{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:37:29Z","timestamp":1786441049931,"version":"build-2736575974"},"reference-count":109,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Concurrent exposure to analgesic and psychotropic drugs is frequent in patients with pain, psychiatric comorbidity, frailty, or acute-care needs. The clinically important question is whether analgesics and psychotropic drugs act on the same metabolic, transporter, receptor, ion-channel, or cellular stress systems. This narrative mechanistic review discusses those points of contact. CYP-mediated inhibition or induction, phenoconversion, altered parent-to-metabolite ratios, and blood\u2013brain barrier transporter effects can change both systemic and central exposure, particularly through CYP2D6, CYP3A4, CYP2C9, CYP2B6, and P-glycoprotein. Pharmacodynamic toxicity may involve serotonergic excess, opioid and GABAergic effects in respiratory-control networks, hERG\/IKr-related loss of repolarization reserve, or dopamine D2 receptor blockade. Non-opioid analgesics and psychotropic background therapy add further pathways involving renal and gastrointestinal vulnerability, hematological toxicity, mitochondrial injury, and altered central nervous system function. At the cellular level, mitochondrial dysfunction, oxidative stress, calcium dysregulation, and endoplasmic reticulum stress are discussed primarily as mechanistic or preclinical contributors unless direct clinical evidence is available. Overall, analgesic\u2013psychotropic co-exposure is presented as a clinically important example of pathway convergence, while pharmacogenomic and computational approaches are interpreted in relation to drug exposure, organ reserve, and patient-specific vulnerability.<\/jats:p>","DOI":"10.3390\/ijms27167168","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:11:16Z","timestamp":1786439476000},"page":"7168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Mechanisms of Acute Drug Toxicity in Polypharmacy: Analgesic\u2013Psychotropic Interactions"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4985-8115","authenticated-orcid":false,"given":"Nikolina","family":"Rijavec","sequence":"first","affiliation":[{"name":"University Psychiatric Clinic Ljubljana, Chengdujska cesta 45, SI-1260 Ljubljana, Slovenia"},{"name":"Department of Psychiatry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4491-6428","authenticated-orcid":false,"given":"Boris","family":"Rijavec","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Anaesthesiology and Surgical Intensive Care, University Medical Centre Ljubljana, Zalo\u0161ka cesta 2, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Masnoon, N., Shakib, S., Kalisch-Ellett, L., and Caughey, G.E. 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