Magic mushroom extracts in lipid membranes

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.

Study at a glance

Abstract

The active hallucinogen of magic mushrooms, psilocin, is being repurposed to treat nicotine addiction and treatment-resistant depression. Psilocin belongs to the tryptamine class of psychedelic compounds which include the hormone serotonin. It is believed that psilocin exerts its effect by binding to the serotonin 5-HT2A receptor. However, recent in-vivo evidence suggests that psilocin may employ a different mechanism to exert its effects. Membrane-mediated receptor desensitization of neurotransmitter receptors is one such mechanism. We compare the impact of the neutral and charged versions of psilocin and serotonin on the properties of zwitterionic and anionic lipid membranes using molecular dynamics simulations and calorimetry. Both compounds partition to the lipid interface and induce membrane thinning. The tertiary amine in psilocin, as opposed to the primary amine in serotonin, limits psilocin's impact on the membrane although more psilocin partitions into the membrane than serotonin. Calorimetry corroborates that both compounds induce a classical melting point depression like anesthetics do. Our results also lend support to a membrane-mediated receptor-binding mechanism for both psilocin and serotonin and provide physical insights into subtle chemical changes that can alter the membrane-binding of psychedelic compounds.