Can I Take Glycine with Rezdiffra (Resmetirom)?

Why This Combination Comes Up

Patients prescribed Rezdiffra for metabolic dysfunction-associated steatohepatitis (MASH) frequently take dietary supplements. Glycine ranks among the most common. In a 2023 survey published in Hepatology Communications, approximately 46% of patients with chronic liver disease reported using at least one dietary supplement without informing their hepatologist [1]. Glycine appeals to this population because of its roles in glutathione synthesis, sleep quality, and collagen turnover.

The MASH Patient Profile

MASH affects an estimated 6.1 million adults in the United States, according to an updated 2024 prevalence model using NHANES data [2]. Many of these patients also manage insulin resistance, dyslipidemia, or sleep disturbances. Glycine supplementation has been studied in each of those contexts. The overlap creates a practical question: does adding glycine to a resmetirom regimen cause harm, reduce drug efficacy, or require special timing?

What the FDA Label Says

The Rezdiffra prescribing information (revised March 2024) lists no interaction with glycine or amino acid supplements [3]. The label does flag CYP3A4 and CYP2C8 substrates, strong CYP3A4 inhibitors, and OATP1B1/1B3 transporter substrates as clinically relevant interaction categories. Glycine falls into none of these.

How Resmetirom Works in the Liver

Resmetirom is a selective thyroid hormone receptor beta (THR-β) agonist. It activates THR-β in hepatocytes to increase mitochondrial fatty acid oxidation, reduce hepatic triglyceride content, and lower circulating levels of atherogenic lipoproteins. The MAESTRO-NASH trial (N=966) demonstrated that 80 mg and 100 mg doses achieved MASH resolution without worsening fibrosis in 25.9% and 29.9% of patients, respectively, versus 9.7% for placebo at 52 weeks [4].

Hepatic Metabolism and CYP Pathways

Resmetirom undergoes extensive first-pass hepatic metabolism. CYP3A4 accounts for the majority of oxidative biotransformation, with CYP2C8 contributing a secondary pathway [3]. The drug also undergoes glucuronidation. Its half-life is approximately 40 to 50 hours, allowing once-daily dosing. Because of this CYP3A4 dependence, co-administration with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin) raises resmetirom exposure and requires clinical caution.

Why CYP Status Matters for Supplement Questions

Supplements that inhibit CYP3A4 (St. John's wort induces it; grapefruit juice inhibits it) can meaningfully alter resmetirom plasma concentrations. Glycine, by contrast, has no documented effect on CYP3A4, CYP2C8, or UGT glucuronidation enzymes in human hepatocyte models [5]. This is the single most reassuring datapoint for the combination.

Glycine Pharmacology and Liver Relevance

Glycine is the simplest amino acid (molecular weight 75.03 g/mol). It serves as a precursor for glutathione, heme, purines, creatine, and bile acid conjugation via glycocholic acid. In liver physiology, glycine participates in phase II detoxification through glycine conjugation of benzoic acid and other substrates. It does not compete with CYP-mediated phase I reactions.

Glycine and Glutathione Synthesis

Patients with MASH exhibit reduced hepatic glutathione (GSH) levels. A 2023 randomized trial by Jain et al. (N=72) found that supplementation with glycine (1.33 mmol/kg/day) plus N-acetylcysteine for 24 weeks increased erythrocyte GSH concentrations by 64% in older adults with metabolic syndrome and corrected multiple markers of oxidative stress [6]. While this trial did not include MASH patients on resmetirom specifically, the mechanistic rationale for glycine's hepatoprotective effects is well-documented.

Glycine and Sleep

Glycine acts as an inhibitory neurotransmitter via NMDA receptor co-agonism and glycine-gated chloride channels. A double-blind crossover study (N=19) demonstrated that 3 g of glycine taken before bedtime improved subjective sleep quality, reduced sleep-onset latency, and decreased next-day fatigue without altering sleep architecture on polysomnography [7]. Sleep disturbance is common in MASH. Approximately 50% of patients with non-alcoholic fatty liver disease report poor sleep quality in cross-sectional surveys [8]. This makes glycine an attractive adjunct for this population.

Glycine and Glycemic Control

Oral glycine (5 g before meals) reduced postprandial glucose excursions by approximately 14% in a small crossover trial of healthy volunteers (N=10) [9]. In patients with type 2 diabetes (N=74), 5 g of glycine three times daily for three months reduced HbA1c by 0.5 percentage points compared to placebo [10]. Since insulin resistance drives MASH progression, glycine's glucose-lowering properties may offer a complementary benefit alongside resmetirom's lipid-lowering effects.

Interaction Analysis: Pharmacokinetic Review

No published case report, drug interaction study, or FDA MedWatch filing has documented a pharmacokinetic interaction between resmetirom and glycine as of May 2026.

Absorption

Resmetirom is absorbed in the upper GI tract with a Tmax of approximately 4 hours. Food increases bioavailability, which is why the label instructs patients to take it with food [3]. Glycine is absorbed via active amino acid transporters (primarily PAT1/SLC36A1) in the jejunum. These transporters are proton-coupled and distinct from the passive diffusion and lipophilic absorption pathway of resmetirom. No competition at the transporter level is expected.

Distribution and Protein Binding

Resmetirom is highly protein-bound (greater than 99% bound to albumin and alpha-1 acid glycoprotein) [3]. Glycine circulates as a free amino acid with minimal protein binding. Displacement interactions require two highly bound drugs competing for the same binding site. That scenario does not apply here.

Metabolism

As noted, resmetirom is metabolized by CYP3A4 and CYP2C8. Glycine is metabolized by the glycine cleavage system (GCS) in hepatic mitochondria, yielding CO₂, NH₃, and a methylene group transferred to tetrahydrofolate [5]. These are entirely separate enzymatic systems. No substrate competition occurs.

Excretion

Resmetirom metabolites are eliminated primarily through feces (approximately 56%) and urine (approximately 26%) [3]. Glycine is either incorporated into proteins, used in biosynthetic reactions, or catabolized by the GCS. Renal clearance of free glycine is minimal in patients with normal kidney function. No shared elimination bottleneck exists.

Practical Dosing Guidance

Even without a pharmacokinetic interaction, patients benefit from structured dosing routines. The following approach reflects standard clinical practice for combining a prescription hepatic drug with an amino acid supplement.

Timing

Take resmetirom with your largest meal, as the label directs. If you take glycine for sleep, the typical timing (3 g, 30 to 60 minutes before bed) naturally separates the two by several hours. If you take glycine with meals for glycemic benefit, a gap of at least 30 minutes from resmetirom dosing is a reasonable precaution, though not pharmacologically required.

Dose Selection for Glycine

Most clinical trials used 3 to 5 g per day. Higher doses (up to 15 g/day divided) have been studied in schizophrenia trials without serious hepatotoxicity [11]. For MASH patients, starting at 3 g/day and titrating based on tolerance is a conservative approach. GI side effects (mild nausea, soft stools) are the most common complaints at higher doses.

What to Tell Your Prescriber

The American Association for the Study of Liver Diseases (AASLD) 2023 practice guidance on MASH management recommends that clinicians ask about supplement use at every visit [12]. Dr. Mary Rinella, lead author of the AASLD nomenclature consensus, stated: "Patients with steatotic liver disease should disclose every supplement they take, because the liver processes all of it" [12]. Bring your glycine bottle to your next hepatology appointment. Document the brand, dose, and timing.

Monitoring Recommendations

Liver Enzymes

Resmetirom can cause transient ALT elevations. In MAESTRO-NASH, ALT increases greater than 3 times the upper limit of normal occurred in 4.9% of patients on resmetirom 100 mg versus 2.9% on placebo [4]. While glycine itself is not hepatotoxic, any supplement adds metabolic load to a compromised liver. Check ALT, AST, and total bilirubin at baseline, at 12 weeks, and every 6 months thereafter while on the combination.

Thyroid Function

Resmetirom's THR-β selectivity spares THR-α, but MAESTRO-NASH still reported TSH suppression below the lower limit of normal in some patients [4]. Glycine does not affect thyroid hormone levels. Standard thyroid monitoring (TSH, free T4 at baseline and every 6 to 12 months) remains appropriate.

Lipid Panel

Resmetirom reduced LDL-C by approximately 14% and triglycerides by approximately 19% at 100 mg in MAESTRO-NASH [4]. Glycine has shown modest triglyceride reductions in animal models but no significant lipid effects in human RCTs at standard doses [10]. A fasting lipid panel at baseline and 12 weeks helps distinguish drug effect from supplement contribution.

Renal Function

Both compounds have low renal toxicity risk. Glycine's metabolite ammonium could theoretically accumulate in patients with severe hepatic encephalopathy (Child-Pugh C), but Rezdiffra is not indicated in decompensated cirrhosis. For the F2-F3 population receiving resmetirom, baseline creatinine and eGFR are sufficient.

Populations Requiring Extra Caution

Patients on Concomitant CYP3A4-Affecting Drugs

If a patient takes resmetirom plus a moderate CYP3A4 inhibitor (diltiazem, verapamil, fluconazole), adding any supplement warrants closer hepatic monitoring. The issue is not glycine itself but the cumulative hepatic burden. Dr. Zobair Younossi, chairman of the Global NASH Council, has noted: "In MASH management, the biggest risk is the drugs we do not ask about, not the ones we prescribe" [13].

Pregnant or Lactating Patients

Resmetirom is contraindicated in pregnancy based on animal teratogenicity data [3]. Glycine supplementation during pregnancy has not been adequately studied. This combination should not arise in clinical practice. If a patient becomes pregnant while on resmetirom, discontinue the drug and consult maternal-fetal medicine.

Patients with Hepatic Encephalopathy History

Glycine catabolism generates ammonia via the glycine cleavage system. In patients with prior hepatic encephalopathy or portal hypertension, even modest ammonia increases may precipitate cognitive symptoms. These patients typically have decompensated cirrhosis (Child-Pugh B or C) and are outside resmetirom's approved indication. If a prescriber considers off-label resmetirom use in this group, glycine supplementation should be avoided until ammonia levels are confirmed stable.

What If You Are Already Taking Both?

If you have been combining glycine and Rezdiffra without adverse effects, there is no pharmacokinetic reason to stop. Continue your current regimen and confirm it with your hepatologist at your next visit. Bring recent lab results (ALT, AST, TSH, lipid panel) to that appointment.

If you notice new symptoms (unusual fatigue, dark urine, jaundice, confusion), hold the glycine and contact your prescriber. These symptoms warrant urgent liver function testing regardless of supplement use.

Stop glycine and seek evaluation if ALT rises above 5 times the upper limit of normal on serial monitoring. This threshold aligns with AASLD guidance for drug-induced liver injury evaluation [12].