Neurologic Health: Three Brain Nutrients

The brain makes up only 2% of a person’s body weight, yet it consumes roughly 20% of the body’s energy when at rest. Many nutrients have been shown to support optimal neurologic and cognitive function. In addition to the well-known omega-3 fatty acid DHA, other nutrients have demonstrated efficacy in supporting cognitive function. Here are snapshots of three:

Phosphatidylserine (PS)

Phosphatidylserine (PS) is an endogenous phospholipid. Although it is less abundant in the body than other phospholipids (i.e., phosphatidylcholine and phosphatidylethanolamine), it still comprises 2–10% of the body’s total phospholipids, with critical functions in apoptosis (programmed cell death), blood clotting, and cell-to-cell communication. The PS molecule consists of a glycerol-phosphate backbone, the amino acid serine, and two fatty acids. As with other phospholipids, PS is a critical component in the structure of membranes, particularly neurons.

In the body, phospholipids form a variety of structures owing to their amphipathic nature, i.e., having both a hydrophobic non-polar tail and a hydrophilic polar head. They can move within the fluid mosaic of cell membranes, which supports cellular communication, selective passage of macromolecules, and other important cellular functions. Phosphatidylserine is the most abundant negatively charged phospholipid in eukaryotic cell membranes. As the major acidic phospholipid in the brain, PS can traverse the blood–brain barrier after oral administration. In animal studies, it has been shown to influence several neurochemical systems, neuronal membranes, cell metabolism, and several neurotransmitters, including serotonin and dopamine (Ma et al., 2022).

Several clinical trials have shown that PS supplementation supports cognitive function. In one randomized, controlled trial, 36 children aged 4 to 14 years experiencing attention-related issues were given 200 mg/day of PS or placebo for two months. Supplementation resulted in significant improvements in attention, impulsive movement, and short-term auditory memory compared with placebo (Hirayama et al., 2014).

Phosphatidylserine has further been shown to support healthy endocrine and adrenal responses to mental stress. In a double-blind study, PS (400 mg, 600 mg, or 800 mg/day) was administered to healthy adults aged 20–45. In the 400 mg/day group, researchers observed blunted ACTH and cortisol responses to the Trier Social Stress Test, along with a positive emotional response compared to placebo (Bruton et al., 2021). Higher doses did not show the same effect. These results suggest that PS may dampen hypothalamic–pituitary–adrenal (HPA) axis stress responses.

PS also supports cognitive function in aging individuals. In a clinical trial, 70 elderly subjects with memory complaints were randomized to receive social support, cognitive training, cognitive training with pyritinol, or cognitive training combined with phosphatidylserine (200 mg twice daily). The PS group showed transient improvements in cognitive and memory function, as well as improved electrophysiological brain function (Manor et al., 2012).

Acetyl L-Carnitine (ALC)

Acetyl L-carnitine (ALC) is an ester of L-carnitine and plays a crucial role in fatty acid transport into mitochondria for energy production. The acetyl group enhances its ability to cross the blood–brain barrier. Preclinical and clinical studies suggest ALC supports cognitive function, focus, neuronal health, antioxidant defense, and mitochondrial energy metabolism (Pennisi et al., 2020).

ALC demonstrates strong antioxidant activity in the central nervous system, attenuating protein and lipid peroxidation while enhancing the activity of other antioxidants. Animal studies suggest protective effects on aging neurons, improved spatial working memory, and potential stimulation of nerve growth factor (Pennisi et al., 2020).

Several clinical trials have demonstrated cognitive benefits in elderly individuals. In one controlled trial, supplementation with 1,500 mg/day of ALC for 45 days led to significant improvements in memory and overall cognitive function in elderly individuals with mild cognitive complaints (Yang et al., 2018). Another large trial showed similar benefits after 90 days of supplementation, with improvements in mood and stress resilience that lasted even after treatment was discontinued. Additional trials corroborated these findings (Malaguarnera et al., 2007).

Citicoline (CDP-Choline)

Citicoline (cytidine 5′-diphosphocholine) is an intermediate in the biosynthesis of phosphatidylcholine. It crosses the blood–brain barrier and supports neuronal membrane synthesis, repair, and turnover. It also enhances levels of neurotransmitters such as acetylcholine, norepinephrine, and dopamine (Fioravanti & Yanagi, 2005).

MRI studies in humans have shown that 500 mg/day of citicoline for 6 weeks increases phosphodiester levels, consistent with enhanced phospholipid turnover. Animal studies indicate citicoline accelerates phospholipid resynthesis, prevents degradation, and protects neurons from free radical damage (Álvarez-Sabín et al., 2013).

Citicoline has been studied extensively in cerebrovascular and cognitive disorders. Long-term use after ischemic stroke has been associated with improved vascular cognitive impairment and quality of life (Álvarez-Sabín et al., 2013). In subjects with mild cognitive impairment or subjective memory complaints, citicoline supplementation (1 g/day) prevented decline and in some cases improved memory function (Almería et al., 2023). In healthy older adults, 12 weeks of citicoline improved episodic memory performance (McGlade et al., 2021).

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References

Álvarez-Sabín, J., Ortega, G., Jacas, C., Santamarina, E., Maisterra, O., Ribo, M., & Molina, C. (2013). Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovascular Diseases, 35(5), 418–426. https://doi.org/10.1159/000348852

Almería, M., Jiménez-Balado, J., Espelt, C., Valls-Pedret, C., Canudas, A. M., & Castellano, B. (2023). Citicoline supplementation prevents cognitive decline in subjects with subjective cognitive complaints and mild cognitive impairment. Frontiers in Aging Neuroscience, 15, 1036335. https://doi.org/10.3389/fnagi.2023.1036335

Bruton, A., Nauman, J., Hanes, D., & Curtis, B. (2021). Phosphatidylserine for the treatment of pediatric attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. Journal of Dietary Supplements, 18(6), 613–627. https://doi.org/10.1080/19390211.2021.1926952

Fioravanti, M., & Yanagi, M. (2005). Citicoline (Cognizin) in cognitive impairment and dementia: A review. CNS Drugs, 19(9), 745–768. https://doi.org/10.2165/00023210-200519090-00002

Hirayama, S., Terasawa, K., Rokkaku, M., Tanimukai, H., & Nakazato, Y. (2014). The effect of phosphatidylserine administration on symptoms of attention-deficit hyperactivity disorder: A randomized, double-blind, placebo-controlled clinical trial. Journal of Human Nutrition and Dietetics, 27(3), 284–291. https://doi.org/10.1111/jhn.12152

Ma, X., Ma, L., Ma, Z., & He, H. (2022). Phosphatidylserine: Benefits, supplementation, and safety. Frontiers in Aging Neuroscience, 14, 975176. https://doi.org/10.3389/fnagi.2022.975176

Malaguarnera, M., Vacante, M., Giordano, M., Motta, M., Bertino, G., Pennisi, G., & Bella, R. (2007). Oral acetyl-L-carnitine therapy reduces fatigue in centenarians: A randomized and controlled clinical trial. The American Journal of Clinical Nutrition, 86(6), 1738–1744. https://doi.org/10.1093/ajcn/86.6.1738

Manor, I., Magen, A., Keidar, D., Rosen, S., Tasker, H., Cohen, T., Richter, Y., & Bloch, B. (2012). The effect of phosphatidylserine containing omega-3 fatty acids on attention-deficit hyperactivity disorder symptoms in children: A randomized controlled trial, followed by an open-label extension. European Psychiatry, 27(5), 335–342. https://doi.org/10.1016/j.eurpsy.2011.05.004

McGlade, E., Agoston, A. M., DiMuzio, J., Zavala, D., Keresztes, A., Yurgelun-Todd, D., & Wilcox, C. E. (2021). Citicoline supplementation improves memory performance in healthy older adults: A randomized, double-blind, placebo-controlled clinical trial. Journal of Clinical and Experimental Neuropsychology, 43(9), 950–961. https://doi.org/10.1080/13803395.2021.2004467

Pennisi, M., Malaguarnera, G., Bella, R., & Lanza, G. (2020). Acetyl-L-carnitine in dementia and other cognitive disorders: A critical update. Neurochemical Research, 45(7), 1428–1444. https://doi.org/10.1007/s11064-020-03005-0

Yang, Y. S., Li, J. L., Cao, Y. M., Li, Q., Yang, H. X., & Yang, W. H. (2018). Acetyl-L-carnitine in the treatment of vascular cognitive impairment: A multicenter, randomized, double-blind, placebo-controlled trial. Frontiers in Aging Neuroscience, 10, 217. https://doi.org/10.3389/fnagi.2018.00217