Cigarette craving contributes substantially to the maintenance of tobacco use disorder. Behavioral strategies to regulate craving may facilitate smoking cessation but remain underexplored. We adapted an emotion-regulation strategy, using proximal/distal self-positioning, to the context of cigarette craving to examine craving regulation in 42, daily smokers (18-25 years old). After overnight abstinence from smoking, before and after smoking their first cigarette of the day, participants viewed videos of natural scenes presenting young adults who were either smoking cigarettes ("smoke") or not ("non-smoke"). Before each video, participants were instructed to imagine themselves either immersed in the scene ("close") or distanced from it ("far"). They rated their craving after each video. Task-based fMRI data are presented for a subsample of participants (N = 21). We found main effects of smoking, instruction, and video type on craving-lower ratings after smoking than before, following the "far" vs. "close" instructions, and when viewing non-smoke vs. smoke videos. Before smoking, "smoke" vs. "non-smoke" videos elicited activation in, orbitofrontal cortex, anterior cingulate, lateral parietal cortex, mid-occipital cortex, ventral striatum, dorsal caudate, and midbrain. Smoking reduced activation in anterior cingulate, left inferior frontal gyrus, and bilateral temporal poles. Activation was reduced in the ventral striatum and medial prefrontal cortex after the "far" vs. the "close" instruction, suggesting less engagement with the stimuli during distancing. The results indicate that proximal/distal regulation strategies impact cue-elicited craving, potentially via downregulation of the ventral striatum and medial prefrontal cortex, and that smoking during abstinence may increase cognitive control capacity during craving regulation.

Background

Negative emotional states contribute to cigarette smoking, and difficulties in regulating these states can hinder smoking cessation. Understanding the neural bases of these difficulties in smokers may facilitate development of novel therapies for Tobacco Use Disorder.

Methods

Thirty-seven participants (18 smokers, 19 nonsmokers; 16-21 years old) completed the Difficulties in Emotion Regulation Scale (DERS), which is comprised of 6 subscales (lack of emotional clarity, lack of emotional awareness, limited access to emotion regulation strategies, nonacceptance of emotional responses, difficulties engaging in goal-directed behaviors, and impulse control difficulties) that combine to provide a total score. Participants also underwent functional magnetic resonance imaging to determine resting-state functional connectivity of the amygdala. Separate ANOVAs were used to determine group differences in self-reports on the DERS. Voxel-wise linear mixed models were performed to determine whether group influenced relationships between whole-brain functional connectivity of the amygdala and scores on the DERS.

Results

Compared with nonsmokers, smokers reported greater difficulties in emotion regulation, denoted by higher total scores on the DERS. Group differences were observed on a subscale of lack of emotional clarity, but no other subscale differences on the DERS were observed. Nonsmokers exhibited a greater negative correlation than smokers between lack of emotional clarity scores and connectivity of the amygdala with the left inferior frontal gyrus. Finally, this amygdala-to-left inferior frontal gyrus connectivity was weaker in smokers than in nonsmokers.

Conclusions

These findings suggest that difficulties in emotion regulation in smokers are at least partially due to lack of emotional clarity. Given the role of the inferior frontal gyrus in understanding emotional states, strengthening connectivity between the amygdala and the inferior frontal gyrus may improve emotional clarity to help smokers regulate their negative emotions, thereby improving their ability to quit smoking.

Cigarette craving contributes substantially to the maintenance of tobacco use disorder. Behavioral strategies to regulate craving may facilitate smoking cessation but remain underexplored. We adapted an emotion-regulation strategy, using proximal/distal self-positioning, to the context of cigarette craving to examine craving regulation in 42, daily smokers (18-25 years old). After overnight abstinence from smoking, before and after smoking their first cigarette of the day, participants viewed videos of natural scenes presenting young adults who were either smoking cigarettes ("smoke") or not ("non-smoke"). Before each video, participants were instructed to imagine themselves either immersed in the scene ("close") or distanced from it ("far"). They rated their craving after each video. Task-based fMRI data are presented for a subsample of participants (N = 21). We found main effects of smoking, instruction, and video type on craving-lower ratings after smoking than before, following the "far" vs. "close" instructions, and when viewing non-smoke vs. smoke videos. Before smoking, "smoke" vs. "non-smoke" videos elicited activation in, orbitofrontal cortex, anterior cingulate, lateral parietal cortex, mid-occipital cortex, ventral striatum, dorsal caudate, and midbrain. Smoking reduced activation in anterior cingulate, left inferior frontal gyrus, and bilateral temporal poles. Activation was reduced in the ventral striatum and medial prefrontal cortex after the "far" vs. the "close" instruction, suggesting less engagement with the stimuli during distancing. The results indicate that proximal/distal regulation strategies impact cue-elicited craving, potentially via downregulation of the ventral striatum and medial prefrontal cortex, and that smoking during abstinence may increase cognitive control capacity during craving regulation.

Background

Although nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies.

Methods

Functional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers.

Results

Connectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal.

Conclusions

Relief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking.

Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal.

Rationale

Policies that establish a standard for reduced nicotine content in cigarettes can decrease the prevalence of smoking in the USA. Cigarettes with nicotine yields as low as 0.05 mg produce substantial occupancy of nicotinic acetylcholine receptors (26%), but women and men respond differently to these cigarettes.

Objective

This study aimed to measure responses to smoking cigarettes that varied widely in nicotine yields, investigating whether sex differences in the effects on craving, withdrawal, and affect would be observed at even lower nicotine yields than previously studied, and in young smokers.

Methods

Overnight abstinent young smokers (23 men, 23 women, mean age 22.18) provided self-reports of craving, withdrawal, and affect before and after smoking cigarettes with yields of 0.027, 0.110, 0.231, or 0.763 mg nicotine, and evaluated characteristics of each cigarette.

Results

Compared to abstinent young men, abstinent young women reported greater negative affect, psychological withdrawal, and sedation, all of which were relieved equally by all cigarettes. Men but not women reported greater craving reduction, perceived nicotine content, and cigarette liking with increasing nicotine dose.

Conclusions

Men may experience less smoking-related relief of craving, and enjoy cigarettes less, if nicotine yields are reduced to very low levels. Conversely, women respond equally well to cigarettes with nicotine yields as low as 0.027 mg as to cigarettes with nicotine yields 28-fold higher (0.763 mg). These differences are relevant for policy regarding reduced nicotine in cigarettes and may influence the efficacy and acceptability of reduced-nicotine cigarettes as smoking cessation aids.

Rationale

Policies that establish a standard for reduced nicotine content in cigarettes can decrease the prevalence of smoking in the USA. Cigarettes with nicotine yields as low as 0.05 mg produce substantial occupancy of nicotinic acetylcholine receptors (26%), but women and men respond differently to these cigarettes.

Objective

This study aimed to measure responses to smoking cigarettes that varied widely in nicotine yields, investigating whether sex differences in the effects on craving, withdrawal, and affect would be observed at even lower nicotine yields than previously studied, and in young smokers.

Methods

Overnight abstinent young smokers (23 men, 23 women, mean age 22.18) provided self-reports of craving, withdrawal, and affect before and after smoking cigarettes with yields of 0.027, 0.110, 0.231, or 0.763 mg nicotine, and evaluated characteristics of each cigarette.

Results

Compared to abstinent young men, abstinent young women reported greater negative affect, psychological withdrawal, and sedation, all of which were relieved equally by all cigarettes. Men but not women reported greater craving reduction, perceived nicotine content, and cigarette liking with increasing nicotine dose.

Conclusions

Men may experience less smoking-related relief of craving, and enjoy cigarettes less, if nicotine yields are reduced to very low levels. Conversely, women respond equally well to cigarettes with nicotine yields as low as 0.027 mg as to cigarettes with nicotine yields 28-fold higher (0.763 mg). These differences are relevant for policy regarding reduced nicotine in cigarettes and may influence the efficacy and acceptability of reduced-nicotine cigarettes as smoking cessation aids.

The use of cigarettes delivering different nicotine doses allows evaluation of the contribution of nicotine to the smoking experience. We compared responses of 46 young adult smokers to research cigarettes, delivering 0.027, 0.110, 0.231, or 0.763 mg nicotine, and conventional cigarettes. On five separate days, craving, withdrawal, affect, and sustained attention were measured after overnight abstinence and again after smoking. Participants also rated each cigarette, and the nicotine metabolite ratio (NMR) was used to identify participants as normal or slow metabolizers. All cigarettes equally alleviated craving, withdrawal, and negative affect in the whole sample, but normal metabolizers reported greater reductions of craving and withdrawal than slow metabolizers, with dose-dependent effects. Only conventional cigarettes and, to a lesser degree, 0.763-mg nicotine research cigarettes increased sustained attention. Finally, there were no differences between ratings of lower-dose cigarettes, but the 0.763-mg cigarettes and (even more so) conventional cigarettes were rated more favorably than lower-dose cigarettes. The findings indicate that smoking-induced relief of craving and withdrawal reflects primarily non-nicotine effects in slow metabolizers, but depends on nicotine dose in normal metabolizers. By contrast, relief of withdrawal-related attentional deficits and cigarette ratings depend on nicotine dose regardless of metabolizer status. These findings have bearing on the use of reduced-nicotine cigarettes to facilitate smoking cessation and on policy regarding regulation of nicotine content in cigarettes. They suggest that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to <0.763 mg/cigarette may contribute to temporary attentional deficits.

Background

Cigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person's sex influences these associations.

Methods

The research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day.

Results

Women reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P < .001). A 3-way interaction of sex, smoking condition, and right anterior circular insular sulcus thickness on craving (P = .033) reflected a negative association of cortical thickness with pre-smoking craving in women only (P = .012). No effects of cortical thickness in the left anterior circular insular sulcus were detected. Nicotine dependence was positively associated with craving (P < .001) across groups and sessions, with no sex differences in this association.

Conclusions

A negative association of right anterior insula thickness with craving in women only suggests that this region may be a relevant therapeutic target for brain-based smoking cessation interventions in women.