The spectrum of adulterants spans from seemingly benign substances like acetaminophen to more hazardous drugs such as cocaine, methamphetamines, kratom, xylazine, and metamizole. The unpredictable nature of these adulterants introduces a layer of uncertainty and complexity to clinical encounters, complicating the diagnostic and therapeutic approaches for healthcare providers.Against this backdrop, this presentation embarks on a deep dive into the acute management of polypharmacy fentanyl overdose, offering insights, strategies, and best practices for navigating the multifaceted challenges posed by adulterants. Through a combination of case studies, evidence-based guidelines, and interactive discussions, participants will gain a comprehensive understanding of the intricacies involved in managing overdoses involving multiple substances.Moreover, the presentation will explore the interplay between adulterants and opioid use disorder, shedding light on the nuanced dynamics that shape patterns of substance use, addiction, and treatment outcomes. By fostering a deeper understanding of the underlying mechanisms driving polypharmacy overdose and opioid-related morbidity, participants will be better equipped to deliver compassionate, evidence-based care to individuals grappling with opioid misuse and its myriad complications.