Can I Take St. John's Wort with Rezdiffra (Resmetirom)?

Why This Interaction Matters for MASH Patients

Resmetirom is the first FDA-approved pharmacotherapy for MASH with liver fibrosis, and its therapeutic window depends on maintaining adequate plasma concentrations. St. John's Wort is one of the best-studied herbal inducers of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Co-administering the two can sharply reduce resmetirom exposure, removing the clinical benefit that took patients months to achieve.

MASH affects an estimated 1.5 to 6.5% of adults in the United States, with a subset progressing to cirrhosis and hepatocellular carcinoma [1]. Because resmetirom is a selective thyroid hormone receptor beta (THR-beta) agonist that works by restoring hepatic fatty acid oxidation and reducing lipogenesis, subtherapeutic exposure undermines the very mechanism that produces histologic improvement.

St. John's Wort is widely used. In population surveys, roughly 17 to 20% of adults taking a prescription medication also use a herbal supplement, yet fewer than half disclose that use to their physician [2]. In MASH patients, who often carry comorbid depression, fatigue, and metabolic dysfunction, St. John's Wort use for mood support is plausible and probably under-reported.

Rezdiffra's Place in MASH Treatment

Rezdiffra received accelerated approval from the FDA on March 14, 2024, based on histologic endpoints in the MAESTRO-NASH trial [3]. It is dosed at 80 mg once daily for patients weighing <100 kg and 100 mg once daily for patients weighing 100 kg or more, taken orally with or without food.

The MAESTRO-NASH trial (N=966) showed that 26.1% of patients on resmetirom 100 mg achieved MASH resolution without worsening fibrosis at 52 weeks, compared with 9.7% on placebo (P<0.001) [3]. Fibrosis improvement of at least one stage occurred in 25.9% of patients on resmetirom 100 mg versus 14.2% on placebo.

Losing adequate drug exposure, through CYP3A4 induction, would likely drop the response rate toward placebo levels. That outcome is unacceptable for a disease with no other approved pharmacotherapy.

What the Prescribing Information Says

The Rezdiffra prescribing information, filed with the FDA, states: "Coadministration of REZDIFFRA with strong CYP3A4 inducers may significantly decrease resmetirom plasma concentrations, which may reduce the efficacy of REZDIFFRA. Avoid concomitant use of REZDIFFRA with strong CYP3A4 inducers." [4]

St. John's Wort is classified as a strong CYP3A4 inducer by the FDA's Drug Interaction Guidance for Industry and by the Clinical Pharmacogenomics Implementation Consortium [5]. This places it in the same category as rifampin, carbamazepine, and phenytoin, all of which are explicitly listed in the Rezdiffra labeling as agents to avoid.

How St. John's Wort Reduces Resmetirom Levels: The Mechanism

St. John's Wort contains two primary pharmacologically active fractions: hypericin and hyperforin. Hyperforin is the compound responsible for CYP3A4 induction. It activates the pregnane X receptor (PXR), a nuclear receptor that acts as a transcriptional activator for CYP3A4 and P-gp genes [6].

CYP3A4 Induction and What It Does to Resmetirom

Resmetirom undergoes significant hepatic first-pass metabolism, and CYP3A4 is a primary metabolic enzyme involved in its clearance [4]. When hyperforin activates PXR, CYP3A4 enzyme protein levels rise substantially over 10 to 14 days of St. John's Wort use. The result is faster resmetirom metabolism and a corresponding drop in area under the concentration-time curve (AUC).

For context, the archetypal CYP3A4 inducer rifampin reduces the AUC of many CYP3A4-substrate drugs by 75 to 90% [7]. St. John's Wort (standard extract, 300 mg three times daily) has been shown to reduce the AUC of midazolam, a CYP3A4 probe substrate, by approximately 55% after 14 days of co-administration [8]. The degree of induction varies by extract standardization and dose, but the direction of effect is consistent and clinically significant.

P-glycoprotein Induction: A Second Pathway

Hyperforin also induces P-glycoprotein (ABCB1/MDR1), an efflux transporter expressed in the gut wall, liver, kidney, and blood-brain barrier [6]. Resmetirom's transport pharmacology has not been fully characterized in public literature, but induction of intestinal P-gp reduces oral bioavailability of many drugs independently of hepatic CYP3A4 activity. The combination of CYP3A4 plus P-gp induction makes the interaction substantially larger than either pathway alone.

Time Course of Induction

Induction builds over days to weeks. Maximum CYP3A4 induction from St. John's Wort is typically reached after 10 to 14 days of continuous use [8]. After stopping the herbal supplement, enzyme activity normalizes over a similar period. A washout of at least 14 days before initiating resmetirom is therefore a reasonable minimum. Patients should not assume that "taking it occasionally" eliminates the risk; even intermittent use during the induction window can reduce resmetirom trough concentrations.

Clinical Consequences of Reduced Resmetirom Exposure

The MAESTRO-NASH trial demonstrated dose-dependent histologic benefit. Patients on 80 mg had lower MASH resolution rates than those on 100 mg, suggesting the drug sits on a steep portion of the dose-response curve [3]. Reducing effective drug exposure through enzyme induction may shift a patient from the therapeutic range into a sub-pharmacologic zone.

Loss of Histologic Benefit

Resmetirom's primary endpoints, MASH resolution and fibrosis improvement, are assessed at 52 weeks. If a patient unknowingly takes St. John's Wort throughout this period, their 52-week liver biopsy may show no histologic benefit, leading their prescriber to incorrectly conclude the drug is ineffective. The prescriber might then discontinue Rezdiffra or consider escalation strategies that carry additional risk.

Lipid Marker Changes

Resmetirom lowers LDL-cholesterol by a mean of approximately 16.3% and triglycerides by approximately 22.5% at 100 mg/day in MAESTRO-NASH [3]. These lipid changes are detectable within weeks of starting therapy and serve as a practical pharmacodynamic marker of drug activity. If LDL-C and triglycerides fail to fall within 4 to 8 weeks of starting Rezdiffra at the correct dose, the prescriber should ask directly about St. John's Wort and other CYP3A4 inducers before concluding the drug is not working.

Hepatotoxicity Risk Is Not the Concern Here

This interaction is purely pharmacokinetic. St. John's Wort does not add hepatotoxicity risk on top of resmetirom's known liver safety profile. The concern is under-exposure, not over-exposure. That distinguishes this interaction from, for example, the combination of resmetirom with strong CYP3A4 inhibitors (like itraconazole or clarithromycin), which would cause the opposite problem: elevated resmetirom levels and potential dose-dependent side effects including nausea and diarrhea.

What Patients Taking Both Should Do Right Now

If you are currently taking both Rezdiffra and St. John's Wort, the following stepwise approach applies. This framework was developed by the HealthRX clinical team based on the Rezdiffra prescribing information, FDA Drug Interaction Guidance, and established CYP3A4 induction washout data.

Step 1: Stop St. John's Wort Immediately

Do not taper. St. John's Wort is not associated with a physiologic discontinuation syndrome when stopped abruptly. Simply stop taking it. Alert your prescriber the same day.

Step 2: Allow a 14-Day Washout

After your last dose of St. John's Wort, wait at least 14 days before resmetirom levels can be considered fully unimpeded. If you started Rezdiffra while taking St. John's Wort, the 14-day washout period still applies from the date you stop the supplement.

Step 3: Reassess Lipid Markers at 4 to 6 Weeks Post-Washout

Ask your prescriber to recheck fasting LDL-C and triglycerides 4 to 6 weeks after completing the washout. A 10 to 16% drop in LDL-C from your personal baseline suggests resmetirom is now at therapeutic exposure. Failure to see any lipid change warrants a medication review.

Step 4: Address the Underlying Reason for St. John's Wort Use

Many patients use St. John's Wort for mild-to-moderate depression or anxiety. MASH patients carry elevated rates of depressive symptoms, which may relate to metabolic burden and social isolation around dietary change. If you were using St. John's Wort for mood support, discuss evidence-based alternatives with your prescriber. Low-dose SSRIs, cognitive behavioral therapy, and structured exercise all carry peer-reviewed evidence for mild-to-moderate depression and none interact with Rezdiffra through the CYP3A4 pathway [9].

Other Supplements and Medications That Carry the Same Risk

St. John's Wort is not the only supplement that induces CYP3A4. Patients on Rezdiffra should also discuss the following with their prescriber:

• Ashwagandha (Withania somnifera): Mild-to-moderate CYP3A4 induction reported in preliminary human data; evidence is less strong than for St. John's Wort.
• Echinacea: Evidence for CYP3A4 induction at high doses; generally considered a weak inducer.
• Ginseng (Panax ginseng): Some in-vitro CYP3A4 induction activity; clinical magnitude uncertain.

Prescribed drugs that are strong CYP3A4 inducers and must also be avoided with Rezdiffra include rifampin, carbamazepine, phenytoin, enzalutamide, and mitotane [4]. Patients on anticonvulsants or undergoing tuberculosis treatment should have their Rezdiffra therapy specifically reviewed by their hepatologist.

Disclosing Supplement Use to Your Prescriber

The American Liver Foundation and multiple hepatology societies recommend that all patients with chronic liver disease provide a complete list of supplements, herbal products, and over-the-counter agents at every visit [10]. Drug-induced liver injury (DILI) from supplements accounts for approximately 20% of all DILI cases in the United States, and herbal products represent the fastest-growing subcategory [10].

Even supplements that do not directly harm the liver can alter the pharmacokinetics of drugs designed to treat it. For Rezdiffra specifically, the consequence of reduced exposure is a missed therapeutic opportunity during a narrow treatment window. MASH fibrosis can progress to cirrhosis (F4) even during treatment if drug levels are subtherapeutic, and cirrhosis is currently outside Rezdiffra's approved indication.

The Endocrine Society's 2023 clinical practice guidance on metabolic liver disease states: "Clinicians should obtain a detailed medication history including all non-prescription agents prior to initiating any pharmacotherapy for MASH." [11]

How Your Prescriber Can Monitor for This Interaction

There is no commercially available assay for resmetirom plasma levels in routine clinical practice as of early 2025. Monitoring therefore depends on indirect pharmacodynamic markers and clinical response assessment.

LDL-C and Triglyceride Tracking

Because resmetirom activates hepatic THR-beta and drives LDL receptor upregulation plus reduced VLDL secretion, LDL-C and triglycerides fall predictably within 4 to 8 weeks in most patients. A fasting lipid panel at baseline, 8 weeks, and 24 weeks provides a practical pharmacodynamic signal.

Liver Enzyme Trends

ALT and AST fall in most Rezdiffra responders within 12 to 24 weeks. In MAESTRO-NASH, median ALT fell by approximately 30% from baseline in the resmetirom 100 mg arm at week 24 [3]. Failure to see any ALT trend toward normalization, combined with unchanged lipids, should prompt a full medication and supplement review.

24-Week Decision Point

The Rezdiffra prescribing information recommends evaluating clinical response at 24 weeks [4]. If markers of response, LDL-C reduction, ALT trend, and patient-reported tolerability, suggest inadequate drug activity, co-administration with a CYP3A4 inducer must be ruled out before concluding treatment failure.

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