Role of endogenous serotonin in psychedelic-like effects of psilocybin in mice
Ines Erkizia-Santamaría, Nerea Martínez-Álvarez, Leyre Salinas-Novoa, J. Javier Meana, Jorge E. Ortega
The International Journal of Neuropsychopharmacology May 25, 2025 DOI: 10.1093/ijnp/pyaf035 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study in rodents Peer reviewed |
|---|---|
| Population | Mice (wild-type, heterozygous and homozygous knockout for serotonin 2A receptor) |
| Interventions | Psilocybin citalopram p-chlorophenylalanine 8-OH-DPAT |
| Dose | 1 mg/kg psilocybin (maximally effective dose) |
| Topics | Psilocybin Serotonin |
| Keywords | Endogeny Hallucinogen Pharmacology |
| Citations | 7 |
| Key findings | Cortical serotonin levels inversely correlate with the acute psychedelic-like effects of psilocybin, as serotonin enhancement by citalopram attenuates and serotonin depletion potentiates the head-twitch response. |
Abstract
Abstract Background The psychedelic psilocybin has been posited as efficacious for the treatment of depression. However, the potential link between the intensity of acute psychedelic effects and long-term therapeutic outcomes remains undiscovered. Moreover, the impact of classical antidepressant drugs that modulate serotonergic activity on psilocybin’s effects is a clinically relevant concern. The aim of the present study was to assess serotonergic mechanisms implicated in the regulation of the intensity of the psilocybin-induced acute effects.
Methods: The head-twitch response (HTR), the most translational behavioral assay to characterize the psychedelic-like effect in rodents was performed. Moreover, the role of endogenous serotonin (5-HT) on psilocybin-induced HTR was studied by in vivo brain microdialysis technique.
Results: Maximally effective psilocybin dose (1 mg/kg) induced progressively lower HTR in heterozygous and homozygous knockout mice for serotonin 2A receptor (5HT2AR), compared to wild type. Synaptic increase of 5-HT by citalopram dose-dependently attenuated psilocybin-induced HTR after both acute and chronic dosing regimens. Conversely, depletion of 5-HT by p-chlorophenylalanine potentiated psilocybin-evoked HTR. Serotonin 1A receptor (5HT1AR) agonist 8-OH-DPAT dose-dependently decreased psilocybin-induced HTR, demonstrating functional interaction between 5HT2AR and 5HT1AR for psychedelic effects.
Conclusions: The present findings reveal an inverse correlation between cortical 5-HT levels and the acute psychedelic-like effects of psilocybin. Consequently, the enhancement of serotonergic activity induced by prior antidepressant treatment may underlie interindividual variability in the acute response to psychedelics. Investigating these mechanisms in relation to the sustained therapeutic outcomes of psilocybin could contribute to optimizing the efficacy of psychedelic-based therapies.
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
Cited by 8
- Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice. Neuropsychopharmacology February 2, 2026
- Psilocybin as a fast-acting and long-lasting antidepressant for adolescence: Proposing NeuroD1 as a biomarker of its long-term plasticity Biomedicine & Pharmacotherapy October 30, 2025
- Dual Modulation of 5-HT2A Receptors and SERT by α-Ethyltryptamine and Its Optical Isomers. ACS Chemical Neuroscience December 17, 2025
- Serotonin Transporter Blockade Reduces the Psychedelic-Like Effects of 4-Methoxy- N -methyl- N -isopropyltryptamine and Related Analogs ACS Chemical Neuroscience May 27, 2026
- Trip killers: Addressing a critical knowledge gap in psychedelic research. Journal of Psychopharmacology May 1, 2026
and 3 more in the library
Cites 32
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- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
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- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
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and 27 more in the library