Herbal Remedies Quietly Reshape Blood Thinner Levels in Healthy Volunteers

Millions of people who take direct oral anticoagulants—the modern class of blood thinners that includes edoxaban—also reach for traditional herbal medicines, often without telling their physicians. In East Asia in particular, herbal formulations with centuries of history in treating cardiovascular and cerebrovascular complaints are routinely co-prescribed or self-administered alongside prescription anticoagulants. Yet rigorous clinical data on whether these herbal products actually change the behavior of direct oral anticoagulants in the body have remained strikingly scarce. A new clinical study published in the Journal of Pharmaceutical Investigation now provides some of the clearest evidence to date that at least two widely used traditional Korean formulations can dramatically alter edoxaban exposure in healthy adults, even when standard blood clotting tests fail to register the change.

The study, led by Ju Hee Kim and Jungbin Song with colleagues at CHA University, Kyung Hee University, and Korea University Guro Hospital, examined three herbal formulations: Bojungikgitang, Ijintang, and Cheongsanggyeontongtang. All three have long histories of symptomatic use in East Asian traditional medicine for cardiovascular and cerebrovascular conditions—precisely the patient populations most likely to be taking anticoagulants. The research team designed a fixed-sequence, two-period clinical trial in which healthy volunteers received a single 60-milligram dose of edoxaban alone, and then received the same dose after repeated dosing with one of the three herbal formulations. The design allowed each participant to serve in part as their own control, isolating the effect of the herbal co-administration from natural interindividual variability in drug handling.

Edoxaban is a direct factor Xa inhibitor, a member of the direct oral anticoagulant family that has largely displaced warfarin in many markets because it requires no routine monitoring and has fewer dietary interactions. Its disposition in the body, however, depends heavily on the efflux transporter P-glycoprotein and, to a lesser extent, on cytochrome P450 3A4 (CYP3A4) metabolism, which produces an active metabolite known as M4. This pharmacological profile makes edoxaban particularly vulnerable to interactions with drugs—and potentially herbal phytochemicals—that inhibit or induce P-glycoprotein or CYP3A4. Strong P-glycoprotein inhibitors such as quinidine and cyclosporine are already known to raise edoxaban levels, while inducers such as rifampin can slash them, and the edoxaban label reflects those established interactions.

To measure what the herbal formulations did to edoxaban, the researchers quantified plasma concentrations of both the parent drug and its active M4 metabolite using liquid chromatography coupled with tandem mass spectrometry, a gold-standard bioanalytical technique aligned with international ICH M10 validation guidance. Pharmacokinetic parameters—the area under the concentration-time curve, peak concentrations, and clearance measures—were compared between treatment periods using linear mixed-effects models, a statistical framework well suited to repeated-measures crossover designs. In parallel, the team assessed pharmacodynamic effects using prothrombin time and activated partial thromboplastin time, the two coagulation assays most commonly used to gauge anticoagulant intensity at the bedside. Finally, in laboratory experiments, the formulations were tested for their capacity to inhibit CYP3A4 activity in vitro.

The pharmacokinetic results were striking in their divergence. Bojungikgitang approximately doubled systemic exposure to edoxaban, effectively reproducing the magnitude of interaction seen with known strong P-glycoprotein inhibitors. At the other extreme, Cheongsanggyeontongtang reduced edoxaban exposure by roughly 40 percent—a reduction in the range that regulators associate with inducers of the drug’s clearance pathways and one that could, in theory, erode the anticoagulant’s protective effect against stroke. Ijintang, by contrast, exerted only minimal effects on the drug’s pharmacokinetic profile. The active metabolite M4 followed the same directional pattern as the parent compound in each case, indicating that the herbal formulations were shifting edoxaban’s overall systemic disposition rather than selectively rerouting its metabolism.

Perhaps the most provocative—and most cautionary—finding came from the pharmacodynamic measurements. Despite the substantial pharmacokinetic shifts, the researchers detected no significant changes in prothrombin time or activated partial thromboplastin time in any of the herbal co-administration groups. In other words, a patient’s exposure to edoxaban could double, or fall by 40 percent, while the standard laboratory coagulation tests remained essentially silent. This dissociation matters because clinicians sometimes lean on coagulation assays when concerns arise about anticoagulant intensity, and the results suggest those assays are poor sentinels for herb-driven changes in edoxaban levels. The therapeutic window of a drug, not the laboratory value alone, ultimately determines whether exposure changes translate into bleeding or thrombotic risk.

The mechanistic work offered clues about how the divergent effects arise. In vitro testing showed negligible inhibition of CYP3A4 by Bojungikgitang and Ijintang and only weak inhibition by Cheongsanggyeontongtang, indicating that direct CYP3A4 blockade is unlikely to explain the doubling of edoxaban exposure seen with Bojungikgitang. The more plausible culprit is interference with P-glycoprotein, the efflux pump that governs edoxaban’s intestinal absorption and biliary excretion. Many phytochemicals common in traditional formulas—including compounds found in ginseng, licorice, and astragalus, herbs represented in some of these formulations—have been shown in laboratory studies to modulate P-glycoprotein and CYP enzymes. The precise constituent responsible for the Bojungikgitang effect, however, remains to be pinned down, and the authors’ data do not permit attribution to a single botanical ingredient.

The clinical context amplifies the significance of the findings. Surveys of Korean medical hospital practice have documented frequent combination therapy between herbal extracts and antiplatelet or anticoagulant drugs in ischemic stroke patients, and Korean medicine clinical practice guidelines for stroke, developed under the National Institute for Korean Medicine Development, formalize herbal care pathways for the same patients who often need anticoagulation. Case reports from around the world have described increased bleeding in patients combining oral anticoagulants with herbal products ranging from saffron to Salvia miltiorrhiza, and St John’s wort has been shown to lower rivaroxaban exposure in controlled human studies. Meanwhile, cohort data have suggested that some concurrent Chinese herbal medicine use may even be associated with fewer major bleeding events, underscoring that the herb-drug interaction landscape is neither uniformly dangerous nor uniformly benign—it is formulation-specific, and largely unmapped.

That is precisely the gap this trial helps to fill. By testing three named, commercially supplied formulations under controlled conditions in healthy volunteers, and by measuring both drug levels and clotting outcomes with validated methods, the Korean team has converted a vague anxiety—herbs might interact with blood thinners—into concrete, quantifiable risk statements: Bojungikgitang approximately doubles edoxaban exposure, Cheongsanggyeontongtang cuts it by about 40 percent, Ijintang is relatively benign, and conventional coagulation tests will not warn you about any of it. The authors conclude that clinical consideration is warranted when edoxaban is combined with Bojungikgitang or Cheongsanggyeontongtang, and the magnitude of the observed changes supports that caution, situating both interactions on par with labeled drug-drug interactions of edoxaban.

Important caveats temper the translation to patient care. The study enrolled healthy volunteers, not the older, multimorbid patients with atrial fibrillation or venous thromboembolism who actually take edoxaban, and it could not assess hard clinical endpoints such as bleeding or stroke. Fixed-sequence designs and modest sample sizes, typical of exploratory interaction studies, also limit generalizability, and the duration of herbal pre-dosing may not capture longer-term induction or adaptation effects. Even so, the work delivers a clear, actionable message for prescribers, pharmacists, and practitioners of traditional medicine alike: herbal formulations are not pharmacologically inert companions to modern anticoagulants. Until larger outcome studies are done, patients taking edoxaban who also use Bojungikgitang or Cheongsanggyeontongtang deserve explicit attention, honest conversations about herbal supplement use, and a healthy skepticism toward coagulation tests that may not reveal what the body is actually doing.

Subject of Research: Herb-drug interactions between traditional Korean herbal formulations and the anticoagulant edoxaban

Article Title: Effects of Bojungikgitang, Ijintang, and Cheongsanggyeontongtang on the pharmacokinetics and pharmacodynamics of edoxaban

Article References: Kim, J. H., Song, J., Kim, M., Kim, H., Cho, H.-Y., & Chung, H. (2026). Effects of Bojungikgitang, Ijintang, and Cheongsanggyeontongtang on the pharmacokinetics and pharmacodynamics of edoxaban. Journal of Pharmaceutical Investigation. https://doi.org/10.1007/s40005-026-00828-z

Image Credits: AI Generated

DOI: 10.1007/s40005-026-00828-z

Keywords: edoxaban, herb-drug interaction, Bojungikgitang, Ijintang, Cheongsanggyeontongtang, pharmacokinetics, pharmacodynamics, direct oral anticoagulants, P-glycoprotein, CYP3A4, traditional Korean medicine, clinical trial