Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product

Kratom is a botanical natural product that has opioid-like effects. Kratom is commonly used to self-treat withdrawal symptoms associated with opioid addiction, as well as pain. Kratom products include pills, extracts, and powders, most of which contain two primary psychoactive constituents: mitragynine and 7-hydroxymitragynine.

Preliminary data from the investigator’s laboratory has shown that these two constituents and extracts made from commercially available kratom products are strong inhibitors of the drug metabolizing enzymes cytochrome P450 (CYP) 2D6 and CYP3A4. These enzymes are responsible for metabolizing more than 50% of marketed drugs, including several opioids, benzodiazepines, and antidepressants. Thus, co-consumption of kratom products with drugs metabolized by CYP2D6 and CYP3A4 could increase the risk of serious adverse effects.

The effects of a well-characterized kratom product on CYP2D6 and CYP3A4 activity will be assessed in healthy volunteers using a ‘cocktail’ approach consisting of the validated probe drugs dextromethorphan and midazolam. Results will (1) provide useful information regarding risks associated with co-consuming kratom with opioids and other CYP2D6 and CYP3A4 drug substrates and (2) inform the design of future kratom-drug interactions studies.

Trial Details

The purpose of this study is to assess the effects of a well-characterized kratom product on CYP2D6 and CYP3A4 activity in healthy volunteers using a cocktail approach consisting of the validated probe drugs dextromethorphan and midazolam. The primary objective is to evaluate the potential for a pharmacokinetic kratom-drug interaction with midazolam, a 'probe' drug for CYP3A4, when administered to participants previously exposed to kratom. Secondary objectives are to evaluate the pharmacokinetics of kratom constituents and the effect of kratom on the pharmacokinetics of dextromethorphan, a probe drug for CYP2D6. Results will be used to develop physiologically-based pharmacokinetic (PBPK) models to predict the likelihood and magnitude of kratom-drug interactions, including those involving opioids. These PBPK models could be adapted to other CYP2D6 and CYP3A4 drug substrates with high abuse potential (e.g., benzodiazepines and 'Z-drugs') and used to inform the design of future kratom-drug interactions studies.

NCT Number NCT04392011

Data attribution

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