Single dose of 5-MeO-DMT alters gene expression in brain and reduces anxiety-like behavior in stressed mice

A new study published in Molecular Psychiatry suggests that the fast-acting psychedelic compound 5-MeO-DMT can reduce anxiety-like behavior in stressed mice while altering the expression of genes linked to neural activity in specific brain regions. The research found that a single dose of 5-MeO-DMT modified expression of immediate early genes and affected behavioral responses up to five days later, offering insights into how this compound might work at the molecular level.

5-MeO-DMT, short for 5-methoxy-N,N-dimethyltryptamine, is a powerful psychedelic substance structurally related to DMT. It occurs naturally in certain plants and the venom of the Incilius alvarius toad and has recently drawn attention for its rapid, intense, and short-lived psychological effects. In clinical settings, 5-MeO-DMT has been explored for its potential to treat depression, anxiety, and addiction.

The compound is known to engage serotonin receptors in the brain, but unlike other psychedelics such as LSD or psilocybin, it binds more strongly to the 5-HT1A receptor, which is commonly linked to anti-anxiety effects. Despite growing interest, little is known about the biological changes it induces in the brain.

To better understand how 5-MeO-DMT affects the brain and behavior, researchers at the Brain Institute of the Federal University of Rio Grande do Norte in Brazil administered a single high dose of 5-MeO-DMT to male mice and analyzed both their gene expression and behavioral responses. The team focused on brain regions involved in anxiety and emotion, including the anterior cingulate cortex, the basolateral amygdala, and the ventral hippocampus. These areas are part of a larger network that regulates fear, emotional responses, and stress.

The study involved multiple groups of mice. Some received a single dose of 5-MeO-DMT and were euthanized at different time points—one hour, five hours, or five days later—so their brain tissue could be analyzed using laser capture microdissection and quantitative PCR to measure levels of gene expression.

The researchers examined several genes known to be involved in synaptic plasticity and neural activity, including Arc, Zif268, BDNF, CREB, NR2A, mTORC1, TRIP8b, and NFkB. Another set of mice was tested for anxiety-like behaviors using two common experimental tools: the elevated plus maze and the open field test. A third group underwent a stressful restraint procedure to test how 5-MeO-DMT affects behavior under acute stress.

One of the main findings was that 5-MeO-DMT caused significant changes in the expression of immediate early genes—especially Arc and Zif268—in the anterior cingulate cortex, basolateral amygdala, and ventral hippocampus. These genes are rapidly activated in neurons and are involved in learning, memory, and synaptic remodeling. One hour after treatment, Arc expression increased in the anterior cingulate cortex and basolateral amygdala but decreased in the ventral hippocampus. Zif268 was upregulated only in the basolateral amygdala.

Five hours after treatment, the researchers observed a decrease in the expression of NR2A, a gene linked to glutamate signaling, in the ventral hippocampus. This was notable because NR2A has been associated with excitatory synaptic activity and learning processes. Interestingly, no significant changes were observed in the expression of several commonly studied plasticity-related genes, such as BDNF or CREB, at any time point. This suggests that 5-MeO-DMT may exert its effects through less conventional molecular pathways.

Five days after treatment, the only significant long-lasting change was an increase in the expression of TRIP8b in the ventral hippocampus. This gene helps regulate ion channels involved in controlling the excitability of neurons and has been implicated in mood regulation and antidepressant effects. No changes were seen in the dentate gyrus or for other genes at this later time point, suggesting that the effects of 5-MeO-DMT on gene expression are both region-specific and transient.

Behaviorally, mice treated with 5-MeO-DMT showed mixed results. In the elevated plus maze, which measures willingness to explore open, unprotected spaces, mice treated with 5-MeO-DMT five days earlier entered open arms more frequently than saline-treated mice, suggesting reduced anxiety. However, in the open field test, those same mice entered the exposed central area less often, a behavior typically associated with increased anxiety. This discrepancy raised questions about whether 5-MeO-DMT has context-dependent behavioral effects or whether it affects general locomotion.

To clarify these findings, the researchers examined mice subjected to a stress challenge. When mice received 5-MeO-DMT five days before undergoing a 20-minute restraint stress, they showed significantly lower baseline levels of corticosterone, the primary stress hormone in rodents. After stress, these mice spent more time in the open arms of the elevated plus maze and in the center of the open field arena—both considered signs of reduced anxiety-like behavior. These results suggest that 5-MeO-DMT can increase resilience to stress, possibly by modifying the stress hormone system and related neural pathways.

An additional behavioral analysis looked at specific exploratory actions, such as head dips over the edges of the maze. Across different groups, mice treated with 5-MeO-DMT showed more unprotected head dips and fewer protected ones, a pattern consistent with reduced anxiety. These effects were seen both in non-stressed mice and in those that had undergone stress, reinforcing the idea that 5-MeO-DMT influences anxiety-like behavior over an extended period.

The study has several limitations. It focused only on male mice, so it’s unclear whether the results apply to females. The researchers also measured only mRNA levels and not the actual proteins produced by the genes. Since many biological effects depend on protein activity, future studies will need to explore whether changes in gene expression translate into functional protein-level changes. Additionally, while the researchers chose a single high dose based on previous work, dose-response effects were not tested in this study.

Despite these limitations, the findings contribute to a growing body of evidence that serotonergic psychedelics can produce long-lasting effects on brain function and behavior after just one administration. In particular, 5-MeO-DMT appears to act through non-traditional pathways, possibly involving its high affinity for the 5-HT1A receptor or its interactions with other targets like the sigma-1 receptor.

The study, “Serotonergic psychedelic 5-MeO-DMT alters plasticity-related gene expression and generates anxiolytic effects in stressed mice,” was authored by Margareth Nogueira, Daiane C. Ferreira Golbert, Richardson Menezes, Raíssa Nóbrega de Almeida, Nicole L. Galvão-Coelho, Andressa N. Siroky, Thiago Z. Lima, Helton Maia, Katarina E. Leão, and Richardson N. Leão.