Novel biosensor helps in the discovery of a psychedelic drug without hallucinogenic effects

Study data published in Cell describe the development of a biosensor that enables monitoring of serotonin dynamics in the brain in real time. Using this biosensor, the researchers were able to study a novel psychedelic compound that appears to relieve depressive symptoms without inducing hallucinogenic experiences.

Although certain psychedelic compounds have shown promise for treating depression, it remains unclear whether the therapeutic properties of these compounds can be separated from the hallucinogenic effects. Psychedelic compounds most commonly target and influence the 5-hydroxytryptamine 2A receptor (5-HT2AR) in neurons by binding the receptor and changing its shape. Different conformational changes are due to different psychological effects.

To better understand the conformational effects of psychedelic compounds, researchers developed psychLight, a genetically encoded biosensor that generates fluorescence in 5-HT2AR.

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The genetic code for a fluorescent protein has been inserted into the genome of mouse models. The ability of psychLight to recognize hallucinogenic compounds was tested by comparing the performance of psychLight to the behavior of the mouse after administration of the compound. Rodents exhibit a characteristic “head-twitch” motion when exposed to hallucinogenic compounds. In studies with several hallucinogenic and non-hallucinogenic drugs, the increased fluorescence of psychLight correlated strongly with the “head twitch” response. Drugs that did not cause a twitching reaction also did not appear fluorescent on psychLight. This close correlation between mouse behavior and psychLight output supports the effectiveness of the biosensor in identifying hallucinogenic properties in myriad compounds.

A drug investigated in psychLight studies, AAZ-A-154, appeared to reduce symptoms of depression without producing hallucinogenic effects. Mice treated with AAZ-A-154 showed neither head twitches nor fluorescence with psychLight. In in vitro studies on cultured rat embryonic cortical neurons, AAZ-A-154 appeared to “promote dendritic growth” and increase “dendritic … complexity” in a manner similar to the antidepressant ketamine. AAZ-A-154 also appeared to decrease anhedon behavior in mice, as evidenced by their decreased immobility during forced swim tests and an increased interest in a sweetened water solution.

The development of psychLight could enable future researchers to test the potential hallucinogenic properties of novel therapeutic compounds. PsychLight also has the potential for real-time monitoring of serotonin dynamics, which could better elucidate the nature of depression and its response to psychedelic drugs. Further investigations into compound AAZ-A-154 are also warranted.

Disclosure: Some study authors stated links with biotech, pharmaceutical, and / or device companies. For a full list of the author’s disclosures, see the original reference.


Dong C, Ly C, Dunlap LE, et al. Psychedelically inspired drug research with a technically developed biosensor. Cell. Published online May 13, 2021. doi: 10.1016 / j.cell.2021.03.043

This article originally appeared on Psychiatry Advisor

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