Novel, Unifying Mechanism for Mescaline in The Central Nervous System: Electrochemistry, Catechol Redox Metabolite, Receptor, Cell Signaling and Structure Activity Relationships

A previously proposed unifying mechanism for abused drugs, based on electron transfer, can also accommodate mescaline. The theory involves redox cycling between a catechol metabolite and its quinone counterpart. This approach aligns with structure-activity relationships for mescaline, other abused drugs, catecholamines, and etoposide. Inefficient demethylation explains mescaline's high dosage requirement and slow onset. Mescaline acts as a nonselective serotonin receptor agonist, and 5-HT2A receptors are involved in its stimulus properties. Electroencephalographic studies show that mescaline elicits spikes in cortical areas, likely originating in nonsynaptic dendritic membranes. The hallucinogen belongs to the class of 2AR agonists that regulate pathways in cortical neurons. Psilocybin has also been included in this unifying framework; it is hydrolyzed to psilocin, which is oxidized to an o-quinone or iminoquinone.

Study at a glance

Abstract

A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting. There is a discussion of receptor binding, electrical effects, cell signaling and other modes of action. Mescaline is a nonselective, seretonin receptor agonist. 5‐HTP receptors are involved in the stimulus properties. Research addresses the aspect of stereochemical requirements. Receptor binding may involve the proposed quinone metabolite and/or the amino sidechain via protonation. Electroencephalographic studies were performed on the effects of mescaline on men. Spikes are elicited by stimulation of a cortical area. The potentials likely originate in nonsynaptic dendritic membranes. Receptor‐mediated signaling pathways were examined which affect mescaline behavior. The hallucinogen belongs to the class of 2AR agonists which regulate pathways in cortical neurons. The research identifies neural and signaling mechanisms responsible for the biological effects. Recently, another hallucinogen, psilocybin, has been included within the unifying mechanistic framework. This mushroom constituent is hydrolyzed to the phenol psilocin, also active, which is subsequently oxidized to an ET o‐quinone or iminoquinone.