A 2020 preclinical study by Morales-Garcia and colleagues investigated whether DMT directly influences adult neurogenesis in the hippocampus. Their findings suggest that DMT not only promotes the formation of new neurons, but also a broader neurogenic environment, with measurable effects on learning and memory in mice. Given that reduced neurogenesis is linked to depression, neurodegenerative diseases, and aging, this research raises important questions about how targeting neuroplasticity, potentially without psychedelic effects, could inform future therapies.
Within the neurogenesis experiment with DMT
The investigators examined whether DMT can activate the subgranular zone (SGZ) of the brain, one of the few regions where new neurons are generated in adults.
To do so, they used both in vitro models (neural stem cells from mouse hippocampus cultured in neurospheres) as well as in vivo experiments in mice, to observe whether DMT influences the proliferation, migration and differentiation of neural stem cells.
DMT is found in many plants used in traditional Amazonian medicine and also in mammals, including the lungs and brain. In the body it acts as a natural neurotransmitter, involved in processes such as nerve signaling and immune response. Previous studies have shown that DMT interacts with the serotonin receptors (especially 5-HT1A and 5-HT2A), but it also binds to the sigma-1 receptor, a protein located mainly in the endoplasmic reticulum. This receptor is involved in cell development, stress management, mitochondrial function, protection of neurons and, more recently, it has been linked to the formation of new neurons.
DMT-induced neurogenesis
In adults, new neurons are formed mainly in two areas of the brain: the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus, a region of the hippocampus. With age, this process slows down, but it is still critical for the learning, memory and emotional balance. It is also reduced in diseases such as Alzheimer's disease and Parkinson's disease.
Previous research had already shown that some components of ayahuasca, such as the β-carbolines (e.g., harmine), can stimulate neurogenesis. This led scientists to ask the following question:
Does DMT alone directly affect the growth of new neurons? And if so, how does it do so?
Isolation of neural stem cells
The researchers isolated neural stem cells from the SGZ of adult mice. When these cells were cultured with certain growth factors, they formed spherical clusters called neurospheres.
After one week, the neurospheres were treated with:
- DMT alone
- DMT together with sigma-1 receptor blockers
- DMT together with serotonin receptor blockers
This made it possible to identify which receptor was responsible for the effects of DMT.
In parallel, experiments were performed in adult mice that received intraperitoneal injections of DMT during:
- Four consecutive days (short-term experiments)
- Twenty-one days (long-term experiments)
The animals were administered BrdU, a marker of new cells, in order to track how many cells were generated, how they migrated and into which cell types they differentiated within the hippocampus.
In the longer-treated mice, the scientists also performed behavioral testing, The aim of the study was to determine whether DMT-induced neurogenesis had an impact on learning and memory by means of the Morris water maze and the novel object recognition test.
DMT regulates multiple stages of adult neurogenesis.
DMT reduces the “stem cell condition” and promotes differentiation.
The first evidence that DMT affects neurogenesis arose when analyzing the stemness markers, proteins present in undifferentiated neural stem cells.
After 7 days of treatment with DMT, the neurospheres showed lower levels of Musashi-1, Nestina and SOX-2, indicating that the cells were beginning to differentiate into other cell types.
This effect disappeared by blocking the sigma-1 receptor, but not by blocking serotonin receptors, which points to sigma-1 as the key element.
DMT increases neural stem cell proliferation.
By analyzing the neurospheres, the researchers observed that DMT increased both the number as the size of these groupings compared to the control group.
We also detected higher levels of cell division markers such as Ki67 and PCNA, confirming that DMT stimulates cell growth. This effect disappeared when the sigma-1 receptor was blocked.
DMT promotes differentiation in different types of brain cells.
One of the most relevant findings was that DMT not only increases cell proliferation, but also guides stem cells to become different types of brain cells:
- Neuronal differentiationincreased expression of β-III-tubulin and MAP-2.
- Differentiation into astrocytesGFAP protein increase
- Oligodendrocyte formationCNPase: increased expression of CNPase
All these effects depended on the activation of the sigma-1 receptor. Unlike other components of ayahuasca, such as harmine, DMT showed an impact of more comprehensive and powerful on different cell types.
DMT activates the neurogenic niche of the hippocampus.
Short-term effects: proliferation and migration
After only four days of treatment, mice that received DMT showed:
- More cells BrdU+/Nestina+ in SGZ (dividing stem cells)
- More BrdU+/DCX+ neuroblasts, i.e., young neurons in the process of migration.
These cells also showed more complex branching. By blocking the sigma-1 receptor, these effects disappeared, while blocking serotonin receptors did not affect them.
Long-term effects: generation of mature neurons.
When the mice were treated with DMT for three weeks, the increase in new brain cells was maintained until their full maturation.
The researchers observed:
- More developing neurons moving through the hippocampus
- Increased number of mature neurons in the dentate gyrus.
In summary, DMT not only initiates the formation of new brain cells, but it also promotes its maturation.
DMT improves learning and memory in mice
To test whether these cellular changes had functional consequences, the researchers assessed cognition using two behavioral tests:
Morris Water Maze
DMT-treated mice learned faster during training, took less time to find the platform, and remembered their location better in subsequent tests.
Recognition of new objects
Mice that received DMT spent more time exploring novel objects, approached them more frequently, and began exploration earlier.
These improvements occurred without changes in motivation or motor skills, indicating that the improvement in memory was directly related to increased neurogenesis.
Activation of the sigma-1 receptor: the key to the neurogenic power of DMT
This study demonstrates that DMT has a strong impact on the adult neurogenesis, influencing all its stages: cell proliferation, migration and maturation.
The sigma-1 receptor emerges as the main mediator of these effects and as a promising target for future treatments, since, unlike the activation of the 5-HT2A receptor, does not produce hallucinogenic effects. This opens the possibility of developing therapies that take advantage of the beneficial effects of DMT on the brain without provoking psychedelic experiences.
In addition, the increase in neurogenesis is associated with antidepressant effects, which could help explain why ayahuasca shows promising results in clinical studies on depression. The authors also highlight that the ability of DMT to stimulate not only neurons, but also astrocytes and oligodendrocytes, could be relevant for the brain repair after injuries and in neurodegenerative diseases.
Conclusion
The study by Morales-Garcia et al. provides strong evidence that DMT, known primarily for its psychedelic effects, also has a profound biological impact in the generation of new brain cells in adults.
Through the activation of the sigma-1 receptor, DMT promotes the growth, development and maturation of neural cells in the hippocampus, resulting in improvements in learning and memory in mice. These findings help to better understand how psychedelics influence brain plasticity and could open the door to new treatments for mood disorders and neurological diseases.
Source: DMT and the Brain: A New Doorway Into Brain Renewal - OPEN Foundation
