Biological Background 
The cell membrane is composed of a phospholipid bilayer, where each phospholipid is amphiphilic in nature, that is, consists of a hydrophobic lipid and hydrophilic phosphate group. The presence of the hydrophilic head group allows the phosphate group to interact with water, the abundant solvent. The hydrophobic tail allows the membrane to be selectively permeable, which acts to only allow hydrophobic (nonpolar) molecules to pass through. This structure allows to cell to manipulate its intracellular environment. For example, the genetic material in the nucleus of the cell, DNA, has a sequence that codes for a transporter gene. This gene can be transcribed by RNA polymerase which results in a strand of messenger RNA (mRNA). This mRNA will be modified and moved into the cytosol, or the “living room” of the cell, or the rough endoplasmic reticulum (RER). Once in the cytosol (or RER), the mRNA can be translated into an amino acid sequence by ribosomes. This primary amino acid folds and results in a protein (peptide). This protein can migrate and if it contains certain amino acids embed itself in the phospholipid bilayer. Since this protein is a transporter, it may allow calcium ions in the cell. In this very sense, since only specific molecules can cross the membrane without a transporter, so when the cell can manipulate the presence of a transporter, the cell controls its intracellular contents. 

The cell membrane is extremely important for many biological functions including cell signaling (communication), structure, and recognition. Phosphatidylserine (PS) is a phospholipid commonly found in the cell membrane, specifically in the inner leaflet. PS plays a crucial role in enzymatic reactions and neurotransmission. Other important roles of PS include acting as an antioxidant and regulating inflammation. 

There are many studies alluding to the fact that PS supplementation is critical to protecting from cognitive decline. The studies investigating PS on cognitive decline tend to be focused on the elderly which may limit the transferability to healthy humans. Other studies investigate the effects of PS on exercise performance and exercise-induced stress. A variety of benefits will be explained below. 

Cognition
Human Findings 
The first paper was first published in 1993 and investigated the treatment of cognitive decline using 300 mg/day of PS. It was seen that the PS-treated group performed significantly better on a variety of cognitive tests after 3 and 6 months of supplementation. The second study was a pilot study conducted in 2013 investigating the effects of PS at 300 mg/day on memory in the elderly for 12 weeks. The test results demonstrate that PS supplementation was able to significantly improve performance on exams testing for memory recall, executive functions, mental flexibility, and recognition. Interestingly, this paper also included that PS supplementation significantly reduced both systolic and diastolic blood pressure. A 2014 study using 100 mg PS and 80 mg phosphatidic acid demonstrated significant positive effects on memory and mood in healthy patients. Another 2013 paper investigating PS supplementation at 200 mg demonstrated that after 8 weeks, children with attention-deficit hyperactivity disorder (ADHD) had significantly improved symptoms and short-term memory. In conjunction with other safe compounds, PS supplementation can be considered for a much healthier and more sustainable treatment for ADHD in children. Finally, a systematic review of the literature conducted in 2022, including 961 subjects, with a dose range from 100-300 mg/day, and a minimum of 6-week supplementation period concluded that PS significantly improved age-related cognitive decline. This systematic review also concludes that no adverse effects were found with PS supplementation at the previously mentioned doses and time frames. 

Animal Findings 
The first article published in 2020 investigated the effect of PS supplementation on the protection of neurons. To do this, the researchers administered trimethyltin to induce neurotoxic effects on the rat brain. Rats were then given PS at 50 mg/kg/day (Rat: 0.34 kg, PS of 0.34 kg rat: 17 mg) for 3-weeks. The rats treated with PS performed significantly better than non-PS treated rats on a variety of behavioral tests. The researchers then stained specific brain regions to visualize neurotoxicity and protection, it was found that the PS-treated group had significantly alleviated the neurodegeneration of trimethyltin when compared to control rats. Lastly, there are many papers in the previous year using phosphatidylserine emulsions or liposomes to treat disorders in mice. One of these papers was published in 2021 where the researchers used phosphatidylserine liposomes to treat post-stroke injuries. The paper concluded that PS liposomes were able to reduce inflammatory markers in specific brain regions, improve immobility time in behavioral tests, and was able to protect neurons from a stroke. 

Phosphatidylserine & Cognition Conclusion 
The literature supports the use of PS supplementation at doses ranging from 100-300 mg/day. 

Exercise
The first paper regarding the effects of PS supplementation on exercise and post-exercise inflammation uses 750 mg/day of PF for 10 days. The subjects performed intermittent cycling and the researchers concluded that PS supplementation was able to improve exercise capacity. The goal of administering PS is not to improve exercise performance but to alleviate the post-exercise rise in cortisol. When considering this new goal for PS administration, there are many trials demonstrating oral PS’s ability to blunt the transient rise in adrenocorticotropic hormone (ACTH) after intense exercise. 

Well-Being 
Well-being is an entirely subjective score, and it can be extremely susceptible to placebo-driven effects. While there are not as many trials investigating the effect of oral PS administration on improving well-being, there are some supporting its use. A paper in 2001 investigated the effect of PS at 300mg in young healthy adults following a stressful environment. It was concluded that PS administration improved mood and feelings of well-being after exposure to an acute stressor in young adults. Another important note is that PS seems to dampen the spike in stress following a stressful environment which is extremely different than a supplement that improves the feeling of well-being despite the environment. In this case, PS allows the body and mental focus to be restored more quickly after a stressful event has occurred which is incredibly helpful throughout the day. The last study mentioned is a 2004 trial investigating PS administration on pituitary-adrenal axis hormones such as ACTH and cortisol, otherwise known as the chronic stress hormones. PS administration demonstrated the ability to reduce this spike in chronic stress hormones and increase positive emotional responses. 

Conclusion 
The world of supplements is widely unknown, and many companies create consuming products with a ton of ingredients, all at suboptimal doses. It is important to formulate a personalized formula with a variety of products at individualized doses and proven quality. Phosphatidylserine is an amazing molecule involved in maintaining cell membrane integrity and brain health. It has proven benefits in human trials and many benefits are yet unexplored. A proper dosage of 100 mg/day, titrated up over a course of weeks with proper documentation can prove useful for exercise, stress resilience, and cognition. 

Literature cited