10 Apr 2020 (Last Modified 03 Jun 2022)
There are two broad approaches to drug discovery, rational drug design and library screening. Rational drug design refers to using our understanding about the pathophysiology of the disease to develop a therapeutic that blocks or restores a critical activity that the disease has disrupted. But, our understanding of health and disease is woefully incomplete, leading us to miss obvious targets and overestimate the importance of others. Library screening refers to screening a library of molecules against an in vitro or in vivo model. Library screening against in vitro models has the same limitation as rational drug design does. Library screening against in vivo models rests on the assumption that the disease and its pathophysiology is conserved across organisms. This assumption may be more valid for some diseases than others (e.g., heart failure vs psychosis).
Whichever approach one takes, the therapeutic must demonstrate its effectiveness in preclinical trials and then clinical trials for safety and tolerability in healthy individuals (Phase I), in the target population (Phase II), and efficacy (Phase III). This process will favor the development of innocuous drugs as the qualities needed to pass Phase I seem to contradict those needed to pass Phase III.
Developing drugs for CNS pathologies is challenging on many levels. We don’t fully understand the pathology. The blood-brain barrier prevents drugs from distributing to the CNS without also distributing to other lipophilic organs or overwhelming pumps that attempt to eject drugs from the brain.
Clinical trials are new, but human experimentation with mind-altering substances is not.