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Single Dose of Psychedelic Triggers Long-Lasting Changes in Mouse Brain Connectivity

By Alexander Beadle

Published: Dec 13, 2021   
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A single dose of 2,5-dimethoxy-4-iodoamphetamine (DOI) – which functions similarly to the psychedelic LSD – can alter the activation of genes and stimulate the creation of new connections in mice brains, according to a new study from scientists at Virginia Tech.

These epigenetic changes may help to explain the long-lasting improvements to mental health identified in other recent psychedelic research projects.

Single-dose of psychedelic shows promise in tackling anxiety and depression

After years of strict prohibition, psychedelics research is now experiencing a revival, with many of the world’s top research institutions beginning to take a keen interest in the medical potential held by psychedelics, such as psilocybin, LSD, and MDMA.

Current scientific literature indicates that these compounds could have long-lasting, beneficial effects for serious mental health conditions, such as treatment-resistant depression (TRD) and post-traumatic stress disorder (PTSD). However, despite numerous studies linking the use of these psychedelics to improvements in mental health, the mechanisms behind these effects are still poorly understood.

In this new study, published in the journal Cell Reports, Virginia Tech researchers trained mice to associate certain visual and smell cues with an electric shock, thus creating a conditioned fear response in the mice. Even when the electric shock was not applied, the mice continued to freeze anxiously whenever they encountered the visual or smell cue. With this fear response established, the researchers treated the mice with a single dose of DOI and re-examined the rodents’ behavior the day after the drug’s active psychedelic effects had worn off.

The researchers found that the conditioned fear response was notably lower in the mice treated with DOI compared to the control group given an inert vehicle, indicating that psychedelics may help to accelerate fear extinction and combat anxiety.

Using other standard behavioral tests, such as the forced swim test, to create a mouse model of depression, the researchers also found improvements that appear to confirm the drug’s ability to combat depressive symptoms at least 24 hours after a single dose of DOI.

Psychedelics trigger long-lasting epigenetic changes in mice

But the Virginia Tech researchers were not satisfied with just identifying these behavioral changes, they wanted to go further and begin to unravel the biological mechanisms that underpin them.

“The thing is, the behavioral data will tell you the result, but it doesn’t tell you why it works in a certain way,” senior study author Chang Lu, a professor of chemical engineering at Virginia Tech, said in a statement.

Using a genomic analysis method created by Lu, the research team were able to study very small samples of brain tissue taken from the mice and analyze these tissues for any meaningful genetic or epigenetic changes.

They found that the neurons in the rodents’ prefrontal cortices developed more dendritic spines after exposure to DOI. Clinical studies have indicated that a reduction of synaptic density in this brain region is associated with depression, and so the ability of DOI to stimulate new neural connections in this area may explain some of the anti-depressant effects seen in psychedelics, the researchers say.

Seven days after administration with DOI, brain tissue samples were again taken from the mice and tested to assess the more long-term effects of the drug. In these samples, the researchers found alterations in chromatin organization within the cortical neurons of DOI-treated mice, but not in the control group. It was determined that these alterations had led to epigenetic changes in the mice, which increased the activation of genes related to synaptic assembly. The researchers believe this could explain how DOI was able to stimulate significant long-lasting change to the rodents’ neurons.

Serotonin receptor mediates the beneficial effects of DOI

While there is still much to learn about how psychedelic drugs act within the human body, it is well-established that the serotonin 5-HT2A receptor plays a significant role in the action of psychedelics. To examine whether this receptor might also be involved in psychedelics’ beneficial effects on mental health, the Virginia Tech researchers repeated the study experiment on a group of laboratory mice that had been specially-bred to lack this serotonin receptor in their brains.

The researchers concluded that this 5-HT2A receptor is essential to the psychedelic-induced synaptic remodeling process, as the mice that lacked this receptor showed no differences in dendritic spine density when their brain tissues were examined. This implies that the serotonin receptor may also be responsible for some of the therapeutic properties of psychedelic drugs, the researchers say, in addition to its known influence on the subjective psychedelic trip.

“Our study highlights the fundamental role of 5-HT2AR in the action of psychedelics and unveils persisting chromatin remodeling events following DOI administration linked to lasting synaptic plasticity and behavioral events,” the researchers wrote.

“If generalizable to other psychedelics currently in clinical studies, these findings could also facilitate the understanding of psycho-pharmacological interventions whose mechanisms of action are not fully understood.”

Understanding these mechanisms is crucial if psychedelic drugs are to be used safely in treating mental health conditions.

The study authors also noted that a number of the epigenomic markers affected in this study had some overlap with genes associated with genetic predisposition to schizophrenia and depression. As a result, they say that caution needs to be taken when studying psychedelics in individuals that are known to be at risk for psychosis.


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