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National Institute on Drug Abuse

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

May, 2000

Research Findings

Treatment Research and Development

A Clinical Profile of Women with PTSD and Substance Dependence

This paper compared the clinical characteristics of two groups of women (those with Post Traumatic Stress Disorder (PTSD) and Substance Use Disorder (SUD) and those with PTSD only) to better understand why some women with PTSD also develop SUD, while others do not. The dual diagnosis women consistently had a more severe clinical profile, including worse life conditions, greater criminal behavior, higher number of lifetime suicide attempts, etc. One discrepant finding, however, was their lower rate of major depression. Interestingly, the two groups did not differ in number or type of lifetime traumas, PTSD onset or severity, family history of substance use, coping style, functioning level, psychiatric symptoms, or sociodemographic characteristics. Najavits, L.M., Weiss, R.D., and Shaw, S.R. Psychology of Addictive Behaviors, 13, pp. 98-104, 1999.

Associations Between Tobacco Smoking and Illicit Drug Use Among Methadone Maintained Opiate Dependent Individuals

Researchers at the University of California at, Los Angeles examined the relationship between levels of cigarette smoking and levels of illicit drug use in 32 patients enrolled in a heroin treatment program. The participants included heavy smokers (20-40 cigarettes per day), nonsmokers, and "chippers" who smoke fewer than 5 cigarettes per day. Breath and urine samples were evaluated over a 7-day period. The findings showed that the amount of cocaine and heroin use was directly related to the level of tobacco use in a stepwise fashion from nonsmokers, to chipper, to heavy smokers. This supports existing evidence suggesting associations between tobacco and opiate and cocaine use, and strongly suggest that smoking cessation should be offered to all methadone maintained individuals. Frosch, D.L., Shoptaw, S., Nahom, D., and Jarvik, M.E. Experimental and Clinical Psychopharmacology, 8, pp. 1-7, 2000.

The Relationship Between Anxiety Levels and Outcome of Cocaine Abuse Treatment

Investigators at Brown University examined how self-reported anxiety levels were related to cocaine use variables and patterns over the course of treatment and at 3 months post-treatment. Patients were 108 cocaine abusers receiving cognitive-behavioral coping skills treatment for their cocaine abuse. Results showed that state anxiety scores significantly declined for all participants from pre- to post-treatment and then remained stable into the follow-up period, regardless of relapse status. Trait anxiety was positively correlated with negative consequences due to cocaine use and negatively correlated with days in treatment. Findings suggest that elevated anxiety scores at pre-treatment subside with time, do not require clinical management of associated anxiety symptoms, and may be a temporary byproduct of experiencing negative consequences due to recent cocaine use. O'Leary, T.A., Rohsenow, D.J., Martin, R., Colby, S.M., Eaton, C.A., and Monti, P.M. American Journal of Drug and Alcohol Abuse, 26, pp. 179-194, 2000.

A Within-Subject Comparison of Three Different Schedules of Reinforcement of Drug Abstinence Using Cigarette Smoking as an Exemplar

In this study, investigators examined three schedules of reinforcement for promoting and sustaining short-term drug abstinence, using cigarette smoking as an exemplar of drug self-administration. The schedules studied were: 1) fixed magnitude of reinforcement for abstinence, 2) progressive increase in magnitude of reinforcement for abstinence with a reset contingency for drug use, and 3) progressive increase in magnitude of reinforcement for abstinence without a reset contingency. Eighteen subjects participated in all three schedules in a counterbalanced order. Each schedule was in effect for five consecutive days. The total amount of reinforcement available was the same during each condition. Findings indicate that the progressive magnitude with a reset schedule was more effective than the other two schedules in sustaining an initial period of abstinence. This study extends and provides further support for results that have been demonstrated in previous studies. Roll, J.M. and Higgins, S.T. Drug and Alcohol Dependence, 58, pp. 103-109, 2000.

A Brief Abstinence Test: Voucher-based Reinforcement of Cocaine Abstinence

Drs. Stitzer, Bigelow, Silverman and colleagues at the Johns Hopkins University School of Medicine and Dr. Cone, NIDA Intramural Research Program, conducted a study to assess the effectiveness of a brief abstinence reinforcement procedure for initiating cocaine abstinence in methadone maintenance patients. On the Monday of test week, 72 cocaine-abusing methadone patients were offered a $100 voucher if urine samples collected on Wednesday indicated they had abstained from cocaine across that 2-day period. A patient was considered abstinent and the voucher delivered if the urine benzoylecgonine concentration decreased by 50% from Monday to Wednesday or the concentration of Wednesday's urine sample was <300 ng/ml. Results indicate 79% of the patients showed urinalysis evidence of abstention from cocaine, Monday to Wednesday of test week. In a sub-sample (n=50), results indicate significantly more patients abstained from cocaine during the test week (84%) than during the same period the week before (36%) or the week after (32%) test week. Robles, E., Silverman, K, Preston, K.L., Cone, E.J., Katz, E., Bigelow, G.E., and Stitzer, M.L. Drug & Alcohol Dependence, 58, pp. 205-212, 2000.

Contingency Management for Accurate Predictions of Urinalysis Test Results and Lack of Correspondence with Self-Reported Drug Use Among Polydrug Abusers

Dr. Schuster and colleagues, Wayne State University School of Medicine, conducted a pilot study to assess the effectiveness of a contingency management procedure to enhance the validity of self-reports of drug use among 63 older (mean age 40.6 years) opiate-dependent poly-drug abusers enrolled in a drug treatment program. Participants in the reinforced prediction condition received vouchers worth $2.50 if their self-report predictions were accurate whereas participants in the non-reinforced prediction condition did not receive anything for accurate predictions. Preliminary results indicate both reinforced and non-reinforced patients were highly accurate in making urine drug screen (UDS) predictions, with predictions being equally accurate for heroin and cocaine but more accurate for positive than for negative UDS results. Although more research is needed to confirm these findings, results suggest poly-drug abusers' predictions of urine screen results might be sufficiently valid such that a program might save UDS costs by testing only those specimens obtained from patients reporting drug-free urines. Downey, K.K., Helmus, T.C. and Schuster, C.R. Psychology of Addictive Behaviors, 14(1), pp. 69-72, 2000.

Gender Differences in Hostility of Opioid-Dependent Outpatients: Role in Early Treatment Termination

In this study, Dr. Nancy Petry and Dr. Warren Bickel evaluated gender differences in hostility and the role of hostility in predicting early treatment termination of opioid-dependent patients. Subjects were 104 patients (68 males and 36 females) in a buprenorphine- maintenance treatment program. Opioid-dependent females scored significantly higher on the Buss-Durkee Hostility Scale, compared to males. Early treatment termination was defined as remaining in treatment less than 30 days, and 13% of males and 25% of females were classified as early terminators. Severity of legal and employment problems and the interaction between hostility and gender were predictors of early treatment termination. Patients with less severe legal problems and patients with greater employment problems were more likely to terminate early from treatment. Higher levels of hostility predicted early treatment termination of female patients, but hostility levels were not associated with treatment termination in male patients. Results from this study show that female heroin addicts have high levels of hostility and suggest that hostility may be an important predictor of premature termination of treatment, especially among opioid-dependent women. These data suggest that hostility should be assessed early in treatment and that increased effort may be needed to enhance participation of hostile women in treatment programs. Petry, N. and Bickel, W. Drug and Alcohol Dependence, 58, pp. 27-33, 2000.

Longer Term Methadone Maintenance, Combined with Some Psychosocial Counseling, is More Effective Than 180-Day Psychosocially Enriched Detoxification Treatment of Opioid Dependence

Investigators from the University of California, San Francisco, compared outcomes of 179 opioid-dependent patients randomly assigned to either a methadone maintenance treatment group or a psychosocially enriched 180-day methadone detoxification group. The methadone maintenance group was eligible for 14 months of methadone maintenance, followed by a 2-month detoxification. Participants in this group were required to attend substance abuse group therapy 1 hour per week for the first 6 months of maintenance, and 1 hour per month of individual therapy. Patients in the detoxification group received methadone only for the first 180 days of their treatment. During this time, they attended 2 hours per week of group therapy; 1 hour per week of cocaine group therapy if they had tested positive for cocaine upon admission to the study; a series of 14 one-hour weekly substance abuse education classes; and 4 weekly individual therapy sessions. This group also received 6 months of aftercare services that included weekly individual and group therapy and liaison services with the criminal justice system, medical clinics, and social service agencies, but no additional methadone after the first 180 days of treatment. Study results showed that more patients in the MMT group remained in treatment for longer periods of time (438.5 days vs. 174 days) and had lower heroin use rates than did shorter-term methadone detoxification patients. Of the MMT group, 77 out of 91 patients were still in the study at the 12-month mark, while only 57 of 88 methadone detoxification patients were still in the study. MMT also resulted in a lower rate of drug use-related HIV-risk behaviors and a lower level of criminal activity. Sees, K.L., Delucchi, K.L., Masson, C., Rosen, A., Clark, H.W., Robillard, H., Banys, P., and Hall, S.M. JAMA, 283, pp. 1303-1310, 2000.

A Comprehensive Guide to the Application of Contingency Management Procedures in Clinical Settings: A Review

Controlled clinical trials have demonstrated the efficacy of contingency management procedures in treating substance use disorders. This paper reviews the rationale of contingency management interventions and provides a review of scientific studies in this area. Research-based guidelines are provided for clinicians and researchers to use when designing and administering contingency management interventions in community-based clinical settings. Petry, N.M. Drug and Alcohol Dependence, 58, pp. 9-25, 2000.

Effects of Cocaine Alone or Cocaine plus GBR 12909 on the Cardiovascular Hemodynamic and Electrophysiology

A safety assessment of the cardiovascular effects of cocaine, GBR12909, and the combination of the two compounds was conducted in animals. The study revealed that 10 mg/kg GBR 12909 given orally had no effect on the cardiovascular effects that were produced by cocaine, when given either before or after the administration of cocaine. The study by M. Smith, J. Ludens, L. Hulesbos, G. Schafer, P. Newton, N. Olivier and J. Terrill was presented as a poster entitled "Effects of Cocaine Alone or Cocaine plus GBR 12909 on the Cardiovascular Hemodynamic and Electrophysiology Parameters in Conscious Unrestrained Beagle Dogs" was presented at the annual meeting of the Society of Toxicology, March 2000.

Long-Term Neurotoxicity Associated with Methamphetamine Abuse

Dr. Thomas Ernst and colleagues at the Harbor-UCLA Medical Center studied long-term changes in brain neurochemistry in abstinent methamphetamine abusers. Using the brain imaging technique, proton magnetic resonance spectroscopy (1H MRS), cerebral metabolite concentrations were measured in the basal ganglia, frontal white matter, and frontal cortex. Twenty-six abstinent methamphetamine abusers (median recency of last methamphetamine use, 4.25 months) with a history of methamphetamine dependence (median total cumulative lifetime exposure, 3.64 kg) were compared to 24 healthy subjects with no history of drug abuse. Results showed that the concentration of N-acetyl-aspartate (NA), a neuronal marker, was reduced in the basal ganglia and frontal white matter in methamphetamine abusers compared to controls. The frontal white matter NA concentration correlated inversely with lifetime methamphetamine use. These methamphetamine users showed significantly reduced total creatine in the basal ganglia, and increased choline-containing compounds and myo-inositol, a glial marker, in the frontal gray matter. These results provide important evidence for long-term neuronal damage and glial abnormalities in abstinent (some up to 21 months) methamphetamine abusers. Ernst, T., et al., Evidence for Long-term Neurotoxicity Associated with Methamphetamine Abuse: A 1H MRS Study. Neurology, 54, pp. 1344-1349, 2000.

Marijuana Users Have Attenuated Activity in the Cerebellum

Dr. Robert Block and associates at the University of Iowa Medical School used PET to measure regional cerebral blood flow in frequent marijuana users. PET scans were acquired after at least 25 hours of monitored abstinence. During the PET scan subjects rested quietly with eyes closed and refrained from speaking. Compared to control subjects, the marijuana users exhibited substantially lower blood flow (18%) in a large region of the posterior cerebellum relative to the rest of the brain. A small relative reduction in blood flow (<2 %) was also observed in the ventral prefrontal cortex (area 11). In contrast, marijuana users exhibited slightly higher blood flow (<2%) in the right anterior cingulate. A reduction in basal cerebellar function may underlie marijuana-induced impairments in motor co-ordination and alterations in the sense of time. Block, R.I., et al., Neuroreport, 11(4), pp. 1-5, 2000.

Effects of Marijuana Use on Brain Volume

Dr. Robert Block and associates at the University of Iowa Medical School used structural MRI to determine whether frequent marijuana use produces lasting alterations in brain anatomy. Automated image analysis procedures were used to measure global and regional brain volumes. Separate measures were taken for gray and white matter. There were no qualitative or quantitative evidence for cerebral atrophy or clinically significant abnormalities in the frequent marijuana users. Nor were there any quantitative differences between controls and frequent marijuana users in any of the volumetric measures. The investigators did find reliable gender differences in volumetric measures, suggesting that the methods were sensitive enough to detect clinically relevant differences in brain volume. Block, R.I., et al., Neuroreport, 11(3), pp. 1-6, 2000.

Functional Deficits in Basal Ganglia of Children with ADHD

Drs. Perry Renshaw and Martin Teicher of Harvard Medical School employed a novel fMRI procedure, T2 relaxometry, to measure steady state blood flow and indirectly assess blood volume in the striatum (caudate and putamen) and to test for medication effects in boys (6-12 years old) with attention deficit/hyperactivity disorder (ADHD). Boys with ADHD had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. These relaxation times strongly correlated with the child's capacity to sit still and with his accuracy in accomplishing an attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with ADHD, although the magnitude and direction of the effect was strongly dependent on the child's un-medicated activity state. These results show that methylphenidate exerted different effects on the putamen--presumably increasing perfusion in the more hyperactive children but decreasing it in ADHD children with normal activity. Behavioral results indicated that methylphenidate substantially decreased the activity of ADHD children who were objectively hyperactive, but exerted little effect on ADHD children not objectively hyperactive. Importantly, these results demonstrate that methylphenidate can exert differential effects that may vary with the biological/behavioral state of the subject and that ADHD symptoms may be closely associated with the functional abnormalities in the putamen, which is a structure mainly involved in the regulation of motor behavior. Anderson, C.M., et al., Functional Deficits in Basal Ganglia of Children with Attention-Deficit/Hyperactivity Disorder Shown with Functional Magnetic Resonance Imaging Relaxometry. Nature Medicine, 6(4), pp. 470 - 473, 2000.

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

Dr. Gary Swan of SRI International conducted 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, March 2000.

Opiates Have a Differential Modulating Role in the Hypothalamic-Pituitary-Adrenal Response Depending on the Presence of Stress

Dr. Yan Zhou in the laboratory of Dr. Mary Jeanne Kreek at the Rockefeller University assessed corticosterone (CORT), ACTH, and pro-opioimelanocortin (POMC) mRNA levels following administration of morphine or saline, and with or without access to water. Morphine (with free access to water) increased ACTH, CORT, and POMC in the hypothalamus while water restriction (and saline administration) increased only ACTH and POMC in the anterior pituitary. However, with morphine and restricted access to water, there were no changes in any of these parameters. Thus, it was concluded that the effects of morphine on HPA activation or POMC mRNA expression depend on the presence of stresses that may reflect a counter-regulatory role of opiates on the stress response and on opioid gene expression. Zhou,Y., Spangler, R., Maggos, C.E., Wang, X.M., Han, J.S., Ho, A. and Kreek, M.J. Hypothalamic-Pituitary-Adrenal Activity and Pro-opiomelanocortin mRNA Levels in the Hypothalamus and Pituitary of the Rat are Differentially Modulated by Acute Intermittent Morphine with or without Water Restriction Stress. Journal of Endocrinology, 163, pp. 261-267, 1999.

Continued Studies in Both Acute and Chronic "Binge" Administration of Cocaine or Morphine in Rats Demonstrate Changes in mRNA Levels and the Need for DARPP-32

Among the most recent findings in drug administration in rats by Dr. Mary Jeanne Kreek's Laboratory of the Biology of Addictive Diseases (Rockefeller University) was an increase in mRNA for _-opioid receptors in the frontal cortex, nucleus accumbens, and amygdala following acute (3 times in one day) "binge" administration of cocaine. Similar acute injections of morphine increased levels of m RNA for preprodynorphin and kappa opioid receptors. Following chronic cocaine administration (3 times a day for 14 days) the expected increases in either plasma ACTH or corticosterone were not seen in mice deficient in the DARRPP-32 gene. This suggests that this gene plays a role in mediating the stimulatory effects of cocaine on the HPA axis. Yuferov, V., Zhou, Y., Spangler, R., Maggos, C.E., Ho, A. and Kreek, M.J. Acute "Binge" Cocaine Increases mu-opioid Receptor mRNA Levels in Areas of the Rat Mesolimbic Mesocortical Dopamine System. Brain Research Bulletin, 48(1), 109-112, 1999; Wang, X.M., Zhou, Y., Spangler, R., Ho, A., Han, J.S. and Kreek, M.J. Acute Intermittent Morphine Increases Preprodynorphin and Kappa Opioid Receptor mRNA Levels in the Rat Brain. Molecular Brain Research, 66, pp. 184-187, 1999; Zhou, Y., Schlussman, S.D., Ho, A., Spangler, R., Fienberg, A.A., Greengard, P. and Kreek, M.J. Effects of Chronic "Binge" Cocaine Administration on Plasma ACTH and Corticosterone Levels in Mice Deficient in DARPP-32. Neuroendocrinology, 70, pp. 196-199, 1999.

Hormone Fluctuations Appear to Affect Cocaine Metabolism and Behavioral Response in Rat

In the Biology of Addictive Disease Laboratory (Rockefeller University) of Dr. Mary Jeanne Kreek, "binge" administration of cocaine increased plasma levels of the cocaine metabolite, benzoylecgonine, more during metestrus-diestrus than during estrus and proestrus. Stereotypic behavior and locomotion were also greater during the same period. Qui–ones-Jenab, V., Ho, A., Schlussman, S.D., Franck, J. and Kreek, M.J. Estrous Cycle Differences in Cocaine-Induced Stereotypic and Locomotor Behaviors in Fischer Rats. Behavioural Brain Research, 101, pp. 15-20, 1999.

A Synthetic Fragment of the Endogenous Peptide, Dynorphin, Could Possibly Be Utilized to Manage Cocaine Addiction and Enhance Pain Relief from Opiate Treatment

Dynorphin A1-13 was administered to healthy non-drug-abusing subjects by Dr. Mary Jeanne Kreek and her colleagues at the Rockefeller University to determine if it affects opioid receptors. Increased levels of prolactin, indicating reduced dopaminergic tone, followed different doses of dynorphin. Pretreatment with antagonists demonstrated the effect was likely due to _-opioid receptors and possibly _-opioid receptors. Another study showed this compound was well tolerated and produced modest, but transient, subjective responses. Finally, when administered to patients with chronic pain in conjunction with reduced opiate medication, some pain relief was noted. Kreek, M.J., Schluger, J., Borg, L., Gunduz, M. and Ho, A. Dynorphin A1-13 Causes Elevation of Serum Levels of Prolactin through an Opioid Receptor Mechanism in Humans: Gender Differences and Implications for Modulation of Dopaminergic Tone in the Treatment of Addictions. Journal of Pharmacology and Experimental Therapeutics, 288(1), pp. 260-269, 1999; King, A.D., Ho, A., Schluger, J., Borg, L., and Kreek, M.J. Acute Subjective Effects of Dynorphin A(1-13) Infusion in Normal Healthy Subjects. Drug and Alcohol Dependence, 54, pp. 87-90, 1999; Portenoy, R.K., Caraceni, A., Cherny, N.I., Goldblum, R., Ingham, J., Inturrisi, C.E., Johnson, J.H., Lapin, J., Tiseo, P.J. and Kreek, M.J. Dynorphin A(1-13) Analgesia in Opioid-Treated Patients with Chronic Pain: A Controlled Study. Clinical Pharmacodynamics, 17(1), pp. 33-42, 1999.

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