The HDAC inhibitor sodium butyrate moderately enhances long-term fear extinction memory retrieval in humans.

Fear extinction and its persistence depend on epigenetic modifications, which can be potentiated by histone deacetylase inhibitors (HDACis). Butyrate (NaBu), a short-chain fatty acid and endogenous HDACi, promotes persistent fear extinction in rodent models by increasing histone acetylation in promoter regions of plasticity- and memory-related genes, thereby enhancing their transcription. To test translational relevance in humans, we conducted a six-arm randomized, triple-blind, placebo-controlled intervention study in 180 healthy participants who underwent a 3-day Pavlovian fear conditioning paradigm. Participants ingested a single dose of NaBu or placebo either before or after extinction learning, the duration of which was additionally manipulated by varying the number of learning trials. NaBu facilitated later retrieval of extinction memory after seven days, both when administered before or after extinction learning, but it did not prevent return of fear during a subsequent reinstatement test. Interestingly, NaBu's effects were contingent on robust extinction learning, emerging only when participants had been exposed to a high number of trials. As no side effects were observed with acute administration of the current dose, these findings support investigating NaBu as a potential adjunct for enhancing extinction-based interventions, such as prolonged exposure therapy, in anxiety disorders.