Aimee L. McRae

Safety and Tolerability of N-Acetylcysteine in Cocaine-Dependent Individuals

A double-blind placebo-controlled crossover Phase I trial was conducted to assess the safety and tolerability of N-Acetylcysteine (NAC) in healthy, cocaine-dependent humans. Thirteen participants attended a three-day hospitalization in which they received placebo or NAC. Subjects were crossed over to receive the opposite medication condition during a second three-day hospitalization, which occurred the following week. Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects reporting side effects did not differ. There were trends for a greater reduction in withdrawal symptoms and craving within the NAC condition. These preliminary results suggest that NAC is well tolerated in healthy, cocaine-dependent individuals and may reduce cocaine-related withdrawal symptoms and craving.

Treatment of marijuana dependence: a review of the literature

Until recently, relatively little research has focused on the treatment of marijuana abuse or dependence; however, marijuana use disorders are now receiving increased attention. This paper reviews the initial clinical trials evaluating the efficacy of outpatient treatments for adult marijuana dependence. Findings from five controlled trials of psychotherapeutic interventions suggest that this disorder appears responsive to the same types of treatment as other substance dependencies. Moreover, these initial studies suggest that many patients do not show a positive treatment response, indicating that marijuana dependence is not easily treated. Strengths and weaknesses of the data are presented. Preliminary data from less controlled studies relevant to the treatment of marijuana dependence are discussed to suggest future research areas. Although very few studies on treatment for marijuana abuse and dependence have been completed, the initial reports identify promising treatment approaches and demonstrate a need for more research on the development of effective interventions.

PTSD and the HPA axis: differences in response to the cold pressor task among individuals with child vs. adult trauma.

Hypothalamic pituitary adrenal (HPA) axis and subjective stress response to a cold-water immersion task, the cold pressor task (CPT), in individuals (N=89) with post-traumatic stress disorder (PTSD) were examined. All tests were conducted at 08:00h after an overnight hospital stay. Plasma adrenocorticotrophin hormone (ACTH), cortisol, and subjective stress were examined at baseline and five post-task time points in controls (n=31), subjects with PTSD as a result of an index trauma during childhood (i.e. before age 18; n=25), and subjects with PTSD as a result of an index trauma as an adult (n=33). Approximately, 50% of individuals in both trauma groups were alcohol dependent, and the impact of this comorbidity was also examined. Subjects with PTSD, regardless of age of index trauma, had a less robust ACTH response as compared to controls. Regardless of the presence or absence of comorbid alcohol dependence, subjects with childhood trauma had lower cortisol at baseline and at all post-task measurement points and did not demonstrate the decrease in cortisol over the course of the 2h monitoring period seen in subjects with adult index trauma and controls. The findings reveal differences in the neuroendocrine response to the CPT in individuals with PTSD compared to control subjects, and differences in PTSD subjects when examined by age of index trauma.

Review of sertraline and its clinical applications in psychiatric disorders

Sertraline (Zoloft®, Pfizer) has been shown in numerous controlled studies to have similar efficacy to other selective serotonin (5-HT) re-uptake inhibitors (SSRIs) in the treatment of depression and anxiety disorders. Further research is indicating that the efficacy of sertraline extends even beyond the treatment of depression and anxiety to include utility in eating disorders, premenstrual dysphoric disorder (PMDD) and possibly substance abuse treatment. Along with other SSRIs, sertraline offers several advantages over older antidepressants, including improved patient tolerability, low risk of lethality in overdose and no dependence potential. In head-to-head comparisons, sertraline appears to be at least as well-tolerated as other SSRIs and may even have a more favourable side effect profile. Low potential for pharmacokinetic drug interactions is another advantage of sertraline. Unlike fluoxetine, fluvoxamine and paroxetine, sertraline is not a potent inhibitor of any of the cytochrome P450 isoenzyme systems. As a result of its proven efficacy, good tolerability and lack of pharmacokinetic interactions, sertraline should be considered first-line in the treatment of anxiety and depressive disorders.

Effects of gender and cigarette smoking on reactivity to psychological and pharmacological stress provocation

We examined the influence of gender and smoking status on reactivity in two human laboratory stress paradigms. Participants were 46 (21 men, 25 women) healthy individuals who completed the Trier Social Stress Task (i.e., performed speech and math calculations in front of an audience) and a pharmacological stress provocation (i.e., administration of corticotrophin releasing hormone (CRH)) after an overnight hospital stay. Approximately half (53%) of the participants were smokers. Cortisol, adrenocorticotrophin hormone (ACTH), physiologic measures (heart rate, blood pressure), and subjective stress were assessed at baseline and at several time points post-task. Men demonstrated higher baseline ACTH and blood pressure as compared to women; however, ACTH and blood pressure responses were more pronounced in women. Women smokers evidenced a more blunted cortisol response as compared to non-smoking women, whereas smoking status did not affect the cortisol response in men. Finally, there was a more robust cardiovascular and subjective response to the Trier as compared to the CRH. Although preliminary, the findings suggest that women may be more sensitive than men to the impact of cigarette smoking on cortisol response. In addition, there is some evidence for a more robust neuroendocrine and physiologic response to acute laboratory stress in women as compared to men.

Community-Dwelling Cocaine-Dependent Men and Women Respond Differently to Social Stressors versus Cocaine Cues

UNLABELLED There are likely to be gender differences in determinants of relapse to drug use following abstinence in cocaine-dependent individuals. Cocaine-dependent women are more likely to attribute relapse to negative emotional states and interpersonal conflict. Cocaine dependence has also been linked to dysregulation of stress response and the hypothalamic pituitary adrenal (HPA) axis which may differ between genders. Subjective and HPA-axis responses to a social evaluative stressor, the Trier Social Stress Test (TRIER), and in vivo cocaine-related cues were examined in the present study. RESULTS There were no gender differences in magnitude of craving responses to the TRIER or the CUE. Both genders had a greater craving response to the CUE than to the TRIER, but the magnitude of the difference was greater for men than women (p=0.04). Cocaine-dependent subjects, compared to the control group, had significantly higher response throughout the TRIER (p<0.0001) and CUE (p<0.0001) testing sessions. There were no gender differences and no gender by cocaine interaction for ACTH responses to the TRIER, although women had lower baseline ACTH (p=0.049). On the CUE task, in contrast, female cocaine-dependent subjects had a more blunted ACTH response than did the other three groups (p=0.02). Female cocaine-dependent subjects also had a lower odds of a positive cortisol response to the TRIER as compared to the other three groups (OR=0.84, 95% CI=[0.02, 1.01]). During the CUE task, cocaine-dependent subjects had overall higher mean cortisol levels (p=0.0001), and higher odds of demonstrating a positive cortisol response to the CUE (OR=2.61, 95% CI=[1.11, 6.11]). No gender differences were found in ACTH responses to the CUE. The results are reviewed in the context of the existing literature on gender differences in cocaine dependence and potential implications for treatment are discussed.

Differences in early onset alcohol use and heavy drinking among persons with childhood and adulthood trauma.

We examined predictors for age at onset of first alcohol use and onset of heaviest alcohol use among men (n = 43) and women (n = 46) with alcohol dependence and PTSD, PTSD only, alcohol dependence only, and controls, with a particular focus on individuals with child versus adult trauma. Using analysis of variance procedures, results showed differences in onset of first alcohol use and heaviest drinking between childhood and adulthood trauma victims. These preliminary results indicate that behavioral mechanisms associated with alcohol use patterns between individuals with childhood and adulthood trauma are dissimilar, suggesting greater psychopathological consequences for individuals with childhood trauma.

Response to Corticotropin-Releasing Hormone Infusion in Cocaine-Dependent Individuals

CONTEXT Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration. OBJECTIVE The primary objective was to examine the hypothalamic-pituitary-adrenal axis and the subjective and physiologic response to CRH in cocaine-dependent individuals and controls. DESIGN A case-control study. SETTING Subjects were admitted to a General Clinical Research Center for testing and abstinence was verified with a urine drug screening. PARTICIPANTS Participants were male controls (n = 23), female controls (n = 24), cocaine-dependent men (n = 28), and cocaine-dependent women (n = 25). Individuals with dependence on other substances (except caffeine or nicotine) or with major depression, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. INTERVENTION Subjects received 1 microg/kg of CRH intravenously. MAIN OUTCOME MEASURES Primary outcomes included plasma corticotropin levels, cortisol levels, and heart rate and subjective measurements. RESULTS Cocaine-dependent individuals exhibited higher stress (P < .001) and craving for CRH compared with controls. A positive correlation (r(s) = 0.51; P < .001) between stress and craving was found in cocaine-dependent subjects. Intravenous CRH elevated heart rates in all groups; however, cocaine-dependent women demonstrated a significantly higher heart rate at all time points (P = .05). Women had higher cortisol responses to CRH (P = .03). No effect of cocaine status was observed. The corticotropin response to CRH was independent of sex and cocaine dependence. Cortisol and corticotropin were positively correlated in the controls and cocaine-dependent men, but not in cocaine-dependent women (r(s) = 0.199; P = .4). CONCLUSIONS There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in hypothalamic pituitary adrenal axis response between the cocaine-dependent and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of nonhypothalamic stress-responsive CRH systems.

Early life trauma and sensitivity to current life stressors in individuals with and without cocaine dependence.

This study investigated the link between exposure to early life trauma, sensitivity to current daily stressors, and cocaine dependence. Individuals with (n = 105) or without (n = 53) cocaine dependence completed the Early Trauma Inventory and the Daily Hassles Scale. In comparison to controls, cocaine-dependent individuals reported almost twice as many daily hassles and perceived those hassles more negatively (p <. 001). For participants with cocaine dependence, a significant relationship between exposure to early life trauma and negative perception of current daily hassles was observed (p <. 01), whereas no such relationship was observed for participants without cocaine dependence. Adverse childhood events may lead to an altered view of the environment that contributes to increased irritability with daily life events among cocaine-dependent individuals.

A Randomized, Placebo- controlled trial of Buspirone for the Treatment of Anxiety in Opioid-dependent Individuals

Anxiety symptoms are common among opioid-dependent individuals. Buspirone, a nonbenzodiazepine anxiolytic, has been used successfully for the treatment of anxiety in alcoholic patients. Its efficacy in opioid-dependent patients has not been previously examined. We conducted a twelve-week, randomized, placebo-controlled trial of buspirone in 36 subjects receiving methadone-maintenance treatment who presented with anxiety symptoms. Measures of anxiety, depression, and substance use were obtained repeatedly during treatment. Buspirone treatment did not significantly reduce anxiety symptoms in opioid-dependent patients. However, buspirone treatment was associated with trends toward reduction in depression scale scores and a slower return to substance use.