Rhynchophylline inhibits methamphetamine dependence via modulating the miR-181a-5p/GABRA1 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a plant species that is routinely devoted in traditional Chinese medicine to treat central nervous system disorders. Rhynchophylline (Rhy), a predominant alkaloid isolated from Uncaria rhynchophylla (Miq.) Miq. ex Havil., has been demonstrated to reverse methamphetamine-induced (METH-induced) conditioned place preference (CPP) effects in mice, rats and zebrafish. The precise mechanism is still poorly understood, thus further research is necessary. AIM OF STUDY: This study aimed to investigate the role of miRNAs in the inhibitory effect of Rhy on METH dependence. MATERIALS AND METHODS: A rat CPP paradigm and a PC12 cell addiction model were established. Microarray assays were used to screen and identify the candidate miRNA. Behavioral assessment, real-time PCR, dual-luciferase reporter assay, western blotting, stereotaxic injection of antagomir/agomir and cell transfection experiments were performed to elucidate the effect of the candidate miRNA and intervention mechanism of Rhy on METH dependence. RESULTS: Rhy successfully reversed METH-induced CPP effect and the upregulated miR-181a-5p expression in METH-dependent rat hippocampus and PC12 cells. Moreover, suppression of miR-181a-5p by antagomir 181a reversed METH-induced CPP effect. Meanwhile, overexpression of miR-181a-5p by agomir 181a in combination with low-dose METH (0.5 mg/kg) elicited a significant CPP effect, which was blocked by Rhy through inhibiting miR-181a-5p. Finally, the result demonstrated that miR-181a-5p exerted its regulatory role by targeting γ-aminobutyric acid A receptor α1 (GABRA1) both in vivo and in vitro. CONCLUSION: This finding reveals that Rhy inhibits METH dependence via modulating the miR-181a-5p/GABRA1 axis, which may be a promising target for treatment of METH dependence.

A Pilot Assessment of the Effects of HIV and Methamphetamine Dependence on Socially Dysregulated Behavior in the Human Behavioral Pattern Monitor.

Deficits in social cognition are seen in both people living with HIV (PWH) and people with a history of methamphetamine (METH) dependence. Dually affected individuals may experience additive negative effects on social cognition due to these conditions. We evaluated social cognition in 4 diagnostic groups (HIV-/METH-, HIV-/METH+, HIV+/METH-, HIV+/METH+). First, we used traditional social-emotional functioning assessments, the Difficulties in Emotion Regulation Scale and the Faux Pas Task, to determine any significant effects of METH dependence and HIV on social cognition. Next, we quantified social cognition using the Human Behavioral Pattern Monitor by evaluating social behavior represented by interaction with novel objects. METH dependence significantly affected social-emotional functions and HIV significantly affected on object interactions, however no significant additive effects were observed using these methods. The nuanced relationship between HIV and METH dependence suggests that other factors (i.e., adaptive life skills) likely mediate social cognition-related behaviors.

RESUMEN: Los déficits en la cognición social se observan tanto en las personas que viven con el VIH (PWH) como en las personas con antecedentes de dependencia de la metanfetamina (METH). Las personas con ambas condiciones pueden experimentar efectos negativos aditivos en la cognición social. Evaluamos la cognición social en 4 grupos de diagnóstico (VIH−/METH−, VIH−/METH+, VIH+/METH−, VIH+/METH+). En primer lugar, utilizamos evaluaciones tradicionales del funcionamiento socioemocional, la Escala de Dificultades en la Regulación Emocional y la Prueba de Faux Pas, para determinar efecto significativo debido a la dependencia de METH y el VIH en la cognición social. Entonces, cuantificamos la cognición social utilizando el Monitor de Patrones de comportamiento humano mediante la evaluación del comportamiento social representado por la interacción con objetos novedosos. La dependencia de METH afectó significativamente las funciones socioemocionales y el VIH afectó significativamente las interacciones con los objetos, sin embargo, no se observaron efectos aditivos significativos al usar estos métodos. La relación compleja entre el VIH y la dependencia de METH sugiere que otros factores (i.e., habilidades adaptativas) probablemente regulan los comportamientos relacionados con la cognición social.

Neural Correlates of Impaired Cognitive Control in Individuals with Methamphetamine Dependence: An fMRI Study.

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.

SLC1A2 Gene Polymorphism Influences Methamphetamine-Induced Psychosis.

SLC1A2 is a gene encoded for the excitatory amino acid transporter 2 which is responsible for glutamate reuptake from the synaptic cleft in the central nervous system. Recent studies have suggested that polymorphisms on glutamate transporters can affect drug dependence, leading to the development of neurological diseases and psychiatric disorders. Our study investigated the association of rs4755404 single nucleotide polymorphism (SNP) of the SLC1A2 gene with methamphetamine (METH) dependence and METH-induced psychosis and mania in a Malaysian population. The rs4755404 gene polymorphism was genotyped in METH-dependent male subjects (n = 285) and male control subjects (n = 251). The subjects consisted of the four ethnic groups in Malaysia (Malay, Chinese, Kadazan-Dusun, and Bajau). Interestingly, there was a significant association between rs4755404 polymorphism and METH-induced psychosis in the pooled METH-dependent subjects in terms of genotype frequency (p = 0.041). However, there was no significant association between rs4755404 polymorphism and METH dependence. Also, the rs455404 polymorphism was not significantly associated with METH-induced mania for both genotype frequencies and allele frequencies in the METH-dependent subjects, regardless of stratification into the different ethnicities. Our study suggests that the SLC1A2 rs4755404 gene polymorphism confers some susceptibility to METH-induced psychosis, especially for those who carry the GG homozygous genotype.

Denial and Diagnosis of Methamphetamine Dependence Severity.

Introduction: Denial, or lack of awareness of problems related to substance misuse, is a common feature of drug use disorders and can affect engagement in treatment and recovery. This study tested for association of denial with severity of symptoms used in the diagnosis of Methamphetamine Dependence. Methods: This secondary analysis used data from 69 participants (52.2% male) who met criteria for the diagnosis of Methamphetamine Dependence on the Structured Clinical Interview for DSM-IV (SCID). The association between diagnostic severity, determined from a SCID summary score (8 items), and denial, measured by the University of Rhode Island Change Assessment Scale (URICA) Precontemplation score, was tested by Pearson correlation. In post hoc t-tests, participants who differed on individual SCID items were compared on the Precontemplation score. The additional URICA subscales (Contemplation, Maintenance, Action) were also tested on a secondary basis. Results: SCID summary scores were negatively correlated with URICA Precontemplation scores (P = .003). Post-hoc tests revealed that participants who denied continued methamphetamine use despite persistent or recurrent problems (SCID item 6) had significantly higher Precontemplation scores than those who endorsed these problems (t = 3.066, P = .003). In contrast, positive correlations were observed between diagnostic severity and greater openness/willingness to change on the URICA (eg, Maintenance, r = .26; P = .01). Conclusions: The findings highlight the importance of a patient's insight regarding their addiction in clinical diagnosis. Because minimizing the impact of methamphetamine use may preclude or delay treatment, it is advised that self-report be supplemented to improve accuracy of diagnosis.

The Vulnerability to Methamphetamine Dependence and Genetics: A Case-Control Study Focusing on Genetic Polymorphisms at Chromosomal Region 5q31.3.

Objectives: Methamphetamine (METH) is a central nervous psychostimulant and one of the most frequently used illicit drugs. Numerous genetic loci that influence complex traits, including alcohol abuse, have been discovered; however, genetic analyses for METH dependence remain limited. An increased histone deacetylase 3 (HDAC3) expression has been detected in Fos-positive neurons in the dorsomedial striatum following withdrawal after METH self-administration. Herein, we aimed to systematically investigate the contribution of HDAC3 to the vulnerability to METH dependence in a Han Chinese population. Methods: In total, we recruited 1,221 patients with METH dependence and 2,328 age- and gender-matched controls. For genotyping, we selected 14 single nucleotide polymorphisms (SNPs) located within ± 3 kb regions of HDAC3. The associations between genotyped genetic polymorphisms and the vulnerability to METH dependence were examined by single marker- and haplotype-based methods using PLINK. The effects of expression quantitative trait loci (eQTLs) on targeted gene expressions were investigated using the Genotype-Tissue Expression (GTEx) database. Results: The SNP rs14251 was identified as a significant association signal (χ2 = 9.84, P = 0.0017). An increased risk of METH dependence was associated with the A allele (minor allele) of rs14251 [odds ratio (95% CI) = 1.25 (1.09-1.43)]. The results of in silico analyses suggested that SNP rs14251 could be a potential eQTL signal for FCHSD1, PCDHGB6, and RELL2, but not for HDAC3, in various human tissues. Conclusion: We demonstrated that genetic polymorphism rs14251 located at 5q31.3 was significantly associated with the vulnerability to METH dependence in Han Chinese population.

Altered EEG Microstates Dynamics During Cue-Induced Methamphetamine Craving in Virtual Reality Environments.

Background: Cue-induced craving is widely considered to be the most important risk factor for relapse during abstinence from methamphetamine (Meth). There is limited research regarding electroencephalography (EEG) microstates of Meth-dependent patients under exposure to drug-related cues. Our objective was to investigate whether EEG microstate temporal characteristics could capture neural correlates of cue-induced Meth craving in virtual reality (VR) environments. Methods: EEG recordings of 35 Meth-dependent patients and 30 healthy controls (HCs) were collected during eyes-open state and cue-induced state, respectively. Group differences and condition differences in temporal parameters of four microstate classes were compared. Results: The results demonstrated the greater presence of microstate B in both Meth-dependent patients and HCs during the cue-induced condition, compared to resting state. In addition, for Meth-dependent patients, microstate C occurred significantly less frequently, along with a tendency of increased occurrence for class D during the cue-induced condition, compared to resting state. However, the change direction of class C and class D in HCs was completely opposite to that of Meth-dependent patients. The cue-induced condition also elicited different changes in transition probability between Meth-dependent patients and HCs. Conclusion: This study explored the features of EEG microstates in Meth-dependent patients during the cue-induced condition, which can improve our understanding of Meth addiction and contribute to the development of effective assessments and intervention tools.

Effects of Acute Moderate- and High-Intensity Aerobic Exercise on Oxygenation in Prefrontal Cortex of Male Methamphetamine-Dependent Patients.

The aim of this study was to explore the influence of different intensities of acute aerobic exercise on brain activation in male methamphetamine (MA)-dependent patients during exercise. Twenty MA-dependent patients were divided randomly into two groups participating in 35 min of either moderate- or high-intensity aerobic exercise. Functional near-infrared spectral imaging (fNIRS) was used to detect hemodynamic changes in prefrontal cortex during the main 25-min exercise stage. The results revealed that high-intensity acute aerobic exercise aroused more cerebral oxygenation changes in the prefrontal cortex and left dorsolateral prefrontal cortex during exercise as compared with moderate-intensity exercise. Furthermore, there was a stronger positive connection observed between orbital frontal cortex and left dorsolateral prefrontal cortex in the high-intensity group than in the moderate-intensity group. Together these results suggest that for submaximal exercise intensities, high-intensity exercise may bring more benefits to male MA-dependent patients than moderate-intensity.

Metabolomics changes after rTMS intervention reveal potential peripheral biomarkers in methamphetamine dependence.

Methamphetamine is one of the most commonly used drugs around the world, leading to serious public health and psychiatric problems. Due to the lackness of objective laboratory evaluation indicators, the molecular mechanisms of methamphetamine dependence still remain unclear. Previous evidence demonstrated that repetitive transcranial magnetic stimulation (rTMS) may be useful in treating drug addiction. The aim of this study was to identify and validate plasma metabolomics biomarkers in patients with methamphetamine use disorder before and after rTMS intervention. An untargeted gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) based metabolomics approach was applied to characterize the metabolic profile of forty methamphetamine dependent subjects and thirty-eight healthy controls in peripheral blood mononuclear cells (PBMCs). Patients were randomized to receive either rTMS or sham over the DLPFC for four weeks (20 daily sessions, 900 pulses per day). Cognitive function were assessed before and after rTMS intervention. Eight PBMC metabolites responsible for distinguishing real rTMS from sham treatment were identified. These metabolites were mainly involved in energy metabolism and oxidative stress. Compared with baseline, the expression of three metabolites was reversed after rTMS intervention: alpha-tocopherol, glyceric acid and fumaric acid. Changes of the alpha-tocopherol were associated with cognitive function improvement following rTMS. These findings suggest that energy metabolism and oxidative stress system may be associated with the effect of rTMS on cognitive function in methamphetamine dependence, and warrant further investigation.

Loneliness, Risky Beliefs and Intentions about Practicing Safer Sex among Methamphetamine Dependent Individuals.

BACKGROUND: Methamphetamine use is a known predictor of riskier sexual behaviors, which can have important public health implications (e.g., HIV-transmission risk). Loneliness also is associated with riskier sexual behaviors, though the relationship between loneliness and beliefs and/or intentions to practice safer sex has not been examined among people dependent on methamphetamine. MATERIALS AND METHODS: Individuals who met DSM-IV criteria for lifetime methamphetamine dependence and current (≤ 18-months) methamphetamine abuse or dependence (METH+ n = 56) were compared to those without severity and recency of methamphetamine use (METH- n = 59). These groups did not differ on social network size or proportion of people with HIV (∼58% HIV+). Participants completed the NIH Toolbox Loneliness Scale and the Sexual Risks Scale's "Norms" and "Intentions" subscales. RESULTS: METH+ individuals were significantly lonelier than METH- controls (t(113) = 2.45, p = .02). Methamphetamine dependence remained significantly associated with greater loneliness, after controlling for HIV status and other relevant covariates (e.g., neurocognitive impairment, history of mood disorder, social network size; F = 3.70, Adjusted R2 = 0.18, p = .0009). Loneliness, above and beyond the aforementioned covariates, was significantly associated with riskier beliefs and intentions to practice safer sex among METH+, but not METH-, individuals (ß = 2.92, p = .02). CONCLUSIONS: Loneliness is prevalent among individuals dependent on methamphetamine, and is uniquely associated with riskier beliefs and intentions regarding practicing safer sex. Findings may aid in identifying individuals at-risk of engaging in riskier sexual behaviors and guide risk prevention strategies.

Prior Methamphetamine Use Disorder History Does Not Impair Interoceptive Processing of Soft Touch in HIV Infection.

INTRODUCTION: Interoception, defined as the sense of the internal state of one's body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing. METHODS: Eighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing. RESULTS: Overall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls. CONCLUSIONS: Our findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

Association of NQO1 levels and its genetic polymorphism with susceptibility to methamphetamine dependence.

BACKGROUND: The quinone oxidoreductase 1 (NQO1) gene was involved in the pathophysiological process of illicit drugs abuse, and its polymorphisms might be associated with methamphetamine (METH) dependence susceptibility. The purpose of this study was to examine the NQO1 mRNA and protein levels and to analyze the 609C/T polymorphism (rs1800566) between METH-dependent patients and controls. METHODS: A total of 392 METH-dependent patients (cases) and 669 healthy controls (controls) were enrolled in the study. The quantitative real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the relative expressions of NQO1 mRNA in PBMCs and protein levels in plasma, respectively. PCR-restriction fragment length polymorphism (RFLP-PCR) and direct-sequencing genotyping were used to detect the alleles and genotypes of NQO1 609C/T polymorphism. RESULTS: The levels of NQO1 mRNA in cases (3.2650 ± 2.2943) was significantly higher than in controls (1.0125 ± 0.7959) (p < 0.001), the plasma protein in cases (0.2368 ± 0.1486) was significantly lower than in controls (0.5844 ± 0.1742) (p < 0.001). The T allele of the 609C/T polymorphism significantly increased the risk of METH dependence (p = 0.032, OR = 1.214, 95%CI = 1.017-1.450). The TC and TC/TT genotypes of 609C/T were observed significantly more frequently in cases than in controls, respectively (TC vs CC: p = 0.012, OR = 1.457, 95% CI = 1.087-1.952; TC/TT vs CC: p = 0.008, OR = 1.460, 95% CI = 1.102-1.935). Similar results were obtained after adjusting for age and sex. We failed to find that any genotype of 609C/T polymorphism affected the mRNA or plasma protein levels in controls, respectively (p > 0.05). CONCLUSION: The findings suggested that NQO1 might play an important role in the pathophysiological process of METH dependence, and the 609C/T polymorphism might contribute to the susceptibility to METH dependence in a Chinese Han population.

Factors associated with methamphetamine withdrawal symptoms among people who inject drugs.

BACKGROUND: Regular methamphetamine (MA) use can result in withdrawal syndrome characterized by fatigue, agitation, depression, and anxiety. No studies that we are aware of have examined the prevalence and predictors of MA withdrawal symptoms among people who inject drugs (PWID). METHODS: PWID were recruited using targeted sampling methods in Los Angeles and San Francisco, California from 2016 to 2017. Survey questions included demographics, drug use, and MA withdrawal symptoms, frequency, and symptom severity. Participants who reported regular MA use (> 12 times in the last 30 days) were included in this analysis (N = 595). Multivariable regression models were developed to examine factors associated with any MA withdrawal, withdrawal frequency, symptom severity, and receptive syringe sharing. RESULTS: MA withdrawal symptoms in the past 6 months were reported by 53 % of PWID, with 25 % reporting weekly withdrawal symptoms, and 20 % reporting very or extremely painful symptoms. In multivariable logistic regression, presence of any MA withdrawal symptoms was positively associated with more frequent MA use and non-injection tranquilizer use and inversely associated with crack cocaine use. Among those reporting any withdrawal, female sex was associated with more frequent withdrawal symptoms. Very or extremely painful withdrawal symptoms were associated with being in residential treatment. Receptive syringe sharing was associated with any MA withdrawal symptoms and weekly frequency of symptoms. CONCLUSION: MA withdrawal symptoms are common among PWID and are associated with receptive syringe sharing. Strategies for implementing MA use treatment, safe supply programs, and syringe services programs targeting people who inject MA are indicated.

Treatment Response Prediction and Individualized Identification of Short-Term Abstinence Methamphetamine Dependence Using Brain Graph Metrics.

Background: The abuse of methamphetamine (MA) worldwide has gained international attention as the most rapidly growing illicit drug problem. The classification and treatment response prediction of MA addicts are thereby paramount, in order for effective treatments to be more targeted to individuals. However, there has been limited progress. Methods: In the present study, 43 MA-dependent participants and 38 age- and gender-matched healthy controls were enrolled, and their resting-state functional magnetic resonance imaging data were collected. MA-dependent participants who showed 50% reduction in craving were defined as responders to treatment. The present study used the machine learning method, which is a support vector machine (SVM), to detect the most relevant features for discriminating and predicting the treatment response for MA-dependent participants based on the features extracted from the functional graph metrics. Results: A classifier was able to differentiate MA-dependent subjects from normal controls, with a cross-validated prediction accuracy, sensitivity, and specificity of 73.2% [95% confidence interval (CI) = 71.23-74.17%), 66.05% (95% CI = 63.06-69.04%), and 80.35% (95% CI = 77.77-82.93%), respectively, at the individual level. The most accurate combination of classifier features included the nodal efficiency in the right middle temporal gyrus and the community index in the left precentral gyrus and cuneus. Between these two, the community index in the left precentral gyrus had the highest importance. In addition, the classification performance of the other classifier used to predict the treatment response of MA-dependent subjects had an accuracy, sensitivity, and specificity of 71.2% (95% CI = 69.28-73.12%), 86.75% (95% CI = 84.48-88.92%), and 55.65% (95% CI = 52.61-58.79%), respectively, at the individual level. Furthermore, the most accurate combination of classifier features included the nodal clustering coefficient in the right orbital part of the superior frontal gyrus, the nodal local efficiency in the right orbital part of the superior frontal gyrus, and the right triangular part of the inferior frontal gyrus and right temporal pole of middle temporal gyrus. Among these, the nodal local efficiency in the right temporal pole of the middle temporal gyrus had the highest feature importance. Conclusion: The present study identified the most relevant features of MA addiction and treatment based on SVMs and the features extracted from the graph metrics and provided possible biomarkers to differentiate and predict the treatment response for MA-dependent patients. The brain regions involved in the best combinations should be given close attention during the treatment of MA.

Dysfunctional personality beliefs and emotion recognition in individuals with methamphetamine dependence.

Previous studies have demonstrated that individuals with methamphetamine dependence have impaired emotion recognition. However, heterogeneity in results from these studies may indicate that individual factors such as personality beliefs moderate emotion recognition deficits. Thus, we aimed to examine the relationship between dimensional estimates of dysfunctional personality beliefs and facial emotion recognition in 86 Australian treatment seekers with methamphetamine dependence. Dysfunctional beliefs were measured using the Personality Beliefs Questionnaire, and emotion recognition was measured with the Ekman's Faces Test. We applied hierarchical regression analyses to test the relationship between beliefs and emotion recognition after accounting for the effects of intelligence. Results indicated that personality beliefs reflecting antisocial and paranoid schemas together accounted for a significant increase in the variance in fear recognition (higher levels of beliefs associated with poorer fear recognition). Further, high levels of passive-aggressive personality beliefs were associated with a tendency to misclassify faces as disgust. Our findings suggest that antisocial, paranoid, and passive-aggressive dysfunctional personality beliefs may underlie inter-individual differences in emotion recognition in methamphetamine dependent individuals. Additional research is required to better understand the relationship between personality and social processing biases, and investigate the direct impact these have on the significant psychosocial impairments present in individuals with methamphetamine dependence.

Neurofunctional Differences Related to Methamphetamine and Sexual Cues in Men With Shorter and Longer Term Abstinence Methamphetamine Dependence.

BACKGROUND: Stimulant use and sexual behaviors have been linked in behavioral and epidemiological studies. Although methamphetamine-related neurofunctional differences have been investigated, few studies have examined neural responses to drug and sexual cues with respect to shorter or longer term methamphetamine abstinence in individuals with methamphetamine dependence. METHODS: Forty-nine men with shorter term methamphetamine abstinence, 50 men with longer term methamphetamine abstinence, and 47 non-drug-using healthy comparison men completed a functional magnetic resonance imaging cue-reactivity task consisting of methamphetamine, sexual, and neutral visual cues. RESULTS: Region-of-interest analyses revealed greater methamphetamine cue-related activation in shorter term methamphetamine abstinence and longer term methamphetamine abstinence individuals relative to healthy comparison men in the ventromedial prefrontal cortex. A significant interaction of group and condition in the anterior insula was found. Relative to healthy comparison participants, both shorter term methamphetamine abstinence and longer term methamphetamine abstinence groups displayed greater sexual cue-related anterior insula activation relative to methamphetamine cues and neutral cues, but there were no differences between shorter term methamphetamine abstinence and longer term methamphetamine abstinence groups in anterior insula responses. Subsequent whole-brain analyses indicated a group-by-condition interaction with longer term methamphetamine abstinence participants showing greater sexual-related activation in the left superior frontal cortex relative to healthy comparison men. Shorter term methamphetamine abstinence participants showed greater superior frontal cortex activation to sexual relative to neutral cues, and longer term methamphetamine abstinence participants showed greater superior frontal cortex activation to sexual relative to neutral and methamphetamine cues. CONCLUSIONS: The findings suggest that abstinence from methamphetamine may alter how individuals respond to drug and sexual cues and thus may influence drug use and sexual behaviors. Given the use of methamphetamine for sexual purposes and responses to natural vs drug rewards for addiction recovery, the findings may have particular clinical relevance.

Decreased GABA concentrations in left prefrontal cortex of methamphetamine dependent patients: A proton magnetic resonance spectroscopy study.

Increasing evidence suggested the dorsolateral prefrontal cortex (DLPFC) is implicated in the pathogenesis of methamphetamine use disorder. Metabolites changes of DLPFC may mediate the progression of addiction. We used proton magnetic resonance spectroscopy (1H-MRS) to examine the changes of metabolites in the left DLPFC in individuals with methamphetamine dependence compared to healthy controls. Fifty patients and twenty age-matched healthy controls participated in this study. The 1H MRS data were automatically fit with linear combination model for quantification of metabolite levels of γ-aminobutyric acid (GABA), glutamate + glutamine (Glx) and other metabolites across groups. The GABA and Glx levels were calculated with the unsuppressed water signal as reference. Methamphetamine users showed reduced GABA and GABA/Glx in left DLPFC than healthy controls. Furthermore, the concentration of GSH, GPC, Ins, NAA, GPC + PCh, NAA + NAAG, Cr + PCr were lower in individuals with methamphetamine dependence compared with controls. The patients group's relative GABA and Glx metabolite concentrations were significantly correlated with age and duration of withdrawal. Our preliminary findings provide the first report of abnormal levels of GABA in left DLPFC of patients with methamphetamine use disorder, indicating that dysregulation of the GABAergic neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of methamphetamine dependence.

Effects of moderate- and high-intensity acute aerobic exercise on food reward and appetite in individuals with methamphetamine dependence.

PURPOSE: Drug addiction is characterised by overvaluation of drug-related rewards and undervaluation of "natural", non-drug-related rewards. Methamphetamine (MA) is the second largest illegally abused drug in the world. Studies have shown that acute aerobic exercise can reduce the incidence of MA-dependent individuals' craving for drug-related cues, but the impact of exercise on food reward in this population has yet to be established. The aim of this study was to determine the effects of moderate and high-intensity acute aerobic exercise on food reward and subjective feelings of appetite in MA-dependent populations. METHODS: Forty-four men, who met the DSM-V criteria for MA dependence, with BMI of 24.7 ±â€¯3.1 kg/m2 and age of 31.9 ±â€¯3.8 years, were randomly assigned to two exercise training groups: moderate- (n = 22; 65%~75% HRmax) or high- (n = 22; ≥ 85% HRmax) intensity. Each group performed a resting control or exercise session for 35 min, 1wk apart, in a counterbalanced order. Food reward (explicit liking, implicit wanting and relative preference) for high or low fat and sweet or savoury food images was assessed by the Leeds Food Preference Questionnaire and subjective feelings of appetite were measured by VAS. RESULTS: Greater relative preference (high: P = .018; moderate: P = .034) and implicit wanting (high: P = .018; moderate: P = .034) for high-fat savoury foods was noted following acute aerobic exercise compared to the control session. Exercise also increased subjective sensations of hunger (F (1,42) =8.28, P = .006). CONCLUSIONS: The current study provides the first evidence that acute aerobic exercise can increase reward for high fat savoury foods and stimulate appetite in MA-dependent individuals. In the context of exercise as a therapeutic option for MA dependence, these changes suggest an improvement in responsiveness to natural, non-drug rewards.

Bayesian computational markers of relapse in methamphetamine dependence.

Methamphetamine use disorder is associated with a high likelihood of relapse. Identifying robust predictors of relapse that have explanatory power is critical to develop secondary prevention based on a mechanistic understanding of relapse. Computational approaches have the potential to identify such predictive markers of psychiatric illness, with the advantage of providing a finer mechanistic explanation of the cognitive processes underlying psychiatric vulnerability. In this study, sixty-two recently sober methamphetamine-dependent individuals were recruited from a 28-day inpatient treatment program, and completed a Stop Signal Task (SST) while undergoing functional magnetic resonance imaging (fMRI). These individuals were prospectively followed for 1 year and assessed for relapse to methamphetamine use. Thirty-three percent of followed participants reported relapse. We found that neural activity associated with two types of Bayesian prediction error, i.e. the difference between actual and expected need to stop on a given trial, significantly differentiated those individuals who remained abstinent and those who relapsed. Specifically, relapsed individuals exhibited smaller neural activations to such Bayesian prediction errors relative to those individuals who remained abstinent in the left temporoparietal junction (Cohen's d = 0.91), the left inferior frontal gyrus (Cohen's d = 0.57), and left anterior insula (Cohen's d = 0.63). In contrast, abstinent and relapsed participants did not differ in neural activation to non-model based task contrasts or on various self-report clinical measures. In conclusion, Bayesian cognitive models may help identify predictive biomarkers of relapse, while providing a computational explanation of belief processing and updating deficits in individuals with methamphetamine use disorder.

An initial randomized controlled trial of behavioral activation for treatment of concurrent crystal methamphetamine dependence and sexual risk for HIV acquisition among men who have sex with men.

Men who have sex with men (MSM) continue to be the largest risk group for HIV infections in the U.S., where crystal methamphetamine abuse heightens risk for HIV infection through greater engagement in condomless anal sex (CAS). Existing treatments lack attention to replacement activities or the role of depressed mood. Behavioral activation (BA) is an evidence-based approach for depression that involves identifying and participating in pleasurable, goal-directed activities. We hypothesize, for MSM abusing crystal methamphetamine, re-learning how to engage in non-drug-using aspects of life would facilitate their ability to benefit from sexual risk reduction (SRR) counseling. Project IMPACT was a pilot randomized-controlled-trial. Forty-six MSM at sexual risk of acquiring HIV who met DSM-IV criteria for crystal methamphetamine dependence were enrolled. Of those MSM, 41 were randomized: 21 were assigned to the intervention, two sessions of SRR, ten sessions of BA with SRR, and one session of relapse prevention; 20 participants were assigned to a control condition (two sessions of SRR). At the acute post-intervention visit, intervention participants reported an average of 3.2 CAS acts with men who were HIV-infected or whose status they did not know, compared to 4.5 among control participants (ß = -0.36; 95% CI: -0.69, -0.02; p = 0.035). At the 6-month post-intervention visit, intervention participants reported 1.1 CAS acts with men who were HIV-infected or whose status they did not know compared to 2.8 among control participants (ß = -0.95; 95% CI: -1.44, -0.46; p < 0.0001). Similarly, intervention participants reported 1.0 CAS acts under the influence of crystal methamphetamine with men who were HIV-infected or whose status they did not know compared to 2.5 among control participants (ß = -0.87; 95% CI: -1.38, -0.36; p = 0.0005). Lastly, intervention participants reported more continuous days abstaining from crystal methamphetamine compared to control (50.1 vs. 39.0, respectively) (ß = 0.25; 95% CI: 0.16, 0.34; p < 0.0001). Findings are encouraging, provide evidence of feasibility and acceptability, and demonstrate initial efficacy for reducing sexual risk for HIV and crystal methamphetamine use.