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.
BMC Neuroscience
March 24, 2026
Michael Fiorillo, Javier González-Maeso
Pretreating male mice with the psychedelic compound DOI, which activates serotonin 5-HT2A receptors, reduced brain inflammation and sickness behaviors caused by a later immune challenge with lipopolysaccharide (LPS). DOI lowered hippocampal levels of the inflammatory cytokines IL-6 and TNF-α, restored normal movement, decreased immobility in a forced swim test, and sped up body-weight recovery. These protective effects were partly preserved in mice lacking the 5-HT2A receptor, suggesting both receptor-dependent and receptor-independent mechanisms. Mice missing the receptor showed exaggerated inflammatory responses to LPS. Higher IL-6 levels in the hippocampus correlated with more depressive-like behavior, while higher IL-13 and IL-2 levels correlated with less immobility.