Robust Methods For Quantifying Neuronal Morphology And Molecular Signaling Reveal That Psychedelics Do Not Induce Neuroplasticity

Classic psychedelics are thought to work by inducing neuroplasticity, often measured as dendritic arbor growth. This study tested whether psychedelics directly activate the TrkB receptor or BDNF/TrkB signaling, and whether they cause morphological growth in primary cortical neurons. Using a multimodal screening platform, the authors found that psychedelics do not directly modulate TrkB or BDNF-TrkB signaling, and that 5-HT2A receptor expression and functional levels are low. Psychedelics did not induce dendritogenesis, unlike BDNF which did. These results challenge previous findings and highlight the need for rigorous methods in studying neuroplasticity.

Study at a glance

Abstract

Induction of neuroplasticity has become the dominant explanatory framework for the rapid and sustained therapeutic effects of classic psychedelics. Within this broad concept, examination of morphological neuronal plasticity, such as dendritic arbor growth, is widely used to assess the neuroplasticity effects of classic and novel psychedelics. At the molecular level, it has been reported that serotonergic psychedelic compounds mediate dendritogenesis via the master molecular regulator of plasticity, TrkB, either directly via BDNF/TrkB signaling potentiation or indirectly through 5-HT2A receptor. To examine these hypotheses in detail, we developed a robust multimodal screening platform for unbiased, semi-automated quantification of cellular morphology and multiplex molecular signaling in the same cortical neurons. We found that in widely used primary neuronal cultures psychedelics do not directly modulate TrkB receptor or BDNF-TrkB signaling. We also found 5HT2a receptor gene expression and functional receptor levels are low, and psychedelics do not induce morphological growth, in contrast to significant dendritogenesis elicited by BDNF. Our results challenge recently published results in the field and indicate a need for rigorous experimental methods to study morphological manifestations of neuroplasticity effects induced by clinically used and experimental therapeutics.