How Ergothioneine Works in the Brain

Ergothioneine is a naturally occurring amino acid antioxidant found in mushrooms and certain plants. Humans do not synthesize ergothioneine but possess a dedicated transporter (OCTN1) that allows it to accumulate in tissues including the brain, suggesting a biologically important role.

Observational studies have associated lower blood ergothioneine levels with age-related cognitive changes in older adults, supporting interest in its potential role in cognitive health.

Based on published research, ergothioneine appears to support brain function through several mechanisms:

• Antioxidant protection. Ergothioneine scavenges free radicals and helps maintain cellular redox balance.
• Inflammation modulation. It influences signaling pathways involved in neuroinflammation.
• Mitochondrial support. Ergothioneine contributes to energy metabolism in neurons.
• Tissue-specific accumulation. The OCTN1 transporter allows ergothioneine to concentrate in brain regions vulnerable to oxidative stress.
• Cellular resilience. Research suggests it may support processes linked to long-term cognitive aging.

While preclinical and observational evidence is substantial, the clinical literature in humans remains limited but emerging.

Clinical Evidence in Older Adults

Zajac et al. (2025) — 16-Week RCT

In a 16-week randomized, double-blind, placebo-controlled trial, 147 adults aged 55 to 79 with subjective memory complaints were assigned to placebo, 10 mg/day, or 25 mg/day ergothioneine. The study reported dose-dependent improvements in prospective memory, sleep initiation, and reaction time, along with within-group improvements in executive function, complex attention, cognitive flexibility, and verbal memory. This represents the first dose-ranging randomized trial evaluating ergothioneine for cognitive outcomes.

Zajac IT, Kakoschke N, Kuhn-Sherlock B, May-Zhang LS. The Effect of Ergothioneine Supplementation on Cognitive Function, Memory, and Sleep in Older Adults With Subjective Memory Complaints: A Randomized Placebo-Controlled Trial. Nutraceuticals. 2025;5(3):15. doi:10.3390/nutraceuticals5030015.

Yau et al. (2024) — Pilot RCT

Yau et al. conducted a double-blind, randomized, placebo-controlled pilot study in 19 adults aged 60 or older with mild cognitive impairment. Participants received ergothioneine (25 mg per capsule) or placebo three times weekly for one year. Supplementation was associated with improvements in learning ability, measured by the Rey Auditory Verbal Learning Test, and stabilization of neurofilament light chain levels, a biomarker associated with neuronal integrity. No safety concerns were reported.

Yau YF, Cheah IK, Mahendran R, et al. Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline in Mild Cognitively Impaired Subjects: A Pilot Study. Journal of Alzheimer's Disease. 2024;102(3):841–854. doi:10.3233/JAD-240245.

Observational Research

Observational studies in older populations have consistently found associations between lower ergothioneine levels and cognitive decline, frailty, and dementia risk. These findings support a potential role for ergothioneine in cognitive aging, although they do not establish causality.

May-Zhang L, Cheah I, Zajac I, Brindal E, Kakoschke N. Ergothioneine for Cognitive Health, Longevity and Healthy Aging: Where Are We Now? Proceedings of the Nutrition Society. 2025. doi:10.1017/S0029665125101754.

Meng X, Ohara T, Nishioka K, et al. Serum Ergothioneine and Risk of Dementia in a General Older Japanese Population: The Hisayama Study. Psychiatry and Clinical Neurosciences. 2025. doi:10.1111/pcn.13893.

Kondoh H, Teruya T, Kameda M, Yanagida M. Decline of Ergothioneine in Frailty and Cognition Impairment. FEBS Letters. 2022;596(10):1270–1278. doi:10.1002/1873-3468.14299.

Summary

Ergothioneine is a unique antioxidant with a dedicated human transporter and increasing clinical interest. Early randomized trials suggest potential benefits for memory, sleep, and cognitive performance in older adults, while observational studies consistently link lower ergothioneine levels to cognitive decline. The current evidence base is promising but still limited, and further large-scale trials are needed.