also been hypothesized that nicotine dependence is manifested differently between men and women (Perkins, 1996), and recent research suggests that men smoke primarily for pharmacological reinforcement provided by nicotine, whereas women smoke primarily for psychological reinforcement obtained through social interaction ISSN print/issn X online # 2006 Society for Research on Nicotine and Tobacco DOI: /

2 628 MENSTRUAL CYCLE PHASE EFFECTS and tension reduction (Berlin et al., 2003; Wetter, Fiore et al., 1999). Given that successful quitting is largely a function of nicotine dependence (Breslau & Johnson, 2000; Breslau, Johnson, Hiripi, & Kessler, 2001; Hyland et al., 2004), apparent gender differences in the expression of dependence may partly explain gender differences in successful cessation. If gender differences in nicotine dependence exist, then gender may influence withdrawal as well. By extension, gender would be expected to influence cessation because successful quitting is also a function of withdrawal experienced (Jarvis, 1994; Piasecki, Kenford, Smith, Fiore, & Baker, 1997). The evidence for gender differences in withdrawal is mixed. Several studies have found no gender influences on physiological, psychological, or behavioral measures of withdrawal following abstinence from smoking (Hughes, 1992; Hughes, Gust, Skoog, Keenan, & Fenwick, 1991; Svikis, Hatsukami, Hughes, Carroll, & Pickens, 1986; Tate, Pomerleau, & Pomerleau, 1993). However, an earlier review by Shiffman (1979) found that women, more frequently than men, reported 13 of 18 possible withdrawal symptoms during the initial days of smoking abstinence. Another study documented gender differences when withdrawal symptoms (greater among women) were assessed retrospectively, though the differences were not observed when these same symptoms were assessed prospectively (Pomerleau, Tate, Lumley, & Pomerleau, 1994). This latter study suggests at least a partial explanation for the varied outcomes of studies examining gender differences in withdrawal, specifically, methodological variation in the timing of withdrawal assessment. The conflicting literature on gender differences in withdrawal suggests that other moderating influences may exist. Although between-study methodological variation is likely to account for some of the disparate findings, some investigators have suggested that hormonal or menstrual phase factors may account, in part, for potential gender differences in withdrawal (Pomerleau, 1996). Since the menstrual cycle is a focus of the present discussion, we provide a schematic and brief description of its essential features here. The menstrual cycle (Figure 1) begins with the first day of blood flow (menses), which marks the onset of the follicular phase, leading to ovulation (around day 14), followed by the luteal phase, which leads into menses (Guyton & Hall, 2000). The follicular and luteal phases have been conceptualized as consisting of the early versus mid/late follicular and the early versus late luteal phases, respectively, though uniform agreement about this four-phase distinction is lacking. Nonetheless, a four-phase distinction may have the added benefit of permitting identification of more subtle hormone behavior relationships within the overall cycle. To illustrate, hormonal changes have an impact on the dopaminergic system Figure 1. Approximate concentrations of progesterone and estrogen during menstrual cycle.

3 NICOTINE & TOBACCO RESEARCH 629 (Morrissette & Di Pialo, 1993) and may lead to symptoms (e.g., depression, irritability) that mimic or enhance tobacco withdrawal symptoms (Gallant, Hamilton, Popiel, Morokoff, & Chakraborty, 1991). If hormone-mediated symptoms augment nicotine withdrawal and craving, then one might expect smoking behavior or withdrawal symptoms to fluctuate across menstrual phases (Perkins, 2001). As with the research discussed to this point, studies of menstrual phase effects on smoking behavior have provided mixed results. At least two studies have shown no phase effects (Allen, Hatsukami, Christianson, & Nelson, 1999; Pomerleau, Mehringer, Marks, Downey, & Pomerleau, 2000). However, some studies have shown an increase in self-reported smoking during the luteal phase, but with conflicting biomarker (e.g., carbon monoxide) results (Allen, Hatsukami, Christianson, & Nelson, 1996; De Bon, Klesges, & Klesges, 1995). Still other studies have shown consistent and significant phase effects with the general finding that smoking increases during the luteal phase (Craig, Parrott, & Coomber, 1992; Marks, Hair, Klock, Ginsburg, & Pomerleau, 1994; Mello, Mendelson, & Palmieri, 1987; Snively, Ahijevych, Bernhard, & Wewers, 2000; Steinberg & Cherek, 1989). Thus some studies have suggested that smoking does fluctuate across the menstrual phase cycle and that the premenstrual (luteal) phase may be particularly associated with increased smoking. Given that smoking rates may naturally fluctuate during the various phases of the menstrual cycle, one might speculate that increases in smoking may be a result of phase-related differences in nicotine withdrawal or nicotine craving. If menstrual phase influences withdrawal or craving, it also will likely significantly influence relapse in women who attempt to quit. Thus an examination of menstrual phase effects on smoking behavior has potentially important clinical implications. The primary goal of this qualitative review is to summarize the effect of menstrual cycle on nicotine withdrawal symptoms or craving. For the sake of brevity, we have chosen to narrow our scope to withdrawal and craving and have omitted studies that examined menstrual cycle effects on smoking behavior. We elected to perform a qualitative review rather than a formal meta-analysis because the former is more suitably applied to a developing area of investigation with relatively few studies and highly varied methodologies (Kazdin, 1998). Method Identification of studies We conducted a comprehensive search of the MEDLINE and PsycInfo databases using the following search terms: (menstrual or menses or menstruation) AND (craving or crave or desire or withdrawal or urge or cue reactivity) AND (tobacco or nicotine or smoker or smoking or cigarette). Within each study identified, reference lists were combed for additional relevant studies. Cue reactivity studies were selected because they entail lab-based methodologies to examine withdrawal and craving (only one such study was identified). All studies presented here have been published; one additional study was in abstract form only and could not be located (Frye, Ward, Bliss, & Garvey, 1992). Studies that examined only gender or general hormonal (i.e., nonmenstrual) differences in withdrawal were omitted, as were studies that reported solely on general symptomatology (e.g., mood) outside the context of smoking. A total of 13 studies were identified and included. Data extraction strategy Relevant findings from the targeted studies were identified and organized by the first author. The remaining authors performed a follow-up review as a quality assurance check on the observations made by the first author. Therefore, each study was reviewed at least twice, once each by two authors working independently. Discrepancies (e.g., disagreements on study inclusion or exclusion, study methodology, or study results) were reconciled by mutual agreement. If studies included additional comparisons (e.g., males, nonsmokers), these groups have not been included here, as they were not a focus of this review. At least one standard definition of withdrawal does not include symptoms of craving for cigarettes (American Psychiatric Association, 1994). However, many studies use measures of withdrawal and craving that include similar and sometimes overlapping constructs. For example, both the Minnesota Withdrawal Scale (Hughes & Hatsukami, 1986) and the Shiffman Jarvik Withdrawal Scale (Shiffman & Jarvik, 1976), which are commonly used to assess nicotine withdrawal, include an item expressing desire or urge to smoke, along with a number of physiological symptoms, such as tension, irritability, and restlessness. In contrast, the Questionnaire on Smoking Urges (QSU; Tiffany & Drobes, 1991), a commonly used craving questionnaire, primarily encompasses ratings of desire and urge, with only minimal emphasis on physiological symptoms of withdrawal. For clarity, if a study specifically reported on craving, desire, or urge as separate from other symptoms of withdrawal (e.g., physiological or affective symptoms), we identified it as a craving outcome; if a study specifically reported non-craving-related symptoms of withdrawal, or reported a withdrawal total score

4 630 MENSTRUAL CYCLE PHASE EFFECTS that incorporated both physical and affective ratings of withdrawal along with ratings of craving (e.g., the MWS total score), then it was identified as a withdrawal outcome. Phase definitions Inconsistent phase definitions, both in terms of labels used (e.g., luteal vs. premenstrual) and days of cycle, posed a challenge with respect to consolidating, comparing, and interpreting findings across studies. Rather than convert all studies to a common menstrual phase metric, we retained the original labels. However, we ordered the phase groups sequentially (Table 1) such that menses is the leading phase, followed by all subsequent phases in order, such that luteal phase is listed last. Results Of the 13 studies identified, 3 examined the naturalistic course of craving, withdrawal, or cue reactivity across the menstrual cycle (i.e., ad libitum smoking); 6 did so under experimental conditions of abstinence, and 4 made comparisons between the two conditions. Given that craving and withdrawal vary as a function of abstinence, we present findings separately for each type of study and summarize these findings in Table 1. Studies under nonabstinent conditions In one study that followed 32 cigarette-smoking women over the course of three menstrual cycles, participants were seen biweekly and provided retrospective accounts of withdrawal symptoms (Allen et al., 1996). Craving was identified separately from other withdrawal symptoms (based on MWS) in addition to the full QSU. Other measures, such as smoking behavior and premenstrual symptoms, also were assessed. Results indicated that withdrawal symptoms such as irritability, restlessness, appetite change, and depressed mood were highest in the late luteal phase as compared with the other phases. Withdrawal symptoms were highly correlated with premenstrual symptomatology, particularly in the late luteal phase (r5.79) but within other phases as well. Results for craving were somewhat mixed, as we found evidence for high craving during the late luteal phase on the single MWS craving item, yet the total QSU score showed no evidence of phase effects. Another study followed nonabstinent female participants smoking ad libitum over five phases of the menstrual cycle (De Bon et al., 1995). Both ratings of craving and withdrawal symptoms (e.g. restlessness, irritability) were obtained. Women reported greater craving and withdrawal in the menstrual phase (bleeding days) relative to ovulation; nonsignificant increases in withdrawal symptomatology were found within the late luteal phase. Finally, one cue reactivity study made betweensubjects comparisons of women in either the follicular or luteal phase who were seeking, but not yet receiving, treatment (Franklin et al., 2004). The cue reactivity session was held immediately following the provision of a cigarette, to reduce the confounding effects of withdrawal. Menstrual phase was based on self-report and a review of the medical chart. Women in the luteal phase reported greater cue-induced craving in response to smoking-related cues than did women in the follicular phase. No group differences were found in reports of withdrawal. In sum, each of these three studies found menstrual-related effects on either withdrawal or craving (or both). Most important, the luteal or late luteal phase was most consistently associated with elevations in craving or withdrawal. This finding is particularly noteworthy given that smoking abstinence was not manipulated, suggesting a high degree of concordance between withdrawal and general menstrual-related symptomatology. Studies involving smoking abstinence Allen and colleagues assessed female smokers during two 5-day smoking abstinence periods, one randomized during the follicular phase and one (counterbalanced) during the late luteal phase (Allen, Hatsukami, Christianson, & Brown, 2000). Women also were randomized to receive a transdermal patch that administered either active nicotine (n516) or placebo (n514). Although there was no overall menstrual phase effect (follicular vs. late luteal) on the single MWS craving item, there was a significant patch6phase interaction, indicating that nicotine replacement attenuated craving within the late luteal phase more so than it did within the follicular phase. However, when craving was examined with a total QSU score, no phase effects were found. Within both active and placebo patch conditions, higher withdrawal (minus craving) was reported by women in the late luteal phase. This study was limited by its small sample size and high rate of attrition, though dropouts did not differ from those who completed the study. In another study that tested menstrual phase effects during a brief period (2 days) of abstinence, women in the midcycle phase (days of cycle, n510) were compared with those in the premenstrual phase (days 25 29, n510; Craig et al., 1992). No phase differences were noted across eight measures of smoking withdrawal, though there was a trend toward greater irritability and depression among the women in the premenstrual or luteal phase (days

5 Table 1. Review study findings: Withdrawal and craving. Study Menstrual group N BS or WS Excluded PMDD Nicotine deprived or nondeprived Phase Outcome Findings Studies under nonabstinent conditions Allen et al., 1996 Follicular [F] Luteal [L] 32 WS No Ad lib smoking Hormonal Late luteal [LL] Withdrawal Craving Withdrawal greater during LL vs. F and L phases; menstrual effects for craving, irritability, restlessness, appetite change, and depressed mood No phase differences in QSU factors; single item of craving for cigarettes was higher during LL vs. F phase Greater withdrawal in M vs. O phases De Bon et al., 1995 Follicular [F] Ovulation [O] Early luteal [EL] 13 WS No Ad lib smoking Self report, basal body temperature, and home Withdrawal Late luteal [LL] ovulation testing Craving Greater craving during M vs. O phases Menstrual [M] Franklin et al., 2004 Follicular [F] 17 BS No Nondeprived (cigarette Medical chart/ Cue reactivity Higher cue-induced craving within L phase Luteal [L] 24 administered self report (craving) immediately prior to cue reactivity session) Withdrawal No significant phase effects Studies of smoking abstinence Allen et al., 2000 Active treatment group BS a No Follicular [F] 16 WS Abstinence Hormonal Withdrawal Greater overall withdrawal in LL phase Late luteal [LL] (transdermal nicotine) anatomical Craving Reduced craving during LL phase Inactive treatment group BS No Follicular [F] Late luteal [LL] 14 WS Abstinence (placebo patch) Hormonal and anatomical Withdrawal Greater overall withdrawal in LL phase Craving No significant phase effects Craig et al., 1992 Midcycle [MC] 10 BS No 2 days of abstinence Not stated Withdrawal No significant phase effects Premenstrual [PM] 10 Craving PM reported greater and more intense urges to smoke than MC O Hara et al., 1989 Follicular [F] 9 BS No 64% across both Self-report Withdrawal Greater withdrawal in L vs. F phases Luteal [L] 13 phases achieved 3-d sustained abstinence (via behavioral therapy) Perkins et al., 2000 Follicular [F] 41 BS No Confirmed abstinence (6 session behavioral therapy) Self-report Withdrawal Greater increase in withdrawal among women quitting in L vs. F phases Luteal [L] 37 Craving No significant phase effects for change in desire to smoke (VAS score) Marks et al., 1999 Early follicular [EF] 12 WS Yes Overnight deprivation Hormonal Withdrawal No significant phase effects on subjective Mid/late follicular [MLF] Mid/late luteal [MLL] Late luteal [LL] followed by controlled dosing of nicotine (nasal administration) responses to nicotine administration Masson & Gilbert, 1999 Early cycle [EC] Late cycle [LC] 24 WS Yes Overnight deprivation followed by controlled dosing of nicotine (inhaled administration) Hormonal Withdrawal No significant phase effects NICOTINE & TOBACCO RESEARCH 631 Downloaded from at Pennsylvania State University on March 5, 2016

6 Table 1. (Continued.) Study Menstrual group N BS or WS Excluded PMDD Nicotine deprived or nondeprived Phase Outcome Findings Studies involving nonabstinence vs. abstinence comparisons Allen et al., 1999 Abstinence group BS a No 16 WS Abstinence Hormonal and anatomical Withdrawal No significant phase effects Follicular [F] Late luteal [LL] Craving No significant phase effects Smoking group BS No Follicular [F] 5 WS Ad lib smoking Hormonal and Withdrawal No significant phase effects Late luteal [LL] 16 anatomical Craving No significant phase effects Pomerleau et al., Early follicular [EF] 9 WS Yes Ad lib smoking Hormonal Withdrawal No significant phase effects 1992 Mid/late follicular [MLF] Late luteal [LL] Craving No significant phase effects 632 MENSTRUAL CYCLE PHASE EFFECTS 12-h abstinent Withdrawal No significant phase effects Pomerleau et al., 2000 History of major depression BS a No Craving No significant phase effects Menstrual [M] 7 WS Ad lib smoking Hormonal Withdrawal No significant phase effects Postmenstrual [PostM] Ovulatory [O] Craving No significant phase effects Postovulatory [PO] Premenstrual [PreM] Postmenstrual [PostM] 3-d abstinent Withdrawal No significant phase effects Premenstrual [PreM] Craving Greater craving during PostM vs. PreM Normal control BS No Menstrual [M] 7 WS Ad lib smoking Hormonal Withdrawal No significant phase effects Postmenstrual [PostM] Ovulatory [O] Craving No significant phase effects Postovulatory [PO] Premenstrual [PreM] Postmenstrual [PostM] 3-d abstinent Withdrawal No significant phase effects Premenstrual [PreM] Craving Greater craving during PostM vs. PreM Snively et al., 2000 Mid/late follicular [MLF] 13 WS Yes 24-h deprived Basal body temperature and Withdrawal No significant phase effects for general withdrawal; higher discomfort within MLF phase Late luteal [LL] hormonal Craving No significant phase effects Ad lib smoking Withdrawal No significant phase effects for general craving; higher discomfort within MLF phase Craving No significant phase effects Note. N, number of subjects per group; BS, between subjects; WS, within subjects; PMDD, premenstrual dysphoric disorder. a Between-subjects analyses reflect group comparisons between parent groups; within-subjects analyses reflect phase comparisons within each parent group. Downloaded from at Pennsylvania State University on March 5, 2016

7 NICOTINE & TOBACCO RESEARCH ). They also reported significantly greater urges to smoke and difficulty in stopping smoking than did women in the midcycle phase. Although the sample size, high attrition, and methodological variation complicate the interpretation of these study results, the findings generally support the notion that the luteal phase is associated with a trend toward increased negative affect, withdrawal, craving, and difficulty with smoking cessation. Two studies offered a behavioral treatment intervention to treatment-seeking smokers. In one, 22 women attempted to quit; 9 coincidentally did so during their follicular phase and 13 did so during their luteal phase (O Hara, Portser, & Anderson, 1989). Within 24 hr after quitting, women in the luteal phase reported greater withdrawal (total score on Shiffman Jarvik Withrawal Questionnaire). This difference was only a trend at 48 hr but was again significant at 72 hr after quitting. However, over onethird of these smokers relapsed within 72 hr (unstated how many smokers in follicular vs. luteal phases), but all participants were included in follow-up analyses. Thus whether abstinence rates were truly a function of menstrual phase is unclear. The second treatment study instructed 103 female participants, who were supported with a cognitive behavioral cessation intervention, to select a quit day (Perkins et al., 2000). Of these, 25 (13 follicular, 12 luteal) relapsed during their first week of abstinence and were omitted from subsequent analyses, leaving 41 and 37 women who successfully quit during their follicular and luteal phases, respectively. Menstrual phase was determined via self-report only. Increases in all withdrawal symptoms (assessed via a visual analog scale [VAS]) were greater among women in the luteal phase, though there were no phase differences in desire to smoke (also assessed via a VAS). Finally, two studies examined the impact of menstrual phase in response to a controlled dosing of nicotine following a period of overnight deprivation. Though not strict studies of abstinence per se, they are included here because they are essentially tests to determine if controlled doses of nicotine can undo the effects of nicotine deprivation. Unlike the studies described above, both studies excluded women with a history of premenstrual dysphoric disorder (PMDD). In one study (Marks, Pomerleau, & Pomerleau, 1999), no significant phase effects were found for subjective responses to nicotine administration, although there was a phase effect for menstrual-related symptomatology. That is, following the nicotine administration, none of the decreases in subjective measures (craving, withdrawal, anxiety, alertness, dizziness) were significantly different between menstrual phases. However, like several studies mentioned above, the small sample size may have precluded detection of differences across the four cycle phases. The other study of controlled dosing of nicotine included 12 women who were users of oral contraceptives and 12 who were not (Masson & Gilbert, 1999). There were no main effects for menstrual phase or contraceptive status, nor the interaction of the two, for either withdrawal or premenstrual symptoms. In sum, four of these studies demonstrated some menstrual-related effects, on either withdrawal or craving (or both), with elevations occurring primarily during the luteal phase. The remaining two studies that did not find significant phase effects were studies of responses to nicotine administration following abstinence. However, both of these studies (Marks et al., 1999; Masson & Gilbert, 1999) excluded women with a history of severe premenstrual distress, which may have led to negative findings. Studies involving nonabstinence vs. abstinence comparisons One study assessed 21 female smokers, randomized and counter-balanced for two menstrual phase cycles (follicular and late luteal) in a controlled inpatient environment (Allen et al., 1999). All smokers underwent 2 days of ad libitum smoking, after which participants were randomized to a 5-day abstinence condition or continued smoking. No significant phase effects on total withdrawal were found for either the abstinence or continued smoking group. Similarly, there were no phase differences on craving (measured by factor scores of QSU). However, there was an interaction between study period, smoking group, and menstrual phase, such that craving increased from the 2-day baseline period to the 5- day experimental period for both the late luteal and follicular phases for the abstinence group, and also for the late luteal phase for the continued smoking group. For women in the follicular phase of the continued smoking group, craving decreased from the baseline to the experimental period. As the authors noted, the controlled setting of this study may have altered the context of smoking or abstinence-related withdrawal. Two studies by Pomerleau and colleagues also compared the effects of menstrual phase and abstinence versus continued smoking on craving and withdrawal. In one study, nine female smokers were studied twice, during each of three menstrual phases (six sessions total; Pomerleau, Garcia, Pomerleau, & Cameron, 1992). For half of the sessions, participants were nonabstinent and smoked ad libitum prior to the testing session; for the remaining sessions, overnight deprivation was required and verified via expired-air carbon monoxide. There were no significant phase effects on

8 634 MENSTRUAL CYCLE PHASE EFFECTS withdrawal. However, given the small sample size, it is worth noting that there was a trend toward greater withdrawal during the early follicular phase when tested within the ad libitum smoking condition, and greater withdrawal during the late luteal phase when tested within the abstinence condition. For both ad lib smoking and abstinence conditions, there were no phase differences on the single item measure of craving. Finally, this study excluded women with a history of PMDD. A more recent study by the same research group examined the possibility that psychiatric history might interact with menstrual phase and abstinence to influence withdrawal and craving (Pomerleau et al., 2000). A total of 14 smokers, half of whom had a history of major depression, entered a similar protocol as the previously described study, with the exception that the ad libitum smoking condition involved five assessments occurring during the course of the menstrual phase (menstrual, postmenstrual, ovulatory, postovulatory, and premenstrual), whereas the abstinence condition, which was 72 hr in length, involved two assessments during the premenstrual (10 12 days following luteinizing hormone surge/ovulation) and postmenstrual (7 9 days after menses) phases. Within the ad libitum smoking condition, there were no significant phase effects on craving for cigarettes or withdrawal. However, when the menstrual phases were collapsed to examine only pre- versus postmenstrual phases, there was a significant effect for craving (no effect for withdrawal), such that craving was higher among women in the postmenstrual (follicular) phase. Whereas overall craving and withdrawal were elevated under conditions of abstinence, again there were no significant menstrual phase differences under this condition. Finally, another study followed female smokers over two menstrual periods and during a period of ad libitum smoking and 24-hr abstinence (Snively et al., 2000). Like several of the previously described studies, this study also excluded women with a history of PMDD. While withdrawal and craving were greater in response to imposed abstinence, there were neither phase effects nor any phase6condition interaction. However, there were differences in discomfort, as measured by a subscale within the Shiffman Jarvik Withdrawal Questionnaire. Specifically, greater psychological discomfort was reported during the mid/late follicular phase, under both abstinence and ad libitum smoking conditions. In sum, the overall findings from the research on abstinence versus nonabstinence comparisons are mixed. However, this group of studies provided some qualified support for phase effects, with some evidence of greater craving or withdrawal during the luteal phase, and some during the follicular phase. These findings were difficult to interpret because other powerful determinants of craving and withdrawal also were being evaluated, namely abstinence versus ad libitum access to smoking. Discussion The present review reported mixed but suggestive findings of an association between withdrawal or craving and menstrual phase. Of the eight study arms across seven studies that included a condition of ad libitum smoking (Allen et al., 1996, 1999; De Bon et al., 1995; Franklin et al., 2004; Pomerleau et al., 1992, 2000; Snively et al., 2000), significant menstrual phase effects were found for withdrawal in three study arms (Allen et al., 1996; De Bon et al., 1995; Snively et al., 2000) and for craving in three study arms (Allen et al., 1996; De Bon et al., 1995; Franklin et al., 2004). In the studies that found significant menstrual phase effects, greater withdrawal or craving was reported by women in later menstrual cycle phases (luteal or premenstrual), though one study found higher discomfort among women in early cycle phases (Snively et al., 2000). The results of studies involving abstinence also were mixed but suggestive. Of the 12 study arms across 10 studies (Allen et al., 1999, 2000; Craig et al., 1992; Marks et al., 1999; Masson & Gilbert, 1999; O Hara et al., 1989; Perkins et al., 2000; Pomerleau et al., 1992, 2000; Snively et al., 2000), significant menstrual phase effects were found for withdrawal in four study arms (Allen et al., 2000; O Hara et al., 1989; Perkins et al., 2000) and for craving in five study arms (Allen et al., 2000; Craig et al., 1992; Pomerleau et al., 2000; Snively et al., 2000). In the studies that found significant menstrual phase effects, five reported higher withdrawal or craving by women in later menstrual cycle phases (luteal or premenstrual), though two studies found higher craving among women in early (follicular) phases (Pomerleau et al., 2000; Snively et al., 2000). Three of these studies examined women engaged in an explicit quit attempt (Craig et al., 1992; O Hara et al., 1989; Perkins et al., 2000); thus, phase effects on withdrawal could be a function of trying to quit and not related to a general worsening of mood in any specific menstrual phase (Perkins et al., 2000). Interpretation and implications Our review of the mixed findings in this developing literature suggests a number of tentative conclusions. It is quite possible that when female smokers are nicotine deprived (e.g., abstinent), withdrawal symptoms become indistinguishable from premenstrual symptoms. Indeed some of the studies in this review noted a moderate to high correlation between premenstrual and withdrawal symptomatology

9 NICOTINE & TOBACCO RESEARCH 635 (Allen et al., 1996, 1999; O Hara et al., 1989; Pomerleau et al., 1992). This finding suggests an overlap in withdrawal and menstrual symptoms (i.e., physiological and affective symptoms of withdrawal may be disguised as menstrual-related symptoms or vice versa). Symptoms of irritability, anxiety, diminished concentration, and depression are common to both experiences. It may be difficult to distinguish menstrual-related symptoms from withdrawal symptomatology. This interpretation is underscored in at least two ways from the literature. First, each of the studies that involved ad libitum smoking found effects on withdrawal despite no manipulation of abstinence or nicotine deprivation. Smokers in some of these studies may have endorsed a variety of nonspecific physical and affective symptoms during the phases of the menstrual cycle when subjective accounts of physical symptoms were at their peak. Second, of the six studies that did not find heightened withdrawal or craving during the luteal phase, four excluded women with a history of severe premenstrual distress (Marks et al., 1999; Masson & Gilbert, 1999; Pomerleau et al., 1992; Snively et al., 2000). How much this exclusion influenced the findings is not clear because none of the studies stated how many women were excluded for this condition. In contrast, none of the seven studies with positive findings suggesting heightened withdrawal or craving during the luteal phase excluded women with such a history. Although PMDD is rare (American Psychiatric Association, 1994), a few individuals with a severe form of the disorder could significantly influence the results. Thus a selection bias may have been in effect for those studies reporting negative findings. Conversely, menstrual-related effects on withdrawal or craving may be explained partly by the presence of women who experience affective disturbances secondary to PMDD and other menstrualrelated hormonal changes (Masson & Gilbert, 1999; Pomerleau et al., 1992). One possible strategy to disentangle the experiences of withdrawal and premenstrual symptomatology might be to administer active versus placebo nicotine replacement therapy to women trying to quit, thereby partially controlling for withdrawal (cf. Allen et al., 2000). Another strategy is to assess only those withdrawal symptoms that do not overlap with premenstrual symptoms, such as a single item of craving (Pomerleau, 1996). However, rather than exploring ways to separate withdrawal from menstrual symptomatology, it might be more important to ask if doing so is of clinical significance. If something distressing is happening during the latter phase of the menstrual cycle, in addition to ascertaining if it is withdrawal, premenstrual symptoms, or an interaction of both, it may be more clinically useful to recognize that sufficient symptomatology exists in the luteal phase to warrant specific treatment efforts. Focused psychosocial interventions or pharmacotherapy may be needed during this time to offset heightened premenstrual or withdrawal distress. There are additional clinical practice implications of this relationship between menstrual phase and smoking behavior (Gritz, Nielsen, & Brooks, 1996; Perkins et al., 2000). Smoking is the only drug of dependence for which quitting begins on a scheduled quit date. In fact, the U.S. Public Health Service practice guidelines for smoking cessation explicitly recommend negotiating a quit date for all smokers interested in quitting (Fiore et al., 2000). This quit date is recommended to take place at least 2 weeks following cessation advice, to allow the smoker (and clinician) to prepare in advance. If women smokers are scheduling their quit date during the menstrual phase associated with increased smoking or heightened withdrawal (perhaps the luteal phase), then successful quitting is undermined. Conversely, one might be able to increase the probability of successful quitting with a well-timed (perhaps follicular phase) quit date. Although the results from this review are not clear enough to warrant a change in clinical practice recommendations, the results suggest that this may be a worthy focus of research. In the treatment studies included here (Craig et al., 1992; O Hara et al., 1989; Perkins et al., 2000), timing of quit attempts was not experimentally manipulated but rather self-determined by study participants or program procedures. To our knowledge, only one study exists in which women have been randomized to quit during any particular phase of their cycle. In this study, 70% of women (23 of 33) who were randomly assigned to quit during the follicular phase successfully quit, compared with 52% of women (17 of 33) randomized to quit during the luteal phase (Eck, Klesges, Meyers, Slawson, & Winders, 1997). Our study group is currently conducting pilot research to further explore this area. New directions for future research Aside from the potential implications mentioned above, however, the most striking implication from this review is the need for further research. Betweenstudy methodological variation likely accounts for many of the discrepant findings in this review. Many studies were substantially underpowered secondary to small sample size, thereby increasing the probability of Type II error (i.e., false negative) with regard to the assessment of menstrual phase effects. Although many of the reported studies used withinsubjects designs, which typically reduce error variance, the small samples more than offset any advantages offered by these designs. Thus future

10 636 MENSTRUAL CYCLE PHASE EFFECTS research in this area should use adequate sample sizes to test menstrual phase effects. Another source of method variance is the manner in which menstrual phases were identified and corroborated. The classification of menstrual phases (including the days of the menstrual cycle that they captured) was rarely consistent across studies, complicating comparisons. Similarly, some studies verified menstrual phase via hormonal corroboration whereas other studies relied on self-report of menstrual phase alone. Recent studies within this review appear to be moving toward a more consistent use of phase definitions, using biological methods to verify menstrual phase. We recommend that future research continue the practice of hormonal. Also, it remains to be determined if it is better to conceptualize the menstrual cycle as consisting of two simple phases (follicular vs. luteal), or four finer phases (early follicular vs. late follicular vs. early luteal vs. late luteal). Hormone level changes do exist within the follicular and the luteal phases, and simple examination of two phases in aggregate may mask more subtle phase differences. Thus it is our opinion that adoption of a four-phase conceptualization is warranted in order to detect potentially important biobehavioral outcomes that vary with hormone level. Finally, the fact that these studies varied with regard to inclusion of women with PMDD presents another area in which future research can make tighter control. The effect of this methodological variability on the findings in this review is unclear. On the one hand, the exclusion of women with PMDD likely excludes outliers within small studies, which may improve interpretability. On the other hand, studies making this exclusion may have been biased toward null findings. Studies that did not make this exclusion did not state how many study participants met this criterion, so it is equally possible that such a bias is spurious, given that PMDD is rare (American Psychiatric Association, 1994). Nonetheless, we recommend that future studies take adequate account of PMDD and report the implications for inclusion or exclusion in their findings. a phenomenon that has been so modestly investigated, a qualitative analysis provides a more subtle and detail-oriented assessment of the state of the art. Second, many studies did not use consistent nomenclature for identifying menstrual phases. Standardizing all studies to a common classification did not seem feasible because different studies used different cycle days to define menstrual phases. Finally, many studies have examined physiological outcomes as a function of menstrual phase. These studies have not been included here because they were not a focus of this review on withdrawal and craving. Conclusions An emerging literature has gone beyond examination of gender differences in smoking behavior and has begun to study menstrual phase effects on withdrawal and craving among women. The purpose of this review was to summarize the findings from this literature. Ample noise existed across the 13 studies included, strongly suggesting a need for further research in this area. Nonetheless, some preliminary evidence suggests that women in the latter phases of the menstrual cycle, in particular the luteal phase, may be particularly prone to greater withdrawal or craving. Although it may be difficult to disentangle these withdrawal-related phenomena from other menstrual-related symptomatology, the clinical implications of menstrual phase effects are noteworthy. If it can be demonstrated in wellcontrolled studies with biological confirmation of menstrual cycle phase that some phases of the cycle are associated with more distress or craving than others, future studies can determine if targeting quit dates to periods of less distress and craving improves treatment outcome. Acknowledgments This review was supported by National Institute of Drug Abuse (NIDA) training grant T32DA (MJC), Component #3 (HPU) of NIDA grant P50DA (KTB), and M01 RR0107 from the MUSC General Clinical Research Center. The authors thank Dr. Carrie Randall for comments on an earlier draft of this manuscript. Limitations A few cautionary notes need to be stated because both the literature reviewed and the methods used to review it may have affected our findings and conclusions. First, the review is based on a qualitative evaluation of a small literature base. The heterogeneity of methods used and the manner in which the results were reported precluded a more quantitative meta-analysis. A potential advantage of the present review methodology is that, in the case of References Allen, S., Hatsukami, D., Christianson, D., & Brown, S. (2000). Effects of transdermal nicotine on craving, withdrawal and premenopausal symptomatology in short-term smoking abstinence during different phases of the menstrual cycle. Nicotine & Tobacco Research, 2, Allen, S., Hatsukami, D., Christianson, D., & Nelson, D. (1996). Symptomatology and energy intake during the menstrual cycle in smoking women. Journal of Substance Abuse, 8, Allen, S., Hatsukami, D., Christianson, D., & Nelson, D. (1999). Withdrawal and pre-menopausal symptomatology during the menstrual cycle in short-term smoking abstinence: Effects of

11 NICOTINE & TOBACCO RESEARCH 637 menstrual cycle on smoking abstinence. Nicotine & Tobacco Research, 1, American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Berlin, I., Singleton, E., Pedarriosse, A., Lancrenon, S., Rames, A., Aubin, H., & Niaura, R. (2003). The Modified Reasons for Smoking Scale: Factorial structure, gender effects and relationship with nicotine dependence and smoking cessation in French smokers. Addiction, 98, Bjornson, W., Rand, C., Connett, J., & Lindgren, P. (1995). Gender differences in smoking cessation after 3 years in the Lung Health Study. American Journal of Public Health, 85, Bohadana, A., Nilsson, F., Rasmussen, T., & Martinet, Y. (2003). Gender differences in quit rates following smoking cessation with combination nicotine therapy: Influence of baseline smoking behavior. Nicotine & Tobacco Research, 5, Breslau, N., & Johnson, E. (2000). Predicting smoking cessation and major depression in nicotine-dependent smokers. American Journal of Public Health, 90, Breslau, N., Johnson, E., Hiripi, E., & Kessler, R. (2001). Nicotine dependence in the United States: Prevalence, trends, and smoking persistence. Archives of General Psychiatry, 58, Collins, B., Wileyto, E., Patterson, F., Rukstalis, M., Audrain- McGovern, J., Kaufmann, V., Pinto, A., Hawk, L., Niaura, R., Epstein, L. H., & Lerman, C. (2004). Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling. Nicotine & Tobacco Research, 6, COMMIT Research Group. (1995). Community Intervention Trial for Smoking Cessation (COMMIT): I. Cohort results from a four-year community intervention. American Journal of Public Health, 85, Craig, D., Parrott, A., & Coomber, J. (1992). Smoking cessation in women: Effects of the menstrual cycle. The International Journal of the Addictions, 27, De Bon, M., Klesges, R., & Klesges, L. (1995). Symptomatology across the menstrual cycle in smoking and nonsmoking women. Addictive Behaviors, 20, Eck, L., Klesges, R., Meyers, A., Slawson, D., & Winders, S. (1997). Changes in food consumption and body weight associated with smoking cessation across menstrual cycle phase. Addictive Behaviors, 22, Fiore, M. C., Bailey, W. C., Cohen, S. J., Dorfman, S. F., Gritz, E. R., Heyman, R. B., Holbrook, J., Jaen, C. R., Kottke, T. E., Lando, H. A., Mecklenbur, R., Mullen, P. D., Nett, L. M., Robinson, L., Stitzer, M., Tommasello, A. C., Villejo, L., & Wewers, M. E. (2000). Treating tobacco use and dependence. Clinical practice guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Fortmann, S., & Killen, J. (1994). Who shall quit? Comparison of volunteer and population-based recruitment in two minimal-contact smoking cessation studies. American Journal of Epidemiology, 140, Franklin, T., Napier, K., Ehrman, R., Gariti, P., O Brien, C., & Childress, A. (2004). Retrospective study: Influence of menstrual cycle on cue-induced cigarette craving. Nicotine & Tobacco Research, 6, Frye, C., Ward, K., Bliss, R., & Garvey, A. (1992). Influence of the menstrual cycle on smoking relapse and withdrawal symptoms. In: F. Keefe (Ed.), Thirteenth annual proceedings for the Society of Behavioral Medicine. Rockville, MD: Society for Behavioral Medicine. Gallant, S., Hamilton, J., Popiel, D., Morokoff, P., & Chakraborty, P. (1991). Daily moods and symptoms: Effects of awareness of study focus, gender, menstrual cycle phase, and day of the week. Health Psychology, 10, Gritz, E., Nielsen, I., & Brooks, L. (1996). Smoking cessation and gender: The influence of physiological, psychological, and behavioral factors. Journal of the American Medical Women s Association, 51, Guyton, A., & Hall, J. (2000). Textbook of medical physiology (10th ed.). Philadelphia: Saunders. Hughes, J. (1992). Tobacco withdrawal in self-quitters. Journal of Consulting and Clinical Psychology, 60, Hughes, J., Gust, S., Skoog, K., Keenan, R., & Fenwick, J. (1991). Symptoms of tobacco withdrawal: A replication and extension. Archives of General Psychiatry, 48, Hughes, J., & Hatsukami, D. (1986). Signs and symptoms of tobacco withdrawal. Archives of General Psychiatry, 43, Hyland, A., Li, Q., Bauer, J., Giovino, G., Steger, C., & Cummings, K. (2004). Predictors of cessation in a cohort of current and former smokers followed over 13 years. Nicotine & Tobacco Research, 6(Suppl.), S363 S369. Jarvis, M. (1994). A profile of tobacco smoking. Special issue: Comparing drugs of dependence. Addiction, 89, Kazdin, A. (1998). Research design in clinical psychology (3rd ed.). Boston: Allyn & Bacon. Klesges, R., Haddock, C., Lando, H., & Talcott, G. (1999). Efficacy of forced smoking cessation and an adjunctive behavioral treatment on long-term smoking rates. Journal of Consulting and Clinical Psychology, 67, Marks, J., Hair, C., Klock, S., Ginsburg, B., & Pomerleau, C. (1994). Effects of menstrual phase on intake of nicotine, caffeine, and alcohol and nonprescribed drugs in women with late luteal phase dysphoric disorder. Journal of Substance Abuse, 6, Marks, J., Pomerleau, C., & Pomerleau, O. (1999). Effects of menstrual phase on reactivity to nicotine. Addictive Behaviors, 24, Masson, C., & Gilbert, D. (1999). Cardiovascular and mood responses to quantified doses of cigarette smoke in oral contraceptive users and nonusers. Journal of Behavioral Medicine, 22, Mello, N., Mendelson, J., & Palmieri, S. (1987). Cigarette smoking by women: Interactions with alcohol use. Psychopharmacology, 93, Morrissette, M., & Di Pialo, T. (1993). Sex and estrous cycle variations of rat striatal dopamine uptake sites. Neuroendocrinology, 58, O Hara, P., Portser, S., & Anderson, B. (1989). The influence of menstrual cycle changes on the tobacco withdrawal syndrome in women. Addictive Behaviors, 14, Perkins, K. (1996). Sex differences in nicotine versus nonnicotine reinforcement as determinants of tobacco smoking. Experimental and Clinical Psychopharmacology, 4, Perkins, K. (2001). Smoking cessation in women: Special considerations. CNS Drugs, 15, Perkins, K., Levine, M., Marcus, M., Shiffman, S., D Amico, D., Miller, A., Keins, A., Ashcom, J., & Broge, M. (2000). Tobacco withdrawal in women and menstrual cycle phase. Journal of Consulting and Clinical Psychology, 68, Piasecki, T., Kenford, S., Smith, S., Fiore, M., & Baker, T. (1997). Listening to nicotine: Negative affect and the smoking withdrawal conundrum. Psychological Science, 8, 184. Pomerleau, C. (1996). Smoking and nicotine replacement treatment issues specific to women. American Journal of Health Behavior, 20, Pomerleau, C., Garcia, A., Pomerleau, O., & Cameron, O. (1992). The effects of menstrual phase and nicotine abstinence on nicotine intake and on biochemical and subjective measures in women smokers: A preliminary report. Psychoneuroendocrinology, 17, Pomerleau, C., Mehringer, A., Marks, J., Downey, K., & Pomerleau, O. (2000). Effects of menstrual phase and smoking abstinence in smokers with and without a history of major depressive disorder. Addictive Behaviors, 25, Pomerleau, C., Tate, J., Lumley, M., & Pomerleau, O. (1994). Gender differences in prospectively versus retrospectively assessed smoking withdrawal symptoms. Journal of Substance Abuse, 6, Scharf, D., & Shiffman, S. (2004). Are there gender differences in smoking cessation, with and without bupropion? Pooled- and metaanalyses of clinical trials of bupropion SR. Addiction, 99, Shiffman, S. (1979). The tobacco withdrawal syndrome. In: N. Krasnegor (Ed.), Cigarette smoking as a dependence process (NIDA Research Monograph No. 23). Rockville, MD: U.S. Public Health Service. Shiffman, S., & Jarvik, M. (1976). Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology, 50, Snively, T., Ahijevych, K., Bernhard, L., & Wewers, M. (2000). Smoking behavior, dysphoric states and the menstrual cycle: Results from the single smoking sessions and the natural environment. Psychoneuroendocrinology, 25, Steinberg, J., & Cherek, D. (1989). Menstrual cycle and cigarette smoking behavior. Addictive Behaviors, 14, Svikis, D., Hatsukami, D., Hughes, J., Carroll, K., & Pickens, R. (1986). Sex differences in tobacco withdrawal syndrome. Addictive Behaviors, 11,