{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:04:22Z","timestamp":1790899462118,"version":"4.1.0"},"reference-count":184,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fentanyl is a synthetic opioid widely used for its potent analgesic effects in chronic pain management and intraoperative anesthesia. However, its high potency, low cost, and accessibility have also made it a significant drug of abuse, contributing to the global opioid epidemic. This review aims to provide an in-depth analysis of fentanyl\u2019s medical applications, pharmacokinetics, metabolism, and pharmacogenetics while examining its adverse effects and forensic implications. Special attention is given to its misuse, polydrug interactions, and the challenges in determining the cause of death in fentanyl-related fatalities. Fentanyl misuse has escalated dramatically, driven by its substitution for heroin and its availability through online platforms, including the dark web. Polydrug use, where fentanyl is combined with substances like xylazine, alcohol, benzodiazepines, or cocaine, exacerbates its toxicity and increases the risk of fatal outcomes. Fentanyl undergoes rapid distribution, metabolism by CYP3A4 into inactive metabolites, and renal excretion. Genetic polymorphisms in CYP3A4, OPRM1, and ABCB1 significantly influence individual responses to fentanyl, affecting its efficacy and potential for toxicity. Fentanyl\u2019s side effects include respiratory depression, cardiac arrhythmias, gastrointestinal dysfunction, and neurocognitive impairments. Chronic misuse disrupts brain function, contributes to mental health disorders, and poses risks for younger and older populations alike. Fentanyl-related deaths require comprehensive forensic investigations, including judicial inspections, autopsies, and toxicological analyses. Additionally, the co-administration of xylazine presents distinct challenges for the scientific community. Histological and immunohistochemical studies are essential for understanding organ-specific damage, while pharmacogenetic testing can identify individual susceptibilities. The growing prevalence of fentanyl abuse highlights the need for robust forensic protocols, advanced research into its pharmacogenetic variability, and strategies to mitigate its misuse. International collaboration, public education, and harm reduction measures are critical for addressing the fentanyl crisis effectively.<\/jats:p>","DOI":"10.3390\/ijms26020444","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T03:38:41Z","timestamp":1736221121000},"page":"444","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The Rise of Fentanyl: Molecular Aspects and Forensic Investigations"],"prefix":"10.3390","volume":"26","author":[{"given":"Cecilia","family":"Barletta","sequence":"first","affiliation":[{"name":"Legal Medicine, Department of Medical, Surgical and Advanced Technologies \u201cG.F. Ingrassia\u201d, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Di Natale","sequence":"additional","affiliation":[{"name":"Legal Medicine, Department of Medical, Surgical and Advanced Technologies \u201cG.F. Ingrassia\u201d, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7880-3450","authenticated-orcid":false,"given":"Massimiliano","family":"Esposito","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, \u201cKore\u201d University of Enna, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Chisari","sequence":"additional","affiliation":[{"name":"\u201cRodolico-San Marco\u201d Hospital, Santa Sofia Street, 87, 95121 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Cocimano","sequence":"additional","affiliation":[{"name":"Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cVanvitelli\u201d, 80121 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Di Mauro","sequence":"additional","affiliation":[{"name":"Legal Medicine, Department of Medical, Surgical and Advanced Technologies \u201cG.F. 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