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 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 affecting the gerbil hippocampus, indicating that we can expect the effects
seen with BC-PS to be retained with S-PS [1-2].
Memory Support
Phosphatidylserine supports memory. 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 mitigates memory impairment from a variety
of amnesic 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 affects 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%.[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, 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 correlated 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 affects NMDA receptor function in the
forebrain of aged mice, and the blockade of prolonged step-through 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, suppresses 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 and Stress
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 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. 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]. Phosphatidylserine also has a potent anti-stress effect in animal
models.
Chronically elevated levels of cortisol may also lead to excessive storage
of bodyfat (in contrast to an acute cortisol rise, which is lipolytic).
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 bodyfat
accumulation from excessive cortisol levels, phosphadylserine could be
effectively stacked with fish oil.
If you have any questions or comments regarding this article, please email
dvdtlsn@bulknutrition.com.
No part of this article may be reproduced in any form without the permission of David Tolson or Mike McCandless. 
