Pharmacokinetics of mitragynine in man

Abstract

Background: Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users.

Methods: Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method.

Results: Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model.

Conclusion: This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic linearity and parameters reported are necessary pharmacological information of Kratom, and there is a possibility for it to be developed medically as a pain killer or better opioid substitute in the future.

Keywords: human; kratom; pharmacokinetics.

Figure 1

Plasma mitragynine concentration–time curve of every subject after the administration of a loading dose: the normal plot (A) and semi-logarithmic plot (B).

Figure 2

The relationship between the maximum plasma concentration (C_max) and loading dose.

Figure 3

The relationship between the area under the curve extrapolated to time to infinity (AUC_0–∞) and loading dose. Abbreviation: hr, hour.

Figure 4

Plasma mitragynine concentration – time curve of one subject with abnormal behavior of blood concentration after the administration of a loading dose: the normal plot (A) and semi-logarithmic plot (B).

Figure 5

Blood pressures (BP) of every subject during the day of the study. Notes: Upper fence represents maximum value, lower fence represents minimum value, the box represents the 25th–75th percentile, the horizontal black line represents the 50th percentile (median). ^•Represents outlying value. *Represents extreme outlying value.

Figure 6

Pulse rates of every subject during the day of the study. Notes: Upper fence represents maximum value, lower fence represents minimum value, the box represents the 25th–75th percentile, the horizontal black line represents the 50th percentile (median). *Represents extreme outlying value.