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National Institute on Drug Abuse

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

September, 1996


Research Findings


Clinical and Services Research


Contribution of ADHD Symptoms to Substance Problems and Delinquency in Conduct-Disordered Adolescents

Researchers examined adolescents with conduct disorder (CD) and substance abuse problems to determine if those with attention deficit hyperactivity disorder (ADHD) symptomatology had more severe delinquency and substance involvement. The study sample consisted of 171 adolescent boys, 13-17 years of age, enrolled in a residential program for substance abusers with behavioral problems. ADHD symptomatology was assessed by self-reports using the Diagnostic Interview Schedule for Children (DISC) and by the use of DISC plus reports of others (parents, program staff, and program teacher). Results showed that boys with either self- or multi-source ADHD had more conduct disorder symptoms, earlier age of conduct disorder onset, more substance dependence diagnoses, and more co-morbid depression and anxiety. Thompson, L.L., Riggs, P.D., Mikulich, S.K., and Crowley, T.J. Journal of Abnormal Child Psychology, 24(3): pp. 325-347, 1996.


An Open Trial of Pemoline in Drug-Dependent Delinquents with Attention-Deficit Hyperactivity Disorder

Research shows that adolescents with conduct disorder and substance use disorders have high rates of co-morbid attention deficit hyperactivity disorder (ADHD). Further, ADHD may contribute to the severity and persistence of substance use disorders and antisocial behaviors. A study was conducted to examine if adolescents with ADHD and substance use disorders could be successfully treated. The study sample consisted of 13 male adolescents with CD, substance use disorder, and ADHD, in a residential program. Patients were treated with pemoline, schedule IV stimulant medication but with a known low abuse potential, at a standard daily dose of 37.5 mg, that was increased over the subsequent 3 weeks to a total of 112.5 to 185.5 mg (=1.2-3.3 mg/kg maximal dosing). All patients took this maximal dose for at least 1 week prior to post-treatment assessment of motility, CHI (Connors Hyperactivity Index), and CPT (Continuous Performance Score). Results showed that hyperactivity and motility declined significantly by 13.9% and 7%, respectively, with pemoline treatment. However, the continuous performance scores did not change. These data indicate that pemoline may be a useful treatment for ADHD in substance-dependent delinquents. Riggs, P.D., Thompson, L.L., Mikulich, S.K., Whitmore, E.A., and Crowley, T.J. Journal of American Academy of Child and Adolescent Psychiatry, 35(8): pp. 1015-1024, August 1996.


Frontal P300 Decrements, Childhood Conduct Disorder, Family History, and the Prediction of Relapse Among Abstinent Cocaine Abusers

Antisocial personality disorder is a frequent co-morbid diagnosis in cocaine dependent patients. A study was conducted in 49 cocaine dependent patients, abstinent for 1-5 months, to examine the following: (1) the neurophysiological effects of pre-morbid antisocial personality symptoms (ASPD; e.g., conduct disorder) occurring before age 15 versus co-morbid or post-morbid ASP symptoms occurring after age 15, (2) comparison of ASPD in patients with a family history of alcoholism and in cocaine dependent patients, (3) to examine the usefulness of P300 in predicting relapse, and (4) examine the time course of P300 decrements in cocaine abusers, with or without ASPD. Patients were assigned according to the presence/absence of a DSM-IIIR diagnosis of ASPD. Analysis of P300 recorded during a visual selective attention task revealed reduced amplitudes at frontal electrode sites among patients with ASPD, relative to the ASPD negative patient and control groups. The frontal P300 decrement was significantly correlated with the number of childhood conduct disorder symptoms, but not with the presence/absence of a family history of alcoholism. Further, discriminant function analysis revealed that P300 amplitude alone accurately identified 71% of the patients who later relapsed, and 53% of the patients who did not. Bauer, L.O., Drug and Alcohol Dependence, In Press.


Safety Dose-Response Study on Lofexidine

Elmer Yu, M.D., from the Philadelphia Medications Development Research Unit, has initiated a safety dose-response study on the alpha-2-noradrenergic agonist, lofexidine, for the alleviation of opiate withdrawal symptoms in opiate dependent individuals. The potential importance of this study is that lofexidine, unlike clonidine, has not historically been associated with decreases in blood pressure that limit the usefulness of clonidine. Other preclinical researchers are determining if lofexidine binds to a different set of receptor subtypes than clonidine.


Impaired Regulation of Arousal in Infants Prenatally-Exposed to Cocaine

Researchers at Yale University have provided evidence of impaired arousal regulation in 3-month old infants prenatally-exposed to cocaine and other drugs. Behavioral state, affective expressiveness, and attention to novel stimuli were the measures of arousal. There were no differences in baseline behavioral state or affective expression prior to stimulus presentation across two groups of 3-month old infants (36 infants prenatally-exposed to cocaine and other drugs, and 27 not exposed to cocaine prenatally). However, the exposed infants were more likely to exhibit a crying state and to display negative affect when novel stimuli were presented. There was no difference in looking time between the two groups. These group results were found when sociodemographic and perinatal factors were controlled. The investigators discuss these findings as to possible sources of differences in arousal regulation, and relative to predictive implications for social and cognitive development. Mayes, L.C., et al., Development and Psychopathology, 8: pp. 29-42, 1996.


Prediction of Treatment Success in Alcohol and/or Cocaine Use Disorders by qEEG

NIDA-funded researcher, Dr. Henry D. Abraham, from the Butler Hospital in Providence, Rhode Island has assessed the ability of quantitative electroencephalography (qEEG) to predict relapse following inpatient treatment for alcohol and/or cocaine use disorders in 27 subjects. Subjects were studied in a drug-free state following treatment and were followed for an assessment of sobriety. At one year after discharge, 39.3% of the subjects had maintained abstinence, and 60.7% had relapsed. Three qEEG variables derived a year earlier predicted relapse with 88.2% sensitivity and 90.0% specificity (p < .0001). Dr. Abraham hypothesized that these preliminary findings may lead to markers for diverse etiologies of relapse.


Changes in Brain Metabolism in Chronic Marijuana Users

Dr. Nora D. Volkow of the Brookhaven National Laboratory and her colleagues recently reported on the effects of chronic marijuana use on brain glucose metabolism. Eight chronic marijuana abusers were evaluated with positron emission tomography (PET). At baseline, the marijuana abusers had significantly lower baseline cerebellar metabolic values than normal subjects. Metabolic response to THC administration revealed an increase in relative cerebellar metabolism in all subjects, but only the marijuana abusers showed metabolic increases in prefrontal cortex, orbitofrontal cortex, and basal ganglia. For the normals, THC either did not change or decreased metabolism in these areas. These results suggest that the lower baseline cerebellar metabolic activity in chronic marijuana abusers could reflect changes in cannabinoid receptors in the cerebellum (a brain structure rich in cannabinoid receptors). Also, the THC-induced activation of the orbitofrontal cortex and basal ganglia in abusers could be one of the underlying neural mechanisms leading to the drive and compulsion to self-administer the drug in addicted individuals. Volkow et al., Brain Glucose Metabolism in Chronic Marijuana Users at Baseline and During Marijuana Intoxication. Psychiatry Research, 67, pp. 29-38, 1996.


Sex Differences in Plasma Cocaine Levels and Subjective Effects after Acute Cocaine Administration

Scott Lukas and colleagues at the Alcohol and Drug Abuse Research Center, McLean Hospital and Harvard Medical School reported that male occasional cocaine users achieved significantly faster peak plasma cocaine levels after an intranasal dose of cocaine hydrochloride. They also reported a greater number of intense effects. Women also differed in their menstrual cycle where peak plasma levels of cocaine were lower in the luteal compared to the follicular phase; subjective reports did not differ. However, heart rates did not differ between males and females, suggesting that females with the lower plasma cocaine had more sensitive cardiovascular sensitivity. These data demonstrate differential effects between the sexes for use of cocaine. Psychopharmacology, 125, pp. 346-354, 1996.


Sleep Improvement by Low Doses of Buprenorphine in Recovering, Dual Dependent (Cocaine and Opiates) Drug Abusers

Dr. Lukas and colleagues have also been studying the disturbed sleep of recovering dual-dependent drug abusers. Findings indicate delays in sleep onset, multiple awakenings and reduced total sleep time with little or no Stage 3 or Stage 4 sleep. Low dose (4 mg/day) significantly increased sleep time, reduced latency, and increased Stage 3 sleep whereas only sleep latency was significantly reduced with a larger dose (8 mg/day).


Cocaine-Associated Agitated Delirium

An increasing number of deaths due to cocaine are characterized by delirium and seemingly violent behavior requiring restraint. NIDA grantee, Dr. Deborah Mash of the University of Miami School of Medicine, together with colleagues in the medical examiners office, are studying the underlying causes of delirium-associated deaths which constitute about 10% of the deaths due to cocaine overdose. They describe in a recent report that victims are most often male, succumbing in the warmer months. Work so far has shown that these psychotic victims have marked reduction of D2 dopamine receptors within the temperature regulatory centers of the hypothalamus and no increases in dopamine recognition sites on the striatal dopamine transporter. It was also pointed out that cocaine per se may not be the sole cause since a similar syndrome was described nearly 150 years ago. Also cocaine-induced changes of dopamine sites may not be the sole cause; other factors such as stress of restraint may exacerbate the situation. American Journal of Emergency Medicine, In Press.


Increase of D3 Dopamine Receptors in Human Cocaine Fatalities

Dr. Mash has also recently reported a 1 to 3 fold increase in the number of D3 receptor binding sites over particular sectors of the striatum and substantia nigra in cocaine overdose victims compared to age-matched and drug-free controls. This receptor has been shown to play a pivotal role in the reinforcing effects of cocaine in, for example, self-administering but not naive, rhesus monkeys. Since this receptor is such an integral part of the brain's reward circuitry in chronic cocaine abusers, it may be a potential site for therapeutic intervention. Journal of Neuroscience, In Press.


Treatment Effects of Acupuncture for Cocaine Abuse

Dr. Milton Bullock and colleagues at the Hennepin County Medical Center in Minneapolis conducted two linked studies to evaluate the potential usefulness of auricular acupuncture (Ac) in the treatment of cocaine addiction. In Study I, residential clients were randomized to true Ac, sham Ac and conventional treatment without Ac. Sham acupuncture consisted of needles in ear points considered to be non-specific for the treatment of substance abuse. Subjects in the specific and non-specific acupuncture groups were blinded to their treatment assignment. In Study II, day treatment clients received conventional psychosocial treatment and were randomized to one of three dose levels of true Ac (28, 16, and 8 treatments). Sham points were not used in Study II. Data were collected from research assistants blinded to the subjects' treatment assignment. Multivariate analyses were performed both to determine outcomes related to placebo and sham treatment factors and to the various Ac conditions. Outcomes examined included cocaine use and craving, treatment effect sizes, treatment attrition rates and health, psychological and social status. The results of this study indicate that Ac did not provide any significant therapeutic benefit for any of the parameters tested over the improvement obtained by conventional psychosocial therapy.


Marijuana Use and Treatment Outcome in Cocaine-Dependent Patients

Dr. Budney and associates at the University of Vermont assessed marijuana use in 186 persons seeking cocaine dependence treatment. Comparisons were made between clients who did and did not report using marijuana, and between marijuana users who did and did not meet diagnostic criteria for marijuana dependence. A high rate of current marijuana use (59%) was observed at intake and the majority of the marijuana users (74%) used marijuana at some point during treatment. Marijuana use at intake was associated with increased psychosocial impairment and substance-use severity. However, no significant adverse relations were observed between marijuana use and any of the treatment outcome measures. That is, regular marijuana use did not interfere with cocaine abstinence during or following treatment. These findings challenge the common assertion that drug-dependent patients must simultaneously cease use of all drugs of abuse to succeed in treatment. Alternative treatment strategies for addressing polydrug use warrant consideration. Budney, A.J., Higgins, S.T., and Wong, C.J. Experimental and Clinical Psychopharmacology, In Press.


Matching Patients to Smoking Treatments

Relatively little is known about individual variation in withdrawal, or the determinants of such variation. Dr. Baker and colleagues at the University of Wisconsin reported findings showing that the course of smoking withdrawal symptoms varies greatly across smokers. Results from two studies reveal that 35-50% of smokers in cessation programs experience withdrawal that follows an "atypical" course over the first 2 months after a quit attempt. Dynamic cluster analysis revealed two clusters of subjects that experienced either a late exacerbation of withdrawal, or a prolonged maintenance of withdrawal symptoms. Women were more likely than men to belong to an atypical cluster, and membership in such a cluster was associated with a higher risk of relapse. This research may identify an important individual difference that predicts relapse vulnerability and may also reveal an important target for future treatments. Piasecki, T.M., Fiore, M.C., Baker, T.B. Profiles in Discouragement: Two studies of Variability in the Time Course of Smoking Withdrawal Symptoms, Submitted to Journal of Abnormal Psychology.


Economic Evaluation of Drug Abuse Treatment Programs

Dr. Michael T. French at the Community-based, Health Services Research Center has published an important review article for the drug abuse treatment field. This study presents a simplified economic evaluation methodology that can be followed by program staff and researchers. The evaluation methodology includes aspects of cost-and-outcome analysis, cost-effectiveness analysis, and benefit-cost analysis. Methods and findings from most of the major economic evaluation studies of drug and alcoholism treatment are discussed. Guidelines for conducting future economic evaluations are presented along with suggestions for how the results can be used for policy purposes and program planning. French, M. Economic Evaluation of Drug Abuse Treatment Programs: Methodology and Findings. Am J Drug Alcohol Abuse, 21: pp. 111-135, 1995. Relatively little is known about individual variation in withdrawal, or the determinants of such variation. Dr. Baker and colleagues at the University of Wisconsin reported findings showing that the course of smoking withdrawal symptoms varies greatly across smokers. Results from two studies reveal that 35-50% of smokers in cessation programs experience withdrawal that follows an "atypical" course over the first 2 months after a quit attempt. Dynamic cluster analysis revealed two clusters of subjects that experienced either a late exacerbation of withdrawal, or a prolonged maintenance of withdrawal symptoms. Women were more likely than men to belong to an atypical cluster, and membership in such a cluster was associated with a higher risk of relapse. This research may identify an important individual difference that predicts relapse vulnerability and may also reveal an important target for future treatments. Piasecki, T.M., Fiore, M.C., Baker, T.B. Profiles in Discouragement: Two studies of Variability in the Time Course of Smoking Withdrawal Symptoms, Submitted to Journal of Abnormal Psychology.


Economic Evaluation of Drug Abuse Treatment Programs

Dr. Michael T. French at the Community-based, Health Services Research Center has published an important review article for the drug abuse treatment field. This study presents a simplified economic evaluation methodology that can be followed by program staff and researchers. The evaluation methodology includes aspects of cost-and-outcome analysis, cost-effectiveness analysis, and benefit-cost analysis. Methods and findings from most of the major economic evaluation studies of drug and alcoholism treatment are discussed. Guidelines for conducting future economic evaluations are presented along with suggestions for how the results can be used for policy purposes and program planning. French, M. Economic Evaluation of Drug Abuse Treatment Programs: Methodology and Findings. Am J Drug Alcohol Abuse, 21: pp. 111-135, 1995.


Methadone Dosing Practices

An important finding from a long-term study by Thomas D'Aunno concerns methadone dosing practices. Preliminary results, which have not yet been published, indicate that average methadone dose levels have improved in comparison to data from 1988 and 1990. The average dose increased from 46 mg/day in 1990 to 59 mg/day in 1995, and the upper dose limit increased from 82 mg/day in 1990 to 94 mg/day in 1995. Consistent with earlier findings (D'Aunno and Vaughn, 1992), treatment programs more likely to have lower dose levels and shorter times in treatment treat higher percentages of clients who are unemployed, African American, young, and male. Units staffed with more physicians are likely to have higher dose levels.


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