Translating Kratom-Drug Interactions: From Bedside to Bench and Back

Abstract

Kratom is a botanical natural product belonging to the coffee family, with stimulant effects at low doses and opioid-like effects at higher doses. During the last two decades, kratom has been purported as a safer alternative to pharmaceutical and illicit drugs to self-manage pain and opioid withdrawal symptoms. Kratom alkaloids, typically mitragynine, have been detected in biologic samples from overdose deaths. These deaths are often observed in combination with other drugs and are suspected to result from polyintoxications. This review focuses on the potential for kratom to precipitate pharmacokinetic interactions with object drugs involved in these reported polyintoxications. The legal status, chemistry, pharmacology, and toxicology are also summarized. The aggregate in vitro and clinical data identified kratom and select kratom alkaloids as modulators of cytochrome P450 (P450) enzyme activity, notably as inhibitors of CYP2D6 and CYP3A, as well as P-glycoprotein-mediated efflux activity. These inhibitory effects could increase the systemic exposure to co-consumed object drugs, which may lead to adverse effects. Collectively, the evidence to date warrants further evaluation of potential kratom-drug interactions using an iterative approach involving additional mechanistic in vitro studies, well designed clinical studies, and physiologically based pharmacokinetic modeling and simulation. This critical information is needed to fill knowledge gaps regarding the safe and effective use of kratom, thereby addressing ongoing public health concerns. SIGNIFICANCE STATEMENT: The botanical kratom is increasingly used to self-manage pain and opioid withdrawal symptoms due to having opioid-like effects. The legal status, chemistry, pharmacology, toxicology, and drug interaction potential of kratom are reviewed. Kratom-associated polyintoxications and in vitro-in vivo extrapolations suggest that kratom can precipitate pharmacokinetic drug interactions by inhibiting CYP2D6, CYP3A, and P-glycoprotein. An iterative approach that includes clinical studies and physiologically based pharmacokinetic modeling and simulation is recommended for further evaluation of potential unwanted kratom-drug interactions.

Fig. 1.

Chemical structures of key indole and oxindole kratom alkaloids. Structures of mitragynine and mitraphylline are numbered to serve as references for the indole and oxindole alkaloids, respectively. Stereochemical differences at C3 and C20 of the indole alkaloids are indicated by the colored boxes. These differences may explain the pharmacokinetic differences observed between those with the 3S configuration (mitragynine, speciogynine, paynantheine) and the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) in human adult participants.

Fig. 2.

Proposed metabolic scheme for mitragynine based on reported in vitro and in vivo evaluations. Boxes suggest the tentative site of metabolism.

Fig. 3.

Identified targets and relevant mechanisms of potential pharmacokinetic kratom-drug interactions after oral administration of kratom (created with https://www.biorender.com/).

Fig. 4.

Proposed iterative approach for rigorous assessment of potential pharmacokinetic kratom-drug interactions (created with https://www.biorender.com/).