(W1130-02-09) Maternal Exposure to Kratom Alkaloids: A Comparative Pharmacokinetic Study of Various Kratom Preparations in Pregnant Rats

Purpose: Mitragyna speciosa (kratom), a tropical plant native to Southeast Asia, has seen a surge in popularity recently due to its alleged pain-relieving and mood-boosting properties. However, there are significant concerns regarding the safety of kratom use during pregnancy. The active compounds in kratom may cross the placental barrier, potentially impacting fetal development. Despite the lack of conclusive evidence on the safety and efficacy of kratom during pregnancy, many women continue to use it for various reasons, such the self-treatment of opioid withdrawal, anxiety, and depression. Multiple case studies have reported the diagnosis of neonatal abstinence syndrome (NAS) in infants following in utero exposure to kratom. Mitragynine, the most abundant alkaloid found in kratom leaves, is a partial µ-opioid receptor agonist and has additional active metabolites. One of these metabolites, 7-hydroxymitragynine (7HMG), is a more potent µ-opioid receptor agonist that activates the β-Arrestin signaling pathway, which is connected to respiratory depression in opioid overdoses. Kratom contains over 40 additional alkaloids, each with their own pharmacology, metabolite profiles, and safety. A comparative pharmacokinetic study was performed in pregnant Sprague Dawley rats to improve the understanding of the potential risks and benefits of kratom use during pregnancy. The study included dosing the rats with different preparations of kratom: OPMS Gold, a commercial organic extract, and lyophilized kratom tea (LKT), an aqueous extract that represents a traditional preparation, and with isolated mitragynine. This approach aimed to assess the pharmacokinetics of various kratom formulations, considering that different preparations might result in varied exposures of mitragynine and its metabolites.

Methods: A comparative pharmacokinetic study in pregnant Sprague Dawley rats was conducted. Either isolated mitragynine, OPMS Gold, or LKT (N=32-40) was administered orally beginning on Gestation Day (GD) 0 as 20 mg/kg mitragynine BID through GD14. 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 was collected and analyzed by validated UPLC-MS/MS methods for mitragynine and its metabolites 7HMG, 9-hydroxycoranantheidine (9HCOR), and mitragynine acid (MTG ACID). For the kratom preparations, additional alkaloids speciogynine, speciociliatine, mitraciliatine, paynantheine, and corynantheidine were also quantified. A noncompartmental analysis was performed using Phoenix (version 8.4.3) to obtain the area under the curve (AUC) calculated from 0 to 8 hours.

Results: In maternal plasma, the AUC for mitragynine was 8.9 h*µg/mL after isolated mitragynine administration, compared to 5.3 and 5.1 h*µg/mL for OPMS Gold and LKT preparations, respectively. Maximum concentrations of mitragynine were 1.66 µg/mL at 1 h, 1.03 µg/mL at 0.5 h, and 1.02 µg/mL at 1 h for isolated mitragynine, OPMS Gold, and LKT preparations, respectively. The AUC metabolite-to-parent ratios were 0.07, 0.15, and 0.90 for 7HMG, MTG ACID, and 9HCOR, respectively after isolated mitragynine; 0.10, 0.09, and 0.93 after OPMS gold; and 0.10, 0.09, and 1.02 after LKT administration. The dose-normalized AUC for speciogynine, speciociliatine, mitraciliatine, paynantheine, and corynantheidine were 0.13, 0.20, 0.22, 0.13, and 0.31 h*µg/mL/mg/kg after OPMS gold and 0.12, 0.17, 0.26, 0.11, and 0.34 h*µg/mL/mg/kg after LKT, respectively. The maximum concentrations for all alkaloids other than mitraciliatine occurred at 0.5 and 1 h for OPMS gold and LKT, respectively. For both preparations, the maximum concentration of mitraciliatine occurred at 2 h, post-dose.

Conclusion: There is increased exposure of mitragynine after oral administration as a solution of isolated mitragynine when compared to formulations of kratom. The kratom formulations were suspensions, which likely decreases absorption and explains the difference in bioavailability. The metabolite profiles are comparable across formulations with 9HCOR as the major metabolite, however the metabolite-to-parent ratio for MTG ACID is 1.7x higher for isolated mitragynine compared to the kratom formulations. This could be explained if the additional alkaloids or their metabolites affect the formation of MTG ACID by CYP2D6. The metabolite-to-parent ratios for 7HMG and 9HCOR are similar across formulations, so the interaction is specific to MTG ACID. Absorption occurs faster when rats are dosed with OPMS Gold, a commercially available organic extract, compared to isolated mitragynine and LKT (T_max, 0.5 vs 1 h). Mitraciliatine’s maximum concentration is reached at 2 h for both OPMS Gold and LKT. In this study, the concentration range of mitraciliatine over 8 h is limited, for OPMS Gold, the minimum concentration is 11.3 ng/mL pre-dose and the maximum is 22.1 ng/mL at 2 h and the variability due to sparse sampling and suspension formulations may have influenced this result. The dose-normalized AUCs for the alkaloids were not different between kratom preparations. Future work will include the analysis of whole fetal tissue, amniotic fluid, and placenta tissues collected during this study to develop a more detailed understanding of the clearance and exposure of mitragynine, its metabolites, and kratom’s other alkaloids during pregnancy. These findings are crucial for understanding the pharmacological effects and potential risks associated with different kratom preparations, especially in terms of maternal and fetal exposure.

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. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants. Pharmaceutics. 2022;14(3):620. doi:10.3390/pharmaceutics14030620
3. Avery BA, Boddu SP, Sharma A, et al. Comparative Pharmacokinetics of Mitragynine after Oral Administration of Mitragyna speciosa (Kratom) Leaf Extracts in Rats. Planta Med. 2019;85(4):340-346. doi:10.1055/a-0770-3683
4. Berthold EC, Kamble SH, Raju KS, et al. Preclinical Pharmacokinetic Study of Speciociliatine, a Kratom Alkaloid, in Rats Using an UPLC-MS/MS Method. J Pharm Biomed Anal. 2021;194:113778. doi:10.1016/j.jpba.2020.113778

Acknowledgements: R21DA055908