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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (Copyright © 2021. Published by Elsevier B.V.)

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 R 2 = 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 ( β  = 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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

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 ± 3.1 kg/m 2 and age of 31.9 ± 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., (Copyright © 2019. Published by Elsevier Inc.)

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., (Published by Elsevier Inc.)

The first objective of the present study was to determine the appropriate dose of methamphetamine (Meth) to induce a successful conditioned place preference (CPP) in mice. The next objective was to examine the effect of a methanolic extract of M. citrifolia unripe fruit (MMC) against Meth-induced CPP in mice. In answering to the first objective, following the preconditioning test, an intraperitoneal injection of a fixed dose of Meth (0.5 or 1 or 2 mg/kg, i.p.) or saline (10 ml/kg, i.p.) was given on alternate days during the 10 days conditioning period followed by a postconditioning test conducted in Meth-free state. The first experiment revealed that 0.5 mg/kg of Meth could be an appropriate fixed low dose to induce CPP in mice. Meanwhile, in other experiments, the effect of MMC and bupropion (BUPR) against the expression, extinction, and reinstatement of Meth (0.5 mg/kg)-induced CPP in mice, respectively, was investigated. In a separate set of studies on each phase, an oral administration of MMC (1, 3 and 5 g/kg, p.o.) or BUPR (20 mg/kg, p.o.) was given 60 min prior to CPP postconditioning testing or extinction testing or reinstatement testing in mice. Extinction trials were conducted in Meth-free state to weaken CPP over the next 5 days. Reinstatement test was conducted by a single low dose priming injection of Meth (0.1 mg/kg, i.p.). The present study, however, failed to establish a successful extinction and reinstatement of Meth-CPP in mice. Further studies using other doses of Meth are warranted for a successful establishment of all phases of Meth CPP in mice. This study also demonstrates that MMC (3 and 5 g/kg, p.o.) and BUPR (20 mg/kg, p.o.) could attenuate the expression of Meth-induced CPP in mice., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Previous studies have suggested that varenicline, an α4β2 nicotinic receptor partial agonist, and α7 nicotinic receptor full agonist, may be effective for the treatment of methamphetamine (MA) dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. This study aimed to determine if varenicline (1 mg BID) resulted in reduced methamphetamine use compared to placebo among treatment-seeking MA-dependent volunteers., Methods: Treatment-seeking MA-dependent volunteers were randomized to varenicline 1 mg twice daily (n = 27) or placebo (n = 25) and cognitive behavioral therapy for 9 weeks. The primary outcomes were the proportion of participants achieving end-of-treatment-abstinence (EOTA, MA-negative urine specimens during weeks 8 and 9) and the treatment effectiveness score (TES, number of MA-negative urine specimens) for varenicline versus placebo., Results: There was no significant difference in EOTA between varenicline (15%, 4/27) and placebo (20%, 5/25; p = 0.9). There was some suggestion that urinary confirmed medication compliance corresponded with EOTA in the varenicline condition, though it did not reach statistical significance, OR = 1.57 for a 100 ng/ml increase in urine varenicline, p = 0.10, 95% CI (0.99, 3.02). There was no significant difference in mean TES in the varenicline condition (8.6) compared to the placebo condition (8.1), and treatment condition was not a statistically significant predictor of TES, IRR = 1.01, p = 0.9, 95% CI (0.39, 2.70)., Conclusions: The results of this study indicate that 1 mg varenicline BID was not an effective treatment for MA dependence among treatment-seeking MA-dependent volunteers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Methamphetamine dependence is associated with heightened impulsivity and diminished quality of life, but the link between impulsivity and changes in quality of life during treatment has not been examined. We aimed to investigate how different elements of impulsivity predict change in quality of life in the 6 weeks after engaging in treatment., Design: Longitudinal, observational cohort study., Setting: Public and private detoxification and rehabilitation facilities in metropolitan Melbourne, Australia., Participants: One hundred and eight individuals with methamphetamine dependence (81 male) tested within 3 weeks of commencing treatment; 80 (74%) were followed-up at 6 weeks., Measurements: The Continuous Performance Test-2 measured impulsive action (cognitive and motor impulsivity); the Delay Discounting Task measured impulsive choice. Quality of life was measured with the World Health Organization Quality of Life Scale-Brief, which includes social, psychological, physical and environment domains. Control variables included age, gender, estimated IQ, depression severity score, methamphetamine dependence severity score, cannabis dependence severity score and treatment modality., Findings: We found that all three forms of impulsivity were significant predictors of change in the social domain: motor impulsivity (β = -0.54, P = 0.013), cognitive impulsivity (β = -0.46, P = 0.029) and impulsive choice (β = -0.26, P = 0.019). Change in the psychological domain was predicted significantly by motor impulsivity (β = -0.45, P = 0.046). Control variables of age and depression were associated significantly with changes in the physical domain., Conclusions: In Australian methamphetamine-dependent individuals, elevated impulsivity predicts lower improvement of social and psychological quality of life in the first 6-9 weeks of treatment., (© 2017 Society for the Study of Addiction.)

Objective: This study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age., Method: T1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels., Results: Following correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers., Conclusions: Methamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment., (Published by Elsevier Inc.)

Background: Inattention is a deficit related to instilling abstinence from methamphetamine (MA) dependence. This study aimed to determine whether ibudilast (IB; 50mg bid) improves attentional abilities compared to placebo during early abstinence from MA dependence., Methods: Attention was assessed in 11 MA-dependent non-treatment seeking participants in a phase IB safety-interaction trial. The Conners' Continuous Performance Test-II (CPT-II), a measure of sustained attention and response inhibition, was administered at baseline and on day 22, 48h post a MA challenge under placebo (P; n=6) or IB 50mg bid (n=5). Group differences were compared using Mann-Whitney U Tests. Groups were similar at baseline in premorbid intellectual functioning, attention deficit hyperactivity symptom scores, impulsivity ratings, and education level, but differed in age. Demographically corrected T-scores for CPT-II performances were utilized., Results: Although no group differences in sustained attention existed at baseline, at follow-up, the IB group (Mdn=44.4) showed reduced variability in response times compared with the P group (Mdn=69.9), U=0.00, z=-2.74, p=.006, r=.83. The IB group (Mdn=45.8) also gave fewer perseverative responses than the P group (Mdn=67.0), U=2.00, z=-2.50, p=.01, r=.75. No other significant differences were observed., Conclusions: Findings suggest that IB may have a protective effect on sustained attention during early abstinence from MA dependence. This may guide thinking about mechanism of action should IB demonstrate efficacy as a treatment for MA dependence., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: The parvalbumin (PV)-containing subgroup of GABAergic neurons is particularly affected in schizophrenia and animal models of psychosis, including after methamphetamine (METH) administration. We investigated whether METH dependence and METH-induced psychosis may involve an effect on DNA methylation of the PVALB promoter., Materials & Methods: The methylation of a PVALB promoter sequence was determined in 100 METH-dependent and 102 control subjects using pyrosequencing., Results: A significant increase in PVALB methylation was observed in METH dependence and METH-induced psychosis. No significant effect on long interspersed nucleotide element-1 methylation, a measure of global DNA methylation, was observed., Conclusion: These results demonstrate a specific association between elevated PVALB methylation and METH-induced psychosis. This finding may contribute to the GABAergic deficits associated with METH dependence.

In this study, to study the effect of rhynchophylline on TH in midbrain of methamphetamine-induced conditioned place preference (CPP) adult zebrafish, place preference adult zebrafish models were established by methamphetamine (40μg/g) and the expression of TH was observed by immunohistochemistry technique and Western blot. Ketamine (150μg/g), high dose of rhynchophylline (100μg/g) group can significantly reduce the place preference; immunohistochemistry results showed that the number of TH-positive neurons in midbrain was increased in the methamphetamine model group, whereas less TH-positive neurons were found in the ketamine group and high dosage rhynchophylline group. Western blot results showed that the expression of TH protein was significantly increased in the model group, whereas less expression was found in the ketamine group, high dosage rhynchophylline group. Our data pointed out that TH plays an important role in the formation of methamphetamine-induced place preference in adult zebrafish. Rhynchophylline reversed the expression of TH in the midbrain demonstrates the potential effect of mediates methamphetamine induced rewarding effect., (Copyright © 2017 Elsevier B.V. All rights reserved.)

To compare the effects of heroin and methamphetamine (METH) addiction on dopamine transporters (DATs) in the same dose and duration, we assessed DAT levels in the striatum by 99m Tc-TRODAT-1 single-photon emission computed tomography (SPECT) brain images in people with heroin and METH dependence. We recruited 21 healthy human controls, 23 heroin-dependent subjects and 25 METH abusers. The heroin- and METH-dependent subjects exhibited negative urine toxicology after undergoing physiological detoxification. All subjects underwent SPECT brain imaging, and specific tracer uptake ratios (SURs) were assessed bilaterally in the regions of interest. A significant SUR reduction in heroin-dependent subjects and METH-dependent subjects compared with healthy controls was found in the left striatum, right striatum, left caudate nucleus, right caudate nucleus, left putamen and right putamen. There were no significant differences in the heroin group and METH group for the left striatum, right striatum, left caudate nucleus, right caudate nucleus, left putamen and right putamen. The scores of craving, HAMA (Hamilton Anxiety Rating Scale), in heroin abusers were lower than in the METH abusers. Our results show that people with heroin and METH dependence who are currently abstinent had lower DAT levels in the striatum than healthy controls. There were no differences in striatal DAT in heroin and METH users. These results suggest that chronic heroin and METH abuse appears to produce similar effects in striatal DAT in humans. METH users may have more serious craving and anxiety symptoms than heroin users with prolonged abstinence., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

White matter (WM) alterations have been reported in methamphetamine (MA) users. However, knowledge about longitudinal changes in WM during abstinence from MA remains unknown. The present study aimed to examine how WM changes in long-term MA abstinent, in particular, whether the WM deficits would recover as the duration of abstinence extended. Twenty male MA dependent individuals and 19 healthy controls (HCs) were recruited and participated in both clinical assessments and diffusion tensor imaging (DTI) scans. The MA group underwent two DTI scans, a baseline scan with a duration of abstinence of 6.4 months and and a follow-up scan with a duration of abstinence of 13.0 months. Tract-Based Spatial Statistics was utilized to conduct baseline DTI analysis of MA group compared with HCs. The clusters with significant group differences of factional anisotropy (FA) were extracted as region of interests (ROIs). Mean values of DTI measurements (FA, mean diffusivity, axial diffusivity and radial diffusivity) were calculated within the ROIs in each subject's native space at baseline and follow-up. The MA group showed significant lower FA in the right internal capsule and superior corona radiate than HCs. The deficits did not recover when the duration of abstinence from MA reached 13 months. No significant correlations were found between FA and clinical measurements. Our results suggested persistent microstructure deficits of WM tracts surrounding the basal ganglia in MA dependent individuals.

Others and we have reported that rhynchophylline reverses amphetamine-induced conditioned place preference (CPP) effect which may be partly mediated by amelioration of central neurotransmitters and N-methyl-d-aspartate receptor 2B (NR2B) levels in the rat brains. The current study investigated the inhibiting effects of rhynchophylline on methamphetamine-induced (METH-induced) CPP in adult zebrafish and METH-induced locomotor activity in tyrosine hydroxylase-green fluorescent protein (TH-GFP) transgenic zebrafish larvae and attempted to confirm the hypothesis that these effects were mediated via regulation of neurotransmitters and dopaminergic and glutamatergic systems. After baseline preference test (on days 1-3), zebrafish were injected intraperitoneally METH (on days 4, 6 and 8) or the same volume of fish physiological saline (on days 5 and 7) and were immediately conditioned. Rhynchophylline was administered at 12h after injection of METH. On day 9, zebrafish were tested for METH-induced CPP. Results revealed that rhynchophylline (100mg/kg) significantly inhibited the acquisition of METH-induced CPP, reduced the content of dopamine and glutamate and down-regulated the expression of TH and NR2B in the CPP zebrafish brains. Furthermore, the influence of rhynchophylline on METH-induced locomotor activity was also observed in TH-GFP transgenic zebrafish larvae. Results showed that rhynchophylline (50mg/L) treatment led to a significant reduction on the locomotor activity and TH expression in TH-GFP transgenic zebrafish larvae. Taken together, these data indicate that the inhibition of the formation of METH dependence by rhynchophylline in zebrafish is associated with amelioration of the neurotransmitters dopamine and glutamate content and down-regulation of TH and NR2B expression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To date, no medication has been approved as an effective treatment for methamphetamine dependence. Topiramate has attracted considerable attention as a treatment for the dependence on alcohol and stimulants. Therefore, this study aimed to evaluate the effect of topiramate for methamphetamine dependence. This study was a double-blind, randomized, placebo-controlled trial. In the present investigation, 62 methamphetamine-dependent adults were enrolled and randomized into two groups, and received topiramate or a placebo for 10 weeks in escalating doses from 50 mg/day to the target maintenance dose of 200 mg/day. Addiction severity index (ASI) and craving scores were registered every week. The Beck questionnaire was also given to each participant at baseline and every 2 weeks during the treatment. Urine samples were collected at baseline and every 2 weeks during the treatment. Fifty-seven patients completed 10 weeks of the trial. There was no significant difference between both groups in the mean percentage of prescribed capsules taken by the participants. At week six, the topiramate group showed a significantly lower proportion of methamphetamine-positive urine tests in comparison with the placebo group (P = 0.01). In addition, there were significantly lower scores in the topiramate group in comparison with the placebo group in two domains of ASI: drug use severity (P < 0.001) and drug need (P < 0.001). Furthermore, the craving score (duration) significantly declined in the topiramate patients compared to those receiving the placebo. In conclusion, the results of this trial suggest that topiramate may be beneficial for the treatment of methamphetamine dependence., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Background: Individuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride., Methods: The anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability., Results: Relative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects., Conclusions: The results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

This study was designed to examine the effect of environmental enrichment during METH administration on the behavioral withdrawal symptoms after drug abstinence in rats. Rats reared in standard (SE) or enriched environment (EE) during induction of METH dependence with bi-daily injections of METH (2mg/kg, at 12-h. intervals) for 14 days. Then, rats were evaluated for behavioral withdrawal symptoms, and also for anxiety (elevated plus maze-EPM) and depression (Forced swim test-FST) over a ten day period of abstinence. The results showed that stereotypic behaviors score and the number of rearing were significantly lower in METH/EE rats compared to the SE group during 1-4 days. Also, The METH/EE group exhibited more weight gain during 6-10 days of abstinence. The METH/EE rats exhibited lower levels of immobility after METH abstinence than control group in the FST. EE had no effect on anxiety-like behavior. This study showed that exposure to EE diminished the severity of withdrawal symptoms and depressive-like behavior during spontaneous withdrawal from METH., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Growing evidence suggests abnormalities in brain morphology including hippocampal structure in patients with methamphetamine (MA) dependence. This study was performed to examine hippocampal volume in abstinent MA users, and to further explore its relationship with cognitive function. 30 abstinent MA users (20 males and 10 females) with average 5.52 months of duration of abstinence and 29 healthy controls (19 males and 10 females) age 18-45 years old were recruited for clinical assessment and imaging scan. FreeSurfer was used to segment the hippocampus bilaterally, and hippocampal volumes were extracted for group and gender comparisons. Cognitive function was measured using the CogState Battery Chinese language version (CSB-C). Analysis of covariance (ANCOVA) controlling for education showed a significant group by gender interaction for the right hippocampal relative volume adjusted for total brain size (p = 0.020); there was a significant difference between male controls and female controls (p < 0.001), but such a difference did not exist between male patients and female patients (p = 0.203). No significant correlations were found between hippocampal volume and cognitive measures. There seems to be a gender difference in how MA affects hippocampal volume in abstinent MA users. Hippocampus might be an important treatment target for cognitive improvement and functional recovery in this patient population, especially in females., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: High level of impulsivity as well as depression is thought to be involved in the maintenance and development of methamphetamine (METH) addiction. However, the relationship between impulsivity and depression has not been studied thoroughly in METH dependence subjects, especially in early METH abstinent subjects. In this study, our objective is to explore the interplay between the depressive symptoms and impulsivity in early METH abstinent subjects., Methods: A total of 182 early abstinent METH dependent subjects (abstinence for 1-7 days) were recruited and the level of impulsivity was measured by the Barratt Impulsiveness Scale (BIS-11). Depressive symptoms and anxiety symptoms were assessed by the short 13-item Beck Depression Inventory (BDI-13) and Beck Anxiety Inventory (BAI) respectively., Results: Global impulsivity of BIS-11 was significantly correlated with depressive symptoms among early METH abstinent subjects (r=0.283, p=0.001). Moreover, all subscales of BIS-11 were also found to be correlated with depressive symptoms: correlation with attentional impulsivity (r=0.202, p=0.006); correlation with motor impulsivity (r=0.267, p=0.001); and correlation with non-planning impulsivity (r=0.177, p=0.017)., Conclusions: This study showed a relationship between impulsivity and depression, which may further the comprehension of motivational elements contributing to the maintenance and development of METH use disorder. Future research would be dedicated to exploring underlying mechanisms of association between impulsivity and depression., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: Association of the brain-derived neurotrophic factor (BDNF) genetic polymorphism rs6265 (Val66Met) with methamphetamine (METH) dependence and METH-induced psychosis was investigated in the Thai population., Materials & Methods: The rs6265 genotype was determined in 100 male METH-dependent subjects and 102 controls using a real-time PCR high-resolution melt (RT-PCR-HRM) assay., Results: The rs6265 genotype demonstrated significant differences in distribution between METH-dependent subjects and controls in which the frequency of GG genotype versus A-allele carriers was associated with METH dependence. Moreover, a significant effect of genotype on the occurrence of psychosis was found, with a lower frequency of GG genotype associated with METH-induced psychosis., Conclusion: The present findings indicate that rs6265 is associated with METH dependence in the Thai population, with the GG genotype greater in METH-dependent subjects but reducing the emergence of METH-dependent psychosis.

Objective: Depression among methamphetamine users is more prevalent in females than males, but gender-specific treatment options for this comorbidity have not been described. Reduced brain phosphocreatine levels have been shown to be lower in female methamphetamine users compared to males, and, of relevance, studies have demonstrated an association between treatment-resistant depression and reduced brain phosphocreatine concentrations. The nutritional supplement creatine monohydrate has been reported to reduce symptoms of depression in female adolescents and adults taking antidepressants, as well as to increase brain phosphocreatine in healthy volunteers. Therefore, the purpose of this pilot study was to investigate creatine monohydrate as a treatment for depression in female methamphetamine users., Methods: Fourteen females with depression and comorbid methamphetamine dependence were enrolled in an 8-week open label trial of 5 g of daily creatine monohydrate and of these 14, 11 females completed the study. Depression was measured using the Hamilton Depression Rating Scale (HAMD) and brain phosphocreatine levels were measured using phosphorus magnetic resonance spectroscopy pre- and post-creatine treatment. Secondary outcome measures included anxiety symptoms, measured with the Beck Anxiety Inventory (BAI), as well as methamphetamine use, monitored by twice weekly urine drug screens and self-reported use., Results: The results of a linear mixed effects repeated measures model showed significantly reduced HAMD and BAI scores as early as week 2 when compared to baseline scores. This improvement was maintained through study completion. Brain phosphocreatine concentrations were higher at the second phosphorus magnetic resonance spectroscopy scan compared to the baseline scan; Mbaseline = 0.223 (SD = 0.013) vs. Mpost-treatment = 0.233 (SD = 0.009), t (9) = 2.905, p <.01, suggesting that creatine increased phosphocreatine levels. Also, a reduction in methamphetamine positive urine drug screens of greater than 50% was observed by week 6. Finally, creatine was well tolerated and adverse events that were related to gastrointestinal symptoms and muscle cramping were determined as possibly related to creatine., Conclusions: The current study suggests that creatine treatment may be a promising therapeutic approach for females with depression and comorbid methamphetamine dependence. This study is registered on clinicaltrials.gov (NCT01514630).

Background: Effective 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., Methods: This 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., Conclusions: Seeking 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We investigated the differential influence of family dysfunction on alcohol and methamphetamine dependence in Japan using the Addiction Severity Index (ASI), a useful instrument that multilaterally measures the severity of substance dependence. The participants in this study were 321 male patients with alcohol dependence and 68 male patients with methamphetamine dependence. We conducted semi-structured interviews with each patient using the ASI, which is designed to assess problem severity in seven functional domains: Medical, Employment/Support, Alcohol use, Drug use, Legal, Family/Social relationships, and Psychiatric. In patients with alcohol dependence, bad relationships with parents, brothers and sisters, and friends in their lives were related to current severe psychiatric problems. Bad relationships with brothers and sisters and partners in their lives were related to current severe employment/support problems, and bad relationships with partners in their lives were related to current severe family/social problems. The current severity of psychiatric problems was related to the current severity of drug use and family/social problems in patients with alcohol dependence. Patients with methamphetamine dependence had difficulty developing good relationships with their father. Furthermore, the current severity of psychiatric problems was related to the current severity of medical, employment/support, and family/social problems in patients with methamphetamine dependence. The results of this study suggest that family dysfunction differentially affects alcohol and methamphetamine dependence. Additionally, family relationships may be particularly related to psychiatric problems in these patients, although the ASI was developed to independently evaluate each of seven problem areas.

Aims Design, setting and participants Interventions Measurements Findings Conclusions This study tested the efficacy and safety of a 12‐week course of lisdexamfetamine in reducing methamphetamine use, an outcome which is associated with improvements in health and wellbeing, in people dependent on methamphetamine.This study was a randomised double‐blind placebo‐controlled trial conducted in six specialist outpatient clinics in Adelaide, Melbourne, Newcastle and Sydney, Australia (2018–2021). Participants were164 adults with methamphetamine dependence, reporting at least 14 use days out of the previous 28 days (62% male, 38% female, < 1% other; mean age 39 years).Participants were randomly allocated 1:1 to a 15‐week regimen of lisdexamfetamine (1‐week induction to 250 mg, 12‐week maintenance regimen, 2‐week reduction; n = 80) or matched placebo (n = 84), followed‐up to Week 19.The primary efficacy measure was past 28‐day methamphetamine use at Week 13. Safety was assessed by adverse event rates. Secondary measures included methamphetamine use during the 12‐week treatment period and treatment satisfaction.Nine randomized participants did not start treatment (five were allocated to lisdexamfetamine and four allocated to placebo) and were excluded from the analyses. Fifty‐seven per cent of participants were retained on study medication to primary end‐point. There was only weak evidence of a lisdexamfetamine benefit at 13 weeks [adjusted difference in days of methamphetamine use = 2.2, 95% confidence interval (CI) = –0.5 to 5.0; P = 0.49]. However, throughout the whole 12‐week treatment maintenance phase, the lisdexamfetamine group had fewer days of methamphetamine use in total (difference = 8.8, 95% CI = 2.7–15.0; P = 0.005). The lisdexamfetamine group reported greater self‐reported treatment effectiveness [odds ratio (OR) = 2.89, 95% CI = 1.67–5.02; P < 0.001] and treatment satisfaction (OR = 3.80, 95% CI = 1.93–7.47; P < 0.001). Adverse events with lisdexamfetamine included nausea. Serious adverse events occurred in four (5%) of participants who received lisdexamfetamine.Lisdexamfetamine appears to reduce methamphetamine use over a 12‐week treatment period, although there is only weak evidence that reduced use is maintained during the last 4 weeks. [ABSTRACT FROM AUTHOR]

Methamphetamine (MA) dependence leads to severe physical and psychological issues. Current treatments, including psychosocial therapies and residential rehabilitation, face limitations such as high relapse rates, cost, and accessibility issues. As a result, there is an urgent need for novel approaches to treat MA dependence that are effective, affordable, and accessible to patients. Psilocybin, the active component in numerous mushrooms of the Psilocybe genus, has shown potential for enhancing psychotherapy for various addiction and mental health issues due to its effects on perception, cognition, and affect. Psilocybin-assisted psychotherapy (PAT) has demonstrated initial safety and efficacy in treating alcohol, cocaine, and nicotine dependence. The case presented here describes a 36-year-old transwoman and daily MA user, who participated in a single-arm open-label clinical trial assessing feasibility and safety of PAT for MA dependence at St. Vincent's Hospital, Sydney. Following inpatient withdrawal management and one session of psilocybin-assisted therapy, she experienced significant cognitive and emotional shifts and sustained MA abstinence. She reported improved mental health over 3 months following treatment completion. She also noted increased self-esteem, mindfulness, and distress tolerance. This study suggests that PAT (following inpatient MA withdrawal management) may offer a scalable, safe, and effective approach for treating MA dependence. However, further research is required to confirm the generalisability and efficacy of PAT for broader populations of people using MA. It is encouraging that this participant, a daily MA user, showed improvements in mood and cognition, in addition to abstinence from MA. [ABSTRACT FROM AUTHOR]

The ability to maintain and manipulate sequential information in working memory, referred to as sequential working memory, plays a vital role in our daily life. While research has shown that methamphetamine abuse affects the neural substrates and the overall functioning of working memory, its specific impact on sequential working memory remains unclear. In this study, we asked 62 abstinent methamphetamine-dependent participants and 59 control participants to complete a digit ordering task in which they saw four digits one-by-one over time and subsequently rearranged them in ascending order. The four digits were presented either randomly in the experimental condition or in ascending order in the control condition. Results show that methamphetamine-dependent participants performed worse than the controls in the experimental condition in which sequential working memory was needed to complete the task, but not in the control condition in which only short-term memory was needed. This finding demonstrates that methamphetamine abuse impairs sequential working memory. [ABSTRACT FROM AUTHOR]

The ability to maintain and manipulate sequential information in working memory, referred to as sequential working memory, plays a vital role in our daily life. While research has shown that methamphetamine abuse affects the neural substrates and the overall functioning of working memory, its specific impact on sequential working memory remains unclear. In this study, we asked 62 abstinent methamphetamine-dependent participants and 59 control participants to complete a digit ordering task in which they saw four digits one-by-one over time and subsequently rearranged them in ascending order. The four digits were presented either randomly in the experimental condition or in ascending order in the control condition. Resul ts show that methamphetamine-dependent participants performed worse than the controls in the experimental condition in which sequential working memory was needed to complete the task, but not in the control condition in which only short-term memory was needed. This finding demonstrates that methamphetamine abuse impairs sequential working memory. [ABSTRACT FROM AUTHOR]

Currently, there is no confirmed drug intervention in the treatment of methamphetamine (MA) dependence. In the present study, we tested the possible influence of venlafaxine in individuals with MA dependence. A total of 52 male patients (mean age: 33.93 years) diagnosed with MA dependence referred to Farabi Hospital in Kermanshah, Iran, was randomly assigned either to enlafaxine or a placebo condition. At the baseline, as well as 4 to 8 weeks later, patients completed questionnaires on depression, withdrawal symptoms, and cravings. The mean scores of withdrawal symptoms (hyperarousal, anxiety, reversed vegetative), depression, and cravings (desire & intention, negative reinforcement, and control) during the study and in both groups had a descending trend. Unlike the effect of the studied groups, the effect of time on the repeated measure model was significant. The mean of inverse symptoms, desire, and control from the fourth week to the end of the study did not have a statistically significant difference. The results showed that venlafaxine can be effective in reducing depression, withdrawal symptoms, and cravings in people who are dependent on MA, though these results were observed in parallel in the placebo group, and as such warrants further study. [ABSTRACT FROM AUTHOR]

IntroductionDenial, 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.MethodsThis 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.ResultsSCID 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).ConclusionsThe 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.

IntroductionInteroception, 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.MethodsEighty-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.ResultsOverall, 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.ConclusionsOur 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.

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 (Cohens d = 0.91), the left inferior frontal gyrus (Cohens d = 0.57), and left anterior insula (Cohens 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.

BackgroundPrevious studies have suggested that varenicline, an α4β2 nicotinic receptor partial agonist, and α7 nicotinic receptor full agonist, may be effective for the treatment of methamphetamine (MA) dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. This study aimed to determine if varenicline (1 mg BID) resulted in reduced methamphetamine use compared to placebo among treatment-seeking MA-dependent volunteers.MethodsTreatment-seeking MA-dependent volunteers were randomized to varenicline 1 mg twice daily (n = 27) or placebo (n = 25) and cognitive behavioral therapy for 9 weeks. The primary outcomes were the proportion of participants achieving end-of-treatment-abstinence (EOTA, MA-negative urine specimens during weeks 8 and 9) and the treatment effectiveness score (TES, number of MA-negative urine specimens) for varenicline versus placebo.ResultsThere was no significant difference in EOTA between varenicline (15%, 4/27) and placebo (20%, 5/25; p = 0.9). There was some suggestion that urinary confirmed medication compliance corresponded with EOTA in the varenicline condition, though it did not reach statistical significance, OR = 1.57 for a 100 ng/ml increase in urine varenicline, p = 0.10, 95% CI (0.99, 3.02). There was no significant difference in mean TES in the varenicline condition (8.6) compared to the placebo condition (8.1), and treatment condition was not a statistically significant predictor of TES, IRR = 1.01, p = 0.9, 95% CI (0.39, 2.70).ConclusionsThe results of this study indicate that 1 mg varenicline BID was not an effective treatment for MA dependence among treatment-seeking MA-dependent volunteers.

ObjectiveThis study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.MethodT1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.ResultsFollowing correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.ConclusionsMethamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.

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. [ABSTRACT FROM AUTHOR]

ObjectivesThis 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder.MethodsThe study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP; Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported ≥20 days of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9.ResultsAnalyses evaluated effects of XR-NTX + BRP to determine the number of "responders" according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield ≥3 responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2).ConclusionsUnder the statistical analysis plan, study "success" required ≥9 responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study.

Longitudinal cohort studies of HIV and substance use disorders play an important role in understanding these conditions, but high rates of attrition can threaten their integrity and generalizability. This study aimed to identify factors associated with attrition in a 5-year observational cohort study of 469 individuals with and without HIV infection and methamphetamine (MA) dependence. Rates of attrition in our four study groups were approximately 24% in HIV-MA-, 15% in HIV+MA-, 56% in HIV-MA+, and 47% in HIV+MA+ individuals. Predictors of attrition in the overall cohort included history of MA, alcohol, and other substance dependence, learning impairment, reduced cognitive reserve, and independence in activities of daily living (all ps < .05), but varied somewhat by clinical group. Of particular note, enrollment in a neuroimaging substudy was associated with significantly boosted rates of retention in the MA groups. Results from this investigation highlight the complexity of the clinical factors that influence retention in cohort studies of HIV-infected MA users and might guide the development and implementation of targeted retention efforts.

BackgroundNearly half of individuals with substance use disorders relapse in the year after treatment. A diagnostic tool to help clinicians make decisions regarding treatment does not exist for psychiatric conditions. Identifying individuals with high risk for relapse to substance use following abstinence has profound clinical consequences. This study aimed to develop neuroimaging as a robust tool to predict relapse.Methods68 methamphetamine-dependent adults (15 female) were recruited from 28-day inpatient treatment. During treatment, participants completed a functional MRI scan that examined brain activation during reward processing. Patients were followed 1 year later to assess abstinence. We examined brain activation during reward processing between relapsing and abstaining individuals and employed three random forest prediction models (clinical and personality measures, neuroimaging measures, a combined model) to generate predictions for each participant regarding their relapse likelihood.Results18 individuals relapsed. There were significant group by reward-size interactions for neural activation in the left insula and right striatum for rewards. Abstaining individuals showed increased activation for large, risky relative to small, safe rewards, whereas relapsing individuals failed to show differential activation between reward types. All three random forest models yielded good test characteristics such that a positive test for relapse yielded a likelihood ratio 2.63, whereas a negative test had a likelihood ratio of 0.48.ConclusionsThese findings suggest that neuroimaging can be developed in combination with other measures as an instrument to predict relapse, advancing tools providers can use to make decisions about individualized treatment of substance use disorders.

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. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is prevalent among individuals, especially women, with methamphetamine dependence. Although aerobic exercise has been shown to affect cognitive function in humans and animals, few related studies have focused on subjects with methamphetamine dependence. Purpose: The aim of this study was to assess the detoxification-related effects of aerobic exercise on cognitive function in women with methamphetamine dependence. Methods: A randomized controlled trial was used with 98 women with methamphetamine dependence undergoing a detoxification program at a mental hospital. The women were distributed using a computer-generated grouping random method into either the study or control group. The investigator conducting the baseline questionnaire, the neuropsychologist assessing the cognitive function, and the data analyst were blinded to group assignment. In addition to hospital routine care, the study group received an aerobic exercise intervention for 3 months. The control group only received hospital routine care. Attention and working memory were measured using the Trail Making Test and Digit Span Test, verbal memory was measured using Logical Memory (LM) and Memory for Persons Data (MPD), and executive function was measured using the Color-Word Stroop Test. Results: Forty-nine participants were randomized into each group, and the valid data of 43 participants in the study group and 46 in the control group were analyzed. The study group showed significantly more improvement over time in terms of Digit Span Test, Trail Making Test, LM-delayed, MPD-5 minutes delayed, MPD-30 minutes delayed, and Color-Word Stroop Test than the control group (p <.05). LM-immediate and MPD-immediate scores showed that the effects of time and the interaction between time and group were significant but that the main effect of group was not. Conclusions/Implications for Practice: Women undergoing detoxification for methamphetamine dependence may practice aerobic exercise to improve attention, working memory, executive function, and parts of verbal memory. Aerobic exercise may be incorporated into detoxification treatment programs to facilitate the recovery of cognitive functions in women. [ABSTRACT FROM AUTHOR]

BackgroundMethamphetamine (METH) use and human immunodeficiency virus (HIV) infection are highly comorbid, and both are associated with increased prevalence of affective distress. Delineating the trajectory of affective distress in the context of METH dependence and HIV infection is important given the implications for everyday functional impairment, adverse health behaviors, and increased risk for adverse health outcomes.MethodsWe conducted a five-year longitudinal investigation involving 133 METH-dependent (74 HIV seropositive) and 163 non-METH-dependent (90 HIV seropositive) persons to examine both long-standing patterns and transient changes in affective distress. Mixed-effect regression models with random subject-specific slopes and intercepts evaluated the effect of METH dependence, HIV serostatus, and related variables on affective distress, as measured by the Profile of Mood States.ResultsTransient changes in affective distress were found to be greater among those with a diagnosis of current MDD, briefer durations of abstinence from METH, and higher quantity of METH consumed. Weak associations were observed among static (time-independent predictors) covariates and long-standing patterns in affective distress.LimitationsStudy lacked data pertaining to the participants' involvement in METH treatment and relied on respondent-driven sampling.ConclusionsOur longitudinal investigation of the trajectory of affective distress indicated that specific and dynamic indices of current METH use were associated with greater transient changes in mood. In the evaluation and treatment of affective distress, recency and quantity of current METH use are important to consider given their association with heightened affective distress and mood instability over time.

Purpose: Methamphetamine is a powerful, highly addictive stimulant which affects the central nervous system. Therefore, this study was aimed at evaluating the efficacy of modafinil in the treatment of patients with MA dependence. Methods: A randomized parallel controlled trial study was designed to compare the effectiveness of take-home, self-administered modafinil treatment in the intervention group and the controlled group in three months. The primary outcome measurements were severity and duration of craving, and selfreported methamphetamine consumption, as confirmed by urine drug test. Results: The relapse rate was 40 and 75% in the intervention and controlled groups, respectively, indicating a decrease in relapse rate of MA in the intervention group (p < 0.05). During the three months, the severity and the duration of drug abuse craving in the intervention group were less than in the controlled group. Patients in the intervention group experienced an increase in retention rate and a decrease in slip rate (p < 0.05) Conclusion: The use of modafinil is not only effective on craving and relapse reduction, but also changes urine drug screens of patients with MA dependence to negative. Thus, modafinil is safely indicated as an effective medication to reduce withdrawal symptoms and the craving of patients with MA dependence. [ABSTRACT FROM AUTHOR]

Aims: Pharmacotherapy for methamphetamine dependence has not yet been developed in Japan or elsewhere in the world. Ifenprodil is a blocker of G protein‐activated inwardly rectifying potassium channels that play a key role in the mechanism of action of addictive substances. Our aim is to examine the safety, efficacy, and outcomes of ifenprodil for the treatment of methamphetamine dependence in a randomized, double‐blind, placebo‐controlled trial. Methods: The recruitment of outpatients with methamphetamine dependence began in January 2018. The patients will be randomized into three arms: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. Placebo or ifenprodil will be taken for 84 days. We will use Cerocral fine granule 4%® (ifenprodil tartrate). Follow‐up assessments will be conducted for 84 d after the drug administration period. All of the patients will be assessed by self‐administered questionnaires and urine tests. The primary outcome will be the presence or absence of methamphetamine use during the 84‐day administration period in the 120 mg/d ifenprodil and placebo groups. Secondary outcomes will include the number of days and percentage of days of abstinence from methamphetamine use, positive urine for methamphetamine, relapse risk, and drug craving. Discussion: This study is the first clinical trial of ifenprodil treatment for methamphetamine dependence and is designed as an intervention test with off‐label drug use. The present study is expected to provide evidence of the effects of ifenprodil treatment on methamphetamine dependence. Trial registry: This trial was registered in the UMIN clinical trial registry (UMIN000030849; date of registration: January 17, 2018). [ABSTRACT FROM AUTHOR]

Abstract The first objective of the present study was to determine the appropriate dose of methamphetamine (Meth) to induce a successful conditioned place preference (CPP) in mice. The next objective was to examine the effect of a methanolic extract of M. citrifolia unripe fruit (MMC) against Meth-induced CPP in mice. In answering to the first objective, following the preconditioning test, an intraperitoneal injection of a fixed dose of Meth (0.5 or 1 or 2 mg/kg, i.p.) or saline (10 ml/kg, i.p.) was given on alternate days during the 10 days conditioning period followed by a postconditioning test conducted in Meth-free state. The first experiment revealed that 0.5 mg/kg of Meth could be an appropriate fixed low dose to induce CPP in mice. Meanwhile, in other experiments, the effect of MMC and bupropion (BUPR) against the expression, extinction, and reinstatement of Meth (0.5 mg/kg)-induced CPP in mice, respectively, was investigated. In a separate set of studies on each phase, an oral administration of MMC (1, 3 and 5 g/kg, p.o.) or BUPR (20 mg/kg, p.o.) was given 60 min prior to CPP postconditioning testing or extinction testing or reinstatement testing in mice. Extinction trials were conducted in Meth-free state to weaken CPP over the next 5 days. Reinstatement test was conducted by a single low dose priming injection of Meth (0.1 mg/kg, i.p.). The present study, however, failed to establish a successful extinction and reinstatement of Meth-CPP in mice. Further studies using other doses of Meth are warranted for a successful establishment of all phases of Meth CPP in mice. This study also demonstrates that MMC (3 and 5 g/kg, p.o.) and BUPR (20 mg/kg, p.o.) could attenuate the expression of Meth-induced CPP in mice. [ABSTRACT FROM AUTHOR]