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National Institute on Drug Abuse

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

May, 1998

Research Findings

Clinical and Services Research

Neuroimaging and Episodic Memory Retrieval

Fred L. Bookstein, Ph.D. at University of Michigan and colleagues have explored interactions between brain areas that may be determinates of cognitive and behavioral operations. They used positron emission tomography (PET) regional cerebral blood flow (rCBF) to study patterns of episodic memory retrieval. Subjects were presented words lists and were asked to process different types of information, reflecting differential levels of processing. Functional connectivity of voxels located within Brodmann areas 10 and 45/47 in the right prefrontal cortex and the left hippocampus with the rest of the brain. Area 10 and left hippocampus showed an opposite pattern of functional connectivity, with a large expanse of bilateral limbic cortices that was equivalent in all tasks. However, during high retrieval, area 45/47 was included in this pattern. The results suggest that activity in portions of the right prefrontal cortex reflects either memory retrieval mode or success, depending on other brain regions that are functionally linked. As researchers parse the concept of emotional memory and the implications of emotion and memory for brain models of addiction, a focus upon systems-level interactions will be crucial. McIntosh, A.R. et al., Human Brain Mapping, 5(4), pp. 323-327, 1997.

Marijuana Intoxication and Disturbed Time Sense

Roy J. Mathew, M.D. and collegues at Duke University Medical Center studied the effects of THC infusion on brain activation in 46 marijuana smokers with regional cerebral blood flow (CBF) measured with positron emission tomography (PET) and magnetic resonance imaging (MRI). This group found, consistent with previous reports, a significant increase in cortical and cerebellar blood flow following THC, but not all subjects showed this effect. Those who showed a decrease in cerebellar blood flow also had a significant alteration in time sense. Alteration in time sense, as demonstrated with these THC results, can cause a distortion in the subjective framework through which an individual views and orients himself/herself, and has implications for episodic memory formation, cognitive thought processes and goal-directed behaviors. The relationship between decreased cerebellar flow and impaired time sense is of particular interest because the cerebellum has been linked to an internal timing system. Brain Research, In Press.

Attention Deficit Disorder among Substance Abusers

Howard Schubiner, M.D. and his colleagues at Wayne State University School of Medicine have been studying the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) in a cross-section sample of adults seeking substance abuse treatment. ADHD is considered to be a genetic and neurobiological disorder with a 5% prevalence rate in all children within the U.S. In a sample of 201 adult substance abusers (106 males and 95 females) 24% were found to meet DSM-IV clinical criteria for ADHD (as a child and as an adult). The gender prevalence in males was 28% and 19% in females, a non-significant difference. Overall, substance abusers with ADHD (compared to substance abusers without ADHD) were more likely to have conduct disorder and antisocial personality disorder (ASPD) and more motor vehicle accidents. Gender effects were noted. While the use of specific types of drugs was not significantly different between the groups of substance abusers with and without ADHD, female substance abusers with ADHD had an increased number of treatments for alcohol abuse and dependence. (The above findings were presented at the at the Fifth Annual Conference on Behavior, Neurobiology, Substance Abuse, and Culture, on October 16, 1997, in Los Angeles, California).

Computerized Scheduling of Nicotine Gum Use

Dr. Albert Jerome from PICS, Inc. in Reston, VA, has received SBIR funding from NIDA to conduct smoking cessation research with a product his company developed called LifeSign. LifeSign is a credit card-sized computer that uses a scheduled, gradual reduction protocol to help smokers quit. Their most recent work combines a customized version of LifeSign with nicotine gum. A randomized outcome study was conducted to collect preliminary data on effectiveness. The experimental group (LS-N), used computer prompts to determine when to begin and stop chewing each piece of nicotine gum. The computer gradually increased intervals between gums until gum use was eliminated completely. The comparison group was standard ad lib gum users in an eight-week self-help study. Findings indicated significantly better treatment outcomes for the LS-N group than for the gum only group across a variety measures. More subjects in the LS-N condition were abstinent at posttreatment (29% vs. 11%); and the percentage of subjects who quit for at least 24-hours was greater in the LS-N condition (76% vs. 39%). Analysis of self-reported gum use showed that the LS-N group used more gum during the first week following a quit attempt and that the amount of gum used during the first week was positively related to abstinence at posttreatment. A recently completed one-year follow-up showed that the relative advantage of the LS-N program was maintained (17% vs. 5% abstinent).

Menstrual Cycle Effects on Tobacco Cessation Symptoms

Dr. Sharon Allen at the University of Minnesota, has conducted a study to examine the effects of the menstrual cycle on smoking behavior in women during continued smoking and quit smoking status. Withdrawal and premenstrual symptomatology during phases of the menstrual cycle were investigated. Preliminary analysis indicated that there were no significant differences in withdrawal symptom scores across menstrual cycle phases in both the continued smoking and quit smoking groups. As expected, premenstrual symptom scores tended to be higher in the late luteal phase compared to the follicular phase in both the continued smoking (p=.03) and quit smoking (p=.0014) groups. Although total withdrawal symptom scores do not differ significantly across cycle phases, these findings suggest that smoking cessation may be more difficult in the late luteal phase due to increased premenstrual symptoms. Christianson, D., Allen, S., Hatsukami, D., Nelson, D. Smoking Withdrawal and Premenstrual Symptomatology Across Menstrual Cycle Phases. Presented at the Society for Research on Nicotine and Tobacco. March, 1998.

Efficacy of Lithium Treatment for Adolescents With Bipolar Disorders and Secondary Substance Dependency

Dr. Barbara Geller and colleagues at the Washington University School of Medicine conducted a 6-week double-blind, placebo-controlled, parallel group clinical trial to assess the efficacy of lithium for 16 male and 9 female adolescents (12-18 years) with a primary DSM-III-R bipolar disorder and secondary substance dependency disorder. Results indicate lithium to be an efficacious treatment for both disorders in terms of concurrently reducing symptoms of psychopathology (e.g., improved mood) and the use of illicit substances. No gender differences were noted. Geller, B., Cooper, T.B., Sun, K., et al. Journal of the American Academy of Child and Adolescent Psychiatry, 37(2), pp. 171-178, 1998.

Efficacy of Imipramine Treatment for Opiate-Dependent Patients With Depressive Disorders

Drs. Nunes, Quitkin, Donovan and colleagues at the New York State Psychiatric Institute and Columbia University conducted a single-blind, placebo-controlled clinical trial to assess the efficacy of imipramine hydrochloride for opiate-dependent patients with a DSM-III-R depressive disorder receiving treatment at community-based methadone maintenance clinics. One hundred and thirty-seven patients were randomized to a 12-week trial. Of these, 53 dropped out (non-compliance did not differ between the imipramine-treated and placebo-treated groups) and 84 completed a minimum adequate trial of at least 6 weeks. Of the 84, 57% receiving imipramine were rated as responders (i.e., reduced substance use and reports of craving; improved mood) compared with 7% receiving the placebo (p<.001). Nunes, E.V., Quitkin, F.M., Donovan, S.J., et al. Archives of General Psychiatry, 55(2), pp. 153-160, 1998.

Progression From Conduct Disorder to Antisocial Personality Disorder Following Treatment for Adolescent Substance Abuse

Drs. Mark Brown, Sandra Brown and colleagues at the University of California, San Diego, conducted a prospective longitudinal study of 137 substance-abusing adolescents (mean age at intake 15.9 years) who met DSM-III-R criteria for Conduct Disorder. Subjects (39% female) recruited from two adolescent inpatient drug treatment programs were interviewed at intake and again 4 years later. Results indicate that four years after treatment 61% (N=84) of the study group met DSM-III-R criteria for Antisocial Personality Disorder (APD), of which males were disproportionately represented (N=60) compared to female subjects (N=24; p<.005). Pretreatment clinical characteristics which predicted post-treatment APD include deviant behavior at or before age 10, greater diversity of deviant behaviors independent of substance use during childhood and early adolescence, and more extensive drug, but not alcohol use during the 30 days before admission to the program. These findings suggest a poorer prognosis for adolescents when conduct disorder is diagnosed independent of drug use, whereas more favorable drug treatment outcomes might be achieved with adolescents whose pretreatment diagnosis of conduct disorder occurred primarily in the context of or subsequent to their use of illicit substances. Myers, M.G., Stewart, D.G., and Brown, S.A. American Journal of Psychiatry, 155(4), pp. 479-485, 1998.

Validity of Substance Use Self-Reports in Dually Diagnosed Outpatients

Dr. Roger Weiss and colleagues at the Department of Psychiatry, Harvard Medical School compared the self reports of substance use with supervised urine samples collected on the same day for subjects participating in two separate studies, each designed to test a new group psychotherapy for patients with coexisting substance use disorder and with either PTSD or bipolar disorder. The mean age of the subjects was 35.2 years. All subjects in the PTSD group were women, by design, and 53.8% of the subjects in the bipolar group were men. Most patients, 69% had both alcohol and drug dependence and 95.6% were dependent on more than one drug. Marijuana and cocaine were the most common primary drugs of abuse. Results indicate that self reports were highly valid. Only 4.7% of cases involved subjects not reporting substance use detected by urine screens. Weiss, R., Najavits, L., Greenfield, S., Soto, J., Shaw, S., Wyner, D. American Journal of Psychiatry, 155, pp. 127-129, 1998.

Association of Antibody to GB Virus C (Hepatitis G Virus) with Viral Clearance and Protection from Reinfection

GB virus C (GBV-C) RNA and envelope antibody (anti-GBV-C) were assessed in samples collected over 6.5 years among injection drug users (IDUs). A marker of GBV-C infection was detected in 110 (94.8%) of 166 IDUs. GBV-C RNA was detected at all visits in 32 IDUs, was never detected in 70 IDUs, was acquired in 7 and was cleared in 8 IDUs. The odds of detecting anti-GBV-C were 103-fold higher in participants without detectable RNA (64/70) than in IDUs with persistent RNA (3/32). Antibody was detected in all 8 instances of viral clearance. GBV-C RNA did not reappear once cleared and no new infections occurred in 61 anti-GBV-C positive IDUs followed for 382 person years, although all reported ongoing drug use. The study findings suggest that RNA testing alone may significantly underestimate the occurrence of GBV-C infection and demonstrate that anti-GBV-C is highly associated with viral clearance and protection from reinfection. Thomas, D.L., Vlahov, D., Alter, H.J., Hunt, J.C., Marshall, R., Astemborski, J., Nelson, K.E.. J Infect Dis, 177, pp. 539-542, 1998.

Amount of Prenatal Cocaine Exposure and Birth Outcomes

Two recent publications from researchers at the University of Florida add to the growing body of evidence for the importance of studying the amount of exposure when examining developmental outcomes associated with use of drugs during pregnancy. In this prospective, longitudinal project, 154 women were identified during pregnancy as using cocaine, and 154 comparison women as not using cocaine, but matched on race, parity, socioeconomic status, and location of prenatal care (which related to level of pregnancy risk). Data analyses included control for marijuana, alcohol, and tobacco use. Although there were no overall differences between the two groups on gestational age, birth weight, or birth length, there was a significant relationship between the amount of cocaine used in the third trimester, and newborn length and head circumference. Similarly, the reported amount of cocaine use in the third trimester was negatively associated with measures of state regulation, alertness, and the ability of the infant to orient to the environment. These findings raise concerns about later developmental abilities of these infants. The researchers are continuing to follow the development of these children. Eyler, F.D., Behnke, M., Conlon, M., Woods, N.S., Wobie, K. Birth Outcome from a Prospective, Matched Study of Prenatal Crack/Cocaine Use: I. Interactive and Dose Effects on Health and Growth. Pediatrics, 101, pp. 229-237, 1998; Eyler, F.D., Behnke, M., Conlon, M., Woods, N.S., Wobie, K. Birth Outcome from a Prospective, Matched Study of Prenatal Crack/ Cocaine Use: II. Interactive and Dose Effects on Neurobehavioral Aassessment. Pediatrics, 101, pp. 237-241, 1998.

Cocaine-Induced Cerebral Vasoconstriction Detected in Humans with Magnetic Resonance Angiography

In a double-blind randomized controlled trial, Mendelson and his colleagues at Harvard Medical School have shown that cocaine is associated with cerebrovascular complications in humans. Twenty-four healthy neurologically normal men (av.age 29 yrs; reporting median cocaine use of 8 lifetime exposures [range, 3 to >40]) were administered iv cocaine 0.4 or 0.2 mg/kg, or placebo. The cerebral magnetic resonance angiography was performed at baseline and 20 min following infusion. Results showed that cocaine induced cerebral vasoconstriction in a dose-related fashion (p=0.03), with angiograms indicative of vasoconstriction in 5/8 and 3/9 subjects at 0.4 or 0.2 mg/kg, cocaine, respectively, compared with 1/7 injected with placebo. These changes occurred at low cocaine doses and in the absence of other risk factors, including polydrug abuse, hypertension, or cerebrovascular disease. Outcome stratification by prior use of cocaine (3-10, 11-40 times, or >40 times) statistically strengthened the relationship between cocaine administration and vasoconstriction in a dose-related manner (p<0.001), further suggesting that cocaine may have a cumulative residual effect in promoting cerebrovascular dysfunction. Kaufman, M.J., Levin, J.M., Ross, M.H., Lange, N., Rose, S.L., Kukes, T.J., Mendelson, J.H., Lukas, S.E., Cohen, B.M., and Renshaw, P.F. JAMA, 279 (5), pp. 376-380, 1998.

Why Different Rules are Required for Polygenic Inheritance

Controversy continues to rage over the best methodology for studying the molecular genetics of drug abuse and addiction. David Comings at the City of Hope Medical Center delineates the issues, arguing that drug abuse like other complex disorders is likely to be polygenic with many genes contributing 5% of the variance or less. Furthermore, he suggests that if, for example, 24 genes are associated with the disorder, it may be that one needs only a fraction of them, say 8, to precipitate the phenotype as defined by diagnostic techniques. But due to heterogeneity, the same 8 or more genes may not be present in everyone with the disorder, and many without the disorder will have a proportion of the purportedly causative genes. Accordingly, some of the more popular methodology for finding these genes, such as haplotype relative risk or sib-pair analyses lose considerable power. In addition, the concept of heterosis is ignored. Heterosis is the situation where the heterozygote is either the causative or protective genotype (cf. Hybrid corn) rather than the homozygote with or without two copies of the mutant allele. The article concludes that both heterogeneity and especially the polygenic nature of the disorders under study need to be considered rather than a more traditional one gene-one disease approach. Comings, D.E. Alcohol, 15(5), pp. 1-10, 1998.

Comparative Treatment Effectiveness: Effects of Program Modality and Client Drug Dependence History on Drug Use Reduction

. This study examined treatment outcome as a function of program modality, clients' lifetime patterns of drug dependence, and their interaction, controlling for current level of drug use at treatment intake. Data were based on almost 3,000 clients who were interviewed at intake and one-year follow-up as part of the national Drug Abuse Treatment Outcome Study (DATOS). Subjects' lifetime patterns of drug dependence were classified into nine groups according to the Diagnostic and Statistical Manual of mental Disorders (DSM-III-R; American Psychiatric Association; 1987) diagnostic criteria and time of onset of drug use career. Outcome measure was the reduction of heroin use or cocaine use. The presence of dependence diagnosis was associated with less improvement when current use level at intake was controlled. Clients dependent on heroin but not currently daily users benefited most from inpatient and residential programs. Methadone programs were also relatively ineffective in reducing cocaine use. Characteristics of the client's drug dependence history, in addition to the current or presenting drug problem, should be assessed to guide treatment planning. The high rate of cocaine dependence among methadone clients, most of whom were dependent on heroin, poses considerable challenge to contemporary opiate substitution treatments. Hser, Y.I., Anglin, M.D., and Fletcher, B. Journal of Substance Abuse Treatment, 15(1), pp. 1-11, 1998.

ERP Amplitude Anomalies in Children at Risk for Substance-use Disorders

Previous research has considered event-related potentials (ERPs) in relation to liability for alcohol and other substance use. This study explored ERPs in preadolescent boys at elevated risk for substance use due to paternal history of substance abuse or dependence. Sons (age 10-12) of fathers with an alcohol-use disorder (ALC, n = 29) were matched by age, IQ, education and parental alcohol use with sons of fathers with a polysubstance abuse or dependence diagnosis (POLY, n = 37). These two groups were matched with a low-risk comparison group (LOW, n = 29) of boys whose fathers had no substance-use disorder diagnosis. No boy in the study met criteria for a substance-use disorder. ERPs were collected from midline (Fz, Ct, Pt) and parietal (P3, P4) electrode leads during an auditory oddball task. ERPs of boys from the ALC and POLY groups showed a slow negative shift prominent at Ct and Pz. This negative shift, evident by 100 ms post-stimulus and lasting for the duration of the 1000-ms recording period, overlapped temporally with N1, N2 and P3 amplitude differences distinguishing the ALC and POLY groups from the LOW group. The ALC and POLY groups differed from each other in N2 amplitude at Ct, which was larger for ALC subjects. These findings offer a possible alternative explanation for previously observed amplitude anomalies noted in children at risk for substance-use disorders and suggest new avenues of inquiry. Brigham, J., Moss, H.B., Murrelle, E.L., Kirisci, L., and Spinelli, J.S. Psychiatry Research, 73(3), pp. 133-146, 1997.

A Discrete Choice Model of Drug Abuse Treatment Location

Goodman and his associates used three years of insurance claims for 9,878 individuals representing 10 large self-insured firms to examine determinants of inpatient care for disorders related to drug abuse. In addition to examining the effects of individual characteristics on treatment utilization, the research focused on the ways in which differences among firms affect the choice of treatment location. The probability of inpatient drug treatment was found to be related to diagnosis of a cocaine problem (abuse or dependence), a diagnosis of drug dependence (versus abuse), and a diagnosis of psychosis. Men were more likely to be hospitalized than women. Controlling for patient risk factors, where patients are employed and have insurance made a substantive difference in the probability of receiving inpatient treatment, with the firm-specific probability varying by as much as 87 percent. Over time, a trend toward more use of outpatient treatment was observed. Goodman, A.C., Nishiura, E. & Hankin, J.R. A Discrete Choice Model of Drug Abuse Treatment Location. Health Services Research, In Press.

Costs and Utilization of Short Term Drug Abuse Treatment

This paper investigates three aspects of drug abuse treatment costs emphasizing systematic differences among employers: predictors of costs, differentials in costs across employers, and differential effects of patient and employer characteristics on treatment costs. The study uses insurance claims data from ten large self-insured employers over a three-year period starting January 1989. Principal findings are (1) marginal inpatient costs generally exceed average costs, implying increasing cost per day as utilization increases; (2) for outpatient treatment, marginal costs are slightly less than average costs, implying outpatient drug treatment maintains slightly decreasing costs as utilization increases; and (3) analyses of cost differences among employers suggest that observed differences among employers and/or their carriers and providers appear to be at least as important as the characteristics of the people covered or the care provided. In summary, policies aimed at reducing drug treatment costs are likely to have differing impacts on different employers. Goodman, A.C., Nishiura, E. & Hankin, J.R. Short Term Drug Abuse Treatment Costs and Utilization: A Multi-Employer Analysis. Medical Care, In Press.

Cost and Usage Impacts of Treatment Initiation

Using insurance claims data from 10 large self-insured firms, a study was carried out to explore the impact of alcohol and drug abuse treatment on subsequent alcohol, drug abuse, and medical treatment utilization and costs. The study provides an analysis of the relationship between type (inpatient or outpatient) and intensity of utilization and costs. Findings indicate that treatment cost models may differ from treatment usage models. For example, inpatient drug treatment was negatively associated with medical treatment in the 6 months following drug treatment initiation, but longer inpatient drug abuse treatment was associated with increasingly higher costs. The cost and utilization models for drug abuse treatment were very similar to those for alcohol treatment. For both, the largest costs of coincident and subsequent treatment were for (1) inpatient treatment, and (2) treatment occurring within 6 months of initiation of drug or alcohol treatment. Goodman, A.C., Nishiura, E., and Humphreys, R.S. Cost and Usage Impacts of Treatment Initiation: A Comparison of Alcoholism and Drug Abuse Treatments. Alcoholism: Clinical and Experimental Research, 21, pp. 931-938, 1997.

Drug Treatment Outcomes and Physical and Sexual Abuse

Relationships between psychopathology, drug treatment outcomes, and history of physical or sexual abuse were examined in a longitudinal study of 330 patients in 26 outpatient programs. Both forms of abuse were found to be associated with higher levels of psychopathology, but with significant gender differences. For women in the study, sexual abuse was associated with higher levels of psychological disturbance, while physical abuse was associated with less disturbance. The inverse relationship was found for men: physical abuse was associated with several types of psychological disturbances, while sexual abuse was associated only with anxiety disorder. The study points to the need to assess histories of sexual and physical abuse in assessing and treating co-occurring psychopathology. Gil-Rivas, V., Fiorentine, R., Anglin, M.D., and Taylor, E. Sexual and Physical Abuse: Do they Compromise Drug Treatment Outcomes? Journal of Substance Abuse Treatment, 14, pp. 351-358, 1997.

Costs and Incentives in A Behavioral Health Carve-Out

A carve-out of mental health and substance abuse services initiated in 1993 by the Group Insurance Commission (GIC) of the Commonwealth of Massachusetts resulted in changes in the costs of those services. Those changes were related to incentives in the contract between the GIC and its managed behavioral health vendor. Total and plan costs were reduced by 30-40 percent after adjusting for trends. Incentives to produce savings of this magnitude not only were a consequence of the payer/ vendor contract but also appeared related to the growth potential of companies in the managed behavioral health care market. Ma, C. and McGuire, T.G. Health Affairs, 17, p. 54, 1998.

Drug Treatment Careers, A Conceptual Framework and Existing Research Findings

While outcomes for any single intervention are important to determine, the treatment careers perspective provides a useful framework to evaluate the long-term effects of multiple sequential interventions, leading to a better understanding of drug dependence and its treatment. The analytic model involves a longitudinal dynamic approach to identify and understand key factors in drug abuse treatment, including treatment seeking, utilization and resistance, entry and reentry, engagement and retention, client treatment matching, and outcomes. Key findings include high resistance to entering treatment by many drugs users, late development of treatment careers relative to addiction and criminal careers, short durations of most treatment episodes, cumulative and facilitative effects of treatment experiences, and beneficial effects of matching clients to treatment. Hser, Y-I., Anglin, M.D., Grella, C., Longshore, D. and Prendergast, M. J of Subs Abuse Treatment, 14(6), pp. 543-558, 1997.

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