Differential Effects of Acute and Chronic Fluoxetine on Psychedelic-Induced Behavior in Mice: Implications for Clinical Trials.
Bo Jarrett Wood, M Frances Vest, Catharine Carfagno, Kyla Rose Bartley, Papori Sharma, Adam L Halberstadt, Bruce E Blough, Kevin S Murnane
ACS pharmacology & translational science March 13, 2026 Peer reviewed DOI: 10.1021/acsptsci.5c00484 via PubMed
Summary
Chronic treatment with fluoxetine, an SSRI, reduces the effectiveness of the psychedelic DOI in male mice, while acute fluoxetine does not affect its response. After stopping fluoxetine for 14 days, the reduced response to DOI returns to baseline levels. Additionally, acute fluoxetine decreases the efficacy of psilocybin without affecting its potency. These findings indicate that SSRIs can change how psychedelics work, which is important for developing treatment strategies for patients on SSRIs.
Study at a glance
| Population | male mice |
|---|---|
| Key finding | Chronic fluoxetine treatment reduces the behavioral efficacy of the psychedelic DOI, and acute fluoxetine attenuates the efficacy of psilocybin. |
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for mood and anxiety disorders, the same conditions under which psychedelic-assisted therapies are gaining renewed interest. However, it remains unclear how SSRI treatment may influence sensitivity to psychedelics, particularly through the shared engagement of serotonergic pathways. Here, we used the head-twitch response (HTR), a well-established behavioral readout of 5-HT2A activation, to investigate how acute, chronic, and discontinued fluoxetine treatment modulates the behavioral effects of R(-)-DOI and psilocybin, where psilocybin was only evaluated in the acute fluoxetine paradigm. In male mice, acute fluoxetine at 10 mg/kg had no effect on DOI-induced HTR, whereas chronic fluoxetine (10 mg/kg for 14 days) produced a downward shift in the DOI dose-response function. This attenuated response following a 14 day discontinuation period was reversed, suggesting that the behavioral consequences of chronic SSRI exposure may return following cessation. Interestingly, acute 10 mg/kg fluoxetine attenuated the efficacy, but not potency, of psilocybin, suggesting that SSRI-psychedelic interactions may vary depending on the pharmacological properties of the psychedelic compound. Together, these findings demonstrate that SSRI treatment history can alter the behavioral efficacy of psychedelics in a way that may be compound specific. These results have important implications for psychedelic-assisted therapies in populations taking SSRIs and highlight the need for translational studies to inform cotreatment strategies and guide clinical trial design.