Varenicline treatment for methamphetamine dependence: A randomized, double-blind phase II clinical trial.

BACKGROUND: Previous studies have suggested that varenicline, an α4ß2 nicotinic receptor partial agonist, and α7 nicotinic receptor full agonist, may be effective for the treatment of methamphetamine (MA) dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. This study aimed to determine if varenicline (1 mg BID) resulted in reduced methamphetamine use compared to placebo among treatment-seeking MA-dependent volunteers. METHODS: Treatment-seeking MA-dependent volunteers were randomized to varenicline 1 mg twice daily (n = 27) or placebo (n = 25) and cognitive behavioral therapy for 9 weeks. The primary outcomes were the proportion of participants achieving end-of-treatment-abstinence (EOTA, MA-negative urine specimens during weeks 8 and 9) and the treatment effectiveness score (TES, number of MA-negative urine specimens) for varenicline versus placebo. RESULTS: There was no significant difference in EOTA between varenicline (15%, 4/27) and placebo (20%, 5/25; p = 0.9). There was some suggestion that urinary confirmed medication compliance corresponded with EOTA in the varenicline condition, though it did not reach statistical significance, OR = 1.57 for a 100 ng/ml increase in urine varenicline, p = 0.10, 95% CI (0.99, 3.02). There was no significant difference in mean TES in the varenicline condition (8.6) compared to the placebo condition (8.1), and treatment condition was not a statistically significant predictor of TES, IRR = 1.01, p = 0.9, 95% CI (0.39, 2.70). CONCLUSIONS: The results of this study indicate that 1 mg varenicline BID was not an effective treatment for MA dependence among treatment-seeking MA-dependent volunteers.

Ibudilast may improve attention during early abstinence from methamphetamine.

BACKGROUND: Inattention is a deficit related to instilling abstinence from methamphetamine (MA) dependence. This study aimed to determine whether ibudilast (IB; 50mg bid) improves attentional abilities compared to placebo during early abstinence from MA dependence. METHODS: Attention was assessed in 11 MA-dependent non-treatment seeking participants in a phase IB safety-interaction trial. The Conners' Continuous Performance Test-II (CPT-II), a measure of sustained attention and response inhibition, was administered at baseline and on day 22, 48h post a MA challenge under placebo (P; n=6) or IB 50mg bid (n=5). Group differences were compared using Mann-Whitney U Tests. Groups were similar at baseline in premorbid intellectual functioning, attention deficit hyperactivity symptom scores, impulsivity ratings, and education level, but differed in age. Demographically corrected T-scores for CPT-II performances were utilized. RESULTS: Although no group differences in sustained attention existed at baseline, at follow-up, the IB group (Mdn=44.4) showed reduced variability in response times compared with the P group (Mdn=69.9), U=0.00, z=-2.74, p=.006, r=.83. The IB group (Mdn=45.8) also gave fewer perseverative responses than the P group (Mdn=67.0), U=2.00, z=-2.50, p=.01, r=.75. No other significant differences were observed. CONCLUSIONS: Findings suggest that IB may have a protective effect on sustained attention during early abstinence from MA dependence. This may guide thinking about mechanism of action should IB demonstrate efficacy as a treatment for MA dependence.

Safety of Intravenous Methamphetamine Administration During Ibudilast Treatment.

BACKGROUND: Methamphetamine dependence is a significant public health concern without any approved medications for treatment. We evaluated ibudilast, a nonselective phosphodiesterase inhibitor, to assess the safety and tolerability during intravenous methamphetamine administration. We conducted a randomized, double-blind, placebo-controlled, within-subjects crossover clinical trial. METHODS: Participants received ibudilast (20 mg twice daily followed by 50 mg twice daily) and placebo, with order determined by randomization, and then underwent intravenous methamphetamine challenges (15 and 30 mg). We monitored cardiovascular effects, methamphetamine pharmacokinetics, and reported adverse events. RESULTS: Ibudilast treatment had similar rates of adverse events compared with placebo, and there was no significant augmentation of cardiovascular effects of methamphetamine. Pharmacokinetic analysis revealed no clinically significant change in maximum concentration or half-life of methamphetamine with ibudilast. CONCLUSIONS: Methamphetamine administration during ibudilast treatment was well tolerated without additive cardiovascular effects or serious adverse events, providing initial safety data to pursue ibudilast's effectiveness for the treatment of methamphetamine dependence.

Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment.

PURPOSES: Restless legs syndrome (RLS) is underdiagnosed and poorly understood by clinicians and the general public alike; accordingly, a broad literature review with information most relevant to general practice is needed to help dispel misconceptions and improve level of care. METHODS: Specifically, this review comprehensively provides an epidemiological analysis of RLS and examines the risk factors and treatment options for RLS by compiling the findings of past RLS studies. These RLS studies were identified through a retrospective PubMed search. The epidemiological analysis was conducted by calculating a weighted mean average of all the relevant general population RLS prevalence studies, separated into geographical/racial categories. RESULTS: A comprehensive analysis of RLS epidemiological studies finds the prevalence rate of RLS to be 5-15% in the general population with 2.5% of adults having symptoms severe enough to require medical intervention. Some of the risk factors for RLS include female gender, pregnancy, low iron levels, lower socioeconomic status, poor health, elderly age, comorbidity with Parkinson's disease, positive family history of RLS, and comorbidity with psychiatric disorders. A wide array of treatment options exist for RLS including pharmacological and nonpharmacologic interventions. CONCLUSIONS: Clinicians' understanding of RLS enigma has recently improved due to the increased intensity of RLS research over the past decade. This review summarizes the current findings in the RLS field as well as providing guidelines for future RLS-related research.

Screening for addictive disorders within a workers' compensation clinic: an exploratory study.

We conducted a cross-sectional study investigating the extent of addictive disorders within a workers' compensation (WC) clinic. We also examined the feasibility of substance abuse screening within the same clinic. In 2009 , 100 patients were asked to complete the World Health Organization's Alcohol, Smoking, Substance Involvement Screening Test (WHO-ASSIST) and the Current Opioid Misuse Measure (COMM). According to the WHO-ASSIST, we found that 46% of WC patients required intervention for at least one substance-related disorder (25% tobacco, 23% sedatives, 8% opioids), and according to the COMM, 46% screened positive for prescription opioid misuse. Importantly, the addition of this screening was brief, economical, and well accepted by patients. Further research should analyze the costs and benefits of detection and intervention of substance-related disorders in this setting.

A haplotype analysis of CYP2E1 polymorphisms in relation to alcoholic phenotypes in Mexican Americans.

BACKGROUND: Studies regarding the association between the 4 polymorphisms of CYP2E1 (CYP2E1*1D, *5B, *6, and *1B) and alcoholism are inconsistent and inconclusive. The purpose of the present study was to clarify previously discordant studies by haplotype analysis in the Mexican American population. METHODS: The 4 polymorphisms of CYP2E1 were studied in 334 alcoholics and 365 controls. Genotype, allele, and haplotype frequency comparisons between alcoholics and controls were assessed. Patterns of linkage disequilibrium (LD) at CYP2E1 were determined. Reconstructed haplotypes were tested for associations with clinical phenotypes (age onset of drinking, Maxdrinks, and smoking status). RESULTS: No significant associations between the 4 polymorphisms of CYP2E1 and alcoholism were revealed by single allele tests. High LD was found between the CYP2E1 c2 and C alleles in Mexican Americans. Eleven haplotypes were present in the 699 participants. The 6 main haplotypes with frequencies higher than 1% made up 97% of the total halpotypes. The frequency of subjects carrying H6 (1C-c2-C-A2) was significantly higher in alcoholics than in controls (p = 0.0001). In contrast, the frequencies of H7 (1C-c2-C-A1) and H10 (1C-c2-D-A1) were significantly lower in alcoholics than in controls (p = 0.0072 for H7 and p = 0.0407 for H10). The frequency of H6 was significantly higher in alcoholics who had late onset of drinking than in nonalcoholic controls. Furthermore, the frequencies of H6 haplotype were also consistently higher in groups who had high number of maximum drinks (9 to 32 drinks) than in controls. When smokers are excluded, the frequencies of H6, H7, and H9 (1C-c2-D-A2) showed statistically significant differences between alcoholics and controls (p < 0.05). Moreover, the association between H6 and alcoholism become more robust when smokers are excluded. Furthermore, the frequency of H1 (1C-c1-D-A2) in alcoholic-smokers was much higher than in alcoholic-nonsmokers (p = 0.0028). In contrast, alcoholic-smokers carried less H2 (1C-c1-D-A1) in comparison with alcoholic-nonsmokers (p = 0.0417). The H3 (1D-c2-C-A2) frequency in alcoholic-smokers was much lower than in alcoholic-nonsmokers (p = 0.0042) and control-smokers (p = 0.0363). CONCLUSIONS: Our data demonstrate that carrying haplotype H6 might enhance susceptibility to developing alcoholism, but possessing the H7 or H10 haplotype appears to decrease this susceptibility. The H6, H7, and H9 haplotypes may play certain roles in different clinical phenotypes in Mexican American alcoholics. In addition, our data suggest that the H1, H2, and H3 haplotypes are associated with alcohol drinking and smoking. These results support that haplotype analysis is much more informative than single allele analysis. Our findings clearly indicate the importance of H6 haplotype in alcohol drinking in Mexican Americans.

Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression.

Proton magnetic resonance spectroscopy ((1)HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline (1)HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR=30/3000 ms, 3 x 3 x 3 cm(3) and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate+glutamine ([Glx]), glutamate ([Glu]), and creatine+phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

Asian-americans, addictions, and barriers to treatment.

Asian-American Pacific Islanders (AAPI) are one of the fastest growing minority groups in America. Due to model minority stereotypes and a lack of empirical data, AAPI have been thought to have lower than expected rates of substance use disorders and behavioral addictions. Recent data demonstrated that this conception is not true for all AAPI subgroups. As an example, rates of alcohol use disorders remain close to that of non-AAPI populations, even among AAPI that experience the flushing syndrome thought to protect from alcoholism. Another example of emerging data shows that methamphetamine dependence is particularly high (approximately 10%) among the Pacific Islander population, which is a startling figure. One behavioral addiction gaining more attention among AAPI is pathological gambling. Recent community surveys have shown that pathological gambling rates among AAPI vary but can be strikingly high. Despite the growing body of evidence that shows that addictive disorders in AAPI are significant and are not absent, there remain many barriers to treatment. These barriers include cultural values, individual factors, and practical issues. This article will review current epidemiological rates of addictive disorders among AAPI, will describe the current treatment barriers that face this population, and will provide practical solutions to breaking down these barriers.

Treatment of patients with schizophrenia and substance abuse disorders.

Approximately half of patients with schizophrenia have a lifetime diagnosis of substance abuse disorders. These dual diagnosis patients are more likely to have poorer outcomes, including more severe psychiatric symptoms with increased hospitalizations, higher utilization of services and frequent homelessness. Assessment and treatment of dually diagnosed patients has evolved over the last twenty years. To date, the strongest evidence for effective management of dual diagnosis patients has been utilization of integrated treatment services, which combines both mental health and substance abuse treatments concurrently. Strategies commonly used include a combination of pharmacological treatment, intensive case management, motivational interviewing, individual and group psychotherapy, and family participation. This chapter summarizes the treatment options available for this population.