Acute effects of cocaine on human brain activity and emotion.

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

The National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Rationale and methods.

The National Institute on Drug Abuse Collaborative Cocaine Treatment Study is a large, multisite psychotherapy clinical trial for outpatients who meet the DSM-IV criteria for cocaine dependence. For 480 randomized patients, the outcomes of 4 treatments are compared for an 18-month period. All treatments include group drug counseling. One treatment also adds cognitive therapy, one adds supportive-expressive psychodynamic therapy, and one adds individual drug counseling; one consists of group drug counseling alone. In addition, 2 specific interaction hypotheses, one involving psychiatric severity and the other involving degree of antisocial personality characteristics, are being tested. This article describes the main aims of the project, the background and rationale for the study design, the rationale for the choice of treatments and patient population, and a brief description of the research plan.

Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study.

BACKGROUND: This was a multicenter investigation examining the efficacy of 4 psychosocial treatments for cocaine-dependent patients. METHODS: Four hundred eighty-seven patients were randomly assigned to 1 of 4 manual-guided treatments: individual drug counseling plus group drug counseling (GDC), cognitive therapy plus GDC, supportive-expressive therapy plus GDC, or GDC alone. Treatment was intensive, including 36 possible individual sessions and 24 group sessions for 6 months. Patients were assessed monthly during active treatment and at 9 and 12 months after baseline. Primary outcome measures were the Addiction Severity Index-Drug Use Composite score and the number of days of cocaine use in the past month. RESULTS: Compared with the 2 psychotherapies and with GDC alone, individual drug counseling plus GDC showed the greatest improvement on the Addiction Severity Index-Drug Use Composite score. Individual group counseling plus GDC was also superior to the 2 psychotherapies on the number of days of cocaine use in the past month. Hypotheses regarding the superiority of psychotherapy to GDC for patients with greater psychiatric severity and the superiority of cognitive therapy plus GDC compared with supportive-expressive therapy plus GDC for patients with antisocial personality traits or external coping style were not confirmed. CONCLUSION: Compared with professional psychotherapy, a manual-guided combination of intensive individual drug counseling and GDC has promise for the treatment of cocaine dependence.

Clinical outcomes following cocaine infusion in nontreatment-seeking individuals with cocaine dependence.

BACKGROUND: In this study we explored if laboratory-based cocaine administration to human subjects was associated with long-term adverse outcomes. METHODS: Twenty-one non--reatment seeking individuals with cocaine dependence were evaluated at baseline and again 5 and 10 months following cocaine infusion in a brain imaging study. Outcomes included computer-driven multidimensional clinical assessments and radioimmunoassay of hair. For comparison, identical data were collected from 19 cocaine-dependent subjects who did not receive the infusion. RESULTS: The infused and noninfused groups did not differ on frequency of cocaine use (corroborated by radioimmunoassay of hair), Addiction Severity Index drug composite score, or Hamilton Rating Scale for Depression score at both follow-up time points. In a time-related trend analysis, both groups showed significant reductions in frequency of cocaine use. CONCLUSIONS: Laboratory-based cocaine administration can be a safe paradigm even in individuals who are not engaged in treatment.

Adjunctive buspirone in benzodiazepine treatment of four patients with panic disorder.

Four patients with panic disorder whose panic attacks responded to benzodiazepine treatment but who suffered persistent anxiety improved after addition of buspirone. Despite its lack of antipanic effect, buspirone may offer an adjunctive benefit when added to benzodiazepines in panic disorder.

The glutamatergic basis of human alcoholism.

OBJECTIVE: Although alcoholism is one of the most common psychiatric diagnoses, understanding of its pathophysiology remains poor. Accumulating evidence suggests that neurophysiological and pathological effects of ethanol are mediated to a considerable extent through the glutamatergic system. This article reviews the evidence of ethanol's effects on glutamatergic transmission and proposes a glutamatergic basis for alcoholism. METHOD: The information was derived from original research. The authors located more than 100 articles from psychiatry and neuroscience journals that related ethanol to glutamatergic transmission. They critically reviewed the neurobiology of the glutamatergic system in alcoholism and synthesized a unifying glutamatergic theory. RESULTS: Acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Prolonged inhibition of the NMDA receptor by ethanol results in development of supersensitivity; acute removal of ethanol causes marked augmentation of activity of postsynaptic neurons, such as those in the noradrenergic system, and, in the extreme, glutamate-induced excitotoxicity. Neurobiological effects of alcoholism, such as intoxication, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol syndrome, can be understood as a spectrum of consequences of ethanol's effect on the glutamatergic system. CONCLUSIONS: A host of findings support the hypothesis that the unifying mechanism of action of ethanol in interference with glutamatergic neurotransmission, especially through the NMDA receptor. Alcoholism may be considered another member of the expanding family of glutamate-related neuropsychiatric disorders. These insights should increase understanding of the biologic vulnerabilities leading to ethanol abuse and dependence and aid development of more effective pharmacologic interventions.

Desipramine in the treatment of adolescents with attention deficit disorder.

Twelve adolescents with attention deficit disorder were treated with desipramine in an open trial to assess its efficacy and safety. Eleven patients improved within 1 month, and improvement was sustained for 6-12 months without significant adverse effects in nine patients.

Cocaine dependence with and without PTSD among subjects in the National Institute on Drug Abuse Collaborative Cocaine Treatment Study.

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.

Postcardiotomy delirium: a critical review.

The literature concerning postcardiotomy delirium contains confusing definitions and contradictory results. In a critical review of the subject, we conclude that cardiac status, the severity of physical illness, the complexity of the surgical procedure, and preoperative organic brain disease are the determining factors in postcardiotomy delirium. Preoperative anxiety, denial, and depression also have some correlation. Age, sex, time on bypass, and preoperative psychological profile seem to have no influence on outcome. No psychological etiology for delirium has been proven consistently. The therapeutic influence of preoperative interviews in preventing postoperative psychiatric complications remains equivocal as do theories implicating sensory deprivation in the intensive care unit. Long-term follow-up studies suggest that psychological problems impair functional recovery from heart surgery. The suggested treatment of patients with delirium includes chemotherapy, psychotherapy, and environmental support. Finally we suggest that investigation of biochemical abnormalities in delirium may prove to be a model for clarifying the role of neurotransmitters in functional psychiatric illnesses.

Treatment matching. Theoretic basis and practical implications.

An extensive knowledge base supports the development of treatment matching methods for alcohol and other drug abuse. Many matching variables have been identified that relate to specific modalities of treatment and to specific levels of care. Physicians and other providers can use many putative matching variables to address patients' substance use problems on a highly individualized basis. These variables include demographic factors (age, gender, culture), typology and severity (age of onset; severity of intoxication; withdrawal; quantity, recency, frequency of substance use), intrapersonal characteristics (psychiatric diagnosis, cognitive function, self-efficacy, stage of change), and interpersonal function (social stability). The evolution of formal criteria for patient placement such as the ASAM criteria is a beneficial, adaptive process that is underway in numerous states, managed care entities, professional provider societies, and provider groups. Currently, matching approaches rely more heavily on consensus recommendations than on empiric matching data. The technology for conducting psychosocial treatment matching studies is rapidly increasing in sophistication. Although predictive validity has not yet been fully demonstrated on a large, multisite basis, the national research portfolio on treatment matching is expanding in size and complexity. This is an essential public health need, given dramatic cost pressures, if addiction services are to continue to grow in quality and availability.

Impact of psychosocial treatments on associated problems of cocaine-dependent patients.

A previous report from the National Institute on Drug Abuse Collaborative Cocaine Treatment Study (P. Crits-Christoph et al., 1999) found relatively superior cocaine and drug use outcomes for individual drug counseling plus group drug counseling compared with other treatments. Using data from that study, the authors examined the relative efficacy of 4 treatments for cocaine dependence on psychosocial and other addiction-associated problems. The 487 patients were randomly assigned to 6 months of treatment with cognitive therapy, supportive-expressive therapy, or individual drug counseling (each with additional group drug counseling), or to group drug counseling alone. Assessments were made at baseline and monthly for 6 months during the acute treatment phase, with follow-up visits at 9 and 12 months. No significant differences between treatments were found on measures of psychiatric symptoms, employment, medical, legal, family-social, interpersonal, or alcohol use problems. The authors concluded that the superiority of individual drug counseling in modifying cocaine use does not extend broadly to other addiction-associated problems.

Feasibility of multidimensional substance abuse treatment matching: automating the ASAM Patient Placement Criteria. American Society of Addiction Medicine.

UNLABELLED: The Patient Placement Criteria published by the American Society of Addiction Medicine (ASAM Criteria) established a non-proprietary standard for matching substance use disorder patients to treatment settings. METHODS: Data from 593 substance dependent adults who were assessed using the first computerized implementation of the ASAM Criteria were analyzed to determine whether the level of care assignments showed significant differences on a variety of clinical measures. RESULTS: The algorithm showed acceptable discrimination between each of three ASAM Levels of Care across numerous clinical subscales. CONCLUSIONS: It is feasible to implement complex, multidimensional criteria for substance abuse treatment that may improve reliability and facilitate validity studies.

Self-help group attendance and participation among cocaine dependent patients.

The authors examined frequency and patterns of self-help group attendance and active participation over a 6-month period among 411 patients receiving treatment in the NIDA Collaborative Cocaine Treatment Study. Nearly two-thirds of patients attended at least one self-help group, and nearly all of these actively participated. Alcoholics Anonymous and Narcotics Anonymous meetings were attended most frequently. Statistical analyses included chi square, one-way analyses of variance, and cluster techniques. While patterns of attendance were relatively consistent over time, findings suggest that a treatment emphasizing the importance of self-help groups is likely to encourage more self-help group attendance and participation over time.

Depressive symptomatology and cocaine-induced pituitary-adrenal axis activation in individuals with cocaine dependence.

The hypothalamic-pituitary-adrenal (HPA) axis plays a role in cocaine dependence and major depressive disorder. The authors examined the correlation between baseline depressive symptomatology and pituitary-adrenal axis activation induced by acute cocaine challenge. Twelve patients with cocaine dependence were administered an iv bolus of cocaine (0.6 mg/kg) and their plasma was assayed for levels of adrenocorticotropic hormone (ACTH) and cortisol. Depressive symptomatology was assessed with total Hamilton rating scale for depression (HRSD) scores and its vegetative and cognitive superfactors. Cocaine produced a mean increase from baseline of 261% for ACTH and 73% for cortisol plasma levels. Changes in ACTH (r=0.69) and cortisol (r=0.59) were positively and significantly correlated with total HRSD scores and its vegetative, but not cognitive, factor symptom cluster. These results suggest that the HPA axis may be involved in affective disturbances associated with the use of cocaine. Implications of these data for the pathophysiology of cocaine dependence are discussed.

Ultrarapid opioid detoxification: effects on cardiopulmonary physiology, stress hormones and clinical outcomes.

This study explored the acute and long-term consequences of ultrarapid opioid detoxification (URD) in individuals with opioid dependence. In an open case series, seven patients underwent URD and subsequent treatment with daily naltrexone. Structured interviews, integrated rehabilitation and hair sampling were employed in the 12-week course of longitudinal follow-up. Cardiac and pulmonary physiology did not change significantly during the anesthesia phase of URD, but plasma ACTH and cortisol levels increased 15- and 13-fold, respectively. Marked withdrawal and tachypnea in all patients and respiratory distress in one patient occurred during the acute post-anesthesia phase. Withdrawal scores were significantly elevated for 3 weeks compared with baseline in the face of minimal self-reported craving for opioids. Anxiety, depression and vegetative symptoms improved gradually. Four patients remained abstinent of opioid use, two reported a brief period of opioid intake and one relapsed into daily opioid consumption. Given its effect on breathing and stress hormones, this procedure should be conducted by experienced anesthesiologists. The fact that URD and subsequent naltrexone treatment appears to cause a dissociation effect in the usual relationship between withdrawal and craving has implications for behavioral pharmacology. Further research is needed on the efficacy, safety, mechanisms and neurobiological sequelae of the procedure.

Buprenorphine treatment of opiate and cocaine abuse: clinical and preclinical studies.

Buprenorphine, an opioid mixed agonist-antagonist, is a potent analgesic that appears to be effective for the treatment of opiate abuse. Recent preclinical studies have shown that buprenorphine also significantly reduces cocaine self-administration by rhesus monkeys for periods up to 120 days. This unexpected finding has led to clinical trials to evaluate buprenorphine's effectiveness for the treatment of dependence on both cocaine and opiates, as defined by DSM-III-R criteria. Buprenorphine's safety in combination with cocaine and opiates and its effects on electroencephalographic sleep patterns and regional cerebral blood flow were evaluated during inpatient studies. Buprenorphine (4 or 8 mg/day given sublingually) did not accentuate the cardiovascular and respiratory changes induced by an acute challenge dose of cocaine (30 mg given intravenously) or morphine (10 mg given intravenously) alone. In an outpatient open trial, buprenorphine significantly reduced both opiate and cocaine abuse by patients who had abused these drugs for more than 10 years. Most of these patients had failed in other drug abuse treatment programs. Reports of needle sharing also decreased significantly, and no patient tested positive for human immunodeficiency virus (HIV). The apparent safety and effectiveness of buprenorphine, combined with a high level of patient acceptance, led the Food and Drug Administration to grant a compassionate extension of the approved period for outpatient buprenorphine treatment from 26 to 52 weeks. Clinical trials of buprenorphine are ongoing. Possible mechanisms underlying buprenorphine-cocaine interactions are now under investigation.

The Addiction Severity Index: a field study of internal consistency and validity.

This study investigated whether the use of the Addiction Severity Index (ASI) in a network of inner-city alcohol and drug abuse clinics under nonideal conditions would yield internally consistent and valid data. A sample of 8,984 ASI scores was collected over a 34-month period. Construct validity was examined by computing the internal consistency of all subscales. Convergent and divergent validity of composite scores and of severity ratings were evaluated using correlation matrices. Findings demonstrated that ASI scores were internally consistent and valid, even though the recommended administration protocol may not always have been followed as faithfully as might be desirable. This robustness bodes well for the use of the ASI in on-line clinical environments. Results should be viewed with caution until the reliability of ASI administration is tested under similar nonideal conditions and until permissible deviations from standard protocol can be quantified.

Predictors of self-help group attendance in cocaine dependent patients.

OBJECTIVE: While referral to self-help groups for patients dependent on drugs other than alcohol has become widespread in the substance abuse treatment field, little is known about the characteristics of people who attend these groups. This study examines particular sociodemographic and clinical characteristics as possible predictors of attendance at self-help groups in the National Institute on Drug Abuse Collaborative Cocaine Treatment Study. METHOD: A multicenter study randomly assigned 487 patients (76.8% men) to one of four psychosocial treatments for cocaine dependence. Patients were treated for 24 weeks. Among other measures, the Weekly Self-Help Questionnaire was administered each week and completed, at least once, by 411 subjects. RESULTS: Approximately two thirds of the patients attended one or more self-help meetings during the 24-week period. Patients initially more likely to attend self-help groups frequently were those who were unemployed, had no religious preference, had more severe baseline drug use and reported treatment for prior substance-related problems. Patients with more severe baseline drug use and those who previously received treatment for substance-related problems were more likely to maintain frequent attendance throughout the study period. Only severity of baseline drug use predicted more frequent attendance during Month 6, although there was a trend in Month 6 favoring more frequent attendance by women. These findings remained significant when treatment condition was added to the models. CONCLUSIONS: Although these findings are consistent with past research on alcohol dependent individuals, they challenge popular clinical notions about the types of people who attend self-help groups. These findings demonstrate that self-help groups can appeal to a wide variety of cocaine dependent patients.

The Addiction Severity Index as a screen for trauma and posttraumatic stress disorder.

OBJECTIVE: The Addiction Severity Index (ASI) includes items to assess patients' history of trauma (physical or sexual). The goal of this study was to assess the sensitivity and specificity of those questions in relation to the Trauma History Questionnaire (THQ), a more thorough measure of lifetime trauma and, in addition, to an actual posttraumatic stress disorder (PTSD) diagnosis. METHOD: At the start of treatment cocaine dependent outpatients (N = 110, 65.5% male) were assessed on the ASI, the THQ and a PTSD symptom checklist as part of a multisite clinical trial. RESULTS: Specificity of the ASI questions was higher than sensitivity for both sexual trauma (specificity = .96, sensitivity = .46) and physical trauma (specificity = .71, sensitivity = .50), while for PTSD the sensitivity of the ASI (.91) was higher than its specificity (.43). Other findings indicated that patients were more likely to report trauma on the THQ than on the ASI (which may be due to the self-report format of the THQ); that the ASI was better at assessing sexual than assessing physical trauma; and that the higher the number of ASI trauma items endorsed, the more likely was the PTSD diagnosis. Finally, PTSD patients had greater severity than non-PTSD patients on other ASI items (e.g., psychological severity, need for treatment). CONCLUSIONS: The ASI trauma questions show stronger utility as a screen for PTSD than for trauma. Results of the study are discussed in light of ways to modify the ASI to screen more accurately for trauma, clinical implications, and limitations of the study method.

Pharmacotherapy of psychiatric syndromes with comorbid chemical dependence.

Because of the paucity of research on the pharmacotherapy of psychiatric syndromes with comorbid psychoactive substance use disorders, treatment guidelines are primarily drawn from general principles of clinical psychopharmacology and the addictive disease model. Effective treatment requires the determination of a discrete psychiatric diagnosis or working differential, consideration of the range of drug effects as they vary over time, and awareness of potential pharmacologic interactions between medication and alcohol or drug use. Either nonspecific prescribing or failure to treat may result in protracted dysfunction, relapse, or medical morbidity and mortality. Pharmacotherapy may also determine whether treatment results in mere abstinence vs. recovery from addictive disease. Primary emphasis on non-pharmacologic strategies and the use of a formal treatment contract increase the likelihood of successful pharmacotherapy outcome.