Psilocin, the active compound in magic mushrooms, and the hormone serotonin both interact with cell membranes in similar ways, potentially contributing to their effects. Using computer simulations and laboratory experiments, researchers found that both molecules insert into lipid membranes and make them thinner. Psilocin penetrates the membrane more than serotonin does, but its chemical structure—a tertiary amine versus serotonin's primary amine—limits its impact on the membrane. Both compounds also lower the melting point of the membrane, a property shared with anesthetics. These findings support the idea that psilocin and serotonin may influence receptors indirectly through the membrane, not just by direct binding, and highlight how small chemical differences alter membrane interactions.
Psilocin, the active form of psilocybin in magic mushrooms, binds more strongly to the serotonin 2A receptor (5-HT2AR) than the natural hormone serotonin does. Using molecular dynamics simulations and free energy calculations, the authors show that this higher binding affinity is due to psilocin's tertiary amine group, not the different position of its hydroxyl group. The binding strength depends on the protonation states of both psilocin and a key receptor residue, aspartate 155. These molecular insights suggest design rules for developing more effective antidepressants.