A disease-first off-patent drug-repurposing engine identified dextromethorphan (DXM) as a compound that could lower the risk of post-traumatic stress disorder (PTSD) when administered soon after exposure to severe stress. DXM combines anti-inflammatory activity, N-methyl-D-aspartate (NMDA) receptor antagonism, sigma-1 receptor agonism, and monoamine re-uptake inhibition, a profile that targets several molecular events observed minutes to hours after trauma. Animal studies confirm neuroprotection when DXM is given within two hours of injury, yet no controlled trial has tested this timing in humans. Abuse potential, a narrow therapeutic window, and the historical failure of other NMDA antagonists in neurotrauma limit enthusiasm for large programs until proof-of-concept data emerges.