Phosphatidylserine

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Phosphatidylserine, or PS, is a compound similar to a dietary fat which is highly prevalent in human neural tissue. It can be synthesized as well as consumed through the diet , but further benefits can be gained through supplementation.

It is vital for cognitive function, but is not necessarily needed as the body synthesizes it. However, Phosphatidylserine (PS) supplementation in older individuals seems to improve memory and cognitive capacity.

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A standard dose of phosphatidylserine (PS) is 100mg, taken 3 times a day to total 300mg daily. This dose seems to be effective as a daily preventative against cognitive decline, and 100mg once daily may provide some degree of benefit (but may be lesser than 300mg).

Studies in children and adolescents for the purpose of attention improvement tend to use 200mg, and a dose of 200-400mg has been used in adult non-elderly humans with success. Animal evidence tends to use a dose correlating to 550mg as well.

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Phosphatidylserine has in your body, and how strong these effects are.

Level of Evidence	Effect	Change	Magnitude of Effect Size	Scientific Consensus	Comments
B	Cognition		Minor	66% See all 3 studies	The interactions of supplemental PS with cognition in healthy persons is not fully researched, but there appears to be a positive influence; this may be secondary to a... show reduction in stress and excitation (the latter resulting in an increase in attention) but increased glucose utilization is an unexplored possibility
B	Cortisol			100% See all 4 studies	A decrease in exercise-induced cortisol has been noted with the bovine cortex sourced PS only, soy based supplements (which are usually the only ones sold now due to fear... show of Creutzfeldt–Jakob disease) have been shown to have outright no effect at doses up to 750mg
B	Cognitive Decline		Minor	75% See all 5 studies	There appears to be a protective effect against cognitive decline with PS supplementation above 300mg when using the bovine cortex form; usage of the soy based PS is not... show yet confirmed to have these effects, although it is possible
C	ADHD in Children		Minor	100% See 2 studies	There appears to be reduced symptoms of both hyperactivity and attention deficit in children given PS, which may be more effective when the PS is complexed with fish oils
C	Attention		Minor	100% See study	The improvement in attention is associated with reducing the symptoms of attention deficit, an increase in attention outright has not yet been demonstrated
C	Working Memory		Minor	100% See study	Improvement in working memory may be due to improved attention
C	Stress		Minor	50% See 2 studies	Possible stress reducing effects that appear independent of cortisol and heart rate, although these effects are unreliable
C	Golf performance		Minor	100% See study	Improved accuracy of golf swings thought to be due to a stress reducing effect
C	Subjective Well-being			100% See study	No significant influence on subjective well being noted
C	Processing Accuracy		Minor	100% See study	Increased processing accuracy has been noted in otherwise healthy persons at 400mg PS daily when testing was conducted in a fatigued state (post exercise)
C	Processing Speed		Minor	100% See study	Increased processing speed has been noted in otherwise healthy persons at 400mg PS daily when testing was conducted in a fatigued state (post exercise) which coincided... show with increase accuracy as well.
C	Testosterone			100% See study	No significant influence on testosterone noted with PS supplementation
C	Fatigue		Minor	50% See 2 studies	Unreliable effects, but a quite notable reduction in fatigue has been noted during intense exercise (85% VO2 max) which resulted in increased time to exhaustion. This was... show not present at lower intensities
C	Memory		Minor	50% See all 3 studies	Increases in memory have been noted in persons with cognitive decline. A memory improving effect in otherwise healthy people is theoretical (secondary to reducing stress,... show has been noted in rodents), but not demonstrated in humans yet
C	HDL-C			100% See study	No significant influence on HDL-C with PS supplementation
C	LDL-C			100% See study	No significant influence on LDL-C with PS supplementation
C	Total Cholesterol			100% See study	No significant influence with PS supplementation on total cholesterol
C	Triglycerides			100% See study	No significant influence on triglycerides seen at rest or during exercise with PS supplementation
C	Blood Pressure			100% See study	No significant alterations in blood pressure noted with PS supplementation
C	Heart Rate			100% See 2 studies	No significant influence on heart rate with PS supplementation
C	Liver Enzymes			100% See study	No significant influence on liver enzymes seen with PS supplementation
C	Reaction Time			100% See study	No significant alterations in reaction time during treatment of cognitive decline
C	Anaerobic Running Capacity		Notable	100% See study	An increase in time to exhaustion has been noted in cycling at 85% of VO2 max with soy based phosphatidylserine (750mg) to the degree of 29+/-8%, which is quite notable.... show This is independent of cortisol, and requires further investigation
C	Fat Oxidation			100% See study	No significant influence on fat oxidation during exercise
C	Oxygenation cost of exercise			100% See study	No significant influence on oxygenation cost of exercise
C	Exercise-induced Oxidation			100% See study	No significant influence on oxidation biomarkers that are increased during exercise
C	Inflammation			100% See study	No significant influence on inflammatory cytokines
C	Muscle Damage			100% See study	No significant influence on serum biomarkers of muscle damage such as creatinine
C	Muscle Soreness			100% See study	No significant influence on perceived muscle soreness
D	Forgetting		Minor	100% See study	A reduced rate of forgetting immediate information (results in 'grasping' information easier) has been noted during treatment of cognitive decline with PS; an inherent... show anti-amnesiac effect is not known
D	Cerebral Glucose Utilization		Minor	100% See study	An increase in glucose utilization has been noted in persons with Alzheimer's to the degree of around 15%; this has not been investigated in otherwise healthy persons
D	Growth Hormone			100% See study	No significant influence on exercise-induced growth hormone
D	Prolactin			100% See study	No significant influence on exercise-induced prolactin
D	Lactate production			100% See study	No significant influence on exercise-induced lactate production

Studies Excluded from Consideration

• Phosphatidylserine confounded with Fish Oil (not a complexed molecule, just the two taken alongside each other)^[1][2]
• Duplication is already in the table^[3]
• Injections, likely not practical^[4][5]

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Edit1. Sources and Structure

1.1. Sources

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.^[6][7] The average dietary intake is said to be approximately 130mg daily.^[6]

Phosphatidylserine (PS) is found in:

• Soy lecithin at around 3% of total phospholipids^[8]
• Neural tissue (with past studies sourcing supplemental PS from bovine cortex, has since fallen out of favor due to risk of bovine spongiform encephalopathy^[9])
• 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

There do not appear to be significant differences between soy sourced PS and bovine cortex sourced PS.^[10][11]

1.2. Structure

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

1.3. Biosynthesis and Biological Relevance

Phosphatidylserine concentrations in the brain appear to decline with age when measuring rat cerebral slices^[12][13] with no significant alterations in red blood cells in humans^[14] (despite some alterations present in rats during the aging process^[15][16]).

After synthesis, PS is then used as a structural component of a cell's lipid bilayer (cell membrane) with the serine molecule facing inwards.^[17] 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)^[18] 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.^[18]

Phosphatidylserine is known to activate Protein kinase C (PKC) with a potency greater than other phospholipids^[19] and may stimulate sodium-potassium ATPase channels.^[20]

Edit2. Neurology

2.1. Attention, ADHD, and Cognition

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.^[21]

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^[22](study duplicated in Medline^[3]) and appears to enhance erythrocytic fish oil fatty acid levels to a level greater than fish oil itself^[23] (a phenomena seen with Krill Oil;^[24] fish oil fatty acids bound as Phosphatidylcholine^[25]).

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) is noted relative to placebo and independent of mood state.^[26]

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

2.2. Stress

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);^[1] 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).^[27] 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.^[28]

Using cortisol as a biomarker, stress levels during cognitive testing appear to be unaffected despite improvement in performance^[26] and some studies in healthy individuals fail to find any salient effect.^[29] Regardless, studies that measure heart rate changes during stress fail to find a significant influence of supplementation.^[1][27][29]

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

2.3. Acetylcholine

Phosphatidylserine supplementation has been noted to increase acetylcholine levels in aged rats in vitro^[30][31][32] which does not appear extend to young rats.^[32]

2.4. Cognitive Decline and Dementia

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.^[33]

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.^[4]

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

2.5. Memory and Learning

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.^[2]

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

Edit3. Exercise and Performance

3.1. Interventions

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.^[55] Elsewhere, supplementation of this dose of soy based PS has failed to alter the exercise-induced changes in lipid peroxidation, muscle soreness, or inflammation.^[56]

Edit4. Interactions with Hormones

4.1. Testosterone

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.^[26]

4.2. Cortisol

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^[5] which was later replicated with 10 days supplementation of 800mg bovine cortex phosphatidylserine in otherwise healthy men subject to exercise.^[57]

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^[26] and 750mg of PS daily for 10 days has twice failed to significantly influence cortisol/ACTH in otherwise healthy exercising men.^[55][56]

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

Edit5. Nutrient-Nutrient Interactions

5.1. Fish Oil (Coingestion)

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.^[2] 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.);^[2] this effect size may be larger than it actually is due to the low sample size (n=8).^[2]

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).^[1]

5.2. Fish Oil (Complexation)

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.^[23][22]

5.3. Ginkgo Biloba

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

Edit6. Safety and Toxicology

6.1. General

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]

6.2. Creutzfeldt–Jakob Disease

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.

References

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2. Richter Y, et al. The effect of phosphatidylserine-containing omega-3 fatty acids on memory abilities in subjects with subjective memory complaints: a pilot study. Clin Interv Aging. (2010)
3. Manor I, et al. Safety of phosphatidylserine containing omega3 fatty acids in ADHD children: A double-blind placebo-controlled trial followed by an open-label extension. Eur Psychiatry. (2013)
4. Argentiero V, Tavolato B. Dopamine (DA) and serotonin metabolic levels in the cerebrospinal fluid (CSF) in Alzheimer's presenile dementia under basic conditions and after stimulation with cerebral cortex phospholipids (BC-PL). J Neurol. (1980)
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6. Phospholipids and sports performance
7. Brain Cephalin, a mixture of Phosphatides. Separation from it of Phosphatidyl serine, Phosphatidyl ethanolamine, and a fraction containing an inositol Phosphatide
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15. How Old Are Dense Red Blood Cells? The Dog's Tale
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19. Kaibuchi K, Takai Y, Nishizuka Y. Cooperative roles of various membrane phospholipids in the activation of calcium-activated, phospholipid-dependent protein kinase. J Biol Chem. (1981)
20. Specht SC, Robinson JD. Stimulation of the (Na + + K + )-dependent adenosine triphosphatase by amino acids and phosphatidylserine: chelation of trace metal inhibitors. Arch Biochem Biophys. (1973)
21. Hirayama S, et al. The effect of phosphatidylserine administration on memory and symptoms of attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled clinical trial. J Hum Nutr Diet. (2013)
22. Manor I, et al. The effect of phosphatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children: a double-blind placebo-controlled trial, followed by an open-label extension. Eur Psychiatry. (2012)
23. Vaisman N, et al. Correlation between changes in blood fatty acid composition and visual sustained attention performance in children with inattention: effect of dietary n-3 fatty acids containing phospholipids. Am J Clin Nutr. (2008)
24. Schuchardt JP, et al. Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations--a comparative bioavailability study of fish oil vs. krill oil. Lipids Health Dis. (2011)
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28. The effect of phosphatidylserine on golf performance
29. Rosadini G, et al. Phosphatidylserine: quantitative EEG effects in healthy volunteers. Neuropsychobiology. (1990-1991)
30. Phosphatidylserine increases acetylcholine release from cortical slices in aged rats
31. Effect of Phosphatidylserine on Acetylcholine Output from the Cerebral Cortex of the Rat
32. Casamenti F, Scali C, Pepeu G. Phosphatidylserine reverses the age-dependent decrease in cortical acetylcholine release: a microdialysis study. Eur J Pharmacol. (1991)
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34. Effect of Phosphatidylserine on Cerebral Glucose Metabolism in Alzheimer's Disease
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46. The effect of plant phosphatidylserine of age—associated memory impairment and mood in the functioning elderly
47. Effects of phosphatidylserine in age‐associated memory impairment
48. Schreiber S, et al. An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline. Isr J Psychiatry Relat Sci. (2000)
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50. Hosokawa T, et al. Psychometric equivalence of the Hasegawa Dementia Scale-Revised with the Mini-Mental State Examination in stroke patients. Percept Mot Skills. (1994)
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56. Kingsley MI, et al. Phosphatidylserine supplementation and recovery following downhill running. Med Sci Sports Exerc. (2006)
57. 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)
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59. Kennedy DO, et al. Acute cognitive effects of standardised Ginkgo biloba extract complexed with phosphatidylserine. Hum Psychopharmacol. (2007)
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