Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.

Identifying addicts with higher risk of relapse would provide the opportunity to implement individualized interventions and increase cessation success rates. Unfortunately, the ability to predict the long-term success of drug-cessation treatments continues to elude researchers. We tested whether brain responses to emotional and cigarette-related pictures were predictive of the ability to abstain from smoking. Smokers interested in quitting (n=180) participated in a smoking cessation clinical trial. Before the initiation of any treatment we recorded event-related potentials (ERPs) evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related images. Cluster analysis was used to assign smokers to two groups based on the amplitude of the late positive potential (LPP) to the experimental stimuli. While both groups showed enhanced responses to cigarette-related cues, one group (n=81) also showed blunted brain responses to intrinsically pleasant stimuli. Smokers in the latter group were significantly less likely to be abstinent at 10, 12, and 24 weeks after their quit date. In conclusion, using event-related potentials, a direct measure of brain activity, we found that smokers with blunted brain responses to intrinsically pleasant stimuli had lower rates of long-term smoking abstinence. This response offers a new biomarker for identifying smokers at higher risk of relapse and for testing the efficacy of new interventions aimed at normalizing brain reward systems’ responses to intrinsically pleasant stimuli.

Importance: Given the actions of varenicline tartrate and bupropion hydrochloride sustained-release (SR) on neurobiological targets related to affect and reward, it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness.Objective: To assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning.Design and Setting: Placebo-controlled randomized clinical trial at a university medical center.Participants: In total, 294 community volunteers who wanted to quit smoking.Interventions: Twelve weeks of varenicline, bupropion SR, or placebo plus intensive smoking cessation counseling (10 sessions, for a total of approximately 240 minutes of counseling).Main Outcome Measures: Prolonged abstinence from smoking and weekly measures of depression, negative affect, and other symptoms of nicotine withdrawal.Results: Significant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit, favoring both active medications compared with placebo. At the 6-month postquit follow-up visit, only the varenicline vs placebo comparison remained significant. Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments, while both active medications improved concentration, reduced craving, and decreased negative affect and sadness compared with placebo, while having little effect (increase or decrease) on anxiety and anger. No differences were noted in self-reported rates of neuropsychiatric adverse events. Conclusions and Relevance:In a community sample, varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable (suppressive) effect on symptoms of depression and other affective measures, with no clear unfavorable effect on neuropsychiatric adverse events. Trial Registration: clinicaltrials.gov Identifier: NCT00507728.

Laboratory studies have demonstrated that cigarette smokers react with significant subjective and autonomic responses (e.g., increased craving and increased heart rate) in the presence of stimuli associated with smoking. Although cue reactivity effects are typically robust, a number of methodological considerations make interpretation and design of cue reactivity studies problematic. Previous research has paid scant attention to the psychometric properties of the cigarette cues presented, and standard cues would enhance comparison and synthesis of studies. In the present study, we evaluated 12 cigarette photos (compared with positive, negative, and neutral photos), used in a separate study, for their ability to evoke self-report of craving in both nicotine-deprived and nondeprived smokers. These photos performed as expected, with cigarette pictures evoking significantly higher craving than neutral pictures and deprived smokers showing a trend toward higher craving than nondeprived smokers. The cigarette picture set was evaluated for internal consistency (Cronbach's alpha = .97) as a 12-item scale and further reduced to multiple 2-item scales with reliability estimates ranging from .70 to .93. A cluster analysis of all pictures showed that, when rated for craving, cigarette pictures clustered together, indicating they had distinct properties compared with positive, negative, and neutral pictures. Effect sizes were calculated for each cigarette picture in both deprived and nondeprived smokers. The craving effect sizes ranged from .57 to .98 for nondeprived smokers, and from .61 to .99 for deprived smokers. The analyses suggest these cigarette pictures have excellent psychometric properties for use in future cue reactivity studies.

Although converging lines of evidence suggest that nicotine and mood are related at a fundamental biological level, this link has not been reliably demonstrated in laboratory studies. In this study, startle probe methodology was used to examine the effects of nicotine administration and deprivation on emotional processes associated with motivation. Smokers (N = 115) completed four laboratory sessions crossing deprivation (12-hr deprived vs. nondeprived) with nicotine spray (active vs. placebo). Participants viewed affective pictures (positive, negative, neutral) and pictures involving cigarette cues, while startle probes were administered. Deprivation decreased startle responding to cigarette cues, suggesting an activation of appetitive processes. Nicotine administration suppressed overall startle responding during deprivation. In addition, during deprivation, random exposure to negative stimuli over two blocks of trials resulted in decreased adaptation of the startle response, suggesting that some sensitization to negative emotional cues may take place during nicotine withdrawal. These effects are consistent with formulations of addiction, stressing that withdrawal may both increase the reinforcement salience of smoking stimuli and decrease habituation to negative emotional stimuli.