Association of postmortem mitragynine positivity with fatal drug toxicity in polysubstance exposures—a restrospective analysis

Introduction Kratom ( Mitragyna speciosa Korth.) and kratom-related product use has increased in the United States, yet their contributions to drug-related death at the population level remain poorly defined. There is no established link between the amount of kratom ingested and the cause of toxic adverse effects, and evidence regarding their potential association with drug toxicity-related death is limited. Objective To evaluate the association between kratom (mitragynine) exposure among decedents and assess its role in polysubstance-related mortality. Methods A statewide retrospective cross-sectional analysis of 61,234 decedents with postmortem toxicology data. Kratom, as indicated by mitragynine measured in postmortem blood, was classified as present or absent. This is not a quantitative measure. The primary outcome was drug toxicity-related death (DTRD), determined by medical examiners. Multivariable logistic regression models estimated adjusted odds ratios (aOR), controlling for demographics, comorbidities, and co-exposure to other substances. Effect modification by sex and sensitivity analyses incorporating opioid exposure burden were performed. Results Mitragynine was associated with increased odds of DTRD (aOR ~ 5–6). Among mitragynine-detected decedents, 85% of cases were classified as DTRD, and >90% had polysubstance exposure. Opioids showed the strongest association with DTRD, followed by cocaine and other stimulants, while benzodiazepines were modestly associated. Alcohol and cannabis were inversely associated with DTRD. Male sex and polysubstance exposure were associated with higher odds of DTRD. Older age and selected comorbidities (cardiac, respiratory, and renal disease) were associated with lower observed odds. Discussion/Conclusion In this statewide cohort, postmortem mitragynine-positive cases were associated with increased odds of DTRD, almost entirely in the context of polysubstance use, while Mitragynine-positive DTRDs without other documented substances were uncommon. The association between postmortem mitragynine-positive cases and DTRD supports its inclusion in toxicological surveillance and risk assessment frameworks.