This is a randomized, double blind, placebo-controlled study of modafinil treatment for cocaine dependence. Patients (n=210), who were actively using cocaine at baseline, were randomized to 8-weeks of modafinil (0 mg/day, 200 mg/day or 400 mg/day) combined with once-weekly cognitive behavioral therapy (CBT). Our primary efficacy measure was cocaine abstinence, based on urine benzoylecgonine (BE) levels, with secondary measures of craving, cocaine withdrawal, retention and tolerability. We found no significant differences between modafinil and placebo patients on any of these measures. However, there was a significant gender difference in that male patients treated with 400 mg/day tended to be more abstinent than their placebo-treated counterparts (p=0.06). Our negative findings might be explained by gender differences and/or inadequate psychosocial treatment intensity in patients with severe cocaine dependence.
modafinil; cocaine; pharmacotherapy; abstinence; addiction
We examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine- and alcohol-dependent and were selected for a randomized, double-blind, placebo-controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self-reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self-reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine-dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials.
Genetic research on cocaine dependence may help clarify our understanding of the disorder as well as provide insights for effective treatment. Since endocannabinoid signaling and dopamine neurotransmission have been shown to be involved with drug reward, genes related to these systems are plausible candidates for susceptibility to cocaine dependence. The cannabinoid receptor 1 (CB1) protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the cannabinoid receptor gene, CNR1, have been previously been associated with substance dependence. In this study, we attempt to replicate a finding associating CNR1 with cocaine dependence in African Americans. Cocaine dependent individuals (n=883) and unaffected controls (n=334) of African descent were genotyped for two single nucleotide polymorphisms (SNPs) in the CB1 gene (rs6454674, rs806368). We observed a significant difference in genotype frequencies between cases and controls for both SNPs (p≤0.05). This study confirms the association between variants in the CNR1 and cocaine dependence. However, considering the substantial co-morbidity of cocaine dependence with other drugs of abuse, additional studies are necessary to determine whether polymorphisms in CNR1 induce a general susceptibility to substance dependence or are specific to cocaine addiction.
Addiction; Association study; Cocaine; Cannabinoid receptor; Genetics; Substance abuse
Progress in understanding the neurobiology of stimulant dependence has enabled researchers to identify medications whose pharmacological effects suggest that they might help patients initiate abstinence or avoid relapse. Several of these medications and a vaccine have shown encouraging results in controlled clinical trials with cocaine-dependent patients. The search for a medical treatment for methamphetamine dependence started more recently, due to the later emergence of this epidemic, but at least one candidate medication has shown promise in early clinical testing. Treatment approaches that combine efficacious medications and empirically proven behavioral interventions, such as voucher-based reinforcement therapy, will almost certainly produce the best results.
While much research has suggested that the integrity of the blind is compromised in psychotropic drug trials, little research has been conducted on blinding in substance abuse trials. The current study examines the integrity of the blind in an outpatient pharmacotherapy trial investigating the effectiveness of amantadine and propranolol in treating cocaine addiction. Results suggest that neither nurses (N=174, kappa = 0.08, p=0.22) nor participants (N=163, kappa = 0.09, p=0.26) could accurately predict treatment assignment. Furthermore, nurses’ perceptions of treatment assignment were significantly related to trial completion, medication compliance and cocaine use—results that may have training implications for medical personnel.
Experimental design; blinding; cocaine; pharmacotherapy
Cocaine use, abuse and dependence remains a pressing public health problem. Based on its mechanism of action, varenicline, an alpha4 beta2 partial agonist seemed to be a likely candidate for treating cocaine dependence.
Cocaine dependent participants (n = 37) were enrolled in a 9-week double-blind placebo controlled clinical trial. Varenicline was titrated up to a target dose of 1 mg BID during the first week of medication.
Varenicline was associated with lower odds of cocaine use than placebo (OR = 2.02, p=0.08), as measured by thrice-weekly urinalysis results. Compared to placebo-treated participants, varenicline treated participants had significantly decreased rates of cocaine reward, as measured by the Multiple Choice Procedure (MCP) (p = .02).
Varenicline appears to decrease cocaine use and reward, suggesting that further investigation of varenicline may be warranted.
cocaine; treatment; pharmacotherapy; contingency management
Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence. While some studies have demonstrated that antidepressants reduce these patients’ depressive symptoms, most studies have not found antidepressants helpful in reducing excessive drinking in these patients. We provide results from a double blind, placebo-controlled trial that evaluated the efficacy of combining approved medications for depression (sertraline) and alcohol dependence (naltrexone) for treating patients with both disorders.
170 depressed, alcohol-dependent patients were randomized for 14 weeks to sertraline (200mg/day), naltrexone (100mg/day), the combination, or placebo, while receiving weekly cognitive behavioral therapy.
The sertraline + naltrexone combination produced a higher alcohol abstinence rate (53.7%; p = .001; odds ratio = 3.7), and a longer delay before relapse to heavy drinking (98 median days; p = .003; d = .54), than the other treatments: naltrexone (21.3% abstinent, 29 days), sertraline (27.5% abstinent, 23 days), or placebo (23.1% abstinent, 26 days). There also was a trend for more patients in the medication combination group not to be depressed by the end of treatment (83.3%; p = .014; odds ratio = 3.6), compared to the other treatments. The serious adverse event rate was 25.9%, with fewer reported by the medication combination group (11.9%; p < .02) than the other treatments.
More depressed, alcohol-dependent patients taking the sertraline + naltrexone combination achieved abstinence from alcohol, delayed relapse to heavy drinking, reported fewer serious adverse events, and tended not to be depressed by the end of treatment.
combining medications; depression; alcohol; sertraline; naltrexone; clinical trial
This goal of this secondary analysis was to examine the combined effect of HCV infection and recent alcohol use on baseline biologic markers of alcohol consumption in two outpatient medication trials for alcohol dependence. In addition, the relationship between Hepatitis C virus (HCV) infection and behavioral risk factors for HCV infection in these clinical populations were examined.
Data (n = 345) from two randomized, placebo-controlled trials of naltrexone and psychosocial treatment for alcohol dependence (Study I, n = 212) and comorbid alcohol and cocaine dependence (Study II, n = 133) were used to examine baseline measures of HCV risk behaviors (injection drug use, needle sharing), and biomarkers of alcohol use (AST, ALT, GGT and CDT) were compared by HCV serostatus first within each study and then across studies.
Although groups had differing sociodemographic profiles (as indicated by race, marital status, level of education) subjects in Study I exhibited no statistically significant differences from the Study II cohort in HCV prevalence (12.7 vs. 20.0 percent, p = 0.07), lifetime history of injection drug use (13.8 vs. 22.0%, p = 0.74), lifetime history of needle sharing (9.1 vs. 18.0 percent, p = 0.62). As such, the data from both studies were analyzed together. Regardless of drinking status, HCV infection was significantly associated with an upward shift in the baseline level of ALT, AST, and GGT (p<0.006 for all measures) and a downward shift in baseline CDT (p = 0.002). When using standard laboratory cutoff values to determine clinically significant elevations, HCV seropositivity was significantly associated with elevations in ALT, AST, GGT (p<0.001), and with decreases in CDT (p = .002).
These data emphasize the importance of evaluating HCV infection and HCV risk behaviors at intake in medication trials for alcohol dependence and also raise questions regarding the use of cut off scores for ALT, AST, GGT and CDT levels as biologic markers of alcohol use in subjects when HCV status is unknown.
Hepatitis C; Alcohol Dependence; CDT (carbohydrate-deficient transferrin); GGT (gamma glutamyl transpeptidase); Risk-Assessment
Recently, we reported that naltrexone at 150mg/day significantly decreased cocaine and alcohol use for men, but not women with co-occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender response to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre-treatment psychiatric problems, or nausea while in treatment. Further research on the impact of pre-treatment and in-treatment gender differences with naltrexone is warranted.
Naltrexone; cocaine dependence; alcohol dependence; adverse events; nausea; treatment attrition
As part of a larger trial of pharmacological and counseling interventions for light smokers, we performed a telephone-screening interview followed by a scheduled time for an in-person eligibility appointment. 202 of the 407 who screened positive and expressed interest in participation failed to attend the first scheduled appointment. This paper examines person, study and study site characteristics that differentiated those who did follow through from those who did not. The study also examined the self-reported quit rates of both groups 12 weeks later, the time of the study termination.
Analyses suggested that non-attendees were more likely to be younger, unemployed, and African American. The most frequently cited reasons for missing the eligibility appointment were work/family obligations, inconvenient appointment times, and personal schedule problems. Those who kept the initial appointment were more likely to report smoking abstinence at 12 weeks.
The study has implications for increasing the utilization of potentially effective treatments for smokers.
Show rate; Lighter Smokers; Scheduled appointments; Clinical trial barriers; Access to treatment; African American smokers
This is a randomized, double blind, placebo-controlled clinical trial that evaluated the efficacy of a higher than typical daily dose of naltrexone (150mg/day), taken for 12 weeks, in 164 patients (n=116 men and n=48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender, and then randomly assigned to naltrexone or placebo, and to either cognitive behavioral therapy, or a type of medical management. The two primary outcomes were cocaine and alcohol use. Significant gender by medication interactions were found for cocaine use via urine drug screens [3-way with time] and self-reports [2-way], for drug severity [2-way], and for alcohol use [2-way]. Type of psychosocial treatment did not affect outcomes. Thus, 150mg/day of naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use, and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women.
naltrexone; cocaine dependence; alcohol dependence; CBT; BRENDA; adverse-events
Acamprosate is a medication shown to be effective for the treatment of alcohol dependence. Although the exact mechanism of action of acamprosate is unknown, evidence suggests that it decreases excitatory amino acid activity by postsynaptic inhibition of the NMDA subtype of glutamate receptors. It is possible that the activity of acamprosate via modulating glutamatergic activity could also reduce craving for cocaine and impact abstinence in cocaine dependence. Therefore, we conducted a double-blind placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence.
Sixty male and female cocaine dependent patients were included in a nine-week double-blind, placebo-controlled trial. After a one-week baseline, patients were randomized to receive acamprosate 666 mg three times daily or identical placebo tablets for eight weeks. The primary outcome measure was cocaine use as determined by twice weekly urine drug screens.
Thirty-six patients (60%) completed the trial, with no significant between-group difference in treatment retention. Percent cocaine positive urine drug screens did not differ between the two groups. Acamprosate was no better than placebo in reducing cocaine craving, reducing cocaine withdrawal symptoms, or improving measures of drug use severity from the Addiction Severity Index. Adverse events in this trial were generally mild and were evenly distributed between the two groups.
Acamprosate was well tolerated but was no more efficacious than placebo in promoting abstinence from cocaine in cocaine dependent patients. Acamprosate does not appear to be a promising medication for the treatment of cocaine dependence.
acamprosate; cocaine; clinical trial; placebo
Atypical antipsychotics may be useful in the treatment of alcohol dependence. Human trials suggest that atypical antipsychotics may reduce alcohol craving and consumption, especially among patients with comorbid psychopathology. Therefore, these medications may be more useful for treating more severely affected alcoholics, such as patients with Type B alcoholism. Type B alcoholics are characterized by an early age of onset of problem drinking, high severity of alcohol dependence, increased psychopathology, and treatment-resistance. Quetiapine is an atypical antipsychotic with a favorable side effect profile, and may be a promising medication for the treatment of alcohol dependence, particularly Type B alcoholism.
Male and female alcoholics (33 Type A and 28 Type B) were included in a 12-week, double-blind, placebo-controlled trial. After detoxification, patients were randomized to receive quetiapine (n = 29), 400 mg/d at bedtime, or placebo (n = 32). The primary outcome measure was the quantity and frequency of alcohol consumption, measured by the timeline follow back.
Forty-seven patients (77%) completed the trial, with no significant between-group differences in treatment retention. Nine quetiapine-treated patients (31%) maintained complete abstinence compared with 2 placebo-treated patients (6%) (χ2 = 6.3, P = 0.012). There was a significant interaction between quetiapine and alcoholic subtype. As predicted, quetiapine- versus placebo-treated Type B alcoholics had significantly fewer days of drinking and fewer days of heavy drinking. Alcohol craving was also significantly reduced in quetiapine-treated compared with placebo-treated Type B alcoholics. Among Type A alcoholics, quetiapine provided no advantage over placebo in improving drinking outcomes.
Quetiapine may be effective for the treatment of alcohol dependence, particularly in the more complicated Type B, early-onset alcoholics.
The goal of this cross-sectional study was to assess the relationship of alcohol craving with biopsychosocial and addiction factors that are clinically pertinent to alcoholism treatment. Alcohol craving was assessed in 315 treatment-seeking, alcohol dependent subjects using the PACS questionnaire. Standard validated questionnaires were used to evaluate a variety of biological, addiction, psychological, psychiatric, and social factors. Individual covariates of craving included age, race, problematic consequences of drinking, heavy drinking, motivation for change, mood disturbance, sleep problems, and social supports. In a multivariate analysis (R2 = .34), alcohol craving was positively associated with mood disturbance, heavy drinking, readiness for change, and negatively associated with age. The results from this study suggest that alcohol craving is a complex phenomenon influenced by multiple factors.
There is a robust relationship between early and later abstinence in smoking cessation, but that relationship has not been explored among other substances of abuse. To assess whether early abstinence during treatment, as opposed to baseline abstinence, predicted later abstinence among cocaine dependent patients, data from two randomized double-blind controlled clinical pharmacotherapy trials were analyzed. Similar to the findings in the smoking cessation literature, results indicate that abstinence in the first two weeks of pharmacotherapy predicted later in-trial abstinence. This finding has implications for both treatment research and for clinical practice, suggesting that patients who do not respond early in treatment may need a more intensive intervention.
genetics; association study; haplotype; addiction; substance abuse; cocaine
This trial compared the efficacy of acamprosate, started at the beginning of detoxification, to acamprosate started at the completion of detoxification, in the treatment of alcohol dependence.
This biphasic clinical trial consisted of a randomized, double-blind, placebo-controlled Detoxification Phase (DP), followed by a 10-week open-label Rehabilitation Phase (RP). Forty alcohol dependent patients were randomly assigned to receive either 1998 mg of acamprosate daily, or matching placebo, during the DP (5–14 days). After completing detoxification, all patients received open label acamprosate (1998 mg daily) in the RP. Outcome measures during the DP included: treatment retention, alcohol withdrawal, alcohol consumption, and oxazepam used. Outcome measures during the RP included: treatment retention and alcohol consumption.
There were no significant outcome differences between acamprosate and placebo-treated patients during the DP. Patients given acamprosate, compared to placebo, during the DP drank more alcohol in the RP.
Starting acamprosate at the beginning of detoxification did not improve DP outcomes. Starting acamprosate after detoxification was completed was associated with better drinking outcomes during subsequent alcohol rehabilitation treatment.
acamprosate; alcoholism; detoxification; clinical trial; placebo
Cocaine induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neurons and is expressed in brain regions that undergo cocaine-induced neuroplasticity. In this study, we hypothesize that polymorphisms in the CDNF gene (CDNF/ARMETL1) contribute to increased risk for cocaine dependence. Cocaine dependent individuals (n=351) and unaffected controls (n=257) of African descent were genotyped for four single nucleotide polymorphisms (SNPs) in the CDNF gene (rs11259365, rs7094179, rs7900873, rs2278871). We observed no significant differences in allele, genotype, or haplotype frequencies between cases and controls for any of the tested SNPs. Our study suggests that there is no association between variants in the CDNF gene and cocaine dependence. However, additional studies using larger sample sizes, comprehensive SNP coverage, and clinically homogenous populations are necessary before confidently excluding CDNF as a significant genetic risk factor for cocaine dependence.
Addiction; Association study; Cocaine; Neurotrophic factor; Genetics; Substance abuse; ARMETL1
Dopaminergic brain systems have been implicated to play a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The cocaine- and amphetamine-regulated transcript peptide (CARTPT) is involved in reward and feeding behavior and has functional characteristics of an endogenous psychostimulant. In this study we tested the hypothesis that variation in the CARTPT gene increases susceptibility to cocaine dependence in individuals of African descent. Genotypes of three HapMap tagging SNPs (rs6894758; rs11575893; rs17358300) across the CARTPT gene region were obtained in cocaine dependent individuals (n=348) and normal controls (n=256). All subjects were of African descent. There were no significant differences in allele, genotype or haplotype frequencies between cases and controls for any of the tested SNPs. Our results do not support an association of the CARTPT gene with cocaine dependence; however, additional studies using larger samples, comprehensive SNP coverage, and different populations are necessary to conclusively rule out CARTPT as a contributing factor in the etiology of cocaine dependence.
genetics; association study; haplotype; addiction; substance abuse; cocaine
This is a double blind, placebo-controlled trial that evaluated the efficacy of disulfiram, naltrexone and their combination in patients with co-occurring cocaine and alcohol dependence.
208 patients were randomized to disulfiram (250mg/day), naltrexone (100mg/day), the combination, or placebo for 11 weeks. Outcomes were in-trial abstinence from cocaine and/or alcohol.
Few safety concerns were reported, although medication adherence was low in a number of patients for both medications, alone or in combination. In the primary analyses (GEE modeling), abstinence from cocaine as measured by cocaine-negative urines and days of self-reported abstinence from cocaine or alcohol did not differ between placebo and any of the medication groups. However, patients taking disulfiram (alone or in combination) were most likely to achieve combined abstinence from cocaine and alcohol. Secondary analyses revealed that patients taking the disulfiram-naltrexone combination were most likely to achieve 3 consecutive weeks of abstinence from cocaine and alcohol.
There was an association between disulfiram treatment and abstinence from cocaine and alcohol. More patients taking the disulfiram-naltrexone combination achieved 3 consecutive weeks of abstinence in treatment than placebo-treated patients.
combining medications; cocaine; alcohol; disulfiram; naltrexone; clinical trial; medication nonadherence
genetics; association study; haplotype; addiction; substance abuse