Cardiomyopathy in Patients With Acute Ischemic Stroke and Methamphetamine Use: Relevance for Cardioembolic Stroke and Outcome.

BACKGROUND: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke. METHODS AND RESULTS: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P<0.001), included more men (78.3% versus 52.8%; P<0.001), and had a significantly higher rate of cardiomyopathy (30.4% versus 14.0%; P<0.01). They were also less likely to have a history of atrial fibrillation (8.7% versus 33.4%; P<0.01) or hyperlipidemia (28.3% versus 51.7%; P<0.01). Compared with patients with cardiomyopathy without methamphetamine use, the patients with cardiomyopathy with methamphetamine use had significantly lower left ventricular ejection fraction (26.0±9.59% versus 32.47±9.52%; P<0.01) but better functional outcome at 3 months, likely attributable to significantly younger age and fewer comorbidities. In the logistic regression model of clinical variables, methamphetamine-associated cardiomyopathy was found to be significantly associated with cardioembolic stroke (odds ratio, 1.79 [95% CI, 1.04-3.06]; P<0.05). CONCLUSIONS: We demonstrate that methamphetamine use is significantly associated with cardiomyopathy and cardioembolic stroke in young adults.

Modeling methamphetamine use disorder in mammals: Sex differences in behavioral, biochemical, and transcriptional consequences.

Methamphetamine (METH) is the most commonly misused amphetamine-type stimulant throughout the globe. METH is very rewarding, and its misuse can lead to a diagnosis of METH use disorder (MUD). Although METH use is observed in both sexes, there are, however, reported differences in the clinical manifestations of METH use and its consequences. These observations indicate the need for more research on the long-term sex-dependent consequences of METH taking in both preclinical and clinical settings. In effect, sex is a biological variable that can impact conclusions drawn from various basic and clinical studies. Thus, the present chapter provides a succinct review of the current state of the research on METH and its sex-associated consequences. In addition to behavioral and cognitive aspects of METH use, we discuss METH-induced changes in neurotransmitter systems and structures in the brain. Thus, the book chapter serves to highlight the significance of sex as a critical element that needs to be considered during discussions of novel therapeutic approaches to MUD.

The role of sex and drug use during adolescence in determining the risk for adverse consequences of amphetamines.

Use of amphetamines during adolescence, a critical period of brain development and reorganization, may lead to particularly adverse outcomes that are long-lasting. Similarly, female users may be uniquely vulnerable to certain aspects of drug use. A recognition of the role of use during adolescence and sex on outcomes of amphetamine and methamphetamine exposure are of critical importance in understanding and treating substance use disorders. This chapter highlights what human research, which has been largely epidemiological, suggests about sex and age differences in drug use patterns and outcomes. We also discuss work in laboratory animals that has typically utilized rats or mice exposed to drugs in a non-contingent manner (i.e., involuntarily) or through volitional self-administration. Lastly, we draw attention to the fact that advancing our understanding of the effects of amphetamine and methamphetamine use, the development of problematic drug taking, and the mechanisms that contribute to relapse will require an emphasis on inclusion of age and sex as moderating factors in future studies.

The pharmacology and neurotoxicology of synthetic cathinones.

The synthetic cathinones are man-made compounds derived from the naturally occurring drug cathinone, which is found in the khat plant. The drugs in this pharmacological class that will be the focus of this chapter include mephedrone, MDPV, methcathinone and methylone. These drugs are colloquially known as "bath salts". This misnomer suggests that these drugs are used for health improvement or that they have legitimate medical uses. The synthetic cathinones are dangerous drugs with powerful pharmacological effects that include high abuse potential, hyperthermia and hyperlocomotion. These drugs also share many of the pharmacological effects of the amphetamine class of drugs including methamphetamine, amphetamine and MDMA and therefore have high potential to cause damage to the central nervous system. The synthetic cathinones are frequently taken in combination with other psychoactive drugs such as alcohol, marijuana and the amphetamine-like stimulants, creating a situation where heightened pharmacological and neurotoxicological effects are likely to occur. Despite the structural features shared by the synthetic cathinones and amphetamine-like stimulants, including their actions at monoamine transporters and receptors, the effects of the synthetic cathinones do not always match those of the amphetamines. In particular, the synthetic cathinones are far less neurotoxic than their amphetamine counterparts, they produce a weaker hyperthermia, and they cause less glial activation. This chapter will briefly review the pharmacology and neurotoxicology of selected synthetic cathinones with the aim of delineating key areas of agreement and disagreement in the literature particularly as it relates to neurotoxicological outcomes.

Dysfunctional feedback processing in male methamphetamine abusers: Evidence from neurophysiological and computational approaches.

Methamphetamine use disorder (MUD) as a major public health risk is associated with dysfunctional neural feedback processing. Although dysfunctional feedback processing in people who are substance dependent has been explored in several behavioral, computational, and electrocortical studies, this mechanism in MUDs requires to be well understood. Furthermore, the current understanding of latent components of their behavior such as learning speed and exploration-exploitation dilemma is still limited. In addition, the association between the latent cognitive components and the related neural mechanisms also needs to be explored. Therefore, in this study, the underlying neurocognitive mechanisms of feedback processing of such impairment, and age/gender-matched healthy controls are evaluated within a probabilistic learning task with rewards and punishments. Mathematical modeling results based on the Q-learning paradigm suggested that MUDs show less sensitivity in distinguishing optimal options. Additionally, it may be worth noting that MUDs exhibited a slight decrease in their ability to learn from negative feedback compared to healthy controls. Also through the lens of underlying neural mechanisms, MUDs showed lower theta power at the medial-frontal areas while responding to negative feedback. However, other EEG measures of reinforcement learning including feedback-related negativity, parietal-P300, and activity flow from the medial frontal to lateral prefrontal regions, remained intact in MUDs. On the other hand, the elimination of the linkage between value sensitivity and medial-frontal theta activity in MUDs was observed. The observed dysfunction could be due to the adverse effects of methamphetamine on the cortico-striatal dopamine circuit, which is reflected in the anterior cingulate cortex activity as the most likely region responsible for efficient behavior adjustment. These findings could help us to pave the way toward tailored therapeutic approaches.

Assessment of rTMS treatment effects for methamphetamine use disorder based on EEG microstates.

Microstates have been proposed as topographical maps representing large-scale resting-state networks and have recently been suggested as markers for methamphetamine use disorder (MUD). However, it is unknown whether and how they change after repetitive transcranial magnetic stimulation (rTMS) intervention. This study included a comprehensive subject population to investigate the effect of rTMS on MUD microstates. 34 patients with MUD underwent a 4-week randomized, double-blind rTMS intervention (active=17, sham=17). Two resting-state EEG recordings and VAS evaluations were conducted before and after the intervention period. Additionally, 17 healthy individuals were included as baseline controls. The modified k-means clustering method was used to calculate four microstates (MS-A∼MS-D) of EEG, and the FC network was also analyzed. The differences in microstate indicators between groups and within groups were compared. The durations of MS-A and MS-B microstates in patients with MUD were significantly lower than that in HC but showed significant improvements after rTMS intervention. Changes in microstate indicators were found to be significantly correlated with changes in craving level. Furthermore, selective modulation of the resting-state network by rTMS was observed in the FC network. The findings indicate that changes in microstates in patients with MUD are associated with craving level improvement following rTMS, suggesting they may serve as valuable evaluation markers.

Alterations in the brain functional network of abstinent male individuals with methamphetamine use disorder.

Methamphetamine is a highly addictive psychostimulant drug that is abused globally and is a serious threat to health worldwide. Unfortunately, the specific mechanism underlying addiction remains unclear. Thus, this study aimed to investigate the characteristics of functional connectivity in the brain network and the factors influencing methamphetamine use disorder in patients using magnetic resonance imaging. We included 96 abstinent male participants with methamphetamine use disorder and 46 age- and sex-matched healthy controls for magnetic resonance imaging. Compared with healthy controls, participants with methamphetamine use disorder had greater impulsivity, fewer small-world attributes of the resting-state network, more nodal topological attributes in the cerebellum, greater functional connectivity strength within the cerebellum and between the cerebellum and brain, and decreased frontoparietal functional connectivity strength. In addition, after controlling for covariates, the partial correlation analysis showed that small-world properties were significantly associated with methamphetamine use frequency, psychological craving, and impulsivity. Furthermore, we revealed that the small-word attribute significantly mediated the effect of methamphetamine use frequency on motor impulsivity in the methamphetamine use disorder group. These findings may further improve our understanding of the neural mechanism of impulse control dysfunction underlying methamphetamine addiction and assist in exploring the neuropathological mechanism underlying methamphetamine use disorder-related dysfunction and rehabilitation.

Lymphocyte-related ratios in methamphetamine-induced psychotic disorder in Taiwan, comparing with patients with schizophrenia.

The lymphocyte-related ratios, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR) are new measures of inflammation within the body. Few studies have investigated the inflammatory response of patients with methamphetamine-induced psychotic disorder. Clinically, the psychotic symptoms and behavioural manifestation of methamphetamine-induced psychotic disorder are often indistinguishable from paranoid schizophrenia. We aimed to determine the differences in these inflammatory markers between patients with methamphetamine-induced psychotic disorder, patients with schizophrenia and healthy individuals. A total of 905 individuals were recruited. The NLR and MLR were found to be higher in both patients with methamphetamine-induced psychotic disorders and patients with schizophrenia compared with healthy controls. There was no significant difference between the three groups in PLR. When compared with the control group, the methamphetamine-induced psychotic disorder group was significantly higher in NLR 27% (95%CI = 11 to 46%, p = 0.001), MLR 16% (95%CI = 3% to 31%, p = 0.013) and PLR 16% (95%CI = 5% to 28%, p = 0.005). NLR of the group with methamphetamine-induced psychotic disorder was 17% (95%CI = 73% to 94%, p = 0.004) less than the group with schizophrenia, while MLR and PLR did not differ significantly between the two groups. This is the first study that investigated the lymphocyte-related ratios in methamphetamine-induced psychotic disorder when compared with patients with schizophrenia and healthy individuals. The results showed that both patients with methamphetamine-induced psychotic disorder and patients with schizophrenia had stronger inflammatory responses than the healthy control. Our finding also indicated that the inflammatory response of methamphetamine-induced psychotic disorder was between those of patients with schizophrenia and healthy individuals.

Structural indices of brain aging in methamphetamine use disorder.

BACKGROUND: Methamphetamine use is surging globally. It has been linked to premature stroke, Parkinsonism, and dementia, suggesting that it may accelerate brain aging. METHODS: We performed a retrospective study to determine if structural indices of brain aging were more prevalent prior to old age (26 - 54 years) in individuals with Methamphetamine Use Disorder (MUD), who were in early abstinence (M ± SD = 22.1 ± 25.6 days) than in healthy control (HC) participants. We compared T1-weighted MRI brain scans in age- and sex-matched groups (n = 89/group) on three structural features of brain aging: the brain volume/cerebrospinal fluid (BV/CSF) index, volume of white matter hypointensities/lesions, and choroid plexus volume. RESULTS: The MUD group had a lower mean BV/CSF index and larger volumes of white matter hypointensities and choroid plexus (p-values < 0.01). Regression analyses showed significant age-by-group effects, indicating different age trajectories of the BV/CSF index and choroid plexus volume, consistent with abnormal global brain atrophy and choroid plexus pathology in the MUD group. Significant age and group main effects reflected a larger volume of white matter hypointensities for older participants across groups and for the MUD group irrespective of age. None of the three measures of brain aging correlated significantly with recent use or duration of recent abstinence from methamphetamine. CONCLUSIONS: Premature brain pathology, which may reflect cerebrovascular damage and dysfunction of the choroid plexus, occurs in people with MUD. Such pathology may affect cognition and thereby efficacy of behavioral treatments for MUD.

Robust identification of a neuromarker of methamphetamine craving.

In the January issue of Cell Reports Medicine, Tian et al.1 apply high-density 128-channel resting-state electroencephalography (EEG) to examine the neurophysiological connectomes in individuals with methamphetamine use disorder (MUD). They identify neurobiological connectome biomarkers for craving prediction in MUD.

Neuronal activation of nucleus accumbens by local methamphetamine administration induces cognitive impairment through microglial inflammation in mice.

More than half of methamphetamine (METH) users present with cognitive impairment, making it difficult for them to reintegrate into society. However, the mechanisms of METH-induced cognitive impairment remain unclear. METH causes neuronal hyperactivation in the nucleus accumbens (NAc) by aberrantly releasing dopamine, which triggers dependence. In this study, to clarify the involvement of hyperactivation of NAc in METH-induced cognitive impairment, mice were locally microinjected with METH into NAc (mice with METH (NAc)) and investigated their cognitive phenotype. Mice with METH (NAc) exhibited cognitive dysfunction in behavioral analyses and decreased long-term potentiation in the hippocampus, with NAc activation confirmed by expression of FosB, a neuronal activity marker. In the hippocampus of mice with METH (NAc), activated microglia, but not astroglia, and upregulated microglia-related genes, Il1b and C1qa were observed. Finally, administration of minocycline, a tetracycline antibiotic with suppressive effect on microglial activation, to mice with METH (NAc) ameliorated cognitive impairment and synaptic dysfunction by suppressing the increased expression of Il1b and C1qa in the hippocampus. In conclusion, activation of NAc by injection of METH into NAc elicited cognitive impairment by facilitating immune activation in mice. This study suggests that immunological intervention could be a therapeutic strategy for addiction-related cognitive disturbances.

Associations between impulsivity and fecal microbiota in individuals abstaining from methamphetamine.

INTRODUCTION: Methamphetamine (MA) abuse is a major public problem, and impulsivity is both a prominent risk factor and a consequence of addiction. Hence, clarifying the biological mechanism of impulsivity may facilitate the understanding of addiction to MA. The microbiota-gut-brain axis was suggested to underlie a biological mechanism of impulsivity induced by MA. METHODS: We therefore recruited 62 MA addicts and 50 healthy controls (HCs) to investigate the alterations in impulsivity and fecal microbiota and the associations between them in the MA group. Thereafter, 25 MA abusers who abstained from MA for less than 3 months were followed up for 2 months to investigate the relationship between impulsivity and microbiota as abstinence became longer. 16S rRNA sequencing was conducted for microbiota identification. RESULTS: Elevated impulsivity and dysbiosis characterized by an increase in opportunistic pathogens and a decrease in probiotics were identified in MA abusers, and both the increased impulsivity and disrupted microbiota tended to recover after longer abstinence from MA. Impulsivity was related to microbiota, and the effect of MA abuse on impulsivity was mediated by microbiota. CONCLUSION: Our findings potentially highlighted the importance of abstention and implicated the significant role of the microbiota-gut-brain axis in the interrelationship between microbiota and behaviors, as well as the potential of microbiota as a target for intervention of impulsivity.

Altered spontaneous neurological activity in methamphetamine use disorders and its association with cognitive function.

BACKGROUND: Methamphetamine (MA) is a widely used and detrimental drug, yet the precise mechanisms by which MA affects cognitive function remain unclear. This study aims to investigate the relationship between cognitive function and brain functional imaging in individuals with MA use disorder (MUD). METHODS: This study involved 45 patients diagnosed with MUD and 43 healthy controls (HC). Cognitive function assessment utilized the MATRICS Consensus Cognitive Battery, and functional data were acquired using a 3.0 Tesla magnetic resonance imaging scanner. RESULTS: The MUD group exhibited lower regional homogeneity (ReHo) values in the bilateral postcentral, the left superior temporal, and the left lingual regions compared to the HC group. Additionally, the MUD group displayed higher amplitude of low-frequency fluctuation (ALFF) values in the bilateral fusiform and the left putamen compared to the HC group, along with lower ALFF values in the bilateral postcentral cortices and the left middle cingulate cortex compared to the HC group (all p < 0.05, with false discovery rate corrected). Linear regression analysis revealed a positive correlation between the ReHo value in the right postcentral cortex and the neuropsychology assessment battery-mazes test (p = 0.014). Furthermore, the ALFF value in the left putamen showed negative correlations with the scores of the digit-symbol coding test (p = 0.027), continuous performance test (p = 0.037), and battery-mazes test (p = 0.024). CONCLUSION: Patients with MUD exhibit altered brain spontaneous neurological activities, and the intensity of spontaneous neurological activity in the left putamen is strongly associated with cognitive function.

An Inpatient Protocol for the Treatment of Methamphetamine Withdrawal in Patients With and Without Opioid Use Disorder.

OBJECTIVE: Increasing rates of methamphetamine (METH) use, use disorders, and related overdoses are a growing public health problem. There are a lack of protocols addressing METH intoxication and withdrawal symptoms that manifest during acute withdrawal treatment resulting in inpatient management difficulties and premature discharges. This report presents a novel treatment protocol comprised of behavior-targeted and pharmacological components that aims to reduce the intensity and duration of METH intoxication and withdrawal related symptoms during early treatment, improve retention, and provide clinicians with a tool to meet this growing problem. METHODS: The protocol was developed by a team of addiction physicians and other clinical staff. Clinical and administrative staff at a community acute stabilization unit were trained and the protocol was implemented with patients presenting with METH use. Pharmacological interventions, including ascorbic acid, antipsychotics, and other sedatives are discussed, as are behavior-based orders. A retrospective quality assurance examination was conducted on patient characteristics and outcomes as well as focus groups with nursing staff. RESULTS: A total of 23 patients consecutively admitted to the unit used the protocol (100% male). Most patients (67%) displayed symptoms of METH use or withdrawal. Behavior-related interventions were used in 52% of patients, while 48% received behavior-related and pharmacological measures. Patient completion of the protocol was 83%, and the protocol's utility was supported by nursing staff. CONCLUSIONS: This retrospective evaluation of a novel METH withdrawal treatment protocol suggests feasibility, tolerability, and preliminary evidence of effectiveness, providing clinicians with a new tool that requires further study.

Mucocutaneous Manifestations of Recreational Drug Use.

Recreational drug use is increasingly common in the dermatology patient population and is often associated with both general and specific mucocutaneous manifestations. Signs of substance use disorder may include changes to general appearance, skin, and mucosal findings associated with particular routes of drug administration (injection, insufflation, or inhalation) or findings specific to a particular drug. In this review article, we provide an overview of the mucocutaneous manifestations of illicit drug use including cocaine, methamphetamine, heroin, hallucinogens, marijuana, and common adulterants to facilitate the identification and improved care of these patients with the goal being to connect this patient population with appropriate resources for treatment.

[The Science of Drug Addiction].

Several causes of drug addiction in people remain unknown. It is known that only a small percentage of those who use potent dependent drugs, such as methamphetamine and heroin, develop addiction. In addition, some studies suggest that the choice of preferred drugs among drug addicts is made proactively according to criteria other than the strength of pharmacological dependence. Therefore, this paper discusses the pathogenesis of drug dependence, focusing on the "self-medication hypothesis" of Khantzian et al.

GxE interaction effects of HCRTR2 single nucleotide polymorphism and adverse childhood experiences on methamphetamine use disorder.

Background: Methamphetamine use disorder (MUD) is a worldwide health concern. The hypothalamic orexin system regulates stress response and addictive behaviors. The genetic variation in the hypocretin receptor 2 (HCRTR2), rs2653349, is associated with substance use disorder.Objectives: We explored the gene-environment (GxE) interaction of rs2653349 and adverse childhood experiences (ACEs) associated with MUD susceptibility.Methods: Four hundred and one individuals (336 males, 65 females) with MUD and 348 healthy controls (288 males, 60 females) completed a self-report questionnaire evaluating ACEs, encompassing childhood abuse and household dysfunction categories, and were genotyped for SNP rs2653349. Methamphetamine use variables were collected using the Diagnostic Interview for Genetic Studies. We used regression analyses to assess the GxE effect on MUD risk.Results: The MUD group had a comparable genotypic distribution for rs2653349 to the control group, albeit with a higher prevalence and number of types of ACEs, correlating with an increased MUD risk (p < .05). No significant genetic impact of rs2653349 on MUD risk was found. However, we observed a GxE interaction effect between the minor allele of rs2653349 and the number of childhood abuse or household dysfunction types, correlating with a reduced MUD risk (OR = -0.71, p = .04, Benjamini-Hochberg adjusted p = .08 and OR = -0.59, p = .045, Benjamini-Hochberg adjusted p = .09, respectively).Conclusion: HCRTR2 SNP rs2653349 has no significant impact on MUD risk, but ACEs may increase this risk. GxE results suggest that rs2653349 could offer protection against developing MUD in individuals experiencing multiple types of ACEs.

Association between drug craving and aggression in Chinese male methamphetamine-dependent patients with and without depressive symptoms.

Depressive symptoms and aggression are common in patients with substance use disorder. Drug craving is one of the main drivers of drug-seeking behavior. This study aimed to explore the relationship between drug craving and aggression in methamphetamine use disorder (MAUD) patients with and without depressive symptoms. Totally, 613 male patients with MAUD were recruited in this study. Patients with depressive symptoms were identified by the 13-item Beck Depression Inventory (BDI-13). Drug craving and aggression were assessed by the Desires for Drug Questionnaire (DDQ) and the Buss & Perry Aggression Questionnaire (BPAQ), respectively. 374 patients (61.01%) were confirmed to meet the criteria of depressive symptoms. Patients with depressive symptoms had significantly higher DDQ and BPAQ total scores than those without depressive symptoms. DDQ desire and intention were positively correlated with verbal aggression and hostility in patients with depressive symptoms, whereas they were correlated with self-directed aggression in patients without depressive symptoms. In patients with depressive symptoms, DDQ negative reinforcement and a history of suicide attempts were independently associated with BPAQ total score. Our study suggests that male MAUD patients have a high incidence of depressive symptoms and that patients with depressive symptoms may have greater drug cravings and aggression. Depressive symptoms may play a role in the association between drug craving and aggression in patients with MAUD.