Scientists (Jose A. Morales-Garcia et al) investigated whether the one of the main components of ayahuasca tea, N,N-Dimethyltryptamine (N,N-DMT), is capable of causing new neuron growth in adults. Through work with cells on slides and mice in mazes the scientists were able to show significant increases in neurogenesis of the hippocampus when DMT was utilized compared to baseline control (no drug) and DTM+inhibitors.
Hypothetical Hypotheses and Solid Takeaways
The Scientists, state their goal with this research, not as a hypothesis, but as a target of knowledge to fill. They say their "main objective of this work was to analyze the possible role of DMT in adult neurogenesis, as well as to elucidate its mechanism of action." This being said, it can also be interpolated from their results that numerous possible hypotheses could have been selected, however the most important I feel readers should take away is: Does DMT promote the differentiation of neuronal stem cells toward the three main neural cellular types?
Through dosing mice with DMT, both DMT+inhibitor, or no drug; then training them with the Morris Water maze experiment, significant behavioral increases in learning were noted in DMT treated mice, as well increases in neurogenesis in the dentate gyrus region of the hippocampus (Fig 1). On top of these observed learning gains, the mice brains also showed increased presence of non-differentiated neuronal stem cell marker proteins as well as an increase level of differentiated neuron marker proteins (Fig 1).
Highlighting the Hippocampus
One of the oldest parts of mammalian brain anatomy, the hippocampus is named because it’s similar looking nature to that of a sea horse, Hippocampus sp. and consists of a densely wrapped central body with a tail that extends from this body which is mirrored in both hemispheres of the brain (Fig 2). Even with a whimsical name, without a functioning hippocampus you wouldn't be able to drive a car, much less remember the laws associated with driving it! Damaged hippocampus results in various issues with spatial reasoning and recollection, most notably is the inability to form new memories (anterograde amnesia). Even Alzheimer's and other forms of dementia damage this region of the brain, typically doing so before other regions. [2] The importance of the hippocampus for base line functioning and higher order planning cannot be understated. Thus the reason for its common use as a region for investigating the importance of memory and spatial reasoning.
Nitty-gritty of Neurogenesis
The process of generating new fully functional neurons, typically found in the hippocampus of the brain, is called neurogenesis; and while observed in mammals to be prevalent in early development, this process is significantly reduced in adults. [4-9] Up until very recently, adult neurogenesis had "no substantial evidence to support it". Pre-natal (before birth) neurogenesis is essential for central nervous system development and plays a fundamental role in brain structure framing. Where the Scientists here describe a very specific location where adult neurogenesis occurs, as the hippocampus plays an integral role in consolidation of short-term, long-term, and spatial memory.
Neurons begin their existence, like all cells in our bodies, as stem cells; through chemical signaling proneural genes are activated and these stem cells start to differentiate towards a neuronal lineage. These neural stem cells then begin binding to and communicating with their neighbor neural stem cells, and through a process of gene activation and deactivation (called the Notch/Delta lateral inhibition) one of the neuronal stem cells differentiates further down the neuron line that specialize in sending electrical signals; while the other goes differentiates down the glial cell line, which act as buffers and support cells that do not send electrical signals (Fig 3).
Ayahuasca: Tryptamine Tea
Traditionally used in South American spiritualistic practices, this entheogenic brew typically consists of a combination of Banisteriopsis caapi vine and the Psychotria viridis leaves (Fig 4). [10-11] This is considered by many to be an ancient biohacking technology with residues being discovered from caves located in southwestern Bolivia in 2010. [12-13] The tea's constituent parts, N,N-DMT from the leaves and MAOIs (see previous UE post for info on MAOIs) from the vine, allow for an effective dose of DMT to affect the human brain through drinking of the brew. If DMT was orally ingested by itself, the body's natural defenses (MAOs) will break it down and very little to no DMT will make it to the brain. The way DMT effects neurons mirror those of psilocin and seratonin (Fig 4) as they share a fundamental structure in the indole tryptamine (see previous UE ost for info on Indoles); effecting 5-HT receptors while triggering cascading gene expression.
Conclusion and Caveats
In this paper the Scientists performed a deep series of tests, from cell and animal culture to behavioral learning, each was utilized and analyzed with methodologies that are strongly accepted within the scientific community. By utilizing mice, learning studies were able to be performed and the behavioral changes due to DMT that were statistically significant in their ability remember where the platform to escape their water maze and reduce their escape times were observed (Fig 5). While the utilization of cell staining and confocal imaging allow for in depth visualization and quantification of cells and their types according to binding fluorescent chemicals to celluar proteins both in vivo (Fig 1) and in vitro (Fig 6). All of the statistical analyses, from analysis of variance (ANOVA) to Tukey's honestly significant difference test, were robust used and seemingly applied appropriately. One of the more important conclusions the Scientists make focuses on how "this information could be very useful for the future development of new treatments against neurodegeneration."
Author caveat: all of the figures that were produced for the paper are in far greater detail about other inhibitors that can be used and more granular description of behavioral learning; however I opted to pair them down to a smaller data set to attempt to increase clarity. While the Scientists note "one of the main limitations that arise when designing a possible drug from the results obtained is to achieve the desired neurogenic effect without causing the patient hallucinogenic effects secondary to treatment with DMT, through the activation of 5-HT2A receptors."
Accept or Reject Hypothetical Hypotheses?
DMT promotes the differentiation of NSCs toward the three main neural cellular types observed in the dentate gyrus of the hippocampus in cellular slide experiments (in vitro) and living organism experiments (in vivo).
Reviewing the data and the conclusions put forth, the hypothesis proposed by the Scientists was supported. The reason for acceptance are quoted below (emphasis and parentheticals mine):
"Our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks"
"This is revealed in vitro by an increase in the number and size of primary neurospheres and an increased expression of [genes which indicate] a high rate of proliferation and loss of stemness after treatment with DMT. Increased proliferation does not indicate neuronal commitment [14]; however, DMT also induced an increase in [genes that suggest differentiation] toward a neuronal phenotype and increasing the total numbers of the neuron that reach neuronal maturity."
"Similar results were observed in vivo, with an increased proliferation rate of the NSCs and a larger population of doublecortin expressing neuroblasts migrating to the hippocampal granular layer to generate new neurons. Moreover, these have a functional impact since DMT treatment during 21 days clearly improved mouse performance in learning and memory tasks, in which the hippocampus is considered to play an essential role. These observations are in agreement with previous works showing that adult hippocampal neurogenesis plays an important role in these cognitive functions . [15-19]"
References
1) Oomen, CA; Girardi, CE; Cahyadi, R; Verbeek, EC; Krugers, H; Joëls, M; Lucassen, PJ (2009). "Opposite effects of early maternal deprivation on neurogenesis in male versus female rats". PLOS One.
2) Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, et al. (March 2016). "Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria". Alzheimer's & Dementia. 12 (3): 292–323.
3) Image created by Audrey Effenberger on May 9th 2019, distributed under a CC Attribution-Share Alike 4.0 International license.
4) Alvarez-Buylla, A., Garcia-Verdugo, J. M. & Tramontin, A. D. A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci. 2, 287–293 (2001). 5) Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000). 6) Ming, G. L. & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005). 7) Altman, J. & Das, G. D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335 (1965). 8) Kornack, D. R. & Rakic, P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc. Natl Acad. Sci. USA 96, 5768–5773 (1999). 9) van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).
10) Erin Blakemore (6 May 2019). "Ancient hallucinogens found in 1,000-year-old shamanic pouch". nationalgeographic.com. Retrieved 7 May 2019.
11) Miller, Melanie J.; Albarracin-Jordan, Juan; Moore, Christine; Capriles, José M. (4 June 2019). "Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America". Proceedings of the National Academy of Sciences. 116 (23): 11207–11212. doi:10.1073/pnas.1902174116. PMC6561276. PMID31061128.
12) MacRae, Edward (March 23, 1999). "The Ritual and Religious Use of Ayahuasca in Contemporary Brazil"(PDF). Geneva, Switzerland. Retrieved 2017-08-14.
13) "Overviews Shamanism – On the Origin of Ayahuasca". Ayahuasca.com. 2008. Retrieved 2013-04-27.
14) Arai, Y. et al. Neural stem and progenitor cells shorten S-phase on commitment to neuron production. Nat. Commun.2, 154 (2011).
15) Drapeau, E. et al. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 100, 14385–14390 (2003). 16) Li, Y. F. et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J. Neurosci. 31, 172–183 (2011). 17) Ramirez-Amaya, V., Marrone, D. F., Gage, F. H., Worley, P. F. & Barnes, C. A. Integration of new neurons into functional neural networks. J. Neurosci. 26, 12237–12241 (2006). 18) Kee, N., Teixeira, C. M., Wang, A. H. & Frankland, P. W. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat. Neurosci. 10, 355–362 (2007). 19) Trouche, S., Bontempi, B., Roullet, P. & Rampon, C. Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory. Proc. Natl Acad. Sci. USA 106, 5919–5924 (2009).
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