In the early 90's, scientists first began to explore this phospholipid for possible effect on physiological and psychological stress reactions caused by exercise. There had been an initial really interesting study in 1981 that had gone seemingly unnoticed that showed in rats, 40 days of exercise and training led to a decrease in PC and PE and an increase in phosphatidylserine and DPG in heart mitochondria. In heart microsomes, there was a reduction in concentrations of PE and phosphatidylserine. phosphatidylserine seemed to be one of the phospholipids used preferentially for muscle during exercise at the detriment of the heart (this won't be mentioned again, but this may be another reason to supplement with phosphatidylserine if you exercise intensely for months or years on end: your heart may be lacking this crucial phospholipid in heart microsomes).

One of the first studies was done in 1990, when apparently it was conjectured that an acute, singular dose of phosphatidylserine might affect exercise induced stress on the various markers of hormonal secretion normal functioning. This early experiment took 8 healthy men on a bicycle ergometer,in double-blind placebo, and each received at 10 minutes before the test, 50 to 75 mg Brain-Cortex-derived phosphatidylserine or placebo. The scientists checked for plasma epinephrine, norepinephrine, dopamine, adrenocorticotropin, cortisol, growth hormone, prolactin, and glucose. The physical stress induced a very clear and pronounced increase in plasma epinephrine, norepinephrine, adrenocorticotropin, cortisol, growth hormone and prolactin, but there no significant change in plasma dopamine and glucose. As the researchers concluded, "pretreatment with both 50 and 75 mg BC-phosphatidylserine significantly blunted the ACTH and cortisol responses to physical stress."¹

In 1992, there were further first hints on the possible use of phosphatidylserine for exercise, in light of stress responses of the body to intense exercise. A placebo controlled study was done on 9 men, at 800 mg phosphatidylserine for 10 days, and it significantly blunted adrenocorticotropin and cortisol response to physical exercise, and did not affect plasma growth hormone or prolactin.²

When under maximal exercise, phosphatidylserine lowered in membranes in untrained but not trained groups. Exercise also significantly lowered phosphatidylserine and PC unsaturated fatty acids in the untrained group. This would indicate that the unsaturated fatty acids used in constructing phosphatidylserine in the body are being fully utilized by the trained group to create phosphatidylserine, whereas the untrained group has not reached a point of physiological adaptation to do so adequately as of yet. Maximal oxygen uptake was negatively correlated with the amount of membrane phosphatidylserine. To quote the researchers, "these results would indicate that both physical training and acute exercise decrease phosphatidylserine and polyunsaturated fatty acids in erythrocyte membranes, possibly due to lipid peroxidation, suggesting limited enhancement of erythrocyte defense mechanisms in adaptation to chronic oxidative stress."³ It appears there is a limit to phosphatidylserine utilization, as there is lipid peroxidation of the fatty acids within phosphatidylserine, and supplemental amounts of phosphatidylserine might allow greater fuel for this process and not consume the membrane phosphatidylserine and allow it to stay at optimal levels. Also, supplemental unsaturated fatty acids, used to construct phosphatidylserine in the human body, may be another route to keep phosphatidylserine levels high in trained individuals.

Another study was done in 1998 that is interesting. Scientists took young males, approximately 26 years old, and tested their Vo2Max to exhaustion (an extreme physical stressor). After the initial trial and before the final one, scientist had participants take either 600 mg of soy-based phosphatidylserine or a maltodextrin placebo for 10 days and then tested their VO2 max again. After this first round of testing the participants that were on the phosphatidylserine were given placebo and retested after 10 days, while the first group given placebo were given phosphatidylserine. This is normal "crossover" design and is done in testing to remove possible placebo effects that are subtle.

After the 10 days of supplementation, the subjects were tested up to 85% VO2 max. Cortisol levels were lower in the phosphatidylserine group throughout (before and after exercise) and the peak was blunted.

Supplementing with phosphatidylserine lead to 35% less cortisol. Peak cortisol levels were 39% lower than placebo!

Scientists also measured subjects' testosterone levels: the phosphatidylserine group had higher testosterone levels! They also looked at lactate and growth hormone, no effect; however, early study that showed at effect on growth hormone if given right before exercise? Hmm... yet no one ever followed through to confirm that result with further experiments.⁴ Near the end of the millennium, 1999, scientists were homing in on the phospholipid complex, which includes phosphatidylserine as a main component, as necessary in trained individuals: such phospholipids were always found in higher levels in trained individuals (up to that point only using endurance athletes, however.) After looking specifically at the calf muscles (a good muscle group to study as they undergo intense stimulation in endurance exercise at a level of trauma similar to high intensity weight training on calves) and found that "endurance training affects skeletal muscle phospholipid content and the rate of incorporation of the blood-borne 14C-palmitic acid into the phospholipid moieties" This most likely means a higher need for the phospholipid complex for hard training, which can be either direct phospholipid supplementation or the the fats helped used in creating such lipids (specifically omega-3 oils).⁵

At that time, since originally phosphatidylserine had been derived from brain cortex, and the “mad cow disease” era was in full swing, there was a process used in more earnestness which could derive phosphatidylserine from soybean;

there was concern whether a derivation from soybean was as effective as the brain cortex source. These concerns were alleviated in 1999 which used brain cortex-derived, soybean-derived, and egg-derived phosphatidylserine, and similar effects were found in rats on a water avoidance test and two way active avoidance test (both high stress events for rats). Scientists found that soybean derived phosphatidylserine improved the rats performance on the tests as well as BC-phosphatidylserine (though egg-derived did not, which I find odd). An interesting note: 15/mgh/kg was used with the rats, wich for a 220 pound

man would be 1500 mg of phosphatidylserine, a considerably hefty dose... makes me wonder if the dosage of phosphatidylserine shouldn't be considerably increased, even if that previous study showed 400mg was ideal, and higher doses actually negated the beneficial effect. Also, the water escape test did not notice effect (they seem to be measuring "psychomotor or spatial discrimination performance", which I feel was negated by the the possible sheer fear response that test caused over the other; as even rat thinking may require a certain level of calm to be increased- I wish they had measured hormonal responses such as cortisol or noradrenaline, two hormones which are primary indicators of stress level even in animals).⁶

In 2004, scientists studied the effects of phosphatidylserine complex, soy lecithin, and phosphatidic acid (which we will see later on here again) on the pituitary adrenal activity (primarily ACTH and cortisol) and also psychological response to a mental and emotional stressor. Given 3 weeks of daily dosage of 400, 600, or 800 mg of phosphatidic acid or placebo. To quote the researchers, "treatment with 400 had pronounced blunting of ACTH and cortisol, but the effect was not seen at higher doses. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg phosphatidic acid showed decreased distress." Also, "these data provide initial evidence for a selective stress dampening effect of phosphatidic acid on the pituitary-adrenal axis, suggesting the potential of phosphatidic acid in the treatment of stress related disorders."⁷ I have no explanation for why the higher doses did NOT show effect; except scientist used four groups of 20 subjects for their experiment and such result anomalies are prevalent in human studies with such low number of subject participants, as such a low amount does not lead to the statistical probability of possible effect or non-effect (p-value) being sufficiently accurate enough.

In 2005 scientists began to experiment on humans with exercise stressors, as initial rat studies had appeared fruitful. One of these first studies (double-blind, placebo-controlled) measured the effect of supplemental phosphatidylserine on soccer players where running was used to simulate a soccer match. They measured cortisol response, perceived muscle soreness, and markers of muscle damage and lipid peroxidation

(which occurs at high levels in intense exercise). Phosphatidylserine had no effect ("supplementation with phosphatidylserine was not effective in attenuating the cortisol response, perceived soreness, and markers of muscle damage and lipid peroxidation following exhaustive running") at 750 mg of soy-derived phosphatidylserine given for 14 days between pre-trial and post_trial (14 days between running tests); however, time to exhaustion increased by 4.2 minutes (+/- 0.7) for phosphatidylserine compared to 3.7 minutes (+/- 4.2%) for placebo.⁸

The lack of much effect from the phosphatidylserine I feel was mostly due to these being experienced soccer players essentially doing what their bodies were adapted highly to do already, thus poor experimental design. In studies later on, we will see when the body is pushed with an actual stressor of significant intensity, phosphatidylserine DOES elicit some nice effects.

A year later, an experiment (double-blind, placebo-controlled) was done on cyclist where performance was increased on an exercise to exhaustion at 85% Vo2max. The time to exhaustion for phosphatidylserine went from 7:51 +/- 1:36 minutes to 9:51 +/- 1:42 minutes.⁹ That is a 26.6% percent increase in time! Massive improvement! And an experiment done to exhaustion, truly testing a stressor that pushes body systems to their limit (especially that lipid peroxidation mentioned earlier). The amount used was 750mg soy-derived phosphatidylserine. It did NOT affect serum cortisol levels or feeling state (self reported level of fatigue or soreness). It was a short term acute dose, not given for an extended time. Thankfully, it was double-blind, placebo-controlled so the results derived from the phosphatidylserine.

Scientist now seemed eager to really see if these experiments would be supported by additional ones showing similar results. In 2006, a study was done on runners running downhill, a sure source of intense delayed onset muscle soreness due to the eccentric nature of such running, Given 750mg for 10 days between a non supplemented period of running, a 4 week washout, and then another downhill running trial. Researchers concluded, "[phosphatidylserine] did not afford additional protection against delayed onset of muscle soreness and markers of muscle damage, inflammation, and oxidative stress that

follow prolonged downhill running."¹⁰ Well, phosphatidylserine seems useless now! Let's look more closely at what they were doing... the running test was on a decline angle of -16.5% from horizontal for 51.0 +/- 1.5 min at 8.7 +/- 0.3 km per hour on four occasions (trials 1-4). It results in approximately 11 minute miles, not a fast pace at all; however, this is a long period of running at such a decline and would incur extreme soreness on anyone, I'd even claim it would be incredibly taxing on phosphatidylserine stores in cell membranes, where that supplementation may have simply not been adequate (scientists were keeping to 750 mg soy-derived supplementation due to previous researchers using it and wanting to keep some variables constant). I wish they had done different levels of dosage, as I feel greater dose would have been study effective. Also, why does no one do the acute supplementation right near exercise time like the first study I gave in this article did? This is a significantly traumatizing exercise event for the human body, and most likely showed no results due to the extreme taxing nature of the exercise.

In 2006 also a literature review was done in the prestigious journal, Sports Medicine, that summed up nicely a study done on the effects of phosphatidylserine at 800/mg a day on exercisers: "800 mg/day moderated exercise-induced changes to the hypothalamo-pituitary-adrenal axis in untrained

participants. Subsequently, this finding was extended to suggest that S-PtdSer 800 mg/day reduced the cortisol response to overtraining during weight training while improving feeling of well-being and decreasing perceived muscle soreness. However, equivocal findings from our laboratory might suggest that the dose required to undertake this neuroendocrine action may vary between participants."¹¹