Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice.
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo, Jason Younkin, Karah N Moore, Jessica L Maltman, Mario de la Fuente Revenga, Jennifer T Wolstenholme, Richard A Glennon, Małgorzata Dukat, Javier González-Maeso
Neuropsychopharmacology February 2, 2026 DOI: 10.1038/s41386-025-02313-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | racemic MDMA S(+)-MDMA R(-)-MDMA fluoxetine DOI |
| Topics | MDMA Serotonin |
| Citations | 3 |
| Key findings | MDMA engages serotonin 2A receptor signaling indirectly via serotonin efflux, and this effect is both stereoselective and sex-dependent in mice. |
Abstract
The psychoactive entactogen 3,4-methylenedioxymethamphetamine (MDMA), widely known as a recreational drug, is gaining renewed attention as a potential psychotherapeutic adjunct for treatment-resistant psychiatric disorders, yet its neurobiological mechanisms - particularly those related to its stereoisomers and sex-specific effects - remain poorly understood. Here, we report stereoselective and sex-dependent actions of MDMA on serotonin (or 5-hydroxytryptamine) 2A receptor (5-HT2AR)-mediated signaling and dendritic structural plasticity in mouse frontal cortex. Using both in vitro and in vivo approaches, we found that racemic MDMA and S(+)-MDMA exhibit weak partial agonism at 5-HT2AR in HEK293 cells, whereas R(-)-MDMA shows negligible functional activity despite higher specific binding affinity. In vivo, S(+)-MDMA elicited a dose-dependent head-twitch response (HTR) in both sexes, while R(-)-MDMA-induced HTR only in females. Correspondingly, S(+)-MDMA increased inositol monophosphate (IP1) accumulation in the frontal cortex of male and female mice, whereas R(-)-MDMA showed minimal effects. Structurally, S(+)-MDMA enhanced dendritic spine density in male frontal cortex in a partially 5-HT2AR-dependent manner, while no spine remodeling was observed in females or with R(-)-MDMA. Pharmacological blockade of the serotonin transporter (SERT) with fluoxetine fully prevented S(+)-MDMA-induced HTR and IP1 signaling, without affecting responses to the direct 5-HT2AR agonist DOI. These findings indicate that MDMA engages 5-HT2AR signaling indirectly via serotonin efflux and that this effect is both stereoselective and sex-dependent in mice, uncovering a previously unrecognized interaction between sex, MDMA stereochemistry, and 5-HT2AR-mediated cortical plasticity, with important implications for the rational design of MDMA-based therapeutics.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 6
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- Psilocybin modulates social behaviour in male and female mice in a time-dependent manner. Neuropsychopharmacology May 25, 2026
- R-MDDMA is a Safer Analogue of MDMA with Therapeutic Potential. ACS Chemical Neuroscience May 6, 2026
- Pretreatment with the psychedelic DOI mitigates LPS-induced hippocampal inflammation and behavioral impairments in mice BMC Neuroscience March 24, 2026
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Cites 45
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