Kratom products have been historically and anecdotally used in south Asian countries for centuries to manage
pain and
opioid withdrawal. The use of kratom products has dramatically increased in the United States. More than 45
kratom alkaloids have been isolated, yet the overall pharmacology of the individual
alkaloids is still not well characterized. The purpose of this chapter is to summarize in vitro and in vivo
opioid activities of the primary kratom
alkaloid mitragynine and its more potent metabolite
7-hydroxymitragynine. Following are experimental procedures described to characterize
opioid receptor activity; receptor binding and functional assays, antinociceptive assays, operant conditioning assays, and respiratory plethysmography. The capacity of
kratom alkaloids to confer tolerance and physical dependence as well as their pharmacokinetic properties are also summarized. The data reviewed here suggest that kratom products and
mitragynine possess low efficacy agonist activity at the
mu-opioid receptor in vivo. In addition, kratom products and
mitragynine have been demonstrated to antagonize the effects of high efficacy mu-
opioid agonists. The data further suggest that
7-hydroxymitragynine formed in vivo by metabolism of
mitragynine may be minimally involved in the overall behavioral profile of
mitragynine and kratom, whereas
7-hydroxymitragynine itself, at sufficiently high doses administered exogenously, shares many of the same abuse- and dependence-related behavioral effects associated with traditional
opioid agonists. The apparent low efficacy of kratom products and
mitragynine at
mu-opioid receptors supports the development of these
ligands as effective and potentially safe medications for
opioid use disorder.