Phosphatidylserine

• Cognitive function
• Brain health
• Memory enhancement
• Stress reduction

• Exercise recovery
• Cortisol regulation
• Immune function support
• Mood improvement
• Attention and focus enhancement

Phosphatidylserine (PS) exerts its biological effects through multiple mechanisms centered on its role as a critical phospholipid component of cell membranes, particularly in the brain. As a major constituent of neuronal membranes, PS plays a fundamental role in maintaining membrane fluidity and integrity, which is essential for proper neurotransmission and cell signaling. PS is asymmetrically distributed in cell membranes, predominantly located in the inner leaflet of the plasma membrane, where it contributes to the membrane’s negative charge and influences protein-membrane interactions. When supplemented, PS can be incorporated into neuronal membranes, potentially enhancing membrane fluidity and function in aging or compromised brains.

PS facilitates neurotransmitter release, receptor function, and signal transduction, thereby supporting overall cognitive processes. It activates protein kinase C (PKC), a key enzyme involved in memory formation and synaptic plasticity. PS also enhances glucose utilization in the brain, potentially improving energy metabolism in neurons and supporting cognitive function, particularly under conditions of stress or fatigue. In the context of neuroprotection, PS inhibits apoptotic signaling pathways, potentially protecting neurons from programmed cell death.

It may also reduce oxidative stress in neural tissues by supporting endogenous antioxidant systems. PS has been shown to modulate inflammatory responses in the central nervous system, potentially reducing neuroinflammation associated with aging and neurodegenerative conditions. PS supplementation can attenuate the hypothalamic-pituitary-adrenal (HPA) axis response to stress, reducing cortisol secretion and potentially mitigating the negative effects of chronic stress on cognitive function and brain health. PS may enhance acetylcholine release and activity, a neurotransmitter critical for learning and memory processes that often declines with age.

It also supports the synthesis and release of dopamine, potentially improving mood, motivation, and attention. PS facilitates the formation and maintenance of synapses, the junctions between neurons that are essential for information processing and memory formation. It may enhance neuroplasticity, the brain’s ability to reorganize and form new neural connections throughout life. PS supports nerve growth factor (NGF) activity, which promotes neuronal survival, differentiation, and growth.

In the context of exercise and physical stress, PS may reduce exercise-induced increases in cortisol and enhance recovery by modulating the body’s stress response. PS also plays a role in immune cell function, particularly in the recognition and clearance of apoptotic cells, which may contribute to its anti-inflammatory effects.

The standard dosage range for phosphatidylserine (PS) is 100-400 mg per day, typically divided into 2-3 doses. Most clinical studies showing cognitive benefits have used doses in the range of 300-400 mg daily. For maintenance and preventive purposes, lower doses of 100-200 mg daily may be sufficient. PS is generally well-tolerated, with minimal side effects reported even at higher doses.

Phosphatidylserine (PS) has moderate oral bioavailability, with approximately 10-20% of an oral dose being absorbed intact. The absorption occurs primarily in the small intestine, where PS is incorporated into mixed micelles with bile salts and other lipids. Once absorbed, PS can cross the blood-brain barrier, allowing

it to reach its primary site of action in the central nervous system. The exact percentage that reaches the brain is not well-established, but studies using radiolabeled PS have confirmed its incorporation into brain tissue following oral administration.

Consumption with a fat-containing meal (enhances micelle formation and absorption), Liposomal delivery systems (may increase absorption by 2-3 fold), Complexation with DHA or EPA (may enhance delivery to the brain due to the brain’s preferential uptake of these fatty acids), Emulsified formulations (improve dispersion and potentially absorption), Enteric-coated formulations (protect from stomach acid degradation), Phosphatidylserine-phosphatidic acid complex (PS-PA complex may have enhanced stability and efficacy), Consumption with phospholipase inhibitors (may reduce degradation in the GI tract), Microencapsulation technologies (protect from degradation during digestion)

Phosphatidylserine is best absorbed when taken with meals, particularly those containing some fat. For cognitive enhancement, dividing the daily dose into 2-3 administrations throughout the day may provide more consistent effects than a single large dose. For stress reduction and cortisol management, taking a dose approximately 30-60 minutes before anticipated stressful events or exercise may be beneficial. For sleep quality improvement, a dose taken 1-2 hours before bedtime may be helpful, though evidence for this specific timing is limited.

When used for cognitive enhancement in academic or professional settings, taking a dose approximately 30-60 minutes before periods requiring heightened cognitive performance may be advantageous. For general brain health and cognitive maintenance, consistency in daily intake is more important than specific timing. If gastrointestinal discomfort occurs, taking PS with food rather than on an empty stomach is recommended.

• Mild gastrointestinal discomfort (uncommon)
• Nausea (rare)
• Indigestion (rare)
• Insomnia (rare, particularly when taken late in the day)
• Headache (rare)
• Potential for increased acetylcholine activity (may theoretically exacerbate conditions with excessive cholinergic activity)

• Individuals taking anticoagulant or antiplatelet medications (theoretical concern due to potential mild anticoagulant effects)
• Pregnancy and lactation (insufficient safety data)
• Individuals with severe liver or kidney disease (limited research in these populations)
• Individuals with bipolar disorder (theoretical concern due to potential neurotransmitter modulation)
• Individuals with known hypersensitivity to soy or sunflower (depending on the source of PS)

• Anticoagulants and antiplatelet drugs (theoretical concern for additive effects, though clinical significance appears minimal)
• Acetylcholinesterase inhibitors (potential for additive effects on cholinergic activity)
• Stimulant medications (potential for additive effects on attention and focus)
• Sedative medications (no significant interactions reported, but theoretical concern for opposing effects)
• Cognitive-enhancing medications (potential for additive effects)
• Cortisol-modulating medications (potential for additive effects on stress hormone regulation)

No official upper limit has been established for phosphatidylserine. Clinical studies have used doses up to 800 mg daily without significant adverse effects. However, most benefits appear to be achieved at doses of 300-400 mg daily, with limited evidence for additional benefits at higher doses. For long-term use, staying within the 100-400 mg daily range is recommended based on the available safety data.

The FDA has acknowledged the safety of PS as a dietary ingredient, and it has been granted GRAS (Generally Recognized As Safe) status for certain food applications. The European Food Safety Authority (EFSA) has also reviewed PS and found no safety concerns at commonly used doses.

In the United States, phosphatidylserine (PS) is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. It is legally available without a prescription. In 2003, the FDA allowed a qualified health claim for PS and cognitive function, stating that ‘very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly.’ However, this claim was heavily qualified with statements about the limited and preliminary nature of the evidence. The FDA requires that products making this claim also state that the scientific evidence is limited and not conclusive.

PS derived from soy lecithin has been granted GRAS (Generally Recognized as Safe) status for certain food applications. The FDA has not established a specific recommended daily allowance (RDA) or upper limit for PS supplementation.

Eu: In the European Union, phosphatidylserine is regulated as a food supplement under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has reviewed health claims related to PS and cognitive function. In 2010, EFSA rejected health claims for PS and cognitive function, stating that a cause-and-effect relationship had not been established between PS consumption and the claimed effects on cognitive function. However, PS remains legally available as a food supplement throughout the EU. Some member states may have specific national regulations regarding PS.

Canada: Health Canada regulates phosphatidylserine as a natural health product (NHP). PS has been included in the Natural Health Products Ingredients Database with approved claims for cognitive health and memory support when used at doses of 100-500 mg per day. Products containing PS must have a Natural Product Number (NPN) to be legally sold in Canada.

Australia: In Australia, phosphatidylserine is regulated by the Therapeutic Goods Administration (TGA) as a complementary medicine. PS is listed in the Australian Register of Therapeutic Goods (ARTG) and is legally available as a dietary supplement. Products containing PS must be registered or listed with the TGA before they can be marketed in Australia.

Medium to High

For standard phosphatidylserine supplements (100-300 mg per day): $0.50-$2.00 per day. For premium formulations (PS complexed with omega-3s, liposomal delivery, etc.): $1.50-$4.00 per day.

Phosphatidylserine represents a moderate to good value for cognitive support, particularly for older adults or those experiencing cognitive decline. The cost-effectiveness varies significantly based on the specific formulation, source, and quality of the product. Soy-derived PS is generally less expensive than sunflower-derived PS or specialized formulations like PS-DHA complexes. For healthy adults seeking cognitive enhancement or stress management, the value proposition is less clear, as benefits may be more subtle and take longer to manifest compared to those with existing cognitive concerns.

When compared to prescription cognitive medications, PS offers a more affordable alternative with fewer side effects, though it may not be as potent for significant cognitive impairment. For athletes using PS for exercise recovery and stress management, the cost may be justified by potential performance benefits, particularly during intense training periods. The value of PS supplementation increases when targeted to specific populations most likely to benefit, such as older adults with mild cognitive impairment or individuals under chronic stress. Long-term supplementation (3-6 months minimum) is typically necessary to realize the full benefits, which should be factored into cost considerations.

Combination products that include PS along with other cognitive-supporting nutrients may offer better value than isolated PS for some individuals, though this depends on the quality and dosing of all components. Overall, PS represents a moderate investment for cognitive health, with the best value found in standardized products from reputable manufacturers that provide at least 100-300 mg of PS per daily serving.

Phosphatidylserine typically has a shelf life of 18-24 months when properly stored, though this can vary based on formulation, packaging, and storage conditions. Liposomal and liquid formulations generally have shorter shelf lives (12-18 months) compared to powdered or encapsulated forms.

Store in a cool, dry place away from direct sunlight and heat. Refrigeration is not typically necessary for capsules or tablets but may extend shelf life, particularly for liquid formulations. Keep containers tightly closed to prevent oxidation. Some manufacturers recommend refrigeration after opening, particularly for liquid or liposomal formulations. Avoid exposure to high temperatures (above 30°C/86°F) as this can accelerate degradation of the phospholipids.

Oxidation (exposure to air and oxygen is the primary degradation pathway for phospholipids), Heat (accelerates oxidation and other degradation processes), Light exposure (particularly UV light can promote oxidation), Moisture (can promote hydrolysis of the phospholipid structure), Microbial contamination (more relevant for liquid formulations), Enzymatic degradation (phospholipases present in some environments can break down PS), pH extremes (highly acidic or alkaline conditions can degrade phospholipids), Transition metals (iron, copper) can catalyze oxidation reactions, Repeated freeze-thaw cycles (for liquid formulations)

Synthesis Methods

Natural Sources

Quality Considerations

Phosphatidylserine (PS) does not have a documented history of traditional medicinal use as an isolated compound, as it was not identified or characterized until modern biochemical techniques became available. However, foods rich in phospholipids, including PS, have been consumed throughout human history, with organ meats (particularly brain tissue) being valued in many traditional cultures for their perceived benefits for mental function. The scientific understanding of phosphatidylserine began in the early 20th century as part of the broader research into phospholipids and cell membrane structure. By the 1960s and 1970s, researchers had established PS as a critical component of cell membranes, particularly in neural tissue.

The potential therapeutic applications of PS for cognitive function were first explored in the 1980s, primarily in Italy and Japan, where researchers began investigating bovine-derived PS for age-related cognitive decline. The first clinical trials showing cognitive benefits of PS supplementation were published in the late 1980s and early 1990s, focusing on elderly populations with cognitive impairment. These early studies primarily used PS derived from bovine brain tissue. In the mid-1990s, concerns about bovine spongiform encephalopathy (BSE or ‘mad cow disease’) led to a shift away from bovine-derived PS toward plant-based sources, primarily soy.

This transition necessitated new research to confirm that plant-derived PS offered similar benefits to the bovine-derived form used in earlier studies. By the early 2000s, PS had gained popularity as a dietary supplement for cognitive health, with expanded research into its effects on stress management, athletic performance, and mood. In 2003, the FDA allowed a qualified health claim for PS and cognitive function, stating that ‘very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of dementia in the elderly.’ However, this claim was qualified with statements about the limited and preliminary nature of the evidence. In recent years, research has expanded to explore PS in combination with other compounds, particularly omega-3 fatty acids, and its potential applications for conditions beyond age-related cognitive decline, including ADHD, stress management, and athletic performance.

Modern PS supplements are primarily derived from soy or sunflower lecithin, with some premium formulations incorporating PS with specific fatty acid profiles or in enhanced delivery systems like liposomes.

Glade MJ, Smith K. Phosphatidylserine and the human brain. Nutrition. 2015;31(6):781-786. doi:10.1016/j.nut.2014.10.014, Whyte AR, Cheng N, Fromentin E, Williams CM. A Randomized, Double-Blinded, Placebo-Controlled Study to Compare the Safety and Efficacy of Low Dose Enhanced Wild Blueberry Powder and Wild Blueberry Extract (ThinkBlue™) in Maintenance of Episodic and Working Memory in Older Adults. Nutrients. 2018;10(6):660. doi:10.3390/nu10060660

Effects of Phosphatidylserine on Cognitive Function in Elderly with Mild Cognitive Impairment (NCT03912532), Phosphatidylserine Supplementation and Cognitive Performance in Young Adults (NCT04021342), Phosphatidylserine and DHA Co-Supplementation for ADHD Symptoms (NCT03683966)