Jae Min Choi, Kwang Wook Jo
Severe traumatic brain injury (TBI) remains difficult to treat because successful control of mass lesions, intracranial pressure, cerebral perfusion, oxygenation, and systemic instability does not ensure that secondary cellular injury has stopped. PubMed/MEDLINE and ClinicalTrials.gov were searched through July 28, 2026, and representative candidates were organized across five overlapping pathophysiological nodes. Evidence was described by study source, purpose, and result direction rather than assigned a formal quality grade. Human evidence was heterogeneous. Glibenclamide/glyburide and hypertonic sodium lactate produced preliminary imaging or physiological signals without demonstrated functional benefit. Riluzole was neutral in an adult randomized trial, whereas a small study in chronic TBI found that minocycline reduced a neuroinflammatory imaging signal but increased plasma neurofilament light. Metformin and N-acetylcysteine plus probenecid provided exploratory pharmacokinetic, biomarker, or safety data. Amantadine provided phenotype-specific clinical proof of principle in traumatic disorders of consciousness. Cerebrolysin showed mixed human evidence, including a favorable day-90 multidimensional ensemble signal that requires independent replication. Deferoxamine and clemastine remain preclinical. We therefore propose a modular pharmacological framework composed of separable investigational modules rather than simultaneous multidrug treatment. Module activation should require optimized foundational care, a matching phenotype, measurable target activation or engagement, and acceptable systemic safety. This framework prioritizes phenotype-enriched, single-module development before any sequential or combination design and does not support routine off-label polypharmacy.