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CORK Bibliography: Craving

75 citations. 2003 to present

Prepared: March 2004

Prepared: March 2003

Ahmed SH; Lin D; Koob GF; Parsons LH. Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels. Journal of Neurochemistry 86(1): 102-113, 2003. (98 refs.)

Previous studies showed that prolonged access to cocaine or heroin self-administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125-1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self-administration. Self-administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self-administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.

al'Absi M; Hatsukami D; Davis GL; Wittmers LE. Prospective examination of effects of smoking abstinence on cortisol and withdrawal symptoms as predictors of early smoking relapse. Drug and Alcohol Dependence 73(3): 267-278, 2004. (69 refs.)

This study addressed the hypothesis that exaggerated mood and cortisol changes during the first 24 h of smoking abstinence are associated with early relapse. Salivary cortisol levels and mood reports were measured during 24-h ad libitum smoking and the first 24-h abstinence period of a quit attempt. Seventy-two habitual smokers (34 women and 38 men) who were interested in smoking cessation participated. Cotinine concentrations in saliva and expired carbon monoxide were measured before and after abstinence and 1 week after the quit date to verify smoking status. Abstinence produced significant withdrawal symptoms in all participants and reduced cotinine and carbon monoxide levels. While participants showed the expected diurnal changes in cortisol levels, those who relapsed within the first week post quitting exhibited a greater drop in morning cortisol concentrations during abstinence relative to their ad libitum smoking levels. Participants who relapsed reported greater withdrawal symptoms, craving for cigarettes, and distress, and they also reported greater reduction in positive affect during the first 24-h period of abstinence than those who maintained abstinence. These results support the hypothesis that early relapse is associated with exaggerated mood and adrenocortical perturbations observed during the first day of abstinence.

Alsene KM; Li Y; Chaverneff F; de Wit H. Role of abstinence and visual cues on food and smoking craving. Behavioural Pharmacology 14(2): 145-151, 2003. (56 refs.)

This study was designed to examine the relationship between cravings for food and cravings for cigarettes by presenting smoking-related or food-related visual cues to smokers who were either smoking-deprived or food-deprived. Fifteen regular cigarette smokers participated in this four-session, within-subject study in which they rated their craving for cigarettes and craving for food under four conditions: after abstaining from smoking, after abstaining from eating, after abstaining from both smoking and eating, or after no abstinence. We found that before presentation of the cues, overnight smoking abstinence increased craving for cigarettes, and overnight food abstinence increased craving for food. In each condition, presentation of cues further increased craving for the object of deprivation: smoking cues further increased craving for cigarettes after smoking abstinence, and food cues further increased craving for food after abstaining from food. Smoking abstinence did not affect craving for food, but food abstinence modestly increased smoking craving. These results indicate that craving for cigarettes or food is specifically increased by both deprivation from the substance and by presentation of substance-related cues.

Beswick T; Best D; Bearn J; Gossop M; Rees S; Strang J. The effectiveness of combined naloxone/lofexidine in opiate detoxification: Results from a double-blind randomized and placebo-controlled trial. American Journal on Addictions 12(4): 295-305, 2003. (33 refs.)

The efficacy of lofexidine/naloxone was compared with lofexidine/placebo in a double-blind, randomized, placebo-controlled trial in 89 opiate-dependent patients. There were no significant differences between the two groups in the proportion of patients completing detoxification or in the length of stay. Patients in the active naloxone group demonstrated gradual reductions in levels of withdrawal and craving over the detoxification period. At completion of detoxification, patients who received naloxone maintained a level of withdrawal consistently lower than that in the placebo group; however, naloxone did not substantially accelerate the resolution of the withdrawal syndrome. Implications for future research are discussed.

Biberman R; Neumann R; Katzir I; Gerber Y. A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation. Addiction 98(10): 1403-1407, 2003. (11 refs.)

Objectives: To compare the effect of oral selegiline plus nicotine patch with placebo plus nicotine patch on smoking cessation rates. Design: Randomized double-blind placebo-controlled trial. Setting: Three community-based clinics. Participants One hundred and nine male and female smokers aged 18-55 years, who smoked at least 15 cigarettes/day. Interventions Oral selegiline, 2.5 mg, or placebo twice/day initiated 1 week before the quit day, followed by 5 mg oral selegiline or placebo twice daily for 26 weeks, plus active nicotine skin patch to all participants for the first 8 weeks only. Measures of continuous abstinence rates up to 52 weeks, withdrawal symptoms, blood pressure and adverse events incidence. Findings: Twenty-five per cent (14 of 56) were continuously abstinent for 52 weeks in the selegiline plus nicotine group compared with 11% (6 of 53) in the placebo plus nicotine group (P = 0.08). Craving for cigarettes was lower in the selegiline plus nicotine group 4 weeks after quit day (P = 0.02).Conclusions: Adding selegiline to nicotine patch was associated with a doubling of the 52-week continuous abstinence rate, but this difference was not statistically significant. Selegiline significantly reduced craving for cigarettes and appeared to mitigate the need for nicotine replacement therapy. The results suggest that selegiline is a promising drug for future smoking cessation research.

Boileau I; Assaad JM; Pihl RO; Benkelfat C; Leyton M; Diksic M et al. Alcohol promotes dopamine release in the human nucleus accumbens. Synapse 49(4): 226-231, 2003. (58 refs.)

Microdialysis experiments in rodents indicate that ethanol promotes dopamine release predominantly in the nucleus accumbens, a phenomenon that is implicated in the reinforcing effects of drugs of abuse. The aim of the present study was to test the hypothesis in humans that an oral dose of ethanol would lead to dopamine release in the ventral striatum, including the nucleus accumbens. Six healthy subjects underwent two [C-11]raclopride PET scans following either alcohol (1 ml/kg) in orange juice or orange juice alone. Subjective mood changes, heart rate, and blood-alcohol levels were monitored throughout the procedure. Personality traits were evaluated using the tridimensional personality questionnaire. PET images were co-registered with MRI and transformed into stereotaxic space. Statistical parametric maps of [C-11]raclopride binding potential change were generated. There was a significant reduction in [C-11]raclopride binding potential bilaterally in the ventral striatum/nucleus accumbens in the alcohol condition compared to the orange juice condition, indicative of increased extracellular dopamine. Moreover, the magnitude of the change in [C-11]raclopride binding correlated with the alcohol-induced increase in heart rate, which is thought to be a marker of the psychostimulant effects of the drug, and with the personality dimension of impulsiveness. The present study is the first report that, in humans, alcohol promotes dopamine release in the brain, with a preferential effect in the ventral striatum. These findings support the hypothesis that mesolimbic dopamine activation is a common property of abused substances, possibly mediating their reinforcing effects.

Bossert JM; Shaham Y. Drug onset cues, conditioned withdrawal, and drug relapse: Comment on McDonald and Siegel (2004). Experimental and Clinical Psychopharmacology 12(1): 15-17, 2004. (24 refs.)

Previous research has shown that under certain conditions environmental cues associated with morphine administration induce drug-opposite conditioned effects that mimic symptoms of opiate withdrawal. R. V. McDonald and S. Siegel (2004) extend these observations by demonstrating that acute exposure to a low dose of morphine induces symptoms of opiate withdrawal in rats previously exposed to a high dose of morphine. They hypothesized that early drug onset cues, repeatedly paired with later, larger drug effects, mediate the paradoxical effect of the low drug dose on behavior. They also hypothesized that conditioned withdrawal symptoms induced by the early drug onset cues may mediate the "priming" effect of drugs on relapse and craving. The authors of this comment discuss the degree to which the literature supports this hypothesis.

Breteler MHM; Hilberink SR; Zeeman G; Lammers SMM. Compulsive smoking: The development of a Rasch homogeneous scale of nicotine dependence. Addictive Behaviors 29(1): 199-205, 2004. (17 refs.)

The unidimensionality of nicotine dependence has not been established firmly yet. The aim of this study was to assess the dimensionality of nicotine dependence, preferably meeting the strict assumptions of the Rasch model. First, we examined the validity of the Fagerstr�m Test for Nicotine Dependence (FTND) [Br. J. Addict. 86 (1991) 1119.] in 1525 smokers who participated in a national survey considering smoking behavior. Two factors were found, suggesting that the FTND does not measure a unidimensional construct. Factor analysis of 19 other dependence items in 512 smokers resulted in four factors of which three were interpretable: compulsive smoking, social problems due to smoking, and physical dependence. We focused on smoking compulsivity. This factor turned out to consist of a four-item Rasch homogeneous scale. Two items of the FTND with face validity of smoking compulsivity were found to fit into the scale. The results of Rasch analysis were in support of a continuum of compulsivity. Difficulty refraining from smoking in places where it is forbidden was found to indicate highest compulsivity. Several correlates with smoking compulsivity were found. We conclude that compulsive smoking is one important dimension of nicotine dependence, which may account for the considerable relapse of this disorder.

Brown ES; Nejtek VA; Perantie DC; Orsulak PJ; Bobadilla L. Lamotrigine in patients with bipolar disorder and cocaine dependence. Journal of Clinical Psychiatry 64(2): 197-201, 2003. (64 refs.)

Background: Bipolar disorder is associated with the highest substance abuse rates of any psychiatric illness. Therefore, treatments that stabilize mood and decrease drug use or cravings are of great interest. Open-label lamotrigine was examined in 30 outpatients with DSM-IV bipolar disorder and cocaine dependence. Lamotrigine was either added to existing medication regimens or used as monotherapy. Method: Lamotrigine was started at a dose of 25 mg/day (12.5 mg/day in those taking valproic acid) and titrated to a maximum dose of 300 mg/day. Subjects received a baseline evaluation including a structured clinical interview and weekly assessments for 12 weeks with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Cocaine Craving Questionnaire (CCQ). At each appointment, a urine sample was obtained, and participants reported drug use during the previous week. The subjects consisted of 13 men and 17 women with cocaine dependence and bipolar I disorder (N = 22), bipolar II disorder (N = 7), or bipolar disorder not otherwise specified (N = 1), with a mean +/- SD age of 35.4 +/- 7.2 years. Data were analyzed using the last observation carried forward on all subjects who completed the baseline evaluation and at least 1 postbaseline assessment. Results: Significant improvement was observed in HAM-D, YMRS, and BPRS scores (p less than or equal to .02). Cravings also significantly decreased as measured by the CCQ (p < .001). Dollar amount spent on drugs decreased nonsignificantly. Lamotrigine was well tolerated, with no subjects discontinuing due to side effects. Conclusion: Lamotrigine treatment was well tolerated in this sample and associated with statistically significant improvement in mood and drug cravings but not drug use. The findings suggest that larger controlled trials of lamotrigine are needed in this population.

Chi H; de Wit H. Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers. Alcoholism: Clinical and Experimental Research 27(5): 780-786, 2003. (47 refs.)

Background: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. Methods: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session. subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. Results: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. Conclusions: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.

Collins ED; Vosburg SK; Hart CL; Haney M; Foltin RW. Amantadine does not modulate reinforcing, subjective, or cardiovascular effects of cocaine in humans. Pharmacology, Biochemistry and Behavior 76(3-4): 401-407, 2003. (40 refs.)

Data from several clinical studies have suggested that amantadine, which has dopaminergic agonist and glutamatergic antagonist effects, may be useful for the treatment of cocaine dependence. The interaction between amantadine and smoked cocaine was examined in 10 cocaine smokers (7 men, 3 women), who participated in a 26-day inpatient study. Participants were maintained on amantadine (0 and 100 mg bid) for 5 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked a sample dose of cocaine base (0, 12, 25, and 50 mg) once, and were subsequently given five choice opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose varied systematically. Cocaine produced stimulant-like reinforcing, subjective, and physiological effects. Amantadine maintenance did not modify the choice to self-administer smoked cocaine. These findings, taken together with the decidedly mixed literature, suggest that amantadine (100 mg bid) will not have a role in the treatment of cocaine dependence.

Cooney JL; Cooney NL; Pilkey DT; Kranzler HR; Oncken CA. Effects of nicotine deprivation on urges to drink and smoke in alcoholic smokers. Addiction 98(7): 913-921, 2003. (33 refs.)

Aim: This study examined the effect of nicotine deprivation on alcohol and smoking urges in a sample of alcohol-dependent smokers in early recovery. Design: Using a within-subjects design, participants underwent two cue-reactivity laboratory sessions in which they rated their urges for alcohol and cigarettes during the following three trials: baseline, neutral cue and mood induction combined with alcohol beverage cue exposure. One session was completed after 34 hours of nicotine deprivation and another in a non-deprived state. Participants: Forty alcohol-dependent heavy smokers recruited from a substance abuse day treatment program. Measurements: Self-reported urge to drink, urge to smoke and salivation. Findings: Results showed that during the non-deprived session, alcohol cue presentations were associated with significant increases in urges to drink and urges to smoke. Acute nicotine deprivation led to increased smoking urges, but was not associated with increased urges to drink alcohol. Conclusions: Findings suggest that the acute effects of smoking cessation are unlikely to increase risk of relapse to alcohol in alcoholic patients who are undergoing treatment.

Cox WM; Brown MA; Rowlands LJ. The effects of alcohol cue exposure on non-dependent drinkers' attentional bias for alcohol-related stimuli. Alcohol and Alcoholism 38(1): 45-49, 2003. (23 refs.)

Aims: The effects of university students' habitual drinking practices and experimental alcohol cue exposure on their attentional bias for alcohol-related stimuli were assessed. Methods: Participants were exposed in vivo to either an alcoholic or nonalcoholic beverage immediately prior to completing a cognitively demanding emotional Stroop task that uses alcohol-related and control words as potential distractors. Results: Regression analyses indicated that, for participants who were low consumers of alcohol, neither level of habitual drinking, type of cue exposure, nor their interaction predicted attentional bias for the alcohol-related stimuli. For high consumers of alcohol who were exposed to the alcoholic beverage (but not those exposed to the non-alcoholic beverage), the amount of alcohol that participants habitually drank significantly predicted the degree of attentional bias. Conclusions: The results indicate that, among non-dependent drinkers (unlike alcohol-dependent participants), alcohol-related attentional bias is not a generalized phenomenon, but occurs only under a specific set of circumstances.

Dallery J; Houtsmuller EJ; Pickworth WB; Stitzer ML. Effects of cigarette nicotine content and smoking pace on subsequent craving and smoking. Psychopharmacology 165(2): 172-180, 2003. (30 refs.)

Rationale: The relative contribution of sensory and pharmacological variables in regulating craving and smoking remains unclear. Rapid smoking procedures and denicotinized cigarettes can be used to further disentangle these factors, and to explore the relationship between craving and smoking. Objective: The present study examined the role of nicotine and sensory cues in mediating craving and smoking, and the relationship between craving and smoking. Methods: Participants (n=15) engaged in one session each of rapid smoking (up to nine cigarettes with puffs taken every 6 s) and normal paced smoking with nicotinized and denicotinized cigarettes (total of four sessions). During the next 3 h, craving and withdrawal assessments and smoking opportunities were scheduled every 15 min. Plasma nicotine levels were measured at baseline, immediately and 15 min after the smoking interventions, and subsequently at the time when the participant first chose to smoke. Results: Craving ratings were equally suppressed immediately after all conditions. After self-paced conditions, both types of cigarettes produced equivalent effects on latency to smoke. Latency to smoke was significantly longer after rapid smoking of nicotinized cigarettes compared to all other conditions. Finally, changes in craving were associated with choices to smoke. Conclusions: The sensory cues associated with smoking suppressed craving ratings regardless of the smoking pace or nicotine content. Only at high doses did nicotine levels play an additional role in acutely suppressing smoking behavior. Small elevations in craving ratings were associated with choices to smoke.

Demmel R; Schrenk J. Sensory evaluation of alcohol-related and neutral stimuli: Psychophysical assessment of stimulus intensity. (rapid communication). Addictive Behaviors 28(2): 353-360, 2003. (9 refs.)

Research on reactivity to alcohol cues yielded conflicting results. While some authors report differences in subjective or physiological responses to drug-related stimuli between addicts and healthy controls, other researchers found no group differences in response patterns. Moreover, a dissociation of self-report and psychophysiological measures of cue reactivity is often observed. To some extent, this might be due to confounding stimulus type (neutral vs. drug-related) and stimulus intensity in cue reactivity research. The purpose of the present study is to match alcoholic and nonalcoholic stimuli according to their empirically assessed intensity. Stimulus intensity is estimated by magnitude estimation. Results clearly indicate that alcohol-related cues differ considerably from water and other neutral stimuli with respect to perceived intensity. Moreover, estimation of stimulus intensity depends on mode of presentation (smell vs. combined smell and taste). Results of previous cue reactivity studies in the alcohol field might have been affected in different degrees by confounding stimulus type and intensity.

Donny EC; Bigelow GE; Walsh SL. Choosing to take cocaine in the human laboratory: Effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement. Drug and Alcohol Dependence 69(3): 289-301, 2003. (41 refs.)

Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers (n=8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from $1 to $16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated.

Epstein AM; King AC. Naltrexone attenuates acute cigarette smoking behavior. Pharmacology, Biochemistry and Behavior 77(1): 29-37, 2004. (54 refs.)

This within-subjects, placebo-controlled laboratory study was designed to examine the effects of naltrexone on cigarette response in 44 chronic smokers (23 male, 21 female). Each participant received either 50-mg oral naltrexone or identical placebo during the morning of the session after maintaining overnight abstinence. Subsequently, the participant was administered a smoking cue (holding lit cigarette) to examine craving and associated features of smoking, and instructed to smoke a cigarette 1 h later. This was followed by a smoking interval in which participants could choose to smoke up to four more cigarettes over a 2-h period. Subjective measures (withdrawal, craving, affect, and side effects) and smoking behavior were assessed throughout the session. Naltrexone significantly reduced the total number of choice cigarettes smoked and expired carbon monoxide levels (P-s <.05). Naltrexone significantly increased total side effects, especially for sedation (P<.01). Further, naltrexone significantly increased overall negative affect, and decreased positive affect I h after smoking the first cigarette (Ps <.05). However, naltrexone did not affect acute withdrawal or smoking urges. Despite mixed findings, women reported more overall naltrexone-induced withdrawal (P<.05) and side effects (P<.08) compared-to men. Although the exact mechanism is unknown, the findings support an opioid antagonist attenuation of smoking behavior.

Flannery BA; Poole SA; Gallop RJ; Volpicelli JR. Alcohol craving predicts drinking during treatment: An analysis of three assessment instruments. Journal of Studies on Alcohol 64(1): 120-126, 2003. (39 refs.)

Objective: The purpose of this investigation was to examine the utility of three craving instruments to predict drinking during treatment. The three assessments used were the Penn Alcohol Craving Scale (PACS), the Alcohol Urge Questionnaire (AUQ) and Items 1-6 of the Obsessive subscale (OBS) of the Obsessive Compulsive Drinking Scale (OCDS). Method: The three instruments were administered during the course of a 9-month, double-blind, placebo-controlled trial of 100 mg/day of naltrexone, and a manual-based psychosocial intervention using the BRENDA manual conducted at the University of Pennsylvania's Treatment Research Center. Participants (133 men and 50 women at the initiation of the study) used these instruments to self-report craving on a weekly or biweekly basis. The weekly number of drinks was reported using the Timeline Followback interview. The data were analyzed with generalized estimating equations using craving scores at I week as the independent variable and number of drinks in the subsequent treatment week as the dependent variable. Results: Each of the three scales predicted drinking during the subsequent treatment week. The PACS was the strongest predictor followed closely by the OBS and then the AUQ. Most important, craving as measured by the three scales was a stronger predictor of subsequent drinking than was drinking during the prior treatment week. Conclusions: Craving assessment provides a useful means of predicting drinking during treatment. Such information would be helpful in designing clinical trials and for many treatment modalities.

Fouquereau E; Fernandez A; Mullet E; Sorum PC. Stress and the urge to drink. Addictive Behaviors 28(4): 669-685, 2003. (20 refs.)

Objective: Understanding why people drink alcohol is important for the health and safety of individuals and the public. The aim of this study was to examine from a cognitive point of view the hypothesized link between drinking and stress. Methods: 25 scenarios were constructed by combining two items, either two life-change events or a social situation and an emotional state. In the initial three experiments, 159 male and 43 female alcoholics and 157 male and 93 female nonalcoholics in France judged the degree to which these scenarios were stressful and subsequently the degree to which they stimulated an urge to drink. In the final experiment, 126 of the male alcoholics were studied at the beginning and end of an inpatient alcohol rehabilitation program. Results: The alcoholics and nonalcoholics, regardless of gender, assigned similar stress values to the scenarios and used the same cognitive rules for combining the stress associated with two items (disjunctive rules for two life-change events and additive ones for a personal emotion combined with a social situation). They differed, however, in how they judged the urge to drink. The nonalcoholics reported little stimulus to drink from any combination of items, whereas the alcoholics not only perceived the individual items as stimulating an urge to drink but also used the same cognitive rule in judging the combined urge to drink of two items as they used in judging the combined stress. After completing rehabilitation, the alcoholics judged the combinations of life-change events as stimulating less stress and less urge to drink. Nevertheless, they continued to use a disjunctive combination rule. Conclusions: Stress and drinking are linked at a fundamental cognitive level among alcoholics, though not among nonalcoholics. Alcoholics should be helped to recognize this link, to reduce their feelings of stress, and to find outlets other than drink.

Franken IHA. Drug craving and addiction: Integrating psychological and neuropsychopharmacological approaches. (review). Progress in Neuro-Psychopharmacology & Biological Psychiatry 27(4): 563-579, 2003. (237 refs.)

In the present review, an integrated approach to craving and addiction is discussed, which is based on recent insights from psychology and neuropsychopharmacology. An integrated model explains craving and relapse in humans by the psychological mechanism of "attentional bias" and provides neuropsychopharmacological mechanisms for this bias. According to this model, cognitive processes mediate between drug stimulus and the subject's response to this stimulus and subsequent behavioral response (e.g., drug use, relapse). According to the model, a conditioned drug stimulus produces an increase in dopamine levels in the corticostriatal circuit, in particular the anterior cingulate gyrus, amygdala, and nucleus accumbens, which in turn serves to draw the subject's attention towards a perceived drug stimulus. This process results in motor preparation and a hyperattentive state towards drug-related stimuli that, ultimately, promotes further craving and relapse. Evidence for this attentional bias hypothesis is reviewed from both the psychopharmacological and the neuroanatomical viewpoints. The attentional bias hypothesis raises several suggestions for clinical approaches and further research.

Franken IHA; Stam CJ; Hendriks VM; van den Brink W. Neurophysiological evidence for abnormal cognitive processing of drug cues in heroin dependence. Psychopharmacology 170(2): 205-212, 2003. (41 refs.)

Rationale. Recent studies provide evidence for specific aspects of cue processing in addictive disorders. Objective. The present study employs event related potentials (ERPs) to investigate heroin related visual information processing Methods. Neutral and heroin related pictures were presented to 19 male abstinent heroin dependent patients and 14 male healthy controls. Results. Patients exhibited larger slow positive wave (SPW) components of the ERP on heroin related pictures than on neutral pictures. Within healthy control subjects there was no difference on the SPW between neutral and heroin pictures. Within heroin dependent patients, mean SPW response to heroin pictures was correlated with post-experiment craving. Conclusion. This study provides neurophysiological evidence that information processing of drug-related information is abnormal in heroin dependent patients. The results provide further evidence for the cognitive and neurobiological accounts of substance dependence such as the incentive-sensitization theory.

Goeders NE. The impact of stress on addiction. European Neuropsychopharmacology 13(6): 435-441, 2003. (97 refs.)

This article will review data obtained from both clinical and preclinical investigations demonstrating that exposure to stress has a significant impact on drug addiction. The preclinical literature suggests that stress increases reward associated with psychomotor stimulants, possibly through a process similar to sensitization. While it is not conclusive that a similar process occurs in humans, a growing clinical literature indicates that there is a link between substance abuse and stress. One explanation for the high concordance between stress-related disorders and drug addiction is the self-medication hypothesis, which suggests that a dually diagnosed person often uses the abused substance to cope with tension associated with life stressors or to relieve symptoms of anxiety and depression resulting from a traumatic event. However, another characteristic of self-administration is that drug delivery and its subsequent effects on the hypothalamo-pituitary-adrenal (HPA) axis are under the direct control of the individual. This controlled activation of the HPA axis may result in the production of an internal state of arousal or stimulation that is actually sought by the individual (i.e., the sensation-seeking hypothesis). During abstinence, exposure to stressors or drug-associated cues can stimulate the HPA axis to remind the individual about the effects of the abused substance, thus producing craving and promoting relapse. Continued investigations into how stress and the subsequent activation of the HPA axis impact addiction will result in the identification of more effective and efficient treatment for substance abuse in humans. Stress reduction, either alone or in combination with pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for addiction.

Groman E; Fagerstrom K. Nicotine dependence: Development, mechanisms, individual differences and links to possible neurophysiological correlates. (review). Wiener Klinische Wochenshrift 115(5-6): 155-160, 2003. (49 refs.)

There is now little doubt that the majority of people who smoke tobacco do so to experience the psychopharmacological properties of the nicotine present in the smoke and that a significant proportion of habitual tobacco users become addicted to the drug nicotine. In the US some 80% and in Europe (Germany) 39% of smokers have been classified as dependent according to the diagnostic guidelines of the American Psychiatric Association. As a result, direct nicotine replacement is used increasingly by many people who want to stop smoking. The objectives of this review are to outline the mechanisms involved in the development and maintenance of nicotine dependence and to link behavioural observations to possible neurophysiologic correlates.

Haney M; Hart CL; Vosburg SK; Nasser J; Bennett A; Zubaran C; Foltin RW. Marijuana withdrawal in humans: Effects of oral THC or divalproex. Neuropsychopharmacology 29(1): 158-170, 2004. (39 refs.)

Abstinence following daily marijuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marijuana withdrawal. Participants (n=7/study), who were not seeking treatment for their marijuana use, reported smoking 6-10 marijuana cigarettes/day, 6-7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marijuana (0,00, 3.04% THC). Active and placebo marijuana were smoked on in-patient days 1-8, while only placebo marijuana was smoked on days 9-14, that is, marijuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9-14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marijuana abstinence decreased ratings of ''anxious', 'miserable', 'trouble sleeping', 'chills', and marijuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marijuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.

Havermans RC; Debaere S; Smulders FTY; Wiers RW; Jansen ATM. Effect of cue exposure, urge to smoke, and nicotine deprivation on cognitive performance in smokers. Psychology of Addictive Behaviors 17(4): 336-339, 2003. (15 refs.)

The primary aim of this investigation was to test the hypothesis that the urge to smoke interferes directly with cognitive performance. Fifty-four smokers were randomly assigned to 1 of 3 groups: (a) ad lib, (b) deprived, or (c) nicotine patch. Participants rated their urge to smoke on continuous visual analogue scales. Cognitive performance was determined by measuring reaction times (RTs) on a Sternberg task. The deprived group reported a higher urge and had longer RTs than the ad lib group when exposed to smoking-related cues. However, the nicotine patch group reported a higher urge in the absence of longer RTs. The results indicated that nicotine deprivation affects cognitive performance and that the urge to smoke only partially mediated RTs.

Heinz A; Lober S; Georgi A; Wrase J; Hermann D; Rey ER; Wellek S; Mann K. Reward craving and withdrawal relief craving: Assessment of different motivational pathways to alcohol intake. Alcohol and Alcoholism 38(1): 35-39, 2003. (44 refs.)

Aims: Craving for the rewarding effects of alcohol may be evoked by conditioned alcohol-like effects whereas conditioned compensatory responses may induce withdrawal relief craving. We tested the hypothesis that drinking in positive emotional states is associated with appetitive reactions to alcohol-associated cues and contributes to reward craving, while conditioned withdrawal is associated with drinking in negative situations and distressful, obsessive preoccupations with alcohol. Methods: In 38 detoxified alcoholics, the Obsessive Compulsive Drinking Scale was used to assess the craving factors 'impaired control', 'interference with social functioning' and 'obsession'. Affective responses to alcohol-associated visual stimuli were measured with the affect-modulated eyeblink startle reflex, positive and negative drinking situations with the Inventory of Drinking Situations (IDS) and withdrawal-like symptoms preceding alcohol intake with the revised Clinical Institute Assessment for Alcohol Scale (CIWA-Ar). Results: Appetitive reactions to alcohol-associated cues correlated positively with drinking in positive situations and contributed significantly to the craving factor 'interference' with social and work functioning. The severity of withdrawal-like symptoms preceding alcohol intake contributed to the craving factor 'obsession'; however, contrary to our hypothesis, this measure of conditioned withdrawal correlated with drinking not only in negative but also in positive situations. Conclusions: Drinking in positive and negative situations, appetitive reactions to alcohol and withdrawal-like symptoms contributed differentially to the craving factors 'obsession' and 'interference', supporting the notion of different craving factors with separate underlying mechanisms.

Heinz A; Schafer M; Higley JD; Krystal JH; Goldman D. Neurobiological correlates of the disposition and maintenance of alcoholism. Pharmacopsychiatry 36(Supplement 3): S255-S258, 2003. (51 refs.)

The last decade witnessed a rapid increase in the knowledge of the etiopathology and treatment of alcoholism. The current disease concept includes psychosocial and neurobiological foundations and consequences of alcoholism. Neurobiological research points to dispositional factors such as a low level of response to alcohol, which is partly heritable and seems to be associated with monoaminergic dysfunction and reduced GABAergic alcohol effects. Chronic alcohol intake stimulates counteradaptive neuroadaptation in central GABAergic and glutamatergic neurotransmission, which increases alcohol tolerance. Neuroadaptation to chronic alcohol effects is not immediately reversed during detoxification and can cause clinical withdrawal once alcohol intake is terminated. Sensitization of the dopaminergic and opioidergic reward system may contribute to alcohol craving and reduced control of alcohol intake. New treatment options include pharmacological approaches and indicate that behavior or motivational therapy and the attendance of patient groups may equally reduce the relapse risk.

Heishman SJ; Singleton EG; Moolchan ET. Tobacco Craving Questionnaire: Reliability and validity of a new multifactorial instrument. Nicotine & Tobacco Research 5(5): 645-654, 2003. (69 refs.)

This study documented the initial reliability and validity of the Tobacco Craving Questionnaire (TCQ), a new multidimensional questionnaire to assess tobacco craving. Current cigarette smokers (n = 213) not attempting to reduce or quit smoking completed the 47-item TCQ and other forms assessing demographics, tobacco and other drug use history, quit attempts, and current mood. Exploratory factor analyses and structural equation modeling indicated that a four-factor solution best described the item structure. Factor subscales derived from the 17 items with significant loadings had low to high internal consistencies and interitem correlations and exhibited low to moderate, positive intercorrelations. Factor scales were significantly correlated with single-item measures of craving, current mood, and daily cigarette smoking. Results indicated that four specific constructs characterized craving for tobacco: (a) Emotionality, or smoking in anticipation of relief from withdrawal symptoms or negative mood, (b) expectancy, or anticipation of positive outcomes from smoking, (c) compulsivity, or an inability to control tobacco use, and (d) purposefulness, or intention and planning to smoke for positive outcomes. These preliminary data suggest that the TCQ is a reliable and valid instrument for assessing tobacco craving in individuals not attempting to reduce or quit smoking.

Hughes JR; Novy P; Hatsukami DK; Jensen J; Callas PW. Efficacy of nicotine patch in smokers with a history of alcoholism. Alcoholism: Clinical and Experimental Research 27(6): 946-954, 2003. (49 refs.)

Background: Smokers with a history of alcohol dependence may have more difficulty quitting, might relapse to alcohol use, and might especially benefit from nicotine replacement therapy for smoking cessation. Methods: One hundred fifteen smokers with a history of alcohol dependence (median of 5 years previously) were randomly assigned to either a 21-mg nicotine patch or placebo in a trial designed to be as, similar as possible to a prior study that examined smokers with no history of alcoholism. Both studies were of heavy smokers with similar levels of nicotine dependence; thus, any differences in trials would be due to a history of alcohol problems per se. Results: In the current trial, adjusted prolonged smoking abstinence in those with a history of alcohol dependence was higher in the active than the placebo group at end-of-treatment (28% vs. 11%; odds ratio, 3.2; p = 0.04) and at 6-month follow-up (24% vs. 6%; odds ratio, 4.9; p = 0.02). Among subjects not lost to follow-up, none reported drinking problems or increases in craving for alcohol. Smoking abstinence was not lower and the odds ratio for nicotine patch therapy was not greater in smokers with a history of alcohol dependence than in smokers with no such history. Conclusions: Heavy smokers with a history of alcoholism benefit from nicotine patch treatment. A history of alcohol problems after a period of stable sobriety does not appear to influence smoking outcomes or response to nicotine replacement. Although no smokers relapsed to alcohol use, a trial that follows up all subjects is needed to verify this.

Hutchison KE; Wooden A; Swift RM; Smolen A; McGeary J; Adler L; Paris L. Olanzapine reduces craving for alcohol: A DRD4 VNTR polymorphism by pharmacotherapy interaction. Neuropsychopharmacology 28(10): 1852-1888, 2003. (28 refs.)

Separate investigations have suggested that olanzapine, a D4 antagonist, decreases craving after a priming dose of alcohol and that the DRD4 variable number of tandem repeats ( VNTR) polymorphism influences the expression of craving after a priming dose of alcohol. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers. Participants were randomly assigned to receive olanzapine ( 5 mg) or a control medication ( cyproheptadine, 4 mg) prior to consuming three alcoholic drinks. Participants completed subjective measures of craving and euphoria after each drink. Participants who were homozygous or heterozygous for the 7 ( or longer) repeat allele of the DRD4 VNTR were classified as DRD4 L, while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals, but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals.

Ingjaldsson JT; Thayer JF; Laberg JC. Preattentive processing of alcohol stimuli. Scandinavian Journal of Psychology 44(2): 161-165, 2003. (41 refs.)

An experiment was conducted to test the automatic analysis of briefly presented alcohol stimuli in alcohol-dependent individuals. Alcoholics and controls were exposed to four different conditions: two brief (30 ms) and two long (130 ms) exposure conditions, each containing alcoholic and non-alcoholic pictures. Heart rate (HR) interbeat intervals were recorded and phasic cardiac responses assessed. Alcoholics had a stronger initial HR deceleration after exposure to masked alcohol slides compared with masked control slides, indicating a preattentive analysis of alcohol stimuli. This initial HR deceleration in the masked condition suggests an automatic attentional focusing to degraded alcohol cues. No such attentional effect was found when the pictures were presented unmasked and were clearly perceived. The implication of these results for the understanding of relapse in addictive behavior is discussed.

Ingjaldsson JT; Thayer JF; Laberg JC. Craving for alcohol and pre-attentive processing of alcohol stimuli. International Journal of Psychophysiology 49(1): 29-39, 2003. (67 refs.)

The present study was designed to test the hypothesis of unconscious attending to alcohol-related information in alcoholics experiencing a high level of craving for alcohol. Subjects included a group of alcoholics (n = 34) divided by a median split on a craving measure into two groups labeled as 'high craving' (n = 18) and 'low craving' (n = 16) alcoholics, and a non-alcoholic control group (n = 39). The cardiovascular reactions of these groups were compared after their exposure to masked and unmasked alcohol and control stimuli. As expected the 'high craving' alcoholics showed an immediate heart rate deceleration after exposure to masked and non-consciously accessible alcohol pictures. The 'high craving' alcoholics reported a small but significant increase in difficulty resisting a drink after exposure to masked alcohol pictures. When the alcohol pictures were presented unmasked a significant increase was found in both high and low craving alcoholics on consciously expressed urges, fidgeting and reduced coping with temptation to drink. The 'high craving' alcoholics had lower tonic heart rate variability compared to the control group and the level of craving was positively associated with salivation during the exposure to all picture types. The findings generally support the psychobiological theory of craving, which suggests that the uncontrollability of the craving experience is rooted in unconscious processing of drug-related information.

Jaakkola MS; Ma JM; Yang GH; Chin MF; Benowitz NK; Ceraso M et al. Determinants of salivary cotinine concentrations in Chinese male smokers. Preventive Medicine 36(3): 282-290, 2003. (24 refs.)

Background. Identifying factors that affect cotinine levels in smokers may be useful for smoking cessation programs. Our aims were to characterize the distribution of salivary cotinine levels in Chinese smokers and to investigate factors that influence cotinine concentrations. Methods. In a cross-sectional study, 600 Chinese adult smokers answered a questionnaire on smoking habits and provided a saliva sample for cotinine analysis. Modification of the relation between number of cigarettes smoked and cotinine concentration by individual characteristics, smoking behavior, and type of tobacco was evaluated. Results. Quadratic model provided the best fit for the relation between number of cigarettes smoked in the previous 24 hours and salivary cotinine concentration. Among those smoking up to 20 cigarettes, the median cotinine concentration was higher among younger subjects, those smoking cigarettes without filter and regular rather than light cigarettes, and those inhaling frequently and deeply. Such trends were not observed among heavier smokers. The increase in cotinine per cigarette tended to be larger in those with lower median cotinine level. Conclusions. Our findings show that smoking behavior-related factors modify the relation between number of cigarettes smoked and salivary cotinine concentration. This suggests that smokers may regulate their smoking behavior to achieve a certain optimum nicotine level.

Janowsky D; Pucilowski O; Buyinza M. Preference for higher sucrose concentrations in cocaine abusing-dependent patients. Journal of Psychiatric Research 37(1): 35-41, 2003. (33 refs.)

Animal studies suggest that preference for relatively high concentrations of sweet solutions and lack of control over sweet solution consumption is related to a preference for alcohol over water. There also is evidence in humans that alcoholics prefer high concentration sweet solutions. This study was designed to determine whether patients with cocaine use disorder also prefer high concentrations of sweet solutions. Methods: Sixteen patients with cocaine abuse/dependency were compared with 16 inpatient controls with an affective disorder as to their preferences for increasing concentrations of sucrose solutions. Patients were administered aqueous sucrose solutions ranging from 0.05 to 0.83 M. They were then asked to rate their degree of preference for, and the degree of sweetness of each solution. Results: Cocaine abusing/dependent patients significantly more often preferred the highest sucrose concentration (0.83M). Conclusions: The above information suggests that cocaine abusing/dependent patients, like alcoholics, and in contrast to inpatient controls, share a preference for high concentrations of sucrose.

John U; Meyer C; Rumpf HJ; Schumann A; Thyrian JR; Hapke U. Strength of the relationship between tobacco smoking, nicotine dependence and the severity of alcohol dependence syndrome criteria in a population-based sample. Alcohol and Alcoholism 38(6): 606-612, 2003. (43 refs.)

Aims: Little is known about the relationship between current and past smoking behaviour and the severity of alcohol dependence. The purpose was to explore the strength of this relationship. Methods: A random population sample of 18 to 64 year-olds from northern Germany was used (n = 4075; participation rate: 70%). It included 761 cigarette smokers fulfilling at least one alcohol-dependence criterion. The severity of alcohol dependence according to the alcohol-dependence syndrome criteria frequency (ASF) was estimated by a standardized questionnaire based on diagnostic instruments of the alcohol dependence syndrome and which included five response categories, from 'never' to 'daily'. Nicotine dependence was diagnosed according to the Diagnostic and Statistical Manual of mental disorders (DSM-IV) with the Composite International Diagnostic Interview (CIDI). As a second measure, the Fagerstrom Test of Nicotine Dependence (FTND) was used. Results: The number of cigarettes and years of daily smoking, nicotine dependence, and the number of nicotine dependence symptoms each showed a relationship with the ASF. Effect size (w) were 0.17-0.21 for chi-squared (chi(2)) tests. In a general linear regression model with the ASF as the dependent variable (R-2 = 0.17), number of years of daily smoking, age at onset of smoking, number of attempts to reduce or quit, the number of nicotine-dependence symptoms according to DSM-IV and the FTND sum score were retained as independent variables. Conclusions: Long-term smoking, a large number of nicotine-dependence symptoms according to DSM and a strong urge to smoke according to the FTND are related with a high ASF.

Johnson JL; Bottorff JL; Moffat B; Ratner PA; Shoveller JA; Lovato CY. Tobacco dependence: Adolescents' perspectives on the need to smoke. Social Science & Medicine 56(7): 1481-1492, 2003. (20 refs.)

To address the need for a better understanding of the perspective of Canadian youths on tobacco dependence, a qualitative study using ethnographic techniques was conducted to describe the patterns of language that they use to describe tobacco dependence and the meaning that it has for them. The study was comprised of three inter-related phases: (1) A secondary analysis of 47 individual unstructured interviews with adolescents was completed to identify the words and phrases they use to explain tobacco dependence; (2) contrast and structural questions focusing on tobacco dependence were developed and used in open-ended interviews with 13 adolescents. Data analysis of the transcribed interviews resulted in a set of 60 key phrases that represented the primary ways youths describe the need to smoke; and (3) interviews were conducted with 14 adolescents that involved an open card sort using the set of 60 key phrases. All card sorts and transcribed interview data were analyzed to identify domains representing types of tobacco dependence and sub-types within each domain. From their descriptions about the need to smoke, five aspects of tobacco dependence were identified: social, pleasurable, empowering, emotional, and full-fledged. This study provides a step in elucidating the construct of tobacco dependence among the young. Further research is required to extend this understanding and to develop appropriate measures.

Katz JL; Higgins ST. The validity of the reinstatement model of craving and relapse to drug use. (editorial). Psychopharmacology 168(1-2): 21-30, 2003. (66 refs.)

Rationale. The reinstatement procedure has been used increasingly as a laboratory model of craving and relapse to drug abuse. With the number of reports involving this procedure growing, its validity as a model of relapse merits discussion. Objectives. The present commentary addresses the validity of the reinstatement procedure in relation to the following three types of models: 1) formal equivalence models, which are assessed on the basis of how well they resemble some phenomenon outside the laboratory (i.e. face validity); 2) correlational models, which are assessed on the basis of how well they predict outcomes of various interventions (such as drug administration or environmental change) when effected outside the laboratory (i.e. predictive validity); and 3) functional equivalence models, which are assessed on the basis of whether the laboratory phenomenon is mechanistically identical or reasonably similar to the phenomenon outside the laboratory (i.e. content validity). Methods. In order to evaluate the reinstatement model, we briefly examined its various forms and uses, and compared preclinical outcomes to what is known about relapse from the clinical literature. Results. In its most general form, the reinstatement model has reasonable face validity; that is, there is a general agreement in appearance or form of the behavior in the model and the clinical target, relapse. This face validity is generally absent for the procedure when it is used as a model of craving. The predictive validity of the model has not been established. Evidence from studies of treatments for drug relapse have not supported the validity of the model, however from studies of the effects of the presentation of various types of stimuli (e.g. drug 'priming') there is mixed evidence supporting predictive validity. With regard to functional equivalence, there is reasonable evidence supporting functional commonalities between drug self-administration in laboratory animals and human drug abusers, which lends support to the validity of the reinstatement model. However, there are several specific areas of departure between the methods and results using the model and clinical practices and observations about relapse, suggesting a lack of functional equivalence. Conclusions. There is reasonable evidence to support the face validity of the model, but at this time, neither its predictive validity nor functional equivalence has been fully established, which underscores the need for caution in generalizing results from the model to the clinical condition.

Kim DJ; Jeong J.; Kim KS; Chae JH; Jin SH; Ahn KJ et al. Complexity changes of the EEG induced by alcohol cue exposure in alcoholics and social drinkers. Alcoholism: Clinical and Experimental Research 27(12): 1955-1961, 2003. (33 refs.)

Background: An understanding of the neurophysiological mechanisms underlying alcohol craving is important in the effective treatment of alcohol dependence. The aim of this study was to examine the utility of the electroencephalogram (EEG) to measure the changes in electrical brain activity of alcoholics when exposed to alcohol-specific cues. Methods: Fifteen adult alcoholic subjects (four women) with a mean age of 35 (SD = 4.5) and 10 healthy social drinking controls (three women) with a mean age of 34 (SD = 5.6) were recruited. Subjects were serially rated for alcohol craving after presentations of pictures of control nonalcoholic and alcohol beverages. After the picture presentation, the EEG was recorded (16,384 data points for each epoch) with eyes closed. The dimensional complexity (D-2) was estimated as a measure of complexity of the EEG. Results: Alcoholic subjects exhibited a significant increase in the D-2 values of the EEG in frontal (F-3, F-4), right posterior temporal (T-6), and occipital (O-1, O-2) regions after viewing alcohol cues compared with viewing other beverage cues. These results indicate that more complex (or higher) cortical activity is induced over specific brain regions of alcoholic subjects by alcohol-specific cues. Changes in subscale of alcohol craving between nonalcoholic and alcohol pictures were correlated with changes in D-2 values in the left frontal (F-3) region in alcoholic subjects. Conclusions: These findings suggest that, when subjects are exposed to alcohol cues, changes in the EEG complexity are induced in frontal, right posterior temporal, and occipital areas, which may be key brain structures for alcohol craving. In addition, nonlinear measures like the D-2 are useful in evaluating alcohol cue-induced brain activity from the EEG.

Klein H; Elifson KW; Sterk CE. Perceived temptation to use drugs and actual drug use among women. (review). Journal of Drug Issues 33(1): 161-191, 2003. (112 refs.)

Much research has been conducted to examine the relationship between various psychological and psychosocial factors and substance use/abuse. Whereas such topics as depression, bipolar disorder, anxiety, self-esteem, optimism/ pessimism, coping, and stress/tension have been studied fairly extensively, others have received much less attention. One such understudied psychosocial factor is perceived level of temptation to use drugs under specified circumstances. This research is based on a study of125 adult women drug users residing in the Atlanta, Georgia metropolitan area, interviewed between August 1997 and August 2000. Street outreach efforts were used to identify potential study participants, with further expansion of the sample done via targeted sampling and ethnographic mapping procedures. The present study examines 16 specific items assessing temptations to use drugs. After describing which circumstances people think will be most likely to bring about greater illegal drug usage, the authors compare perceptions to actual drug use behaviors. Multivariate analyses are conducted to examine the role that perceived temptations to use drugs play in predicting actual drug use when the effects of demographic variables, background experiences, childhood maltreatment experiences, other psychosocial measures, and exposure to substance abusers are taken into account. A multivariate model explaining nearly one-half of the variance in actual drug abuse is derived, and retained several of the temptations-to-use drugs items.

Koob GF. Alcoholism: Allostasis and beyond. (review). Alcoholism: Clinical and Experimental Research 27(2): 232-243, 2003. (102 refs.)

Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.

Lee JH; Ku JG; Kim K; Yang BH; Kim SH; Wiederhold BK et al. Experimental application of virtual reality for nicotine craving through cue exposure. Cyberpsychology & Behavior 6(3): 275-280, 2003. (10 refs.)

Research has shown that many smokers experience an increase in the desire to smoke when exposed to smoking-related cues. Cue exposure treatment (CET) refers to the manualized, repeated exposure to smoking-related cues, aimed at the reducing cue reactivity by extinction. In this study, we constructed a virtual reality system for evoking a desire of nicotine, which was based on the results of a Questionnaire of Nicotine-craving. And we investigated the effectiveness of the virtual reality system as compared to classical device (pictures). As a result, we reached the conclusion that virtual reality elicits more craving symptoms than the classical devices.

Lin SK; Wu SH; Yang YS; Pan WHT. Drug addiction: The neurochemical perspective of brain in drug-seeking behavior. Journal of Food and Drug Analysis 11(4): 344-352, 2003. (73 refs.)

A critical challenge of the investigation in the neurobiological mechanism of drug addiction is how acute actions become transformed into chronic effects that underlie the compulsive drug-seeking and craving in addiction. Repeated administrations of psychostimulants can enhance the behavioral response upon reinstatement of the drug, a prominent phenomenon known as behavioral sensitization. It has been implicated that the neuronal changes brought about by sensitization in the mesocorticolimbic pathways have close relationship with compulsive drug seeking in addicts. Dopamine and glutamate are the two major neurotransmitters involved in the sensitization of abused drugs. The authors reviewed literature pertinent to amphetamine and cocaine addiction in order to address the recent important concepts and findings in dopaminergic and glutamatergic neurochemical systems of mesolimbic and mesocortical circuits associated with drug-related behavior. The present review also discusses the role of associative learning as manifested in the relationship between environmental cues of drug administration and intractable drug-seeking behavior.

Longoria J; Brown ES; Perantie DC; Bobadilla L; Nejtek VA. Quetiapine for alcohol use and craving in bipolar disorder. (letter). Journal of Clinical Psychopharmacology 24(1): 101-102, 2004. (8 refs.)

The authors examine the effect of quetiapine on mood and alcohol-related outcome measures in the subset of participants who had alcohol craving at baseline. A total of 17 subjects with bipolar disorder and cocaine dependence, after signing an Institutional Review Board approved informed consent, volunteered to participate in a 12-week, open-label, add-on study using quetiapine with a biweekly assessment schedule. Fourteen of the 17 total subjects reported experiencing alcohol craving at baseline, 9 of these had comorbid alcohol dependence or abuse diagnoses, and 8 were active alcohol users during the study. Subjects were evaluated at baseline and subsequent visits with the 17-item Hamilton Depression Rating (HRSD), Young Mania Rating (YMRS), Brief Psychiatric Rating (BPRS) Scales, and modified Cocaine Craving Questionnaire. Subjects experienced significant improvements in HRSD, BPRS, and YMRS scores. No correlations were observed between changes in alcohol craving or use and psychiatric symptom measures with the exception of VAS-DAY and HRSD. Quetiapine was associated with significant reduction in alcohol craving and number of days of alcohol use per week.

Margolin A; Kantak K; Copenhaver M; Avants SK. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. Journal of Addictive Diseases 22(2): 49-61, 2003. (35 refs.)

Based on pre-clinical studies suggesting that magnesium (Mg) reduces cocaine self-administration and potentiates the antinociceptive effects of morphine, we conducted a preliminary randomized clinical trial investigating Mg for the treatment of illicit cocaine and opiate use. Eighteen methadone-maintained patients who used illicit opiates and cocaine received either Mg (732 mg/day) or placebo for 12 weeks. Overall, findings showed that the percentage of urine screens testing positive for opiates in the Mg group (22.6%) was half that of the placebo group (46.4%), p =.04; the difference was even greater in the "medication compliant" sample (Mg: 16.3%, placebo: 47.9%), p =.02. Cocaine craving was lower in the Mg compared to the placebo group, but there was no difference between groups in cocaine use. These preliminary findings suggest that Mg may have a beneficial effect for reducing illicit opiate use. It is possible that a higher dose of Mg than was used in this study may be needed to decrease cocaine use.

Novak A; Burgess ES; Clark M; Zvolensky MJ; Brown RA. Anxiety sensitivity, self-reported motives for alcohol and nicotine use, and level of consumption. Journal of Anxiety Disorders 17(2): 165-180, 2003. (38 refs.)

We examined the relationship between anxiety sensitivity, alcohol and nicotine use, and drinking and smoking motives in a nonclinical university population. Participants (n = 293) completed the 16-item Anxiety Sensitivity (AS) Index and a drinking and smoking history questionnaire. Sixty percent of participants completed the Drinking Motives Questionnaire and 29% completed the Smoking Motives Questionnaire. Level of alcohol and cigarette consumption was not related to AS but was related to motives. AS was directly related to coping-related drinking and moderated the relationship between level of smoking and mood-related smoking motives. Although AS may be more predictive of coping-related drinking motives than of level of alcohol consumption, given the relationship between these types of drinking motives and abusive drinking, high AS individuals might be an at-risk group due to their reasons for drinking. In addition, striking differences were found between drinkers who smoke and those who do not smoke, suggesting that this subgroup may also represent an at-risk group of drinkers.

Otto MW; Safren SA; Pollack MH. Internal cue exposure and the treatment of substance use disorders: Lessons from the treatment of panic disorder. Journal of Anxiety Disorders 18(1): 69-87, 2004. (92 refs.)

Despite early recognition of the importance of internal cues (craving sensations and emotional states) for relapse in substance use disorders, relatively little attention has been devoted to exposure-based treatments targeting these cues. Drawing upon research on the conceptualization and treatment of panic disorder, we discuss the application of internal (largely emotional) cue exposure for substance use disorders. Our model for this discussion was based on the role of exposure to feared sensations of anxiety in the treatment of panic disorder and benzodiazepine (BZ) discontinuation. Shared research strategies between panic disorder and substance use-studies of biological provocation and anxiety sensitivity-were discussed, as were gender differences in drug-use motives. In accordance with research on anxiety sensitivity, provocation effects, and the treatment of benzodiazepine withdrawal, we discussed the potential value of internal cue-exposure strategies for individuals who use substances as a way to cope with negative affect.

Patkar AA; Gottheil E; Berrettini WH; Hill KP; Thornton CC; Weinstein SP. Relationship between platelet serotonin uptake sites and measures of impulsivity, aggression, and craving among African-American cocaine abusers. American Journal on Addictions 12(5): 432-447, 2003 5. (79 refs.)

We investigated whether platelet-tritiated paroxetine binding, a measure Of serotonin uptake sites, and behavioral measures of impulsivity, aggression, and craving differed between cocaine-dependent subjects and controls and whether paroxetine binding was related to these behavioral measures. One hundred and five African-American cocaine-dependent outpatients and 44 African-American controls were studied. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of impulsivity, aggression, and craving were performed. The Bmax values of paroxetine binding were significantly reduced among cocaine patients compared to controls. Cocaine patients showed significantly higher scores on certain measures Of sensation seeking, impulsivity, and aggression as compared to controls. Furthermore, paroxetine binding showed a significant negative correlation with most measures of sensation seeking, impulsivity; and aggression-though not craving - among cocaine patients. Our findings indicate that densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions.

Pomerleau OF; Fagerstrom KO; Marks JL; Tate JC; Pomerleau CS. Development and validation of a self-rating scale for positive- and negative-reinforcement smoking: The Michigan Nicotine Reinforcement Questionnaire. Nicotine & Tobacco Research 5(5): 711-718, 2003. (54 refs.)

Positive- and negative-reinforcement consequences of smoking were assessed using a self-report inventory. Data from 429 current smokers (348 women, 81 men) were subjected to an exploratory factor analysis, with concurrent validation of resulting scales in 288 current smokers (235 women, 53 men), controlling for sex and age. The solution with three factors-positive reinforcement, negative reinforcement, and smoking patterns-provided the clearest and most interpretable factor solution. The Michigan Nicotine Reinforcement Questionnaire (M-NRQ), which yields positive- and negative-reinforcement scales, was developed based on these results. Positive-reinforcement smoking was associated with higher scores on novelty seeking, reward dependence, alcohol dependence, and pleasurable sensations upon early smoking experimentation, and with lower scores on displeasurable sensations and nausea upon early smoking experimentation. Negative-reinforcement smoking was associated with higher scores for nicotine dependence, depression, anxiety, and harm avoidance. The M-NRQ has potential as a diagnostic tool for individualizing behavioral intervention and pharmacotherapy and also may be useful in identifying new phenotypes for genetic research on smoking.

Robinson TE; Berridge KC. Addiction. Annual Review of Psychology 54: 25-53, 2003. (54 refs.)

The development of addiction involves a transition from casual to compulsive patterns of drug use. This transition to addiction is accompanied by many drug-induced changes in the brain and associated changes in psychological functions. In this article we present a critical analysis of the major theoretical explanations of how drug-induced alterations in psychological function might cause a transition to addiction. These include: (a) the traditional hedonic view that drug pleasure and subsequent unpleasant withdrawal symptoms are the chief causes of addiction; (b) the view that addiction is due to aberrant learning, especially the development of strong stimulus-response habits; (c) our incentive-sensitization view, which suggests that sensitization of a neural system that attributes incentive salience causes compulsive motivation or "wanting" to take addictive drugs; and (d) the idea that dysfunction of frontal cortical systems, which normally regulate decision making and inhibitory control over behavior, leads to impaired judgment and impulsivity in addicts.

Rohsenow DJ; Monti PM; Colby SM; Gulliver SB; Swift RM; Abrams DB. Naltrexone treatment for alcoholics: Effect on cigarette smoking rates. Nicotine & Tobacco Research 5(2): 231-236, 2003. (33 refs.)

Naltrexone (NTX), by its pharmacological action in the mesolimbic pathways, should decrease reinforcement from nicotine as well as from alcohol. By means of this mechanism, NTX could result in temporary increases in smoking followed by decreased smoking rates among alcoholics not motivated to quit smoking. The change from pretreatment in smoking rates of 73 recently abstinent alcoholics in a 12-week clinical trial of NTX vs. placebo during alcoholism treatment was compared during 8 of the 12 weeks. Only smokers compliant with NTX were included in the analyses. NTX was associated with decreased smoking at every time point, but the effect was significant at only one time point. When alcohol relapsers were excluded, NTX patients showed decreased smoking at every time point, but the effect was significant at only two time points, a reduction of about five cigarettes per day. When smoking stage of change was included in the analyses, NTX showed no significant main or interaction effects on smoking rate. Pre-contemplators showed significantly less change in smoking rate than all other patients at the first and last four time points. Therefore, NTX alone currently does not show promise for promoting smoking reduction among recently abstinent alcoholics who have not sought or been given smoking cessation treatment. Further research is needed on possible effects with smokers motivated to quit smoking and on other methods of promoting smoking cessation among alcoholics.

Saladin ME; Drobes DJ; Coffey SF; Dansky BS; Brady KT; Kilpatrick DG. PTSD symptom severity as a predictor of cue-elicited drug craving in victims of violent crime. Addictive Behaviors 28(9): 1611-1629, 2003. (69 refs.)

This study examined posttraumatic stress disorder (PTSD) symptom severity as a predictor of cue-elicited craving among alcohol- and cocaine-dependent individuals with a history of at least one physical and/or sexual assault. Approximately half of the sample had current PTSD. Severity of PTSD symptoms was measured via the Impact of Events Scale��Revised (IES-R) total severity score. Subjects listened to four trials of a brief narrative imagery script followed by the presentation of an in vivo cue. The script presentation consisted of a description of either the subject's worst traumatic event or a neutral scene. The in vivo cues consisted of the presentation of either the subject's preferred drug or neutral cues. Craving was measured in response to both the script and in vivo cues. Results indicated a high degree of correlation between self-report craving and (a) PTSD symptom severity, (b) type of substance use disorder (SUD) [alcohol dependence (AD) vs. cocaine dependence (CD)], and (c) sex and race of participant. A series of stepwise multiple regressions indicated that PTSD severity was significantly predictive of trauma cue-elicited craving and drug cue-elicited craving. The results are discussed in the context of current research, theory, and clinical practice.

Sattar SP; Grant K; Bhatia S; Petty F. Potential use of olanzapine in treatment of substance dependence disorders. Journal of Clinical Psychopharmacology 23(4): 413-415, 2003. (10 refs.)

Notes that treatment of substance-dependence disorders (SDDs) is complex and multifaceted. The authors present 3 cases where olanzapine used for the treatment of intense anxiety, decreased substance use and cravings. Two of the 3 patients did not have any psychotic illness. In Case 1, a 50-yr-old married, White male was diagnosed with alcohol dependence. Because of increased irritability and anxiety as well as decreased sleep, olanzapine was administered. In addition, the S participated in individual, group, and marital therapy. At last contact, he reported sobriety and decreased cravings for 3 mos. In Case 2, a 35-yr-old single, African American male was diagnosed with schizoaffective disorder bipolar type and cocaine dependence. Treatment with olanzapine was found to decrease symptoms of paranoia and auditory hallucinations; he also described significantly decreased cravings for cocaine and maintained sobriety for more than 3 mos until last contact. In Case 3, a 47-yr-old married, White male was diagnosed with bipolar disorder and alcohol dependence. He was given olanzapine and continued to use it after discharge, maintaining sobriety for the next 6 mos. These cases suggest potential benefits of olanzapine in substance use disorders.

Sayette MA; Martin CS; Hull JG; Wertz JM; Perrott MA. Effects of nicotine deprivation on craving response covariation in smokers. Journal of Abnormal Psychology 112(1): 110-118, 2003. (112 refs.)

Most models of craving propose that when cravings are strong, diverse responses -- thought to index an underlying craving state -- covary. Previous studies provided weak support for this hypothesis. The authors tested whether nicotine deprivation affects degree of covariation across multiple measures related to craving. Heavy and light smokers (N = 127) were exposed to smoking cues while either nicotine deprived or nondeprived. Measures included urge ratings, affective valence, a behavioral choice task assessing perceived reinforcement value of smoking, and smoking-related judgment tasks. Results indicated higher correlations in the nicotine-deprived than in nondeprived group. The measures principally responsible for this effect loaded onto a single common craving factor for nicotine-deprived but not nondeprived smokers. These findings suggest that, under certain conditions, measures of craving-related processes covary.

Sayette MA; Wertz JA; Martin CS; Cohn JF; Perrott MA; Hobel J. Effects of smoking opportunity on cue-elicited urge: A facial coding analysis. Experimental and Clinical Psychopharmacology 11(3): 218-227, 2003. (39 refs.)

The authors analyzed smokers' facial expressions using the Facial Action Coding System (P. Ekman & W. V. Friesen, 1978) under varying smoking opportunity conditions. In Experiment 1, smokers first were told that they either could (told-yes) or could not (told-no) smoke during the study. Told-yes smokers reported higher urges than did told-no smokers. Unexpectedly, told-yes smokers became increasingly likely to manifest expressions related to negative affect and less likely to evince expressions related to positive affect, compared with told-no smokers. In Experiment 2, smokers were more likely to show positive affect-related expressions if the delay was 15 s than if it was 60 s. Craving may be related to both a desire to use and an impatient desire to use immediately.

Shearer J; Wodak A; van Beek I; Mattick RP; Lewis J. Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction 98(8): 1137-1141, 2003. (14 refs.)

Aims: To establish the feasibility of conducting a placebo-controlled clinical trial of dexamphetamine replacement therapy for cocaine dependence and to obtain preliminary data. Design: Double-blind randomized placebo-controlled trial. Participants: Thirty cocaine-dependent injecting drug users.Intervention Subjects were assigned randomly to receive 60 mg/day dexamphetamine (n=16) or placebo (n=14) for 14 weeks. Measurements Immunoassay and mass spectrometric techniques were used to identify cocaine metabolites in urine. Subjects were screened using the Composite International Diagnostic Interview and DSM-IV The Opiate Treatment Index, Brief Symptom Inventory, Severity of Dependence Scale and visual analogue craving scales were used to collect pre- and post-self-report data. Findings Treatment retention was equivalent between groups; however, outcomes favoured the treatment group with no improvements observed in the placebo control group. The proportion of cocaine-positive urine samples detected in the treatment group declined from 94% to 56% compared to no change in the placebo group (79% positive). While the improvements were not significant between groups, within-group analysis revealed that the treatment group reduced self-reported cocaine use (P=0.02), reduced criminal activity (P=0.04), reduced cravings (P<0.01) and reduced severity of cocaine dependence (P<0.01) with no within-group improvements found in the placebo group. Conclusions: A definitive evaluation of the utility of dexamphetamine in the management of cocaine dependence is feasible and warranted.

Shiffman S; Shadel WG; Niaura R; Khayrallah MA; Jorenby DE; Ryan CF et al. Efficacy of acute administration of nicotine gum in relief of cue-provoked cigarette craving. Psychopathology 166(4): 343-350, 2003. (45 refs.)

Rationale: Acute cravings, often provoked by exposure to smoking cues, appear to be important triggers for smoking relapse. Relief of acute craving may therefore be an important step in preventing relapse. Objectives: This study was undertaken to assess the effectiveness of nicotine gum in relieving acute craving. Methods: A multi-center, randomized, placebo-controlled study was conducted with smokers (n=296) who quit by using either active or inactive gum for 3 days. On their third day of abstinence, smokers participated in a laboratory session in which they were exposed to a provocative smoking cue, chewed active or inactive gum, and then rated their craving at 5-min intervals for 35 min. Results: Craving initially decreased in both groups. After 15 min, however, the smokers using active nicotine gum experienced significantly greater craving reductions. Conclusions: These results suggest that nicotine gum can effectively reduce acute craving following exposure to smoking cues.

Singleton EG; Anderson LM; Heishman SJ. Reliability and validity of the Tobacco Craving Questionnaire and validation of a craving-induction procedure using multiple measures of craving and mood. Addiction 98(11): 1537-1546, 2003. (32 refs.)

Aims: To determine the reliability and validity of the Tobacco Craving Questionnaire (TCQ) and the validity of imagery scripts to elicit self-reported tobacco craving. Design Active imagery of three auditory scripts that described no-. low- and high-intensity of smoking urge. Participants Current cigarette smokers (24 men, 24 women) not attempting to quit or reduce smoking. Measurements: After each imagery condition, participants completed the 47-item TCQ, a Mood Form and Visual Analog Scale (VAS) questions. Findings Reliability of measures was demonstrated by internal consistency and unidimensionality of the four TCQ factors across imagery conditions. Criterion-related validity was demonstrated by an orderly increase in scores on the TCQ and VAS craving measures as a function of craving intensity of the imagery scripts. Increases in effect size parameters and parallel decreases in the stability of test-retest reliability for all craving measures indicated the validity of the imagery procedure. Convergent and discriminant validity were established by the craving scripts increasing self-reported craving, the no-craving (positive-affect) script increasing positive mood, the no-craving script not affecting craving and the craving scripts not affecting positive mood. Conclusions: Findings further demonstrated the reliability and validity of the TCQ as a multi-factorial instrument to assess the construct of tobacco craving and suggested that the lability of craving, rather than inconsistency and instability in its measurement, was responsible for observed effects.

Sofuoglu M; Dudish-Poulsen S; Brown SB; Hatsukami DK. Association of cocaine withdrawal symptoms with more severe dependence and enhanced subjective response to cocaine. Drug and Alcohol Dependence 69(3): 273-282, 2003. (17 refs.)

The purpose of this two part study was to better characterize cocaine users based on self-reported cocaine withdrawal symptoms by examining screening data and response to smoked cocaine in the human laboratory. The first study sample included male and female non-treatment seeking cocaine users who were screened as potential subjects for inpatient studies. Of the 555 subjects, 462 (82%) endorsed symptoms consistent with DSM-IV criteria for cocaine withdrawal. Cocaine users who met criteria for cocaine withdrawal, compared with those who did not, reported a significantly higher amount of cocaine use and a history of medical and psychosocial problems. Cocaine users meeting DSM-IV withdrawal criteria, which included endorsement of depression, were also more likely to have a history of depression, to have seriously considered suicide, and to have had chemical dependency treatment even when amount spent on cocaine was covaried. The second study sample, which was a subset of Study I, included those who participated in human cocaine studies following the phone screening. Cocaine users who met criteria for cocaine withdrawal (n=34), compared with those who did not (n=10), had enhanced subjective ratings of `high' and `feel the effect of last dose' in response to a single delivery of 0.4 mg/kg of smoked cocaine. These results suggest that history of cocaine withdrawal symptoms may be associated with enhanced cocaine responses and greater severity of cocaine dependence.

Soyka M; Aichmuller C; Bardeleben UV; Beneke M; Glaser T; Hornung-Knobel S et al. Flupenthixol in relapse prevention in schizophrenics with comorbid alcoholism: Results from an open clinical study. European Addiction Research 9(2): 65-72, 2003. (79 refs.)

Substance use, especially alcoholism, has been recognized as a significant problem in schizophrenic patients, though only a few studies on the effects of pharmacotherapy in these patients have been conducted so far. The thioxanthene neuroleptic flupenthixol, which can be given intramuscularly (i.m.) for improving compliance, has been studied as a possible anti-craving drug both in animal models of alcoholism and some clinical studies. Pilot studies suggest that comorbid schizophrenics with substance use may benefit from treatment with flupenthixol. Efficacy of flupenthixol (10-60 mg) in reducing alcohol consumption of dual diagnosis patients was studied in an open 6-month clinical trial in 27 schizophrenics with comorbid alcoholism; 21 patients entered the intention-to-treat analysis; 14 subjects were completers and 13 dropped out. Six patients completely abstained from alcohol during treatment. Alcohol consumption was significantly reduced compared to baseline (4 weeks before treatment as measured by timeline follow-back interview). In general, while patients showed a marked improvement concerning alcohol consumption, only a slight improvement in psychopathology was recorded. Overall tolerability was good. These data indicate a probable beneficial effect of flupenthixol in schizophrenic patients with comorbid alcoholism. Although the efficacy of flupenthixol as an anti-craving drug in dual diagnosis patients has to be explored in further studies, the drug may be considered a promising medication for these patients.

Soyka M; Chick J. Use of acamprosate and opioid antagonists in the treatment of alcohol dependence: A European perspective. American Journal on Addictions 12(Special): S69-S80, 2003. (72 refs.)

In thirteen of sixteen placebo-controlled trials in Europe, acamprosate increased abstinence in detoxified alcohol-dependent patients. It is approved in most EU countries. Its action at N-methyl-D-aspartate (NMDA) receptors appears to account for many of its effects. The number needed to treat in the fifteen trials suitable for meta-analysis has been calculated at 8.15. Trials of naltrexone in Europe have shown less clear evidence of efficacy than trials of acamprosate, whether abstinence or relapse to heavy drinking is used as the outcome criterion. With reduction in heavy drinking days as the criterion, naltrexone compared favorably to acamprosate in an open study in moderate alcohol dependence; one double-blind study has pointed to an advantage of the combination of naltrexone with acamprosate over either drug. To date, there are no trials published of nalmefene in European clinics. While many centers routinely offer a trial of acamprosate to newly detoxified patients aiming for abstinence, naltrexone usage varies. Some centers suggest naltrexone not only for patients aiming for abstinence but also for patients for whom continued drinking is a therapeutic possibility or a clinical inevitability.

Spanagel R. Alcohol addiction research: From animal models to clinics. Best Practice & Research. Clinical Gastroenterology 17(4): 507-518, 2003. (58 refs.)

Addictive behaviour evolves only on the basis of voluntary drug intake. As a consequence, when designing an animal model that covers several aspects of alcohol dependence and other alcohol related-diseases a necessary precondition is that the animal has voluntary access to alcohol. Animal models on voluntary alcohol consumption have a long-standing tradition in biomedical research on alcoholism. However, preference studies allow only limited conclusions regarding alcohol dependence and addictive behaviour. Therefore, new animal models have been developed that mimic different aspects of human alcohol dependence such as craving, relapse and loss of control over drinking. These models include the reinstatement model, the alcohol deprivation model and the point-of-no-return model. These models have now been pharmacologically validated using anti-craving compounds that are used clinically for treating alcoholics. In conclusion, there appears to be a good correspondence between the events that induce relapse and loss of control over alcohol-taking behaviour in laboratory animals and those that provoke relapse and loss of control in humans.

Stewart J. Stress and relapse to drug seeking: Studies in laboratory animals shed light on mechanisms and sources of long-term vulnerability. American Journal on Addictions 12(1): 1-17, 2003. (98 refs.)

Pharmacological approaches to drug abuse have tended to be guided by the primary drug used, though substitution has been the guiding principle in some instances (e.g., methadone maintenance in opioid addiction). Alternatively, blockade or antagonism of the effects of the primary drug being abused has been tried (e.g., naltrexone to treat opioid or alcohol addiction). Though reportedly successful in some populations, it is not clear that these approaches effectively control craving for 'highs' or euphoric experiences or a return to drug use as a response to stressful life experiences. Recent studies of the factors that induce craving and relapse to drug use in both humans and laboratory animals, such as drug-related cues, re-exposure to the drug itself, or exposure to stressful events, have shown that the effects of these different events are mediated by dissociable neurochemical circuitry. Another finding is that the motivation underlying drug seeking induced by events that precipitate relapse is intensified by the duration and amount of pre-exposure to a drug and the passage of time since withdrawal of the drug. One implication is that whatever approach is taken, treatment will have to be multifaceted and maintained over an extended period after the initial termination.

Stoltenberg SF. Serotonergic agents and alcoholism treatment: A simulation. Alcoholism: Clinical and Experimental Research 27(12): 1853-1859, 2003. (27 refs.)

Background: Those with early-onset alcoholism may better respond to ondansetron (a 5-HT3 receptor antagonist) than to selective serotonin reuptake inhibitor (SSRI) treatment, whereas those with late-onset alcoholism may present the reverse response pattern. Johnson and colleagues proposed a model that attempts to explain the observed treatment response patterns of those with early and late alcoholism onset by focusing on the influence of a common genetic variant in the serotonin transporter regulatory region (5-HTTLPR) on serotonin (5-HT) and dopamine (DA) system function. Methods: The present study formalizes and extends Johnson's descriptive model into a computer simulation consisting of differential equations. For each of 16 conditions defined by genotype, drinking status, diagnostic status, and drug treatment, data were generated by 100 simulation runs. Results: In every condition, the S/_ genotype (S/S and S/L) had higher extracellular 5-HT levels than did the L/L genotype. The S/_ genotype also had higher rates of postsynaptic DA firing than did the L/L genotype with the exception of the SSRI treatment condition, where the firing rates were similar. Drinking generally increased levels of extracellular 5-HT, reduced rates of presynaptic 5-HT firing, and increased rates of postsynaptic DA firing. Drinking produced increases in DA activation that were greater for the L/L genotype in the SSRI treatment condition and for the S/_ genotype in the ondansetron treatment condition. Conclusions: Genotype at 5-HTTLPR may influence relative reward of drinking alcohol while a person is under pharmacological treatment for alcoholism. Alternatively, 5-HTTLPR genotype may influence pathways of alcohol craving. Clinical studies should examine these hypotheses.

Strong DR; Brown RA; Ramsey SE; Myers MG. Nicotine dependence measures among adolescents with psychiatric disorders: Evaluating symptom expression as a function of dependence severity. Nicotine & Tobacco Research 5(5): 735-746, 2003. (42 refs.)

Using methods based in item response theory, we examined a structured interview assessment of Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) nicotine dependence and the Modified Fagerstrom Tolerance Questionnaire (mFTQ) symptoms to explore the expression of particular symptoms as a function of level of nicotine involvement in a sample of 191 adolescents with psychiatric disorders. Despite our attempts to capture a broad range of smokers, 64% of teens were daily smokers and 68% met DSM-IV criteria for nicotine dependence. This paper describes the relative severity of DSM-IV and mFTQ items, as well as each item's ability to discriminate among individuals at various levels of nicotine involvement. Comparisons across measures revealed that the mFTQ was not particularly sensitive to individual variation in DSM-IV symptom counts, suggesting the physiological components were not strongly related to the predominantly cognitive and behavioral components of the DSM-IV nicotine dependence syndrome. However, the mFTQ relative to the DSM-IV consistently showed stronger relationships to the immediate consequences of nicotine deprivation (urge, craving), supporting the conceptualization of the mFTQ as measuring nicotine exposure. These analyses provide us with some preliminary understanding of the severity of particular symptoms and the order in which symptoms are likely to be expressed across levels of nicotine dependence.

Tapert SF; Brown GG; Baratta MV; Brown SA. fMRI BOLD response to alcohol stimuli in alcohol dependent young women. Addictive Behaviors 29(1): 33-50, 2004. (86 refs.)

Background: Cue reactivity in alcohol dependent adults has revealed autonomic, cognitive, and neural responses to alcohol-related stimuli that differ from those of nonabusers. Cue reactivity and craving responses have not been studied in youth. Method: Alcohol-dependent young women (n=8) and female light social drinkers (n=9) ages 18-24 were administered an alcohol cue reactivity task during functional magnetic resonance imaging (fMRI) to examine brain response to alcohol-related words. Results: Alcohol dependent young women demonstrated significantly more blood oxygen level dependent (BOLD) response than nonabusers during alcohol word presentation trials relative to neutral word trials in subcallosal, anterior cingulate, left prefrontal, and bilateral insular regions (P<.025). However, controls showed greater response to alcohol words in some right hemisphere cortical regions. Increased craving after cue exposure correlated with increased subcallosal cortex BOLD response to alcohol cues (r=.87) among alcohol dependent subjects. Conclusions: This pilot study corroborates previous reports of increased limbic and frontal response to substance cues and extends these findings to young alcohol dependent women. This limbic reaction may underlie the elevated physiological response and altered cognitive reactions to alcohol stimuli that are observed in alcohol dependent individuals.

Tapert SF; Cheung EH; Brown GG; Frank LR; Paulus MP; Schweinsburg AD et al. Neural response to alcohol stimuli in adolescents with alcohol use disorder. Archives of General Psychiatry 60(7): 727-735, 2003. (80 refs.)

Background: Cue reactivity studies in alcohol-dependent adults have shown atypical physiological, cognitive, and neural responses to alcohol-related stimuli that differ from the responses of light drinkers. Cue reactivity and its neural substrates are unclear in youth. We hypothesized that teens with alcohol use disorder would show greater brain response than nonabusing teens to alcohol images relative to neutral beverage images in limbic and frontal brain regions. Methods: We tested the hypotheses in a cross-sectional functional magnetic resonance imaging study. Adolescents aged 14 to 17 were recruited from local high schools. Teens with alcohol use disorders (n = 15) and demographically similar infrequent drinkers (n = 15) met strict exclusion criteria (no left-handedness or neurological, other psychiatric, or other substance use disorders). Diagnoses were determined by means of structured and semistructured clinical interviews. Subjects were shown pictures of alcoholic and nonalcoholic beverage advertisements during blood oxygen level-dependent functional magnetic resonance imaging. Self-reports of craving were obtained before and after cue exposure. Results: Teens with alcohol use disorders showed substantially greater brain activation to alcoholic beverage pictures than control youths, predominantly in the left anterior, limbic, and visual system areas (P < .05; cluster threshold, 515 muL). The degree of brain response to the alcohol pictures was highest in youths who consumed more drinks per month and reported greater desires to drink. Conclusions: These results confirm previous studies by demonstrating an association between the urge to drink alcohol and blood oxygen use in areas of the brain previously linked to reward, desire, positive affect, and episodic recall. This study extends this relationship to adolescents with relatively brief drinking histories using visual alcohol stimuli, and suggests a neural basis for response to alcohol advertisements in youths with drinking problems.

Thomas CP; Wallack SS; Lee S; McCarty D; Swift R. Research to practice: Adoption of naltrexone in alcoholism treatment. Journal of Substance Abuse Treatment 24(1): 1-11, 2003. (38 refs.)

Naltrexone, a prescription medication, was approved in December 1994 as an adjunct to counseling in treatment of alcoholism and alcohol abuse, representing the first new medication for alcoholism in several decades. Initial controlled trials indicated that it is effective in preventing relapse, while later trials show mixed results. Although many physicians and others treating alcoholism have found naltrexone to be very helpful in treatment, it is still a technology that has not been used widely. In this study, we examine which clinicians have adopted naltrexone into practice for what reasons, and what clinical and nonclinical factors acted as barriers to its use. In our mail survey of alcoholism treatment clinicians, 80% of physicians and 45% of nonphysicians report prescribing or recommending naltrexone at least rarely, but only 15% of physicians, even among addiction specialists, prescribe naltrexone often. The strongest barriers to adoption of naltrexone were financing and inadequate knowledge about the medication, followed by lack of sufficient evidence regarding effectiveness. Clinicians were most likely to adopt naltrexone if they were affiliated with treatment programs that actively promoted its use. We conclude that in order for a new substance abuse treatment medication to be widely adopted in clinical practice, information about it must be properly directed, clinicians must be convinced of its effectiveness, it must be adequately financed, and the treatment organizations in which clinicians work must promote its use.

van den Eijnden RJJM; Spijkerman R; Fekkes D. Craving for cigarettes among low and high dependent smokers: Impact of norharman. Addiction Biology 8(4): 463-472, 2003. (35 refs.)

Besides nicotine, other chemicals in tobacco smoke, such as norharman, may contribute to the addictive properties of cigarettes. More specifically, elevated blood plasma levels of norharman may reduce feelings of craving among tobacco-dependent individuals. To test this hypothesis, plasma concentrations of norharman were measured in 38 male smokers (at least 15 cigarettes per day) at three time-points on 3 different days spread over a 4-month period. The first measurement (T0) was conducted in the morning at 8.30 a.m., after 12 hours of smoking abstinence. The T1 and T2 measurements were conducted at 13.00 p.m. and 16.30 p.m., during a period of ad libitum smoking (after the T0 measurement, participants were not restricted in their smoking behaviour). At each of the nine time-points, craving was assessed by means of a shortened version of the Questionnaire of Smoking Urges. The Fagerstrom Test of Nicotine Dependence was used to obtain an indication of nicotine dependence. The results showed that, after a period of smoking abstinence, craving was stronger in those with a high tobacco dependence than in those with a low tobacco dependence. After resumption of smoking, craving declined to a similar low level in both low and high dependent smokers. Measurements during periods of ad libitum smoking indicate that plasma levels of norharman are related negatively to craving among low nicotine-dependent smokers, but not among high dependent smokers.

Voglewede JP Jr; Noel NE. Predictors of current need to smoke in inmates of a smoke-free jail. Addictive Behaviors 29(2): 343-348, 2004. (11 refs.)

A popular correctional policy has been the implementation of smoking bans for inmates. Although there is little cigarette smoking research with this population, research with other groups suggests that high levels of post-cessation cravings are associated with smoking relapse. The present study analyzed the relationship of demographic and smoking history variables, length of time incarcerated, and future intention to smoke upon release with current need to smoke in jail inmates. Participants were 150 male inmates housed in a smoke-free county jail who were intensively interviewed about smoking behavior as part of a larger study. Results indicated that stated future intention to smoke predicted current need to smoke in inmates, while length of time in jail did not. Nicotine dependence was not related either to the current need to smoke or future intention to smoke. These findings were consistent with previous inmate smoking research and have clinical implications for inmate smokers.

Waters AJ; Shiffman S; Bradley BP; Mogg K. Attentional shifts to smoking cues in smokers. Addiction 98(10): 1409-1417, 2003. (25 refs.)

Aims Many theories of addiction assume that responses to drug cues maintain drug use and precipitate relapse. There is evidence that measures derived from experimental cognitive psychology yield important information about cue reactivity. We used a pictorial version of the visual probe task to evaluate: (i) whether minimally deprived smokers attend differentially to smoking cues (attentional bias): (ii) whether this bias is related to self-reported craving and dependence; and (iii) whether it predicted outcome in a subsequent cessation attempt. Design Participants took part in a structured smoking cessation program. Each participant completed the visual probe task roughly 2 weeks before quitting while non-deprived. Setting A research smoking cessation clinic. Participants 141 heavy smokers seeking treatment for smoking cessation. Measurements The computerized attentional bias measure and self-reported urge were taken in a laboratory session. Participants also monitored their smoking and craving on electronic diaries both when smoking ad libitum and for up to 6 weeks post-cessation. Findings Participants were faster and more accurate in responding to a visual probe that replaced a smoking picture than to a neutral picture, indicating that they showed attentional bias towards the smoking cues. Attentional bias on the first half of the task correlated with pre-task craving, indicating that the bias may tap motivational processes, but it did not predict outcome in smoking cessation. Conclusions The visual probe task can add useful information about attentional responses to drug cues. Further work is required to uncover the theoretical significance and utility of this measure.

Weinstein A; Feldtkeller B; Feeney A; Lingford-Hughes A; Nutt DJ. A pilot study on the effects of treatment with acamprosate on craving for alcohol in alcohol-dependent patients. Addiction Biology 8(2): 229-232, 2003. (18 refs.)

This study investigated the effects of treatment with acamprosate on craving for alcohol by using a contextual priming task with alcohol and neutral words and craving questionnaires (ACQ, OCDS) in alcohol-dependent patients who abstained from alcohol for 6 weeks. The acamprosate-treated group (n = 16) were given 666 mg t.d.s. with standard group-work aimed at abstinence. The unmedicated control group (n = 13) received only standard group therapy. The results showed that the acamprosate treated group was faster in their responses to craving-related stimuli and scored lower on craving questionnaires during week 6 compared with week 2. Our results suggest that acamprosate may play a role in reduction of craving for alcohol after 6 weeks of treatment.

Weiss RD; Griffin ML; Mazurick C; Berkman B; Gastfriend DR; Frank A et al. The relationship between cocaine craving, psychosocial treatment, and subsequent cocaine use. American Journal of Psychiatry 160(7): 1320-1325, 2003. (33 refs.)

Objective: Regular measurement of craving during treatment for cocaine dependence can monitor patients' clinical status and potentially assess their risk for drug use in the near future. Effective treatment can reduce the correlation between craving and subsequent drug use by helping patients abstain despite high craving. This study examined the relationship between cocaine craving, psychosocial treatment, and cocaine use in the ensuing week. Method: In the National Institute on Drug Abuse Collaborative Cocaine Treatment Study, which compared four psychosocial treatments for cocaine dependence, a three-item craving questionnaire was administered weekly to 449 patients to see whether it predicted cocaine use in the ensuing week. Cocaine use was assessed with self-reports and urine screening. Results: With control for the previous week's cocaine use, a higher composite score on the craving questionnaire was associated with greater likelihood of cocaine use in the subsequent week; each 1-point increase on the composite score of the craving questionnaire increased the likelihood of cocaine use in the ensuing week by 10%. However, among patients who received individual plus group drug counseling, the treatment condition with the best overall cocaine use outcome, increased craving scores were not associated with greater likelihood of cocaine use in the subsequent week. Conclusions: A three-item cocaine craving questionnaire predicted the relative likelihood of cocaine use during the subsequent week. Moreover, the relationship between craving and subsequent cocaine use varied by treatment condition, suggesting that the most effective treatment in the study might have weakened the link between craving and subsequent use.

Wurst FM; Bechtel G; Forster S; Wolfersdorf M; Huber P; Scholer A et al. Leptin levels of alcohol abstainers and detoxification patients are not different. Alcohol and Alcoholism 38(4): 364-368, 2003. (38 refs.)

Aims: Leptin is a cytokine-type peptide hormone, recently implicated as a putative state marker of alcohol use and in craving. Our goal was to evaluate the potential of leptin as a state and trait marker and to rule out the role of current alcohol intoxication on leptin levels. Methods: Eighteen alcohol withdrawal patients (16 males, 2 females) whose blood contained 202 mg/dl (median) of ethanol at hospitalization, who had a median age of 43.5 years and had consumed 1075 g of ethanol (median) in the last 7 days were included in the study. Leptin was determined in samples at day 1 (when still intoxicated) and day 7 of withdrawal. Expected leptin levels were calculated with a formula. For comparison, 27 blood samples of 18 abstinent persons, matched for gender, age and body mass index were used. Furthermore, mean cell volume, gamma-glutamyl transferase (GGT), blood glucose, cholesterol, triglycerides and body composition (bioimpedance device) were determined. For statistical analysis, SPSS 11 was used. Results: Expected leptin levels were 1.71 ng/ml (median), leptin measured at day 1 was 2.65 ng/ml (median) and 2.85 ng/ml on day 7 for the alcohol withdrawal patients and 2.2 ng/ml (median) for the abstainers. These concentrations were not significantly different. Significant correlations were found between leptin day 1 and expected leptin levels, percentage fat body mass, cigarettes smoked per day, GGT and blood alcohol concentration. Conclusions: Our preliminary data do not support the hypothesis of leptin as a state or trait marker and suggest only a minor influence of acute intoxication on leptin levels in alcohol detoxification patients.

Zernig G; Giacomuzzi S; Riemer Y; Wakonigg G; Sturm K; Saria A. Intravenous drug injection habits: Drug users' self-reports versus researchers' perception. Pharmacology 68(1): 49-56, 2003. (28 refs.)

The present study was designed to obtain human data on the speed of intravenous (i.v.) injection of cocaine, heroin, and morphine as well as on the rate of onset of their subjective effects and their duration in order to improve the accuracy of animal and human experimental models of i.v. drug abuse. To that end, a questionnaire was submitted both to clients of a substitution therapy outpatient clinic and to members of the drug abuse research community. It was found that i.v. drug abusers injected cocaine, heroin, or morphine much faster and also experienced the drug effects much faster than assumed by the drug abuse researchers. The time course of the reemergence of craving was also greatly misjudged by the researchers. On the other hand, the i.v. drug users' self-reports were internally consistent and corresponded well to data obtained in several different human behavioral laboratories. Interestingly, more than half of the i.v. drug users reported that injection speed was not important when injecting cocaine (57%), heroin (72%) or morphine (73%) under conditions that guarantee a maximum effect, suggesting that the rate of the rise in the brain concentration of a drug of abuse is less important for its reinforcing effect and, thus, for its abuse liability, than previously assumed, at least within the time frame of an i.v. drug injection.

Zywiak WH; Westerberg VS; Connors GJ; Maisto SA. Exploratory findings from the Reasons for Drinking Questionnaire. (rapid communication). Journal of Substance Abuse Treatment 25(4): 287-292, 2003. (20 refs.)

Marlatt and Gordon's (1985) relapse prevention therapy has received widespread interest and application. The categorization of relapse precipitants was one of the original central features of this model. In more recent iterations of this therapy, increasing emphasis has been placed on coping strategies. In the present article, exploratory findings from a prospective naturalistic alcohol treatment study employing the Reasons for Drinking Questionnaire are reported. A relapse precipitants scoring algorithm is presented allowing relapses to be categorized as either negative affect relapses, social pressure relapses, or craving/cued relapses. Exploratory findings suggest that social pressure relapses are more likely to repeat, and that negative affect and craving/cued relapses are more severe. Perhaps most interestingly, craving/cued relapses appear to subside during the first 6 months following treatment initiation, but subsequent risk for this type of relapse returns if the client has relapsed. However, these findings are still early in a continuing exploration of these issues in relapse prevention.