Chemical ecology and convergent evolution of natural hallucinogens: From ecological defense to conserved neural targets

Natural hallucinogenic compounds like mescaline and psilocybin evolved independently across plants, fungi, and animals through a 'building-block' biosynthetic logic that repurposes primary metabolism. These molecules likely function as defensive agents or manipulators of herbivore and pollinator behavior, not primarily for human psychoactivity. Endogenous mammalian tryptamines appear to serve cytoprotective and stress-response roles via sigma-1 receptors, not hallucinogenic functions. Across kingdoms, these compounds converge on conserved neural targets such as serotonergic systems, making human psychoactivity an evolutionary by-product of molecules selected for ecological interactions with animals sharing deeply conserved receptor architectures.

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Abstract

Natural hallucinogenic compounds have arisen independently across plants, fungi, and animals, evolving into a diverse chemical arsenal that includes phenethylamines, indolealkylamines, and terpenoid scaffolds. Beyond clinical and cultural frameworks, their ecological origins and evolutionary trajectories may help explain why such potent modulators of perception, emotion, and cognition persist in nature. Here, integrating chemical ecology, comparative genomics, biosynthetic logic, and evolutionary biology, we propose that these molecules may function as defensive agents or symbiosis-associated manipulators of herbivore and pollinator behavior. A "building-block" biosynthetic logic links primary metabolism to convergent psychotropic scaffolds via a recurrent set of tailoring reactions, including decarboxylations and methylations. Recent advances illuminate mescaline biosynthesis in cacti, horizontal gene transfer of psilocybin clusters in fungi, and symbiont-derived alkaloids in grasses. We also assess the debate surrounding endogenous mammalian tryptamines, arguing that the leading hypothesis points toward sigma-1 receptor-mediated cytoprotection and stress responses, supported by convergent pharmacological and cellular evidence, rather than inherent hallucinogenic functions. Across kingdoms, natural hallucinogens appear to converge on conserved neural targets, including serotonergic and other neuromodulatory systems that are shared across phyla. From this perspective, human psychoactivity is likely an evolutionary by-product of molecules selected for ecological interactions with animals possessing deeply conserved receptor architectures. Framing hallucinogens through chemical ecology not only clarifies their origins but also highlights translational opportunities in target discovery, pathway engineering, and sustainable production, while emphasizing the need to integrate conservation, ethical sourcing, and benefit-sharing into the current hallucinogenic renaissance.