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Brain, Behavior, and Immunity Jun 2024Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are...
Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.
PubMed: 38838836
DOI: 10.1016/j.bbi.2024.05.038 -
Addiction Biology Jun 2024Abuse of methamphetamine has aroused concern worldwide. Stimulant use and sexual behaviours have been linked in behavioural and epidemiological studies. Although...
AIMS
Abuse of methamphetamine has aroused concern worldwide. Stimulant use and sexual behaviours have been linked in behavioural and epidemiological studies. Although methamphetamine-related neurofunctional differences are reported in previous studies, only few studies have examined neurofunctional changes related to methamphetamine and sexual cues in methamphetamine dependence from short- to long-term abstinence.
METHODS
Neurofunctional changes were measured using a cue-reactivity task involving methamphetamine, sexual, and neutral cues in 20 methamphetamine abusers who were evaluated after a short- (1 week to 3 months) and long-term (10-15 months) abstinence.
RESULTS
Five brain regions mainly involved in the occipital lobe and the parietal lobe were found with the group-by-condition interaction. Region-of-interest analyses found higher sexual-cue-related activation than other two activations in all five brain regions in the long-term methamphetamine abstinence group while no group differences were found. Negative relationships between motor impulsivity and methamphetamine- or sexual-cue-related activations in the left middle occipital gyrus, the superior parietal gyrus and the right angular gyrus were found.
CONCLUSIONS
The findings suggested that methamphetamine abstinence may change the neural response of methamphetamine abusers to methamphetamine and sexual cues, and the neurofunction of the five brain regions reported in this study may partly recover with long-term methamphetamine abstinence. Given the use and relapse of methamphetamine for sexual purposes, the findings of this study may have particular clinical relevance.
Topics: Humans; Cues; Amphetamine-Related Disorders; Methamphetamine; Male; Adult; Sexual Behavior; Magnetic Resonance Imaging; Parietal Lobe; Female; Occipital Lobe; Brain; Central Nervous System Stimulants; Young Adult; Impulsive Behavior; Brain Mapping; Time Factors
PubMed: 38837586
DOI: 10.1111/adb.13405 -
Ecotoxicology and Environmental Safety Jul 2024Methamphetamine (Meth) is a potent psychostimulant with well-established hepatotoxicity. Gut microbiota-derived short-chain fatty acids (SCFAs) have been reported to...
Methamphetamine (Meth) is a potent psychostimulant with well-established hepatotoxicity. Gut microbiota-derived short-chain fatty acids (SCFAs) have been reported to yield beneficial effects on the liver. In this study, we aim to further reveal the mechanisms of Meth-induced hepatic injuries and investigate the potential protective effects of SCFAs. Herein, mice were intraperitoneally injected with 15 mg/kg Meth to induce hepatic injuries. The composition of fecal microbiota and SCFAs was profiled using 16 S rRNA sequencing and Gas Chromatography/Mass Spectrometry (GC/MS) analysis, respectively. Subsequently, SCFAs supplementation was performed to evaluate the protective effects against hepatic injuries. Additionally, Sigma-1 receptor knockout (S1R) mice and fluvoxamine (Flu), an agonist of S1R, were introduced to investigate the mechanisms underlying the protective effects of SCFAs. Our results showed that Meth activated S1R and induced hepatic autophagy, inflammation, and oxidative stress by stimulating the MAPK/ERK pathway. Meanwhile, Meth disrupted SCFAs product-related microbiota, leading to a reduction in fecal SCFAs (especially Acetic acid and Propanoic acid). Accompanied by the optimization of gut microbiota, SCFAs supplementation normalized S1R expression and ameliorated Meth-induced hepatic injuries by repressing the MAPK/ERK pathway. Effectively, S1R knockout repressed Meth-induced activation of the MAPK/ERK pathway and further ameliorated hepatic injuries. Finally, the overexpression of S1R stimulated the MAPK/ERK pathway and yielded comparable adverse phenotypes to Meth administration. These findings suggest that Meth-induced hepatic injuries relied on the activation of S1R, which could be alleviated by SCFAs supplementation. Our study confirms the crucial role of S1R in Meth-induced hepatic injuries for the first time and provides a potential preemptive therapy.
Topics: Methamphetamine; Animals; Receptors, sigma; Sigma-1 Receptor; Fatty Acids, Volatile; Mice; Gastrointestinal Microbiome; Male; Chemical and Drug Induced Liver Injury; Mice, Knockout; Liver; Mice, Inbred C57BL; Oxidative Stress; Feces
PubMed: 38833980
DOI: 10.1016/j.ecoenv.2024.116538 -
Frontiers in Psychiatry 2024Methamphetamine is currently one of the most commonly used addictive substances with strong addiction and a high relapse rate. This systematic review aims to examine the...
INTRODUCTION
Methamphetamine is currently one of the most commonly used addictive substances with strong addiction and a high relapse rate. This systematic review aims to examine the effectiveness of physical activity in improving negative emotions, cognitive impairment, and drug craving in people with methamphetamine use disorder (MUD).
METHODS
A total of 17 studies out of 133 found from Embase and PubMed were identified, reporting results from 1836 participants from MUD populations. Original research using clearly described physical activity as interventions and reporting quantifiable outcomes of negative mood, cognitive function and drug craving level in people with MUD were eligible for inclusion. We included prospective studies, randomized controlled trials, or intervention studies, focusing on the neurological effects of physical activity on MUD.
RESULTS
Taken together, the available clinical evidence showed that physical activity-based interventions may be effective in managing MUD-related withdrawal symptoms.
DISCUSSION
Physical exercise may improve drug rehabilitation efficiency by improving negative emotions, cognitive behaviors, and drug cravings.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024530359.
PubMed: 38827441
DOI: 10.3389/fpsyt.2024.1402533 -
MedRxiv : the Preprint Server For... May 2024Methamphetamine Use Disorder (MUD) is associated with substantially reduced quality of life. Yet, decisions to use persist, due in part to avoidance of anticipated...
Methamphetamine Use Disorder (MUD) is associated with substantially reduced quality of life. Yet, decisions to use persist, due in part to avoidance of anticipated withdrawal states. However, the specific cognitive mechanisms underlying this decision process, and possible modulatory effects of aversive states, remain unclear. Here, 56 individuals with MUD and 58 healthy comparisons (HCs) performed a decision task, both with and without an aversive interoceptive state induction. Computational modeling measured the tendency to test beliefs about uncertain outcomes (directed exploration) and the ability to update beliefs in response to outcomes (learning rates). Compared to HCs, those with MUD exhibited less directed exploration and slower learning rates, but these differences were not affected by aversive state induction. These results suggest novel, state-independent computational mechanisms whereby individuals with MUD may have difficulties in testing beliefs about the tolerability of abstinence and in adjusting behavior in response to consequences of continued use.
PubMed: 38826438
DOI: 10.1101/2024.05.17.24307491 -
Harm Reduction Journal May 2024Efforts to distribute naloxone have equipped more people with the ability to reverse opioid overdoses but people who use drugs are often reluctant to call 911 due to...
BACKGROUND
Efforts to distribute naloxone have equipped more people with the ability to reverse opioid overdoses but people who use drugs are often reluctant to call 911 due to concerns for legal repercussions. Rural communities face unique challenges in reducing overdose deaths compared to urban communities, including limited access to harm reduction services as well as greater concerns about stigma and privacy.
METHODS
The Rural Opioid Initiative was funded in 2017 to better understand the health-related harms associated with the opioid crisis in rural US communities and consists of eight studies spanning ten states and 65 counties. Each study conducted semi-structured qualitative interviews with people who use drugs to understand contextual factors influencing drug use and health behaviors. We analyzed qualitative data from seven studies with data available at the time of analysis to understand peer response to overdose.
RESULTS
Of the 304 participants interviewed, 55% were men, 70% were white, 80% reported current injection drug use, and 60% reported methamphetamine use. Similar to what has been found in studies focused on urban settings, people who use drugs in rural communities use a range of strategies to reverse overdoses, including non-evidence-based approaches. Several reported that multiple doses of naloxone are needed to reverse overdose. Three themes emerged around the willingness to call 911, including (1) hesitancy to call 911 for fear of legal consequences, (2) negative perceptions or experiences with law enforcement officers, and (3) efforts to obtain medical intervention while avoiding identification/law enforcement involvement.
CONCLUSION
People who use drugs employ multiple strategies to attempt overdose reversal, including non-evidence-based approaches. Greater education about the most effective and least harmful strategies is needed. Reluctance to call 911 is rooted in concerns about potential legal consequences as well as perceptions about law enforcement officers, which may be heightened in rural communities where people who use drugs are more easily identified by law enforcement. People who use drugs will go to great strides to connect their peers to needed medical services, suggesting that comprehensive interventions to reduce interactions with law enforcement officers and eliminate legal consequences for reporting overdoses are critical.
Topics: Humans; Female; Male; Rural Population; Adult; Drug Overdose; Harm Reduction; Narcotic Antagonists; Naloxone; Middle Aged; Qualitative Research; United States; Young Adult; Drug Users
PubMed: 38822387
DOI: 10.1186/s12954-024-01007-9 -
The Journal of Emergency Medicine Mar 2024Methamphetamine-associated cardiomyopathy (MACM) is a known complication of methamphetamine use; however, risk factors and outcomes of patients with MACM are not well...
BACKGROUND
Methamphetamine-associated cardiomyopathy (MACM) is a known complication of methamphetamine use; however, risk factors and outcomes of patients with MACM are not well understood.
STUDY OBJECTIVES
This study aims to identify risk factors, emergency department (ED) interventions, and outcomes for MACM.
METHODS
This case-control study was conducted between 2012 and 2020 at two academic EDs. ED patients ≥18 years with an index visit that included documented methamphetamine use were included. Patients with documented MACM during follow-up (3 months-3 years) were considered cases (MACM). A control group comprised of patients with documented methamphetamine use but no known MACM was matched at a 2:1 ratio. Logistic regression was used to model risk factors for MACM.
RESULTS
A total of 9833 patients with methamphetamine use were identified. From this, 160 MACM patients were matched to 322 controls. The mean age was 48.4 years, and 143 patients (29.7%) were female. MACM patients were more likely to be admitted on their index visit (45.6% vs. 34.8%, p = 0.021). Significant variables associated with MACM included: admission at the index visit (odds ratio [OR] 1.51), diabetes (OR 3.02), kidney disease (OR 5.47), and pulmonary disease (OR 2.39). MACM patients had more ED visits in the follow-up period (10.1 vs. 7, p = 0.009) and were admitted at a higher rate across all visits (32.5% vs. 15.4%, p = 0.009). Additionally, MACM patients had significantly longer hospital stays than controls (mean 18 additional days, p = 0.009).
CONCLUSION
Patients who developed MACM had traditional risk factors for heart failure and experienced significantly more ED visits, more hospitalizations, and longer hospital stays than matched controls.
PubMed: 38816259
DOI: 10.1016/j.jemermed.2024.03.019 -
ACS Applied Materials & Interfaces Jun 2024The growing number of acute drug abuse overdoses demands the development of innovative detoxification strategies for emergency purposes. In this study, an innovative...
The growing number of acute drug abuse overdoses demands the development of innovative detoxification strategies for emergency purposes. In this study, an innovative approach for the application of porous Zr-based metal-organic frameworks for the treatment of acute overdoses of popular drugs of abuse including amphetamine, methamphetamine, cocaine, and MDMA is presented. A comprehensive approach determining the efficacy and the kinetics of drug removal, considering dosage, adsorption time, and adsorption mechanisms, was tested and corroborated with density functional theory (DFT) modeling. The experimental results showed high removal efficiency reaching up to 90% in the case of the application of the NU-1000 metal-organic framework. The difference Raman spectroscopy method presented in this study corroborated with DFT-based vibrational analysis allows the detection of drug adsorbed in the MOF framework even with as low a concentration as 5 mg/g. Additionally, the drug adsorption mechanisms were modeled with DFT, showing the π-π stacking in a vast majority of considered cases. The performance and influence on the living organisms were evaluated throughout the and experiments, indicating that Zr-based MOFs could serve as efficient, organic, safe drug adsorbents.
Topics: Metal-Organic Frameworks; Adsorption; Zirconium; Density Functional Theory; Animals; Porosity; Methamphetamine
PubMed: 38815127
DOI: 10.1021/acsami.4c02450 -
Journal of Integrative Neuroscience May 2024Methamphetamine (METH) is a highly addictive drug that directly affects the central nervous system. METH use not only harms the user's health but also poses risks and...
BACKGROUND
Methamphetamine (METH) is a highly addictive drug that directly affects the central nervous system. METH use not only harms the user's health but also poses risks and costs to society. Prolonged METH dependence has been shown to impair cognition, which may be the primary factor in impulsive drug-seeking behaviors and high relapse rates. However, the molecular mechanisms underlying METH addiction and METH-induced cognitive decline remain poorly understood.
METHODS
To illuminate the potential molecular mechanisms underpinning METH addiction, we compared serum protein expression levels between 12 long-term METH users and 12 healthy controls using label-free quantitative proteomics. Bioinformatic analyses were conducted to determine functional networks and protein-protein interactions.
RESULTS
In total, 23 differentially expressed proteins were identified between the two groups. The differentially expressed proteins were related to cognitive dysfunction, neuroinflammation, immune impairment, metabolic disturbances, and calcium binding and regulation.
CONCLUSIONS
These 23 proteins may underpin the multi-system damage induced by chronic METH exposure. Our findings provide novel insights into the molecular basis of METH addiction and inform potential prevention and treatment strategies for individuals with METH dependence.
Topics: Humans; Amphetamine-Related Disorders; Male; Methamphetamine; Cognitive Dysfunction; Adult; Proteomics; Central Nervous System Stimulants; Female; Young Adult
PubMed: 38812388
DOI: 10.31083/j.jin2305107 -
Psychiatry Investigation May 2024Methamphetamine use disorder (MUD) is a global health condition that impairs a person's health which may result in morbidity and mortality. Inflammation is a crucial...
OBJECTIVE
Methamphetamine use disorder (MUD) is a global health condition that impairs a person's health which may result in morbidity and mortality. Inflammation is a crucial process playing a vital role in MUD. For this reason, it is necessary to examine biochemical parameters for follow-up and treatment alternatives.
METHODS
We aimed to reveal the relationship between inflammatory response and MUD by evaluating peripheral hemogram parameters, leukocyte count, subtypes, and their ratios to each other, systemic immune inflammation index (SII), monocyte/high-density lipoprotein (HDL) ratio, and human C-reactive protein (CRP) in adult men with MUD. We included 76 adult male participants in the patient group and 70 adult male participants in the control group. We calculated the neutrophil/lymphocyte rate (NLR), monocyte/lymphocyte rate (MLR), platelet/lymphocyte rate (PLR), and basophil/lymphocyte rate (BLR). In addition, we obtained the SII and the monocyte/HDL rate.
RESULTS
The patients' leukocyte (p<0.001), platelet (p<0.001), plateletcrit (PCT) (p=0.002), neutrophil (p<0.001), monocyte (p=0.002), CRP (p<0.001), NLR (p=0.001), PLR (p=0.004), MLR (p=0.009), SII (p<0.001) and monocyte/HDL ratio (p<0.001) were higher than the control group. We observed a significant and positive relationship between the daily methamphetamine intake, and methamphetamine use duration (p=0.002), PCT (p=0.044), neutrophil (p=0.021), NLR (p=0.001), PLR (p=0.004), MLR (p=0.029), and SII (p<0.001). Daily methamphetamine intake had a significant and positive effect on SII. A one-unit increase in daily methamphetamine intake elevated SII by 165.53 units.
CONCLUSION
The results confirm the presence of peripheral subclinical inflammation and systemic immune inflammation in adult men with MUD.
PubMed: 38811000
DOI: 10.30773/pi.2023.0199