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Director's Report to the National Advisory Council on Drug Abuse
February, 1996

Research Findings

Clinical and Services Research

Improved Regional Cerebral Blood Flow in Chronic Cocaine Polydrug Users Treated with Buprenorphine

Since chronic cocaine and polydrug abuse has been associated with regional abnormalities in cerebral perfusion which could be partially reversible with buprenorphine (Holman et al., J Nucl Med, 34: pp. 723-727, 1993), the authors investigated separation of cerebral perfusion effects of abstinence from those of buprenorphine treatment. Fifteen cocaine and heroin dependent men (all part of an inpatient drug abuse treatment research program) were studied with 99mTC-hexamethylpropyleneamine oxime (HMPAO) brain SPECT. The subjects were randomly assigned after detoxification to receive placebo or either 6 or 12 mg daily buprenorphine treatment. SPECT studies were performed at baseline, after maximum dosage was reached, and after tapering of the drug. The number and location of perfusion defects were counted. Results showed that subjects receiving buprenorphine had a significant reduction in the number of defects between baseline and maximum buprenorphine dose as compared with placebo (4+5.4 decrease versus 4.8+4.7 increase, p=0.006). The differences were dose-related. However, improvement was temporary, with return to baseline after tapering off. Thus, data suggest that buprenorphine treatment, and not abstinence from drug use alone, leads to temporary improvement in regional cerebral perfusion abnormalities in chronic cocaine- and heroin-dependent men. Jonathan M. Levin, Jack Mendelson, B. Leonard Holman, Siew K. Teoh, Basem Garada, Richard B. Schwartz, and Nancy Mello. J. Nucl Med, 36(7), pp. 1211-1215, 1995.

The Residual Cognitive Effects of Heavy Marijuana Use in College Students.

According to the authors, heavy use of marijuana is associated with cognitive impairment in college undergraduate students. They enrolled two groups of students: 65 "heavy users" (38M,27F), who had smoked marijuana a median of 29 days in the past 30 days (range 22-30), and who also displayed cannabinoids in their urine; and 64 "light users" (31M,33F) who had smoked a median of 1 day in the last 30 days (range 0-9) and who displayed no urinary cannabinoids. All the subjects were assessed by several neuropsychological tests when they were abstinent from marijuana and other drug use for at least 19 hours before testing. The outcome measures were: general intellectual functioning, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Heavy users displayed significantly greater impairment than light users on attention/executive functions, as evidenced by greater preservations on card sorting and reduced learning of word lists. These differences remained after controlling for potential confounding variables, such as estimated levels of pre-morbid cognitive functioning, and for use of alcohol and other substances in the two groups. Whether this cognitive impairment is due to a residue of drug in the brain, a withdrawal effect from the drug or a frank neurotoxic effect of the drug, is not clear. Harrison G. Pope, Deborah Yurgelun-Todd. JAMA, in press. On the other hand, Block and Ghoneim [Psychopharmacology, 110: pp. 21-228, 1993] have also reported similar findings of impairment of cognition in adult marijuana abusers, and Fried reported impairment of attention/executive functioning in 9-12 year old children who were exposed prenatally to marijuana. Arch Toxicology, in press.

Subjective and Cardiovascular Responses to Nicotine Combined with Alcohol in Male and Female Smokers

The cardiovascular and subjective effects of nicotine and alcohol in combination have rarely been examined. Thus, the investigators enrolled 18 smokers (9 males, 9 females) [smoking rate of 17.7+0.5 cigarettes/day; 5.2+0.6 years] who were also moderate alcohol drinkers (15 drinks [50-250 g alcohol] per week). The subjects were given an acute administration of nicotine (20 ug/kg per presentation) or placebo by measured-dose nasal spray every 30 min. for 2 hours following consumption of diet tonic water with or without alcohol (0.5 g/kg). Subjective (visual analog scale, Profile of Mood States, Addiction Research Center Inventory) and cardiovascular (heart rate, systolic and diastolic blood pressure) were assessed. Nicotine increased head rush, dizziness, and most stimulant effects (i.e., jitteriness, tension, and arousal and decreased fatigue and relaxed state), while alcohol increased perceived intoxication, head rush, dizziness, and jitteriness, with no other stimulant effects. Nicotine and alcohol generally produced additive subjective and cardiovascular effects when consumed together, although nicotine attenuated sedating and intoxicating effects of alcohol alone. Further, there were several interaction effects on subjective measures involving gender. Nicotine plus alcohol tended to attenuate some subjective effects due to one drug or the other alone in men but enhanced the effects of either alone in women. These findings indicate that nicotine and alcohol generally have additive subjective and cardiovascular effects, but that men and women differentially respond on some subjective measures to the combination of alcohol and nicotine. Kenneth A. Perkins, J.E. Sexton, A. DiMarco, J.E. Grobe, A. Scierka, and R.L. Stiller. Psychopharmacology, 119: pp.205-212, 1995.

Acute Tolerance to Nicotine in Smokers: Lack of Dissipation within 2 Hours

In order to understand the development and dissipation of acute tolerance to nicotine and explain the temporal patterns of nicotine self-administration in smokers, the investigators examined the time course of dissipation of acute tolerance to nicotine (20 ug/kg by measured-dose nasal spray) in 16 smokers (8 males, 8 females). The smokers participated in four sessions differing on pretreatment exposure or time interval prior to nicotine challenge: placebo 30 min. before, or nicotine 30, 60, or 120 min. before challenge. Subjective, cardiovascular, thermal pain detection, and behavioral performance were measured. Significant acute tolerance was shown on most subjective measures and for heart rate. In contrast, nicotine pretreatment resulted in acute sensitization of finger temperature (vasoconstriction) response, which dissipated with lengthening interval. Acute tolerance did not develop on thermal detection and behavioral performance measures. These findings demonstrate that acute tolerance develops quickly to some subjective and cardiovascular effects of nicotine. However, acute tolerance to most effects did not dissipate over 2 hours, suggesting that, following acute tolerance development during initial exposure, most smokers generally obtain similar magnitude of effects from each subsequent nicotine exposure [i.e., cigarettes smoked later in the day]. Kenneth A. Perkins, J.E. J.E. Grobe, Shari L. Mitchell, Jennifer Goettler, Anthony Caggiulla, Richard Stiller, and Annette Scierka. Psychopharmacology, 118: pp.164-170, 1995.

Drive to Smoke and Dopamine Blockade

Dr. Joseph McEvoy and colleagues from Duke University Medical Center conducted a study in which ten patients with schizophrenia participated in 120-minute free-smoking sessions when actively psychotic and free of antipsychotic medications, and again after the initiation of haloperidol, a classical antipsychotic drug. The study showed that schizophrenic patients smoke more when treated with haloperidol than during a medication-free state. Preliminary evidence exists that shows that smoking decreases in patients switched from haloperidol to the atypical antipsychotic clozapine. Further work in a larger cohort with a more longitudinal study design is now underway. Haloperidol Increases Smoking in Patients with Schizophrenia, Psychopharmacology, 1995; and Clozapine Decreases Smoking in Patients with Chronic Schizophrenia, Society of Biological Psychiatry, 1995.

Coping with Depression in Smoking Cessation

Dr. Richard A. Brown and colleagues from Butler Hospital, employing a randomized, two-group designed study, compared standard smoking cessation treatment and standard smoking cessation treatment plus cognitive-behavioral treatment for depression in smokers with a history of major depressive disorder. Preliminary results suggest that adding cognitive-behavioral treatment for depression to standard smoking cessation treatment for smokers with a history of MDD results in significant posttreatment effects on smoking outcomes. However, these effects have not been maintained at longer term follow-up. It appears that a higher potency of treatment intended to address depressive symptoms and negative mood may be necessary for a full treatment response in this at risk group of smokers.

Neurobehavioral Functioning Among Cocaine Abusers

Dr. Tony L. Strickland, of the Charles R. Drew University of Medicine & Science, presented preliminary findings from his ongoing NIDA-funded research study on neurobehavioral functioning among cocaine abusers of different ethnic backgrounds at the National Academy of Neuropsychology Fifteenth Annual Meeting held in San Francisco, CA on November 1-3, 1995. Ninety-seven subjects (32 black females, 16 black females, 26 white females, 13 white males) have been evaluated in accordance with the study protocol, which includes measures of prior drug utilization, psychosocial and neuropsychological functioning, and brain structure and blood flow. Preliminary analyses revealed significant neuropsychological impairment on measures of memory, learning, and attention, but unimpaired functions on measures of language and visuoperceptual functioning. Neuroimaging (MRI) showed no abnormalities except in one subject with a small lesion in the basal ganglia. MRS data showed no significant differences between male and female cocaine users in both the gray and white matter regions.

Maternal Psychological Distress and Development of Cocaine-Exposed Infants

New evidence from NIDA-supported research at Case Western Reserve University supports the importance of examining both direct toxic effects and indirect effects (e.g., parental functioning) when studying the influence of maternal drug use during pregnancy on infant development. In this project, cocaine-exposed and non-exposed infants and their mothers are being followed longitudinally from birth. Postpartum psychological distress (measured by the Brief Symptom Inventory) was higher in the cocaine-using women. Using hierarchical multiple regression analysis to assess the relative effects of gestational age, psychological distress, and maternal cocaine use, both cocaine exposure and maternal postpartum psychological distress had independent negative effects on infant cognitive outcomes (Bayley Scales) in the second year of life. Prenatal cocaine exposure also marginally predicted motor outcome on the Bayley Scales, whereas maternal psychological distress was unrelated to infant motor outcome. This project is continuing its longitudinal examination of maternal psychological factors, as well as maternal substance use, on the outcomes of the offspring. Singer, L., Arendt, R., Minnes, S., et al. Increased Psychological Distress in Post-Partum, Cocaine-Using Mothers. Journal of Substance Abuse, 7: pp.165-174, 1995; Singer, L., Farkas, K., Arendt, et al. Maternal Cocaine Use and Psychological Distress Affect Infant Development Outcome. Pediatric Research, 34: p. 272A, 1995.

Behavior Therapy for Substance Abusers

Eighty two adult and older adolescent (17%) subjects were enrolled in a study designed to assess the efficacy of a behavioral approach (i.e., combined elements of urge control training, behavioral contracting, and imaginal rehearsal of consequences of drug use) through a randomized comparison with a group discussions/peer support condition that focused on the expression of thoughts and feelings associated with drug use. Results suggest the behavioral condition is more effective in reducing drug use 12 months after entry into treatment, and more effective across gender, age, educational level, and type of drug used (e.g., opiate; cocaine; marijuana). Greater improvement was also noted in subjects enrolled in the behavioral intervention on measures of school/employment attendance, family relationships, and number of contacts with the police. Azrin NH, McMahon PT, Donohue B, Besalel VA, Lapinski KJ. Behav. Res. Ther. 32(8): pp. 857-866, 1994.

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