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

Research Findings

Treatment Research and Development

National Costs of Heroin Dependence

The MEDSTAT Group, Inc. in Washington, D.C. evaluated the costs of heroin addiction in the United States, both to the addict and society at large. Using a cost-of-illness approach, costs were estimated in four broad areas: medical care, lost productivity, crime, and social welfare. In 1996 the estimated cost of heroin addiction in the United States was US$21.9 billion. Of these costs, productivity losses accounted for approximately US$11.5 billion (53%), criminal activities US$5.2 billion (24%), medical care US$5.0 billion (23%), and social welfare US$0.1 billion (0.5%). The large economic burden resulting from heroin addiction highlights the importance of investment in prevention and treatment. Mark, T.L., Woody, G.E., Juday, T., and Kleber, H.D. The Economic Costs of Heroin Addiction in the United States. Drug Alcohol Depend, 61, pp. 195-206, 2001.

Treatment Costs with Buprenorphine/Naloxone Combination

Investigators from the Yale University School of Medicine evaluated the potential economic impact of the buprenorphine/naloxone combination in the context of practice in the United States. In comparison to treatment provided through methadone clinics, buprenorphine/naloxone therapy in office practice may be associated with increased medication, physician, and nursing costs, but reduced costs for dispensing, toxicology screens, counseling and administration. It may also result in markedly reduced costs for patients; especially travel costs, resulting in net savings for society as a whole. A review of controlled studies suggests that buprenorphine/naloxone is not likely to be any more or less effective than methadone, but since it will be less expensive in the long run, it may be more cost-effective than methadone when provided to comparable groups of patients. Because of the convenience of office-based treatment, buprenorphine/naloxone may increase access to opiate substitution for some addicts. To the extent that treatment is provided to additional high-cost patients who are involved in extensive criminal activity or who undergo multiple detoxifications each year, net cost savings could be substantial. To the extent that treatment is extended to better adjusted addicts who are employed, married and experience fewer adverse effects from their addiction, costs could increase. The total cost impact will depend on which addict sub-populations make greatest use of the treatment opportunity presented by buprenorphine/naloxone. Rosenheck, R., and Kosten, T. Buprenorphine for Opiate Addiction: Potential Economic Impact. Drug Alcohol Depend., 63, pp. 253-262, 2001.

Bupropion Does Not Alter Subjective Effects of Cocaine

The antidepressant drug bupropion shares some pharmacological features with cocaine and was proposed as a potential medication for the treatment of cocaine dependence. Investigators from Yale University School of Medicine examined interactions between this drug and cocaine in humans. The effects of cocaine were evaluated prior to and during bupropion maintenance in nonopioid-dependent cocaine abusers. Prior to bupropion maintenance, subjects underwent an experimental session during which repeated cocaine doses (0, 50, 100 mg/70 kg) were administered intranasally. Then subjects were maintained on bupropion (150 and 300 mg per day) and underwent experimental sessions as before. Cocaine, regardless of bupropion, produced dose-related increases in several stimulant-like self-reports, performance and cardiovascular measures. Bupropion decreased POMS ratings of friendliness and vigor, regardless of cocaine dose. Bupropion enhanced and attenuated cocaine-induced increases in ratings on the LSD and BG subscales of the ARCI, respectively. These results suggest that bupropion does not alter the acute subjective or cardiovascular effects of cocaine in a robust manner. Oliveto, A., McCance-Katz, F.E., Singha, A., Petrakis, I., Hameedi, F., and Kosten, T.R. Effects of Cocaine Prior to and During Bupropion Maintenance in Cocaine-Abusing Volunteers. Drug Alcohol Depend, 63, pp. 155-167, 2001.

Pergolide Found Not Useful for Cocaine Dependence

Investigators from the Medical University of South Carolina in Charleston conducted a double blind, multiple dose comparison study of pergolide versus placebo for the treatment of cocaine dependence. The study participants included 255 patients who met criteria for cocaine dependence without comorbid alcohol dependence. The completion rates significantly favored placebo (48.9%) over the low dose (33.3%) and high dose (21.5%) pergolide subjects. Treatment effectiveness scores were significantly higher for the placebo group (31.7) than for the low dose (25.2) and high dose (14.2) pergolide groups. There were no significant differences in side effect profiles after first dose of pergolide or placebo, or at study termination. Results suggest that pergolide is not efficacious in the treatment of cocaine dependence; therefore caution regarding the outpatient use of pergolide in similar populations is warranted. Malcolm, R., Herron, J., Sutherland, S.E., and Brady, K.T. Adverse Outcomes in a Controlled Trial of Pergolide for Cocaine Dependence. J Addict Dis, 20, pp. 81-92, 2001.

Fluoxetine Found Not Effective for Depression and Cocaine Dependence in Addicts

Investigators from the Substance Abuse Research Center, University of Texas Medical School Houston evaluated efficacy of antidepressant fluoxetine in the treatment of depression and cocaine dependence in cocaine addicts. Sixty-eight male and female individuals 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 cocaine use and 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. The 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. Fluoxetine Treatment of Cocaine-Dependent Patients with Major Depressive Disorder. J. Drug Alcohol Depend, 63, pp. 207-214, 2001.

The D1 Receptor Antagonist Ecopipam Enhanced the Subjective Effects of Cocaine

Investigators from the Columbia University Medical School, NY, examined the efficacy of a dopamine D1 antagonist in the treatment of cocaine dependence, because animal and human studies suggested that drugs from this class decrease cocaine self-administration and block cocaine's discriminative stimulus and subjective effects. The influence of the selective D1 antagonist, ecopipam (SCH 39166), on the reinforcing, cardiovascular, and subjective effects of cocaine in humans was examined. Ten non-treatment-seeking cocaine smokers residing on an inpatient research unit were maintained on placebo and ecopipam (100 mg p.o.) in random order using a within-subjects, crossover design. Cocaine self-administration (0, 12, 25, and 50 mg) was tested beginning on the 5th day of each 8-day maintenance condition. A six-trial choice procedure (cocaine vs. $5 merchandise vouchers) was utilized, with sessions consisting of one sample trial, when participants smoked the cocaine dose available that day, and five choice trials, when participants chose between smoking the available cocaine dose or receiving one merchandise voucher. In the presence of cocaine placebo, ecopipam significantly decreased cocaine craving while increasing alcohol and tobacco craving. In the presence of active cocaine, ecopipam increased cocaine self-administration (12 mg) and increased ratings of "good drug effect," "high," "stimulated," and dose quality (25 and 50 mg). Ecopipam produced small but significant increases in blood pressure, regardless of cocaine dose. Authors concluded that maintenance on the long-acting D1 antagonist enhanced cocaine self-administration and its subjective effects compared to placebo. These data suggest that chronic antagonism of the dopamine D1 receptor may not be a useful approach for the treatment of cocaine abuse. Haney, M., Ward, A.S., Foltin, R.W., and Fischman, M.W. Effects of Ecopipam, a Selective Dopamine D1 Antagonist, on Smoked Cocaine Self-Administration by Humans. Psychopharmacology (Berl), 155, pp. 330-337, 2001.

Naltrexone with Relapse Prevention Therapy Helpful in the Treatment of Cocaine Dependence

Investigators from the University of Texas Medical School-Houston evaluated in a double-blind, placebo-controlled clinical trial the joint action of naltrexone (NTX) in combination with relapse prevention (RP) therapy for the treatment of cocaine dependence. Eighty-five participants who achieved initial abstinence during the intake evaluation and detoxification phase of the study were randomized into 1 of 4 combined NTX (0 vs. 50 mg) by therapy (RP vs. Drug Counseling) experimental conditions for the 12-week outpatient treatment phase of the study. A random effects regression model to test for group differences on percentage of cocaine-positive urines indicated a significant time by medication by therapy interaction, suggesting less cocaine use over time among subjects receiving RP-50 mg naltrexone than by those in the other conditions. No differences were found for retention or time until first cocaine-positive urine. Naltrexone was well tolerated by participants and medication compliance was satisfactory. These results are consistent with the notion that substance use in dependent patients can be reduced with a combination of coping skills training and pharmacologic treatments. Naltrexone and Relapse Prevention Treatment for Cocaine-Dependent Patients. Schmitz, J.M., Stotts, A.L., Rhoades, H.M., and Grabowski, J. Addict Behav, 26, pp.167-180, 2001.

Psychotherapy for Comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and Psychoactive Substance Use Disorder (PSUD)

Investigators from Columbia University Medical School suggest that relapse prevention is an appropriate initial treatment for cocaine addicts with ADHD because it is well suited to manage both substance abuse and comorbid symptomatology such as impulsivity, distractibility, and avoidance. ADHD is one of the most common comorbid diagnoses with PSUD, and it is important that efficacious psychotherapies be developed to complement psychopharmacological approaches. Clinicians should consider psychotherapy as part of a multimodal treatment approach that includes medication and perhaps family therapy. Aviram, R.B, Rhum, M., and Levin, F.R. Psychotherapy of Adults with Comorbid Attention-Deficit/Hyperactivity Disorder and Psychoactive Substance Use Disorder. J Psychother Pract Res, 10, pp. 179-186, 2001.

Bupropion Worsens Mood during Marijuana Withdrawal

Investigators from the Columbia University Medical School, NY, examined symptoms of withdrawal after daily marijuana smoking, which include increased irritability and depression. Similar mood symptoms are reported by cigarette smokers during nicotine abstinence. Given the successful use of sustained-release bupropion in treating nicotine dependence, they investigated how maintenance on bupropion influenced symptoms of marijuana withdrawal compared to maintenance on placebo. Ten marijuana smokers were maintained outpatient on active (300 mg/day) or placebo (0 mg/day) bupropion for 11 days, and were then maintained inpatient on the same bupropion dose for 17 days. For the first 4 inpatient days, participants smoked active marijuana [2.8% delta9-tetrahydrocannabinol (THC)] 5 times/day. For the remaining inpatient days, they smoked placebo marijuana (0.0% THC) 5 times/day. Participants were then maintained outpatient on the alternate dose of bupropion for 11 days, followed by a second inpatient residential stay, paralleling the first. Medication administration was double-blind. Mood, psychomotor task performance, food intake, and sleep were measured daily during each inpatient phase. Bupropion had few behavioral effects when participants smoked active marijuana. During marijuana withdrawal, ratings of irritability, restlessness, depression, and trouble sleeping were increased by bupropion compared to placebo maintenance. These data suggest that bupropion does not show promise as a potential treatment medication for marijuana dependence. Haney, M., Ward, A.S., Comer, S.D., Hart, C.L., Foltin, R.W., and Fischman, M.W. Bupropion SR Worsens Mood during Marijuana Withdrawal in Humans. Psychopharmacology (Berl),155, pp. 171-179, 2001.

Cognitive Therapy and Brain Perfusion Deficits

Cognitive behavior therapy is currently a mainstay of treatment for cocaine dependence. It is a complex learning process with a goal of formation of new relationships between mood, thought, and behavior. The capacity to respond to such "psychosocial" intervention is largely dependent on a patient's cognitive flexibility. The investigators from the Yale University Medical School proposed that changes in cognitive function that occur during the period of early recovery from heavy drug abuse are multi-determined, reflecting alterations at many levels of regulation of cerebral function. Previous studies demonstrated deficits in neuropsychological performance and abnormalities in brain perfusion or metabolism in chronic cocaine abusers, which improve during abstinence. Cerebral perfusion was chosen as a marker for recovery from cocaine's complex pharmacological effects, which outlast its serum half-life. Investigators hypothesized that a measure of change in cerebral perfusion during early abstinence from cocaine will correlate with a measure of the capacity to learn new behavior and they presented several cases, which demonstrate an association between the response to cognitive behavior therapy and improvement in cerebral perfusion. This correlation encourages systematic clinical studies of the relationship between cerebral perfusion and the response to cognitive therapy in recovery from cocaine dependence. Gottschalk, C., Beauvais, J., Hart, R., and Kosten, T. Clinical Case Conference Cognitive Function and Cerebral Perfusion During Cocaine Abstinence. Am J Psychiatry, 158, pp. 540-545, 2001.

Propranolol May Reduce Symptoms of Autonomic Arousal Associated with Early Cocaine Abstinence and Improve Treatment Outcome

Investigators from the University of Pennsylvania School of Medicine and the Department of Veterans Affairs Medical Center in Philadelphia evaluated the utility of propranolol in the treatment of cocaine dependence in an 8-week, double-blind, placebo-controlled trial in 108 cocaine dependent subjects. The primary outcome measure was quantitative urinary benzoylecgonine levels. Secondary outcome measures included treatment retention, addiction severity index results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms, and adverse events. Propranolol treated subjects had lower cocaine withdrawal symptom severity but otherwise did not differ from placebo treated subjects in any outcome measure. However, in a secondary, exploratory analysis, subjects with more severe cocaine withdrawal symptoms responded better to propranolol in comparison to placebo. In these subjects, propranolol treatment was associated with better treatment retention and lower urinary benzoylecgonine levels as compared with the placebo treatment. Propranolol may be useful only for the treatment of cocaine dependent patients with severe cocaine withdrawal symptoms. Kampman, K.M., Volpicelli, J.R., Mulvaney, F., Alterman, A.I., Cornish, J., Gariti, P., Cnaan, A., Poole, S., Muller, E., Acosta, T., Luce, D., and O'Brien, C. Effectiveness of Propranolol for Cocaine Dependence Treatment May Depend on Cocaine Withdrawal Symptom Severity. Drug Alcohol Depend, 63, pp. 69-78, 2001.

The Therapeutic Workplace is an Efficacious and Self-Sustaining Treatment for Heroin and Cocaine Addicts

Dr. Silverman at Johns Hopkins University School of Medicine conducted a study that integrated abstinence reinforcement into a work setting, using salary that drug abusers earn for work to reinforce drug abstinence. Patients are paid to work, but they must provide drug-free urine samples to gain daily access to the workplace. In Phase 1 of this study, each participant's "job" is to work in a job skills training program where they are paid in vouchers exchangeable for goods and services. Results showed that Phase I effectively promoted long-term abstinence from heroin and cocaine in poor, chronically unemployed pregnant and postpartum women. In Phase 2, successful participants were hired as regular employees of a real income-producing business. Participants must still provide drug-free urine samples to maintain access to the workplace each day, but in this phase they earn regular paychecks instead of vouchers. Findings from Phase 2, suggest that the therapeutic workplace business could be financially feasible and self-sustaining. As well as being utilized for unskilled and chronically unemployed people, the therapeutic workplace intervention could be applied to treat drug-addicted individuals who are skilled and already employed. In addition, the therapeutic workplace could be created around different types of jobs and businesses. Silverman, K., Wong, C.J., Svikis, D., Stitzer, M.L., and Bigelow, G.E. The Therapeutic Workplace: A Promising Treatment for Heroin and Cocaine Addiction among the Chronically Unemployed. In Proceedings of 2001 ONDCP International Technology Symposium: Counterdrug Research and Development: Technologies for the Next Decade.

Alcohol Dependence Among Cocaine-Dependent Outpatients: Demographics, Drug Use, Treatment Outcome and Other Characteristics

In this study data were obtained from 302 adults (70% men) enrolled in outpatient treatment for cocaine dependence. Individuals who did and those who did not meet criteria for alcohol dependence were compared on demographics, drug use, treatment outcome and other variables. With regard to cocaine use, alcoholics were more likely than non-alcoholics to report an intranasal route of administration, use of cocaine in social settings, more simultaneous use of cocaine and alcohol, and more adverse consequences of their cocaine use. With regard to alcohol use, alcoholics reported consuming alcohol more frequently and in larger amounts, had longer drinking histories, and were more likely than non-alcoholics to report increases in alcohol consumption when using cocaine. Alcoholics were heavier cigarette smokers than non-alcoholics and reported more severe employment, legal, family, and psychiatric problems. There were overall improvements in both groups from intake through 12 months after treatment. With regard to treatment retention and cocaine abstinence, alcoholics had better outcomes than non-alcoholics when treated with intensive behavioral counseling plus incentives, but the reverse was true when treated with control treatments. Compared with nonalcoholic cocaine dependent subjects, codependent patients exhibit a wider array of problems, many of which merit treatment attention. This study underscores the importance of a comprehensive treatment approach for the significant majority of cocaine dependent patients who are also dependent on alcohol or nicotine. Heil, S.H., Badger, G.J., and Higgins, S.T. Journal of Studies on Alcohol, 62, (1), pp. 14-22, 2001.

The Effectiveness of Incentives in Enhancing Treatment Attendance and Drug Abstinence in Methadone-Maintained Pregnant Women

In this study Dr. Hendree Jones and colleagues at Johns Hopkins University examined the effectiveness of short-term contingency management for eliminating cocaine use and increasing full day treatment attendance with pregnant methadone-maintained women randomly assigned to either an escalating voucher incentive schedule (n=44) or non-incentive (n=36) condition. Full day treatment attendance and urine toxicologies for cocaine and heroin were assessed for 14 days. The escalating voucher incentive schedule significantly increased full day treatment attendance and drug abstinence compared to the non-incentive schedule. These findings suggest that reinforcing the co-occurrence of two required behaviors (treatment attendance and abstinence from illicit drug use) is effective, and may be an important adjunct to methadone pharmacotherapy for treating pregnant drug dependent women. Jones, H., Haug, N., Silverman, K., Stitzer, M. and Svikis, D. Drug and Alcohol Dependence, 61, pp. 297-306, 2001.

Clinical and Psychosocial Characteristics of Substance-Dependent Pregnant Women with and without PTSD

This study compared psychiatric and psychosocial functioning in 123 pregnant opiate- and/or cocaine-dependent women with and without a comorbid diagnosis of posttraumatic stress disorder (PTSD). Participants were enrolled in a comprehensive perinatal drug treatment program and completed assessments upon admission. Lifetime diagnostic prevalence of PTSD (Structured Clinical Interview for DSM-IV Disorders (SCID) confirmed) among the sample was 19%. Participants with PTSD (n=24) reported greater need for psychiatric treatment, were more likely to report a previous suicide attempt, and had more previous drug treatments than participants without PTSD (n=99). Women with PTSD were twice as likely to have lifetime Axis I and Axis II disorders and had higher rates of abuse than women without PTSD. Lifetime sexual abuse and ASI family/social composite scores were significant predictors of PTSD. The results suggest that pregnant drug-dependent women with comorbid PTSD may benefit from specialized treatment services for trauma and/or abuse issues. Moylan, P., Jones, H., Haug, N., Kissin, W., and Svikis, D. Addictive Behaviors, 26, pp. 469-474, 2001.

Targeting Behavioral Therapies to Enhance Naltrexone Treatment of Opioid Dependence: Efficacy of Contingency Management and Significant Other Involvement

In this study 127 recently-detoxified opioid dependent individuals were randomly assigned to one of three conditions delivered over 12 weeks: 1) Thrice weekly naltrexone plus weekly cognitive-behavioral therapy (CBT); 2) Naltrexone and CBT plus contingency management (CM) with the delivery of vouchers contingent on naltrexone compliance and drug-free urine specimens, or 3) Naltrexone, CBT, CM plus significant other involvement (SO+CM), where a family member was invited to participate in up to six family counseling sessions. Outcomes included retention in treatment, compliance with naltrexone, and the number of drug-free urines. In this study Dr. Carroll and her colleagues at Yale University found that contingency management was associated with significant improvements in retention (7.4 versus 5.6 weeks) and reduction in opioid use (19 versus 14 opioid free urine specimens). Significant effects for the SO condition over CM on retention, compliance and drug use outcomes were seen only for the subgroup that attended at least one family meeting. The significant other condition was associated with improvements in family functioning. Behavioral therapies such as contingency management may enhance compliance with naltrexone maintenance. Carroll, K.M., Ball, S.A., Nich, C., O'Connor, P., Eagan, D.A., Frankforter, T.L., Triffleman, E.G., Shi, J., and Rounsaville, B.J. Targeting Behavioral Therapies to Enhance Naltrexone Treatment of Opioid Dependence. Archives of General Psychiatry, 58, pp. 755-761, August 2001.

Problem Gambling and Cocaine Dependence: Implications for Diagnostic Screening

Dr. Cunningham-Williams presented data from her paper (Cunningham-Williams, et al, 2000) on the risk factors for pathological gambling among drug users, including being male, of African American ethnicity, meeting criteria for Antisocial Personality Disorder, and being dependent on any illicit drug. This presentation was awarded the 2001 Young Investigator Award by the American Society of Addiction Medicine (ASAM) for the best abstract submitted by a young investigator. Cunningham-Williams, R. M., presentation to the American Society of Addiction Medicine, April 2001.

Functional Imaging of Neural Responses to Expectancy and Experience of Monetary Gains and Losses

Dr. Hans Breiter and colleagues at the NMR Center of Massachusetts General Hospital used BOLD fMRI to map the brain areas activated during expectancy and delivery of monetary reward. These regions overlapped with the regions that were activated by cocaine infusions in a prior study by this investigator. Normal subjects viewed one of three stimuli, each of which generated a specific expectancy regarding monetary gains or losses. The stimuli consisted of a circle divided into three equal segments and a spinning arrow. In one stimulus, the 'good' stimulus, two of the three parts denoted a monetary gain, with the third part denoting a zero outcome. A second stimulus was 'bad' in that two segments predicted a monetary loss, with the third segment again having a zero outcome. The third stimulus had one gain segment, one loss segment, and a zero segment. Brain images were obtained during the expectancy phase while the arrow was spinning and during the outcome phase when the arrow pointed to one of the segments. A widespread brain network was activated during both the expectancy and outcome phases, including regions of the orbitofrontal cortex, ventral striatum, and extended amygdala. In addition, expectancies determined the neural responses to identical outcomes. In the context of the 'good' spinner, an outcome of $0 represented a relative loss (absence of gain), and there was a marked decrease in the BOLD signal to a $0 outcome, similar to an actual monetary loss. But in the context of the 'bad' spinner, a $0 outcome represented a relative gain (absence of loss), and there was a marked increase in the BOLD signal, similar to an actual monetary gain. These data show that the response to reward in these ventral striatal regions are not driven by the presence and absolute magnitude of the reward, but rather by cognitively driven expectancies anticipated outcomes. Breiter, H.C. et al., Functional imaging of neural responses to expectancy and experience of monetary gains and losses. Neuron, 30, pp. 619-639, 2001.

Amygdala Response to both Positively and Negatively Valenced Stimuli

Dr. Hugh Garavan and colleagues at the Medical College of Wisconsin used BOLD fMRI to determine whether the amygdala is differentially tuned to hedonic vs. aversive stimuli. Prior studies have reported activation of the amygdala during drug craving, and so it is important to establish the basic information being processed by the amygdala. The amygdala has long been associated with emotional processing, and a dominant view is that the amygdala responds either exclusively or primarily to negative affective stimuli. In the present study, normal female subjects viewed pictures that varied in emotional content and arousal level selected from a widely used and validated picture set (International Affective Picture System). There was no difference in the amygdala response between negatively and positively valenced pictures, nor were there differences in the laterality of activation. There were differences with respect to interactions with the arousing properties of the pictures. The amygdala response to negatively valenced pictures was influenced by the level of arousal induced, whereas the response to the positive pictures was independent of the level of induced arousal. These results suggest that, at least in female subjects, amygdala activation occurs to both positive and negative emotional stimuli. Garavan et al., Neuroreport, 12, pp. 1-5, 2001.

Neurotoxic Effects in Detoxified Methamphetamine Users

Drs. Volkow, Chang and colleagues at the Brookhaven National Laboratory assessed functional changes in brain regions for 15 detoxified methamphetamine (METH) abusers using positron emission tomography (PET) to determine brain glucose metabolic rate. Twenty-one control subjects were scanned for comparison. Results indicated that whole brain metabolism in the METH abusers was 14% higher than that of the comparison subjects, and this increase was most notable in the parietal cortex. Following normalization for whole brain metabolism, the METH abusers exhibited significantly lower metabolism in the thalamus and striatum. The parietal cortex is a region devoid of any substantial dopaminergic innervation, so the hypermetabolism seen in this region in the METH abusers must be affecting circuits other than those modulated by dopamine. In addition, the researchers suggest the lower metabolism in the striatum and thalamus is likely a reflection of the functional consequence of METH in dopamine circuits. Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Franceschi, D., Sedler, M.J., Gatley, S.J., Hitzemann, R., Ding, Y.S., Wong, C., and Logan, J. Higher Cortical and Lower Subcortical Metabolism in Detoxified Methamphetamine Abusers. American Journal of Psychiatry, 158(3), pp. 383-389, 2001.

Dopamine Transporter Reduction in Detoxified Methamphetamine Users

In a study by Drs. Volkow, Chang and colleagues at the Brookhaven National Laboratory, METH neurotoxicity to dopamine transporter (DAT) was characterized in human METH abusers. Further, this work examined the functional significance of METH's effect on the DAT. Dopamine transporter levels were measured in fifteen detoxified METH abusers, who were evaluated subsequently to determine gross motor and cognitive function. Results indicate that the METH abusers not only showed a significant reduction of dopamine transporter in the striatum relative to the control subjects, but they also displayed substantial memory impairment and motor slowing. Importantly, these data reveal that METH at doses taken by human abusers of the drug leads to significant reductions of DATs that are directly associated with cognitive and motor impairments. Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Leonido-Yee, M., Franceschi, D., Sedler, M.J., Gatley, S.J., Hitzemann, R., Ding, Y.S., Logan, J., Wong, C., and Miller, E.N. Association of Dopamine Transporter Reduction with Psychomotor Impairment in Methamphetamine Abusers. American Journal of Psychiatry, 158(3), pp. 377-382, 2001.

Obesity-Dopamine Link

To better understand the cerebral mechanisms underlying pathological overeating and subsequent obesity, Dr. Gene-Jack Wang and colleagues at the Brookhaven National Laboratory conducted an investigation to assess whether severely obese individuals had differences in the amount of brain dopamine D2 receptors compared with normal-weight individuals. Ten self-selected males and females meeting all study criteria underwent PET scanning, and results indicated that in obese individuals, there was a significantly lower number of available D2 receptors in brain striatum, and that low amounts of such receptors were negatively correlated with body mass index (BMI). If dopamine deficiency perpetuates pathological eating as a way of compensating the decreased activation of these circuits, strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals. Wang, G.J., Volkow, N.D., Logan, J., Pappas, N.R., Wong, C.T., Zhu, W., Netusil, N., and Fowler, J.S. Brain Dopamine and Obesity. The Lancet, 357(9253), pp. 354-357, 2001.

Psychiatric Comorbidity of Methamphetamine Dependence in a Forensic Sample

The association between psychiatric symptoms and methamphetamine (METH) dependence was examined. A survey was administered to 1,580 arrestees sampled from the 14 most populous counties in California. The survey included items assessing demographic profile, history of substance dependence, and psychiatric symptomatology. METH-dependent individuals (defined as those having used the drug, unsuccessfully tried to decrease use and/or felt addicted within 12 months of the assessment) were significantly more likely to report depressive symptoms and suicidal ideation than individuals denying METH dependence, even after controlling for demographic profile and dependence on other drugs. METH-dependent individuals also were more likely to report a need for psychiatric assistance at the time of the interview. These findings suggest that METH-dependent individuals are at greater risk to experience particular psychiatric symptoms. There was a significant dependence-by-gender effect, with dependent females reporting significantly more overall symptomatology compared to females reporting no dependence; males significantly differed only with respect to depression. Further study to determine the etiology of these symptoms is warranted. Kalechstein, A.D., Newton, T.F., Longshore, D., Anglin, M.D., van Gorp, W.G., and Gawin, F.H. Psychiatric Comorbidity of Methamphetamine Dependence in a Forensic Sample. Journal of Neuropsychiatry & Clinical Neurosciences, 12(4), pp. 480-484, 2000.

Examination of Cortical Motor Threshold Via Transcranial Magnetic Stimulation in Drug-Free, Cocaine-Dependent Patients

Transcranial magnetic stimulation (TMS) provides a noninvasive method of examining cortical inhibitory and excitatory processes and cortical excitability in awake subjects. Evidence from clinical and electroencephalographic data suggest that cortical excitability may be abnormal in some psychiatric populations. Chronic cocaine abuse influences a number of neurotransmitters that are involved in the excitatory/inhibitory balance of the cerebral cortex; therefore, this pilot study was conducted to ascertain the possible utility of TMS in examining cortical excitability in a population of chronic cocaine abusers. The right and left motor thresholds of 10 cocaine-dependent subjects and 10 normal controls were examined using single pulse TMS. The resting motor thresholds resulting from stimulation of the right or the left motor cortical regions were significantly elevated in cocaine-dependent subjects compared with the controls. These data suggest that chronic cocaine use significantly alters cortical excitability via increased inhibition or decreased excitability. This finding may reflect adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures. Boutros, N.N., Lisanby, S.H., Tokuno, H., Torello, M.W., Campbell, D. Berman, R., Malison, R., Krystal, J.H., and Kosten, T. Elevated Motor Threshold in Drug-free, Cocaine-Dependent Patients Assessed with Transcranial Magnetic Stimulation. Biological Psychiatry, 49(4), pp. 369-373, 2001.

Examination of the Role of Endogenous Brain Dopamine in Methamphetamine-Induced Dopaminergic Neurotoxicity

To evaluate the role of endogenous dopamine (DA) in methamphetamine (METH)-induced neurotoxicity, the neuroprotective effects of reserpine and alpha-methyl-p-tyrosine (AMPT) were examined. Mice pretreated with reserpine developed long-term reductions in striatal DA axonal markers, suggesting that vesicular stores of DA were not crucial for the development of METH neurotoxicity. To test whether cytoplasmic DA might be involved, these DA stores were depleted with AMPT before METH administration. As lower core body temperature is a known neuroprotector and AMPT and reserpine are known to lower body temperature, this study was repeated at both 28ºC and 33ºC. At the lower temperature, complete neuroprotection was observed, but no protection was seen at the increased level. The study demonstrates that when the hypothermic effects of reserpine and AMPT were controlled, METH toxicity was fully expressed, suggesting that endogenous DA plays little if any role in METH-induced neurotoxicity. Yuan, J., Callahan, B.T., McCann, U.D., and Ricaurte, G.A. Evidence Against an Essential Role of Endogenous Brain Dopamine in Methamphetamine-induced Dopaminergic Neurotoxicity, Journal of Neurochemistry, 77(5), pp. 1338-1347, June 2001.

Effects of Methadone Maintenance on Cerebral Metabolism

Regional cerebral metabolic rate for glucose (rCMRglc) was evaluated using the PET [18F] fluorodeoxyglucose method in three groups: four opiate-dependent subjects currently receiving methadone maintenance therapy (MMT), four withdrawn from methadone (MW) and five controls who were without substance abuse disorders (C). Analyses uncovered a significant difference in rCMRglc in the anterior cingulate gyrus between MW and C groups, with the MMT group showing intermediate differences that were not statistically different. These findings suggest that neurobiologic abnormalities can persist in the brain of an opiate user several years after detoxification from methadone. Galynker, I.I., Watras-Ganz, S., Miner, C., Rosenthal, R.N., Des Jarlais, D.C., Richman, B.L., and London, E. Cerebral Metabolism in Opiate Dependent Subjects: Effects of Methadone Maintenance. The Mount Sinai Journal of Medicine, 67(5,6), pp. 381-386, 2000.

Mental Imagery of Personal Drug Use Induced Craving that was Associated with Activations of Specific Areas of Paralimbic and Limbic Systems

Kilts and associates from Emory University composed scripts personalized from interviews with each subject - of cocaine use situations, anger incidences, as well as control (neutral) memories of a beach or forest scene. These were then read to the subjects immediately after which water (O15) PET studies were initiated, followed by questionnaires assessing craving and anger. Compared to the neutral condition, drug use imagery was associated with activation of the amygdala (R>L), the left insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus accumbens. There were also some significant decreases in parts of the right frontal and left temporal cortices. When compared to the anger imagery, drug use imagery was associated with activation in limbic and paralimbic brain structures, including the bilateral insula and subcallosal cortices, the left posterior caudate nucleus, and the anterior cingulate. The amount of increase (number of pixels) in these areas was correlated with craving self-reported scores. Conspicuously absent were increases in the prefrontal association cortices suggesting that activation of these areas in other paradigms have a qualitatively different component. These results give insight into which brain areas are involved in what may be characterized as self-generated craving. The caveat is that there are other interpretations as to what the imagery represents in terms of the drug-craving process in the field. Kilts, K.D.,Schwetzer, J.B., Quinn, C.K., Gross, R.E., Faber, T.L., Muhammad, F., Ely, T.D., Hoffman, J.M., and Drexler, K.P.G., Archives of General Psychiatry, 58, pp. 334-341, 2001.

Serotonin Transporters Upregulate with Chronic Cocaine Use

Mash and colleagues examined the status of the serotonin transporter in subgroups of individuals coming to post-mortem with cocaine overdose deaths. Transporter densities were increased in the nucleus accumbens and both the anterior and posterior sectors of the striatum. By contrast, those subjects who had presented with excited delirium did not have the same elevations in the posterior striatum. Also, upregulation was found in the substantia nigra for overdose victims but not for those with delirium. These results suggest that those cocaine abusers experiencing excited delirium may be a different, distinct phenotype than those without this condition. Mash, D.C., Staley, J.K., Izenwasser, S., Basile, M., and Ruttenber, A.J., Journal of Chemical Neuroanatomy, 20, pp. 271-280, 2000.

Reduced Vasoconstriction in Woman Compared to Men and during Different Phases of the Menstrual Cycle after Cocaine May be a Protective Factor

Dr. Marc Kaufman and colleagues studied cerebral blood flow with dynamic susceptibility contrast magnetic resonance imaging in occasional cocaine users: men and woman at different phases of the menstrual cycle. In men, there was a 20% reduction in blood flow, while there was no reduction during the follicular stage of women and a 10% reduction during the luteal phase. It is conceivable that this difference could account in part to the lesser neuronal injury in women and implies that gonadal steroids or the factors they modulate may be therapeutic agents for reducing cocaine-induced cerebrovascular disorders. Kaufman, M.J., Levin, J.M., Maas, L.C., Kudes, T.J., Villafuerte, R.A., Dostal, K., Lukas, S.E., Mendelson, J.H., Cohen, B.M., and Renshaw, P.F., Biological Psychiatry, 49(9), pp. 774-781, 2001.

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