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Acetylcholinesterase inhibitors (AChEIs) are used off-label, in both adult and pediatric patients, to help further neuro-recovery after traumatic brain injury (TBI). Evidence is limited and piecemeal. This review describes how TBI affects the cholinergic system and consolidates evidence supporting or refuting the use of AChEIs following TBI. NCBI MEDLINE search included all articles published through March 2021 on AChEI use in acute and post-acute adult TBI rehabilitation (treatment began &lt;90 days or ≥90 days since injury, respectively), and in pediatric TBI rehabilitation. Further, we checked  ClinicalTrials.gov  for ongoing trials using AChEIs for TBI rehabilitation in the United States. 27 original articles from NCBI Medline, published through March 2021, were included. The use of AChEIs following TBI in acute and post-acute rehabilitation settings, in both adult and pediatric patients, along with medication side effects, is discussed. Most studies showed benefits with only moderate effect sizes because of small sample sizes. Reported side effects are minimal and stop soon after AChEIs is discontinued. Conclusions are limited by paucity of research; but fortunately, a large randomized controlled trial is ongoing, and more are needed to truly determine the efficacy of AChEIs in helping with recovery from TBI.

Acetylcholinesterase inhibitors to enhance recovery from traumatic brain injury: a comprehensive review and case series