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Mode of action of psilocybin

Presented by
Prof. Scott Thompson, University of Colorado School of Medicine, CO, USA
ECNP 2022
In recent years, research on the potential of psychedelics as treatment for severe depression has seen a renaissance. Prof. Scott Thompson (University of Colorado School of Medicine, CO, USA) reviewed the current knowledge regarding the mode of therapeutic actions of psychedelics, and psilocybin in particular.

Psychedelics like psilocybin mechanistically act as agonists to the 5-HT2A serotonin receptors in the brain [1]. Common knowledge believes that the therapeutic action of psychedelics has to be related to this neurobiological effect, together with the intense, sometimes life-changing, but subjective alteration in consciousness these drugs induce [2,3]. However, using a mouse model, Prof. Thompson and colleagues recently showed that the therapeutic action of psilocybin does not require the activation of 5-HT2A receptors [4]. In addition, they showed that psilocybin induces restoration of stress-impaired excitatory synaptic function in the hippocampal brain. As such, it is not yet known which type of receptors in the brain are involved in the therapeutic action of psilocybin.

“These findings also suggest the possibility to design drugs that have the therapeutic effect of psychedelics without having intense mind-altering properties,” Prof. Thompson stated.

  1. Thompson S, et al. Mechanisms underlying the antidepressant actions of psychedelics: preclinical insights and questions. Abstract S20.02, ECNP Congress 2022, 15–18 October, Vienna, Austria.
  2. Yaden DB, Griffiths RR. ACS Pharmacol Transl Sci. 2020;4:568–572.
  3. Preller KH, et al. Curr Biol. 2017;27:451–457.
  4. Hesselgrave N, et al. Proc Natl Acad Sci USA. 2021;118:e2022489118.


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