SAMe, a naturally occurring condensation of the amino acid methionine and ATP, is crucial for methylation in the body. As a methyl donor, SAMe helps maintain cellular membrane integrity (repairing damaged proteins) and the fluidity of the lipid bilayer in nerve cell membranes (via formation of phosphatidyl choline) and generates glutathione, the body's major antioxidant. (For research reviews, see Brown et al. 2000, 2009.) Although SAMe has the EEG signature of a tricyclic antidepressant, it also enhances the function of the dopamine system (beneficial in treatment of TBI, attention-deficit/hyperactivity disorder [ADHD], and Parkinson's disease) (Brown et al. 2009). In primates, SAMe reduced impairments and facilitated recovery from lesions in motor and dorsolateral prefrontal cortex. In a pilot DBRPC study of 44 patients, SAMe significantly improved survival when given within 24 hours of ischemia or hemorrhagic stroke (Monaco et al. 1996) (Table 39–6). In a DBRPC study of 30 patients with TBI, 1 month of SAMe decreased mean postconcussion symptom scores by 77% compared with 49% in the placebo group. Statistically significant improvements in headache and vertigo were documented (Bacci Ballerini et al. 1983). The fact that methylene tetrahydrofolate reductase and B₁₂ cofactor regenerate methionine may explain why Vitamin B₁₂ (1,000 g/day) and folate (800 g/day) can enhance response to SAMe (Brown et al. 2009). Because SAMe rapidly oxidizes when it is exposed to oxygen, the method of manufacturing and sealing tablets in individual blister packs is important for full potency. Also, some brands contain higher proportions of inactive isomers. Therefore, it is essential to use only brands that have demonstrated consistent efficacy in clinical trials and clinical practice.