Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants

Abstract

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1–2 vs. 2.5–4.5 h), lower area under the plasma concentration-time curve (430–490 vs. 794–5120 nM × h), longer terminal half-life (24–45 vs. ~12–18 h), and higher apparent volume of distribution during the terminal phase (960–12,700 vs. ~46–130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.

Kratom Alkaloids: A Blueprint?

“…7HMG content in the dosed kratom product was below the LLOQ, but 7HMG formed after metabolism of mitragynine was quantified in plasma samples, and metabolite to parent exposure ratio ((AUC 7HMG / AUC mitragynine ) × 100) was 26.5%. 5 Corynantheidine was not specifically investigated in this clinical study, but it was one of four alkaloids (mitragynine, 7-hydroxymitragynine, and speciociliatine) available systemically after oral doses of either lyophilized kratom tea or a commercial kratom product (OPMS) in male rats. 2…”

Kratom Alkaloid Mitragynine: Inhibition of Chemotherapy-Induced Peripheral Neuropathy in Mice is Dependent on Sex and Adrenergic and Opioid Receptors

“…There is also a severe lack of studies investigating the pharmacokinetics of MG in humans, with only two published to date. The first of which was conducted in male subjects only, while the second included four female subjects but statistical analysis between male and female participants were not reported (Tanna et al, 2022;Trakulsrichai et al, 2015). Given the lack of pharmacokinetic studies and the variability in kratom product selection and preparation, it is difficult to form any conclusions on how the kinetics of MG and other kratom alkaloids may contribute to individual differences in behavioral responses such as mechanical hypersensitivity.…”

Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats

“…Pharmacokinetic and Pharmacodynamic Consequences of CYP3A Inhibition on Mitragynine Metabolism in Rats. Kamble et al kratom alkaloids after an oral dose of kratom tea; in that study mitragynine showed fast absorption (T max , 1 hr) with an elimination half-life of 45.3 h (Tanna et al, 2022).…”

“…The opioidergic activity of kratom is often attributed to its most abundant bioactive alkaloid mitragynine and its metabolite, 7-hydroxymitragynine (7HMG). Mitragynine is reported to be 66% of the total alkaloidal fraction of kratom, whereas 7HMG analyzed in freshly prepared extracts are below the lower limit of quantification (0.01 %w/w), suggesting 7HMG is not biosynthesized in Mitragyna leaves (Hassan et al, 2013;Singh et al, 2020;Tanna et al, 2022).…”

“…7HMG is also found as a circulating metabolite after mitragynine administration in mice, rats, dogs, and humans (Hiranita et al, 2020;Maxwell et al, 2020;Berthold et al, 2022;Tanna et al, 2022). Mitragynine binds to a number of receptors including the μ-opioid receptor (MOR), to which 7HMG also binds (Obeng et al, 2019).…”