In plain terms: Ergothioneine (L-Ergothioneine) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
Ergothioneine (L-Ergothioneine)
The evidence as the record states it
Cheah et al. (Biochem Biophys Res Commun, 2016; PMID 27444382), Wu et al. (Antioxidants, 2022; PMID 36139790) and Wu et al. (2021; PMID 34673145): observational studies linking low plasma ergothioneine to cognitive decline; association only. Cheah et al. (Antioxid Redox Signal, 2017; PMID 27488221): the first administration of pure ergothioneine to healthy volunteers; it was absorbed and retained, with low urinary excretion, and markers of oxidative damage and inflammation showed decreasing trends that were mostly not significant, so no antioxidant effect in people is established. Yau et al. (J Alzheimers Dis, 2024; PMID 39544014): randomized double-blind placebo-controlled pilot, 19 adults aged 60 or over with mild cognitive impairment, 25 mg three times a week for a year; Rey Auditory Verbal Learning Test performance improved and plasma neurofilament light chain was stable against placebo; safety markers unchanged; funding not stated in the indexed record, authors declare no conflicts. Unreplicated. Grade C on this one trial, scoped to its population and endpoint.
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What this grade covers and what it does not
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.