Introduction

Phosphatidylserine is the major phospholipid of brain synaptic membranes. It has been studied extensively and is considered to be an important brain cell nutrient. It plays a crucial role in several membrane-linked activites such as enzyme activation, liposome function, ion permeability, maintenance of the cell's internal environment, secretory vesicle release, cell-to-cell communication, and cell growth regulation. As a supplement, phosphatidylserine is most well known as a cognitive enhancement agent, but also may offer significant protection against the hormonal effects of acute and chronic stress.

It should be noted that most of the studies carried out on phosphatidylserine used bovine brain cortex-derived phosphaditylserine (BC-PS). However, this is not acceptable for supplemental use because of the risk of infectious encephalopathies (such as mad cow disease). Phosphatidylserine supplements use soybean-derived phosphatidylserine (S-PS), which is made by enzymatically preparing soybean lecithins and l-serine by a phosphlipase D reaction, and has a significantly different fatty acid composition than BC-PS. Despite this, experiments indicate that S-PS and BC-PS are functionally similar – as with BC-PS, S-PS restores scopolamine-induced memory impairments by oral, IP, and intracerebroventricular administration, as well as preventing ischemic damage in the gerbil hippocampus, indicating that we can expect the effects seen with BC-PS to be retained with S-PS [1-2].

Memory improvement

Phosphatidylserine improves memory in several models of age-associated memory impairment. Among these is the Morris water maze, a test of spatial memory in which few substances prove effective as cognitive enhancers. Orally administered S-PS improves performance in both the escape test and spatial probe test in aged rats, which indicates an improvement in both reference memory and working memory [1]. Additionally, phosphatidylserine facilitates acquisition of active avoidance in shuttle-box and pole jumping tests in aged rats [2]. Phosphatidylserine also prevents or mitigates memory impairment from a variety of amnestic agents, such as scopolamine, reserpine (an animal model of Parkinsonism), and cycloheximide [2-3].

Cognitive improvement has not been demonstrated with short-term supplementation in young or adult animals, although phosphatidylserine does modify some brain electrophysiological and biochemical parameters in young animals [4]. Animals treated with BC-PS during the postnatal development period display higher choice accuracy and more adaptive maze-running strategies in the 8 arm radial maze [5], and improved performance in a passive avoidance task as adults [2].

Phosphatidylserine also prevents many age-related physical changes in the nervous systems of experimental animals. In aged rats, spine density is decreased by approximately 10-12%, and in the cholinergic neuronal population in some areas of the brain, cell number is reduced by approximately 20%, soma area by 19%, cell maximal diameter by 9%, and total area covered by cholinergic profiles by 33%. Phosphatidylserine administration prevents all of these changes [10].

In humans, cognitive enhancement from phosphatidylserine was first reported in 1986. Since then, over 10 double-blind, placebo-controlled trials have found BC-PS to improve memory in humans showing many levels of age-related memory impairment (from mild cognitive impairment to Parkinson's patiens with Alzheimer's), including a study with 494 elderly patients in Italy which showed improved cognitive performance with no side effects [1, 6]. No studies have been conducted in healthy adult humans, although EEG changes have been found [7].

Mechanism of action

Phosphatidylserine modifies glucose metabolism in the brain, catecholamine and acetylcholine release, NMDA receptor density and function, and muscarinic acetylcholine receptor density, and all of these effects are corelated to the behavioral changes following acute administration [2].

The primary mechanism of action appears to be an enhancement of cholinergic transmission. Phosphatidylserine administration to old rats restores acetylcholine release to the level of young rats, as well as increasing acetylcholine receptor density. A cholingergic mechanism is also indicated by the reversal of scopolamine-induced amnesia. Phosphatidylserine increases cholinergic function in multiple ways. First, it enhances the activity of Na+,K+-ATPase, which helps maintain membrane potential. Secondly, it increases Ca2+ uptake into K+-depolarized corticol synaptosomes, and this is an important event in neurotransmitter release. Finally, phosphatidylserine affects exocytosis of neurotransmitters by interacting with membrane-binding proteins [1].

In addition to cholinergic mechanisms, phosphatidylserine may improve memory by increasing the turnover of dopamine and/or norepinephrine (NE) in the brain. In vivo, phosphatidylserine increases turnover of NE in the hypothalamus and dopamine in the striatum. It also increases dopamine release in the limbic area and cerebral cortex of aged animals to normal levels [2]. Chronic phosphatidylserine also prevents the age-associated deficits in NMDA receptor function in the forebrain of aged mice, and the blockade of prolonged step-trhough latency caused by cycloheximide suggests serotonergic mechanisms [2-3].

All of this indicates that in addition to specific mechanisms, phosphatidylserine may improve brain function through more non-specific mechanisms. It has been shown that exogenous phospholipids can provide an extra supply for endogenous phospholipid turnover in membranes. Phosphatidylserine mediates a variety of processes related to synaptic plasticity, information storage, and glutamatergic transmission [8]. It also acts as an antioxidant, supresses cytotoxic factors such as TNF-alpha and nitric oxide, interacts with nerve growth factor (NGF), and increases brain glucose concentration [1, 9-10], so the effect on memory could be due to any combination of these factors.

Cortisol, stress, and depression

In addition to the effect on memory, phosphatidylserine reduces circulating levels of the stress hormone cortisol. In one study, healthy men were given 800 mg phosphatidylserine for 10 days and the release of cortisol and ACTH in response to physical exercise was blunted, suggesting that phosphatidylserine counteracted the stress-induced activation of the hypothalamo-pituitary-adrenal axis [11]. In another study, IV administration of BC-PS was compared with placebo, and it blunted the ACTH and cortisol response to bicycle ergometer exercise [12]. Finally, a double-blind cross-over study on 11 male subjects undergoing intensive weight training for two weeks found that 800 mg of S-PS decreased post-exercise cortisol levels and reduced the muscle soreness and psychological depression associated with overtraining [13]. This indirectly indicates that phosphatidylserine administration could improve athletic performance by reducing the detrimental effects associated with overtraining.

Related to the effect on cortisol is the effect phosphatidylserine has on stress and depression. One study was done in young adults with neuroticism scores above the median, in which 300 mg of phosphatidylserine was administered for one month and associated with less feelings of stress and an overall better mood [14]. A study in elderly women with major depressive disorders found only 200 mg daily of phosphatidylserine to cause a significant improvement in depressive symptamology [15]. Phosphatidylserine also has a potent anti-stress effect in animal models – in rats, it prevented restraint-induced hyperthermia and decreased incidence of gastric ulcers from restraint-plus-cold treatment [16].

Chronically elevated levels of cortisol may also lead to excessive storage of bodyfat (in contrast to an acute cortisol rise, which is lipolytic). For more discussion of this, I recommend Modern Living, the Beer Belly and Syndrome X by Par Deus.

Dosage and toxicity

Phosphatidylserine administration has proven safe in clinical trials, with no effect on biochemical and hematological safety parameters, blood pressure, or heart rate and no adverse events with 600 mg daily [17]. For memory improvement, 100-600 mg daily is effective, while 300-800 mg daily dose-dependently results in significant cortisol reduction and mood improvement. Because of the price, I would recommend 100-200 mg daily and then a higher dose during periods of exceptionally high stress or overtraining. To reduce or prevent bodyfat accumulation from excessive cortisol levels, phosphadylserine could be effectively stacked with fish oil and Ab-Solved.


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