Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action
This mini‑review argues that 5‑HT2A activation is only one facet of serotonergic psychedelic action, which also involves other serotonin receptors (5‑HT1A, 5‑HT2C), neurotrophin receptors (e.g. TrkB), promotion of neuroplasticity and possible protein post‑translational modifications. It highlights efforts to develop non‑hallucinogenic derivatives that retain therapeutic neuroplastic effects while minimising the intense psychedelic experience.
Authors
- John McCorvy
- Lindsay Cameron
Published
Abstract
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2Areceptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2Areceptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1Aand 5-HT2Creceptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.
Research Summary of 'Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action'
Introduction
Cameron and colleagues frame serotonergic psychedelics (for example LSD, psilocybin/psilocin, DMT, and certain phenethylamines) as rapidly acting agents with therapeutic promise across a range of neuropsychiatric conditions, including depression, anxiety, PTSD, substance use disorders (SUDs), anorexia, and chronic pain. Although these compounds are conventionally defined by agonism at the serotonin 5-HT2A receptor—the receptor most consistently linked to the subjective, hallucinogenic effects—the authors argue that 5-HT2A activation alone is unlikely to explain the full spectrum of therapeutic actions. They note that classic psychedelics show broad polypharmacology, binding multiple 5-HT subtypes and other targets (for example TrkB and several dopamine and adrenergic receptors), and that some downstream effects (notably induction of neuroplasticity) may depend on non-5-HT2A mechanisms. The review therefore sets out to summarise recent findings that extend beyond 5-HT2A signalling, to highlight alternative or complementary molecular targets (including 5-HT1A, 5-HT2C, TrkB and potential covalent protein modifications via transglutaminase 2), and to introduce the concept of nonhallucinogenic or ‘‘second-generation’’ psychedelic analogues that might retain therapeutic plasticity while minimising perceptual effects. The authors also emphasise gaps in mechanistic understanding, translational challenges (including safety, cost and regulatory barriers), and the need to disentangle hallucinogenic from therapeutic pathways.
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Cameron, L. P., Benetatos, J., Lewis, V., Bonniwell, E. M., Jaster, A. M., Moliner, R., Castrén, E., McCorvy, J. D., Palner, M., & Aguilar-Valles, A. (2023). Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action. The Journal of Neuroscience, 43(45), 7472-7482. https://doi.org/10.1523/JNEUROSCI.1384-23.2023
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