Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions

Abstract

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.

Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers

“…It is obvious from the preceding section that mitragynine and other related alkaloids are substrates for multiple CYP isoforms and hence may interfere with metabolisms of clinical drugs. Preclinical research on mitragynine and related alkaloids on DDI is limited but has been gaining attention within the last 10 years ( Hanapi et al, 2013 ; Lim et al, 2013 ; Kamble et al, 2020 ; Todd et al, 2020 ; Tanna et al, 2021 ). Here, the focus is on the effect of mitragynine and related alkaloids on DMEs from in vitro preclinical research, and their utility to predict clinical DDI.…”

“…Mitragynine has been repeatedly shown in different in vitro studies to potently inhibit CYP2D6 with K i values ranging from 1.1 to 13 µM ( Hanapi et al, 2013 ; Kamble et al, 2020 ; Todd et al, 2020 ; Tanna et al, 2021 ). Using the static mechanistic model, Tanna et al (2021) revealed that kratom preparation sold in the U.S. market could cause significant DDI with drugs primarily metabolized by CYP2D6 if more than 9 g kratom extract containing 83 mg mitragynine ( Todd et al, 2020 ) was taken with AUCR > 1.25.…”

Kratom Use Within the Context of the Evolving Opioid Crisis and the COVID-19 Pandemic in the United States

“…All of these databases are in the public domain. The data that were extracted and used for these analyses are included as a supplemental table . neurotransmitter systems in the central nervous system (Kruegel et al, 2016;Varadi et al, 2016;Obeng et al, 2020;Todd et al, 2020).…”

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

“…The major active alkaloid found in kratom is mitragynine, along with more than 40 other minor alkaloids. [11][12][13][14][15][16] In recent years, we have become interested in the chemistry and pharmacology of kratom alkaloids as probes to understand opioid receptor function. 11,[17][18][19][20][21][22][23] Previous reports from our group reported that mitragynine (possessing an indole core), its oxidation product 7OH (possessing an indolenine core), and mitragynine pseudoindoxyl (MP, a skeletal rearrangement product of 7OH with a spiro-pseudoindoxyl core) (Figure 1A), are all opioid antinociceptive agents 18,19 and Gprotein biased MOR agonists.…”

“…Therefore, SC11, SC12 and SC13 (all C9 substituted 7OH analogs) were chosen as leads from the series of compounds synthesized. SC11-13 were evaluated in the PathHunter assay, 18,22 which we and others 12 have previously used to measure β-arrestin2 activity of the parent natural products. In this assay, like morphine (Emax=31%), SC11-13 were found to recruit β-arrestin2 with greatly reduced efficacy (Emax<20%) compared to DAMGO (Appendix 1-Figure 1C).…”