Neuroscience letters
September 25, 2022
Alaina M Jaster, Jason Younkin, Travis Cuddy et al.
53 citations
The psychedelic compound DOI triggers more head-twitch behavior—a mouse proxy for human psychedelic effects—in female C57BL/6J mice than in males, a sex difference not seen in 129S6/SvEv mice. The 5-HT2A receptor antagonist volinanserin fully blocked this behavior in both sexes. Despite greater behavioral sensitivity in females, brain and plasma levels of DOI were lower in females 30 and 60 minutes after injection, and no sex difference appeared in frontal-cortex IP1 accumulation. These findings indicate strain-dependent and sex-related differences in the behavioral and pharmacokinetic responses to DOI, underscoring the need to include sex as a biological variable in preclinical psychedelic research.
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.