One in five people in the US currently experiences a mental illness, and yet, despite significant clinical and pharmacological efforts, little progress has been made against this "silent plague." Recently, however, a number of unconventional psychoactive drugs--notably ketamine, MDMA (ecstasy), psilocybin, and others--have shown dramatic, unprecedented clinical efficacy in treating depression, post-traumatic stress disorder (PTSD), and anxiety disorders, among others. Perhaps because of a history of sociopolitical and legal barriers to the study of these compounds, much still remains to be elucidated about their underlying neural mechanisms. It would appear that the time has come not only to develop a clearer picture of the mechanisms of their psychoactive activity per se, but also to decipher their pharmacological connections to normal and pathological cognitive processes. This can now be done at several scales (from molecular-level to the whole-brain) by using genetically encoded fluorescent biosensors, which non-invasively report drug-induced functional perturbations. In this talk, recent biosensor highlights will be described, promising data on psychoactives presented, and specific future directions sketched. By leveraging biosensors and psychoactive drugs, a mechanistic foundation can built from which real cures to mental illness can be found.
