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Objective: This study attempted to examine the brain's sensitivity to monetary rewards of different magnitudes in cocaine abusers and to study its association with motivation and self-control., Method: Sixteen cocaine abusers and 13 matched healthy comparison subjects performed a forced-choice task under three monetary value conditions while brain activation was measured with functional magnetic resonance imaging. Objective measures of state motivation were assessed by reaction time and accuracy, and subjective measures were assessed by self-reports of task engagement. Measures of trait motivation and self-control were assessed with the Multidimensional Personality Questionnaire., Results: The cocaine abusers demonstrated an overall reduced regional brain responsivity to differences between the monetary value conditions. Also, in comparison subjects but not in cocaine abusers, reward-induced improvements in performance were associated with self-reports of task engagement, and money-induced activations in the lateral prefrontal cortex were associated with parallel activations in the orbitofrontal cortex. For cocaine abusers, prefrontal cortex sensitivity to money was instead associated with motivation and self-control., Conclusions: These findings suggest that in cocaine addiction 1) activation of the corticolimbic reward circuit to gradations of money is altered; 2) the lack of a correlation between objective and subjective measures of state motivation may be indicative of disrupted perception of motivational drive, which could contribute to impairments in self-control; and 3) the lateral prefrontal cortex modulates trait motivation and deficits in self-control, and a possible underlying mechanism may encompass a breakdown in prefrontal-orbitofrontal cortical communication.

Objective: Noninvasive brain imaging techniques are a powerful tool for researching the effects of drug abuse on brain activation measures. However, because many drugs have direct vascular effects, the validity of techniques that depend on blood flow measures as a reflection of neuronal activity may be called into question. This may be of particular concern in event-related functional magnetic resonance imaging (fMRI), where current analytic techniques search for a specific shape in the hemodynamic response to neuronal activity., Method: To investigate possible alterations in task-related activation as a result of drug abuse, fMRI scans were conducted on subjects in four groups as they performed a simple event-related finger-tapping task: users of cocaine, nicotine, or cannabis and control subjects., Results: Activation measures, as determined by two different analytic methods, did not differ between the groups. A comparison between an intravenous saline and an intravenous cocaine condition in cocaine users found a similar null result. Further in-depth analyses of the shape of the hemodynamic responses in each group also showed no differences., Conclusions: This study demonstrates that drug groups may be compared with control subjects using event-related fMRI without the need for any post hoc procedures to correct for possible drug-induced cardiovascular alterations. Thus, fMRI activation differences reported between these drug groups can be more confidently interpreted as reflecting neuronal differences.

Objective: Research on the effects of cannabis on the brain and behavior has been surprisingly scarce. In humans, laboratory studies document toxicity and psychoactive effects of cannabinoids. However, among substance abuse patients, only a few studies have prospectively examined the relationship of cannabis use to remission or relapse of use of other substances. Because cannabis is a widely used substance, the authors examined whether cannabis use during follow-up after discharge from inpatient treatment affected cocaine, alcohol, and/or heroin use., Method: Two hundred fifty patients 18 years old or older from an inpatient psychiatric/substance abuse setting participated in a Psychiatric Research Interview for Substance and Mental Disorders. All patients were diagnosed according to DSM-IV as having current alcohol, cocaine, and/or heroin dependence. Sustained remission was defined as at least 26 weeks without use following hospital discharge. Data were analyzed with Cox proportional hazards models., Results: About one-third of the patients (N=73) used cannabis after hospital discharge. Postdischarge cannabis use substantially and significantly increased the hazard of first use of any substance and strongly reduced the likelihood of stable remission from use of any substance. Examination of specific substances indicated that cannabis use affected first use of alcohol, stable remission, and subsequent relapse of alcohol use as well as first use of cocaine and stable remission but was unrelated to heroin outcomes., Conclusions: Potential negative clinical implications of cannabis use should be considered when treating dependence on other substances and planning aftercare. Clinical and laboratory research is needed to provide understanding of the mechanisms of cannabinoids in relapse to alcohol and cocaine use.

Objective: Physicians may prescribe buprenorphine for opioid agonist maintenance treatment outside of narcotic treatment programs, but treatment guidelines for patients with co-occurring cocaine and opioid dependence are not available. This study compares effects of buprenorphine and methadone and evaluates the efficacy of combining contingency management with maintenance treatment for patients with co-occurring cocaine and opioid dependence., Method: Subjects with cocaine and opioid dependence (N=162) were provided manual-guided counseling and randomly assigned in a double-blind design to receive daily sublingual buprenorphine (12-16 mg) or methadone (65-85 mg p.o.) and to contingency management or performance feedback. Contingency management subjects received monetary vouchers for opioid- and cocaine-negative urine tests, which were conducted three times a week; voucher value escalated during the first 12 weeks for consecutive drug-free tests and was reduced to a nominal value in weeks 13-24. Performance feedback subjects received slips of paper indicating the urine test results. The primary outcome measures were the maximum number of consecutive weeks abstinent from illicit opioids and cocaine and the proportion of drug-free tests. Analytic models included two-by-two analysis of variance and mixed-model repeated-measures analysis of variance., Results: Methadone-treated subjects remained in treatment significantly longer and achieved significantly longer periods of sustained abstinence and a greater proportion drug-free tests, compared with subjects who received buprenorphine. Subjects receiving contingency management achieved significantly longer periods of abstinence and a greater proportion drug-free tests during the period of escalating voucher value, compared with those who received performance feedback, but there were no significant differences between groups in these variables during the entire 24-week study., Conclusions: Methadone may be superior to buprenorphine for maintenance treatment of patients with co-occurring cocaine and opioid dependence. Combining methadone or buprenorphine with contingency management may improve treatment outcome.

Objective: The authors assessed whether individual differences in drinking history as well as lifetime incidence of comorbid cocaine or marijuana use disorder underlie differential patterns of brain atrophy in subjects with alcohol dependence., Method: Segmented magnetic resonance images were used to compare whole brain cerebral gray matter and white matter in 134 male subjects age 30-50 with alcohol dependence, either alone or with comorbid cocaine or marijuana use disorder., Results: Across all subjects, drinking history variables correlated negatively with both gray matter and white matter after age was controlled. Alcohol-dependent subjects with no comorbid substance use disorder (N=51) showed a steeper negative correlation between age and the gray matter/white matter ratio than did alcohol-dependent subjects with a comorbid lifetime cocaine use disorder diagnosis (N=50). Alcohol-dependent subjects with comorbid cocaine use disorder tended to have a steeper negative correlation between age and white matter (adjusted for intracranial volume) than did alcohol-dependent subjects with no comorbid substance use disorder. After age and the greater estimated cumulative alcohol consumption of alcohol-dependent subjects with comorbid cocaine use disorder were controlled in a multiple regression analysis, however, comorbid cocaine use disorder did not account for any independent variance in any volumetric measure., Conclusions: Brain atrophy among subjects with alcohol dependence reflects individual differences in exposure to alcohol, and the data provide mixed evidence that comorbid cocaine use disorder may exacerbate white matter atrophy in alcoholism.

Objective: Although suicidal behavior is frequent among cocaine-dependent patients, it has been little studied. Therefore, the author examined the characteristics of cocaine-dependent patients who had attempted suicide., Method: Cocaine-dependent patients who had attempted suicide (N=84) were compared with cocaine-dependent patients who had never attempted suicide (N=130) on clinical, personality, psychiatric, and physical variables., Results: Significantly more of the patients who had attempted suicide were female and had a family history of suicidal behavior; they reported significantly more childhood trauma and were significantly more introverted, neurotic, and hostile. They had also had significantly more comorbidity with alcohol and/or opiate dependence, major depression, and physical disorders., Conclusions: The clinical implications are that family, childhood, personality, psychiatric, and physical risk factors contribute to suicidal behavior in cocaine-dependent patients. Comorbidity appears to be an important determinant of suicidal behavior.

Objective: Deficits in dopaminergic function may contribute to hypertrophy of striatal structures associated with typical neuroleptic treatment. In light of a body of research that has associated chronic cocaine use with extrapyramidal symptoms and striatal dopaminergic depletion, the authors looked for evidence of striatal dysmorphology in patients with chronic cocaine dependence., Method: Caudate, putamen, and total brain volumes were quantified by means of magnetic resonance imaging in 25 cocaine-dependent and 20 healthy subjects., Results: Normalized caudate and putamen volumes were 3.40% and 9.18% larger, respectively, in the cocaine-dependent subjects., Conclusions: These observations suggest that deficits in dopaminergic function associated with cocaine dependence may contribute to striatal hypertrophy.

Objective: Identification of brain activity associated with craving is important for understanding the neurobiology of addiction., Method: Brain activity was measured in cocaine addicts and healthy subjects by functional magnetic resonance imaging (fMRI) while the subjects watched videotapes designed to elicit happy feelings, sad feelings, or the desire to use cocaine. The subjects indicated the onset of drug craving or emotional response, allowing comparison of groups before and after such feelings., Results: Robust activation of the anterior cingulate was evident in patients watching cocaine-cue tapes but not in patients watching happy or sad tapes or in healthy subjects under any condition. Anterior cingulate activation preceded the reported onset of craving and was evident in patients who did not report craving. In contrast, patients showed less activation than healthy subjects during the cocaine-cue tapes in areas of the frontal lobes. After the reported onset of craving, cocaine-dependent subjects showed greater activity than healthy subjects in regions that are more active in healthy subjects when they watch sad tapes than when they watch happy tapes, suggesting a physiologic link between cocaine-cue responses and normal dysphoric states. Dynamic aspects of regional brain activations, but not the location of activations, were abnormal in cocaine-dependent subjects watching sad tapes, suggesting more general affective dysregulation. Patients showed low activation of sensory areas during initial viewing of all videotapes, suggesting generalized alteration in neuroresponsiveness., Conclusions: Cocaine cues lead to abnormally high cingulate and low frontal lobe activation in cocaine addicts. Addicts also show more general abnormalities in affect-related brain activation.

Objective: Cocaine-related cues have been hypothesized to perpetuate drug abuse by inducing a craving response that prompts drug-seeking behavior. However, the mechanisms, underlying neuroanatomy, and specificity of this neuroanatomy are not yet fully understood., Method: To address these issues, experienced cocaine users (N=17) and comparison subjects (N=14) underwent functional magnetic resonance imaging while viewing three separate films that portrayed 1 ) individuals smoking crack cocaine, 2) outdoor nature scenes, and 3) explicit sexual content. Candidate craving sites were identified as those that showed significant activation in the cocaine users when viewing the cocaine film. These sites were then required to show significantly greater activation when contrasted with comparison subjects viewing the cocaine film (population specificity) and cocaine users viewing the nature film (content specificity)., Results: Brain regions that satisfied these criteria were largely left lateralized and included the frontal lobe (medial and middle frontal gyri, bilateral inferior frontal gyrus), parietal lobe (bilateral inferior parietal lobule), insula, and limbic lobe (anterior and posterior cingulate gyrus). Of the 13 regions identified as putative craving sites, just three (anterior cingulate, right inferior parietal lobule, and the caudate/lateral dorsal nucleus) showed significantly greater activation during the cocaine film than during the sex film in the cocaine users, which suggests that cocaine cues activated similar neuroanatomical substrates as naturally evocative stimuli in the cocaine users. Finally, contrary to the effects of the cocaine film, cocaine users showed a smaller response than the comparison subjects to the sex film., Conclusions: These data suggest that cocaine craving is not associated with a dedicated and unique neuroanatomical circuitry; instead, unique to the cocaine user is the ability of learned, drug-related cues to produce brain activation comparable to that seen with nondrug evocative stimuli in healthy comparison subjects.

Objective: The authors investigated the occurrence of pathological gambling among cocaine-dependent outpatients, its influence on short-term outcome of treatment, and comparative characteristics of patients with and without pathological gambling., Method: The subjects were 313 cocaine-dependent (200 also opiate-dependent) outpatients in clinical trials of medication for cocaine dependence. Pathological gambling (DSM-III-R criteria) was assessed with the Diagnostic Interview Schedule, and sociodemographic and socioeconomic characteristics were determined with the Addiction Severity Index. Outcome was defined as time in treatment (proportion of maximum scheduled time) and proportion of cocaine-positive urine samples during treatment., Results: Pathological gambling had a lifetime occurrence rate of 8.0% and a current (past month) occurrence of 3.8%. Onset preceded the onset of cocaine dependence in 72.0% of the patients (and preceded onset of opiate dependence in 44.4%). Patients with pathological gambling (lifetime or current) did not differ significantly from other patients in length of treatment or proportion of cocaine-positive urine samples. Those with lifetime pathological gambling were significantly more likely to have tobacco dependence (84.0% versus 61.1%) and antisocial personality disorder (56.0% versus 19.8%), to be unemployed (84.0% versus 49.3%), to have recently engaged in illegal activity for profit (64.0% versus 38.5%), and to have been incarcerated (62.5% versus 33.9%)., Conclusions: Pathological gambling is substantially more prevalent among cocaine-dependent outpatients than in the general population. Patients with pathological gambling differ from other cocaine-dependent outpatients in some sociodemographic characteristics but not in short-term outcome of treatment for cocaine dependence.

Objective: Previous human postmortem experiments have shown an abnormally high number of dopamine uptake sites in the striatum of chronic cocaine users, which might contribute to cocaine withdrawal symptoms such as depression and suicidality. Previous inconsistencies in results were perhaps related to selective radioligand affinity changes or a coexisting loss of dopamine neurons., Method: In the present study, binding of the cocaine analog [3H]WIN 35428 to the dopamine transporter was assayed in postmortem striatal samples from 15 cocaine-using subjects and 15 matched comparison subjects to determine whether there were differences in number of binding sites or in affinity. Binding to the vesicular monoamine transporter, a measure of total dopaminergic terminals, was also assessed by using the radioligand (+)-[3H]dihydrotetrabenazine (DTBZ)., Results: Striatal [3H]WIN 35428 binding sites were significantly more numerous in the cocaine users: the mean Bmax value was 9.0 fmol bound/microg protein (SD = 2.8) for the cocaine users but only 6.0 (SD = 1.7) for the comparison subjects. Severity of chronic cocaine use was significantly related to [3H]WIN 35428 binding level. [3H]DTBZ binding was significantly lower in the cocaine users (mean = 330 nCi/mg, SD = 42) than in the comparison subjects (mean = 374, SD = 68)., Conclusions: The present results confirm that cocaine users have a high number of dopamine transporter binding sites on dopaminergic neurons, despite an apparent low number of total dopamine terminals. These abnormalities may contribute to the abnormalities in subjective experience and behavior characteristic of chronic cocaine abusers.

Objective: The DSM-IV work group asked researchers and clinicians to subtype substance dependent individuals according to the presence or absence of physiological symptoms. A recent report from the Collaborative Study on the Genetics of Alcoholism demonstrated that among alcohol-dependent men and women, a history of tolerance or withdrawal was associated with a more severe clinical course, especially for individuals with histories of alcohol withdrawal. This article evaluates similar distinctions among subjects in the collaborative study who were dependent on marijuana, cocaine, amphetamines, or opiates., Method: Structured interviews gathered information from 1,457 individuals with a lifetime diagnosis of marijuana dependence, 1,262 with histories of cocaine dependence, 647 with amphetamine dependence, and 368 subjects with opiate dependence. For each drug, the clinical course was compared for subjects whose dependence included a history of withdrawal (group 1), those dependent on each drug who denied withdrawal but reported tolerance (group 2), and those who denied both tolerance and withdrawal (group 3)., Results: The proportion of dependent individuals who denied tolerance or withdrawal (group 3) ranged from 30% for marijuana to 4% for opiates. For each substance, individuals in groups 1 and 2 evidenced more severe substance-related problems and at least a trend for greater intensities of exposure to the drug; those reporting withdrawal (group 1) showed the greatest intensity of problems., Conclusions: The designation of dependence in the context of tolerance or withdrawal identifies individuals with more severe clinical histories. These results support the importance of the designation of a physiological component to dependence, especially for people who have experienced a withdrawal syndrome.

Objective: This pilot study examined the effect of a modified motivational therapy intervention on outpatient treatment adherence and completion for patients with comorbid depressive disorder and cocaine dependence., Method: Depressed cocaine patients, stabilized with antidepressant medications on an inpatient psychiatric unit, were consecutively assigned on discharge to motivational therapy (N = 11) or treatment-as-usual (N = 12) during the first month of outpatient care. Patients were compared on treatment adherence and completion and on 1-year rehospitalization rates., Results: Motivational therapy patients attended significantly more treatment sessions during month 1, completed 30 and 90 days of outpatient care at higher rates, and experienced fewer psychiatric rehospitalizations and days in the hospital during the first year from entry into outpatient treatment., Conclusions: An outpatient program combining individual and group motivational therapy sessions holds promise for improving treatment adherence and completion among depressed patients with cocaine dependence.

Objective: The authors examined whether striatal dopamine transporters were altered in acutely (96 hours or less) abstinent cocaine-abusing subjects, as suggested by postmortem studies., Method: [123I] beta-CIT and single photon emission computed tomography were used to assess striatal dopamine transporter levels in 28 cocaine-abusing subjects and 24 comparison subjects matched as a group for age and gender., Results: Results showed a significant (approximately 20%) elevation in striatal V3" values in acutely abstinent cocaine-abusing subjects relative to comparison subjects. An inverse correlation between dopamine transporter level and Hamilton Depression Rating Scale score was also observed., Conclusions: These findings indicate more modest elevations in striatal dopamine transporters in cocaine-abusing subjects than noted in previous postmortem reports and suggest a possible relationship between cocaine-related depression and dopamine transporter binding.

Objective: This study examined the prevalence of lifetime traumatic events and current symptoms of posttraumatic stress disorder (PTSD) among treatment-seeking cocaine-dependent outpatients and compared patients with and without PTSD on current substance use, psychopathology, and sociodemographic characteristics., Method: The subjects were 122 adult cocaine-dependent outpatients participating in a treatment outcome study of psychosocial therapy. In addition to standard self-report and interview measures of psychopathology and substance use, the subjects completed the Trauma History Questionnaire and the PTSD Checklist before entering treatment., Results: These patients experienced a large number of lifetime traumatic events (mean = 5.7); men experienced more general disasters and crime-related traumas than women, and women experienced more physical and sexual abuse than men. According to self-report measures, 20.5% of the subjects currently met the DSM-III-R criteria for PTSD; the rate of PTSD was 30.2% among women and 15.2% among men. Patients with PTSD had significantly higher rates of co-occurring axis I and axis II disorders, interpersonal problems, medical problems, resistance to treatment, and psychopathology symptoms than patients without PTSD. Psychopathology symptoms represented the most consistent difference between the two groups and provided the best prediction of PTSD status in a logistic regression. However, the groups did not differ significantly in current substance use or sociodemographic characteristics., Conclusions: These findings underscore the value of screening substance abusers for PTSD, because it can identify a small but substantial number who might require additional treatment. Further studies of the relationship between PTSD and substance abuse appear warranted.

Objective: Earlier platelet and postmortem brain studies have found alterations in serotonin transporter function in ethanol-abusing human subjects. The present investigation tested the hypothesis that brain serotonin transporter function is altered in chronic users of ethanol and cocaine, which might be related to a common serotonin transporter promoter polymorphism., Method: Serotonin transporter binding sites, serotonin transporter mRNA levels, and serotonin transporter promoter variants were quantified in postmortem samples from a group of human subjects who had been ethanol users or cocaine users and then compared to those of a matched group of comparison subjects. Quantitative autoradiographic and in situ hybridization assays were performed in midbrain samples that contained the dorsal and median raphe nuclei (the location of serotonin cell bodies that innervate the forebrain)., Results: There was a significant overall cocaine-by-ethanol-by-genotype interaction. Dorsal raphe [125I]CIT binding to the serotonin transporter was lower in cocaine users than in comparison subjects. In addition, serotonin transporter binding and serotonin transporter mRNA levels varied significantly by genotype. It was also found that serotonin transporter binding in subjects with either the short or heterozygote genotype was significantly higher in the ethanol-user subjects., Conclusions: Serotonin transporter binding sites were regulated in a region-specific and substance-specific pattern, which was not simply a local response to functional blockade. Also, a reciprocal relationship appeared to exist between cocaine and ethanol effects in the dorsal raphe, which may have interesting clinical implications for dual-diagnosis patients. It is possible that serotonin transporter promoter genotype may play a complex role in chronic ethanol dependence.

Objective: Functional magnetic resonance imaging (MRI) was used to test whether brain activation was detectable in regions previously associated with cocaine cue-induced craving., Method: Blood oxygenation level dependent (BOLD) functional activation was measured during presentation of audiovisual stimuli containing alternating intervals of drug-related and neutral scenes to six male subjects with a history of crack cocaine use and six male comparison subjects., Results: Significant activation was detected in the anterior cingulate and left dorsolateral prefrontal cortex in the cocaine-using group. In addition, a correlation between self-reported levels of craving and activation in these regions was found., Conclusions: These results suggest that functional MRI may be a useful tool to study the neurobiological basis of cue-induced craving.