CNSPulse

USING NEUROIMAGING TO ELUCIDATE PSYCHEDELIC MECHANISMS OF ACTION ON BRAIN CIRCUITS

Yvette Sheline — University of Pennsylvania

2026 ASCP Annual Meeting

This talk will review the relatively sparse literature on imaging results in psychedelics. In addition, it will describe results from imaging psychedelics in mood disorders. It is well known that psychedelics can induce powerful acute changes in perception of self, the environment and time. Further, in clinical trials, a single dose of psilocybin can produce rapid symptom relief in depression, addiction and anxiety. These acute effects last for approximately 6 hours and persist for 24 hours-21 days and are related to agonism of the 5-HT2A receptor. Newer shorter duration of action psychedelics, while sharing similar pharmacology to other classical psychedelics also have distinct actions. Among these are greater selectivity of the 5-HT1A receptor than the 2A receptor. Given the preponderance of 1A receptors in the limbic system this offers an opportunity to examine differential effects on limbic networks. Understanding the effects of psychedelics on human brain networks is critical to insights about their therapeutic mechanisms. This talk will describe studies using functional connectivity (FC) to delineate whole brain and regional changes in connectivity. In broad strokes, for psilocybin these changes involve profound and pervasive changes in FC across large swaths of the cerebral cortex, most prominently in association networks. The result is network desynchronization which reduces correlations within networks and decreases anticorrelations between networks, producing networks that are less segregated. In addition we will examine the relationship between the subjective psychedelic experience (30 item Mystical Experience Questionnaire, MEQ30) and brain changes. Newer short acting psychedelics 5-MeO-DMT and DMT have not as yet been used in imaging experiments however the potential for these ultra-fast and ultra-short acting psychedelics to shed light on brain mechanisms will be discussed. The potential for new insights is especially promising given their 300 fold selectivity for 5-HT1A over 5-HT2A receptors. Potential limbic mechanisms in neuroplasticity and symptom resolution will be discussed.

References

  1. Siegel J, Subramanian S, Perry D, et al. Psilocybin desynchronizes the human brain. Nature. 2024; 632: 131.
  2. Ramaekers J, Reckweg, J., Jason N. Benefits and challenges of ultra-fast, short-acting psychedelics in the treatment of depression. Am J Psychiatry. 2025; 182: 33.