Activity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors

Kratom alkaloids have mostly been
evaluated for their opioid activity
but less at other targets that could contribute to their physiological
effects. Here, we investigated the in vitro and in vivo activity of
kratom alkaloids at serotonin receptors (5-HTRs). Paynantheine and
speciogynine exhibited high affinity for 5-HT1ARs and 5-HT2BRs, unlike the principal kratom alkaloid mitragynine. Both
alkaloids produced antinociceptive properties in rats via an opioid
receptor-independent mechanism, and neither activated 5-HT2BRs in vitro. Paynantheine, speciogynine, and mitragynine induced
lower lip retraction and antinociception in rats, effects blocked
by a selective 5-HT1AR antagonist. In vitro functional
assays revealed that the in vivo 5-HT1AR agonistic effects
may be due to the metabolites 9-O-desmethylspeciogynine
and 9-O-desmethylpaynantheine and not the parent
compounds. Both metabolites did not activate 5-HT2BR, suggesting
low inherent risk of causing valvulopathy. The 5-HT1AR
agonism by kratom alkaloids may contribute to the mood-enhancing effects
associated with kratom use.