Treatment Of Methamphetamine Dependence Research Articles

Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers.

Methamphetamine use is increasing in the US. Although there are no Food and Drug Administration (FDA)-approved medications for methamphetamine dependence, preclinical and clinical studies suggest that methamphetamine users may benefit from treatments that enhance cholinergic neurotransmission. Consequently, we determined the safety and the efficacy of varenicline treatment, a partial agonist at α4β2 and a full agonist at α7 nicotinic acetylcholine receptors, to reduce positive subjective effects produced by smoked methamphetamine. Additionally, the effects of treatment with varenicline on the cardiovascular and reinforcing effects of methamphetamine were determined. We conducted a double-blind, placebo-controlled, within-subjects trial of varenicline vs. placebo in methamphetamine-dependent volunteers who were not seeking treatment. Participants were randomly assigned to receive one dose of varenicline (0, 1, or 2mg) po BID, titrated up to the target dose over days 1-7, during each of three separate inpatient phases. Safety measures included the frequency, duration, severity, and relatedness of adverse events reported. Positive subjective effects included 'Any drug effect', 'High', 'Good effects', 'Stimulated', and 'Drug liking', which were rated by participants before and for 1h after smoking methamphetamine (0, 10, and 30mg). There were no serious adverse events and no differences in adverse events reported during the three phases. Varenicline (2mg) significantly reduced ratings of 'Any drug effect' and 'Stimulated', as well as attenuated ratings of 'High', 'Drug liking', and 'Good effects', produced by methamphetamine (30mg). The ability of varenicline to attenuate the positive subjective effects of methamphetamine in the laboratory suggests that varenicline should continue to be explored as a treatment for methamphetamine dependence.

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

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. 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. 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. Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

Exercise for methamphetamine dependence: Rationale, design, and methodology

BackgroundEffective pharmacotherapies to treat methamphetamine (MA) dependence have not been identified, and behavioral therapies are marginally effective. Based on behavioral studies demonstrating the potential efficacy of aerobic exercise for improving depressive symptoms, anxiety, cognitive deficits, and substance use outcomes, the study described here is examining exercise as a potential treatment for MA-dependent individuals. MethodsThis study is randomizing 150 participants with MA dependence at a residential treatment facility for addictive disorders to receive either a thrice-weekly structured aerobic and resistance exercise intervention or a health education condition. Recruitment commenced in March, 2010. Enrollment and follow-up phases are ongoing, and recruitment is exceeding targeted enrollment rates. ConclusionsSeeking evidence for a possibly effective adjunct to traditional behavioral approaches for treatment of MA dependence, this study is assessing the ability of an 8-week aerobic and resistance exercise protocol to reduce relapse to MA use during a 12-week follow-up period after discharge from residential-based treatment. The study also is evaluating improvements in health and functional outcomes during and after the protocol. This paper describes the design and methods of the study.

Psychometric properties of the Barratt Impulsiveness Scale in patients with gambling disorders, hypersexuality, and methamphetamine dependence

Although the Barratt Impulsiveness Scale (BIS; Patton, Stanford, & Barratt, 1995) is a widely-used self-report measure of impulsivity, there have been numerous questions about the invariance of the factor structure across clinical populations (Haden & Shiva, 2008, 2009; Ireland & Archer, 2008). The goal of this article is to examine the factor structure of the BIS among a sample consisting of three populations exhibiting addictive behaviors and impulsivity: pathological gamblers, hypersexual patients, and individuals seeking treatment for methamphetamine dependence to determine if modification to the existing factors might improve the psychometric properties of the BIS. The current study found that the factor structure of the BIS does not replicate in this sample and instead produces a 12-item three-factor solution consisting of motor-impulsiveness (5 items), non-planning impulsiveness (3 items), and immediacy impulsiveness (4 items). The clinical utility of the BIS in this population is questionable. The authors suggest future studies to investigate comparisons with this modified version of the BIS and other impulsivity scales such as the UPPS-P Impulsive Behavior Scale in clinical populations when assessing disposition toward rash action.

A Cognitive Behavioral Therapy-Based Text Messaging Intervention for Methamphetamine Dependence

Psychosocial treatments for methamphetamine dependence are of limited effectiveness. Thus, a significant need exists for add-on therapy for this substance user disorder. The aim of this study was to develop and test a novel text messaging intervention for use as an adjunct to cognitive behavioral group therapy for methamphetamine users. Text messaging has the potential to support patients in real-time, around the clock. We convened two meetings of an expert panel, held three focus groups in current and former users, and conducted 15 semi-structured interviews with in-treatment users in order to develop a fully automated, cognitive behavioral therapy-based text messaging intervention. We then conducted a randomized, crossover pre-test in five users seeking treatment. Participants’ ratings of ease of use and functionality of the system were high. During the pre-test, we performed real-time assessments via text messaging on daily methamphetamine use, craving levels, and the perceived usefulness of messages; 79% of scheduled assessments were collected. The odds of messages being rated as “very” or “extremely” useful were 6.6 times (95% CI: 2.2, 19.4) higher in the active vs. placebo periods. The intervention is now ready for testing in randomized clinical trials.

Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence.

BackgroundMethamphetamine-abuse is a worldwide health problem for which no effective therapy is available. Inhibition of methamphetamine-induced transporter-mediated dopamine (DA) release could be a useful approach to treat methamphetamine-addiction. We assessed the potencies of bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone (MDPV) to block DA uptake or to inhibit methamphetamine-induced DA release in HEK-293 cells expressing the human DA transporter.FindingsBupropion, methylphenidate, and MDPV inhibited methamphetamine-induced DA release with relative potencies corresponding to their potencies to block DA uptake (potency ranks: MDPV > methylphenidate > bupropion).ConclusionsBupropion and methylphenidate antagonize the effects of methamphetamine in vitro and may be potential candidates for the treatment of stimulant addiction. However, drugs that very potently antagonize the effect of methamphetamine are likely to also exhibit considerable abuse liability (MDPV > methylphenidate > bupropion).

Methylphenidate vs. resperidone in treatment of methamphetamine dependence: A clinical trial

Background and aimsCurrently, there is no widely accepted evidence-based pharmacotherapy regime for the treatment of psychostimulant dependence. Yet, different pharmacological approaches have been tried in the treatment of MA addiction. The present study was conducted to compare efficiency of methylphenidate which is relatively easily accessible in our country, with resperidone for this purpose. MethodsEighty-six patients with MA dependence according to criteria defined by DSM IV-TR were divided into two groups. Patients in group R were given oral resperidone 1mg daily for 1week; then 2mg daily in a divided dose for 3weeks. Patients in group M were given oral methylphenidate 10mg daily for 2weeks, 7.5mg daily for 1week, then 5mg daily for 1week. They were evaluated for drug craving, psychological, neurologic and somatic symptoms at the start and end of the study. FindingsBoth drugs were useful for lowering drug craving in patients; however resperidone was more effective (6.31±8.31 vs.19.6±12.45 cravings per week, respectively). The effects of resperidone were more notable in lowering frequency and intensity of psychiatric, neurologic, cardiac and somatic symptoms of the patients after discontinuation of MA abuse; however methylphenidate was effective too; though with a lower potency. ConclusionThe present study confirmed that both methylphenidate and resperidone can successfully be used for treatment of MA dependence, in order to reduce drug craving and psychological, neurologic, and somatic problems in patients. However, the efficacy of methylphenidate was estimated to be less than that of resperidone for this purpose.

Does Posttraumatic Stress Disorder Affect Post-Treatment Methamphetamine Use?

Objective: Although trauma is a well-established risk factor for substance use disorders, little is known about the association between posttraumatic stress disorder (PTSD) and treatment outcomes among methamphetamine users. In the present study, we examine the relationship between PTSD and post-treatment methamphetamine use outcomes, hospitalizations, and overall psychiatric impairment. Methods: Using data from 526 adults in the largest psychosocial clinical trial of methamphetamine users conducted to date, this study examined (a) treatment outcomes of methamphetamine users with concomitant PTSD 3 years after psychosocial treatment for methamphetamine dependence and (b) PTSD symptom clusters as risk factors for post-treatment relapse to methamphetamine use. Results: PTSD was associated with poorer methamphetamine use outcomes; methamphetamine use frequency throughout the 3-year follow-up was significantly greater among individuals with a PTSD diagnosis, and those with PTSD had more than five times the odds of reporting methamphetamine use in the 30 days prior to the follow-up interview, odds ratio (OR) = 5.2, 95% CI [2.0–13.3]. Additionally, higher levels of other Axis I psychopathology were observed among methamphetamine users with PTSD. Avoidance and arousal symptoms predicted post-treatment methamphetamine use. Conclusions: Addressing these high-risk PTSD symptoms and syndromes in methamphetamine users may be helpful as a means of improving treatment outcomes in this population.

The Development of Antibody-based Immunotherapy for Methamphetamine Abuse: Immunization, and Virus-Mediated Gene Transfer Approaches

Methamphetamine is a highly addictive psychostimulant that has been seriously abused worldwide, and currently there are no approved medications for the treatment of its abuse. Conventional treatments for drug addiction mainly seek to use small molecule agonists or antagonists to target the drug receptors in the brain, but unfortunately it is difficult to find a similar small molecule for the treatment of methamphetamine dependence. Alternatively, anti-methamphetamine antibodies can sequester the drug in the bloodstream and reduce the amount of drug available to the central nervous system, acting as peripheral pharmacokinetic antagonists. This review describes the development of antibody-based immunotherapies, classified into active and passive immunizations, for the treatment of methamphetamine addiction. Furthermore, an alternative therapeutic approach, using a recombinant adeno-associated virus-mediated gene transfer technique to achieve in vivo expression of characterized anti-methamphetamine monoclonal antibodies, is proposed in this article.

Aripiprazole for the treatment of methamphetamine dependence: a randomized, double‐blind, placebo‐controlled trial

To test aripiprazole for efficacy in decreasing use in methamphetamine-dependent adults, compared to placebo. Participants were randomized to receive 12 weeks of aripiprazole or placebo, with a 3-month follow-up and a platform of weekly 30-minute substance abuse counseling. The trial was conducted from January 2009 to March 2012 at the San Francisco Department of Public Health. Ninety actively using, methamphetamine-dependent, sexually active adults were recruited from community venues. The primary outcome was regression estimated reductions in weekly methamphetamine-positive urines. Secondary outcomes were study medication adherence [by self-report and medication event monitoring systems (MEMS)], sexual risk behavior and abstinence from methamphetamine. Participant mean age was 38.7 years, 87.8% were male, 50.0% white, 18.9% African American, and 16.7% Latino. Eighty-three per cent of follow-up visits and final visits were completed. By intent-to-treat, participants assigned to aripiprazole had similar reductions in methamphetamine-positive urines as participants assigned to placebo [risk ratio (RR) 0.88, 95% confidence interval (CI): 0.66-1.19, P = 0.41]. Urine positivity declined from 73% (33 of 45 participants) to 45% (18 of 40) in the placebo arm and from 77% (34 of 44) to 44% (20 of 35) in the aripiprazole arm. Adherence by MEMS and self-report was 42 and 74%, respectively, with no significant difference between arms (MEMS P = 0.31; self-report P = 0.17). Most sexual risk behaviors declined similarly among participants in both arms (all P > 0.05). There were no serious adverse events related to study drug, although participants randomized to aripiprazole reported more akathisia, fatigue and drowsiness (P < 0.05). Compared with placebo, aripiprazole did not reduce methamphetamine use significantly among actively using, dependent adults.

Role of GIRK Channels in Addictive Substance Effects

G-protein-activated inwardly rectifying potassium (GIRK) channels are widely expressed in the central nervous system, including brain regions related to reward, and play an important role in mediat- ing the signal transduction pathways of various addictive substances. Studies of GIRK knockout mice have suggested the involvement of GIRK channels in the mechanisms that underlie the effects of addictive substances. Human studies have shown that differences in the genetic sequence of one of the four GIRK channel subunits, GIRK2, are asso- ciated with analgesic requirements in patients who undergo major open abdominal surgery. Animal and human studies also showed the possi- ble therapeutic effects of GIRK channel inhibitors in the treatment of methamphetamine dependence and alcoholism. These findings suggest that GIRK channels may be a key molecular target in the reward system for the treatment of addiction.

The Development of Antibody-based Immunotherapy for Methamphetamine Abuse: Immunization, and Virus-Mediated Gene Transfer Approaches

Methamphetamine is a highly addictive psychostimulant that has been seriously abused worldwide, and currently there are no approved medications for the treatment of its abuse. Conventional treatments for drug addiction mainly seek to use small molecule agonists or antagonists to target the drug receptors in the brain, but unfortunately it is difficult to find a similar small molecule for the treatment of methamphetamine dependence. Alternatively, anti-methamphetamine antibodies can sequester the drug in the bloodstream and reduce the amount of drug available to the central nervous system, acting as peripheral pharmacokinetic antagonists. This review describes the development of antibody-based immunotherapies, classified into active and passive immunizations, for the treatment of methamphetamine addiction. Furthermore, an alternative therapeutic approach, using a recombinant adeno-associated virus-mediated gene transfer technique to achieve in vivo expression of characterized anti-methamphetamine monoclonal antibodies, is proposed in this article. Keywords: Adeno-associated virus, antibody, gene therapy, immunization, methamphetamine abuse, vaccine, antagonists, immunotherapy

Modafinil Abrogates Methamphetamine-Induced Neuroinflammation and Apoptotic Effects in the Mouse Striatum

Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4×5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2×90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.

Reanalysis of Methamphetamine Dependence Treatment Trial

Reanalysis of Methamphetamine Dependence Treatment Trial

A randomized, placebo-controlled trial of aripiprazole for the treatment of methamphetamine dependence and associated psychosis

Objectives. The objectives of this study were to determine the efficacy and safety of aripiprazole for treatment of psychosis, retention and abstinence in patients with methamphetamine dependence. Methods. This was a double-blind study where 37 methamphetamine dependent patients with history of psychosis were randomly assigned to receive aripiprazole (5–10 mg daily, N = 19) or placebo (N = 18) for 8 weeks. Follow-up evaluation was scheduled on day 7, 14, 28, 42 day 56 after enrolment. Results. Participants on aripiprazole were retained significantly longer in treatment (48.7 days, SD =4.0) compared to placebo (37.1 days, SD =5.0). The Kaplan–Meier survival analysis showed that participants on aripiprazole were less likely to drop out of the study than the placebo group (P =0.02, χ2 =5.3). Psychotic symptoms significantly decreased among those on aripiprazole as compared to placebo (P < 0.05). However, no statistically significance was found between the two groups in maintaining abstinence (generalised estimation equation (GEE) analysis, P = 0.41). No serious adverse events were reported in either group. Conclusion. Aripiprazole was no more effective than placebo in maintaining abstinence from methamphetamine use. However, it facilitated treatment retention and reduced the severity of psychotic symptoms. Aripiprazole was found to be generally safe and well tolerated.

Gender, Brain-Derived Neurotrophic Factor Val66Met, and Frequency of Methamphetamine Use

Frequency of pretreatment methamphetamine (MA) use is an important predictor of outcomes of treatment for MA dependence. Preclinical studies suggest females self-administer more MA than males, but few clinical studies have examined potential sex differences in the frequency of MA use. Estrogen increases expression of brain-derived neurotrophic factor (BDNF), which has effects on MA-induced striatal dopamine release and protects against MA-induced neurotoxicity. We examined potential effects of sex, the Val66Met polymorphism in BDNF, and their interaction on frequency of MA use among 60 Caucasian MA-dependent volunteers screening for a clinical trial. Data was taken from 60 Caucasian MA-dependent volunteers screening for a clinical trial. Females reported significantly more pretreatment days with MA use in the past 30 days than males. There was a significant interaction between sex and BDNF Val66Met, with the highest frequency of MA use among females with Val/Val genotype. These results, although preliminary, add to the literature documenting sexual dimorphism in response to stimulants, including MA, and suggest a potential biological mechanism involving BDNF that might contribute to these differences. Additional research characterizing the biological basis of altered response to MA among females is warranted.

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

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. 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. 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. 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.

COMT Val158Met, BDNF Val66Met, and OPRM1 Asn40Asp and Methamphetamine Dependence Treatment Response

COMT Val158Met, BDNF Val66Met, and OPRM1 Asn40Asp and Methamphetamine Dependence Treatment Response

Impaired Cognitive Performance in Subjects with Methamphetamine Dependence during Exposure to Neutral versus Methamphetamine-Related Cues

Background: Chronic methamphetamine abuse is associated with cognitive deficits that may impede treatment in methamphetamine-dependent patients. Exposure to methamphetamine-related cues can elicit intense craving in chronic users of the drug, but the effects of exposure to drug cues on cognitive performance in these individuals are unknown. Objectives: This study assessed whether exposure to methamphetamine-related visual cues can elicit craving and/or alter dual task cognitive performance in 30 methamphetamine-dependent subjects and 30 control subjects in the laboratory. Methods: Reaction time, response errors, and inhibition errors were assessed on an auditory Go–No Go task performed by adult participants (total N = 60) while watching neutral versus methamphetamine-related video cues. Craving was assessed with the Within-Session Rating Scale modified for methamphetamine-dependent subjects. Results: Exposure to methamphetamine-related cues elicited craving only in methamphetamine-dependent subjects. Even in the absence of methamphetamine cues, methamphetamine-dependent subjects exhibited slower reaction times and higher rates of both inhibition and response errors than control subjects did. Upon exposure to methamphetamine cues, rates of both response errors and inhibition errors increased significantly in methamphetamine-dependent subjects. Control subjects exhibited no increase in inhibition errors and only slightly increased rates of response errors upon exposure to methamphetamine cues. Response error rates, but not inhibition error rates or reaction times, during methamphetamine cue exposure were significantly associated with craving scores in methamphetamine-dependent subjects. Conclusions and Significance: Methamphetamine-dependent individuals exhibit cognitive performance deficits that are more pronounced during exposure to methamphetamine-related cues. Interventions that reduce cue reactivity may have utility in the treatment of methamphetamine dependence.

Response of limbic neurotensin systems to methamphetamine self-administration

Methamphetamine (METH) abuse is personally and socially devastating. Although effects of METH on dopamine (DA) systems likely contribute to its highly addictive nature, no medications are approved to treat METH dependence. Thus, we and others have studied the METH-induced responses of neurotensin (NT) systems. NT is associated with inhibitory feedback action on DA projections, and NT levels are elevated in both the nucleus accumbens and dorsal striatum after noncontingent treatment with high doses of METH. In the present study, we used a METH self-administration (SA) model (linked to lever pressing) to demonstrate that substitution of an NT agonist for METH, while not significantly affecting motor activity, dramatically reduced lever pressing but was not self-administered per se. We also found that nucleus accumbens NT levels were elevated via a D1 mechanism after five sessions in rats self-administering METH (SAM), with a lesser effect in corresponding yoked rats. Extended (15 daily sessions) exposure to METH SA manifested similar NT responses; however, more detailed analyses revealed (i) 15 days of METH SA significantly elevated NT levels in the nucleus accumbens shell and dorsal striatum, but not the nucleus accumbens core, with a lesser effect in the corresponding yoked METH rats; (ii) the elevation of NT in both the nucleus accumbens shell and dorsal striatum significantly correlated with the total amount of METH received in the self-administering, but not the corresponding yoked METH rats; and (iii) an NT agonist blocked, but an NT antagonist did not alter, lever-pressing behavior on day 15 in SAM rats. After 5 days in SAM animals, NT levels were also elevated in the ventral tegmental area, but not frontal cortex of rats self-administering METH.