Phosphatidylserine (PS)

A Remarkable Brain Cell Nutrient

Parris M. Kidd, PhD

This document is an overview of the published scientific information on Phosphatidylserine. The statements in this document have not been evaluated by the Food and Drug Administration. No claims are made herein for any particular product or that any product is intended to diagnose, treat, cure, or prevent any disease.

© Lucas Meyer, Inc. Third Edition April 1998

Phosphatidylserine, A Remarkable Brain Cell Nutrient

Phosphatidylserine, or PS, is a naturally occurring, phospholipid nutrient. PS is essential to the functioning of all the cells of the body, but is most concentrated in the brain. Its relative abundance in this organ reflects its proven involvement in an assortment of nerve cell functions, including nerve transmitter release and synaptic activity. Clinical studies have suggested that PS can support brain functions that tend to decline with age. Until recently, PS was only available from animal sources (brain), and occurred in commercial lecithins only in trace amounts; however, a plant source for PS has now been developed. This review is intended as a source of information about PS and its support of mental functions.

A. Behavior	B. System and Pathways
C. Center and Local Circuits	D. Neuron
E. Microcircuits	F. Synapse
G. Membranes, Molecules, Ions	The levels of organization of the brain. From Shepherd, 1988. Neurobiology. Oxford University Press

As Virgil put it long ago,"Time bears away all things, even our minds" (ca. 34 B.C.). Cognitive decline in the healthy can begin as early as the fifth decade of life. Census figures suggest that more than 30 million U.S. citizens are over 65; of these more than half are likely experiencing impaired capacities to recall names and numbers, to manipulate words, or to concentrate at work and maintain focus while at play. Progressive loss of mental functions can have a telling effect on personal productivity, can damage self-esteem, and brings considerable distress to many aging adults.

A pyramidal cell from the hippocampus, the main memory center of the brain. The leaves on this tree-shaped cell shown ad d1 and d2 on the diagram at left, may represent sites of memory fixation; their numbers decline with age. From Nunze et al, 1987.

The fundamental contributions of PS at the level of the individual brain cell are actually expressed in the performance of the brain as a whole. Human trials dating back to the 1970s indicate that when consumed as a supplement to the diet, PS can benefit diverse measures of cognitive functions. In the peer-reviewed literature, there are currently on record some 64 human studies on PS, of which 17 were conducted double blind. The findings from the clinical trial data are unequivocal: dietary supplementation with PS can alleviate, ameliorate, and sometimes reverse age-related decline of memory, learning, concentration, word skills, and mood. PS also may improve the body's capacities to cope with stress and maintain the internal circadian rhythms.

Double-Blind U.S. Trials Conducted with PS

As people age, they inevitably lose some sharpness in the higher-level functions of memory, and cognition (defined most simply as the capacity to think and reason). These functions have been found to decline during middle age and later life, often in people who are clinically healthy. The decline can become evident as early as the fifth decade of life. As memory and cognition slows, nerve cell density falls - a kind of "dropout" occurs, partly in nerve cell number and also in the density of the synaptic connections within the network.

Seventeen Double-Blind Clinical Trials with Phosphatidylserine

Over the adult life span, healthy individuals can lose as much as half (50%) of their ability to perform everyday tasks related to memory and cognition. Research is proceeding at a fast pace in this field, with the hope of slowing brain deterioration at an early stage, thereby to conserve the quality of mental function in later life.

Results from clinical trials conducted in the U.S. and Europe indicate that dietary supplementation with PS can play an important role in the support of mental functions in the aging brain.

Clinical trials are never easy to design and carry out, and those on mental function may be more difficult than most. Any good clinical trial must be based on solid reasoning and painstaking attention to the details of trial design, as well as to competent statistical analysis of the data generated from the trial. First, a starting hypothesis must be developed, to be tested valid or invalid. Next, proven statistical techniques are used to randomly assign a number of subjects to each dosing group. These groups are matched as closely as possible by age, state of health, and other relevant factors; usually, without the investigators knowing which is which, there are one or more dosing groups and one group is given a fake dosing or placebo.

At the end of the trial period, data from the groups are analyzed and cross-comparisons are made; for each comparison, a statistical probability (p value) is derived which quantifies the probability that the observed differences could have occurred by chance. The lower the p value, the greater the chance that the observed difference is real.

From the statistical comparisons between any two sets of data, p <0.05 (p less than or equal to 0.05) suggests a 95 percent probability or better that the observed difference did not arise by chance. A p <0.01 extends this probability to 99 percent or better. Most investigators accept the 95 percent level of significance, which amounts to a 1 in 20 (or lower) chance of being wrong. A p <0.1 level of significance (90 percent probability, 1 in 10 or lower chance of being wrong) can be taken as a "trend." It can be taken to mean that a real difference exists between the groups, and that greater statistical significance could emerge if, for example, patient group sizes had been larger or measuring techniques more precise.

Among the clinical trials conducted with PS, most were done with subjects who had experienced measurable losses in memory, judgment, abstract thought, and other higher mental functions, and sometimes also changes in personality and behavior. In these trials data was generated by detecting categories of affected functions, applying tests that measure such functions, and tracking changes on the tests with time in the PS and the placebo groups.

So far, two double blind, randomized, placebo-controlled trials of PS have been conducted primarily in the United States. Both were multicenter studies coordinated by T. H. Crook, PhD, from the Memory Assessment Clinics (MAC) of Bethesda, Maryland.

Crook et al, 1991. This study involved, in addition to Dr. Crook's MAC, clinicians from the Vanderbilt University School of Medicine in Nashville, Tennessee, the Stanford University School of Medicine in Palo Alto, California, and Fidia Pharmaceutical Corporation of Italy.

One hundred forty-nine (149) subjects, age 50-75, were studied. PS was given at 300mg per day (lOOmg three times per day), versus a placebo, for 12 weeks. Assessments were done at baseline, then at week three after beginning dosing (B+3w), week six (B+6w), week nine (B+9w), week 12 (B+12w), and lastly at week 16 (End+4w, four weeks after stopping the dosing). The subjects' compliance was good - they took their treatments reliably - and PS was well tolerated. By the first evaluation period, three weeks into the trial (B+3w), trends (p<O.l) were noted in three of the five primary variables and all favored PS:

• Learning names and faces (Name-Face Acquisition)
• Recalling names and faces (Name-Face Delayed Recall)
• Facial recognition (Delayed Non-Matching)

These trends did not hold up through the full 12 weeks of the trial, however. For a more meaningful trial outcome, the researchers turned to a subgroup or "cluster" of 57 subjects who were relatively more memory-impaired. These Cluster 2 subjects were slightly older (64.3 average age versus 61.6 for Cluster 1), and seemed to benefit more from PS. In the above three categories, Cluster 2 were found to have improved significantly at week 12 of dosing (B+12w), and the improved Facial Recognition persisted four weeks after these subjects stopped taking PS. Cluster 2 subjects were also significantly improved at (End+4w) on:

• Telephone number recall
• Misplaced objects recall
• Paragraph recall (Wechsler Memory Scale-Logical Memory Subtest)
• Ability to concentrate while reading, conversing, performing tasks

In addition to these improvements, the Cluster 2 subjects showed overall global improvement in cognitive status at dosing week 12 (B+12w), as assessed from detailed interviews conducted "blind" by trained interviewers. The investigators suggested PS might prove clinically valuable for Cluster 2 subjects. As a model they took Name-Face Acquisition. Here, PS had improved Cluster 2's performance by an average two points. They calculated that for this one measurable parameter of higher mental function, PS had "rolled back the clock" by roughly 12 years. In other words, from being at a "cognitive age" equivalent to a person age 64, Cluster 2 subjects were restored, on average, to a cognitive age of 52. In the authors' words, "The magnitude of effect may be considered significant by many subjects and clinicians" (p. 648).

Crook et al, 1992. This second U.S.-based, multicenter study teamed Dr. Crook's Memory Assessment Clinics with Vanderbilt University and with ExPharma of Italy. Fifty-one (51) subjects were studied who were 55-85 years of age (average 71 years). This study was also conducted double blind and randomized, with 300mg PS given daily versus placebo for 12 weeks. Assessments occurred at B+3w, B+6w, B+9w, and B+12w. The most thorough assessment occurred at B+12w, the end of dosing and the last time point of the study. No post-dosing follow-up assessment was done.

By week 12, the end of the dosing period, the PS-treated subjects showed the following improvements (statistically significant, p<0.05):

• Memory for names of familiar persons; names of interviewers or clinic staff
• Recall of the location of frequently misplaced objects
• Recall of details of events from the previous day
• Recall of details of events from within the past week

Using similar statistical sorting techniques as in the previous study, the authors again identified a subgroup of subjects who derived additional benefits from PS. This cluster had relatively mild cognitive impairment to begin with, as compared with the whole group entering the study. The PS group within this cluster benefited significantly on the variables listed above and on two others.

• Ability to maintain concentration
• Two measures of overall global improvement in cognitive status

On the psychiatric rating scale, this mildly impaired cluster improved on five of seven cognitive functions. On four of these five functions, benefits from PS were apparent at (B+3w), or as early as three weeks after the beginning of dosing. As in the previous study, these results suggested that PS can benefit particular aspects of cognitive functioning in the mildly impaired.

Judging from the outcomes of these two well-designed, U.S.-based multicenter studies on PS, it seems that this phospholipid nutrient makes important contributions to the support of mental function.

Double-Blind European Trials with PS

Consistent with the findings from the two excellent double-blind trials conducted in the USA, are the outcomes of the 15 other double blind trials conducted with PS in Europe. 15 Representative trials are summarized below.

Delwaide et al, 1986. This group at the University of Liege in Belgium did a trial on 35 hospitalized subjects, ages 65-91. All had mild to moderate memory and cognitive loss. The trial involved three kinds of evaluations - the Crichton Scale, the Peri Scale developed at Delwaide's "Le Peri" Psychogeriatric Unit, and a psychometric "circle crossing" test. The PS group was given 300mg per day versus the placebo group for six weeks. Subjects were evaluated at baseline, then at (B+lw) and at (B+6w) the end of dosing, then once more at (End+3w), three weeks post-dosing.

The PS group improved on all three rating scales. On the Crichton and Circle Crossing tests trends favored PS, and on the Peri Scale improvement reached significance for the total score (p<0.04). This scale assigns ratings based on 49 items, each differently weighted according to its practical significance for daily living activities. When the 49 items were grouped into ten categories, PS was linked to improvement in all ten. The authors commented, "...the changes observed in the present study reflect an improvement in behavior which can be useful for subjects and their families" (p. 139).

Palmieri et al, 1987. This trial was coordinated between three clinics in Italy. It involved 87 subjects with moderate cognitive deterioration whose ages ranged from 55-80 (mean 73.1 years). PS was given at a 3 x 100mg daily dose versus placebo, and evaluation repeated at 60 days (B+60d). PS was then discontinued, and follow-up evaluation done at day 90 (End+30d, 30 days after cessation of dosing).

The PS group benefited on tests that measured attention, concentration and short-term memory. Five-Word Acquisition improved significantly, while Five-Word Recall was highly significantly improved (p<0.005, or only five chances in 1,000 of the finding being in error).

PS also was linked to improvements in activities related to daily living, and specifically to a lessening of apathy and withdrawal. These were measured using 12 items from the

• Geriatric Rating Scale of Plutchik et al (revised-1977). Items that were improved included:
• Self-sufficiency - activities of daily living (significant p<O.05);
• Sleep disturbances (significant, p<0.05);
• Disadapted behavior; initiative; overall behavioral deficit (highly significant at p<0.002, or two chances in1,000 that the finding was in error.

On these latter items, the benefits from PS roughly equated to lessened apathy and withdrawal. The authors states, “phosphatidylserine appears to exert an action in two distinct contexts: one relating to the cognitive effects of vigilance, attention, and short-term memory, and the other relating to behavioral aspects such as apathy, withdrawal and daily living..." (p. 81).

Nerozzi et al, 1987. This was a small study conducted in Italy. It involved 48 subjects, 6080 years of age. The PS group received 300mg (3 x lOOmg) daily versus the placebo group. The study ran 60 days. Statistically, PS showed a positive effect on delayed memory recollection, tested as deferred memory in the absence of visual stimuli.

Villardita and co-workers, 1987. This was yet another multicenter trial conducted in Italy. It involved 170 subjects, average age 65.7 and range 55-80 years, with mild to moderate cognitive deterioration. The PS group received 300mg (3 x lOOmg) daily versus the placebo group. The study ran 90 days; a battery of neuropsychological tests was given at 45 days (B+45d), then at 90 days (B+9Od).

By the end of the dosing period at 90 days, 12 of the 24 test batteries had reached statistical significance in favor of PS. Improvements on the three tests for Attention and Vigilance were all highly significant (p < 0.01). Semantic functions (word manipulations) are linked to memory. PS significantly improved performance on the Rey Auditory Verbal Learning Test (immediate recall), and on the Semantic Memory Test (immediate and delayed recall) as well as the Block Tap Test Backward and the Set Test. From the improvements on these and the other cognitive tests, Villardita and collaborators concluded that PS can benefit brain-based processes upon which may rest the more complex cognitive mechanisms.

Amaducci and the SMID group, 1988. This multicenter trial was conducted in Italy, and involved 21 co-investigators working in seven neurology research centers. The 142 subjects studied were 40-80 years of age, and all had experienced gradual but progressive mental decline over at least six months. PS was given at 200mg per day (2 x lOOmg) versus placebo, and the dosing period was three months. Assessments occurred at the end of dosing (B+3mo), then at three months after the end of dosing (End+3mo), and again at six months past the end of dosing (End+6mo). Trends favoring PS were seen in a subgroup with relatively severe impairment. By (End+3 mo), three months after PS dosing was ceased, the following had become significant:

• The Set Test (highly significant, p < 0.005, 5/1,000 chance of being wrong);
• Daily Living, Information, Personal Memory, Nonpersonal Memory (significant, P<0-05)-

Those given placebo decline on all measures during this period. A major finding from this study was that PS could “break through” after the subject stopped taking it, to produce benefits that reached statistical significance as much as three months later. This, despite the PS dose being only 200 mg per day (2 X 100 mg).

Cenacchi et al, 1993. This double-blind trial is to date (mid-1995) the largest and longest running trial ever conducted with PS. It involved 425 subject of ages 65-93. (average age 77+ years), recruited at 23 institutions in northern Italy and supervised by a large number of investigators. All subjects had moderate to severe cognitive decline. They were give PS at 300 mg per day versus placebo for six months. They were assessed at baseline, then at (B+3mo) and again at (B+6mo). For statistical analysis, the pooled (B+3mo and B+6mo) scores were compared with the Baselines.

Total Recall (p<0.008) time (months)	Long-Term Storage (p<0.008) time (months)
Long-Term Retrieval (p<0.004) time (months)	Long-Term Retr Cons (p<0.007) time (months)

The Plutchik Geriatric Rating Scale (GRS) and the BSRT (Buschke Selective Reminding Test) were used to evaluate benefits. The GRS scored (a) activities of daily living or ADL, measuring the degree of need for help; and (b) withdrawal-apathy or WA, behavior related to communication and other aspects of social interaction. The BSRT provided data on memory and learning capacities; two lists of seven words were used to evaluate (1) Total Recall (TR), (2) Long-Term Storage (LTS), (3) Long-Term Retrieval (LTR), and (4) LongTerm Retrieval Consistent (LTRc).

After statistical analysis, the scores for ADL were not significant, while the WA scores were significant at p<0.01 for the PS group. The memory and learning scores (BSRT) were highly significant (p<0.01) in favor of PS for all four variables that were assessed.

When this key trial is evaluated together with the other double blind trials conducted with PS, it becomes clear that in mature adults PS can help maintain cognition, concentration, and related mental functions. Thus, particularly if accompanied by exercise and a good diet, PS may help individuals maintain mental fitness in order to meet the challenges of daily life.

Other studies on PS and cognitive function conducted in Europe were not double blind, yet produced results consistent with those from the double-blind studies. These include:

1. Cognitive loss, mild: improved short-term memory, mood and behavior (Caffara and Santamaria, 1987, open trial);
2. Cognitive loss, mild: improved attentive function and social interest (Sinforiani et al, 1987, open trial);
3. Cognitive loss, mild-moderate: improved memory and recall, improved socialization and participation (Granata and DiMichele, 1987, open trial);
4. Cognitive loss, mild-moderate: improved cognition and behavior (Puca et al, 1987, exploratory open trial);
5. Cognitive loss, moderate: global improvement (Allegro et al, 1987, open trial).

Global Effects of PS on Brain Function - EEG, PET

In another double-blind trial, Ransmayr and collaborators (1987) worked with elderly subjects and documented improved brain physiology (flicker-fusion frequency) from PS, linked to improved vigilance, concentration, and motor reaction. Subsequent studies, particularly with EEG (ElectroEncephaloGraphy) indicate PS can globally enhance brain performance.

Quantitative EEG methods are now widely in use to provide information about the brain as a whole. Rosadini et al (1991) used EEG to study PS effects in eight volunteer men 21-28 years of age. Baseline EEGs were done, then PS was administered intravenously according to a double-blind design. PS boosted the alpha rhythm an average 15-20 percent, and without detectable adverse effects. This EEG rhythm is most indicative of acetylcholinecholinergic activity in the brain; in aging and cognitive deterioration it is often found to be lowered.

EEG can be particularly informative when combined with neuropsychological testing. Engel and coworkers (1992) did a double-blind study on 33 subjects with mild cognitive deterioration. Subjects took 300mg PS daily, or a placebo. The trial had a crossover design: both dosing phases lasted eight weeks, with an eight-week "washout" period between. PS boosted EEG "power" values up towards the normal level, and more of the PS subjects benefited on the clinical global improvement ratings. PS benefits carried over through the ensuing washout and dosing phases.

PET (Positron Emission Tomography) and related "imaging" techniques measure regional energy states in parts of the brain. PET tracks glucose metabolism or other indexes of energy generation, and from these data generates dramatic metabolic "maps" of the whole brain, complete with semi-quantitative color gradations. PET has now become sufficiently refined to provide semi-quantitative "maps" of brain activity as a whole. PET and other state-of-the-art imaging are particularly exciting because they can help detect and "track" cognitive decline without invading the body or seriously inconveniencing the subject under study.

Recently, Heiss and collaborators (1993) successfully employed PET to correlate cognitive impairment with impaired brain metabolism. They did a controlled clinical trial on 40 subjects with mild to moderate cognitive impairment. After neuropsychological testing, brain metabolism was periodically mapped by PET. All subjects began the trial with abnormally lowered resting metabolism; over the six months of the study only the group given PS (4 x 100 mg per day) did not decline further on their tests or in their resting brain metabolism as mapped by PET.

This trial also utilized a new twist, namely Activation PET: mapping with PET while the subject is taking a test. As the subject proceeds with the test, the brain "lights up" on PET, its metabolism becoming increased or "activated." PS subjects showed a significantly greater degree of activation upon taking a test, than did subjects not given PS. Also, the superior activation by the PS group was accompanied by significant improvements on their test performances. Data on a representative 10 subjects from each group indicated that PS stabilized cognitive decline for the six months of the study, while also stabilizing resting brain metabolism and boosting brain activation. However, another paper from the Heiss team reported that the PS effect faded after the four-month timepoint. They suggested progressive pathological changes in this particular patient sample might have "overcome" the PS effect (Heiss et al, 1994).

Phosphatidylserine can also be of benefit for abnormal seizure activity. Based on findings that PS (used in combination with GABA, gamma-amino-butyric acid) could ameliorate experimental seizure activity in rats, Loeb and collaborators (1987) administered PS+ GABA to human subjects suffering from sporadic seizure abnormalities, for periods ranging from 30 to 90 days. The combination worked against absence seizures; one-third of the subjects experienced a greater than 50 percent reduction of this seizure type. In a subsequent trial (Cocito et al, 1994), a one-time acute administration of PS did not work as well. This is not surprising, since PS is a fat-soluble nutrient and would be expected to require at least several days' dosing to build up in the nerve cell membranes.

Interestingly, the combination PS+GABA when given intravenously to rats had an immediate calming effect on seizure activity (Loeb, 1989). This effect could only achieved by combining GABA with PS, and not with PC or other phospholipid. PS may have increased the bioavailability of GABA to the brain.

R

L

PET imaging of the brain of a 59-year-old female. The color scale semi-quantitatively indicates regional glucose metabolism at three brain levels, with red being most intense and blue, least intense (se color scale). Upper, before PS; lower, after 500 mg PS daily for three weeks. Metabolism is increased in almost all brain regions. From Klinkhammer 1990.

Phosphatidylserine Effects on Adaptability and Mood

PS can benefit brain dysfunctions other than the strictly cognitive. In an exploratory open trial by Funfgeld and Nedwidek (1987) on subjects with dopamine transmitter deficiency, 8 of the 12 subjects given PS showed improvement. Another patient improved when the PS intake was increased. This trial went for only 3 weeks; a longer dosing period and customized dosing might have produced more consistent results. In a previous study (Argentiero and Tavolato, 1980), subjects exhibiting severe cognitive deficit combined with motor impairment responded to intravenous PS (about 35 mg, administered as 200 mg total bovine brain cortex phospholipids). As their motor performance improved, they showed elevations in homovanillic acid (a marker for the transmitter dopamine) in their cerebrospinal fluid.

PS can have beneficial effects on mood. In a double blind trial conducted on elderly women, PS brought about consistent improvement of memory and behavior (Maggioni and others, 1990). In an open trial, Manfredi's group (1987) obtained statistically significant improvement of various "psycho-organic" parameters in elderly women given 50 mg PS per day intramuscularly. The addition of the nutrient PS to a conventional drug regimen led to marked improvements in asthenia, insomnia, anxiety, and capacity for recollection, versus the drug regimen alone (all p<O.OS). A trend towards improvement was seen for vertigo and depression. Findings from the 1995 trial by Gindin and collaborators suggested PS can also improve mood in elderly men. Sengupta and fellow researchers (1981) documented significantly lowered PS levels in the membranes of platelets and red cells drawn from subjects with clinical depression.

Changes in scores (mean +/-SD) of the Hamilton rating scale following phosphatidylserine treatment (400 mg/day for 60 days) in patients with mild depression *p<0.001 v. baseline (signed Rank test). Note sustained PS effects 30 days after discontinuation. From Rabboni et al, 1990.

Supplementation with PS may also help conserve hypothalamic function and benefit the aging hypothalamus-pituitary-adrenal axis (HPAA). One example is the Early Cortisol Escape Phenomenon. In young, healthy people the oral administration of 1 mg of dexamethasone (DEX, a synthetic glucocorticoid) normally suppresses the production of cortisol and other adrenal steroids for more than 24 hours. In contrast, many older people do not show this suppression by DEX. Called Early Cortisol Escape, this phenomenon of escape from DEX suppression is thought to indicate disintegration or dysfunction of the HPAA in the elderly. Nerozzi's group (1987) found that oral supplementation with PS restored DEX suppression in a group of 14 institutionalized elderly (ages 66-78; p<0.02). Rabboni et al (1990) administered PS at 400 mg/day to 30 elderly outpatients diagnosed either with (a) Alzheimer's, (b) dementia resulting from stroke, or (c) mild depression. PS benefited all 3 groups by 30 days, and normalized DEX suppression in those 9 patients who began the study with abnormal DEX resistance.

Further evidence that PS can benefit the aging HPAA comes from Masturzo and collaborators (1990), who did an open, placebo-controlled trial on institutionalized elderly men (ages 6585, average age 73.7) with disturbed 24-hour circadian rhythm of thyrotropin (TSH) hormone secretion. While those on placebo deteriorated further, PS restored the daily rhythm of TSH secretion to a level comparable with the young male adult controls (mean age 22.3 years; p<0.001). In another human study (Nizzo et al, 1978), the intravenous administration of PS in liposome form led to "spikes" of growth hormone release. This effect was interpreted as likely the result of activation of dopamine metabolism in the pituitary gland by PS.

Stressful conditions typically elicit the release of cortisol, ACTH, and related stress hormones into the circulation. Phosphatidylserine appears able to down-regulate cortisol release, even in the healthy young adult. Intense muscle workouts often raise blood levels of the stress hormones, and when cortisol remains elevated muscle can be broken down and amino acid uptake compromised. In 1992, Monteleone's group reported on an open, placebo-controlled trial of young, healthy men subjected to exercise-induced stress. Oral intake of PS, for 10 days prior to a session of bicycling to near-exhaustion, lowered the cortisol production normally associated with strenuous exercise. This confirmed findings from a 1990 study by the same group, in which PS was given intravenously just prior to exercise.

These findings of benefit from PS to stress coping and the HPAA axis must be considered somewhat preliminary due to the small sizes of the trials. Yet they are consistent with an influence of PS on brain function at all levels of complexity and integration. Further controlled trials may well confirm a clinically significant influence of PS on the body's age-related capacities to integrate its nervous, immune, and hormone systems.

PS is a Building Block for Cell Membranes

PS is not abundant in common foods, so it is limited in the human diet. Moreover, the body can make it only through a complex series of reactions and with substantial investment of energy. Given orally, PS is rapidly absorbed and readily crosses the blood-brain barrier to reach the brain. There, its sites of action appear to be exclusively in cell membrane.

Membranes are the major work surfaces of all known cells, and PS is a universal cell membrane building block. Nerve cells especially depend on membranes to carry out their specialized functions. The generation of the electrical current, the transmission of the current along the cell, and the relaying of the current across the cell-to-cell chemical synapse are all membrane-driven events. Membrane proteins play key roles in all these processes, and PS is important for regulating the activities of such proteins.

PS and other phospholipids (PL, for short) are large "lipid" molecules that hold together the diversity of large molecules in the cell's membrane systems. The PL pack together side-to-side, and in a two-layer molecular sandwich (a bilayer), creating a membrane matrix into which the proteins and other membrane constituents are inserted and secured. The phospholipids of the membrane literally are a solvent for the proteins of the membrane.

PS phospholipids are one of five phospholipid classes that fulfill these physico-chemical functions. The others are phosphatidylcholines (PC), ethanolamines (PE), and inositols (PI); and the sphingomyelins, which have a molecular organization different from the phosphatidyls.

Each phosphatidyl molecule has a head group that contains phosphorus and one other chemical subgroup, which in the case of PS is serine. To the head group is attached a three-carbon backbone which is structurally identical to glycerol. Extending from this glycerol backbone are two so-called tails, each of which is a fatty acid. The sphingomyelins do not have the glycerol backbone, and carry only one fatty acid tail. The different phospholipids and their biological activities are identified and characterized via their differing head groups. The unique atomic and electronic topography of the head piece of the PS molecule destines it for a preferential association with membrane "integral proteins," that is enzymes, receptors, and ion channels that insert deep into the membrane. The head piece is identical between bovine source and soy source PS, just as it is identical with PS from bacteria, algae, or fungi.

The two tails of the PS molecule are fatty acids. As with the other phospholipids, the fatty acid tails of PS have a high rate of turnover. What is more, the tail patterns vary between the various organs. While position 1 almost always carries a saturated or monounsaturated fatty acid, position 2 can carry a variety of fatty acids. Thus PS from blood has mostly C18:1 (oleic acid, OA) or C20:4 (arachidonic acid, AA) in the 2 position. In the testes, C14:0 and C20:4/AA predominate. In PS from the brain, no C20:4/AA is found in Tail 2, and instead mostly C18:1/OA is present.

PS Supports Multiple Membrane Functions in Nerve Cells

Nerve cell functions that have been linked to PS include the conduction of the nerve impulse; the accumulation, storage, and release of the nerve transmitter substances; and nerve transmitter action by way of "receptors" located on the target cell surface. PS also is important for "housekeeping" in the nerve cell, by supporting the processes of homeostasis.

The membranes of nerve cells are particularly high in PS. The outermost membrane of the cell, called simply the cell membrane, is a kind of master switch for the cell. Among those cell functions which the cell membrane controls are:

• Entry of nutrients into the cell, and the exit of waste products
• Movements of charged atoms (ions) into and out of the cell
• Passage of molecular messages from outside the cell to its interior
• Cell movement, shape changes, flattening or expansion
• Cell-to-cell communication and other associations

The membrane-based ion pumps, transport molecules, enzymes, and receptors which manage these master-switch activities are proteins, but all depend on the phospholipid membrane matrix for their full functional capacity and for their coordinated activity. PS seemingly has the specialized function of helping to anchor many of these proteins in the matrix. Also, PS carries a negatively charged amino headgroup which tends to associate preferentially with ATPases, kinases, receptors, and other key membrane proteins. These specific PS-protein associations may be the ultimate key to the remarkable global effects of PS on the brain as a whole (Pepeu et al, 1996).

Left: Molecular organization of phosphatidylserine (PS). Right: PS is preferentially distributed in the bilayer portion of the cell membrane that faces the cells interior. PS associates with key membrane proteins.

The influences of PS at the level of the individual membrane proteins amount to essential contributions at a "micro-level" of the cell membrane. PS therefore facilitates an array of cell functions that build on membrane functions. As examples:

• Maintenance of the cell's internal environment: PS in the cell membrane is essential for the ATPase enzymes that regulate cellular sodium-potassium AND calcium-magnesium balance (see Toffano, 1987). Due to their constant electrical activity, generated by ion movements across their membranes, nerve cells rely heavily on the ATPase enzymes. In cell membrane preparations isolated from the brains of aged rats treated with PS, the cholesterol/phospholipid ratio and ATPase activities were found to be reversed towards values characteristic of younger rats.
• Signal transduction: The many different receptors on cell membranes, and the enzymes within the membrane to which they are closely linked, rely heavily on membrane phospholipids for their activities. PS is known to regulate the binding of opiates and glutamate to their receptors, to enhance olfactory bulb sensitivity in turtles, and to restore prolactin receptor density in aging rats. PS also has potent activation effects that are important for protein kinase C, a major signal transduction complex, and for adenylate cyclase signal transduction activity in the rat hypothalamus (see Zanotti et al, 1987).
• Secretory vesicle release: Most cells secrete hormones, nerve transmitters, or other materials to the outside environment by way of membrane-coated micro-packages called secretory vesicles. In fact, vesicle secretion is the major means by which nerve transmitters are released from the nerve cell axon endings. PS may help prepare the cell membrane and/or the vesicle membrane for the two to fuse with each other and thereby release the secretory packet to the outside (see Nishizuka, 1984). PS also seems to revitalize acetylcholine stores in the brains of aged rats (see Pepeu et al, 1996).
• Cell-to-cell communication: PS is the key to a unique mechanism for cell-to-cell communication that involves release of part of the PS headgroup as a "lyso-PS" (see Toffano, 1987).
• Cell-to-cell recognition: PS helps anchor and stabilize antigens and receptors linked to the cell membrane. Enzymes (amino-PL translocases) can "flip" PS from the inner half of the bilayer to the outer half. PS accumulating in this location apparently signals that this particular cell has become "old" and should be "recycled" (Schlegel et al, 1996). Immune cells then recognize this signal and eliminate the worn-out cell. Such "flip-flopping" of PS may also be important for nerve cell receptor function. In animal experiments, age-related receptor abnormalities were partially normalized by dietary PS (see Cohen and Mueller, 1992).
• Cell growth regulation: Growth factors are small molecules, usually proteins, that pass between cells and regulate cell proliferation and renewal. The growth factors usually operate by turning on or off specific cell membrane receptors. Nerve growth factor (NGF) is one of the most important growth factors for nerve tissue. In animal studies PS partially blocked NGF receptor decline related to aging, and in "test tube" experiments PS stimulated NGF synthesis and release from cultured PC12 nerve cells (see Nunzi, 1990).

In vitro ("test tube") experiments indicated that PS could confer protection on nerve cells from toxic attack (Latorraca et al, 1993). The authors suggested PS had antioxidant effects, but their data also seem consistent with enhanced cellular detoxification capacity linked to improvements in membrane-based cell functions.

Numerous experimental studies have been conducted with PS in animals, as reviewed in Toffano (1987). The results with PS in animals overwhelmingly support the clinical conclusions drawn from the human studies. In the rat brain, PS stimulated acetylcholine output from the cerebral cortex; stimulated dopamine synthesis by strongly activating tyrosine hydroxylase, and induced dopamine release from dopaminergic neurons; and, in aged rats, reset lagging circadian and estrus rhythms and reversed fading EEG signals that correlated with fading memory function (see Aporti et al, 1986). Structurally, PS protected the hippocampus (a major memory center) from the loss of dendrite connections that normally occurs with aging (see Nunzi et al, 1987). This constellation of benefits from PS to animal brains at the biochemical level correlated with improvements in spatial memory and passive avoidance seen in aged rats, as well as their capacities to cope with stress (reviewed in Pepeu et al, 1996).

Nunzi and co-workers (1992) found that in the rat hippocampus, a fall-off in nerve growth factor receptor density occurs with aging. PS reversed this receptor density decline and seemed to enhance NGF production.

The above described array of anti-aging effects demonstrated with PS on animal models of brain decline are unique to the PS molecule - other phospholipids did not effectively substitute for PS in such experiments, nor did the amino acid serine (reviewed in Toffano, 1987).

Phosphatidylserine, vesicle secretion, and cell-to-cell communication. Left: in the healthy cell, PS is confined to the inner leaflet of the cell membrane (upper); exposed at the outer face of a secretory vesicle (middle), PS can promote membrane-membrane fusion and release of the vesicle (bottom). Right: the lyso head of PS can be released from the cell (top) and act as a primary messenger to nearby cells (bottom). From Toffano (1987).

The Safety and Bioavailability of Phosphatidylserine

A relatively large number of clinical trials have been conducted with PS (minimum of 34 published, of which 17 were conducted double blind). PS has emerged from this extensive clinical examination with an excellent safety record.

Cenacchi and collaborators (1987) reviewed laboratory findings from 130 subjects given 300mg of PS daily for up to 60 days during clinical trials. They found lowering of uric acid levels and (liver) SGPT, which, though statistically significant, were clinically negligible. Side effects from the clinical trials also were negligible; Cenacchi et al, (1993) reported from their large six-month trial with 425 subjects that "adverse events were very few, and clinically unimportant. These observations are remarkable in the light of the large number of subjects enrolled in this study, who represent a sample of the geriatric population commonly encountered in clinical practice" (p. 131). For the course of the trial, these elderly subjects were allowed to stay on the wide range of pharmaceutical medications common to their population and no adverse interactions with PS became evident.

No danger is evident from long-term intake of PS. Preclinical toxicological studies on rats and dogs indicated PS was safe when taken by the oral route (see Heywood et al, 1987). Dogs survived 70 grams per day of PS for one year without apparent damage at the histological level. No reproductive studies appear to be available.

Phosphatidylserine has good bioavailability by the oral route. Following oral dosing to rats, radioactively labeled PS appears in the blood at about 30 minutes. After a few more minutes uptake begins into the liver and, later, the brain. In the brain PS can be enzymatically converted to PE (phosphatidylethanolamine) and seemingly serves as a backup reservoir for this other important cell membrane phospholipid. PE in its turn can be enzymatically converted to PC (phosphatidylcholine). PS gets into the mitochondria, which are the cells' energy producing compartments. There PS serves as a ready source of PE, which is known to be centrally involved in the inner membranes that regulate the production of chemical and electrical energy.

One possible basis for the versatile biological actions of PS administered orally, is that the fatty acid at Tail 2 is subject to being shuffled, either (a) during the course of absorption, (b) while the molecule is in an intestinal cell, (c) after its delivery to an organ. The tails of PS are shuffled to suit the needs of the cell as they change over time, or as the PS "parent molecule" is transported from tissue to tissue, cell to cell, or perhaps even from spot to spot within a membrane. Enzymes (hydrolases, acyltransferases) that remove or replace Tail 2 are present in the digestive juices, in the intestinal lining cells, and in the membranes of all the other cells of the body. The acyltransferases are used to remove fatty acids from PS (or other phospholipids), and replace them with other fatty acids, depending on the functional needs of the cell.

The odds are infinitely small that the fatty acid of Tail 2 on a PS molecule is going to stay in position all the way from oral administration until the parent molecule reaches a nerve cell. Removal of Tail 2 may facilitate passage across the blood-brain barrier, and the evidence indicates that the nerve cell membranes re-mold the tails of the PS parent molecules to suit their functional needs.

Conclusion: PS Can Boost Multiple Brain Functions

After a quarter century of research with PS on human subjects, laboratory animals, cells in culture and molecules in the test tube, it is clear that this nutrient has profound value to the human brain. PS has been intensively studied for cognitive decline. Substantial amounts of mechanistic, experimental and clinical data are available on PS, and the findings overwhelmingly indicate PS is highly effective and is safe to take. The fact that PS is an orthomolecule, i.e., intrinsic to all the body's cells, is predictive of its safety for both short-term and long-term use. A reasonable supplementation strategy with PS is to begin at 300 mg per day with meals for a month, then go into a maintenance mode at a lower level of intake (100 to 200 mg daily). There is no indication of potential problems from long-term supplementation with PS.

As a general rule, because PS is so safe the more severe the subject's problems the more aggressive can be the supplementation strategy. Patients with severe memory problems can be kept on all their other supplements and medications, and be given PS with their meals at 300 to 500 mg per day on an ongoing basis. Subjects afflicted with motor problems may respond better at 500 mg per day. Mood problems may require a starting dose of 400 mg per day. For age-related cognitive decline (ARCD), a daily intake of 300 mg may be appropriate.

PS is far more abundant in the brain than in the other organs, and to date has the most clinical significance as a brain nutrient. Nerve cell homeostasis, renewal, and specialized functions all involve membrane-based processes that rely on phosphatidylserine. Dietary supplementation with PS can benefit brain functions from the most basic to the most sophisticated. PS can slow the loss of brain functions, and in some cases partially rejuvenate them (Crook et al, 1991).

One effect that PS manifests as an orthomolecule, is that it works to keep the brain's processes within normal limits, raising them when they are low and lowering them when they are high. Thus PS boosts the weak stress response in the elderly person, and calms down exaggerated stress response in the healthy young person. PS may also benefit children as evidenced by findings from a pilot study on ADD (Attention Deficit Disorder).

The fight-or-flight response is a basic, universal response to stress of any kind, and occurs in response to physical as well as mental stress. Stressful conditions typically cause cortisol, ACTH (adreno-cortico-trophic-hormone) and other stress hormones to be released into the circulation, even in the young and healthy. Thus young men who vigorously ride stationary bicycles in the laboratory show a surge of ACTH and cortisol release as a result of their strenuous exercise. PS given to these athletes prior to starting exercise produced an impressive degree of down-regulation of the stress hormones. PS may have the capacity to "normalize" the stress-induced activation of the hypothalamic-pituitary-adrenal axis, and so improve athletic training capacity (Monteleone et al, 1992).

To date, in excess of 64 human studies have been completed with PS, 17 of these being double blind. The clinical findings consistently indicate that supplementation with PS can benefit memory, learning, concentration, semantic skills, and control over mood. Dr. Thomas Crook and the Memory Assessment Clinics developed tests for cognitive function that are currently the state of the art; their findings indicate ARCD-Age-Related Cognitive Decline-is well underway in otherwise-healthy persons by the fifth decade of life. Crook et al's 1991 double-blind trial established that PS could turn back the clock on brain aging: on name-face recall PS reversed more than 12 years' worth of cognitive decline. This solid clinical finding suggests that if supplementation with PS can be started during the fifth decade, the chances for ameliorating further progressive loss of the brain's higher functions will be markedly improved.

While PS appears to be the best single means currently available for conserving the intellect, its membrane-based action mechanisms make it compatible with other nutrient classes like the antioxidants, the B vitamins, and the minerals. PS also has proven compatibility with many of the pharmaceuticals that are in common use by the elderly (Cenacchi et al, 1993); as an orthomolecule it is unlikely to interfere with the actions of the few pharmaceuticals available for cognitive decline, and as a pro-homeostatic nutrient it should actually complement their actions.

As a safe and effective dietary supplement, particularly when employed in conjunction with exercise and lifestyle revision PS has proven potential to improve the quality of life for the young, the middle aged, and the elderly. With benefits so diverse they are unmatched or exceeded by any other known intervention, PS is indispensable for conserving (and sometimes for restoring) memory, learning, concentration, and other higher mental capacities threatened by the wear and tear of modern life.

Click here for product availability

Bibliography

Allegro L, Favaretto V, Ziliotto G, 1987. "Oral phosphatidylserine in elderly subjects with cognitive deterioration-an open study." Clin. Trials J. 24: 104-108.

Amaducci L, the SMID Group, 1988. "Phosphatidylserine in the dosing of Alzheimer's disease: results of a multicenter study." Psychopharmacol. Bull. 24: 130-134.

Aporti F, et al, 1986. "Age-dependent spontaneous EEG bursts in rats: effects of brain phosphatidylserine." Neurobiology of Aging 7: 115-120.

Argentiero V, Tavolato B, 1980. "Dopamine (DA) and serotonin metabolic levels in the cerebrospinal fluid (CSF) in Alzheimer's presenile dementia under basic conditions and after stimulation with cerebral cortex phospholipids (BC-PL)." Journal of Neurology (Zeitschrift fur Neurologie) 224: 53-58.

Bruni A, Toffano G, 1982. "Lysophosphatidylserine, a short-lived intermediate with plasma membrane regulatory properties." Pharmacological Res. Comms. 14: 469-484.

Caffarra P, Santamaria V, 1987. "The effects of phosphatidylserine in subjects with mild cognitive decline. An open trial." Clin. Trials J. 24: 109-114.

Cenacchi B, Baggio C, Palin E, 1987. "Human tolerability of oral phosphatidylserine assessed through laboratory examinations." Clin. Trials J. 24: 125-130.

Cenacchi B, et al, 1993. "Cognitive decline in the elderly: A double blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration." Aging Clin. Exp. Res. 5: 123-133.

Cocito L, et al, 1994. "GABA and phosphatidylserine in human photosensitivity: a pilot study." Epilepsy Research 17: 49-53.

Cohen SA, Mueller WE, 1992. "Age-related alterations of NMDA-receptor properties in the mouse forebrain: partial restoration by chronic phosphatidylserine dosing." Brain Research 584: 174-180.

Crook TH, et al, 1991. "Effects of phosphatidylserine in age-associated memory impairment." Neurol. 41: 644-649.

Crook TH, et al, 1992. "Effects of phosphatidylserine in Alzheimer's disease." Psychopharmacol. Bull. 28: 61-66.

Delwaide PJ, et al, 1986. "Double-blind randomized controlled study of phosphatidylserine in demented subjects." Acta Neurol. Scand. 73: 136-140.

Delwaide PJ, et al, 1989. "Effects of phosphatidylserine (BC-PS) on aged brain in normal subjects and senile demented patients." In, Phospholipids in the Nervous System: Biochemical and Molecular Pathology, ed. Bazan NG, Horrocks LA, Toffano G. Liviana Press, Padova, Italy.

Engel RR, et al, 1992. "Double-blind cross-over study of phosphatidylserine vs. placebo in subjects with early cognitive deterioration of the Alzheimer type." Eur. Neuropsychopharmacol. 2: 149-55.

Folstein MF, et al, 1975."Minimentalstate." J.PsychiatricRes. 12: 189-198.

Funfgeld EW, et al, 1989. "Double-blind study with phosphatidylserine (PS) in Parkinsonian patients with senile dementia of Alzheimer's type (SDAT)." Progr. Clin. Biol. Res. 317: 1235-1246.

Funfgeld EW, Nedwidek P, 1987. "Neurohomologous phosphatidylserine in Parkinsonian subjects with associated disorders of cerebral metabolism." Clin. Trials J. 24: 42-61.

Gindin J, et al, 1995. "The effect of plant phosphatidylserine on age-associated memory impairment and mood in the functioning elderly." Geriatric Institute for Education and Research, and Department of Geriatrics, Kaplan Hospital, Rehovot, Israel.

Granata Q, DiMichele J, 1987. "Phosphatidylserine in elderly patients. An open trial." Clin. Trials J. 24: 99-103.

Heiss WD, et al, 1993. "Activation PET as an instrument to determine therapeutic efficacy in Alzheimer's Disease." Annals N.Y. Acad. Sci. 695: 327-31.

Heiss WD, et al, 1994. "Long-term effects of phosphatidylserine, pyritinol, and cognitive training in Alzheimer's Disease." Cognitive Deterioration 5: 88-98.

Hershkowitz M, Diver A, Rabinowitz M, 1989. "Long-term treatment of dementia Alzheimer type with phosphatidylserine: effect on receptors and microviscosity of lymphocyte and thrombocyte membrane." In, Phospholipids in the Nervous System: Biochemical and Molecular Pathology, ed. Bazan NG, Horrocks LA, Toffano G. Liviana Press, Padova, Italy.

Hershkowitz M, et al, 1989. "Long-term treatment of dementia Alzheimer type with phosphatidylserine: effect on cognitive functioning and performance in daily life." In, Phospholipids in the Nervous System: Biochemical and Molecular Pathology, ed. Bazan NG, Horrocks LA, Toffano G. Liviana Press, Padova, Italy.

Heywood R, Cozens DD, Richold M, 1987. "Toxicology of a phosphatidylserine preparation from bovine brain (BC-PS)." Clin. Trials J. 24: 25-32.

Klinkhammer P, Szelies B, Heiss WD, 1990. "Effect of phosphatidylserine on cerebral glucose metabolism in Alzheimer's Disease." Dementia 1: 197-201.

Latorraca S, et al, 1993. "Effect of phosphatidylserine on free radical susceptibility in human diploid fibroblasts." J. Neural Transmission [P-D Sect] 6: 73-77.

Loeb C, et al, 1987. "Preliminary evaluation of the effect of GABA and phosphatidylserine in epileptic patients." Epilepsy Res. 1: 209-212.

Loeb C, 1989. "Antiepileptic activity of GABA and phosphatidylserine.." In Phospholipids in the Nervous System: Biochemical and Molecular Pathology, ed. Bazan NG, Horrocks LA, Toffano G. Liviana Press, Padova, Italy.

Lombardi GF, 1989. "Terapia farmacologica con fosfatidil serina in 40 pazienti ambulatoriali con sindrome demenziale senile." Minerva Medica 80: 599-602. [Translated from the Italian]

Maggioni M, et al, 1990. "Effects of phosphatidylserine therapy in geriatric subjects with depressive disorders." Acta Psychiatr. Scand. 81: 265-270.

Manfredi M, et al, 1987. "Risultati clinici della fosfatidil-serina in 40 donne affete da turbe psico-organiche, in eta climaterica e senile." La Clinica Terapeutica 120: 33-36. [Translated from the Italian]

Masturzo P, et al, l990. "TSH circadian secretions in aged men and effect of phosphatidylserine dosing." Chronobiologia 17: 267-274.

Monteleone P, et al, 1990. "Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans." Neuroendocrinol. 52: 243-248.

Monteleone P, et al, 1992. "Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men." Eur. J. Clin. Pharmacol. 41: 385-388.

Nerozzi D, et al, 1987. "Fosfatidilserina e disturbi della memoria nell'anziano." La Clinica Terapeutica 120: 399-404. [Translated from the Italian]

Nishizuka Y, 1984. "Turnover of inositol phospholipids and signal transduction." Science 225. 1365- 137Q.

Nizzo MC, et al, 1978. "Brain cortex phospholipids liposomes-effects on CSF HVA, 5HIAA and on prolactin and somatotropin secretion in man." J. Neural Transmission 43: 93-102.

Nunzi MG, et al, 1987. "Dendritic spine loss in hippocampus of aged rats. Effect of brain ~ phosphatidylserine administration." Neurobiology of Aging 8: 501-510.

Nunzi MG, et al, 1990. "Therapeutic properties of phosphatidylserine in the aging brain." In, Phospholipids: Biochemical, Pharmaceutical, and Analytical Considerations, ed. Hanin I and Pepeu G. New York: Plenum Press.

Palmieri G, et al, 1987. "Double-blind controlled trial of phosphatidylserine in subjects with senile mental deterioration." Clin. Trials J. 24: 73-83.

Papahadjopoulos D, 1978. "Calcium-induced phase changes and fusion in natural and model membranes." In, Membrane Fusion, ed. Poste G and Nicholson GL. Amsterdam: Elsevier/North-Holland.

Pepeu G, Pepeu IM, Amaducci L, 1996. "A review of phosphatidylserine pharmacological and clinical effects. Is phosphatidylserine a drug for the aging brain?" Pharmacol Res 33(2),73-80.

Plutchik R, et al, 1970. "Reliability and validity of a scale for assessing the functioning of geriatric subjects." J. Am. Geriatric Society 18: 491-500.

Puca FM, et al, 1987. "Exploratory trial of phosphatidylserine efficacy in mildly demented subjects." Clin. Trials J. 24: 94-98.

Rabboni M, et al, 1990. "Neuroendocrine and behavioral effects of phosphatidylserine in elderly patients with abiotrophic or vascular dementia or mild depression. A preliminary trial." Clin Trials J. 27, 230-40.

Ransmayr G, et al, 1987. "Double-blind placebo-controlled trial of phosphatidylserine in elderly subjects with arteriosclerotic encephalopathy." Clin. Trials J. 24: 62-72.

Rosadini G, et al, 1991. "Phosphatidylserine: quantitative EEG effects in healthy volunteers." Neuropsychobiology 24: 42-48.

Schlegel RA, et al, 1996. "Mechanisms for recognition and phagocytosis of apoptotic lymphocytes by macrophages." In, Mechanisms of Lymphocyte Activation and Immune Regulation Vl, ed. Gupta and Cohen. Plenum Press New York.

Sengupta N, Datta SC, Sengupta D, 1981. "Platelet and erythrocyte membrane lipid and phospholipid patterns in different types of mental patients." Biochemical Med 25, 267-75.

Sinforiani E, et al, 1987. "Cognitive decline in aging brain: therapeutic approach with phosphatidylserine."Clin.TrialsJ.24: 115-124.

Toffano G, et al, 1978. "Modification of noradrenergic hypothalamic system in rat injected with phosphatidylserine liposomes." Life Sciences 23: 1093.

Toffano G, 1987. "The therapeutic value of phosphatidylserine effect in the aging brain." In, ~ Lecithin: Technological, Biological, and Therapeutic Aspects, ed. Hanin I and Ansell GB, ft pp. 137-146. New York: Plenum Press.

Toffano G, et al, 1987. "Pharmacokinetics of radiolabelled brain phosphatidylserine." Clin. Trials J. 24: 18-24.

Villardita C, et al, 1987. "Multicentre clinical trial of brain phosphatidylserine in elderly; subjects with mental deterioration." Clin. Trials J. 24: 84-93.

Zannoti A, et al, 1987. "Pharmacological properties of phosphatidylserine: effects on memory function." In, Nutrients and Brain Function, ed. Essman WB, pp. 95-102. New York: Karger.

Zauli C, et al, 1984. "Evidence for a dopaminergic inhibitory effect of orally-administered; phosphatidylserine on prolactin secretion in humans." Neuroendocrinol Lett 6, 37-47.

Click here for product availability