<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Clinically used antidepressants suffer from various side effects. Therefore, we searched for a safe antidepressant with minimal side effects among food ingredients that are distributed to the brain. Here, we focused on <jats:styled-content style="fixed-case">ERGO</jats:styled-content> (ergothioneine), which is a hydrophilic antioxidant and contained at high levels in edible golden oyster mushrooms. <jats:styled-content style="fixed-case">ERGO</jats:styled-content> is a typical substrate of carnitine/organic cation transporter <jats:styled-content style="fixed-case">OCTN</jats:styled-content>1/<jats:styled-content style="fixed-case">SLC</jats:styled-content>22A4, which is expressed in the brain and neuronal stem cells, although little is known about its permeation through the <jats:styled-content style="fixed-case">BBB</jats:styled-content> (blood–brain barrier) or its neurological activity.</jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To clarify the exposure of <jats:styled-content style="fixed-case">ERGO</jats:styled-content> to brain and the possible antidepressant‐like effect after oral ingestion, <jats:styled-content style="fixed-case">ERGO</jats:styled-content> or <jats:styled-content style="fixed-case">GOME</jats:styled-content> (golden oyster mushroom extract) which contains 1.2% (w/w) <jats:styled-content style="fixed-case">ERGO</jats:styled-content> was mixed with feed and provided to mice for 2 weeks, and then <jats:styled-content style="fixed-case">ERGO</jats:styled-content> concentration and antidepressant‐like effect were evaluated by <jats:styled-content style="fixed-case">LC</jats:styled-content>‐<jats:styled-content style="fixed-case">MS</jats:styled-content>/<jats:styled-content style="fixed-case">MS</jats:styled-content> and <jats:styled-content style="fixed-case">FST</jats:styled-content> (forced swimming test) or <jats:styled-content style="fixed-case">TST</jats:styled-content> (tail suspension test), respectively.</jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Diet containing <jats:styled-content style="fixed-case">ERGO</jats:styled-content> or <jats:styled-content style="fixed-case">GOME</jats:styled-content> greatly increased the <jats:styled-content style="fixed-case">ERGO</jats:styled-content> concentrations in plasma and brain, and significantly decreased the immobility time in both <jats:styled-content style="fixed-case">FST</jats:styled-content> and <jats:styled-content style="fixed-case">TST</jats:styled-content>. The required amount of <jats:styled-content style="fixed-case">GOME</jats:styled-content> (~37 mg/day) to show the antidepressant‐like effect corresponds to at most 8 g/day in humans. In mice receiving <jats:styled-content style="fixed-case">GOME</jats:styled-content>‐containing diet, doublecortin‐positive cells showed a significant increase from the basal level, suggesting promotion of neuronal differentiation.</jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Thus, orally ingested <jats:styled-content style="fixed-case">ERGO</jats:styled-content> is transported across the <jats:styled-content style="fixed-case">BBB</jats:styled-content> into the brain, where it may promote neuronal differentiation and alleviate symptoms of depression at plausibly achieved level of daily ingestion.</jats:sec>