Molecular psychiatryJul 5, 2024

The psychedelic 5-MeO-DMT changes brain plasticity genes and reduces anxiety in stressed mice

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Updated Mar 25, 2026

Abstract

5-MeO-DMT altered mRNA expression of immediate early genes in multiple brain regions of mice.

A single dose of 5-MeO-DMT affected gene expression of Arc and Zif268 in the anterior cingulate cortex, basolateral amygdala, and ventral hippocampus.
NR2A expression decreased in the ventral hippocampus 5 hours after 5-MeO-DMT administration.
A long-term increase in TRIP8b, associated with neuronal activity modulation, was observed in the ventral hippocampus after 5 days.
Mice treated with 5-MeO-DMT exhibited mixed anxiolytic and anxiogenic effects in behavioral tests 24 hours and 5 days post-treatment.
Pre-treated mice exposed to acute stress had lower corticosterone levels and showed robust anxiolytic effects after 5-MeO-DMT administration.

Simplified

Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. However, a comprehensive mechanism of action is still lacking. Here, we investigated how a single dose of the short-acting 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) acts on gene expression from microdissected brain regions (anterior cingulate cortex - ACC; basolateral amygdala - BLA; ventral hippocampus CA1 region - vCA1 and dentate gyrus-DG) of naive and stressed mice. Specifically, we compared gene expression of Arc, Zif268, BDNF, CREB, mTORC1, NR2A, TRIP8b, and NFkB in mice injected with 5-MeO-DMT or saline at different time points (1 h, 5 h, or 5 days prior). 5-MeO-DMT altered mRNA expression of immediate early genes Arc and ZiF268 in the ACC, BLA, and vCA1, while NR2A expression was decreased after 5 h in the vCA1. We also found a long-term increase in TRIP8b, a gene related to the modulation of neuronal activity, in the vCA1 after 5 days. Behaviorally, 5-MeO-DMT treated mice showed mixed anxiolytic and anxiogenic effects in the elevated plus maze and open field test 24 h or 5 days after treatment. However, pre-treated mice subjected to acute stress showed both lower corticosterone levels and robust anxiolytic effects of 5-MeO-DMT administration. Together, our findings provide insights into the molecular actions of 5-MeO-DMT in the brain related to anxiolytic effects of behavior.

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The psychedelic 5-MeO-DMT changes brain plasticity genes and reduces anxiety in stressed mice

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