Phosphatidyl Serine, Memory and Cortisol: A Primer


We are all consuming Phosphatidyl Serine each day, with average values in the Western diet reaching around 130mg. 50% of the body’s stores of this phospholipid are found in the brain, demonstrating how important this nutrient is to neural function. Both in neural cells and elsewhere, phosphatidyl serine makes up between 7-10% of the lipid content of cell membranes – that’s very significant. It is the properties that phosphatidyl serine infers on the membrane that is responsible for it’s therapeutic effect.

How does Phosphatidyl Serine work?
This phosphalipid works in a number of ways. Primarily, it improves the balance of phospholipids that form cell membranes. This is relevant all across the body, but especially so in the brain and central nervous system. This replenishment of the phospholipids makes neurons more sensitive to the neurotransmitters that are active in the local environment; the consequence is that the ‘synaptic fidelity’ is increased (in layman’s terms, the signal is sharper). Many individuals report improved memory as a result. They also feel sharper and form clearer sentences.

As secondary effect of this improved synaptic fidelity can be seen in the hippocampus and hypothalamus. Both areas work together to regulate cortisol, the primary stress hormone released by the adrenal cortex. When these parts of the brain feel that there is insufficient cortisol reaching them, the hypothalmus releases a hormone called CRH which ultimately stimulates the adrenals into pumping out more cortisol. This system works fine until the hippocampus and hypothalamus lose their sensitivity to the cortisol; when this happens, they need a significantly higher level to feel satisfied and the adrenals are co-opted into overworking. The end result is chronically-elevated cortisol levels. The introduction of Phosphatidyl Serine reverse the insensitivity at these brain neurons, meaning that these specific areas of the brain are satisfied with much less cortisol. The end result: the hypothalamus no longer stimulates the adrenals in the same way, the cortisol levels fall. As such, phosphatidyl serine is not a ‘cortisol blocker’, it simply reverses the factors that would otherwise push cortisol up too high.

Some research suggests that Phosphatidyl Serine can act as a blocker of glutamate, an excitatory neurotransmitter that is required for learning but, should levels climb too high, can also interfere with the ability to relax and/or sleep.

What the research says about Phosphatidyl Serine

There has been a reasonable amount of research done on Phosphatidyl Serine and it’s affects on athletes. Several studies show no benefits, but the majority show that the phospholipid reduces the exercise-induced increase in cortisol levels, and attenuates disturbances in mood or perception of fatigue. In terms of the science, phosphatidyl serine definitely gets the thumbs-up for athletic recovery.

However, when it comes to memory enhancement or reducing cortisol levels in the ‘general population’ there has been mixed results in the literature. This is not surprising, as most scientists designing studies prove hopelessly inept in choosing representative sample groups and simply select whoever volunteers (normally students). Whereas all the athletes in the studies are put under stress, this method of testing ‘normal’ individuals is unsuitable; you get 100 volunteers, of which only 10 may actually have high cortisol levels. A poor way to to test a nutrient that primarily works by bringing cortisol levels back to normal. That being said, there is plenty of scientific support for phospatidyl serine boosting brain processing speed, concentration, sleep quality and (of course) reduction of excessive cortisol. These conclusions are inconsistent, but this seems due to the problems I have outlined rather than the poor performance of the supplement itself.

In clinical experience, I note that the majority of people with high cortisol or fluctuating cortisol over the course of the day do get a noticeable benefit from using phosphatidyl serine (although those individuals with high night-time cortisol levels will likely benefit even more from using melatonin to reset the circadian rhythms). Most people with ‘normal’ levels of cortisol will not benefit from phosphatidyl serine, although at least 1 in 5 of this group will notice improvements in mental function and sleep quality from using the phosphatidyl serine. There are several people who, despite having normal cortisol levels, simply could not sleep well until they introduced phosphatidyl serine. I am not aware of any signals or signs that would alert as to which normal-cortisol-level individuals would benefit from this item so, given the near absence of side-effects, the approach here remains ‘try it and see’.

What dosage of Phosphatidyl Serine is useful?

As with most nutritional agents, there is no one dosage that is suitable for all. The higher your cortisol levels, the more Phosphatidyl Serine you are likely to need. In some cases, when evening cortisol is particularly high, the only thing that will effectively bring down the glucocorticoid hormone is the use of melatonin.

However, both scientific research and clinical experience tell us that between 400-1000mg of Phospatidyl Serine appears to be the most suitable. I tend to start with a dosage of 200mg with breakfast and then the same with dinner, then doubling both after several days. Some individuals notice improvements at the lower dosage, but most require the 800mg per day.

It is worth noting that, if you are using the Phosphatidyl Serine powder, be aware that all powders available are provided as a 20% concentration. This means you will need 1g of the powder in order to achieve 200mg dosage of the actual phospholipid we are taking about.

When should I take Phosphatidyl Serine?
As mentioned above, I prefer to split the dosage across the day, eg. with breakfast and then again at dinner. However, plenty of people chose to use it once per day and have success doing so. In any case, because it is a phospholipid, consuming this product alongside fats should help absorption. This mean that, should you take it away from a meal, you might want to add a couple of grams of fish oil alongside it.

What is interesting is how the exact time that the evening dose of Phosphatidyl Serine is taken can have a big impact on the sleep-enhancing effect produced; a lot of individuals find that taking it just before bed can improve their sleep, as it’s effect can linger a few hours longer to support good quality sleep into the 4-7am range. However, some sensitive people can feel over-stimulated if they take it just before bed, so a trial is warranted to determine what works best for you.

My test results show high cortisol yet Phosphatidyl Serine did nothing for me. Why?
There are four common reasons why this phospholipid may not have helped you:
insufficient dosage. Many people who have trialled 400mg per day notice nothing, yet reap the rewards when they double the dosage/
poor absorption. Taking fats alongside the supplement is known to help with absorption, although individuals who do not release bile effectively may miss out on absorption. With that in mind, hydrochloric acid production is important for the release of bile. Olive oil and bitter herbs can also help the release of bile.
increases in cortisol are induced by cytokines. Phosphatidyl serine normalises cortisol levels through it’s affects in the brain, reducing the release of CRH and ACTH. However, bacterial, viral or fungal infections trigger an increase in cortisol production through a different mechanisms as they produce cytokines (often referred to as immune system messengers, although they do a lot more than that). This means that the modulation of the hypothalamic-pituitary-adrenal axis by the phosphatidyl serine is not actually that relevant to the big rise in cortisol levels, caused through immune system activation, and therefore makes little difference.
It is actually helping but imbalances elsewhere are too significant for you to notice the difference. Any marked imbalance at the adrenal function, thyroid output or in regards to testosterone/estrogen levels will generally overwhelm your ability to notice the improvements that Phosphatidyl Serine can bring to the table.

Are there any side-effects from Phospatidyl Serine?

I do not see any side-effects in the traditional sense, although it is worth noting that different individuals react in different ways. Because of the way that this phospholipid enhances synaptic fidelity, the communication of both inhibitory/calming neurotransmitters and excitatory neurotransmitters can be enhanced relatively quickly. This normally has a very noticeable effect on calming the brain overall, but there are some occasions when the dopamine signalling is enhanced to the point that the brain is switched into ‘on’ mode. This is not necessarily unpleasant, but can definitely ruin sleep quality.

Should you notice this effect, there is no reason to avoid Phosphatidyl Serine (in fact, the opposite is true; if you notice a response to the nutrient, it is a strong indication that it was missing). Instead, you should lower the dosage and avoid taking it near bed-time so that your sleep is not disturbed. You will often be able to tolerate it better – and later in the day – after a few weeks of doing so.

Phosphatidyl Serine is one of the most useful supplements available on the market, especially in individuals who have struggled to sleep well for a sustained period of time and whose sleep problems have not been resolved fully by addressing hormone and neurotransmitter balance directly. It is not the cheapest item out there and will not work for everyone, but it does remain a star in the line-up and I would not hesitate to recommend it to support healthy cortisol rhythms and sleep quality should first-line approaches prove unsuccessful.

Selected references:

Hellhammer J et al. Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress. Stress (2004).

Monteleone P, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology. (1990)

Monteleone P, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Clin Pharmacol. (1992)

Nerozzi, D., et al., Early cortisol escape phenomenon reversed by phosphatidylserine (Bros*) in elderly normal subjects. Clin. Trials J. 26:33-38, 1989

Starks MA et al. The effects of phosphatidylserine on endocrine response to moderate intensity exercise. J Int Soc Sports Nutr (2008).

Suzuki S, et al. Oral administration of soybean lecithin transphosphatidylated phosphatidylserine improves memory impairment in aged rats. J Nutr. (2001)

Wells AJ et al. Phosphatidylserine and caffeine attenuate postexercise mood disturbance and perception of fatigue in humans. Nutr Res. 2013.