Aimee-Noelle Swanson

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.

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.

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.

Failure to Return for HIV Test Results: A Pilot Study of Three Community Testing Sites

Background: Individuals at elevated risk of contracting HIV frequently fail to return for their test result. Because rapid HIV antibody testing is still not widely implemented, failure to return for test results under conditions of standard testing remains a problem. Methods: Direct field observation and semistructured interviews with clients (N = 16) and test counselors (N = 16) of 3 community HIV testing sites were conducted. Results: Clients faced 5 barriers to receiving their result: (1) fear, (2) busyness, (3) apathy,(4) inebriation at the time of testing, and (5) testing “on a whim.” Motivators that encouraged clients to receive their results were (1) positive counselor/client interactions, (2) client-friendly policies regarding picking up the test result, (3) clients’ psychological “need to know,” (4) incentives for picking up the result, and (5) established protocols for contacting clients who fail to return. Conclusion: Findings highlight the need for interventions to improve the return rate for HIV results.

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.

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.

COMT Val158Met, BDNF Val66Met, and OPRM1 Asn40Asp and methamphetamine dependence treatment response: preliminary investigation.

Methamphetamine (MA) dependence is a significant source of deleterious consequences to individual and public health including HIV infection, psychological distress, and cardiovascular disease. No medications have been approved for MA dependence and response to behavioral therapy is variable. The identification of genetic markers for MA dependence treatment response could have significant utility via the identification of responsive sub-groups as well as the biological processes underlying variability in treatment response. Yet no studies have examined potential genetic markers of response to treatment for MA dependence. We performed an exploratory study examining potential associations between three well described single nucleotide polymorphisms (SNPs) with putative involvement in MA dependence, catechol-O-methyltransferase (COMT) Val158Met, brain-derived neurotrophic factor (BDNF) Val66Met, and the mu opioid receptor (OPRM1) Asn40Asp polymorphisms, and treatment outcome among participants of a randomized, double-blind, placebo-controlled trial of modafinil, with contingency management and cognitive behavioral therapy, for MA dependence. Treatment outcome was assessed via Treatment Effectiveness Score (TES, mean MA-negative urine drug screens during treatment), a standard indicator of treatment outcome in MA dependence. Of 71 participants in the main trial 1, four African American and 2 Asian participants were excluded to avoid issues related to population stratification and four participants did not consent to DNA collection leaving 61 Non-Hispanic Caucasians (referred to as Caucasians) and Hispanic Caucasians (Hispanics) who were genotyped for the three SNPs. We examined main effects for genotype, as well as potential medication by genotype interactions, on TES using t tests and linear regression models among Hispanics and Caucasians separately. Cohens effect size (d) for genotype and medication effects by genotype were also calculated. To maximize power, participants with Val/Val genotype were compared to Met carriers (Val/Met or Met/Met genotype) for COMT Val158Met and BDNF Val66Met and participants with AsnAsn genotype were compared to Asp carriers (Asn/Asp or Asp/Asp genotype) for OPRM1 Asn40Asp. Hispanics were significantly (p < 0.05) younger (mean age 32.7 years, standard deviation 8.2, minimum 19.6, maximum 46.0) relative to Caucasians (mean age 43.2 years, standard deviation 9.9, minimum 23.3, maximum 64.8) but there were no significant differences in age, gender, or baseline methamphetamine use by genotype for any of the three SNPs. Genotype frequencies did not differ from those expected under Hardy-Weinberg equilibrium. There was a significant main effect for BDNF Val66Met on TES among Caucasians (p = 0.039; Table), but not Hispanics, with mean TES significantly higher among Val/Val Caucasians relative to Caucasian Met carriers. The effect size for BDNF Val66Met on TES in Caucasians was large (d = 0.78). There were no significant main effects of COMT Val158Met or OPRM1 Asn40Asp on TES in either ethnicity although effect sizes for the Met allele of COMT Val158Met in Hispanics and the Asp allele of OPRM1 Asn40Asp in Caucasians were in the moderate range (Table). Table Treatment effectiveness score (TES) and Cohens effect size (d) for genotype and medication by genotype among methamphetamine dependent participants There was a significant genotype by medication interaction for COMT Val158Met among Hispanics (p = 0.009; Table), with TES significantly higher and a large effect size for modafinil relative to placebo among participants with Val/Val genotype but not among Met carriers. All six Caucasian Val/Val participants were in the placebo group and therefore a medication by COMT Val158Met interaction could not be assessed in Caucasians. There were no significant genotype by medication interactions for BDNF Val66Met or OPRM1 Asn40Asp in either ethnicity. Results of this study must be interpreted considering the studys limitations. This was an exploratory study aimed at providing preliminary data on the pharmacogenetics of response to treatment for MA dependence and results require replication in prospective studies and additional samples. Participants were genotyped retrospectively following a clinical trial and therefore findings may be due to chance. Finally, the small cell sizes for comparisons by genotype and genotype by medication interactions provide limited power to detect statistically significant differences and precluded employment of a Bonferroni correction for multiple comparisons or a genome wide significance level. Despite these limitations, we know of no previous studies examining genetic markers of MA dependence treatment response and therefore results of this study are important for guiding the design of future pharmacogenetic studies of MA dependence. We provide effect size estimations for genotype effects on treatment outcome with these future studies in mind. We found a significant main effect for BDNF Val66Met genotype on treatment outcomes in MA dependence with worse outcomes among Caucasian Met carriers. The BDNF Val66Met Met allele is associated with reduced neuronal activity-dependent BDNF secretion, deficits in memory and hippocampal function 2, and lower subjective response to amphetamine 3 which may affect response to treatment for MA dependence. In particular, altered memory function among Met carriers may interfere with efforts to quit MA with the cognitive behavioral platform provided in this study. If future studies confirm worse outcomes in Met carriers, then medications targeting the BDNF signaling pathway and TrkB, the BDNF receptor, may be candidates for treating MA dependence, particularly in carriers of the Met allele. There were no significant main effects for COMT Val158Met or OPRM1 Asn40Asp on treatment outcome, although effect sizes were moderate for the COMT Val158Met Met allele in Hispanics and the OPRM1 Asn40Asp Asp allele in Caucasians. Reduced COMT function, higher prefrontal cortex dopamine levels 4, and better cognitive performance associated with the COMT Val158Met Met allele 5 could result in improved outcomes in Met carriers. In alcohol dependence, the OPRM1 Asn40Asp Asp allele is associated with altered stress responsivity, increased subjective response to alcohol, and lower rates of relapse to heavy drinking with naltrexone treatment 6 while a haplotype containing OPRM1 Asn40Asp, but not OPRM1 Asn40Asp alone, was associated with subjective response to amphetamine 7. Putative reductions in mu opioid receptor function with the Asp allele may result in increased ability to quit MA similar to the case with naltrexone treatment in alcoholism. Future studies should examine MA dependence treatment outcomes and these SNPs in adequately powered clinical samples. The interaction between modafinil and COMT Val158Met observed in our study of MA dependence is similar to findings from a study of cognitive effects of modafinil in healthy sleep deprived adults which also found response to modafinil only among Val/Val participants 8. The Val allele is associated with lower prefrontal dopaminergic and cognitive function relative to the Met allele 4, 5. Response to modafinil, a medication with dopaminergic and cognitive enhancing effects, may be limited to Val/Val participants who experience a deficit in dopaminergic and cognitive functioning relative to Met carriers that is ameliorated by treatment with modafinil. Additional studies examining COMT Val158Met as a potential marker of response to modafinil, as well as other dopaminergic and cognitive enhancing medications, in stimulant dependence are warranted. Although results of this exploratory study are preliminary, they provide the first data on potential genetic moderators of MA dependence treatment response and may guide the design of future prospective pharmacogenetic studies in MA dependence.

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.

Evaluating the Accessibility of HIV Testing Organizations

Consumer-based indicators were developed to evaluate the accessibility of private and public nonhospital HIV testing organizations. A comprehensive roster of 148 nonhospital HIV testing organizations in Los Angeles County was constructed from publicly available listings. A telephone survey protocol was used to contact sites and assess consumer relevant accessibility measures. Only 50% of the sites could be contacted and indicated that HIV testing was available. Hence, a consumer who tried to reach one site had only a 50-50 chance of success. HIV testing sites differed with regard to how frequently they offered testing; whether they offered anonymous and/or confidential testing; what types of counseling they provided; how quickly test results were available; and how friendly, helpful, attentive, and knowledgeable about testing procedures their attendants were. HIV testing sites must make their services accessible and be perceived by consumers as responsive if they are to be effective service providers.