Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors
Maxemiliano V. Vargas, Lee E. Dunlap, Chunyang Dong, Samuel J Carter, Robert J Tombari, Shekib A. Jami, Lindsay P. Cameron, Seona D Patel, Joseph J. Hennessey, Hannah N Saeger, John D. Mccorvy, John A Gray, Lin Tian, David E. Olson
Science February 16, 2023 DOI: 10.1126/science.adf0435 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | In vitro and in vivo (rodent) models |
| Topics | Neuroplasticity Serotonin |
| Citations | 467 |
| Key findings | Intracellular 5-HT2ARs, not cell-surface ones, mediate the plasticity-promoting effects of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. |
Abstract
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.
In the evidence
This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.
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Intracellular 5-HT2A receptors, not cell-surface ones, mediated the plasticity-promoting effects of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms.
Synthesized
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State of the evidence: Serotonin Supports
Intracellular 5-HT2A receptors, rather than cell-surface ones, mediate psychedelic-induced cortical plasticity, which the authors say explains why serotonin does not engage similar plasticity.
Synthesized
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study | |
| Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission Male mice | 2021 | Multidisciplinary experimental study with in vivo electrophysiology, optogenetics, behavioral paradigms, molecular biology, and conditional knockout mice |
Citations in the library
Cited by 365
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action. Journal of Neuroscience November 8, 2023
- Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player? Neuropsychopharmacology March 1, 2024
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications. Brain Sciences January 25, 2025
and 360 more in the library
Cites 19
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
and 14 more in the library