The Spirit Molecule, 5-MeO-DMT, and Cerebral Organoids

Updated: Aug 22, 2018

By Zach Finzi

When we bring up the term psychedelics, some may think of the underground Acid House rave scene defined by LSD in the 80s. Others may visualize fractal spirals and neon colors streaked across melting depictions of mushrooms inspired by the work of psilocybin. Perhaps some even think of hypotheses postulated concerning DMT induced brain development in ancestral homo sapiens during sleep. It is however, far less common to think in terms of medicine and psychotherapeutic treatment for psychiatric disorders.


Since the 1960s, psychedelic agonists such as lysergic acid diethylamide (LSD), psilocybin (‘magic’ mushrooms), and dimethyltryptamine (DMT the ‘spirit molecule’) have been publicly outlawed and illegalized due to significant integration into post WWII America. Before the criminalization of these psychoactive agonists, significant research was conducted on the utilization of these drugs as a form of psychotherapy for their emotional, spiritual, and cognitive effects. While shying away from the eye of science, the usage of Ayahuasca (brew consisting of DMT-containing vegetation) has been retained as an entheogen (chemical substance ingested via plants for religious and spiritual purpose) among Amerindian groups and populations within South America. It is now being hypothesized that such prevalence in usage may be motivated by antidepressive effects exhibited in these populations.


While little understanding exists concerning the neuropharmacological effects of Ayahuasca, or DMT, we are now experiencing a resurgence in research related to psychoactive agonists. In a recent study, a related metabolite, or similarly structured molecule, to dimethyltryptamine called 5-MeO-DMT was introduced to 45-day old cerebral organoids. Similar to the work of Gregorio Cortez in the critically acclaimed movie Spy Kids, cerebral organoids can be conceptualized as smaller replicants of human brains. These organoids can mimic structural and functional aspects of the human brain and contain remarkable similarities such as the presence of the cerebral cortex, ventral forebrain, hippocampus, and long term potentiation (LTP) functionality. LTP is a neural mechanism hypothesized to play a role in learning. Human stem cells were suspended in a rotating chamber, which allowed growth of the cells in 3 dimensions, for 45 days until the organoids were fully developed. The cerebral organoids were then exposed to 5-MeO-DMT at a dosage of 13 µm for 24 hours before analysis. These organoids were compared to non-exposed 5-MeO-DMT organoids and assessed for differences in protein formation following the treatment period. It was hypothesized that 5-MeO-DMT would bind to serotonin receptor 5-HT2A/2C, due to structural similarity to serotonin, as well as the σ-1 receptor.


Researchers found significant differences between the cerebral organoids exposed to 5-MeO-DMT. This was reflected by the differences in protein formation over the 24 hour treatment period. First, notable changes in LTP were found throughout organoids with complex patterns of LTP occurring in various regions. Researchers noted similarities in complex activation of LTP during fluctuations between dream states during sleep. Additionally, reduced formation of the protein mGluR5 was observed which has been implicated in previous research as playing a role in development of rewarding responses to drugs of abuse. Removal of this protein has also been associated with reduced ethanol and nicotine consumption in rat models, suggesting a role for this molecule in addiction. It was also observed that the internal filament structure (cytoskeleton) of neurons underwent significant reorganization, allowing for the formation of dendritic spines (micro-modulatory connections between neurons). More specifically exposure to 5-MeO-DMT showed higher production of the protein EPHB2 which has been shown to be related to deficient neurons in the hippocampus when in low concentrations. Lastly, higher quantities of integrins (proteins attached to the external surface of cells) were found, which is a similar finding to patients suffering from major depressive disorder who showed positive effects from pharmacological treatment. More simply, 5-MeO-DMT exposure to cerebral organoids showed similar protein changes to neurons of major depressive patients which responded well to antidepressants.



The usage of cerebral organoids is still a new field, and the comparability to human brains is still being examined to determine how applicable these findings are. However, the striking similarities indicate that these organoids may be able to show higher resolution to the activity of our brain than examining animal brains. With this in mind, the results of this study are in the wake of decades of exile that psychoactive agonists like DMT have faced. Similar alterations to LTP between dream states and organoids exposed to 5-MeO-DMT could explain the mystery behind alterations to consciousness that occur in psychoactive states. Observations such as these could lead to further understanding of what it means to be conscious and how that occurs within the neurons of our brain. Additionally, psychopharmacological exposure to this DMT metabolite could pave the way for understanding neurological issues that arise in cases of addiction and depression. DMT is still not well understood, however these findings could resurface the investigation of its mystical entheogenic use, and subsequent effect on spirituality, consciousness, and the brain.


References:


Dakic, V., Nascimento, J. M., Sartore, R. C., de Moraes Maciel, R., de Araujo, D. B., Ribeiro, S.,

... & Rehen, S. K. (2017). Short term changes in the proteome of human cerebral

organoids induced by 5-MeO-DMT. Scientific Reports, 7.

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