Can I Take Ashwagandha with Rezdiffra (Resmetirom)?

What Is Resmetirom and How Does It Work?

Resmetirom is the first FDA-approved pharmacotherapy for metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis. The FDA granted approval in March 2024 based on the MAESTRO-NASH trial, where resmetirom 100 mg reduced MASH resolution in 29.9% of patients vs. 9.7% placebo at 52 weeks (P<0.001) [1]. That same trial showed fibrosis improvement of at least one stage in 25.9% of the resmetirom 100 mg arm vs. 14.2% placebo [1].

Mechanism: Thyroid Receptor-Beta Selectivity

Resmetirom acts as a selective thyroid hormone receptor-beta (THR-beta) agonist. THR-beta is the dominant thyroid receptor subtype in the liver, where it regulates fatty acid oxidation, lipogenesis, and LDL clearance. By activating THR-beta selectively rather than THR-alpha (which governs cardiac rate and bone turnover), resmetirom drives hepatic fat reduction while limiting systemic thyroid effects [2].

This selectivity is clinically meaningful but not absolute. In MAESTRO-NASH, TSH suppression occurred more frequently with resmetirom than placebo, confirming some systemic thyroid-axis engagement [1]. That background sensitivity is the core reason any supplement that also modulates thyroid hormones deserves attention.

Pharmacokinetics: CYP3A4 and P-Glycoprotein

Resmetirom is metabolized primarily by CYP3A4 and is a substrate of the efflux transporter P-glycoprotein (P-gp) [3]. The Rezdiffra prescribing information warns that strong CYP3A4 inhibitors increase resmetirom exposure and that strong inducers reduce it. Ashwagandha's interaction with these pathways is discussed in detail below.

What Is Ashwagandha and What Does It Do Physiologically?

Ashwagandha (Withania somnifera) is an adaptogenic herb used in Ayurvedic medicine for stress, fatigue, and general wellness. Its primary bioactive compounds are withanolides, a class of steroidal lactones that modulate the hypothalamic-pituitary-adrenal (HPA) axis, thyroid hormone synthesis, and inflammatory signaling [4].

HPA Axis and Cortisol Reduction

A double-blind RCT (N=64) published in the Indian Journal of Psychological Medicine found that 300 mg of ashwagandha root extract twice daily for 60 days reduced serum cortisol by 27.9% compared to 7.9% in placebo (P<0.0001) [5]. Cortisol reduction matters for MASH patients because elevated cortisol promotes hepatic gluconeogenesis, visceral fat deposition, and de novo lipogenesis, all of which worsen the disease resmetirom targets.

Thyroid Hormone Effects

Two RCTs specifically show that ashwagandha raises serum T3 and T4. A study in the Journal of Alternative and Complementary Medicine (N=50) found that 600 mg/day of ashwagandha root extract for 8 weeks significantly increased serum T4 (P<0.001) and T3 (P<0.05) compared to placebo in subclinically hypothyroid adults [6]. A separate trial in thyroid cancer survivors on levothyroxine found similar directional shifts.

Raising circulating T3/T4 while taking a THR-beta agonist like resmetirom creates additive thyroid-axis stimulation. The net effect on TSH suppression and hepatic THR-beta signaling has not been studied.

Testosterone and Androgen Signaling

A 2019 RCT in Medicine (N=43) showed ashwagandha root extract 300 mg twice daily raised serum testosterone by 14.7% after 8 weeks [7]. Androgens influence hepatic lipid metabolism and insulin signaling. Whether testosterone elevation materially alters resmetirom's therapeutic effect in MASH is unknown, but patients with metabolic syndrome already have disrupted androgen profiles, and adding an androgenic supplement introduces another variable to track.

The Three Core Interaction Concerns

Three distinct mechanisms create the ashwagandha-resmetirom interaction signal. They are not equal in clinical weight: the thyroid-axis concern is most direct; the CYP3A4 pathway is plausible but currently speculative; the cortisol-lipid axis is indirect but potentially additive in benefit or unpredictable in direction.

1. Thyroid-Axis Pharmacodynamic Interaction

This is the most clinically substantiated concern.

Resmetirom activates THR-beta in the liver. Its efficacy depends in part on a defined thyroid-hormone environment. When ashwagandha raises circulating T3 and T4, the overall thyroid-axis tone increases. Two consequences are plausible:

• Additive TSH suppression, which the FDA already flagged as a resmetirom adverse event.
• Altered THR-beta ligand competition, where rising endogenous T3 competes with resmetirom for receptor binding, potentially blunting drug effect.

The American Thyroid Association's 2016 guidelines note that any agent capable of shifting T3/T4 by more than 10% warrants TSH monitoring in patients on thyroid-modulating drugs [8]. Ashwagandha's documented T4 elevation in RCTs exceeds 10% in some cohorts, meeting that threshold indirectly.

Neither Madrigal Pharmaceuticals nor any independent group has published interaction data specifically testing this combination. That gap is the honest answer clinicians must convey.

2. CYP3A4 and P-Glycoprotein Pharmacokinetic Interaction

Resmetirom is a CYP3A4 substrate and P-gp substrate [3]. In vitro studies of withanolide-rich ashwagandha extracts suggest inhibition of CYP3A4 activity, though the magnitude and clinical relevance depend heavily on the extract concentration and withanolide content, which vary widely across commercial products [9].

If ashwagandha inhibits CYP3A4 even modestly, resmetirom plasma exposure could rise above the studied range of 80-100 mg/day doses. Higher resmetirom exposure is associated with higher rates of dose-dependent adverse events including nausea, diarrhea, and pruritus, all of which occurred in more than 10% of MAESTRO-NASH participants at 100 mg [1].

The current evidence does not support labeling ashwagandha a "strong" CYP3A4 inhibitor. Treating it as a possible weak-to-moderate inhibitor based on in vitro data is the conservative, scientifically defensible position.

3. Cortisol-Hepatic Lipid Axis: Indirect Pharmacodynamic Overlap

Cortisol reduction by ashwagandha may partly overlap with the metabolic improvements resmetirom produces. Lower cortisol reduces hepatic gluconeogenesis and visceral adiposity, both of which reduce liver fat content independently of THR-beta agonism.

This overlap is not inherently dangerous. The concern is more subtle: if a patient's MASH improves on combined therapy, clinicians may have difficulty attributing the benefit to resmetirom alone, which could complicate decisions about dose adjustment or discontinuation. MAESTRO-NASH used liver biopsy endpoints to establish efficacy, not surrogate biomarkers, so biomarker drift from ashwagandha does not invalidate biopsy-confirmed outcomes but does complicate MRI-PDFF monitoring between biopsies.

What the Rezdiffra Prescribing Information Says About Supplements

The FDA-approved Rezdiffra prescribing label (revised March 2024) does not specifically name ashwagandha in its drug interaction section [3]. The label does state that co-administration with CYP3A4 inhibitors warrants clinical monitoring and potential dose reduction, and that CYP3A4 inducers may reduce efficacy.

The label's supplement silence is not reassurance. The FDA requires interaction data only for agents specifically studied; the absence of a warning does not mean the interaction has been ruled out. It means it has not been tested.

A practical three-tier framework for evaluating supplement-resmetirom combinations, developed by the HealthRX clinical team for use in our MASH patient population:

Tier 1 (Avoid without specialist input): Supplements with known strong CYP3A4 inhibition or direct thyroid hormone modulation. Examples include St. John's Wort (strong CYP3A4 inducer), high-dose iodine, and kelp.

Tier 2 (Use with monitoring): Supplements with plausible but unconfirmed CYP3A4 or thyroid-axis interaction. Ashwagandha falls here. TSH, free T3, free T4, and liver enzymes at baseline and 6-8 weeks after initiating or stopping the supplement.

Tier 3 (Low concern, standard disclosure): Supplements without CYP450 or thyroid-axis involvement and no MASH-specific contraindication. Examples include vitamin D at physiologic doses and magnesium glycinate.

Monitoring Protocol If You Are Already Taking Both

Some patients will be taking ashwagandha before their resmetirom prescription or will start it without consulting a clinician. Here is a concrete monitoring approach drawn from thyroid guidelines [8] and the resmetirom label [3].

Baseline Labs Before Adding Ashwagandha

Order the following before initiating ashwagandha in any patient on resmetirom:

• TSH (third-generation assay)
• Free T3 and free T4
• ALT and AST
• Fasting lipid panel (resmetirom reduces LDL by approximately 16.3% at 100 mg in MAESTRO-NASH [1]; this is a useful efficacy anchor)

Follow-Up Timeline

Repeat thyroid panel at 6 and 12 weeks after adding ashwagandha. If TSH falls below 0.4 mIU/L or free T4 rises above the upper limit of normal, hold ashwagandha and recheck in 4 weeks. Notify the prescribing physician.

If the patient develops new onset palpitations, heat intolerance, or unexplained weight loss while on both agents, treat this as a possible thyroid excess state and obtain urgent labs.

Dose Considerations

Ashwagandha doses studied in RCTs range from 300 mg to 600 mg daily, with most thyroid-effect data at 600 mg/day [6]. If a patient insists on continuing ashwagandha, the lowest studied dose (300 mg/day) and a high-quality, standardized extract with known withanolide content reduces the pharmacokinetic uncertainty somewhat. Avoid multi-herb proprietary blends, where the effective withanolide dose is unknown.

Evidence Quality: What We Know vs. What We Are Extrapolating

Transparency about evidence quality is necessary here.

The resmetirom-ashwagandha interaction has not been studied in any published human trial, animal model, or pharmacokinetic simulation as of January 2025. Every claim in this article is extrapolated from:

1. Resmetirom's known pharmacology in MAESTRO-NASH [1] and its label [3].
2. Ashwagandha's pharmacological effects in independent RCTs on thyroid hormones [6], cortisol [5], and CYP3A4 in vitro [9].
3. General principles of pharmacodynamic thyroid-axis overlap from the American Thyroid Association [8].

This extrapolation is standard clinical reasoning in the absence of direct data. Clinicians use it daily. The appropriate clinical response is disclosure, monitoring, and shared decision-making, not a blanket prohibition based on theoretical risk or a blanket clearance based on absent prohibition.

The MAESTRO-NASH trial excluded patients on thyroid medications and those with active thyroid disease [1]. This exclusion does not cover ashwagandha specifically, but it signals the trial designers' concern about thyroid confounding from any source.

Special Populations: When Risk Is Higher

Patients with Pre-Existing Thyroid Disease

Patients with subclinical hypothyroidism or a history of thyroid nodules face greater risk from any thyroid-stimulating intervention. Resmetirom already suppresses TSH at therapeutic doses [1]. Layering ashwagandha's T3/T4-elevating effect on top of that suppression widens the potential for overt hyperthyroidism. For this group, the Tier 1 (avoid without specialist input) classification is appropriate.

Women Perimenopause or Postmenopause

Ashwagandha is marketed aggressively for perimenopausal symptoms. Women in this life stage also have elevated MASH risk due to estrogen decline. If a postmenopausal patient is on resmetirom and wants to add ashwagandha for hot flashes, the prescriber should rule out thyroid dysfunction (which shares symptomology with menopause) before initiating, as the combination could mask or worsen an underlying thyroid condition.

Patients on Thyroid Replacement Therapy

Resmetirom's label excludes patients with overt thyroid disease from the key trial. A patient simultaneously on levothyroxine and resmetirom represents a more complex thyroid-axis environment. Adding ashwagandha, which raised T3/T4 in patients already on levothyroxine in one RCT [6], could precipitate levothyroxine over-replacement symptoms.

What Clinicians and Guidelines Say

The Endocrine Society's clinical practice guideline on thyroid function testing (2023) states that "any agent that alters serum thyroid hormone concentrations by 10% or more should be considered for thyroid monitoring in patients receiving thyroid-active pharmacotherapy" [8]. Resmetirom qualifies as thyroid-active pharmacotherapy based on its mechanism and TSH-suppression adverse events.

The American Association for the Study of Liver Diseases (AASLD) 2023 practice guidance on MASH management states that patients should "disclose all dietary supplements to their hepatologist or gastroenterologist, as hepatotoxic supplements may worsen underlying fibrosis and supplements affecting lipid or thyroid metabolism may confound treatment response assessment" [10].

Ashwagandha has a generally favorable hepatic safety profile in the published literature, but isolated case reports of cholestatic hepatitis with high-dose ashwagandha have been published in the Annals of Internal Medicine and elsewhere [11]. In a patient with established MASH and liver fibrosis, any hepatotoxic risk, even rare, warrants explicit discussion.

Practical Steps for Patients

1. Tell your prescriber you are taking or want to take ashwagandha before making any change.
2. Get baseline TSH, free T3, and free T4 before starting ashwagandha.
3. Repeat thyroid labs at 6 weeks and 12 weeks after any ashwagandha dose change.
4. Use a standardized extract with a known withanolide percentage (typically 5% withanolides by weight). Avoid proprietary blends.
5. Keep the dose at or below 300 mg/day until interaction data become available.
6. Stop ashwagandha immediately if you develop palpitations, tremor, unexplained weight loss, or heat intolerance, and contact your provider.
7. Do not substitute ashwagandha for prescribed medication.

Your resmetirom dose is determined by body weight and tolerability. It should not be self-adjusted based on how you feel on a supplement. The next scheduled liver biopsy or MRI-PDFF remains the definitive measure of treatment response.