Beyond the 5-HT2AReceptor: Classic and Nonclassic Targets in Psychedelic Drug Action
Journal of Neuroscience – November 08, 2023
Source: OpenAlex
Summary
Serotonergic psychedelics like psilocybin profoundly promote neuroplasticity, rewiring neural networks that may treat conditions like depression and anxiety. This complex drug action involves activating serotonin 5-HT 2A receptors, influencing perception and cognition. Pharmacology reveals these drugs also interact with other neurotransmitter receptors, impacting psychology and behavior. Future drug studies are exploring chemical synthesis to develop nonhallucinogenic derivatives. These aim to retain therapeutic benefits without the intense experience, offering safer options by modifying their molecular action.
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-HT 2A receptors, 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-HT 2A receptor 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-HT 1A and 5-HT 2C receptors, 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.