OBJECTIVE:This study aimed to characterize the pharmacokinetics of blood alcohol and acetaldehyde, quantify acute psychomotor impairment, and evaluate the influence of beverage type under standardized alcohol dosing in healthy Han Chinese adults. METHODS:Eleven participants with the ALDH2*1/*1 genotype consumed baijiu, beer, and red wine on separate occasions at a standardized alcohol dose of 0.8 g/kg. Blood alcohol concentrations and blood acetaldehyde concentrations were measured for 8 h. Psychomotor function was evaluated with four validated tasks, and mood states were assessed with the Profile of Mood States and the Biphasic Alcohol Effects Scale. RESULTS:The earliest blood alcohol concentration peak was observed in six participants after baijiu, four after red wine, and one after beer; similarly, the earliest blood acetaldehyde concentration peak occurred in six participants after baijiu, two after red wine, and three after beer. All beverages induced time-dependent psychomotor impairments (P <0.05), but no significant differences were detected between beverage types (P >0.05). Mood state assessments also revealed significant time effects (P <0.05). Notably, blood acetaldehyde concentrations were negatively correlated with hand-eye coordination (pursuit rotor task, r = -0.368, P = 0.035), whereas blood alcohol concentrations were positively correlated with subjective stimulation (r = 0.544, P = 0.001). DISCUSSION:Although alcohol absorption kinetics differ among beverage types, likely due to concentration-dependent effects on gastric emptying, the acute effects on psychomotor function and mood remain comparable at equivalent alcohol doses. This suggests that beverage type does not influence the extent of functional impairment. CONCLUSION:Although different alcoholic beverages exhibit distinct pharmacokinetic profiles, their acute effects on psychomotor function and mood are comparable when equivalent doses of alcohol are consumed. These findings suggest that blood alcohol concentration, rather than beverage type, is the primary determinant of alcohol-induced impairment.

Immune cells are those involved in or related to immune responses, found throughout immune organs and the body. The discipline of immunometabolism, which merges immunology with metabolism, has gained significant attention in recent years. This emerging field focuses on the metabolic processes and mechanisms of various immune cells, aiming to uncover how these cells’ metabolism influences disease onset and progression. Research in immunometabolism spans several diseases, including chronic inflammatory conditions, infectious diseases, cardiovascular disorders, and cancer, highlighting the critical role of immune cell metabolism in these diseases. Mental illnesses, characterized by brain function abnormalities due to biological, psychological, and environmental factors, lead to impairments in cognitive, emotional, volitional, and behavioral functions. Conditions such as schizophrenia, neurodegenerative diseases (Alzheimer’s disease AD, Parkinson’s disease PD), anxiety, and depression are associated with significant metabolic changes. The intersection of neuroimmunology and immunometabolism has become a focal point for understanding the regulation of mental illnesses by immune cells’ metabolic alterations. This review systematically examines how metabolic reprogramming of central and peripheral immune cells contributes to the pathogenesis of mental disorders, and critically evaluates emerging therapeutic strategies targeting these immunometabolic pathways—including pharmacological modulators (HK2 inhibitors, kynurenine pathway modulators, CD38 checkpoint targeting), lifestyle interventions (ketogenic diet, exercise), and their translational challenges. By integrating mechanistic insights with therapeutic perspectives, this review aims to provide fresh insights into disease mechanisms and inform the development of precision diagnostic and therapeutic approaches for mental disorders.

Synthetic cannabinoids (SCBs) represent a rapidly expanding and chemically diverse class of new psychoactive substances, deliberately designed to mimic the effects of natural cannabis. However, their high potency and full agonism at cannabinoid receptors lead to severe public health risks. The primary mechanism of SCBs' action involves the robust activation of CB1 and CB2 receptors, which in turn trigger a cascade of downstream events. This includes the profound dysregulation of key neurotransmitter systems, critical ion channel functions, and essential intracellular signaling pathways, culminating in widespread cellular dysfunction and damage. This comprehensive review delves into the multifaceted pathogenesis through which SCBs induce systemic harm. It systematically examines the clinical evidence and molecular mechanisms that connect SCB exposure to a spectrum of adverse outcomes, including life-threatening cardiovascular toxicities, significant neurological and psychiatric disorders, respiratory system diseases, digestive system diseases, and nephrotoxicity, and so forth. The point of this review, elucidating the intricate mechanisms underlying SCB toxicity, will be crucial, as this knowledge is the key to unlocking targeted therapies and effectively mitigating the severe health consequences of their abuse.

Purpose To establish a UPLC-MS/MS method for the simultaneous determination of chlorpheniramine (CPM) and its metabolites, desmethylchlorpheniramine (DCPM) and didesmethylchlorpheniramine (DDCPM), in blood and saliva, and to evaluate the feasibility of using saliva as an alternative biological matrix for CPM exposure assessment. Methods A UPLC-MS/MS method was established for the simultaneous determination of CPM, DCPM, and DDCPM in blood and saliva. Mobile phase A consisted of water and mobile phase B consisted of acetonitrile. After comparing eight extraction solvents, dichloromethane–acetonitrile (1:1, v/v) was selected for liquid–liquid extraction. An aliquot of 0.1mL of sample was mixed with internal standard and extraction solvent, vortexed, and centrifuged. The supernatant was filtered, and 5μL was injected for analysis. Six healthy volunteers received a single oral dose of 8mg CPM capsules. Blood and saliva samples were collected simultaneously at predetermined time points after administration, and saliva sampling continued until 18 days after the initial 48h period. Pearson correlation analysis was performed using SPSS 27.0 (α=0.05), the saliva-to-blood concentration ratio (S/P) was directly calculated, and pharmacokinetic parameters were calculated using DAS 2.0 software. Results The established UPLC-MS/MS method enabled simultaneous qualitative and quantitative analysis of CPM and its metabolites in blood and saliva, with method validation results meeting all acceptance criteria. After a single oral dose of 8mg CPM, the elimination half-life (t1/2) of CPM in saliva was (81.4±21.9) h and the time to peak concentration (Tmax) was (5.06±1.82) h; in blood, t1/2 was (35.8±17.4) h and Tmax was (2.13±0.58) h. For DCPM, t1/2 in saliva was (54.3±43.0) h and Tmax was (52.8±9.60) h; in blood, t1/2 was (19.0±5.54) h and Tmax was (48.12±1.62) h. The concentration range of DDCPM was 1.02–2.86ng/mL in blood and 1.00–1.53ng/mL in saliva. CPM concentrations in saliva and blood showed a positive correlation across all time points (r=0.848±0.09, P<0.05), and the concentration–time profiles also demonstrated a significant positive correlation (r=0.778±0.091, P<0.05). The S/P ratio was 2.38±0.98. Conclusions This study systematically elucidates, for the first time, the pharmacokinetic characteristics of CPM and its metabolites in saliva, demonstrating a strong positive correlation between salivary and blood CPM concentrations and a longer detection window in saliva. Saliva can serve as a non-invasive alternative matrix for CPM exposure assessment, providing a new technical approach and scientific basis for poisoning diagnosis in children and adults, therapeutic drug monitoring, and forensic toxicology analysis.

Ketamine is a synthesized anesthetic drug that was used extensively as a surgical anesthetic in the 1960s. Currently, ketamine is being investigated extensively for its potential as a treatment for depression. However, the addictive nature of ketamine has become an issue that cannot be ignored at this stage. As of now, there is no clear understanding of the changes in striatal metabolites and their relative metabolic pathways under the addictive effect of ketamine. In this study, a stable model of ketamine-induced conditioned place preference (CPP) was established. Non-targeted metabolomics and targeted metabolomics techniques, based on the ultra-performance liquid chromatography-Q Exactive hybrid quadrupole-Orbitrap mass spectrometry (UHPLC-QE/MS) and the UHPLC-MS platform, were employed to uncover the metabolic characteristics and neurotransmitter profiles of the striatum after ketamine abuse in mice. Potential biomarkers and related differential metabolic pathways of this model have been revealed. In non-targeted metabolomics analysis, striatal differential metabolites mainly involve pathways related to arginine synthesis, purine metabolism, and morphine addiction. In targeted metabolism, the striatum of mice receiving ketamine showed an increase in the content of the neurotransmitter kynurenine (Kyn) and a decrease in the content of the neurotransmitter dopamine (DA). Our study suggested that Kyn and DA metabolism disturbances might be associated with ketamine-induced CPP phenotypes and provided a new perspective for investigating the addiction mechanisms of ketamine.

Lactylation, an emerging form of post-translational modification derived from lactate, plays a pivotal role in numerous cellular processes such as tumor proliferation, metabolism, inflammation, and embryonic development. However, the precise molecular mechanisms by which lactylation controls these biological functions in both physiological and pathological contexts remain elusive. This review summarizes the latest reported regulatory mechanisms of protein lactylation in various diseases since 2024, introducing the latest research progress regarding the regulatory functions of protein lactylation in pathological processes, with particular attention to the regulatory mechanisms of non-histone lactylation modification in diseases. Finally, it outlines the potential of targeted lactylation therapy, proposes the main directions for future research, and emphasizes its scientific significance for future studies.

In forensic practice, the estimation of postmortem interval has been a persistent challenge. Recently, there has been an increasing utilization of metabolomics techniques combined with machine learning methods for postmortem interval estimation. When examining metabolite changes from a global perspective, rather than relying on specific substance changes, estimating postmortem interval through machine learning methods is more precise and entails fewer errors. Prior studies have investigated the use of metabolomics to estimate postmortem interval. Nevertheless, most of them focused on analyzing the metabolomic properties of a single organ or biofluid concerning a specific temperature. In this study, we employ the GC-MS platform to identify metabolites in the liver, kidney, and quadriceps femoris muscle of mechanically suffocated Sprague Dawley rats at various temperatures. Multivariable statistical analysis was used to determine differential compounds from the original data. The machine learning method was used to establish models for the estimation of postmortem interval under various ambient temperatures. As indicated by the results, liver, kidney, and quadriceps femoris muscle samples were screened for 24, 18, and 19 differential metabolites respectively, associated with postmortem interval under various ambient temperatures. Based on the metabolites listed above, the support vector regression models were established by utilizing single-organ and multi-organ metabolomics data for postmortem interval estimation. The multi-organ model showed a higher estimation accuracy. Also, a comprehensive generalization postmortem interval estimation model was established with multi-organ metabolomics data and temperature variables, which can be used for the postmortem interval estimation within the temperature range of 5–35℃. These results demonstrate that a multi-organ model utilizing metabolomics techniques can accurately estimate the postmortem interval under various ambient temperatures. Meanwhile, this research establishes a strong foundation for the practical application of metabolomics in postmortem interval estimation.

Schizophrenia (SCZ), a chronic psychiatric disorder, is characterized by cognitive impairment, hallucinations, and delusions, with current antipsychotic treatments offering limited efficacy and considerable side effects. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown promise in treating neurological and psychiatric conditions, though its precise mechanisms in schizophrenia remain unclear. Using network pharmacology, this study predicts CBD’s targets and pathways in schizophrenia, highlighting LPS-induced neuroinflammation and implicating 5-HT1AR-MAPK signaling as one potential contributor. In vitro, CBD (10 mg/kg, i.p.) treatment significantly reduced pro-inflammatory cytokines (e.g., NO, IL-1β, IL-6, TNF-α) and modulated the 5HT1AR-MAPK pathway, including increased 5HT1AR expression and decreased MAPK/ERK1/2 phosphorylation (p < 0.05). In vivo, CBD alleviated SCZ-like symptoms in a ketamine-induced animal model, reducing anxiety in the open field (p < 0.01) and elevated plus maze tests (p < 0.01), improving spatial memory in the Y-maze (p < 0.01) and social behavior (p < 0.0001) after 5 consecutive days of treatment. Critically, we validated CBD’s central anti-inflammatory effects by demonstrating reduced pro-inflammatory cytokine levels in both plasma and brain tissues (p < 0.05). Further correlation analysis established a direct link between brain cytokine suppression and behavioral improvements, integrating in vitro findings from BV2 microglial cells with in vivo neuroinflammatory and behavioral outcomes.These findings suggest the potential therapeutic benefits of CBD for SCZ, though further research, particularly clinical trials, is required to validate its efficacy and establish it as a novel therapeutic strategy.

Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is associated with chronic abuse leading to schizophrenia-like cognitive deficits. The gut-brain axis may play a role in mediating substance-induced neurotoxicity; however, its involvement in ketamine-induced cognitive impairment remains poorly understood. Here, chronic ketamine exposure was administered intraperitoneally to C57BL/6N mice to examine its effects on gut microbiota homeostasis and associated amino acid metabolism. Cognitive deficits were evaluated using the Y-maze and novel object recognition (NOR) tests. Hippocampal ultrastructure was assessed by transmission electron microscopy (TEM). Multi-omics integration included 16S rRNA sequencing, untargeted and targeted plasma metabolomics, and Spearman correlation analysis. The results showed that ketamine-exposed mice exhibited significant cognitive impairments, including impaired spontaneous alternation in the Y-maze (P < 0.05) and a reduced discrimination index in the NOR test (P < 0.01). TEM analysis revealed hippocampal mitochondrial damage, accompanied by chromatin condensation. Gut microbiota analysis indicated dysbiosis, with a notable increase in Lachnospiraceae, Bacteroidaceae, Helicobacteraceae, and Rikenellaceae and a decrease in Verrucomicrobiaceae and Prevotellaceae at the family level. Plasma amino acid levels were also disrupted, with a significant decrease in L-glutamine, L-lysine, L-threonine and an increase in L-cysteic acid. Furthermore, strong correlations were observed between the abundance of Bacteroides, branched-chain amino acids (BCAAs), and cognitive scores (|ρ| > 0.6, P < 0.05). This study identifies the microbiota-amino acid-mitochondrial axis as the underlying mechanism driving ketamine-induced neurotoxicity. It highlights the correlation between gut microbiota-associated amino acid reprogramming and this process, offering potential targets for microbiome-based interventions to combat substance-related cognitive impairments.

ObjectiveTo establish a rapid analysis method for cyanide based on a ratiometric fluorescent probe, providing a quantitative strategy for on-site visual and rapid detection of cyanide.MethodsA dual-emission ratiometric fluorescent probe （AuNCs-FL） was constructed by using bovine serum albumin （BSA）-stabilized gold nanoclusters （AuNCs, fluorescence emission at 660 nm） as the responsive signal unit and fluorescein （FL, emission at 515 nm） as the internal reference.ResultsThe etching effect of cyanide on AuNCs resulted in fluorescence quenching at 660 nm, while the fluorescence intensity of FL at 515 nm remained unchanged, enabling a rapid response analysis of cyanide shift from red to green fluorescence. The developed probe enabled rapid analysis of cyanide within 3 min, with a limit of detection （LOD） of 3.4 mg/L and a visual detection range of 10-100 mg/L.ConclusionThe AuNCs-FL fluorescent probe is structurally simple, low-cost, and easy to operate, delivering rapid and accurate results. It also avoids the interference from sulfides encountered in commercial cyanide test kits, making it suitable for the on-site rapid detection of suspected powder samples in cyanide poisoning cases.

In recent years, the abuse of ketamine as a recreational drug has been growing, and has become one of the most widely abused drugs. Continuous using ketamine poses a risk of drug addiction and complications such as attention deficit disorder, memory loss and cognitive decline. Ketamine-induced neurotoxicity is thought to play a key role in the development of these neurological complications. In this paper, we focus on the molecular mechanisms of ketamine-induced neurotoxicity. According to our analyses, drugs in causing neurotoxicity are closely associated with programmed cell death (PCD) such as apoptosis, autophagy, necroptosis, pyroptosis, and Ferroptosis. Therefore, this review will collate the existing mechanisms of programmed death in ketamine-induced neurotoxicity as well as explore the possible mechanisms by outlining the mechanisms of programmed death in other drug-induced neurotoxicity, which may be helpful in identifying potential therapeutic targets for neurotoxicity induced by ketamine abuse.

Background: Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It has attracted considerable attention for its rapid antidepressant effects in recent years, but ketamine-induced psychotic-like symptoms limit its clinical application. The molecular mechanisms and key targets underlying ketamine-induced psychiatric disorders remain unclear. Aims and Objectives: In this study, we utilized multi-brain region transcriptome data and bioinformatics methods to identify the key genes and pathways involved. Materials and Methods: First, we obtained transcriptome data of ketamine-treated and control brain tissues (including frontal cortex, hippocampus, striatum, and amygdala) from public databases (GEO). Simultaneously, we retrieved psychiatric disorder-related gene sets from the GeneCards database. For each brain region sample, we performed single-sample gene set enrichment analysis (ssGSEA) to calculate enrichment scores for the psychiatric disorder gene set and assess differences between groups. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene modules associated with the high-expression phenotype and conducted Gene Ontology (GO) functional annotation. In each brain region, differentially expressed genes (DEGs) between the high-expression and control groups were identified and intersected with WGCNA modules to obtain candidate key genes. Based on these candidates, we used three machine learning algorithms (least absolute shrinkage and selection operator (LASSO) regression, support vector machine recursive feature elimination (SVM-RFE), and Random Forest) to obtain 12 sets of candidate feature genes, comparing model performance using receiver operating characteristic (ROC) curves and area under the curve (AUC). Results: The results indicated that the LASSO model for the frontal cortex exhibited the best performance, identifying nine feature genes (Galr1, Cbr3, Crem, Fosl2, Mypn, Maff, Rhbg, Tslp, Klra2). Further GO/KEGG enrichment analysis and protein-protein interaction (PPI) network analysis highlighted the close association of Fosl2 and Maff with ketamine-induced psychiatric disorders. Comparison with our prior proteomic data on the prefrontal cortex of a ketamine model revealed a markedly downregulated protein Cbr3. Subsequent quantitative polymerase chain reaction (qPCR) assays in a ketamine-induced psychiatric disorder mouse model confirmed these findings: Cbr3 was significantly downregulated, while Fosl2 and Maff were significantly upregulated in the prefrontal cortex, consistent with our analysis. Thus, Cbr3, Fosl2, and Maff were identified as core genes in ketamine-induced psychiatric disorders. Finally, we evaluated the correlation between these core genes and immune cell infiltration, and analyzed their functions in humans using Genotype-Tissue Expression (GTEx) data and genome-wide association study (GWAS) loci. Conclusion: This study comprehensively applied gene set enrichment, WGCNA, and machine learning to multi-brain region transcriptomes to systematically screen for potential core genes of ketamine-induced psychiatric disorders, with preliminary qPCR validation. These findings provide new insights into molecular markers and mechanisms in this field.

Introduction: Alcohol abuse often precipitates traffic accidents or other mishaps due to its impact on psychomotor ability and subjective emotions. The multifaceted nature of impairment is chiefly influenced by dosage, yet there remains a dearth of research concerning the effects of alcohol consumption on driving ability among female Chinese individuals across varying doses. This study aims to investigate the influence of three different alcohol doses on changes in alcohol metabolism, psychomotor performance, and subjective response in Chinese females. Materials and Methods: Three dosage levels (0.2 g/kg, 0.6 g/kg, and 1.0 g/kg) were administered to 11 subjects with the genotype ADH1B*1/*2-ADH1C*1/*1-ALDH2*1/*1 in an acute drinking challenge. Blood pressure and heart rate were monitored using an electronic wrist blood pressure monitor at specific intervals, while blood alcohol concentration (BAC) and blood acetaldehyde concentration (BAAC) were analyzed via headspace gas chromatography. Psychomotor function was evaluated using auditory simple reaction time (ASRT), visual choice reaction time (VCRT), pursuit rotor task (PRT), and digit symbol substitution test (DSST). The Biphasic Alcohol Effects Scale (BAES) was employed to measure excitement and inhibition emotions. Data analysis utilized repeated-measures analyses of variance. Results: Across the three dosage levels, no significant differences in blood pressure and heart rate were observed compared to predrinking levels. Notably, at doses of 0.6 g/kg and 1.0 g/kg, BAC and BAAC exhibited significant increases compared to baseline levels at various postdrinking time points. Reaction times for ASRT and VCRT were notably prolonged at 1 and 2 h postdrinking with a dose of 1.0 g/kg, while DSST showed increased reaction time and decreased accuracy at 1 h postdrinking. Conversely, no significant differences were detected in other tests or at lower doses (0.2 g/kg and 0.6 g/kg). Moreover, BAES scores for excitement and inhibition remained consistent across different alcohol doses compared to predrinking levels. In addition, the findings suggest a correlation between psychomotor impairment and BAC. Conclusion: The findings of this study align with previous trends, indicating that higher alcohol doses exacerbate impairments in psychomotor functions, leading to heightened risks of traffic accidents or other incidents.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits both therapeutic potential and abuse liability. However, the spatial distribution of ketamine across brain regions remains poorly characterized. Meanwhile, elucidating the mechanism underlying ketamine-induced psychiatric disorders through the investigation of metabolite alterations in the specific brain regions targeted by ketamine is of crucial significance. This study investigated the neurochemical effects of chronic ketamine administration in C57BL/6 mice using in situ mass spectrometry imaging (MSI) and metabolomics. Mice treated with ketamine (30 mg/kg daily for 15 days) exhibited increased anxiety-like behaviors without cognitive deficits. MSI revealed ketamine accumulation in the cerebral cortex, midbrain, and cerebellum, while the key neurotransmitter γ-aminobutyric acid (GABA) distribution shifted toward thalamic and striatum regions. The prefrontal cortex and cerebellum were selected as targeted brain regions for metabolomics analysis based on the MSI results. In metabolomics results, 73 and 134 differential metabolites in the prefrontal cortex and cerebellum were identified, respectively, predominantly linked to Alanine, aspartate, and glutamate metabolism, Estrogen signaling pathway, and GABAergic synapse pathways. This study integrated behavioral assessments, in situ MSI, and metabolomics to visually resolve and multidimensionally correlate ketamine's spatial distribution in the brain with region-specific metabolic changes in a ketamine-induced anxiety model. The findings reveal distinct neurochemical disruptions across brain regions and offer a groundwork for further elucidating the mechanisms of ketamine-related anxiety.

Ketamine, a psychoactive substance strictly regulated by international drug conventions, is classified as a "new type drug" due to its excitatory, hallucinogenic, or inhibitory effects. The etiology of ketamine-induced psychiatric symptoms is multifaceted, with the immune regulatory mechanism being the most prominent among several explanatory theories. In recent years, the interaction between the immune system and nervous system have garnered significant attention in neuropsychiatric disorder research. Notably, the infiltration of peripheral lymphocytes into the central nervous system has emerged as an early hallmark of certain neuropsychiatric disorders. However, a notable gap exists in the current literature, regarding the immune regulatory mechanisms, specifically the peripheral immune alterations, associated with ketamine-induced psychiatric symptoms. To address this void, this article endeavors to provide a comprehensive overview of the pathophysiological processes implicated in psychiatric disorders or symptoms, encompassing those elicited by ketamine. This analysis delves into aspects such as nerve damage, alterations within the central immune system, and the regulation of the peripheral immune system. By emphasizing the intricate crosstalk between the peripheral immune system and the central nervous system, this study sheds light on their collaborative role in the onset and progression of psychiatric diseases or symptoms. This insight offers fresh perspectives on the underlying mechanisms, diagnosis and therapeutic strategies for mental disorders stemming from drug abuse.

Background: Ketamine demonstrates therapeutic potential but also high abuse liability. The neurobiological mechanisms underlying its addiction remain unclear. This study employs integrated metabolomics and proteomics to investigate alterations in endogenous metabolites and proteins across brain regions and plasma in a rat model of ketamine addiction. Materials and Methods: A ketamine addiction model was established by repeated administration (20 mg/kg) in Sprague–Dawley rats, with behavioral validation through conditioned place preference (CPP). Prefrontal cortex (PFC), striatum, and plasma samples were analyzed using ultra-high-performance liquid chromatography-Q-Orbitrap mass spectrometry-based metabolomics and TMT-based quantitative proteomics. Multivariate statistics and joint multiomics pathway analysis were applied. Results: Ketamine administration induced significant CPP (P < 0.05). Proteomics revealed 245 differentially expressed proteins in the PFC, enriched in dopaminergic, glutamatergic, and GABAergic synapses, and 188 in the striatum related to Alzheimer’s disease, retrograde endocannabinoid, and cAMP signaling. Plasma proteomics showed 156 differential proteins, primarily involved in complement, coagulation cascades, glycolysis, and gluconeogenesis. In the PFC, 60 metabolites were altered, like amino sugar and nucleotide sugar metabolism, while 132 metabolites in the striatum were linked to retrograde endocannabinoid signaling (ECS), dopaminergic synapse, and purine metabolism. Plasma metabolomics identified significant changes, such as arginine and proline metabolism. Joint multiomics pathway analysis highlighted consistent disruptions in glutamate/glutamine metabolism, retrograde ECS, purine metabolism, etc., across tissues. Conclusion: Ketamine addiction induces system-wide alterations in energy metabolism and neurotransmitter systems, with pronounced effects in the PFC and striatum, and detectable changes in plasma. These findings elucidate key enriched and interconnected metabolic pathways, advancing our mechanistic understanding of ketamine addiction and revealing potential targets for intervention.

Ketamine (Ket) is a globally widely used injectable anesthetic and recreational drug that can lead to persistent behavioral deficits and induce psychotic states. Immune pathogenesis is believed to play a pivotal role in psychological symptoms and abnormal behavior. However, the role of the immune system, particularly peripheral immune changes, in ketamine-induced behavioral deficits and even psychotic symptoms remains largely elusive. This study aimed to explore the potential role of the peripheral immune system in ketamine-induced behavioral abnormalities in mice. Continuous administration of high-dose ketamine in C57/B6J mice induced abnormalities representative of anxiety-depressive-like behavior or memory-cognitive behavior, accompanied by morphological changes, elevated levels of inflammatory cytokines, and enhanced expression of markers representing astrocyte activity in the hippocampus and prefrontal cortex. Furthermore, flow cytometry was used to analyze changes in the number and composition of immune cells in the peripheral blood of mice after high-dose ketamine administration. The results showed a significant increase in peripheral T lymphocytes, especially CD4+ lymphocytes, while NK cells and B lymphocytes did not exhibit significant changes. Additionally, there was a significant increase of CD4+ lymphocytes in the hippocampus and prefrontal cortex of the mice. Based on these findings, in vivo neutralization of CD4+ lymphocytes surprisingly reversed the anxiety-depressive-like behavior or memory-cognitive behavior of the mice and partially or fully restored brain tissue morphology and the expression of astrocyte activity molecules. Our results indicate that peripheral CD4+ lymphocytes play a crucial role in ketamine-induced behavioral abnormalities, and the presence of CD4+ lymphocytes may participate in and promote ketamine-induced anxiety, depressive-like behavior, and memory-cognitive dysfunction.

Methamphetamine (METH) abuse is frequently associated with persistent depressive symptoms, representing a major contributor to psychiatric comorbidity in substance use disorders; however, the underlying mechanisms remain poorly defined. Here, we show that binge METH exposure induces robust and persistent depressive-like behaviors in mice, accompanied by systemic cytokine elevation and expansion of Ly6C hi inflammatory monocytes in the peripheral circulation. These monocyte-derived macrophages infiltrated the medial prefrontal cortex (mPFC) via the choroid plexus and meninges in a CCR2-dependent manner. Single-cell RNA sequencing of mPFC immune cells identified distinct proinflammatory CCR2 + macrophage subsets enriched for IL-1β expression, which in turn amplified neuronal CCL2 production, establishing a self-sustaining macrophage–microglia crosstalk that perpetuated local inflammation. Pharmacological inhibition or genetic disruption of CCR2 prevented immune infiltration, reduced neuroinflammation, preserved synaptic integrity, and rescued both depressive-like and cognitive deficits. Together, these findings identify CCR2-dependent monocyte infiltration as a key mechanism linking METH exposure to affective dysfunction and highlight the CCL2/CCR2 axis as a potential therapeutic target in substance use–associated mood disorders.

Clinical studies have demonstrated the ability of ketamine to induce rapid antidepressant actions. However, considering the side effects such as neurotoxicity and abuse potential, the safety profile of prolonged use of ketamine still needs to be investigated. To provide evidence for toxicity studies of ketamine as an antidepressant.Rat’s locomotor activity and mood changes changes were observed by elevated plus-maze experiments. Untargeted metabolomics analysis of rat plasma and prefrontal cortex tissues was performed by UHPLC-QE/MS to screen differential expression metabolites and explore differential metabolic pathways. The number of entries into (0.80 ± 1.17 times, p < 0.05) and duration in (12.48 ± 13.65s, p < 0.01) open-arms were significantly lower than that of the control group (3.40 ± 1.62 times, 59.74 ± 23.32s), showing stronger anxiety degree.After withdrawal, the anxiety of rats was relieved. 74 differential metabolites were screened in the plasma of ketamine group, involving cysteine and methionine metabolism, valine and isoleucine biosynthesis, glutamine and glutamate metabolism. After one week of withdrawal, the cysteine and methionine metabolic pathways were still significantly different with the saline group; 87 metabolites in the prefrontal cortex significantly changed, which involved purine metabolism, ascorbic acid, and aldose metabolism pathways.