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National Institute on Drug Abuse

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

February 1997

Research Findings

Clinical and Services Research

Cigarette Smoking and Brain Monoamine Oxidase A Inhibition Dr. Joanna Fowler and colleagues at the Brookhaven National Laboratory compared brain monoamine oxidase A (MAO A) in nonsmokers and in smokers with [11C]clorgyline and positron emission tomography. Results revealed that tobacco smoke exposure was associated with a significant reduction in brain MAO A. These findings are similar to results obtained by this group showing a reduction of brain MAO B in smokers. Because MAO A inhibitors are effective antidepressants, the authors suggest that MAO A inhibition should be considered as a potential contributing factor in the high rate of smoking in depression as well as in the development of more effective strategies for smoking cessation. Fowler, J.S., Volkow, N.D., Wang, G.-J., Pappas, N., Logan, J., Shea, C., Alexoff, D., MacGregor, R. R., Schyler, D.J., Zezulkova, I., & Wolf, A.P. Brain Monoamine Oxidase A Inhibition in Cigarette Smokers. Proc. Natl. Acad. Sci., 93, pp. 14065-14069, 1996.

Smoking Increases Dose-Dependent [3H]-Nicotine Binding in Human Postmortem Brain
Dr. Sherry Leonard has demonstrated in human postmortem brain a significant increase in [3H]-nicotine binding in subjects who had life-long smoking histories until death. However, binding in life-time smokers who had quit at least two months prior to death did not differ from subjects who never smoked. Increased binding was observed in both hippocampus and thalamus and due to an increase in receptor number (Bmax), with no change in receptor affinity (Kd). Furthermore, among those who had life-long smoking histories, the number of binding sites was correlated with degree of smoking, as measured by average number of packs per day. Similar dose-dependent increases in brain nicotinic receptor numbers have been reported in rodents; this is the first reported in humans. The results suggest that increases in nicotinic receptor levels in the human brain may underlie nicotine tolerance and addiction in smokers. Breese, C.R., Marks, M.J., Logel, J., Adams, C.E., Sullivan, B. Collins, A.C., & Leonard, S. Effect of Smoking History on [3H]-Nicotine Binding in Human Postmortem Brain. J Pharm Exp Ther, In Press.

Linkage of 7-nicotinic Receptor to a Neurophysiological Deficit in Schizophrenia

Using a genome-wide linkage analysis, an auditory suppression deficit seen in most schizophrenic patients and many of their (non-schizophrenic) relatives, was linked to a dinucleotide polymorphism at chromosome 15q14, the site of the 7-nicotinic receptor. The deficit has to do with an abnormal suppression or gating of the evoked response to the second of paired auditory stimuli. This is one of several physiological markers that are associated with schizophrenic diagnosis. In rodents the deficit is normalized by selective stimulation of the 7-nicotinic receptor; high doses of nicotine in schizophrenics demonstrates similar normalization. Smoking is highly prevalent in schizophrenic patients, and it has been hypothesized that they may be self-medicating a neurophysiological deficit. These data support this notion, demonstrating a genetic link. Freedman, R., Coon, H., Mules-Worsley, M., Orr-Urtreger, A., Olincy, A., Davis, A., Polymeropoulos, M., Holik, J., Hopkins, J., Hoff, M., Rosenthal, J., Waldo, M.C., Reimherr, F., Wender, P., Yaw, J.,Young, D.A., Breese, C.R., Adams, C., Patterson, D., Adler, L.E., Kruglyak, L., Leonard, S., & Byerley, W. Linkage of a Neurophysiological Deficit in Schizophrenia to a Chromosome 15 Locus. Proceedings of the National Academy of Science, January 21, 1997.

Smoking Has a Differential Effect on Cognitive Performance and Electrophysiological Measures Depending on Task Difficulty Post-smoking response times improved (decreased) for simple "oddball" tasks, both auditory and visual, but only in smokers whose breath carbon monoxide levels did not change substantially after smoking. This was accompanied by an increase in P300 amplitudes in the visual condition only. However, smokers as a group (i.e., pooled for carbon monoxide changes) did not significantly differ in performance before and after smoking. By contrast, post-smoking response times worsened for a memory task for memory sets of 6 items. There was a concomitant decrease in P300 amplitudes and latency. These results suggest that cigarette smoking may have enhancing effects for simple tasks, but is detrimental to more complex tasks reflected both in cognitive performance and electrophysiological responses. Ilan, A.B., & Polich, J. The Effects of Smoking on ERPs in Simple and Demanding Tasks. Psychophysiology, 33, S47 (presented at the meetings of the Society for Psychophysiological Research, Vancouver, B.C., Canada), 1996.

LSD Effects on Brain Dr. Henry David Abraham of the Butler Hospital in Providence, RI recently published an article entitled "LSD-Like Panic from Risperidone in Post-LSD Visual Disorder" in the Journal of Clinical Psychopharmacology. Dr. Abraham found that there was an unanticipated worsening of visual symptoms and induction of panic anxiety in patients, who had taken LSD 4-20 years ago, given risperidone, an antagonist of the serotonin-2 receptor. The exacerbation of visual disturbances and flashback-like experiences suggests that LSD could act as an excitotoxin at serotonin-2 receptor, cause dysfunction of inhibitory cortical interneurons and result in disinhibition of visual processors.

Neuropsychological Functioning in Cocaine Abuse NIDA-funded researcher Dr. Tony L. Strickland, Ph.D., of Charles R. Drew University of Medicine & Science and the University of California at Los Angeles (UCLA) School of Medicine, presented preliminary findings from his ongoing NIDA-funded research study on neurobehavioral functioning among cocaine abusers at the National Academy of Neuropsychology Sixteenth Annual Meeting on November 1, 1996. The focus of this paper was on neuropsychological effects of chronic cocaine use following sustained abstinence. Subjects included 37 males and 34 female freebase cocaine abusers with verifiable abstinence of between 5 and 18 months. The sample was 72% African-American and 28% Euro-American with similar representation by gender. Statistical analyses revealed significant impairment on measures of attention-concentration, memory, academic achievement, with visuospatial, motor, language and executive functioning measures less consistently impaired. Interestingly, despite a substantial gender disparity in cocaine exposure, women appeared no more impaired on neuropsychological measures than men. Curiously, greater cocaine exposure did not appear to result in greater neuropsychological impairment. An abstract of the paper will be published in the journal Archives of Clinical Neuropsychology.

Beneficial Effects of Thiamine on Recognition Memory and P300 in Abstinent Cocaine Dependent Patients Researchers evaluated the effects of thiamine versus placebo on memory task performance and event-related electroencephalographic potentials in 8 abstinent cocaine dependent patients. Patients orally ingested 5 g of thiamine and 5 g of a lactose placebo on two separate days scheduled approximately one week apart. The order of administration was randomized. Double blind procedures were followed. Approximately three hours after ingesting the capsules, patients completed Stemberg's (1975) memory scanning task during which performance and event-related potentials (P300) were recorded simultaneously. Thiamine was found to significantly improve recognition accuracy and P300 amplitude, at the midline parietal (Pz) electrode. The improvement was most reliable under conditions of increased memory load. These preliminary findings justify a further examination of the relationship between thiamine's hypothesized effects on central nervous system cholinergic function, and the direct and indirect effects of cocaine alone. Eston, C. and Bauer, L. Psychiatry Research, In Press.

The Effects of Anabolic Steroids on Driving Performance as Assessed by the Iowa Driver Simulator Perry and his colleagues at the University of Iowa studied the effects of physiologic (100 mg/wk) and supraphysiologic (250 and 500 mg/wk) doses of testosterone cypionate (TC) on automobile driving using the Iowa Driver Simulator. Six normal subject volunteers were studied off TC and on TC once steady-state concentrations were achieved after at least three weeks of dosing. Despite the administration of supraphysiologic TC doses an increase in aggressive driving behavior was not detected. Likewise, corresponding psychometric testing using the Buss-Durkee Hostility Inventory to assess aggression was unable to detect any change in aggression in the test subjects. Aggressive driving behavior may be increased by testosterone administration as reported by others, but according to the authors, the drug itself may not be responsible for these effects. Since altered driving behavior may be multifactorial in nature, supraphysiologic doses greater than 500 mg/wk and a semi-controlled research environment may be necessary to produce these effects. Ellingwood V.L., Perry P.J., Yates W.R., MacInode W.R., Watson G., Arndt S., and Holman T.L., American Journal of Drug and Alcohol Abuse, In Press.

Evidence for a Sex-Specific Residual Effect of Cannabis on Visuospatial Memory
Pope and his colleagues at Harvard Medical School used a novel computerized battery of neuropsychological tests of attention to assess residual cognitive impairment in marijuana users. They compared 25 college students who were heavy marijuana smokers (who had smoked a median of 29 days in the last 30 days) with 30 students who were light smokers (who had smoked a median of 1 day in the last 30 days). All subjects were tested after a supervised period of abstinence from marijuana and other drugs lasting at least 19 hours. Although there were no significant differences between the overall heavy and light smokers on the four subtests of attention, marked and significant differences were found between heavy- and light-smoking women on the subtest examining visuospatial memory. On this test, subjects were required to examine a 6x6 "checkerboard" of squares in which certain squares were shaded. The shaded squares were then erased and the subject was required to indicate with the mouse which squares had formerly been shaded. Increasing numbers of shaded squares were presented at each trial. The heavy-smoking women remembered significantly fewer squares on this test, and they made significantly more errors than light-smoking women. These differences persisted despite different methods of analysis and consideration of possible confounding variables. The authors suggest that it may be important to study the residual effects of marijuana on men and women separately, particularly since women have been greatly under-represented in previous studies in this area. Pope, H.G. Jr., Jacobs, A., Mialet, J.P., Yurgelun-Todd, D., and Gruber, S. Psychotherapy and Psychosomatics, In Press.

Abnormal Cerebral Metabolism in Polydrug Abusers During Early Withdrawal: a 31P MR Spectroscopy Study
Mendelson and his colleagues (Harvard Medical School) performed phosphorus magnetic resonance spectroscopy (31P MRS) at 1.5 T on nine polysubstance abusing men. All nine patients met DSM-III-R criteria for concurrent cocaine and heroin dependence, were neurologically normal, were negative for the human immunodeficiency virus, and had normal clinical brain MRI scans. Patients were scanned 2-7 days after admission to a drug treatment unit. Eleven age-matched control subjects also were studied. The ISIS localized phosphorus spectra were obtained from a 5-cm thick axial brain slice and a 100-cc white matter volume. In the brain slice, the phosphorus metabolite signal expressed as a percentage of total phosphorus signal was 15% higher for phosphomonoesters, 10% lower for nucleotide triphosphates (beta-NTP), and 7% lower for total nucleotide phosphates in polydrug abusers compared with those in controls. Phosphodiesters, inorganic phosphate, phosphocreatine, total phosphorus, pH, and free magnesium concentration were unchanged. None of these parameters correlated with the methadone dose or the number of days abstinence. Single photon emission computed tomographic imaging of a subgroup of the patients revealed abnormal cerebral perfusion in 80% of the patients scanned. These data suggest that cerebral high energy phosphate and phospholipid metabolite changes result from long term drug abuse and/or withdrawal and that these changes can be detected and studied by 31P MRS. Christensen, J.D., Kaufman, M.J., Levin, J.M., Mendelson, J.H., Holman, B.L., Cohen, B.M., and Renshaw, P.F., Magnetic Resonance Medicine, 35(5): pp. 658-663, May 1996.

Divergent Effects of Cocaine on Cytokine Production by Lymphocytes and Monocyte/Macrophages Acute intravenous administration of cocaine in humans resulted in increased production of tumor necrosis factor alpha (TNFA) in lymphocytes but decreased production in macrophages. Transmigration of "memory" T lymphocytes was inhibited by cocaethylene in an in vitro model of the blood-brain barrier (BBB) composed of human brain microvascular cells and human fetal astrocytes. Added cocaethylene and TNFA significantly increased the permeability of the model BBB to HIV-1 in a time-and concentration-dependent manner. Fiala, M., Gan, X-H., Newton, T., Chiapelli, F., Shapshak, P., Kermani, V., Kung, M.A., Diagne, A., Martinez, O., and Graves, M. Advances in Experimental Medicine and Biology, 4(2): pp. 145-156, 1996.

Problem-Service "Matching" in Addiction Treatment
McLellan his colleagues have conducted a study to identify specific patient problems and to match professional services to those problems in four drug abuse treatment programs. Ninety-four new patients from an Employee Assistance Program entered treatment and were randomly assigned to either: Standard Treatment - patients were treated in the usual manner; or Matched Services - patients received at least three professional sessions directed at their significant employment, family, or psychiatric problems. Matched patients stayed in treatment longer, were more likely to complete treatment, and had better post treatment outcomes than patients receiving treatment as usual in these programs. The strategy of matching appropriate services to patients' specific treatment problems was clinically and administratively practical, attractive to patients, and responsible for a 20-30% increase in effectiveness. McLellan, A.T., Grissom, G.R., Zanis, D., Randall, M., Brill, P., and O'Brien, C.P. Problem-Service "Matching" In Addiction Treatment: A Prospective Study in Four Programs, Arch. Gen Psychiatry, In Press.

Risk Reduction Approach for Discharged Methadone Patients
In a study of discharged methadone patients, Zanis, McLellan, Alterman, and Cnaan randomly assigned methadone patients discharged 1 year earlier to either a standard referral condition (n=14) or an enhanced outreach counseling intervention (n=27) to determine if these high-risk patients could be re-engaged into treatment. Two weeks following the intervention, 17 (63%) of the patients assigned to the enhanced outreach condition and 1 (7%) of the patients in the standard condition had reenrolled in treatment. The authors conclude that this strategy may be an effective risk reduction approach for discharged methadone patients. It may also have further implications for outreach efforts. Zanis, D.A., McLellan, A.T., Alterman, A.I., & Cnaan, R.A. American Journal of Psychiatry, 153: pp. 1095-1096, 1996.

Effect of Maternal Substance Abuse on the Cost of Neonatal Care
Norton and his colleagues recently reported on a study of the effects of maternal substance abuse on the costs to neonatal care in 54 Maryland hospitals in 1991. Investigators controlled for individual hospital effects and correlated observations within hospitals. The findings suggest that exposure to drugs in newborns resulted in significantly higher total hospital charges at almost double those of non-exposed newborns (p <.01). The results demonstrated a consistent pattern of effects on charges, mortality, and resource use in the hospital of drug-exposed newborns due, in part, to longer lengths of stay and higher intensity care per day. Exposure to alcohol was found to be much less significant. The investigators suggest that their results confirm the policy concern that maternal substance abuse has severe consequences for the baby's health and that these cost are often borne by others. Norton, E.C., Zarkin, G.A., Calingaert, B. & Bradley, C.J. The Effect of Maternal Substance Abuse on the Cost of Neonatal Care, Inquiry, 33: pp. 247-257, 1996.

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