UC Davis

The ability to promote neural plasticity in the prefrontal cortex through the use of psychedelics and other psychoplastogens provides immense promise in the treatment of mental illnesses such as depression, post-traumatic stress disorder, and substance use disorder. With the advent of these new therapeutics, understanding the underlying mechanisms of action becomes critical to ensure they are used to their full potential and future psychoplastogen-based medicines can be rationally designed. We sought to determine some of the mechanisms through which psychoplastogens promote plasticity and produce therapeutic behavioral effects. Using molecular, cellular, and behavioral data we demonstrated the importance of 5-HT2A subcellular localization in relation to promoting neural plasticity, serotonin transporter-independent mechanisms of R-MDMA, and how the male sex hormone testosterone modulates the plasticity promoting properties of psychoplastogens. These findings further the understanding of psychoplastogen mechanisms of action, have implications in rational psychoplastogen drug design, how patient populations can be stratified for optimal therapeutic efficacy, and exploring how endogenously produced N-methyltryptamines may play a role in modulating consciousness.