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.
Keywords: Lipid-drug interactions; Magic mushrooms; Molecular dynamics (MD) simulations; Psilocin; Psychedelic drugs; Serotonin.
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