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

Abstract

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500-4000 mg dried kratom leaf powder (6.65-53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine C_max increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine T_max was 1.0-1.3 h after single and 1.0-1.7 h after multiple doses; for 7-hydroxymitragynine T_max, it was 1.2-1.8 h and 1.3-2.0 h. Steady-state mitragynine concentrations were reached in 8-9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T_1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20-0.31 after a single dose and decreased (0.15-0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations.

Keywords: 7-hydroxymitragynine; analytical toxicology; kratom; mass spectrometry; metabolism; mitragynine.

Figure 1

Chemical structures of mitragynine and 7-hydroxy-mitragynine.

Figure 2

LC-MS/MS chromatograms of blank plasma, plasma fortified at the lower limit of quantification (0.5 ng/mL) for mitragynine and 7-hydroxymitragynine and an authentic plasma sample collected at 1.33 h after the participant received 13.3 mg of mitragynine in 1000 mg of dried kratom leaf, achieving plasma concentrations of 46 ng/mL of mitragynine and 7.3 ng/mL of 7-hydroxymitragynine. Arrows in the blank chromatogram indicate retention time of mitragynine and 7-hydroxymitragynine.

Figure 3

Mean plasma concentration profiles of (a) mitragynine (including standard deviation bars) after a single dose (SD); (b) mitragynine after 15 multiple doses (MD); (c) 7-hydroxymitragynine after an SD; (d) 7-hydroxymitragynine after 15 MD mitragynine for all four dried kratom leaf powder doses. Each dose was administered to a different cohort of healthy male and female subjects.

Figure 4

Mean ratios of 7-hydroxymitragynine/mitragynine plasma concentrations after (a) single (SD) and (b) multiple (MD) oral 6.65–53.2 mg mitragynine doses in dried kratom leaf powder.

Figure 5

Trough plasma (a) mitragynine and (b) 7-hydroxy-mitragynine concentrations (including standard deviation bars) on days 1–15 of consecutive 6.65–53.2 mg mitragynine doses in dried kratom leaf powder during the attainment of steady-state concentrations.

Figure 6

Study design showing dosing and in-person clinical visits (single dose (SD) follow-up phase days 1, 2, 3, 5, 7, and pre-dose day 10; 15 multiple doses (MDs), follow-up phase days 25, 26, 27, 29, 31, 34, 40, and 47), including two intensive pharmacokinetic (PK) days after a single oral mitragynine dose and on the last of 15 consecutive 6.65–53.2 mg daily mitragynine doses of dried kratom leaf powder.