Proceedings of the National Academy of Sciences of the United States of AmericaJun 24, 2026

Natural hallucinogens evolved similarly as ecological defenses and affect shared brain targets

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Updated Jun 25, 2026

Abstract

Natural hallucinogenic compounds have evolved independently across various organisms, creating a diverse chemical arsenal.

These compounds may serve as defensive agents or manipulators of herbivore and pollinator behavior.
A building-block biosynthetic logic connects primary metabolism to psychotropic compounds through specific chemical reactions.
Recent studies reveal insights into the biosynthesis of mescaline in cacti, psilocybin in fungi, and alkaloids in grasses.
Debate exists regarding the role of endogenous mammalian tryptamines, with evidence suggesting a focus on cytoprotection rather than hallucinogenic effects.
Natural hallucinogens may target conserved neural systems, influencing perception and behavior across different animal species.
This perspective underscores the potential for integrating ecological considerations with hallucinogen research and production.

Simplified

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.

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Natural hallucinogens evolved similarly as ecological defenses and affect shared brain targets

Abstract

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