Sex-specific increased reactivity of the PVT and prolonged PVT→CeA circuit engagement following psilocin administration

A new animal study suggests that psychedelics like psilocin do not act uniformly across individuals, but instead engage emotion-related brain circuits in a sex-dependent way.

In this new animal study, researchers found that psychedelics like psilocin do not act uniformly across individuals, but instead engage emotion-related brain circuits in a sex-dependent way. The finding that females show stronger and more prolonged activation of the PVT→CeA pathway—a circuit involved in stress, fear, and emotional salience—implies that psychedelic effects on emotional processing may differ systematically between males and females.

Clinically, this raises the possibility that therapeutic responses to psychedelic-assisted treatments could vary by sex, including differences in intensity, duration, and emotional impact of the experience. It suggests a need for sex-specific dosing strategies, monitoring, and integration approaches, rather than assuming a one-size-fits-all model. More broadly, the study reinforces that “set and setting” alone do not explain variability underlying neurobiology, including sex differences in brain circuitry, is also a key driver.

The identification of the PVT→CeA circuit as a target of psilocin provides a more precise mechanistic link between psychedelics and emotional regulation. This could guide future research toward circuit-based models of treatment, helping refine interventions for disorders involving fear, anxiety, and stress but it also highlights the need for caution when translating animal findings directly to humans.

Abstract

“The psychedelic psilocybin has shown therapeutic potential, yet underlying neural mechanisms remain poorly understood. We investigated the impact of psilocin—the active metabolite of psilocybin—on basal activity and reactivity within the paraventricular nucleus of the thalamus (PVT) and PVT projections to central amygdala (CeA) in rats. Psilocin administration increased PVT c-Fos expression and selectively engaged PVT→CeA neurons in females, but not males.

Psilocin enhanced PVT reactivity to an aversive air-puff stimulus, with effects primarily driven by passive responders. In PVT→CeA neurons, psilocin prevented time-dependent reductions in stimulus-evoked activity and maintained reactivity across timepoints in females but not males. The sustained engagement of PVT→CeA circuitry was driven by active responders.

These findings identify sex-specific modulation of thalamic-limbic circuitry and behavior by psilocin, implicating PVT→CeA circuitry in the neural and behavioral effects of psychedelic compounds, advancing our understanding of how psychedelics modulate emotional brain circuits to further inform potential therapeutic mechanisms.”

Effinger, D.P., Hoffman, J.L., Quadir, S.G. et al. Sex-specific increased reactivity of the PVT and prolonged PVT→CeA circuit engagement following psilocin administration. Nat Commun (2026). Read Paper

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