Cocaine-dependent Men Research Articles

Neural Correlates of Impulse Control During Stop Signal Inhibition in Cocaine-Dependent Men

Altered impulse control is associated with substance use disorders, including cocaine dependence. We sought to identify the neural correlates of impulse control in abstinent male patients with cocaine dependence (PCD). Functional magnetic resonance imaging (fMRI) was conducted during a stop signal task that allowed trial-by-trial evaluation of response inhibition. Fifteen male PCD and 15 healthy control (HC) subjects, matched in age and years of education, were compared. Stop signal reaction time (SSRT) was derived on the basis of a horse race model. By comparing PCD and HC co-varied for stop success rate, task-related frustration rating, and post-error slowing, we isolated the neural substrates of response inhibition, independent of attentional monitoring (of the stop signal) and post-response processes including affective responses and error monitoring. Using region of interest analysis, we found no differences between HC and PCD who were matched in stop signal performance in the pre-supplementary motor area (pre-SMA) previously shown to be associated with SSRT. However, compared with HC, PCD demonstrated less activation of the rostral anterior cingulate cortex (rACC), an area thought to be involved in the control of stop signal inhibition. The magnitude of rACC activation also correlated negatively with the total score and the impulse control subscore of the Difficulty in Emotion Regulation Scale in PCD. The current study thus identified the neural correlates of altered impulse control in PCD independent of other cognitive processes that may influence stop signal performance. Relative hypoactivation of the rACC during response inhibition may represent a useful neural marker of difficulties in impulse control in abstinent cocaine-dependent men who are at risk of relapse.

A Bayesian hierarchical framework for spatial modeling of fMRI data

Applications of functional magnetic resonance imaging (fMRI) have provided novel insights into the neuropathophysiology of major psychiatric, neurological, and substance abuse disorders and their treatments. Modern activation studies often compare localized task-induced changes in brain activity between experimental groups. Complementary approaches consider the ensemble of voxels constituting an anatomically defined region of interest (ROI) or summary statistics, such as means or quantiles, of the ROI. In this work, we present a Bayesian extension of voxel-level analyses that offers several notable benefits. Among these, it combines whole-brain voxel-by-voxel modeling and ROI analyses within a unified framework. Secondly, an unstructured variance/covariance matrix for regional mean parameters allows for the study of inter-regional (long-range) correlations, and the model employs an exchangeable correlation structure to capture intra-regional (short-range) correlations. Estimation is performed using Markov Chain Monte Carlo (MCMC) techniques implemented via Gibbs sampling. We apply our Bayesian hierarchical model to two novel fMRI data sets: one considering inhibitory control in cocaine-dependent men and the second considering verbal memory in subjects at high risk for Alzheimer’s disease.

Daily stressor sensitivity, abuse effects, and cocaine use in cocaine dependence

This study highlights respondent sensitivity to daily hassles as it relates to situational cocaine use and perceived long-term effects of adverse events in childhood. Data were drawn from a larger study on stress reactivity in cocaine dependent individuals. Participants ( n = 104) were cocaine dependent men and women without comorbid posttraumatic stress disorder (PTSD). They completed the Early Trauma Inventory (ETI), the Daily Hassles Scale (DHS), the Inventory of Drug-Taking Situations (IDTS), and the Time-Line Follow-Back (TLFB; for 90 days prior to interview). There were no gender differences in the amount or frequency of cocaine use, although the patterns of use differed between male and female users. Overall, there were some associations in the patterns of cocaine use and sensitivity to daily hassles, particularly the use in response to conflict with others. Early negative life events were positively related to response to daily hassles, but current triggers were more relevant. Reactivity to cocaine cues was related to daily hassle sensitivity among women only. Limitations and implications of the findings are discussed.

Reduced Plasma Nitric Oxide End Products in Cocaine-dependent Men

Chronic cocaine abusers experience brain and peripheral vascular dysfunction, the severity of which tends to be greater in men than women. The mechanisms underlying these effects of cocaine are unknown. Because nitric oxide (NO) abnormalities play key roles in development of vascular dysfunction in several disorders, we determined whether vascular nitric oxide end product (NOx) levels, which can serve as markers of systemic vascular NO production, are reduced in cocaine-dependent (CD) subjects. Plasma samples from 24 CD men, 12 CD women, and matched comparison subjects (19 men, 14 women) were analyzed with a Sievers 280i nitric oxide chemiluminescence detection analysis system. NOx levels in comparison in women and men were 24.9 ± 6.6 and 23.3 ± 5.7 μmol/L, and in CD women and men were 22.5 ± 8.4 and 13.0 ± 9.6 μmol/L, respectively. ANCOVA analysis, adjusted for lifetime smoking, indicated group (P < 0.0005) and sex (P = 0.04) effects, both of which survived posthoc Scheffe tests. Reduced NOx levels in CD men drove the group difference. These data suggest that chronic cocaine abuse is associated with reduced NOx levels in men, although the finding also may be attributable to factors indirectly related to cocaine abuse, including cohort differences in other drug use or lifestyle factors. These findings warrant additional studies to more directly characterize vascular NO turnover in cocaine abusers and to establish whether NO abnormalities contribute to cocaine-associated vascular dysfunction and to sex differences in cocaine's effects.

Sex differences in medial and lateral orbitofrontal cortex hypoperfusion in cocaine-dependent men and women

The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making. This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls. Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men. In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P=0.001), right lateral (P=0.002), and medial (P<0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (P<or=0.001). Similar bilateral OFC decreases were observed in male cocaine-dependent subjects at rest. In contrast, cocaine-dependent women showed lower rCBF in the medial, but not lateral, OFC relative to sex-matched healthy controls after placebo infusion (P<0.01). Male cocaine-dependent subjects also showed decreased rCBF (P<0.01) in the bilateral anterolateral temporal cortex and anterior cingulate, whereas decreased rCBF was observed in female cocaine-dependent subjects in the bilateral superior frontal gyri. Large and diffuse areas of increased rCBF were observed after placebo infusion in cocaine-dependent men, but not in women, relative to sex-matched healthy controls. rCBF appears to be reduced in the bilateral OFC in cocaine-dependent men and in the medial OFC in cocaine-dependent women. Sex differences in the medial and lateral OFC rCBF may be relevant to understanding relapse characteristics differentiating men and women addicted to cocaine.

A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence

Prior studies have demonstrated inefficacy among dopamine receptor antagonists for treating cocaine dependence. An alternative approach would be to investigate the ability of indirect inhibitors of cortico-mesolimbic dopamine release, such as the 5-HT 3 receptor antagonist ondansetron, to reduce cocaine's reinforcing effects. We hypothesized that ondansetron might be more efficacious than placebo at reducing cocaine intake and promoting abstinence in cocaine-dependent individuals. In a pilot randomized, double-blind, 10-week controlled trial, 63 treatment-seeking, cocaine-dependent men and women received ondansetron (0.25 mg, 1.0 mg, or 4.0 mg twice daily) or placebo. Up to three times per week, participants were assessed on several measures of cocaine use, including urine benzoylecgonine. Cognitive behavioral therapy was administered weekly. Ondansetron was well tolerated, causing no serious adverse events. The ondansetron 4.0 mg group had the lowest dropout rate among all treatment groups and a greater rate of improvement in percentage of participants with a cocaine-free week compared with the placebo group ( p = 0.02), whereas the ondansetron 1.0 mg group had a lower rate of improvement in percentage of weekly mean non-use days than did placebo recipients ( p = 0.04). These results suggest the possibility of a non-linear dose–response function, with evidence supporting efficacy for the 4.0 mg group.

A 12-year follow-up study of psychiatric symptomatology among cocaine-dependent men

This prospective longitudinal study examines patterns of psychiatric symptomatology among men admitted to treatment for cocaine dependence in 1988–1989. Study participants were interviewed at treatment intake, and at 1 year, 2 years and 12 years after treatment. The Hopkins Symptom Checklist-58 (SCL) and Natural History Interview were administered at the 4 time points. Of the 266 study participants interviewed at the 12-year follow-up, 138 (52%) had been cocaine abstinent for 5 years or more. Repeated measures ANOVA assessed changes in SCL scores over time for cocaine-abstinent and non-abstinent men. Both groups had similarly high mean SCL scores at treatment intake, and reductions in symptom severity 1 year after treatment. By 12-year follow-up, the abstinent group reported significantly lower SCL scores than the non-abstinent group on 4 of the 5 symptom measures. Additionally, cocaine-abstinent men reported lower rates of depressive and psychotic disorders, and lower use of psychopharmacologic and inpatient treatment than non-abstinent men. These findings suggest that severe psychiatric symptomatology persists among individuals unable to achieve a stable recovery from cocaine dependence.

Neuroimaging study of sex differences in the neuropathology of cocaine abuse

Female and male substance abusers differ in their disease patterns and clinical outcomes. An important question in addiction neuroscience thus concerns the neural substrates underlying these sex differences. This article aims to examine what is known of the neural mechanisms involved in the sex differences between substance abusers. We reviewed neuroimaging studies that addressed sex differences in cerebral perfusion deficits after chronic cocaine use and in regional brain activation during pharmacologic challenge and cue-induced craving. We also present results from a preliminary study in which cocaine-dependent men and women participated in script-guided imagery of stress- and drug cue-related situations while blood oxygenation level-dependent signals of their brain were acquired in a 1.5T scanner. Spatial pre-processing and statistical analysis of brain images were performed. Regional brain activation was compared between stress and drug cue trials in men versus women. The results of our study showed greater activation in the left uncus and right claustrum (both, statistical threshold of P = 0.01, uncorrected; extent = 10 voxels) in men (n = 5) during drug cue trials compared with stress trials. No brain regions showed greater activation during stress trials compared with drug cue trials. In contrast, women (n = 6) showed greater activation in the right medial and superior frontal gyri during stress trials compared with drug cue trials at the same statistical threshold. No brain regions showed more activation during drug cue trials than during stress trials. The studies reviewed underscore the need to consider sex-related factors in examining the neuropathology of cocaine addiction. Our preliminary results also suggest important sex differences in the effect of stress- and drug cue-associated brain activation in individuals with cocaine use disorder.

Imaging Brain Mu-Opioid Receptors in Abstinent Cocaine Users: Time Course and Relation to Cocaine Craving

Cocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomography (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence. Regional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 cocaine users over 12 weeks of abstinence on a research ward and in 16 healthy control subjects. Mu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 week and in the anterior cingulate and anterior frontal cortex after 12 weeks. Increased binding in some regions at 1 day and 1 week was positively correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amount of cocaine used per day of use during the 2 weeks before admission and with urine benzoylecgonine concentration at the first PET scan. These results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.

A gender specific psychometric analysis of the early trauma inventory short form in cocaine dependent adults

This study evaluated the gender specific psychometric properties of the Early Trauma Inventory-Short Form (ETI-SF) in a clinical sample of cocaine dependent men ( N=58) and women ( N=34). Participants were administered the ETI-SF, the Childhood Trauma Questionnaire Short Form (CTQ-SF), and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Tests of internal consistency, convergent validity, and predictive validity were conducted separately by gender. Findings indicated that the ETI-SF demonstrated good internal consistency; Cronbach's alpha ranged from 0.73 to 0.80 for men and from 0.70 to 0.77 for women. The measure also demonstrated good convergence with the CTQ-SF in both sexes, indicating that reports of child maltreatment are consistent across interview and self-report measures. Further, predictive validity was demonstrated by the ability of various ETI-SF scales to predict the co-occurrence of psychiatric disorders commonly associated with early trauma. These included lifetime diagnosis of PTSD in men and women, the lifetime diagnosis of major depressive disorder in men, and the lifetime diagnoses of alcohol use disorders in women. The findings support the utility of the ETI-SF as a clinical research tool to obtain data on specific types of early trauma in drug abusing samples.

Differences at Treatment Entry Between Opioid-Dependent and Cocaine-Dependent Males and Females

Objectives This study compared the psychosocial characteristics and psychiatric diagnoses of opioid-dependent and cocaine-dependent men and women. Methods Opioid-dependent patients fulfilled a current opioid but not current cocaine dependence diagnosis (n = 115); cocaine-dependent patients fulfilled a current cocaine but not current opioid dependence diagnosis (n = 144). All enrolled in a treatment research clinic. Participants completed a demographic questionnaire, the Addiction Severity Index, and the Structured Clinical Interview for the DSM-IV, Axes I and II. Analyses included comparisons between males (n = 153) and females (n = 106) to examine possible interactive effects of sex with primary drug of abuse. Results Greater number and problem severity for cocaine versus opioid dependent patients was found across multiple domains, and was especially notable for alcohol problems, family/social difficulties, and psychiatric comorbidity. Women differed from men by having more medical and employment problems, higher rates of lifetime Major Depression, and lower rates of personality disorders. Discussion There are substantial differences between cocaine and opioid dependent patients, and between females and males within dependence types. Assessment and treatment planning for patients and resource allocation by substance abuse treatment programs should recognize these differences. Efforts to match substance-abusing patients to treatments can benefit from recognition of differences between cocaine and opioid dependent females and males.

The neural correlates of cue-induced craving in cocaine-dependent women.

Drug use reminders are associated with localized changes in brain activity related to intense drug wanting or craving in cocaine-dependent men. While cocaine dependence is prevalent and disabling in women, and certain clinically relevant sex differences exist, there is an absence of knowledge related to the neural correlates of cocaine craving in cocaine-dependent women. The differential neural response to imagery depicting cocaine use and neutral imagery was defined by using [15O]H2O positron emission tomography (PET) imaging in eight cocaine-dependent women. Results were compared with a matched group of eight cocaine-dependent men. Cocaine-related imagery was associated with relative increases in cocaine craving and increases in regional cerebral blood flow in the superior temporal gyrus, dorsal anterior and posterior cingulate cortex, nucleus accumbens area, and the central sulcus. Compared with the results of an identical PET study in matched cocaine-dependent men, conditioned cocaine craving in women was associated with less activation of the amygdala, insula, orbitofrontal cortex, and ventral cingulate cortex and greater activation of the central sulcus and widely distributed frontal cortical areas. These findings suggest the presence of sex differences in the functional anatomy of cue-induced cocaine craving associated with drug dependence. Such differences may reflect sex differences in conditioned associations to cocaine use, in affective and other corollaries of cocaine craving, or in their volitional regulation and may underlie apparent sex differences in the effects of cocaine abstinence and the expectations of treatment outcome. Some support for the need for sex-specific strategies for treatment of cocaine dependence is also furnished by the findings of this study.

Followup of cocaine-dependent men and women with antisocial personality disorder

Long-term outcomes following drug treatment were examined for cocaine-dependent men ( N = 453) and women ( N = 254) with and without antisocial personality disorder (ASP). In-depth assessments were conducted at treatment intake in 1991–93 and at 1 and 5 years following treatment discharge. Overall, 47.2% of the males and 34.3% of females were diagnosed with ASP using DSM-III-R criteria derived from the Diagnostic Interview Schedule. All groups reduced their cocaine, marijuana, and alcohol use; reduced their levels of psychological distress; and improved in functioning (e.g., employment, arrests, residential status). At Year 5 ASP was associated with an increased likelihood of heavy alcohol use and additional substance abuse treatment among men, whereas women with ASP were more likely to report psychological problems and to receive mental health treatment and other services than either women without ASP or men with ASP. The findings suggest the need to address the specific treatment needs of male and female cocaine abusers with ASP.

Alcohol and cocaine interactions and aggressive behaviors.

This chapter presents (1) a review of several studies on the relationship between violent/aggressive behavior and the use of cocaine and/or the use of alcohol; and (2) findings from our study of cocaine-dependent men, illustrating deviant and violent behavior before and during cocaine addiction careers. As had been found in previous research, use of alcohol and cocaine seemed to increase the likelihood of the cocaine users in our sample engaging in deviant or violent behaviors. The extent of deviant or violent behavior, in our sample, during periods of cocaine use, periods of cocaine-alcohol use, periods of alcohol use only, and periods of abstinence for both alcohol and cocaine are discussed. Changes in the nature of the deviant or violent behaviors prior to and after the onset of cocaine addiction are also described.

Childhood trauma and suicidal behavior in male cocaine dependent patients.

A consecutive series of 100 male cocaine dependent patients were interviewed about suicidal behavior and completed the 34-item Childhood Trauma Questionnaire (CTQ) to determine whether childhood trauma is associated with suicidal behavior in cocaine dependent men. Patients who had attempted suicide (n = 34) reported significantly higher scores for childhood emotional abuse, physical abuse, sexual abuse, and emotional and physical neglect than patients who had never attempted suicide (n = 66). In this study, various childhood traumas were found to be significantly associated withsuicidal behavior among adult male cocaine dependent patients.

Neural activity related to anger in cocaine-dependent men: a possible link to violence and relapse.

This study examined the neural correlates of cue-induced anger in cocaine-dependent men in an initial investigation of possible neurobiological explanations for the putative association between cocaine addiction and violence. We used positron emission tomography (PET) to localize alterations in regional cerebral blood flow (rCBF) during mental imagery of a personal anger-associated scene and of an emotionally neutral scene in ten cocaine-dependent men. Compared to the emotionally neutral imagery control condition, anger was associated with marked decreases in rCBF in multiple areas of the frontal cortex (particularly the right inferior frontal gyrus), left posterior insula, left fusiform gyrus, and midbrain. Conversely, this same inferior frontal area was activated by anger imagery in nicotine-dependent men. Anger was also associated with increases in rCBF in the right fusiform gyrus, right and left middle occipital gyri, left post-central gyrus, left medial frontal gyrus, left cuneus, and in the left anterior cingulate gyrus. The study showed that cue-induced anger in cocaine-dependent men was associated with decreased activity in frontal cortical areas involved in response monitoring and inhibition. The lack of this association in nicotine-dependent men suggests a possible deficit in anger regulation associated with cocaine dependence and a possible link between cocaine dependence, violence, and relapse.

Differential effects of treatment modality on psychosocial functioning of cocaine-dependent men

Differential effects of treatment modality on psychosocial functioning of cocaine-dependent men

Differential effects of treatment modality on psychosocial functioning of cocaine-dependent men.

Changes in psychosocial functioning, including depression, anxiety, somatization, obsessive-compulsiveness, interpersonal sensitivity, confidence in the ability to resist taking drugs in different situations, and social adjustment are examined for male veterans entering treatment for cocaine dependence. The sample was comprised of African Americans (66%), Hispanics (8%), and Whites (26%) with a mean age of 35 years at intake. Participants were assessed at the end of 1 year and 2 years; during the follow-up period, participants utilized different combinations of treatment modalities. Paired t-tests showed significant improvement between intake and follow-up, both at the end of 1 year and 2 years, on the Beck Depression Inventory, on the depression, anxiety, obsessive-compulsiveness, and interpersonal sensitivity scores of the Symptom Check List (SCL-58), and in four role areas of social adjustment on the Social Adjustment Inventory. There were no significant differences between intake and follow-up on the somatization subscale of the SCL-58 and on the Drug Taking Confidence Questionnaire (DTCQ). Measures taken at Year 2 were not significantly different from Year 1. Repeated measures analysis of variance revealed that treatment modality did not differentially affect psychosocial functioning on nearly all measures, except on somatization, confidence in the ability to resist taking drugs in different situations, and social adjustment involving leisure time. However, a combination of inpatient, high-intensity outpatient, and self-help group participation and a combination of outpatient and self-help group participation were better than a combination of inpatient, low-intensity outpatient, and self-help participation in increasing the confidence in the ability to resist cocaine use in different situations and to reduce symptoms of somatization.

Cocaine Tolerance: Behavioral, Cardiovascular, and Neuroendocrine Function in Men

Cocaine tolerance was assessed by comparing the acute effects of cocaine in drug-abstinent men who reported occasional cocaine use (n = 6) and in men who met DSM-III-R diagnostic criteria for dependence on both cocaine and opiates (n = 6). Peak plasma cocaine levels were equivalent in the two groups, and pharmacokinetic analyses revealed no significant differences in cocaine levels at any time. Cocaine induced a significantly greater increase in ACTH in the occasional cocaine users than in the cocaine dependent men (p < .01). Heart rate and systolic and diastolic blood pressure increases after cocaine were also significantly greater in the occasional cocaine users than in the cocaine-dependent men (p < .05). These neuroendocrine and physiologic differences were paralleled by significantly greater subjective reports of “high” and “euphoria” by the occasional cocaine users (p < .03 to .0001). These data are consistent with the conclusion that tolerance to cocaine’s physiologic, neuroendocrine, and subjective effects may occur as a function of chronic use.

Variations in psychosocial functioning associated with patterns of progression in cocaine-dependent men

This study examined the relationship between patterns of progression of cocaine use and psychosocial functioning in a sample of cocaine-dependent men who were veterans. Four patterns of progression were examined: mild-severe, moderate-severe, mild-moderate-severe, and severe only. Analysis of variance and post hoc analysis with Duncan grouping revealed significant differences among cocaine users with different patterns of progression in terms of negativism, problem index for situations involving unpleasant emotions, problem index for situations involving urges, depression, somatic anxiety, and medical problems in the family. However, there were no significant differences on sensation seeking, confidence to resist taking cocaine in different situations, obsessive compulsiveness, somatization, attention deficit, and social adjustment. Cocaine users with a severe-only pattern of progression were significantly more dysfunctional than those with mild-moderate-severe progression in terms of negativism, problem index for situations involving unpleasant emotions, depression, and somatic anxiety. Cocaine users with mild-moderate-severe progression had significantly less somatic anxiety than those with mild-severe progression and had less negativism and a lower problem index for urges than those with moderate-severe progression. Logistic regression analysis revealed unique behavioral variables associated with different patterns of progression. The implications of these findings for treatment are discussed.