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Psychosomatic Medicine 68:299-306 (2006)
© 2006 American Psychosomatic Society

ORIGINAL ARTICLES

Reduction in Cortisol After Smoking Cessation Among Users of Nicotine Patches

Michael Ussher, PhD, Robert West, PhD, Phil Evans, PhD, Andrew Steptoe, PhD, Andy McEwen, PhD, Angela Clow, PhD and Frank Hucklebridge, PhD

From the Division of Community Health Sciences (Psychology) (M.U.), St. George’s, University of London, London, United Kingdom; the Department of Epidemiology and Public Health (R.W., A.S., A.M.), University College London, United Kingdom; and the Departments of Psychology (P.E., A.C.) and Human and Health Sciences (F.H.), University of Westminster, London, United Kingdom.

Address correspondence and reprint requests to Michael Ussher, PhD, Division of Community Health Sciences (Psychology), St. George’s, University of London, Cranmer Terrace, London SW17 ORE, U.K. E-mail: mussher{at}sgul.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Cortisol has been shown to decline after stopping smoking and this decline has been associated with smoking relapse and with reports of increased withdrawal severity and distress. We examined whether a decrease in cortisol is evident in smokers trying to quit using nicotine patches and whether cortisol is related to withdrawal symptoms, smoking urges, subjective stress, nicotine dependence, and smoking relapse.

Methods: Among 112 smokers trying to quit using 15-mg patches, salivary cortisol and reports of stress, withdrawal, and urges were measured before quitting smoking and up to 6 weeks of abstinence among abstinent smokers using 15-mg nicotine patches. Thirty participants both remained abstinent and provided cortisol samples at all measurement times.

Results: Relative to preabstinence, there was a significant decline in cortisol after abstinence of 1 day, and after 1, 2, and 6 weeks (p < .05). The decline in cortisol on the first day of abstinence was positively associated with reported cigarette consumption (p < .01) and tended (nonsignificant) to be associated with smoking relapse at 6 weeks (p = .07). A lower absolute level of cortisol, but not the change in cortisol, on the first day of abstinence was significantly associated with increased reports of urges, withdrawal symptoms, and stress (p < .05), independently of reported cigarette consumption.

Conclusions: Smokers using 15-mg nicotine patches are likely to experience a decline in cortisol on stopping smoking. This decline is likely to be greater among heavier smokers and may predict relapse to smoking. Those with lower cortisol after cessation may experience increased withdrawal symptoms, urges to smoke, and subjective stress.

Key Words: cortisol • smoking cessation • nicotine patches • urges to smoke • stress • withdrawal symptoms

Abbreviations: HPA = hypothalamic–pituitary–adrenocortical; NRT = nicotine replacement therapy; FTND = Fagerström Test for Nicotine Dependence; CO = carbon monoxide; PPM = parts per million; RPM = revolutions per minute; °C = degrees centigrade; S-IgA = salivary immunoglobulin-A; nmol/L = nanomole/liter; ACTH = adrenocorticotrophic hormone; SD = standard deviation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Stoppingsmoking is associated with a desire to smoke and with psychological withdrawal symptoms such as depression, restlessness, and irritability (1). However, the biological markers of tobacco withdrawal are less well understood. Such phenomena are useful as objective markers of withdrawal severity, as potential predictors of smoking relapse and as mediators of treatment effects. Recent research with animals has implicated the hypothalamic–pituitary–adrenocortical (HPA) system in smoking relapse (2) and cortisol is the primary peripheral HPA hormone in humans. Cortisol modulates central nervous system activity during stress, and its production has been linked to the ability to cope with stress demands (3). Regular cigarette smokers have been found to have elevated cortisol relative to nonsmokers (4–6) and smoking has been shown to stimulate the release of cortisol (7–10). This effect has been attributed to nicotine exposure (7,8,11,12). Cortisol interacts with several neurotransmitters that mediate the effects of nicotine (e.g., dopamine, ß-endorphin, acetylcholine [(13,14]), and cortisol may be linked to nicotine metabolism in that sensitivity to nicotine tends to be reduced under conditions of enhanced corticosteroid activity 15).

A number of studies have shown that, among those not using pharmaceutical aids to smoking cessation, there is a rebound decrease in cortisol on stopping smoking. A significant decline in cortisol, relative to presmoking abstinence levels, has been reported after abstinence of 4 hours (16), 12 hours (17), 24 hours (6), 2 days and 9 days (18), 2 weeks (19), 31 days (20,21), and 6 weeks (22). Other studies have reported either no change in cortisol (23,24) or an increase in cortisol after smoking cessation (25). In addition, two studies observed no change in cortisol, relative to preabstinence, among those using 10-mg, 20-mg, or 30-mg nicotine patches (24) or using 21-mg patches (26). However, all the studies reporting no change in cortisol or an increase in cortisol after cessation were limited by small sample sizes, by only considering the first few days of temporary smoking deprivation and by only including a small minority of women, and recent evidence suggests that the initial decline in cortisol on stopping smoking may be more pronounced for women than for men (6). A greater decline in cortisol on stopping smoking has also been found to predict relapse to smoking at 1 week (6) and to be associated with increased distress (19) and severity of withdrawal (6). The mechanism underlying this phenomenon is not clear. It is possible that there is increased nicotine receptor sensitivity associated with a reduction in cortisol (15) leading to an exacerbation of withdrawal symptoms and increased relapse. Additionally, the stimulating effects of cortisol may contribute to the reinforcing properties of smoking, in which case a dramatic decrease in cortisol might be distressing for the smoker.

The change in cortisol from the first few days of smoking abstinence through to several weeks of abstinence has not been assessed within a single study before. In the present investigation, we also sought to confirm the previous report of a reduction in cortisol predicting smoking relapse at 1 week (6) through examining whether cortisol predicts relapse up to 6 weeks after the quit day. We also aimed to confirm whether cortisol during smoking cessation is related to withdrawal symptoms (6) and, in addition, we assessed whether cortisol is related to tobacco dependence/consumption and to reports of subjective stress and urges to smoke. The present study was carried out as a secondary analysis of data from a larger study of smokers trying to quit using nicotine patches (27). The aim of the larger study was not primarily to evaluate the impact of nicotine patches per se, but rather to examine the effect of exercise on smoking abstinence. Therefore, a control group using placebo patches was not included and the primary aim of the present study was not to evaluate the impact of nicotine patches; rather, we had an opportunity, as part of the larger trial, to examine cortisol during ad libitum smoking and during the first day of abstinence through to 6 weeks of abstinence, and to relate cortisol to smoking relapse, to tobacco dependence/consumption, and to reports of withdrawal symptoms, urges to smoke, and stress.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Sample
One hundred and twelve men and women aged 18 to 65 years, smoking at least 10 cigarettes a day for at least 3 years, and who were motivated to stop smoking, were recruited through newspaper advertisements or referral from their physician. Recruitment took place between January 2000 and March 2001. Smokers with a current psychiatric illness, substance misuse problem, or pregnancy were excluded. Participants provided written consent and the local ethics committee gave its approval.

Design and Treatment Regimen
A single group of smokers was tracked while smoking and then for up to 6 weeks of smoking abstinence. All participants attended six individually based weekly smoking cessation treatment sessions and a follow-up session 2 weeks after the final treatment. Treatment sessions took place in a dedicated room in the Psychology Department at St. George’s Hospital Medical School. A cognitive–behavioral format was used incorporating self-monitoring, goal setting, preparing for high-risk situations, and coping with tobacco withdrawal (28). All participants were required to stop smoking at their second visit and then to use one 15-mg 16-hour nicotine patch each day (irrespective of their initial level of smoking consumption) throughout the treatment program (29,30). All the statistical tests were two-tailed and SPSS version 12 was used throughout.

Measures
At the initial visit, 1 week before smoking cessation, data were collected relating to demographics and smoking characteristics, including nicotine dependence (Fagerström Test for Nicotine Dependence [FTND] [31]), expired air carbon monoxide (CO) level using a Bedfont Smokerlyzer and physical activity levels by self-report (32). Further self-reports of physical activity levels were obtained after 1 week and 6 weeks of smoking abstinence. After each week of smoking abstinence, participants reported whether they had smoked since the previous visit (33) and abstinence was verified with expired CO concentration (cutoff: 10 ppm). If a participant reported smoking, or if they failed to attend an appointment and it could not be rescheduled within 48 hours, they were excluded from the program and were recorded as having lapsed. Excluded smokers were offered support from another stop smoking clinic. Use of nicotine patches was also recorded.

Salivary Cortisol
Salivary cortisol has been shown to accurately reflect plasma-free and therefore physiologically active cortisol (34), and because salivary cortisol has been shown to be more highly related to serum adrenocorticotrophin than is serum cortisol, salivary cortisol may more accurately reflect activity in the hypothalamic–pituitary–adrenal axis (35). To obtain samples of salivary cortisol, saliva was collected by the participants placing a cotton dental roll under their tongue for a timed period of 2 minutes, after which the roll was returned to a plastic tube (Salivette; Sarstedt Ltd.). Participants were asked to refrain from food and drink (except water) for at least 30 minutes before each saliva sample (36), and the time since the last meal was recorded. Additionally, participants were required to avoid alcohol on each day that a saliva sample was taken (37).

For all participants, the primary presmoking abstinence measure of cortisol was taken 1 week before smoking cessation. To examine the stability of the primary preabstinence cortisol measure, a second preabstinence measure of cortisol was taken at the session at which the participants quit smoking. To minimize the acute effects of smoking on cortisol, participants were required to abstain from smoking for at least 30 minutes before the preabstinence samples (10), and participants reported the time since their last cigarette. Those participants remaining abstinent from smoking were asked to provide further saliva samples after abstinence of 1 day, 1 week, 2 weeks, and 6 weeks. For the sample taken on the first day of abstinence, all participants had achieved at least 24 hours of abstinence. On each day of testing, a single saliva sample was taken. To avoid the effects of awakening and meals on cortisol response (36,38,39), all saliva samples were taken between 4:00 pm and 5:00 pm. Moreover, cortisol levels in a spot sample taken in the late afternoon (9 hours postawakening) correlate strongly with a more complete estimate of diurnal cortisol activity (39). For those unable to attend the clinic between 4:00 pm and 5:00 pm, a Salivette was provided, the participant was asked to take the sample independently at between 4:00 and 5:00 pm, to record the time at which the sample was taken, and to refrigerate the sample until it could be returned at the next appointment. Insulated cold packs were provided for transporting the samples to the clinic. Before assay, all the saliva samples were stored at –20°C. Samples were thawed and then spun at 3500 rpm for 10 minutes to recover the saliva. Cortisol concentration was determined by an enzyme-linked immunoassay developed specifically for the determination of cortisol in saliva (Salimetrics LLC). Assay reliability met the manufacturer’s specifications.

This study was carried out using a subsample of participants from a larger study (27), and a minority of the participants in the present study also provided a salivary immunoglobulin-A (S-IgA) sample at the same time points as for cortisol. It would have been interesting to relate cortisol levels to S-IgA levels; however, there were insufficient numbers of participants providing samples for both S-IgA and cortisol to make any statistically meaningful comparison of these two measures (only 19 participants provided cortisol and S-IgA at all five measurement times). Consequently, the data on S-IgA were reported separately (40).

Urges to Smoke, Withdrawal Symptoms, and Stress
Urges to smoke have been shown to reliably predict relapse to smoking (41), yet no previous study has related urges to smoke to cortisol during smoking cessation. These urges tend to be strongest in the first week of smoking abstinence (42); therefore, on each day during the first week of abstinence, participants responded on a six-point scale to the question "How strong is your desire to smoke?" (0 = no urges to 5 = extremely strong [43]). In addition, at the end of the first week of abstinence, participants were asked "How strong have the urges to smoke been in the last week?" (0 = not at all to 5 = extremely strong [(43]). At 1 week preabstinence and 1 week postabstinence, participants used the Mood and Physical Symptoms Scale 44) to rate (1 = not at all, 4 = somewhat, 7 = extremely) the presence of the tobacco withdrawal symptoms of "depressed," "irritable," "restless," "hungry," "poor concentration," "disturbed sleep," and "anxiety." Subjective stress has been associated with both smoking (45) and with cortisol (46), and reports of distress have been associated with a decrease in cortisol after smoking cessation (19). Therefore, on each occasion when a saliva sample was taken, all participants were asked "Could you tell us how stressed you feel right now?"(1 = not at all, 2 = slightly, 3 = somewhat, 4 = very, 5 = extremely).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
At baseline (1 week before smoking cessation), 112 smokers provided data (see Table 1). After cessation, data were only collected for those maintaining continuous abstinence from smoking as confirmed by an expired CO of <10 ppm. Rates of continuous abstinence at each time after the quit day were: 1 day 89.3% (100 of 112), 1 week 83.0% (93 of 112), 2 weeks 67.0% (75 of 112), and 6 weeks 53.6% (60 of 112). Among those abstinent, the numbers providing cortisol were: 1 day 82.0% (82 of 100), 1 week 71.0% (66 of 93), 2 weeks 76.0% (57 of 75), and 6 weeks 81.7% (49 of 60). In 19 cases, the saliva sample had insufficient volume to execute the cortisol assay. In other cases, the Salivette was not returned. Thirty participants were both abstinent for 6 weeks and provided all five cortisol samples (see Table 2A). There was a significantly lower number of women among those who provided cortisol at all five measurement times (n = 30) versus those who did not provide all five samples (n = 82) (chi-squared = 6.71, p = .012, number of females: n = 30: 15 of 30 [50.0%], n = 82: 62 of 82 [75.6%]). There were no other significant differences between these two samples. At all measurement points the data for cortisol concentration (nmol/L) were found to be strongly positively skewed (see Table 2A, B). Therefore, nonparametric tests were used for all analyses of the cortisol data.


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  		TABLE 1. Baseline Characteristics for the Total Study Sample (N = 112) and for the Subgroup Who Were Both Abstinent From Smoking to 6 weeks and Provided Cortisol Samples at All Five Measurement Times (N = 30)

 

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  		TABLE 2. Comparisons for Cortisol Concentration Between Presmoking Cessation and Each Measure After Cessation for Abstinent Smokers

 

Changes in Cortisol After Smoking Cessation
There is evidence to suggest that the initial decline in cortisol on stopping smoking may be more pronounced for women than for men (6); therefore, at the outset, we examined changes in cortisol for males versus females. Using Mann-Whitney tests, there was no evidence to suggest that gender was significantly related to the absolute level of cortisol at preabstinence or on the first day of abstinence, nor was gender significantly related to the change in cortisol between preabstinence and the first day or first week of cessation. On this basis, there was no justification for analyzing the data separately by gender and for all the analyses the data for men and women were combined. To examine changes in cortisol across time in the same group of participants, the primary analysis used the subgroup who were both abstinent throughout and provided all five cortisol samples (n = 30). Wilcoxon tests, with planned comparisons, showed that relative to 1-week preabstinence, cortisol concentrations (nmol/L) were significantly reduced after smoking abstinence of 1 day, 1 week, 2 weeks, and 6 weeks (see Table 2 and Fig. 1). There was a nonsignificant trend for cortisol to increase between 1 day and 6 weeks of abstinence (see Fig. 1).


Figure 118
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  		Figure 1. Mean cortisol concentration for those providing data across all five measurement points (n = 30, standard error bars are shown). • = Presmoking abstinence measure taken one week before the quit day. *Decrease in cortisol between preabstinence and each further measurement time significant at p < .05.

 

A secondary analysis included all those who provided a cortisol sample at any time point and were abstinent from smoking (Table 2B). For this analysis, sample sizes differed at each measurement time (abstinence of: 1 day n = 82, 1 week n = 66, 2 weeks n = 57, and 6 weeks n = 49). Wilcoxon tests showed a significant reduction in cortisol between preabstinence and abstinence of 1 day, 1 week, and 6 weeks. There was no evidence of a significant difference in cortisol between preabstinence and 2 weeks of abstinence or between abstinence of 1 day and 6 weeks.

Cortisol and Smoking Relapse
For analyses relating cortisol to smoking relapse, tobacco dependence/consumption, urges to smoke, tobacco withdrawal, and stress, the primary outcomes for cortisol were the change in cortisol between 1 week preabstinence and 1 day postabstinence and the absolute level of cortisol after 1 day of abstinence (see Table 3). For these analyses, to maximize the sample size, all those providing data at these measurement times were included (see Table 2B).


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  		TABLE 3. Summary of Significant Associations Between Cortisol and Other Outcome Variables (Using Mann-Whitney Tests and Spearman’s Rank Correlation Coefficient)

 

Using Mann-Whitney tests, there was a nonsignificant trend for a greater decline in cortisol between preabstinence and 1 day of abstinence to predict relapse at 6 weeks (Z = 1.8, p = .073, n = 82). There was no evidence for this change in cortisol being significantly related to relapse at 1 or 2 weeks. Absolute levels of cortisol at preabstinence or on the first day of abstinence were not found to be significantly related to rates of relapse at any time (Mann-Whitney).

Using Pearson’s correlation coefficient, there were significantly higher rates of smoking relapse at 6 weeks of abstinence among those with higher expired CO scores at preabstinence (r = 0.307, p = .001) and higher scores for urges to smoke for the first week of abstinence (r = 0.261, p = .013). Relapse rates at this time were not shown to be significantly related to FTND score, reported cigarette consumption, gender, age, or to the change in withdrawal symptoms between preabstinence and 1 week of abstinence.

Cortisol and Tobacco Dependence/Consumption
A greater decline in cortisol between preabstinence and 1 day of abstinence was significantly related to reports of smoking a greater number of cigarettes (Spearman’s rank correlation coefficient, rho = 0.3, p = .008, n = 82) and tended (nonsignificant) to also be related to higher FTND score (p = .089) and expired CO at preabstinence (p = .051). Higher cortisol at 1 week preabstinence was significantly related to reports of greater cigarette consumption (Spearman’s rho = 0.2, p = .013, n = 112), but was not found to be significantly related to either preabstinence expired CO or to FTND score. Cortisol after 1 day of abstinence was not shown to be significantly associated with FTND, preabstinence expired CO, or reported cigarette consumption.

Cortisol and Urges to Smoke
Using Spearman’s correlation coefficient, the rating of urges to smoke across the first week of abstinence was not shown to be related to the change in cortisol between preabstinence and 1 day of abstinence or to absolute levels of cortisol on the first day of abstinence. Neither was the change in cortisol between preabstinence and the first day of abstinence significantly associated with reports of urges on any day in the first week of cessation. However, lower absolute levels of cortisol on the first day of abstinence were significantly associated with reports of higher urges to smoke on the third and fourth days of abstinence (rho = 0.239, p = .047; rho = 0.299, p = .012, respectively), but not with reports of urges on any other day during the first week of abstinence.

Cortisol and Tobacco Withdrawal Symptoms
Scores for the individual withdrawal items were summed to produce a composite item. There was no evidence for changes in composite withdrawal scores between preabstinence and 1 week postabstinence being related to changes in cortisol between preabstinence and 1 day or 1 week of abstinence. However, a lower absolute level of cortisol on the first day of abstinence was significantly associated with a greater increase in composite withdrawal scores between preabstinence and 1 week of abstinence (Spearman’s rho = 0.262, p = .023) and to higher absolute levels of composite withdrawal after 1 week of abstinence (rho = 0.288, p = .012).

Cortisol and Perceived Stress
Changes in reports of stress between preabstinence and the first day of abstinence were not shown to be related to changes in cortisol between these times (Spearman’s rho). However, lower absolute cortisol on the first day of abstinence was significantly associated with reports of higher levels of stress at this time (Spearman’s rho = 0.234, p = .047).

Potential Confounders of Changes in Cortisol After Smoking Cessation
Stability of Cortisol Measures
A Wilcoxon test showed no significant difference between the primary preabstinence measure of cortisol taken 1 week before cessation and a secondary preabstinence measure of cortisol taken on the quit day. This suggests that the primary preabstinence measure provides a reliable measure of cortisol during ad libitum smoking. To maximize the sample size, for all analyses of changes in cortisol, the preabstinence measure taken 1 week before smoking cessation was used as the single preabstinence measure. In addition, cortisol measures at all time points were significantly correlated with each other (all at p ≤ .01, range: Spearman’s rho = 0.3–0.8). This suggests that single daily measures of salivary cortisol are stable for an individual relative to other individuals.

Use of Nicotine Patches
Nearly all the participants reported using patches on a daily basis after 1 week and 2 weeks of abstinence (92.4%, 61 of 66; 93.0%, 53 of 57). However, after 6 weeks, only 63.3% (31 of 49) of those remaining abstinent and providing a cortisol sample reported using patches. A Mann-Whitney test showed no significant difference in the change in cortisol (dependent variable) between preabstinence and 6 weeks of abstinence according to whether or not patches were used (independent variable) at 6 weeks (Z = 0.996, p = .319; patch used [n = 31]: median cortisol at preabstinence [nmol/L] = 3.78, at 6 weeks = 1.21; patch not used [n = 18]: median cortisol at preabstinence = 2.36, at 6 weeks = 1.60). Neither was there any evidence of use of patches at 6 weeks being significantly related to the change in cortisol between preabstinence and 1 day of abstinence or to cortisol at preabstinence.

Other Potential Confounders
Using Spearman’s rank correlations and Mann-Whitney tests, neither the absolute level of cortisol at preabstinence or on the first day of abstinence nor the change in cortisol between preabstinence and the first day of cessation were significantly related to self-reported physical activity levels, assignment to exercise or control condition in the larger trial (27), time since last cigarette (mean [standard deviation] hours since last cigarette = 1.1 [0.9]), or last meal at 1 week preabstinence, location of cortisol sample (home versus clinic), or age. Overall, there was no evidence that any of the variables examined confounded the findings of a reduction in cortisol after stopping smoking.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
This study is the first to report a significant reduction in cortisol after smoking cessation among users of nicotine-replacement therapy. Heavier smokers showed a significantly greater decline in cortisol after smoking cessation and had significantly higher cortisol at preabstinence. This suggests that the reduction in cortisol after smoking cessation may be related to a fall in nicotine levels or to a reduction in levels of other constituents of tobacco smoke (11). The decline in cortisol was not related to preabstinence expired CO or FTND score. This may be because CO and FTND are less sensitive markers of nicotine intake than is cigarette consumption. FTND contains a number of items unrelated to nicotine intake (31) and CO has a short half-life (47) and so is relatively unstable. The elevated cortisol at preabstinence, relative to postcessation, could not have been the result of acute effects of smoking, because cortisol was measured more than 30 minutes after smoking and cortisol levels were not found to be related to the time since the last cigarette. Rather, the higher levels of cortisol at preabstinence are likely to be the result of the sustained effects of repeated smoking (4,5,48).

This is also the first study to examine changes in cortisol at several time points from the first few days of abstinence through to 6 weeks of abstinence. Relative to preabstinence, there was a sharp decline in cortisol on the first day of abstinence followed by a nonsignificant trend for cortisol to increase through to 6 weeks (see Fig. 1). This initial sharp decline in cortisol followed by a tendency for cortisol to increase may be the result of smokers having counterregulatory mechanisms to avoid hypercortisolism, and therefore there may temporarily be a reduced efficiency of the feedback mechanism that maintains cortisol levels (23,48). The finding that cortisol concentrations did not increase significantly between abstinence of 1 day and 6 weeks supports the argument for the reduction in cortisol being an "offset" effect (49) related to the removal of the effects of smoking. The finding of no relationship between gender and cortisol is inconsistent with previous studies (6,50) and requires confirmation.

As consistent with most studies of smokers not using nicotine-replacement therapy, we observed a significant reduction in cortisol despite the use of 15-mg nicotine patches. Moreover, the cortisol reduction was maintained at 6 weeks of abstinence irrespective of whether the participants were still using patches at that time. This may be because patches deliver lower levels of nicotine in arterial blood relative to smoking (51). Alternatively, the slow, steady delivery of nicotine from a transdermal patch may be a less effective stimuli for cortisol release versus smoking, or higher-dose patches may be required for pronounced cortisol release (26). The latter hypotheses are consistent with findings of dose-dependent increases in cortisol after nicotine administration (11) and cigarette smoking (52). It is also conceivable that the relationship between plasma nicotine and cortisol follows a hysteresis curve, as has been found for the relationship between nicotine and other physiological processes (53), in which case a small decline in the plasma level of nicotine could produce a large decrease in cortisol secretion. A final possibility is that cortisol may be regulated by components in cigarette smoke other than nicotine, and nicotine-replacement therapy alone may be insufficient to have a major impact on cortisol.

There was a nonsignificant trend for a reduction in cortisol after smoking abstinence to predict relapse to smoking at 6 weeks. This result is consistent with a previous finding for the decline in cortisol predicting relapse at 1 week (6) and may be a reflection of the relationship between cortisol decrease and tobacco dependence/consumption. Further studies are required to establish whether cortisol is a reliable predictor of relapse. The influence of cortisol on smoking abstinence could also be investigated through administering hydrocortisone or cortisol-stimulating adrenocorticotrophic hormone (ACTH [(54]) to abstaining smokers.

Previous studies have demonstrated a significant relationship between a reduction in cortisol during smoking abstinence and increased withdrawal severity 6) or distress (19). We did not confirm this report. However, a lower absolute level of cortisol on the first day of abstinence was significantly related to increased reports of withdrawal symptoms, urges to smoke, and stress. Moreover, these relationships were independent of the smokers’ reported cigarette consumption or nicotine dependence. Further work is needed to establish whether absolute levels of cortisol or the reduction in cortisol is the more sensitive marker of withdrawal severity. The mechanisms mediating the relationship among cortisol, withdrawal, urges to smoke, and relapse are not clear. The finding of an association between lower cortisol and increased reports of these symptoms is also incongruent with the general finding that cortisol is positively associated with subjective stress (3). It is possible that cortisol mediates the effects of nicotine (14) such that cortisol contributes to the reinforcing properties of cigarettes. Consequently, a sudden decrease in cortisol may cause the smoker distress. It is also possible that low levels of cortisol may reduce the physiological capacity to respond to environmental demands during smoking abstinence and so increase subjective stress. This may be especially the case because abstinent smokers show an attenuated cortisol response to stress, and this attenuated response predicts relapse to smoking (55). Cortisol has also been found to downregulate nicotine receptor binding (15); therefore, very low levels of cortisol on the first day of abstinence may result in increased withdrawal symptoms, stress, desire to smoke, and relapse as a result of a rebound effect of increased nicotine receptor sensitivity. Alternatively, some unknown psychosocial or biological factor (e.g., dopamine, see [(14]) may simultaneously affect cortisol, urges to smoke, withdrawal symptoms, and stress.

This study is limited in that it was carried out as a secondary data analysis 27), and it was not possible to include a control group using placebo patches; therefore, we were unable to adequately assess whether the use of nicotine patches moderated the decline in cortisol after smoking cessation. It is possible that there are placebo effects of patches on cortisol; for example, the reassurance provided by wearing a patch may reduce cortisol levels after cessation. Because we did not have a control group using placebo patches, nor a control group without patches, it was not possible to examine any such placebo effects and further studies are needed to assess these effects. However, it is highly unlikely that placebo effects alone would account for the dramatic decline in cortisol after smoking abstinence. Moreover, the decline in cortisol was associated with increased stress, and if there were a placebo effect of wearing patches, one might have expected a decline in cortisol to be associated with reduced stress. Neither did our study assess whether higher doses of patch counteract a dramatic reduction in cortisol after quitting smoking. The current study did not include a comparison group of continuing smokers. In the absence of such a control group, we examined cortisol before smoking abstinence at two times: on the quit day and 1 week before quitting, and we found no significant differences between the cortisol levels at these times. This suggests that the preabstinence measure of cortisol is reliable, and it is highly unlikely that a group of smokers, on arbitrarily defined days, would show a significant reduction in cortisol while continuing to smoke relative to two previous measures.

All the participants received cognitive–behavioral support, and it is possible that this social support lowered cortisol levels (3). In the present investigation, the program of behavioral support began before smoking cessation and therefore cannot account for the sudden reduction in cortisol after smoking cessation. To examine the effect of cognitive–behavioral support on cortisol levels during smoking cessation, studies are required that include a control group that does not receive this support.

We sampled cortisol at one time point on each day of measurement and at a time of day when cortisol was likely to be relatively stable. However, cortisol has been shown to have a marked diurnal pattern in relation to time of awakening (38,39), and this pattern has been shown to be present during the first few days of smoking cessation (6,26). In the present study, repeated measures of cortisol across each day of testing may have provided a more sensitive indication of changes in cortisol. Also, it would have been useful to have more frequent sampling of cortisol during the first week of abstinence.

Cortisol is secreted in response to any physical or psychological stress, so it would have been valuable to measure and control for other possible sources of stress independent of smoking. In addition, cortisol has wide-reaching effects, so secondary tests of other variables affected by cortisol (e.g., blood sugar, self-report of fatigue) would have been helpful to distinguish a direct effect or an indirect effect of cortisol. A final limitation of the study is that at the outset the smokers were not screened for endocrine diseases (e.g., Morbus Cushing). It is common to have a skewed data set for cortisol; however, without a medical check, it is not possible to know whether some of the extreme outliers for cortisol were related to disease.

Our findings have a number of practical implications, including: 1) despite the use of 15-mg 16-hour nicotine patches, smokers are likely to experience a decline in cortisol on the first day of smoking cessation, which is maintained through to 6 weeks of abstinence; 2) heavier smokers are more likely to experience this decline in cortisol; 3) those smokers who have lower levels of cortisol on the first day of abstinence are more likely to experience withdrawal symptoms, urges to smoke, and stress during the first week of abstinence; and 4) there may be a tendency (our finding approached significance) for those experiencing a greater decline in cortisol on the first day of abstinence to have an increased likelihood of relapse.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

The authors were supported by grants from Cancer Research U.K. (CE1198/0101) and from the Central Research Fund of the University of London. We thank Sara Sen for valuable laboratory work.

DOI:10.1097/01.psy.0000204926.27215.a1


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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