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1.  Neural Substrates of Abstinence-Induced Cigarette Cravings in Chronic Smokers 
Craving is a hallmark of drug dependence, including dependence on nicotine. Many studies have examined the neural substrates of cravings elicited by smoking-related cues. Less is known about the neural basis of unprovoked, abstinence-induced cravings, despite the contributions of such cravings to smoking relapse. To fill this gap, we used arterial spin labeled (ASL) perfusion MRI to characterize the neural substrates of abstinence-induced cravings to smoke. Fifteen chronic smokers were scanned during a resting state on two separate occasions: (1) smoking satiety and (2) abstinence (following ≥ 12 hours of smoking deprivation), in counterbalanced order. Smoking abstinence state (vs. satiety) was associated with increased cerebral blood flow (CBF) in anterior cingulate cortex (ACC)/medial orbitofrontal cortex (OFC) and left OFC. Abstinence-induced cravings to smoke were predicted by CBF increases (abstinence minus satiety) in: right OFC, right dorsolateral prefrontal cortex (DLPFC), occipital cortex, ACC, ventral striatum/nucleus accumbens, thalamus, amygdala, bilateral hippocampus, left caudate, and right insula. These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse.
PMCID: PMC2153440  PMID: 18094242
Addiction; Cerebral Blood Flow; Cortex; Mesolimbic; Nicotine; Neuroimaging
2.  Effects of Varenicline on Smoking Cue–Triggered Neural and Craving Responses 
Archives of general psychiatry  2011;68(5):516-526.
Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue–elicited craving.
A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal.
Center for the Study of Addictions, University of Pennsylvania, Philadelphia.
Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated “this is not a Quit Smoking Study” and “smokers may be contemplating but not currently considering quitting.”
Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t=3.77) and elicited subjective reports of craving (P=.006). Craving reports correlated with increased activity in the posterior cingulate (t=4.11). Administration of varenicline diminished smoking cue– elicited ventral striatum and medial orbitofrontal cortex responses (t values from −3.75 to −5.63) and reduced self-reported smoking cue–elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t=5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r=−0.74).
Varenicline’s reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.
PMCID: PMC3743240  PMID: 21199958
3.  24-hr smoking abstinence potentiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum 
Psychopharmacology  2008;204(1):25-35.
Exposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence.
In the present study we evaluated the effect of 24-hr smoking abstinence on brain responses to smoking-related cues using functional magnetic resonance imaging (fMRI).
Eighteen adult smokers underwent fMRI scanning following smoking as usual (satiated condition) and following 24-hr abstinence (abstinent condition). During scanning they viewed blocks of photographic smoking and control cues.
Following abstinence, greater activation was found in response to smoking cues compared to control cues in parietal (BA 7/31), frontal (BA 8/9), occipital (BA 19) and central (BA 4) cortical regions and in dorsal striatum (putamen) and thalamus. In contrast, no smoking cue > control cue activations were observed following smoking as usual. Direct comparisons between conditions (satiated vs. abstinent) showed greater brain reactivity in response to smoking cues following abstinence. In addition, positive correlations between pre-scan craving in the abstinent condition and smoking cue activation were observed in right dorsomedial prefrontal cortex (dmPFC) including superior frontal gyrus (BA 6/10), anterior cingulate gyrus (BA 32) and supplementary motor area (BA 6).
The present findings indicate smoking abstinence significantly potentiates neural responses to smoking-related cues in brain regions subserving visual sensory processing, attention and action planning. Moreover, greater abstinence-induced craving was significantly correlated with increased smoking cue activation in dmPFC areas involved in action planning and decision making. These findings suggest that drug abstinence can increase the salience of conditioned cues which is consistent with incentive-motivation models of addiction.
PMCID: PMC2810714  PMID: 19107465
cue-reactivity; craving; nicotine dependence; fMRI; smoking; dorsal striatum
4.  Presentation of Smoking-Associated Cues Does Not Elicit Dopamine Release after One-Hour Smoking Abstinence: A [11C]-(+)-PHNO PET Study 
PLoS ONE  2013;8(3):e60382.
The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [11C]-(+)-PHNO positron emission tomography (PET) scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [11C]-(+)-PHNO binding potential (BPND) (an indirect measure of dopamine release) between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET) overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.
PMCID: PMC3612056  PMID: 23555962
5.  In vivo Brain Imaging of Human Exposure to Nicotine and Tobacco 
While most cigarette smokers endorse a desire to quit smoking, only 14–49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may result in improved pharmacological and behavioral interventions for this condition. Research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this chapter is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include reduced global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in α4β2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen (accompanied by an overall upregulation of these receptors). These findings indicate that smoking enhances neurotransmission through cortico–basal ganglia–thalamic circuits by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these and possibly other factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco-dependent smokers, such as improvements in attentional performance, mood, anxiety, and irritability.
PMCID: PMC2893588  PMID: 19184649
6.  Cue-Elicited Craving in Heroin Addicts at Different Abstinent Time: An fMRI Pilot Study 
Substance Use & Misuse  2012;47(6):631-639.
Objective: We evaluated the effect of short-term and long-term heroin abstinence on brain responses to heroin-related cues using functional magnetic resonance imaging (fMRI). Methods: Eighteen male heroin addicts following short-term abstinence and 19 male heroin addicts following long-term abstinence underwent fMRI scanning while viewing heroin-related and neutral images. Cue-elicited craving and withdrawal symptoms in the subjects were measured. Results: Following short-term abstinence, greater activation was found in response to heroin cues compared to neutral cues in bilateral temporal, occipital, posterior cingulate, anterior cingulate, thalamus, cerebellum, and left hippocampus. In contrast, activations in bilateral temporal and occipital and deactivations in bilateral frontal, bilateral parietal, left posterior cingulate, insula, thalamus, dorsal striatum, and bilateral cerebellum were observed following long-term abstinence. Direct comparisons between conditions showed greater brain reactivity in response to smoking cues following short-term abstinence. In addition, short-term abstinence had more serious withdrawal symptoms than the long-term. Conclusion: The present findings indicate that compared to short-term, long-term abstinence manifests less serious withdrawal symptoms and significantly decreases neural responses to heroin-related cues in brain regions subserving visual sensory processing, attention, memory, and action planning. These findings suggest that long-term abstinence can decrease the salience of conditioned cues, thereby reducing the risk of relapses. The study's limitations are noted.
PMCID: PMC3359800  PMID: 22329835
abstinence; cue-reactivity; craving; heroin dependence; fMRI
7.  Incubation of cue-induced cigarette craving during abstinence in human smokers 
Biological psychiatry  2011;69(7):708-711.
Abstinent drug users remain at risk for relapse long after withdrawal subsides. Animal studies indicate that responses to drug-related cues not only persist, but increase, with abstinence, a phenomenon termed “incubation of drug craving”. It is unknown if cue-induced craving increases, decreases, or remains constant with abstinence in humans. We investigated effects of abstinence on cue-induced craving in cigarette smokers.
Eighty-six non-treatment-seeking, adult smokers (≥ 10 cigarettes daily) were paid to abstain for 7 (Group 1), 14 (Group 2), or 35 (Groups 3, 4) days. Abstinence was verified daily. Groups 1, 2, and 3 underwent a single cue session on the final abstinence day (7, 14, or 35). Group 4 viewed cues on days 7, 14, and 35.
Between and within groups, smoking-cue-induced craving increased with abstinence on some measures. Cue-induced craving was greater in Group 3 (35-day) compared to Group 1 (7-day). Within Group 4, cue-induced craving was greater at 35 than 14 days. Cue-induced craving did not decrease with abstinence on any measure.
We present initial evidence of incubation of cue-induced craving in humans. The observation that cue-induced craving increases with abstinence, even as “background” craving and withdrawal symptoms subside, may have treatment implications.
PMCID: PMC3027849  PMID: 20817135
cue-induced craving; incubation of craving; addiction; relapse; cigarette smoking
8.  Smoking Withdrawal in Smokers With and Without Posttraumatic Stress Disorder 
Nicotine & Tobacco Research  2011;14(3):372-376.
Previous research on smoking withdrawal in posttraumatic stress disorder (PTSD) has been limited by the use of retrospective and observational methods and has lacked repeated assessments on the first day of abstinence and evaluation of the conditioned effects of smoking.
Smokers with (n = 17; 59% female) and without (n = 30; 17% female) PTSD completed 3 randomly ordered experimental sessions using a 2 (group: PTSD vs. non-PTSD) × 3 (smoking condition: usual brand vs. nicotine free vs. no smoking) design. Before the smoking manipulation, participants completed self-report measures of smoking urges and withdrawal, followed by withdrawal assessment after the smoking manipulation.
Compared with smokers without PTSD, smokers with PTSD exhibited higher craving (χ12 = 16.60, p < .001) and habit withdrawal (χ12 = 10.38, p = .001) following overnight abstinence. PTSD smokers also exhibited worsening negative affect throughout the morning when not smoking a cigarette (χ12 = 11.30, p = .004). After smoking, smokers with PTSD reported diminished relief from craving (χ12 = 6.49, p = .011), negative affect (χ12 = 4.51, p = .034), arousal (χ12 = 6.46, p = .011), and habit withdrawal (χ12 = 7.22, p = .007), relative to smokers without PTSD.
Results of this preliminary investigation suggested that after overnight abstinence, PTSD smokers experienced worse withdrawal symptoms and greater urges to smoke for both positive and negative reinforcement. Research on smoking withdrawal early in the course of smoking abstinence in PTSD could inform interventions targeting abstinence early in the quit attempt.
PMCID: PMC3281234  PMID: 22025546
9.  Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at:
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website:
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website:
The objective of this evidence-based analysis was to determine the effectiveness and cost-effectiveness of smoking cessation interventions in the management of chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Tobacco smoking is the main risk factor for COPD. It is estimated that 50% of older smokers develop COPD and more than 80% of COPD-associated morbidity is attributed to tobacco smoking. According to the Canadian Community Health Survey, 38.5% of Ontarians who smoke have COPD. In patients with a significant history of smoking, COPD is usually present with symptoms of progressive dyspnea (shortness of breath), cough, and sputum production. Patients with COPD who smoke have a particularly high level of nicotine dependence, and about 30.4% to 43% of patients with moderate to severe COPD continue to smoke. Despite the severe symptoms that COPD patients suffer, the majority of patients with COPD are unable to quit smoking on their own; each year only about 1% of smokers succeed in quitting on their own initiative.
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. Smoking cessation can help to slow or halt the progression of COPD. Smoking cessation programs mainly target tobacco smoking, but may also encompass other substances that can be difficult to stop smoking due to the development of strong physical addictions or psychological dependencies resulting from their habitual use.
Smoking cessation strategies include both pharmacological and nonpharmacological (behavioural or psychosocial) approaches. The basic components of smoking cessation interventions include simple advice, written self-help materials, individual and group behavioural support, telephone quit lines, nicotine replacement therapy (NRT), and antidepressants. As nicotine addiction is a chronic, relapsing condition that usually requires several attempts to overcome, cessation support is often tailored to individual needs, while recognizing that in general, the more intensive the support, the greater the chance of success. Success at quitting smoking decreases in relation to:
a lack of motivation to quit,
a history of smoking more than a pack of cigarettes a day for more than 10 years,
a lack of social support, such as from family and friends, and
the presence of mental health disorders (such as depression).
Research Question
What are the effectiveness and cost-effectiveness of smoking cessation interventions compared with usual care for patients with COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on June 24, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations (1950 to June Week 3 2010), EMBASE (1980 to 2010 Week 24), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, and the Centre for Reviews and Dissemination for studies published between 1950 and June 2010. A single reviewer reviewed the abstracts and obtained full-text articles for those studies meeting the eligibility criteria. Reference lists were also examined for any additional relevant studies not identified through the search. Data were extracted using a standardized data abstraction form.
Inclusion Criteria
English-language, full reports from 1950 to week 3 of June, 2010;
either randomized controlled trials (RCTs), systematic reviews and meta-analyses, or non-RCTs with controls;
a proven diagnosis of COPD;
adult patients (≥ 18 years);
a smoking cessation intervention that comprised at least one of the treatment arms;
≥ 6 months’ abstinence as an outcome; and
patients followed for ≥ 6 months.
Exclusion Criteria
case reports
case series
Outcomes of Interest
≥ 6 months’ abstinence
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Nine RCTs were identified from the literature search. The sample sizes ranged from 74 to 5,887 participants. A total of 8,291 participants were included in the nine studies. The mean age of the patients in the studies ranged from 54 to 64 years. The majority of studies used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD staging criteria to stage the disease in study subjects. Studies included patients with mild COPD (2 studies), mild-moderate COPD (3 studies), moderate–severe COPD (1 study) and severe–very severe COPD (1 study). One study included persons at risk of COPD in addition to those with mild, moderate, or severe COPD, and 1 study did not define the stages of COPD. The individual quality of the studies was high. Smoking cessation interventions varied across studies and included counselling or pharmacotherapy or a combination of both. Two studies were delivered in a hospital setting, whereas the remaining 7 studies were delivered in an outpatient setting. All studies reported a usual care group or a placebo-controlled group (for the drug-only trials). The follow-up periods ranged from 6 months to 5 years. Due to excessive clinical heterogeneity in the interventions, studies were first grouped into categories of similar interventions; statistical pooling was subsequently performed, where appropriate. When possible, pooled estimates using relative risks for abstinence rates with 95% confidence intervals were calculated. The remaining studies were reported separately.
Abstinence Rates
Table ES1 provides a summary of the pooled estimates for abstinence, at longest follow-up, from the trials included in this review. It also shows the respective GRADE qualities of evidence.
Summary of Results*
Abbreviations: CI, confidence interval; NRT, nicotine replacement therapy.
Statistically significant (P < 0.05).
One trial used in this comparison had 2 treatment arms each examining a different antidepressant.
Based on a moderate quality of evidence, compared with usual care, abstinence rates are significantly higher in COPD patients receiving intensive counselling or a combination of intensive counselling and NRT.
Based on limited and moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving NRT compared with placebo.
Based on a moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving the antidepressant bupropion compared to placebo.
PMCID: PMC3384371  PMID: 23074432
10.  Abstinence-Induced Changes in Self-Report Craving Correlate with Event-Related fMRI Responses to Smoking Cues 
Drug cues have been shown to activate brain regions involved in attention, motivation, and reward in addicted users. However, as studies have typically measured responses in only one state (ie drug abstinence), it is unclear whether observed activations represent amplification by abstinence or stable responses. Thus, the present study was designed to evaluate the stability of event-related responses to visual drug cues in dependent smokers (n = 13) using event-related functional magnetic resonance imaging measures. Imaging was conducted following smoking as usual and following overnight abstinence, and self-reported craving measures were obtained before, during, and after scanning. Analysis of hemodynamic response (HDR) amplitudes in each of 13 regions of interest revealed larger responses to smoking compared to control cues in ventral anterior cingulate gyrus (vACG) and superior frontal gyrus. Responses to smoking cues in these and all other regions revealed no effects of abstinence/satiety, thus supporting the notion that cue-elicited brain responses are relatively stable. However, while the abstinence manipulation did not alter group-level responses to smoking cues, at the individual level, abstinence-induced changes in craving (abstinence minus satiety) were positively correlated with changes in HDR amplitude to smoking cues in frontal regions including left inferior frontal gyrus, left vACG, and bilateral middle frontal gyrus. These results suggest that brain responses to smoking cues, while relatively stable at the group level following short-term abstinence, may be modulated by individual differences in craving in response to abstinence—particularly in regions subserving attention and motivation.
PMCID: PMC1571136  PMID: 15920499
magnetic resonance imaging; tobacco use disorder; smoking
11.  Sex Differences in Negative Affect and Lapse Behavior During Acute Tobacco Abstinence: A Laboratory Study 
Heightened negative affect during acute tobacco abstinence in women relative to men could be an important factor underlying sex differences in smoking motivation. However, little controlled experimental work addresses this hypothesis. The current study investigated sex differences in withdrawal-related negative affect, time to start smoking on a lab analogue smoking lapse task, and the interrelation between sex, withdrawal-related negative affect, and smoking lapse behavior. Following a baseline session, current smokers (women: n = 68, men: n = 131) attended two counterbalanced lab sessions (16 hours smoking abstinence and ad libitum smoking) during which they completed self-report measures of mood and withdrawal symptoms followed by a laboratory analogue smoking lapse task. In this task participants are monetarily rewarded for delaying smoking. Performance on this task serves as an analogue model of smoking lapse behavior by measuring smoker’s capability to resist temptation to smoke under conditions where abstinence is advantageous. Females showed greater abstinence induced increases in composite negative affect as well as several particular negative affect states (i.e., POMS Anger, Anxiety, Depression, and Confusion, ps < .05) but no differences in abstinence induced changes in other forms of affect or craving. Females also exhibited marginally greater abstinence induced decreases in their willingness to delay smoking for money (p = .10), which was mediated by abstinence induced increases in anger (p < .05). These results suggest that differential sensitivity to abstinence induced negative affect, particularly anger, could underlie sex specific smoking patterns. Negative affect during tobacco abstinence may be an important factor for understanding and treating nicotine addiction in women.
PMCID: PMC3962304  PMID: 23834551
sex differences; negative affect; nicotine withdrawal; abstinence; smoking
12.  Functional brain imaging of tobacco use and dependence 
Journal of psychiatric research  2005;40(5):404-418.
While most cigarette smokers endorse a desire to quit smoking, only about 14% to 49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may (in conjunction with other lines of research) result in improved pharmacological (and behavioral) interventions. Many research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this paper is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include: a reduction in global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in α4β2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen. Taken together, these findings indicate that smoking enhances neurotransmission through cortico-basal ganglia-thalamic circuits either by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco dependent subjects, such as improvements in attentional performance, mood, anxiety, and irritability.
PMCID: PMC2876087  PMID: 15979645
Tobacco dependence; Functional magnetic resonance imaging; Positron emission tomography; Autoradiography; Prefrontal cortex; Review
13.  Smoking-Cue Induced Brain Activation In Adolescent Light Smokers 
Using fMRI, we examined whether or not adolescents with low levels of nicotine exposure (light smokers) display neural activation in areas shown to be involved with addiction in response to smoking-related stimuli.
Twelve adolescent light smokers (aged 13 to17, smoked 1 to 5 cigarettes per day) and 12 non-smokers (ages 13 to 17, never smoked a cigarette) from the San Francisco Bay Area underwent fMRI scanning. During scanning they viewed blocks of photographic smoking and control cues. Smoking cues consisted of pictures of people smoking cigarettes and smoking-related objects such as lighters and ashtrays. Neutral cues consisted of everyday objects and people engaged in everyday activities.
For smokers, smoking cues elicited greater activation than neutral cues in the mesolimbic reward circuit (left anterior cingulate (T=7.88, p<.001), right hippocampus (T=6.62, p<.001) and right parahippocampal gyrus (T=4.70, p<.001)). We found activation from smoking cues versus neutral cues within both the left and right frontal medial orbital regions (T=5.09, p<.001 and T=3.94, p=.001 respectively), which may be unique to adolescents. Non-smokers showed no significant difference in activation between smoking-related cues and neutral cues.
Our finding that smoking cues produced activation in adolescent light smokers in brain regions seen in adult and heavy teen smokers suggests that even at low levels of smoking, adolescents exhibit heightened reactivity to smoking cues. This paper adds to the existing literature suggesting that nicotine dependence may begin with exposure to low levels of nicotine, underscoring the need for early intervention among adolescent smokers.
PMCID: PMC3058837  PMID: 21185518
fMRI; adolescent nicotine addiction; adolescent smoking; brain imaging
14.  Smoking History, Nicotine Dependence, and Changes in Craving and Mood during Short-Term Smoking Abstinence in Alcohol Dependent vs. Control Smokers 
Addictive behaviors  2010;36(3):244-247.
The goal of this study was to compare lifetime cigarette smoking, severity of nicotine dependence, and subjective effects of short-term tobacco abstinence in abstinent alcohol dependent (AD) and control smokers.
AD (n=119) and control (n=55) ever smokers were compared on tobacco use history and nicotine dependence. Negative affect and craving to smoke were examined in a subsample of currently smoking AD (N=34) and control (N=19) participants during a six-hour period of tobacco abstinence using the Profile of Mood States (POMS) and the Questionnaire on Smoking Urges-Brief (QSU-B).
Although AD smokers did not differ from controls on heaviness of smoking, they were more likely to meet lifetime criteria for nicotine dependence. AD smokers also reported more withdrawal symptoms and were more likely to endorse withdrawal-related depressed mood during past smoking reduction or abstinence periods. During short-term abstinence, AD smokers were more likely to report high craving to smoke for negative affect relief within the first 150 minutes of tobacco abstinence, but did not differ from controls on overall craving to smoke or withdrawal-related negative affect on the POMS.
Results support previous findings that AD smokers have a greater prevalence of nicotine dependence and more severe nicotine withdrawal, with a greater propensity toward withdrawal-related depressed mood. These results, along with our novel finding that greater craving to smoke in abstaining smokers with AD is specific to negative affect-related craving, suggest that negative reinforcement may be a particularly salient factor in the maintenance of tobacco use among individuals with AD.
PMCID: PMC3021180  PMID: 21106299
tobacco; withdrawal; comorbidity
15.  Effects of acute tobacco abstinence in adolescent smokers as compared with nonsmokers 
Abstinence effects such as nicotine withdrawal and mood changes contribute to the maintenance of cigarette smoking in adult smokers and emerging reports on adolescent smokers suggest they may experience similar subjective effects when deprived. This study aimed to prospectively document tobacco abstinence induced changes during the first 48 hours of abstinence in adolescent smokers compared with nonsmokers, to distinguish effects distinct from typical adolescent lability.
57 adolescent smokers and 44 adolescent nonsmokers were assessed during a 48 hour inpatient session. Characteristic nicotine withdrawal symptoms, cravings for cigarettes, and mood symptoms were measured at 13 time points following initiation of abstinence.
The only abstinence related effects observed were changes in craving for tobacco and feelings of anger. Tobacco craving increased and peaked quickly following initiation of abstinence and displayed a slight decrease towards the end of the 48 hour abstinence period, while anger symptoms peaked after more prolonged abstinence. Overall, smokers’ symptoms and cravings were positively associated with amount of daily smoking but not with reports of dependence or biological measures of extent of use.
We observed that among adolescent smokers, the primary effects associated with abstinence from cigarettes are relatively minimal and include a heightened and persistent craving to smoke and increases in anger. Although smokers had greater negative mood symptoms compared with nonsmokers, the presence and severity of most of these symptoms appear to be minimally altered by abstinence and not associated with dependency or biological indicators of amount of tobacco use.
PMCID: PMC2527725  PMID: 18565437
16.  Effects of smoking abstinence on smoking-reinforced responding, withdrawal, and cognition in adults with and without attention deficit hyperactivity disorder 
Psychopharmacology  2012;227(1):19-30.
Individuals with attention deficit hyperactivity disorder (ADHD) have a more difficult time quitting smoking compared to their non-ADHD peers. Little is known about the underlying behavioral mechanisms associated with this increased risk.
This study aims to assess the effects of 24-h smoking abstinence in adult smokers with and without ADHD on the following outcomes: smoking-reinforced responding, withdrawal, and cognitive function.
Thirty-three (n=16 with ADHD, 17 without ADHD) adult smokers (more than or equal to ten cigarettes/day) were enrolled. Each participant completed two experimental sessions: one following smoking as usual and one following biochemically verified 24-h smoking abstinence. Smoking-reinforced responding measured via a progressive ratio task, smoking withdrawal measured via questionnaire, and cognition measured via a continuous performance test (CPT) were assessed at each session.
Smoking abstinence robustly increased responding for cigarette puffs in both groups, and ADHD smokers responded more for puffs regardless of condition. Males in both groups worked more for cigarette puffs and made more commission errors on the CPT than females, regardless of condition. Smoking abstinence also increased ratings of withdrawal symptoms in both groups and smokers with ADHD, regardless of condition, reported greater symptoms of arousal, habit withdrawal, and somatic complaints. Across groups, smoking abstinence decreased inhibitory control and increased reaction time variability on the CPT. Abstinence-induced changes in inhibitory control and negative affect significantly predicted smoking-reinforced responding across groups.
Smokers with ADHD reported higher levels of withdrawal symptoms and worked more for cigarette puffs, regardless of condition, which could help explain higher levels of nicotine dependence and poorer cessation outcomes in this population. Abstinence-induced changes in smoking-reinforced responding are associated with changes in inhibitory control and negative affect regardless of ADHD status, a finding that may lead to novel prevention and treatment programs.
PMCID: PMC3624067  PMID: 23247366
ADHD; Nicotine; Reinforcement; Self-administration
17.  Nicotine content and abstinence state have different effects on subjective ratings of positive versus negative reinforcement from smoking 
Despite the well-known adverse health consequences of smoking, approximately 20% of US adults smoke tobacco cigarettes. Much of the research on smoking reinforcement and the maintenance of tobacco smoking behavior has focused on nicotine; however, a number of other non-nicotine factors are likely to influence the reinforcing effects of smoked tobacco. A growing number of studies suggest that non-nicotine factors, through many pairings with nicotine, are partially responsible for the reinforcing effect of smoking. Additionally, both clinical studies and preclinical advances in our understanding of nicotinic receptor regulation suggest that abstinence from smoking may influence smoking reinforcement. These experiments were conducted for 2 reasons: to validate a MRI-compatible cigarette smoking device; and to simultaneously investigate the impact of nicotine, smoking-associated conditioned reinforcers, and smoking abstinence state on subjective ratings of smoking reinforcement. Participants smoked nicotine and placebo cigarettes through an fMRI compatible device in an overnight-abstinent state or in a nonabstinent state, after having smoked a cigarette 25 minutes prior. Outcome measures were within-subject changes in physiology and subjective ratings of craving and drug effect during the smoking of nicotine or placebo cigarettes on different days in both abstinence states. Cigarette type (nicotine vs. placebo) had a significant effect on positive subjective ratings of smoking reinforcement (“High”, “Like Drug”, “Feel Drug”; nicotine>placebo). In contrast, abstinence state was found to have significant effects on both positive and negative ratings of smoking reinforcement (“Crave”, “Anxiety”, “Irritability”; abstinence > nonabstinence). Interaction effects between abstinence and nicotine provide clues about the importance of neuroadaptive mechanisms operating in dependence, as well as the impact of conditioned reinforcement on subjective ratings of smoking-induced high.
PMCID: PMC3565023  PMID: 23219727
nicotine; smoking; placebo; abstinence; subjective ratings; conditioned reinforcement
18.  Generalized craving, self-report of arousal, and cue reactivity after brief abstinence 
Nicotine & Tobacco Research  2009;11(7):823-826.
Numerous studies report smokers’ increased craving and physiological arousal when exposed to cigarette stimuli. These responses are attributed to learning processes (e.g., classical conditioning) and are associated with motivational factors that maintain nicotine dependence. However, much less is known about the degree to which these responses are maintained or diminished during quitting.
Treatment-seeking smokers (N = 104) were randomly assigned to continue smoking or to enter a 2-week treatment program. Abstainers (n = 25) were continuously abstinent for 14–17 days at the time of testing. Control subjects (n = 38) continued to smoke at their usual rate. Participants who were assigned to treatment but resumed smoking during the study (n = 41) were considered to be relapsers. Approximately 2 weeks after baseline measurements, abstainers and controls viewed a series of neutral (n = 12) and cigarette (n = 12) pictures, rating them for craving and arousal (feelings of calm vs. excitement).
Non-cued craving (measured during exposure to neutral cues) was diminished in abstaining smokers. However, cigarette cues produced craving increases of the same magnitude in both abstainers and controls, showing that these cues still had evocative power for both groups. Abstaining smokers, who were not physiologically monitored, had lower self-reports of arousal to cigarette pictures than did controls, but the groups did not differ in arousal to neutral pictures.
These findings suggest that the foundations of cue-induced craving, generalized craving, and physiological arousal associated with craving may arise from separate processes.
PMCID: PMC2699928  PMID: 19477914
Addictive behaviors  2012;38(2):1527-1531.
Negative mood situations increase craving to smoke, even in the absence of any tobacco deprivation (e.g. “stressors”). Individual differences in effects of negative mood situations on craving have received relatively little attention but may include variability between men and women. Across two separate within-subjects studies, we examined sex differences in craving (via the QSU-brief) as functions of brief smoking abstinence (versus satiation; Study 1) and acute induction of negative mood (versus neutral mood; Study 2). Subjective ratings of negative affect (via the Mood Form) were also assessed. In study 1, we compared the effects of overnight (>12 hr) abstinence versus non-abstinence on craving and affect in adult male (n=63) and female (n=42) smokers. In study 2, these responses to negative versus neutral mood induction (via pictorial slides and music) were examined in male (n=85) and female (n=78) satiated smokers. Results from each study were similar in showing that craving during the abstinence and negative mood induction conditions was greater in women than men, as hypothesized, although the sex difference in craving due to abstinence was only marginal after controlling for dependence. Craving was strongly associated with negative affect in both studies. These results suggest that very acute negative mood situations (e.g. just a few minutes in Study 2), and perhaps overnight abstinence, may increase craving to smoke to a greater extent in women relative to men.
PMCID: PMC3462895  PMID: 22726579
sex; abstinence; negative mood; craving; affect; smoking
20.  Brain fMRI Responses to Smoking-Related Images Prior to and During Extended Smoking Abstinence 
Reactivity to smoking-related cues may play a role in the maintenance of smoking behavior and may change depending on smoking status. Whether smoking cue-related functional MRI (fMRI) reactivity differs between active smoking and extended smoking abstinence states currently is unknown.
We used fMRI to measure brain reactivity in response to smoking-related versus neutral images in 13 tobacco-dependent subjects prior to a smoking cessation attempt and again during extended smoking abstinence (52 ± 11 days) aided by nicotine replacement therapy.
Pre-quit smoking cue induced fMRI activity patterns paralleled those reported in prior smoking cue reactivity fMRI studies. Greater fMRI activity was detected during extended smoking abstinence than during the pre-quit assessment subcortically in the caudate nucleus and cortically in prefrontal (BA 6, 9, 44, 46), primary somatosensory (BA 1,2,3), temporal (BA 22, 41, 42), parietal (BA 7, 40) anterior cingulate (BA 24, 32), and posterior cingulate (BA 31) cortex.
These data suggest that during extended smoking abstinence, fMRI reactivity to smoking versus neutral stimuli persists in brain areas involved in attention, somatosensory processing, motor planning, and conditioned cue responding. In some brain regions, fMRI smoking cue reactivity is increased during extended smoking abstinence in comparison to the pre-quit state, which may contribute to persisting relapse vulnerability.
PMCID: PMC3742373  PMID: 19968401
abstinence; addiction; caudate nucleus; fMRI; nicotine
21.  Effects of Acute Abstinence, Reinstatement, and Mecamylamine on Biochemical and Behavioral Measures of Cigarette Smoking in Schizophrenia 
Schizophrenia research  2007;91(1-3):217-225.
Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. We compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting.
Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/day × 3 days) in a randomized, counterbalanced manner.
Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement.
1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS.
PMCID: PMC1913717  PMID: 17293085
nicotinic acetylcholine receptor; mecamylamine; cigarette smoking; nicotine withdrawal; tobacco craving; schizophrenia
22.  Sex differences in availability of β2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers 
Archives of general psychiatry  2012;69(4):418-427.
Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and in response to nicotine replacement therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β2 subunit (β2*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women and men.
To examine β2*-nAChR availability between male and female smokers and nonsmokers. To determine relationships between β2*-nAChR availability and tobacco smoking characteristics and female sex steroid hormones.
Male (n=26) and female (n=28) tobacco smokers participated in one [123I]5-IA-85380 ([123I]5-IA) single photon emission computed tomography (SPECT) scan at 7–9 days of abstinence. Age-matched male (n=26) and female (n=30) nonsmokers participated in a single [123I]5-IA SPECT scan. All participants completed 1 magnetic resonance imaging study.
Academic Imaging Center
Tobacco smokers (n=54) and age- and sex-matched nonsmokers (n=56).
Main Outcome Measure
[123I]5-IA SPECT images were converted to equilibrium distribution volumes and analyzed using regions-of-interest.
β2*-nAChR availability was significantly higher in male smokers compared to male nonsmokers in striatum, cortex and cerebellum, but female smokers did not have higher β2*-nAChR availability than female nonsmokers in any region. In women, β2*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the day of the scan. In female smokers, on the day of the scan, progesterone levels were positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal.
The regulatory effects of nicotine in the brain, i.e., tobacco-smoking induced upregulation of β2*-nAChRs, appear to be distinctly different between men and women, and female sex hormones likely play a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. In order to treat female smokers more effectively, it is critical that non-nicotinic mediated medications are explored.
PMCID: PMC3508698  PMID: 22474108
β2-nicotinic acetylcholine receptor; SPECT; tobacco smoking; sex difference; progesterone; nicotine
23.  Intentional Modulation of the Late Positive Potential in Response to Smoking Cues by Cognitive Strategies in Smokers 
PLoS ONE  2011;6(11):e27519.
Attentional bias is considered an important concept in addiction since it has been found to correlate with subjective craving and is strongly associated with relapse after periods of abstinence. Hence, investigating in ways to regulate attention for drug cues would be of major clinical relevance. The present study examined deliberate, cognitive modulation of motivated attention for smoking cues in smokers. The effects of three different reappraisal strategies on an electrophysiological measure of attentive processing were investigated. Early and late LPP components in response to passively viewed neutral and smoking pictures were compared with LPPs in response to smoking pictures that were reappraised with three different reappraisal strategies. Results show that when smokers actively imagine how pleasant it would be to smoke (pleasant condition), their early LPP in response to smoking cues increases, but when smokers actively focus on an alternative stimulus (distraction condition) or think of a rational, uninvolved interpretation of the situation (rational condition), smoking-related late LPP amplitude decreases to the processing level of neutral stimuli. Present results are the first to indicate that smoking cue-elicited LPP amplitudes can be modulated by cognitive strategies, suggesting that attentive processing of smoking cues can be intentionally regulated by smokers with various levels of dependence. Although cognitive strategies can lead to enhanced processing of smoking cues, it is not completely clear whether cognitive strategies are also successful in reducing smoking-related motivated attention. Although findings do point in this direction, present study is best considered preliminary and a starting point for other research on this topic. A focus on the distraction strategy is proposed, as there are indications that this strategy is more successful than the rational strategy in decreasing LPP amplitude.
PMCID: PMC3210181  PMID: 22087333
24.  Examining the effects of initial smoking abstinence on response to smoking-related stimuli and response inhibition in a human laboratory model 
Psychopharmacology  2013;231(10):2145-2158.
Research is needed on initial smoking abstinence and relapse risk.
This study aims to investigate the effects of different durations of initial abstinence on sensitivity to smoking-related stimuli and response inhibition in the context of a larger battery of outcome measures.
Smokers were randomly assigned to receive payment contingent on smoking abstinence across all 15 study days (15C) or just the final 2 days (2C). Smoking status and subject ratings were assessed daily. Participants completed fMRI sessions at baseline and day 14 during which they completed craving ratings after exposure to smoking-related and neutral stimuli and performed a response inhibition task. On day 15, participants completed a smoking preference session involving 20 exclusive choices between smoking and money.
The payment contingencies were effective in producing greater smoking abstinence in the 15C vs. 2C conditions. Ratings of withdrawal decreased, while ratings of ease and confidence in abstaining increased in the 15C vs. 2C conditions across the 15-day study. 15C participants were less likely to choose the smoking option in the preference session. 15C participants reported greater reductions in craving compared to the 2C participants in the presence of smoking-related and neutral stimuli (i.e., decreases in generalized craving), but no differences were noted in cue reactivity per se or in response inhibition.
Results systematically replicate prior observations that a period 2 weeks of initial abstinence decreases the relative reinforcing effects of smoking and improves other outcomes associated with relapse risk compared to the initial day or two of a cessation effort, and extends them by underscoring the importance of generalized rather than cue-induced craving in relation to relapse risk during the initial weeks of smoking cessation.
PMCID: PMC4123458  PMID: 24337077
Cigarette smoking; Abstinence; Reinforcement; Nicotine withdrawal; Craving; Contingency management; Financial incentives; Cue reactivity; Response inhibition
25.  Ventral Striatal Dopamine Release in Response to Smoking a Regular vs a Denicotinized Cigarette 
Prior studies have demonstrated that both nicotine administration and cigarette smoking lead to dopamine (DA) release in the ventral striatum/nucleus accumbens. In tobacco-dependent individuals, smoking denicotinized cigarettes leads to reduced craving, but less pleasure, than smoking regular cigarettes. Using denicotinized cigarettes and 11C-raclopride positron emission tomography (PET) scanning, we sought to determine if nicotine is necessary for smoking-induced DA release. Sixty-two tobacco-dependent smokers underwent 11C-raclopride PET scanning, during which they smoked either a regular or denicotinized cigarette (double-blind). Change in 11C-raclopride binding potential (BP) in the ventral striatum from before to after smoking was determined as an indirect measure of DA release. Cigarette craving, anxiety, and mood were monitored during scanning. Smoking a regular cigarette resulted in a significantly greater mean reduction in ventral striatal 11C-raclopride BP than smoking a denicotinized cigarette. Although both groups had reductions in craving and anxiety with smoking, the regular cigarette group had a greater improvement in mood. For the total group, change in BP correlated inversely with change in mood, indicating that greater smoking-induced DA release was associated with more smoking-related mood improvement. Thus, nicotine delivered through cigarette smoking appears to be important for ventral striatal DA release. Study findings also suggest that mood improvement from smoking is specifically related to ventral striatal DA release.
PMCID: PMC2777990  PMID: 18563061
dopamine; nicotine; tobacco; ventral striatum; positron emission tomography; 11C-raclopride

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