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Director's Report to the National Advisory Council on Drug Abuse
February, 2001

Research Findings

Treatment Research and Development

Task Persistence Predicts Success at Smoking Cessation

Dr. Thomas Brandon and colleagues at the University of South Florida conducted a study to determine if persistence on frustrating tasks predicts success at quitting smoking among patients in a standard smoking cessation program. Task persistence was assessed in 144 smokers by measuring mean time spent solving difficult anagrams and time spent tracing geometric figures viewed through a mirror. Following smoking cessation treatment, subjects were followed for 12 months. Results indicated that the anagram and mirror tracing measures of persistence were negatively correlated with nicotine dependence. Further, persistence on the mirror-tracing task predicted successful treatment outcome. Individuals who exhibited greater task persistence were more successful at maintaining abstinence. Nath, V., Juliano, L.M., Lazev, A.B., Irvin, J.E., Stavros, R.A., Herzog, T.A. and Brandon, T.H. Paper presented at Association for the Advancement of Behavior Therapy, New Orleans, November 2000.

Tobacco Withdrawal in Women and Menstrual Cycle Phase

This study examined tobacco withdrawal, mood measures, and menstrual discomfort in 78 premenopausal women who quit smoking during either the follicular (days 1-14 postmenstrual onset) or luteal (day 15+ postmenstrual onset) phase of the menstrual cycle. Women quitting during the luteal phase reported significantly greater increases in tobacco withdrawal and self-reported depressive symptoms than women quitting during the follicular phase. Results indicate that in order to attenuate withdrawal and negative affect in female smokers, they should consider selecting a quit-smoking day early in the follicular phase. Perkins, K.A., Levine, M.D., Marcus, M.D., Shiffman, S., D'Amico, D., Miller, A., Keins, A., Ashwom, J., and Broge, M. Journal of Consulting and Clinical Psychology, 68, pp. 176-180, 2000.

Toward a Developmental Family Therapy: The Clinical Utility of Research on Adolescence

Dr. Howard Liddle and colleagues at the University of Miami focus on selected determinants of adolescent growth and development and discuss how this knowledge can have a direct and clinically useful impact on the design of treatment. The authors describe how an understanding of normative processes and developmental psychopathology in adolescent-parent relationships (e.g., attachment; conflict), biological maturation (e.g., puberty; sexuality) and cognitive development (concrete versus abstract thinking) informed the development of multidimensional family therapy for drug abusing youth. Liddle, H. A., Rowe, C., Diamond, G., Sessa, F.M., Schmidt, S. and Ettinger, D. Journal of Marital and Family Therapy, 26 (4), pp. 485-500, 2000.

A Multivariate Process Model of Adolescent 12-Step Attendance and Substance Use Outcome Following Inpatient Treatment

Dr. Mark Myers and colleagues at the University of California, San Diego, examined (1) the relationship between attendance at community-based 12-step meetings and substance use outcome after discharge from an inpatient drug treatment program and (2) a process model of how 12-step attendance affects motivation, coping and self-efficacy which, in turn, affects substance use outcome. Adolescents (N=99; 14-18 years; 60% female) were assessed at 3 and 6 months post-treatment. Results indicate modest beneficial effects of 12-step attendance that were mediated by motivation-for-abstinence but not by abstinence-focused coping or by feelings of self-efficacy. Although average attendance dropped considerably during the second 3-month period, abstainers attended approximately twice as many 12-step meetings during the first 3 months as did adolescents who relapsed. Myers, M.G., Brown, S.A. and Kelly, J.F. Psychology of Additive Behaviors, 14(4), pp. 376-389, 2000.

Comparing LAAM, Buprenorphine and Methadone

A 17-week randomized study of 220 patients compared three times a week levomethadyl acetate (LAAM, 75 to 115 mg) and buprenorphine (16 to 32 mg), and daily high-dose (60 to 100 mg) and low-dose (20 mg) methadone as treatments for opioid dependence. 51 percent of subjects completed the trial. LAAM, buprenorphine, and high-dose methadone substantially reduced the use of illicit opioids compared with low-dose methadone. 12 or more consecutive opioid-negative urine specimens occurred in 36% of the LAAM group, 26% of the buprenorphine group, 28% of the high-dose methadone group, and 8% of the low-dose methadone group (P=0.005). The mean (SE) number of days that a patient remained in the study was significantly higher for those receiving LAAM (896), buprenorphine (964), and high-dose methadone (1054) than for those receiving low-dose methadone (704, P<0.001). Continued participation in the study was also significantly more frequent among patients receiving high-dose methadone than among those receiving LAAM (P=0.02). Johnson R.E., Chutuape, M.A. Strain, E.C., Walsh, S.L., Stitzer, M.L. and Bigelow, G.E. A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence. N Engl J Med, 343(18), pp 1290-1297, 2000.

Elevated Liver Enzymes with Buprenorphine and a History of Hepatitis

Liver enzyme levels were evaluated among 120 individuals before treatment and following a minimum of 40 days of buprenorphine treatment (2, 4, or 8 mg/70 kg/day). Among patients with a history of hepatitis, AST and ALT levels significantly increased (p < .05). The odds of observing an increase in AST were dependent upon buprenorphine dose (p < .05; odds ratio = 1.23 per 1 mg increase in dose). These results suggest that liver enzyme levels should be monitored carefully when patients with hepatitis are treated with buprenorphine. Petry, N.M., Bickel, W.K., Piasecki, D., Marsch, L.A. and Badger, G.J. Elevated Liver Enzyme Levels in Opioid-Dependent Patients with Hepatitis Treated with Buprenorphine. Am J Addict, 9(3), pp. 265-269, 2000.

Thrice Weekly Versus Daily Buprenorphine Maintenance

Retention was 71% in the daily and 77% in the 3x/week conditions. The proportion of opioid-positive urine tests decreased significantly from baseline in both groups and averaged 57% (daily) and 58% in 3x/week. There were no significant differences between groups in self-reported number of bags of heroin used for any day of the week, or in medication compliance (92%, 91%) and counseling attendance (82%, 82%). At an equivalent weekly dose of 112 mg/70 kg, thrice-weekly and daily sublingual buprenorphine appear comparable in efficacy with regard to retention and reductions in illicit opioid and other drug use. Schottenfeld, R.S., Pakes, J., O'Connor, P., Chawarski, M., Oliveto, A., and Kosten, T.R. Biol Psychiatry, 47(12), pp 1072-1079, 2000.

Disulfiram Treatment for Cocaine Dependence

Preliminary results in 15 completers showed that the total number of weeks abstinent from cocaine was significantly greater on disulfiram than on placebo (mean +/- SD: 7.8 +/- 2.6 vs. 3.3 +/- 0.5, p <.05) and the number of days to achieving 3 weeks of continuous cocaine abstinence was significantly lower with disulfiram than with placebo (24.6 +/- 15.1 vs. 57.8 +/- 7.7, p <.01). The number of cocaine-negative urine tests during the trial were also higher on disulfiram (14.7) than on placebo (8.6); furthermore, subjects in the disulfiram group achieved consistently higher rates of cocaine-negative urine tests in each 3-week interval and the increase over time was faster in the disulfiram group. George, T.P., Chawarski, M.C., Pakes, J., Carroll, K.M., Kosten, T.R. and Schottenfeld, R.S. Disulfiram vs Placebo for Cocaine Dependence in Buprenorphine-Maintained Subjects: A Preliminary Trial. Biol Psychiatry, 47(12), pp 1080-1086, 2000.

Initiating Cocaine Abstinence with $100

On Monday of the test week, 72 cocaine-abusing methadone patients were offered a $100 voucher if urine samples collected on Wednesday indicated that they had abstained from cocaine across that 2-day period. Overall, 79% of study patients showed urinalysis evidence of abstention from cocaine between Monday and Wednesday of the test week. In a sub-sample with complete data (n = 50), almost all patients (94%) decreased their benzoylecgonine concentration from Monday to Wednesday of the test week, a significantly greater percent than decreased the week before (56%) or after (48%) the test week. Furthermore, significantly more patients abstained from cocaine from Monday to Wednesday of the test week (84%) than the week before (36%) or after (32%). This highly efficacious procedure may have clinical application where reliable abstinence initiation is desired, either on a temporary basis (e.g. sobriety sampling) or at the start of longer-term interventions. It may also be possible to use the brief abstinence test as an experimental model to assess the effects of other therapeutic interventions on abstinence initiation in treatment settings. Robles, E., Silverman, K., Preston, K.L., Cone, E.J., Katz, E., Bigelow, G.E., and Stitzer, M.L. The Brief Abstinence Test: Voucher-Based Reinforcement of Cocaine Abstinence. Drug Alcohol Depend, 58(1-2), pp. 205-12, 2000.

Quitting Spit Tobacco with Transdermal Nicotine

In withdrawal from spit tobacco, nicotine patch was effective in increasing short-term abstinence compared to placebo patch, and in reducing craving and withdrawal signs and symptoms. Mint snuff reduced craving and withdrawal symptoms, but was not effective in enhancing treatment outcome. Hatsukami, D.K., Grillo, M., Boyle, R., Allen, S., Jensen, J., Bliss, R., and Brown, S. Treatment of Spit Tobacco Users with Transdermal Nicotine System and Mint Snuff. J Consult Clin Psychol, 68(2), pp. 241-249, 2000.

Minors Purchase Snuff at Corporate- and Independently-Owned Convenience Stores

Two underage males attempted to purchase moist snuff at each of 90 convenience stores. Two corporate owned chains with the largest number of convenience stores were selected (n = 45), along with a random sample of 45 independently owned convenience stores that held current tobacco licenses. Overall, underage buyers were sold snuff on one out of four purchase attempts. Sales occurred significantly more often in independent stores (35.6%) than in corporate stores (13.3%). An important variable associated with sales was whether the store clerk requested identification. Hanson, K., Hatsukami, D., Boyle, R. and Brown, S. Addict Behav, 25(2), pp. 289-293, 2000.

fMRI Study of Cocaine Craving

Dr. H. Garavan and colleagues at the Medical College of Wisconsin presented cocaine abusers and healthy comparison subjects with videotapes showing cocaine use, heterosexual activity, or nature scenes during BOLD fMRI scans. Cocaine users exhibited activations in the frontal cortex, parietal cortex, insula, anterior cingulated and posterior cingulated. Similar regional activations were seen during presentation of the sexual tape in both cocaine abusers and comparison subjects. In the cocaine users only 3 regions (anterior cingulate, insula, and parietal cortex) showed larger activations to the cocaine video compared to the sexual video. Cocaine users exhibited less activation to the sexual tape compared to the control subjects. Results suggest that cocaine craving is not associated with a unique neuroanatomical circuit, but that drug cues are more evocative than sexual stimuli for cocaine abusers. Garavan, H. et al., American Journal of. Psychiatry, 157, pp. 1789-1798, 2000.

Stress Imagery and Drug-Cue Imagery both Induce Similar Psychological and Physiological Reactivity

Dr. Sinha and colleagues report that personalized imagery of a stressful situation and of a drug cue situation that had been followed by taking cocaine both induce increased cocaine craving, subjective anxiety, heart rate and cortisol levels compared a neutral image. In addition increases in negative emotions (e.g., sadness, anger, fear) and decreases in positive emotions (e.g., joy) were also reported by the subjects. These results support the hypothesis that psychological stress-induced and drug cue-induced craving produce similar patterns of psychobiological activation. One implication for treatment would be that the craving state would be a reasonable target for intervention. Sinha, R., Fuse, T., Aubin, L.-R. and O'Malley, S.S. Psychopharmacology, 152, pp. 140-148, 2000.

Brain, Blood and Hair GHB Concentrations Following Fatal Ingestion

Dr. Stephen J. Kish and colleagues reported post mortem results of brain, blood and hair levels of the club drug, gamma-hydroxybutyrate (GHB), in a 22-year old woman, who died following a single GHB exposure. This case report confirmed the drug exposure through analysis of her blood and brain, and analysis of her hair indicated an absence of GHB or any other drugs of abuse in the hair segments, suggesting that the subject was not a chronic user of GHB or other drugs. GHB is a CNS depressant that has been used to induce anesthesia, treatment of narcolepsy, and for opiate and alcohol withdrawal. It has been used as a food supplement and by bodybuilders for its supposed enhancement of growth hormone release. GHB recently has been used as a sexual assault drug, as at specific doses it causes amnesia. This drug is becoming more and more widely used as a drug of abuse. Importantly, this report reinforces the finding, which is generally not widely appreciated, that GHB alone can result in overdose death, and it clearly points to the dangers of this drug.

Effect of Cocaine Administration on MRS in Basal Ganglia

Dr. Christensen and colleagues at McLean Hospital used proton MRS to assay the effect of intravenous cocaine administration on water and metabolite concentrations in the basal ganglia in cocaine abusers. Cocaine, but not placebo, produced dose-dependent increases in choline-containing compounds and N-acetylaspartate (a neuronal marker). Christensen, J.D. et al., Biological Psychiatry, 48, pp. 685-692, 2000.

Buprenorphine Changes in mu-Opioid Receptor Availability in Heroin Addicts

Using (11-C) carfentanil as a radiotracer in a PET study to assay mu opioid receptors Dr. Zubieta and colleagues at Wayne State Univ, studied male heroin-dependent subjects undergoing treatment with buprenorphine. Heroin users had greater opioid receptor binding availability in the orbitofrontal cortex and anterior cingulate compared to healthy comparison subjects during placebo studies. Buprenorphine produced dose-dependent reductions in opioid receptor availability. Zubieta, J. et al., Neuropsychopharmacology, 23, pp. 326-334, 2000.

MDMA Abuse and High-Risk Sexual Behaviors in Gay Men

Dr. R. Klitzman and colleagues of Columbia University had gay and bisexual men in 3 New York City dance clubs complete an anonymous questionnaire. About 33% reported using MDMA at least monthly. MDMA use was strongly correlated with a history of unprotected sexual activity, even after controlling for age, ethnicity, and other forms of drug abuse (including alcohol). Klitzman, R. et al., American Journal of Psychiatry, 157, pp. 1162-1164, 2000.

Cocaine Plus/Minus Alcohol on Neurocognitive Performance

Dose-related effects of cocaine on the CNS, with or without chronic alcohol use, were measured by performance on a battery of neurobehavioral tests. Fifty-six chronic cocaine users were evaluated following 1-3 days of enforced abstinence and again after 4 wks of abstinence. In addition to using cocaine, approximately half of the volunteers reported consuming more than 10 alcohol-containing drinks per week. After controlling for the effects of age, sex, and intelligence on performance, dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose were found. When the influences of cocaine and alcohol on neurobehavioral performance were taken separately, cocaine and alcohol each selectively affected performance on different neurobehavioral tests after 1-3 days of abstinence, with these effects persisting after 4 wks of abstinence. Bolla, K.I., Funderburk, F.R., and Cadet, J.L. Differential Effects of Cocaine and Cocaine + Alcohol on Neurocognitive Performance. Neurology, 54(12), pp. 2285-2292, 2000.

Review of Clinical Studies of MDMA on Serotonin-Induced Neurotoxicity

(+)3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a brain serotonergic neurotoxin in experimental animals, including nonhuman primates. It is also an increasingly popular recreational drug of abuse, and doses of MDMA that are used recreationally overlap with those that produce serotonin [5-hydroxytryptamine (5-HT)] neurotoxicity in animals. This article reviews findings from clinical studies of MDMA-induced serotonin neuro-toxicity. Studies in human MDMA users probing for evidence of brain serotonergic neurotoxicity show that some MDMA users may incur MDMA-related 5-HT neural injury and, possibly, functional sequelae. MDMA users have selective decrements in cerebrospinal fluid 5-hydroxyindoleacetic acid and brain 5-HT transporters, similar to nonhuman primates with documented MDMA-induced neurotoxicity. Functional abnormalities seen in MDMA users that may be related to 5-HT injury include cognitive deficits, altered sleep architecture, altered neuroendocrine function, altered behavioral responses to 5-HT selective drugs, and increased impulsivity. McCann, U.D., Eligulashvili, V., and Ricaurte, G.A (+)3,4-Methylenedioxymethamphetamine ('Ecstasy')-induced Serotonin Neurotoxicity: Clinical Studies. Neuropsychobiology, 42(1), pp. 11-16, 2000.

Review of Animal Studies of MDMA on Serotonin-Induced Neurotoxicity

The popular recreational drug, (+)3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a potent and selective brain serotonin [5-hydroxytryptamine (5-HT)] neurotoxin in animals. MDMA-induced 5-HT neurotoxicity can be demonstrated using a variety of neurochemical, neuroanatomical and, more recently, functional measures of 5-HT neurons. Although the neurotoxic effects of MDMA in animals are widely accepted, the relevance of the animal data to human MDMA users has been questioned, largely because dosages of drugs used in animals are perceived as being much higher than those used by humans. In the present paper, the authors review the extensive body of data showing that MDMA produced toxic effects on brain 5-HT neurons in animals and present new data indicating that levels of the type 2 vesicular monoamine transporter are reduced in MDMA-treated animals, providing further indication of MDMA's 5-HT neurotoxic potential. Further, the authors show, using principles of interspecies scaling, that dosages of MDMA known to be neurotoxic in animals fall squarely in the range of dosages used typically by recreational MDMA users. Ricaurte, G.A., Yuan, J., and McCann, U.D. (+)3,4-Methylenedioxymethamphetamine ('Ecstasy')-induced Serotonin Neurotoxicity: Studies in Animals. Neuropsychobiology, 42(1), pp. 5-10, 2000.

Improvement in Gambling Behavior was Seen Following a Randomized, Double-Blind, Crossover Study Using the Selective Serotonin Reuptake Inhibitor (SSRI), Fluvoxamine

Dr. Hollander and associates at Mt. Sinai School of Medicine entered advertisement-recruited and referral subjects into a 16-week double-blind study using measures of gambling urge and gambling behavior as outcome variables to determine the effect of the SSRI, fluvoxamine. Co-morbid disorders (including drug abuse) were excluded; the subjects did not undergo concomitant psychosocial or supportive therapies. Subjects taking either the placebo or SSRI during the first 8 weeks improved but those taking placebo during the second 8 weeks (having switched from SSRI) got worse while the SSRI subjects continued to improve. These data suggest that this SSRI can be effective in treating pathological gambling - a form of addiction. While the study, was limited in sample size and the elimination of common comorbid disorders (e.g., drug abuse), it is a first step in discovering the underlying mechanisms involved in addictive disorders. Hollander, E., DeCaria, C.M., Finkell, J.N., Begaz, T., Wong, C.M. and Cartwright, C. Biological Psychiatry, 47, pp. 813-817, 2000.

Two Approaches Using Reusable Gel Pad Microarray were Developed to Search for Expression of Single Nucleotide Polymorphisms (SNPs)

Dr. Mary Jeanne Kreek and her colleagues at Rockefeller University collaborated with Dr. Mirzabekov of Argonne National Laboratory to develop an assay that uses a gel-pad microarray to determine the genotype of the mu opioid receptor gene in human DNA samples. They tested the genotype of the coding region, looking for the presence of two naturally occurring single nucleotide polymorphisms (SNPs). Gel-pad microarray technology is unique because the arrays are reusable. This study is significant because methods of genotyping using arrays are still being developed and are generally prohibitively expensive. The use of reusable arrays might reduce the cost significantly, making genotyping assays rapid and routine. LaForge, K.S., Shick, V., Spangler, R., Proudnikov, D., Yuferov, V., Lysov, Y., Mirzabekov, A., and Kreek, M.J. Amer. J. Med. Genet., 96, pp. 604-615, 2000.

Sequence Variants of the Opioid Preceptor Gene OPRM1 were Associated with Substance Dependence

In a study carried out, in part by Dr. Berrettini and colleagues, all known functionally relevant regions of the OPRM1 gene were analyzed by multiplex sequence comparison in 250 cases and controls. Forty-three variants were identified and 52 different haplotypes predicted in a subgroup of African-Americans. By clustering techniques, the haplotypes were classified by similarity into two groups, one of which was significantly more frequent in substance-dependent individuals. The following were characteristic variants among these individuals: -1793T→A, -1699Tins, -1320A-G, -111C-T, +17C-T(A6V). This study is important because it provides a successful example of associating gene pattern variants with a substance abusing phenotype. Hoehe, M.R., Kopke, K., Wendel, B., Rohde, K., Flachmeier, C., Kidd, K.K., Berrettini, W.H., and Church, G.M. Hum Mol Genet, 9(19), pp. 2895-2908, 2000.

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