Is kratom contributing to deaths in polypharmacy cases? A scoping review

Kratom (Mitragyna speciosa) is used by an estimated 10-16 million Americans for self-management of pain, anxiety, and opioid use disorder, yet its causal contribution to associated deaths remains unresolved. This scoping review maps the available evidence on kratom's role in polypharmacy-associated adverse outcomes, characterizes the pharmacological mechanisms through which kratom may contribute to harm in a co-substance context, identifies forensic and methodological barriers to causal attribution, and distinguishes the risk profile of traditional kratom from emerging semisynthetic 7-hydroxymitragynine (7- OH) products. A systematic literature search was conducted through April 2026 using PubMed Advanced Search Builder across fourteen discrete queries spanning pharmacological, epidemiological, clinical, and regulatory domains, supplemented by citation tracking and targeted grey literature review. Polysubstance use is the dominant pattern in kratom-associated fatalities across five independent data sources, with polydrug rates around 80%. Two pharmacologically coherent mechanisms support a plausible contributory role for kratom in polypharmacy deaths: additive and synergistic central nervous system (CNS) depression via μ-opioid receptor overlap and CYP enzyme-mediated pharmacokinetic amplification of co-substance toxicity. Concentrated semisynthetic 7-OH products, commercially emergent since 2023, produce substantially greater exposure to a potent MOP agonist than traditional kratom preparations, creating a distinct pharmacological hazard profile; however, their comparative polypharmacy fatality risk has not been established. Six fundamental data gaps prevent causal confirmation and limit evidence-based regulatory response. Closing them requires coordinated federal investment in forensic, pharmacokinetic, pharmacogenomic, and surveillance research.