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Director's Report to the National Advisory Council on Drug Abuse
February, 2002

Research Findings

Treatment Research and Development

Motivational Interviewing with Cocaine-Dependent Patients: A Pilot Study

Drs. Stotts, Schmitz, Rhoades, and Grabowski at the University of Texas Medical School at Houston, evaluated a brief Motivational Interviewing (MI) intervention for cocaine-dependent patients during an outpatient detoxification program prior to entry to a relapse prevention treatment study. In this study, 105 cocaine dependent patients (84 men and 21 women) were randomly assigned to the MI intervention or the detox-only conditions. Findings from this pilot study indicate that although the participants completed the detoxification program at equal rates, completers who received the MI intervention increased use of behavioral coping strategies and had fewer cocaine positive urine samples on beginning the primary treatment. MI patients with lower initial motivation were more likely to complete detoxification. These findings support the use of Motivational Interviewing with cocaine-dependent patients and provide the impetus for further MI treatment research with this population. Stotts, S.L., Schmitz, J.M., Rhoades, H.M., and Grabowski, J. Journal of Consulting and Clinical Psychology, 69(5), pp. 858-862, 2001.

Fluoxetine Treatment of Cocaine-Dependent Patients with Major Depressive Disorder

Dr. Joy Schmitz and Colleagues at the University of Texas at Houston examined the efficacy of fluoxetine treatment for cocaine dependent patients with major depressive disorder. Sixty-eight male and female patients with both DSM-IV diagnoses of cocaine dependence and major depressive disorder were randomly assigned to one of two medication conditions (placebo vs. 40 mg per day) as part of a double-blind, placebo-controlled clinical efficacy trial of fluoxetine for the treatment of this dual diagnosis. During the 12-week outpatient treatment phase all participants also received individual cognitive-behavioral psychotherapy targeting both the cocaine use and the depression. Depressive symptoms remitted as a function of time in treatment, with no significant medication effects found. Fewer cocaine positive urines were found during the first 6 weeks of treatment in the placebo group compared with the 40 mg group. Cocaine use and depressive symptoms during treatment were significantly correlated. These findings fail to support the role of fluoxetine for treatment of cocaine use and depression in dually-diagnosed patients. Schmitz, J.M., Averill, P., Stotts, A.L., Moeller, F.G., Rhoades, H.M., and Grabowski, J. Drug and Alcohol Dependence, 1: 63(3), pp. 207-214, August 2001.

Exposure Therapy in the Treatment of PTSD Among Cocaine-Dependent Individuals: Preliminary Findings

In a study conducted by Dr. Kathleen Brady and Colleagues, Medical University of South Carolina, 39 individuals participated in an outpatient, 16 session individual, manual-guided psychotherapy designed to treat concurrent Posttraumatic Stress Disorder and cocaine dependence. Therapy consisted of a combination of imaginal and in-vivo exposure therapy techniques to treat PTSD symptoms and cognitive-behavioral techniques to treat cocaine dependence. Although the dropout rate was high, treatment completers (i.e., patients who attended at least 10 sessions; n= 15) demonstrated significant reductions in all PTSD symptom clusters and cocaine use from baseline to end of treatment. Significant reductions in depressive symptomatology, as measured by the Beck Depression Inventory, and psychiatric and cocaine use severity, as measured by the Addiction Severity Index, were also observed. These improvements in PTSD symptoms and cocaine use were maintained over a 6-month follow-up period among treatment completers. The average pre- to post treatment effect size was 1.80 for PTSD symptoms and 1.26 for drug and alcohol use severity. Baseline comparisons between treatment completers and noncompleters revealed significantly higher avoidance symptoms, as measured by the Impact of Events Scale, and fewer years of education among treatment non-completers as compared to completers. This study provides preliminary evidence to suggest that exposure therapy can be used safely and may be effective in the treatment of PTSD in some individuals with cocaine dependence. However, this study is limited by the uncontrolled nature of the study design, small number of subjects, and high drop out rate. Brady, K.T., Dansky, B.D., Back, S.E., Foa, E.B., and Carroll, K.M. Journal of Substance Abuse Treatment, 21(1), pp. 47-54, 2001.

Influence of Antisocial Personality Subtypes on Drug Abuse Treatment Response

Dr. King and colleagues, Johns Hopkins University, examined the impact of antisocial personality disorder and other psychiatric comorbidity on drug use and treatment retention in 513 new admissions to methadone maintenance treatment. Patients were classified into one of four groups: antisocial personality disorder only (APD), antisocial personality disorder plus other psychiatric disorder (APD Mixed) other psychiatric disorder, and no psychiatric disorder. Patients completed research assessments and were then followed for one year of treatment. Patients with APD had longer histories of heroin and cocaine use than non-APD patients and were more likely to meet criteria for cocaine dependence. Distinct clinical profiles emerged that differentiated APD Only from APD Mixed. APD Only patients exhibited higher rates of cocaine and heroin use, whereas those with APD Mixed exhibited higher rates of benzodiazepine use. Self-report measures supported urinalysis results, but group differences did not affect treatment retention. These differences in clinical profiles should be considered when evaluating treatment performance in substance abusers with antisocial personality disorder. King, V.L., Kidorf, M.D., Stoller, K.B., Carter, J.A., and Brooner, R.K. Journal of Neurological and Mental Dis., 189(9), pp. 593-601, 2001.

Tobacco Use and Quit Attempts Among Methadone Maintenance Clients

Dr. Kimber Richter at the University of Kansas conducted a survey in a 4-county metropolitan area to establish the prevalence of cigarette smoking and interest in quitting among methadone clients. Findings show that 77% of the clients smoked cigarettes. Three quarters of the current smokers had attempted to quit at least once, with an average of 5 attempts. Most smokers (80%) were very or somewhat interested in quitting. The quit ratio among methadone maintenance treatment clients was 12 %, compared with 50% nationwide. The authors suggest that future research into smoking behaviors and viable treatment options for methadone maintained clients is important.
Richter, K.P., Gibson, C.A., Ahluwalia, J.S., and Schmelzle, K.H. American Journal of Public Health, 91, pp. 296-299, 2001.

Acupuncture for the Treatment of Cocaine Addiction

A large multi-site study was conducted to investigate the effectiveness of auricular acupuncture as a treatment for cocaine addiction. Six-hundred and twenty cocaine-dependent adults, who were addicted to cocaine alone or to both cocaine and opiates and were receiving methadone maintenance, were randomized to one of three conditions: auricular acupuncture, a needle-insertion control, or a relaxation control. All patients also received drug counseling. Results showed that there was a significant overall reduction in cocaine use, but no differences by treatment condition. There were also no differences between the conditions in treatment retention. The authors conclude that this study does not support the use of acupuncture as a stand-alone treatment for cocaine addition or when patients receive only minimal concurrent psychosocial treatment. They suggest that further research is needed to examine acupuncture’s contribution to addiction treatment. Margolin, A., Kleber, H.D., Avants, S.K., Konefal, J., Gawin, F., Stark, E., Sorensen, J., Midkiff, E., Wells, E., Jackson, T.R., Bullock M., Culliton, P.D., Boles, S., Vaughan, R. JAMA, 287, pp. 55-63, 2002.

Enhanced Cognitive-Behavioral HIV Prevention Intervention for Adolescents Abusing Alcohol and Other Drugs

Dr. Robert Malow and colleagues at the University of Miami have designed an intervention to reduce HIV risk behaviors among adolescents in inpatient substance abuse treatment. An initial efficacy study showed that, compared to a Health-Promotion group intervention, an enhanced cognitive-behavioral intervention produced significantly better condom use skills and more favorable attitudes toward condoms. Malow, Deviux, and Rosenberg, Addictions Newsletter, 8, pp. 2 –14, 2001.

Buprenorphine Treatment of Pregnant Opioid-dependent Women: Maternal and Neonatal Outcomes

Researchers at the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine reported an open-label prospective study that examined maternal and neonatal safety and efficacy outcome measures during and following prenatal buprenorphine exposure. Three opioid-dependent pregnant women received 8 or 12 mg sublingual buprenorphine tablets daily for 15-16 weeks prior to delivery. Results showed that buprenorphine in combination with comprehensive prenatal care was safe and effective in these women. Prenatal exposure to buprenorphine resulted in normal birth outcomes, a mean of 4.33 days (minimum possible=4) hospitalization, and a 'relatively mild' neonatal abstinence syndrome comprised primarily of tremors (disturbed), hyperactive moro and shortened sleep after feeding. The infants required no pharmacological treatment. Onset of neonatal abstinence signs occurred within the first 12 h after birth, peaked by 72 h and returned to below pre-12 h levels by 120 h. It is concluded that buprenorphine has potential utility for the treatment of pregnant opioid-dependent women. Johnson, R.E., Jones, H.E., Jasinski, D.R., Svikis, D.S., Haug, N.A., Jansson, L.M., Kissin, W.B., Alpan, G., Lantz, M.E., Cone, E.J., Wilkins, D.G., Golden, A.S., Huggins, G.R., and Lester, B.M. Buprenorphine Treatment of Pregnant Opioid--Dependent Women: Maternal and Neonatal Outcomes. Drug Alcohol Depend, 63(1), pp. 97-103, 2001.

Enadoline, A Selective Kappa Opioid Agonist: Comparison with Butorphanol and Hydromorphone in Humans

The availability of the highly selective and specific kappa opioid agonist enadoline provides an opportunity to explore the function of kappa receptors in humans and their potential utility as a target for substance abuse pharmacotherapy development. The purpose of this study was to characterize the pharmacodynamic effects of enadoline, a selective kappa agonist, and to compare it with butorphanol, a mixed mu/kappa agonist, and hydromorphone, a mu agonist, in humans. Pilot evaluation (n=3) served to establish intramuscular doses of enadoline (20, 40, 80, and 160 microg/70 kg), butorphanol (1.5, 3, 6, and 12 mg/70 kg), and hydromorphone (1.5, 3, and 6 mg/70 kg) of comparable activity. These acute doses were examined under double-blind, placebo-controlled and constrained randomized conditions with a minimum of 72 h between tests in volunteers with polysubstance abuse histories (n=6). Physiological and subject- and observer-rated measures were collected 30 min before and for 4 h after administration. The results showed that enadoline significantly increased measures of sedation, confusion and dizziness, produced visual distortions and feelings of depersonalization, and increased urinary output. The highest dose (160 microg/70 kg) was not tolerated and led to psychotomimetic effects. Hydromorphone produced prototypic mu opioid effects including respiratory depression, miosis, and euphoria. Butorphanol was most similar to hydromorphone and shared few effects with enadoline. These results provide information with respect to the potential use and safety of kappa agonists for clinical indications. Walsh, S.L., Strain, E.C., Abreu, M.E., and Bigelow, G.E. Enadoline, A Selective Kappa Opioid Agonist: Comparison with Butorphanol and Hydromorphone in Humans. Psychopharmacology (Berl), 157(2), pp. 151-162, 2001.

Enadoline and Butorphanol: Evaluation of Kappa-agonists on Cocaine Pharmacodynamics and Cocaine Self-administration in Humans

Preclinical studies have demonstrated that kappa-opioid agonists can attenuate the neurochemical and behavioral effects of cocaine that are related to its reinforcing efficacy, suggesting that kappa-agonists may serve as pharmacotherapies for cocaine dependence. This 8-week inpatient study examined the ability of enadoline, a selective and high-efficacy kappa-agonist, and butorphanol, a mixed agonist with intermediate efficacy at both mu- and kappa-receptors, to reduce the direct pharmacodynamic effects and self-administration of intravenous cocaine in humans (n = 8). Acute doses of intramuscular enadoline (20, 40, and 80microg/kg), butorphanol (1.5, 3, and 6 mg/70 kg) and placebo were examined separately as pretreatments during each of three test sessions with cocaine in a constrained random order. A cocaine dose-effect session (0, 20, and 40 mg cocaine i.v., 1 h apart) examined direct pharmacodynamic interactions on subjective and physiological indices; self-administration sessions examined choice behavior for cocaine (40 mg i.v. for six trials) versus money 1) in the presence of a sample cocaine dose with money choices presented in ascending value, and 2) in the absence of a sample dose with money choices presented in descending values. Enadoline (80 microg/70 kg) significantly (p < 0.05) reduced some of the positive subjective effects of cocaine (e.g., ratings of "high"), while butorphanol failed to modify subjective responses. Both agents were safely tolerated in combination with cocaine without adverse physiological responses. Cocaine self-administration was significantly greater across all pretreatment conditions when the sample dose was given and ascending money choices were used. Enadoline and butorphanol failed to modify cocaine self-administration. These data suggest that these kappa-agonists may be safely administered in the presence of cocaine but do not produce significant attenuation of cocaine's direct effects or self-administration under these acute dosing conditions. Walsh, S.L., Geter-Douglas, B., Strain, E.C., Bigelow, G.E. Enadoline and Butorphanol: Evaluation of Kappa-agonists on Cocaine Pharmacodynamics and Cocaine Self-administration in Humans. J Pharmacol Exp Ther., 299(1), pp. 147-158, 2001.

Human Therapeutic Cocaine Vaccine: Safety and Immunogenicity

The safety and immunogenicity of a therapeutic cocaine vaccine, TA-CD, was assessed in a randomized, double blind, phase I clinical trial conducted in 34 former cocaine abusers. The patients received a course of 3 injections of 13 ug, 82 ug, or 709 ug of vaccine over the course of 2 months. In a one-year follow-up study on 15 patients, antibody levels correlated with vaccine dose and number of injections. Antibody levels peaked at 3 months and declined to baseline by 1 year. The vaccine was well tolerated and had no serious drug-related adverse events. This group speculates that TA-CD will be most effective for relapse prevention in cocaine abusers who are motivated to maintain abstinence, as it is likely that some subjects may attempt to overcome the anti-cocaine antibody effect through use of sufficiently large amounts of cocaine. TA-CD may be most effective at reducing the priming effect of using small amounts of cocaine. Kosten, T.R., Rosen, M., Bond, J., Settles, M., St. Clair Roberts, J., Shields, J., Jack, L., and Fox, B. Human Therapeutic Cocaine Vaccine: Safety and Immunogenicity. Vaccine, 2959, pp. 1-9, 2001.

Low Level of DA D2 Receptors in Methamphetamine Abusers Associated with Metabolism in Orbitofrontal Cortex.

Drs. Nora Volkow, Linda Chang, and colleagues at the Brookhaven National Laboratory conducted a positron emission tomography (PET) study to explore the association between low levels of dopamine D2 receptors and reduced levels of metabolism in the orbitofrontal cortex of methamphetamine abusers. Twelve abstinent methamphetamine abusers were scanned and compared to normal, matched controls, and results showed that dopamine D2 receptors were significantly lower in caudate and putamen. This measure was correlated with decreased metabolism in the orbitofrontal cortex. Similar reductions in D2 receptors have also been observed in cocaine-, alcohol-, heroin-dependent individuals as well as in pathologically obese individuals. It was concluded that brain changes may contribute to compulsive drug taking and the inability to stop. Volkow, N.D., Chang, L., et al., American Journal of Psychiatry, 158, pp. 2015-2021, 2001.

Dopamine Transporter Loss in Methampetamine Abusers Recovers in Protracted Abstinence

Studies in methamphetamine abusers have revealed significant loss of dopamine transporters (DATs) in methamphetamine abusers (MAs). The question of predisposition to neurodegenerative disorders, such as Parkinson’s disease, is unclear and may depend on the nature and degree of recovery. The purpose of this study by Drs. Volkow, Chang and colleagues was to determine the effects of protracted abstinence on the loss of DATs in the striatum using PET in MAs at both 6 weeks and again at 6 months, as well as on performance on a battery of neuropsychological tests. Study results showed significant recovery (16-19%) of DATs in striatum after prolonged abstinence (at least 9 months). Neuropsychological evaluation revealed slight improvement on some tests; however, these results were not significant. This lack of behavioral improvement did not parallel the neurobiologic recovery observed suggesting that the increase in DATs was not sufficient for complete recovery. Volkow, N.D., Chang, L., et al., Journal of Neuroscience, 21(23), pp. 9414-9418, 2001.

Context of Uncertainty Modulates Subcortical Response to Predictability

Dr. Berns and colleagues at Emory University School of Medicine used BOLD fMRI to investigate regional brain activity associated with both increases and decreases in predictability. Normal, healthy humans were presented with four horizontally arranged square stimuli and were told to press a key when one of the squares was illuminated in a specific color. A repetitive, i.e. predictable, spatial sequence of varying predictability was embedding in a larger random sequence. Activations in the right dorsolateral prefrontal cortex and the right caudate nucleus were positively correlated with increasing predictability, whereas the left posterior parietal cortex exhibited a negative correlation. The activation in the caudate nucleus exhibited an order effect, i.e., the caudate was activated only during transitions from high to low predictability but not from low to high predictability. Thus, activation of the caudate nucleus in response to changes in predictability is sensitive to the larger context of such changes. Bischoff-Grethe et al., J. Cognitive Neuroscience, 13(7), pp. 986-993, 2001.

Beautiful Faces Have Variable Reward Value

Dr. Breiter and colleagues at the NMR Center of Massachusetts General Hospital used BOLD fMRI to map the brain areas activated during presentation of human faces that varied in attractiveness. Subjects were healthy normal heterosexual males. One group of subjects provided a subjective rating for each face for attractiveness. A second group of subjects were presented with the same faces and were required to keep pressing a key in order to keep the face on the display. Thus, the amount of key presses provided a behavioral index of attractiveness that complemented the subjective ratings. There was a dissociation between the subjective and behavioral measures in that male and female faces were both rated as attractive, but more key presses were made to keep the female faces visible than the male faces. A third group of subjects was presented passively with the faces during the fMRI scans. Passive viewing of beautiful female faces activated the same network of brain regions previously observed during cocaine administration and monetary rewards. Prominent among these regions is the nucleus accumbens, basal forebrain, ventral tegmental area, and orbitofrontal cortex. In addition, activation of this set of paralimbic and subcortical regions was more related to key-press behavior than the subjective ratings. These results suggest that activity in this reward network reflect factors other than the aesthetic assessments. These data provide further evidence for a generalized reward network in the human brain. Breiter et al., Neuron, 32, pp. 1-20, 2001.

Networks in Brain Responding to the Hedonic Value of Stimuli

Dr. Breiter and colleagues at the NMR Center of Massachusetts General Hospital used BOLD fMRI to map the brain areas activated during presentation of noxious thermal stimuli. Heating the skin to 46o C activated two different networks of brain regions. One network corresponds to structures comprising classical pain pathways. The second network was similar to the areas previously observed during presentation of stimuli with hedonic value including cocaine administration, monetary rewards, and attractive human faces. Prominent among these regions is the nucleus accumbens, basal forebrain, and ventral tegmental area. There was also dissociation in these two networks with respect to the time course of activation. The regions in the reward network exhibited an early peak of activation whereas the structures in the classical pain pathways exhibited a relatively delayed peak in activation. These data suggest that regions in a network in the human brain respond to the net hedonic value of a stimulus, whether rewarding or aversive. Breiter et al., Neuron, 32, pp. 927-946, 2001.

Comparison of Three Decision-Making Tasks in Cocaine Abusers

Dr. Monterosso and colleagues at the Treatment Research Center of the University of Pennsylvania tested the relationship between 3 different decision-making tasks. Cocaine-dependent subjects were tested on an outpatient basis before entry to a treatment program. Subjects were tested on a delayed discounting task where they had to choose between smaller-sooner rewards and larger-later rewards, the Bechara Gambling Task that requires choices involving small rewards associated with small punishments versus large rewards associated with large punishments, and the Rogers Decision-Making Task that requires choices based on higher or lower probability gambles. Drug abusers have previously been shown to be impaired on each of these tasks, but it is unclear whether these tasks test the same underlying cognitive process. Performance on the delayed discount task was positively correlated with Gambling Task performance, but performance on neither of the two tasks was correlated with performance on the Rogers Decision-Making Task. However, performance on these two tasks was weakly correlated with reaction times on the Roger’s Decision-Making task. On the other hand, there was no relationship between performance on these tasks and a psychometric index of impulsivity (Zuckerman Sensation Seeking Scale). These data suggest that there is a partial commonality to the cognitive functions assessed by these three tasks, possibility related to processing of delayed reward or assessment of risk, but that this functionality is not related to a common personality measure of impulsivity. Monterosso et al., Addiction, 96, pp. 1825-1837, 2001.

Neuropsychological Performance in Long-Term Cannabis Users

Drs. Pope, Yurgelun-Todd, and colleagues at McLean Hospital investigated whether long-term, heavy marijuana smokers exhibited residual cognitive impairments. Three groups of subjects were given a battery of neuropsychological tests. The first group consisted of current heavy users, who had smoked cannabis and, who were smoking daily at study entry. The second group consisted of former heavy users, who had smoked fewer than 12 times in the last 3 months. The third group consisted of control subjects, who had smoked no more than 50 times in their lives. Subjects underwent 28-day washout from cannabis use. Marijuana use was observed by urine samples. On days 0, 1, 7, and 28, subjects were administered neuropsychological test battery to assess general intellectual function, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Current heavy users scored significantly below control subjects on recall of word lists early during the first week of the abstinence period (days 0, 1 and 7). This performance deficit was associated with users' urinary cannabinoid concentrations at study entry. There were virtually no significant differences among the groups on any of the test results by the end of 28-day abstinence period, however. There were also no significant associations between cumulative lifetime cannabis use and test scores. Thus, heavy marijuana use does not appear to lead to long-term residual cognitive deficits. Rather, memory impairments in heavy cannabis users appear to be reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use. Pope et al., Arch Gen Psychiatry, 58, pp. 909-1015, 2001.

Positive Subjective Effects are Enhanced when Smoking Marijuana after Drinking Ethanol

Drs. Lukas and Orozco of McLean Hospital have found that individuals who smoke marijuana after ethanol had increased levels of THC in plasma compared to those who had placebo ethanol but only on the rising part of the curve. Once THC reached peak levels, there was no difference among groups with respect to THC levels at several measured intervals. Subjective effects were also affected following ethanol, but these were dependent somewhat on the strength of the marijuana dose. For those with a heavier ethanol (0.7 g/kg), latency to marijuana effects increased significantly with the increase of THC strength, but the number of euphoric events decreased, as did the duration of the euphoria. By contrast, those with half the ethanol dose (0.35 g/kg), did not differ from those with placebo ethanol in latency to effect, but had increasing numbers and duration of euphoric events with increased THC strength. (Those with placebo ethanol also had increasing number and duration of euphoria but significantly less.) These results are opposite to a previous report where prior marijuana reduced the psychoactive effects of ethanol. Importantly and in contrast, the results indicate why the combination of these drugs is popular in natural settings. Lukas, S.E. and Orozco, S., Drug Alcohol Depend., 64, pp. 143-149, 2001.

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