Synaptic balancing: A biologically plausible local learning rule that provably increases neural network noise robustness without sacrificing task performance.

We introduce a novel, biologically plausible local learning rule that provably increases the robustness of neural dynamics to noise in nonlinear recurrent neural networks with homogeneous nonlinearities. Our learning rule achieves higher noise robustness without sacrificing performance on the task and without requiring any knowledge of the particular task. The plasticity dynamics-an integrable dynamical system operating on the weights of the network-maintains a multiplicity of conserved quantities, most notably the network's entire temporal map of input to output trajectories. The outcome of our learning rule is a synaptic balancing between the incoming and outgoing synapses of every neuron. This synaptic balancing rule is consistent with many known aspects of experimentally observed heterosynaptic plasticity, and moreover makes new experimentally testable predictions relating plasticity at the incoming and outgoing synapses of individual neurons. Overall, this work provides a novel, practical local learning rule that exactly preserves overall network function and, in doing so, provides new conceptual bridges between the disparate worlds of the neurobiology of heterosynaptic plasticity, the engineering of regularized noise-robust networks, and the mathematics of integrable Lax dynamical systems.

Role of random electric fields in relaxors.

PbZr(1-x)Ti(x)O3 (PZT) and Pb(Mg1/3Nb2/3)(1-x)Ti(x)O3 (PMN-xPT) are complex lead-oxide perovskites that display exceptional piezoelectric properties for pseudorhombohedral compositions near a tetragonal phase boundary. In PZT these compositions are ferroelectrics, but in PMN-xPT they are relaxors because the dielectric permittivity is frequency dependent and exhibits non-Arrhenius behavior. We show that the nanoscale structure unique to PMN-xPT and other lead-oxide perovskite relaxors is absent in PZT and correlates with a greater than 100% enhancement of the longitudinal piezoelectric coefficient in PMN-xPT relative to that in PZT. By comparing dielectric, structural, lattice dynamical, and piezoelectric measurements on PZT and PMN-xPT, two nearly identical compounds that represent weak and strong random electric field limits, we show that quenched (static) random fields establish the relaxor phase and identify the order parameter.

Dehydration affects cerebral blood flow but not its metabolic rate for oxygen during maximal exercise in trained humans.

Intense exercise is associated with a reduction in cerebral blood flow (CBF), but regulation of CBF during strenuous exercise in the heat with dehydration is unclear. We assessed internal (ICA) and common carotid artery (CCA) haemodynamics (indicative of CBF and extra-cranial blood flow), middle cerebral artery velocity (MCA Vmean), arterial-venous differences and blood temperature in 10 trained males during incremental cycling to exhaustion in the heat (35°C) in control, dehydrated and rehydrated states. Dehydration reduced body mass (75.8 ± 3 vs. 78.2 ± 3 kg), increased internal temperature (38.3 ± 0.1 vs. 36.8 ± 0.1°C), impaired exercise capacity (269 ± 11 vs. 336 ± 14 W), and lowered ICA and MCA Vmean by 12-23% without compromising CCA blood flow. During euhydrated incremental exercise on a separate day, however, exercise capacity and ICA, MCA Vmean and CCA dynamics were preserved. The fast decline in cerebral perfusion with dehydration was accompanied by increased O2 extraction (P < 0.05), resulting in a maintained cerebral metabolic rate for oxygen (CMRO2). In all conditions, reductions in ICA and MCA Vmean were associated with declining cerebral vascular conductance, increasing jugular venous noradrenaline, and falling arterial carbon dioxide tension (P aCO 2) (R(2) ≥ 0.41, P ≤ 0.01) whereas CCA flow and conductance were related to elevated blood temperature. In conclusion, dehydration accelerated the decline in CBF by decreasing P aCO 2 and enhancing vasoconstrictor activity. However, the circulatory strain on the human brain during maximal exercise does not compromise CMRO2 because of compensatory increases in O2 extraction.

Large dynamic scissoring mode displacements coupled to band gap opening in the cubic phase of the methylammonium lead halide perovskites.

Hybrid perovskites are a rapidly growing research area, having reached photovoltaic power conversion efficiencies of over 25 %. There is a increasing consensus that the structures of these materials, and hence their electronic structures, can not be understood purely from the time and space averaged crystal structures observable by conventional methods. We apply a symmetry-motivated analysis method to analyse X-ray pair distribution function data of the cubic phases of the hybrid perovskites MAPb$X_3$ ($X$ = I, Br, Cl). We demonstrate that, even in the cubic phase, the local structure of the inorganic components of MAPb$X_3$ ($X$ = I, Br, Cl), are dominated by scissoring type deformations of the Pb$X_6$ octahedra. We find these modes to have a larger amplitude than equivalent distortions in the $A$-site deficient perovskite ScF$_3$ and demonstrate that they show a significant departure from the harmonic approximation. Calculations performed on an inorganic perovskite analogue, FrPbBr3show that the large amplitudes of the scissoring modes are coupled to a dynamic opening of the electronic band gap. Finally, we use density functional theory calculations to show that the organic MA cations reorientate to accommodate the large amplitude scissoring modes.

Gabapentin versus chlordiazepoxide for outpatient alcohol detoxification treatment.

BACKGROUND: Benzodiazepines are used to treat alcohol withdrawal (AW) but cause cognitive impairment, sedation, and ataxia, and interact with alcohol. Nonbenzodiazepine anticonvulsants are promising and possibly safer alternatives for the treatment of AW. OBJECTIVE: To compare follow-up measures of Epworth Sleepiness Scale (ESS), Penn Alcohol Craving Scale (PACS), ataxia rating, and Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) symptoms between alcohol-dependent individuals randomized to treatment with gabapentin or chlordiazepoxide. METHODS: A randomized, double-blind study was conducted in US veterans with alcohol withdrawal (DSM-IV criteria). Subjects requiring hospitalization or taking benzodiazepines or nonbenzodiazepine anticonvulsants were excluded. Twenty-six participants were randomized: 17 received gabapentin and 9 received chlordiazepoxide. Gabapentin doses were 1200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each. Chlordiazepoxide doses were 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each. CIWA-Ar, ESS, PACS scales and evaluation for ataxia were administered daily. RESULTS: Follow-up mean ESS and PACS scores did not differ significantly between treatment groups in the early treatment period (days 1-4) but were lower (mean difference -3.70; 95% CI -7.21 to -0.19; p = 0.04) and (mean difference -6.05; 95% CI -12.82 to 0.72; p = 0.08), respectively, at the end of the treatment period (days 5-7) in gabapentin-treated subjects. CIWA-Ar scores were reduced similarly in both groups. Ataxia was not observed. No significant adverse events were noted. Limitations include our small sample size and 35% loss to follow-up at the end of the treatment period. CONCLUSIONS: In ambulatory veterans with symptoms of alcohol withdrawal, gabapentin treatment resulted in significantly greater reduction in sedation (ESS) and a trend to reduced alcohol craving (PACS) by the end of treatment compared to chlordiazepoxide treatment. Although limited by the small sample size, the suggestion of reduction in sleepiness and less craving warrants replication of the study with a larger sample.

Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.

CONTEXT: Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD). OBJECTIVE: To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD. DESIGN, SETTING, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure. INTERVENTION: Risperidone (up to 4 mg once daily) or placebo. MAIN OUTCOME MEASURES: The Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V). RESULTS: Change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively. CONCLUSION: Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00099983.

Bilateral contact ground reaction forces and contact times during plyometric drop jumping.

Drop jumping (DJ) is used in training programs aimed to improve lower extremity explosive power. When performing double-leg drop jumps, it is important to provide an equal stimulus to both legs to ensure balanced development of the lower legs. The aim of this study was to bilaterally analyze the ground reactions forces and temporal components of drop jumping from 3 heights. Ten recreationally active male subjects completed 3 bounce-drop jumps from 3 starting heights (0.2, 0.4, and 0.6 m). Two linked force platforms were used to record left- and right-leg peak vertical force, time to peak force, average force, ground contact time, impulse and time differential. Between-height and between-leg comparisons for each variable were made using a multivariate analysis of variance with post hoc Wilcoxon tests (p < 0.05). Results indicated that force and time variables increased as drop jump height increased (p < 0.0001). Post hoc analyses showed that at 0.2- and 0.4-m bilateral differences were present in the time to peak force, average force, and impulse. No bilateral differences for any variables were shown at 0.6-m starting height. The contact time for all jumps was <0.26 seconds. At 0.2 m, only 63% of the subjects had a starting time differential of <0.01 seconds, rising to 96.3% at 0.6 m. The results indicated that 0.6 m is the suggested drop jump height to ensure that no bilateral differences in vertical forces and temporal components occur; however, shorter contact times were found at the lower heights.

CYP2D6 Expression in Veterans Experiencing Opioid Overdose: A Postmortem Review.

PURPOSE: The purpose is to characterize the CYP2D6 genotype and predict the phenotype of decedents of opioid overdose to determine if the ultrarapid (UM) phenotype is over-represented in opioid overdose deaths. CYP2D6 is the enzyme responsible for metabolism of various opioids implicated in overdose. The UM group may be at greater risk for overdose due to the rapid metabolism of hydrocodone, oxycodone, or tramadol to more active/potent metabolites than their peers with (poor) PM, (intermediate) IM, or (extensive) EM metabolic phenotypes. PATIENTS AND METHODS: Blood samples obtained during autopsy following an opioid overdose from 75 US military veteran decedents prescribed hydrocodone, oxycodone, or tramadol from one VA medical center were analyzed. DNA extraction, CYP2D6 genotyping, and copy number variation (CNV) testing were performed using the iPLEX® genotyping assay and MassARRAY. Phenotype prediction was based on Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations. Toxicology results were obtained from Medical Examiner reports of the deceased. Prescription medication information was extracted from archived medical records. RESULTS: The majority of the sample had a phenotype of EM metabolizer (75%), with 7% of the total sample having a UM metabolizer phenotype. In addition to hydrocodone, oxycodone, and tramadol (found in 41% of opioid positive samples), other opioids found in toxicology tests included diacetylmorphine, fentanyl, buprenorphine, and methadone. Two or more substances, including alcohol, benzodiazepines, and other potentially sedating medications, were found in nearly half of the opioid positive toxicology samples. CONCLUSION: In this study, 7% of veteran decedents of opioid overdose had CYP2D6 UM metabolic phenotype. The small sample size precludes a conclusion that the frequency of UM phenotype is greater than expected in North American Caucasian groups. The findings in this study do not support the hypothesis that the UM phenotype is over-represented in opioid overdose.

Electric field effect on short-range polar order in a relaxor ferroelectric system.

Short-range polar order in the relaxor ferroelectric material PbMg1/3Nb2/3O3-28%PbTiO3 (PMN-28PT) have been studied using neutron diffuse scattering. An external electric field along the [110] direction can affect the diffuse scattering in the low temperature rhombohedral/monoclinic phase. Diffuse scattering intensities associated with [110] short-range polarizations are partially suppressed, while those arising from [11¯0] polarizations are enhanced. On the other hand, short-range polar order along other equivalent 〈110〉 directions, i.e., [101], [101¯], [011], and [011¯] directions, are virtually unaffected by the field. Our results, combined with previous work, strongly suggest that most parts of short-range polar order in PMN-xPT relaxor systems are robust in the low temperature phase, where they couple strongly to ferroelectric polarizations of the surrounding ferroelectric domains, and would only respond to an external field indirectly through ferroelectric domain rotation.

Efficacy of long-acting, injectable versus oral naltrexone for preventing admissions for alcohol use disorder.

INTRODUCTION: Approximately 17 million Americans and 300 000 veterans have an alcohol use disorder (AUD). Both oral naltrexone (NTX) and long-acting, injectable naltrexone (LAI NTX) are FDA-approved to treat AUD. LAI NTX is often reserved for patients with adherence concerns due to considerable differences in drug cost and administration requirements. To date, there are no randomized trials comparing efficacy of LAI NTX to oral NTX. This retrospective cohort study compared clinical outcomes in veterans treated with LAI NTX or oral NTX. METHODS: Health care utilization in veterans at 1 Veterans Affairs facility treated for AUD with oral NTX and LAI NTX was compared. The primary outcome was 90-day alcohol-related hospital admissions per patient (ARA90). Secondary outcomes included 90-day outpatient clinic and emergency department visits and 30-day alcohol-related admissions (ARA30). Inclusion criteria included first-time prescription of NTX for AUD from January 1, 2015, through December 1, 2015. Veterans receiving concurrent acamprosate or disulfiram were excluded. RESULTS: Seventy-nine patients were included with 65 in the oral NTX group and 14 in the LAI NTX group. The ARA90 was 0.17 for the oral NTX group and 0.64 for the LAI NTX group (P = .06). The oral NTX group had significantly fewer ARA30 than the LAI NTX group (P < .01). Oral NTX also had significantly lower health care utilization for all other parameters. DISCUSSION: Oral NTX was associated with lower health care utilization compared to LAI NTX in this veteran population. This indicates that LAI NTX may not provide additional benefit justifying the cost. This study had several limitations. Randomized trials comparing efficacy between oral NTX and LAI NTX are needed.

A retrospective chart review of opioid represcribing following nonfatal overdose at a Veterans Affairs hospital.

INTRODUCTION: Opioid-related overdoses have risen despite extensive media coverage and apparent awareness of this public health crisis. Emergency department visits related to opioid use nearly tripled from 2004 to 2011. Patients with mental illness are more likely to be prescribed opioids and have higher rates of overdose. This retrospective chart review sought to determine if opioid represcribing occurred after patients were treated for a nonfatal opioid overdose (NFO) at a Veterans Affairs hospital. METHODS: Patients who experienced an NFO between 2009 and 2013 were included and charts reviewed until January 1, 2016. Review of the electronic medical record (EMR) was performed to determine if and when opioids were again prescribed after NFO. RESULTS: Fifty-six veterans met the inclusion criteria. A new opioid prescription was issued to 82% of patients within 3 months following the index NFO date. The average daily morphine equivalent dose prescribed before (122 mg) and after (120 mg) NFO did not differ. A subsequent opioid overdose event occurred in 25% of patients, and there was 1 fatal event. Only 1 patient had medication overdose on the problem list of their EMR. DISCUSSION: Despite experiencing NFO, veterans continued to be prescribed opioids without significant changes in the drug or dose; some experienced repeated overdose events, possibly due to poor communication and documentation of NFO. Pharmacists can play a key role in clinical interventions and education of patients and prescribers.

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.

Bupreorphine:a new pharmacotherapy for opioid addictions treatment.

The federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with the disease of addiction by providing increased access to options for treatment. Previously, only methadone maintenance, approved for use only through specially regulated clinics, was available to treat opioid addiction. DATA allows any physician choosing to take a short specialty training course and become certified to prescribe buprenorphine. Buprenorphine and buprenorphine/ naloxone (Subutex, Suboxone) can be prescribed by certified physicians in a traditional office setting to treat patients with opioid dependence. Clinical studies indicate buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and reducing illicit opioid use. Sublingual buprenorphine is more effective than clonidine or clonidine/naltrexone in short-term opioid detoxification treatment. Buprenorphine provides an additional tool to treat opioid addiction and improve the quality of lives of these patients. More physicians are needed to treat patients with addiction. DATA facilitates this by removing existing barriers and increasing access to treatment.

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.

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.

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.

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.

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.