Nature communications
November 20, 2025
Alaina M Jaster, Thomas M Hadlock, Belle Buzzi et al.
9 citations
A single dose of the psychedelic psilocybin reduces conditioned behavior and withdrawal caused by the opioid oxycodone in male mice but not in females. This sex-specific effect is mediated by the 5-HT2A receptor in frontal cortex pyramidal neurons that project to the nucleus accumbens. Psilocybin also alters epigenomic regulation after repeated oxycodone exposure and induces sex-specific structural plasticity in the nucleus accumbens independently of the 5-HT2A receptor. Female frontal cortex and nucleus accumbens show fewer changes at gene enhancer regions in response to psilocybin, repeated oxycodone, or their combination compared to males, with the frontal cortex displaying more pronounced sex differences at the epigenomic level.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 2, 2026
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al.
3 citations
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
ACS chemical neuroscience
December 17, 2025
Justin M Silverman, Michael Fiorillo, Jason Younkin et al.
1 citation
α-Ethyltryptamine (AET), a synthetic tryptamine once used as an antidepressant, acts through a dual mechanism involving both direct activation of the 5-HT2A receptor and indirect serotonin release via the serotonin transporter (SERT). In vitro, AET and its isomers displaced ketanserin from the 5-HT2A receptor with micromolar affinity, but only the S(+)-AET isomer showed weak partial agonist activity. In mice, all forms of AET produced a head-twitch response that was blocked by a 5-HT2A antagonist and also by fluoxetine, indicating that SERT-mediated serotonin release contributes to its behavioral effects. This dual pharmacology distinguishes AET from classical psychedelics and aligns it with MDMA-like compounds, suggesting potential for modulating mood and cognition.