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.
Highlights
According to the US Department of Health and Human Services, opioids were responsible for more than 42,000 deaths in the US in 2016, the highest in recorded history[1]
Our chemical and in vitro studies support previous studies suggesting that the purported efficacy of kratom against pain is mediated at least in part by kratom alkaloids that function as biased ligands of the μ-opioid receptors
These findings further highlight the value of pursuing mitragynine and related alkaloids as an alternative strategy to treat pain, as, consistent with previous literature, our findings suggest that they have less abuse liability than classic opiates such as morphine
Summary
Consistent with the claim that kratom can be effective in the treatment of pain, extracts from this plant demonstrated opioid-receptor mediated analgesic effects in mouse model s tudies[9] This activity has generally been attributed to alkaloids that the plant produces, of which mitragynine (1) and 7-hydroxymitragynine (2) (Fig. 1) have been the focus of multiple pharmacological investigations[10,11,12,13]. We employed untargeted metabolomics to determine which alkaloids vary in content across commercial kratom products We isolated these relevant alkaloids and compared their biological effects in vitro, including activity at the μ-opioid receptors and inhibitory effects on CYP isoforms involved in the metabolism of opioids and other drugs. Our ultimate objective with this study was to capture the variability of commercial kratom products being employed by US consumers and to evaluate (based on vitro studies) the potential implications of this variability in terms of safety and efficacy
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