Neural mechanisms underlying psilocybin’s therapeutic potential – the need for preclinical in vivo electrophysiology

Rebecca Smausz, Joanna Neill, John Gigg

Research output: Contribution to journalReview articlepeer-review


Psilocybin is a naturally occurring psychedelic compound with profound perception-, emotion- and cognition-altering properties and great potential for treating brain disorders. However, the neural mechanisms mediating its effects require in-depth investigation as there is still much to learn about how psychedelic drugs produce their profound and long-lasting effects. In this review, we outline the current understanding of the neurophysiology of psilocybin’s psychoactive properties, highlighting the need for additional preclinical studies to determine its effect on neural network dynamics. We first describe how psilocybin’s effect on brain regions associated with the default-mode network (DMN), particularly the prefrontal cortex and hippocampus, likely plays a key role in mediating its consciousness-altering properties. We then outline the specific receptor and cell types involved and discuss contradictory evidence from neuroimaging studies regarding psilocybin’s net effect on activity within these regions. We go on to argue that in vivo electrophysiology is ideally suited to provide a more holistic, neural network analysis approach to understand psilocybin’s mode of action. Thus, we integrate information about the neural bases for oscillatory activity generation with the accumulating evidence about psychedelic drug effects on neural synchrony within DMN-associated areas. This approach will help to generate important questions for future preclinical and clinical studies. Answers to these questions are vital for determining the neural mechanisms mediating psilocybin’s psychotherapeutic potential, which promises to improve outcomes for patients with severe depression and other difficulty to treat conditions.

Original languageEnglish
Pages (from-to)781-793
Number of pages13
JournalJournal of Psychopharmacology
Issue number7
Early online date30 May 2022
Publication statusPublished - 1 Jul 2022


  • 5HT2a receptor
  • Gamma rhythm
  • default-mode network
  • neural network
  • neuroplasticity
  • parvalbumin
  • psilocybin
  • psychedelic medicine


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