been shown to increase total glutathione levels, glutathione reductase activity, decreased oxidized glutathione, and glutathione oxidation ratio (Adibhatla and Hatcher, 2005).

In rat models, the availability of choline to the fetus influences neurogenesis in the fetal brain (Craciunescu et al., 2003), and choline status in early life influences neurogenesis rates in the adult hippocampus (Glenn et al., 2007), an area of the brain that is often dysfunctional in TBI. Additionally suggesting choline mechanisms of action relevant to TBI are the fact that in rodents, choline deficiency is associated with lipid peroxidation in liver (Ghoshal et al., 1984, 1990) and that deletion of a choline metabolism gene results in mitochondrial dysfunction in the liver, sperm, testis, heart, and kidney (Johnson et al., 2010). A list of human studies (years 1990 and beyond) evaluating the effectiveness of CDP-choline in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phase in humans is presented in Table 9-1; this also includes supporting evidence from animal models of TBI. The table includes the occurrence or absence of adverse effects in humans.


In 1998, the Institute of Medicine (IOM) recognized choline as an essential nutrient (IOM, 1998; Zeisel and da Costa, 2009) and set the Adequate Intake (AI) for choline at 550 mg/day and 425 mg/day for men and women 19 years of age and older, respectively. These levels were set based on the dietary intakes of the U.S. population, and on the development of liver damage seen with lower intake. The Tolerable Upper Intake Level (UL) for choline is 3.5 g/day for adults 19 years of age or older, based on fishy body odor and hypotension (IOM, 1998).

Choline is found in a variety of foods including eggs and liver. Deficiency has been clearly linked to atherosclerosis, neurodevelopmental diseases, and liver disease (Penry and Manore, 2008). The human body is unable to synthesize sufficient choline via direct methylation of phosphatidylethanolamine to phosphatidylcholine, so choline must also be acquired via the diet. Analysis of choline intake has suggested a high level of deficiency in the U.S. population (Fischer et al., 2005; Jensen et al., 2007). Choline deficiency has been linked to a variety of secondary disease processes, such as liver disease; cardiac, neurodegenerative and neurodevelopmental problems; and breast cancer (Li and Vance, 2008; Zeisel, 2006). In addition, it is estimated that up to 50 percent of the population carries genetic variations that require increased choline intake (Zeisel and da Costa, 2009).

Direct choline therapy, when administered in doses higher than the intestine can absorb, often leads to malodor that is unacceptable to participants. The use of forms of choline that are efficiently absorbed and avoid this problem is desirable. All the studies reported by the committee have used CDP-choline, an endogenous compound and intermediary of the synthesis of phosphatidylcholine. CDP-choline was originally identified as the key intermediary in the biosynthesis of phosphatidylcholine by Kennedy in 1956 (2003), and is now also sold as a dietary supplement. However, there is no evidence that CDP-choline is the most effective form, and other forms of choline could be tested in future TBI studies.

CDP-choline has been used in the treatment of cerebrovascular disorders for many years, under a variety of protocols and to ameliorate various conditions. In several European countries, for example, CDP-choline is frequently prescribed for cognitive impairment and in the treatment of Parkinson’s disease.

CDP-choline is generally considered safe; the side effect most noted in clinical trials has been mild diarrhea, with leg edema, back pain with headache, tinnitus, insomnia, vision

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