Phosphatidylserine

Phosphatidylserine (PS) is a naturally occurring phospholipid that exists in all species, and comprises a portion of the phospholipid pool in human brain (15%), lungs (7.4%), testes (6.4%), kidneys (5.7%), liver (3.8%), skeletal muscle (3.3%), heart (3.2%) and blood plasma (0.2%) with an estimated 60g total PS storage in the body where half exists in neural tissue.^[1][2] The average dietary intake is said to be approximately 130mg daily.^[1]

Phosphatidylserine (PS) is found in:

• Soy Lecithin at around 3% of total phospholipids^[3]
• Neural tissue (with past studies sourcing supplemental PS from bovine cortex, has since fallen out of favor due to risk of bovine spongiform encephalopathy^[4])
• Krill oil is said to be a source, but the majority of the phospholipids (which, as a group, have been confirmed repeatedly) are from phosphatidylcholine and a PS content per se has not been confirmed

Phosphatidylserine (PS) is a structure somewhat similar to a triacylglyceride (storage form of dietary fat), but with two fatty acids (diacylglyceride) with the final bonding site on glycerol occupied by a phosphatadic acid molecule and serine amino acid. Various compounds may be called phosphatidylserine given they have that one serine containing group; the other two fatty acid chains are irrelevant to the naming, but not necessarily the function, and may differ depending on source.

Phosphatidylserine is a triglyceride structure with one fatty acid replaced with a phosphatic acid and a serine amino acid, and is a phospholipid structure due to this

Phosphatidylserine concentrations in the brain appear to decline with age when measuring rat cerebral slices^[5][6] with no significant alterations in red blood cells in humans^[7] (despite some alterations present in rats during the aging process^[8][9]).

After synthesis, PS is then used as a structural component of a cell's lipid bilayer (cell membrane) with the serine molecule facing inwards.^[10] When included in the structure of the cell membrane, it seems to contribute to and increase cell fluidity and have positive influences on the enzymes Na+/K+ stimulated ATPase (upregulation) and acetylcholinesterase (downregulation)^[11] which may lead to its effects on cognition. There was an upper limit of enzymatic activation noted at 1umol/mg membrane protein, but this cannot be easily translated into an upper dosage.^[11]

Phosphatidylserine is known to activate Protein kinase C (PKC) with a potency greater than other phospholipids^[12] and may stimulate sodium-potassium ATPase channels.^[13]

The first source of supplemental phosphatidylserine was that from the bovine cortex, and while on a molecular level and for some practises there are no significant differences between bovine cortex and soy lecithin based phosphatidylserine^[14][15] the reduction in cortisol seen with bovine cortex PS injections^[16] and oral supplementation^[17] does not appear to occur with soy lecithin based PS when orally supplemented.^[18][18]

Relative to the commonly supplemented soy lecithin based phosphatidylserine, the PS derived from bovine brain tissue is structurally the same yet implicated in reducing cortisol (maybe due to other compounds in the extract), but the bovine brain derived PS is no longer used due to concerns over Creutzfeldt–Jakob disease

Phosphatidylserine has recently started to be extracted from sunflower oil, and at this moment in time there do not appear to be much research into its effects in living organisms nor a known reason to supplement over soy lecithin based phosphatidylserine.

There is currently a lack of information on phosphatidylserine sourced from sunflower oil

2 months of supplementation of 200mg Phosphatidylserine (PS) appears to improve symptoms of global and subscale attention deficit and hyperactivity disorders in children with ADHD, and secondary to improving symptoms of ADHD an improvement in short-term auditory memory and impulsivity was noted.^[19]

Other studies in children with ADHD have noted promise when pairing PS with fish oil supplementation, with some using a phosphatidylserine structure with the fish oil fatty acids (EPA and DHA) attached to the glycerol backbone^[20](study duplicated in Medline^[21]) and appears to enhance erythrocytic fish oil fatty acid levels to a level greater than fish oil itself^[22] (a phenomena seen with krill oil;^[23] fish oil fatty acids bound as phosphatidylcholine^[24]).

In otherwise healthy young adults given 400mg PS for 2 weeks, a significant improvement in processing speed (20%) and accuracy (13% more correct responses, 39% less wrong responses) pre-exercise (but not post-exercise) is noted relative to placebo and independent of mood state.^[18]

Phosphatidylserine appears to promote attention and reduce symptoms of ADHD, and when the phosphatidylserine molecule contains the fish oil fatty acids then it may promote attention to an even greater degree

Stress has been noted to be reduced with doses as low as 60mg in otherwise healthy men, although this study is confounded with the inclusion of fish oil (and stress was only significantly reduced at rest in high stressed persons);^[25] it has been replicated elsewhere with phosphatidylserine in isolation with 42 days supplementation of 200mg phosphatidylserine (as protein bar) where induced stresses were less than control (and associated with less beta-1 wave function in the right hemisphere).^[26] This same dose and supplementation vessel has been used in young golfers given 200mg phosphatidylserine for 42 days, where a 21.6% increase in drive accuracy (percentage of straight shots) was thought to be secondary to a stress reducing effect.^[27]

Using cortisol as a biomarker, stress levels during cognitive testing appear to be unaffected despite improvement in performance^[18] and some studies in healthy individuals fail to find any salient effect.^[28] Regardless, studies that measure heart rate changes during stress fail to find a significant influence of supplementation.^[25][26][28]

Phosphatidylserine supplementation appears to exert anti-stress effects in otherwise healthy persons without stress disorders following prolonged supplementation, and this appears to possibly be independent of the classical biomarkers of stress reduction (cortisol, heart rate)

The anti-stress effect appears to be somewhat different than other supplements and not 100% reliable, and it is uncertain how phosphatidylserine is doing this. It does, however, appear to extend to both soy lecithin based and bovine cortex based phosphatidylserine

Phosphatidylserine supplementation has been noted to increase acetylcholine levels in aged rats in vitro^[29][30][31] which does not appear extend to young rats.^[31]

Several studies have noted that prolonged supplementation of phosphatidylserine to rats during the aging process can reduce the rate of cognitive decline or otherwise show trends to reverse it in the range of 15-50mg/kg daily.^[32]

It has been noted that administration of 200mg (intravenous injection) of phospholipids to patients with Alzheimer's is able to increase dopamine and serotonin metabolites, which are normally reduced in cognitive decline.^[33]

Phosphatidylserine has been found to preserve glucose metabolism during Alzheimer's disease by 13.5–16% following ingestion of 500mg phosphatidylserine^[34] which may be a mechanism underlying its observed benefit in some instances.^[35][36][37]

In studies assessing cognitive decline in Alzheimer's via the MMSE, there appears to be a collection of studies suggesting no effect with 500mg for 3 weeks^[34] but benefit with 300mg of phosphatidylserine from bovine cortex for 8 weeks^[36] or 12 weeks^[37] and has been noted to have benefit with 400mg over 6 months to a level greater than pyritinol.^[38] One study using the MMSE as a rating scale in elderly persons with age-related cognitive decline (but not diagnosed Alzheimer's) has also noted an improvement with 300mg bovine cortex phosphatidylserine.^[39]

In other cognitive disease states, persons with Parkinson's disease given bovine cerebral phosphatidylserine note some degree of improvement on EEG parameters^[40] and in general dementia 300mg of bovine cortex phosphatidylserine has noted some degree of benefit within 3 weeks of a 6 week trial^[41] and has improved memory and depressive symptoms in persons suffering from geriatric depression.^[42]

In persons with age-related cognitive decline associated with pathology, there appears to be a large body of evidence to support the role of bovine cortex phosphatidylserine in alleviating symptoms at 300mg daily. However, there is a lack of evidence to support the role of soy lecithin-based phosphatidylserine in this role and some suspicion that it may not be as effective

PS supplementation has been implicated in increased spatial memory in aged rats at 50mg/kg (human equivalent of 8mg/kg or 550mg for a 150lb person)^[43] and has been noted at lower concentrations (5-20mg/kg) when injected into aged rats, where improvements in grooming and behaviour retention are noted.^[44]

Studies in non-aged rats (to establish a nootropic effect rather than cognitive rehabilitative effect) using 50mg/kg bodyweight for 27 days was able to significantly enhance brightness discrimination (indicative of memory formation) without significantly affecting anxiety or depressive symptoms.^[45]

There appears to be a memory promoting effect of phosphatidylserine supplementation in rats that occurs in cognitively damaged models, aged rat models, and young rats as well; the dosage used in these rat studies is higher than usual (around 500mg for a non-obese human) but not unfeasibly high

The first report of cognitive improvment in elderly humans with aging associated mental impairment (non-pathological) was 3 months of 300mg soy-based phosphatidylserine (PS), in which scores on the Wechsler Memory test improved with particular improvement in visual memory;^[46] this was later replicated with 300mg PS over 12 weeks^[47] and two studies have noted that PS supplementation appears to aid in face recognition in elderly persons at this dose.^[47][48]

Other studies note that 100 or 300mg daily for 6 months has failed to outperform placebo on the Rivermead behavioral memory test (test catered for 'everyday memory problems'^[49]) while scores on the Hasegawa dementia scale (HDS-R; used for dementia assessment similar to the MMSE^[50]) improved relative to placebo, and MMSE score improved as well.^[51] Improvements in the former parameter has been noted elsewhere in elderly persons with memory complaints when using a phosphatidylserine molecule complexed with DHA^[52] or phosphatidylserine from bovine cortex at 100mg^[53] but soy based phosphatidylserine up to 600mg daily (6 months) has been noted to fail with similar methodology.^[54]

In studies that assess more quantifiable parameters, supplementation of PS (where fish oil fatty acids were added to the structure) reported an improvement in immediate word recall by 42% in elderly subjects.^[55]

In healthy elderly adults, there appears to be benefit associated with long term supplementation of phosphatidylserine which seems to be more catered towards preventing dementia; benefits to practical cognition, such as working memory and cognition in everyday situations (or at least rating scales thought to be indicative of this), seems somewhat mixed and may be restricted to PS complexed with fish oils

During intermittent moderate intensity cycling in which soy based phosphatidylserine was consumed for 10 days at 750mg noted that time to exhaustion increased by 29+/-8% when cycling at 85% intensity, and that this improvement was independent of any changes in fat oxidation or cortisol changes.^[56] Elsewhere, supplementation of this dose of soy based PS has failed to alter the exercise-induced changes in lipid peroxidation, muscle soreness, or inflammation.^[57]

400mg PS delivered via a protein bar format (some nutrient confounds) for 2 weeks in college-aged males does not alter the fluctuations of testosterone during weight-bearing exercise.^[18]

It was initially reported that phosphatidylserine obtained from bovine cortex was able to reduce the exercise-induced increase in ACTH and cortisol following intravenous injections of 50-75mg^[16] which was later replicated with 10 days supplementation of 800mg bovine cortex phosphatidylserine in otherwise healthy men subject to exercise.^[17]

Studies using soy lecithin-derived phosphatidylserine noted that 400mg PS delivered via a protein bar format (some nutrient confounds) for 2 weeks in college-aged men does not appear to significant alter exercise-induced changes in cortisol nor ACTH^[18] and 750mg of PS daily for 10 days has twice failed to significantly influence cortisol/ACTH in otherwise healthy exercising men.^[56][57]

This apparent discrepancy appears to be either due to other molecules that may coexist with bovine cortex but not soy lecithin (eg. sphingomyelin) or the fatty acids bound to the glycerol backbone in the relative sources.

Phosphatidylserine derived from the bovine cortex appears to reduce cortisol in high concentrations, there is no evidence to support the role of soy based phosphatidylserine in this role and evidence to actively disprove an ability of PS to suppress cortisol or ACTH

Fish oil (the fatty acids EPA and DHA) are components of phosphatidylserine (PS) derived from bovine cerebral cortex but not from soy lecithin, and some authors mention that combination therapy of both fatty acids with PS would lead to better results.^[55] Both phospholipids and polyunsaturated fatty acids are constituents of lipid membranes,^[58] and are thought by some to work synergistically.

300mg phosphatidylserine paired with 37.5mg of fish oil fatty acids has been noted to improve delayed word recall in older individuals by 42% relative to baseline (no placebo control) with immediate recall not affected nor was any other tested parameter (attention, reaction time, working memory, etc.);^[55] this effect size may be larger than it actually is due to the low sample size (n=8).^[55]

In adult men (non-elderly) using capsules containing fish oil (25% DHA, 5% EPA) and phosphatidylserine (20-22%) at 300mg daily (total PS 60-66mg) noted reduced stress levels in subjects who reported higher baseline chronic stress levels; those with lower stress failed to see an effect to chronic stress, but both groups experienced a lessening of percieved stress during testing (to a lower magnitude in the low stress group).^[25]

Phosphatidylserine, as a phospholipid, may be bound to two fatty acids; connection of the phosphatidylserine molecule to fish oil fatty acids (EPA and DHA) results in a complexed form that has been used in a few studies with benefit.^[22][20]

Ginkgo biloba is a cognitive enhancing herb, with at least one study noted that despite inefficacy with 120mg of ginkgo that complexing this herb with phosphatidylserine results in enhanced memory, with a degree greater than that seen with ginkgo complexed with phosphatidylcholine (which also outperformend ginkgo in isolation).^[59]

Further testing is required, but the two agents may be synergistic

Supplementation of up to 600mg phosphatidylserine (soy based) for 12 weeks in elderly persons has been noted to not be associated with any adverse effects.^[60]

Creutzfeldt–Jakob disease (CJD) is the human version of mad cow disease, a neurodegenerative disease caused by infectious proteins known as prions. A risk factor for CJD is consuming neural tissue of other living species, and it was believed that extracting phosphatidylserine from bovine cortex (main source of PS in the past) ran a risk of CJD.

Despite no reported cases of CJD from phosphatidylserine supplementation, modern supplements use PS derived from soy lecithin due to a higher safety profile.