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

Research Findings - Treatment Researchand Development

Ethnic Differences in Comorbidity Among Substance Abusing Adolescents Referred to Outpatient Therapy

Dr. Michael Robbins and colleagues at the University of Miami examined differences in psychiatric comorbidity between African-American and Hispanic substance-abusing adolescents referred for outpatient therapy. Study participants included 167 substance-abusing adolescents and their family members who completed an intake assessment. As part of the intake assessment, adolescents and parents were administered the Diagnostic Interview Schedule for Children-Predictive Scales to screen for the presence of nine psychiatric diagnoses representing both externalizing and internalizing disorders. In this study both African-American and Hispanic youths presented with high-above-threshold symptom rates of co-occurring disorders. However, both adolescents and parents reported that Hispanic youths (78.3% and 83.9%, respectively) demonstrated greater rates of externalizing than African-American youths (65.2% and 70.1%, respectively). African-American youth (40%) reported significantly more symptoms of agoraphobia than Hispanic youths (19.5%). The results of this study have implications for understanding the development of substance abuse across ethnic groups and for developing treatment approaches that are sensitive to the needs of each group. Robbins, M.S., Kumar, S., Walker-Barnes, C., Feaster, D., Briones, E. and Szapocznik, J. Journal of the American Academy of Child and Adolescent Psychiatry, 41(4), pp. 394-401, April 2002.

Gender Differences in Psychiatric Comorbidity Among Adolescents with Substance Use Disorders

As part of a Stage I behavioral therapy development project, Dr. William Latimer at Johns Hopkins University examined gender differences in the rates of psychiatric disorders among 135 adolescents with one or more psychoactive substance use disorders. Consistent with expectations, male adolescents exhibited a higher rate of ADHD and Conduct Disorder than did females, and females exhibited a higher rate of Major Depressive Disorder than did males. Unexpectedly, rates of ADHD and Conduct Disorder were fairly high among females, despite being significantly lower than for males, and rates of dysthymia, "double depression" (i.e., major depression and dysthymia), and bipolar disorder were equivalent between genders. This study helps to identify common gender differences-and similarities-in comorbidities among adolescent substance abusers, one key to developing effective screening, assessment, and treatment interventions. Latimer, W.W., Stone, A., and Winters, K.C. Experimental and Clinical Psychopharmacology, 10, pp. 310-315, August 2002.

Gambling Behavior in Adolescent Substance Abuse

Dr. Yifrah Kaminer and colleagues at the University of Connecticut assessed gambling behavior among adolescents in outpatient substance abuse treatment. Of 97 adolescents assessed via diagnostic interviews and self-report, 34% had never gambled; 57% participated in social or nonpathological gambling; 8% were considered at-risk or transition gamblers; and 1% met criteria for pathological gambling. Compared to studies of adolescents without drug abuse disorders, this treatment population exhibited similar or lower gambling behavior. While a strong connection has been reported between gambling and drug abuse among adults, this study suggests that this connection may develop after adolescence, and sets the stage for further studies of the etiology and treatment of both disorders. Kaminer, Y., Burleson, J.A., and Jadamec, A. Substance Abuse, 23, pp. 191-198, 2002.

Urine Toxicology Samples in Cocaine Treatment Trials: How Many Need to Be Tested?

Investigators Delucchi and colleagues at the University of California San Francisco empirically evaluated how often urine sample should be conducted for cocaine testing by examining the weekly variation in cocaine metabolite (benzoylecgonine-BE) concentration between pairs of weekly urine samples from a clinical trial of a treatment for cocaine dependence. Twice weekly samples were collected and agreement between pairs was estimated for quantitative and qualitative measures of BE. Results indicate substantive intra-week variation with correlations never exceeding 50% and approximately 20% disagreement among samples that used cutoff values in place of quantitative levels. Group averages over time however, were much more stable. Findings suggest a single quantitative measure may not be representative but when collected several weeks over several individuals a representative picture of the group's behavior emerges. These findings suggest at least 2 samples per week may be needed to accurately represent the cocaine use of an individual. Delucchi, K.L., Batki, S.L., Moon, J., Jacob, P., and Jones, R.T. Journal of Addictive Diseases, 21, pp. 17-26, 2002.

Depression and Stages of Change for Smoking in Psychiatric Outpatients

Investigators Acton, and colleagues at the University of California San Francisco examined psychiatric outpatients on measures of depression and various transtheoretical model constructs related to smoking and thoughts about abstinence from smoking. Those who had never smoked showed lower rates of diagnosed major depressive disorder (MDD). Participants in early stages of change did not show more MDD or depressive symptoms, but did report more negative thoughts about quitting. This study suggests psychiatric outpatients seeking mental health treatment may be amenable to smoking cessation interventions and interventions that are matched to the readiness to change are likely to be important. Acton, G.S, Prochaska, J.J., Kaplan, A.S., Small, T. and Hall, S. Addictive Behaviors, 26, pp. 621-631, 2001.

The Feasibility of Enhancing Psychiatric Outpatients' Readiness to Change Their Substance Abuse

Dr. Kate Carey and colleagues at Syracuse University evaluated the feasibility and acceptability of a brief motivational intervention for 22 outpatients with severe and persistent mental illness and drug use problems. The intervention consisted of four individual sessions that were guided by the therapeutic principles of motivational interviewing. The median time for completion of the intervention was 28 days. Preliminary results demonstrate the feasibility of the motivational intervention in this population. It was possible to retain psychiatric outpatients in the intervention, and the patients reported positive perceptions of the intervention. Readiness to change and involvement in treatment increased between the pre-intervention and post intervention assessments. However, many of the post intervention gains were not been maintained at 3-month follow-up. Preliminary findings from this Stage I behavioral development study support the feasibility and acceptability of a 4 session motivational intervention for use with persons who have serious and persistent mental illness and a substance use disorder. Karey, K.B., Carey, M.P., Maisto, S.A., and Purnine, D.M., Psychiatric Services, 53(5), pp. 602-608, May 2002.

Cognitive-Behavioral Treatment of Bipolar Disorder and Substance Abuse: A Preliminary Randomized Study

Dr. Joy Schmitz and colleagues at the University of Texas evaluated the feasibility and potential efficacy of cognitive-behavioral therapy (CBT) in conjunction with pharmacotherapy for patients diagnosed with bipolar disorder and substance use disorder. In this study 46 randomly assigned outpatients received up to 12 weeks of medication monitoring (MM) plus individual CBT (MM + CBT) or medication monitoring only. Sixty percent of the subjects in the medication monitoring plus the cognitive-behavioral therapy group completed treatment compared with 33% of the subjects in the medication monitoring only group, with session attendance also significantly higher in the combined treatment group (MM + CBT). The two groups did not differ in substance use outcomes during treatment, but there was some indication of greater improvement in the MM + CBT group with regard to outcomes related to medication compliance and mood symptoms. This study is a preliminary attempt to develop and evaluate a new, integrated treatment approach for patients with bipolar disorder who have coexisting substance abuse. Schmitz, J.M., Averill, P.A., Sayre, S., McCleary, P., Moeller, F.G., and Swann, A. Addictive Disorders and Their Treatment, 1(1), pp. 17-24, March 2002.

Feasibility of Computerized Scheduled Gradual Reduction for Adolescent Smoking Cessation

Dr. William Riley and colleagues at PICS, Inc. conducted two small pilot studies to determine the feasibility of using a computerized (hand-held) scheduled gradual reduction approach to smoking cessation in group support and in minimal contact modalities with adolescent smokers. The results of these two small trials suggest that a computerized scheduled gradual reduction approach may be an accepted and potentially efficacious approach for smoking cessation among adolescent smokers. Riley, W., Jerome, A., Behar, A., Zack, S. Substance Use and Misuse, 37, pp. 255-63, 2002.

Impaired Autonomic Activation in Substance Dependent Individuals when Making Decisions with Negative Future Consequences

Bechara and colleagues at the University of Iowa tested the hypothesis that substance abusers who perform disadvantageously on a decision-making instrument, the gambling task (GT), have a deficit in the somatic signals that help guide their decision in the advantageous direction. Skin conductance response (SCR) was assessed as an index of somatic state activation. Forty-six substance dependent subjects, 49 normal controls, and 10 patients with ventromedial prefrontal (VM) lesions were studied. A subgroup of substance-dependent subjects showed defective performance on the GT coupled with impaired anticipatory SCR, but normal SCR to punishment, and normal acquisition of conditioned SCR to an aversive loud sound, similar to the pattern observed with the VM lesioned patients. This supports the hypothesis that the poor decision-making in some substance abusers is associated with defective somatic state activation, and may be due to a dysfunctional VM cortex. A dysfunctional VM cortex underlying the "myopia" for the future in some substance abusers may be one of the mechanisms underlying the transition from casual substance taking to compulsive and uncontrollable behavior. Bechara et al., Neuropsychologia, 40, pp. 1675-1689, 2002.

Are Decision-making Deficits in Substance Abusers Due to Myopia for the Future or Hypersensitivity to Reward?

In another study, Bechara and colleagues at the University of Iowa investigated whether the impaired performance of substance abusers on the Gambling Task (GT) is due to hypersensitivity to reward or inability to project the future consequences of choices in the present ('myopia for the future'). In order to dissociate these two possibilities, a variant version of the GT was used, in which the good decks yielded high immediate punishment but higher delayed reward, whereas the bad decks yielded low immediate punishment and lower delayed reward. Substance-dependent subjects who were not impaired on the original GT performed normally on the variant GT. Substance-dependent subjects who were impaired on the original GT showed two levels of performance on the variant GT. One subgroup (36% of the sample) performed poorly on the variant GT, and showed similar behavioral and physiological impairments to patients with ventromedial prefrontal lesions. The other subgroup (64% of the sample) performed normally on the variant task, but had abnormally large autonomic responses to reward, i.e., large SCR after receiving reward (reward SCR) and large SCR in anticipation of outcomes that yield large reward. These results suggest 3 distinct sub-groups of substance abusers with respect to decision-making abilities. One sub-population is without impairments that can be detected by any measure of the GT paradigm. Another sub-population is similar to VM patients in that they are insensitive to the future, both positive and negative. A third sub-population is hypersensitive to reward, so that the presence or the prospect of receiving reward dominates their behavior. These finding may provide a basis for predicting treatment response and potential for relapse. Bechara et al., Neuropsychologia, 40, pp. 1690-1705, 2002.

Neural Substrates of Decision Making

As decision-making is central to motivated behavior, understanding its neural substrates can help identify the deficits that characterize various maladaptive behaviors. Healthy adults (20) performed a risk-taking task during PET with 15O-labeled water. A computerized card game was used to test the ability to weigh short-term rewards against long-term losses. A control task matched all components of the risk-taking task except for decision-making and the difference between responses to contingent and non-contingent reward and punishment. Decision-making activated orbital and dorsolateral prefrontal cortex, anterior cingulate, insula, inferior parietal cortex and thalamus predominantly on the right side, and cerebellum predominantly on the left side. In an exploratory analysis, 'guessing' produced activation of sensory-motor associative areas, and amygdala on the left side, whereas informed decision-making activated areas that subserve memory (hippocampus, posterior cingulate) and motor control (striatum, cerebellum). The findings provide a framework for future investigations of decision-making in maladaptive behaviors. Ernst et al., Decision-making in a Risk-taking Task: A PET Study. Neuropsychopharmacology, 26(5), pp. 682-691, 2002.

Evidence of Reduced Cognitive Inhibition in Methamphetamine-Dependent Individuals

Nordahl and colleagues at the University of California, Davis used a computerized single-trial version of the Stroop Test to examine selective attention and priming in methamphetamine-dependent (MD) subjects to investigate clinical observations that methamphetamine abusers are highly distractible and have difficulty focusing. Eight MD men (31.7+/-7.2 years of age) and 12 comparison subjects were tested. Relative to the comparison subjects, the MD subjects exhibited significantly greater interference despite intact priming, consistent with the distractibility they show clinically. Error rates did not differ between the groups. The dissociation between explicit attentional performance and priming effects suggests that some attentional functions are not as affected by long-term methamphetamine use as others. Salo et al., Psychiatry Res., 111, pp. 65-74, 2002.

Cognitive Function in Methamphetamine Abusers Uncovers Interactive Gender Differences

Chang and colleagues at the Brookhaven National Laboratory investigated regional cerebral blood flow (relative rCBF) and cognitive function in abstinent methamphetamine (METH) users. Twenty METH-dependent participants and 20 age- and gender-matched controls were evaluated with perfusion MRI and neuropsychological tests. Decreased relative rCBF was seen bilaterally in putamen/ insular cortices (right: -12%; left: -10%) and in the right lateral parietal brain region (-11%)in the METH users but increased relative rCBF bilaterally in the left temporo-parietal white matter (+13%), the left occipital brain region (+10%) and the right posterior parietal region (+24%). Interaction effects were observed between METH and gender in the right occipital cortex and a midline brain region; female METH users showed increased relative rCBF (+15% both regions) whereas the male METH users had decreased relative rCBF (-10% and -18%, respectively). METH users performed within normal ranges on standard neuropsychological testing; however, they were slower on tasks on the California Computerized Assessment Package, especially working memory tasks. Findings indicate that METH abuse is associated with persistent physiologic changes in the brain, and these changes are accompanied by slower reaction times on computerized measures of cognitive function. Chang et al., Perfusion MRI and Computerized Cognitive Test Abnormalities in Abstinent Methamphetamine Users. Psychiatry Research: Neuroimaging. 114(2), pp. 65-79, 2002.

Relationship Between High Risk Sex and Methamphetamine in HIV+ Men Who Have Sex with Men

Previous research has demonstrated an association between methamphetamine (METH) use and high-risk sex among HIV- men who have sex with men (MSM); however, little is known about the sexual risk behaviors of HIV+ METH-using MSM. The purpose of this study was to explore personal motivators of METH use among HIV+ MSM, and to elaborate upon the interaction between METH use and risky sex. Thematic analysis of qualitative data from 25 HIV+ MSM (aged 27-57 yrs) revealed METH use was associated with high rates of anal sex, low rates of condom use, multiple sex partners, sexual marathons, and anonymous partners. Motivations associated with METH use included: sexual enhancement and self-medication of the negative affect associated with HIV+ serostatus. A variety of treatment approaches are used to describe how client insights into motivations can be used by clinicians to promote change in drug use and sexual risk behavior. Semple et al., Motivations Associated with Methamphetamine Use among HIV+ Men Who Have Sex with Men. Journal of Substance Abuse Treatment. 22(3), pp. 149-156, 2002.

Reduced Frontal White Matter Integrity In Cocaine Dependence

Lim and colleagues at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York used a new magnetic resonance imaging method, diffusion tensor imaging (DTI), to investigate changes in white matter fiber tracts associated with cocaine use. Compared to 13 age-matched controls, the 12 cocaine-dependent subjects had reduced fractional anisotropy, a measure of the integrity of myelinated fiber tracts, in ventral, but not dorsal, prefrontal regions. These findings were consistent with the hypothesis that cocaine dependence involves alterations in orbitofrontal connectivity, and supplement prior studies showing metabolic and neurochemical changes in the orbitofrontal cortex in cocaine abusers. Lim et al., Biol Psychiatry, 51, pp. 890-895, 2002.

Higher Levels of CSF of Homovanillic Acid in Recently Abstinent Cocaine-dependent Patients

Alec Roy and colleagues performed lumbar punctures on 30 cocaine-dependent male patients abstinent for an average of 28 days and compared homovanillic acid levels to 69 male controls. The average concentration among the cocaine patients was about 30% higher than in the controls (33.6 ng/ml vs. 25.4 ng/ml). The distribution of levels in the patients was fairly constant over the range from 12 to 57 ng/ml; the controls had a larger range but 75% had levels less than the patients' average. There was overlap for the patients as well in as much as 30% had levels less than the controls' average. The data support increased dopamine turnover perhaps due to a dysregulated system in these recently abstinent patients. Roy et al., Am J Psychiat 159(6), pp. 1053-1055, 2002.

Relationship Between Cocaine Craving and Depressive Symptomatology

Elman and his colleagues studied the relationship between self-reported cocaine craving following cocaine administration (0.2 mg/kg, i.v.) and depressive symptoms in 33 cocaine-dependent individuals. Scores on the Hamilton Rating Scale for Depression (HRSD) were positively correlated with the intensity of cocaine-primed craving, even after controlling for baseline spontaneous craving, age, gender, frequency of use, time since last use, monetary expenditure on cocaine and Addiction Severity Index Drug Composite Score. These data support the hypothesis that depressive symptomatology affects cocaine-primed craving and that this relationship is relatively specific to symptoms defined by the HRSD and not to a number of other clinical and demographic variables. Elman et al., J Psychopharmacol., 16, pp. 163-167, 2002.

Standardized Neuropsychological Measures of Apathy and Depression in the Cocaine Abstinence Syndrome

The cocaine abstinence syndrome has been associated with a range of symptoms, including apathy and depression. Although initial studies reported high prevalence rates of "apathy/amotivation" and depression, validated rating scales of apathy were not then available. A validated measure of apathy was used to test whether newly abstinent cocaine-dependent subjects would report increased apathy compared with non-cocaine-using control subjects. Because apathy and depression are dissociable in other neuropsychiatric syndromes, testing to determine whether they were dissociable in recently abstinent cocaine-dependent subjects was also conducted. Following four days of monitored abstinence, 11 cocaine-dependent subjects and 19 non-drug-using control subjects were administered standardized tests of apathy and depression. Cocaine-dependent subjects had elevated scores on the apathy rating scale compared with the control group, but the groups did not differ in ratings of depression. These data suggest that apathy is present during the initial phases of abstinence for a subset of cocaine-dependent individuals. Kalechstein et al., Apathy Syndrome in Cocaine Dependence. Psychiatry Research. 109(1), pp. 97-100, 2002.

Neuropsychological Performance in Users of Crack-Cocaine Alone or in Combination with Alcohol

Little data exist on the neuropsychological effects of crack-cocaine dependence or crack-cocaine and alcohol dependence. This study examined cognitive function in abstinent crack dependent and crack and alcohol dependent individuals at 6 wks and 6-mo abstinence. A comprehensive neuropsychological battery, including the MicroCog computerized assessment, was administered to 20 abstinent crack dependent Ss, 37 abstinent crack and alcohol dependent Ss, and 29 normal controls. Depression was examined as a covariate, and the association between substance use variables and neuropsychological performance was examined. Results show that the 2 substance dependent groups had similar neuropsychological profiles at 6 wks abstinent, with both groups exhibiting significant cognitive impairment in a wide range of functions compared to controls. The substance dependent groups were still impaired significantly at 6 mo 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 et al., Neuropsychological Performance of Individuals Dependent on Crack-Cocaine, or Crack-Cocaine and Alcohol, at 6 Weeks and 6 Months of Abstinence. Drug & Alcohol Dependence, 66(2), pp. 161-171, 2002.

Probing Brain Reward System Function In Major Depressive Disorder: Altered Response to Dextroamphetamine

Busto and colleagues at the University of Toronto tested the hypothesis that the dopaminergic component of the brain system related to reward is dysfunctional in depressed individuals. It was hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to anhedonic symptoms. The behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured using a double-blind, placebo-controlled, randomized, parallel study design. The subjects were 40 medication-free patients with depressive disorder (22 assigned to dextroamphetamine and 18 to placebo) and 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo). Severity of depression as measured by the Hamilton Rating Scale for Depression was highly correlated with the rewarding effects of dextroamphetamine in the depressed group (model R(2) = 0.63; interaction P =.04). Furthermore, patients with the most severe symptoms reported rewarding effects 3.4-fold greater than controls. The results showing the presence of a hypersensitive response in the brain reward system of depressed patients may reflect a basal hypofunctional state contributing to symptoms of anhedonia. These results provide a basis for the high degree of co-morbidity between stimulant abuse and depression. Busto et al., Arch Gen Psychiatry, 59, pp. 409-416, 2002.

Dopamine Transport Function is Elevated in Cocaine Users but Not Those with Excited Delirium

Mash and colleagues have assessed dopamine transporter (DAT) function in the post-mortem brain tissue of individuals with chronic cocaine abuse. These results are consistent with previous studies indicating adaptive increases in DAT-binding site density. By contrast, levels of dopamine uptake were not elevated in victims of excited cocaine delirium. These individuals experience paranoia and marked agitation prior to death. It is speculated that these symptoms may result from an uncompensated increase in dopamine without increased re-uptake at the pre-synapse. Mash et al., J Neurochem., 81, pp. 292-300, 2002.

Potentially Functional Polymorphism in the Promoter Region of Prodynorphin Gene May be Associated with Protection Against Cocaine Dependence or Abuse

Mary Jeanne Kreek and her associates studied the promoter region of the prodynorphin gene that has been shown to contain one, two, three, or four copies of a 68-base pair tandem repeat. It has been shown that this opioid peptide plays a modulating role in the effects of cocaine (among other drugs). Three or four copies of the repeat were shown to increase the transcription activation. Accordingly, this area was analyzed in cocaine abusers and in dependent patients and compared to ethnic-matched controls. It was discovered that the Relative Risk for the greater number of tandem repeats (3 + 4) was significantly low, suggesting that possession of one of these alleles was a protective factor in cocaine abuse or dependence. The number of patients was too small for a completely separate analysis for each ethnic group, though the risk in African American subjects was strong enough to demonstrate a significant effect. Chen et al., Am J Med Genet (Neuropsychiat Genet) 114, pp. 429-435, 2002.

Measures of Impulsivity, Aggression, and Sensation-seeking were Confirmingly Higher in Cocaine-dependent Individuals but Neither These Characteristics Nor the Patients Themselves were Distinguished by Polymorphisms of the Serotonin Transporter

In another study, Patkar and associates investigated several personality measures in 44 patients seeking treatment for cocaine dependence as well as gene variants in the serotonin transport. The results showed much higher scores for nearly all scales of the Buss-Durkee and for the Disinhibition and Thrill/adventure subscales of the Sensation Seeking (SSS) inventory. There was a modest difference for the Barratt Impulsivity (BIS) inventory, especially the Cognitive Subscale. Two different polymorphisms were examined and neither has variants that were related to any of the personality measures even though it had been shown that many of these measures were heritable. Patkar et al., Psychiatric Res, 110, pp. 103-115, 2002.

Effects of Smoked Marijuana on Brain Perfusion and Cognition

O'Leary and colleagues at the University of Iowa used PET imaging to assess the effects of smoked marijuana on brain activation related to cognitive performance. Regional cerebral blood flow (rCBF) was imaged before and after smoking of marijuana in 12 recreational marijuana users in a double-blinded, placebo study design. The subjects performed an auditory attention task while being imaged. Smoking marijuana did not significantly alter mean behavioral performance on the attention task. Despite dramatic increases in heart rate and blood pressure following smoking of marijuana, there was no change in global cerebral blood flow. Marijuana increased rCBF predominately in "paralimbic" regions such as the orbital and medial frontal lobes, insula, temporal poles, and anterior cingulate, as well as in the cerebellum. Activations in these areas most likely reflect marijuana's mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. Most intriguingly, there was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, or in basal ganglia or hippocampus, which have a high density of cannabinoid receptors. O'Leary et al., Neuropsychopharmacology, 26, pp. 802-816, 2002.

Effects of Frequent Marijuana Use on Memory-Related Regional Cerebral Blood Flow

In another study, O'Leary and colleagues at the University of Iowa used PET imaging of regional cerebral blood flow (rCBF) to examine changes in memory-related brain activation in frequent marijuana users after 26 hours of monitored abstinence. During initial learning, marijuana users, relative to control subjects, required an average of 2.7 more presentations to learn a word list to criterion and 3.1 more presentations during subsequent relearning. In single-trial recall, marijuana users recalled 23% more items than control subjects from the end of a list, but 19% less from the middle, suggesting that marijuana users have an increased reliance on short-term memory. Memory-related blood flow in marijuana users, relative to non-using control subjects, was decreased in the prefrontal cortex, increased in regions of cerebellum, and exhibited altered lateralization in the hippocampus. These findings indicate that during early abstinence marijuana users differed most in brain activity related to episodic memory encoding. O'Leary, et al., Pharmacol. Biochem. Behav., 72, pp. 237-250, 2002.

Increased Number of Opioid Receptors on Erythrocytes of Opioid Abusers

Patkar and associates assayed for mu opioid receptors on erythrocytes in opioid-dependent subjects. Overall there were significantly more in the dependent subjects but the distribution was bimodal where one subgroup has very high levels and the other was indistinguishable from normal subjects. Those with high levels showed distortions of the erythrocytes, suggesting a cause for the high prevalence of anemia in these subjects. Zeiger et al., Addict Biol., 7(2), pp. 207-217, 2002.

Buprenorphine Maintenance and Opioid Drug-Seeking Behavior in Humans

Greenwald and colleagues at Wayne State University contrasted the effects of daily versus alternating-day administration of high versus low buprenorphine doses on the choice of, and operant responding for, hydromorphone versus money. Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet dose conditions using a double-blind, within-subject, randomized crossover design. All participants received: buprenorphine doses of 2mg daily; 4 mg/placebo on alternating days; 16 mg daily; and 32 mg/placebo on alternating days for 2 weeks for each drug condition. In test sessions, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg, i.m. in different sessions) alternatives using an eight-trial, non-independent progressive ratio schedule (FR 100, 200,12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average buprenorphine doses (regardless of daily versus alternate-day schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline heroin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by high-dose buprenorphine. These results demonstrate that high-dose buprenorphine attenuates opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alternative reinforcement. These beneficial effects were retained when high-dose buprenorphine was administered on alternate days. Greenwald et al., Psychopharmacology, 160, pp. 344-352, 2002.

Perfusion Deficits in Cocaine and Alcohol Dependent Individuals

Cocaine abuse has been associated with widely distributed areas of significant cerebral blood flow (CBF) reductions or hypo-perfusion as well as CBF hyper-perfusion, but these perfusion abnormalities have not been examined using newer technologies such as statistical parametric mapping (SPM). These areas of abnormal CBF may be more likely among those who abuse cocaine and alcohol together. Using SPECT with HMPAO for CBF, investigators compared proportional scaling (PS) to histogram normalization (HEQ) in SPM among 20 controls and 32 recently abstinent cocaine abusers. The cocaine abusers were separated into two groups (12 cocaine plus alcohol abusers and 20 cocaine alone abusers) and both groups compared to the 20 controls for brain areas of hypo- and hyper-perfusion. Sensitivity to hypo-perfusion was greater with HEQ than PS. Hypo-perfused areas were more likely in the 12 alcohol plus cocaine abusers than in the 20 cocaine alone abusers or 20 controls, and hyper-perfused areas were significantly more likely among the cocaine abusers than controls. The type of CBF abnormality varied by brain location with hypo-perfusion significantly more likely in occipital and temporal cortex or cerebellum and hyper-perfusion more likely in frontal and parietal cortex. These abnormalities in brain perfusion are consistent with previous non-SPM approaches that showed more hypo-perfusion in cocaine abusers than controls and appear to reflect vasospasm and potential compensations in cerebral blood flow. Gottschalk, P., and Kosten, T. Cerebral Perfusion Defects in Combined Cocaine and Alcohol Dependence. Drug Alcohol Depend., 68(1), pp. 95., September 2, 2002.

Buproprion Enhances Smoking Abstinence in Nicotine-Dependent Schizophrenic Smokers

Schizophrenic patients have high rates of cigarette smoking compared with the general population. The investigators compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. They also examined how antipsychotic class predicts smoking cessation outcomes with bupropion. Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects. Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [BUP,8/16 (50.0%), PLA, 2/16 (12.5%); chi(2) = 5.24, df = 1, p <.05], and reduced CO levels during the trial [Medication x Time interaction; Z = 3.09, p <.01]. Positive schizophrenia symptoms were not altered by BUP, but negative symptoms were significantly reduced. Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP. Major side effects were dry mouth, gastrointestinal symptoms, headache, and insomnia. These results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP. George, T.P., Vessicchio, J.C., Termine, A., Bregartner, T.A., Feingold, A., Rounsaville, B.J.,and Kosten, T.R. A Placebo Controlled Trial of Bupropion for Smoking Cessation in Schizophrenia. Biol Psychiatry, 52(1). pp. 53-61, July 1, 2002.

Deficits in Sensory Gating and Attention May be Associated with Increased Proneness to Developing Psychotic Symptoms During Cocaine Use

Factors increasing vulnerability of a cocaine user to develop psychotic symptoms are unknown. Deficits in sensory gating and attention, such as those occurring in idiopathic psychosis, might represent experimentally tractable factors contributing to vulnerability to cocaine-induced paranoia. Severity of cocaine-induced paranoid symptoms was assessed with the Cocaine Experience Questionnaire (CEQ) in 30 abstinent cocaine-dependent individuals. Sensory gating was assessed in a paired-click auditory evoked potential paradigm (S1 and S2) using the S2/S1 attenuation ratio of the P50 evoked response as the primary outcome measure. The Wender-Utah Rating Scale (WURS) for attention deficit was also administered. Subjects were divided into those with high CEQ scores (n = 10) and those with low CEQ scores (n = 20). The mean P50 ratios were significantly higher for the high CEQ subjects compared with the low CEQ group (F = 4.6, p <.04). The WURS did not correlate with the total CEQ but correlated with the CEQ Severity subscale, r =.432, p <.02. The data suggest that deficient P50 sensory gating and attention deficits may be associated with increased proneness to developing psychotic symptoms in the context of cocaine use. Boutros, N.N., Gelernter, J., Gooding, D.C., Cubells, J., Young, A., Krystal, J.H., and Kosten, T. Sensory Gating and Psychosis Vulnerability in Cocaine-dependent Individuals: Preliminary Data. Biol Psychiatry, 51(8), pp. 683-686, April 15, 2002.

Heavy MDMA Users Show Increased Impulsivity

Moeller and associates assessed heavy (> one use/week; > 50 uses total), infrequent (< one use/week; < 30 uses total), and non-users of MDMA on a performance measure of impulsivity and on the Barratt Impulsiveness Scale. Heavy (but not infrequent) users had increased impulsivity on the Barratt and more commission errors as well as fewer correct responses on the performance measure. The performance measure required subjects to view quickly-presented five-digit numbers and determine if successive numbers were the same or different. Not only were the heavy users worse for errors as a group, but their errors were significantly correlated with the amount of self-reported MDMA use. The correlation was especially strong (r = .69; p < .003) for the performance measure when a memory element was introduced. While this study is limited by a small sample size, and the possibility of confounding effects of other drugs, it is suggestive that MDMA use is associated with impulsivity warranting further study. Moeller, F.G., Dougherty, D.M., Steinberg, J.L., Swann, A.C., Silverman, P.B., Ruiz, P., Barratt, E.S. Heavy "Ecstasy" Use is Associated With Increased Impulsivity. Journal of Addictive Disorders and Their Treatment, 1, pp. 47-52, 2002.

Opioid Dependence is Associated with Perturbation of HPA Axis

Alteration in noradrenergic regulation as well as alteration in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxy-phenethylene glycol (MHPG), and cortisol. Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients. Stine, S.M., Southwick, S.M., Petrakis, I.L., Kosten, T.R., Charney, D.S., and Krystal, J.H. Yohimbine-induced Withdrawal and Anxiety Symptoms in Opioid-dependent Patients. Biol Psychiatry, 51(8), pp. 642-651, April 15, 2002.

Inhibition of Cortisol Synthesis Does not Reduce Cocaine or Opioid Use in Humans Maintained on Methadone

Stress plays an important role in substance abuse problems. For example, in studies with rodents stress induces reinstatement of opioid and cocaine self-administration. In addition, attenuation of the stress response by pharmacological adrenalectomy using ketoconazole, a cortisol synthesis inhibitor, reduces cocaine self-administration in rodents. In contrast, studies in primates and humans have produced conflicting results using cortisol synthesis inhibitors for attenuating cocaine-related behaviors and subjective effects. To explore the treatment implications of these findings, ketoconazole's (600-900 mg daily) ability to reduce heroin and cocaine use was compared with placebo in 39 methadone maintained patients with a history of cocaine abuse or dependence during a 12-week double blind trial. Contrary to the predicted effects, both heroin and cocaine use increased after patients were stabilized on methadone and ketoconazole. Depressive and withdrawal symptoms improved no more with ketoconazole than with placebo treatment, and side effects were greater on ketoconazole than placebo. As reported before with methadone treatment, morning cortisol levels were significantly lower than normal values throughout the clinical trial, but were not lower with ketoconazole than placebo treatment. Thus, in agreement with the negative results from acute dosing studies in primates and humans, chronic ketoconazole treatment does not appear to reduce cocaine or opioid use in humans maintained on methadone. Kosten, T.R., Oliveto, A., Sevarino, K.A., Gonsai, K., and Feingold, A. Ketoconazole Increases Cocaine and Opioid Use in Methadone Maintained Patients. Drug Alcohol Depend, 66(2), pp. 173-180, April 1, 2002.

Effects of Oral THC Maintenance on Smoked Marijuana Self-Administration

Studies have shown that the Delta (9)-tetrahydrocannabinol (Delta (9)-THC) concentration in marijuana cigarettes is an important factor for the maintenance of marijuana self-administration. Yet the impact of oral Delta (9)-THC treatment on marijuana self-administration is unknown. Because other agonist therapies have been demonstrated to be effective for the treatment of substance use disorders, the objective of this study was to evaluate the influence of oral Delta (9)-THC maintenance on choice to self-administer smoked marijuana. During this 18-day residential study, 12 healthy research volunteers received one of three doses of oral Delta (9)-THC capsules (0, 10, 20 mg QID) for 3 consecutive days, followed by 3 consecutive days of matching placebo. The order of active Delta (9)-THC administration was counterbalanced. Each morning, except on days 6, 12, and 18, participants smoked the 'sample' marijuana cigarette (1.8% Delta (9)-THC w/w) and received a $2 voucher (redeemable for cash at study's end). Following the sample, volunteers participated in a four-trial choice procedure during which they had the opportunity to self-administer either the dose of marijuana they sampled that morning or to receive the $2 voucher. Relative to placebo Delta (9)-THC maintenance, participants' choice to self-administer marijuana was not significantly altered by either of the two active Delta (9)-THC maintenance conditions. Some 'positive' subjective drug-effect ratings following the sample marijuana cigarette were reduced: by day 3 of active oral Delta (9)-THC maintenance, participants' rating of 'Good Drug Effect' and 'High' were significantly decreased. Smoked marijuana-related total daily caloric intake was not significantly altered under any maintenance conditions. Finally, the effects of smoked marijuana on psychomotor task performance were only minimally affected by oral Delta (9)-THC maintenance. These data indicate that participants' choice to self-administer marijuana was unaltered by the oral Delta (9)-THC dosing regimen used in the present investigation. Hart, C.L., Haney, M., Ward, A.S., Fischman, M.W., and Foltin, R.W. Effects of Oral THC Maintenance on Smoked Marijuana Self-administration. Drug Alcohol Depend, 67(3), pp. 301-309, August 1, 2002.

Intravenously Administered Buprenorphine May Have Abuse Liability in Nonopioid-Dependent Individuals Who Abuse Heroin

Several sources indicate that intravenously administered buprenorphine may have significant abuse liability in humans. This study evaluated the reinforcing effects of intravenously administered buprenorphine (0, 2, and 8 mg) in detoxified heroin-dependent participants during a 7.5-week inpatient study. Participants (n = 6) were detoxified from heroin over a 1.5-week period immediately after admission. Testing subsequently occurred in three 2-week blocks. During the first week of each 2-week block, the reinforcing effects of buprenorphine were evaluated. Participants first received a dose of buprenorphine and $20 and then were given either the opportunity to self-administer the dose or $20 during choice sessions. During the second week of each 2-week block, the direct effects of heroin were measured to evaluate potential long-lasting antagonist effects of buprenorphine. Progressive ratio break-point values were significantly higher after 2 and 8 mg of buprenorphine compared with placebo. Correspondingly, several positive subjective ratings increased after administration of active buprenorphine relative to placebo. Although there were few differences in peak effects produced by 2 versus 8 mg of buprenorphine, the higher buprenorphine dose generally produced longer-lasting effects. Heroin also produced dose-related increases in several subjective effects. Peak ratings produced by heroin were generally higher than peak ratings produced by buprenorphine. There was little evidence of residual antagonism produced by buprenorphine. These results demonstrate that buprenorphine served as a reinforcer under these conditions, and that it may have abuse liability in nonopioid-dependent individuals who abuse heroin. Comer, S.D., Collins, E.D., and Fischman, M.W. Intravenous Buprenorphine Self-administration by Detoxified Heroin Abusers. J Pharmacol Exp Ther, 301(1), pp. 266-276, April 2002.

Bupropion May be as Effective as Methylphenidate, When Combined with Relapse Prevention Therapy, for Cocaine Abusers with ADHD

There are few published studies assessing the efficacy of pharmacologic treatments for attention-deficit hyperactivity disorder (ADHD) among substance abusers seeking treatment. Eleven patients who met DSM-IV diagnostic criteria for cocaine dependence and adult ADHD were entered into a 12-week single-blind trial of divided daily doses of bupropion (BPR). All patients received weekly individual standardized relapse prevention therapy. Treatment compliance and retention were good. Patients reported significant reductions in attention difficulties, hyperactivity and impulsivity. Self-reported cocaine use, cocaine craving, and cocaine positive toxicologies, also decreased significantly. In a previously published trial, 12 patients who met similar diagnostic criteria for adult ADHD and cocaine dependence were entered into a 12-week trial of divided daily doses of sustained-release methylphenidate (MPH). Improvements observed on BPR were similar to, and did not differ from those previously observed with MPH. These preliminary data suggest that BPR may be as effective as sustained-release MPH, when combined with relapse prevention therapy, for cocaine abusers with adult ADHD. However, a future study directly comparing BPR to MPH in a double-blind placebo-controlled trial is needed. Levin, F.R., Evans, S.M., McDowell, D.M., Brooks, D.J., and Nunes E. Bupropion Treatment for Cocaine Abuse and Adult Attention-Deficit/Hyperactivity Disorder. J Addict Dis., 21(2), pp.1-16, 2002.

Addition of Naloxone to Buprenorphine May deter the Parenteral Abuse of Buprenorphine/Naloxone, but Does Not Enhance the Therapeutic Efficacy of Buprenorphine

Buprenorphine is an opioid agonist-antagonist used in the treatment of opioid dependence. Naloxone has been combined with buprenorphine to decrease the parenteral abuse potential of buprenorphine. This addition of naloxone may also confer further opioid blockade efficacy. The objective of this study was to test the opioid blockade efficacy of sublingual buprenorphine/naloxone versus buprenorphine alone and determine whether: (1) the blockade efficacy of buprenorphine/naloxone varies between the time of expected maximal and minimal effects of naloxone, (2) the blockade efficacy of buprenorphine/naloxone and buprenorphine varies as a function of maintenance dose level, and (3) there are adaptive changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine. Residential subjects (n=6) were maintained on different double-blind dose levels of buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg) and buprenorphine (32 mg) for 6-day periods and challenged with parenteral doses of hydromorphone (12 mg) in laboratory sessions. There was no evidence of additional opioid blockade efficacy conferred by combining naloxone with buprenorphine. Higher doses of buprenorphine/naloxone provided greater blockade of hydromorphone effects. Changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine were minimal. The addition of naloxone to buprenorphine may deter the parenteral abuse of buprenorphine/naloxone, but it does not enhance the therapeutic efficacy of buprenorphine. The blockade efficacy of buprenorphine/ naloxone is dose related; however, doses up to 32/8 mg buprenorphine/naloxone provide only partial blockade when subjects receive a high dose of an opioid agonist. Strain, E.C., Walsh, S.L., and Bigelow, G.E. Blockade of Hydromorphone Effects by Buprenorphine/Naloxone and Buprenorphine. Psychopharmacology (Berl), 59(2), pp. 161-166, January 2002.

Gender, Family/Social Environment, and Years of Education Influence Treatment Dropouts in Addicts

Determining pre-treatment variables that predict attrition in an outpatient cocaine abuse program is critically important in efforts to enhance retention and ultimately improve client outcome. Potential predictors have been identified, such as treatment history, deviant behaviors, and level of drug use; however there is not widespread agreement on their applicability across treatments and populations. This study examines the relationship of demographic, drug use severity, and psychosocial factors with treatment attrition and the time of dropout. One hundred and sixty-five individuals from the Houston area, seeking treatment for cocaine dependence, completed a pre-treatment assessment battery prior to starting 12 weeks of outpatient treatment. A series of regression analyses showed that treatment dropouts were more likely to be separated from their spouses, have poorer family/social functioning, have fewer years of education, and to be female. Those participants with higher education levels and those with poorer psychiatric functioning tended to remain in treatment longer. The implications of these findings are discussed. Sayre, S.L., Schmitz, J.M., Stotts, A.L., Averill, P.M., Rhoades, H.M., and Grabowski, J.J. Determining Predictors of Attrition in an Outpatient Substance Abuse Program. Am J Drug Alcohol Abuse, 28(1), pp. 55-72, 2002.

Cocaine Addicts have Decreased Cortical Gray Matter Concentration in Comparison to Controls

Structural deficiencies within limbic and prefrontal regions may contribute to the characteristic drug-seeking and drug-taking behaviors that prevail in persons dependent on cocaine. To date, a focal structural analysis of the brains of cocaine patients has not been undertaken. Investigators used voxel based morphometry in conjunction with statistical parametric mapping on the structural magnetic resonance images of cocaine-dependent (n = 13) and cocaine-naive individuals (n = 16) to assess differences between the two groups in gray and white matter concentration. Authors report a decrease in gray matter concentration in the ventromedial orbitofrontal, anterior cingulate, anteroventral insular, and superior temporal cortices of cocaine patients in comparison to controls (p <.01 corrected for multiple comparisons). The average percentage decrease in gray matter concentration within a region ranged from 5% to 11%. White matter concentration did not differ between groups. Authors conclude that the brains of cocaine patients are structurally dissimilar from those of nondrug-using controls. The differences were detected in regions involved in decision-making, behavioral inhibition and assignation of emotional valence to environmental stimuli and, hence, may contribute to some of the behavioral deficits characteristic of chronic cocaine users. Franklin, T.R., Acton, P.D., Maldjian, J.A., Gray, J.D., Croft, J.R., Dackis, C.A., O'Brien, C.P., and Childress, A.R. Biol Psychiatry, 51(2), pp. 134-142, January 15, 2002.

Effects of Infusion Rate of Intravenously Administered Morphine on Physiological, Psychomotor, and Self-reported Measures in Humans

The rate of onset of a drug effect is commonly believed to contribute to a drug's abuse liability. The purpose of this study was to investigate the profile of physiological, psychomotor, and self-reported effects of infusion rate (a key means of manipulating onset of drug action) of intravenously administered morphine, the prototypical analgesic with a known abuse liability in human participants. Two doses of morphine sulfate (5 and 10 mg/70 kg, i.v.) and a placebo dose (0 mg/70 kg, i.v.) were administered to healthy volunteers under three infusion rates (2 min bolus, 15 min, and 60 min). Faster infusions of morphine produced greater positive subjective effects than slower infusions on visual analog scale measures of good drug effect, drug liking, and high. Faster infusions also resulted in greater self-reported drug effects and opioid agonist effects, without producing significant physiological or psychomotor impairment. Importantly, faster rates of drug infusion produced significantly higher morphine plasma levels than slower rates, and morphine plasma levels followed a similar pattern and timing of peak effect as the self-reported effects of the drug. Moreover, morphine produced dose-dependent increases in self-reported drug effects, opioid agonist effects, and morphine plasma levels in the study. Results suggest that the pharmacokinetic properties of a drug, including the dosage administered and the rate at which it is administered may function to jointly affect the abuse liability of the drug. Marsch, L.A., Bickel, W.K., Badger, G.J., Rathmell, J.P., Swedberg, M.D., Jonzon, B., and Norsten-Hoog, C. J. Pharmacol Exp Ther., 299(3), pp. 1056-1065, December 2001.

Outcomes and Service Use Among Homeless Persons with Serious Mental Illness and Substance Abuse

This study compared baseline characteristics and clinical improvement after 12 months among 5,432 homeless persons with a diagnosis of serious mental illness with and without a comorbid substance use disorder. The results showed that clients with dual diagnoses were worse off than those without dual diagnoses on most clinical and social adjustment measures. Clients with dual diagnoses also had poorer outcomes at follow-up on 15 (62 percent) of 24 outcome measures. However, among clients with dual diagnoses, those who reported extensive participation in substance abuse treatment showed clinical improvement comparable to or better than that of clients without dual diagnoses. On measures of alcohol problems, clients with dual diagnoses who had a high rate of participation in self-help groups had outcomes superior to those of other clients with dual diagnoses. Clients with dual diagnoses who received high levels of professional services also had superior outcomes in terms of social support and involvement in the criminal justice system. Homeless persons with dual diagnoses had poorer adjustment on most baseline measures and experienced significantly less clinical improvement than those without dual diagnoses. However, those with dual diagnoses who received extensive substance abuse treatment showed improvement similar to those without at 12 months. Gonzalez, G., and Rosenheck, R.A. Psychiatr Serv., 53(4), pp. 437-446, April 2002.

A Pilot Placebo-Controlled Study of Fluvoxamine for Pathological Gambling

The objective of this study was to evaluate the efficacy of fluvoxamine in the treatment of pathological gambling. Thirty-two patients were treated for 6 months in a double-blind, placebo-controlled study of fluvoxamine 200 mg/day. Outcome measures included reduction in money and time spent gambling per week. Longitudinal mixed effects models and completers analyses were used for estimation and hypothesis testing. Fluvoxamine was not statistically significantly different from placebo in the overall sample. However, fluvoxamine was statistically significantly superior to placebo in males and in younger patients. The power of the study was limited by the high (59%) placebo-response rate. Fluvoxamine may be a useful treatment for certain subgroups of patients with pathological gambling. Several methodological recommendations are made for future pharmacological trials of pathological gambling. Blanco, C., Petkova, E., Ibanez, A., and Saiz-Ruiz, J. Ann Clin Psychiatry, 14(1), pp. 9-15, March 2002.

The Subjective Effects of Nicotine: Methodological Issues, A Review of Experimental Studies, and Recommendations for Future Research

This paper reviews findings from placebo-controlled human experimental studies of the effects of nicotine on subjective experience. Studies are grouped according to whether participants were smokers (significantly nicotine deprived, minimally nicotine deprived) or non-smokers. Within each category, studies are also grouped according to method of nicotine administration (e.g., smoked tobacco, nasal spray) and nicotine dose. The results show that: (1) there is a linear relationship between nicotine dose and measures of drug high (e.g., rush, euphoria) in significantly nicotine-deprived smokers; (2) there appear to be few positive or negative main effects of nicotine on mood in minimally nicotine-deprived smokers; (3) nicotine has positive effects (e.g., increases head rush) and negative effects (e.g., tension) in non-smokers; (4) stronger effects of nicotine on mood emerge when individual difference variables (e.g., neuroticism) and situational contingencies (e.g., exposure to stressful stimuli) are examined. The investigator suggests additional studies with minimally nicotine-deprived smokers and non-smokers are needed to further specify the conditions under which nicotine affects mood and other subjective experience. Kalman, D. Tobacco Res., 4(1), pp. 25-70, February 2002.

Locating Nucleobase Lesions Within DNA Sequences by MALDI-TOF Mass Spectral Analysis of Exonuclease Ladders

Investigators at the University of Minnesota Cancer Center and Department of Medicinal Chemistry studied the location of carcinogen-modified nucleobases (DNA adducts) within DNA sequences as a critical factor affecting their promutagenic properties and persistence in DNA. They report the use of controlled exonuclease digestion followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to directly map modified nucleobases within DNA. The DNA sequence is determined by mass spectral analysis of the DNA ladders produced by sequential removal of nucleotides with either 5'-->3' or 3'-->5' exonuclease. Individual mononucleotides are identified from the mass differences between adjacent peaks corresponding to singly charged ions of the products of enzymatic cleavage. Chemically modified nucleotides are detected and identified by their molecular weight. The resolution and mass accuracy of this approach are sufficient to identify nucleobase modifications differing in mass by as little as 2 Da. No a priori information on the DNA sequence or adduct type is required. The investigators demonstrated the general applicability of this method by sequencing synthetic oligonucleotides containing a range of nucleobase modifications: O(6)-methylguanine, peroxynitrite-induced oxidative lesions (oxaluric acid, oxazolone, cyanuric acid), and the N(2)-guanine adduct of (+,-)-7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydribenzo [a]pyrene. Sequence information is also obtained for DNA oligodeoxynucleotides containing O(6)-pyridyloxobutylguanine, despite the ability of this lesion to block 3'-phosphodiesterase. Tretyakova, N., Matter, B., Ogdie, A., Wishnok, J.S., and Tannenbaum, S.R. Chem Res Toxicol., 14(8), pp. 1058-1070, August 2001.

Formation of Benzo[a]pyrene Diol Epoxide-DNA Adducts at Specific Guanines within K-ras and p53 Gene Sequences: Stable Isotope-Labeling Mass Spectrometry Approach

The mutagenicity of a prominent tobacco carcinogen, benzo[a]pyrene (B[a]P), is believed to result from chemical reactions between its diol epoxide metabolite, (+)-anti-7r,8t-dihydroxy-c9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE), and DNA, producing promutagenic lesions, e.g., (+)-trans-anti-7R,8S,9S- trihydroxy-10S-(N(2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo [a]pyrene (N(2)-BPDE-dG). Previous studies used the DNA repair enzyme UvrABC endonuclease in combination with ligation-mediated PCR (LMPCR) to demonstrate an increased reactivity of BPDE toward guanine nucleobases within codons 157, 248, and 273 of the p53 tumor suppressor gene. These sites are also "hot spots" for mutations observed in lung tumors of smokers, suggesting an involvement of B[a]P in the initiation of lung cancer. However, the LMPCR approach relies on the ability of the repair enzyme to excise BPDE-induced lesions, and thus the slowly repaired lesions may escape detection. Furthermore, BPDE-DNA adduct structure and stereochemistry cannot be determined. In the present work, the investigators performed a direct quantitative analysis of N(2)-BPDE-dG originating from specific guanine nucleobases within p53- and K-ras-derived DNA sequences by using a stable isotope labeling-mass spectrometry approach recently developed in the authors laboratory. (15)N-labeled dG was placed at defined positions within DNA sequences derived from the K-ras proto-oncogene and p53 tumor suppressor gene, the two genes most frequently mutated in smoking-induced lung cancer. (15)N-labeled DNA was annealed to the complementary strands, followed by BPDE treatment and liquid chromatography-electrospray ionization tandem mass spectrometry analysis (HPLC-ESI-MS/MS) of N(2)-BPDE-dG lesions. The extent of adduct formation at (15)N-labeled guanine was determined directly from the HPLC-ESI-MS/MS peak area ratios of (15)N-N(2)-BPDE-dG and N(2)-BPDE-dG. BPDE-induced guanine adducts were produced non-randomly along K-ras and p53 gene-derived DNA sequences, with over 5-fold differences in adduct formation depending on sequence context. N(2)-BPDE-dG yield was enhanced by the presence of 5-Me substituent at the cytosine base-paired with the target guanine nucleobase, an endogenous DNA modification characteristic for CpG dinucleotides within the p53 gene. In the K-ras-derived DNA sequence, the majority of N(2)-BPDE-dG adducts originated from the first position of the codon 12 (GGT), consistent with the large number of G --> T transversions observed at this nucleotide in smoking-induced lung cancer. On the contrary, the pattern of N(2)-BPDE-dG formation within the p53 exon 5 sequences did not correlate with the mutational spectrum in lung cancer, suggesting that factors other than N(2)-BPDE-dG formation are responsible for these mutations. The stable isotope labeling HPLC-ESI-MS/MS approach described in this work is universally applicable to studies of modifications to isolated DNA by other carcinogens and alkylating drugs. Tretyakova, N., Matter, B., Jones, R., and Shallop, A. Biochemistry, 41(30), pp. 9535-9544, July 30, 2002.

Prevalence of Cigarette Smoking in Pregnant Women Participating in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) in Minneapolis and Saint Paul, Minnesota, USA

It is important to determine the prevalence of cigarette smoking among pregnant low-income women and to evaluate their smoking cessation patterns in order to target appropriate interventions. Ethnically diverse pregnant women aged 15-45 years were recruited from Minneapolis or Saint Paul Women, Infants, and Children (WIC) clinics before their third trimester. Serum cotinine levels were assayed for 98 women and compared with self-report. The women were unaware that their smoking status would be validated. Twenty-one (21%) women had a positive serum cotinine value (>/=3 ng/mL); 16 (76%) admitted smoking within the previous 24 h before interview and five denied smoking. Of the five, four had cotinine levels that could suggest passive smoke exposure. Thirty-seven women (38%) admitted cigarette smoking during the pregnancy but before knowing that they were pregnant; 18 (49%) of these denied current smoking at the interview and also presented with negative cotinine levels. These data suggest that some participants in WIC make a concerted effort to quit smoking when they find out they are pregnant, and are generally truthful when reporting their smoking habits during pregnancy. Ross, J.A., Swensen, A.R., and Murphy, S.E. Paediatr Perinat Epidemiol., 16(3), pp. 246-248, July 2002.

Cigarette Smoking and Lung Cancer: Chemical Mechanisms and Approaches to Prevention

Much is now known about the carcinogens in cigarette smoke, their conversion to forms that react with DNA, and the miscoding properties of the resulting DNA adducts that cause the many genetic changes known to exist in human lung cancer. The chronic exposure of pulmonary DNA to a multitude of metabolically activated carcinogens is consistent with our current understanding of cancer as a disease resulting from many changes in key genes regulating growth. This review illustrates how this solid foundation of knowledge can be used to find new ways to prevent lung cancer. Three prevention-related topics are discussed: human uptake of tobacco carcinogens as a way of assessing risk and investigating mechanisms; individual differences in the metabolic activation and detoxification of carcinogens, which may relate to cancer susceptibility; and chemo-prevention of lung cancer in smokers and ex-smokers. These new approaches are necessary as adjuncts to education and cessation efforts, which despite some success have not eliminated tobacco smoking. Hecht, S.S. Lancet Oncol., 3(8), pp. 461-469, August 2002.

Quantitation of Metabolites of 4-(methylnitrosamino)-1-(3-pyridyl) -1-butanone After Cessation of Smokeless Tobacco Use

Two major metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were previously shown to be highly persistent in human urine after cessation of cigarette smoking. The authors hypothesized that NNK or its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was sequestered in the lung. In this study, the investigators further evaluated this hypothesis by quantifying the NNK metabolites, NNAL and its glucuronides (NNAL-Gluc), in urine and plasma after cessation of smokeless tobacco use, in which NNK is administered p.o. rather than by inhalation. Thirteen male nonsmokers, 11 snuff dippers and 2 tobacco chewers, in the study. Urine and plasma were obtained at baseline and at intervals 2-126 days after cessation of smokeless tobacco use. The distribution half-lives t(1/2alpha) (days) of NNAL (1.32 +/- 0.85 versus 3.35 +/- 1.86) and NNAL-Gluc (1.53 +/- 1.22 versus 3.89 +/- 2.43) were significantly shorter in smokeless tobacco users than in smokers. There were no significant differences in the terminal half-lives t(1/2beta) (days) of NNAL (26.3 +/- 16.7 versus 45.2 +/- 26.9) and NNAL-Gluc (26.1 +/- 15.1 versus 39.6 +/- 26.0) in smokeless tobacco users and smokers. Baseline levels as well as renal clearance of the NNK metabolites correlated with number of tins or pouches of smokeless tobacco consumed. Ratios of (S)-NNAL:(R)-NNAL and (S)-NNAL-Gluc:(R)-NNAL-Gluc in urine were significantly (3.1-5.7 times) higher 7 days after cessation than at baseline in both smokeless tobacco users and smokers, indicating stereoselective retention of (S)-NNAL. Collectively, the results of this study suggest that there is a receptor in the human body, possibly in the lung, for (S)-NNAL, the more carcinogenic NNAL enantiomer. These data may have considerable implications for understanding mechanisms of tumor induction by NNK. Hecht, S.S., Carmella, S.G., Ye, M., Le, K.A., Jensen, J.A., Zimmerman, C.L., and Hatsukami, D.K. Cancer Res., 62(1), pp. 129-134, January 1, 2002.

Human Urinary Carcinogen Metabolites: Biomarkers for Investigating Tobacco and Cancer

Measurement of human urinary carcinogen metabolites is a practical approach for obtaining important information about tobacco and cancer. This review presents currently available methods and evaluates their utility. Carcinogens and their metabolites and related compounds that have been quantified in the urine of smokers or non-smokers exposed to environmental tobacco smoke (ETS) include trans, trans-muconic acid (tt-MA) and S-phenylmercapturic acid (metabolites of benzene), 1- and 2-naphthol, hydroxyphenanthrenes and phenanthrene dihydrodiols, 1-hydroxypyrene (1-HOP), metabolites of benzo[a]pyrene, aromatic amines and heterocyclic aromatic amines, N-nitrosoproline, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (NNAL and NNAL-Gluc), 8-oxodeoxyguanosine, thioethers, mercapturic acids, and alkyladenines. Nitrosamines and their metabolites have also been quantified in the urine of smokeless tobacco users. The utility of these assays to provide information about carcinogen dose, delineation of exposed vs. non-exposed individuals, and carcinogen metabolism in humans is discussed. NNAL and NNAL-Gluc are exceptionally useful biomarkers because they are derived from a carcinogen- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- that is specific to tobacco products. The NNAL assay has high sensitivity and specificity, which are particularly important for studies on ETS exposure. Other useful assays that have been widely applied involve quantitation of 1-HOP and tt-MA. Urinary carcinogen metabolite biomarkers will be critical components of future studies on tobacco and human cancer, particularly with respect to new tobacco products and strategies for harm reduction, the role of metabolic polymorphisms in cancer, and further evaluation of human carcinogen exposure from ETS. Hecht, S.S. Carcinogenesis, 23(6), pp. 907-922, June 2002.

A Population-based Study of Cigarette Smoking Among Illicit Drug Users in the United States

The investigators describe smoking patterns among illicit drug users, assess whether cigarette smoking is more prevalent among illicit drug users than it is among non-users and explore how smoking relates to level and type of drug use. The sample consisted of adult responses to the 1997 National Household Survey on Drug Abuse (n = 16,661). Multivariate analyses used SUDAAN to adjust standard errors for the sampling design and controlled for age, race, sex, education, depression, treatment history and alcohol. The results show that 71% of recent illicit drug users smoked cigarettes at least once in the past month. Their adjusted odds of being a smoker were much greater than for the general population (OR = 3.07, P < 0.0001). Their quit rate, although substantial, was half that of non-users (23% versus 56%, P=0.0001). Odds of being a smoker were higher for poly- versus monodrug users (OR = 2.35, P=0.0020) and rose with increased drug use (OR = 1.36, P=0.0374). Illicit drug users who perceived smoking to be risky were four times less likely to smoke (OR = 0.23, P=0.0008). The results suggest that although most recent illicit drug users smoke, some are able to quit. Clinicians, policy makers and user advocates should address tobacco use in drug treatment and in harm reduction interventions. Richter, K.P., Ahluwalia, H.K., Mosier, M.C., Nazir, N., and Ahluwalia, J.S. Addiction, 97(7), pp. 861-869, July 2002.

A Screening Trial of Amantadine as a Medication for Cocaine Dependence

This screening trial evaluated whether amantadine hydrochloride (100 mg bid) demonstrated sufficient clinical efficacy compared to placebo to recommend development as a pharmacotherapy for cocaine dependence. Participants were randomized to amantadine (n=34) or placebo (n=35) conditions in a 16-week, placebo-controlled, double blind trial with three times per week group counseling. Amantadine-treated participants were retained significantly longer than placebo. Based on results of a joint probability index for urine drug testing results (i.e. the proportion of cocaine-metabolite free urine samples divided by the number of participants assigned to the condition), participants assigned to amantadine were found to be significantly more likely to be cocaine abstinent on the last day of 8-weeks of treatment than participants assigned to placebo. Results at the end of 16 weeks of treatment were similar. Standard measures of urine drug testing consistently favored the amantadine condition over placebo, although not at levels of statistical significance. There was no statistical significance infrequency or severity of reported adverse events by treatment condition. Participants assigned to amantadine exhibited greater reductions in global staff ratings of cocaine dependence severity from baseline to termination compared with placebo. There were no significant differences in frequency or severity of reported adverse events by treatment condition. These results provide moderate support for further study of amantadine for the treatment of cocaine dependence. Shoptaw, S., Kintaudi, P.C., Charuvastra, C., and Ling, W. Drug Alcohol Depend., 66(3), pp. 217-224, May 1, 2002.


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