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Director's Report to the National Advisory Council on Drug Abuse - February, 2004

Research Findings - Treatment Research and Development

Modafinil and Cocaine: A Double-blind, Placebo-controlled Drug Interaction Study

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. The neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. The results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Dackis, C.A., Lynch, K.G., Yu, E., Samaha, F.F., Kampman, K.M., Cornish, J.W. et al. Drug Alcohol Depend., 70(1), pp. 9-37, 2003.

Tiagabine Increases Cocaine-Free Urines in Cocaine-Dependent Methadone-Treated Patients: Results of a Randomized Pilot Study

Dr. Gerardo Gonzalez and colleagues evaluated the safety and efficacy of the GABAergic agent tiagabine in reducing cocaine use among methadone-treated patients. A ten-week randomized double-blind placebo-controlled trial was conducted at the Opiate Treatment Research Program, Veteran's Affairs Connecticut Healthcare System in West Haven, Connecticut, USA. The participants were 45 cocaine-dependent methadone-treated patients who were predominately Caucasian (75.6%), male (77.8%) and never married (53%) with an average age of 38 years (SD = 6.5). Comparison groups received tiagabine 12 mg/day (n = 15), tiagabine 24 mg/day (n = 15) or placebo (n = 15). Treatment retention was over 80% for all treatment groups. The sample mean (+/- SE) of cocaine-free urines for the first week after study entry and before tiagabine was started was 1.16 (0.19) urines/week. During weeks 9 and 10 cocaine-free urines increased significantly from baseline by 33% with high-dose tiagabine (24 mg/day), by 14% with low-dose tiagabine (12 mg/day) and decreased by 10% with placebo (hierarchical linear model, Z= 2.03; P < 0.05). Self-reported cocaine use also decreased significantly more with active medications than with placebo. The results suggest that tiagabine at 24 mg/day was well tolerated among these methadone-treated patients with only one reporting headache and appears to be a promising GABAergic medication that moderately improves cocaine-free urines. Gonzalez, G., Sevarino, K., Sofuoglu, M., Poling, J., Oliveto, A., Gonsai, K. et al., Addiction, 98(11) pp. 1625-1632, 2003.

Effects of Triazolam Pretreatment on Behavioral and Physiological Effects of Cocaine in Humans

There is evidence to suggest that gamma-aminobutyric acid (GABA) agonists may attenuate the behavioral effects of cocaine and may be effective pharmacotherapies for cocaine abuse and dependence. Dr. Craig Rush and colleagues from the University of Kentucky examined the effect of triazolam (0 and 0.5 mg), a GABA (A) modulator, combined with oral cocaine (0 and 300 mg) in 10 individuals with recent histories of cocaine use. Volunteers received each of the four possible drug combinations in mixed order. Drug effects were assessed using a battery of subject-rated drug-effect questionnaires and physiological indices. Cocaine alone produced prototypical stimulant-like subject-rated drug effects (e.g., increased ratings of High, Like Drug, and Willing to Take Drug Again) and triazolam produced sedative-like effects. Triazolam pretreatment did not significantly attenuate the subject-rated effects of cocaine. Haga, J.L., Baker, R.W. and Rush, C.R. Behavioral and Physiological Effects of Cocaine in Humans Following Triazolam. Pharmacol Biochem Behav., 76(3-4), pp. 383-392, December 2003.

Deficiencies in Dietary Polyunsaturated Fatty (PUFA) Acids May Contribute to Aggression in Cocaine Addicts

Many substance abusers have poor dietary habits. Dr. Laure Buydens-Branchey and colleagues at the State University of New York examined the correlation of plasma fatty acids (FA) profiles with aggression in 24 cocaine-dependent patients admitted to an inpatient substance abuse unit. Six had a past history of aggression and 18 did not. A comparison of the FA levels of aggressive and non-aggressive patients performed 4 days after their admission did not reveal any significant difference in saturated FAs or monounsaturated FAs. Aggressive patients had significantly lower levels of the n-6 polyunsaturated fatty acid (PUFA) docosapentaenoic acid (DPA), of total n-3 PUFAs and of the n-3 PUFA docosahexaenoic acid (DHA), and a marginally significant increase in the ratio of n-6 to n-3 PUFAs. Measurements performed 18 days after admission showed that most FAs increased in both patient groups. Some PUFAs, especially those of the n-3 series, increased more sharply in the aggressive patients. These data suggest that the aggressive individuals might have been deficient in n-3 rich nutrients and support the evidence indicating a possible link between an n-3 deficiency and aggression in humans. Buydens-Branchey, L., Branchey, M., McMakin, D.L. and Hibbeln, J.R. Drug Alcohol Depend., 71(3), pp. 319-323, September 2003.

Plasma Polyunsaturated Fatty Acids May Play A Role In Relapse Rates of Cocaine Addicts

There is evidence to suggest that polyunsaturated fatty acids (PUFAs) may play a role in the pathophysiology of depressive and aggressive disorders. In animals, there is evidence that PUFAs could play a role in substance abuse through their action on central serotonergic and dopaminergic systems. Dr. Laure Buydens-Branchey and colleagues at the State University of New York examined the association of plasma PUFAs with relapse rates in 38 cocaine addicts discharged after a period of detoxification on an inpatient unit. PUFA status was assessed at baseline, shortly after admission. Resumption of substance use was assessed 3 months, 6 months and 1 year following discharge. Subjects who relapsed at 3 months had significantly lower baseline levels of total n-6 PUFAs, linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) and total n-3 PUFAs when compared to non-relapsers by ANCOVAs with age and weight as covariates. Lower baseline total n-6 PUFAs, LA and AA continued to predict relapse 6 months and 12 months following discharge. Age, marital status, educational level, cocaine use parameters or psychopathology did not differ between relapsers and non-relapsers. These data suggest the existence of a causal relationship between n-6 or n-3 status and relapse vulnerability in cocaine addicts, and provide a rationale for the exploration of possible relationships between relapse to addictive disorders and PUFA status in observational and interventional trials. Buydens-Branchey, L., Branchey, M., McMakin, D.L. and Hibbeln, J.R. Psychiatry Res. 120(1), pp. 29-35, August 2003.

Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone

Dr. Paul Fudala and colleagues conducted a multi-center, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial. The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated. In conclusion, buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting. Fudala, P.J., Bridge, T.P., Herbert, S., Williford, W.O., Chiang, C.N., Jones, K. et al., N Engl J Med., 349(10) pp. 949-958, 2003. Transferring Methadone-Maintained Outpatients to the Buprenorphine Sublingual Tablet: A Preliminary Study There is no accepted algorithm to transfer opioid-dependent patients from methadone (METH) to its new alternative, buprenorphine (BUP). Five outpatients transferred (double blind, double dummy) from METH 60 mg/day (with one day at 45 mg) to BUP 8 mg s.l. tablet. Relative to METH maintenance, BUP decreased opioid agonist symptoms (transfer day 1) and increased withdrawal symptoms (days 1 and 2) and blood pressure (day 2). Self-reported heroin use did not increase from METH maintenance levels. It may be feasible to transfer outpatients on METH 60 mg/day to BUP 8 mg/day s.l. tablet, although this pilot protocol needs refinements to improve tolerability and clinical efficacy. Greenwald, M.K., Schuh, K.J. and Stine, S.M. Am J Addict, 12(4), pp. 365-374, 2003.

Protease Inhibitors Used for Treatment of HIV May Produce Opiate Withdrawal in Methadone-Maintained Patients

Dr. Elinore McCance-Katz and colleagues at the Medical College of Virginia examined the interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV infection, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone in opiate addicts. L/R was associated with significant reductions in the methadone area under the concentration-time curve, maximum concentration, and minimum concentration, as well as increased methadone oral clearance and increased opiate withdrawal symptoms, whereas ritonavir use alone modestly and non-significantly increased methadone concentrations. Because lopinavir is a potent inducer of methadone metabolism, treatment with L/R requires clinical monitoring and may require increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism. McCance-Katz, E.F., Rainey, P.M., Friedland, G. and Jatlow, P. Clin Infect Dis., 37(4), pp. 476-482, August 2003.

Nicotine Withdrawal and Depressive Symptomatology During Short-Term Smoking Abstinence: A Comparison of Postmenopausal Women Using and Not Using Hormone Replacement Therapy

This study investigated whether taking medications for transdermal hormone replacement therapy (HRT) influenced smoking-cessation variables in postmenopausal women undergoing short-term abstinence from cigarettes. Women were recruited into two groups according to their pre-enrollment medication status--those currently on HRT (n = 17) or those not on HRT (n = 13). The HRT group had their previous medication replaced with a standard 0.1 mg estradiol transdermal system and 2.5 mg of Cycrin daily. After 2 weeks of medication adjustment, participants continued smoking as usual for 1 week, at which time baseline measurements were taken. Participants were then instructed to quit smoking for the remaining 2 weeks. They were provided with smoking-cessation counseling and monitored for abstinence. Data were collected during five clinic visits on all dependent measures: Minnesota Nicotine Withdrawal Scale, Beck Depression Inventory (BDI) scale, Profile of Mood States, Motor Speed Tasks, and Reaction Time Test. Contrary to the hypothesis, the exogenous hormone use did not have a differential effect on most of the dependent variables during the first 2 weeks of smoking abstinence. One exception was depressive symptomatology: the BDI change scores (week 2 - baseline) differed significantly for the HRT and non-HRT groups (p = .045), with women in the HRT group experiencing an increase in depressive symptomatology. This finding, though preliminary, may have clinical implications for postmenopausal women who attempt to quit smoking while on HRT, particularly since depressed mood following abstinence is associated with a relapse to smoking. Allen, S.S., Hatsukami, D.K. and Christianson, D. Nicotine Tob Res., 5(1), pp. 49-59, 2003.

A Preliminary Placebo-Controlled Trial of Selegiline Hydrochloride for Smoking Cessation

Dr. Tony George and colleagues studied the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride compared with placebo for smoking cessation in nicotine-dependent cigarette smokers. Forty subjects with DSM-IV nicotine dependence were randomized to: 1) selegiline hydrochloride (5 mg p.o. twice daily) or 2) placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects. Selegiline hydrochloride increased trial end point (week 8) 7-day point prevalence smoking cessation rates (selegiline hydrochloride, 9/20 [45.0%]; placebo, 3/20 [15.0%], odds ratio = 4.64, 95% CI, 1.02-21.00, p <.05), and smoking cessation rates during the last 4 weeks of the trial (selegiline hydrochloride, 6/20 [30.0%]; placebo, 1/20 [5.0%], odds ratio = 8.14, 95% CI, 0.88-75.48, p =.07) in comparison with placebo. Six-month follow-up 7-day point prevalence smoking cessation rates were reduced compared with trial end point (selegiline hydrochloride, 4/20 [20.0%]; placebo, 1/20 [5.0%], odds ratio = 4.75, 95% CI, 0.48-46.91, p =.18). Treatment retention was similar between drug and placebo groups (p =.13), and selegiline hydrochloride was well tolerated in cigarette smokers. This preliminary study suggests that selegiline (10 mg/day) is safe for use and enhances smoking cessation rates compared with placebo in nicotine-dependent cigarette smokers. George, T.P., Vessicchio, J.C., Termine, A., Jatlow, P.I., Kosten, T.R. and O'Malley, S.S. Biol Psychiatry, 53(2), pp. 136-143, 2003.

Treatment of Adolescent Smokers with the Nicotine Patch

This study examined the effects of the nicotine patch on craving and withdrawal symptoms, safety, and compliance among adolescents. The secondary goal was to conduct a preliminary investigation of the effectiveness of the nicotine patch in helping adolescents quit smoking. The study design was a double-blind, placebo-controlled, randomized trial of the nicotine patch. The intervention also provided intensive cognitive-behavioral therapy and a contingency-management procedure. Participants (n=100) attended 10 treatment visits over 13 weeks. Compared with the placebo patch group, the active nicotine patch group experienced a significantly lower craving score and overall withdrawal symptom score (p=.011 and p=.025, respectively), as well as a time trend toward lower scores (p<.001) in craving only. Moreover, the nicotine patch appeared safe for adolescents to use. No differences by treatment group were found in experiencing adverse events, except that the participants in the placebo patch group reported more headaches than those in the active nicotine patch group. As another measure of safety, the overall mean salivary cotinine levels were significantly lower at 1, 6, 8, and 10 weeks post quit (all p<.05) compared with baseline levels, although these results were confounded by dropouts. Additionally, a significant number of participants were compliant with using the nicotine patch daily. Finally, point prevalence (7-day and 30-day abstinence rates) and survival analysis of participant abstinence indicated no significant differences between treatment groups. The results of this study suggest that the nicotine patch is a promising medication and a larger clinical trial of the nicotine patch among adolescents is warranted. Hanson, K., Allen, S., Jensen, S. and Hatsukami, D. Nicotine Tob Res., 5(4), pp. 515-526, 2003. Efficacy of Nicotine Patch in Smokers with a History of Alcoholism 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. 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. 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. Heavy smokers with a history of alcoholism benefit from nicotine patch treatment. Hughes, J.R., Novy, P., Hatsukami, D.K., Jensen, J. and Callas, P.W. Alcohol Clin Exp Res., 27(6), pp. 946-954, 2003.

Maternal Vaccination Against Nicotine Reduces Nicotine Distribution to Fetal Brain in Rats

Vaccination of adult male rats against nicotine has been shown to reduce nicotine distribution to the brain. The current study examined whether vaccination of female rats before pregnancy would reduce the distribution to fetal brain of a single nicotine dose administered during gestation. Female rats immunized with a nicotine conjugate vaccine received a single dose of nicotine 0.03 mg/kg i.v. on gestational day 16 to 22. Five minutes later, vaccinated rats had substantially higher bound and lower unbound serum nicotine concentration and lower brain nicotine concentration than controls. Fetal brain nicotine concentration was reduced by 43% in vaccinated rats, comparable to the reduction in the maternal brain nicotine concentration. The whole-fetus nicotine concentration was not altered by vaccination. A similar experiment was performed in which pregnant rats were passively immunized with rabbit nicotine-specific IgG 7 or 21 mg/kg just before nicotine dosing. The effects of passive immunization on nicotine distribution in the mother were IgG dose-related and the higher dose reduced nicotine distribution to fetal brain by 60%. These data suggest that vaccine effects on nicotine distribution to serum and brain are similar in pregnant female rats to those previously reported in adult males. Vaccination of female rats before pregnancy, or passive immunization during pregnancy, can reduce the exposure of fetal brain to a single dose of maternally administered nicotine. Keyler, D.E., Shoeman, D., LeSage, M.G., Calvin, A.D. and Pentel, P.R. J Pharmacol Exp Ther., 305(2) pp. 587-592, 2003.

A Preliminary Study on Effects of Intravenous Nicotine on Cerebral Glucose Metabolism

Nicotine, when self-administered by smoking tobacco products, is reported to enhance positive mood in seasoned smokers. NIDA-funded researchers posited that since most drugs of abuse have been shown to decrease regional cerebral metabolic rate(s) for glucose (rCMRglc), in humans, nicotine might similarly reduce rCMRglc. Positron emission tomography (PET) with [F-18]fluorodeoxyglucose was used to assess the effects of intravenous nicotine (1.5 mg) on cerebral glucose metabolism in six healthy male volunteers (21-38 years of age). PET scans during placebo and nicotine were performed, and measures of mood and 'feeling state' were self-reported. Data were analyzed using analysis of variance. Nicotine reduced global glucose metabolism by 9.51% compared to placebo control, with reductions in most of the 30 individual regions tested. Nine regions demonstrated statistically significant bilateral effects, although the statistical model did not separate these effects from a global effect. The subjects reported both positive and negative effects of nicotine on mood/feeling state. The widespread decreases in cerebral metabolism are consistent with the many effects of nicotine on cognition and mood. The findings indicate that nicotine resembles other drugs of abuse in reducing brain metabolism, perhaps by a common mechanism. Stapleton, J.M., Gilson, S.F., Wong, D.F, Villemagne, V. L., Dannals, R.F., Grayson, R.F., Henningfield, J.E and London, E.D. Intravenous Nicotine Reduces Cerebral Glucose Metabolism: A Preliminary Study. Neuropsychopharmacology, 28(4), pp. 765-772, April 2003.

rCBF Effects of Nicotine Versus Mecamylamine

The effects of acute nicotine and smoking on brain function were investigated in separate studies, with the primary goal of identifying neural systems that mediate these effects. In Study 1, 18 healthy volunteer cigarette smokers received a single session during which they smoked a nicotine-containing cigarette, smoked a de-nicotinized cigarette, and received i.v. nicotine injections in conjunction with smoking a de-nicotinized cigarette. In Study 2, 16 Ss smoked a nicotine-containing and de-nicotinized cigarette in each of two sessions two hours after receiving either the nicotinic antagonist, mecamylamine or placebo, orally. Regional cerebral blood flow (rCBF) was assessed, and subjective measures of smoking withdrawal symptoms were collected. A principal-components analysis identified 3 factors consisting of frontal, striatal, and reticular systems. Nicotine increased normalized rCBF in the left frontal region and decreased rCBF in the left amygdala. The rCBF in the right hemisphere reticular system was related to nicotine dose in an inverted-U-shaped pattern and was strongly related to both the self-reported craving for cigarettes and to the addiction scale of a smoking motivation questionnaire. The effects of mecamylamine on rCBF were generally opposite to those of nicotine. Rose, J.E., Behm, F.M., Westman, E.C., Mathew, R.J., London, E.D, Hawk, T.C., Turkington, T.G. and Coleman, R.E. PET Studies of the Influences of Nicotine on Neural Systems in Cigarette Smokers. American Journal of Psychiatry, 160(2), pp. 323-333, February 2003.

Comparison of EEG Tracing in Abstinent Methamphetamine Users and Normal Controls

Quantitative EEG has been used to characterize abnormalities in brain function in a number of disorders, including cocaine dependence, but has not been used to characterize abnormalities associated with methamphetamine dependence. Methamphetamine exposure is associated with long-lasting reductions in markers for DA neurons in preclinical models and probably in humans. Researchers at UCLA studied 11 methamphetamine-dependent subjects and 11 non-drug using volunteers to test the hypothesis. Methamphetamine-dependent subjects were hospitalized for four days to document abstinence while the non-drug using volunteers were studied as outpatients. EEG power was log-transformed prior to analysis. Conventional EEG tracings were interpreted by a qualified electroencephalographer, who was blinded to the subjects' identity. The four-day abstinent, methamphetamine-dependent volunteers had increased EEG power in the delta and theta bands. Power in the alpha and beta bands did not differ between the groups. Within the methamphetamine-dependent group, a majority of the conventional EEGs were abnormal (64%) compared to 18% in the no drug controls. Abstinent methamphetamine-dependent subjects have also been shown to demonstrate qEEG abnormalities that are consistent with a generalized encephalopathy. Newton, T.F, Cook, I.A, Kalechstein, A.D., Duran, S., Monroy, F, Ling, W. and Leuchter, A.F. Quantitative EEG Abnormalities in Recently Abstinent Methamphetamine Dependent Individuals. Clinical Neurophysiology, 114(3), pp. 410-415, March 2003.

Cingulate Hypoactivity in Cocaine Users During a GO-NOGO Task as Revealed by Event-Related Functional Magnetic Resonance Imaging

Dr. Hugh Garavan and colleagues at the Medical College of Wisconsin used functional magnetic resonance imaging to investigate whether chronic cocaine use leads to a neural dysfunction resulting in an inability to withhold pre-potent responses. Chronic cocaine abusers and normal comparison subjects were scanned while performing a GO-NOGO task in which successful performance required prepotent behaviors to be inhibited. Chronic cocaine abusers exhibited significantly less task-related activation in the cingulate, pre-supplementary motor and insula cortex. This hypoactivity was observed for both successful NOGOs and errors of commission in chronic cocaine users relative to cocaine-naive controls. This attenuated response, in the presence of comparable activation levels in other task-related cortical areas, suggests cortical and psychological specificity in the locus of drug abuse-related cognitive dysfunction. The results suggest that addiction may be accompanied by a disruption of brain structures critical for the higher-order, cognitive control of behavior. Kaufman, J.N., Ross, T.J., Stein, E.A., Garavan, H. Journal of Neuroscience, 23(21), pp. 7839-7843, 2003.

Increased Activation in the Right Insula during Risk-Taking Decision Making Is Related to Harm Avoidance and Neuroticism

Dr. Martin Paulus and colleagues at University of California, San Diego used functional magnetic resonance imaging (fMRI) to investigate the role of the insula in risk-taking and decision making in normal human subjects. They hypothesized that the degree of risk-taking is related to the degree of activation in the insular cortex. Seventeen healthy, right-handed subjects performed a risk-taking decision-making task during functional magnetic resonance imaging (fMRI) using a fast event-related design. This investigation yielded three main findings. First, right insula (BA 13) activation was significantly stronger when subjects selected a "risky" response versus selecting a "safe" response. Second, the degree of insula activation was related to the probability of selecting a "safe" response following a punished response. Third, the degree of insula activation was related to the subjects' degree of harm avoidance and neuroticism as measured by the TCI and NEO personality questionnaires, respectively. These results are consistent with the hypothesis that insula activation serves as a critical neural substrate to instantiate aversive somatic markers that guide risk-taking decision-making behavior. Paulus, M.P., Rogalsky, C., Simmons, A., Feinstein, J.S. and Stein, M.B. Increased Activation in the Right Insula During Risk-Taking Decision Making is Related to Harm Avoidance and Neuroticism. NeuroImage, 19(4), pp. 1439-1448, August 2003.

Exploring the Neurological Substrate of Emotional and Social Intelligence

Dr. Antoine Bechara and colleagues at the University of Iowa investigated whether deficits in poor judgment in decision-making, especially in the personal and social realms was related to measures of emotional intelligence. Emotional intelligence has been defined as an array of emotional and social abilities, competencies and skills that enable individuals to cope with daily demands and be more effective in their personal and social life. Patients with lesions to the ventromedial (VM) prefrontal cortex, insula cortex or amygdala have defective somatic markers and tend to exercise poor judgment in decision-making. The subjects in this study were twelve patients with focal, stable bilateral lesions of the VM cortex or amygdala or the right insular cortices, and 11 patients with focal, stable lesions in structures outside the neural circuitry thought to mediate somatic state activation and decision-making. Subjects were tested on the Emotional Quotient Inventory (EQ-I), a standardized psychometric measure of various aspects of emotional and social intelligence. Subjects were also tested on various other procedures designed to measure decision-making (the Gambling Task), social functioning, as well as personality changes and psychopathology; standardized neuropsychological tests were applied to assess their cognitive intelligence, executive functioning, perception and memory as well. Patients with lesions in the somatic marker circuitry had significantly lower emotional intelligence and poorer judgment in decision-making compared to the other patients with brain lesions. The patients with lesions in the somatic marker circuitry also had disturbances in social functioning, in spite of normal levels of cognitive intelligence (IQ) and the absence of psychopathology based on DSM-IV criteria. The findings provide preliminary evidence suggesting that emotional and social intelligence is different from cognitive intelligence. They suggest, moreover, that the neural systems supporting somatic state activation and personal judgment in decision-making may overlap with critical components of a neural circuitry subserving emotional and social intelligence, and is independent of the neural system supporting cognitive intelligence. Bar-On, R., Tranel, D., Denburg, N.L. and Bechara, A. Exploring the Neurological Substrate of Emotional and Social Intelligence. Brain, 126, pp. 1790-1800, 2003.

Human Striatal Response to Salient Non-rewarding Stimuli

Dr. Gregory Berns and colleagues at Emory University used functional magnetic resonance imaging to investigate whether activation of the striatum in normal human subjects is related specifically to reward-related stimuli or processes salient events, regardless of their reward value. Saliency refers to an event that both is unexpected and elicits an attentional-behavioral switch (i.e., arousing). Flickering visual distractors presented in the background of an ongoing task were used as the salient events. Distractor salience was manipulated by altering the frequency of distractor occurrence with infrequently presented distractors that were considered more salient. In the first experiment (19 subjects), the distractors were made behaviorally relevant by defining a subset of them as targets requiring a button press. In the second experiment (17 subjects), the distractors were not behaviorally relevant (i.e., they did not require any response). The fMRI results revealed increased activation in the nucleus accumbens after infrequent (high salience) relative to frequent (low salience) presentation of distractors in both experiments. Caudate activity increased only when the distractors were behaviorally relevant. These results demonstrate a role of the striatum in coding non-rewarding salient events. In addition, a functional subdivision of the striatum according to the behavioral relevance of the stimuli is suggested. Zink, C.F., Pagnoni, G., Martin, M., Dhamala, M. and Berns, G.S. Human Striatal Response to Salient Non-Rewarding Stimuli. Journal of Neuroscience, 23(22), pp. 8092-8097, 2003.

Psychosocial Stress and the Duration of Cocaine Use in Non-treatment-Seeking Individuals with Cocaine Dependence

Dr. Igor Elman and colleagues at McLean Hospital investigated whether there was link between psychosocial stress and cocaine dependence. Thirty-six non-treatment-seeking individuals were administered computerized multidimensional instruments, including the Profile of Mood States (POMS) and Speilberger State-Trait Anxiety Inventory (STAI), the Addiction Severity Index (ASI) and the Hamilton Rating Scale for Depression (HRSD). Based on the median POMS tension-anxiety scale score the entire sample was divided into two groups, those with high and low levels of stress. The two groups (n = 16 and 20) were similar in terms of age, gender distribution, and severity of addiction. Compared with the low stress group, high-stress individuals displayed significantly longer duration of cocaine use, greater POMS, STAI-state, STAI-Trait, and HRSD scores. These results extend prior reports implicating stress in the course of cocaine dependence to non-treatment-seekers and suggest that the stress-cocaine link may be generalizable to psychosocial stress and negative affective states. Karlsgodt, K.H., Lukas S.E., and Elman I. Psychosocial Stress and the Duration of Cocaine Use in Non-treatment Seeking Individuals with Cocaine Dependence. American Journal of Drug and Alcohol Abuse, 29(3), pp. 539-551, August 2003.

Multiple Neuronal Networks Mediate Sustained Attention

Dr. Hugh Garavan and colleagues at the Medical College of Wisconsin used functional magnetic resonance imaging to determine the neural substrates of sustained attention (vigilance). Twenty five normal subjects were scanned while performing a rapid visual information processing (RVIP) task. Performance of the RVIP task activated a network of frontal, parietal, occipital, thalamic, and cerebellar regions, whereas deactivations were seen in the anterior and posterior cingulate, insula, and the left temporal and parahippocampal gyrus. Good task performance, as defined by better detection of target stimuli, was correlated with enhanced activation in predominantly right fronto-parietal regions and with decreased activation in predominantly left temporo-limbic and cingulate areas. Factor analysis revealed that these performance-correlated regions were grouped into two separate networks comprised of positively activated and negatively activated intercorrelated regions. Poor performers failed to significantly activate or deactivate these networks, whereas good performers either activated the positive or deactivated the negative network, or did both. The fact that both increased activation of task-specific areas and increased deactivation of task-irrelevant areas mediate cognitive functions underlying good RVIP task performance suggests two independent circuits, presumably reflecting different cognitive strategies, can be recruited to perform this vigilance task. These results provide a basis for investigating brain mechanisms of sustained attention deficits in substance abusers. Lawrence, N.S., Ross, T.J., Hoffmann, R., Garavan, H. and Stein, E.A. Multiple Neuronal Networks Mediate Sustained Attention. Journal of Cognitive Neuroscience, 15, pp. 1028-1038, 2003.

Preliminary Evidence of Hippocampal Dysfunction in Adolescent MDMA (Ecstasy) Users

Dr. Leslie Jacobsen and colleagues published the results of an exploratory study designed to assess the potential cognitive and neurobiological effects of the use of MDMA in adolescence. Six adolescent MDMA users and six non-using adolescents that were matched on age, gender, IQ, and other drug use were asked to perform a series of tasks that tested their attentional and memory capabilities. In tests that measured performance on simple, selective, and divided attention tasks, MDMA users were found to have significantly longer reaction times, but no differences in accuracy. Adolescent MDMA users were found to differ in hippocampal activation pattern during working memory tasks from non-using adolescents, but this difference was only present at the most difficult level of the tasks, and was also found to be greatest among those individuals that had most recently used MDMA. This study is the first to demonstrate these differences among adolescent MDMA users that, when compared with the majority of users studied as adults, have comparatively little lifetime exposure to the drug. Jacobsen, L.K., Mencl, E.W., Pugh, K.R., Skudlarski, P. and Krystal, J.H. Preliminary Evidence of Hippocampal Dysfunction in Adolescent MDMA ("ecstasy") Users: Possible Relationship to Neurotoxic Effects. Psychopharmacology, DOI: 10.1007/s00213-003-1679-4, November 28, 2003.

Magnetic Resonance Spectroscopy of Neurotransmitters in the Human Brain

Dr. Edward Novotny and colleagues published a review of recent advances in magnetic resonance spectroscopy (MRS) that included an overview of the application of advanced MRS techniques to children and adolescents. Novotny, E.J., Fulbright, R.K., Pearl, P.L., Gibson, K.M. and Rothman, D.L. Magnetic Resonance Spectroscopy of Neurotransmitters in Human Brain. Ann Neurol. 54, Suppl 6:S25-31, 2003.

Enzymatic Assay for Perfluoro-tagged Metabolites of L-DOPA Using Crude Lysate from E. coli Transformed with pKKAADCII

Dr. Sherry Dingman and colleagues have developed isomers of L-DOPA tagged with multiple fluorine atoms and have demonstrated that the tagged isomers are converted by the enzyme L-aromatic acid decarboxylase, a naturally occurring enzyme in dopaminergic neurons, into molecules of fluorine-tagged dopamine. This finding suggests that these isomers have the potential to follow the native neuronal pathway for dopamine synthesis and may thus be useful in magnetic resonance studies of dopamine function in the brain. Moreover, the assays used provide a new tool for the screening of new compounds for use in fluorine imaging of neural pathways. Dingman S., Snyder-Leiby T., Mack D.J., Thomas R. and Guo C. Applied Microbiology and Biotechnology, DOI: 10.1007/s00253-003-1485-2, November 21, 2003.

Variable-Density Spiral 3D Tailored RF Pulses

Dr. V. Andrew Stenger and colleagues reported the development of a new protocol that allows for functional magnetic resonance imaging of neural activity using an excitation pulse of shortened duration. The shortened duration results in a decrease in susceptibility artifacts, which hinder our ability to image many brain structures that lie in close proximity to air-bone interfaces (i.e., the sinuses of the skull). Stenger, V.A., Boada, F.E., and Noll, D.C. Variable-Density Spiral 3D Tailored RF Pulses. Magnetic Resonance in Medicine, 50(5), pp. 1100-1106, 2003.

Reduced Cortical Gray Matter Density in Human MDMA (Ecstasy) Users: A Voxel-based Morphometry Study

In a preliminary study to determine if MDMA (Ecstasy) use resulted in morphological alterations in the brain, a team of NIDA-supported scientists employed voxel-based morphometric techniques to compare the concentration of gray and white matter in the brain of MDMA polydrug users to polydrug users that had never used MDMA. Their results demonstrated that a number of areas of the cerebral cortex, as well as cerebellum and midline brainstem, had reduced gray matter concentrations. These alterations in brain structure may underlie or contribute to reported neuropsychiatric impairments in MDMA users. Cowan, R.L., Lyoo, I.K., Sung, S.M., Ahn, K.H., Kim, M.J., Hwang, J., Haga, E., Vimal, R.L., Lukas, S.E. and Renshaw, P.F. Reduced Cortical Gray Matter Density in Human MDMA (Ecstasy) Users: A Voxel-Based Morphometry Study. Drug and Alcohol Dependence, 72(3), pp. 225-235, 2003.

Specific and Somatotopic Functional Magnetic Resonance Imaging Activation in the Trigeminal Ganglion by Brush and Noxious Heat

In an investigation of the utility of functional magnetic resonance imaging in elucidating the peripheral processing of pain information, Dr. David Borsook and colleagues used fMRI to measure activation in the trigeminal ganglion to noxious and innocuous stimuli. They found that the activation patterns were somatotopically organized, with the signal localized to the areas of the ganglion that corresponded to the known anatomical segregation of the ophthalmic, maxillary and mandibular divisions of the trigeminal nerve. They further found that the two stimulus types produced opposite activation patterns, with noxious stimuli producing an increase and innocuous stimuli producing a decrease in the fMRI signal. These findings are the first demonstration that MRI can detect functional changes in the trigeminal ganglion and illustrate that fMRI can be used to detect changes at the peripheral stages of neural processing in response to pain and other somatosensory modalities, providing evidence that functional neuroimaging may be useful in evaluating the effects of pain therapies. Borsook, D., DaSilva, A.F., Ploghaus, A., and Becerra, L. Specific and Somatotopic Functional Magnetic Resonance Imaging Activation in the Trigeminal Ganglion by Brush and Noxious Heat. J. Neurosci., 23(21), pp. 7897-7903, 2003.

Neural Circuitry Underlying Pain Modulation: Expectation, Hypnosis, Placebo

Borsook and colleagues reviewed their own and other previous studies on the cognitive aspects of the perception of pain. This review underscores the fact that the context in which pain is experienced, for instance, whether the pain is expected or not, greatly affects the specific areas of the brain that are activated in functional neuroimaging studies and, importantly, also affects how painful a stimulus is judged to be. As an example, if a painful stimulus is always preceded by a specific cue, activation increases in the rostral anterior cingulate cortex and in the insula when the cue is presented, and the magnitude of the pain, as assessed by the subject, is less than if the same stimulus were delivered without the preceding cue. If, however, an ambiguous signal is presented, activation occurs in the ventromedial prefrontal cortex and the mid-cingulate cortex. Under these conditions, the stimulus is reported to be more painful than if no cue is given. These data demonstrate that the perception of pain is strongly modulated by psychological factors and, by associating such factors with specific regions of the brain, may point the way toward more effective therapies and means of assessing their efficacy. Ploghaus, A., Becerra, L., Borras, C. and Borsook, D. Neural Circuitry Underlying Pain Modulation: Expectation, Hypnosis, Placebo. Trends in Cognitive Science, 7(5), pp. 197-200, 2003.

Family Transmission for Use, Abuse, and Dependence of Marijuana

Researchers in the program project of Thomas Crowley, University of Colorado, have shown family transmission of three levels of marijuana use, abuse, and dependence in a clinic-referred sample of adolescents. This study expands the literature that had previously only focused on use in adolescents or abuse and dependence in adults. Risk ratios ranged from 1.5 to 3.3; spousal correlations ranged from .33 to .70; parent-offspring correlations ranged from .17 to .30, and sibling correlations ranged from .34 to .44. The proportion of variance attributed to parent transmission ranged between 25% and 44%. These results document the not surprising observation of significant risk of transmission from parents, environmental influence from siblings, and assertive mating for all levels of marijuana use. Hopfer, C.J., Stallings, M.C., Hewitt, J.K., and Crowley, T.J. Family Transmission of Marijuana Use, Abuse, and Dependence. Journal of the American Academy of Child and Adolescent Psychiatry, 42(7), pp. 834-841, 2003.

Limbic Activation by Procaine in Female Cocaine-addicted Subjects Produces a Different Pattern of rCBF than Males

In a study in which procaine-a limbic system activator-was administered to female cocaine patients, there was a muted activation response in comparison to a matched comparison group. While this was unexpected because it was hypothesized that the limbic system would be sensitized in cocaine-addicted subjects, this result was nevertheless similar to that found with males. But other patterns of activation, and inactivation, did not follow the pattern of male addicted subjects. In particular, there were differences in the orbitofrontal cortex where females showed little change compared to controls following either saline or procaine while males did show changes. Specifically, decreased activation following saline was seen in males but not in females. Conversely, increased activation in this same region was seen in males following procaine but there was no increase in females relative to controls. Other sex pattern differences were observed suggesting that cocaine had differential effects on the neuronal structures of men and women. Since the hypothesized activation due to sensitization did not occur in either male or female addicted subjects, it is now suggested that these findings reflect changes in the cholinergic and/or the serotonergic 3 receptors. Adinoff, B., Devous, M.D., Sr., Best, S.E., Harris, T.S., Chandler, P., Frock, S.D., and Williams, M.J. Regional Cerebral Blood Flow in Female Cocaine-Addicted Subjects Following Limbic Activation. Drug and Alcohol Dependence, 71, pp. 255-268, 2003.

Failure to Find an Association for Haplotypes of the Mu Opioid Receptor in Severe Opioid Dependence

The mu opioid receptor has several polymorphisms and is the molecular target for both endogenous opioid peptides and exogenous opioids that make it an excellent candidate for study in comparison of opioid dependent individuals. However, Ashwin Patkar, Wade Berrettini and associates analyzed five SNPs (T-1793A, -1699t insertion, A-1320G, C+17T, AND A+118G) and showed no frequency differences between index cases of severe opioid dependence and a careful comparison group. However, there were significant differences in allele frequencies of these polymorphisms between European and African Americans. Crowley, J.J., Oslin, D.W., Patkar, A.A., Gottheil, E., DeMaria, P.A., Jr., O'Brien, C.P., Berrettini, W.H., and Grice, D.E. A Genetic Association Study of the Mu Opioid Receptor and Severe Opioid Dependence. Psychiatric Genetics, 13, pp. 169-173, 2003.

Stress Induced by Imagery Increases Cocaine Craving in Cocaine-dependent Individuals

Sinha and colleagues at Yale University and collaborators induced stress in cocaine-dependent individuals by imagery recall of a stressful event and assessed physiological and cognitive responses compared to imagery of a neutral experience. Increases were seen on a cocaine craving scale, anxiety scale, heart rate, blood pressure, and plasma levels of cortisol, prolactin and epinephrine. Similar increases were seen for induced craving by imagery of drug paraphernalia. These data suggest both stress and drug-related cues activate the HPA axis as well as the noradrenergic/sympatho-adreno-medullary system. Accordingly stress may play an important role in drug-taking and relapse. Sinha, R., Talih, M., Malison, R., Cooney, N., Anderson, G.M. and Kreek, M.J. Hypothalamic-Pituitary-Adrenal Axis and Sympatho-Adreno-Medullary Responses During Stress-Induced and Drug Cue-Induced Cocaine Craving States. Psychopharmacology, 170, pp. 62-72, 2003.

Induced Craving in Cocaine Dependent Subjects Produces Distinctive Electrocortical Profiles as Assessed by qEEG

Reid, Prichep and colleagues at NYU School of Medicine induced craving by paraphernalia handling, video viewing, and guided imagery relevant to cocaine environment of the subjects. Distinctive EEG patterns were observed for the two eyes-open situations (paraphernalia and video) that manifested as increased beta activity and decreased delta in the frontal cortex and an increased beta in the occipital cortex. Guided imagery (eyes closed) induced an increase in delta and theta in the frontal cortex and an increase in beta in the occipital cortex. Some of the behavioral measures (e.g., increased anxiety) correlated with these electrocortical measures. These data support other studies of cerebral blood flow and demonstrate that cocaine craving may be topographically mapped and subsequently analyzed for functional relevance. Reid, M.S., Prichep, L.S., Ciplet, D., O'Leary, S., Tom, M.L., Howard, B., Rotrose, J., and John, E.R. Quantitative Electroencephalographic Studies of Cue-Induced Cocaine Craving. Clinical Electroencephalography, 34(3), pp. 110-123, 2003.

PTSD Symptom Severity as a Predictor of Cue-Elicited Drug Craving in Victims of Violent Crime

Dr. Michael Saladin and colleagues at the Medical University of South Carolina, examined posttraumatic stress disorder (PTSD) symptom severity as a predictor of cue-elicited craving among alcohol-and cocaine-dependent individuals with a history of a 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 1) PTSD symptom severity, 2) type of substance use disorder (SUD) (alcohol dependence vs. cocaine dependence), and 3) 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. Saladin, M.E., Drobes, D.J., Coffey, S.F., Dansky, B.S., Brady, K.T. and Kilpatrick, D.G. Addictive Behaviors, 28, pp. 1611-1629, 2003.

"Who Gets In?": Recruitment and Screening Processes of Outpatient Substance Abuse Trials

In this study Dr. Shelly Sayre and colleagues at the University of Texas in Houston conducted a brief telephone screening interview with 1759 callers seeking treatment at the Treatment Research Clinic over a 16 month period in order to examine the effectiveness of various recruitment methods in attracting eligible participants and to identify screening variables that characterized eligible and ineligible callers. Callers referred by friends and family were more likely to be eligible than callers from other referral sources. Callers seeking treatment for cocaine abuse who reported more severe alcohol/substance abuse problems were more likely to be eligible for treatment protocols, while those with severe problems in other psychosocial areas (legal, medical, and psychiatric) were often excluded. Alcohol and nicotine dependent callers reporting severe alcohol problems were more likely to be eligible but otherwise were not different from callers who were ineligible. The effectiveness of recruitment methods may not be the same for different types of substance use disorders. This study underscores the importance of having a sensitive screening assessment for recruiting a homogeneous yet representative sample for outpatient substance abuse clinical trials. Sayre, S.L., Evans, M., Hokanson, P.S., Schmitz, J.M., Stotts, A.L., Averill, P. and Grabowski, J. Addictive Behaviors, 29, pp. 389-398, 2004.

Cross Cultural Evaluation of Smokers Risk for Panic and Anxiety Pathology: A Test in a Russian Epidemiological Sample

Dr. Michael Zvolensky and colleagues evaluated the main and interactive effects of level of smoking (cigarettes per day) and anxiety sensitivity (fear of anxiety and anxiety related sensations) in predicting panic and anxiety variables in an epidemiologically-defined sample of smokers from Moscow (n=95). The combination of high levels of anxiety sensitivity and smoking predicted agoraphobic avoidance, but not frequency of panic attacks during the past week. These findings suggest anxiety sensitivity may moderate the relation between level of smoking and prototypical panic psychopathology variables (panic attacks and agoraphobic avoidance) even after controlling for the theoretically-relevant factors of alcohol abuse and negative affect. Zvolensky, M.J., Kotov, R., Antipova, A.V., and Schmidt, N.B. Behaviour Research and Therapy, 41(10), pp. 1199-1215, October 2003.

Pretreatment Task Persistence Predicts Smoking Cessation Outcome

Dr. Thomas Brandon and colleagues at the University of South Florida, conducted a study to test whether persistence on difficult tasks is associated with nicotine dependence and independently predictive of success at smoking cessation. This study was based on R. Eisenberger's (1992) learned industriousness theory that states that individuals display differing degrees of persistence depending on their history of reinforcement for effortful behavior. These differences may influence the development, maintenance, and cessation of addictive behaviors. In the present study, a pretreatment measure of task persistence (mirror tracing) completed by 144 smokers predicted sustained abstinence through 12 months of follow-up. Moreover, persistence predicted outcome independent of other significant predictors: gender, nicotine dependence, negative affect, and self-efficacy. Brandon, T.H., Juliano, L.M., Irvin, J.E., Lazev, A.B. and Simmons, V.N. Journal of Abnormal Psychology, 112, pp. 448-456, 2003.

Sex Differences in the Effects of Stressful Life Events on Changes in Smoking Status

Dr. Sherry McKee and colleagues associated with the Yale TTURC examined stressful life events associated with substance use to determine if there are sex-specific responses to stress resulting in changes in smoking status. A community-based sample of ever smokers from the Americans' Changing Lives study was used to examine the interactive effects of sex and stressful life events on the likelihood of two outcomes; relapse among former smokers and failure to quit among current smokers. Results indicated that stressful life events appear to have a greater deleterious effect on continued abstinence and the ability to quit smoking for women when compared to men. In particular, health and financial events are important risk factors for women and tobacco use. McKee, S.A., Maciejewski, P.K., Falba, T., and Mazure, C.M. Addiction, 98, pp. 847-855, 2003.

Perceived Barriers to Quitting Smoking Among Alcohol Dependent Patients in Treatment

Researchers at Brown University investigated the perceived barriers to smoking among alcohol-dependent smokers (n=96) in an inner-city residential substance abuse treatment program. Information on barriers to smoking is important in order to design effective intervention programs addressing the concerns of alcoholic patients. The majority of respondents to the questionnaire reported withdrawal-related barriers such as expecting to feel irritable, anxious, restless, and about half expected intolerable urges to smoke if they were to quit smoking. However, concerns about effects on sobriety and needing cigarettes to cope with feeling down were also endorsed by almost half of the patients. Providing corrective feedback about these barriers could be useful when addressing smoking with patients who have alcohol abuse or dependence. Asher, M.K., Martin, R.A., Rohsenow, D.J., MacKinnon, S.V., Traficante, R., and Monti, P.M. Journal of Substance Abuse Treatment, 24, pp. 169-174, 2003.

Past Alcohol Problems Do Not Predict Worse Smoking Cessation Outcomes

Smokers with a past history (PH) of alcohol problems are heavier smokers and more nicotine dependent than smokers with no history of alcohol problems (NH). To test the hypothesis that PH smokers are less likely to be able to quit smoking than NH smokers, Dr. Hughes and colleagues at the University of Vermont conducted a secondary analysis of PH vs. NH smokers, all of whom were highly nicotine dependent (> 30 cigs/day). The findings indicate that heavy PH smokers are not less able to quit on a given attempt compared to heavy NH smokers. Thus a past history of alcohol problems (independent of nicotine dependence) does not predict a worse outcome on a given quit attempt. Hughes, J.R. and Callas, P.W. Drug and Alcohol Dependence, 71, pp. 269-273, 2003.

The Relationship Between Cocaine Craving, Psychosocial Treatment, and Subsequent Cocaine Use

A three-item craving questionnaire was administered weekly to 449 patients in the NIDA Collaborative Cocaine Treatment Study, to see whether it predicted cocaine use in the ensuing week. The results showed that 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. 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 by helping patients abstain despite high craving. Weiss, R.D., Griffin, M.L., Mazurick, C., Berkman, B., Gastfriend, D.R., Frank, A., Barber, J.P., Blaine, J., Salloum, I. and Moras, K. American Journal of Psychiatry, 160, pp. 1320-1325, 2003.

Community Reinforcement Therapy (CRA) Contributes to Outcome in CRA Plus Vouchers Studies

Dr. Steven Higgins and colleagues at the University of Vermont examined differences in treatment outcome between individuals receiving Community Reinforcement Approach therapy (CRA) plus voucher incentives contingent on abstinence and those receiving Vouchers alone. Study participants included 100 cocaine dependent adults randomly assigned to one of the two conditions. Voucher therapy lasted 12 weeks and the CRA therapy lasted 24 weeks and included monitored disulfiram therapy for those eligible and willing to take it. Previous research has demonstrated an effect of voucher incentives on retention. In this study, those receiving CRA with voucher incentives showed better treatment retention rates, used cocaine at a lower frequency during treatment, and reported a lower frequency of alcohol intoxication both during treatment and at 2 year follow-up. CRA plus vouchers condition also improved employment outcomes. Overall researchers concluded that CRA with vouchers provides an additional benefit over and above voucher incentives alone, particularly in terms of retention, reduced cocaine use during treatment, reduced drinking to intoxication, and employment. Higgins, S.T., Sigmon, S.C., Wong, C.J., Heil, S.H., Badger, G.J., Donham, R., Dantona, R.L. and Anthony, S. Journal of the Archives of General Psychiatry, 60(10), pp. 1043-1052, October, 2003.

New Treatment for Incarcerated Women with Post-Traumatic Stress Disorder (PTSD) and Substance Use Disorders (SUDs)

Dr. Caron Zlotnick and colleagues at Brown University and Harvard Medical School piloted a cognitive behavioral therapy, Seeking Safety with 17 incarcerated women with PTSD and SUDs as an adjunct to usual treatment provided by the prison. Of those receiving the treatment 53% no longer met criteria for PTSD at the end of treatment and 3 months following treatment 46% still no longer met criteria for PTSD. Although 35% reporting the use of illicit substances within three months of release from prison, overall results show a significant decrease in drug use from baseline. Measures of client satisfaction suggest the treatment is appealing to women and has the potential to be beneficial especially for PTSD symptoms. These results must be considered preliminary given the uncontrolled nature of the trial and the small number of participants. Zlotnick, C., Najavits, L.M., Rohsenow, D.J. and Johnson, D.M. Journal of Substance Abuse Treatment, 25(2), pp. 99-105, September, 2003.

Single or Dual Drug Targets are Equally Effective in a Brief Abstinent Test Procedure

Dr. Maxine Stitzer and colleagues at Johns Hopkins University compared response of methadone maintained cocaine and opioid users to voucher incentives when receipt of $200.00 in incentives was contingent on abstinence from either a single target, cocaine, or two targets, cocaine and opioids during a four day abstinence test. Participants were equally likely to initiate and maintain abstinence from cocaine in both conditions but they were more likely to initiate and maintain abstinence from heroin in the dual target condition. This research refutes the notion that adding a second target might interfere with participant's ability to initiate cocaine abstinence and suggests that it may facilitate abstinence from multiple drugs. Correia, C.J., Dallery, J., Katz, E.C., Silverman, K., Bigelow, G. and Stitzer, M.L. Experimental and Clinical Psychopharmacology, 11(4), pp. 302-308, November, 2003.

Client Commitment Language During Motivational Interviewing Predicts Drug Use Outcomes

Dr. William R. Miller and colleagues at the University of New Mexico coded tapes of motivational interviewing sessions for strength of utterances related to motivation, desire, commitment, need, readiness, and reasons to change. Participants could be divided into three groups based on proportion of days abstinent (PDA) before and after treatment, those with High PDA, before and after (maintainers), those with Low PDA before and High PDA after treatment (changers) and Low PDA before and after (stragglers). Commitment strength (CS) during the client evaluation of a change plan predicted PDA outcome group. Although strength of desire, need, and reasons to change each predicted CS, CS itself was more predictive of PDA outcome suggesting that CS may be a pathway through which these other variables influence behavior. Amrhein, P.C., Miller, W.R., Yahne, C.E., Palmer, M. and Fulcher, L. Journal of Consulting and Clinical Psychology, 71(5), pp. 862-878, October 2003.

Gambling Urges in Pathological Gambling: A Functional Magnetic Resonance Imaging Study

Gambling urges in Pathological Gambling (PG) often immediately precede engagement in self-destructive gambling behavior. Drs. Marc Potenza, Bruce Rounsaville and colleagues conducted a study of the neural correlates of gambling urges underlying PG to help direct research into effective treatments. Echoplanar functional magnetic resonance imaging was used to assess brain function during viewing of videotaped scenarios with gambling, happy, or sad content. Participants rated the quality and magnitude of their emotional and motivational responses. Men with PG (n = 10) reported mean +/- SD greater gambling urges after viewing gambling scenarios vs. control subjects (n = 11) (5.20 +/- 3.43 vs. 0.32 +/- 0.60; chi2 1,19 = 21.71; P<.001). The groups did not differ significantly in their subjective responses to the happy (P =.56) or sad (P =.81) videotapes. The most pronounced between-group differences in neural activities were observed during the initial period of viewing of the gambling scenarios: PG subjects displayed relatively decreased activity in frontal and orbitofrontal cortex, caudate/basal ganglia, and thalamus compared with controls. Distinct patterns of regional brain activity were observed in specific temporal epochs of videotape viewing. For example, differences localized to the ventral anterior cingulate during the final period of gambling videotape viewing, corresponding to the presentation of the most provocative gambling stimuli. Although group differences in brain activity were observed during viewing of the sad and happy scenarios, they were distinct from those corresponding to the gambling scenarios. In men with PG, gambling cue presentation elicits gambling urges and leads to a temporally dynamic pattern of brain activity changes in frontal, paralimbic, and limbic brain structures. When viewing gambling cues, PG subjects demonstrate relatively decreased activity in brain regions implicated in impulse regulation compared with controls. Potenza, M.N. Steinberg, M.A., Skudlarski, P., Fulbright, R.K., Lacadie, C.M., Wilber, M.K., Rounsaville, B.J., Gore, J.C., and Wexler, B.E. Archives of General Psychiatry, 60(8), pp. 828-836, August 2003.

Prevalence of Alcohol and Drug Use in an Adolescent Training Facility

Dr. Lyn Stein and colleagues at the NIDA-funded Center for Alcohol and Addiction, Brown University, conducted a study of the substance use and crime histories of incarcerated male adolescents. Chart reviews of 186 adolescents indicated that drug use was highly prevalent, with 88.7% using alcohol and 95.7% using marijuana. Ethnic differences in drug use were found, with Caucasian, non-Hispanic adolescents significantly more likely to use cocaine, hallucinogens, and heroin than were adolescents of other ethnicities. Among the crimes committed, possession of a controlled substance was the most prevalent, with 31.8% of adolescents involved. These results provide important guidance for developing targeted behavioral treatments to reduce incarcerated adolescents' use of drugs and involvement in drug-related crimes. Lebeau-Craven, R., Stein, L., Barnett, N., Colby, S.M., Smith, J.L.and Canto, A.L. Substance Use & Misuse, 38(7), pp. 825-834, June 2003.

Participation in 12-Step-Based Fellowships Among Dually-Diagnosed Persons

Dr. Magura and colleagues of the National Development and Research Institutes and the Mental Health Empowerment Project, New York, investigated dually-diagnosed participants' involvement in traditional and targeted 12-Step groups. A total of 277 participants recruited from targeted 12-Step groups comprised of dually-diagnosed substance abusers with mental health problems (Double Trouble Recovery, DTR) were interviewed about their involvement in 12-Step groups, and the role of these groups in recovery. Participants reported extensive 12-Step involvement, with 85% reporting at least weekly attendance, and 46% reporting "Always sharing" at meetings. Most participants (83%) rated attendance at DTR as very important to their recovery, and 76% rated other group members as very important to recovery. Respondents with a diagnosis of schizophrenia were more likely to attend DTR than were respondents with other mental health diagnoses. Barriers cited to attending 12-Step meetings included lack of meeting availability (often because of discharge from programs where meetings took place), and logistics such as transportation. This study suggests that participants view targeted 12-Step groups as beneficial to recovery, and identifies issues to consider in developing targeted groups. Laudet, A.B., Magura, S., Vogel, H.S. and Knight, E.L. Alcoholism Treatment Quarterly, 21(2), pp. 19-39, 2003.

Psychiatric and Substance Dependence Comorbidities, Sexually Transmitted Diseases, and Risk Behaviors among Methamphetamine-Dependent Gay and Bisexual Men Seeking Outpatient Drug Abuse Treatment

Findings regarding psychiatric and substance dependence comorbidities, lifetime rates of infectious disease, and high-risk sexual behaviors are reported from a large sample of urban gay and bisexual men seeking outpatient behavioral drug abuse treatment in L.A. Over one-quarter of participants met criteria for lifetime anxiety disorder and over one-half of the sample met criteria for lifetime depressive disorders. Compared to those without psychiatric diagnoses, significant differences were observed in lifetime prevalence of sexually transmitted infections among those who have generalized anxiety disorder, specific phobia and major depressive disorder, social phobia, and bipolar disorder. Differences in infectious disease prevalence did not correspond to significantly different rates of high-risk sexual behaviors. Findings indicate that gay and bisexual men seeking outpatient treatment for methamphetamine dependence are likely to experience psychiatric comorbidity and to have high rates of infectious disease, including HIV, syphilis and gonorrhea. Shoptaw, S., Peck, J., Reback C.J., and Rotheram-Fuller, E. Journal of Psychoactive Drugs, 35, pp. 161-168, 2003.


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