Kratom (Mitragyna speciosa) for pain management: a systematic review of preclinical evidence and limited clinical data

Introduction Kratom ( Mitragyna speciosa ) has gained attention as a potential analgesic due to its major alkaloid, mitragynine, which exhibits atypical opioid activity with reduced β-arrestin recruitment. Despite traditional use for pain relief in Southeast Asia, its efficacy and safety remain debatable. This study aimed to assess the preclinical evidence and the limited human data available regarding the analgesic effects and safety of kratom. Methods A systematic search was conducted on PubMed, ScienceDirect, Cochrane Library, Springer, Scopus, and Google Scholar on March 17, 2026. Eligible studies included preclinical and human studies investigating kratom or mitragynine for pain-related outcomes and/or adverse events. Results Forty-four studies were included, comprising 28 preclinical studies and 16 human studies. Preclinical data consistently demonstrated dose-dependent antinociceptive and anti-inflammatory effects, primarily in experimental models. In humans, mitragynine did not significantly alter pain threshold or tolerance, while kratom decoction modestly increased pain tolerance in an experimental pain paradigm in healthy volunteers. Both preparations were generally well tolerated at single low-to-moderate doses, with only mild, transient adverse effects reported. Conclusions Preclinical evidence suggests antinociceptive effects of kratom and its alkaloids through μ-opioid receptor–mediated mechanisms. However, the available human evidence remains scarce and inconsistent. Therefore, the current evidence is insufficient to support the clinical efficacy of kratom for pain management. While short-term exposure appears generally well tolerated, long-term safety data are lacking, and chronic or high-dose use may be associated with dependence or withdrawal risk. Further studies are required to clarify these findings. Protocol registration CRD420251174598