PROJECT SUMMARY/ABSTRACT Evidence from human imaging, postmortem analysis, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of both neuropsychiatric and neurodegenerative diseases. Structural changes—including retraction of dendritic arbors, loss of dendritic spines, and reductions in synapse density—lead to functional deficits that manifest as impaired cognition, decreased motivation, anhedonia, high anxiety, and increased impulsivity. Thus, therapeutic strategies aiming to restore PFC structure/function have broad therapeutic potential. Psychoplastogens—small molecules that promote structural and functional neuroplasticity in the PFC—produce both rapid and long-lasting therapeutic effects after a single administration. However, many psychoplastogens, including ketamine and serotonergic psychedelics, induce hallucinations, which greatly limit their therapeutic potential and clinical scalability. Fortunately, increasing evidence suggests that the hallucinogenic effects of ketamine and psychedelics may not be necessary for their therapeutic properties, and our group recently introduced the first non-hallucinogenic psychoplastogens. The advent of non-hallucinogenic psychoplastogens represents an exciting new direction for the treatment of many brain disorders, but there is an urgent need to further optimize their efficacy and safety profiles. Our primary goals are to, 1) establish robust synthetic strategies to psychoplastogenic natural products and chemical scaffolds that are amenable to medicinal chemistry, 2) develop high-throughput cellular assays for assessing psychoplastogen efficacy and safety, and 3) advance new in vivo assays uniquely suited to evaluate the long-lasting effects of psychoplastogens. Taken together, these efforts will enable structure- activity relationship (SAR) studies of key psychoplastogenic scaffolds, filling the gap in our knowledge about which structural motifs are critical for both psychoplastogenic and hallucinogenic effects. Ultimately, the work described here will enable the rational design of safer, non-hallucinogenic alternatives to psychedelics for treating a wide variety of neuropsychiatric and neurodegenerative diseases.