Effects of Soy Lecithin Phosphatidic Acid and Phosphatidylserine Complex (PAS) on the Endocrine and Psychological Responses to Mental Stress

Abstract

Phosphatidylserine, derived from cow brains, has been shown previously to dampen the ACTH and cortisol response to physical stress. Further research investigated the influence of soy lecithin phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. In this study, we investigated the effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) supplementation on pituitary adrenal reactivity (ACTH, cortisol) and on the psychological response (Spielberger State Anxiety Inventory stress subscale) to a mental and emotional stressor. Four groups of 20 subjects were treated for three weeks with daily dosages of either 400 mg PAS, 600 mg PAS, 800 mg PAS, or placebo before exposure to the Trier Social Stress Test (TSST). Treatment with 400 mg PAS resulted in a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol responses to the TSST, but did not affect heart rate. The effect was not seen with larger doses of PAS. With regard to the psychological response, 400 mg PAS seemed to exert a specific positive effect on emotional responses to the TSST. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg PAS showed decreased distress. These data provide initial evidence for a selective stress dampening effect of PAS on the pituitary-adrenal axis, suggesting the potential of PAS in the treatment of stress related disorders.

Full text

Effects of Soy Lecithin Phosphatidic Acid
and Phosphatidylserine Complex (PAS) on the Endocrine
and Psychological Responses to Mental Stress
J. HELLHAMMER
a,b,
*, E. FRIES
b
, C. BUSS
b
, V. ENGERT
b
, A. TUCH
b
, D. RUTENBERG
c
and D. HELLHAMMER
b
a
Neuropattern, Trier, Germany;
b
Department for Psychobiology, University of Trier, Germany;
c
Lipogen Ltd., Haifa, Israel
(Received 7 February 2004; Revised 17 May 2004; In final form 28 May 2004)
Phosphatidylserine, derived from cow brains, has been shown previously to dampen the ACTH and
cortisol response to physical stress. Further research investigated the influence of soy lecithin
phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. In this
study, we investigated the effects of soy lecithin phosphatidic acid and phosphatidylserine complex
(PAS) supplementation on pituitary adrenal reactivity (ACTH, cortisol) and on the psychological
response (Spielberger State Anxiety Inventory stress subscale) to a mental and emotional stressor. Four
groups of 20 subjects were treated for three weeks with daily dosages of either 400 mg PAS, 600 mg
PAS, 800 mg PAS, or placebo before exposure to the Trier Social Stress Test (TSST). Treatment with
400 mg PAS resulted in a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol
responses to the TSST, but did not affect heart rate. The effect was not seen with larger doses of PAS.
With regard to the psychological response, 400 mg PAS seemed to exert a specific positive effect on
emotional responses to the TSST. While the placebo group showed the expected increase in distress
after the test, the group treated with 400 mg PAS showed decreased distress. These data provide initial
evidence for a selective stress dampening effect of PAS on the pituitary– adrenal axis, suggesting the
potential of PAS in the treatment of stress related disorders.
Keywords: ACTH; Cortisol; Phosphatidic acid; Phosphatidylserine; STAI; Stress
INTRODUCTION
In this study we investigated a possible stress dampening
effect of soy lecithin phosphatidic acid and phosphatidyl-
serine complex (PAS) on endocrine, autonomic and
psychological measures evoked by the trier social stress
test (TSST).
Phospholipids have the very important biological
function of constituting the basis of all biological cell
membranes. Phosphatidylserine was first derived from
cow brains (Bovine Cortex Phosphatidylserine—BCPS).
Different studies showed that single intravenous treatment
(50 and 75 mg, respectively) as well as repeated oral intake
(800 mg per day for 10 days) of BCPS reduced ACTH- and
cortisol responses to physical stress (Monteleone et al.,
1990, 1992). Since 1992, soy lecithin phosphatidylserine,
the first 100% solvent free phosphatidylserine, has become
available, and this has excellent bioavailability by the oral
route (Shinitzky, 1999). In a first clinical trial, 72 subjects
aged 60–80 years, were randomly assigned to placebo and
therapy groups and treated for three months with 300 mg
phosphatidylserine and phosphatidic acid daily. The
results indicated a strong and significant positive effect
of treatment on memory and mood (Gindin et al., 1993,
1995). Benton et al. (2001) demonstrated a positive effect
of a one month treatment with 300 mg/day phosphatidyl-
serine on perceived stress during a stressful mental
arithmetic task. These data suggest a possible beneficial
effect on hypothalamus – pituitary –adrenal axis (HPA)
responsivity under psychological stress. Based on these
data, we were interested to explore effects of phosphati-
dylserine and phosphatic acid (PAS) on subjects under
mental stress conditions. As seen under physical stress, we
expected to see a blunted ACTH and cortisol response in
both men and women, associated with an attenuated heart
rate and psychological stress response. We further
expected a dose dependent effect of PAS, increasing
from 400 to 800 mg. To study PAS effects, we used
ISSN 1025-3890 print/ISSN 1607-8888 online q2004 Taylor & Francis Ltd
DOI: 10.1080/10253890410001728379
*Corresponding author. Address: Department for Psychobiology, University of Trier–FB I, Johanniterufer 15, D - 54290 Trier, Germany.
Tel.: þ49-651-2013464. Fax: þ49-651-2012934. E-mail: juliane.hellhammer@uni-trier.de
Stress, June 2004 Vol. 7 (2), pp. 119–126

the TSST, a stress protocol that has been developed in
this laboratory.
A recent meta-analysis of Dickerson and Kemeny (2004)
compared 208 laboratory studies of acute psychological
stressors. The analysis showed that the TSST (Kirschbaum
et al., 1993) is the best standardised and most efficient
psychological stress protocol for studies on HPA-reactivity
in humans. Concerning psychological parameters, the TSST
leads to a moderate increase in fear. The biological response
comprises an increase in circulating ACTH, cortisol,
prolactin, growth hormone, norepinephrine and epinephrine
concentrations, and increased heart rate and blood pressure
(e.g. Kirschbaum et al., 1993). Thus, we decided to use the
TSST protocol to assess stress dampening effects of PAS.
The study examined the effects of three dosages of PAS
versus placebo.
METHODS
This was a double-blind, single centre study. The study
duration was 4 weeks. Eighty panelists were invited to the
laboratory for pre-tests and for the experiment. They were
assigned to one of the four treatment groups (20 subjects
per group; 10 males and 10 females): per day, the first
group used placebo, the second group received
400 mg/day PAS, the third group 600 mg/day PAS and
the fourth group 800 mg/day PAS. Soy lecithin PAS
complex capsules as well as placebo capsules were
provided by Lipogen Ltd., Haifa, Israel.
PAS is a complex of phospholipids of which every
“100 mg” PAS capsule consists of 100 mg phosphadityl-
serine (PS) and 125 mg phosphatic-acid (PA), plus 270 mg
of other inert phospholipids (PC, PI, PE, Lyso Phospho-
lipids) and 5 mg silicon dioxide (anti-caking material). PAS
is patent protected (US 6,410,522 published in June 25,
2002). The placebo was maize starch and the capsules
looked identical to the PAS capsules.
SUBJECTS
Eighty subjects (adults age 20– 45) were recruited for the
study. All of the women were using oral contraceptives.
Groups were matched for sex and socioeconomic status.
As seen from Fig. 1, the mean age did not differ among the
four groups (Fð3;75Þ¼0:11; p¼0:95). Further, the four
treatment groups did not differ with respect to stress load and
depression (Gindin et al., 1993, 1995) as measured with the
Patient Health Questionnaire (PHQ; Spitzer et al.,1999;
Loewe et al.,2002)(Fð33;174Þ¼0:80; p¼0:77) when
entering the study.
Inclusion Criteria
Good medical health was verified by a clinical
examination, the patient health questionnaire and a
hemogram. The hemogram included assessments of
glutamate– pyruvate transaminase, gamma-glutamyl
transferase, creatinine, leukocytes, erythrocytes (haemo-
globin, haematocrit, mean corpuscular volume, mean
corpuscular haemoglobin, mean corpuscular haemoglobin
concentration), thrombocytes and leukocyte (lymphocyte,
basophil, eosinophil, monocyte and neutrophil counts).
Exclusion Criteria
The following exclusion criteria were applied: subjects
with a history of mental illness, subjects who used any
systemic medication considered to affect the endocrine or
behavioural measures, subjects who were pregnant or
nursing, subjects participating in any other clinical study,
subjects regarded by the investigator as not being able to
complete the study, subjects deemed to be physically
unhealthy.
Subjects were recruited by e-mail and newspaper
advertising. Pre-screening and introduction to the study
were conducted by telephone and an appointment for the
medical pre-examination was made. The medical pre-
examination and the hemogram allowed exclusion of
medically unhealthy subjects. Altogether, 85 subjects
were pre-screened, 5 subjects were excluded according to
the exclusion criteria or for personal reasons. As the great
majority of the women were using oral contraceptives, we
decided to keep the groups homogenous by including oral
contraceptive use as a further inclusion criterion for
women. The study finally included healthy male and
female non-smoking subjects between the age 20 and 45.
Subjects were assigned to one of the four treatment
groups. Ten males and 10 females were randomly assigned
FIGURE 1 *One male subject withdrew during the study (available TSST data in this group only for 19 subjects).
J. HELLHAMMER et al.120

to each group, carefully matched for socioeconomic
status. Subjects were provided with extensive information
on the study and read and signed a written informed
consent form. Subjects received 100 Euro for their
participation in the study. The protocol was approved by
the Landesa
¨rztekammer Rheinland-Pfalz (ethical com-
mission of the state’s Chamber of Medicine).
PROCEDURES
Before entry into the study, subjects were pre-screened by
the investigator for the criteria indicated above in the
subject selection section. A medical history was also taken
from each subject.
One day before initiation of treatment, salivary cortisol
levels were assessed in all subjects (at 4 p.m.) in order to
establish a pre-treatment salivary cortisol baseline level, to
exclude hyper- or hypocortisolism and to familiarise the
subjects with the saliva sampling procedure.
Groups received their respective test product dosage
three weeks before the TSST exposure. Each test product
consisted of 21 daily containers with 8 identical capsules
each containing in sum, either 400, 600, 800 mg PAS
(as “100 mg” PAS per capsule), or placebo (i.e. 0– 4
placebo capsules per day for PAS-treated subjects, or
8 placebo capsules for the controls). Subjects were
instructed to take any three capsules at breakfast, any three
capsules at lunch and the last two capsules at dinner in the
evening, every day. For compliance inspection, each
subject was instructed to bring all the empty containers of
the treatment capsules on the last day of treatment
(the TSST exposure date) and to use daily a salivette
before bedtime. Subjects expected that product levels
would be assessed in these saliva samples. On the last day
of treatment (day 21) subjects took the three capsules in
the morning as usual. In the early afternoon they attended
the TSST. Immediately before the introduction to the
TSST (90 min before TSST exposure) the last three
capsules were taken in the presence of the investigator.
Trier Social Stress Test (TSST)
Every subject spent about 165 min in the laboratory for an
introduction to the TSST, a pre-experimental resting
period (90 min), the TSST itself (15 min) and a post-
experimental resting period (60 min). After a first
instruction the subject was led to experimental room #1,
which served as the rest and preparatory area.
To gain spontaneous subjective responses about side
effects of the test products, subjects were asked upon
arrival in the laboratory if they experienced any
psychological or physical changes during drug intake.
Forty-five minutes after arrival, subjects received an
indwelling catheter in a forearm vein for the collection of
blood samples. This first resting phase was necessary to
exclude potential activation of the hypothalamic–
pituitary– adrenal axis (HPA), possibly confounding later
responsivity to the TSST. At the end of the resting
period the first saliva and blood samples were collected.
A detailed protocol of the TSST has been described
elsewhere by Kirschbaum et al. (1993). For a detailed
description of our study protocol on TSST-day, see Fig.2.
Before the TSST, each proband was introduced to the
testing room (#2) and instructed to stand behind a
microphone in front of a two-man committee. The subject
was informed that the whole session would be video- and
tape-recorded and that the committee was trained in
behavioural observation. The experimenter instructed the
subject to deliver a 5-min speech as if for a job application,
for which he/she had 3 min to prepare, and that a second task
would follow. After the free speech, the subject had to solve a
mental arithmetic task (counting backwards from 2083 to 0
in steps of 17) asquickly and correctly as possible for 5 min.
Before and after the TSST subjects filled out
two questionnaires, the “MDBF Mehrdimensionaler
Befindlichkeitsfragebogen” (Steyer et al., 1987) aiming
at assessing psychological well-being, and the German
version of the State scale of the Spielberger State/Trait
Anxiety Inventory (Spielberger et al., 1970) by Laux et al.
(1981). The MDBF consists of 24 items (each with a five-
level response scale) measuring three bipolar dimensions
FIGURE 2 Experimental procedure.
PAS AND RESPONSES TO MENTAL STRESS 121

of acute psychological well-being: “good – bad disposi-
tion” (e.g. content, unhappy), “alertness – fatigue” (e.g.
tired, rested) and “calmness–agitation” (e.g. tense,
composed). A high MDBF-score indicates psychological
well-being, and low scores indicate low mood. After the
TSST procedure subjects stayed for another hour during
which six more blood and saliva samples were collected.
Post-experimental Resting
The subject returned to experimental room #1, where the
post-test assessments and debriefing took place. Saliva and
blood samples were collected directly after the stress test
and after a further 10 min and later at 15 min intervals. The
STAI and MDBF were once again administered
immediately after the stress test. At the end, the subject
was debriefed, by being informed about the nature of the
experiment and the behaviour of the experimenters.
ACTH, Cortisol and Heart Rate Measurements
As shown in Fig. 2, blood and saliva samples were
collected 2 min before, and 1, 10, 20, 30, 45 and 60 min
after the TSST. Salivary and serum cortisol levels were
assessed in all samples, while ACTH was only determined
at 22 and þ1 min, respectively. For ACTH, two blood
samples were collected in EDTA-Monovettes (Sarstedt,
Nu
¨mbrecht). After centrifugation for 10 min at 68C and
1000 g, plasma aliquots were stored at 2208C until
analysis. ACTH levels where determined via chemilumi-
niscent immunoassay (Nichols Institute Diagnostics, Bad
Nauheim, Germany). Monoclonal mouse-ACTH anti-
bodies for immobilisation, and biotinylated polyclonal
goat-ACTH with a chemiluminescent avidin-complex
were added to the sample. Luminescent detection of the
hormone-antibody sandwich was measured using a
commercial readout system (Auto-CliniLumat LB 952,
Berthold, Bad Wildbad, Germany). This assay has a lower
and upper detection threshold of 0.5 –1550 pg/ml respect-
ively, inter-assay variation ranged from 4.6 to 7.0% and
intra-assay variation was between 3.4 and 3.8%. Serum
cortisol was assessed by a commercial ELISA kit (IBL,
Hamburg). The intra- and interassay variabilities were
below 5 and 10%, respectively.
Subjects obtained saliva samples using Salivette
sampling devices (Sarstedt, Nu
¨mbrecht, Germany). Saliva
samples were stored at 2208C until assay. After thawing,
saliva samples were centrifuged at 3000 rpm for 5 min,
which resulted in a clear supernatant of low viscosity.
Cortisol concentrations were determined employing a
commercial kit immunoassay with luminescence detec-
tion (IBL, Hamburg). This assay has a detection limit of
0.4134 nmol/l, an intra-assay variability of 4.5– 7.7% and
an inter-assay variability of 6.2– 11.5%; to reduce error,
all samples of one participant were analysed in one assay.
Heart rate was recorded by Polar Vantage NV heart rate
measurement devices. Data were transmitted by a Polar-
Electro interface to a personal computer and imported to
the Polar Precision Performance SW program (Version
4.00.020, Polar Electro Oy 2003).
STATISTICS
Data were compared by analysis of variance (ANOVA).
Since all women were taking oral contraceptives, serum
cortisol concentrations were higher, while ACTH and
salivary cortisol concentrations were lower than in the
men. To adjust for such gender differences, we compared
net increases from baseline between treatment groups and
controls. In the case of serum and salivary cortisol
measurements, the data were analysed by ANOVA with
repeated measures comparing the increase for each time
point after the TSST to baseline. The data set was cleaned
for extreme values ranging more than 2 s.d. from the
mean. Since the study objective predicted dampening
effects of PAS on plasma ACTH and serum cortisol, and
salivary cortisol concentrations in response to the
psychosocial stressor (TSST), we compared differences
between treatment groups and the placebo group by one-
tailed tests of significance.
RESULTS
As shown in Figs. 3– 5, treatment with 400 mg of PAS daily
resulted in a significant blunting of the HPA response to
psychological stress. Evidently, PAS exerts a central
dampening effect on HPA axis stress responses, as can be
seen from a significantly blunted ACTH response (Effect of
group: Fð1;32Þ¼6:58; p¼0:008) to the TSST (Fig. 3).
Subjects treated with 400 mg PAS showed a strong
reduction in the increase in (total) serum cortisol
concentration (Main Effect Time Fð2:8;84:3Þ¼24:03;
p,0:001 and Main Effect Group Fð1;30Þ¼2:84; p¼
0:05; Fig. 4), which was even more pronounced for the
biologically active, free steroid fraction, as assessed in
saliva (Main Effect Time Fð2;65:1Þ¼4:21; p¼0:001
and Main Effect Group Fð1;33Þ¼5:24; p¼0:015).
Here, the 400 mg treatment group showed only about 20%
of the salivary cortisol response when compared to
placebo (Fig. 5). In both measures there was no significant
interaction for group by time (serum cortisol
Fð2:8;84:3Þ¼0:62;p¼0:38; saliva cortisol:
Fð2;65:1Þ¼0:574;p¼0:28), indicating that treatment
with 400 mg PAS dampens the serum and salivary cortisol
response to the TSST to all time points.
Comparing 600 mg PAS daily with placebo, no
treatment effects were found for the increase in ACTH
(Fð1;32Þ¼1:17;p¼0:29), or the increase in serum
cortisol (Fð1;32Þ¼0:20;p¼0:66), or the increase in
salivary cortisol concentration (Fð1;35Þ¼1:73;
p¼0:20). The same was found for subjects treated with
800 mg PAS daily. Comparisons with placebo treated
subjects showed no significant treatment effects for
the increase in ACTH (Fð1;32Þ¼1:2;p¼0:28),
J. HELLHAMMER et al.122

FIGURE 3 Effects of PAS on the ACTH response to the TSST. Baseline levels were 26.57 pg/ml (placebo), 21.3 pg/ml (400 mg), 21.29 pg/ml (600 mg)
and 25.28 pg/ml (800 mg), respectively.
FIGURE 4 Effects of PAS on the serum cortisol response to the TSST. Baseline levels were 122.45 ng/ml (placebo), 129.54 ng/ml (400 mg),
107.13 ng/ml (600 mg) and 121.54ng/ml (800 mg), respectively.
PAS AND RESPONSES TO MENTAL STRESS 123

or the increase in serum cortisol (Fð1;34Þ¼0:14;
p¼0:71), or the increase in salivary cortisol
(Fð1;35Þ¼0:60;p¼0:44).
Also, no treatment effects were found for the heart rate
response to the TSST, as well as for effects on total anxiety
scores and mood under stress. Since no mood changes
were observed in the MDBF, and knowing that the 20
STAI items assess a spectrum of mood and stress, not
specific for the TSST, we expected that PAS may have
exerted only specific effects on stress measures of the
STAI. To test this hypothesis, we performed a factor
analysis of STAI responses to the TSST of an independent
sample of 113 subjects, matched for age and sex from the
data bank of this laboratory. A principal component
analysis (Promax rotation) was performed and three
factors were extracted, assessing nervousness (F1),
relaxation (F2) and distress (F3), respectively. The
Eigenvalues and percentages of explained variance of
the three factors were F1 ¼6:14=30:7%;F2 ¼1:51=7:6%
and F3 ¼1:42=7:1%). Commonalities ranged from 21 to
71. Reliabilities (Cronbach’s alpha) were for F1 ¼0:76;
F2 ¼0:77 and F3 ¼0:75;respectively.
Indeed, subjects treated with 400 mg PAS daily did not
show the expected increase on the distress subscale (F3), as
the control group did. Thus, 400 mg PAS resulted in a
significant reduction of the psychological stress response to
the TSST, when compared to placebo (Fig.6;two-tailed
t-test for the increase; tð34Þ¼2:026; p¼0:05), and there
was a similar tendency in the 800 mg group. When all three
treatment groups were analysed together and compared to
placebo, PAS significantly prevented the expected increase
in stress after the TSST (Mean increase value in the placebo
group with n¼20 : 1.05; mean increase value in the PAS
group with n¼53 : 20.755; two tailed t-test of the
increase: tð71Þ¼1:941; p¼0:056).
DISCUSSION
The data obtained from this study demonstrate the first
evidence of a pronounced dampening effect of 400 mg
PAS daily on the reactivity of the pituitary – adrenal axis to
stress. For the other two treatment groups (600 and 800 mg
PAS daily) these effects became weaker with increasing
dosages, and did not reach a sufficient level of
significance. This study was not designed to study PAS
effects with respect to body weight and gender, and
sample sizes did not allow more detailed statistical post
hoc analyses. An explorative data analysis, however,
revealed that women in this study had significantly lower
body weight, so they received relatively more PAS per kg
than men. Indeed, it seemed that PAS effects were even
more pronounced in men when compared to women, as
well as in individuals with lower PAS/body weight ratios
(data not shown). The fact that the effects of PAS were not
seen with increasing dosage still needs to be clarified.
In the TSST, women routinely show blunted ACTH and
cortisol responses, when compared to men. Many studies
FIGURE 5 Effects of PAS on the salivary cortisol response to the TSST. Baseline levels were 11.58 nmol/l (placebo), 10.54 nmol/l (400 mg),
8.49 nmol/l (600 mg) and 12.38 nmol/l (800 mg), respectively.
J. HELLHAMMER et al.124

have been undertaken to understand the gender differences
of the stress response. However, sex differences have not
been explained by effects of sex steroids—they even
persist in postmenopausal women (see, for review,
Kudielka et al. (2004)). Consequently, the magnitude of
the PAS effect was expected to be smaller in women, but
still in proportion to the changes in men. As mentioned
above, we did not expect gender effects on PAS action.
Thus, group size and statistical error did not allow the
necessary analyses. However, with the evidence available
to date, we cannot exclude that PAS exerts stronger
actions in men.
The mechanisms by which PAS affects HPA reactivity
are still unknown. Interestingly, the heart rate response to
stress was not dampened, questioning whether PAS has an
effect at the hypothalamic level. It is important to note that
PAS dampens but does not eliminate stress reactivity.
Furthermore, basal cortisol levels remained unaffected.
Thus, PAS does not seem to interfere with the integrity of
the pituitary– adrenal axis.
Uncontrollability, unpredictability and uncertainty,
resulting in strain and worry, combined with ego-
involvement, are considered the key psychological
elements of both distress and HPA axis activation. From
this viewpoint, 400 mg PAS daily seems to exert a rather
specific effect on this biobehavioral response to the TSST,
as shown for a distress subscale, derived from the
Spielberger State Anxiety Inventory. While the placebo
group showed the expected increase in distress, the
400 mg treatment group even showed a slight decrease in
distress, suggesting a quicker habituation to a new
stressor, which may then result in a dampened HPA
response.
The protocol of this study did not allow discrimination
between effects of chronic and acute PAS treatment. Thus,
we do not know yet if a bolus treatment alone can exert a
similar stress dampening effect as the chronic treatment.
There is currently strong evidence that an enhanced
reactivity of the pituitary– adrenal axis is related to several
mental and physical diseases, such as depression, some
types of abdominal obesity and the metabolic syndrome
(Chrousos, 2000; Pasquali et al., 2000). The striking effect
of 400 mg PAS daily in dampening the stress response may
be promising with respect to possible clinical application
in stress related disorders. This view is supported by the
fact that no side effects were observed in this study.
Acknowledgements
This study was initiated and financed by Lipogen Ltd.,
Haifa, Israel.
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