Depressive DisordersPsilocybin

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines

This rodent study suggests that activating serotonin 2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. The study also suggests that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor. It highlights the need for full mechanistic understanding of how these molecules produce therapeutic effects.

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Authors

  • David Olson
  • Lindsay Cameron
  • Maxemiliano Vargas

Published

ACS Chemical Neuroscience
individual Study

Abstract

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

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Research Summary of '5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines'

Editorial

βBlossom's Take

This is a useful mechanistic paper because it tests a question that sits underneath much of the current optimism, whether 5-HT2A activation is also required for the antidepressant-like effects of psychedelic tryptamines. The findings strengthen the receptor story, but they also keep the therapeutic and hallucinogenic effects tied closely together rather than neatly separating them.

Study Details

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