Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy
Shyam H. Kamble, Francisco León, Tamara I. King, Erin C. Berthold, Carolina Lopera‐Londoño, Raju S. Kanumuri, Aidan J. Hampson, Abhisheak Sharma, Bonnie A. Avery, Lance Richard McMahon, Christopher R. McCurdy
Abstract
Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a μ-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG) is a mitragynine metabolite that is a more potent and efficacious opioid than its parent mitragynine. 7-HMG contributes to mitragynine’s antinociceptive effects in mice, but evidence suggests it may also have a higher abuse potential. This in vitro study demonstrates that 7-HMG is stable in rodent and monkey plasma but is unstable in human plasma. Surprisingly, in human plasma 7-HMG is converted to mitragynine pseudoindoxyl, an opioid that is even more potent than either mitragynine or 7-HMG. This novel metabolite is formed in human plasma to a much greater extent than in the preclinical species tested (mouse, rat, dog, and cynomolgus monkey) and due to its μ-opioid potency may substantially contribute to the pharmacology of kratom in humans to a greater extent than in other tested species.