Pharmacological Reviews最新文献

{"title":"Thrombin generation and the pharmacodynamics of parenteral anticoagulants.","authors":"Joseph R Shaw, Cheryl L Maier, Michaël Hardy, François Mullier, Jonathan Douxfils, Kenichi Tanaka, Bianca Rocca, Hugo Ten Cate, Paul Y Kim, Marc Carrier, Jean M Connors, Jerrold H Levy","doi":"10.1016/j.pharmr.2026.100135","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100135","url":null,"abstract":"<p><p>Parenteral anticoagulants are mainstay therapies in critical care and perioperative settings because of their unique pharmacological properties, but they have a narrow therapeutic window. This emphasizes the need to thoroughly understand their pharmacodynamics effects on hemostasis. Thrombin generation assays provide a comprehensive measure of coagulation and can characterize class-specific anticoagulant effects. We reviewed the literature with a focus on parenteral anticoagulants to define the role of thrombin generation as a pharmacodynamic measure of anticoagulation status. We contextualize these results in light of findings from a prior review on the effects of oral anticoagulants on thrombin generation and consider our findings in view of results stemming from comparative anticoagulation-focused epidemiologic research. This review provides proof of principle that, from a pharmacodynamics perspective, not all anticoagulants are the same. They exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects, such as unfractionated or low-molecular-weight heparins, are better able to suppress thrombin generation than selective direct inhibitors, such as bivalirudin, argatroban, direct oral anticoagulants, or factor XI(a) inhibitors. We propose a conceptually valid theoretical framework, grounded in mechanistic rationale, supported by experimentation, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants. The knowledge reviewed herein may support the future development of more personalized approaches to anticoagulation treatment. Our findings contribute a foundation upon which future anticoagulation research can be based and warrant further investigation. SIGNIFICANCE STATEMENT: From a pharmacodynamic perspective, not all anticoagulants are the same. Oral and parenteral anticoagulants exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects are better able to suppress thrombin generation than selective direct inhibitors. This review proposes a theoretical framework, grounded in mechanistic rationale, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100135"},"PeriodicalIF":17.3,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856949","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":"Pregnane X receptor in disease: From xenobiotic sensor to therapeutic target.","authors":"Yue Gao, Qingqing Yu, Lingzhi Zhang, Zijian He, Xiao Li, Weibin Ou, Xingrui Wu, Shicheng Fan, Huichang Bi","doi":"10.1016/j.pharmr.2026.100133","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100133","url":null,"abstract":"<p><p>The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor that serves as a classical and central regulator of xenobiotic metabolism and endogenous metabolic homeostasis. Recent studies have revealed that PXR plays critical roles in the pathogenesis and progression of diseases across multiple organ systems, including hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine disorders. Notably, PXR activation can exert protective effects by improving metabolic balance, reducing inflammation, and preventing fibrosis; however, it may promote disease progression in certain settings, highlighting its dual roles. Advances in pharmacological research have led to the identification of numerous PXR agonists and antagonists, including endogenous ligands, natural products, and synthetic compounds, many of which show therapeutic potential. This review summarizes recent progress on the pharmacological roles of PXR in organ-specific diseases and provides an overview of current strategies targeting PXR, offering new insights into its potential as a therapeutic target. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor traditionally recognized as a master regulator of xenobiotic metabolism. Growing evidence demonstrates that PXR plays important roles beyond drug metabolism, regulating the pathogenesis and progression of hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine diseases. This review summarizes current knowledge on PXR's organ-specific functions and pharmacological modulation, highlighting PXR as a promising drug target across multiple disease contexts.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100133"},"PeriodicalIF":17.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777986","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":"Emerging mechanistic trends and clinical efficacy for methotrexate: Applications to inflammatory bowel disease.","authors":"Jeehyun Karen You, Theresa T Pizarro, Tommaso L Parigi","doi":"10.1016/j.pharmr.2026.100132","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100132","url":null,"abstract":"<p><p>Methotrexate (MTX) was among the first steroid-sparing agents introduced for the treatment of inflammatory bowel disease (IBD). Its efficacy is well established for Crohn's disease, though studies of its use in ulcerative colitis have largely reported negative results, with only some, although inconsistent, findings suggesting limited benefit. In this review, we provide a comprehensive and up-to-date evaluation of MTX's use in IBD, including its key mechanisms of action(s), therapeutic value, as well as emerging targets that underscore the complexity of this drug and the biological landscape it alters. Despite its longstanding use, the full spectrum of MTX's effects contributing to its efficacy in IBD remains incompletely understood. Although multiple pathways have been implicated, the relative importance of each remains nebulous, and additional, unidentified functions may play a role, particularly in contexts not pertaining to immunomodulation. We highlight recent findings that poise MTX as an unexpected but promising agent for mucosal healing. We also provide a detailed evaluation of clinical studies, encompassing randomized controlled trials and observational data, highlighting MTX's effectiveness, differences in route of administration, safety profile, and limitations as they pertain to the management of IBD. As therapeutic targets for IBD evolve, we discuss MTX's future positioning by exploring clinical perspectives regarding its utility and examine the latest evidence that indicates there may be novel, previously unexplored, therapeutic potential. By bridging mechanistic insights with clinical evidence, this review underscores MTX's enduring, albeit niche, position in IBD therapy and highlights key areas for future investigation to optimize its use. SIGNIFICANCE STATEMENT: Methotrexate remains a valuable, though underutilized, therapeutic option for the management of inflammatory bowel disease. This review provides a comprehensive overview of methotrexate's pharmacology, integrating emerging mechanistic insights and clinical data to reframe its role beyond immunomodulation, particularly at the gastrointestinal mucosal interface, thereby identifying novel avenues for future research that may expand its clinical utility in inflammatory bowel disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100132"},"PeriodicalIF":17.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639389","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":"Epithelial cells in chronic obstructive pulmonary disease exacerbations: Targets for lung repair.","authors":"Wei Ji, Hayriye Akel Bilgic, Maarten van den Berge, Huib A M Kerstjens, Gert Folkerts, Reinoud Gosens, Saskia Braber","doi":"10.1016/j.pharmr.2026.100131","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100131","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic respiratory symptoms and persistent, often progressive, loss of lung function. Patients, particularly those with severe disease, frequently experience exacerbations triggered by viral and bacterial infections. Exacerbations are closely linked to the rapid decline in lung function, accounting for more than 50% of the accelerated loss over the lifetime of a patient with COPD. Airway epithelial cells play a central role in the development of COPD exacerbations. As the first line of defense, these cells form tight intercellular junctions, creating a protective barrier against pathogens and producing mucus and antimicrobial peptides to eliminate bacteria and viruses. Upon pathogen recognition via pattern recognition receptors, epithelial cells initiate inflammatory responses by releasing cytokines and chemokines that recruit immune cells. This inflammation can become dysregulated in COPD, contributing to tissue damage and exacerbation severity. Furthermore, airway epithelial cells are particularly important in promoting lung repair and restoring homeostasis. They modulate inflammation resolution, promote extracellular matrix remodeling, and support lung regeneration. In COPD, chronic inflammation and repeated exacerbations impair epithelial function, disrupt repair mechanisms, and hinder lung regeneration, contributing to irreversible damage. This review highlights the crucial role of airway epithelial cells in COPD exacerbations, focusing on their regulatory functions in maintaining barrier integrity, managing inflammation and promoting epithelial lung repair. Moreover, current and future therapeutic strategies aimed at enhancing epithelial barrier function, controlling airway inflammation, and supporting lung recovery and regeneration are discussed, highlighting key directions for future investigation. SIGNIFICANCE STATEMENT: Chronic obstructive pulmonary disease exacerbations represent a pharmacologically actionable period characterized by epithelial barrier disruption, dysregulated inflammation, and impaired repair. This review positions airway epithelial cells as central orchestrators of these processes, regulating host defense, immune interactions, and regenerative responses. By targeting epithelial dysfunction during exacerbations, this review highlights the potential therapies that go beyond symptom relief and support lung repair and modify disease progression.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100131"},"PeriodicalIF":17.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717662","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":"International Union of Basic and Clinical Pharmacology. CXXI. Apelin receptor pharmacology in the human cardiovascular system and emerging clinical applications.","authors":"Anthony P Davenport, Thomas L Williams, Duuamene Nyimanu, Robyn G C Macrae, Rhoda E Kuc, Fiona A Chapman, Peiran Yang, Neeraj Dhaun, Janet J Maguire","doi":"10.1016/j.pharmr.2026.100130","DOIUrl":"https://doi.org/10.1016/j.pharmr.2026.100130","url":null,"abstract":"<p><p>The apelin receptor binds 2 families of endogenous peptide, apelin and Elabela, but unusually these share little sequence similarity in the N-terminal sequences of the binding domains. Cryo-electron microscopy, X-ray crystallography combined with AlphaFold has yielded a molecular map of the interaction of amino acids with the apelin receptor in complex with endogenous peptides and biased ligands. In the early embryo, the apelin signaling pathway is essential for cardiovascular development, with receptor knockout models displaying severe cardiovascular defects. In adults, the principal short-term effects of [Pyr¹]apelin-13, infused into healthy volunteers was increased cardiac output and decreased peripheral resistance without side effects. Importantly, these beneficial effects of systemic apelin were retained in patients with heart failure and pulmonary arterial hypertension. In chronic kidney disease, [Pyr¹]apelin-13 showed additional therapeutic potential, increasing glomerular filtration rate while reducing proteinuria. Identification of these favorable actions in disease has sparked the development of more effective agonists with improved pharmacokinetics and pharmacodynamics profiles. Among these are G protein-biased peptide agonists, designed to minimize receptor desensitization by reducing internalization via the β-arrestin pathway. These have shown efficacy in proof-of-concept studies and in animal models of pulmonary arterial hypertension, one of the most promising therapeutic targets. This review focuses on the clinical pharmacology of the apelin receptor, exploring the pathophysiology of diseases where the apelin signaling pathway is dysregulated that have emerged during the last 5 years. SIGNIFICANCE STATEMENT: This review focuses on the pharmacology of the apelin receptor where structural analysis has generated a molecular map of interaction with endogenous ligands, apelin and Elabela, as well as with peptide and small molecule agonists. Novel unbiased and biased apelin agonists are progressing through the clinic targeting pathophysiological conditions where the apelin signaling pathway is dysregulated.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100130"},"PeriodicalIF":17.3,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531593","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":"Preclinical abuse potential testing using behavioral economics and drug self-administration demand-curve analysis: A strategy to improve resolution of drug stratification for regulatory control.","authors":"Matthew L Banks, S Stevens Negus, Neil B Varshneya, Chad J Reissig, Dominic Chiapperino, Justin C Strickland, Derek D Reed, Steven R Hursh, David N Kearns","doi":"10.1016/j.pharmr.2025.100112","DOIUrl":"10.1016/j.pharmr.2025.100112","url":null,"abstract":"<p><p>New chemical entities (NCEs) that act on the central nervous system are synthesized in pharmaceutical drug development programs for investigational purposes or by clandestine laboratories for illicit purposes. One component in the regulatory evaluation process of any NCE is abuse potential assessment, which involves both preclinical and human laboratory experiments to compare a NCE with an established and validated positive control that has known abuse potential in humans. Although multiple procedures are available in both preclinical and human laboratories, this review has focused on preclinical drug self-administration procedures because these results are heavily weighted in the regulatory evaluation process. Preclinical drug self-administration procedures have demonstrated high predictive validity for human abuse potential, and procedures that use simple fixed-ratio schedules of reinforcement, as recommended by the current U.S. Food and Drug Administration guidance, have good sensitivity for detecting drug reinforcement and abuse potential. However, these procedures have displayed poor resolution for ranking NCEs along an abuse-potential continuum that may inform controlled substance schedule placement. This review discusses the utility of behavioral economic/demand-curve experimental designs as a method to improve the resolution for differentiating relative reinforcing strength across drugs and ranking abuse potential for considerations of regulatory control. Theoretical benefits of demand-curve analysis are considered, and experimental parameters that optimize those benefits are reviewed. The influence of chronic drug exposure and history on demand-curve metrics of drug reinforcing strength and abuse potential is also reviewed. Future directions are highlighted toward empirically determining the utility of behavioral economic approaches for preclinical abuse potential assessment. SIGNIFICANCE STATEMENT: Simple fixed-ratio schedules of reinforcement have good sensitivity for detecting drug reinforcement and abuse potential but have poor resolution for ranking chemical entities along an abuse-potential continuum. Behavioral economic/demand-curve approaches maybe a method to increase resolution for abuse potential assessment. Accordingly, a preclinical abuse potential algorithm incorporating both simple fixed-ratio schedules and behavioral economic/demand-curve methods is described. Finally, the manuscript describes how individual subject traits and state variables, including chronic drug exposure and history, impact behavioral economic metrics of drug abuse potential.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100112"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119863","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":"Gut microbiome and bile acid metabolism in liver disease: Mechanisms, clinical implications, and therapeutic opportunities.","authors":"Huiping Zhou, Yi Huang, Chen Chen, Meiyi Song, Phillip B Hylemon","doi":"10.1016/j.pharmr.2026.100120","DOIUrl":"10.1016/j.pharmr.2026.100120","url":null,"abstract":"<p><p>The intricate interplay between the gut microbiome and bile acid metabolism via the gut-liver axis is fundamental to hepatic homeostasis. Perturbations in this axis are increasingly implicated in the pathogenesis of diverse liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. This review integrates current understanding of hepatic bile acid synthesis, enterohepatic circulation, and gut microbial bile acid transformations, detailing how bile acids function as signaling molecules through nuclear receptors including farnesoid X receptor, pregnane X receptor, vitamin D receptor, constitutive androstane receptor, and G-protein-coupled receptors; G protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), and sphingosine-1-phosphate receptor 2. We explore disease-specific alterations in gut microbiota composition and bile acid profiles in metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and liver cancers, focusing on mechanisms linking gut dysbiosis, impaired intestinal barrier function, altered bile acid signaling, inflammation, and immune modulation to liver injury and progression. Furthermore, we discuss the clinical implications, highlighting the potential of microbiome signatures and bile acid profiles as diagnostic and prognostic biomarkers. Therapeutic strategies targeting the gut-liver axis, including probiotics, fecal microbiota transplantation, farnesoid X receptor agonists, and fibroblast growth factor 19 analogs, are reviewed. Finally, we address current challenges and future directions, emphasizing the need for multiomics integration, functional studies, and personalized medicine approaches to leverage the gut-liver axis for improved liver disease management. SIGNIFICANCE STATEMENT: Disruption of the gut microbiome-bile acid-liver axis is now recognized as a unifying mechanism driving multiple liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. Unraveling the molecular and microbial interactions within this axis offers fundamental insights into disease pathogenesis and reveals novel therapeutic opportunities. Integrating multiomics technologies with artificial intelligence-based analytics will accelerate the discovery of predictive biomarkers and personalized interventions, advancing the field toward precision-based liver disease treatment protocols.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100120"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317921","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":"The neuropharmacological basis of placebo analgesia: Mechanisms and clinical applications in the context of chronic pain.","authors":"Damien C Boorman, Lewis S Crawford, Zahra Siddiqi, Loren J Martin, Luke A Henderson, Kevin A Keay","doi":"10.1016/j.pharmr.2025.100111","DOIUrl":"10.1016/j.pharmr.2025.100111","url":null,"abstract":"<p><p>The therapeutic value of placebo analgesia to treat conditions of chronic pain is both underappreciated and understudied. It is now abundantly clear that chronic pain is caused by a complex array of biological adaptations, including changes to neural, endocrine, and immune function, which undoubtedly explains why it is so difficult to treat. Paradoxically, however, this also presents a unique opportunity for placebo interventions by offering several biological targets that could lead to analgesic relief for chronic pain patients. In this review, we first outline the problem of chronic pain, highlighting the similarities and differences between acute and chronic pain mechanisms. Next, we comprehensively review studies investigating the neurobiological and neuropharmacological mechanisms underlying placebo analgesia in acute and chronic pain contexts. We conclude that the neural mechanisms and neuropharmacology of placebo analgesia in the context of chronic pain are currently poorly understood and deserve specific focus for future research. Finally, we discuss the range of therapeutic possibilities for placebo interventions to provide clinically relevant and meaningful pain relief to chronic pain patients, many of which could be quickly, easily, and ethically implemented into clinical practice today. SIGNIFICANCE STATEMENT: Chronic pain remains a significant global health challenge as it is often resistant to conventional treatments. This review synthesizes our current knowledge of the neurobiology of acute and chronic pain and highlights key overlaps in the mechanisms of placebo analgesia. We highlight how placebo-based strategies, including expectancy modulation, pharmacological conditioning, and open-label placebos, could be ethically integrated into clinical practice to enhance pain management. These approaches offer a promising avenue to activate endogenous pain relief systems, reduce opioid reliance, and personalize treatment for both placebo responders and nonresponders. Harnessing placebo mechanisms presents a largely underused yet promising approach to chronic pain management, with the potential to refine existing treatment strategies and address the global burden of chronic pain.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100111"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044222","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":"Erratum to \"Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action\" [Pharmacological Reviews 78 (2025) 100101].","authors":"Fatima Dakroub, Bassel Awada, Samar Abdelhady, Abdullah A Shaito, Ali H Eid, Joseph Walker, Stefania Mondello, Corina O Bondi, Federico Moro, Bahaa Elgendy, Kevin K Wang, Elisa R Zanier, Yehia Mechref, Firas Kobeissy","doi":"10.1016/j.pharmr.2026.100114","DOIUrl":"10.1016/j.pharmr.2026.100114","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100114"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137709","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":"The role of polysubstance use in the development, maintenance, and treatment of stimulant use disorders.","authors":"Mia I Rough, Michael A Nader","doi":"10.1016/j.pharmr.2026.100119","DOIUrl":"10.1016/j.pharmr.2026.100119","url":null,"abstract":"<p><p>Stimulant use disorders represent a significant public health challenge, with no U.S. Food and Drug Administration (FDA) pharmacotherapies currently available. A growing concern is that stimulant use rarely occurs in isolation. Instead, it often involves sequential or simultaneous use of multiple substances. This review explores the mechanistic, epidemiological, clinical, and preclinical dimensions of polysubstance use involving stimulants, particularly cocaine and methamphetamine. Key gaps in the existing literature are identified to underscore the critical need for polysubstance use research across epidemiological, clinical, and preclinical domains. Additionally, the review highlights the importance of fostering interdisciplinary collaborations across these domains to inform the development of more effective interventions for stimulant use disorders and to mitigate the widespread harm caused by substance use globally. SIGNIFICANCE STATEMENT: Stimulant use rarely occurs in isolation and is frequently accompanied by polysubstance use, which increases health risks and complicates prevention and treatment strategies. This review highlights critical gaps in research examining polysubstance use involving stimulants and emphasizes the urgent need for the study of the co-use of drugs and interdisciplinary collaboration. Addressing these gaps is essential to inform the development of effective interventions for stimulant use disorders.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100119"},"PeriodicalIF":17.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197906","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}