(M1130-10-66) Pharmacokinetics of Mitragynine, a Kratom Alkaloid, in Pregnant Rats: Implications for Maternal and Fetal Health

Purpose: Mitragyna speciosa (kratom) is a natural supplement that has gained popularity in recent years for its purported pain-relieving and mood-enhancing effects.¹ However, concerns have been raised about the safety of kratom use during pregnancy, as active compounds in kratom may cross the placenta and affect fetal development. Despite the lack of evidence supporting the safety and efficacy of kratom use during pregnancy, many women continue to use this substance for various reasons, including opioid withdrawal management, anxiety, and depression. In fact, there are multiple case studies published reporting the diagnosis of neonatal abstinence syndrome (NAS) in infants following in utero exposure to kratom. Mitragynine is the most abundant alkaloid found in kratom leaves, is a partial µ-opioid receptor agonist, and is known to have additional active metabolites. One of these metabolites, 7-hydroxymitragynine, is a more potent µ-opioid receptor agonist that has also been found to have high abuse potential.² It could even accumulate in the fetus after mitragynine crosses the placental barrier and is further metabolized. A pharmacokinetic study of isolated mitragynine was conducted in pregnant Sprague Dawley rats with the ultimate goal of improving the understanding of the potential risks and benefits of kratom use during pregnancy.

Methods: A pharmacokinetic study in pregnant Sprague Dawley rats was conducted. Isolated mitragynine was administered orally beginning on Gestation Day (GD) 0 through GD14 as 20 mg/kg BID. Samples were taken at various time points following the final dose (pre-dose, and 0.25, 0.5, 1, 2, 4, 6, and 8 hours post-dose). Maternal plasma and whole fetuses were collected and analyzed by a validated LC-MS/MS method for mitragynine and its metabolites (7-hydroxymitragynine (7HMG), 9-hydroxycoranantheidine (9HCOR), mitragynine acid (MTG ACID), and mitragynine pseudoindoxyl (MGPI). Concentration-time data for both maternal plasma and fetal tissue were subjected to non-compartmental analysis using Phoenix (version 8.4.3). These methods are further illustrated in Figure 1.

Results: In maternal plasma, the AUC for mitragynine was 8.9 h*µg/mL. The metabolite-to-parent ratios were 0.001, 0.07, 0.15, and 0.90 for MGPI, 7HMG, MTG ACID, and 9HCOR, respectively. The maximum concentration of mitragynine was found as 1.66 µg/mL at 1 h. In the whole fetal tissue, the AUC for mitragynine was 6.4 h*µg/g. The metabolite-to-parent ratios in fetal tissue were 0.04, 0.07, and 1.32 for MTG ACID, 7HMG, and 9HCOR, respectively. MGPI was not present above the limit of quantification in fetal tissue. The maximum fetal concentration of mitragynine was found as 1.32 µg/g at 1 h. The fetal-to-maternal AUC ratios were 0.80, 1.06, 0.72, and 0.20 for 7HMG, 9HCOR, mitragynine, and MTG ACID, respectively.

Conclusion: This preliminary study confirms fetal exposure to mitragynine and its metabolites after oral administration of mitragynine. Similar AUC metabolite-to-parent ratios of 7HMG in both maternal plasma and fetal tissue indicates the 7HMG does NOT accumulate in the fetus. The fetal-to-maternal AUC ratios of mitragynine and 7HMG (0.72 vs. 0.80) signify similar transfer across the placental barrier. The fetal-to-maternal AUC ratio of MTG ACID is low, so it is neither crossing the placental barrier nor forming in the fetal tissue. 9HCOR is found at relatively higher levels in fetal tissue compared to maternal plasma, potentially due to accumulation during the dosing period. 9HCOR has similar opioid receptor activities as mitragynine, however the abuse potential has not yet been established. In conclusion, the findings of this study highlight the potential risks associated with kratom use during pregnancy and the need for further research to fully understand the impact of this substance on maternal and fetal health. The rat model used in this study provides a valuable tool for investigating the pharmacokinetics and toxicity of kratom alkaloids in pregnancy, and may help inform clinical guidelines for the safe and effective use of kratom in pregnant women.

References: 1. Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. 2018;134:108-120. doi:10.1016/j.neuropharm.2017.08.026
2. Hemby SE, McIntosh S, Leon F, Cutler SJ, McCurdy CR. Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7-hydroxymitragynine. Addiction Biology. 2019;24(5):874-885. doi:10.1111/adb.12639

Acknowledgements: Supporting grants: R21DA055908 and TL1TR001428 and UL1TR001427

Illustration of methods