Abstract: Cortical atrophy underlies a wide variety of brain diseases including depression, post-traumatic stress disorder, and substance use disorder. Recently, our group discovered that psychedelics and related molecules, such as DMT, LSD, and MDMA, rapidly promote the growth of cortical neurons, providing a potential explanation for their long-lasting therapeutic effects after a single dose. However, these first-generation compounds suffer from one or more issues that limit their clinical scalability including hallucinogenic effects, cardiotoxicity, and psychostimulant properties. I will discuss the development of chemical and molecular tools for studying the mechanism(s) of action of psychedelics as well as our efforts to engineer non-hallucinogenic analogs of these compounds that produce similar sustained therapeutic behavioral effects after a single administration. Understanding the fundamental biochemical mechanisms that give rise to compound-induced neuroplasticity will be essential for developing safer and more effective neurotherapeutics for a variety of brain disorders.