Faculty Bibliography

Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double-blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow back method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P=.02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P=.02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.

OBJECTIVE:To examine the change in total symptoms, and symptom clusters, of depression in newly abstinent opioid-dependent individuals being treated with depot naltrexone (Depotrex; Biotek, Inc., Wellesley, MA). METHOD/METHODS:In a series of opioid-dependent patients (N = 34) treated with naltrexone maintenance and relapse prevention therapy, mood was assessed with a 17-item Hamilton Depression (HAM-D) Scale and subscale scores at baseline, and after naltrexone induction at 2- and 4-week post-baseline. Data were analyzed using generalized estimated equation (GEE) models. RESULTS:Patients demonstrated high baseline affective burden and significant improvement of depression scores over a 4-week period post-baseline (F(2.66) = 8.88; p = .0004). Somatic and cognitive-affective subscale scores significantly declined as well as the seven individual item scores. By contrast, the "late insomnia" item score significantly increased at 2 weeks post-baseline. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:Naltrexone induction and maintenance in newly abstinent opioid-dependent individuals does not appear to be associated with worsening of depression; however, it may be associated with sleep impairment early in treatment.

OBJECTIVE:Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, positron emission tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is linked to cocaine-seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. The authors hypothesized that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. METHOD/METHODS:Prior to treatment, cocaine-dependent subjects underwent two PET scans using [(11)C]raclopride, before and after the administration of a stimulant (methylphenidate), for measurement of striatal dopamine D(2/3) receptor binding and presynaptic dopamine release. RESULTS:Both of the outcome measures were lower in the volunteers who did not respond to treatment than in those who experienced a positive treatment response. CONCLUSIONS:These findings provide insight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.

BACKGROUND:There is a need for novel approaches to the treatment of stimulant abuse and dependence. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse, with direct effects on decreased use and craving. In addition, exercise has the potential to improve other health domains that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight gain, quality of life, and anhedonia, since it has been shown to improve many of these domains in a number of other clinical disorders. Furthermore, neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes. The current manuscript presents the rationale, design considerations, and study design of the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) CTN-0037 Stimulant Reduction Intervention using Dosed Exercise (STRIDE) study. METHODS/DESIGN/METHODS:STRIDE is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. This study will evaluate individuals diagnosed with stimulant abuse or dependence who are receiving treatment in a residential setting. Three hundred and thirty eligible and interested participants who provide informed consent will be randomized to one of two treatment arms: Vigorous Intensity High Dose Exercise Augmentation (DEI) or Health Education Intervention Augmentation (HEI). Both groups will receive TAU (i.e., usual care). The treatment arms are structured such that the quantity of visits is similar to allow for equivalent contact between groups. In both arms, participants will begin with supervised sessions 3 times per week during the 12-week acute phase of the study. Supervised sessions will be conducted as one-on-one (i.e., individual) sessions, although other participants may be exercising at the same time. Following the 12-week acute phase, participants will begin a 6-month continuation phase during which time they will attend one weekly supervised DEI or HEI session. CLINICAL TRIALS REGISTRY/BACKGROUND:ClinicalTrials.gov, NCT01141608 http://clinicaltrials.gov/ct2/show/NCT01141608?term=Stimulant+Reduction+Intervention+using+Dosed+Exercise&rank=1.

BACKGROUND: Clinical trials testing the effectiveness of interventions for addictions, HIV transmission risk, and other behavioral health problems are important to advancing evidence-based treatment. Such trials are expensive and time-consuming to conduct, but the underlying effect sizes tend to be modest, and often findings are disappointing, failing to show evidence of treatment effects. OBJECTIVES: To demonstrate how appropriate covariation for baseline severity can enhance detection of treatment effects. METHODS: Explication and case example. RESULTS: Baseline severity (the score of the outcome measure at baseline, prior to randomization) is often strongly associated with outcome in such studies. Covariation for baseline score may enhance detection of treatment effects, because the variance explained by the baseline score is removed from the error variance in the estimate of the difference in outcome between treatments. Alternatively, the effect of treatment may manifest in the form of a baseline-by-treatment interaction. Common interaction patterns include that treatment may be more effective among patients with higher levels of baseline severity, or treatment may be more effective among patients with low severity at baseline ('relapse prevention' effect). Such effects may be important to developing treatment guidelines and offer clues toward understanding the mechanisms of action of treatments and of the disorders. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This article illustrates principles of covariation for baseline and the baseline-by-treatment interaction in nontechnical graphical terms, and discusses examples from clinical trials. Implications for the design and analysis of clinical trials are discussed, and it is argued that covariation for baseline severity of the outcome measure and testing of the baseline-by-treatment interaction should be considered for inclusion in the primary outcome analyses of treatment effectiveness trials of substantial size.

Background: Predictors of smoking cessation (SC) treatment outcome were explored in a multisite clinical trial of SC treatment at community-based, outpatient, substance abuse rehabilitation programs affiliated with the National Drug Abuse Treatment Clinical Trials Network. Objectives: To explore baseline demographic and clinical predictors of abstinence during treatment. Methods: Cigarette smokers from five methadone maintenance programs and two drug and alcohol dependence treatment programs were randomly assigned to SC treatment as an adjunct to substance abuse treatment as usual or to substance abuse treatment as usual. SC treatment consisted of group counseling (weeks 1-8) plus transdermal nicotine patch treatment (21 mg/day, weeks 1-6; 14 mg/day, weeks 7-8). Demographic and clinical predictors of smoking abstinence were evaluated among those patients assigned to the active SC condition (N = 153) using logistic regression. Results: Abstinence during treatment was positively associated with younger age, Hispanic or Caucasian (as opposed to African American) ethnicity/race, employment or student status, fewer cigarettes per day at baseline, lower severity of the primary substance problem at baseline, and higher methadone doses (among the subsample in methadone treatment). Conclusions and Scientific Significance: During future efforts to improve SC treatments among drug- and alcohol-dependent patients, consideration should be given to adequate treatment to reduce the severity of the primary drug or alcohol problem, tailoring treatments for patients with greater severity of smoking and of the primary substance problem, and culturally sensitive interventions. Analysis of predictors of outcome may be a useful tool for treatment development

There is growing concern that results of tightly controlled clinical trials may not generalize to broader community samples. To assess the proportion of community dwelling adults with cannabis dependence who would have been eligible for a typical cannabis dependence treatment study, we applied a standard set of eligibility criteria commonly used in cannabis outcome studies to a large (N=43,093) representative US adult sample interviewed face-to-face, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Approximately 80% of the community sample of adults with a diagnosis of cannabis dependence (N=133) would be excluded from participating in clinical trials by one or more of the common eligibility criteria. Individual study criteria excluded from 0% to 41.0% of the community sample. Legal problems, other illicit drug use disorders, and current use of fewer than 5 joints/week excluded the largest percentage of individuals. These results extend to cannabis dependence concerns that typical clinical trials likely exclude most community dwelling adults with the disorder. The results also support the notion that clinical trials tend to recruit highly selective samples, rather than adults who are representative of typical patients. Clinical trials should carefully evaluate the effects of eligibility criteria on the generalizability of their results. Even in efficacy trials, stringent exclusionary criteria could limit the representativeness of study results.

Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of cocaine dependence. We hypothesized that memantine, a low potency, uncompetitive NMDA receptor antagonist, would be safe and effective in the treatment of cocaine dependence, particularly in preventing relapse to cocaine use in abstinent individuals. Cocaine dependent patients (N=112) were enrolled. The trial began with a 2-week placebo lead-in period during which patients received high-value voucher contingency management to induce abstinence. Participants were then randomized to receive either memantine 20mg bid (N=39) or placebo (N=42) for 12-weeks in combination with individual relapse-prevention therapy. The randomization was stratified by abstinence status during the lead-in period. The primary outcome was the weekly proportion of days of cocaine use. There were no significant differences in cocaine use outcome between the groups treated with memantine versus placebo. Thus, the efficacy of memantine 40 mg/d for the treatment of cocaine dependence was not supported. Urine-confirmed abstinence during the lead-in period was achieved by 44% of participants, and was a strong predictor of subsequent cocaine abstinence during the trial. This suggests that this clinical trial design, an intensive behavioral intervention during a lead-in period, resolves cocaine dependent patients into two subgroups, one that rapidly achieves sustained abstinence and may not need a medication, and another that displays persistent cocaine use and would most likely benefit from a medication to help induce abstinence. Targeting the latter subgroup may advance medication development efforts.

OBJECTIVE:To explore racial/ethnic difference in OROS-methylphenidate (OMPH) efficacy when added to nicotine patch and counseling for treating nicotine dependence among smokers with attention deficit hyperactivity disorder (ADHD). METHOD/METHODS:Participants were adult smokers with ADHD (202 whites and 51 non-whites) randomly assigned to OMPH or placebo in a multi-site, randomized controlled trial. Study outcomes were complete, prolonged, and point-prevalence abstinence at the end of treatment, and weekly ratings of ADHD symptoms, tobacco withdrawal symptoms, and desire to smoke. RESULTS:The rate of four-week complete abstinence (no slips or lapses) was significantly higher with OMPH than placebo among non-white (OMPH=42.9%, placebo=13.3%, chi(2)(1)=5.20, p=0.02) but not white participants (OMPH=23.1%, placebo=23.5%, chi(2)(1)=0.00, p=0.95). Patterns of prolonged and point-prevalence abstinence among non-whites were similar but fell short of statistical significance. OMPH reduced ADHD symptoms in both race/ethnic groups, and produced greater reductions in desire to smoke and withdrawal symptoms among the non-white than white participants. Change in desire to smoke, but not in withdrawal or ADHD symptoms predicted abstinence. The ability of OMPH to reduce desire to smoke among non-whites appeared to mediate the medication's positive effect on abstinence. CONCLUSION/CONCLUSIONS:Differential efficacy favoring non-whites of a medication for achieving smoking cessation is a potentially important finding that warrants further investigation. OROS-MPH could be an effective treatment for nicotine dependence among a subgroup of smokers.

Women in drug treatment struggle with co-occurring problems, including trauma and post-traumatic stress disorder (PTSD), which can heighten HIV risk. This study examines the impact of two group therapy interventions on reduction of unprotected sexual occasions (USO) among women with substance use disorders (SUD) and PTSD. Participants were 346 women recruited from and receiving treatment at six community-based drug treatment programs participating in NIDA's Clinical Trials Network. Participants were randomized to receive 12-sessions of either seeking safety (SS), a cognitive behavioral intervention for women with PTSD and SUD, or women's health education (WHE), an attention control psychoeducational group. Participants receiving SS who were at higher sexual risk (i.e., at least 12 USO per month) significantly reduced the number of USO over 12-month follow up compared to WHE. High risk women with co-occurring PTSD and addiction may benefit from treatment addressing coping skills and trauma to reduce HIV risk.