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1.  A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence 
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.
PMCID: PMC3378797  PMID: 22377391
modafinil; cocaine; pharmacotherapy; abstinence; addiction
2.  A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence 
Drug and alcohol dependence  2013;133(1):94-99.
Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs.
The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings.
Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate.
Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.
PMCID: PMC3786029  PMID: 23810644
topiramate; cocaine; alcohol; clinical trial; placebo
3.  Why do those who request smoking treatment fail to attend the first appointment? 
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.
PMCID: PMC2453507  PMID: 17931823
Show rate; Lighter Smokers; Scheduled appointments; Clinical trial barriers; Access to treatment; African American smokers
4.  A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence 
Addictive behaviors  2010;36(3):217-221.
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.
PMCID: PMC3018663  PMID: 21112155
acamprosate; cocaine; clinical trial; placebo
5.  A Double-Blind, Placebo-Controlled Pilot Trial of Quetiapine for the Treatment of Type A and Type B Alcoholism 
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.
PMCID: PMC3193934  PMID: 17632217
6.  Initiating acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence 
Addictive behaviors  2009;34(6-7):581-586.
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.
PMCID: PMC2729436  PMID: 19345510
acamprosate; alcoholism; detoxification; clinical trial; placebo
7.  The Search for Medications to Treat Stimulant Dependence 
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.
PMCID: PMC2797110  PMID: 18497715
8.  Biomarkers for the Development of New Medications for Cocaine Dependence 
Neuropsychopharmacology  2013;39(1):202-219.
There has been significant progress in personalized drug development. In large part, this has taken place in the oncology field and been due to the ability of researchers/clinicians to discover and develop novel drug development tools (DDTs), such as biomarkers. In cancer treatment research, biomarkers have permitted a more accurate pathophysiological characterization of an individual patient, and have enabled practitioners to target mechanistically the right drug, to the right patient, at the right time. Similar to cancer, patients with substance use disorders (SUDs) present clinically with heterogeneous symptomatology and respond variably to therapeutic interventions. If comparable biomarkers could be identified and developed for SUDs, significant diagnostic and therapeutic advances could be made. In this review, we highlight current opportunities and difficulties pertaining to the identification and development of biomarkers for SUDs. We focus on cocaine dependence as an example. Putative diagnostic, pharmacodynamic (PD), and predictive biomarkers for cocaine dependence are discussed across a range of methodological approaches. A possible cocaine-dependent clinical outcome assessment (COA)—another type of defined DDT—is also discussed. At present, biomarkers for cocaine dependence are in their infancy. Much additional research will be needed to identify, validate, and qualify these putative tools prior to their potential use for medications development and/or application to clinical practice. However, with a large unmet medical need and an estimated market size of several hundred million dollars per year, if developed, biomarkers for cocaine dependence will hold tremendous value to both industry and public health.
PMCID: PMC3857653  PMID: 23979119
addiction & substance abuse; biomarker; drug discovery/development; molecular & cellular neurobiology; psychostimulants; biomarkers; cocaine dependence; drug development tools; addiction
9.  The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction 
Annals of human genetics  2013;78(1):33-39.
The risk for drug addiction is partially heritable. Genes of the dopamine system are likely candidates to harbor risk variants, as dopamine neurotransmission is involved in mediating the rewarding effects of drugs of abuse. One functional SNP in DRD2, rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre and post-synaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (n=336) and African American (n=1034) cocaine addicts and European American (n=656) and African American (n=668) controls. We also analysed the role of rs1076560 in opioid dependence by genotyping European American (n=1041) and African American (n=284) opioid addicts. rs1076560 was found to be nominally associated with opioid dependence in European Americans (p=0.02, OR=1.27) and African Americans (p=0.03, OR=1.43). When both opioid addicted ancestral samples were combined, rs1076560 was significantly associated with increased risk for drug dependence (p=0.0038, OR=1.29). This association remained significant after correction for multiple testing. No association was found with cocaine dependence. These data demonstrate the importance of dopamine gene variants in the risk for opioid dependence and highlight a functional polymorphism which warrants further study.
PMCID: PMC4013426  PMID: 24359476
dopamine; genetics; drug addiction; rs1076560; DRD2
10.  Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.06.019.
Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence.
Alcohol dependent subjects (n = 40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM).
There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6-13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial.
Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.
PMCID: PMC3866905  PMID: 23916324
treatment; pharmacotherapy; alcohol dependence; nicotine dependence; varenicline
11.  Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic Activation Elicited by Subliminal Drug Cues 
The Journal of Neuroscience  2014;34(14):5038-5043.
Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen—a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals—could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing—that which occurs outside of awareness—before it evolves into a less manageable state.
PMCID: PMC3972727  PMID: 24695721
addiction; baclofen; cocaine; cues; fMRI; subliminal
12.  Study Blinding and Correlations Between Perceived Group Assignment and Outcome in a Cocaine Pharmacotherapy Trial 
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.
PMCID: PMC3172694  PMID: 18770080
Experimental design; blinding; cocaine; pharmacotherapy
13.  A Double Blind, Placebo-Controlled Trial that Combines Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence 
The American journal of psychiatry  2010;167(6):668-675.
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.
PMCID: PMC3121313  PMID: 20231324
combining medications; depression; alcohol; sertraline; naltrexone; clinical trial
14.  Case-control association study of WLS variants in opioid and cocaine addicted populations 
Psychiatry research  2013;208(1):62-66.
The opioid receptor family is involved in the development and maintenance of drug addiction. The mu-opioid receptor (MOR) mediates the rewarding effects of multiple drugs, including opiates and cocaine. A number of proteins interact with MOR, potentially modulating MOR function and altering the physiological consequences of drug use. These mu-opioid receptor interacting proteins (MORIPs) are potential therapeutic targets for the treatment of addiction. The Wntless (WLS) protein was recently identified as a MORIP in a yeast two-hybrid screen. In this study, we conducted a case-control association analysis of 16 WLS genetic variants in opioid and cocaine addicted individuals of both African-American (opioid n=336, cocaine n=908) and European-American (opioid n=335, cocaine n=336) ancestry. Of the analyzed SNPs, 3 were nominally associated with opioid addiction and 4 were nominally associated with cocaine addiction. None of these associations were significant following multiple testing correction. These data suggest that the common variants of WLS analyzed in this study are not associated with opioid or cocaine addiction. However, this study does not exclude the possibilities that rare variants in WLS may affect susceptibility to drug addiction, or that common variants with small effect size may fall below the detection level of our analysis.
PMCID: PMC3665700  PMID: 23566366
drug addiction; cocaine addiction; opioid addiction; genetics
15.  Combined effects of alcohol and hepatitis C: a secondary analysis of alcohol use biomarkers and high-risk behaviors from two medication trials for alcohol dependence 
Addictive behaviors  2009;35(2):123-128.
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.
PMCID: PMC2784285  PMID: 19783106
Hepatitis C; Alcohol Dependence; CDT (carbohydrate-deficient transferrin); GGT (gamma glutamyl transpeptidase); Risk-Assessment
16.  Low frequency genetic variants in the mu-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine 
Neuroscience letters  2013;542:71-75.
The μ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute –Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24–0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study.
PMCID: PMC3640707  PMID: 23454283
OPRM1; addiction; cocaine; heroin; rare variants; genetics
17.  Gender Differences in Predictors of Treatment Attrition with High Dose Naltrexone in Cocaine and Alcohol Dependence 
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.
PMCID: PMC2657877  PMID: 19034737
Naltrexone; cocaine dependence; alcohol dependence; adverse events; nausea; treatment attrition
18.  Gender Differences with High Dose Naltrexone in Cocaine and Alcohol Dependent Patients 
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.
PMCID: PMC2600888  PMID: 17664051
naltrexone; cocaine dependence; alcohol dependence; CBT; BRENDA; adverse-events
19.  Neuronal calcium sensor-1 and cocaine addiction: A genetic association study in African-Americans and European Americans 
Neuroscience letters  2012;531(1):46-51.
Genes involved in drug reward pathways are plausible candidates for susceptibility to substance use disorders. Given the prominent role of dopamine in drug reward, dopamine receptor-interacting proteins (DRIPs) such as the neuronal calcium sensor-1 (NCS-1) protein have been hypothesized to play a role in the pathophysiology of cocaine addiction (CA). In this study, we investigated whether genetic variants in the NCS-1 gene confer risk to CA. We genotyped 8 SNPs (rs4837479, rs7849345, rs3824544, rs10819611, rs947513, rs2277200, rs7873936 and rs1342043) in our discovery sample (cases n = 796, controls n = 416) of African descent. Confirmation of associated or trending SNPs (rs7849345, rs10819611, rs1342043) was attempted using a replication sample of African American (AA) ethnicity (cases n = 335, controls n = 336) and European-American (EA) ancestry (cases n = 336, controls n = 656). Secondary sex specific analysis was also carried out for each SNP in both AA and EA individuals. Genotyping of the discovery cohort showed significant genotypic (p = 0.0005, corrected q-value) as well as allelic (p = 0.005, corrected q-value) associations of rs1342043 with CA in AAs; however, this marker could not be confirmed in either the AA or EA replication sample. Combined analysis of all AA samples (n = 1883) for rs1342043 showed a significant association with CA (genotypic p = 0.0001, allelic p = 0.002) with a gender specific effect for males (allelic p = 0.005, genotypic p = 0.0003). Our data suggest that genetic variants in the NCS-1 gene contribute to susceptibility of CA in individuals of African descent.
PMCID: PMC3895491  PMID: 22999924
Addiction; Cocaine; NCS-1; African Americans; European Americans
20.  A Placebo-Controlled Randomized Clinical Trial of Naltrexone in the Context of Different Levels of Psychosocial Intervention 
Alcoholism, clinical and experimental research  2008;32(7):10.1111/j.1530-0277.2008.00698.x.
Naltrexone is approved for the treatment of alcohol dependence when used in conjunction with a psychosocial intervention. This study was undertaken to examine the impact of 3 types of psychosocial treatment combined with either naltrexone or placebo treatment on alcohol dependency over 24 weeks of treatment: (1) Cognitive-Behavioral Therapy (CBT) + medication clinic, (2) BRENDA (an intervention promoting pharmacotherapy) + medication clinic, and (3) a medication clinic model with limited therapeutic content.
Two hundred and forty alcohol-dependent subjects were enrolled in a 24-week double- blind placebo-controlled study of naltrexone (100 mg/d). Subjects were also randomly assigned to 1 of 3 psychosocial interventions. All patients were assessed for alcohol use, medication adherence, and adverse events at regularly scheduled research visits.
There was a modest main treatment effect for the psychosocial condition favoring those subjects randomized to CBT. Intent-to-treat analyses suggested that there was no overall efficacy of naltrexone and no medication by psychosocial intervention interaction. There was a relatively low level of medication adherence (50% adhered) across conditions, and this was associated with poor outcome.
Results from this 24-week treatment study demonstrate the importance of the psychosocial component in the treatment of alcohol dependence. Moreover, results demonstrate a substantial association between medication adherence and treatment outcomes. The findings suggest that further research is needed to determine the appropriate use of pharmacotherapy in maximizing treatment response.
PMCID: PMC3812909  PMID: 18540910
Alcohol Dependence; Treatment; Naltrexone; Psychotherapy
21.  Atomoxetine for Treatment of Marijuana Dependence: A Report on the Efficacy and High Incidence of Gastrointestinal Adverse Events in a Pilot Study 
Drug and alcohol dependence  2008;94(0):10.1016/j.drugalcdep.2007.10.020.
Marijuana users consistently demonstrate impairments in attention, executive function and response inhibition, which resemble deficits seen in attention deficit hyperactivity disorder (ADHD). We hypothesized that targeting the cognitive deficits associated with chronic marijuana use through ADHD medications may help identify a therapeutic agent for marijuana dependence.
Thirteen subjects participated in an 11-week open label study to determine the feasibility, safety and tolerability of atomoxetine for individuals seeking treatment for marijuana dependence. The Time-Line Follow-Back measured marijuana use 90 days prior to study entry (p-TLFB) and weekly during the study (s-TLFB) along with weekly qualitative urine drug screen (UDS). For the eight subjects who completed the trial, the TLFB data showed a trend toward reduction in use with an increase in percent days abstinent (p=0.06). Analysis of weekly UDSs did not confirm the TLFB trend with 94% of all possible UDSs positive for THC through out the study.
Marijuana dependent subjects taking atomoxetine experienced an inordinate number of gastrointestinal (GI) adverse events. Overall, 10 of 13 subjects (77%) experienced a mild to moderate GI adverse event defined as nausea, vomiting, dyspepsia, and loose stools. Atomoxetine is of limited utility in the treatment of cannabis dependence and is associated with clinically significant GI adverse events.
PMCID: PMC3812929  PMID: 18182254
Marijuana Dependence; Atomoxetine; ADHD
22.  Predictors of Treatment Outcome in Outpatient Cocaine and Alcohol Dependence Treatment 
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.
PMCID: PMC3777818  PMID: 19219669
23.  Further evidence for association between genetic variants in the cannabinoid receptor 1 (CNR1) gene and cocaine dependence: Confirmation in an independent sample and meta-analysis 
Addiction biology  2011;18(4):702-708.
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.
PMCID: PMC3223560  PMID: 21790903
Addiction; Association study; Cocaine; Cannabinoid receptor; Genetics; Substance abuse
24.  Results of an initial clinical trial of varenicline for the treatment of cocaine dependence 
Drug and Alcohol Dependence  2011;121(1-2):163-166.
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.
PMCID: PMC3262950  PMID: 21925806
cocaine; treatment; pharmacotherapy; contingency management
25.  Covariates of Craving in Actively Drinking 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.
PMCID: PMC2925315  PMID: 20716308

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