Faculty Bibliography

AIM: To analyze pooled data from the Cocaine Rapid Evaluation Screening Trial (CREST). Pooling data from these small pilot trials into four major drug classes permitted data exploration for treatment and covariate effects with increased sample size. DESIGN: Small pilot trials were conducted to screen fifteen medications as prospective treatments for cocaine dependence. Studies included a flexible 2-week to 4-week screening/baseline period followed by an 8-week randomized treatment condition. Participants were randomized equally to one of up to three active medications or placebo. SETTING: Five Medications Development Research Units at the five academic centers of University of Cincinnati, New York University, University of Pennsylvania, University of California Los Angeles and Boston University. PARTICIPANTS: The pooled data set consisted of 357 total subjects. Standardized inclusion and exclusion criteria were employed in subject selection to enhance consistency of cocaine-dependent study participants across all sites (see reports on individual trials in this supplement for details). All participants provided at least two urine samples that were positive for cocaine metabolite during a two-week period prior to being randomized. INTERVENTION: All subjects in these trials, those randomized to placebo and active medications, received active treatment in the form of evidence-based cognitive behavioral therapy. MEASURES: Quantitative urine benzoylecgonine (BE), self-report of cocaine use, and total Brief Substance Craving Scale (BSCS) scores were compared between each class of medication and its matched-placebo group. FINDINGS: Regression analysis of pooled data did not identify any statistically significant differences between treatment and matched-placebo for any of the four classes. Exploration of the effects of baseline covariates indicated that gender and African American status were associated significantly with outcome. Female gender was consistently associated with poorer outcomes for medication and placebo groups, while the direction of association between African American status and outcome differed by treatment groups. Retention was also examined: dropout rates may have been somewhat higher for placebo than treatment groups during the early active-treatment period. Classification trees were used to identify characteristics of subjects who were abstinent for at least two weeks during the eight-week trial; only 4.0% of females while 17.9% of males achieved this criterion. CONCLUSIONS: Results presented here may prove useful for planning future clinical trials for therapies targeting cocaine dependence

AIMS: In the current study, nefazodone, an antidepressant with dual action on serotonin and norepinephrine reuptake as well as 5-HT(2A) receptor antagonist effects, was studied in subjects with cocaine dependence and depressive symptoms, to determine its efficacy in reducing cocaine use. DESIGN: An 8-week, double blind, placebo-controlled design was used. SETTING: The study was conducted at the Medication Development Research Unit (MDRU) at the VA Boston Healthcare System and the Manhattan Department of Veterans Affairs (DVA) Medical Center. PARTICIPANTS: Subjects (n = 69) met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and had Hamilton Depression Scores of 12 or higher. INTERVENTION: Subjects were assigned randomly to receive nefazodone 200 mg twice daily (n = 34) or matching placebo (n = 35). All subjects received individual counseling. MEASUREMENTS: Urinary measurements of benzoylecgonine (BE, three times per week) and self-reports of cocaine use were the primary outcome measures. Secondary outcome measures included assessments of psychiatric functioning, cocaine craving and social functioning. FINDINGS: Median weekly BE declined more rapidly in the nefazodone than in the placebo group. Median urine BE at baseline was, however, significantly greater in nefazodone than in the placebo group. Scores for strength of cocaine craving also decreased more rapidly in the nefazodone group compared to the placebo group. Both groups had equivalent improvement in mood, psychosocial functioning and self-reported cocaine use. CONCLUSIONS: These results suggest that nefazodone administration can reduce cocaine craving after it has been administered for several weeks. Although the nefazodone group had a greater rate of decrease in BE levels than the placebo group, the interpretation of this finding is obscured by significant group differences in baseline BE levels

The role of 12-step programs and 12-step-oriented treatments for dually diagnosed individuals (DDI) remains unclear. Here are presented the results of a pilot study in which 10 seriously mentally ill patients received a modified 12-step facilitation (TSF) therapy emphasizing engagement of DDI in a specialized 12-step program for DDI. Participants significantly increased their 12-step attendance and decreased their substance use during the 12 weeks of treatment. Larger and longer-term studies are needed to assess the efficacy of modified TSF for DDI relative to other treatments, and to determine what forms of TSF are most effective in this population.

Alcohol use disorders (AUDs) include a spectrum of alcohol-related disorders such as alcohol misuse, abuse, and dependence. AUDs are a group of common, chronic diseases caused by a complicated interaction between biological, psychological, social, and cultural factors. Approximately two-thirds of all American adults, 18 years of age and older, drink some alcohol during the course of a year. Moreover, approximately 7.5% of the United States population (approximately 14 million people) meet criteria for alcohol abuse or dependence. At present, there are two types of medications that are used to treat alcoholism. The first are aversive medications, with disulfiram being the most commonly used. By causing an aversive reaction when taken with alcohol, these medications deter further alcohol consumption through negative reinforcement. However, they are limited in utility unless given in a supervised setting. The second, are those that have anti-craving effects. One of the medications, naltrexone, an opiate antagonist, was first approved by the Food and Drug Administration in 1994. Since there is a limited number of biological interventions for alcoholism at present, most treatment consists of nonpharmacologic psychosocial treatments.

(from the journal abstract) Despite a growing body of literature indicating an increase in alcohol use disorders (AUDs) among the elderly, this group of patients has historically been ignored. The elderly are a vulnerable group who suffer a disproportionate amount of physical and psychosocial distress. Any alcohol use in this population, but especially excessive use, poses unique problems biologically, psychologically, and socially. This article will summarize the classification, prevalence, assessment, and treatment of AUDs in the elderly, with an emphasis on the special needs and unique aspects of engaging and treating this patient population.

Surveillance data suggests that use of ecstasy in the U.S. is predominantly among white adolescent and young adults. To investigate ecstasy use among substance users in New York City we added questions to ongoing efforts to recruit heroin and cocaine users. Of 715 participants recruited, 58.3% were injection drug users (IDUs). The median age was 32 (range 17-64), 76.4% were male, 49.0% were currently homeless, 62.4% were Hispanic, 27.3% were black, and 34.5% were born outside the United States. Overall, 23.4% used ecstasy in their lifetime and 11.9% had used in the last-6 months. In multivariate logistic regression, correlates of lifetime ecstasy use included younger age, being born in the U.S., and current homelessness. We observed a significant interaction between injection drug use and race where, compared to black non-IDUs, Hispanic non-IDUs, and white IDUs were significantly more likely to have a history of lifetime ecstasy use while black IDUs were significantly less likely. These findings are limited to persons who use other drugs, but suggest that further investigation of ecstasy use in minority populations is warranted.

The objective of the study was to explore correlates of suicidal ideation among African Americans in a community-based cohort in Baltimore, Md. Participants had initiated use of heroin, crack, or cocaine by means other than injection in the prior 10 years. An interview-administered questionnaire collected information regarding drug use history, depressive symptoms, drug dependence, and suicidal thoughts and attempts within the past six months. Multiple logistic regression was used to identify factors independently associated with suicidal ideation. Of 148 persons, median age was 27 years, and 60.8% were female. Suicidal ideation was reported by 21.6% of participants. Those reporting suicidal ideation were significantly more likely to be dependent on two or more drugs (adjusted odds ratio=2.93, 95% confidence interval = 1.25, 6.88). Our findings underscore the need to integrate treatment for psychiatric comorbidity and drug dependence and target these services toward young, African-American drug users.

Biological drive states exert homeostatic control in part by increasing the reinforcing effects of environmental incentive stimuli. An apparent by-product of this adaptive response is the enhanced acquisition of drug self-administration behavior in food-restricted (FR) animals. While previous research has demonstrated increased central sensitivity to rewarding effects of abused drugs and direct dopamine (DA) receptor agonists in FR subjects, the underlying neurobiology is not well understood. Recently, it was demonstrated that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958 produces a stronger activation of striatal extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element-binding protein (CREB) in FR relative to ad libitum (AL) fed rats. The main purpose of the present study was to characterize the involvement and mechanisms of interaction between NMDA receptor function and the augmented cellular responses to D-1 DA receptor stimulation in nucleus accumbens (NAc) of FR rats. In experiment 1, Western immunoblotting was used to demonstrate that i.c.v. injection of SKF-82958 (20 microg) produces greater phosphorylation of the NMDA NR1 subunit and calcium-calmodulin kinase II (CaMK II) in NAc of FR as compared with AL rats. In experiment 2, pretreatment of subjects with the NMDA antagonist, MK-801 (1.0 mg/kg, i.p.) decreased SKF-82958-induced activation of CaMK II, ERK1/2 and CREB, and reversed the augmenting effect of FR on activation of all three proteins. In experiment 3, pretreatment with the mitogen-activated protein kinase/ERK kinase inhibitor SL-327 (60 mg/kg, i.p.) suppressed SKF-82958- induced activation of ERK1/2 and reversed the augmenting effect of FR on CREB activation. These results point to specific neuroadaptations in the NAc of FR rats whereby D-1 DA receptor stimulation leads to increased NMDA NR1 subunit phosphorylation and consequent increases in NMDA receptor-dependent CaMK II and ERK1/2 signaling, and increased NMDA receptor/ERK1/2-dependent phosphorylation of the nuclear transcription factor, CREB. The upregulated cellular responses to D-1 DA agonist challenge may play a role in the augmentation of drug reward and appetitive instrumental learning during periods of food restriction