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Director's Report to the National Advisory Council on Drug Abuse - September, 2003



Research Findings - Treatment Research and Development

Effect of Smoking Reduction on Later Cessation: A Pilot Experimental Study

It is unclear whether reducing the number of cigarettes in smokers not trying to quit increases or decreases the likelihood of future quitting. Investigators at the University of Vermont conducted a pilot study in which smokers not currently interested in quitting (n=67) were randomized to two groups. Experimental participants received behavioral treatment and NRT (choice of gum, patch, or inhaler) to reduce smoking by 50% over 4 weeks, followed by brief advice to quit. Usual-care participants receive only brief advice to quit and NRT if they decided to quit. The results suggest that adding a reduction option neither increases nor undermines interest in cessation. Higher than expected rates of attempted cessation and quitting in the usual-care group suggest that recruited smokers had above average motivation to quit. Thus, a replication test in a less-motivated group of smokers is needed. Carpenter, M.J., Hughes, J.R. and Keely, J.P. Nicotine and Tobacco Research, 5(2), pp. 155-162, April 2003.

Ethnic Differences in Smoking Withdrawal Effects Among Adolescents

At the University of Memphis, smoking withdrawal effect information was collected from 75 adolescents making a quit attempt during a school-based smoking cessation program. A strong need to smoke was the most common withdrawal effect, followed by irritability and difficulty concentrating. Most participants experienced two or more withdrawal effects during the quit attempt, and withdrawal effects were evident in those smoking less than daily. Significant ethnic differences were found, with African Americans reporting significantly fewer withdrawal effects than Caucasians. After controlling for smoking frequency, African Americans were still less likely to report irritability, difficulty concentrating, and restlessness. Participants who chose to use nicotine replacement during the quit attempt were more likely to report difficulty concentrating, restlessness, and feeling miserable. Reidel, B.W., Robinson, L.A., Klesges, R.C. and McLain-Allen, G. Addictive Behaviors, 28(1), pp. 129-140, 2003.

Correlates of Substance Use Disorder Among Psychiatric Outpatients: Focus on Cognition, Social Role Functioning and Psychiatric Status

Dr. Kate Carey and her colleagues at Syracuse University conducted this study that compared psychiatric outpatients who were never, former, and current substance abusers on psychiatric, social, and cognitive functioning. Fifty-six outpatients with schizophrenia spectrum and bipolar disorders volunteered to complete diagnostic and social role function interviews, self-report inventories, and neuropsychological tests. Multinomial logic regression analyses indicated that current and former substance abusers reported greater subjective feelings of distress than those who never abused substances. Contrary to expectations, however, both groups of substance abusers performed better on nonverbal cognitive tests compared with those who never abused. Differences in social functioning were also observed: former abusers demonstrated better instrumental role functioning than those who never abused substances. These findings challenge assumptions about the additive effects of comorbid disorders on cognitive and social functioning. Carey, K.B., Carey, M.P., and Simons, J.S. Journal of Neurological and Mental Disorders, 191(5), pp. 300-308, May 2003.

Comparative Profiles of Women with PTSD and Comorbid Cocaine or Alcohol Dependence

Drs. Back, Sonne, Killeen, Dansky, and Brady, at the Medical University of South Carolina examined the differences in substance abuse severity, trauma history, posttraumatic stress disorder (PTSD) symptomatology and psychiatric comorbidity among treatment-seeking women (N=74) with PTSD and either comorbid cocaine or alcohol dependence. Women in the cocaine/PTSD group, compared with the alcohol/PTSD group, demonstrated greater occupational impairment (e.g., greater severity on the employment subscale of the Addiction Severity Index, less monthly income, fewer days worked in the past month), more legal problems (e.g., greater number of months incarcerated and arrests for prostitution), and greater social impairment (e.g., fewer number of close friends, less likely to be married). Women in the alcohol/PTSD group evidenced higher rates of exposure to traffic accidents, other situations involving serious injury, and other stressful life events. Rates of major depression and social phobia were higher among the alcohol/PTSD group than the cocaine/PTSD group. Women in the alcohol/PTSD group scored higher on the CAPS avoidance, hyperarousal, and total subscale scores. These findings enhance our understanding of the substance-specific profiles of women with PTSD and comorbid substance use disorders, and may have important implications for the design of treatment interventions for substance abusing women with co-occurring psychiatric disorders. Back, S.E., Sonne, S.C., Killeen, T., Dansky, B.S., and Brady, K.T. American Journal of Drug and Alcohol Dependence, 29(1), pp. 169-189, 2003.

Cognitive Impairment, Retention, and Abstinence Among Cocaine Abusers in Cognitive-Behavioral Treatment

In this study Dr. Efrat Aharonovich and her colleagues at Columbia University examined the relationship between cognitive impairment and two treatment outcomes, cognitive-behavioral therapy completion and drug abstinence among cocaine dependent individuals involved in a clinical trial that consisted of once weekly individual, manualized cognitive-behavioral therapy plus medication (either gabapentin or placebo). Cognitive-behavioral therapy (CBT) depends on adequate cognitive functioning in patients, but prolonged cocaine use may impair cognitive functioning. In this study 18 carefully screened non-depressed cocaine dependent patients in a psychopharmacological clinical trial were administered the MicroCog computerized battery to assess cognitive performance at treatment entry. T-tests were used to compare cognitive functioning between completers (patients remaining in treatment at least 12 weeks) and dropouts. The results indicated that the treatment completers demonstrated significantly better cognitive performance at baseline than patients who dropped out of treatment. Abstinence from cocaine use also appeared to be related to cognitive functioning, as patients with high cognitive proficiency scores had significantly more negative urines than patients with low cognitive proficiency scores. Cognitive domains that significantly distinguished between treatment completers and dropouts were attention, mental reasoning and spatial processing. This study provides preliminary evidence that impairments in cognitive functioning may impede the ability of chronic cocaine abusers to benefit from cognitive-behavioral therapy. Aharonovich, E., Nunes, E., and Hasin, D. Drug and Alcohol Dependence, 71(1), July 2003.

Data Entry Productivity Improved by Increasing Reinforcer Magnitude

Conrad Wong, Ken Silverman and colleagues at The Johns Hopkins University examined data entry productivity in drug abusers participating in the therapeutic workplace program, a behavioral treatment program which requires submission of a drug free urine in exchange for entry into a employment environment. Using an ABA reversal design, these investigators examined the effects of reinforcement magnitude on a group of people who had not responded well to monetary reinforcement for data entry productivity. Of six participants tested, four showed the highest rates of responding in the high magnitude reinforcement condition. The two participants with the lowest overall response rates, showed less robust changes to the magnitude manipulation. These findings suggest that therapeutic workplace productivity may be improved by increasing reinforcer magnitude. Wong, C.J., Sheppard, J.M., Dallery, J., Bedient, G., Robles, E., Svikis, D. and Silverman, K. Effects of Reinforcer Magnitude on Data-Entry Productivity in Chronically Unemployed Drug Abusers Participating in a Therapeutic Workplace, Experimental and Clinical Psychopharmacology, 11 (1), pp. 46-55, 2003.

Contingency Management Intervention Helps People with Antisocial Personality Disorder

Richard Rawson and colleagues at UCLA Integrated Substance Abuse Programs examined the retention of methadone maintained drug abusers with and without Antisocial Personality Disorder (ASP) in four treatment conditions: standard methadone maintenance, contingency management, cognitive behavioral therapy, and cognitive behavioral therapy plus contingency management and found a strong effect of treatment condition on outcome for those with antisocial personality disorder. This effect was largely due to a strong response to the contingency management interventions by individuals with ASP who were more likely to abstain from cocaine use when reinforced for abstinence with a voucher. These findings suggest that interventions like contingency management that provide timely reinforcement for treatment participation may be an efficacious way to engage individuals with ASP. Messina, A., Farabee, D. and Rawson, R. Treatment Responsivity of Cocaine-dependent Patients with Antisocial Personality Disorder to Cognitive-Behavioral and Contingency Management Interventions. Journal of Consulting and Clinical Psychology, 17 (3), pp. 320-329, 2003.

Pregnant Women With Drug-Using Partners Have Poorer Treatment Outcomes

Hendree Jones and a colleague at Johns Hopkins University School of Medicine surveyed pregnant women enrolled in a comprehensive treatment program for addiction regarding their male partners and found that 50% of their partners used drugs. Additionally, results showed that male drug-using partners had more unemployment, current legal involvement and less education than drug-free partners. Additionally, male drug-using partners were less likely to be supportive of the pregnant woman's recovery efforts and more likely to give them money to buy drugs. Treatment retention data indicated that women with drug-using partners are retained in treatment for a shorter time. Findings suggest treatments that target the drug-using male partners may improve treatment outcomes for women with such partners. Tuten, M. and Jones H.E. A Partner's Drug-Using Status Impacts Women's Drug Treatment Outcome. Drug and Alcohol Dependence, 70 (1), pp. 327-330, 2003.

Wives of Substance-Abusing Men are at Risk of Exposure to HIV

Dr. Fals-Stewart and colleagues at the Research Institute on Addictions and the San Diego VA Medical Center assessed the HIV risk behaviors of 144 men in treatment for substance abuse and their wives. Almost all wives (96%) reported having sexual intercourse with their husbands during the year before treatment, and of these, 78% reported not regularly using condoms during intercourse. Of all husbands in the study, 40% reported engaging in risky behaviors, including having unprotected sex with a partner other than their wives, and/or engaging in risky needle practices. Almost three-fourths of wives (71%) reported they were not aware of their husbands' risky behaviors, and so unknowingly were at indirect risk for HIV. These results suggest the need for effective HIV risk reduction strategies for married couples in which husbands abuse drugs. Fals-Stewart, W., Birchler, G.R., Hoebbel, C., Kashdan, T.B., Golden, J., and Parks, K. An Examination of Indirect Risk of Exposure to HIV among Wives of Substance-abusing Men. Drug and Alcohol Dependence, 70, pp. 65-76, 2003.

Behavioral Family Counseling Improves Naltrexone Adherence and Substance Abuse Outcomes

Dr. Fals-Stewart at the Research Institute on Addictions and Dr. O'Farrell at Harvard University studied the impact of Behavioral Family Counseling on naltrexone adherence and substance abuse among 124 opioid-dependent men and their family members. All patients were prescribed 50mg/day naltrexone, and a platform treatment of weekly individual and group counseling. Patients were randomly assigned to either Behavioral Family Counseling (in which a family member participated by observing and reinforcing the patient's ingestion of naltrexone), or to Treatment-As-Usual (in which patients attended individual sessions weekly with a counselor to discuss compliance with the naltrexone). Men receiving BFC had significantly higher naltrexone adherence, treatment attendance, and rates of abstinence than men receiving TAU. This study adds to the evidence that behavioral treatments involving family members can improve outcomes of pharmacological treatments for drug abuse. Fals-Stewart, W. and O'Farrell, T.J. Behavioral Family Counseling and Naltrexone for Male Opioid-Dependent Patients. Journal of Consulting and Clinical Psychology, 71, pp. 432-442, 2003.

Latent Cognitive Abilities of Drug-Abusing Patients and Associated Risk Factors

Dr. Fals-Stewart at the Research Institute on Addictions and Dr. Bates at Rutgers conducted a study to clarify the latent structure of the neuropsychological abilities of drug-abusing patients. Using the results of a battery of 15 neuropsychological screening instruments, an exploratory factor analysis was conducted on 329 patients entering drug abuse treatment, and followed with a confirmatory factor analysis with a subsequent 258 patients entering treatment. A multi-factor solution fit the data best, with four factors emerging: Executive Functioning, Verbal Ability, Speed, and Memory. Drug-related factors associated with scores in these four domains included number of years of substance use disorders, years of regular alcohol use, and percentage of days of heavy drinking in the past year. The results of this study contribute methodological tools for further studying cognitive functioning among drug-abusing patients, and suggest potential risk factors for key aspects of cognitive functioning for this population. Fals-Stewart, W. and Bates, M.E. The Neuropsychological Test Performance of Drug-Abusing Patients: An Examination of Latent Cognitive Abilities and Associated Risk Factors. Experimental and Clinical Psychopharmacology, 11, pp. 34-45, 2003.

Cognitive Behavior Group Therapy (CBT) and Psychoeducation Group Therapy (PET) for Adolescent Substance Abusers

A total of 88 adolescents were randomly assigned to 8 weeks of CBT or PET for treatment of substance abuse. On average, adolescents in both treatment groups significantly improved in terms of drug use, based on self reported use (Teen-Addiction Severity Index) and objective urinalysis. While there were no significant overall differences between 3-month and 9-month drug outcomes for adolescents in CBT or PET, variables such as age and the presence of comorbid Conduct Disorder predicted differential success in treatment. These findings highlight the need for additional refinement of CBT group therapy for adolescent drug abuse, and the importance of including mediation and moderation analyses in treatment studies. Kaminer, Y., Burleson, J.A. and Goldberger, R. Cognitive-behavioral Coping Skills and Psychoeducation Therapies for Adolescent Substance Abuse. Journal of Nervous and Mental Disease, 190, pp. 737-745, 2002.

Gambling Behavior in Adolescent Substance Abusers

Dr. Kaminer and colleagues from the University of Connecticut assessed the gambling behavior of 97 adolescents receiving outpatient treatment for substance use disorders. In this sample, 34% had never gambled, 57% were classified as non-pathological gamblers, 8% were identified as "in transition" gamblers, and 1% met criteria for pathological gambling. Adolescent boys were more likely to gamble than girls, and younger age of onset of gambling behavior was associated with being female, history of suicide attempts, more symptoms of Cluster B personality disorders, and other factors. Importantly, none of the gambling adolescents had ever been referred for treatment. While these findings suggest that the prevalence of gambling behavior among substance abusing adolescents is similar to a non-substance abusing population, they also suggest that identification and treatment of problematic gambling behavior is not being adequately addressed for this population. Kaminer, Y., Burleson, J.A.and Jadamec, A. Gambling Behavior in Adolescent Substance Abusers. Substance Abuse, 23, pp. 191-198, 2002.

Identifying Active Ingredients of Double Trouble in Recovery Self-Help Groups

Dr. Magura of the National Development and Research Institute and colleagues conducted a study of potential active ingredients in self-help groups for substance abusing adults with co-morbid psychiatric disorders (Double Trouble in Recovery). These researchers interviewed members of 24 DTR groups at baseline and then re-interviewed participants 12 months later. Of the three ingredients hypothesized to be important elements of self-help treatment--the therapeutic value of assuming a helper role, reciprocal learning among group members, and provision of emotional support--both the helper role and reciprocal learning were related to drug abuse outcomes, but emotional support was unrelated to outcomes. These results suggest areas of emphasis for self-help treatments in order to streamline treatment and maximize success. Magura, S., Laudet, A.B., Mahmood, D., Rosenblum, A., Vogel, H.S. and Knight, E.L. Role of Self-Help Processes in Achieving Abstinence Among Dually Diagnosed Persons. Addictive Behaviors, 28, pp. 399-413, 2003.

Mediators of Abstinence Outcomes for Double Trouble in Recovery Self-Help Groups

Dr. Magura of the National Development and Research Institute and colleagues compared several mediation models of treatment outcome. Specifically, the researchers tested the degree to which two common factors (internal locus of control and sociability) and two treatment-specific factors (spirituality and instillation of hope) mediated the relationship between 12-step group affiliation and outcomes (drug use and health promoting behavior). Interviews with members of 24 DTR self-help groups at baseline and at 12-month follow-up revealed that internal locus of control and sociability mediated the relationship between 12-step affiliation and both outcomes, whereas spirituality and the instillation of hope mediated only the relationship between 12-step affiliation and health promoting behavior. The authors argue that these results suggest an explanation for the effectiveness of 12-step self-help treatments that may be more acceptable to addiction and mental health professionals because of its roots in well-documented social learning principles. Magura, S., Knight, E.L., Vogel, H.S., Mahmood, D., Laudet, A.B. and Rosenblum, A. Mediators of Effectiveness in Dual-Focus Self-Help Groups. The American Journal of Drug and Alcohol Abuse, 29, pp. 301-322, 2003.

Brief Strategic Family Therapy (BSFT) and Group Therapy for Treating Adolescent Behavior Problems and Substance Abuse

Dr. Santisteban and colleagues at the University of Miami tested the relative efficacy of BSFT and group therapy among 126 Hispanic adolescents referred for treatment for behavior problems. BSFT cases showed significantly greater pre- to post-intervention improvement in parent reports of adolescent conduct problems and delinquency, adolescent reports of marijuana use, and observer ratings and self reports of family functioning. Adolescents participating in BSFT showed significantly greater improvement in adolescent conduct problems and delinquency, marijuana use, and family functioning. Further, more adolescents in group therapy had deteriorations in behavior problems, drug use, and family functioning. These results extend prior findings on the efficacy of family interventions to a sample of Hispanic adolescents. Santisteban, D.A., Coatsworth, J.D., Perez-Vidal, A., Kurtines, W.M., Schwartz, S.J., LaPerierre, A. and Szapocznik, J. Journal of Family Psychology, 17, pp. 121-133, 2003.

Error-Rate-Related Caudate and Parietal Cortex Activation During Decision-Making

Dr. Martin Paulus and colleagues at the University of California, San Diego used fMRI during performance of a two-choice prediction task to investigate the relationship between error-rate related behavioral changes during decision-making and activation patterns in the caudate and parietal cortex. Activation in the caudate and parietal cortex was related to success-rates. At low error rates, participants utilized success-related behavioral strategies by decreasing switching responses and increasing response predictability, which were associated with activation changes in the caudate and parietal cortex. Therefore, less response switching and increased response predictability during decision-making can be directly related to the degree of activation in the caudate and posterior parietal cortex. Verney, S.P., Brown, G.G., Frank, L. and Paulus, M.P. Neuroreport, 14(7), pp. 923-928, May 2003.

Cognitive Efficiency in Stimulant Abusers With and Without Alcohol Dependence

Dr. Sara Nixon and colleagues at the University of Oklahoma investigated whether concurrent stimulant and alcohol abuse had a synergistic effect on cognitive ability. The study sample included detoxified men and women who met criteria for dependence of (a) alcohol only (ALC)m stimulants only (STIM) (n = 15), and both alcohol and stimulants (A/STIM) along with age- and education-matched community controls. Subjects were tested in a cognitive battery that included tasks that measured visual spatial skills, problem solving and abstraction, short-term memory, cognitive flexibility, and gross motor speed were administered to participants. For each test, both speed and accuracy were assessed and an efficiency ratio (accuracy/time) was derived. An overall performance index of cognitive efficiency was calculated from the average of these efficiency ratios. Controls performed statistically significantly better in relation to the A/STIM and STIM groups (p < 0.01), but not the ALC group. Individual comparisons revealed that the ALC group performed significantly better than the STIM group, although the ALC group did not differ from either the control or A/STIM groups (pŁ 0.05). These findings suggest that the cognitive effects of chronic stimulant abuse are not additive with those of alcohol abuse. That is, singly addicted stimulant abusers demonstrated similar or greater neurocognitive impairments than individuals who abuse alcohol and stimulants concurrently. The reason for this pattern is speculative but may be attributed to alcohol's opposing actions on cerebrovascular effects brought on by stimulant abuse. Lawton-Craddock, A., Nixon, S.J. and Tivis, R. Alcoholism-Clinical and Experimental Research, 27(3), pp. 457-464, March 2003.

Multinuclear Magnetic Resonance Spectroscopy of High-Energy Phosphate Metabolites in Human Brain Following Oral Supplementation of Creatine-Monohydrate

Dr. Perry Renshaw and colleagues at McLean Hospital, Harvard Medical School investigated whether treatment for cocaine dependence would improve cerebral energy metabolism in the frontal lobes of cocaine abusers. Relative concentrations of phosphocreatine (PCr) and creatine (Cr) were used as markers for cerebral energy metabolism. Relative PCr and Cr levels were derived from T-2 relaxation times in 1H Magnetic Resonance Spectroscopy (1H-MRS). Cocaine dependent (CD) subjects were studied before and after 8 weeks of cocaine dependence treatment. At baseline, left frontal lobe ratios of PCr/Cr were 0.406+/-0.081 in CD subjects and 0.411+/-0.016 in comparison subjects. After treatment, these ratios increased 14.3% (0.464 vs. 0.406; p=0.006) in CD subjects, remaining unchanged in comparison subjects (2.9%, 0.399 vs. 0.411; p=0.480). At baseline, PCr levels of non-responders were 17.8% lower (0.375 vs. 0.442; p=0.042) than those of responders, defined as 25% decrease in urine cocaine metabolites. After treatment, CD subjects had increased PCr levels: 18.4% (0.444 vs. 0.375; p=0.035) for non-responders and 10.4% (0.488 vs. 0.442; p=0.092) for responders. These results are consistent with decreased cerebral metabolism during treatment, measured as increased PCr. This is the first report using H-1 MRS T-2 relaxometry to measure a change in human brain energetics. Lyoo, I.K., Kong, S.W., Sung, S.M., Hirashima, F., Parow, A., Hennen, J., Cohen, B.M. and Renshaw, P.F. Psychiatry Res., 123(2), pp. 87-100, June 2003.

Early-Onset Cannabis Use and Cognitive Deficits: What is the Nature of the Association?

Drs. Harrison Pope, Deborah Yurgelun-Todd, and colleagues at McLean Hospital, Harvard Medical School investigated whether individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life. The study sample included both heavy cannabis users (n=122) and subjects (n=87) with minimal cannabis exposure. All subjects underwent a 28-day period of abstinence from cannabis, monitored by daily or every-other-day observed urine samples. Early-onset cannabis users were compared with late-onset users and with controls, using linear regression controlling for age, sex, ethnicity, and attributes of family of origin. Early-onset users (who began smoking before age 17) differed significantly from both the late-onset users (who began smoking at age 17 or later) and from the controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. However, after adjusting for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant. The findings indicate that early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from the present data. The difference may reflect (1) innate differences between groups in cognitive ability, antedating first cannabis use; (2) an actual neurotoxic effect of cannabis on the developing brain; or (3) poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture. Pope, H.G., Gruber A.J., Hudson, J.I., Cohane, G., Huestis, M.A. and Yurgelun-Todd D. Drug And Alcohol Dependence, 69(3), pp. 303-310, April 2003.

Influence of Acetylcholine Levels on the Binding of a SPECT Nicotinic Acetylcholine Receptor Ligand [I-123]5-I-A-85380

Dr. Giles Tamagnan and colleagues at Yale School of Medicine used SPECT imaging to determine whether increases in acetylcholine (ACh) levels induced by an acetylcholinesterase inhibitor, physostigmine, inhibit in vivo binding of [I-123]5-iodo-3-(2(S)-2-azetidinyl-methoxy) pyridine (5-I-A-85380), ligand for the high-affinity type nicotinic ACh receptor (nAChR). Baboons were used for seven studies with a bolus plus constant infusion equilibrium paradigm. After achieving equilibrium at 5 h, physostigmine (0.02 (n=1), 0.067 (n=3), and 0.2 (n=3) mg/kg) was administered intravenously and data were acquired for up to 8 h. To confirm equilibrium conditions, [I-123]5-I-A-85380 plasma levels were measured in four studies, including all studies with 0.2 mg/kg physostigmine. Prior to physostigmine administration, thalamic activities were stable, with changes of 1.1%/h or less, except in one study with a gradual increase of 4.2%/h. Thalamic activities were decreased by 15% in one study with 0.067 mg/kg and 14-17% in all studies with 0.2 mg/kg physostigmine administration (P=0.009). In these studies with 0.2 mg/kg physostigmine administration, [I-123]5-I-A-85380 plasma levels showed a transient or a sustained increase after physostigmine administration that would have increased thalamic activities. These results suggest that elevated ACh levels induced by physostigmine can effectively compete in vivo with [I-123]5-I-A-85380 binding at nAChRs. However, decreased thalamic activities could have been caused by other mechanisms, including internalization of the receptor with an associated decreased affinity for radioligand. Fujita M., Al-Tikriti, M.S., Tamagnan, G., Zoghbi, S.S., Bozkurt, A., Baldwin, R.M. and Innis R.B. Synapse, 48(3), pp. 116-122, June 2003.

Arterial Spin Labeling Perfusion fMRI with Very Low Task Frequency

Dr. John Detre and colleagues at the University of Pennsylvania investigated whether arterial spin labeling (ASL) perfusion contrast MRI was superior to the more commonly used blood oxygenation level-dependent (BOLD) contrast for studies involving slow or low frequency neural activation. Drug administration studies and exposure to videotape stimuli in cue-reactivity studies would be examples of slow or low-frequency events that are difficult to study with BOLD fMRI because baseline drift effects result in poor sensitivity for detecting slow variations in neural activity. On the other hand, drift effects are minimized in arterial spin labeling (ASL) perfusion contrast, primarily as a result of successive pairwise subtraction between images acquired with and without labeling. Recent data suggest that ASL contrast shows stable noise characteristics over the entire frequency spectrum, which makes it suitable for studying low-frequency events in brain function. The present study investigated the relative sensitivity of ASL and BOLD contrast in detecting changes in motor cortex activation over a spectrum of frequencies of experimental design, where the alternating period between the resting state and activation is varied from 30 s up to 24 hr. The results demonstrate that 1) ASL contrast can detect differences in motor cortex activation over periods of minutes, hours, and even days; 2) the functional sensitivity of ASL contrast becomes superior to that of BOLD contrast when the alternating period between the resting state and activation is greater than a few minutes; and 3) task activation measured by ASL tends to have less intersubject variability than BOLD contrast. The improved sensitivity of the ASL contrast for low task frequency and longitudinal studies, along with its superior power for group analysis, is expected to extend the range of experimental designs that can be studied using fMRI. Wang, J.J., Aguirre, G.K., Kimberg, D.Y., Roc, A.C., Li, L. and Detre J.A., Magnetic Resonance In Medicine, 49(5), pp. 796-802, May 2003.

Cognitive Effects of the Dopamine Receptor Agonist Pergolide

Dr. Mark D'Esposito of University of California, Berkeley investigated the effects of dopamine agonists on human cognitive performance. The effects of a single dose of pergolide on a variety of cognitive tests, including tests of memory and of frontal/executive function were tested in young healthy subjects. Across this battery of tasks, the only tasks reliably affected by pergolide were delayed response tasks. Across four variants, the authors observed that the effect of pergolide was more beneficial for subjects with greater working memory capacities. Kimberg D.Y. and D'Esposito M., Neuropsychologia, 41(8), pp. 1020-1027, 2003.

Temporal Prediction Errors in a Passive Learning Task Activate Human Striatum

Dr. Gregory Berns and colleagues at Emory School of Medicine and Baylor School of Medicine used fMRI to investigate whether the striatum participates in processing information about the predictability of rewarding stimuli. The present study sought to determine whether the striatum primarily processes information about stimuli that are unpredictable in character (what stimulus arrives next), unpredictable in time (when the stimulus arrives), or unpredictable in amount (how much arrives). Using a passive conditioning task and fMRI in human subjects, the authors found that positive and negative prediction errors in reward delivery time correlated with BOLD changes in human striatum, with the strongest activation lateralized to the left putamen. For the negative prediction error, the brain response was elicited by expectations only and not by stimuli presented directly; that is, striatal activation occurred when juice was expected but not delivered rather than when nothing was expected and nothing delivered. McClure, S.M., Berns, G.S., and Montague, P.R., Neuron 38(2), pp. 339-346, April 2003.

Sex-Related ERP Differences in Deviance Detection

Dr. Geoffery Potts and colleagues at Rice University used dense sensor array (128 channel) event-related potential recordings (ERPs) to examine the effect of sex on neural mechanisms of auditory mismatch detection. ERPs of 32 right-handed subjects (16 males) were recorded to frequent (85%, 880 Hz) and infrequent (15%, 1480 Hz) tones. There were no sex differences in mismatch negativity (80-180 ms), however, the fronto-central P2 (180-260 ms) was less positive in males (F=12.56, P<0.005) and the N2 (260-340 ms) was more negative in males (F=6.28, P<0.05). The increased negativity in males spanning the P2 and N2 may index a top-down process of attention bias towards novelty. This result supports the hypothesis of an adaptive, sexually dimorphic processing of novel events in humans. Nagy, E., Potts, G.F. and Loveland, K.A., International Journal of Psychophysiology, 48(3), pp. 285-292, June 2003.

Orbitofrontal Cortex Dysfunction in Abstinent Cocaine Abusers

This NIDA supported study tested for structural (i.e., tissue composition) abnormalities that could underlie the cognitive deficits in executive function seen in cocaine abusers. To determine white and gray matter densities, voxel-based morphometry of T1-weighted brain scans were evaluated in cocaine abusers and non-drug user controls. There were no group differences in frontal cortex white matter; however, gray matter density in the cocaine users was significantly reduced in the frontal, medial and lateral orbitofrontal and middle/dorsal cingulate gyrus in the right hemisphere cortices. The results corroborate and extend previous findings of defective frontal cortical activation (indexed by cerebral blood flow) in cocaine abusers to include other brain areas not previously described. Bolla, K.I., Eldreth, D.A., London, E.D. Kiehl, K.A., Mouratidis, M., Contoreggi, C., Matochik, J.A., Kurian, V., Cadet, J-L., Kimes, A.S., Funderburk, F.R., and Ernst, M. Orbitofrontal Cortex Dysfunction in Abstinent, Cocaine Abusers Performing a Decision-Making Task. NeuroImage, 19(3), pp. 1085-1094, July 2003.

Frontal Cortical Tissue Composition in Abstinent Cocaine Abusers

Cocaine abusers exhibit impairment of executive cognitive functions that are mediated by the frontal cortex. This work tested for structural (i.e., tissue composition) abnormalities that may underlie such performance deficits. Abstinent for 20 days, cocaine abusers (n = 14) and a non-drug-using comparison group (n = 11) underwent magnetic resonance imaging (T1-weighted scans of the brain). Gray matter and white matter tissue densities were determined and results demonstrated cocaine abusers had significantly lower gray matter tissue density than did the non-drug users in 10 of 13 small volumes analyzed in the frontal cortex. No group differences were found in white matter density of the frontal cortex. These results extend previous findings of defective frontal cortical activation (indexed by cerebral blood flow) in cocaine abusers to include abnormalities in gray matter tissue density in the same frontal cortical regions. Matochik, J.A., London, E.D., Eldreth, D.A., Cadet, J-L, and Bolla, K.I. Frontal Cortical Tissue Composition in Abstinent Cocaine Abusers: A Magnetic Resonance Imaging Study. NeuroImage, 19(3), pp. 1095-1102, July 2003.

Predictor of Cocaine's Euphoric Effects

This study evaluated the association between negative affective symptoms during initial abstinence and euphorigenic response to experimentally administered cocaine. Cocaine-dependent individuals, after achieving 5 days of abstinence in a hospital setting, were administered 40mg of cocaine intravenously on the fifth day of abstinence, and were asked to rate the subjective effects produced by the drug. The associations between irritability, self-reported depression, and the subjective ''high'' produced by cocaine were evaluated. Increased levels of irritability and depression were significantly positively correlated with heightened response to experimentally administered cocaine as indexed by self-reported subjective ''high.'' The positive association between irritability and subjective ''high'' remained after controlling for self-reported depressive symptoms. The opponent process model predicts that increased levels of negative affect should be associated with administered euphoric response to cocaine; however, the opposite was observed. If these findings are replicated in a larger sample, then it may be necessary to reconsider the applicability of the opponent process model to cocaine addiction in humans. Newton, T.F., Kalechstein, A.D., Tervo, K.E., and Ling, W. Irritability Following Abstinence from Cocaine Predicts Euphoric Effects of Cocaine Administration. Addictive Behaviors, 28(4), pp. 817-821, June 2003.

Methamphetamine Dependence is Associated with Neurocognitive Impairment in the Initial Phases of Abstinence

This study documented the association between neurocognitive impairment and methamphetamine (METH) dependence in a sample of 27 METH dependent individuals who achieved 5 to 14 days of continuously monitored abstinence and in 18 control subjects. METH-dependent individuals performed significantly worse than control subjects on neurocognitive measures sensitive to attention/psychomotor speed, on measures of verbal learning and memory, and on executive systems measures sensitive to fluency. These findings are the first to demonstrate that METH dependence is associated with impairments across a range of neurocognitive domains in a sample of users whose abstinence was continuously monitored with the use of urine screening. Kalechstein, A.D., Newton, T.F., and Green. M. Methamphetamine Dependence is Associated with Neurocognitive Impairment in the Initial Phases of Abstinence. Neuropsychiatry Clinical Neuroscience, 15, pp. 215-220, May 2003.

Self-Regulated Dosing of Morphine Resulted in Increased Total Consumption in a Rat Model

Kreek and associates at Rockefeller University provided an experimental session whereby rats could increase their dosage of morphine by choosing a lever that delivered a larger amount of morphine that increased if the rat persisted in choosing that lever. The comparison group could experience only a fixed amount with every selection. However, while there was an increase in total consumption, there was not an increase in rate. This pattern is a good model for dose escalation in the human situation where rate does not increase but total consumption does. In addition, [35S]GTP_S binding was significantly lower in the self-escalating group of rats, suggesting receptor desensitization following morphine stimulation. Kruzich, P.J., Chen, A.C.H., Unterwald, E.M. and Kreek, M.J. Synapse, 47, pp. 243-249, 2003.

Relapse was Significantly Reduced with Buprenorphine and Relapse-Prevention Therapy in Treatment-Seeking Heroin Addicts

Dr. Kakko and other investigators working with Mary Jeanne Kreek in Sweden focused on patients who would not qualify for methadone treatment in Sweden. Accordingly, patients could be ethically randomized into buprenorphine and placebo groups (20 each) and followed for one year. Both groups received relapse-prevention therapy. All of the subjects in the placebo group dropped out of treatment after drug use was demonstrated by urinanalysis. By contrast, only 25% dropped out of the buprenorphine group, most of whom had drug-free urines throughout the period. In addition, the treatment group members who were still participating were assessed for improvement in addiction severity and found to have significantly improved. The results suggest that buprenorphine and intensive psychosocial treatment is safe and highly efficacious to add to the arsenal of potential treatments for heroin dependence. Kakko, J., Svanborg, K.D., Kreek, M.J., and Heilig, M. The Lancet, 361, pp. 662-668, 2003.

Depression is Not Necessarily Counter-Indicative for Smoking Cessation

Dr. Hitsman and colleagues at Brown University completed a meta-analysis study to determine if smokers with a lifetime history of depression are less likely to be successfully treated to quit smoking than those who have no history of depression. Fifteen studies of 2,984 smokers published between 1966-2000 included assessments of both history of depression and smoking cessation outcome. Only two of thirteen studies showed a significant association between history of depression and abstinence of three months or less; only one of twelve showed that history of depression was associated with abstinence of six months or more. In addition, the depression-abstinence association did not differ between females and males at either time point. Hitsman, B., Borelli, B., McCargue, D.E., Spring, B., and Niaura, R. Journal of Consulting and Clinical Psychology, 71(4), pp. 657-663, 2003.

Up- and Down-Regulation of Genes in Rat Caudate Putamen After Binge Cocaine Administration

Using microarrays in triplicate (deemed far superior to single arrays) investigators at Rockefeller University demonstrated 21 up-regulated genes that were immediate early genes for transcription factors, effecter proteins, and a number of phosphatases. Down-regulation was seen for 17 genes including many associated with energy metabolism in mitochondria. Also found was a differential expression of somatostatin receptor (SSTR2) (not know to be cocaine-response, as well as the clock gene Per2. Yuferov, V., Kroslak, T., LaForge, K.S., Zhou, Y.H., Ho, A., and Kreek, M.J. Synapse, 48, pp. 157-169, 2003.

Sex Differences were Found in Limbic Responsiveness Using a Procaine Challenge and Assessed by SPECT

Dr. Adinoff and colleagues at University of Texas Southwestern Medical Center administered procaine by slow intravenous infusion to healthy female and male volunteers (controls for other studies) and compared the resultant stimulation to saline infusion. In between group comparisons of the relative increases in regional cerebral blood flow, females had a significantly greater increase in the left amygdala while males had a significantly greater increase in the left insula and marginally greater increase in the right insula. In both instances, the significant increase was relative since both males and females had significant increases following procaine relative to saline -- for females the increase was considerable greater in the amygdala while in males it was in the insula. Subjective differences to the procaine were assessed but were not found to be different between the sexes. This study is among the first to demonstrate differential limbic responsiveness to pharmacological challenge. It remains to be demonstrated whether this reflects the differential emotional responses often reported in the literature. Adinoff, B., Devous, M.D., Sr., Best, S.E., Chadler, P., Alexander, D., Payne, K., Harris, T.S., and Williams, M.J. NeuroImage,18, pp. 697-706, 2003.

The Fetal Brain has a Different Pattern of Expression of Cannabinoid Receptor mRNA Compared to Adult

Yasmin Hurd at Karolinska Institute and colleagues at SUNY, Downstate have for the first time determined the expression of the cannabinoid receptor in the fetal (20 week) brain. While the adult brain showed high expression throughout the brain, expression in fetal brain was much more heterogeneous. The highest concentration was in the limbic structures of the hippocampus and amygdala. It is not clear what this might mean functionally; it is speculated that these might be the most vulnerable to prenatal exposure. Wang, X., Dow-Edwards, D., Keller, E., and Hurd, Y.L. Neuroscience, 118, pp. 681-694, 2003.

Preliminary Evidence for Linkage to Chromosomes 3 and 9 for Substance Dependence

Vulnerability M. Stallings and colleagues working in T. Crowley's center at the University of Colorado have performed a genome-wide search in treatment-referred adolescent volunteers. A phenotype was defined as the average number of dependence symptoms (total number for all illicit substances divided by the number of substances). Analyses revealed Lod "peaks" at 3q24-25 and 9q34 that are not far from locations reported previously by other researchers. A number of candidate genes are associated with these areas; it will remain for future work to replicate these results and assess the functionality of these candidate genes. Stallings, M.C., Corley, R.P., Hewitt, J.K., Krauter, K.S., Lessem, J.M., Mikulich, S.K., Rhee, S.H., Smolen, A., Young, S.E., and Crowley, T.J. Drug and Alcohol Dependence, 70, pp. 295-307, 2003.

Haplotypes at the OPRM1 Locus are Associated with Susceptibility to Substance Dependence

In the laboratory of Joel Gelernter at Yale University, a technique that investigated the relationship between various substance dependence profiles and gene variants revealed a significant associated between the allele -2044A (and haplotypes containing this allele) and patients with "alcohol plus opioid" dependence. This was true, however, only in European Americans. There was no difference between African American patients and controls, possibly reflecting frequency differences between these groups for the -2044A allele of the µ-opiate receptor gene (OPRM1). Whether these differences are "true" will depend on future studies with a greater number of subjects. For the time being, these data suggest that in European Americans, the OPRM1 may play a role in the pathophysiology of a diagnosis-specific form of substance dependence. Luo, X., Kranzler, H.R., Zhao, H., and Gelernter, J. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 120B, pp. 97-108, 2003.

Stress Increases Cocaine Craving as well as HPA Axis and Sympatho-Adreno-Medullary Responses

Rajita Sinha of Yale University and colleagues measured physiological, hormonal, and subjective responses to cocaine-related and stress-related imagery in treatment-seeking individuals. Both stress and cocaine images induced activation of the hypothalamic-pituitary-adrenal axis determined by increases in plasma of ACTH, cortisol, prolactin as well as norepinephrine and epinephrine. Pulse rate and blood pressure also increased. These were largely correlated with increases in subjective ratings of craving and, to a lesser extent, anxiety. These data suggest that stress is a factor in inducing craving in recovering cocaine dependence and that stress and drug reward systems overlap with possible implications for treatment. Sinha, R., Talih, M., Malison, R., Cooney, N., Anderson, G.M. and Kreek, M.J. Psychopharmacology, (Epub ahead of print), July 4, 2003.

Attenuated Adrenocortical and Blood Pressure Responses to Psychological Stress in Ad Libitum and Abstinent Smokers

Dr. al'Absi and colleagues examined the effects of ad libitum smoking and abstinence on adrenocortical and cardiovascular responses to acute psychological stress in dependent cigarette smokers. They evaluated differences among abstinent smokers, smokers who continued to smoke at their normal rate, and nonsmokers in salivary cortisol concentrations, systolic and diastolic blood pressure (BP), heart rate (HR), and mood reports. Measurements were obtained during rest and in response to acute psychological stress (public speaking) in one session (stress session) and during continuous rest in a control session. Thirty-eight smokers (21 women) and 32 nonsmokers (18 women) participated. Smokers were assigned to either abstain from smoking the night prior to and the day of each session, or to continue smoking at their normal rate before each session. All groups showed significant stress-induced changes in BP and HR. Smokers, regardless of their assigned condition, showed attenuated systolic BP responses to the public-speaking stressor when compared to nonsmokers. While resting cortisol levels were greater among smokers than nonsmokers, no cortisol response to the acute stressor was demonstrated in either ad libitum or abstinent smokers. These results indicate that chronic smoking diminishes adrenocortical and cardiovascular responses to stress, and that short-term abstinence does not correct these alterations. al'Absi, M., Wittmers, L.E., Erickson, J. et al. Attenuated Adrenocortical and Blood Pressure Responses to Psychological Stress in Ad Libitum and Abstinent Smokers. Pharmacol. Biochem. Behav., 74, pp. 401-410, 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 our 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 Withdrawal and Depressive Symptomatology During Short-Term Smoking Abstinence: A Comparison of Postmenopausal Women Using and Not Using Hormone Replacement Therapy. Nicotine. Tob. Res., 5, pp. 49-59, 2003.

"Outer-Directed Irritability": A Distinct Mood Syndrome in Explosive Youth With a Disruptive Behavior Disorder?

A sample (N = 20) of disruptive youth (aged 10-18 years) entering a divalproex treatment study of temper and irritable mood swings was compared to normal controls (N = 18) on measures of aggression/irritability directed against others (externalizing symptoms) and on aggression/ irritability against self, anxiety, and depression (internalizing symptoms). All patients met DSM-IV criteria for a disruptive behavior disorder (oppositional defiant disorder of conduct disorder) in addition to research criteria. "Outer-directed irritability" most clearly distinguished patients from controls (effect size 4.1) and did not correlate with other mood measures. Patients and controls showed no to minimal differences on internalizing symptoms. Disruptive behavior disordered children and adolescents characterized by outer-directed irritability exist, can be identified, and should be further investigated, especially since they are potentially treatable. Donovan, S.J., Nunes, E.V., Stewart, J.W. et al. "Outer-Directed Irritability": A Distinct Mood Syndrome in Explosive Youth with a Disruptive Behavior Disorder? J. Clin. Psychiatry, 64, pp. 698-701, 2003.

Lack of Effect of 5HT(3) Antagonist in Mediating Subjective and Behavioral Responses to Cotinine

This study determined whether granisetron, a 5HT(3) receptor antagonist, would enhance the efficacy of the nicotine patch. Subjects were randomly assigned to one of the three granisetron conditions (N=43 for 2 mg/day; N=43 for 1 mg/day; N=42 for 0 mg/day) and asked to take the assigned medication daily during 15 days of tobacco abstinence. Because the investigators were interested in interactions between cotinine and serotonin, all groups were also treated with a 21-mg nicotine patch. Assessments of withdrawal symptoms were made for 1 week during baseline smoking and several times during the experimental period. There was a near but non-significant difference among groups on a measure of tobacco withdrawal and no significant differences on global measures of drug effects or physiological measures. The data do not strongly support the hypothesis that 5HT(3) agonism is the mechanism by which cotinine offsets the effects of nicotine. Hatsukami, D.K., Jensen, J., Brauer, L.H. et al. Lack of Effect of 5HT(3) Antagonist in Mediating Subjective and Behavioral Responses to Cotinine. Pharmacol. Biochem. Behav., 75, pp. 1-7, 2003.

Efficacy of Nicotine Patch in Smokers with a History of Alcoholism

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. 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. Hughes, J.R., Novy, P., Hatsukami, D.K. et al. Efficacy of Nicotine Patch in Smokers with a History of Alcoholism. Alcohol Clin. Exp. Res., 27, pp. 946-954, 2003.

Desipramine and Contingency Management for Cocaine and Opiate Dependence in Buprenorphine Maintained Patients

To test the efficacy of combining CM with these medications the investigators designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement. Kosten, T., Oliveto, A., Feingold, A. et al. Desipramine and Contingency Management for Cocaine and Opiate Dependence in Buprenorphine Maintained Patients. Drug Alcohol Depend., 70, pp. 315-325, 2003.

Bupropion Treatment for Cocaine Abuse and Adult Attention-Deficit/Hyperactivity Disorder

Eleven patients who met DSM-IV diagnostic criteria for cocaine dependence and adult ADHD were entered into a 12-week single-blind trial of divided daily doses of bupropion (BPR). All patients received weekly individual standardized relapse prevention therapy. Treatment compliance and retention were good. Patients reported significant reductions in attention difficulties, hyperactivity and impulsivity. Self-reported cocaine use, cocaine craving, and cocaine positive toxicologies, also decreased significantly. In a previously published trial, 12 patients who met similar diagnostic criteria for adult ADHD and cocaine dependence were entered into a 12-week trial of divided daily doses of sustained-release methylphenidate (MPH). Improvements observed on BPR were similar to, and did not differ from those previously observed with MPH. These preliminary data suggest that BPR may be as effective as sustained-release MPH, when combined with relapse prevention therapy, for cocaine abusers with adult ADHD. However, a future study directly comparing BPR to MPH in a double-blind placebo-controlled trial is needed. Levin, F.R., Evans, S.M., McDowell, D.M. et al. Bupropion Treatment for Cocaine Abuse and Adult Attention-Deficit/Hyperactivity Disorder. J. Addict. Dis., 21, pp.1-16, 2002.

Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth

Pregnant women who were self-identified as smokers (>/=10 cigarettes per day throughout pregnancy) or nonsmokers were recruited for study participation. Maternal blood was collected for cotinine concentrations. Umbilical artery cord blood was collected at delivery for arterial pH and catecholamine concentrations. Cord blood was obtained from 51 subjects, including 21 smokers and 30 nonsmokers. Median epinephrine concentrations [304 pg/mL versus 597 pg/mL (Mann-Whitney U = 170; p = 0.006)] and median norepinephrine concentrations [3148 pg/mL versus 6558 pg/mL (Mann-Whitney U = 191; p = 0.006)] were significantly lower in smokers compared with nonsmokers, respectively. After controlling for gestational age, route of delivery, and arterial pH, log-transformed epinephrine concentrations between smokers and nonsmokers were statistically significant (p = 0.03), with a similar trend for log-transformed norepinephrine concentrations (p = 0.07). Analyses of the data using cotinine <20 ng/mL to classify nonsmokers also showed differences in epinephrine concentrations between groups (p = 0.02). These results are consistent with results from animal studies showing that catecholamine concentrations may be affected by prenatal nicotine exposure. Further studies are needed to validate these findings and to examine the specific mechanism by which these differences may arise. Oncken, C.A., Henry, K.M., Campbell, W.A. et al. Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth. Pediatr. Res., 53, pp. 119-124, 2003.

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

This article describes psychiatric and substance dependence comorbidities, lifetime rates of infectious disease, and reported high-risk sexual behaviors for methamphetamine-dependent, gay and bisexual men at entry to outpatient drug abuse treatment in Los Angeles. A total of 82 participants met criteria for lifetime depressive disorders; 44 participants met criteria for lifetime anxiety 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 (higher rates of genital gonorrhea), specific phobia and major depressive disorder (higher rates of oral gonorrhea), social phobia (higher rates of syphilis) and bipolar disorder, type I (higher rates of HIV). 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. et al. Psychiatric and Substance Dependence Comorbidities, Sexually Transmitted Diseases, and Risk Behaviors among Methamphetamine-Dependent Gay and Bisexual Men Seeking Outpatient Drug Abuse Treatment. J. Psychoactive Drugs, 35, Suppl 1, pp. 161-168, 2003.

Selegiline Enhances Smoking Cessation Rates in Nicotine-Dependent Cigarette Smokers

Since dopaminergic mechanisms appear to be involved in nicotine dependence, the investigators from the Yale Medical School examined the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride and compared with placebo for smoking cessation in nicotine-dependent cigarette smokers. Forty subjects with DSM-IV nicotine dependence were randomized to selegiline hydrochloride (5 mg p.o. twice daily) or placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects. Selegiline hydrochloride statistically significantly increased end point prevalence smoking cessation rates and smoking cessation rates during the last 4 weeks of the trial in comparison with placebo. Six-month follow-up smoking cessation rates were also greater for the selegiline group than for placebo. Treatment retention was similar between drug and placebo groups, and selegiline hydrochloride was well tolerated in cigarette smokers. George, T.P., Vessicchio, J.C., Termine, A., Jatlow, P.I., Kosten, T.R. and O'Malley, S.S. A Preliminary Placebo-Controlled Trial of Selegiline Hydrochloride for Smoking Cessation. Biol Psychiatry. 53(2), pp.136-143, January 15, 2003.

Neuroleptic Olanzapine Worsens Cocaine Treatment Outcome

Evidence suggests dopaminergic and serotonergic involvement in the reinforcing effects of cocaine. Olanzapine, which blocks dopamine D2 receptors, as well as serotonin receptors 5HT2A and 5HT2C, was anticipated to reduce the euphoric effects of cocaine and to attenuate cocaine craving. Therefore, it was tested for its ability to reduce cocaine use in cocaine dependent patients. Thirty patients received either olanzapine (10 mg/day) or identical placebo in a 12-week, double blind, placebo controlled, pilot trial. Outcome measures included treatment retention, qualitative urine benzoylecgonine tests, cocaine craving, clinical global impression scores, and results from the addiction severity index. Treatment retention was slightly, but significantly, better in the placebo-treated subjects and placebo-treated subjects were more likely to be abstinent from cocaine during the trial compared to olanzapine-treated subjects. Olanzapine was not superior to placebo in any outcome measure. The results do not support the usefulness of olanzapine for the treatment of cocaine dependence. Kampman, K.M., Pettinati, H., Lynch, K.G., Sparkman, T. and O'Brien, C.P. A Pilot Trial of Olanzapine for the Treatment of Cocaine Dependence. Drug Alcohol Depend., 70(3), pp. 265-273, June 5, 2003.

Modafinil Blunts Cocaine Euphoria

Modafinil, a novel medication for the treatment of narcolepsy, is now being studied as a potential treatment for cocaine dependence. The neurotransmitter actions of modafinil appear to be opposite to cocaine-induced neuroadaptations affecting GABA, dopamine and glutamate circuits. Safety of modafinil was tested in combination with intravenous cocaine (30 mg). Seven subjects received a baseline 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. The results showed 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. Modafinil pretreatment did not intensify cocaine-induced craving, but significantly blunted cocaine euphoria. The results suggest that modafinil may potentially be an effective medication for the treatment of cocaine dependence. Dackis, C.A., Lynch, K.G., Yu, E., Samaha, F.F., Kampman, K.M., Cornish, J.W., Rowan, A., Poole, S., White, L. and O'Brien, C.P. Modafinil and Cocaine: A Double-Blind, Placebo-Controlled Drug Interaction Study. Drug Alcohol Depend. 70(1), pp. 29-37, May 1, 2003.

Buspirone Attenuates the Objective and Subjective Opiate Withdrawal Symptoms

Effectiveness of buspirone in attenuating opiate withdrawal symptoms in heroin addicts and methadone-maintained patients was examined in twenty hospitalized male chronic opiate users. For the first five days, patients received doses of methadone that were decreased to 30 mg and were maintained on this dose for the following three days. Methadone was then discontinued, and patients were randomly assigned to buspirone or placebo treatment from day nine to seventeen. The buspirone dose was 15 mg on day nine and 30 mg from day ten to day seventeen. Treatment was double-blind. Withdrawal symptoms were measured with the Objective Opiate Withdrawal Scale (OOWS) and the Subjective Opiate Withdrawal Scale (SOWS). Buspirone-treated patients had significantly lower scores on the OOWS on days thirteen (p=.040), fourteen (p=.025), fifteen (p=.035), and seventeen (p=.035). They also had lower scores on the SOWS on days sixteen (p=.050). Rose, J.S., Branchey, M., Wallach, L. and Buydens-Branchey, L. Effects of Buspirone in Withdrawal from Opiates. Am J Addict.,12(3), pp. 253-259, May-June 2003.

Low Plasma Cholesterol Levels are Associated with Greater Rates of Relapse in Detoxified Cocaine Addicts

Recent studies suggest an association of low plasma levels of cholesterol with various psychiatric disorders. The investigators explored relationships between cholesterol levels and relapse rates in a group of cocaine addicts who had undergone inpatient detoxification. The total cholesterol levels of 38 cocaine addicts were determined while they were hospitalized. Drug use was subsequently assessed 3, 6, and 12 months after patients were discharged from the hospital. Comparisons of the cholesterol levels of relapsers and nonrelapsers by analyses of covariance with age and weight as covariates revealed significantly lower cholesterol values in patients who relapsed at 3 months (p =.046), 6 months (p =.030), and 12 months (p =.019) after discharge. Buydens-Branchey, L. and Branchey, M. Association Between Low Plasma Levels of Cholesterol and Relapse in Cocaine Addicts. Psychosom Med. 65(1), pp. 86-91, January-February, 2003.


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