Ergothioneine | Supplementopedia

Overview

Ergothioneine (EGT) is a naturally occurring, sulfur‑containing amino acid derivative first isolated from the mushroom Claviceps purpurea in 1909. In humans, it is taken up via the highly specific transporter OCTN1 (SLC22A4) and functions primarily as a potent intracellular antioxidant and metal‑chelating molecule, helping to maintain redox balance across a wide range of tissues.

Benefits

Cellular antioxidant protection: Clinical and pre‑clinical studies show EGT scavenges reactive oxygen and nitrogen species, reducing oxidative damage in liver, kidney, and cardiovascular tissues.
Neuro‑protective effects: In rodent models, EGT mitigates neuronal loss after ischemic insult and improves performance on memory tasks, suggesting a role in preserving cognition.
Cardiovascular health: Observational data link higher plasma EGT concentrations with a lower incidence of coronary artery disease and reduced arterial stiffness.
Metabolic support: In vitro and animal work indicate EGT improves mitochondrial function and insulin sensitivity, though human trials remain limited.
Immune modulation: EGT modulates cytokine production (e.g., reduces IL‑6, TNF‑α) and enhances the function of immune cells such as neutrophils and macrophages.
Overall, the evidence positions EGT as a broad‑spectrum cytoprotectant rather than a disease‑specific drug.

How It Works

Redox‑active thioether: Ergothioneine’s primary mechanism is its redox‑active thioether that can donate electrons without undergoing irreversible oxidation, allowing repeated scavenging of •OH, superoxide, and peroxynitrite.
Metal Chelation: EGT chelates transition metals (Fe²⁺, Cu²⁺), preventing Fenton-type generation of free radicals.
Mitochondrial Protection: Inside cells, it is concentrated in mitochondria, where it stabilizes the mitochondrial membrane potential and protects the electron‑transport chain from oxidative overload.
OCTN1 and Nrf2–Keap1 Pathway: Via the OCTN1 transporter, EGT accumulates in high‑traffic tissues (brain, retina, kidney) and interacts with the Nrf2–Keap1 pathway, up‑regulating endogenous antioxidant enzymes (SOD, catalase).
Protein Thiol Status: Additionally, EGT’s ability to maintain protein thiol status helps preserve enzyme activity under stress.
Together, these actions reduce oxidative stress‑induced signaling, limit lipid peroxidation, and preserve cellular energetics.

Dosage

Human supplementation studies have most commonly employed 5–25 mg per day of pure ergothioneine, taken with food to enhance OCTN1‑mediated absorption.
A 10 mg daily dose is widely regarded as “nutritionally adequate” based on average dietary intake (~1–5 mg/day) and shows measurable increases in plasma EGT within 2–4 weeks.
General antioxidant support: 5–10 mg/day.
Cognitive/ neuro‑protective trials: 15–25 mg/day, divided into two doses (morning and evening).
Clinical trials in metabolic disease: up to 30 mg/day (under medical supervision).
Because EGT is water‑soluble and has a short plasma half‑life (~2–3 h), split dosing may maintain more stable plasma levels.
Individuals with renal impairment may require lower doses (≤5 mg) until safety is confirmed.

Safety & Side Effects

Ergothioneine is considered GRAS (Generally Recognized as Safe) by the FDA at typical supplemental levels (≤30 mg/day).
Reported adverse events are rare and generally mild (e.g., transient gastrointestinal discomfort).
No clinically significant drug interactions have been documented, though its metal‑chelating property could theoretically affect the absorption of iron or copper supplements; spacing them ≥2 h apart is advised.
Pregnancy & lactation: insufficient human data; avoid high doses (>20 mg).
Severe renal impairment: reduced clearance may increase plasma levels; consult a clinician.
Known OCTN1 deficiency (rare genetic variants): may affect uptake and efficacy.
Overall, EGT exhibits a high safety margin, but long‑term (>12 months) high‑dose data are still limited.

Chemistry

Ergothioneine is a thiol‑containing derivative of histidine.
IUPAC name: (2‑S‑methyl‑3‑[2‑(sulfinyl)‑1‑hydroxy‑3‑pyrrolyl]‑L‑histidine).
Molecular formula: C₁₀H₁₆N₂O₃S.
Molecular weight: 229.30 g·mol⁻¹.
Structure: A histidine backbone with a thio‑methyl group at the imidazole nitrogen and an N‑alkylated sulfur (–S–CH₃) that is oxidized to a sulfide‑sulfoxide (S–O). The 2‑sulfoxide confers strong antioxidant capacity while maintaining high water solubility (≈ 1 g/L at 25 °C). The molecule is stable at neutral pH, resistant to gastric acid, and retains activity after standard food‑processing temperatures.

Sources & Quality

Ergothioneine is most abundant in edible mushrooms (especially Boletus spp., Pleurotus spp., and Lentinula edodes), where it can reach 4–10 mg · kg⁻¹ fresh weight.
Commercially, EGT is extracted from cultivated mushroom mycelia using aqueous or ethanol‑based extraction followed by chromatography (e.g., ion‑exchange or HPLC) to achieve >95 % purity.
Synthetic routes (e.g., solid‑phase peptide synthesis) are also available but are more costly.
For supplements, quality markers include: ≥95 % purity, absence of heavy metals (<0.5 ppm), and verification of the OCTN1‑compatible stereochemistry (L‑form).
Products certified by third‑party labs (e.g., USP, NSF) provide assurance of consistency and lack of contaminants such as mycotoxins.