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Director's Report to the National Advisory Council on Drug Abuse - February, 2003



Research Findings - Treatment Research and Development

Brain Reward System Activity In Major Depression and Comorbid Nicotine Dependence

Busto and colleagues at the Center for Addiction and Mental Health, University of Toronto, studied the response to oral d-amphetamine as a probe for the functioning of the brain reward system in nicotine-dependent, non-medicated subjects with a diagnosis of major depressive disorder (MDD) and 16 nicotine-dependent, control subjects. Smoking did not modify the response to d-amphetamine in MDD or control subjects, but decreased overall negative mood state during placebo sessions. A significant correlation between depression severity (Hamilton depression scale) and d-amphetamine rewarding effects was found in MDD smoker subjects. Severity of depression was significantly correlated with increased rewarding effects of d-amphetamine. Thus, chronic nicotine use does not modify response to d-amphetamine even though the brain reward system may be dysfunctional in subjects with major depression. Cardenas, et al., J. Pharmacol. Exp. Ther., 302, pp. 1265-1271, 2002.

Activation in Medial Temporal Lobe and Visuospatial Neural Circuits Elicited by Smoking Cues

Huettel and colleagues at Duke University used BOLD fMRI to investigate the neural substrates modulated by visual smoking cues in nicotine-deprived smokers and a nonsmoking comparison group. Subjects viewed a pseudo-random sequence of smoking images, neutral nonsmoking images, and rare targets (photographs of animals). Subjects pressed a button whenever a rare target appeared. In smokers, the fMRI signal was greater after exposure to smoking-related images than after exposure to neutral images in medial temporal lobe circuits activated by addictive drugs (right posterior amygdala, posterior hippocampus, ventral tegmental area, and medial thalamus) as well visuospatial attention regions (bilateral prefrontal and parietal cortex and right fusiform gyrus). None of these areas was activated in nonsmokers by the smoking images. In nicotine-deprived smokers, smoking cues are processed like rare targets in that they activate attentional regions as well as medial temporal lobe regions. Due et al., Am. J. Psychiatry, 159, pp. 954-960, 2002.

Dissociable Prefrontal Brain Systems for Attention and Emotion

LaBar and colleagues at Duke University used fMRI to determine whether attentional and emotional functions are segregated into dissociable prefrontal networks in the human brain. Normal subjects discriminated infrequent and irregularly presented attentional targets (circles) from frequent standards (squares) while novel distracting scenes, parametrically varied for emotional arousal, were intermittently presented. Targets differentially activated middle frontal gyrus, posterior parietal cortex, and posterior cingulate gyrus. Novel distracters activated inferior frontal gyrus, amygdala, and fusiform gyrus, with significantly stronger activation evoked by the emotional scenes. The anterior cingulate gyrus was the only brain region with equivalent responses to attentional and emotional stimuli. These results show that attentional and emotional functions are segregated into parallel dorsal and ventral streams that extend into prefrontal cortex and are integrated in the anterior cingulate. Yamasaki et al., Proc. Natl. Acad. Sci., 99, pp. 11447-11451, 2002.

Relationships among BOLD, CBV, and CBF Changes in Rat Brain

Li and colleagues at the Medical College of Wisconsin used fMRI to compare arterial cerebral blood flow (CBF (A)) and total cerebral blood volume (CBV (T)) in rats. Urethane-anesthetized rats were examined under graded hypercapnia conditions (7.5% and 10% CO (2) ventilation) for changes in blood oxygenation level-dependent (BOLD) contrast and and CBV (T) using a monocrystalline iron oxide nanocolloid (MION) contrast agent. It was found that the relationship between CBV (T) and CBF (A) under transient conditions is similar to the power law under steady-state conditions. In addition, the transient relationship between CBV (T) and CBF (A) was region-specific. Voxels with large (<15%) BOLD signal changes from hypercapnia (7.5% CO(2) ventilation) had a larger power index (alpha = 3.26), a larger maximum possible BOLD response, and shorter T(*) (2) caused by deoxyhemoglobin, compared to voxels with smaller BOLD signal changes. These results suggest that to avoid overestimation of the cerebral metabolic rate of oxygen changes seen using fMRI, caution should be taken to not include voxels with large veins and a large BOLD signal. Wu et al., Magnetic Resonance in Medicine, 48, pp. 987-993, 2002.

Cerebral Perfusion Imaging Using Arterial Spin Labeling at 1.5 and 4.0 Tesla

Detre and colleagues at the University of Pennsylvania compared arterial spin labeling (ASL) perfusion MRI using a pulsed ASL (PASL) technique at 4T with PASL and continuous ASL (CASL) techniques at 1.5T. ASL imaging was performed in normal subjects both in the resting state and during motor activation. Although in the resting-state the 4T PASL exhibited the greatest signal to noise and contrast to noise ratios, the functional data acquired using 4T PASL did not show significantly improved sensitivity to motor cortex activation compared with the 1.5T functional data. In addition, the 4T PASL exhibited reduced fractional perfusion signal change and increased intersubject variability. Wang et al., Magnetic Resonance in Medicine, 48, pp. 242-254, 2002.

GABAergic Mechanisms of Heroin-Induced Brain Activation

Li and colleagues at the Medical College of Wisconsin used fMRI in rats to test whether heroin activates dopamine projection cells by stimulating opiate receptors on inhibitory interneurons that inhibit gamma-aminobutyric acid (GABA) release. Acute, systemic administration of heroin produced a significant blood oxygen level-dependent (BOLD) signal increase in cortical regions, including prefrontal cortex, cingulate, and olfactory cortex. In contrast, a significant signal decrease was seen in several subcortical areas, including the caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. Pretreatment with naloxone, eliminated and post treatment with naloxone reversed the heroin-induced BOLD signal changes. Pretreatment with gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, significantly attenuated the heroin-induced BOLD signal changes. It is suggested that opiates' pharmacological actions can, at least in part, be mediated by inhibiting brain GABA release. Xi, et al. Magnetic Resonance in Medicine, 48, pp. 838-843, 2002.

Brain Dopamine D2 Receptors Predict Reinforcing Effects of Stimulants: Replication

Volkow and colleagues at the Brookhaven National Laboratory determined the replicability of previous findings characterizing the relationship between striatal dopamine (DA) D2 receptors and self-reports of "drug liking". PET scans were performed in seven, non-drug abusing subjects administered intravenous methylphenidate, a psychostimulant that acts like cocaine to increase DA by blocking DA transporters. Measures were taken twice to assess stability. Results were consistent with previous findings. DA D2 measures were significantly correlated with "drug liking" in both evaluations (r = 0.82, 0.78); subjects with the lowest levels of receptors reported the higher ratings of "drug liking", whereas those subjects with the highest levels of receptors reported consistently lower ratings of "drug liking". These results provide further evidence that striatal DA D2 receptors modulate reinforcing responses to stimulants in humans and may underlie predisposition for drug abuse. Also, these results provide evidence that high levels of DA D2 receptors may be protective for drug abuse. Finally, these results corroborate the involvement of DA D2 receptors in the perception of the reinforcing effects of psychostimulants in human subjects. Volkow, N.D., Wang ,G-J., Fowler, J.S., Thanos, P., Logan, J., Gatley, S.J., Gifford, A., Ding, Y-S., Wong, C., and Pappas, N. Brain DA D2 Receptors Predict Reinforcing Effects of Stimulants in Humans: Replication Study. Synapse, 46, pp. 79-82, 2002.

Childhood Emotional Neglect May Influence Monoamine Function in Adults

Childhood stress has been shown in animal models and implied in humans to influence the vulnerability to drug abuse in adults. Roy has demonstrated that abstinent cocaine-abusing adults with retrospective reports of childhood neglect had low levels of both 5-HIAA, the metabolite of serotonin, and HVA, the metabolite of dopamine in significant correlation with symptom scores. Aggression and behavioral disorders, including suicide, are associated with low serotonergic function that may have developmental antecedents in childhood environment. The relevance to drug abuse vulnerability needs to be explored. Roy, A., Psychiatry Research, 112, pp. 69-75, 2002.

Dopamine Metabolite, HVA, in CSF Fails to Correlate with Cocaine Craving in Recently Abstinent Patients in Treatment

Roy and colleagues assessed 20 cocaine patients on a locked treatment ward for visually cued cocaine craving following lumbar puncture to determine the level of the dopamine metabolite, homovanillic acid and the serotonin metabolite, 5-hydroxy-indoleacetic acid. No correlation between either of these measures and craving scores was found. This was true when only the patients whose craving scores increased the most were compared with those whose scores did not change. These results must be considered in light of extant hypotheses regarding the role of dopamine in cocaine craving. Roy, A., Berman, J., Bienvenido G. and Roy, M. Journal of Psychopharmacology, 16(3), pp. 227-229, 2002.

P300 Event-Related Potentials Are Associated with Risk of Substance Abuse

Iacono and colleagues at the University of Minnesota have followed a population sample of twins and have now determined that P300 amplitudes are significantly smaller in at-risk adolescent offspring– those whose parents have a diagnosed alcohol or substance abuse or anti-social personality disorder. This was true whether or not the adolescent was or was not abusing substances or had a psychiatric diagnosis. Furthermore, adolescents who were not abusing drugs at age 17 but began abusing by age 20 had smaller P300 amplitudes than those who did not take drugs by age 20. Thus, not only is a lower amplitude P300 a possible biological marker for at-risk substance use based on father's diagnosis, but it is also predictive of who might become a drug abuser regardless of parental history. The authors suggest that the P300 may be an endophenotype underlying and common to a constellation of disorders including substance abuse but also including other externalizing disorders – conduct disorder, etc. Iacono, W.G., Carlson, S.R., Malone, S.M., and McGue, M. Archives of General Psychiatry, 59(8), pp. 750-757, August 2002.

Relationships Among Brain Metabolites, Cognitive Function, and Viral Load in Antiretroviral-Naive HIV Patients

Dr. Chang and her colleagues conducted an evaluation of antiretroviral-naive individuals that minimized the confounding effects of antiretroviral treatment on the relationship among cerebral metabolite concentrations, cognitive function, and clinical variables. Antiretroviral-drug-naive, HIV+ individuals (45) and control subjects (25) were tested. As measures of dementia severity increased, frontal lobe myoinositol concentration [MI], choline concentration [CHO], and total creatine [CR] were elevated, and basal ganglia [CR] was decreased. HIV+ patients showed slowing on fine motor and psychomotor function, and deficits on tests of executive function. Lower CD4 counts and elevated plasma viral loads were associated with elevated frontal white matter [MI], which in turn correlated with performance decrements on the Stroop tasks. These findings suggest that systemic factors may lead to glial proliferation in the frontal white matter, which in turn may contribute to deficits on executive function in HIV+ patients. Metabolite concentrations, rather than metabolite ratios, should be measured since [CR], a commonly used reference for metabolite ratios, varies with disease severity in both frontal lobe and basal ganglia. Chang, L. Ernst, T., Mallory D., Ames, N., Gaiefsky, M., and Miller, E. Relationships among Brain Metabolites, Cognitive Function, and Viral Loads in Antiretroviral-naive HIV Patients, NeuroImaging, 17(3), pp. 1638-1648, November 2002.

Neuropsychological Performance in Individuals Following Six Weeks or Six Months of Abstinence from Abuse of Crack-Cocaine or Crack-Cocaine Plus Alcohol

To evaluate the extent that crack dependence and crack and alcohol dependence may lead to severe and persistent neuropsychological deficits over a wide range of domains, Fein and colleagues at Neurobehavioral Research, Inc. examined cognitive function in abstinent crack-dependent and crack- and alcohol-dependent individuals at 6 weeks and 6 months abstinence. A comprehensive neuropsychological battery was administered to 20 abstinent crack-dependent subjects, 37 abstinent crack- and alcohol-dependent subjects, and 29 normal controls. Depression was examined as a covariate, and the association between substance use variables and neuropsychological performance was examined. Both substance-dependent groups had similar neuropsychological profiles at 6 weeks abstinence, with both groups exhibiting significant cognitive impairment across a wide range of variables compared to the controls. The substance-dependent groups continued to show significant impairment after 6 months of abstinence. Only mild effects of depression on neuropsychological performance were observed. The strongest predictor of brain damage associated with substance dependence in this sample was dose (particularly quantity and duration of peak dose). DiSclafani, V., Tolou-Shamas, M., Price, L.J., and Fein, G. Neuropsychological Performance of Individuals Dependent on Crack-Cocaine, or Crack-Cocaine and Alcohol, at 6 Weeks and 6 Months of Abstinence. Drug and Alcohol Dependence, 66(2), pp. 161-171, April 2002.

Prefrontal Cortical Volume Reduction Associated with Frontal Cortex Function Deficit in 6-Week Abstinent Crack-Cocaine Dependent Men

Fein and colleagues examined regional cortical volumes in 6-week abstinent men dependent on crack-cocaine (n=17) only or on both crack-cocaine and alcohol (n=29) to evaluate possible prefrontal cortical volume reduction, along with associated impairments in frontal-mediated functions, and to look for any differences between these groups. Magnetic resonance imaging (MRI) of the brain and neuropsychological assessment were performed on all dependent subjects who had been abstinent for six weeks as well as on 20 normal controls. Cortical volume was quantified in the prefrontal, parietal, temporal and occipital regions. The crack-only and crack-plus-alcohol subjects showed comparable reductions in prefrontal gray matter volume compared to the controls; this reduction was negatively associated with performance impairments in the executive function domain. Dependence on crack (with or without concomitant alcohol dependence) was associated with reduced prefrontal cortical volume. Crack dependence with concomitant alcohol dependence was not associated with greater prefrontal volume reductions than crack dependence alone. The existence of these findings at 6-week abstinence indicates that they are not a result of acute cocaine or alcohol exposure. The association of reduced prefrontal cortical volume with cognitive impairments in frontal cortex mediated abilities suggests that this reduced cerebral volume has functional consequences. Fein, G., DiSclafani, V., and Meyerhoff, D.J. Prefrontal Cortical Volume Reduction Associated with Frontal Cortex Function Deficit in 6-week Abstinent Crack-Cocaine Dependent Men. Drug and Alcohol Dependence, 68(1), pp. 87-93, September 2002.

Efficacy for CBT and CM

Dr. Richard Rawson and colleagues at UCLA Integrated Substance Abuse Programs compared contingency management (CM) and group cognitive behavioral therapy (CBT) to combined CM and CBT and usual care (methadone maintenance) as a treatment for patients with cocaine and opiate dependence. Urinalysis results one week after treatment show that participants assigned to the CM groups had significantly superior in treatment outcomes whereas those receiving CBT only were not more likely to be drug free in treatment than those in methadone maintenance alone. However, at the 26 week and 52 week follow-up all three groups outperformed methadone maintenance alone. Results of this study suggest that both CM and CBT alone and in combination are efficacious for reducing drug use 6 and 12 months after treatment completion. Rawson, R.A., Huber, A., McCann, M., Shoptaw, S., Farabee, D., Reiber, C., and Ling, W. A Comparison of Contingency Management and Cognitive-Behavioral Approaches during Methadone Maintenance Treatment for Cocaine Dependence. Arch. Gen. Psychiatry, 59(9), pp. 817-824, September 2002.

Dissemination of Contingency Management Methods

Dr. Nancy Petry at University of Connecticut School of Medicine reviewed recent advances in the dissemination of contingency management (CM) techniques including ways researchers have reduced costs by implementing programs based on intermittent schedules of reinforcement and clinic privileges. The review notes clinic needs often differ from the ways CM has been used in research. For example, clinicians report the need to reinforce abstinence from more than one drug of abuse, while research has typically focused on a single drug of abuse. The need for training programs for community clinicians is particularly noteworthy. The review highlights some of the ways in which findings from research can be implemented clinically and suggests that researchers and clinicians can learn from one another's experiences to bring CM procedures into practice and improve outcomes in the treatment of substance use disorders. Petry, N.M., and Simcic, F., Jr. Recent Advances in the Dissemination of Contingency Management Techniques: Clinical and Research Perspectives. J. Subst. Abuse Treat., 23(2), pp. 81-86, September 2002.

Smoking Cessation in Methadone Maintenance

Dr. Steve Shoptaw and colleagues at the Friends Research Institute evaluated the efficacy of relapse prevention and contingency management interventions for smoking cessation in methadone maintained patients in a 2 X 2 design using nicotine replacement therapy as a platform pharmacotherapy. One-hundred and seventy-five smokers received 12 weeks of NRT and were assigned to one of four conditions: 1) patch only; 2) relapse prevention + patch; 3) contingency management + patch; or 4) relapse prevention + contingency management + patch. During treatment, those assigned to receive contingency management showed statistically higher rates of smoking abstinence than those not assigned to receive contingencies. At follow-up there were no significant differences between conditions. Participants provided more opiate and cocaine-free urines during weeks when they met criteria for smoking abstinence than during weeks when they did not meet these criteria. The authors conclude that contingency management optimized outcomes using NRT for reducing cigarette smoking during treatment for opiate dependence, although long-term effects are generally not maintained. Findings document strong associations between reductions in cigarette smoking and reductions in illicit substance use during treatment. Shoptaw, S., Rotheram-Fuller, E., Yang, X., Frosch, D., Nahom, D., Jarvik, M.E., Raswon, R.A., and Ling, W. Addiction, 97(10), pp. 1317-1328, October 2002.

Depressive Symptoms and Readiness to Quit Smoking Among Cigarette Smokers in Outpatient Alcohol Treatment

Researchers at Brown University and the Miriam Hospital examined whether length of alcohol abstinence and depressive symptoms were related to motivational readiness to consider smoking cessation among patients in alcohol treatment. Participants were 253 adults enrolled in a smoking cessation trial. Findings show that a greater number of days since last drink were associated with greater readiness to quit smoking, but only among patients with low scores on a depression scale. The findings suggest that alcoholic smokers with low depressive symptoms are more receptive to quitting smoking after sustained alcohol abstinence. Hitsman, B., Abrams, D.B., Shadel, W.G., Niaura, R., Borreli, B., Brown, R., Emmons, K.M., Swift, R.M., Monti, P.M., Rohsenow, D.J., and Coby, S.M. Psychology of Addictive Behaviors, 16(3), pp. 264-268, 2002.

Suicide Attempts in Substance Abusers: Effects of Major Depression in Relation to Substance Use Disorders

Dr. Aharonovich and colleagues at Columbia University in New York, investigated whether subtypes of DSM-IV depression predict suicidal behavior among patients with substance dependence. In this study, major depression among 602 patients with substance dependence was classified as occurring before dependence, during abstinence, or exclusively during periods of substance use. The findings indicate that all three types of depression increased the risk for making a suicide attempt. Major depression that occurred before the patient became substance dependent predicted severity of suicidal intent. Major depression that occurred during abstinence predicted number of suicide attempts. These results suggest the importance of establishing DSM-IV subtypes of depression based on the timing of the occurrence of depression in relation to substance dependence in evaluating suicidal risk among substance-dependent patients. Aharonovich, E., Xinhua, L., Nunes, E., and Hasin, D. American Journal of Psychiatry, 159, pp. 1600-1602, September 2002.

Substance Abuse and the Need for Money Management Assistance Among Psychiatric Inpatients

Dr. Marc Rosen and colleagues at the VA Connecticut Healthcare System, the VA Medical Center in Los Angeles, California, and the VA Bedford Medical Center in Massachusetts, evaluated the relationship between substance abuse and clinician-rated need for money management assistance, using data from a survey of psychiatric inpatients at four VA hospitals (N= 236). Multivariate analytic techniques were used to control for sociodemographic factors and psychopathology. Alcohol and drug use severity both were modestly associated with need for assistance. The effect of substance use severity was greater in patients who were also diagnosed with a major mental illness. Clinicians indicated that 27 patients (11% of the sample) required an involuntary payee and 21 of the 27 (78%) had a Substance Abuse diagnosis. Only drug use severity was significantly associated with the need for a payee. These data describe a substantial unmet need for money management assistance in psychiatric inpatients, particularly among those with substance abuse disorders. Patients who mismanage their funds may benefit from financial advice, case management, or the assignment of a payee who may restrict direct access to funds. Rosen, M., Rosenheck, R., Shaner, A., Eckman, T., Gamache, G., and Krebs, C. Drug and Alcohol Dependence, 67, pp. 331-334, May 2002.


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