Alternative Medicine Review Volume 13, Number 3 2008

PhosphatidylserineIntroduction

Phosphatidyiserine (PS), a ubiquitous, endogenously oc-curring phospholipid, is the major acidic phospholipid in the brain.PS and other phosphoüpids make up the basic structural compo-nents of the cell membrane. These membrane phospholipids playan important role in cell-to-cell communication and transfer ofbiochemical messages into the cell, which trigger cellular responses."The proper functioning of these processes is of ultimate impor-tance, especially in the central nervous system. It is theorized thatPS enhances cellular metabolism and communication by influenc-ing the Huidity of cell membranes.'"* Oral supplementation of PShas been shown to affect neuronal membranes, cell metabolism, andspecific neurotransmitter systems, including acetylcholine, norepi-nephrine, serotonin, and dopamine.'"* Numerous clinical trials haveestablished that PS exerts significant benefit for cognition, especial-ly those functions that tend to decline with age, including memory,learning, vocabulary skills, and concentration.^

BiochemistryPS is formed in the body from the amino acid L-serine, glycerophosphate, and two fatty acids. Some PS is

converted to phosphatidylethanolamine, which is in turn converted to phosphatidylcholine. Pbosphatidylethanolaminecan also be eniymatically converted to phosphatidylserine; however, these conversions are energy costly.^

PharmacokineticsPharmacokinetic studies indicate exogenous PS crosses the blood-brain barrier, where it appears to have an

affinity for the hypothalamus. Oral administration results in peak levels in 1-4 hours.

Mechanisms of ActionAnimal experiments suggest PS has a trophic (growth supportive) effect on the brain. Compared to younger

rats, older rats normally have fewer and smaller brain neurons and decreased cell surface-receptor density for nervegrowth factor (NGF). These receptors mediate the actions of NGF to enhance neuronal differentiation and otheraspects of neuroplasticity. As rats age, they show declines in NGF-receptor density in the cerebellum, hippocampus,and other brain zones. When dosed with PS, older rats retain more and larger brain neurons along with higher NGF-receptor density. In addition, when older rats are subjected to maze tests, a subpopulation that normally tests signifi-cantly more impaired than the average shows the most improvement in cognition and NGF-receptor density whendosed with PS.''

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PS dosing in aged rats increases dopamine re-lease from the striatum and stimulates acetylcholine re-lease from the cerebral cortex, in addition to preventingage-induced loss of dendritic spines in the hippocampalpyramidal neurons and atrophy oí cholinergic cells inthe basal forebrain.''

Human studies using PET scanning to investi-gate brain glucose utilization in Alzheimer's patients not-ed increases in glucose utilization in PS-supplementedpatients, especially in the temporo-parietal areas, whichare specifically affected by Alzheimer's disease (AD).^ "

PS may also protect cells from damage pro-duced by free radicals. A significant decrease in damageto cultured buman fibroblasts from the enzymatic oxi-dation of acetaldehyde by xanthine oxidase was noted incultures pre-treated with PS.'^

Clinical ApplicationsAge-Associated Memory Impairment/Cognitive Decline

Studies of phosphatidylserine dosing in age-associated memory impairment indicate PS is an effec-tive remedy for this common malady. The largest of thesestudies, a multi-center, placebo-controlled study of 494elderly patients, resulted in significant improvements inbehavioral alterations (loss of motivation, initiative, in-terest in the environment, and socialization), memory,and learning in the PS group (300 mg/day) comparedto placebo.' At least a dozen other studies, most using300 mg/day, note similar significant improvements inlearning, memory, concentration, and recall.^

Alzheimer's DiseasePhosphatidylserine has received attention for

treatment of AD. Generally, PS produces significantImprovement in anxiety, motivation, memory, and cog-nition.'''^ '"* At daily doses of 200-300 mg for up to sixmonths, PS consistently improved clinical global im-pression and activities of daily living. In a double-blind,placebo-controlled trial involving 425 patients withmoderate-to-severe cognitive loss, PS significantly im-proved memory, learning, motivation, socialization, andgeneral "adaptability to the environment."' In anotherplacebo-controlled study of 142 AD patients, PS wasgiven (200 mg/day) for three months, and the patientswere followed for 24 months. A subgroup of patientswith severe cognitive impairment demonstrated

significant improvements based on the Blessed Demen-tia Scale (activities of daily living, information process-ing, personal and non-personal memory) three monthsafter treatment cessation.''' In other studies, most using300-400 mg/day, improvement tended to be the great-est in those with less severe cognitive impairment,"*'^""'''and in one study were transient, fading after 16 weeks.**

Attention Deficit/Hyperactivity DisorderUse of PS in combination with omega-3 fatty

acids shows promise in the management of attentiondeficit/hyperactivity disorder (ADHD). Vaisman etal conducted a double-blind trial with omega-3 PS, re-cruiting 60 children (3:1 ratio of boys:girls) with AD-HD-like symptoms (average age 9 years)."" The childrenwere randomized to three groups: (1) canola oil (con-trols), (2) fish oil (providing 250 mg DHA/EPA daily),and (3) an omega-3/PS combination (providing 300mg PS and 250 mg DHA/EPA daily). No stimulantmedications or other dietary supplements were admin-istered during the trial period (80-100 days; average 91days). Tiie group receiving omega-3 PS had the highestproportion of children whose symptoms improved.

The children's sustained visual attention anddiscrimination were assessed using the Test of Variablesof Attention (TOVA). The TOVA ADHD Index nor-malized score improved over controls for both the ome-ga-3 PS and the fish oil groups, but significantly morein the PS group (p<0.001).This indicates that omega-3PS improved attention performance (and more dramat-ically than fish oil) compared to the control group. Theomega-3 PS group also manifested a significantly higherratio of symptom clearance than the control group, with11/18 of the omega-3 PS children becoming asymp-tomatic versus 3/21 of the control children (p<0.05).Of the fish oil group, 7/21 became asymptomatic -not statistically significantly different from controls.Omega-3 PS ameliorated the Inattention symptoms ofADHD to a greater degree than equivalent amounts ofDHA/EPA from other dietary sources.

DepressionMaggioni et al studied the effects of oral PS

(300 mg/day) on depressed geriatric patients not ex-hibiting dementia and noted significant improvementin depressive symptoms after 30 days. Memory andbehavioral symptoms were also improved compared toplacebo.'^'«

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Chronic Stress/Hyper cortisoUsmit appears PS might modulate Cortisol release

in stressful situations. In a study of exercise-induced

stress, both ACTH and cortisol were lower after exer-

cise in healthy volunteers taking 800 mg/day PS versus

placebo. It was thought that PS affected hypothalamic

release of corticotropin-releasing factor, an activator of

the hypothalamic-pituitary-adrcnal axis in response to

stress.'"' Tliis may provide some insight into the eflect

of PS on depression, as hypercortisolism is a common

finding in depression.

Side Effects and ToxicityTlie oral LD̂ ^̂ in rats is >5 g/kg body weight,

and no teratogenicity was noted in rats and rabbits; mu-

tagenic testing was negative."" In a tolerability and tox-

icity study of 130 patients, no significant changes were

noted in CBC or serum chemistry results, except for a

significant decrease in the liver enzyme alanine amino-

transferase (ALT) and uric acid levels.^'

DosageTherapeutic dosages range from 200-800 mg

daily, depending on condition. For example, the recom-

mended dosage ior AD ranges from 200-400 mg daily,

300 mg daily for ADHD and depression, and 800 mg dai-

ly for chronic stress. An optimal daily intake for healthy

individuals has not been established. Oral administration

of PS is the preferred route of administration.

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2. Amaducci L, Crook T H , Lippi A, er al. Use otphosphatidylserine in Alzheimer's Disease. Ann N Y

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14. Maggioni M, Picotti GB, Bondiolotti GP, et al. Effectsof phosphatidylserine therapy ¡n geriatric patientswich depressive disorders. Acta Psycbiatr Scand1990:81:265-270.

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16. Vaisman N, Kaysar N, Zaruk-Adashii Y, et al.Correlation between changes in blood faccy acidcomposition and visual sustained accenckin performancein children wich inaccention: effect of diecary n-3fatty acids containing phospholipids. Ämj Clin Nutr2008;87:1170-1180.

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