In male mice, a single acute dose of fluoxetine at 10 mg/kg did not change the head-twitch response to DOI, while 14 days of fluoxetine at the same dose reduced DOI sensitivity, and this reduction resolved after 14 days without the drug, according to a recent preclinical study on SSRI and psychedelic interactions.
For psilocybin, acute 10 mg/kg fluoxetine lowered the efficacy of the head-twitch response without altering potency, suggesting that interactions can differ by psychedelic compound.
These findings are from male mice and do not establish clinical outcomes in people. They indicate that SSRI treatment history can modulate psychedelic-evoked behaviors in a compound-specific and reversible way. Bottom line: in mice, chronic fluoxetine dampens DOI responses, and acute fluoxetine can blunt psilocybin efficacy, with effects that may fade after discontinuation.