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.

Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study.

BACKGROUND: Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans. METHODS: Adult, non-treatment seeking, MA-dependent volunteers (N=11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15 mg, and MA 30 mg participants rated 12 subjective drug effects on a visual analog scale (VAS). RESULTS: As demonstrated by statistically-significant ibudilast × MA condition interactions (p<.05), ibudilast reduced several MA-related subjective effects including High, Effect (i.e., any drug effect), Good, Stimulated and Like. The ibudilast-related reductions were most pronounced in the MA 30 mg infusions, with ibudilast 100mg significantly reducing Effect (97.5% CI [-12.54, -2.27]), High (97.5% CI [-12.01, -1.65]), and Good (97.5% CI [-11.20, -0.21]), compared to placebo. CONCLUSIONS: Ibudilast appeared to reduce reward-related subjective effects of MA in this early-stage study, possibly due to altering the processes of neuroinflammation involved in MA reward. Given this novel mechanism of action and the absence of an efficacious medication for MA dependence, ibudilast warrants further study to evaluate its clinical efficacy.

Intimate partner violence and reproductive health among methamphetamine-using women in los angeles: a qualitative pilot study.

Abstract Among women, methamphetamine (meth) use has been associated with intimate partner violence (IPV); however, few studies have looked at the context of IPV. This qualitative pilot study explored the experiences of meth-using women in Los Angeles County regarding: (1) IPV in their most recent primary relationship; (2) use of contraception and reproductive health services; and (3) meth use during pregnancy. Participants (n=30) were recruited through community advertising and at three addiction treatment centers to participate in 15-20 minute, semi-structured interviews recorded with handwritten transcripts. The team analyzed transcripts for key themes. Participants reported IPV (n=19, 63%) as recipients (50%), perpetrators (40%), and/or both (27%), occurring mainly during active meth use or withdrawal. While most (n=25) continued meth use during at least one pregnancy, some (n=5, 17%) identified pregnancy as a motivation to quit or reduce use, suggesting an opportunity for intervention. Though most women knew about free and low-cost reproductive health services, few accessed them, with 33% citing aspects of meth use itself as a barrier. One-third (45/133) of reported pregnancies were terminated by abortion. Most women (67%) began using before age 18, suggesting need for screening and intervention among adolescents.

Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use.

AIMS: Two previous randomized trials found an effect for bupropion in reducing methamphetamine use in the subgroup with lower frequency of methamphetamine use at baseline. This study aimed to replicate these results by comparing bupropion versus placebo in methamphetamine-dependent participants with less than daily methamphetamine use at baseline. METHODS: Methamphetamine-dependent volunteers reporting methamphetamine use on ≤29 of past 30 days were randomized to bupropion 150 mg twice daily (n = 41) or placebo (n = 43) and out-patient counseling for 12 weeks. The primary outcome was the proportion achieving end-of-treatment (EOT) methamphetamine abstinence (weeks 11 and 12) for bupropion versus placebo. A post-hoc analysis compared EOT abstinence by medication adherence assessed via plasma bupropion/hydroxybupropion level. RESULTS: There was no significant difference in EOT abstinence between bupropion (29%, 12 of 41) and placebo (14%, six of 43; P = 0.087). Among participants receiving bupropion, EOT abstinence was significantly higher in participants assessed as medication adherent by plasma bupropion/hydroxybupropion levels (54%, seven of 13) compared to non-adherent participants (18%, five of 28; P = 0.018). Medication adherence by plasma levels was low (32%). CONCLUSIONS: Bupropion may be efficacious for reducing methamphetamine in people with less than daily baseline methamphetamine use, but the evidence remains inconclusive.

Up in smoke? A preliminary open-label trial of nicotine replacement therapy and cognitive behavioral motivational enhancement for smoking cessation among youth in Los Angeles.

In 2008-2009, we conducted a 6-week, open-label trial of transdermal nicotine replacement therapy and practical counseling for 34 adolescents seeking smoking cessation in Los Angeles. Dependent outcomes were study retention, use of the patch, and 7-day quit status at the end-of-study and at follow-up visits. Predictors of outcomes included cigarette dependence, withdrawal symptoms, demographic and psychiatric measures, and other substance use. Variables significant in bivariate analysis (p < .10) were retained in a multivariate model. Subjects had significant pre-to-post reductions in quit rates, dependence, and withdrawal symptoms. Subjects also reported a high number of comorbidities. Implications for clinicians are discussed.

Cigarette smoking as a target for potentiating outcomes for methamphetamine abuse treatment.

INTRODUCTION AND AIMS: Cigarette smoking occurs frequently among individuals with methamphetamine (MA) dependence. Preclinical and clinical evidence has suggested that the common co-abuse of MA and cigarettes represents a pharmacologically meaningful pattern. METHODS: The present study is a secondary analysis of a randomised, placebo-controlled trial of bupropion treatment for MA dependence (bupropion n = 36; placebo n = 37). A hierarchical logistic modelling approach assessed the efficacy of bupropion for reducing MA use separately among smokers and non-smokers. Among smokers, relations between cigarettes smoked and MA use were assessed. RESULTS: Smoking status did not affect treatment responsiveness in either the bupropion condition or the placebo condition. In the placebo condition, increased cigarette use was associated with an increased probability of MA use during the same time period. This effect was not observed in the bupropion condition. DISCUSSION AND CONCLUSIONS: Initial smoking status did not impact treatment outcomes. Among smokers, results suggest that bupropion may dissociate cigarette and MA use. The effect was modest and a precise pharmacological mechanism remains elusive. Cholinergic systems may be relevant for MA use outcomes. Future studies should continue to assess the role of smoking in MA treatment outcomes.

Placebo-group responders in methamphetamine pharmacotherapy trials: the role of immediate establishment of abstinence.

Treatment responses of placebo groups in addiction medicine trials have important implications for research methodology and clinical practice, however studies examining placebo group responses in addiction medicine are scarce. Extant data suggest the importance of early treatment responsiveness for long-term outcomes. Among methamphetamine-(MA) dependent individuals randomized to placebo pill plus behavioral support conditions in pharmacotherapy development trials, we hypothesized that immediate abstinence would be a necessary but insufficient predictor for end-of-trial (EOT) abstinence. The study is a secondary analysis of participants (n = 184; 36% female) in the placebo condition of three randomized, placebo-controlled methamphetamine dependence pharmacotherapy trials. Receiver operating characteristic (ROC) curve analyses assessed the predictive power of initial abstinence, assessed by thrice weekly urine samples, for EOT abstinence. Sixty percent of individuals with complete abstinence in the first two weeks of treatment were abstinent at EOT, while 18% of people who failed to meet this standard were abstinent at EOT. Early response was related to retention at EOT and 12-month follow-up. Findings suggest that the inability to achieve at least three MA negative screenings in the first two weeks is associated with greater than 90% likelihood of treatment failure. A third week of screening added minimally to the prediction of EOT outcomes. The prediction of treatment failure was more precise than the prediction of treatment success. The absence of a clinical response in the first two weeks of treatment among participants in the placebo group signals high risk of treatment failure. The majority of information regarding response in the placebo group from a 12-week trial is obtained early in the trial.

A retrospective analysis of two randomized trials of bupropion for methamphetamine dependence: suggested guidelines for treatment discontinuation/augmentation.

BACKGROUND: Two clinical trials have shown efficacy for bupropion in treating methamphetamine (MA) dependence among those with moderate baseline MA use. However, treatment response is highly variable and it is unclear what duration of treatment is necessary to determine if maintaining the treatment course is indicated or if discontinuation or augmentation is appropriate. The present study assessed the relationship among early bupropion treatment response for moderate MA users and end-of-treatment (EOT) abstinence. These data provide estimates of the duration of treatment and the degree of responsiveness required to persist in bupropion treatment. METHODS: Participants with moderate baseline MA use in the bupropion condition of two randomized double-blind placebo controlled trials were included. The relationship between early treatment response and EOT outcomes was assessed with Receiver Operating Characteristic (ROC) curves. RESULTS: With thrice weekly urine drug testing, excellent predictive power was established in the first two weeks of treatment. The inability to achieve at least three MA negative samples in the first two weeks is associated with greater than 90% likelihood of treatment failure. More closely approximating clinical settings, once-weekly testing featured reliable predictive power within three weeks, suggesting that the failure to produce at least two clean samples in the first three weekly visits confers high risk of treatment failure. DISCUSSION: The findings provide preliminary evidence to guide clinical decisions for moderate MA users receiving bupropion. The results are consistent with data from the smoking cessation literature and may highlight the importance of early response in addiction treatment.

Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence.

OBJECTIVE: To compare modafinil to placebo for reducing methamphetamine (MA) use, improving retention, and reducing depressive symptoms and MA cravings. Rates of adverse events and cigarette smoking with modafinil versus placebo were also compared. METHODS: Following a 2-week, non-medication lead-in period, 71 treatment-seeking MA-dependent participants were randomly assigned to modafinil (400mg once daily; N=34) or placebo (once daily; N=37) for 12 weeks under double-blind conditions. Participants attended clinic thrice-weekly to provide urine samples analyzed for MA-metabolite, to complete research assessments, and to receive contingency management and weekly cognitive behavioral therapy (CBT) sessions. RESULTS: There were no statistically significant effects for modafinil on MA use, retention, depressive symptoms, or MA cravings in pre-planned analyses. Outcomes for retention and MA use favored modafinil in a post hoc analysis among participants with low CBT attendance and among participants with baseline high-frequency of MA use (MA use on >18 of past 30 days), but did not reach statistical significance in these small subgroups. Modafinil was safe and well tolerated and did not increase cigarette smoking. CONCLUSIONS: Modafinil was no more effective than placebo at 400mg daily in a general sample of MA users. A post hoc analysis showing a trend favoring modafinil among subgroups with baseline high-frequency MA use and low CBT attendance suggests that further evaluation of modafinil in MA users is warranted.

Staff strategies for improving HIV detection using mobile HIV rapid testing.

This paper examines the performance of 13 mobile testing units (MTUs) and rapid HIV testing technology in Los Angeles County as reflected in the relationship between the cognitive strategies used by MTU staff regarding instructions to clients about picking up their test results and returning for test results, and following up with those clients who did not return, and the spatial distribution of MTUs and AIDS rates in 2003. Maps were created using geographic information systems (GIS) data on 93 MTU testing locations and 2003 AIDS cases data. MTU staff (N = 45) were interviewed and several themes were identified. MTU testing locations were clustered near high AIDS rate areas. Staff reports were obtained on 24 clients in the past 6 months who received HIV-negative test results and 24 clients during the same time period who received HIV-positive test results. Staff strategies that were used included keeping clients with them while rapid test results were being processed and adjusting to clients' schedules when arranging for picking up test results. Some staff used tangible incentives such as vouchers for area businesses to encourage preliminary HIV-positive clients to return for confirmatory test results. Staff also sought to convince clients who preliminarily tested HIV-positive to convert from anonymous to confidential testing in order to facilitate clients' linkage to treatment. The GIS findings and client risk data support the Centers for Disease Control and Prevention policy of implementing MTUs and rapid testing in large urban communities with high AIDS rates.

Pilot safety evaluation of varenicline for the treatment of methamphetamine dependence.

Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4b2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over one week to reach 1 mg twice daily, and then was co-administered with 30 mg methamphetamine, delivered in 10 intravenous (iv) infusions of 3 mg each. Varenicline was found to be safe in combination with iv methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence.

Increasing the reach of HIV testing to young Latino MSM: results of a pilot study integrating outreach and services.

BACKGROUND: In the U.S., HIV infections are increasing among men who have sex with men (MSM), particularly young, racial/ethnic minority MSM. OBJECTIVE: To examine the feasibility of increasing HIV testing among young Latino MSM by integrating tailored outreach strategies with testing, counseling, and HIV medical services. DESIGN: Descriptive study comparing demographic characteristics, behaviors, and HIV test results of clients from the intervention period with clients who tested during other time periods. RESULTS: Clients in the intervention period were younger and more likely to be Latino than those in other time periods. In addition, clients who received outreach were more likely than those who did not receive outreach to report methamphetamine use, sex with an HIV-positive person, and sex with a sex worker. CONCLUSION: Venue-based and selective media outreach, in combination with linking rapid testing to HIV care, may help overcome some of the barriers to testing among high-risk young Latino MSM.

Predicting adherence to treatment for methamphetamine dependence from neuropsychological and drug use variables.

Although some individuals who abuse methamphetamine have considerable cognitive deficits, no prior studies have examined whether neurocognitive functioning is associated with outcome of treatment for methamphetamine dependence. In an outpatient clinical trial of bupropion combined with cognitive behavioral therapy and contingency management (Shoptaw, S., Heinzerling, K.G., Rotheram-Fuller, E., Steward, T., Wang, J., Swanson, A.N., De La Garza, R., Newton, T., Ling, W., 2008. Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend 96, 222-232.), 60 methamphetamine-dependent adults completed three tests of reaction time and working memory at baseline. Other variables that were collected at baseline included measures of drug use, mood/psychiatric functioning, employment, social context, legal status, and medical status. We evaluated the relative predictive value of all baseline measures for treatment outcome using Classification and Regression Trees (CART; Breiman, L., Friedman, J.H., Olshen, R.A., Stone, C.J., 1984. Classification and Regression Trees. Wadsworth, Belmont, CA.), a nonparametric statistical technique that produces easily interpretable decision rules for classifying subjects that are particularly useful in clinical settings. Outcome measures were whether or not a participant completed the trial and whether or not most urine tests showed abstinence from methamphetamine abuse. Urine-verified methamphetamine abuse at the beginning of the study was the strongest predictor of treatment outcome; two psychosocial measures (e.g., nicotine dependence and Global Assessment of Functioning) also offered some predictive value. A few reaction time and working memory variables were related to treatment outcome, but these cognitive measures did not significantly aid prediction after adjusting for methamphetamine usage at the beginning of the study. On the basis of these findings, we recommend that research groups seeking to identify new predictors of treatment outcome compare the predictors to methamphetamine usage variables to assure that unique predictive power is attained.

HIV partner notification: predictors of discussion and agreements from provider reports.

This study examines organizational, provider, client, and test-event level predictors of HIV partner notification (PN) discussion and agreements based on providers' most recent HIV-positive post-test counseling session. Staff (n = 621) were sampled from for-profit, nonprofit, and county government HIV testing organizations (N = 159) in Los Angeles County from 2003 to 2007. Among providers who conducted an HIV-positive post-test counseling session (n = 204), 65% discussed PN but only 10% had confirmed agreement to provider-involved PN (PIPN). In multi-level regression analyses PN discussion was predicted by provider HIV-test training and knowledge, and patients requesting a test while presenting HIV/AIDS symptoms. The strongest predictor of PIPN agreement was public health HIV testing settings followed by counseling by program managers or infectious disease specialists across settings. None of the injecting drug users or patients presenting with AIDS, but not requesting a test, agreed to PIPN. Organizational and provider-level interventions on PN will be needed to realize cost-effective benefits of expanded HIV testing and counseling.

Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence.

OBJECTIVE: To compare bupropion to placebo for reducing methamphetamine (MA) use, increasing retention, and reducing the severity of depressive symptoms and MA-cravings. A secondary objective compared bupropion to placebo for reducing cigarette smoking among MA dependent participants. METHODS: Following a 2-week, non-medication baseline screening period, 73 treatment-seeking MA dependent participants were randomly assigned to bupropion sustained release (150 mg twice daily; N=36) or placebo (twice daily; N=37) for 12-weeks under double-blind conditions. Participants attended clinic thrice weekly to provide urine samples analyzed for MA-metabolite, to complete research measures and assessments, and to receive contingency management and weekly cognitive behavioral therapy sessions. RESULTS: There were no statistically significant effects for bupropion relative to placebo on MA use verified by urine drug screens, for reducing the severity of depressive symptoms or MA-cravings, or on study retention. In a post hoc analysis, there was a statistically significant effect of bupropion treatment on MA use among participants with lighter (0-2 MA-positive urines), but not heavier (3-6 MA-positive urines) MA use during baseline (OR=2.81, 95% CI=1.61-4.93, p<0.001 for MA-free week with bupropion among light users). Bupropion treatment was also associated with significantly reduced cigarette smoking, by almost five cigarettes per day (p=0.0002). CONCLUSION: Bupropion was no more effective than placebo in reducing MA use in planned analyses, though bupropion did reduce cigarette smoking. Post hoc findings of an effect for bupropion among baseline light, but not heavy, MA users suggests further evaluation of bupropion for light-MA users is warranted.