Effect of low-energy shock wave therapy on intravesical epirubicin delivery in a rat model of bladder cancer.

OBJECTIVES: To study the efficacy of low-energy shock wave therapy (LESW) on enhancing intravesical epirubicin (EPI) delivery in a rat model of bladder cancer (BCa). MATERIALS AND METHODS: A total of 100 female Fischer rats were randomly allocated into five groups: control; BCa; LESW; EPI; and EPI plus LESW. After BCa induction by N-butyl-N-(4-hydroxybutyl)nitrosamine, EPI (0.6 mg/0.3 mL of EPI diluted in 0.3 mL saline) or saline (0.6 mL) was administered and retained in the bladders for 1 h with or without LESW treatment (300 pulses at 0.12 mJ/mm2 ). This was repeated weekly for 6 weeks. Survival was then calculated, rats were weighed and their bladders were harvested for bladder/body ratio estimation, histopathological examination, p53 immunostaining, miR-210, hypoxia-inducible factor (HIF)-1α, tumour necrosis factor (TNF)-α and interleukin (IL)-6 relative gene expression and fluorescence spectrophotometric drug quantification. Heart and blood samples were also collected for assessment of the safety profile and toxicity. RESULTS: The EPI plus LESW group had significantly lower mortality rates, loss of body weight and bladder/body ratio. Histopathological results in terms of grossly visible bladder lesions, mucosal thickness, dysplasia formation and tumour invasion were significantly better in the combined treatment group. The EPI plus LESW group also had statistically significant lower expression levels of p53 , miR-210, HIF-1α, TNF-α and IL-6. LESW increased urothelial concentration of EPI by 5.7-fold (P < 0.001). No laboratory variable exceeded the reference ranges in any of the groups. There was an improvement of the indicators of EPI-induced cardiomyopathy in terms of congestion, hyalinization and microvesicular steatosis of cardiomyocytes (P = 0.068, 0.003 and 0.046, respectively) in the EPI plus LESW group. CONCLUSIONS: The combined use of intravesical EPI and LESW results in less BCa invasion and less dysplasia formation, as LESW increases urothelial permeability of EPI and enhances its delivery into tumour tissues, without subsequent toxicity.

Functional and molecular evaluation of using aliskiren during acute and chronic partial ureteral obstruction in rat solitary kidney.

AIMS: To study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. MAIN METHODS: Sixty male Sprague-Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-ß1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. KEY FINDINGS: After two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-ß1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks. SIGNIFICANCE: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

A cholecystokinin B receptor antagonist and cocaine interaction, phase I study.

AIMS: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681. METHODS: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose. RESULTS: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA. CONCLUSION: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

National Rehabilitation Center programme performance measures in the United Arab Emirates, 2013.

The aim of this study was to measure the performance of the National Rehabilitation Center (NRC) programme and the services it provides. A 6-point tool was developed based on international standards with appropriate performance measures. The elements of the tool were applied to the electronic data files for 2013. The results showed that there were some operational, quality and data system issues. Some items were easily accessible, e.g. capacity, waiting time, family involvement. Others were difficult to sort and find and some were not available in the electronic system and had to be retrieved from other sources, e.g. programme effectiveness. There was a high no-show rate for appointments (46%) and readmission rate (52%) and most families did not attend family sessions (72%). This was a valuable exercise which identified gaps in operations and records. The findings were shared with the different teams to help improve the quality of data and services and the tool will be used for annual performance evaluations.

Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial.

AIM: Bupropion was tested for efficacy to achieve methamphetamine (MA) abstinence in dependent, non-daily users. METHODS: A randomized, double-blind, placebo-controlled trial, with 12-week treatment and 4-week follow-up, was conducted with 204 treatment-seeking participants having MA dependence per DSM-IV, who used MA on a less-than-daily basis. 104 were randomized to matched placebo and 100 to bupropion, sustained-release 150mg, twice daily. Participants were seen three times weekly to obtain urine for MA and bupropion assays, study assessments, and thrice weekly, 90-min, group psychotherapy. There was no biomarker for placebo adherence. The primary outcome was achievement of abstinence throughout the last two weeks of treatment; 'success' requiring at least two urine samples during each of Weeks 11 and 12, and all samples MA-negative (<300ng/mL). RESULTS: Bupropion and placebo groups did not differ significantly in the percentage achieving abstinence for the last 2 weeks of treatment (chi-square, p=0.32). Subgroup analysis of participants with lower baseline MA use (≤18 of last 30 days before consent) also revealed no difference in success between groups (p=0.73). Medication adherence per protocol (detectable bupropion, >5ng/mL, in ≥50% of urine samples from Study Weeks 1-10 and ≥66% of urine samples from Weeks 11 to 12) was achieved by 47% of participants taking bupropion. CONCLUSIONS: These data indicate that bupropion did not increase abstinence in dependent participants who were using MA less-than-daily. Medication non-adherence was a limitation in this trial. Psychosocial therapy remains the mainstay of treatment for MA dependence. Further research on subgroups who may respond to bupropion may be warranted.

Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction.

BACKGROUND: Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile. METHODS: In this double-blind, placebo-controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways. RESULTS: At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function. CONCLUSION: Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

An Evaluation of Substance Abuse Treatment and HIV Education on Safe Sex Practices in Cocaine Dependent Individuals.

Background. There is a strong association between crack/cocaine use and increased sexual risk behavior, but little research on the efficacy of HIV education for decreasing such behavior in crack/cocaine-addicted individuals in substance abuse treatment. Method. Datasets from two cocaine dependence trials including either one or three HIV education sessions, respectively, were analyzed for changes over time in the proportion of participants practicing safe sex. A pooled dataset from two earlier trials not offering HIV education was also analyzed. Results. We included 83 participants from the 1-session trial and 65 participants from the 3-session trial. Both sets of participants evidenced a significant increase in the proportion of participants having safe sex with casual partners. Participants in the 3-session HIV education study also evidenced a significant increase in the proportion of participants having safe sex with regular partners. In the trials without HIV education, no change in safe sex practices was found, and change in condom use was observed only among female participants. Conclusions. These findings are consistent with recommendations that HIV education/counseling should be provided to individuals in substance abuse treatment. A randomized controlled trial to confirm these results may be warranted. This trial is registered with NCT00033033, NCT00086255, NCT00015106, and NCT00015132.

Fine-grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis.

BACKGROUND: As reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate (N=69) or placebo (N=71) in a 13-week clinical trial. The study found that topiramate did not appear to reduce methamphetamine use significantly for the primary outcome (i.e., weekly abstinence from methamphetamine in weeks 6-12). Given that the treatment responses varied considerably among subjects, the objective of this study was to identify the heterogeneous treatment effect of topiramate and determine whether topiramate could reduce methamphetamine use effectively in a subgroup of subjects. METHODS: Latent variable analysis was used for the primary and secondary outcomes during weeks 6-12 and 1-12, adjusting for age, sex, and ethnicity. RESULTS: Our analysis of the primary outcome identified 30 subjects as responders, who either reduced methamphetamine use consistently over time or achieved abstinence. Moreover, topiramate recipients had a significantly steeper slope in methamphetamine reduction and accelerated to abstinence faster than placebo recipients. For the secondary outcomes in weeks 6-12, we identified 40 subjects as responders (who had significant reductions in methamphetamine use) and 65 as non-responders; topiramate recipients were more than twice as likely as placebo recipients to be responders (odds ratio=2.67; p=0.019). Separate analyses of the outcomes during weeks 1-12 yielded similar results. CONCLUSIONS: Methamphetamine users appear to respond to topiramate treatment differentially. Our findings show an effect of topiramate on the increasing trend of abstinence from methamphetamine, suggesting that a tailored intervention strategy is needed for treating methamphetamine addiction.

Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

OBJECTIVES: Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. METHODS: In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. RESULTS: Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. CONCLUSIONS: Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial.

AIMS: Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. DESIGN: Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. SETTING: The trial was conducted at eight medical centers in the United States. PARTICIPANTS: One hundred and forty methamphetamine-dependent adults took part in the trial. MEASUREMENTS: The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. FINDINGS: In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. CONCLUSIONS: Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.

Selegiline transdermal system (STS) as an aid for smoking cessation.

INTRODUCTION: This study examined the efficacy and safety of selegiline transdermal system (STS) and brief repeated behavioral intervention (BRBI) for smoking cessation in heavy smokers. We hypothesized that the quit rate of subjects who received STS and BRBI would be significantly greater than that of those who received placebo patch and BRBI. METHODS: This was a double-blind, placebo-controlled parallel-group study in which 246 men and women were randomized to receive either STS (n = 121) or placebo patch (n =125) for 9 weeks. Recruitment targeted heavy smokers, defined as individuals with self-reported use of ≥15 cigarettes/day in the 30 days prior to enrollment, who had smoked cigarettes for the past 5 years, and had an expired CO level ≥9 ppm during screening. RESULTS: Although STS was well tolerated, the overall results indicated that STS with BRBI was not more effective than placebo plus BRBI for smoking cessation (p = .58). CONCLUSIONS: The results are discussed in relation to interventions for heavy smokers. Although 2 trials using oral selegiline both showed trends toward improved abstinence, these results indicate that STS with BRBI was not an effective aid for smoking cessation at the end of treatment (10 weeks), 14, or 26 weeks.

Modafinil for the treatment of methamphetamine dependence.

AIM: Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo. METHODS: This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, who all had a DSM-IV diagnosis of methamphetamine dependence; 68 participants to placebo, 72 to modafinil 200mg, and 70 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome measure was a methamphetamine non-use week, which required all the week's qualitative urine drug screens to be negative for methamphetamine. RESULTS: Regression analysis showed no significant difference between either modafinil group (200 or 400mg) or placebo in change in weekly percentage having a methamphetamine non-use week over the 12-week treatment period (p=0.53). Similarly, a number of secondary outcomes did not show significant effects of modafinil. However, an ad-hoc analysis of medication compliance, by urinalysis for modafinil and its metabolite, did find a significant difference in maximum duration of abstinence (23 days vs. 10 days, p=0.003), between those having the top quartile of compliance (>85% of urines were positive for modafinil, N=36), and the lower three quartiles of modafinil 200 and 400mg groups (N=106). CONCLUSIONS: Although these data suggest that modafinil, plus group behavioral therapy, was not effective for decreasing methamphetamine use, the study is probably inconclusive because of inadequate compliance with taking medication.

Advantages of Joint Modeling of Component HIV Risk Behaviors and Non-Response: Application to Randomized Trials in Cocaine-Dependent and Methamphetamine-Dependent Populations.

The HIV risk-taking behavior scale (HRBS) is an 11-item instrument designed to assess the risks of HIV infection due to self-reported injection-drug use and sexual behavior. A retrospective analysis was performed on HRBS data collected from approximately 1,000 participants pooled across seven clinical trials of pharmacotherapies for either the treatment of cocaine dependence or methamphetamine dependence. Analysis faced three important challenges. The sample contained a high proportion of missing assessments after randomization. Also, the HRBS scale consists of two distinct behavioral components which may or may not coincide in response patterns. In addition, distributions of responses on the subscales were highly concentrated at just a few values (e.g., 0, 6). To address these challenges, a single probit regression model was fit to three outcomes variables simultaneously - the two subscale totals plus an indicator variable for assessments not obtained (non-response). This joint-outcome regression model was able to identify that those who left assessment early had higher self-reported risk of injection-drug use and lower self-reported risky sexual behavior because the model was able to draw on information on associations among the three outcomes collectively. These findings were not identified in analyses performed on each outcome separately. No evidence for an effect of pharmacotherapies was observed, except to reduce missing assessments. Univariate-outcome modeling is not recommended for the HRBS.

A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram.

BACKGROUND: A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. AIMS: This study examined the safety of combining cocaine (30 mg i.v.) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. RESULTS: The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. CONCLUSIONS: Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (≤ 250 mg/d) may not be as problematic as some may assume.

Interventions for HIV and hepatitis C virus infections in recreational drug users.

Recreational drug use and infections are 2 of the major problems in the world today. Both cause serious health problems, such as immunologic impairment leading to opportunistic infections and medical comorbidity, including medical complications associated with, for example, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections. Effective and safe interventions (prevention and pharmacologic treatment) are possible for drug-dependent patients with single or dual infections with HIV and HCV if patients in drug treatment programs are closely monitored for adherence and compliance to treatment regimens.

Drug interactions between antiretroviral medications and medications used in the treatment of drug addiction: research needs.

Today substance dependence is one of the major public health problems in the world with millions of people abusing legal and illegal drugs. In addition, almost one-third of the world's population suffers with one or more infections. Both drugs of abuse and infections are associated with serious medical and health consequences, some of which may be exacerbated by the occurrence of pharmacokinetic and/or pharmacodynamic interactions between medications used in the treatment of these conditions when they co-occur. This review briefly discusses issues surrounding clinical management related to drug interactions experienced by substance abusing patients. The emphasis of this paper is on the research needed to further study the extent, nature, and underlying molecular/genetic mechanism(s) of interactions between drugs of abuse, medications used in the treatment of drug addiction, and co-occurring infections.

Association between Genotype of the Serotonin Transporter-Linked Polymorphic Region of the Serotonin Transporter Gene and Age of Onset of Methamphetamine Use: a Preliminary Analysis.

Early-onset methamphetamine use increases the lifetime prevalence of methamphetamine dependence. An earlier onset of methamphetamine use leads to greater damage to the terminal ends of serotonin neurons, more reduction in serotonin transporter (5-HTT) density, and an increased propensity toward further methamphetamine use. Because the 5-HTT-linked polymorphic region (5'-HTTLPR) within the promoter region of the 5-HTT gene leads to differential expression of the 5-HTT, we examined, for the first time, whether there is a differential association between the long (L) and short (S) alleles of the 5'-HTTLPR and the age of first methamphetamine use (AMU). The study included 120 methamphetamine-dependent adults of European descent. Diagnosis of methamphetamine dependence and AMU were collected using structured questionnaires, and the 5'-HTTLPR genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism method. Statistical analysis with the general linear model detected a significant interactive effect of 5'-HTTLPR genotypes (SS vs. L-carriers) and gender, associated with AMU (F = 3.99; p = 0.048). Further analysis of 5'-HTTLPR effects on AMU in males and females separately showed that the SS genotype compared with L-carriers had about two times greater risk of an earlier onset of methamphetamine use in men (hazard ratio = 1.839; 95% confidence interval = 1.042-3.246; p = 0.036) but not in women. Together, our findings in this preliminary study suggest a greater risk for earlier onset methamphetamine use associated with the SS genotype of the 5'-HTTLPR among methamphetamine-dependent Caucasian males.

Modafinil for the treatment of cocaine dependence.

AIM: Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo. METHODS: This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days. RESULTS: The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p>0.79). However, two secondary outcomes showed significant effects by modafinil 200mg: the maximum number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p<0.02). CONCLUSIONS: These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.

Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals.

BACKGROUND: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60 mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies.

Marijuana neurobiology and treatment.

Marijuana is the number one illicit drug of abuse worldwide and a major public health problem, especially in the younger population. The objective of this article is to update and review the state of the science and treatments available for marijuana dependence based on a pre-meeting workshop that was presented at ISAM 2006. At the workshop, several papers were presented addressing the neurobiology and pharmacology of marijuana and treatment approaches, both psychotherapy and medications, for marijuana withdrawal. Medicolegal and ethical issues concerning marijuana medical use were also discussed. Concise summaries of these presentations are incorporated in this article, which is meant to be an updated review of the state of the science. Major advances have been made in understanding the underpinning of marijuana dependence and the role of the CNS cannabinoid system, which is a major area for targeting medications to treat marijuana withdrawal and dependence, as well as other addictions. Behavioral therapies are efficacious for facilitating abstinence from marijuana. Nefazadone, Marinol, and buspirone are showing early positive signals for efficacy in ameliorating marijuana withdrawal symptoms. Effective psychotherapeutic approaches are available and promising medications studies need to be confirmed in outpatient trials. The next few years looking promising for translational research efforts to make treatment widely accessible to patients with marijuana dependence.