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World Journal of Neuroscience, 2017, 7, 140-171
http://www.scirp.org/journal/wjns
ISSN Online: 2162-2019
ISSN Print: 2162-2000
DOI: 10.4236/wjns.2017.71011 February 9, 2017
Effect of Zembrin® on Brain Electrical Activity
in 60 Older Subjects after 6 Weeks of Daily
Intake. A Prospective, Randomized,
Double-Blind, Placebo-Controlled,
3-Armed Study in a Parallel Design
Wilfried Dimpfel1, Nigel Gericke2, Samir Suliman3, Gwladys N. Chiegoua Dipah3
1Justus-Liebig-University, Giessen, Germany
2HG & H Pharmaceuticals (Pty) Ltd., Bryanston, South Africa
3NeuroCode AG, Wetzlar, Germany
Abstract
Zembrin® is a botanical functional food and dietary
supplement ingredient
sold in the USA, and Canada
for enhancing mood, decreasing anxiety and
stress and improving cognitive function under stress. It is a proprietary e
x-
tract of a cultivated selection of
Sceletium tortuosum
. The present investig
a-
tion aimed at the measurement of the effect of 25 or 50 mg of Zembrin®
in
comparison to placebo after daily repetitive
intake for 6 weeks. Sixty healthy
male (n = 32) and female (n = 28) right-
handed subjects between 50 and 80
years old (59.7 ± 5.43 and 56.7 ± 5.88 years, respectively) were recruited.
The
EEG was recorded bipolarly from 17 surface electrodes (CATEEM®) befo
re
and 1 h after intake. Six cognitive tests were performed: d2-
test, memory test,
calculation performance test, reaction time test, number identifying test and
number connection test.
Three questionnaires were included: Profile of Mood
States, Hamilton Anxiety Rating Scale
and a sleep questionnaire. Quantitative
EEG revealed increases of delta activity during performance of the d2-
test, the
number identification and number connection test in the fronto-
temporal
brain region. Higher theta activity was seen during relaxation and perfo
r-
mance of the d2-test after intake of 50 mg of Zembrin®. Statistically consp
i-
cuous increases of alpha1 spectral power were seen in the relaxed state. With
respect to alpha2 spectral power larger increases were observed in the centro
-
occipital region. Discriminant analysis revealed a projection of Zembrin®
data
into the vicinity of the calming preparation Calmvalera tablets and a Gin
k-
go-Ginseng mixture. Statistically significant improvement during perfo
r-
mance of the arithmetic calculation test and number connection test was do-
How to cite this paper:
Dimpfel, W.,
Gericke,
N., Suliman, S. and Chiegoua
Dipah
, G.N. (2017) Effect of Zembrin®
on
Brain Electrical Activity
in 60 Older Sub-
jects after 6 Weeks of Daily Intake. A Pro
s-
pective, Randomized, Double
-Blind, Pla-
cebo
-Controlled, 3-Armed Study in a Pa-
rallel Design
.
World Journal of Neuro
s-
cience
,
7
, 140-171.
https://doi.org/10.4236/wjns.2017.71011
Received:
December 21, 2016
Accepted:
February 6, 2017
Published:
February 9, 2017
Copyright © 201
7 by authors and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
W. Dimpfel et al.
141
cumented. The HAM-A anxiety score revealed a statistically significant de-
crease (
p
= 0.03) after six weeks. Zembrin®
showed significant activity on
three levels of evidence: questionnaires, psychometry and qua
ntitative EEG.
The results indicate that in healthy people Zembrin®
improves some aspects of
cognitive function, decreases anxiety, and may enhance mood.
Keywords
Sceletium tortuosum
, Zembrin®, EEG, Psychophysiology, Spectral Power,
CATEEM®, Psychometry, Anxiety, Stress, Cognitive
1. Introduction
Since the first discovery of human electric activity by Hans Berger [1] electroen-
cephalographic measurements were performed not only for diagnostic purposes
but increasingly also during exposure to numerous mental challenges aiming at
a better understanding of cognitive and emotional processes. Spectral and mul-
tivariate analysis of EEG oscillations during mental activity in man had already
been reported more than 40 years ago [2]. Spectral and multivariate analysis of
EEG oscillations during mental activity in man had already been reported more
than 40 years ago. Subsequently, reflection of cognitive challenges in the quan-
titative EEG was reported to differ according to special tasks [3]. The physiology
of mindfulness has been related to EEG oscillations also recently [4]. Using
questionnaires a relationship between mood and EEG spectra was reported [5].
Due to the intimate relationship between psychometric testing and EEG spectral
signatures it was even suggested that cognitive testing could be replaced by
quantitative EEG measurements [6]. Quantitative EEG measurements in the re-
laxed state and during performance of cognitive tests are therefore well suited to
describe functional changes of brain activity induced by intake of food [7] [8],
food supplements [9] or drugs [10].
Zembrin® is a botanical functional food and dietary supplement ingredient
currently sold in the USA, Canada, Brazil, Malaysia, and South Africa. It is a
proprietary extract of a low-alkaloid cultivated selection of
Sceletium tortuosum
,
and is used by healthy people for enhancing mood, decreasing anxiety and stress
and improving cognitive function under stressful situations. Preclinical [11] as
well as clinical evidence [12] [13] [14] [15] has been reported with respect to its
safety, tolerability, and its efficacy in changing brain function in healthy subjects.
A successful double-blind, randomized, placebo-controlled study in parallel de-
sign was performed in order to test the psychophysiological effects of Zembrin®
after intake of a single dose [16]. In this study Zembrin® was shown to increase
alpha waves during relaxation and delta and theta waves during cognitive chal-
lenges. Beta2 waves increased during mental performance in the presence of the
higher dosage of Zembrin® in parietal, occipital and temporal brain regions.
The present investigation aimed at the objective measurement of the effect of
two dosages of Zembrin® after daily repetitive intake during 6 weeks. The expe-
W. Dimpfel et al.
142
rimental design included 3 levels of evidence: a questionnaire, psychometric
testing and recording of quantitative EEG during performance of psychometric
tests. It was hoped to confirm the results from the first study on acute dosing
and objectify functional effects on the brain after daily repetitive intake for 6
weeks.
2. Material and Methods
2.1. Subjects
Sixty healthy male (n = 32) and female (n = 28) right-handed subjects between
50 and 80 years old (59.7 ± 5.43 and 56.7 ± 5.88 years, respectively) and fluent in
German language were recruited and gave informed consent. Their body mass
index was >18.5 or <33.0. Criteria for exclusion were:
Participation in another clinical trial within the last 30 days.
Positive pregnancy test (day A) or lactating.
Cancellation of informed consent.
Psychiatric or neurologic disease including epilepsy, cerebrovascular distur-
bance or traumatic injury.
Important or untreated disease including severe uncontrolled diabetes, ische-
mia, infarct, unstable angina pectoris or uncontrolled high blood pressure.
Clinically relevant allergic symptoms.
Detection of alcohol at the time of initial examination (day SC) or on study
day A and B (positive alcohol test).
Detection of drugs (positive drug test) at the time of initial examination (day
SC) or drug abuse within the last 6 months.
Consumption of clinically relevant medication during last fourteen days be-
fore and during the active study period based on the notification of the subject
or his case history.
Consumption of medication with primarily central action (
i.e.
psychotropic
drugs or centrally acting antihypertensive).
Known intolerance/hypersensitivity (allergy) to plant derived extracts or any
of the ingredients of the investigational product (anamnestic).
Presence of a rare genetic disease such as fructose intolerance, glucose-galac-
tose malabsorption or sucrase-isomaltase deficiency (anamnestic).
Consumption of unusual quantities or misuse of coffee (more than 4 cups a
day), tea (more than 4 cups a day) or tobacco (more than 20 cigarettes per day).
Smoking on day A and day B.
For safety reasons ECG was recorded in addition to a clinical examination. In
addition, a pregnancy test, an alcohol test, a drug test and a blood examination
was performed. For the blood and urine analysis MVZ Labordiagnostik Mittel-
hessen GmbH, Ursulum 1, D-35389 Giessen, Germany was responsible.
2.2. Psychometric Testing
Six cognitive test were performed before and 1 h after intake of trial prepara-
W. Dimpfel et al.
143
tions: d2-Test (d2-Test), Memory Test (ME-Test), Calculation Performance
Test (CPT-Test), Reaction Time Test (RT-Test), Number Identifying Test
(NIT-Test), Number Connection Test (NCT-Test). An overview on the time
line of an experimental day is given in Figure 1.
The duration of the tests was 3 minutes in general except for the d2-test,
which lasted 5 minutes. In comparison to the psychometric tests as already pub-
lished [17] 3 more tests were presented: Reaction Time Test, Number Identifying
Test and Number Connection Test. Result of the reaction time test is given in
milliseconds. Results from all other tests are given according to the formula: to-
tal number of answers multiplied by the percentage of correct answers divided
by 10,000.
2.3. EEG Recording
The EEG was recorded bipolarly from 17 surface electrodes according to the In-
ternational 10/20-system [18] with Cz as physical reference electrode (Computer
aided topographical electroencephalometry: CATEEM®) using an electro cap.
Before psychometric testing 6 minutes were recorded under the resting “eyes
open” condition. For a detailed description of the procedure please refer to [10].
EEG data were recorded twice: before (baseline) and 1h after the intake of the
medication. Between the measurements subjects spent their time in the facility’s
recreation room. All experiments took place at the same time of the day (starting
at 7 o’clock in the morning). Quantitative evaluation was performed by using
source density analysis except for the recording condition “eyes closed” [19] [20].
2.4. Questionnaires
The Profile of Mood States (POMS) is a psychological rating scale used to assess
transient, distinct mood states. The POMS assessment provides a rapid method
of assessing transient, fluctuating active mood states. It is an ideal instrument for
measuring and monitoring treatment change in clinical, medical, and addiction
counseling centers. It is also well suited to clinical drug trials because its sensi-
tivity to change allows you to accurately document the effects of drugs on mood
Figure 1. Time line of the experimental day A and B. Performance: Eyes open (EO), Eyes
closed (EC) and different cognitive tests, d2-Test (d2-Test), Memory Test (ME-Test),
Calculation Performance Test (CPT-Test), Reaction Time Test (RT-Test), Number
Identifying Test (NIT-Test), Number Connection Test (NCT-Test).
W. Dimpfel et al.
144
state. The POMS is a standard validated psychological test formula [21] [22].
The questionnaire contains 65 words/statements that describe feelings people
have. The test is required to indicate for each word or statement how one has
been feeling in the past week including today.
Score 1: Dejection (Niedergeschlagenheit)
Score 2: Sullenness (Missmut)
Score 3: Fatigue (Müdigkeit)
Score 4: Thirst for action (Tatendrang)
The Hamilton Anxiety Rating Scale (HAM-A, [23]) (Hamilton Anxiety Scale,
CIPS: Collegium Internationale Psychiatriae Scalarum) is a psychological ques-
tionnaire used to rate the severity of a patient’s anxiety. Anxiety can refer to
things such as “a mental state, a drive, a response to a particular situation, a
personality trait and a psychiatric disorder”. It was published by [23]. The scale
consists of 14 items designed to assess the severity of a patient’s anxiety. Each of
the 14 items contains a number of symptoms, and each group of symptoms is
rated on a scale of zero to four, with four being the most severe. All of these
scores are used to compute an overarching score that indicates a person’s anxiety
severity. The questionnaire was performed on day A and day B.
The sleep questionnaire used was the so-called “Schlaffragebogen” B (SF-B)
and is used for quantitative and qualitative description and evaluation of sleep
behavior and sleep experience (CIPS: Collegium Internationale Psychiatriae
Scalarum). The SF-B comprises 31 questions and refers to the past two weeks
[24].
2.5. Statistical Evaluation
EEG data from the first recording session before intake of the capsules are given
as absolute numbers (µV2). For explorative statistical evaluation of efficacy
against placebo the non-parametric Wilcoxon test was used. For mathematical
differentiation of the different mental loads the linear discriminant analysis ac-
cording to Fischer was used. Results from the first three discriminant functions
were projected into space (X, Y and Z coordinates), whereas results from the
fourth to sixth discriminant functions were coded into red, green and blue color,
respectively, followed by an additive color mixture (so-called RGB-mode). In
order to document statistically the different electric reaction of the brain to var-
ious cognitive loads, data from test were compared to the data obtained during
eyes open (6 minutes) at the beginning. Comparison of 25 mg or 50 mg Zem-
brin® capsules versus placebo was accomplished by evaluation of the second re-
cording of the day 60 minutes after intake. Spectral power of EEG data from the
first recording (baseline) was set to 100% and electrophysiological changes pro-
duced by placebo or Zembrin® 25 mg or 50 mg capsules are depicted as %-
changes thereof. Estimation of the number of subjects to be included into the
study was performed by considering data from earlier experimental trials as ob-
tained under a similar experimental design.
W. Dimpfel et al.
145
3. Results
3.1. Data Set Analysis/Fundamental Basis
Efficacy evaluation took place on three different levels of evidence: filling out
different questionnaires (POMS, HAM-A, SF-B), performance of six psychome-
tric tasks and recording of quantitative EEG during performance of the psycho-
metric tasks. Sixty subjects were recruited and asked to visit the lab at two expe-
rimental days 6 weeks apart during which they had to take in daily placebo, 25
mg or 50 mg of Zembrin®. Electric brain activity was recorded under several dif-
ferent conditions. First recording was always done in a relaxed state with open
and eyes closed. After this, 6 different mental challenges were presented during
quantitative EEG recording. EEG data are documented initially as absolute spec-
tra power (µV2) for each electrode position (brain area) and each frequency
range (delta to beta2). There were no major differences between the three groups
with respect to median values of spectral power in the six frequency ranges. Ab-
solute power values from the baseline recording with respect to all recording
conditions were therefore set to 100%. Drug induced changes are documented as
pre-post intake comparison in % of these baseline values for every recording
condition. An overview on the absolute spectral power values during recording
in the relaxed state on the first and on the last day is given in Table 1 and Table
2.
Table 1. Absolute spectral power values depicted as µV2 for each electrode position for the placebo group, the 25 mg and 50 mg of
Zembrin® groups with respect to all frequency ranges (delta to beta2). Data are given for the recording on the first day (acute). M
= median value. E = indicates electrode positions according to the so-called 10/20 system [18]. Pl = placebo; 25 mg = ZEMBRIN®
25 mg and 50 mg = ZEMBRIN® 50 mg.
Absolute values of “eyes open” 0 h Acute
E
Delta
Theta
Alpha1
Alpha2
Beta1
Beta2
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Cz
1.90
1.66
1.43
0.44
0.65
0.43
0.66
0.60
0.75
0.44
0.76
0.71
0.69
1.50
0.82
1.46
1.64
0.89
Fz
2.28 2.31 2.17 0.60 0.75 0.73 0.70 0.86 0.86 0.55 0.77 0.66 0.67 0.88 0.82 1.14 1.41 0.97
F3
2.74 2.49 2.83 0.65 0.64 0.66 0.73 0.79 1.07 0.53 0.73 0.89 1.37 1.45 1.38 3.41 2.26 2.17
C3
1.53 1.62 1.51 0.42 0.51 0.38 0.63 0.77 0.87 0.63 1.07 1.06 1.51 1.84 1.58 1.90 2.03 1.38
P3
1.07
1.29
1.01
0.29
0.35
0.34
0.36
0.39
0.71
0.45
0.54
0.74
0.69
0.78
0.80
0.67
0.61
0.58
Pz
1.11 1.62 1.42 0.39 0.61 0.36 0.48 0.64 0.57 0.53 0.59 0.58 0.73 1.10 0.93 0.79 0.79 0.76
P4
0.91 1.39 1.12 0.25 0.38 0.38 0.43 0.41 0.55 0.52 0.72 0.88 0.78 1.03 1.05 0.62 0.88 0.67
C4
1.78 1.51 1.31 0.52 0.62 0.38 0.68 0.70 0.83 0.76 1.41 0.92 1.35 1.93 1.61 2.10 2.50 1.62
F4
2.59
2.27
2.80
0.71
0.68
0.69
0.75
0.76
1.11
0.62
0.87
0.83
0.96
1.42
1.05
2.18
2.20
1.96
F7
7.96 7.86 8.59 1.46 1.83 1.63 1.39 1.41 2.37 1.48 1.41 2.10 2.18 2.01 2.68 4.79 2.72 4.21
T3
2.75 3.90 3.75 0.81 1.26 1.02 1.26 1.37 2.13 1.32 1.59 2.18 2.91 2.53 2.35 5.25 3.60 2.83
T5
2.20 2.92 2.31 0.67 0.94 0.72 0.93 1.11 1.71 1.21 1.29 1.67 1.73 2.26 2.02 2.40 1.75 1.62
01
2.73
3.34
3.81
0.64
0.95
0.74
0.83
0.99
0.92
0.85
1.34
1.13
1.61
1.92
1.85
2.88
2.47
2.60
02
2.50 3.08 2.69 0.77 0.84 0.66 0.80 0.93 1.31 0.82 1.14 1.13 1.72 1.75 1.63 2.46 3.13 2.11
T6
2.17 3.82 3.15 0.70 0.95 1.01 0.97 1.09 2.29 1.47 1.91 1.89 2.04 2.44 2.65 2.17 2.33 1.53
T4
3.41 4.14 3.52 0.90 0.84 0.89 1.22 1.08 1.98 1.29 1.64 2.00 2.38 2.85 2.63 3.35 3.25 2.85
F8
6.12
6.30
9.01
1.34
1.56
1.49
1.45
1.73
2.37
1.27
2.00
2.10
2.28
3.32
2.63
4.02
6.28
3.88
M
2.43 2.27 2.23 0.57 0.73 0.66 0.79 0.81 1.00 0.71 1.11 1.22 1.27 1.71 1.55 2.25 2.20 1.94
W. Dimpfel et al.
146
Table 2. Absolute spectral power values depicted as µV2 for each electrode position for the placebo group, the 25 mg and 50 mg of
Zembrin® groups with respect to all frequency ranges (delta to beta2). Data are given for the recording on the last day (after repeti-
tive dosing). M = median value. E = indicates electrode positions according to the so-called 10/20 system [18]. Pl = placebo; 25
mg = ZEMBRIN® 25 mg and 50 mg = ZEMBRIN® 50 mg.
Absolute values of “eyes open” 0 h Repetitive
E
Delta
Theta
Alpha1
Alpha2
Beta1
Beta2
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Pl
n = 20
25 mg
n = 20
50 mg
n = 19
Cz
2.06 2.23 1.89 0.52 0.59 0.45 0.47 0.50 0.72 0.47 0.62 0.57 0.75 1.02 0.81 1.33 1.58 1.02
Fz
2.71 3.05 2.58 0.72 0.77 0.75 0.79 0.63 1.05 0.46 0.54 0.56 0.78 0.83 0.78 1.30 1.06 1.03
F3
2.35 4.37 3.37 0.59 0.78 0.90 0.69 0.81 1.35 0.53 0.57 1.01 1.29 1.22 1.07 2.54 2.14 2.17
C3
1.60 2.37 1.57 0.46 0.71 0.39 0.60 0.68 0.78 0.69 0.96 0.72 1.60 1.82 1.28 1.55 2.52 1.55
P3
1.01 1.11 1.00 0.34 0.35 0.33 0.43 0.40 0.98 0.46 0.59 0.79 0.63 0.89 0.82 0.82 0.84 0.59
Pz
1.50 1.27 1.73 0.44 0.43 0.54 0.60 0.47 0.80 0.46 0.49 0.91 0.81 0.93 0.97 0.71 0.77 0.70
P4
1.31 0.91 1.02 0.38 0.30 0.31 0.74 0.33 0.69 0.47 0.63 0.59 0.75 0.68 0.75 0.64 0.74 0.59
C4
1.84 1.75 1.28 0.53 0.44 0.45 0.81 0.68 0.96 0.74 1.09 0.98 1.84 1.76 1.33 1.97 2.02 1.25
F4
2.52 3.39 2.46 0.56 0.66 0.58 0.65 0.70 1.15 0.60 0.71 1.00 1.24 1.11 1.09 1.74 2.14 2.58
F7
12.17 10.72 10.44 1.72 1.77 1.67 1.90 1.70 2.49 1.50 1.49 2.32 2.45 2.33 2.63 3.47 3.88 3.77
T3
3.07 4.13 4.73 0.67 0.92 0.91 0.88 1.00 2.06 1.14 1.95 2.07 2.43 2.57 3.25 3.28 2.93 3.16
T5
2.71 2.83 2.00 0.84 0.73 0.62 1.29 1.06 1.53 1.25 1.19 1.29 1.54 1.79 1.24 1.79 1.54 1.56
01
2.84 4.34 3.08 0.73 1.02 0.76 0.86 0.89 0.95 0.83 1.13 0.87 1.35 2.59 1.28 2.00 3.60 1.86
02
2.63 3.01 2.36 0.80 0.80 0.74 1.02 0.89 1.00 0.85 1.15 0.90 2.29 1.25 1.97 2.14 2.11 2.06
T6
3.43 2.78 2.72 1.04 0.68 0.82 1.11 1.02 2.79 1.49 1.39 2.07 2.55 2.20 2.54 1.66 1.78 1.54
T4
3.15 3.40 3.17 0.78 0.95 0.77 1.12 1.48 1.64 1.11 1.42 1.43 2.65 3.51 2.35 2.67 4.61 3.27
F8
7.64 7.66 8.40 1.20 1.46 1.39 1.26 1.34 2.29 1.01 1.58 2.13 1.82 3.03 2.61 3.72 4.83 3.54
M
2.65 2.96 2.61 0.64 0.71 0.68 0.82 0.73 1.20 0.72 1.00 1.07 1.49 1.74 1.28 1.94 2.19 1.66
Analysis of the spectral power in all participating subjects before intake of trial
preparations revealed significant test-specific changes with respect to single
brain regions (electrode positions) and defined frequency ranges in comparison
to the recording during the relaxed state. For sake of easier overview two func-
tionally related brain areas are defined as regions of interest (ROI): the fronto-
temporal area represented by electrode positions Fz,3,4,7,8 T3456 and the centro-pa-
rieto-occipital area represented by electrode positions C3,4 Pz,3,4 O1,2. With re-
spect to delta power increases were observed during performance of all tests, in
comparison to the relaxed state, which were statistically significant in compari-
son to the relaxed state except for the reaction time test (RT) and number con-
nection test (NCT). Theta waves increased during performance of the d2-con-
centration test (d2-test), the number identification and number connection test
in a significant manner in comparison to the relaxed state. Alpha1 frequencies
were attenuated in the memory test, the calculation test and both number identi-
fication and connection tests. Alpha2 waves were attenuated during performance
W. Dimpfel et al.
147
of all tests except for the d2-test. Beta waves changed only slightly. Details and
statistical significances are given in Table 3 for the fronto-temporal region of
interest. Changes in the centro-parieto-occipital area were a little bit different.
Increases in the slow wave frequencies delta and theta are not so prominent, but
attenuation of alpha and beta1 waves was highly significantly stronger in com-
parison to data recorded during the relaxed state. Details are documented in Ta-
ble 4.
3.2. Efficacy of Zembrin® in the Relaxed State (EO)
Zembrin® was administered as a single 25 mg or 50 mg dose on the first experi-
mental day and then continued daily for six weeks. Measurements took place on
the first day (day A) and one day after the continuous intake for 6 weeks (day B).
Results of the placebo group are depicted in Figure 2 (first day). Concomitant
performance of psychometric tests and EEG recordings revealed quantitative
differences between placebo and the two dosages of Zembrin® with respect to all
recording conditions.
Effects of the lower dosage of 25 mg Zembrin® in comparison to placebo re-
vealed statistically significant increases of spectral delta and theta power in cen-
tral brain regions and at electrode position T4 during the “eyes open” recording
condition on the first recording day (Figure 2). On the last day, only some de-
creases of slow waves (C3 and F8) and increases of beta power emerged (not
shown). The higher dosage of 50 mg of Zembrin® induced statistically significant
Table 3. Changes of spectral power during tests in comparison to the recording condition
“eyes open” in relaxed state at fronto-temporal electrode positions (Fz3478 T3456). Eyes open
(EO), d2-concentration test (d2-Test), memory test (ME-Test), arithmetic calculation test
(CPT-Test), reaction time test (RT-Test), number identification test (NIT), number con-
nection test (NCT). P-values calculated according to sign test.
Fz3478 T3456
[µV2] n = 59
Delta
Theta
Alpha1
Alpha2
Beta1
Beta2
Eyes open
3.00
0.83
1.04
1.29
2.02
2.70
d2-Test
3.79
0.96
1.14
1.08
2.08
3.86
p =
0.006
0.004
ME-Test
4.09
0.88
0.91
1.03
1.88
2.64
p =
0.000005
0.000001
0.0002
0.02
CPT-Test
3.99
0.91
0.98
1.06
1.65
2.44
p =
0.003
0.002
0.04
0.06
RT-Test
3.22
0.82
1.03
0.96
1.87
2.76
p =
0.02
0.00007
NIT-Test
3.96
0.96
0.98
1.07
2.00
2.79
p =
0.002
0.02
0.04
NCT-Test
3.63
0.93
1.00
1.10
1.99
3.05
p =
0.008 0.07
0.036
0.04
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148
Figure 2. Effects of Zembrin® on spectral frequencies in different regions of the brain on
the first recording day (acute). Changes of spectral power are depicted in percent of the
pre-drug baseline recording on the ordinate. Electrode positions are labeled as C for cen-
tral, F for frontal, P for parietal, T for temporal and O for occipital. Even numbers de-
scribe data from the right hemisphere, uneven numbers from the left hemisphere. Red
bars: delta, orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spec-
tral power. Error probability is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
Table 4. Changes of spectral power during tests in comparison to the recording condition
“eyes open” in relaxed state at centro-parietal-occipital electrode positions (C34Pz34O12).
Eyes open (EO), d2-concentration test (d2-Test), memory test (ME-Test), arithmetic cal-
culation test (CPT-Test), reaction time test (RT-Test), number identification test (NIT),
number connection test (NCT).
P
-values calculated according to sign test.
C34Pz34O12
[µV2] n = 59
Delta
Theta
Alpha1
Alpha2
Beta1
Beta2
Eyes open
1.73
0.52
0.74
0.77
1.44
1.73
d2-Test
2.07
0.53
0.51
0.48
0.85
1.62
p =
0.000005
0.00002
0.00000001
0.000005
ME-Test
1.76
0.48
0.52
0.55
1.01
1.52
p =
0.00002
0.00000001
0.0000003
0.000001
0.009
CPT-Test
1.79
0.45
0.44
0.49
0.86
1.38
p =
0.07 0.00002
0.00000001
0.00000001
0.00000001
RT-Test
1.54
0.43
0.49
0.57
1.06
1.61
p =
0.07
0.00000001
0.00000001
0.00007
0.00007
NIT-Test
1.70
0.51
0.48
0.51
0.95
1.39
p =
0.00002
0.0000003
0.0006
0.07
NCT-Test
1.98
0.51
0.47
0.47
0.69
1.20
p =
0.0006
0.000001
0.00000001
0.00007
0.004
increases of theta frequencies at C4 and T4 as well as increases of alpha1 frequen-
cies in 6 different brain regions. On the last day (day B), dominant increases of
theta activity were observed mostly in fronto-temporal brain areas. In addition,
alpha wave increases were seen not only in fronto-temporal areas but also in the
parietal region at electrode positions P3 (not shown).
W. Dimpfel et al.
149
3.3. Efficacy of Zembrin® during Performance
of the d2-Concentration Test (d2)
During performance of the d2-concentration test (d2) a dose dependent effect
was observed at the first day of recording. Whereas the lower dosage of 25 mg
hardly induced spectral changes, the higher dosage induced statistically signifi-
cant increases of local delta, theta and alpha1 spectral power in comparison to
placebo, mainly in frontal and temporal brain areas (electrode positions F3, F4, T3
and T4). Complete data with respect to all brain areas are documented in Figure
3. Differences in comparison to placebo at the last day of recording were less
pronounced with respect to delta and theta power. However, with respect to al-
pha1 waves a statistically conspicuous increase was observed in central and pa-
rietal brain areas in the presence of the higher dosage (not shown). A significant
increase of alpha2 spectral power was only seen within the right hemisphere at
the central and temporal area. There was also some indication of a temporal in-
crease of beta waves at the last day (not shown).
3.4. Efficacy of Zembrin® during Performance of the
Memory Test (ME)
During performance of the memory test (ME) on the first day of recording sta-
tistically significant focal increases of delta power emerged in frontal (Fz and F7)
and temporal areas (T3 and T4) already in the presence of the lower dosage. In
the presence of the higher dosage a trend to increases of central delta power was
seen. Within the right temporal lobe (T4) and centrally (C4) statistically signifi-
cant increases of alpha1 and alpha2 spectral power emerged besides a conspi-
Figure 3. Effect of Zembrin® in comparison to placebo on spectral frequencies in different
regions of the brain on the first recording day during performance of the d2-test (d2).
Changes of spectral power are depicted in percent of the pre-drug baseline recording on
the ordinate. Electrode positions are labeled as C for central, F for frontal, P for parietal,
T for temporal and O for occipital. Even numbers describe data from the right hemis-
phere, uneven numbers from the left hemisphere. Red bars: delta, orange: theta, yellow:
alpha1, green: alpha2, turquoise: beta1, blue: beta2 spectral power. Error probability is
marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
W. Dimpfel et al.
150
cuous increase of beta power in the temporal lobe. Complete data with respect to
all brain areas are documented in Figure 4. At the last day (day B) of recording
no spectral changes were observed in the presence of the lower dosage of Zem-
brin®. In the presence of the higher dosage some statistically conspicuous in-
creases of alpha1 power were detected in the central, temporal and occipital re-
gion in comparison to placebo (not shown).
3.5. Efficacy of Zembrin® during Performance of the
Arithmetic Calculation Test (CPT)
During performance of the arithmetic calculation test (CPT) hardly any change
of spectral power was detected in the presence of the lower dose of Zembrin® on
the first day of recording. In the presence of the higher dose a statistically signif-
icant increase of all frequencies was recognized at the right central electrode po-
sition C4 and of alpha2 and beta at C3. Statistically significant increases of alpha1
and alpha2 spectral power were seen in central and right temporal regions.
Likewise, statistically significant increases of beta1 and beta2 power in central,
temporal and occipital brain areas were recognized. Complete data with respect
to all brain areas are documented in Figure 5. On the last day of recording after
repetitive dosing no statistically significant changes of spectral power were
found. Increases of alpha power were observed in central and parietal brain
areas, but did not reach statistical significance (not shown).
3.6. Efficacy of Zembrin® during Performance of the
Reaction Time Test (RT)
During performance of the reaction time test (RT) on the first day (day A) of
Figure 4. Effect of Zembrin® in comparison to placebo on spectral frequencies in different
regions of the brain on the first recording day during performance of the memory-test
(ME). Changes of spectral power are depicted in percent of the pre-drug baseline record-
ing on the ordinate. Electrode positions are labeled as C for central, F for frontal, P for
parietal, T for temporal and O for occipital. Even numbers describe data from the right
hemisphere, uneven numbers from the left hemisphere. Red bars: delta, orange: theta,
yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spectral power. Error probabil-
ity is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
W. Dimpfel et al.
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Figure 5. Effect of Zembrin® in comparison to placebo on spectral frequencies in different
regions of the brain on the first recording day during performance of the arithmetic cal-
culation test (CPT). Changes of spectral power are depicted in percent of the pre-drug
baseline recording on the ordinate. Electrode positions are labeled as C for central, F for
frontal, P for parietal, T for temporal and O for occipital. Even numbers describe data
from the right hemisphere, uneven numbers from the left hemisphere. Red bars: delta,
orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spectral power.
Error probability is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
recording no spectral changes were observed after intake of the lower dose.
However, after intake of the higher dose highly significant focal increases of del-
ta and theta power were documented for the right central electrode position C4,
similar to changes as observed during arithmetic calculation (CPT). In addition,
a tendency to increases of alpha1 and alpha2 power was recognized in fronto-
temporal brain areas (alpha1 statistically significant in the right temporal lobe at
T4 and T6, alpha2 at positions T3 and T6). Complete data with respect to all brain
areas are documented in Figure 6. After the repetitive dosing, only marginal
spectral changes were observed during performance of the reaction time test.
Some statistically conspicuous increases of beta power were seen in the presence
of both dosages (not shown).
3.7. Efficacy of Zembrin® during Performance of the
Number Identification Test (NIT)
During performance of the number identification test (NIT) statistically conspi-
cuous or significant increases of delta power were recognized in all temporal
brain areas on the first day of recording in the presence of the lower dosage. Af-
ter intake of the higher dosage some increases of theta spectral power reached
statistical significance in comparison to placebo. These changes were accompa-
nied by a highly significant increase of alpha2 power in the temporal lobe at
electrode position T6 and frontally at F7. Finally, a trend of beta wave increase
became visible. Complete data with respect to all brain areas are documented in
Figure 7. After 6 weeks of daily intake of Zembrin® no major changes of spectral
power except for some decreases of power in the alpha and beta range were seen
(not shown).
W. Dimpfel et al.
152
Figure 6. Effect of Zembrin® in comparison to placebo on spectral frequencies in different
regions of the brain on the first recording day during performance of the reaction time
test (RT). Changes of spectral power are depicted in percent of the pre-drug baseline re-
cording on the ordinate. Electrode positions are labeled as C for central, F for frontal, P
for parietal, T for temporal and O for occipital. Even numbers describe data from the
right hemisphere, uneven numbers from the left hemisphere. Red bars: delta, orange:
theta, yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spectral power. Error
probability is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
Figure 7. Effect of Zembrin® in comparison to placebo on spectral frequencies in different
regions of the brain on the first recording day during performance of the number identi-
fication test (NIT). Changes of spectral power are depicted in percent of the pre-drug
baseline recording on the ordinate. Electrode positions are labeled as C for central, F for
frontal, P for parietal, T for temporal and O for occipital. Even numbers describe data
from the right hemisphere, uneven numbers from the left hemisphere. Red bars: delta,
orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spectral power.
Error probability is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
3.8. Efficacy of Zembrin® during Performance of the
Number Connection Test (NCT)
During performance of the number connection test (NCT) on the first day of
recording statistically significant increases of spectral power were observed in
W. Dimpfel et al.
153
the presence of the lower dosage only with respect to frontal theta power (elec-
trode positions F7 and F8). However, in the presence of the higher dosage statis-
tically significant increases of alpha1 and alpha2 power were recognized in fron-
tal (F3 and F4) central (C3 and C4), temporal (T4, 5, 6) and occipital brain areas
(O1,2). With respect to beta1 power only less prominent increases were seen.
Complete data with respect to all brain areas are documented in Figure 8. After
6 weeks of daily intake, fronto-temporal increases of alpha1 power were still vis-
ible but did not reach statistical significance in comparison to placebo. Signifi-
cant increases of theta power were confined to electrode positions C3 and T3 (not
shown).
3.9. Efficacy of Zembrin® in Brain Regions of Interest
Since different brain areas are functionally connected, analysis of the efficacy of
Zembrin® was calculated for two regions of interest: the fronto-temporal area
and the centro-occipital area. There is an obvious dose dependence with respect
to administration of Zembrin®, since the lower dose induced a statistically sig-
nificant increase of delta waves only during performance of the number identi-
fication test on the first day. Statistically significant increases of spectral power
in the presence of the higher dose were observed during several tests on both
days of recording. There was a highly significant increase of delta and theta
power during performance of the d2-test on the first day of recording (
p
< 0.01
and
p
< 0.05, respectively). During the number connection test, highly signifi-
cant increases of alpha1 and alpha2 spectral power were recognized on the first
day of recording. On the last day of recording, a highly significant increase of
Figure 8. Effect of Zembrin® in comparison to placebo on spectral frequencies in different
regions of the brain on the first recording day during performance of the number con-
nection test (NCT). Changes of spectral power are depicted in percent of the pre-drug
baseline recording on the ordinate. Electrode positions are labeled as C for central, F for
frontal, P for parietal, T for temporal and O for occipital. Even numbers describe data
from the right hemisphere, uneven numbers from the left hemisphere. Red bars: delta,
orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spectral power.
Error probability is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
W. Dimpfel et al.
154
theta power emerged. With respect to the d2-test now some increase of theta
power and a highly significant increase of alpha1 power were seen. During the
memory test and the number connection test a significant increase of alpha1
power was documented. An overview for the fronto-temporal area is given in
Figure 9.
In the centro-occipital region the lower dose of 25 mg induced statistically
significant increases of delta and theta power during relaxation on the first re-
cording day. The higher dose of 50 mg induced conspicuous (delta and alpha1)
or statistically significant (theta) increases of spectral power. The lower dose in-
duced a statistically conspicuous increase of beta2 and the higher dose highly
significant increases of beta1 and beta2 besides a conspicuous increase of alpha1
power during performance of the arithmetic calculation test. During perfor-
mance of the reaction time test both dosages led to statistically significant in-
creases of theta power. Performance of the number identification test induced
increase of delta, alpha1 and alpha2 waves. Performance of the number connec-
tion test induced a highly significant increase of alpha1, significant increase of
alpha2 and a conspicuous increase of beta1 power. In the presence of the higher
dose most of the recording conditions showed changes of spectral power on the
first day, less on the last day. Details are given in Figure 10.
3.10. Efficacy of Zembrin® with Respect to Repetitive Dosing
The question now arose if the daily repetitive dosing of Zembrin® had induced
long lasting changes of spectral power in any of the brain regions after 6 weeks.
In order to test this possibility, data recorded at the baseline of the first day were
set to 100% and spectral power at baseline of the last day was expressed as % of
the results of the first day. Results showed that both dosages of Zembrin® had
induced long lasting changes of brain responses during all test conditions. For
example, during the relaxed state delta and theta power at electrode position P4,
Pz and T6 were lower after six weeks daily intake of 25 mg Zembrin® in a signifi-
cant manner. After intake of 50 mg Zembrin® delta and theta power were signif-
icantly higher at F3 and C3 (Figure 11). During performance of the d2-test the
lower dosage significant higher delta activity was induced in comparison to the
first day of recording. Larger increases of delta and theta spectral power were
observed at electrode positions F3, C3 and F8 in comparison to the original re-
cordings on the first day after daily intake of 50 mg of Zembrin® (Figure 12).
After intake of the lower dosage of Zembrin® for 6 weeks a long- lasting change
of the brain’s response during performance of the memory test was observed as a
statistically significant increase of delta spectral power at electrode position T4.
Increases of delta, theta power were seen during performance of the memory test
after repetitive intake of the higher dosage in comparison to baseline recording
on the first day in frontal (F3), central (C3) and occipital (O1) electrode positions
(Figure 13). During performance of the arithmetic calculation test no long-
lasting changes of excitability except for delta power at T4 were seen. Statistically
significant general increases of power of all frequencies were observed at baseline
recording on the last day after repetitive intake of the higher dosage of Zembrin®
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155
Figure 9. Effect of Zembrin® (25 mg = yellow bars; 50 mg = red bars) on spectral power in all frequency ranges during recording
condition “eyes open” and during performance of tests in comparison to placebo (grey bars) at fronto-temporal electrode posi-
tions (Fz3478 T3456) on day A (first recording) and day B (last recording). Statistical significance according non-parametric
Wilcoxon test is indicated by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
W. Dimpfel et al.
156
Figure 10. Effect of Zembrin® (25 mg = yellow bars; 50 mg = red bars) on spectral power in all frequency ranges during recording
condition “eyes open” and during performance of tests in comparison to placebo (grey bars) at centro-occipital electrode posi-
tions (Cz,3,4 O1,2) on day A (first recording) and day B (last recording). Statistical significance according non-parametric Wil-
coxon test is indicated by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
W. Dimpfel et al.
157
Figure 11. Documentation of permanent changes induced by Zembrin® in comparison to
placebo on spectral frequencies in different regions of the brain in percent of the results
of the first recording day during relaxation. Electrode positions are labeled as C for cen-
tral, F for frontal, P for parietal, T for temporal and O for occipital. Even numbers de-
scribe data from the right hemisphere, uneven numbers from the left hemisphere. Red
bars: delta, orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1, blue: beta2 spec-
tral power. Error probability according to non-parametric Wilcoxon test is marked by
stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
Figure 12. Documentation of permanent changes induced by Zembrin® in comparison to
placebo on spectral frequencies in different regions of the brain in percent of the results
of the first recording day during performance of the d2-test. Electrode positions are la-
beled as C for central, F for frontal, P for parietal, T for temporal and O for occipital.
Even numbers describe data from the right hemisphere, uneven numbers from the left
hemisphere. Red bars: delta, orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1,
blue: beta2 spectral power. Error probability according to non-parametric Wilcoxon test
is marked by stars: * =
p
< 0.10; ** =
p
< 0.05.
at frontal (F3), central (C3) and temporal (T6) areas (Figure 14). In addition, be-
ta2 power was higher in central (Cz and C4) and frontal areas (F4 and F8) than on
the first day of recording during this test. During performance of the reaction
time test no major changes were observed after repetitive intake of the lower
W. Dimpfel et al.
158
Figure 13. Documentation of permanent changes induced by Zembrin® in comparison to
placebo on spectral frequencies in different regions of the brain in percent of the results
of the first recording day during performance of the memory-test. Electrode positions are
labeled as C for central, F for frontal, P for parietal, T for temporal and O for occipital.
Even numbers describe data from the right hemisphere, uneven numbers from the left
hemisphere. Red bars: delta, orange: theta, yellow: alpha1, green: alpha2, turquoise: beta1,
blue: beta2 spectral power. Error probability according to non-parametric Wilcoxon test
is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
Figure 14. Documentation of permanent changes induced by Zembrin® in comparison to
placebo on spectral frequencies in different regions of the brain in percent of the results
of the first recording day during performance of the arithmetic calculation test. Electrode
positions are labeled as C for central, F for frontal, P for parietal, T for temporal and O
for occipital. Even numbers describe data from the right hemisphere, uneven numbers
from the left hemisphere. Red bars: delta, orange: theta, yellow: alpha1, green: alpha2,
turquoise: beta1, blue: beta2 spectral power. Error probability according to non-parame-
tric Wilcoxon test is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
dosage. Statistically significantly higher alpha1 and alpha2 power became visible
after intake of the higher dosage frontally (F3) and temporally (T6) (Figure 15).
Strongest differences with respect to spectral power of the first day were ob-
served during performance of the number identification and number connection
W. Dimpfel et al.
159
tests. During performance of these tests significantly higher spectral power was
seen within all frequency ranges at several brain regions after daily intake of 50
mg of Zembrin® (Figure 16 and Figure 17).
Figure 15. Documentation of permanent changes induced by Zembrin® in comparison to
placebo on spectral frequencies in different regions of the brain in percent of the results
of the first recording day during performance of the reaction time test. Electrode posi-
tions are labeled as C for central, F for frontal, P for parietal, T for temporal and O for
occipital. Even numbers describe data from the right hemisphere, uneven numbers from
the left hemisphere. Red bars: delta, orange: theta, yellow: alpha1, green: alpha2, tur-
quoise: beta1, blue: beta2 spectral power. Error probability according to non-parametric
Wilcoxon test is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
Figure 16. Documentation of permanent changes induced by Zembrin® in comparison
to placebo on spectral frequencies in different regions of the brain in percent of the re-
sults of the first recording day during performance of the number identification test.
Electrode positions are labeled as C for central, F for frontal, P for parietal, T for tem-
poral and O for occipital. Even numbers describe data from the right hemisphere, un-
even numbers from the left hemisphere. Red bars: delta, orange: theta, yellow: alpha1,
green: alpha2, turquoise: beta1, blue: beta2 spectral power. Error probability according
to non-parametric Wilcoxon test is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
W. Dimpfel et al.
160
Figure 17. Documentation of permanent changes induced by Zembrin® in comparison to
placebo on spectral frequencies in different regions of the brain in percent of the results
of the first recording day during performance of the number connection test. Electrode
positions are labeled as C for central, F for frontal, P for parietal, T for temporal and O
for occipital. Even numbers describe data from the right hemisphere, uneven numbers
from the left hemisphere. Red bars: delta, orange: theta, yellow: alpha1, green: alpha2,
turquoise: beta1, blue: beta2 spectral power. Error probability according to non-parame-
tric Wilcoxon test is marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01.
3.11. Efficacy of Zembrin® in Brain Regions of Interest after
Repetitive Intake
In order to see if 6 weeks of Zembrin® intake resulted in long lasting changes of
the EEG spectra, frequency changes were compared by setting data from the first
day to 100% for monitoring the difference. In the fronto-temporal region con-
spicuous increases of theta and alpha1 power were registered during perfor-
mance of the d2-test. During performance of the memory test statistically signif-
icantly more beta2 spectral power was produced in comparison to the first day
recording. The same increase was seen during performance of the arithmetic
calculation test, where also alpha1 and beta1 power showed higher values. Dur-
ing performance of the reaction time test increases of alpha1, alpha2 and beta1
power increases were observed. Delta, theta and both beta frequencies went up
in a statistically significant manner during performance of the number identifi-
cation test, whereas all frequencies showed a statistically significant increase of
spectral power during performance of the number connection test. An overview
is depicted in Figure 18.
In the centro-occipital region also different responses of the brain to various
challenges were detected in comparison to the begin of the study. Obvious delta
power increases were seen during all tests except for the d2-test. Theta frequen-
cies were stronger enhanced during the memory test, the reaction time test and
number identification test. Highly statistically significant higher power values
were registered during performance of the reaction time and number identifica-
tion test. Beta1 and beta2 power values were larger during arithmetic calculation
and both number tests. Details are given in Figure 18.
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161
Figure 18. Documentation of changes of electric baseline patterns in particular brain regions of interest (ROI) after 6 weeks of
repetitive dosing of placebo (grey bars), 25 mg of Zembrin® (yellow bars) or 50 mg of Zembrin® (red bars) Ordinate: spectral pow-
er in % of the recordings of the first day before intake at the experimental day. Left side: fronto-temporal region, right side: centro-
occipital region. Changes are given for all frequency ranges: delta, theta, alpha1, alpha2, beta1 and beta2 waves. Statistical differ-
ences to placebo are marked by stars: * =
p
< 0.10; ** =
p
< 0.05; *** =
p
< 0.01 according to Non-parametric Wilcoxon test.
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162
3.12. Efficacy of Zembrin® Documented by Discriminant Analysis
Discriminant analysis is a statistical tool to separate large data sets from each
other. In the past, data from several studies dealing with the effects of clinically
used pharmaceutical drugs and botanical extracts were fed into this type of
analysis based on 102 different EEG parameters (17 brain areas times 6 frequen-
cy ranges). Through this data set, a matrix of discriminant functions was built,
on which data from new investigative products can be compared. If preparations
cluster together in space (x, y and z coordinates), a similar CNS clinical indica-
tion can be assumed. If the color is also similar a related mechanism of action is
very probable. Data obtained after intake of Zembrin® were projected into the
vicinity of products with proven calming action including Calmvalera and a
Ginkgo-Ginseng preparation tested earlier. At some distance (blue, more in the
back) the antidepressant drug fluoxetine and the calming preparation Neurexan
(red) were projected, however, with a different color. The effect of Zembrin® in
comparison with other drugs and preparations is documented in Figure 19.
3.13. Efficacy of Zembrin® during Psychometric Testing
Performance of psychometric testing revealed statistically significant improve-
ment in two different tests: CPT = arithmetic calculation test and NCT = num-
ber connection test (Table 5). Performance of the difficult arithmetic calculation
test was statistically significant better in the presence of both dosages of Zem-
Figure 19. Result of discriminant analysis based on all brain regions and frequencies (102
parameters). Results from the first three discriminant functions are depicted with the
space coordinates x, y and z. Results from the next three discriminant functions are de-
picted as RGB colour mixture like in TV technology. Pl = placebo; Zemb25 = 25 mg
ZEMBRIN®, Zemb50 = 50 mg ZEMBRIN®. If preparations cluster together in space (x, y
and z coordinates) a similar clinical indication can be assumed. If the color is also similar,
a related mechanism of action is very probable. This is for Ginkgo/Ginseng the case.
W. Dimpfel et al.
163
Table 5. Mental performance (definition see under methods, reaction time is given in
ms) in cognitive tests 1 h after intake of 25 mg Zembrin® (Zem25), 50 mg Zembrin® (Zem
50) or placebo. SD = standard deviation.
p
-values are documented according to two-sided
T-test for independent samples.
Mental performance in cognitive tests on day A and day B 1 h after intake
Day A (acute)
Day B (repetitive)
Performance of d2 Test (d2)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
1 h
Mean
11.02
11.57
11.11
12.18
12.46
12.38
SD ±3.02 ±2.95 ±2.69 ±3.61 ±2.82 ±2.67
Performance of Memory Test (ME)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
1 h
Mean
6.51
7.05
6.60
7.10
6.51
7.73
SD ±1.93 ±2.51 ±2.42 ±2.51 ±2.18 ±1.93
Performance of Arithmetic Calculation (CPT)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
1 h
Mean
2.41
4.09
3.86
2.67
3.26
3.19
SD ±1.68 ±2.54 ±2.14 ±2.34 ±2.49 ±2.82
p
< 0.02
p
< 0.03
Performance of Reaction Time Test (RT)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
1 h
Mean
420.73
419.29
420.96
408.75
405.96
412.53
SD ±39.53 ±37.83 ±48.54 ±30.78 ±41.76 ±37.65
Performance of Number Identifying Test (NIT)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
1 h
Mean
28.42
29.80
28.60
29.59
30.28
29.96
SD ±.97 ±1.76 ±3.74 ±2.24 ±2.23 ±1.75
Performance of Number Connection Test (NCT)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
1 h
Mean
125.43
162.06
137.32
140.08
162.51
138.59
SD ±54.45 ±31.49 ±42.22 ±48.68 ±29.96 ±32.49
p
< 0.01
p
< 0.09
brin® on the first day (day A), whereas improvement in the number connection
test (NCT) was only significant in the presence of the lower dosage, however, on
both recording days. However, both performance values were also considerably
higher after repetitive dosing, but did not reach statistical significance.
A comparison of all tests between the baseline of the first day and the baseline
of the last day was calculated in order to see if the intake of Zembrin during 6
weeks had resulted in better performance.
This was the case with respect to nearly all tests but statistical significance in
comparison to placebo was only reached with respect to the lower dose for the
number identifying test, and for the d2-test after intake of the higher dose.
However, improvement was also seen with respect to the number connection
test in the placebo group. Complete data are given in Table 6.
W. Dimpfel et al.
164
Table 6. Mental performance (definition see under methods; reaction time is given in
ms) in cognitive tests before intake of 25 mg Zembrin® (Zem25), 50 mg Zembrin® (Zem
50) or placebo at beginning of the trial and after 6 weeks of daily intake. SD = standard
deviation.
p
-value in NCT is documented according to two-sided T-test for independent
samples.
Performance of cognitive tests on day A and day B before intake (0h)
Performance of d2 Test (d2)
Placebo
Zem25
Zem50
Day A (acute)
Mean
10.12
10.60
10.41
SD 3.07 2.98 3.05
Day B (repetitive)
Mean
11.50
11.85
11.91
SD 3.45 2.81 2.31
p
< 0.10
Performance of Memory Test (ME)
Placebo
Zem25
Zem50
Day A (acute)
Mean
5.90
6.82
6.22
SD 2.59 3.25 2.82
Day B (repetitive)
Mean
6.14
7.25
6.48
SD 2.90 2.51 2.40
Performance of Arithmetic Calculation Test (CPT)
Placebo
Zem25
Zem50
Day A (acute)
Mean
2.17
3.33
2.97
SD 1.75 2.86 2.93
Day B (repetitive)
Mean
2.63
3.40
2.53
SD 2.02 2.94 1.76
Performance of Reaction Time Test (RT)
Placebo
Zem25
Zem50
Day A (acute)
Mean
431.15
432.52
422.36
SD 32.32 29.77 47.44
Day B (repetitive)
Mean
419.57
417.30
421.90
SD 40.21 39.99 35.70
Performance of Number Identifying Test (NIT)
Placebo
Zem25
Zem50
Day A (acute)
Mean
29.10
28.63
28.23
SD 1.91 2.97 4.18
Day B (repetitive)
Mean
28.32
30.64
28.89
SD 6.09 0.89 2.79
p
< 0.01
Performance of Number Connection Test (NCT)
Placebo
Zem25
Zem50
Day A (acute)
Mean
115.88
139.90
110.66
SD 43.33 27.97 42.12
Day B (repetitive)
Mean
137.60
150.27
127.82
SD 36.53 29.21 31.20
p
< 0.10
W. Dimpfel et al.
165
3.14. Efficacy of Zembrin® as Determined by Filling out
Questionnaires
Three questionnaires were filled out after intake of the three preparations: The
Profile of Mood States (POMS), The Hamilton Anxiety Scale (HAM-A) and the
“Schlaffragebogen” SF-B. Results obtained by the POMS revealed improvement
with respect to all score values, but statistical conspicuousness was only reached
with respect to thirst of action (S4) with the lower dosage on day A and with re-
spect to sullenness (S2) and fatigue (S3) on day B with the higher dosage. Details
are given in Table 7.
Evaluation of the HAM-A questionnaire revealed lower scores at day B in the
presence of both dosages. However, a statistically significant lower score on day
B was only recognized for the higher dosage (
p
< 0.03). Details are given in Ta-
ble 8.
Results from the “Schlaffragebogen SF-B” did not reveal differences with re-
spect to score values before or after intake of both dosages of Zembrin®. Aver-
aged score values are given in Table 9.
4. Discussion
Quantitative EEG measurements have been extensively used in the past to cha-
racterize drug action on the brain [10] [17]. Interpretation of the major neuro-
transmitter activities underlying frequency changes has become possible through
preclinical experiments using several selective neurotransmitter agonists and
antagonists. For example, delta waves have been shown to reflect actions of ace-
tylcholine, theta waves actions of norepinephrine. Pharmacological intervention
with the serotonergic system resulted in changes of alpha1 frequencies [25],
whereas dopaminergic activity could be recognized by changes of alpha2 waves
[26]. Finally, changes in the glutamatergic transmitter system were reflected in
changes of beta1 activity [11] and GABA-ergic modulation was recognized by
changes in beta2 frequencies [27].
Table 7. Result from POMS score questionnaire. S1 = Dejection (Niedergeschlagenheit), S2 = Sullenness (Missmut), S3 = Fatigue
(Müdigkeit), S4 = Thirst for action (Tatendrang). Zem25 = 25 mg Zembrin®, Zem50 = 50 mg Zembrin®.
POMS-questionnaire
Day A (acute)
Day B (repetitive)
S1
Dejection
S2
Sullenness
S3
Fatigue
S4
Thirst for action
S1
Dejection
S2
Sullenness
S3
Fatigue
S4
Thirst for action
Placebo
n = 20
Mean
0.35
0.48
1.61
2.54
0.39
0.39
2.06
2.64
SD 0.64 0.90 1.30 1.43 0.78 0.60 1.60 1.52
Zem25
n = 20
Mean
0.19
0.26
1.16
3.19
0.10
0.21
1.59
2.84
SD 0.28 0.46 1.05 1.07 0.19 0.43 1.50 1.19
Placebo_Zem25
p
< 0.10
Zem50
n = 19
Mean
0.24
0.23
1.20
2.85
0.20
0.14
1.29
2.47
SD 0.32 0.36 1.11 1.14 0.31 0.20 1.04 1.45
Placebo_Zem50
p
< 0.08
p
< 0.09
W. Dimpfel et al.
166
Table 8. Comparison of HAMA scores (Hamilton Anxiety Scale) on the first and last day
after repetitive intake. Zem25 = 25 mg Zembrin®, Zem50 = 50 mg Zembrin®. Difference
between day A and day B: * =
p
< 0.03.
HAMA (Hamilton Anxiety Scale)
Day A (acute)
Day B (repetitive)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
Mean
10.80
7.90
11.05 *
9.30
6.65
6.37 *
SD 5.63 4.27 7.40 6.73 5.55 5.12
Table 9. Results from Schlaffragebogen SF-B (questionnaire). Zem25 = 25 mg Zembrin®,
Zem50 = 50 mg Zembrin®.
SF-B (Schlaffragebogen B)
Day A (acute)
Day B (repetitive)
Placebo
Zem25
Zem50
Placebo
Zem25
Zem50
Mean
3.49
3.64
3.60
3.63
3.63
3.57
SD 0.77 0.44 0.58 0.75 0.64 0.47
After finding evidence for an acute dose dependent action of Zembrin® on
electric brain activity in an earlier study [16], the present experimental series
aimed at collecting evidence on its efficacy after daily repetitive dosing for 6
weeks. EEG’s were recorded during several conditions and gave similar starting
values in terms of absolute power in the relaxed state. Performance of different
cognitive tests revealed that electric activity changed according to the particular
test with high statistical significance in comparison to the relaxed state. Efficacy
of Zembrin® was observed with respect to all frequencies.
In the fronto-temporal region (this brain region has been recognized to be
very important for memory retrieval [28], increases of delta activity during per-
formance of the d2-test, the number identification and number connection test
were observed in the presence of Zembrin®. These additional increases of delta
waves in comparison to baseline indicate a more positive intense brain activity
and mental activation. Based on the evidence that delta waves reflect the activity
of the cholinergic transmitter system, Zembrin® seems to modulate this activity.
Acetylcholine is used in electric circuits related to cognitive processing. Higher
theta activity was seen in this brain area during relaxation and performance of
the d2-test on both recording days after intake of the higher dosage of Zembrin®.
Frontal increases of theta waves are regularly observed during concentration and
higher attention related to memory [29] and reflect consciousness [30]. Addi-
tional increases after intake of Zembrin® may therefore be interpreted as an in-
crease of attention. The marked influence of these neurochemical systems also
on prefrontal memory processes has been widely described [31]. Statistically
conspicuous increases of alpha1 spectral power as seen in the relaxed state after
intake of Zembrin® must be regarded as a state of increased calmness. Biochem-
ically this corresponds to increases of serotonergic activity possibly also reflect-
W. Dimpfel et al.
167
ing improvement of mood. It is interesting that one of the reported mechanisms
of action of Zembrin® is serotonin reuptake inhibition [32]. With respect to al-
pha2 spectral power, which has been related to cognitive and memory perfor-
mance [33], larger statistically significant increases were observed during per-
formance of the memory test and number connection test in the fronto-tem-
poral region. Alpha2 waves are under the control of dopamine [26]. A relatively
selective role for prefrontal dopamine in spatial memory was reported more than
three decades ago [34]. Increases of alpha2 waves were observed also in the cen-
tro-occipital region. These waves are normally attenuated within this brain re-
gion during strong mental activity. Less attenuation of alpha2 activity may
therefore indicate a less stressful experience of the tests. In the fronto-temporal
region a statistically conspicuous increase was only observed during perfor-
mance of the number identifying test. No major changes of spectral beta power
were recognized except for the performance of the arithmetic calculation test
(CPT) in the centro-occipital brain region. Here, both dosages of Zembrin® ex-
erted statistically conspicuous and significantly different increases of spectral
power in comparison to placebo. However, this effect was probably due to un-
usual low power during the placebo condition and do not reflect a true effect of
Zembrin® (Figure 10).
Discriminant analysis revealed a clear separation not only between placebo
and verum, but also with respect to different recording conditions on both re-
cording days. This can be taken as evidence that the lower dosage also exerted
enough efficacy to be separated by this kind of analysis (not shown). A second
approach using the discriminant analysis for comparison with other CNS drug
and preparation profiles revealed a projection of the Zembrin® data into the vi-
cinity of calming preparations like Calmvalera. The activity interpreted from the
discriminant analysis projection is consistent with the increases of alpha1 spec-
tral power observed during different recording conditions. Zembrin® also pro-
jected in the vicinity of a cognition enhancing mixture of the botanicals Gink-
go/Ginseng. From this, a positive effect on cognition may be interpreted for
Zembrin®, supported by the detailed frequency analysis on single dose activity.
Regarding the effect of daily intake of Zembrin® during 6 weeks, the data of
the two baselines recorded on the first and last day before intake of the prepara-
tions were compared. Data from the first day were set to 100% as reference. As
documented, spectral power had not changed over time with respect to the re-
laxed state, but consisted in test dependent increases of spectral power in many
brain regions. The strongest changes were seen with respect to beta power when
performing the arithmetic calculation (CPT), number identification (NIT) and
number connection test (NCT). This indicates that the repetitive intake of Zem-
brin® has led to a measurable different electric response of the brain in the pres-
ence of mental loads, meaning the reactivity of the brain had changed. Due to
this, change of responses to various challenges on this second experimental day
are somewhat different in comparison to the recording of the first day. With re-
spect to the two previously specified regions of interest, differences between the
W. Dimpfel et al.
168
two experimental days were statistically conspicuous or significant during per-
formance of all tests, but not in the relaxed state (eyes open). Very strong dif-
ferences are noted between the first and last recordings taken before intake of
Zembrin®..These differences were also documented with respect to beta power
during several different tests (Figure 18). This suggests that daily intake has also
modulated glutamatergic and GABA-ergic neurotransmission. This interpreta-
tion is in line with preclinical ex vivo testing in the hippocampal slice prepara-
tion, where Zembrin® was able to attenuate the amplitude of the population
spike by interfering with glutamatergic transmission (to be published). Similar
effects in this model have been seen with all calming and antidepressant drugs.
Positive effects of Zembrin® on cognition may therefore be indirect and based on
its calming or anxiolytic action, as it is well known that stress negatively affects
executive function. Another explanation with respect to the positive action of
Zembrin® on cognitive function parameters reported in a previous clinical study
[15] may be inhibition of phosphodiesterase 4, reports earlier [32].
Results from psychometric testing revealed improvements from both dosages
during performance of the arithmetic calculation test (CPT) on the first experi-
mental day and in the presence of the lower dosage during performance of the
number connection test (NCT) on both experimental days. Evaluation from the
POMS questionnaire revealed improvements of all scores, but no statistical sig-
nificance was reached, probably due to high scatter of score values. Sullenness
and fatigue scores decreased statistically conspicuously (
p
< 0.09) on the last ex-
perimental day. With respect to the HAM-A anxiety scale a comparison of the
score obtained after repetitive intake of 50 mg of Zembrin® with the starting
score on the first experimental day revealed a statistically significant decrease of
the score (
p
= 0.03). This behavioral result is consistent with the changes seen in
brain electric activity in response to mental loads after repetitive dosing.
5. Conclusion
In summary, this double-blind, randomized, placebo-controlled clinical study
revealed a dose dependent effect of Zembrin® on three levels of evidence: at the
level of questionnaires, at the level of psychometry, and the level of quantitative
EEG. The overall results support the use of Zembrin® as a functional food with
potential to improve mental health and enhance well-being with respect to cog-
nitive function, anxiety, stress and mood. Facing an ever-increasing level of
stress and anxiety (for example to lose the job) or a decline of cognitive function
in the elderly, the results of this clinical study open the door to better cope with
daily life. A future controlled clinical study on Zembrin® should be considered in
subjects suffering from exam-related anxiety, to investigate activity on the cog-
nitive- function, perceived stress and anxiety.
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