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5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.

Lindsay P. Cameron, Seona D Patel, Maxemiliano V. Vargas, Eden V Barragan, Hannah N Saeger, Hunter T Warren, Winston L. Chow, John A Gray, David E. Olson

ACS Chemical Neuroscience February 1, 2023 DOI: 10.1021/acschemneuro.2c00718 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Rodents
Intervention tryptamine-based psychedelics
Topics Depression Neuroplasticity Psilocybin Serotonin
Keywords 5-Methoxy-N,N-Dimethyltryptamine Psychoplastogen Structural plasticity Psychedelics hallucinogens Entheogens Psychotropics Neuroscience brain research Neural science Neurobiology Psychological medicine Behavioral health Pharmacology drug mechanisms
Citations 113
Key findings Activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents.

Abstract

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

Comparable studies

Other preclinical and animal studies on psilocybin for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat Flinders Sensitive Line rats and Flinders Resistant Line rats 2019 Experimental study
Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors Male and female mice 2024 Experimental study
Rapid-acting antidepressant drugs modulate affective bias in rats Rats 2024 Experimental animal study
A Single Administration of Psilocybin Persistently Rescues Cognitive Deficits Caused by Adolescent Chronic Restraint Stress Without Long-Term Changes in Synaptic Protein Gene Expression in a Rat Experimental System with Translational Relevance to Depression. Adult female rats subjected to adolescent chronic restraint stress 2023 Randomized controlled trial

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Depression Neuroplasticity Psilocybin Serotonin

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