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 DOI: 10.1021/acsptsci.5c00484 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice |
| Interventions | Fluoxetine R(-)-DOI Psilocybin |
| Dose | 10 mg/kg |
| Duration | 14-day chronic treatment, 14-day discontinuation period |
| Topics | Serotonin |
| Keywords | Ssris Head twitch response Psychedelics Psychoactivity |
| Key findings | Chronic fluoxetine treatment reduced the head-twitch response to DOI in male mice, and acute fluoxetine attenuated the efficacy of psilocybin, showing that SSRI history can alter psychedelic effects in a compound-specific way. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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and 33 more in the library