Beyond the 5-HT2AReceptor: Classic and Nonclassic Targets in Psychedelic Drug Action

Summary & key facts

This paper reviews how classic psychedelics like psilocybin and LSD affect the brain. It says these drugs mainly work by turning on a serotonin receptor called 5-HT2A in the outer brain, which changes perception, thinking, and feelings. The authors explain that other receptors and growth-factor systems also get involved. They point out that psychedelics seem to boost neuroplasticity, which means the brain can form new connections, and that researchers are trying to make drugs that keep these possible benefits without causing hallucinations. The review stresses that the biology is complex and that more research is needed before we know how to use these ideas safely in medicine.

Key facts:

• Psilocybin and LSD mainly act by activating a serotonin receptor named 5-HT2A that sits in the brain's cortex. A receptor is a protein that responds when a chemical signal like serotonin is present.
• Turning on the 5-HT2A receptor is linked to changes in perception, thinking, and emotions that people report during a psychedelic experience.
• These drugs appear to promote neuroplasticity. Neuroplasticity means the brain makes new connections or rewires existing networks, which might help explain longer-lasting psychological effects.
• The review notes that other serotonin receptors, such as 5-HT1A and 5-HT2C, and growth-factor receptors like TrkB also interact with these drugs, so 5-HT2A is not the whole story.
• Researchers are exploring nonhallucinogenic versions of these compounds that aim to keep therapeutic benefits but remove the intense psychedelic effects to reduce risk.
• The authors discuss a possible role for changes to proteins after they are made in the cell as another way these drugs could work, but this idea is still under investigation.
• The paper is a review of existing evidence. It describes plausible mechanisms and therapeutic potential but does not claim that these drugs are proven treatments yet and emphasizes more work is required.

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-HT2A 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-HT2A 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-HT1A and 5-HT2C 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.

Topics

Chemical synthesis and alkaloids Neurotransmitter Receptor Influence on Behavior Psychedelics and Drug Studies

Categories

Clinical Psychology Psychology Social Sciences

Tags

Action (physics) Drug Drug action Medicine Pharmacology Physics Psychology Quantum mechanics

Substances

LSD Psilocybin

Conditions & symptoms

Anxiety Depression Substance abuse disorder Addiction or harmful habbits Anxiety or worry Sadness or low mood