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This study investigated whether neurofeedback (NFB) training and swimming exercise (Swim) would reduce the stress, anxiety, depression, severity of dependence, and cravings in patients addicted to methamphetamines. Participants were allocated randomly to four groups: control group, NFB, Swim, and NFB/Swim. All groups completed the study questionnaire before and after treatment. The NFB, Swim, and NFB/Swim groups reported significantly less stress, cravings, and severity of dependence than the control group. The Swim and NFB/Swim groups had significantly lower depression scores than the control group. Also, the NFB/Swim group experienced less anxiety than the control group. However, the NFB/Swim group had lower levels of stress than the Swim group, and lower levels of anxiety and severity of dependence than the NFB group. These findings suggest that NFB training along with swimming exercise was effective in managing methamphetamine-related behavioral disturbances, which may help patients to manage their cravings. [ABSTRACT FROM AUTHOR]

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]

Background: Goutengsan (GTS) is a traditional Chinese medicine formula that can improve multiple nervous system diseases, such as methamphetamine (MA) dependence. However, the mechanism how GTS treats MA dependence remains unclear. This study was aimed to investigate the action mechanism of GTS on MA dependence using network pharmacology, in vivo / in vitro experimental validation, pharmacokinetics, and tissue distribution in the brain. Materials and Methods: The bioactive ingredients from GTS and possible targeted genes for treating MA dependence were predicted using network pharmacology. The binding of key components of GTS to the predicted proteins was studied using molecular docking, and the key components were verified by HPLC. The effects of GTS on an MA-induced model in rats and SH-SY5Y cells were studied. The regulatory effects of GTS on the expressions of predicted MAPK pathway-related proteins in rat brain tissues and SH-SY5Y cells were validated. Furthermore, the plasma exposure and brain tissue distribution of GTS ingredients for MA dependence treatment and MAPK pathway regulation were studied in mice. Results: Network pharmacology screened 53 active ingredients, and 287 potential targets of GTS, and showed the MAPK pathway was among the most relevant pathways. Molecular docking showed that key active ingredients (e.g., 6-gingerol, liquiritin and rhynchophylline) bound strongly with MAPK core targets, such as MAPK3, and MAPK8. Five compounds of GTS were detected by HPLC, including 6-gingerol, chlorogenic acid, liquiritin, 5-o-methylviscumaboloside and hesperidin. GTS had a therapeutic effect on MA-dependent rats, and reduced hippocampal CA1 damage and relative expressions of p-MAPK3/MAPK3, p-MAPK8/MAPK8 in brain tissues induced by MA. GTS counteracted aberrant alterations in cAMP, 5-TH and cellular morphology induced by MA induction and exerts therapeutic effects on MA-induced SH-SY5Y cell models. GTS also can antagonize the high expressions of MAPK-related proteins in MA-induced SH-SY5Y cells. Pharmacokinetic experiment revealed the four ingredients of GTS (e.g., chlorogenic acid, 5-o-methylviscumaboloside, hesperidin and rhynchophylline) were exposed in the plasma and brain, which demonstrates its pharmacological effect on MA dependence. Conclusion: GTS treats MA dependence by regulating the MAPK pathway via multiple bioactive ingredients. The network pharmacology, experimental validation and pharmacokinetics integrated strategy is efficient in discovering the key pharmacological mechanism of herbal formulae. [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]

Objective: To explore the relationship between relapse tendency and psychological craving in female methamphetamine (MA)-dependent young adults, focusing on the roles of self-control and future time perspective. Methods: A total of 340 MA-dependent young adults from two women's compulsory isolation drug rehabilitation centers in Sichuan Province were included. Participants were assessed with the Relapse Tendency Questionnaire (RTQ), Obsessive Compulsive Drug Use Scale (OCDUS), Drug Abuser Self-Control Ability Questionnaire (DASAQ) and General Future Time Perspective Scale (GFTPQ). The moderated mediation model was analyzed by using the SPSS macro program PROCESS (version4. 2). Results: The RTQ scores were positively correlated with the OCDUS scores (r=0.45, P<0.001). The DASAQ scores partially mediated the relationship between the scores of OCDUS and RTQ. accounted for 37.91% of the total effect. The GFTP scores moderated the relationship between the scores of the OCDUS, DASAQ and RTQ (B=0. 18. 0. 19, P<0.001). Conclusion: The influence of psychological craving on relapse tendency in female MA-dependent young adults exhibits a moderated mediating effect, suggesting the potential of enhancing self-control and future time perspective for preventing relapse and improving detoxification efficiency. [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.

BackgroundGoutengsan (GTS) is a traditional Chinese medicine formula that can improve multiple nervous system diseases, such as methamphetamine (MA) dependence. However, the mechanism how GTS treats MA dependence remains unclear. This study was aimed to investigate the action mechanism of GTS on MA dependence using network pharmacology, in vivo/in vitro experimental validation, pharmacokinetics, and tissue distribution in the brain.Materials and MethodsThe bioactive ingredients from GTS and possible targeted genes for treating MA dependence were predicted using network pharmacology. The binding of key components of GTS to the predicted proteins was studied using molecular docking, and the key components were verified by HPLC. The effects of GTS on an MA-induced model in rats and SH-SY5Y cells were studied. The regulatory effects of GTS on the expressions of predicted MAPK pathway-related proteins in rat brain tissues and SH-SY5Y cells were validated. Furthermore, the plasma exposure and brain tissue distribution of GTS ingredients for MA dependence treatment and MAPK pathway regulation were studied in mice.ResultsNetwork pharmacology screened 53 active ingredients, and 287 potential targets of GTS, and showed the MAPK pathway was among the most relevant pathways. Molecular docking showed that key active ingredients (e.g., 6-gingerol, liquiritin and rhynchophylline) bound strongly with MAPK core targets, such as MAPK3, and MAPK8. Five compounds of GTS were detected by HPLC, including 6-gingerol, chlorogenic acid, liquiritin, 5-o-methylviscumaboloside and hesperidin. GTS had a therapeutic effect on MA-dependent rats, and reduced hippocampal CA1 damage and relative expressions of p-MAPK3/MAPK3, p-MAPK8/MAPK8 in brain tissues induced by MA. GTS counteracted aberrant alterations in cAMP, 5-TH and cellular morphology induced by MA induction and exerts therapeutic effects on MA-induced SH-SY5Y cell models. GTS also can antagonize the high expressions of MAPK-related proteins in MA-induced SH-SY5Y cells. Pharmacokinetic experiment revealed the four ingredients of GTS (e.g., chlorogenic acid, 5-o-methylviscumaboloside, hesperidin and rhynchophylline) were exposed in the plasma and brain, which demonstrates its pharmacological effect on MA dependence.ConclusionGTS treats MA dependence by regulating the MAPK pathway via multiple bioactive ingredients. The network pharmacology, experimental validation and pharmacokinetics integrated strategy is efficient in discovering the key pharmacological mechanism of herbal formulae.

Introduction: New knowledge was projected into the ICD-11 classification in clinical manifestation of mental disorder associated with gambling. The independent diagnostic category of gambling disorder according to ICD-11 should not be assessed, contrary to pathological gambling in ICD-10, if the onset of impaired control over gambling behaviour is corresponding to use of the methamphetamines. The aim of the study: To detect the prevalence of gambling/pathological gambling according to ICD-10 classification among methamphetamine users with dependence in treatment, and with selected micro case-illustrations indicate the necessity to revise the diagnosis by the implementation of new ICD-11criteria. Patients and methods: It was retrospective, descriptive, clinical study of the medical records of 178 patients treated for methamphetamine dependence with the addition of three selected micro case-illustrations, which provided the opportunity to present different diagnostic assessment according to ICD-11 and its patognomic significance. results: Gambling behaviour was detected in 30% of the patients treated for dependence on methamphetamines, in the same time 18% had the the diagnosis of pathological gambling according to ICD-10. The new diagnostic approach according to ICD-11 was documented with use of qualitative method by three micro case-illustrations. Discussion and conclusion: The findings of the study have shown the high prevalence of the impaired control over gambling behaviour among the patients in treatment due to dependence on methamphetamines, which in large part of them, had the neurobiological base due to the direct effects of dopamine on the CNS, so as it is sometimes in the treatment of Parkinson disease by dopamine agonists. According to ICD-11 it is not an independent diagnostic category, but it is only behavioural sign induced by psychoactive substance. Finally, the authors are discussing the consequences of the change in diagnostic assessment and the number of inevitable changes in the clinical practice after the adoption of ICD-11. [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]

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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. [ABSTRACT FROM AUTHOR]

Objective　 To investigate the effects of different dosages of gastrodin onTLR4/ MyD88 / NFκB signal pathway in the hippocampus of methamphetamine (meth)dependence rats. Methods　The conditioned place preference (CPP) model of meth was established, meth (10mg/kg) was administered (i.p, 14 d), and then, different dosages (10, 30, 100 mg/kg) of gastrodin were used to intervene in 14 days. Western blotting and RTqPCR were used to explore the expression level of protein and mRNA of key factors in TLR4/ MyD88 / NF-κB signal pathway in hippocampus. Results　Gastrodin decreased the protein and mRNA expression of TLR4, MyD88, TRAF6, NF-κBp65 in a dose-dependent manner (P < 0.001, P < 0.01 or P < 0.05), and the protein expression of p-NF-κB p65 was reduced with showing a significant dose-response relationship ( P < 0.01 or P < 0.05) . Gastrodin increased the protein and mRNA expression of IκB-α with showing a significant dose-response relationship ( P < 0.01 or P < 0.05) . Gastrodin reduced the protein expression of p-IκB-α ( P < 0.01) . Conclusion　Gastrodin intervention has a protective effect against hippocampal neuroinflammation in methamphetamine-dependent CPP rats, and is closely related to the function of TLR4/MyD88/NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Objective　To study the effect of TLR4/MyD88/NF- κB signal pathway on the hippocampus of methamphetamine (MA) dependent conditioned place preference (CPP) rats, and inhibition of Toll like receptor 4 (TLR4) by specific inhibitor TAK-242, thereby reducing MA induced hippocampal neuroinflammation. Methods 　We established a model of MA (10 mg/kg, ip, 14 d) dependent CPP in rats. Rats were randomly divided into 4 groups： normal saline group, MA group, TAK-242 group, and MA+TAK-242 group. TAK-242 group and MA+TAK-242 group were intraperitoneally injected with inhibitor TAK-242 (3 mg/kg), and MA+TAK-242 group was intraperitoneally injected with MA (10 mg/kg) one hour later. Protein and mRNA expression of TLR4, MyD88, TRAF6, IκB- α, p-IκB- α, NF- κ B p65, p-NF-Κb p65 in hippocampus of MA dependent CPP rats were tested by Western Blot test and fluorescent quantitative PCR, respectively. Results　Compared with normal saline group, the expression of protein and mRNA of TLR4, MyD88, TRAF6, NF- κBp65 in MA group increased (P < 0.001 or P < 0.01).The protein of IκB- α and mRNA expression of lactamase decreased (P < 0.01), the expression of p-IκB- α and p-NF- κBp65 increased (P < 0.01 or P < 0.05). Compared with MA group, the protein and mRNA expression of TLR4, MyD88, TRAF6, NF- κBp65 in MA+TAK-242 group decreased (P < 0.001, P < 0.01 or P < 0.05) . The expression of IκB- α protein and mRNA was increased (P < 0.01), the expression of p-IκB- α and p-NF- κBp65 decreased (P < 0.01 or P < 0.05). Conclusions　MA dependency can be achieved by activating TLR4/MyD88/NF- κ B signal pathway, which can induce neuroinflammation on the hippocampus of methamphetamine-dependent CPP rats. The use of specific TLR4 inhibitors can attenuate MA induced neuroinflammation. [ABSTRACT FROM AUTHOR]

Background and Objectives: This study was conducted to compare the personality type and alexithymia between opiates dependents, concurrent opiates and methamphetamine users and control groups presenting to drug abuse treatment centers in Kerman in 2020. Methods: In this cross-sectional analytical study, three groups with a sample size of 130 participants were recruited through convenience sampling from six drug abuse treatment centers (two governmental and four private centers) in Kerman, 2020. The first group comprised opiates-only users. The second group included concurrent opiates and methamphetamine users. The third group included never-drug users. The data were collected using three questionnaires including a demographic questionnaire, the Friedman and Rosenman personality types questionnaire and Toronto Alexithymia Scale. Comparison of variables between the three groups was done using multivariable multinomial logistic regression. Results: The research outcomes indicated a higher chance of type A personality in the opiates with methamphetamine dependents (adjusted odds ratio (AOR):1.97; 95% confidence interval (95% CI): 3.64, 1.06) compared to the control group. The chance of severe alexithymia was higher among opiates dependents (AOR: 1.86; 95% CI: 3.27, 1.06) and concurrent opiates and methamphetamine users (AOR: 2.7; 95% CI: 4.83, 1.51) compared to the control group. The concurrent opiates and methamphetamine users were more likely to be male (AOR: 3.1; 95% CI: 6.25, 1.53), single (AOR: 2.6; 95% CI: 4.72, 1.43) and unemployed (AOR: 4.01; 95% CI: 9.09, 1.77) compared to the control group. Compared to the control group, the opiates dependents (AOR: 4.14; 95% CI: 7.71, 2.22) and the opiates with methamphetamine dependents (AOR: 1.95; 95% CI: 3.69, 1.03) were more likely to have education levels lower than secondary school diploma. Conclusion: Considering the relationship between the personality type and alexithymia with opiates and methamphetamine use, early screening, continuous care, and necessary trainings are required to prevent drug dependency in high-risk people, especially at younger ages.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]

ObjectivesMethamphetamine (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.MethodsIn 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.ResultsThe 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.ConclusionWe demonstrated that genetic polymorphism rs14251 located at 5q31.3 was significantly associated with the vulnerability to METH dependence in Han Chinese population.

BackgroundCue-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.MethodsEEG 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.ResultsThe 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.ConclusionThis 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.

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. [ABSTRACT FROM AUTHOR]

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. 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. 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 (β = 2.92, p =.02). 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. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

Abstract 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 0.05). 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.

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]

Abstract 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).

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.

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. [ABSTRACT FROM AUTHOR]

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]

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. [ABSTRACT FROM AUTHOR]

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.

• Methamphetamine users showed reduced GABA levels in left DLPFC than healthy controls. • The concentration of GSH, GPC, Ins, NAA, GPC + PCh, NAA + NAAG, Cr + PCr were lower. • GABA and Glx concentrations were significantly correlated with age and duration of withdrawal. 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. [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]

Background and purpose: Monoamine oxidase A (MAOA, Xp11.3; OMIM: 309850) can modulate the level of neurotransmitters in the central nervous system. A 30 bp variable number of tandem repeat (VNTR) genetic polymorphism on the promoter region of the MAOA can modulate the transcriptional activity of the gene. Association between this polymorphism and dependency to methamphetamine was investigated. Subjects and methods: A total of 65 methamphetamine abusers (52 males and 13 females) and 635 healthy controls (525 males and 110 females) were included in the present case–control study. Genotypic analysis for the MAOA VNTR polymorphism was determined by conventional PCR. Based on transcriptional activity of the VNTR alleles, the alleles were categorized into two classes: L allele (2R and 3R alleles) and H allele (3.5R, 4R and 5R alleles), which have low and high transcriptional activities, respectively. Results: Our data show that the H allele significantly increases the risk of methamphetamine dependence in males (OR = 2.03, 95% CI: 1.04–3.67, P = 0.037). The H allele seems positively associated with the risk of dependency to methamphetamine among females, but the observed OR did not reach the significance level, probability due to small sample size of the patients. Conclusion: The present study supports the role of the VNTR polymorphism on the promoter region of the MAOA on methamphetamine dependence.

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]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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. This study aimed to investigate the role of miRNAs in the inhibitory effect of Rhy on METH dependence. 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. 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. 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. [Display omitted] • Rhy reverses METH-induced CPP effect and the upregulated miR-181a-5p level in METH-dependent rat hippocampus and PC12 cells. • Agomir 181a combined with METH elicits a significant CPP effect, which is blocked by Rhy through inhibiting miR-181a-5p. • Rhy inhibits METH dependence via modulating the miR-181a-5p/GABRA1 axis. [ABSTRACT FROM AUTHOR]

BackgroundTopiramate (TPM) is suggested to be a promising medication for treatment of methamphetamine (METH) dependence, but the molecular basis remains to be elucidated.MethodsAmong 140 METH-dependent participants randomly assigned to receive either TPM (N = 69) or placebo (N = 71) in a previously conducted randomized controlled trial, 50 TPM- and 49 placebo-treated participants had a total 212 RNA samples available at baseline, week 8, and week 12 time points. Following our primary analysis of gene expression data, we reanalyzed the microarray expression data based on a latent class analysis of binary secondary outcomes during weeks 1–12 that provided a classification of 21 responders and 31 non-responders with consistent responses at both time points.ResultsBased on secondary outcomes, 1,381, 576, 905, and 711 differentially expressed genes at nominal P values

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. [ABSTRACT FROM AUTHOR]

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 (40 μg/g) and the expression of TH was observed by immunohistochemistry technique and Western blot. Ketamine (150 μg/g), high dose of rhynchophylline (100 μg/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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 12 h after injection of METH. On day 9, zebrafish were tested for METH-induced CPP. Results revealed that rhynchophylline (100 mg/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 (50 mg/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. [ABSTRACT FROM AUTHOR]

Objectives: This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone+ bupropion as a pharmaco-therapy for methamphetamine (MA) use disorder. Methods: The 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 medi cation adherence platform. Participants met Diagnostic and Statisti cal Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported ≥20 days of MA use in the 30 days priorto 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. Results: Analyses 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). Conclusions: Under 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]