The CSAT Methamphetamine Treatment Program: Research Design Accommodations for “Real World” Application

To examine whether overlapping cognitive deficits exist in currently drug-abstinent chronic methamphetamine (MA) abusers and schizophrenia (SZ) patients. Both SZ and chronic MA abuse are associated with frontostriatal disruption as well as deficits in cognitive control, such as selective attention. To identify overlapping cognitive profiles, we compared performance of the 2 groups on the Stroop attention task. Data were analyzed from 69 MA abusers who had been MA-abstinent for differing periods of time and from 23 SZ patients and 38 non-substance-abusing controls. The MA abusers in early abstinence displayed more Stroop interference than the SZ patients (P=0.004), long-term abstinent MA abusers (P=0.009), and controls (P=0.002). In the MA abusers, the magnitude of Stroop interference correlated positively with longer drug use (P=0.01) and negatively with longer drug abstinence (P=0.04). No correlations were found between psychotic symptoms and task performance. On this task of attentional selection, only the MA abusers in early stages of abstinence showed performance deficits compared with controls. More research is needed to further elucidate overlapping patterns between MA abuse and SZ.

In 1998, responding to national and regional epidemiological data indicating that methamphetamine (MA) abuse was a growing problem in the United States, the Center for Substance Abuse Treatment (CSAT) initiated a multisite MA treatment study. Through a collaborative approach among CSAT, seven treatment sites, and a coordinating center, the study compares the clinical and cost effectiveness of a manualized, cognitive-behavioral outpatient treatment developed by the Matrix Center in Los Angeles to the treatment approches currently employed by the treatment sites. The study also explores technology transfer issues associated with integrating the Matrix approach within existing treatment settings. CSAT's approach to the initiation and management of this type of study is discussed.

Background: Methamphetamine (MA) abuse is a health concern among drug abuse patients in Iran. Objectives: This study aimed at determining the prevalence of MA dependence among a group of female methadone users and investigating the current psychological well-being, high risk sexual and criminality behaviors, and the status of receiving MA treatment. Methods: This study was a cross-sectional survey conducted in Iran. The study was conducted at 5 central female-only methadone services in Tehran and Karaj, during years 2011 to 2013. A questionnaire was devised to collect baseline data. The general health questionnaire-28 and the Opiate Treatment Index were used to assess psychological well-being, and criminality and high-risk sexual behaviors. Results: Overall, 245 females were registered at these sites. Of them, 201 females (82%) were dependent on MA while on treatment. Duration of MA dependence was 6 years. However, only 14.3% of the participants reported lifetime MA treatment. No participant was on MA treatment. Participants reported high rates of MA-related depression (76.4%), anxiety (68.4%), social dysfunction (41.2%), and somatic symptoms (38.2%), respectively. Untreated MA dependence in methadone treatment was associated with engagement in high-risk sexual behaviors (43.8%) and criminality (28.7%). Only 10% of the participants reported receiving a lifetime matrix model. All of them reported that the Matrix model was long and it was not easily available in methadone services. Conclusions: The study showed that the high prevalence for MA dependence and its adverse health impacts while receiving MA treatment remained the same. Effective psychosocial treatments should be delivered for MA dependence among female methadone users.

Heinzerling, Keith G. MD, MPH; McCracken, James T. MD; Swanson, Aimee-Noelle PhD; Ray, Lara A. PhD; Shoptaw, Steven J. PhD Author Information

Deficient Strategic Control of Verbal Encoding and Retrieval in Individuals With Methamphetamine Dependence.

Background: Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. Objectives: (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals. Methods: Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60 mg daily). Results: The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n = 5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment. Conclusion: Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.

The abuse of methamphetamine (MA) has increased in the United States over the past 15 years and is associated with considerable negative social, psychological, and health effects, including symptoms of depression. Infection with the hepatitis C virus (HCV), which is independently associated with increased risk of depression, is common among MA users, possibly due to high rates of transmission risk behaviors in this cohort (eg, injection drug use). Given the prevalence of depression among HCV-infected individuals and MA users separately, the current study aimed to determine whether HCV infection and MA dependence are associated with additive effects on depression. Focused psychiatric evaluations were conducted on 39 individuals with both MA dependence and HCV infection (MA + HCV +), 57 persons with only MA dependence (MA + HCV -), and a comparison sample of 46 participants with neither risk factor (MA - HCV -). Consistent with prior research, greater self-reported symptoms of depression were observed in the MA + groups relative to MA - HCV - participants; however, there was no evidence to suggest an additive effect of HCV infection. Surprisingly, the prevalence of current and lifetime diagnoses of Major Depressive Disorder (MDD) did not differ across the study groups. Results from this study suggest that HCV infection does not confer an additive effect on the severity of depressive symptoms or the prevalence of major depression in persons with MA dependence.

Association between polymorphisms in GAD genes and methamphetamine (METH) dependence was investigated in the Thai population. Genotypes of rs769404 and rs701492 in GAD1 and rs2236418 in GAD2 polymorphisms were determined in 100 METH-dependent male subjects and 102 matched controls. The genotype and allele frequencies of rs2236418 (GAD2) were associated with METH dependence and METH with psychosis, in which the G allele was related to increased risk. The presence of the rs769404-rs701492 (GAD1) C-C haplotype was associated with METH psychosis. This study indicates that genetic variability in GAD1 and GAD2 contributes to risk of METH dependence and METH psychosis in the Thai population and indicates the role of the GABAergic system in these disorders.

Rivastigmine reduces “likely to use methamphetamine” in methamphetamine-dependent volunteers

Background: Methamphetamine (MA) dependence is a health concern in Iran (Persia). One main impacted group is female methadone patients. Objectives: The aim of this paper was to briefly report the prevalence of MA dependence among female methadone patients in 3 large cities of Iran. The other aim was to report the status of psychological well-being and social functioning among MA-dependent and non-MA dependent participants. Methods: In the first survey of Iran, 570 females were recruited from 38 main methadone clinics in Mashhad, Karaj, and Isfahan. A researcher-designed questionnaire was used to collect baseline demographics, details of MA use, and treatment history. Results: Of them, 266 females were MA-dependent. In other words, the prevalence of MA dependence among females was 46.6%. The length of MA dependence was 5 years. The adverse health impacts of high doses of methadone use were the main self-reported reasons for MA dependence. These adverse health impacts included depression (n = 118, 44.36%), oversleeping (n = 88, 33.08%), and low physical energy to do the housework (n = 60, 22.55%). However, lifetime MA treatment was only 25%. The prevalence of MA dependence was significantly associated with poor psychological well-being (P < 0.01) and social dysfunction (P < 0.01) among MA dependent females compared with non-MA dependent females. Conclusions: Methamphetamine dependence was common and associated with serious health problems. Special treatment services should be provided for these females.

Despite the worldwide extent of methamphetamine (MA) dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Previous human laboratory findings indicate that rivastigmine, a cholinesterase inhibitor, reduces craving for MA. We therefore performed a double‐blind, placebo‐controlled, crossover pilot study of the safety and tolerability of varenicline in eight MA‐dependent subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4β2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over 1 week to reach 1 mg bid, and then was co‐administered with 30 mg MA, delivered in ten intravenous infusions of 3 mg each. Varenicline was found to be safe in combination with MA, producing no cardiac rhythm disturbances or alterations in vital signs. No adverse neuropsychiatric sequelae were detected during varenicline titration and following MA administration. The results suggest that varenicline warrants further investigation as a potential treatment for MA dependence. Supported by P50DA018185 (SS), P20DA022539 (EDL) and MOI RR00865 (UCLA GCRC).

Impaired cognitive and behavioral control has often been observed in people who use methamphetamine (MA). However, a comprehensive understanding of the neural substrates underlying these impairments is still lacking. The goal of the present study was to study the neural correlates of impaired cognitive control in individuals with MA dependence according to DSM-IV criteria. Eighteen individuals with MA dependence and 21 healthy controls were investigated using Stroop task, fMRI, and an impulsivity questionnaire. Overall, patients were found to have significantly poorer accuracy on the Stroop task and higher self-rated impulsivity. Comparing brain activations during the task, decreased activation in the dorsolateral prefrontal cortex (DLPFC), anterior midcingulate cortex (aMCC), and dorsal striatum was observed in individuals with MA dependence, compared to healthy controls. Altered fMRI signal in DLPFC and aMCC significantly correlated with impaired behavioral task performance in individuals with MA dependence. Furthermore, significantly lower and pronounced brain activations in the MA group were additionally detected in several sensory cortical regions, i.e., in the visual, auditory, and somatosensory cortices. The results of the current study provide evidence for the negative impact of chronic crystal meth consumption on the proper functioning of the fronto-cingulate and striatal brain regions, presumably underlying the often-observed deficits in executive functions in individuals with MA use disorder. As a new finding, we also revealed abnormal activation in several sensory brain regions, suggesting the negative effect of MA use on the proper neural activity of these regions. This blunted activation could be the cause of the observed deficits in executive functions and the associated altered brain activation in higher-level brain networks.

Objective: Extrapyramidal side-effects (EPSE) are frequent in patients treated with antipsychotics and comorbid substance use disorders (SUDs). Methamphetamine has been shown to act as a dopaminergic neurotoxin. We aimed to determine whether EPSE occur more often in patients with psychotic disorders and co-occurring methamphetamine (MA) use disorders, and we examined the relationship between MA use, antipsychotic type, dose and EPSE. Methods: This study was a secondary analysis of data from three separate primary studies. Across all studies, psychiatric and SUD diagnoses were determined using the SCID-I for DSM-IV. EPSE were determined using the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating scale (BARS), and the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia. Participants were classified as having any EPSE if they scored above the cutoff on any of the EPSE scales (SAS, BARS, AIMS). We analyzed data using multivariable logistic regression analysis. Results: The sample included 102 patients with non-affective or affective psychotic disorders. Of the total sample, 65.7% were male, 54.9% had schizophrenia spectrum disorders, 20.5% bipolar type I disorder with psychotic features, 11.7% schizoaffective disorder and 12.7% had substance-induced psychosis. A diagnosis of a methamphetamine use disorder (abuse or dependence) was present in 25.5% of participants. EPSE occurred in 38.2% of patients and were significantly associated with MA use in the unadjusted and adjusted analysis, ORadj = 4.01, 95% CI [1.07, 14.98], p = .039. Patients with MA dependence and MA use >3 years were significantly more likely to have EPSE. We found a significant interaction effect between MA use disorders and standardized antipsychotic dose on the occurrence of EPSE, ORadj = 1.01, 95% CI [1.00, 1.01], p = .042, with MA users having a disproportionally higher likelihood of having EPSE compared to MA non-users as antipsychotic dosage increased. There were no significant associations of EPSE with comorbid alcohol, cannabis, or methaqualone use disorders. Conclusions: Patients with a MA use disorder were significantly more likely to have EPSE with evidence for a dose-response effect. Clinicians should carefully titrate antipsychotic dosage from lower to higher doses to avoid EPSE in patients with MA use disorders.

Chronic use of methamphetamine has been associated with significant negative consequences in users, including cognitive deficits, which have a negative impact on clinical outcomes. This thesis aimed to examine the impact of methamphetamine dependence on several different aspects of cognition (decision making, response inhibition and delay discounting) while factoring in background characteristics, during early treatment and to determine if cognitive deficits recover with abstinence in methamphetamine users during early treatment efforts. It was found that methamphetamine dependent individuals had important cognitive deficits in response inhibition and decision making as they enter treatment and that these deficits are not significantly improved after early abstinence efforts. Thus, treatment approaches may need to accommodate or rehabilitate these cognitive deficits.

The effects of early exposure to MK-801 during environmental enrichment on spatial memory, methamphetamine self-administration and cue-induced renewal in rats