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CORK Bibliography: Craving and Drugs

54 citations. January 2007 to present

Prepared: March 2008

Alisky JM. Cholinesterase inhibitors might alleviate methamphetamine-induced delusions, hallucinations and cognitive impairment, while reducing craving and addiction. (letter). World Journal of Biological Psychiatry 7(4): 269-269, 2006. (5 refs.)

Allen SS; Bade T; Hatsukami D; Center B. Craving, withdrawal, and smoking urges on days immediately prior to smoking relapse. Nicotine & Tobacco Research 10(1): 35-45, 2008. (76 refs.)

Rates of smoking relapse remain high, despite the wide availability of cessation aids. Presumably factors such as craving, withdrawal symptoms, and smoking urges are key contributors to relapse, but empirical support for this presumption is not conclusive and is complicated by the high variability in symptoms across individuals and time, as well as by the lack of an absolute symptom threshold for response. Data were analyzed from 137 female smokers, aged 18-40 years, who completed 30 days of a protocol for a longitudinal smoking cessation trial. Subjects were assigned a quit date and followed regardless of subsequent smoking status. At baseline, subjects completed written measures of nicotine craving, withdrawal symptoms, and smoking urges. They also completed these measures daily for 30 days, beginning on their quit date, Scores were standardized within subjects and graphed to identify temporal symptom patterns. A total of 26 women quit smoking and 111 relapsed (at least one cigarette puff). The intensity of subjects' craving, withdrawal, and smoking urges Factors 1 and 2 peaked on the day of relapse by an average of 1.4, 1.1, 1.2, and 1.1 standard deviations, respectively, with symptoms rising during the previous 2-5 days and dropping precipitously over the 2 days subsequent to relapse. Additionally, women who relapsed had higher absolute (unstandardized) symptom scores on their quit day than those who were abstinent for 30 days. These findings imply that escalation of withdrawal symptoms, craving, and smoking urges during a quit attempt may contribute to smoking relapse. Frequent symptom monitoring might be clinically important for relapse prevention.

Andreou C. Making a clean break: Addiction and Ulysses contracts. Bioethics 22(1): 25-31, 2008. (14 refs.)

I examine current models of self-destructive addictive behaviour, and argue that there is an important place for Ulysses contracts in coping with addictive behaviour that stems from certain problematic preference structures. Given the relevant preference structures, interference based on a Ulysses contract need not involve questionably favouring an agent's past preferences over her current preferences, but can actually be justified in terms of the agent's current concerns and commitments. Note: A Ulysses contract refers to the Homer's Odyssey and the occassion when Ulysses instructed others to tie him to the mast of the ship so that he would not be able to lured by the songs of the Sirens. Thus, this article deals with an individuals efforts to involve others to help them cope with addictive desires, even when in the moment of craving this agreement may be denounced.

Beckham JC; Dennis MF; McClernon FJ; Mozley SL; Collie CF; Vrana SR. The effects of cigarette smoking on script-driven imagery in smokers with and without posttraumatic stress disorder. Addictive Behaviors 32(12): 2900-2915, 2007. (65 refs.)

The study investigated the effects of smoking a nicotinized or denicotinized cigarette on craving, affect and posttraumatic stress disorder (PTSD) symptoms while recalling neutral, stressful and traumatic events in smokers with and without PTSD. Smokers completed laboratory sessions during which they were presented with audiotapes of personalized scripts followed by smoking a cigarette. The effect of the script and cigarette conditions on dependent variables was evaluated. There was a main effect of script type across groups for smoking craving, negative affect and PTSD symptoms, with increased symptoms in trauma and stressful conditions. Responses were significantly higher in PTSD smokers. Smoking either cigarette type resulted in decreased craving, negative affect and PTSD symptoms in both groups. A second script presentation following smoking elicited similar responses, suggesting the ameliorative effect of having smoked a cigarette was short-lived. These results support that context and non-pharmacologic effects of smoking are important variables in smoking craving and mood, particularly in smokers with PTSD.

Billieux J; Van der Linden M; Ceschi G. Which dimensions of impulsivity are related to cigarette craving? Addictive Behaviors 32(6): 1189-1199, 2007. (60 refs.)

Cigarette smoking is a very important health problem and represents the largest preventable risk factor for premature death in developed countries. A considerable body of research indicates that impulsivity is a central etiological concept in many theoretical models of tobacco addiction. The aim of this study is to analyse which dimensions of impulsivity are related to cigarette craving. To this end, 40 undergraduate psychology students were screened using the revised Questionnaire on Smoking Urges (QSU-12) and the French adaptation of the UPPS Impulsive Behavior Scale (UPPS). This scale identifies four distinct components associated with impulsive behaviour: urgency, lack of premeditation, lack of perseverance, and sensation seeking. The results showed that urgency is a significant predictor of tobacco cravings, while depression and anxiety are not.

Bruehl AM; Lende DH; Schwartz M; Sterk CE; Elifson K. Craving and control: Methamphetamine users' narratives. Journal of Psychoactive Drugs Supplement 3: 385-392, 2006. (46 refs.)

In this article the authors explore the experience of craving of methamphetamine users and seek to illuminate how differences in craving contribute to use patterns. Using in-depth interviewing, data were collected from 82 active methamphetamine users in the metropolitan Atlanta area. The constant comparison method common in grounded theory guided the data analysis. Narrative responses corresponded with three types of craving described in the literature: cue-, drug- and withdrawal-induced. However, the narratives also problematize this typological view as well as the characterization of craving as invariably leading to drug use. Types of craving cues were sometimes inseparable, and users indicated that the different types of craving could occur in the same situation. Further, many users described being able to overcome craving through personalized methods of control. This study complements the largely quantitative work on craving and highlights the importance of improving drug abuse treatment and harm reduction programs.

Cabioglu MT; Ergene N; Tan U. Smoking cessation after acupuncture treatment. International Journal of Neuroscience 117(5): 571-578, 2007. (30 refs.)

Acupuncture is applied, especially in treatment of pain, hemiplegia, obesity, and psychological illnesses including addiction. Recently, ear and body acupuncture have been frequently used in the treatment of smoking. An increase in levels of endorphin, enkephalin, epinephrine, norepinephrine, serotonin, and dopamine in the central nervous system and plasma has been reported as the most important mechanism of acupuncture. That is, acupuncture application may increase the levels of endorphin, enkephalin, epinephrine, norepinephrine, serotonin, and dopamine in the central nervous system and plasma. The authors think that acupuncture application provides the patients with deterioration in the taste of smoking, decrease in desire of smoking, and the obstruction of psychological symptoms that appear as a result of smoking cessation. Because of these effects it is presumed that acupuncture application may be used as an important method for smoking cessation treatment.

Camprodon JA; Martinez-Raga J; Alonso-Alonso M; Shih MC; Pascual-Leone A. One session of high frequency repetitive transcranial magnetic stimulation (rTMS) to the right prefrontal cortex transiently reduces cocaine craving. Drug and Alcohol Dependence 86(1): 91-94, 2007. (20 refs.)

Background: Cocaine dependence is a public health problem affecting 2 million individuals in USA. Craving is a predictor of subsequent cocaine use and is related to changes in brain activity in networks involving the prefrontal cortex. Methods: We investigated the efficacy of one session of high frequency repetitive transcranial magnetic stimulation (rTMS) to reduce craving in cocaine addicted subjects. Six patients underwent two sessions of 10 Hz rTMS over left or right dorsolateral prefrontal cortex (DLPFC). Before, immediately after and 4 h after rTMS we measured craving using visual analogue scales. Results: Right. but not left, DLPFC stimulation significantly reduced craving over time (F(2,10)= 11.07, p=0.0029). The reduction was 19% (13.4-24.6%) from baseline and disappeared after 4 h. The interaction of time by site of stimulation for craving was also significant (F(2,25) = 6.13, p = 0.0068). Conclusion: One session of 10 Hz rTMS over right, but not left, DLPFC transiently reduces craving in cocaine dependent individuals. These results highlight the potential of non-invasive neuromodulation as a therapeutic tool for cocaine addiction.

Cappelleri JC; Bushmakin AG; Baker CL; Merikle E; Olufade AO; Gilbert DG. Confirmatory factor analyses and reliability of the modified Cigarette Evaluation Questionnaire. Addictive Behaviors 32(5): 912-923, 2007. (11 refs.)

We examined the validity and reliability of the modified Cigarette Evaluation Questionnaire (mCEQ) that assesses the degree to which subjects experience the reinforcing effects of smoking. Data came from three phase II clinical trials (n=626, n=627, n=312) on varenicline for smoking cessation. Comparative fit indexes and non-normed fit indexes from a confirmatory factor analysis exceeded 0.90. Cronbach's alpha for internal consistency reliability exceeded 0.70 for the Smoking Satisfaction domain and the Psychological Reward domain but was less than 0.70 for the Aversion domain; test-retest reliability generally exceeded 0.70 on the three multi-item domains and two single items. The validity and, in general, the reliability of the postulated multidimensional framework of the mCEQ are confirmed and supported by the analyses of three independent studies, with multi-item domains on Smoking Satisfaction (satisfying, taste good, enjoy smoking), Psychological Reward (calm down, more awake, less initable, help concentrate, reduce hunger), and Aversion (dizziness, nauseous), as well as the single-item assessment on Enjoyment of Respiratory Tract Sensations and on Craving Reduction.

Chiu YH; Lee TH; Shen WW. Use of low-dose topiramate in substance use disorder and bodyweight control. Psychiatry and Clinical Neurosciences 61(6): 630-633, 2007. (14 refs.)

In recent years topiramate has been used for psychiatric patients, mainly for controlling substance use and food intake. A total of 46 patients who received topiramate treatment during the study period were identified from a computer database. Nineteen had received topiramate for at least I month. Twelve patients received topiramate for anticraving effects (alcohol, n = 9; heroin/amphetamine, n = 1; meperidine, n = 1; and nicotine, n = 1). On an average dosage of 112.5 mg/day, nine of the 12 patients (excluding three alcoholic patients) achieved complete or partial remission from the substance use disorders. The present results show that six of the nine patients achieved full or partial remission from alcohol use disorder on a dosage of 100 mg/day. Topiramate was also used to control seven patients' bodyweight (mean bodyweight change, 1.53 kg). Four of them achieved bodyweight loss in the I-month follow up, with an average change of 2.65 kg. Based on the present findings topiramate <100 mg/day may be effective in treating patient with alcohol use disorder, and that topiramate has not shown remarkable benefit of bodyweight loss.

Colamussi L; Bovbjerg DH; Erblich J. Stress- and cue-induced cigarette craving: Effects of a family history of smoking. Drug and Alcohol Dependence 88(2/3): 251-258, 2007. (47 refs.)

Individuals with multiple smokers among first-degree relatives (FH+) are significantly more likely to be persistent smokers themselves. The mechanisms underlying this relationship are unknown. An independent line of research has suggested that persistent smoking is more common among smokers with heightened levels of cigarette craving after being exposed to smoking cues and stressors. The present study experimentally tested the hypothesis that FH+ smokers would exhibit stronger stress- and cue-induced craving reactions compared to FH- smokers. We also explored gender and ethnicity-related differences in these effects. To that end, 160 smokers were recruited by advertisement and exposed to neutral (changing a light bulb), stressful (dental work), and smoking (lighting up after a meal) situations, using script-guided imagery under controlled laboratory conditions. Participants completed craving questionnaires before and after each condition. Supporting the hypotheses, even after controlling smoking history and strength of habit, FH+ smokers (n = 86) displayed stronger craving reactions to both dental and smoking imagery (p's < 0.05) than FH- smokers (n = 74). Interestingly, women had higher stress-, but not smoking cue-induced cravings, than men, with FH+ women exhibiting the highest levels of stress-induced craving. Findings suggest a mechanism through which a family history of smoking leads to poorer cessation success, especially among women.

Cropley M; Ussher M; Charitou E. Acute effects of a guided relaxation routine (body scan) on tobacco withdrawal symptoms and cravings in abstinent smokers. Addiction 102(6): 989-993, 2007. (20 refs.)

Aims: To examine the acute effects of a guided relaxation routine (body scan) on desire to smoke and tobacco withdrawal symptoms in overnight abstinent smokers. Design: Experimental. Participants: Thirty individuals reporting to smoke 10 or more cigarettes daily for at least 3 years. Intervention Participants were assigned randomly to complete a 10-minute body scan (experimental group n = 15) or listen to a natural history passage for 10 minutes (control group n = 15). Measurement: Ratings of strength of desire to smoke and smoking withdrawal symptoms were assessed at baseline, immediately after the interventions, and 5, 10 and 15 minutes post-intervention. Findings There was a significant group x time interaction for strength of desire to smoke. The mean desire to smoke rating was significantly lower in the body scan group relative to the control group immediately after the intervention, and 5 minutes post-intervention. The body scan group also reported lower ratings of irritability, tension and restlessness, relative to the controls. Conclusions: A brief body scan intervention reduces strength of desire to smoke and some tobacco withdrawal symptoms in temporarily abstaining smokers. The body scan may be beneficial as a technique for managing cigarette cravings and withdrawal.

De Jong CAJ; Gongora VC; Engelhardt P; Breteler MHM. Effects of craving self-report measurement on desire for heroin in opioid dependent individuals. Substance Use & Misuse 41(13): 1695-1704, 2006. (17 refs.)

This study aims to investigate whether the administration of questionnaires measuring subjective craving induces more craving for opiates compared to questionnaires measuring other subjective states. The study was conducted in 2000. The sample was composed of 53 patients that were treated as inpatients and outpatients for their opioid dependence syndrome. Participants were assigned randomly into four groups. Both a craving and negative affect condition were presented to each group. The administration of the Visual Analogue Scale (VAS) preceded and followed each condition. Findings of the present study show that the administration of questionnaires measuring instant as well as general craving does not have a distinctive effect on measures of unidimensional craving compared to a questionnaire focused on anxiety and depression states. Because of the small sample, the results should be interpreted cautiously.

Dijkstra BAG; De Jong CAJ; Bluschke SM; Krabbe PFM; van der Staak CPF. Does naltrexone affect craving in abstinent opioid-dependent patients? Addiction Biology 12(2): 176-182, 2007. (41 refs.)

Naltrexone blocks the opioid receptors that modulate the release of dopamine in the brain reward system and therefore blocks the rewarding effects of heroin and alcohol. It is generally assumed that naltrexone leads to reduction of craving, but few studies have been performed to prove this. The purpose of the present study was to examine the effect of the administration of naltrexone on craving level after rapid opioid detoxification induced by naltrexone. A naturalistic study was carried out in which patients were followed during 10 months after rapid detoxification. Data about abstinence, relapse, and naltrexone use were collected by means of urine specimens. Craving was measured by the visual analogue scale craving, the Obsessive Compulsive Drug Use Scale, and the Desires for Drug Questionnaire. Results showed that patients who relapsed in opioid use experienced obviously more craving than abstinent people. Patients who took naltrexone did not experience significant less craving than those who did not. These results suggest that the use of opioids is associated with increased craving and that abstinence for opioids is associated with less craving, independent of the use of naltrexone. This is in contrast to the general opinion. Because of the naturalistic design of the study, no firm conclusions can be drawn, but the results grounded the needs of an experimental study.

Donny, EC; Houtsmuller, E.; Stitzer, ML. Smoking in the absence of nicotine: Behavioral, subjective and physiological effects over 11 days. Addiction 102(2): 324-334, 2007. (32 refs.)

Aims: Sensorimotor stimuli associated with tobacco smoking influence smoking behavior; however, current research has focused almost exclusively on the effects of brief, laboratory-based exposure to smoking-related stimuli. The purpose of this experiment was to characterize the effects of smoking stimuli delivered in the absence of nicotine over an extended (11-day) exposure. Design, setting and participants: Thirty adult regular smokers participated in an in-patient study. After assessing preferred brand smoking, participants were assigned randomly to one of three groups corresponding to subsequent smoking conditions: nicotine-containing cigarettes, de-nicotinized cigarettes or no smoking. Measurements: Measures of smoking reinforcement, subjective effects, physiological effects, withdrawal/craving and puff topography were taken repeatedly during both periods of free access and controlled assessments during abstinence. Findings: Daily de-nicotinized cigarette use declined immediately by 1.7 cigarettes/day compared to the preferred brand baseline and declined by another 3.5 cigarettes over time; participants smoking de-nicotinized cigarettes also demonstrated a 31% decline in the number of puffs earned on a progressive ratio, a measure of the motivation to smoke, during the study. Subjective ratings of smoking were largely negative throughout the study in the de-nicotinized group, while the nicotine-containing condition reported increasingly positive subjective effects with repeated exposure. Acute craving suppression following smoking remained evident throughout the study regardless of nicotine content. Conclusions: These effects highlight the importance of non-nicotinc sensorimotor stimuli as determinants of the maintenance of smoking behavior and suggests that extinction of conditioned reinforcement in the absence of nicotine progresses slowly.

Duncan E; Boshoven W; Harenski K; Fiallos A; Tracy H; Jovanovic T et al. An fMRI study of the interaction of stress and cocaine cues on cocaine craving in cocaine-dependent men. American Journal on Addictions 16(3): 174-182, 2007. (61 refs.)

Acute stress is associated with relapse in cocaine addiction, possibly through the activation of craving-related neural circuitry. Neural responses to cocaine cues and acute stress were investigated in an fMRI study. Ten male participants mentally reenacted personalized scripts about cocaine use and a neutral experience both with and without a stressor present (anticipation of electrical shock). Interaction analysis between script type and stress condition revealed greater activation of the posterior cingulate cortex and of the parietal lobe during the cocaine script in the presence of the stressor. These data suggest that stress may precipitate relapse in cocaine addiction by activating brain areas that mediate reward processing and the attentional and mnemonic bias for drug use reminders.

Ebbert JO; Dale LC; Severson H; Croghan IT; Rasmussen DF; Schroeder DR et al. Nicotine lozenges for the treatment of smokeless tobacco use. Nicotine & Tobacco Research 9(2): 233-240, 2007. (44 refs.)

Nicotine lozenges have been shown to increase tobacco abstinence rates in cigarette smokers, but they have not been evaluated in smokeless tobacco (ST) users. We conducted an open-label, one-arm, phase II clinical trial to evaluate the efficacy of the 4-mg nicotine lozenge for the treatment of withdrawal and craving associated with tobacco abstinence among ST users. Eligible subjects received 4-mg nicotine lozenges for 6 weeks followed by a 6-week taper. Subjects completed daily tobacco withdrawal diaries, and data on lozenge use, adverse events, and lozenge acceptability were collected. Urine anabasine was collected at 3 and 6 months for biochemical confirmation of self-reported tobacco abstinence. Participants were 30 ST users with a mean age of 35.4 years (SD=6.5) using an average of 4.2 cans or pouches (SD=3.2) of ST per week for a mean of 15.1 years (SD=6.5). Among subjects continuously tobacco abstinent for the first 2 weeks, no significant increases in composite withdrawal symptoms were observed, compared with baseline symptoms, whereas craving decreased significantly. Biochemically confirmed 7-day point-prevalence tobacco abstinence was 53% (95% CI=34%-72%) at 12 weeks (end of treatment) and 47% (95% CI=28%-66%) at 6 months. Few adverse events attributable to the nicotine lozenge occurred, and the lozenge was perceived as helpful in assisting subjects quit ST. The use of the 4-mg nicotine lozenge appears promising for the clinical treatment of withdrawal symptoms and craving associated with tobacco abstinence in ST users. Future phase III clinical trials investigating the efficacy of nicotine lozenges are warranted.

Fattore L; Spano MS; Deiana S; Melis V; Cossu G; Fadda P. An endocannabinoid mechanism in relapse to drug seeking: A review of animal studies and clinical perspectives. (review). Brain Research Reviews 53(1): 1-16, 2007. (178 refs.)

Detoxification from drug abuse is strongly threatened by the occurrence of renewed episodes of drug intake. in human addicts, relapse to drug seeking may take place even after a considerably long period from the last drug consumption. Over the last decade, the endocannabinoid system has received remarkable attention due to its unique features, including its rewarding properties closely resembling those of the most commonly abused substances and its multiple therapeutic implications. Although limited at present, evidence is now emerging on a possible participation of the endogenous cannabinoid system in the regulation of relapsing phenomena. Both stimulation and blockade of the central cannabinoid CB-sub1 receptor have proved to play an important role in drug- as well as in cue-induced reinstatement of drug seeking behavior. Indeed, while CB-sub1 receptor stimulation may elicit relapse not only to cannabinoid seeking but also to cocaine, heroin, alcohol and meth amphetamine, this effect is significantly attenuated, when not fully prevented, by pretreatment with the CB-sub1 receptor antagonist rimonabant. However, corroborating data on the involvement of the cannabinoid system in stress-induced reinstatement are still rather scarce. The present review attempts to collect data obtained from different laboratories using diverse experimental approaches, to provide a comprehensive picture of the recent evidence of a relationship between the cannabinoid system and the neurobiological mechanisms leading to relapse. For each class of abused drugs, the conspicuous progress made in delineating the role of the endocannabinoid system in relapse to drug seeking has been examined by placing particular emphasis on the findings obtained from behavioral studies. After summarizing findings and implications emerging from the reviewed studies, we conclude by briefly discussing what information is still missing and how missing information might be obtained.

Fehr C; Hohmann N; Grunder G; Dielentheis TF; Buchholz HG; Chechko N et al. Tiagabine does not attenuate alcohol-induced activation of the human reward system. Psychopharmacology 191(4): 975-983, 2007. (52 refs.)

Rationale: The rewarding effects of ethanol and other drugs of abuse are mediated by activation of the mesolimbic dopamine system. Recent neuroimaging studies in primates and humans suggest that cocaine-induced dopamine stimulation might be diminished by drugs augmenting gamma-aminobutyric acid A (GABA-A) receptor function such as the GABA transaminase inhibitor vigabatrin. Objectives The objective of this study was to test the property of the selective GABA transporter 1 (GAT1) inhibitor tiagabine to block ethanol-induced activation of the mesolimbic reward system in an i.v. ethanol challenge. Materials and methods Twenty nonaddicted healthy volunteers underwent an i.v. ethanol challenge after 1 week of tiagabine (15 mg/day) administration. Neuronal activation was measured using [F-18]-fluoro-deoxyglucose positron emission tomography (PET). Results Tiagabine did not prevent ethanol-induced stimulation of the mesolimbic reward system but augmented ethanol-induced hypometabolism within areas of the visual system and the cerebellum. Tiagabine alone also decreased neuronal metabolism within parts of the right temporal cortex that are highly enriched with GABA-ergic neurons. Conclusions Our ethanol challenge imaging study does not provide supporting evidence that the GAT1 inhibitor tiagabine diminishes the rewarding effects of ethanol. Further PET imaging studies using established anticraving compounds, such as the mu-opioid receptor antagonist naltrexone and antiepileptic drugs affecting the GABA-ergic system more broadly, will provide additional important insights on the interaction between the GABA-ergic and the brain reward system in vivo and the suitability of GABA-ergic drugs as anticraving compounds.

Gilbert DG; Sugai C; Zuo YT; Rabinovich NE; McClernon FJ; Froeliger B. Brain indices of nicotine's effects on attentional bias to smoking and emotional pictures and to task-relevant targets. Nicotine & Tobacco Research 9(3): 351-363, 2007. (65 refs.)

Aversive and smoking-related stimuli are related to smoking urges and relapse and can be potent distractors of selective attention. It has been suggested that the beneficial effect of nicotine replacement therapy may be mediated partly by the ability of nicotine to reduce distraction by such stimuli and thereby to facilitate attention to task-relevant stimuli. The present study tested the hypothesis that nicotine reduces distraction by aversive and smoking-related stimuli as indexed by the parietal P3b brain response to a task-relevant target digit. We assessed the effect of nicotine on distraction by emotionally negative, positive, neutral, and smoking-related pictures immediately preceding target digits during a rapid visual information processing task in 16 smokers in a double-blind, counterbalanced, within-subjects design. The study included two experimental sessions. After overnight smoking deprivation (12+ hr), active nicotine patches were applied to participants during one of the sessions and placebo patches were applied during the other session. Nicotine enhanced P3b responses associated with target digits immediately subsequent to negative emotional pictures bilaterally and subsequent to smoking-related pictures only in the right hemisphere. No effects of nicotine were observed for P3bs subsequent to positive and neutral distractor pictures. Another measure of attention, contingent negative variation amplitude in anticipation of the target digits also was increased by nicotine, especially in the left hemisphere and at posterior sites. Together, these findings suggest that nicotine reduces the distraction by emotionally negative and smoking-related stimuli and promotes attention to task-related stimuli by modulating somewhat lateralized and task-specific neural networks.

Grusser SM; Morsen CP; Wolfling K; Flor H. The relationship of stress, coping, effect expectancies and craving. European Addiction Research 13(1): 31-38, 2007. (45 refs.)

Based on theoretical models of craving and addiction, this study investigated the association between stress-related variables and negatively and positively reinforcing dimensions of craving ( relief and reward craving) in 150 opiate addicts, 150 alcohol addicts and 150 non-addicted controls. Stress-distress was the most powerful predictor of both dimensions of craving, followed by a lack of positive coping strategies whereas expectancies of substance effects seemed to be less important. Positive coping strategies were related to reduced craving only when they were accompanied by low stress-distress. In non-addicted subjects, only positive coping strategies were negatively related to craving. This study confirms the important role of stress-distress for the occurrence of craving in addicts.

Haberstick BC; Timberlake D; Ehringer MA; Lessem JM; Hopfer CJ; Smolen A et al. Genes, time to first cigarette and nicotine dependence in a general population sample of young adults. Addiction 102(4): 655-665, 2007. (45 refs.)

Aim: To examine variation in nicotine dependence scores and covariation between different dependence symptoms. Design: A 12-year, nationally representative, probability-based survey of adolescent health-related behaviors and their outcomes during young adulthood in the United States. The genetic contribution to nicotine dependence was evaluated in the sibling-pairs sample of the US National Longitudinal Study of Adolescent Health. Measurements Nicotine dependence (ND) was assessed using the Fagerstrom Test for Nicotine Dependence (FTND) and Heaviness of Smoking Index (HSI) in 1154 young adults, between the ages of 18 and 25 years, who were from twin, full sibling and half-sibling pairs. Findings: Dependence in this sample was common and varied in degree. Total HSI scores evidenced moderate to large heritable contributions (61%, 95% confidence interval (CI): 0.46-0.72), as did the quantity of cigarettes smoked (52%, 95% CI: 0.39-0.63) and urgency to smoke (55%, 95% CI: 0.38-0.68). Multivariate modeling identified a highly heritable underlying factor (76%, 95% CI: 0.56-0.91) that influenced the covariation of dependence symptoms and loaded most heavily on how soon after waking a smoker uses his or her first cigarette. The quantity of cigarettes smoked per day also evidenced residual genetic influences that were not common to other dependence-related behaviors. Conclusions: In this sample of young adults from the general population, both genes and individual-specific environments are important etiological factors in ND. The urgency to smoke, as measured by the time to first cigarette, may be the most informative measure on the FTND for genetic studies of nicotine dependence.

Havermans RC; Mulkens S; Nederkoorn C; Jansen A. The efficacy of cue exposure with response prevention in extinguishing drug and alcohol cue reactivity. Behavioral Interventions 22(2): 121-135, 2007. (24 refs.)

It has been suggested that drug cue-elicited urges and psychophysiological reactions are the results of Pavlovian conditioning processes and that it should be possible to extinguish these responses with cue exposure with response prevention. It has already been shown that subjective cue-elicited urges can be extinguished, but it is unclear whether this is also true for cue-elicited psychophysiological arousal. This was tested in the present study in a heterogeneous sample of drug and alcohol dependent patients. It was found that cue-elicited urges can indeed be extinguished. However, such a clear pattern of extinguished cue reactivity was not found for the psychophysiological measures. Furthermore, the extinction of drug urges was not specific for cue exposure treatment. It is concluded that cue-elicited psychophysiological arousal does not underlie subjective cue reactivity and may not reflect Pavlovian conditioned drug responding.

Hopper JW; Su Z; Looby AR; Ryan ET; Penetar DM; Palmer CM et al. Incidence and patterns of polydrug use and craving for ecstasy in regular ecstasy users: An ecological momentary assessment study. Drug and Alcohol Dependence 85(3): 221-235, 2006. (57 refs.)

Background: Previous studies employing retrospective assessments methods found that regular ecstasy users frequently use alcohol, marihuana and other drugs in combination with ecstasy. Methods: Twenty-two participants (13 males, 9 females) wore a wrist actigraph/data recorder to record real-time drug use and ecstasy craving for 6 weeks. Rates of alcohol and drug use on ecstasy use versus non-use nights, and before, during, and after ecstasy use were analyzed with generalized estimation equations (GEE). Craving was modeled with GEE and linear mixed models. Results: Approximately 70% of ecstasy uses occurred on Friday or Saturday nights. No drug was significantly more likely to be used on ecstasy use nights than comparison Friday and Saturday nights. On nights ecstasy was used, in general across all drugs assessed, use was more likely before and during than after ecstasy intoxication, while alcohol use was also more likely before than during ecstasy intoxication. Though low overall, craving for ecstasy increased over 24 h before use and was higher on Friday nights of weeks ecstasy was used on weekends than weeks it was not used. Conclusions: Use of ecstasy on a particular night may not be associated with any greater likelihood of using any other intoxicating drug, and use of other drugs on nights involving ecstasy use may simply reflect a �natural history� of drug-use nights that begins with alcohol, progresses to more intoxicating drugs, and ends with little drug use. Confirmation of these findings awaits further advances in the application of ecological momentary assessment methodologies.

Hyman SM; Fox H; Hong KIA; Doebrick C; Sinha R. Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment. Experimental and Clinical Psychopharmacology 15(2): 134-143, 2007. (56 refs.)

Background: Naltrexone is a nonaddictive medication that blocks the euphoric effects of opioids. However, naltrexone treatment is associated with high rates of noncompliance and opioid relapse, possibly because it does not reduce stress and protracted withdrawal symptoms during early recovery. Prior clinical and preclinical research has indicated that both stress and drug-cue-related arousal response is associated with craving and vulnerability to relapse in a range of drug-using populations. Aims: To examine opioid craving and the subjective and cardiovascular response to stress and drug cues in naltrexone-treated opioid abusers. Method: Eleven men and three women engaged in naltrexone treatment for opioid dependence. They were exposed to personalized stress, drug-cue, and neutral-relaxing imagery in a single laboratory session. Subjective (craving, emotion) and cardiovascular (heart rate, systolic blood pressure, and diastolic blood pressure) measures were assessed. Results: Stress and drug-cue-related imagery significantly increased opioid craving, anxiety, and negative emotions and significantly decreased positive emotions compared to neutral imagery. Selective emotional responses were greater in the stress condition than in the drug-cue condition. Only stress-related imagery was associated with an increased cardiovascular response. Conclusions: Naltrexone-treated opioid abusers demonstrate vulnerability to stress and drug-cue-induced craving and arousal responses that may contribute to the high rates of noncompliance and relapse among opioid-dependent individuals undergoing naltrexone treatment. Pharmacological and behavioral interventions that specifically target the negative affectivity that co-occurs with drug-cue and stress-induced craving could be of benefit in improving naltrexone treatment outcomes in opioid dependence.

Ikegami A; Olsen CM; D'Souza MS; Duvauchelle CL. Experience-dependent effects of cocaine self-administration/conditioning on prefrontal and accumbens dopamine responses. Behavioral Neuroscience 121(2): 389-400, 2007. (79 refs.)

Experiments were performed to examine the effects of cocaine self-administration and conditioning experience: on operant behavior, locomotor activity, and nucleus accumbens (NAcc) and prefrontal cortex (PFC) dopamine (DA) responses. Sensory cues were paired with alternating cocaine and nonreinforcement during 12 (limited training) or 40 (long-term training) daily operant sessions. After limited training, NAcc DA responses to cocaine were significantly enhanced in the presence of cocaine-associated cues compared with nonreward cues and significantly depressed after cocaine-paired cues accompanied a nonreinforced lever response. PFC DA levels were generally nonresponsive to cues after the same training duration. However, after long-term training, cocaine-associated cues increased the magnitude of cocaine-stimulated PFC DA levels significantly over levels observed with nonreinforcement cues. Conversely, conditioned cues no longer influenced NAcc DA levels after long-term training. In addition, cocaine-stimulated locomotor activity was enhanced by cocaine-paired cues after long-term, but not after limited, training. Findings demonstrate that cue-induced cocaine expectation exerts a significant impact on dopaminergic and behavioral systems, progressing from mesolimbic to mesocortical regions and from latent to patent behaviors as cocaine and associative experiences escalate.

Juliano LM; Houtsmuller EJ; Stitzer ML. A preliminary investigation of rapid smoking as a lapse-responsive treatment for tobacco dependence. Experimental and Clinical Psychopharmacology 14(4): 429-438, 2006. (41 refs.)

Lapses within the first 2 weeks of a smoking cessation attempt are strongly associated with a return to regular smoking (S. L. Kenford et al., 1994). Unfortunately, little is known about how to prevent an initial lapse from progressing to a full relapse, and presently there are no validated lapse-responsive therapeutic interventions. The present study tested the efficacy and feasibility of rapid smoking plus counseling as a novel lapse-responsive intervention. Sixty-seven participants enrolled in a smoking treatment program involving brief counseling and a 9-week course of bupropion. Beginning on the quit day, participants' smoking behavior was tracked daily for 14 days. Once an early smoking lapse was identified, participants were randomly assigned to receive either 3 sessions of rapid smoking plus counseling or no intervention (usual care). Consistent with previous research, participants who smoked during the first 2 weeks of the quit attempt had significantly poorer 6-month outcomes (3% abstinent) than did those who did not smoke (64% abstinent). Compared with early abstainers, early lapsers were more nicotine dependent and reported greater cravings and lower confidence in their ability to abstain from smoking during the first 48 hours of abstinence. As expected, rapid smoking produced a variety of aversive effects, including increased nausea, dizziness, and vomiting as well as sharply decreased cravings to smoke. However, rapid smoking did not improve abstinence outcomes relative to usual care. Although rapid smoking has been shown to be an effective treatment for initial smoking cessation, in this preliminary study the authors failed to demonstrate its effectiveness as a lapse-responsive treatment.

Kalivas PW; O'Brien C. Drug addiction as a pathology of staged neuroplasticity. (review). Neuropsychopharmacology 33(1): 166-180, 2008. (147 refs.)

Using addictive drugs can evolve from controlled social use into the compulsive relapsing disorder that characterizes addiction. This transition to addiction results from genetic, developmental, and sociological vulnerabilities, combined with pharmacologically induced plasticity in brain circuitry that strengthens learned drug-associated behaviors at the expense of adaptive responding for natural rewards. Advances over the last decade have identified the brain circuits most vulnerable to drug-induced changes, as well as many associated molecular and morphological underpinnings. This growing knowledge has contributed to an expanded understanding of how drugs usurp normal learning circuitry to create the pathology of addiction, as evidenced by involuntary activation of reward circuits in response to drug-associated cues and simultaneous reports of drug craving. This new understanding provides unprecedented potential opportunities for novel pharmacotherapeutic targets in treating addiction. There appears to be plasticity associated with the addiction phenomenon in general as well as changes produced by addiction to a specific class of addicting drugs. These findings also provide the basis for the current understanding of addiction as a chronic, relapsing disease of the brain with changes that persist long after the last use of the drug. Here, we describe the neuroplasticity in brain circuits and cell function induced by addictive drugs that is thought to underlie the compulsions to resume drug-taking, and discuss how this knowledge is impelling exploration and testing of novel addiction therapies.

Kotlyar M; Mendoza-Baumgart MI; Li ZZ; Pentel PR; Barnett BC; Feuer RM; Smith EA; Hatsukami DK. Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge. Tobacco Control 16(2): 138-142, 2007. (25 refs.)

Objective: To compare nicotine pharmacokinetics and subjective effects of three new smokeless tobacco potential reduced exposure products (PREPs; Ariva, Revel and Stonewall) with moist snuff (Copenhagen) and medicinal nicotine (Commit lozenge). Methods: 10 subjects completed a randomised, within-subject, crossover study. Subjects used one product for 30 min at each of the five laboratory sessions. Maximal nicotine concentration (C-max) was determined and area under the concentration time curve (AUC) was calculated for a 90-min period (during use and 60 min after use). Nicotine craving, withdrawal symptoms and ratings of product effects and liking were measured during product use. Results: Nicotine AUC and Cmax were higher for Copenhagen than for any other product (p < 0.002) and higher for Commit than for either Ariva or Revel (p < 0.001). C-max for Commit was also higher than for Stonewall (p=0.03). Craving was lowest during use of Copenhagen (p < 0.03). Craving during use of Stonewall, Ariva and Commit was lower than during use of Revel (p < 0.05). Withdrawal symptom score during use of Copenhagen was lower than during use of Revel (p=0.009). Copenhagen scores were higher (p < 0.005) than all other products in several measures of drug effects and liking (feel good effects, satisfaction, liking and desire for product, and strength of product). Conclusion: The new smokeless tobacco PREPs result in lower nicotine concentrations and equivalent or lower reductions in subjective measures compared with medicinal nicotine. Since health effects of PREPs are largely unknown, medicinal nicotine should be preferentially encouraged for smokers or smokeless tobacco users wishing to switch to lower-risk products.

Kwak SM; Na DL; Kim G; Kim GS; Lee JH. Use of eye movement to measure smokers' attentional bias to smoking-related cues. Cyberpsychology & Behavior 10(2): 299-304, 2007. (25 refs.)

Smokers have attentional biases towards smoking-related cues, and such cues elicit cravings. Smokers also feel anxious during nicotine deprivation, and anxiety may exacerbate attentional biases toward aversive cues. We examined the attentional bias of smokers (n = 14) and a control group of nonsmokers (n = 16) towards smoking-related and aversive cues. Using an eye-tracking device, we measured eye movement when smoking-related, aversive, and control cues were presented simultaneously. We analyzed the number of initial fixations, and gaze duration, to identify the attentional bias. Smokers initially fixed their gaze on aversive cues, and maintained their gaze longer on smoking-related cues, in comparison to the control group. These results suggest that smokers show biased attentional orientation to smoking-related and aversive cues.

LaRowe SD; Saladin ME; Carpenter MJ; Upadhyaya HP. Reactivity to nicotine cues over repeated cue reactivity sessions. Addictive Behaviors 32(12): 2888-2899, 2007. (35 refs.)

The present study investigated whether reactivity to nicotine-related cues would attenuate across four experimental sessions held 1 week apart. Participants were nineteen non-treatment seeking, nicotine-dependent males. Cue reactivity sessions were performed in an outpatient research center using in vivo cues consisting of standardized smoking-related paraphernalia (e.g., cigarettes) and neutral comparison paraphernalia (e.g., pencils). Craving ratings were collected before and after both cue presentations while physiological measures (heart rate, skin conductance) were collected before and during the cue presentations. Although craving levels decreased across sessions, smoking-related cues consistently evoked significantly greater increases in craving relative to neutral cues over all four experimental sessions. Skin conductance was higher in response to smoking cues, though this effect was not as robust as that observed for craving. Results suggest that, under the described experimental parameters, craving can be reliably elicited over repeated cue reactivity sessions.

Madayag A; Lobner D; Kau KS; Mantsch JR; Abdulhameed O; Hearing M et al. Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. Journal of Neuroscience 27(51): 13968-13976, 2007. (59 refs.)

Cocaine produces a persistent reduction in cystine-glutamate exchange via system x(c)(-) in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System x(c)(-) influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens, which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system x(c)(-) activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered before daily cocaine to determine the impact of increased cystine -glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered before cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2 -3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered before daily cocaine also prevented the persistent reduction in system x(c)(-) activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in [S-35] cystine transport via system x(c)(-), basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least 3 weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system x(c)(-) activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking.

Martinotti G; Romanelli R; Di Nicola M; Reina D; Mazza M; Janiri L. Oxcarbazepine at high dosages for the treatment of alcohol dependence. American Journal on Addictions 16(3): 247-248, 2007. (6 refs.)

The article investigates the efficacy and safety of oxcarbazepine (OXC) in the management of borderline personality disorder and bipolar II disorder in a person with alcohol use disorder. To investigate the efficacy and safety of OXC on alcohol drinking indices and craving, the researchers compared OXC at different dosages in a 90-day randomized open-label trial. Abstinence from alcohol was evaluated on the basis of a family member interview through determining blood alcohol concentration. Safety parameters were monitored through electrocardiography, urinalysis, and hematological and clinical chemical analyses of blood samples at the start and at the end of the investigation. The authors suggest the necessity of further studies with specific samples to fully diagnosed patients.

McBride D; Barrett SP; Kelly JT; Aw A; Dagher A. Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers: An fMRI study. Neuropsychopharmacology 31(12): 2728-2738, 2006. (55 refs.)

Cues associated with drug taking can trigger relapse, drug seeking, and craving in addicted individuals. Behavioral studies suggest that drug availability and withdrawal can affect the individual response to drug cues. Moreover, the importance of subjective craving in cue-induced relapse has been questioned and an alternative model put forward according to which drug cues trigger habitual drug-seeking behaviors independently of craving. We used functional magnetic resonance imaging to compare the brain response to smoking and control videotapes in 20 healthy smokers, while varying their expectancy to smoke and abstinence levels. The neural response to cigarette cues was strongly modulated by expectancy and, to a lesser extent, abstinence. In people expecting to smoke immediately after the scan, smoking cues activated brain areas implicated in arousal, attention, and cognitive control. However, when subjects knew they would not be allowed to smoke for 4 h, there was almost no brain activation in response to smoking cues, despite equivalent reported levels of craving. In the dorsolateral prefrontal cortex, the neural response was a function of both craving and expectancy. Thalamo-cingulate connectivity, thought to be an index of arousal, was greater during expectancy than nonexpectancy. Our findings confirm the importance of expectancy in the neural response to drug cues, and lend support to the theory that these cues act on brain areas involved in arousal and attention.

McClung CA; Nestler EJ. Neuroplasticity mediated by altered gene expression. (review). Neuropsychopharmacology 33(1): 3-17, 2008. (200 refs.)

Plasticity in the brain is important for learning and memory, and allows us to respond to changes in the environment. Furthermore, long periods of stress can lead to structural and excitatory changes associated with anxiety and depression that can be reversed by pharmacological treatment. Drugs of abuse can also cause long-lasting changes in reward-related circuits, resulting in addiction. Each of these forms of long-term plasticity in the brain requires changes in gene expression. Upon stimulation, second messenger pathways are activated that lead to an enhancement in transcription factor activity at gene promoters. This stimulation results in the expression of new growth factors, ion channels, structural molecules, and other proteins necessary to alter the neuronal circuit. With repeated stimulation, more permanent modifications to transcription factors and chromatin structure are made that result in either sensitization or desensitization of a circuit. Studies are beginning to uncover the molecular mechanisms that lead to these types of long-term changes in the brain. This review summarizes some of the major transcriptional mechanisms that are thought to underlie neuronal and behavioral plasticity.

McGeary JE; Esposito-Smythers C; Spirito A; Monti PM. Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients. Pharmacology, Biochemistry and Behavior 86(2): 401-406, 2007. (42 refs.)

Background: The VNTR polymorphism in the Dopamine D4 receptor gene (DPD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroirnaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship. Method: Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene (L >= 7 [n=25], S=< 7 [n=52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items, thought to be most related to the intermediate phenotype of urge. Results: The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also tionsignificantly related to DRD4 status. Carriers of the long variant of the DPD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes. Discussion: Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.

Munafo MR; Mannie ZN; Cowen PJ; Harmer CJ; McTavish SB. Effects of acute tyrosine depletion on subjective craving and selective processing of smoking-related cues in abstinent cigarette smokers. Journal of Psychopharmacology 21(8): 805-814, 2007. (50 refs.)

We investigated the impact of the administration of a tyrosine-depleting amino acid mixture compared to a balanced mixture on measures of mood, craving and selective processing of smoking-related cues in healthy cigarette smokers instructed to abstain from smoking for 12 h prior to, and during, the experiment. A modified Stroop task was used to index selective processing of smoking-related cues. We observed evidence for an increase in subjective craving among males, and an attenuation of the selective processing of smoking-related cues compared to control cues among females, in the tyrosine-depleting condition compared to the balanced condition. No effects of mixture were observed on measures of subjective mood. These results tentatively support for the role of dopaminergic neurotransmission in mediating the response of cigarette smokers to smoking-related cues. In addition, these results also provide further evidence for sex differences in the factors that maintain cigarette smoking, in particular with respect to conditioned reinforcement of smoking behaviour, and suggest that the relationship between subjective craving and selective processing of smoking-related cues may differ in males and females.

Naqvi NH; Rudrauf D; Damasio H; Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science 315(5811): 531-534, 2007. (29 refs.)

A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.

Olausson P; Jentsch JD; Krueger DD; Tronson NC; Nairn AC; Taylor JR. Orbitofrontal cortex and cognitive-motivational impairments in psychostimulant addiction. Annals of the New York Academy of Sciences. Linking Affect to Action: Critical Contributions of the Orbitofrontal Cortex 1121: 610-638, 2007. (200 refs.)

Addiction is characterized by compulsive drug use despite adverse consequences. The precise psychobiological changes that underlie the progression from casual use to loss of control over drug-seeking and drug-taking behavior are not well understood. Here we report that short-term cocaine exposure in monkeys is sufficient to produce both selective deficits in cognitive functions dependent on the orbitofrontal cortex (OFC) concurrent with enhancements in motivational processes involving limbic-striatal regions. Additional findings from behavioral studies and analyses of the synaptic proteome provide new behavioral and biochemical evidence that cocaine-induced neuroadaptations in cortical and subcortical brain regions result in dysfunctional decision-making abilities and loss of impulse control that in combination with enhancements of incentive motivation may contribute to the development of compulsive behavior in addiction.

Rezaishiraz H; Hyland A; Mahoney MC; O'Connor RJ; Cummings KM. Treating smokers before the quit date: Can nicotine patches and denicotinized cigarettes reduce cravings? Nicotine & Tobacco Research 9(11): 1139-1146, 2007. (24 refs.)

The present study investigated whether treatment with the combination of denicotinized cigarettes and 21-mg nicotine patch for 2 weeks before a designated quit date could lessen cravings for smoking, thereby helping smokers abstain from smoking. The study was a randomized controlled clinical trial conducted at Roswell Park Cancer Institute, Buffalo, New York, in 2004 and 2005. Patients included 98 adult heavy smokers (using 20 or more cigarettes/day). Half of the subjects received 2 weeks of combination of denicotinized cigarettes (Quest 3) and 21-mg nicotine patch for 2 weeks before the quit date. The remaining smokers were switched to light cigarettes (Quest 1) during the 2 weeks before the quit date. After the quit date, all subjects received counseling for smoking cessation and were provided nicotine patches for up to 8 weeks after the quit date. Self-reported cravings for smoking, withdrawal symptoms, and smoking abstinence were measured at predetermined intervals using phone-based surveys and in clinical visits. The group that used denicotinized cigarettes and nicotine patch before quitting reported less frequent and less intense cravings for cigarettes in the 2 weeks before and after the designated quit date. Self-reported withdrawal symptoms and quit rates did not differ significantly between the groups. The use of a denicotinized cigarette combined with the nicotine patch appears to lessen cravings to smoke in the immediate postcessation period. A larger, better-powered study is needed to test if this treatment combination has merit for increasing quit rates.

Schnoll RA; Patterson F; Lerman C. Treating tobacco dependence in women. Journal of Women's Health & Gender-based Medicine 16(8): 1211-1218, 2007. (53 refs.)

Tobacco dependence poses unique health risks for women (e. g., obstetrical and perinatal complications, cervical cancer), and compared with men, the rate of lung cancer among women has been steadily increasing over the past 50 years. However, the rate of decline in smoking rates in the United States over the past decade has been far slower for women than for men. Unfortunately, less than two thirds of physicians who care exclusively for women provide formal assistance to patients who smoke. Barriers to smoking cessation that are unique to women include concerns about weight gain and negative emotional reactions following cessation. Recent data suggest that timing in the menstrual cycle may influence quitting success. Outcomes may be poorer for women than for men treated with nicotine replacement therapies (NRT), possibly because women experience more severe withdrawal symptoms, report poorer compliance with NRT, and exhibit greater sensitivity to nonnicotine factors, such as the sight, smell, and sensations of smoking, compared with men. There is also evidence suggesting that women have significantly higher rates of nicotine metabolism than men, particularly when using oral contraceptives. In contrast, data suggest that nonnicotine pharmacotherapies, such as bupropion and varenicline, have equivalent efficacy for women and men, and behavioral treatments that focus on postcessation weight reduction and negative mood management may be particularly beneficial for women. Overall, additional research is needed to examine the potential effectiveness and safety of pharmacotherapies for pregnant women who smoke. Greater attention to the unique needs of female smokers may allow healthcare providers to optimize delivery of pharmacotherapy and behavioral counseling to aid their female patients to quit smoking.

Shiffman S; Balabanis MH; Gwaltney CJ; Paty JA; Gnys M; Kassel JD et al. Prediction of lapse from associations between smoking and situational antecedents assessed by ecological momentary assessment. Drug and Alcohol Dependence 91(2/3): 159-168, 2007. (65 refs.)

Smoking is associated with particular moods and activities, but it is not known whether there are individual differences in these associations and whether these differences are associated with success in smoking cessation. We assessed such associations using ecological momentary assessment: real-world, real-time data, collected by palm-top computer. Two hundred and fourteen smokers participating in a smoking cessation study provided data during ad lib smoking at baseline. Participants recorded moods and activities each time they smoked and, for comparison, at randomly selected non-smoking occasions. Situational associations with smoking were captured by examining the associations between smoking and antecedents considered relevant to lapse risk: negative affect (NA), arousal, socializing with others, the presence of others smoking, and consumption of coffee and alcohol. The associations varied across participants, confirming individual differences in situational smoking associations. Survival analyses revealed that only the NA pattern predicted first lapse. The effect was only seen in EMA assessments of NA smoking, and was not captured by questionnaire measures of negative affect smoking, which did not predict lapse risk. Moreover, the effect was not mediated by nicotine dependence.

Sinha R; Li CSR. Imaging stress- and cue-induced drug and alcohol craving: Association with relapse and clinical implications. Drug and Alcohol Review 26(1): 25-31, 2007. (69 refs.)

Stress- and drug-related cues are majorfactors contributing to high rates of relapse in addictive disorders. Brain imaging studies have begun to identify neural correlates of stress and drug cue-induced craving states. Findings indicate considerable overlap in neural circuits involved in processing stress and drug cues with activity in the corticostriatal limbic circuitry underlying both affective and reward processing. More recent efforts have begun to identify the relationships between neural activity during stress and drug cue exposure and drug relapse outcomes. Findings suggest medial prefrontal, anterior and posterior cingulate, striatal and posterior insula regions to be associated with relapse outcomes. Altered function in these brain regions is associated with stress-induced and drug cue-induced craving states and an increased susceptibility to relapse. Such alterations can serve as markers to identify relapse propensity and a more severe course of addiction. Efficacy of pharmacological and behavioral treatments that specifically target stress and cue-induced craving and arousal responses may also be assessed via alterations in these brain correlates.

Stasiewicz PR; Brandon TH; Bradizza CM. Effects of extinction context and retrieval cues on renewal of alcohol-cue reactivity among alcohol-dependent outpatients. Psychology of Addictive Behaviors 21(2): 244-248, 2007. (25 refs.)

Pavlovian conditioning models have led to cue-exposure treatments for drug abuse. However, conditioned responding to drug stimuli can return (be renewed) following treatment. Animal research and a previous study of social drinkers indicated that extinction is highly context dependent but that renewal could be reduced by the inclusion of a cue from the extinction context. This study extends this research to a clinical sample. Alcohol-dependent outpatients (N = 143) completed an extinction trial to reduce craving and salivation responses to alcohol cues. They were then randomized to renewal tests in either the same context as extinction, a different context, the different context containing an extinction cue, or the different context with cue plus a manipulation to increase the salience of the cue. Contrary to predictions, the different context did not produce the expected renewal effect. Although the generalization of extinction effects beyond the cue-exposure context is a positive clinical finding, it is inconsistent with basic research findings on the context dependence of extinction. Possible explanations for this inconsistency are discussed.

Taylor AH; Ussher MH; Faulkner G. The acute effects of exercise on cigarette cravings, withdrawal symptoms, affect and smoking behaviour: A systematic review. (review). Addiction 102(4): 534-543, 2007. (70 refs.)

Aim: To review the effects of a single session of exercise on cigarette cravings, withdrawal symptoms and smoking behaviour. Methods A systematic search and critical appraisal of all 14 relevant studies. Results All 12 studies that compared a bout of exercise with a passive condition reported a positive effect on cigarette cravings, withdrawal symptoms and smoking behaviour. Two other studies that compared two intensities of exercise revealed no differences in outcomes. Single and multi-item measures of cigarette cravings, withdrawal symptoms and negative affect decreased rapidly during exercise and remained reduced for up to 50 minutes after exercise. Effect sizes for seven studies that assessed 'strength of desire to smoke' showed a mean reduction, 10 minutes after exercise, of 1.1 (SD 0.9). Four studies reported a two- to threefold longer time to the next cigarette following exercise. Cravings and withdrawal symptoms were reduced with an exercise intensity from as high as 60-85% heart rate reserve (HRR) (lasting 30-40 minutes) to as low as 24% HRR (lasting 15 minutes), and also with isometric exercise (for 5 minutes). All but one study involved participants temporarily abstaining for the purposes of the experiment. Distraction was probably not the primary reason for the effects. Conclusions: Relatively small doses of exercise should be recommended as an aid to managing cigarette cravings and withdrawal symptoms. Further research to understand the mechanisms involved, such as stress reduction or neurobiological mechanisms, could lead to development of more effective and practical methods to reduce withdrawal phenomena.

Thuerauf N; Lunkenheimer J; Lunkenheimer B; Sperling W; Bleich S; Schlabeck M et al. Memantine fails to facilitate partial cigarette deprivation in smokers: No role of memantine in the treatment of nicotine dependency? Journal of Neural Transmission 114(3): 351-357, 2007. (50 refs.)

The efficacy of Memantine in the treatment of nicotine dependency in humans remained to be evaluated. The aims of our pilot study were to investigate (1) the effectiveness of Memantine in facilitating smoking reduction and (2) the influence of memantine on the perception of nicotine. In order to achieve these aims we conducted a placebo controlled double-blind parallel group study in smokers (n = 20 per group). Before the beginning of the treatment-phase (10/20mg Memantine per day) all participants were instructed to reduce smoking (partial deprivation). Before and during partial deprivation we registered the daily cigarette consumption and craving estimates. Following nasal stimulation with nicotine enantiomers hedonic and intensity estimates and the discrimination ability were assessed. Memantine failed to facilitate smoking reduction and did not influence the perception of nicotine with the exception of a weak reduction of olfactory intensity estimates reaching statistical significance for one nicotine enantiomer only.

Toll BA; O'Malley SS; McKee SA; Salovey P; Krishnan-Sarin S. Confirmatory factor analysis of the Minnesota Nicotine Withdrawal Scale. Psychology of Addictive Behaviors 21(2): 216-225, 2007. (50 refs.)

The authors examined the factor structure of the Minnesota Nicotine Withdrawal Scale (MNWS) using confirmatory factor analysis in 3 clinical research samples of smokers trying to quit (N = 723). Three confirmatory factor analytic models, based on previous research, were tested with each of the 3 study samples at multiple points in time. A unidimensional model including all 8 MNWS items was found to be the best explanation of the data. This model produced fair to good internal consistency estimates. Additionally, these data revealed that craving should be included in the total score of the MNWS. Factor scores derived from this single-factor, 8-item model showed that increases in withdrawal were associated with poor smoking outcome for 2 of the clinical studies. Confirmatory factor analyses of change scores showed that the MNWS symptoms cohere as a syndrome over time. Future investigators should report a total score using all of the items from the MNWS.

Toll BA; Schepis TS; O'Malley SS; Mckee SA; Krishnan-Sarin S. Subjective reactivity to the first cigarette of the day as a predictor of smoking relapse: A preliminary study. Drug and Alcohol Dependence 89(2/3): 302-305, 2007. (22 refs.)

We examined subjective responses to smoking the first cigarette of the day and investigated how these responses related to smoking cessation treatment outcome. Data from participants (N = 207) in a clinical trial of message framing for smoking cessation with bupropion, obtained prior to the targeted quit day, were used to examine indices of craving, withdrawal, and affect before and after smoking the first cigarette of the day. After smoking the initial cigarette, craving, withdrawal symptoms, and negative affect were lessened, and positive affect increased. Greater decreases in craving as measured by the questionnaire on smoking urges-brief (QSU-Brief) predicted relapse at the end of treatment (6 weeks) and at the 3-month follow-up time point. These associations do not appear to be mediated by established measures of dependence. Thus, this preliminary study provides evidence that there are significant changes in craving, withdrawal, and affect related to smoking the first cigarette of the day, with the largest of these changes observed for craving. Moreover, changes in tobacco craving in response to the first cigarette of the day may be a novel predictor of smoking relapse that should be tested in future studies.

Tong C; Bovbjerg DH; Erblich J. Smoking-related videos for use in cue-induced craving paradigms. Addictive Behaviors 32(12): 3034-3044, 2007. (39 refs.)

Environmental cues (e.g., the sight of a cigarette) have long been recognized as important triggers for craving in smokers. Available imaging technologies (e.g., fMRI) allow investigation of the neural mechanisms for cue-induced craving, but there stands a need for a cue-delivery system compatible with an MRI environment. We developed a standardized set of 24 high-resolution videos, 12 containing cigarette smoking scenes (e.g., lighting up), and 12 containing neutral scenes (e.g., reading a book), each 30 s long, with comparable lighting, visual complexity, and background filmed by a professional cinematographer. Study participants were 20 smokers (mean age = 37.7 years, 50% female). Each was exposed to the 24 videos in a random order under laboratory conditions. Dependent measures included heart rate, blood pressure, skin conductance, skin temperature, and self-reported craving (0-100) following each video. Overall findings indicated that smokers had greater reactivity to the smoking videos than to neutral videos (p<.01). Follow-up univariate analyses revealed significant cue effects on self-reported craving, galvanic skin response, and skin temperature. Interestingly, exploratory examination of gender revealed that men had higher blood pressure and skin temperature responses than women, and that women had higher responses when viewing videos of women smoking than when viewing men smoking. Results support this set of videos as an effective tool for investigation of cue-elicited craving, and raise the possibility of unique gender effects in cue reactivity.

Volkow ND; Fowler JS; Wang GJ; Swanson JM; Telang F. Dopamine in drug abuse and addiction: Results of imaging studies and treatment implications. (review). Archives of Neurology 64(11): 1575-1579, 2007. (32 refs.)

Imaging studies have provided new insights on the role of dopamine (DA) in drug abuse and addiction in the human brain. These studies have shown that the reinforcing effects of drugs of abuse in human beings are contingent not just on DA increases per se in the striatum (including the nucleus accumbens) but on the rate of DA increases. The faster the increases, the more intense the reinforcing effects. They have also shown that elevated levels of DA in the dorsal striatum are involved in the motivation to procure the drug when the addicted subject is exposed to stimuli associated with the drug (conditioned stimuli). In contrast, long-term drug use seems to be associated with decreased DA function, as evidenced by reductions in D2 DA receptors and DA release in the striatum in addicted subjects. Moreover, the reductions in D2 DA receptors in the striatum are associated with reduced activity of the orbitofrontal cortex (region involved with salience attribution and motivation and with compulsive behaviors) and of the cingulate gyrus (region involved with inhibitory control and impulsivity), which implicates deregulation of frontal regions by DA in the loss of control and compulsive drug intake that characterizes addiction. Because DA cells fire in response to salient stimuli and facilitate conditioned learning, their activation by drugs will be experienced as highly salient, driving the motivation to take the drug and further strengthening conditioned learning and producing automatic behaviors (compulsions and habits).

Walker MS; Vidrine DJ; Gritz ER; Larsen RJ; Yan Y; Govindan R et al. Smoking relapse during the first year after treatment for early-stage non-small-cell lung cancer. Cancer Epidemiology, Biomarkers and Prevention 15(12): 2370-2377, 2006. (59 refs.)

Background: Non-small-cell lung cancer patients who continue to smoke after cancer diagnosis are more likely to experience disease recurrence, decreased treatment efficacy, and treatment complications. Despite this, many continue to smoke, with estimates ranging from 13% to similar to 60%. Methods: Participants were 154 early-stage, non-small-cell lung cancer patients who had smoked within 3 months before surgery. Patients were followed for 12 months after surgery to assess smoking status and duration of continuous abstinence after surgery. Predictors included medical, smoking history, psychosocial, and demographic characteristics. Results: At some point after surgery, 42.9% of patients smoked; at 12 months after surgery, 36.9% were smoking. Sixty percent of patients who lapsed did so during the first 2 months after surgery. Smoking at follow-up was predicted by shorter quit duration before surgery, more intense Appetitive cravings (expectation of pleasure from smoking), lower income, and having a higher level of education. Time until the first smoking lapse was predicted by shorter quit duration before surgery, more intense Appetitive cravings to smoke, and lower income. Among those who lapsed, greater delay before the lapse was associated with abstinence at the 12-month follow-up assessment. Conclusions: Nearly half of non-small-cell lung cancer patients return to smoking after surgery if they have recent smoking histories. Most initial lapses happen within 2 months and occur in response to more recent smoking and more intense cravings. Findings suggest that interventions to prevent relapse should target those who wait until cancer surgery to quit smoking and should be started as soon as possible after treatment.

Wang Z; Faith M; Patterson F; Tang K; Kerrin K; Wileyto EP et al. Neural substrates of abstinence-induced cigarette cravings in chronic smokers. Journal of Neuroscience 27(51): 14035-14040, 2007. (63 refs.)

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 magnetic resonance imaging 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 (after >= 12 h 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 the right OFC, right dorsolateral prefrontal cortex, 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.

Waters AJ; Carter BL; Robinson JD; Wetter DW; Lam CY; Cinciripini PM. Implicit attitudes to smoking are associated with craving and dependence. Drug and Alcohol Dependence 91(2/3): 178-186, 2007. (57 refs.)

The Implicit Association Test (IAT) has been used to assess automatic affective responses to drug cues. Smokers (n=57) completed the IAT at four experimental sessions. They abstained from smoking before two of the sessions (AB) and smoked normally before the other two sessions (NON). At one AB (and NON) session, they smoked a cigarette about 40 min before completing the IAT (S), and at the other they did not smoke (NS). Overall, participants exhibited a negative IAT effect, indicating that they found the classification task easier when smoking was paired with bad than when smoking was paired with good. Using repeated measures ANOVA, the IAT effect was made less negative by pre-session abstinence, and made more negative by smoking. It was most negative in the NON-S condition. Using Generalized Estimating Equations analyses, the IAT effect was positively associated with pre-task craving ratings assessed on the Questionnaire of Smoking Urges-Brief but was not associated with a physiological measure of automatic affective responses (startles while viewing smoking versus neutral pictures). The IAT effect was associated with scores on the Fagerstrom Test for Nicotine Dependence. In sum, automatic affective responses assessed with the smoking IAT are associated with measures of smoking motivation and dependence. reserved.

Zilberman ML; Tavares H; Hodgins DC; El-Guebaly N. The impact of gender, depression, and personality on craving. Journal of Addictive Diseases 26(1): 79-84, 2007. (33 refs.)

Craving plays an important role in the addictive behavior process. The impact of gender, emotional state and personality on craving, however, has been understudied. Ninety-six women and 86 men seeking treatment for substance dependence were investigated regarding the association between personality factors (assessed by the Temperament and Character Inventory), depressive/anxiety symptomatology (assessed by the Beck Depression Inventory and the Beck Anxiety Inventory), and craving intensity (rated in the 7-day and the 24-hour periods prior to assessment). Recency of substance use and impulsivity were significantly associated with craving intensity for both women and men. Regression analyses revealed that depression best predicted craving for women, but not for men. These results suggest that while recent substance use and impulsivity can be important predictors of craving across gender, depression plays a critical role in craving among women. This finding underscores the need for vigorous assessment and treatment of comorbid symptomatology in women entering addiction treatment.