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Phosphatidylserine: A Comprehensive Reference

1. Identity: Chemical Name, Classification, and Structure

Phosphatidylserine is a phospholipid — more specifically a glycerophospholipid — which consists of two fatty acids attached in ester linkage to the first and second carbon of glycerol, and serine attached through a phosphodiester linkage to the third carbon of the glycerol. This unique structural feature distinguishes it from closely related phospholipids such as phosphatidylcholine and phosphatidylethanolamine, which bear different head groups at the same glycerol position.

What sets PS apart is the connection of the third carbon of glycerol to a serine amino acid — a distinctive feature that imparts unique properties to PS and gives rise to its asymmetric distribution within the cell membrane, which contributes to its vital role in cellular functions.

Phosphatidylserine is biosynthesized in bacteria by condensing the amino acid serine with CDP (cytidine diphosphate)-activated phosphatidic acid. In mammals, phosphatidylserine is produced by base-exchange reactions with phosphatidylcholine and phosphatidylethanolamine. More precisely, PS is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum.

PS features two fatty acid chains extending from the glycerol backbone. These fatty acids exhibit variability in terms of length and saturation, giving rise to a diverse array of phosphatidylserine species within biological membranes. The specific composition of fatty acids in PS plays a crucial role in determining the fluidity and stability of the cell membrane.

Common abbreviations and synonyms used in scientific literature include PS, PtdSer, and Ptd-L-Ser. PS is the major acidic phospholipid class that accounts for 13–15% of the phospholipids in the human cerebral cortex.

2. Natural Sources and Occurrence

It was originally isolated from lipid of cerebral origin, the cephalins (Folch, 1948), and it is particularly enriched in the brain where it comprises 10–20% of the total phospholipid pool, and especially in the synaptic membrane zones.

The average daily phosphatidylserine intake in a Western diet is estimated to be 130 mg. Phosphatidylserine may be found in meat and fish. Only small amounts are found in dairy products and vegetables, with the exception of white beans and soy lecithin. Phosphatidylserine is found in soy lecithin at about 3% of total phospholipids.

Although the body can synthesize phosphatidylserine, the body obtains most phosphatidylserine from dietary sources. Phosphatidylserine is present in small amounts in most foods, notably beef brain, fish (mackerel, tuna), chicken heart, liver, and white beans.

Phosphatidylserine is a phospholipid nutrient found in fish, green leafy vegetables, soybeans, and rice. Brain tissue, particularly bovine brain cortex, historically contained by far the highest concentrations of PS.

3. Common Forms and Preparations

Phosphatidylserine is commercially available in several forms, differing principally in their biological source and resulting fatty acid composition.

• Bovine brain cortex-derived PS (BC-PS): Initially, phosphatidylserine supplements were derived from bovine cortex. Research interest in phosphatidylserine supplementation began in the late 1980s and early 1990s, when studies using bovine (cow) brain-derived PS showed promising results for Alzheimer's disease and age-related cognitive decline. However, concerns about bovine spongiform encephalopathy (BSE, or "mad cow disease") led the FDA to conclude in 2003 that phosphatidylserine supplements should not be derived from bovine brain tissue from countries where BSE exists.
• Soy-derived PS (S-PS): As a result, nearly all phosphatidylserine supplements on the market today are derived from plant sources — primarily soy lecithin or sunflower lecithin — which have a different fatty acid composition than the original bovine-derived form. Phosphatidylserine can be obtained from lecithin by enzymatic headgroup modification or by precipitation of the fraction of negatively charged lipids from raw lecithin followed by purification and eventually recrystallization into the water-soluble sodium salt.
• Sunflower-derived PS: Sunflower-derived PS is increasingly available for soy-free formulations. The evidence base is smaller but the molecule is identical.
• PS combined with omega-3 fatty acids: Preparations that bind PS to docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) have been developed and tested in clinical trials, particularly in children with ADHD and in elderly populations with memory complaints.

Phosphatidylserine sourced from plants differs in fatty acid composition from that sourced from animals. This distinction is scientifically significant because brain-derived PS contains predominantly DHA as its fatty acid, whereas plant-derived forms contain mainly linoleic acid.

Regulatory status for safety varies by source: Phosphatidylserine is not approved by the U.S. Food and Drug Administration (FDA) to treat any medical conditions, but the FDA has determined that phosphatidylserine derived from fish, soy lecithin and sunflower are generally recognized as safe (GRAS).

4. Traditional and Historical Use

Phosphatidylserine does not carry a history of traditional herbal or folk medicine use in the same sense as botanical remedies; it was not isolated as a distinct chemical entity until the mid-twentieth century. It was originally isolated from lipid of cerebral origin, the cephalins, by Folch in 1948. Prior to its chemical characterization, the phospholipid-rich fractions of animal brain tissue were used empirically in some European medical traditions as tonics or strengthening preparations, though such preparations were not standardized to PS content and would have contained a complex mixture of brain lipids.

Scientific interest in phosphatidylserine as a supplement began in the 1970s and accelerated sharply during the 1980s and 1990s, driven largely by Italian and Scandinavian researchers investigating cognitive aging. PS and its health benefits have been known to the scientific and nutrition communities since the 1970s. Numerous studies have been conducted in order to establish its efficacy in a variety of cognitive and mental functions. The early clinical literature focused almost exclusively on bovine cortex-derived PS (BC-PS) in aging populations, particularly those with Alzheimer's disease or related dementias. Following BSE concerns in the 1990s, research shifted to plant-derived forms, and the ingredient became a widely marketed dietary supplement in the United States, Europe, and Japan from the late 1990s onward.

5. Key Constituents and Established Mechanisms of Action

5.1 Role as a Structural Membrane Component

Phosphatidylserine is a key component of the cell membrane, where it is primarily located in the inner leaflet. Its polar head group and hydrophobic fatty acid tails allow it to contribute to the overall structure and fluidity of the membrane. Additionally, the asymmetric distribution of phosphatidylserine, with a higher concentration in the inner leaflet, helps maintain the membrane's asymmetry, which is crucial for various cellular processes, such as cell signaling and the recognition and clearance of apoptotic cells.

PS is a phospholipid component, usually kept on the inner-leaflet (the cytosolic side) of cell membranes by an enzyme called flippase. When a cell undergoes apoptosis, phosphatidylserine is no longer restricted to the cytosolic part of the membrane, but becomes exposed on the surface of the cell. With PS exposed, phagocytes recognize the cell as apoptotic and engulf it. Following this, anti-inflammatory cytokines are released by macrophages and microglia.

5.2 Signal Transduction and Neuronal Signaling

In the plasma membrane, PS is localized exclusively in the cytoplasmic leaflet where it forms part of protein docking sites necessary for the activation of several key signaling pathways. These include the Akt, protein kinase C (PKC) and Raf-1 signaling that is known to stimulate neuronal survival, neurite growth and synaptogenesis. Modulation of the PS level in the plasma membrane of neurons has significant impact on these signaling processes.

All PKC isoforms, independent of their calcium requirements, are strictly dependent on PtdSer for their activity. In a membrane model, the concentration of PtdSer influences the specificity of brain PKC.

5.3 Neurotransmitter Systems

Neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. The effectiveness of oral administration of phosphatidylserine on neuronal membranes and on neurotransmitters such as acetylcholine, norepinephrine, dopamine and serotonin is scientifically well-documented. Additionally, exogenous PS stimulates electroencephalographic (EEG) evidence of increased cholinergic neurotransmission in healthy men and women.

5.4 Relationship with DHA

Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. DHA facilitates this mechanism by increasing PS production in neurons, while ethanol has the opposite effect because it inhibits the DHA-induced increase in PS production.

5.5 Hypothalamic-Pituitary-Adrenal (HPA) Axis Modulation

PS has been found to modulate the hypothalamic-pituitary-adrenal axis, which regulates the body's stress response and cortisol release. The precise mechanism by which PS dampens HPA axis reactivity is not fully established, but it is hypothesized that PS incorporation into neuronal and pituitary membranes modulates receptor sensitivity and signaling cascades that govern cortisol secretion.

5.6 Neuroinflammation

Phosphatidylserine is an anionic phospholipid in the eukaryotic membrane and is abundant in the brain. Accumulated studies have revealed that PS is involved in the multiple functions of the brain, such as activation of membrane signaling pathways, neuroinflammation, neurotransmission, and synaptic refinement. Those functions of PS are related to central nervous system (CNS) diseases.

5.7 Age-Related Decline

Phosphatidylserine is required for healthy nerve cell membranes and myelin. Aging of the human brain is associated with biochemical alterations and structural deterioration that impair neurotransmission. PtdSer concentration in the nervous tissue membranes varies with age, brain areas, cells, and subcellular components.

6. Pharmacokinetics and Absorption

Radioactively labeled phosphatidylserine could be detected in the blood 30 minutes after ingestion and subsequently in the brain after passing through the liver and the blood-brain barrier. Phosphatidylserine is very likely not absorbed whole in the small intestine, but rather broken down into its components, which are then re-synthesized into phosphatidylserine after absorption. Subsequently, phosphatidylserine is primarily transported to the liver and brain, where it is stored.

The majority of phosphatidylserine is decarboxylated in the mucosal cells of the intestine into other phospholipids, primarily phosphatidylethanolamine. Despite this partial intestinal decarboxylation, intact PS and its metabolic intermediates still reach circulation and brain tissue.

Oral phosphatidylserine has been reported to be highly bioavailable in humans and to cross the blood–brain barrier. Exogenous phosphatidylserine is taken up and increasingly incorporated into neuronal cell membranes as extracellular phosphatidylserine concentration increases.

Supplemental phosphatidylserine is absorbed in the gastrointestinal tract and incorporated into cell membranes, particularly in the brain. Taking phosphatidylserine with a meal is generally recommended, possibly to enhance absorption through co-ingestion with dietary fats, which may facilitate micellar solubilization and intestinal uptake of this lipophilic compound. The phospholipid structure of PS allows it to be incorporated into chylomicrons and other lipoprotein particles for transport, and it crosses the blood-brain barrier, where it can be incorporated into neuronal membranes.

7. Scientific Evidence by Area of Use

7.1 Age-Related Cognitive Decline and Memory

Overview of evidence: This is the most extensively studied area and the basis for PS's FDA-qualified health claim. However, the strength and generalizability of evidence is complicated by the shift from bovine cortex-derived to plant-derived PS.

The Italian multicenter trial (Cenacchi et al., 1993, PMID 8323999): A total of 494 elderly patients (aged between 65 and 93 years) with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global Deterioration Scale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty-nine patients dropped out within the 6-month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine-treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. This was a large, well-designed, double-blind, placebo-controlled trial using bovine cortex-derived PS.

Systematic review and meta-analysis (Korean Journal of Food Science and Technology, 2021): In this systematic review, the effects of PS on cognitive function in the elderly population were examined. The literature search included PubMed, EMBASE, Cochrane, and Web of Science databases. Subsequently, nine studies, including five randomized controlled trials and four pre-post studies, were selected. There were 961 participants in the selected studies; PS dosage varied from 100 to 300 mg/d, and the experimental period ranged from 6 weeks to 6 months. Five out of the nine selected studies were assessed to have a 'low' risk of bias, whereas the other four studies were assessed to have 'some concerns' regarding the risk of bias. The results of the meta-analysis concluded that PS had a positive effect on the memory of older adults with cognitive decline.

RCT in older adults with mild cognitive impairment (MCI): A 2024 randomized, double-blind, placebo-controlled trial published in the Journal of Affective Disorders examined PS-containing supplements in Chinese older adults with MCI and found cognitive improvements, noting it is one of the first RCTs to discuss that a phosphatidylserine-containing supplement improved cognitive function for older adults with MCI.

Dosing in cognitive studies: PS derived from soy has been tested at doses from 300–600 mg/d in clinical trials.

Limitations and cautions: A panel of the European Food Safety Authority concluded that a cause and effect relationship cannot be established between the consumption of phosphatidylserine and "memory and cognitive functioning in the elderly", "mental health/cognitive function" and "stress reduction and enhanced memory function." This conclusion follows because bovine brain cortex- and soy-based phosphatidylserine are different substances and might, therefore, have different biological activities. Therefore, the results of studies using phosphatidylserine from different sources cannot be generalized. The EFSA's position represents a materially more conservative stance than the FDA's qualified health claim. Research interest began in the 1980s when bovine brain-derived PS showed promising results for Alzheimer's disease and cognitive decline — but that form is no longer available due to BSE safety concerns. Modern supplements derived from soy or sunflower lecithin have a different fatty acid composition and have shown considerably weaker cognitive benefits.

FDA qualified health claim (2003): In 2003, the FDA permitted two qualified health claims for phosphatidylserine supplements derived from soy or bovine sources: (1) "Consumption of phosphatidylserine may reduce the risk of dementia in the elderly," and (2) "Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly." These are qualified claims, meaning the FDA simultaneously required that the claims include a disclaimer noting that the "FDA concludes that there is little scientific evidence supporting this claim." This unusual pairing of a permitted claim with a contradictory disclaimer reflects the state of the evidence: promising but far from definitive.

Overall evidence strength for cognitive decline: Moderate for bovine-derived PS, especially in populations already experiencing cognitive decline. Preliminary and inconsistent for plant-derived PS in healthy adults and those with MCI.

7.2 Alzheimer's Disease

Alterations in phosphatidylserine metabolism have been linked to various pathological conditions, including Alzheimer's disease, Parkinson's disease, and depression. A double-blind, crossover trial (PMID 1633433) examined bovine cortex PS in patients with early Alzheimer's-type dementia and is among the early controlled trials in this population, though the sample sizes were small. The bulk of early Alzheimer's trials used bovine cortex PS that is no longer commercially available. More recent research discusses the alterations of PS in different CNS diseases, and the possibility of PS to serve as a therapeutic agent for neurodegenerative diseases. At present, the evidence for plant-derived PS in established Alzheimer's disease is insufficient to draw firm conclusions, and no regulatory body has approved PS as a treatment for Alzheimer's disease.

7.3 Stress Response and Cortisol Modulation

This area has some of the most consistent human clinical evidence for phosphatidylserine, though study populations are often small.

Bovine cortex PS and exercise-induced cortisol (Monteleone et al., 1992): BC-PS has been reported to attenuate serum cortisol and adrenocorticotropic hormone (ACTH) responses to staged cycling exercise. 800 mg BC-PS supplementation lowered cortisol response by 30%, whereas 400 mg showed no significant results compared to placebo.

Soy PS and resistance training: 800 mg S-PS has been reported to reduce the cortisol response to intensive resistance training by 20%. PS had no effect on testosterone levels in that study. These findings suggest that PS partly counteracts the stress-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis.

Soy PS and endocrine response to exercise (Starks et al., 2008, JISSN, PMC2503954): This study aimed to examine the influence of short-term supplementation with a moderate dose of PS (600 mg per day) on plasma concentrations of cortisol, lactate, growth hormone and testosterone before, during, and following moderate intensity exercise in healthy males. Ten healthy male subjects participated in the study. Each subject was assigned to ingest 600 mg PS or placebo per day for 10 days using a double-blind, placebo-controlled, crossover design. PS supplementation with 600 mg per day for 10 days blunts the cortisol response to exercise-induced stress. In addition, PS significantly increases the testosterone to cortisol ratio. These findings suggest that PS is an effective supplement for combating exercise-induced stress. PS supplementation promotes a desirable hormonal balance for athletes and might attenuate the physiological deterioration that accompanies overtraining and/or overstretching.

Chronically stressed subjects and HPA normalization: Compared to placebo, supplementation with a daily dose of PAS 400 was effective in normalizing the ACTH (p=0.010), salivary (p=0.043) and serum cortisol responses (p=0.035) to the Trier Social Stress Test in chronically high but not in low stressed subjects. Supplementation with PAS 200 did not result in any significant differences in these variables. There were no significant effects of supplementation with PAS on heart rate, pulse transit time, or psychological stress response. In chronically stressed subjects, supplementation with PAS 400 can normalize the hyper-responsivity of the HPA axis to an acute stressor.

Overall evidence strength for cortisol modulation: Moderate. Multiple small double-blind, placebo-controlled crossover studies consistently show cortisol blunting at doses of 400–800 mg/day, with the effect appearing dose-dependent and possibly intensity-dependent. Previous studies utilized stress levels up to 85% peak VO2 max while some studies stressed individuals to exhaustion. This suggests that phosphatidylserine administration may have a rate-limited effect that is dependent upon the intensity level, indicating that the effect is based on a nutritional improvement rather than a pharmacological effect.

7.4 Athletic Performance and Exercise Recovery

PS has been demonstrated to speed up recovery, prevent muscle soreness, improve well-being, and might possess ergogenic properties in athletes involved in cycling, weight training and endurance running. PS has been reported to be an effective supplement for combating exercise-induced stress and preventing the physiological deterioration that accompanies too much exercise.

Performance and muscle damage markers: Studies using less than 800 mg of S-PS supplementation showed beneficial effects on performance and markers of muscle damage. 750 mg of S-PS resulted in an increased time to exhaustion during stage intermittent cycling exercise, and tended to improve sprint and exercise performances during exhaustive intermittent running when compared to placebo. 600 mg and 300 mg S-PS significantly lowered creatine kinase levels 24 hours after a 90-minute run; however, none of the studies showed an effect on cortisol response at these doses, establishing the effective dose at 800 mg S-PS per day for short-term application (10–15 days) for cortisol blunting.

Systematic review conclusion: Evidence remains insufficient to firmly endorse the use of phosphatidylserine for its impact on athletic performance. Available RCTs are generally small, short in duration, and heterogeneous in design, dose, and outcome measures.

7.5 Attention-Deficit/Hyperactivity Disorder (ADHD) in Children

A medical food formulation of PS combined with DHA and EPA has been developed for the dietary management of certain lipid imbalances associated with attention-deficit/hyperactivity disorder (ADHD) in children. A medical food is formulated to be administered enterally under the supervision of a physician and is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements are established by medical evaluation.

RCT by Manor et al. (2012): One RCT from 2012 (Manor et al.) in 36 children with ADHD found 200 mg/day PS plus 120 mg DHA for 2 months significantly improved attention, impulse control, and short-term memory versus placebo.

Safety trial and open-label extension (Vakhapova et al.): Phosphatidylserine already has an established safety profile in children (Manor et al., 2013). However, as the compound can be purchased "over the counter," it is extremely difficult to perform placebo-controlled trials.

Network meta-analysis (PMC10977718, 2024): In terms of improving attention, hyperactivity, and total score of Conners' teacher rating scale (CTRS), pycnogenol, phosphatidylserine+omega-3, and zinc were among the most effective agents. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Parent, phosphatidylserine was among the optimal agents.

Overall evidence strength for ADHD: Preliminary. Limited data exist for children. Two trials used PS in children with ADHD without significant adverse effects, but the evidence base is too small for firm conclusions. The PS-DHA combination appears more relevant given the mechanistic rationale, but the number of well-powered RCTs is insufficient for confident recommendation.

7.6 Depression and Mood

Alterations in phosphatidylserine metabolism have been linked to various pathological conditions, including depression. Some early clinical trials with bovine cortex PS in elderly depressed patients showed modest improvements in mood scores, but this work has not been replicated with plant-derived PS to a degree sufficient for conclusions. Evidence in this domain remains preliminary and largely preclinical.

8. Body Systems and Health Areas Associated with Phosphatidylserine

• Central nervous system / brain: Primary and most studied area. PS is a naturally occurring membrane phospholipid found in high concentrations in brain tissue. PS plays an important role in a host of cellular functions including mitochondrial membrane integrity, presynaptic neurotransmitter release, postsynaptic receptor activity and activation of protein kinase C in memory formation.
• Endocrine system / HPA axis: Modulation of cortisol and ACTH responses, as documented in multiple human intervention trials.
• Immune system and inflammation: PS is involved in neuroinflammation, with effects on anti-inflammatory cytokine release by macrophages and microglia upon recognition of apoptotic cells.
• Cardiovascular / coagulation: PS plays a physiological role in coagulation; when externalized on cell surfaces it provides a catalytic surface for coagulation factor assembly — see Safety section.
• Skeletal muscle: Evidence, primarily from exercise physiology studies, suggests PS may reduce markers of exercise-induced muscle damage (e.g., creatine kinase).
• Mitochondrial function: PS plays an important role in mitochondrial membrane integrity.

9. Dosage Forms and Dosages Reported in Studies

The following dosages are those documented in scientific literature and regulatory sources, cited as reported:

• Phosphatidylserine is a membrane phospholipid commonly supplied as a dietary supplement in doses of 100–400 mg/day, with most clinical trials using 300 mg/day.
• PS dosage in the 2021 systematic review and meta-analysis of nine studies varied from 100 to 300 mg/d, and the experimental period ranged from 6 weeks to 6 months.
• PS derived from soy has been tested at doses from 300–600 mg/d in clinical trials.
• A dose of 100 mg of bovine- or plant-derived phosphatidylserine was used three times daily (i.e., 300 mg/day) for up to 6 months in some trials.
• Some trials used 1 to 3 capsules per day of a specific product containing soy-derived phosphatidylserine 100 mg/capsule, docosahexaenoic acid (DHA) 19.5 mg/capsule, and eicosapentaenoic acid (EPA) 6.5 mg/capsule, for 15 weeks.
• 800 mg BC-PS supplementation lowered cortisol response by 30%, whereas 400 mg showed no significant results compared to placebo in exercise studies.
• The Starks et al. study used 600 mg per day for 10 days in healthy males performing exercise.
• 600 mg and 300 mg S-PS significantly lowered creatine kinase levels 24 hours after a 90-minute run.
• In the ADHD pediatric trial, 200 mg/day PS plus 120 mg DHA was used for 2 months in 36 children with ADHD.
• The review by Glade and Smith (2015) summarized that exogenous PS (300–800 mg/d) is absorbed efficiently in humans and crosses the blood-brain barrier.

Dosage forms available include oral capsules, softgels, powders, and functional food preparations. Soy-derived PS standardized to ≥20% phosphatidylserine content is commonly recommended. Many products use PS complex, which contains additional phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol) — this mirrors the phospholipid profile of natural brain tissue.

10. Safety Considerations and Interactions

10.1 General Tolerability

Clinical studies have showed that PS has no side effects and is well tolerated. Based on current knowledge, phosphatidylserine is safe and well-tolerated: 300 milligrams per day for almost four months caused no significant side effects.

Phosphatidylserine has a favorable safety profile at standard doses. Common side effects include mild gastrointestinal upset, primarily at higher doses (600+ mg/day). Nausea is occasionally reported, usually resolves with dose reduction or splitting across meals.

Common side effects of phosphatidylserine include sleeplessness (insomnia), gas (flatulence), and stomach upset.

10.2 Regulatory Safety Status

Phosphatidylserine is not approved by the U.S. FDA to treat any medical conditions, but the FDA has determined that phosphatidylserine derived from fish, soy lecithin and sunflower are generally recognized as safe (GRAS). ECA Healthcare, Inc. has determined that its phosphatidylserine (PS) from sunflower lecithin is Generally Recognized As Safe (GRAS).

10.3 Anticoagulant and Antiplatelet Interactions

Phosphatidylserine plays a physiological role in blood clotting. When externalized on cell surfaces, it provides a catalytic surface for coagulation factor assembly. Individuals taking anticoagulant or antiplatelet medications should exercise caution due to phosphatidylserine's role in blood clotting — there is a theoretical interaction with blood thinners. This theoretical interaction has not been confirmed in published clinical cases but represents a biologically plausible concern.

10.4 BSE / Prion Risk (Historical)

Research interest in phosphatidylserine supplementation began in the late 1980s and early 1990s, when studies using bovine (cow) brain-derived PS showed promising results for Alzheimer's disease and age-related cognitive decline. However, concerns about bovine spongiform encephalopathy (BSE, or "mad cow disease") led the FDA to conclude in 2003 that phosphatidylserine supplements should not be derived from bovine brain tissue from countries where BSE exists. This is why virtually all commercial PS supplements today are plant-derived.

10.5 Soy Allergy

Individuals with soy allergy should use sunflower-derived PS products to avoid soy allergens. If you have a shellfish allergy, look for phosphatidylserine made from sunflower or other non-shellfish sources.

10.6 Pregnancy and Lactation

Research is ongoing to learn more about whether or not phosphatidylserine is safe to take if pregnant or thinking about becoming pregnant or breastfeeding. Many manufacturers do not recommend taking this supplement if pregnant or planning on becoming pregnant or breastfeeding.

10.7 Cholinergic and Other Medication Interactions

Phosphatidylserine has no known severe or serious interactions with other drugs. However, given its stimulatory effects on cholinergic neurotransmission, PS could theoretically interact additively or synergistically with anticholinesterase medications (e.g., donepezil, rivastigmine used in Alzheimer's disease) or cholinergic agonists, though this has not been formally evaluated in human studies.

10.8 EFSA Position

A panel of the European Food Safety Authority concluded that a cause and effect relationship cannot be established between the consumption of phosphatidylserine and "memory and cognitive functioning in the elderly," "mental health/cognitive function," and "stress reduction and enhanced memory function." EFSA's rejection of these health claims reflects a more stringent assessment framework compared to the FDA's qualified health claim approach.

Summary of Evidence Strength

• Age-related cognitive decline (bovine-derived PS): Moderate — multiple RCTs and a meta-analysis show significant effects, but the source form is no longer commercially available.
• Age-related cognitive decline (plant-derived PS): Preliminary to weak — trials are smaller and results less consistent; EFSA has declined to approve a health claim.
• Cortisol/HPA axis modulation: Moderate — multiple small, controlled human trials with consistent direction of effect at 400–800 mg/day.
• Athletic performance and recovery: Preliminary — small trials show some benefits on cortisol and muscle damage markers; insufficient evidence for ergogenic claims.
• ADHD in children: Preliminary — very limited number of RCTs; too few participants for firm conclusions.
• Alzheimer's disease treatment: Insufficient (plant-derived PS) — no approved indication; best evidence was for BC-PS no longer in use.
• Depression and mood: Insufficient human evidence at this time.

References

• Wikipedia: Phosphatidylserine
• ScienceDirect Topics: Phosphatidylserine (Agricultural and Biological Sciences overview)
• ScienceDirect Topics: Phosphatidylserine (Medicine and Dentistry overview)
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• 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):149–55. PMID 1633433
• Effect of phosphatidylserine on cognitive function in the elderly: A systematic review and meta-analysis. Korean J Food Sci Technol. 2021;53:278–289
• Starks MA, et al. The effects of phosphatidylserine on endocrine response to moderate intensity exercise. J Int Soc Sports Nutr. 2008;5:11. PMC2503954
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• Phosphatidylserine, inflammation, and central nervous system diseases. PMC9382310
• Effects of a food supplement containing phosphatidylserine on cognitive function in Chinese older adults with mild cognitive impairment: A randomized double-blind, placebo-controlled trial. J Affect Disord. 2024
• Alzheimer's Drug Discovery Foundation: Phosphatidylserine — Cognitive Vitality for Researchers
• Safety of phosphatidylserine containing omega-3 fatty acids in non-demented elderly: a double-blind placebo-controlled trial followed by an open-label extension. PMC3136416
• Phosphatidylserine in the brain: Metabolism and function. Progress in Lipid Research. 2014;56:1–18. ScienceDirect
• Cleveland Clinic: Phosphatidylserine — What It Is, Benefits, Side Effects & Uses
• FDA GRAS Notice 000636: Phosphatidylserine derived from Sunflower Lecithin
• Safety and efficacy of antioxidant therapy in children and adolescents with ADHD: A systematic review and network meta-analysis. PMC10977718
• Glade MJ, Smith K. Phosphatidylserine and the human brain. Nutrition. 2015;31(6):781–786