Citicoline (CDP-choline), or cytidine 5-diphosphocholine (CDPc), readily crosses the blood-brain barrier and dissociates into choline, an acetylcholine precursor, and cytidine, a ribonucleoside. Dempsey and Raghavendra Rao (2003) showed that in animals, CDPc prevented TBI-induced neuronal loss in the hippocampus, decreased cortical contusion volume, and improved neurological recovery. CDPc also enhances incorporation of the choline moiety into phospholipids, synthesis of phospholipids, and cerebral mitochondrial lipid metabolism (Petkov et al. 1992). In addition to increasing phospholipid synthesis, CDPc improves the regulation of cellular energy charge and the functioning of neurotransmitters and receptors by increasing the ability of adenosine triphosphatase to break down adenosine triphosphate (ATP) (to generate energy in mitochondria) and by improving the function of Na⁺/K⁺-adenosine triphosphatase (to maintain cellular membrane potential), which is crucial for cell membrane integrity and electrical transmission. The choline moiety is partially converted into betaine, a methyl donor to homocysteine, yielding methionine, which is incorporated into proteins. CDPc has been used in Europe and Japan to treat stroke, dementia, and TBI. A review of studies is presented in Table 39–5 (also see Poole and Agrawal 2008; Spiers and Hochanadel 1999). Animal studies have shown that CDPc protected cerebral cortex and hippocampus by decreasing edema and blood-brain barrier breakdown. Human studies indicate increased cerebral blood flow, reduced infarct volume, accelerated recovery of consciousness, and improved recovery of cognitive, memory, verbal, and motor deficits (see Table 39–5) (Fioravanti and Yanagi 2005; Mitka 2002; Secades and Lorenzo 2006). Human studies have been variable in quality (Poole and Agrawal 2008). Clinically, we find CDPc beneficial in mild, moderate, or severe TBI, immediately after injury or years later, for cognitive function, memory, mental clarity, and state of consciousness. CDPc is well tolerated with minimal side effects.