Mitragynine

Co-administration with full opioid agonists (morphine, oxycodone, fentanyl, heroin, methadone) carries the highest acute fatality risk. Mitragynine's reduced respiratory depression ceiling (via beta-arrestin-2 non-recruitment) does not eliminate risk when combined with full agonists that do recruit beta-arrestin-2. Multiple fatality case reports involve opioid co-exposure.

Mitragynine is a probable cause of drug-induced liver injury, predominantly cholestatic pattern (R ratio median 3.4). Comprehensive scoping review identified 26 case reports, 7 DILI Network cases, and 25 FDA database cases. Pre-existing hepatic impairment increases both DILI risk and accumulation due to impaired CYP3A metabolism.

Acute kidney injury has been documented in severe kratom overdose complicated by rhabdomyolysis and compartment syndrome. No data exist on mitragynine clearance or safety in patients with pre-existing renal impairment. Relative contraindication due to absence of safety data rather than established direct nephrotoxicity.

Kratom use during pregnancy produces neonatal abstinence syndrome (NAS) with symptoms including oral intolerance, restlessness, irritability, and vomiting. Perceived safety as a 'natural' product does not confer safety in pregnancy. Clinical outcomes remain poorly characterized beyond case reports.

Co-administration with non-opioid CNS depressants — benzodiazepines, alcohol, gabapentinoids, sedating antihistamines, barbiturates — increases risk of respiratory depression, excessive sedation, and death. While individual risk is lower than with concurrent full opioid agonists, the combination remains a major contributor to kratom-associated mortality.

Co-administration with CYP3A substrates that have narrow therapeutic indices — including midazolam, triazolam, tacrolimus, cyclosporine, certain antiretrovirals — risks clinically significant increases in co-drug plasma concentrations. A fatal case possibly attributable to CYP-mediated potentiation of quetiapine toxicity has been reported.

Kratom use is an emerging concern for perioperative care. Regular users may exhibit cross-tolerance to opioid analgesics, complicating pain management. Abrupt cessation risks withdrawal. Hemodynamic instability and agitation have been reported in surgical patients with kratom use history (Vance 2026).