A new study found that giving mice 5-MeO-DMT, a short-acting psychedelic, leads to a long-lasting increase of dendritic spine density in the medial frontal cortex region of their brains, potentially countering the neural changes produced by depression. The psychological effects of the drug were shorter lasting than those of another psychedelic, psilocybin – it only lasted for about 4-5 minutes compared to 14 minutes on average. The study was published in Neuropsychopharmacology.
5-MeO-DMT, short for 5-methoxy-N,N-dimethyltryptamine, is a psychedelic substance found naturally in certain species of toads, plants, and seeds. It has been used for centuries in traditional shamanic and spiritual practices by indigenous cultures in parts of South America and other regions. When consumed, inhaled, or smoked, 5-MeO-DMT induces intense and often short-lived psychedelic experiences, characterized by profound changes in perception, ego dissolution, and altered sensory perceptions. Users commonly report feelings of unity with the universe and intense spiritual insights.
The use of 5-MeO-DMT can also lead to adverse physical symptoms like nausea, increased heart rate, and dilated pupils, along with intense psychological reactions such as anxiety, confusion, and panic. Users may experience hallucinations and disorientation. For these reasons, it is considered an illicit drug in many countries, including the United States.
However, recent studies have shown a promising potential of certain psychedelics for treating mental illnesses when administered in precisely prescribed doses and under controlled conditions. Studies have reported that 5-MeO-DMT might have potential in mitigating symptoms of depression and anxiety. Compared to psilocybin, effects of 5-MeO-DMT start more quickly, within a minute of inhalation, and last shorter – less than 20 minutes. This makes 5-MeO-DMT potentially more convenient for clinical application than psilocybin.
Study author Sarah J. Jefferson and her colleagues wanted to examine whether the administration of 5-MeO-DMT to mice could lead to changes in the dendritic spine density in the medial frontal cortex region of the brain. Dendritic spines are small, finger-like protrusions on the branches of nerve cells called dendrites. They act like communication points where nerve cells receive signals from other nerve cells.
A previous study found that individuals with depression have reduced signaling activity of neural cells in this region of the brain. Another study reported reduced dendritic spine density in this region after chronic stress and that a certain antidepressant drug can restore it. If 5-MeO-DMT also increased dendritic spine density in mice, that would mean that it might have the potential to counter these neural changes related to depression in humans.
The researchers performed a series of experiments. Mice were kept in cages with 2-5 mice per cage. They had access to food and water at will and a 12h light-dark cycle (light was kept on between 7:00 AM and 7:00 PM). In the experiments, mice were injected with either a saline solution (control condition), psilocybin or 5-MeO-DMT. Usually, all mice were cycled through all treatment types. The researchers tested different doses of the two drugs.
The researchers used magnetic tags placed on ears of these mice to record head movement. In this way, they detected the head-twitch response. In research on mice, changes to the head-twitch response frequency can be used as an indicator of psychological effects of drugs. The researchers consider them to be analogous to behavior changes induced by hallucinogenic effects of the drug on humans.
The researchers also recorded social ultrasonic vocalization of male mice when placed in a chamber with a female mouse. This vocalization is used for communication between mice. Its decrease might be taken to indicate social withdrawal, stress, anxiety or depression-like states, but also psychological effects of drugs like 5-MeO-DMT.
The researchers performed surgery on the mice during which they opened their skulls and installed a glass window over the medial frontal cortex region of the brain. This allowed the imaging of this part of the brain in live mice. They used two-photon imaging for this purpose. Two-photon imaging is a specialized microscopy technique used in biological research to capture high-resolution images of living tissues and cells. It is particularly suitable for studying brain tissue as it can capture images of deep layers of the brain.
The results showed that 5-MeO-DMT induced brief head-twitch responses in mice regardless of dose that was used. Higher doses led to more heat-twitch responses. The peak of these responses typically lasted 4-5 minutes for all doses. In contrast, the peak of head twitch responses lasted 14 minutes on average in mice injected with psilocybin.
5-MeO-DMT resulted in almost complete stop of ultrasonic vocalization (the reduction was -99.9% of normal), while psilocybin decreased these vocalizations by only 30% on average. This effect of 5-MeO-DMT was also greater than the effect of ketamine, an anesthetic known for its ability to induce a trance-like state of sedation, pain relief, and altered consciousness. Ketamine reduced ultrasonic vocalizations by around 62%.
To examine changes in the medial frontal cortex region of the brain, researchers conducted two imaging sessions before injecting the mice with 5-MeO-DMT or some of the other solutions. After that, imaging was done every second day for a week and once again after a month. Results showed that a single dose of 5-MeO-DMT led to a rapid increase of dendritic spine density by about 10-15%, same as psilocybin. This increase was persistent and observable even after one month. It also elevated the pace of formation of dendritic spines. However, unlike after treatment with psilocybin, there was no increase in the size of dendritic spines.
“This study yielded two main conclusions. First, 5-MeO-DMT modifies innate behaviors by increasing head-twitch response and suppressing social ultrasonic vocalizations. Notably, for head-twitch response, the effect of 5-MeO-DMT is significantly briefer than that of psilocybin at all doses tested. Second, 5-MeO-DMT induces structural plasticity in the medial frontal cortex by evoking a long-lasting increase in dendritic spine density, although intriguingly there is no effect on spine size,” the researchers concluded.
The study sheds light on the effects of 5-MeO-DMT on mice, which could be indicative of its likely effects on humans. However, it should be noted that this was a study on mice and effects on humans might not be the same.
The paper, “5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice”, was authored by Sarah J. Jefferson, Ian Gregg, Mark Dibbs, Clara Liao, Hao Wu, Pasha A. Davoudian, Samuel C. Woodburn, Patrick H. Wehrle, Jeffrey S. Sprouse, Alexander M. Sherwood, Alfred P. Kaye, Christopher Pittenger, and Alex C. Kwan.
