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

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 several biological areas, such as apoptosis (programmed cell death), blood clotting, and cell-to-cell communication.1 The PS molecule consists of a glycerol-phosphate backbone, the alpha-amino acid serine, and two fatty acids. As with other phospholipids, PS is a critical component in the structure of membranes, particularly neurons.2

In the body, phospholipids form a variety of structures owing to their amphipathic nature, i.e., having both a hydrophobic “water-fearing” non-polar tail and hydrophilic (“water-loving”) 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.3 As the major acidic phospholipid in the brain, PS can traverse the blood-brain barrier after oral administration.4 In animal studies, it has been shown to influence several neurochemical systems, neuronal membranes, cell metabolism, and several neurotransmitters, including serotonin and dopamine.†5-7  

Several clinical trials have shown that PS supplementation supports cognitive function.†

Several clinical trials have shown that PS supplementation supports cognitive function.† In one randomized, controlled clinical trial, 36 children, aged 4 to 14 years, who were experiencing attention-related issues were given 200 mg/d of PS or placebo for two months.8 PS supplementation resulted in significant improvements in attention, impulsive movement, and short-term auditory memory as compared with placebo. PS was well-tolerated and showed no adverse effects. 

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/d) was administered to healthy women and men 20 to 45 years old.9 In the groups receiving 400 mg/d of PS only, researchers observed a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol responses to the Trier Social Stress Test (TSST). There was also a positive effect on emotional responses to the TSST at 400 mg/d. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg PS showed a decrease. The effect was not seen with larger doses. These results suggest that PS may dampen hypothalamic-pituitary-adrenal (HPA) axis stress responses.† 

Phosphatidylserine also supports cognitive function in aging individuals.† In a clinical trial, 70 elderly subjects with cognition complaints were randomly allocated to four groups: 17 patients received only social support, 18 patients received cognitive training twice a week, 17 patients received cognitive training combined with pyritinol 2 x 600 mg/d, and 18 patients received cognitive training combined with phosphatidylserine (200 mg BID). Researchers concluded that PS supplementation combined with cognitive training led to transient improvement of cognitive and memory function, as well as improved electrophysiological brain function.†10 

Acetyl L-Carnitine

Acetyl L-carnitine (ALC) is a physiologic peptide crucial for fatty acid transport. It is an ester of the amino acid derivative L-carnitine and has been shown in preclinical and clinical research to support healthy cognitive function, concentration and focus, enhance nerve cell function, regenerate peripheral nerve cells, provide antioxidant protection, and promote cellular energy production.† It also plays a major role in the healthy functioning of the mitochondria. It is also required for helping transport fatty acids into the mitochondria, where they can be used as fuel.†11 Acetyl L-carnitine supports cardiovascular health by providing antioxidant protection and promoting cellular energy production and has been shown to support the reproductive system.†12,13  

Most importantly, several clinical trials have demonstrated that ALC supplementation preserves and improves overall cognitive function in the elderly.

The addition of the acetyl group in ALC improves transport across the blood-brain barrier.†14,15 Although the precise mechanisms of action are unknown, research indicates that its influence may be related to its effects on neural transmission and cellular energy metabolism.†16 A study of the antioxidant activity of ALC in the central nervous system found that supplementation with attenuated protein oxidation and lipid peroxidation also enhanced the activity of other antioxidants at the same time.†17 Animal research suggests a protective effect of ALC on aging neurons,18 and that this effect might be mediated by its antioxidant activity.†19 Acetyl L-carnitine also appears to improve spatial working memory in animal research.†20 It may also support healthy cellular function in aging by increasing cellular ATP production,21 as well as affect Nerve Growth Factor.†22

Most importantly, several clinical trials have demonstrated that ALC supplementation preserves and improves overall cognitive function in the elderly. In a controlled clinical trial, ALC was given to elderly individuals with mild cognitive complaints.23 After 45 days of supplementation at 1,500 mg/d, significant improvements in cognitive function (especially memory) were observed. Another large clinical trial of ALC in a similar group of elderly individuals found that 1,500 mg/d for 90 days significantly improved memory, mood, and responses to stress.24 The favorable effects lasted at least a month after treatment was discontinued. Other controlled and open-label clinical trials have corroborated these findings.25-28 

Citicoline

Citicoline (Cytidine 5’-diphosphocholine, or CDP-choline) is a mononucleotide composed of ribose, cytosine, pyrophosphate, and choline. It is an endogenous compound and a rate-limiting intermediate in the biosynthesis of phosphatidylcholine.29-33 One indication of phospholipid synthesis and turnover is the increased production of phosphodiesters; this has been confirmed by MRI in human subjects taking 500 mg/d of CDP-choline for 6 weeks.†34 Animal studies suggest that citicoline protects cell membranes by accelerating resynthesis of phospholipids, preventing their degradation and subsequent susceptibility to free radicals.† Citicoline has been shown in preclinical and clinical research to support cerebrovascular health.† Citicoline crosses the blood-brain barrier and, in addition to its role in supporting synthesis of phospholipids, supports sphingomyelin35 and increases neurotransmitters such as norepinephrine, acetylcholine, and dopamine in the CNS.†36 Because of these effects on the adrenergic and dopaminergic activity within the CNS, citicoline has also been used to support motor functions of the CNS.†37-40

Initially introduced to support cerebrovascular circulation and recovery, citicoline is marketed as a prescription drug in Japan, Spain, France, and Italy, and as a dietary supplement in the USA.†41 In early research, it was found to enhance the incorporation and metabolism of blood glucose into the brain. Additionally, it was shown to increase cerebral blood flow rate and decrease the accumulation of lactate within the brain.†