Phosphatidylserine (PS) is a major lipid of mammalian cell membranes,^[1] comprising 15% of the total phospholipids in the human brain.^[2] It was originally extracted from the brains of cattle in the 1990s^[3] but has since been derived from soy due to safety concerns in regards to Mad Cow Disease.^[4][2] PS is sometimes studied alongside the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), since PS is attached to DHA molecules in the brain.^[2]

Overall, the results of randomized controlled trials of phosphatidylserine (PS) have been inconsistent. Trials examining PS for cognition in adults over age 50 have somewhat consistently showed benefits at dosages of 100–300 mg per day for 2–6 months, although more research is needed to clarify these benefits.^[5][4][6][7] PS supplementation also might reduce perceived stress levels in people with high chronic stress, though studies of PS for stress have serious limitations and have shown mixed results.^[8][9][10] PS has also been studied in the context of physical activity, though studies have shown even less consistent results here.^{[11][12][13][14][15]}

Many trials examining phosphatidylserine (PS) do not comment on adverse events.^{[11][12][13][14][15][8][10][16]} However, in the trials that do, there does not appear to be a significantly increased risk of adverse events compared to the control group.^{[17][2][7][5]}

Four randomized controlled trials (RCTs) of PS in adults over age 50, using dosages of 300–600 mg per day over periods of 3–6 months, did not note any significant increase in adverse effects in the PS groups compared to the control groups.^{[17][2][7][5]} Similarly, a 15-week trial of PS in children with ADHD observed no major adverse events in the participants given PS, although there were some cases of gastrointestinal discomfort.^[18] One of the trials in older adults noted that any PS-associated gastrointestinal discomfort may be minimized by consuming PS with food.^[5]

While several RCTs have examined PS supplementation in athletes,^{[11][12][13][14]} they did not comment on adverse events; it's worth noting that three of these studies used high dosages of PS (600 mg or 750 mg per day) for shorter durations (7 to 10 days).^[11][12][13] Likewise, of three RCTs of PS in people with chronic stress,^[8][9][10] only one study commented on adverse event rates; that study, which had 60 total participants, only noted 2 adverse events among participants taking PS, compared to 9 adverse events in the participants who took a placebo.

Phosphatidylserine (PS) affects the hypothalamus-pituitary-adrenal axis (HPA axis). The HPA axis is a hormonal signaling pathway which operates under a feedback loop. Perceived stress stimulates the hypothalamus to release corticotropin-releasing factor (CRF), which in turn stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH promotes the release of cortisol from the adrenal glands on the kidneys. Cortisol acts on multiple systems in the body in order to meet its needs in times of stress. Higher levels of cortisol decrease the production of CRF and thereby end the feedback cycle. PS may reduce ACTH and cortisol levels.^[8][10]

Supplemental PS can cross the blood-brain barrier, where it supports communication between neurons^[19] and affects memory, learning and language processes.^[20]