POLYPHARMACOLOGY OF MITRAGYNA SPECIOSA (“KRATOM”) ALKALOIDS

Abstract

The nation’s persistent opioid epidemic requires innovative treatment interventions. Mitragyna speciosa, or kratom, is a plant native to Southeast Asia that contains dozens of potentially active alkaloids. The most abundant and best characterized of these alkaloids is mitragynine, which accounts for up to 66% of crude alkaloid extracts. Kratom preparations have been traditionally used for their analgesic properties and as a mild stimulant to combat work fatigue. Over the past decade, kratom has become a popular drug in the United States, where pulverized kratom leaves are used for self-medication of pain, mood disorders, and opioid withdrawal symptoms. There are, however, no FDA-approved uses for kratom, and the vast majority of scientific research on kratom alkaloids focuses on their opioid receptor activity. To understand the promise and perils associated with kratom use, it is essential to elucidate the mechanisms underlying kratom’s pharmacology, including activities at other non-opioid targets. Based on kratom’s psychoactive profile, which includes acute antidepressant and anxiolytic effects, analgesic effects, and cardiac adverse effects at high doses, we hypothesized that certain kratom alkaloids have activity at serotonin (5-hydroxytryptamine, 5-HT) and alpha-adrenergic G protein- coupled receptors (GPCRs). The binding affinity and functional activity of selected kratom alkaloids—including mitragynine, speciogynine, and paynantheine—the three most abundant alkaloids were evaluated at 5-HT1ARs, 5-HT1BRs, 5-HT2ARs, 5-HT2BRs, 5-HT2CRs, 5-HT5Rs, 5-HT6Rs, and 5-HT7Rs. Mitragynine has been comprehensively demonstrated to be a mu-opioid receptor (MOR) partial agonist, however, a growing literature suggests an adrenergic component of mitragynine-mediated antinociception. To explore mitragynine's adrenergic action, we examined mitragynine's activity at G protein-dependent signaling pathways mediated by human alpha 1 (α1ARs) and alpha 2 adrenergic receptors (α2ARs). Results from the current study provide a better understanding of the complex polypharmacology of kratom alkaloids that contributes to its unique physiological effects.