Cognition Improvement by Phosphatidylserine

by Ari Magill, MD

Phosphatidylserine (PS) is a promising supplement that has been investigated since the 1980s for its cognitive-enhancing properties. PS sounds like it might be related to serine, the amino acid, and indeed has it as part of its composition. However, it functions as a distinct molecule.

It is a phospholipid, a special class of molecule that comprises the cell membrane. A Spanish researcher from the 1940s, Jordi Folch Pi, noted that PS was more highly concentrated in the brain than in other tissues, even though it is less common than other phospholipids.1

The Takeaway:

Though evidence for cognitive improvement from phosphatidylserine is significant, taking in combination with an omega-3 fatty acid might aid in its efficacy.
These molecules have a lipid-“loving” water-repulsing side, and a head group that readily interacts with water, a hydrophilic side. Phospholipids align to form a hydrophobic core, which is composed of long-chain fatty acids, surrounded on both sides with a hydrophilic surface. This unique combination allows the cell to keep out ions and other large molecules unless they are selectively shuttled via receptors and ion channels sitting on the membrane.

A key feature of PS is that it has a negative charge facing toward the cell interior, called the cytoplasm.1 This gives it different properties from most other phospholipids and enables it to bind positively charged proteins within the cell, allowing them to “dock” onto the membrane.

Neurological Activities

One function of PS is helping to activate protein kinase B, which enhances neuron survival. Another role is helping to activate a different enzyme called protein kinase C, which plays critical roles in brain function, including learning and memory.a This activates many important proteins, including NMDA [N-methyl-D-aspartate] receptors, a glutamate receptor that plays a starring role in memory consolidation. Decreases are seen with advancing age and correlate with age-associated memory decline. This is visible on a cellular level in elderly rats, where projections that enable neuronal communication, called dendrites, were preserved in those administered PS.2

Bovine Cortex-Sourced PS Used Initially

Earlier clinical studies in the 1980s and 1990s used bovine cortex-sourced phosphatidylserine (BC-PS).

Cenacchi et al assessed the effect of BC-PS on 494 elderly subjects with moderate-to-severe cognitive impairment.3 Participants were divided into a treatment (whose members were given 300 mg of BC-PS daily) and a placebo arm. Assessments of cognitive and behavioral ability were performed just prior to study initiation and then at three and six months. Those treated showed significant improvement in both behavioral and cognitive assessment scores.

Another study on BC-PS examined the effect of BC-PS on 149 subjects with age-associated memory impairment, who were administered either 100 mg BC-PS three times daily or placebo.4 Those treated with BC-PS performed better on tests of learning and on assessments of daily living activities requiring memory. More severely impaired participants improved the most on the supplement, which was evident on extensive neuropsychological testing.

Crook et al studied 51 subjects meeting clinical criteria of probable Alzheimer’s disease (AD) and demonstrated improvement in cognitive function at 12 weeks on BC-PS, with the greatest impact being seen in those in earlier stages of disease.5 Engel et al studied 33 subjects with mild dementia and found that BC-PS had a beneficial effect on global clinical rating scores and also had normalized EEG readings.6

Soy Replaces Bovine Cortex as Source of PS

In later studies, out of concern for risk of transmission of bovine spongiform encephalopathy (aka mad cow disease), BC-derived PS was largely superseded by soy-derived phosphatidylserine (S-PS).

One study used S-PS on 18 otherwise healthy elderly subjects with age-associated cognitive decline. It showed improvements in those given S-PS over 12 weeks at a dosage of 300 mg daily.7 A later study by Jorrisen et al on 120 older individuals meeting strict guidelines for age-associated memory impairment failed to demonstrate any improvement from taking S-PS over 12 weeks, at a dosage of either 300 mg or 600 mg daily.8

A more recent study on 78 subjects with memory problems, compared a dosage of 300 mg S-PS to placebo over six months.9 Overall, neuropsychological testing did not show a cognitive benefit of S-PS. However, analysis of those who had lower scores at the beginning of the study did demonstrate significant improvement in memory scores, specifically in delayed verbal recall. A later study showed positive cognitive change following S-PS administration over 12 weeks to 30 older subjects with memory complaints,10 but there was no placebo control group.

One of the main chemical differences between BC-PS and S-PS is the latter lacks DHAb in its lipid component. To overcome this deficit, Richter et al performed a six-week study on eight elderly participants who complained of memory problems. They combined 300 mg of safely-sourced PS with 37.5 mg EPAc and DHA,11 and used a formulated brand of PS where omega 3 was attached to its backbone (PS-omega 3). Supplementation improved delayed verbal recall by 42 percent.

Vakhapova et al examined a unique formulation of long-chain omega 3 and safely sourced PS (PS-DHA).12 A total of 157 subjects were enrolled to receive either the equivalent of 300 mg of PS and 79 mg of combined DHA and EPA in the form of PS-DHA or placebo over 15 weeks. Participants receiving PS-DHA had significantly improved immediate verbal recall. Further cognitive benefits were seen in a subset of subjects who had better cognitive scores at the beginning of the study had more benefits. An extension study for an additional 15 weeks performed on 122 people found that cognitive improvements were maintained on 100 mg daily of PS-DHA.13


The evidence for cognitive benefit from PS supplementation is significant. Unfortunately, the most convincing data come from bovine cortex-derived PS, which is no longer available due to risk of mad cow disease transmission. Taking DHA along with PS may improve its efficacy, but combined formulations are not obtainable. Plant-derived PS is readily available without a prescription at health food stores and on Amazon at around $27 for a bottle of 60 tablets.


a Kinases are enzymes that add a phosphate group (a molecule containing phosphorus and four oxygens) to proteins. Doing so changes the shape and activates it so it can perform its function (or alternatively deactivating it).

b DHA, or docosahexaenoic acid, is a long-chain omega 3 fatty acid that plays an important structural role in brain cells as well as those composing the skin and eyes (specifically the retina).

c EPA, or eicosapentaenoic acid, is another important long-chain omega 3 fatty acid in the brain and body. It may have anti-inflammatory effects and a positive effect on mood.


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  2. Amaducci L, et al. Use of phosphatidylserine in Alzheimer’s disease. Ann N Y Acad Sci. 1991;640(1):245-249. doi: 10.1111/j.1749-6632.1991.tb00227.x.
  3. Cenacchi T, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging (Milano). 1993;5(2):123-133. doi: 10.1007/BF03324139.
  4. Crook TH, et al. Effects of phosphatidylserine in age‐associated memory impairment. Neurology. 1991;41(5):644-649. doi: 10.1212/wnl.41.5.644.
  5. Crook TH, et al. Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull. 1992;28(1):61-66.
  6. Engel RR, et al. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol. 1992;2(2):149-155. doi: 10.1016/0924-977x(92)90025-4.
  7. 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;37(4):302-307.
  8. Jorissen BL, et al. The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment. Nutr Neurosci. 2001;4(2):121-134. doi: 10.1080/1028415x.2001.11747356.
  9. Kato-Kataoka A, et al. Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints. J Clin Biochem Nutr. 2010;47(3):246-255. doi: 10.3164/jcbn.10-62.
  10. Richter Y, et al. The effect of soybean-derived phosphatidylserine on cognitive performance in elderly with subjective memory complaints: a pilot study. Clin Interv Aging. 2013;8:557-563. doi: 10.2147/CIA.S40348.
  11. 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;5:313-316. doi: 10.2147/CIA.S13432.
  12. Vakhapova V, et al. Phosphatidylserine containing ω–3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: a double-blind placebo-controlled trial. Dement Geriatr Cogn Disord. 2010;29(5):467-474. doi: 10.1159/000310330.
  13. Vakhapova V, et al. Phosphatidylserine containing omega-3 Fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: results from an open-label extension study. Dement Geriatr Cogn Disord. 2014;38(1-2):39-45. doi: 10.1159/000357793.

About the Author

Dr. Ari Magill is a holistic neurologist and medical consultant based in Mesa, AZ. He received medical school training at University of Texas Southwestern in Dallas and residency training at the University of Arizona in Tucson. He is passionate about finding innovative treatments for cognitive impairment, emphasizing lifestyle change and natural supplements.