Studies of the effects of phosphatidylserine (PS) on cognition have shown inconsistent results; some randomized controlled trials (RCTs) have found improvements with supplementation in only one or two subdomains (of several) within a given cognitive assessment tool, whereas other RCTs have found improvements in the overall score of the assessment tool used. However, most RCTs to date have had the limitation of a short duration for examining cognition, usually 1 to 3 months. More, and longer, trials are needed to clarify PS’s effects on cognition.

Several trials have been done on PS supplementation in older adults. One 1993 RCT of PS supplementation in older adults noted improvements in both cognition and withdrawal/apathy scores in the participants taking PS but no improvements in activities of daily living. While this early study is dated, it was quite large and long, with nearly 500 participants and a duration of 6 months.^[7]

Unfortunately, more recent research hasn't clarified PS's potential cognitive benefits for older adults. One 15-week RCT of PS plus omega-3 fatty acids supplementation in older adults saw improvements in the supplemented participants on one of two measures of immediate recall, but not on 8 other measures of cognition. However, a newer RCT by the same researchers, which set out to measure slightly different outcomes and used a lower dose of PS, found improvements both in two subdomains and the overall score on one set of cognitive assessments, but no improvement on another cognitive assessment.^[5][4] And, although a small 2-month pilot RCT of PS supplementation (plus phosphatidic acid, a precursor of PS) in people with Alzheimer's disease found that the participants who received supplements experienced a slower decline in 7 activities of daily living than those given a placebo, the participants did not have improvements in memory, mental status, or mood.^[6]

The effects of PS supplementation on cognition have also been studied in young and middle-aged adults with no known health conditions, but much more research is needed. One small 2008 study found that 6 weeks of supplementation with 200 mg of PS did not affect any measures of cognitive function after a cognitively stressful task. However, the participants who’d taken PS did have slightly different EEG readings in the brain both before and after the test task, which might be indicative of higher levels of relaxation.^[21] PS has also been studied in young and midlife adults in combination with Gingko biloba^[22] and magnesium L-threonate;^[20] while these studies found positive effects on memory, it's hard to say how much of the effects can be attributed to PS.

Most of the literature on PS and stress focuses on participants performing physical activity as the stressor. However, one researcher conducted three randomized controlled trials in nonathletic populations. These trials don’t provide a clear picture of benefits of PS supplementation for cortisol or perceived stress, although there is some evidence of benefit in participants with a history of high chronic stress. However, study sample characteristics, conflicts of interest, and the fact that the lead author was the same in all three studies reduce our confidence in these findings.

The most recent of these studies, which was conducted in 2014, found no significant effects of phosphatidylserine or phosphatidic acid supplementation on levels of cortisol or adrenocorticotropic hormone (ACTH) following a social stress challenge, although a post-hoc subgroup analysis found some benefit for chronically stressed participants taking the highest level of supplementation; further research would be needed to confirm this result.^[8] A similar 2012 study, in which adult male participants supplemented with omega-3 fatty acids in addition to PS, also only found that supplementation had a significant effect in the subgroup of participants with high chronic stress levels; however, in the 2012 study, the size of the cortisol response to acute social stress in the high-chronic-stress subgroup was actually higher after 12 weeks of supplementation (though still lower than that in the low-chronic-stress subgroup). In addition, the high-chronic-stress participants who received PS reported lower perceived stress levels than the participants who received a placebo.^[9] Finally, a 2004 study found that when participants who were given either a placebo or 400 mg, 600mg, 800 mg of PS daily for 3 weeks were then subjected to a social stress test, only the participants who had taken 400 mg daily had lower cortisol, ACTH, and distress scores than the placebo group.^[10] However, all three of these randomized controlled trials appear to be funded by the companies which provided the supplements for these trials, reducing our confidence in the findings of these studies.

In glossary:randomized controlled trials (RCTs) where athletic populations are examined, PS did not consistently improve the outcomes examined.

In an RCT examining cycling, participants in a crossover RCT took 600 mg of PS for 10 days before performing a bout of cycling beginning at a moderate intensity (65% VO_2max) and ending at a high intensity (85% VO_2max). Cortisol Area Under The Curve was lower after PS supplementation, but lactate, testosterone, and growth hormone levels were not different after PS supplementation compared to placebo.^[11]

PS supplementation improved cycling time to exhaustion at 85% VO_2max by a surprising amount, from nearly 8 minutes to nearly 10 minutes in the PS group. The placebo group had no improvement in time to exhaustion. However, performance at lower intensities (45%–65% VO_2max), serum cortisol levels, fatigue levels, tranquility levels, and fuel source utilization rates (carbohydrates versus fat) were not different between the two groups. The participants took a large dose of PS (750 mg) for 10 days before the cycling bout.^[12]

However, PS did not improve biomarkers after downhill running; a later RCT by most of the same authors, also featuring 750 mg of PS daily, explored PS supplementation for 7 days before a bout of prolonged downhill running. The run was on average 51 minutes in duration, at a steep gradient (16.5% decline), and at 8.7 kilometers per hour (or 5.4 miles per hour). Exercise like this, featuring a lot of eccentric muscle activity, is excellent at inducing muscle soreness and inflammation. However PS did not reduce muscle soreness, or biomarkers of muscle damage, inflammation, or oxidative stress, compared to placebo.^[13]

In a crossover RCT, physically active college males took 400 mg of PS for 14 days, and then performed a bout of lower body resistance training. They had no changes to mood, serum cortisol levels, or serum testosterone levels after PS supplementation, compared to placebo. In this RCT, participants were also tested on cognition, where the participants in the PS group performed better on 1 of 3 metrics related to performing simple math problems quickly, compared to placebo.^[15]

Participants taking a combined PS (400 mg) and caffeine (100 mg) supplement for 2 weeks reduced their fatigue ratings immediately after resistance training, compared to placebo. However caffeine is known to reduce fatigue ratings,^[23], so it is difficult to say how much PS contributed. Outcomes that PS might have improved, such as mood and cognition, were not improved with supplementation compared to placebo.^[14]

While there are some mechanistic reasons to think that phosphatidylserine (PS) might benefit children with ADHD, the evidence for its effectiveness is weak.

PS, which is an important component of cell membranes, belongs to a class of organic compounds called phospholipids. Children with ADHD may have lower serum levels of phospholipids^[24] and lower levels of phospholipids in the basal ganglia and prefrontal cortex regions of the brain.^[25] Stimulant medications to treat ADHD work on some of these regions of the brain,^[26] suggesting a possible connection between phospholipids and ADHD medication and thus a possible, if tenuous, mechanism by which PS supplementation could benefit ADHD.

However, there is little evidence that PS is actually effective for childhood ADHD. A 2021 meta-analysis of 3 randomized controlled trials found that 200–300 mg/day of PS improved the subdomain of inattention, but not the subdomain of hyperactivity-impulsivity or overall ADHD symptom scores, in children with ADHD. However, each of these 3 findings were of borderline statistical significance, and two of the three PS supplements also contained omega-3 fatty acids. Furthermore, all three of the trials were ranked as having a substantial risk of bias and being of low or very low quality.^[16]

Most of the literature on PS and stress focuses on participants performing physical activity as the stressor. However, one researcher conducted three randomized controlled trials in nonathletic populations. These trials don’t provide a clear picture of benefits of PS supplementation for cortisol or perceived stress, although there is some evidence of benefit in participants with a history of high chronic stress. However, study sample characteristics, conflicts of interest, and the fact that the lead author was the same in all three studies reduce our confidence in these findings.

The most recent of these studies, which was conducted in 2014, found no significant effects of phosphatidylserine or phosphatidic acid supplementation on levels of cortisol or adrenocorticotropic hormone (ACTH) following a social stress challenge, although a post-hoc subgroup analysis found some benefit for chronically stressed participants taking the highest level of supplementation; further research would be needed to confirm this result.^[8] A similar 2012 study, in which adult male participants supplemented with omega-3 fatty acids in addition to PS, also only found that supplementation had a significant effect in the subgroup of participants with high chronic stress levels; however, in the 2012 study, the size of the cortisol response to acute social stress in the high-chronic-stress subgroup was actually higher after 12 weeks of supplementation (though still lower than that in the low-chronic-stress subgroup). In addition, the high-chronic-stress participants who received PS reported lower perceived stress levels than the participants who received a placebo.^[9] Finally, a 2004 study found that when participants who were given either a daily placebo or 400 mg, 600mg, 800 mg of PS daily for 3 weeks were then subjected to a social stress test, only those who had taken 400 mg daily had lower cortisol, ACTH, and distress scores than the placebo group.^[10] However, all three of these randomized controlled trials appear to be funded by the companies which provided the supplements for these trials, reducing our confidence in the findings of these studies.

In randomized controlled trials (RCTs) of phosphatidylserine (PS) in athletic populations, PS did not consistently improve the outcomes examined.

A pair of 2006 RCTs from a team of UK researchers tested PS supplementation in cycling and downhill running. The participants in the PS groups in both studies took a large dose of PS (750 mg) for 10 days before the exercise bout. In the cycling study, time to exhaustion in the PS group improved significantly compared to that of the placebo group. The increase in the PS group was dramatic — from nearly 8 minutes to nearly 10 minutes. No significant differences were found in any of the other outcomes the study measured, including lower-intensity performance, fatigue levels, and serum cortisol levels.^[12] The second study didn't report on the participants' time to exhaustion, but focused on muscle soreness and biomarkers of muscle damage and exercise-induced inflammation and oxidative stress. The study found no significant differences between the participants who received PS and those who received a placebo.^[13]

Unlike the 2006 cycling study, which found no significant difference in cortisol, a 2008 crossover study of PS supplementation and cycling found that participants' post-exercise cortisol area under the curve was lower after PS supplementation. The study found no significant difference in the other outcomes. This RCT looked at the participants' serum cortisol, lactate, testosterone and growth hormone after a bout of moderate-intensity to high-intensity cycling, conducted after 10 days of supplementation with either 600 mg of PS or a placebo.^[11] Another crossover study, this one in resistance-trained young men, also found no significant differences in post-exercise mood, serum cortisol levels, or serum testosterone levels between participants who had taken 400 mg of PS for 14 days and those who had taken a placebo. However, participants in the PS group did perform better on 1 of 3 metrics related to performing simple math problems quickly.^[15]

The participants who took a combined PS (400 mg) and caffeine (100 mg) supplement for 2 weeks reduced their fatigue ratings immediately after resistance training, compared to a placebo. However, caffeine is known to reduce fatigue ratings,^[23] so it is difficult to say how much PS contributed. Outcomes whose improvements could have more clearly been attributed to PS, such as mood and cognition, were not improved with supplementation compared to a placebo.^[14]