Neuropsychopharmacology最新文献

{"title":"Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics","authors":"Justin C. Strickland, Hayleigh E. Tilton, Noah M. Patton, Ryan Vandrey, C. Austin Zamarripa, Tory R. Spindle, Dustin C. Lee, Cecilia L. Bergeria, David Wolinsky, Jost Klawitter, Cristina Sempio, Jorge Campos-Palomino, Uwe Christians, Matthew T. Feldner, Jessica G. Irons, Marcel O. Bonn-Miller","doi":"10.1038/s41386-025-02232-x","DOIUrl":"10.1038/s41386-025-02232-x","url":null,"abstract":"Cannabis products premixed with caffeine are increasingly present in the United States marketplace. Despite emergence of this product class, no human laboratory data have directly evaluated the isolated impact of caffeine on Δ9-tetrahydrocannabinol (Δ9-THC) effects as well as additional impacts of other common co-administered cannabinoids. This double-blind, randomized, placebo-controlled, within-subject crossover study evaluated potential pharmacodynamic and pharmacokinetic interactions between/among Δ9-THC, caffeine, and cannabidiol (CBD). Participants (N = 20; 10 men/10 women) completed outpatient laboratory sessions in which oral Δ9-THC (7.5 mg cumulative), caffeine (180 mg cumulative), and/or CBD (105 mg cumulative) were co-administered in a cumulative dosing design. Primary outcomes included subjective effects indicative of abuse liability (e.g., drug high), performance effects that underlie safety risk (e.g., simulated driving), and plasma cannabinoid/caffeine concentrations. Caffeine co-administration produced minimal changes in Δ9-THC-induced subjective effects, performance, or metabolism, although signals for perceived driving impairment were observed. In contrast, CBD, when co-administered with Δ9-THC and caffeine increased outcomes associated with abuse liability (e.g., drug high, p = 0.002) and performance impairment versus Δ9-THC alone. CBD also increased plasma Δ9-THC (p = 0.004) and 11-OH-Δ9-THC (p < 0.001) concentrations compared with dose conditions without CBD co-administration. These data provide the first direct assessment of the pharmacodynamic and pharmacokinetic effects of Δ9-THC and caffeine when co-administered in humans. The robust alteration of Δ9-THC-induced effects and Δ9-THC pharmacokinetics by CBD further emphasizes the importance of considering full cannabinoid profiles. Broadly, these data highlight the importance of considering drug combinations and interactions in future cannabis regulatory decision-making.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1827-1835"},"PeriodicalIF":6.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connectome harmonics: a novel method exploring the psychedelic experience","authors":"Connor. J. Haggarty","doi":"10.1038/s41386-025-02217-w","DOIUrl":"10.1038/s41386-025-02217-w","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1757-1758"},"PeriodicalIF":6.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N,N-dimethyltryptamine effects on connectome harmonics, subjective experience and comparative psychedelic experiences","authors":"Jakub Vohryzek, Andrea I. Luppi, Selen Atasoy, Gustavo Deco, Robin L. Carhart-Harris, Christopher Timmermann, Morten L. Kringelbach","doi":"10.1038/s41386-025-02190-4","DOIUrl":"10.1038/s41386-025-02190-4","url":null,"abstract":"Exploring the intricate relationship between brain’s structure and function, and how this affects subjective experience is a fundamental pursuit in neuroscience. Psychedelic substances offer a unique insight into the influences of specific neurotransmitter systems on perception, cognition and consciousness. Specifically, their impact on brain function propagates across the structural connectome — a network of white matter pathways linking different regions. To comprehensively grasp the effects of psychedelic compounds on brain function, we used a theoretically rigorous framework known as connectome harmonic decomposition. This framework provides a robust method to characterize how brain function intricately depends on the organized network structure of the human connectome. We show that the connectome harmonic repertoire under N,N-dimethyltryptamine (DMT) is reshaped in line with other reported psychedelic compounds - psilocybin, lysergic acid diethylamide (LSD) and ketamine. Furthermore, we show that the repertoire entropy of connectome harmonics increases under DMT, as with those other psychedelics. Importantly, we demonstrate for the first time that measures of energy spectrum difference and repertoire entropy of connectome harmonics index the intensity of subjective experience of the participants in a time-resolved manner reflecting close coupling between connectome harmonics and subjective experience.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1768-1776"},"PeriodicalIF":6.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02190-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic treatment with fluoxetine regulates mitochondrial features and plasticity-associated transcriptomic pathways in parvalbumin-positive interneurons of prefrontal cortex","authors":"Elias Jetsonen, Giuliano Didio, Ilida Suleymanova, Indrek Teino, Eero Castrén, Juzoh Umemori","doi":"10.1038/s41386-025-02219-8","DOIUrl":"10.1038/s41386-025-02219-8","url":null,"abstract":"Chronic treatment with fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI), is known to promote neural plasticity. The role of fluoxetine in plasticity has been particularly tied to parvalbumin-positive interneurons, a key population of GABAergic neurons that regulate inhibitory tone and network stability. While our previous studies have highlighted fluoxetine-induced plasticity in the visual cortex and hippocampus, its cell-type-specific effects in the prefrontal cortex (PFC) remain unclear. This study aims to investigate the effects of chronic fluoxetine treatment on PV-positive (PV+) cells, identified using PV-IRES-Cre-driven reporter expression in the PFC. Using Translating Ribosome Affinity Purification (TRAP), we found that fluoxetine treatment altered the expression of 50 distinct biological pathways. Downregulated pathways are involved in mitochondrial ATP production, including components of the electron transport chain, and ribosomes. Upregulated pathways were associated with phosphatase activity, ion channel function, and cytoskeletal remodeling —molecules broadly implicated in synaptic signaling and plasticity-related processes. In FACS-sorted cells, mitochondrial DNA (mtDNA) expression was significantly increased in PV+ cells of the PFC, while intracellular ATP levels remained unchanged. Immunohistochemical analyses demonstrated reduced PV expression and weakened perineuronal nets in specific PFC subregions, suggesting a plasticity-permissive state in PV+ cells. TOMM22 signal intensity in PV+ cells showed a slight but significant increase in the prelimbic region, suggesting potential compensatory mitochondrial biogenesis despite transcriptomic downregulation of mitochondrial genes. Our findings reveal that chronic fluoxetine induces coordinated transcriptional, structural alterations in PV+ cells of the PFC, including shifts in mitochondrial-related gene expression and plasticity-associated pathways. These changes may contribute to region-specific shifts in cortical inhibition and plasticity, complementing previous reports of fluoxetine-mediated behavioral modulation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1864-1874"},"PeriodicalIF":6.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02219-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of β-Arrestin 2 in the antinociceptive and side effect profile of morphine and the novel mu opioid receptor agonists, kurkinorin and kurkinol","authors":"Ross van de Wetering, Amy F. Alder, Andrew Biggerstaff, Katya Sellen, Dan Luo, Rachel S. Crowley, Thomas E. Prisinzano, Bronwyn M. Kivell","doi":"10.1038/s41386-025-02214-z","DOIUrl":"10.1038/s41386-025-02214-z","url":null,"abstract":"The development of safer mu opioid receptor (MOR) agonists with reduced side effects is a key focus of pain research. Some studies have suggested that MOR agonists with reduced β-arrestin 2 (βArr2) signaling (i.e. G-protein biased agonists) may have greater therapeutic windows. However, there have been a several conflicting reports, and it is not clear what role, if any, βArr2 signaling plays in MOR-mediated analgesia, tolerance, or side effects. Therefore, we used βArr2 knockout mice to systematically investigate the causal role of βArr2 signaling in antinociception, antinociceptive tolerance, respiratory depression, constipation, and reward induced by morphine and the two novel MOR agonists, kurkinorin and kurkinol. Kurkinorin and kurkinol exhibited potent antinociceptive effects that were reversed by MOR knockout. Unlike morphine or kurkinorin, our most G-protein biased agonist, kurkinol, showed no significant tolerance after seven days of ~2×ED50 dosing. However, in a chemotherapy-induced neuropathic pain model, all three compounds were ineffective after 20 days of ~ED50 dosing, indicative of tolerance. All compounds exhibited significant MOR-dependent side effects, though kurkinorin had reduced gastrointestinal and respiratory depressive effects compared to morphine despite exhibiting less G-protein bias. Knockout of βArr2 significantly increased antinociceptive potency for morphine and kurkinorin but not kurkinol, and otherwise had no significant impact on tolerance or any side effect tested. These results largely suggest that βArr2 signaling does not drive MOR-mediated antinociceptive tolerance, respiratory depression, constipation, or reward and do not support the development of G-protein biased compounds as a broadly effective strategy to reduce side effects.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1777-1786"},"PeriodicalIF":6.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02214-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal separation disrupts noradrenergic control of adult coping behaviors","authors":"Chayla R. Vazquez, Léa J. Becker, Chao-Cheng Kuo, Solana A. Cariello, Ayah N. Hamdan, Ream Al-Hasani, Susan E. Maloney, Jordan G. McCall","doi":"10.1038/s41386-025-02201-4","DOIUrl":"10.1038/s41386-025-02201-4","url":null,"abstract":"Early life stress (ELS) profoundly impacts the brain and correlates with negative affective behaviors in adulthood. The locus coeruleus (LC), a stress-responsive brainstem nucleus that supplies most of the brain with norepinephrine (NE), is known to modulate negative affect. Using repeated maternal separation stress (MSS), we investigated the impact of ELS on the LC and stress-related behaviors in adulthood. We performed ex vivo cell-attached electrophysiology across the lifespan to reveal that MSS significantly increased LC firing during early development and adulthood but not in pre-adolescence and adolescence. We next examined potential changes in the expression of genes linked to LC function. In adulthood, MSS decreased mRNA levels for both the alpha-2A adrenergic receptor and dopamine beta-hydroxylase, the enzyme necessary for NE synthesis. At the behavioral level, MSS increased locomotion in approach-avoidance exploratory assays and increased immobility in the forced swim test. While forced swim increased LC cFos expression, a marker for neuronal excitation, in both No MSS and MSS mice, this increase was significantly lower in MSS mice than in No MSS controls. We further showed that MSS decreased the number of LC cells, possibly underlying the difference in cFos induction and gene expression between MSS and No MSS mice. Finally, we showed that inhibiting the LC in No MSS mice increased immobility time, but did not affect MSS immobility. Instead, LC inhibition in MSS mice increased climbing time. Together, this study demonstrates that MSS dysregulates LC-NE activity across the lifespan and disrupts LC regulation of coping strategies during stressful events.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1795-1806"},"PeriodicalIF":6.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02201-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connectome-based encoding of subjective drug responses to acute oral methamphetamine","authors":"Lester G. Rodriguez Santos, Hanna Molla, Marzieh Babaeianjelodar, Harriet de Wit, Sarah W. Yip","doi":"10.1038/s41386-025-02215-y","DOIUrl":"10.1038/s41386-025-02215-y","url":null,"abstract":"Methamphetamine is a widely abused drug, and its chronic use is associated with significant negative physical and mental health consequences. Individual differences in subjective responses to acute methamphetamine have been previously linked to vulnerability for future misuse. However, the neural mechanisms underlying these individual differences remain poorly understood, particularly at the functional connectome level. Resting state functional connectivity data following an acute methamphetamine challenge was acquired from 83 healthy adults using a randomized, double-blind, placebo-controlled, cross-over study design (two sessions per participant; 165 total sessions) and used to generate brain-behavior predictive models of subjective response using five-fold cross-validation. Heart rate served as a control variable to assess the specificity of the predictive models to subjective versus physiological effects. External generalizability was tested using data from a separate sample of 22 healthy adults acquired using a similarly rigorous placebo-controlled design. Connectome-based predictive models successfully predicted individual differences in subjective response (rho(ρ)=0.25, p = 0.02) but not cardiovascular effects (ρ = 0.08, p = 0.199), as driven by individual differences in predominantly sensorimotor connections. Similar associations between connectivity within the identified network and subjective responses were observed in the external replication sample (ρ = 0.37, p = 0.044). These findings suggest that individual differences in subjective response to methamphetamine reflect distinct neural effects, particularly alterations of motor/sensory network function. These associations are specific to subjective responses and thus cannot easily be accounted for by pharmacokinetic factors. Together these findings suggests that individual differences in the functional connectome encode for differences in subjective methamphetamine effects that may contribute to differences in susceptibility for escalation in use.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1787-1794"},"PeriodicalIF":6.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"For those with schizophrenia, does cannabidiol make cannabis use safer?","authors":"Anya K. Bershad","doi":"10.1038/s41386-025-02199-9","DOIUrl":"10.1038/s41386-025-02199-9","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1755-1756"},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02199-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood and neuronal extracellular vesicle mitochondrial disruptions in schizophrenia","authors":"A. Ankeeta, Ashutosh Tripathi, Bindu Pillai, Yizhou Ma, Joshua J. Chiappelli, Jessica N. Jernberg, Keiko Kunitoki, Xiaoming Du, Si Gao, Bhim M. Adhikari, Consuelo Walss-Bass, Giselli Scaini, Peter Kochunov, Anilkumar Pillai, L. Elliot Hong","doi":"10.1038/s41386-025-02204-1","DOIUrl":"10.1038/s41386-025-02204-1","url":null,"abstract":"The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders, including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated with brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p = 0.0002) and neuronal EVs (p = 0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r = 0.53, 0.53; p = 0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r = 0.29, 0.49; p = 0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell-free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1836-1844"},"PeriodicalIF":6.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of USP22 alleviates LPS-induced microglial inflammation and mouse depressive-like behaviors via KAT2A","authors":"Yan Lu, Yuhan Zheng, Xiaoru Sun, Yujie Song, Yilu Zhou, Fuyi Shen, Rongrong Huang, Zhendong Xu","doi":"10.1038/s41386-025-02207-y","DOIUrl":"10.1038/s41386-025-02207-y","url":null,"abstract":"Depression is a chronic mental illness that has emerged as the second most prevalent disease globally, characterized by symptoms such as low mood, reduced interest, and cognitive impairment. The onset of depression has been associated with microglial inflammation, but the molecular mechanisms behind this are not well understood. Here, we investigated the mechanisms involved in the roles of microglial inflammation in promoting depression by establishing a mouse model of inflammation-related depression via lipopolysaccharide (LPS) administration. We found that LPS treatment led to microglial activation and increased the deubiquitinating enzyme, USP22, expression in the mouse hippocampus. Further, knockdown of USP22 in microglia inhibited depressive-like behaviors and intracerebral inflammation in the mouse model. Moreover, subsequent mechanistic analyses revealed that KAT2A, which serves as a ubiquitination substrate, is modulated by USP22, thereby influencing mitochondrial damage and oxidative stress in microglia. Our findings indicate that USP22 facilitates oxidative stress and inflammatory responses in microglia through the deubiquitination of KAT2A, providing a promising target for the development of therapeutic strategy for the depression treatment.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1904-1912"},"PeriodicalIF":6.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02207-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}