The molecular basis of the antidepressant action of the magic mushroom extract, psilocin

Ali Asghar Hakami Zanjani*, Teresa Quynh Tram Nguyen, Luise Jacobsen, Himanshu Khandelia

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Magic mushrooms, and their extract psilocybin, are well-known for their psychedelic properties and recreational use. Psilocin, the bio-active form of psilocybin, can potentially treat various psychiatric diseases. Psilocin putatively exerts its psychedelic effect as an agonist to the serotonin 2A receptor (5-HT2AR), which is also the receptor for the neurological hormone serotonin. The two key chemical differences between the two molecules are first, that the primary amine in serotonin is replaced with a tertiary amine in psilocin, and second, the hydroxyl group is substituted differently on the aromatic ring. Here, we find that psilocin can bind to 5-HT2AR with an affinity higher than serotonin, and provide the molecular logic behind the higher binding affinity of psilocin using extensive molecular dynamics simulations and free energy calculations. The binding free energy of psilocin is dependent upon the protonation states of the ligands, as well as that of the key residue in the binding site: Aspartate 155. We find that the tertiary amine of psilocin, and not the altered substitution of the hydroxyl group in the ring is responsible for the increased affinity of psilocin. We propose design rules for effective antidepressants based on molecular insights from our simulations.

Original languageEnglish
Article number140914
JournalBBA Proteins and Proteomics
Issue number4
Number of pages9
Publication statusPublished - 1. Jul 2023

Bibliographical note

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  • 5-HTR
  • GPCR
  • Magic mushrooms
  • Molecular dynamics (MD) simulations
  • Psilocin
  • Serotonin receptor


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