N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

N,N-dimethyltryptamine (DMT), a naturally occurring compound found in plants like ayahuasca and in animal tissues including the brain, is known for its hallucinogenic properties and effects on perception, emotion, and cognition. It acts as an agonist on serotonin receptor subtypes 1A and 2A, and also binds to the sigma-1 receptor (S1R) with lower affinity. The S1R, a transmembrane protein found in the CNS, is implicated in various cellular functions, including neurogenesis. Adult neurogenesis, the generation of new neurons in the adult brain, primarily occurs in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus. This process is crucial for brain function and is impaired in neurodegenerative diseases. Stimulating adult neurogenesis is a potential therapeutic strategy for neurological and psychiatric disorders. Given the known neurogenic effects of other ayahuasca components, this study aimed to analyze DMT's role in adult neurogenesis and its mechanism of action.

Existing literature establishes DMT's presence in various biological systems and its interaction with serotonin receptors and the sigma-1 receptor. Studies have linked these receptors to various intracellular signaling cascades and functions within the central nervous system. The role of adult neurogenesis in brain health and its impairment in neurodegenerative diseases is well documented. Research has explored the potential of stimulating neurogenesis as a therapeutic approach for various neurological and psychiatric conditions. Previous research on other ayahuasca components has shown their neurogenic potential, providing the context for investigating DMT's role in this process.

The study used adult male C57/BL6 mice. Neural stem cells (NSCs) were isolated from the SGZ of the hippocampus and cultured to form neurospheres (NS). NS were treated with DMT (1 μM) alone or in combination with various receptor antagonists (B10163 for S1R, methiothepin for 5-HT1A/2A, ritanserin for 5-HT2A, and WAY100635 for 5-HT1A). Proliferation and growth were analyzed by quantifying NS number and size. Immunoblotting and immunocytochemistry were used to assess the expression of stemness markers (musashi-1, nestin, SOX-2), proliferation markers (ki67, PCNA), and neuronal differentiation markers (β-III-tubulin, MAP-2). In vivo studies involved intraperitoneal injections of DMT (2 mg/kg) alone or with antagonists for 4 or 21 days. BrdU was used to label proliferating cells. Immunohistochemistry was performed to assess neurogenesis in the hippocampus. Behavioral tests were conducted to assess cognitive function. Statistical analysis included one-way ANOVA and two-way mixed ANOVA.

In vitro studies showed that DMT reduced the expression of stemness markers (musashi-1, nestin, SOX-2) in cultured neurospheres, suggesting a shift away from the undifferentiated state. This effect was reversed by the S1R antagonist B1063, indicating S1R involvement. DMT increased the expression of proliferation markers (ki67, PCNA), and this effect was also blocked by B1063. In vivo studies demonstrated that DMT increased the number of newly generated neurons in the SGZ of the hippocampus. This neurogenic effect was blocked by the S1R antagonist. Mice treated with DMT performed better in memory tests than control mice, with this improvement being blocked by the S1R antagonist. These findings suggest that DMT promotes neurogenesis in the hippocampus via S1R activation.

The study's findings strongly support the hypothesis that DMT promotes adult neurogenesis in the hippocampus through activation of the S1R. The in vitro and in vivo data consistently show that DMT stimulates proliferation of neural progenitors and the generation of new neurons, enhancing cognitive function. The crucial role of the S1R in mediating this effect is clearly demonstrated by the antagonist experiments. The results have implications for understanding the mechanisms underlying the effects of ayahuasca and for developing potential therapeutic strategies for neurodegenerative diseases and other conditions characterized by impaired neurogenesis. Further research should explore the downstream signaling pathways involved and the long-term effects of DMT on neuronal integration and circuit function.

This study provides robust evidence that DMT, a component of ayahuasca, stimulates adult neurogenesis in the hippocampus via S1R activation, leading to improved cognitive performance. These findings highlight the potential therapeutic value of DMT and suggest further investigation into its mechanisms of action and potential applications in treating neurodegenerative diseases. Future research could focus on the long-term effects of DMT on neuronal survival and integration, as well as exploring potential clinical applications.

The study used a specific mouse model and limited doses of DMT. The generalizability of findings to other species and broader dose ranges requires further investigation. The behavioral tests used focused primarily on memory; additional behavioral measures might provide a more comprehensive assessment of cognitive function. Further studies are needed to understand the long-term effects of DMT on neurogenesis and its potential impact on the brain's overall structure and function.