Science (New York, N.Y.)Feb 16, 2023

Psychedelics may boost brain plasticity by activating 5-HT2A receptors inside cells

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

Decreased dendritic spine density in the cortex is linked to various neuropsychiatric diseases.

Activation of serotonin 2A receptors (5-HT2ARs) is crucial for promoting cortical neuron growth associated with psychedelics.
Not all 5-HT2AR agonists lead to neuroplasticity, indicating variability in their effects.
Intracellular 5-HT2ARs were shown to mediate the plasticity-promoting effects of psychedelics.
Serotonin does not activate the same plasticity mechanisms as psychedelics, suggesting a difference in receptor engagement.
The findings point to intracellular 5-HT2ARs as a potential target for therapeutic interventions.

Simplified

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.

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Competing interests

Competing Interests. DEO is a co-founder of Delix Therapeutics, Inc., serves as the Chief Innovation Officer and Head of the Scientific Advisory Board, and has sponsored research agreements with Delix Therapeutics. Delix Therapeutics has licensed technology from the University of California, Davis. The sponsors of this research were not involved in the conceptualization, design, decision to publish, or preparation of the manuscript.

PubMed

Psychedelics may boost brain plasticity by activating 5-HT2A receptors inside cells

Abstract

Full Text

Funding

Competing interests

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Abstract

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