The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine

Background and Purpose Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the mu opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious mu receptor agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent evidence suggests that 7-OH mitragynine formed as a metabolite is sufficient to explain the anti-nociceptive effects of mitragynine. However, the ability of 7-OH mitragynine to induce mu receptor-dependent respiratory depression has not yet been studied. Experimental Approach Respiration was measured in awake, freely moving, male CD-1 mice, using whole body plethysmography. Anti-nociception was measured using the hot plate assay. Morphine, mitragynine, 7-OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally. Key Results The respiratory depressant effects of mitragynine showed a ceiling effect, whereby doses higher than 10 mg center dot kg(-1) produced the same level of effect. In contrast, 7-OH mitragynine induced a dose-dependent effect on mouse respiration. At equi-depressant doses, both mitragynine and 7-OH mitragynine induced prolonged anti-nociception. Inhibition of CYP3A reduced mitragynine-induced respiratory depression and anti-nociception without affecting the effects of 7-OH mitragynine. Conclusions and Implications Both the anti-nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced respiratory depression. These data suggest that such 'metabolic saturation' at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic.

Automated summary

The study found differential effects of Mitragynine and its metabolite, 7-OH Mitragynine, on mouse respiration and anti-nociception. Mitragynine showed a ceiling effect on respiratory depression, while 7-OH Mitragynine had dose-dependent effects. Inhibition of CYP3A reduced the respiratory depressant effects and anti-nociception induced by Mitragynine, but had no effect on the effects of 7-OH Mitragynine. These findings suggest that metabolic saturation may contribute to the improved safety profile of Mitragynine.