CTs that neglect to test mechanisms of drug actions in humans put only the drugs at risk, not scientific knowledge. Translationally adequate drug tests a hypothesis of how the drug interacts with the brain target, then tests how the brain changes as a result of those interactions, then demonstrates in humans the optimal drug-target conditions to ensure efficacy, and only then if, how, and under what conditions patient symptoms and functional impairments change. With these steps, translational medicine can best enhance scientific knowledge of brain functions, as well as provide clinically important information. The mechanistic hypothesis testing associated with a drug-target focus in drug development should have other benefits. Knowledge of the brain and its targets for intervention will be advanced. A CT outcome that does not confirm a brain mechanism threatens a sector of scientific theory and practice. This threat motivates investigators to assess with care whether the failure of prediction from current knowledge when tested in humans was due to methods, practices, intervening factors such as drug metabolism, or limits in what we know about the brain and
