Thione

Other Names

(2S)-3-(2-mercapto-1H-imidazol-5-yl)-2-(trimethylammonio)propanoate(2S)-3-(2-sulfanylidene-1,3-dihydroimidazol-4-yl)-2-(trimethylazaniumyl)propanoate(2S)-3-(2-Thioxo-2,3-dihydro-1H-imidazol-4-yl)-2-(trimethylammonio)propanoate(alpha-S)-alpha-carboxy-2,3-dihydro-N,N,N-trimethyl-2-thioxo-1H-imidazole-4-ethanaminium inner salt(alphaS)-alpha-Carboxy-2-mercapto-N,N,N-trimethyl-1H-imidazole-4-ethanaminium inner salt2-Mercapto-histidine trimethylbetaine2-Mercaptohistidine trimethyl betaine2-Thiol-L-histidine trimethylbetaineBetaine of 2-thiol-L-histidineEGTERGErgothioneineErgothionineErythrothioneineL-ErgothioneineN,N,N-Trimethyl-2-mercapto-L-histidine betaineSympectothionThiasineThiolhistidine-betaineThiolhistidinebetaineThioneine[1-Carboxy-2-(2-mercaptoimidazol-4-yl)ethyl]trimethylammonium hydroxide inner salt

Synopsis

Thione (Ergothioneine): A Comprehensive Reference

Overview and Nomenclature

In biochemistry and nutritional science, the term thione most precisely designates a class of organic sulfur compounds characterized by a C=S (carbon–sulfur double bond) rather than the C–SH sulfhydryl group of classic thiols. Within the dietary supplement and natural-ingredient landscape, "thione" is used both as a functional chemical descriptor and as a common shorthand name for the compound L-ergothioneine — the best-characterized naturally occurring dietary thione with established biological relevance in humans.

Chemically, ergothioneine is the betaine of histidine with a sulfur atom attached to the imidazole ring. It should not be considered a thiol compound, but rather a thione, a derivative of thiourea. This structural feature is central to its extraordinary chemical stability and distinguishes it sharply from more familiar dietary antioxidants such as glutathione.

Ergothioneine is a unique, naturally occurring sulfur-containing derivative of histidine, chemically designated as (2S)-3-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-2-(trimethylammonio) propanoate. It is also referred to in the scientific literature as 2-mercapto-histidine trimethylbetaine and abbreviated variously as EGT, ERGO, or ET.

A derivative of histidine (2-mercapto-histidine trimethylbetaine), ergothioneine was first isolated in 1909 from the ergot fungus Claviceps purpurea, from which its name was derived. Its structure was determined in 1911.

Chemical Identity and Tautomeric Forms

Structurally, ergothioneine is a tautomer. Unusual among the thiol antioxidants, at physiological pH, ergothioneine exists primarily in its thione form and has a very high redox potential. These unique properties mean that ergothioneine is much more resistant to autooxidation in comparison with other thiols such as glutathione, and is a very effective antioxidant and cytoprotectant, with metal chelation properties as well.

Its remarkable stability arises from its predominant "thione" tautomeric form at physiological pH, which confers exceptional resistance to autoxidation and degradation, even under conditions of elevated temperature or variable pH.

Its midpoint potential for a thiol is unusually high, being +0.06 V versus −0.2 to −0.4 V for typical thiols including glutathione. Its reaction with hydroxyl radicals (OH•) is virtually instantaneous, while it reacts only more slowly with H₂O₂ and/or O₂•−.

Natural Sources and Biosynthesis

Ergothioneine is produced only by fungi and some cyanobacteria and mycobacteria from histidine, with cysteine and methionine providing the sulfur and methyl groups, respectively. Only certain bacteria and fungi can biosynthesize EGT, such as Neurospora crassa, Mycobacterium smegmatis, Chlorobium limicola, and Methylobacterium strains.

Plants absorb EGT produced by microorganisms in the soil via their roots, whereas animals and humans acquire EGT only through their diet. Edible mushrooms are the food source most enriched in EGT, while other dietary sources include some meat products, oat bran and beans. Other foods with high ERGO content include red beans, oat bran and liver.

Mushrooms are the best dietary sources of ergothioneine, accounting for about 95% of total dietary intake. The highest amounts are found in shiitake (24.4 mg per cup), enoki (19.4 mg per cup), maitake (12.2 mg per cup), and oyster (11.3 mg per cup). Some mushrooms, such as the chanterelle (Cantharellus cibarius) and the common white button mushroom (Agaricus bisporus), contain negligible amounts of ergothioneine.

In humans, ergothioneine is acquired exclusively through the diet and accumulates in erythrocytes, bone marrow, liver, kidney, seminal fluid, and eyes.

Common Supplement Forms and Preparations

Ergothioneine as a dietary supplement is commercially available in several forms. It is produced either by extraction from mushrooms or by synthetic chemical means. Current bioproduction methods for ERG primarily depend on fermenting edible mushrooms. However, with the advancement in synthetic biology, an increasing number of genetically engineered microbial hosts have been developed for ERG production, including Escherichia coli, Saccharomyces cerevisiae, and Corynebacterium glutamicum.

The novel food synthetic l-ergothioneine is produced by a one-pot patented manufacturing process. Commercially, the compound is sold as standalone oral capsules (typically containing pure L-ergothioneine), as part of liposomal liquid formulations (such as preparations combining ergothioneine with glutathione, vitamin C, and selenium), and as an ingredient in cosmetic formulations. It has been widely used as a dietary supplement and cosmetic additive.

Traditional and Historical Use

Ergothioneine itself was unknown as a discrete molecule until the twentieth century, and no traditional pharmacopoeia describes it by name. However, the primary dietary vehicle for ergothioneine — edible and medicinal mushrooms — has a long, well-documented history of therapeutic use.

Medicinal use of mushrooms has been documented since ancient times, and in the modern world, mushrooms have a longstanding history of use in Eastern medicine. Recent interest in plant-based diets in Westernized countries has brought increasing attention to the use of mushrooms and mushroom-derived compounds in the prevention and treatment of chronic diseases.

While its formal isolation and identification are rooted in modern science, the medicinal use of ergothioneine-rich sources, especially mushrooms, dates back centuries in traditional medicine systems across Asia and Europe. Healers and herbalists often prized mushrooms such as shiitake, maitake, and reishi for their restorative properties, using them in tonics and remedies to promote vitality, longevity, and overall wellness — benefits now partially attributed to ergothioneine's potent antioxidant and cytoprotective effects.

Historically, these medicinal mushrooms were combined with other botanicals like ginseng, astragalus, or licorice root, creating synergistic herbal formulations intended to support immune function, reduce fatigue, and enhance the body's resilience to stress. The presence of ergothioneine in these combinations likely amplified the antioxidative and anti-inflammatory benefits, even if practitioners at the time did not know the specific compound responsible.

The scientific history of ergothioneine proper begins with its isolation. It was first discovered by French chemist Charles Tanret in 1909, who purified it from the ergot fungus (hence the name, ergothioneine). Ergot, a fungal disease affecting grains, was initially the primary source identified for ergothioneine. This fungus forms toxic compounds that were historically known to cause health issues in humans. However, it also contained ergothioneine, a beneficial amino acid antioxidant, which subsequently piqued the interest of researchers.

Over the last decade, the naturally occurring modified amino acid L-ergothioneine has gained much attention as a potential therapeutic compound. The compound was not widely studied for its pharmacological properties until the identification, in the early 2000s, of a dedicated mammalian transport protein, which provided the first compelling evidence that ergothioneine may serve an essential biological function.

Key Active Constituents and Mechanisms of Action

Chemical Structure and Tautomerism

L-Ergothioneine (EGT) is a natural thiourea derivative of histidine and exists in two forms: thiol and thione forms. Under physiological conditions, EGT mainly exists in the form of thione, which renders it ideal thermal stability and pH stability. This prevalence of the thione form is what earns the molecule its informal name as a "dietary thione."

The OCTN1 Transporter: Evidence for Essentiality

A defining feature separating ergothioneine from most other dietary antioxidants is the existence of a highly specific mammalian transporter dedicated to its absorption and cellular distribution. Mammals cannot synthesize Ergothioneine, but possess a highly specific organic cation transporter OCTN1 (now known as solute carrier family 22 member 4, SLC22A4) allowing for efficient absorption of Ergothioneine from one's daily diet, leading to accumulation of Ergothioneine in tissues and organs of humans and other animals.

This transporter is present in immune cells, in the brush border of intestinal cells, in the lumen of renal proximal tubule cells, in tracheal cells, in the lungs and, albeit to a lesser extent, in the uterus, pancreas, heart, spleen, bone marrow and placenta. In recent years, some research groups have been suggesting the adoption of the name Ergothioneine transporter (ETT), due to its high affinity for this exogenous molecule.

OCTN1 increases the initial cellular uptake of ergothioneine, which cannot pass through membranes due to its hydrophilic nature, by several hundred times. Moreover, ergothioneine is taken up and accumulated in mitochondria. It has also been described that the ergothioneine concentration in the body differs between different tissues and tends to be increased in areas of inflammation or injury.

Genetic knockout of SLC22A4 in multiple organisms has been shown to increase organism susceptibility to oxidative stress, damage and inflammation. This finding has been used to support the hypothesis that ergothioneine functions as a "conditionally essential" micronutrient.

Free Radical Scavenging

Ergothioneine has been shown to have antioxidant properties since it is able to neutralize hydroxyl radicals and inhibit the production of oxidizing species by metal ions such as Fe²⁺ or Cu²⁺. EGT can scavenge reactive oxygen species (ROS) and chelate divalent metal cations such as iron and copper.

Nrf2 Pathway Activation

In vitro and in vivo evidence demonstrates that EGT exerts neuroprotective effects through multiple mechanisms: scavenging reactive oxygen species, suppressing neuroinflammatory cytokines (TNF-α, IL-1β, IL-6), activating Nrf2 antioxidant pathways, and preserving mitochondrial integrity.

Anti-inflammatory Activity

EGT modulates multiple pathological mechanisms, including oxidative stress, neuroinflammation, and mitochondrial dysfunction, which are implicated in neuronal loss. Its anti-inflammatory properties operate through the regulation of cytokines and the inhibition of proinflammatory pathways, contributing to the mitigation of systemic and neural inflammation.

Mitochondrial Protection

Ergothioneine neutralizes reactive oxygen species (ROS), limits lipid peroxidation, and maintains redox homeostasis, particularly in tissues prone to oxidative injury such as the liver, brain, and kidneys. Its long tissue residence time and transporter-mediated uptake enhance its potential as a diet-derived therapeutic antioxidant.

Gut Microbiome Interactions

An ABC transporter specific for Ergothioneine has recently been discovered in gastrointestinal microbes. This indicates dietary Ergothioneine was competitively absorbed and metabolized by gut microbes, which may potentially affect its absorption in humans.

Scientific Evidence by Area of Use

Cognitive Health and Neuroprotection

The strongest and most consistent body of evidence for ergothioneine relates to cognitive health and neuroprotection, though it currently rests largely on observational and mechanistic data, with a small number of clinical trials.

In a prospective elderly cohort in Singapore (n=470, mean age 73), lower baseline ergothioneine levels were associated with poorer baseline cognitive performance and faster rates of decline in function in multiple cognitive domains over 5 years of follow-up.

Observational data consistently associate low blood ergothioneine levels with cognitive impairment, neurodegenerative diseases, cardiovascular disorders, frailty and mortality. Ergothioneine, a unique dietary amino-thione absorbed via the OCTN1 transporter, has recently gained attention for its potential as a neuroprotective, longevity-promoting compound.

A key interventional trial has been conducted in Singapore. This randomized, double-blinded, placebo-controlled study (ClinicalTrials.gov identifier: NCT03641404) was conducted at the Investigational Medicine Unit, National University Hospital, Singapore. Elderly MCI subjects, 60–90 years of age were randomly assigned to receive either placebo or ergothioneine (25 mg) capsules, administered orally three times a week, blinded to both subject and administrator for the entire duration of the study.

Interventional trials in older adults suggest that ergothioneine supplementation may improve cognition, memory, sleep quality and stabilize neurodegeneration biomarkers, with no safety concerns at doses up to 25 mg/day. Mechanistic studies reveal that ergothioneine acts through multiple pathways: mitigating oxidative stress, reducing neuroinflammation, preserving mitochondrial function and potentially modulating neurogenesis and NAD⁺ metabolism, although some mechanisms require further investigation.

Beyond antioxidation, ergothioneine exerts neuroprotective effects relevant to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. It modulates multiple pathological mechanisms, including oxidative stress, neuroinflammation, and mitochondrial dysfunction, which are implicated in neuronal loss.

Evidence strength: Although a confluence of data suggests that ergothioneine acts as a powerful, pleiotropic cytoprotectant agent, and supplemental ergothioneine is already marketed direct to consumers for its anti-ageing and anti-inflammatory effects, controlled human intervention trials are just beginning to directly investigate the effects of ergothioneine supplementation in humans. The current picture is therefore encouraging but remains preliminary; larger confirmatory RCTs are needed.

Cardiovascular Health and Mortality

Epidemiological evidence for a cardiovascular-protective association with higher ergothioneine levels is among the strongest observational findings in this area.

In a larger, longer-term prospective Swedish cohort (n=3,236 participants with median follow-up of 21.4 years), higher plasma levels of ergothioneine were associated with significantly lower risk of coronary disease, cardiovascular mortality and overall mortality (hazard ratios per 1 SD increment of ergothioneine were 0.85, 0.79 and 0.86, respectively).

High plasma ergothioneine levels have been associated with significantly reduced cardiovascular mortality, and overall mortality, risks in humans.

The demonstrated cytoprotectant effect of ergothioneine has led many to suggest a potential therapeutic role for this compound in chronic conditions that involve ongoing oxidative stress and inflammation, including cardiovascular and metabolic diseases. However, the in vivo effects of ergothioneine and its underlying therapeutic mechanisms in the whole organism are not as clear.

Evidence strength: The cardiovascular data are observational (prospective cohort). No controlled clinical intervention trials with cardiovascular endpoints have been reported. The associations are robust across studies but cannot establish causality.

Metabolic Syndrome and Inflammation

The ErgMS study is a single-centre, randomised, double-blind, placebo-controlled, 3-arm parallel, pilot intervention trial, which aims to supplement participants with either placebo, 5 or 30 mg/day ergothioneine for 12 weeks. Measurements of metabolic syndrome risk factors, serum markers of oxidative stress (lipid peroxidation), inflammation, blood platelet function and liver function take place at baseline, and after 6 weeks and 12 weeks of supplementation. In addition, investigators examine if there are any changes in the serum metabolome in response to ergothioneine supplementation.

Evidence strength: The ErgMS study is the first study to address the question of whether ergothioneine supplementation has health benefits for people with metabolic syndrome. Study results will provide preliminary data as to which dose may improve inflammatory markers in adults with metabolic syndrome and will inform dose and primary outcome selection for a definitive randomised controlled trial. This is an area of active but early-phase clinical investigation.

Ocular Health

Ergothioneine is notably concentrated in the eye. Persistent oxidative damage can initiate or exacerbate several common blinding eye conditions, including age-related macular degeneration (AMD), cataracts, diabetic retinopathy (DR), dry eye syndrome, and glaucoma. Preclinical and biochemical studies have examined ergothioneine as a candidate protective agent against these conditions. Researchers are investigating ergothioneine to determine if it can reduce swelling (inflammation) in the lungs and damage in the liver, kidneys, and brain.

Evidence strength: Largely preclinical (in vitro and animal models). No robust clinical trials in ocular disease have been published to date.

Kidney Health

One product (Ergo4Health/Kidney: 0.75 mg L-ergothioneine plus 1250 IU Vitamin D2 per capsule, 2× daily) was evaluated; the reported results for 3 and 6 months indicate moderate improvement in the estimated glomerular filtration rate (eGFR), decreased creatinine and blood urea nitrogen levels at 3 months (not significant at 6 months), and improved quality of life.

Evidence strength: Very limited; the study cited is preliminary, of small scope, and the results were not sustained at 6 months. Further controlled research is required.

Aging and Longevity

An increasing body of evidence suggests ergothioneine may be an important dietary nutrient for the prevention of a variety of inflammatory and cardiometabolic diseases; and ergothioneine has alternately been suggested as a vitamin, 'longevity vitamin' and nutraceutical.

EGT plays a critical role in human health as a potent antioxidant with extensive neuroprotective, cardioprotective, and anti-aging properties. Its inability to be synthesized endogenously by humans, coupled with the existence of a dedicated cellular transporter, elevates its status to that of a "conditionally essential nutrient" or "longevity vitamin," making dietary acquisition a must.

Few clinical studies, which were not well-powered or well-designed, have been performed. Observational studies suggest a link between higher intake levels and healthy aging, likely by mitigating oxidative stress damage.

Evidence strength: Mechanistic and observational. No long-term randomized controlled trials on aging endpoints have been published.

Skin Health

Ergothioneine has attracted commercial interest as a cosmetic ingredient due to its antioxidant and UV-absorbent properties. It has an ability to absorb ultraviolet light, giving it a role in preventing DNA damage associated with UV exposure. It is incorporated into topical formulations and oral supplements marketed for skin health. However, the clinical trial evidence specific to skin outcomes from ergothioneine supplementation in humans is very limited and has not been independently replicated in high-quality RCTs.

Pharmacokinetics: Absorption, Distribution, and Metabolism

In a study investigating the uptake and pharmacokinetics of L-ergothioneine (ET), a dietary thione with free radical scavenging and cytoprotective capabilities, after oral administration to humans: after oral administration, ET is avidly absorbed and retained by the body with significant elevations in plasma and whole blood concentrations, and relatively low urinary excretion (less than 4% of administered ET).

Ergothioneine cannot cross cell membranes, and human cells rely on a specific transporter, OCTN1 (now known as SLC22A4), to transport dietary ingested ergothioneine to different parts of the body, including liver, spleen, kidney, heart, eyes, and brain.

S-methyl ergothioneine and hercynine have been identified as likely metabolites of ET in the body. Their levels are highly correlated with ET in blood and most tissues (although the brain typically has higher levels of hercynine). However, their function remains unknown.

After ingestion, ET is rapidly cleared from the circulation and then avidly retained in the body with minimal metabolism.

Body Systems and Health Domains

Beyond cognition, ergothioneine shows promise in supporting other physiological systems relevant to ageing, including cardiovascular, metabolic, gut, eye, auditory, liver, kidney, immune, skin and lung health.

Central Nervous System: Low blood EGT levels correlate with cognitive decline and dementia, supporting its role as a conditionally essential micronutrient for healthy aging.
Cardiovascular System: High plasma ergothioneine levels have been associated with significantly reduced cardiovascular mortality and overall mortality risks in humans.
Hepatic System: Ergothioneine maintains redox homeostasis, particularly in tissues prone to oxidative injury such as the liver.
Renal System: Ergothioneine concentrates in the kidney and has been assessed in preliminary studies of kidney function markers.
Ocular System: In humans, ergothioneine accumulates in erythrocytes, bone marrow, liver, kidney, seminal fluid, and eyes.
Immune System: Its anti-inflammatory properties operate through the regulation of cytokines and the inhibition of proinflammatory pathways, contributing to the mitigation of systemic and neural inflammation.

Dosage Forms and Dosages Reported in Studies

The following dosages are reported directly from the cited scientific literature; they do not constitute recommendations.

Elderly MCI subjects were randomly assigned to receive ergothioneine (25 mg) capsules administered orally three times a week in a randomized, double-blinded, placebo-controlled study.
The ErgMS study aimed to supplement participants with either placebo, 5 or 30 mg/day ergothioneine for 12 weeks.
The EFSA applicant intended to use the novel food in quantities of up to 5 mg per serving in alcohol-free beverages, cereal bars, milk, fresh dairy products and chocolate; the applicant also proposed providing the novel food as a food supplement with a daily dose of up to 30 mg/day for adults and 20 mg/day for children.
One kidney-focused clinical protocol used a preparation of 0.75 mg L-ergothioneine plus 1250 IU Vitamin D2 per capsule, taken twice daily.

Safety Profile and Toxicology

Ergothioneine has been subjected to formal regulatory safety assessments by both the U.S. Food and Drug Administration and the European Food Safety Authority.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on synthetic L-ergothioneine, marketed as Ergoneine®, as a novel food submitted pursuant to Regulation (EC) No 258/97 of the European Parliament and of the Council. Considering the NOAEL of 800 mg/kg bw per day, which was based on two subchronic toxicity studies in rats, and the maximum estimated intake levels for L-ergothioneine from all sources, the Panel concludes that the margins of safety of 470 for adults (except pregnant and breastfeeding women) and of 216 for children above 3 years of age are sufficient.

Rats treated with oral L-ergothioneine daily for 90 days at doses of 400, 800, and 1600 mg/kg showed no associated mortality, changes in food consumption or body weight, or macroscopic changes at necropsy. At high doses there was some intermittent alopecia and minor hematological changes considered non-adverse. Hematological changes were generally dose and gender specific. The no-observed-adverse-effect-level (NOAEL) of 800 mg/kg/day (human equivalent dose = 129 mg/kg) used in safety assessments by the FDA and EFSA came from this study.

In recognition of its safety, L-ergothioneine has received Generally Recognized as Safe (GRAS) status from the FDA. In Europe, L-ergothioneine (marketed as Ergoneine) was endorsed by the European Commission's EFSA panel in 2016, confirming its safety for use in foods and supplements.

A supplementary EFSA assessment calculated the following maximum anticipated daily intakes of L-ergothioneine from the novel food, in addition to the background diet: 2.82 mg/kg body weight per day for infants, 3.39 mg/kg bw per day for toddlers and 1.31 mg/kg bw per day for adults including pregnant and breastfeeding women. The Panel considers that based on the overall toxicological data the NOAEL of 800 mg/kg bw per day also pertains to pregnant and breastfeeding women as well as to young children and infants.

Notable Drug Interactions

Because ergothioneine is transported into cells by OCTN1/SLC22A4, drugs that use the same transporter may interact with its uptake and distribution. Ergothioneine might interact with drugs like metformin, gabapentin, and certain chemotherapeutics.

Possible concern with drug interactions, especially metformin and gabapentin, arises because both of these agents are also transported, at least in part, via OCTN1/SLC22A4. Competitive transport via this shared pathway is the mechanistic basis for the theoretical interaction; the clinical significance in humans has not been prospectively studied.

Populations of Note

The target population for the EFSA-assessed novel food is children above 3 years of age and the general adult population, except pregnant and breastfeeding women — an exclusion that reflects precautionary regulatory practice rather than evidence of demonstrated harm; the subsequent EFSA supplementary assessment found the safety margins adequate across all groups.

Research Limitations and Outstanding Questions

Current evidence positions ergothioneine as a promising nutritional intervention for promoting cognitive resilience and systemic health in ageing, although larger, long-term interventional trials are needed to confirm causality and optimize use.

Supplementation protects against oxidative stress in preclinical studies, but human data is limited. The majority of mechanistic understanding comes from in vitro cell culture and animal models, which may not fully translate to humans. The few intervention trials published or underway are of short duration, limited sample size, and often pilot in design.

In general, ET is considered an intracellular antioxidant. However, the precise physiological purpose of ET and the consequences of ET deficiency are still unclear.

Although the effect of ergothioneine in vivo is under preliminary research, its physiological role in humans is unknown.

References

Health Conditions

Health conditions that Thione may help support.

No conditions available.

Body Systems

Body systems that Thione may help support.

No body systems available.