Naturally occurring psychedelics have therapeutic potential for anxiety, depression, migraine, and addiction. Their effects may arise from binding to serotonin receptors or by altering neuronal membrane properties. Using all-atom MD simulations, three tryptamine compounds (dimethyltryptamine, bufotenine, and 5-MeO-DMT) in neutral and charged forms were studied in a model bilayer membrane. All compounds partition into the bilayer and change membrane properties to different extents. Neutral tryptamines partition almost completely; dimethyltryptamine and 5-MeO-DMT cross the membrane spontaneously, but bufotenine does not, despite having the greatest effect on membrane structure. Protonated compounds only partially partition and cannot cross the membrane. Subtle chemical structure changes significantly influence partitioning and membrane passage.
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.