Monitoring Changes in Neural Plasticity Induced by 5-Methoxy-N,N-Dimethyltryptamine in Cortical Organoids

Dylan Oates

Program: Master’s Program in Cell and Molecular Biology
Date: Wednesday, November 12, 2025
Time: 11:00 am
Location: Donald P. Shiley BioScience Center Gold Auditorium
Zoom: https://SDSU.zoom.us/j/82019762133

Abstract

Monitoring Changes in Neural Plasticity Induced by 5-Methoxy-N,N-Dimethyltryptamine in Cortical Organoids

Although clinically taboo, psychedelics have recently emerged as promising breakthrough medication to treat a variety of neuropsychiatric disorders such as major depression, addiction, and post traumatic stress disorder (PTSD). Several studies have demonstrated that their profound effects on mood are facilitated via widespread and enduring changes in synaptic and structural plasticity in the brain. For instance, serotonergic psychedelics such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) can alter the transcriptomic profile in the brain, including genes involved in cytoskeleton organization, synapse formation and neuroimmune signaling.

However, most of the previous studies have been conducted in vivo in rodents, which are not reliable for detailed investigation in a high throughput manner, or in vitro in 2-dimensional cultures, which do not recapitulate the complex biology of the human brain. Furthermore, there are no studies on the neurodevelopmental impact of these drugs.

We aim to bridge these gaps by examining the impact of a psychedelic compound 5-MeO-DMT on neurodevelopment using a cortical organoid model. 5-MeO-DMT is structurally similar to serotonin and has the capability to pleiotropically bind to a variety of receptors.

We hypothesized that the consequences of drug exposure will vary at different time points based on the population of receptors present at the time of exposure, giving insight to the downstream effects of particular signaling cascades. We examined these consequences via fluorescent confocal microscopy and RNA sequencing, as well as measured changes in electrophysiology by multi-electrode array (MEA) electrophysiology. We found that drug exposure early in organoid development immediately increased levels of proliferation, diversified cell type population, increased maturation rates of neurons, and altered the extracellular matrix composition.

The electrophysiology profiles showed that 5-MeO-DMT exposure not only increased electrical activity, but also increased synchronous bursts across the organoid network. While further research should be conducted to fully comprehend the precise mechanisms by which these changes occur, we robustly showcase the developmental effects of 5-MeO-DMT using a human iPSC-based model.