The safety and efficacy of kratom (Mitragyna speciosa) for treatment of
pain is highly controversial. Kratom produces more than 40 structurally related
alkaloids, but most studies have focused on just two of these,
mitragynine and
7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC-MS metabolomics, revealing two distinct chemotypes that contain different levels of the
alkaloid speciofoline. Both chemotypes were confirmed with
DNA barcoding to be M. speciosa. To evaluate the
biological relevance of variable speciofoline levels in kratom, we compared the
opioid receptor binding activity of speciofoline,
mitragynine, and
7-hydroxymitragynine.
Mitragynine and
7-hydroxymitragynine function as partial agonists of the human µ-
opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-
opioid receptors. Importantly,
mitragynine and
7-hydroxymitragynine demonstrate functional selectivity for
G-protein signaling, with no measurable recruitment of β-
arrestin. Overall, the study demonstrates the unique binding and functional profiles of the
kratom alkaloids, suggesting potential utility for managing
pain, but further studies are needed to follow up on these in vitro findings. All three
kratom alkaloids tested inhibited select
cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these
enzymes.