Respiratory effects of oral mitragynine and oxycodone in a rodent model

Abstract

Rationale Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial μ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway. Objectives Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188–197, 2020). Methods Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride. Findings Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related. Conclusions Consistent with mitragynine’s pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.

Kratom safety and toxicology in the public health context: research needs to better inform regulation

“…However it most robustly generalized to a nonscheduled alpha-adrenergic drug, lofexidine, which was approved by the FDA for treating opioid withdrawal, and the over-the-counter cold medicine, phenylephrine ( Reeve et al, 2020 ). These findings are consistent with the characterization of MG’s diverse pharmacology that includes effects at several opioid receptors in addition to agonism at adrenergic, serotonergic, D2-dopaminergic and adenosine receptors as discussed in Section 4.3 and other reviews and studies ( Kruegel et al, 2016 ; Kruegel et al, 2019 ; Henningfield et al, 2022c ; Qu et al, 2023 ; McCurdy et al, 2024 ).…”

“…Although some organizations warned of opioid-type kratom overdose risks, the main mechanism of opioid overdose, respiratory depression, does not appear to be a substantial risk from kratom due to differences in the mechanisms of action and signaling pathways of MG and 7OHMG. Evidence suggests that this may reflect their relative weak recruitment of beta-arrestin at opioid receptors (e.g., Kruegel et al, 2016 ; Kruegel et al, 2019 ; Henningfield et al, 2022c ; Qu et al, 2023 ; McCurdy et al, 2024 ). As discussed, MG’s relatively weak respiratory effects as compared to morphine-like opioids may also reflect the “balanced agonist effects of diverse kratom alkaloids and metabolites” ( Hill et al, 2022 ; Qu et al, 2023 ).…”

“…Presently, there are no published data describing a physiological pathway by which MG or other kratom alkaloids might produce acute lethality in animals in doses many times that of human intake ( Henningfield et al, 2022c ). However, such pathways by which MG or another kratom alkaloid could produce lethality in nonhuman animals warrant further research ( Annuar et al, 2024 ).…”

Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder

“…Reduced respiratory depression of mitragynine compared to codeine was reported more than 50 years ago [14]. Furthermore, mitragynine and 7-hydroxymitragynine are also bound to adrenergic (α 1 and α 2 ) and serotonergic (5-HT 1A and 5-HT 2B ) receptors, producing a different profile of effects than prototypical opioids [16,[21][22][23]. Currently, based on this unique pharmacology, there is substantial interest in the development of synthetic medicinal compounds built on the chemical scaffolding of kratom alkaloids for analgesia, namely, for the treatment of opioid withdrawal and opioid use disorder [17,19,24].…”

Clinical Implications of Kratom (Mitragyna speciosa) Use: a Literature Review

“…MG possesses a poly-pharmacological profile and a primary opiate receptor activity, with preliminary evidence suggesting the possibility of mu-opioid receptor (MOR) activity without β-arrestin-2 recruitment in the signaling pathway [ 10 •]. Recent evidence has shown that high doses (between 20 and 400 mg/kg) of oral MG do not exert respiratory depression compared to oxycodone in animal models [ 11 ]. However, information related to the safety profile of MG is still quite limited.…”