Medical and government agencies frequently point to kratom’s interactions with other drugs as evidence of the plant’s danger to users. In fact, a 2019 study found that 87% of kratom-related deaths involved other drugs. (Corkery et al., 2019)
However, researchers still don’t know exactly how kratom changes the breakdown of drugs in the body — a process called “drug metabolism.” As a result, the exact risks of combining kratom with other drugs remain unclear.
But one team of researchers set out to bridge the knowledge gap. In October, they published a study that examines how kratom affects key drug-metabolizing enzymes in the liver and intestine. Because these enzymes are responsible for metabolizing “~70% of the top 200 most prescribed drugs” (Tanna et al., 2020, pg 7), the researchers’ conclusions are especially relevant for anyone who uses kratom alongside their medications.
The researchers conducted their study by analyzing kratom extracts they prepared from “three commercially available kratom products.” (Tanna et al., 2020, pg 8) Their first conclusion was that mitragynine, one of kratom’s primary alkaloids, is a “potent reversible inhibitor of CYP2D6.” (Tanna et al., 2020, pg 13)
CYP2D6 is an enzyme that’s found in the liver. Its primary function is to clear toxins or drugs from the body. When drugs inhibit CYP2D6 — preventing the enzyme from doing its job — certain medications can remain in the blood for longer, making them more potent. As a result, the mitragynine in kratom could alter the effectiveness of medications metabolized by the CYP2D6 enzyme, such as codeine, tamoxifen, and others.
The research team also concluded that “[mitragynine is] a time-dependent inhibitor of CYP3A,” a family of human genes. (Tanna et al., 2020, pg 13) Like the CYP2D6 enzyme, the CYP3A genes are responsible for several bodily processes, including drug metabolism. This means that the mitragynine in kratom could also alter the effectiveness of any medication or drug processed by CYP3A enzymes, potentially leading to heightened potency and adverse effects.
Finally, the researchers also found that mitragynine is a modest inhibitor of a third enzyme, CYP2C9. (Tanna et al., 2020, pg 16) Similar to CYP2D6 and CYP3A enzymes, CYP2C9 metabolizes a variety of therapeutic drugs. However, the researchers noted that mitragynine had “minimal interaction risk” with other drugs processed by the CYP2C9 enzyme. (Tanna et al., 2020, pg 16)
The researchers also observed that kratom’s interaction risk with other drugs is “expected to be higher at higher doses.” As a result, those taking more kratom with their medications have a higher risk of adverse interactions and effects. (Tanna et al., 2020, pg 18)
Despite the volume of their conclusions, the authors emphasized that there’s still more to know. While they successfully investigated the inhibiting activity of mitragynine, they stated that “Other alkaloids, including paynantheine and speciogynine, which combined represent ~15% of total alkaloid content, may [also] contribute to potential kratom-drug interactions.” (Tanna et al., 2020, pg 19)
Tanna, R. S., Tian, D.-D., Cech, N. B., Oberlies, N. H., Rettie, A. E., Thummel, K. E., & Paine, M. F. (2020). Refined prediction of pharmacokinetic kratom-drug interactions: time-dependent inhibition considerations. Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1124/jpet.120.000270Download
Bressler, R. (2006). Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs. Geriatrics, 61(11), 12–18.
Zhang, W., Ramamoorthy, Y., Tyndale, R. F., & Sellers, E. M. (2003). Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 31(6), 768–772. https://doi.org/10.1124/dmd.31.6.768Download
Fasinu, P. S., Tekwani, B. L., Avula, B., Chaurasiya, N. D., Nanayakkara, N. P. D., Wang, Y.-H., Khan, I. A., & Walker, L. A. (2016). Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine. Malaria Journal, 15(1). https://doi.org/10.1186/s12936-016-1509-xDownload
Corkery, J. M., Streete, P., Claridge, H., Goodair, C., Papanti, D., Orsolini, L., Schifano, F., Sikka, K., Körber, S., & Hendricks, A. (2019). Characteristics of deaths associated with kratom use: Journal of Psychopharmacology. https://doi.org/10.1177/0269881119862530Download