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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse

September, 2000

Research Findings

Treatment Research and Development

Acute and Protracted Cocaine Abstinence in an Outpatient Population, Effect on Mood, Sleep and Withdrawal Symptoms

Drs. Coffey, Dansky, Carrigan, and Brady at the Medical University of South Carolina evaluated cocaine abstinence over 28 days in a sample of 24 male and female cocaine-dependent outpatients. Abstinence-related symptoms including mood, anxiety, sleep, concentration, and craving were monitored at 2, 5, 10, 14, 21, and 28 days following last cocaine use. Consistent with findings from inpatient studies of cocaine abstinence, linear improvements in negative affect, low cocaine craving, and increases in cognitive skills were reported over the 28 days. Also consistent with inpatient studies of cocaine withdrawal, an aphasic withdrawal syndrome was not observed in this outpatient sample. Unlike inpatient studies, no disturbances in sleep were reported. Coffey, S. Dansky, B., Carrigan, M., Brady, K. Drug and Alcohol Dependence, 59, pp. 277-286, June 2000.

Gender Differences in Adolescent Drug Abuse: Issues of Comorbidity and Family Functioning

Dr. Gayle Dakof, University of Miami, investigated gender differences in patterns of co-morbidity and family functioning among a sample of 95 youths (42 girls) referred by juvenile justice (80%), education (10%) and social welfare (10%) for substance abuse treatment. Findings indicate that male and female adolescent substance users (13-17 years) entering treatment do differ. The girls not only used drugs and engaged in externalizing behaviors as extensively as did their male counterparts but they also were distinguished by their higher levels of internalizing symptoms and family dysfunction. Dakof, G. Journal of Psychoactive Drugs, 32(1), pp. 25-32, 2000.

HIV Testing, Drug Use and STD Prevalence Among Juveniles Entering a Rhode Island Correctional Facility

Dr. David Pugatch and colleagues at Brown University surveyed the medical records of 312 incarcerated juveniles (91% boys) to determine the incidence of voluntary HIV testing during their detention stay. Results indicate 69% were tested, 5% reported a history of an STD, 49% used marijuana and 8% used a "hard drug"(e.g., cocaine, heroin and LSD). Results indicate that although adolescents in juvenile detention centers frequently engage in HIV-associated risk-taking behaviors, many youth at high risk for HIV are not being tested. Pugatch, D., Ramratnan, M., Feller, A., Price, D., and Riggs, S. Journal of Correctional Health Care, 6(2), pp. 197-205, 2000.

Anger Management Group Treatment for Cocaine Dependence: Preliminary Outcomes

Drs. Patrick Reilly and Michael Shopshire at the University of California, San Francisco, conducted a pilot study to examine a manual-guided 12-week cognitive-behavioral anger management group treatment in a sample of 59 men and 32 women who were cocaine dependent and reported frequent and intense episodes of anger. Levels of anger, negative affect, and anger control were measured at baseline, weekly during treatment, and at 3-month post treatment follow-up. Of the sample, 55% completed the anger management group treatment, 50% remained abstinent from cocaine. The participants increased their ability to control their anger and related negative affect across the 12 months of treatment. Preliminary findings suggest that anger management group treatment may help cocaine-dependent individuals with anger control problems manage their anger. Reilly, P. and Shopshire, M. American Journal of Drug and Alcohol Abuse, 26 (2), pp. 161-177, 2000.

Prevalence of Attention-Deficit Hyperactivity Disorder and Conduct Disorder Among Substance Abusers

Dr. Schubiner and colleagues at Wayne State University evaluated the prevalence of ADHD and conduct disorder among adults admitted to 2 drug addiction treatment centers. Two hundred and one participants were selected randomly from the 2 treatment sites. Standardized clinical interviews were conducted using the Structured Clinical Interview for DSM-IV, the Addiction Severity Index, and DSM-IV criteria for ADHD. Forty-eight or 24% of the participants met DSM-IV criteria for ADHD. The prevalence of ADHD was 28% in men (30/106) and 19% in women (18/95;NS). Seventy-nine participants (39%) met criteria for conduct disorder, and 34 of these individuals also had ADHD. Over two thirds of those with ADHD in this sample also met criteria for conduct disorder. Individuals with conduct disorder and/or ADHD represent a significant proportion of those seeking treatment for psychoactive substance use disorders. They appear to have greater comorbidity and may benefit from a treatment approach that addresses these comorbidities through medical and behavioral therapies. Schubiner, H., Tzelepis, A., Milberger, S., Lockhart, N., Kruger, M., Kelley, B., Schoener, E. Journal of Clinical Psychiatry, 61(4), pp. 244-251, April, 2000.

Development of Major Depression After Treatment for Smoking Cessation

Dr. Janice Tsoh and colleagues at the University of California, San Francisco, examined the incidence and predictors of major depression in the 12 months after treatment for smoking cessation. In this study 304 participants (172 women) were recruited from two trials of smoking cessation; both trials provided group cognitive-behavioral mood management, but one group received treatment with nicotine gum and the other received nortriptyline or placebo. The Inventory to Diagnose Depression was administered at follow-up assessments. Among the 304 participants, 14.1% (N=43) reported a major depressive episode within 12 months after the treatment for smoking cessation. The incidence rates across trials were similar. About half (N= 170, 55.9%) of the participants were abstinent from smoking at the end of treatment. Results indicate that history of depression, baseline Beck Depression Inventory score, college education, and age at smoking initiation were significant predictors of major depression after smoking cessation treatment. Patients who achieved abstinence from smoking showed a risk of developing depressive episodes similar to those who failed to achieve abstinence. Patients who had a history of depression were more likely to experience depressive episodes after treatment for smoking cessation. Tsoh, J. Humfleet, G., Munoz, R., Reus, V., Hartz, D., Hall, S. American Journal of Psychiatry, 157(3), pp. 368-374, March 2000.

Group Therapy for Patients with Bipolar and Substance Dependence: Results of a Pilot Study

This paper reports a behavioral therapy development study of a treatment designed specifically for patients with coexisting bipolar disorder and substance use disorder. The treatment in this study, Integrated Group Therapy (IGT), was developed to integrate therapeutic approaches that are relevant to each disorder. This was an open trial in which patients (N=45) with substance dependence and bipolar disorder received either IGT or monthly assessments, but no experimental treatment. Relative to the control group, patients receiving IGT had significantly better outcomes on the ASI composite score, percentage of months abstinent, and likelihood of achieving 2 or 3 consecutive abstinent months. IGT appears to be a promising treatment for these patients who have traditionally had poor outcomes. A study comparing this treatment with another active psychotherapy treatment is warranted. Weiss, R.D., Griffin, M.L., Greenfield, S.F., Najavits, L.M., Wyner, D., Soto, J.A. and Hennen, J.A. Journal of Clinical Psychiatry, 61, pp. 361-67, 2000.

Post-Treatment Outcomes of Adolescent Females Referred for Conduct Disorder and Substance Use Disorders

Dr. Elizabeth Whitmore and colleagues, University of Colorado, investigated whether symptoms associated with substance abuse/dependence, conduct disorder and other psychiatric disorders were reduced in adolescents (13-19 years) admitted to a multi-component outpatient drug treatment program. Although the results indicate improvement in three areas (i.e., delinquency and conduct disorder [CD]; attention deficit hyperactivity disorder [ADHD]; educational/vocational status), substance involvement and level of depression did not improve. Unlike results from a concomitant study with boys, no pre-treatment variables predicted post-treatment drug use or conduct outcomes among the girls. And only two post-treatment factors (peer problems and number of ADHD symptoms) were found related to CD and the substance use disorders outcomes. Whitmore, E.A., Mikulich, S.K., Ehlers, K.M. and Crowley, T.J. Drug and Alcohol Dependence, 59, pp. 131-141, 2000.

Effectiveness of the Minnesota Model Approach in the Treatment of Adolescent Drug Abusers

Dr. Ken Winters and colleagues at the University of Minnesota assessed adolescents with substance use disorders eligible to enroll in a 12-step drug treatment program. Youths were evaluated 6- and 12-month post-treatment in terms of their drug use outcomes. Three groups of adolescents participated in the study: those (n=101) who completed treatment, those (n=39) who did not, and those (n=66) on a waiting list. Among treatment completers, residential and outpatient samples were also compared. Results indicate completing treatment was associated with far superior outcomes compared to those who did not complete treatment or receive any at all. Percentage of treatment completers reporting abstinence one-year post treatment was 23% compared to 2.6% for non-completers and 3.0% for those on the wait-list. No differences were found between residential and outpatient groups or was gender or age a factor. Winters, K.C., Stinchfield, R.D., Opland, E., Weller, C. and Latimer, W.W. Addiction, 95(4), pp. 601-612, 2000.

"Recreational" MDMA Use Depletes Serotonin but Not Dopamine

Dr. Stephen J. Kish and colleagues (in Toronto and Washington, DC) performed a neurochemical analysis of an autopsied brain of a 26-year-old male with a nine-year history of acute and chronic MDMA use to determine the neurotoxic effects of the recreational drug MDMA (Ecstasy). The brain was examined and neuropathically compared to neurologically normal subjects. Histopathological analysis disclosed no dopamine related abnormalities in the brains of the control subjects or the MDMA user. The lack of change in the dopaminergic markers (e.g., striatal dopamine, the dopamine transporter and the vesicular monoamine transporter) and in nigral cellularity may explain the lack of anti-Parkinsonian response to dopaminergic therapy in the MDMA user that has been previously reported. In contrast, striatal levels of serotonin and of its metabolite 5-hydroxyindoleactic acid were decreased in the MDMA user by 71-80% of the levels in the normal subjects. Part of this reduction could be the result of toxic damage to striatal serotonin nerve terminals and/or acute reversible depletion of neurotransmitter stores. This study is the first to demonstrate that recreational use of MDMA can cause actual depletion of tissue stores of serotonin that may account for some of the behavioral effects during drug taking and withdrawal but not sufficient release of striatal dopamine. Kish, S.J., Furukawa, Y., Ang, L. and Kalasinsky, K.S. Striatal Serotonin But Not Dopamine is Depleted in Brain of a Human (Ecstasy) User. Neurology, 55(2), pp. 294-296, 2000.

Stimulant Dependence Affects HIV-Related Neuronal Injury

Since either HIV infection or abuse of CNS stimulants is associated with brain damage and dysfunction, magnetic resonance spectroscopy (MRS) was used to examine the combined effects of HIV infection and stimulant dependence on frontostriatal circuitry. It was hypothesized that HIV-positive/stimulant dependent (HIV+/STIM+) subjects would show increased N-acetylaspartate (NAA), a putative marker of neuronal integrity, compared to the controls (HIV-/STIM-) and HIV+ nonusers (HIV+/STIM-). Elevations in choline (Cho) and myoinositol (MI) were predicted in the HIV+/STIM+ group, reflecting abnormalities in cellular integrity, with smaller increases in HIV+/STIM- and HIV-/STIM+ subjects. Finally, elevated creatine (Cr) was expected in the white matter of the STIM+ groups based on findings from a previous study. Contrary to predictions, results showed no reliable or significant differences in Cho, Cr, or MI across groups. Significant group differences were observed, however, in NAA in the anterior cingulate gyrus (p < 0.05), with NAA lowest in HIV+/STIM+, highest in HIV-/STIM-, and at an intermediate level in the HIV+/STIM- and HIV-/STIM+ subjects with levels significantly correlated with measures of neuropsychological functioning (r ranging from -.50 to -38; p < 0.01 to p = 0.05). Although these data suggest that stimulant dependence does potentiate HIV-related neuronal injury, it cannot be determined at this time if the decrease in neuropsychological functioning is due to dendritic (i.e., reversible) changes or irreversible neuronal death. Taylor, M.J., Alhassoon, O.M. Schweinsburg, B.C. Videen, J.S. Grant, I. MR Spectroscopy in HIV and Stimulant Dependence, Journal of the International Neuropsychological Society, 6, pp. 83-85, 2000.

Impaired Evaluation of Future Consequences in Drug Abusers

Dr. Steven Grant of the Clinical Neurobiology Branch, DTR&D and colleagues at the Brain Imaging Center examined the performance of drug abusers on a neuropsychological test that requires evaluation of long-term outcomes in the presence of a complex set of mixed reward/punishment contingencies (the Gambling Task). In order to control for generalized deficits related to choice and planning, subjects were also administered the Wisconsin Card Sorting task. Drug abusers performed much more poorly on the Gambling Task than controls, but did not differ from controls on the Wisconsin Card Sorting Task. The results show that drug abusers are more likely to make maladaptive decisions in the Gambling Task that result in long-term losses exceeding short-term gains, similar to persistent drug use despite long-term adverse consequences. Furthermore, as the Gambling Task was developed to characterize subjects with orbitofrontal lesions, the results suggest that drug abusers may have dysfunction of the orbitofrontal cortex. Grant, S. et al., Drug Abusers Show Impaired Performance in a Laboratory Test of Decision-Making. Neuropsychologia, 38, pp. 1180-1187, 2000.

Chronic Effects of Marijuana as a Function of Age of First Use

Since a significant degree of brain development occurs during adolescence, males and females with a history of teenage marijuana use received both positive emission tomography (PET) to assess cerebral blood flow (CBF) and magnetic resonance imaging (MRI) scans to evaluate brain volume. Median age of first marijuana use was the variable used to stratify the volunteers into Early (< age 17) or Late (> age 17) use. Primary findings related to age of first use include: 1) those who were identified as Early users had smaller whole brain and percent cortical gray matter and percent white matter volumes compared to those who started use later, suggesting that the mechanism of this effect has more to do with brain development than with atrophy; 2) functionally, males who began use Early, had significantly higher resting CBF compared to the Late males but was not significantly different from females, supporting additional changes in gonadal and pituitary hormones that alter development; these changes, in turn, are related to global CBF and to reduction in gray matter; 3) both males and females who started using marijuana younger were physically smaller in height and weight, with the effects being greater in males. Since THC suppresses the release of prolactin, growth hormone and gonadotropin and because the adolescent growth period for males starts earlier and lasts longer than for females, starting marijuana use early would expose males longer to the adverse effects of reduced growth hormone release. Overall, these findings suggest that exposure to marijuana (and possibly other drugs) at certain critical periods such as during early adolescence, may alter normal patterns of development. Wilson, W., Mathew, R., Turkington, T., Hawk, T., Coleman, R.E., and Provenzale, J. Brain Morphology Changes and Early Marijuana Use: A Magnetic Resonance and Positron Emission Tomography Study. Journal of Addictive Diseases, 19, pp. 1-22, 2000.

Blood Flow Changes in Substance Abuse and PTSD

PET studies of regional cerebral blood flow during performance of an auditory continuous performance task have been conducted in subjects with PTSD and no substance abuse, substance abuse and no PTSD, PTSD and comorbid alcohol and cocaine abuse, and PTSD and only comorbid alcohol use, and normal control subjects. Although there were no differences in task performance, the PET results indicate that comorbid cocaine use exacerbates the pathophysiological changes in cortical and sub-cortical activity in subjects with PTSD. Cocaine-abusing PTSD subjects have increased regional brain blood flow in brain regions of the amygdala and periacquaductal grey compared to normals. In contrast, cocaine-abusing PTSD subjects have decreased frontal regional blood flow. Cocaine-abusing PTSD subjects have increased regional blood flow in the amygdala compared to cocaine abusers without comorbid PTSD and PTSD patients who only abuse alcohol, indicating that neither cocaine use alone nor PTSD alone is responsible for the elevations in observed blood-flow elevation. These data indicate a clear interaction between cocaine use and PTSD that cannot be explained by other factors. Given the high rate of substance abuse comorbidity in PTSD, these findings are relevant to the diagnosis and treatment of comorbid cocaine abuse in patients with PTSD. Semple, W.E., et al. Higher Brain Blood Flow at Amygdala and Lower Frontal Cortex in PTSD Patients with Comorbid Cocaine and Alcohol Abuse Compared to Normals. Psychiatry: Interpersonal and Biological Processes, 63, pp. 65-74, 2000.

A Mendelian Genetic Model for Smoking Behavior was Supported in an Analysis of Three-Generation Families

Gary Swan of SRI International conducted a complex segregation analysis in three generation-families to determine the best model for transmission of smoking behavior. This is the first study to date to use three generations for this determination. It was found that the best-fitting model was that of a dominant major gene with low estimated frequency and residual familial correlations. These correlations demonstrate strong influence of mothers (negative) and spouses (positive) toward smoking behavior. However, it should be noted that the sample was selected from those participating in a longitudinal study of aging and health and not selected for smoking behavior per se. Therefore, it is presumed that these results underestimate genetic transmission because heavy-smoking individuals are less likely to volunteer for the study, and many more smokers in the registry may have already died. Nevertheless, these results encourage future linkage studies. Cheng, L.S., Swan, G.E., and Carmelli, D. A Genetic Analysis of Smoking Behavior in Family Members of Older Adult Males. Addiction, 95(3), pp. 427-435, 2000.

A Genetic Variant Associated with Low Levels of a Dopamine Enzyme (Beta-Hydroxylase) Is also Associated with Cocaine-induced Paranoia

It had been shown that low levels of dopamine beta-hydroxylase (DBH) protein I plasma or cerebrospinal fluid are associated with greater vulnerability to positive psychotic symptoms. The question is whether a gene variant that is associated with that protein would be more prevalent in that circumscribed group of cocaine addicts who endorse paranoia symptoms. There is a gene variant of DBH that associates with plasma activity in European-Americans. Significantly more frequent low DBH-associated Haplotypes (p < .0003) was prevalent in cocaine-induced paranoia addicts than in addicts who did not endorse paranoia symptoms. Cubells, J.F., Kranzler, H.R., McCance-Katz E., Anderson G.M., Malison R.T., Price L.H., and Gelernter J. A Haplotype at the DBH Locus, Associated with Low Plasma Dopamine Beta-hydroxylase Activity, Also Associates with Cocaine-induced Paranoia. Molecular Psychiatry, 5(1), pp. 56-63, 2000.

Various Significant Genetic Influences Are Associated with Transitions between Levels of Use of Illicit Drugs

Using phone interviews of more than 3000 male-male twin pairs conditional probabilities were determined for different illicit drugs between levels of use, from exposure to dependence and addiction. Marijuana had the highest conditional probabilities for the transition from exposure to use, from use to use more than five times, and from use more than five times to regular use. Heroin had a higher rate of transition to regular use than amphetamines, cocaine, psychedelics, or sedatives. Finally, cocaine had the highest conditional probability for transition from regular use to abuse/dependence. Tsuang, M.T., Lyons, M.J., Harley, R.M., Xian, H., Eisen, S., Goldberg, J., True W.R., and Faraone S.V. Genetic and Environmental Influences on Transitions in Drug Use. Behavior Genetics, 29(6), pp. 473-479, 1999.

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