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Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained 'mentally demanding' tasks

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Abstract

Single doses of the traditional herbal treatment Panax ginseng have recently been shown to lower blood glucose levels and elicit cognitive improvements in healthy, overnight-fasted volunteers. The specific mechanisms responsible for these effects are not known. However, cognitive improvements may be related to the glycaemic properties of Panax ginseng. Using a double-blind, placebo-controlled, balanced-crossover design, 27 healthy young adults completed a 10 minute “cognitive demand” test battery at baseline. They then consumed capsules containing either ginseng (extract G115) or a placebo and 30 minutes later a drink containing glucose or placebo. A further 30 minutes later (i.e. 60 minutes post-baseline/capsules) they completed the “cognitive demand” battery six times in immediate succession. Depending on the condition to which the participant was allocated on that particular day, the combination of capsules/drink treatments corresponded to a dose of: 0mg G115/0mg glucose (placebo); 200mg G115/0mg glucose (ginseng); 0mg G115/25g glucose (glucose) or 200mg G115/25g glucose (ginseng/glucose combination). The 10 minute “cognitive demand” battery comprised a Serial Threes subtraction task (2 min); a Serial Sevens subtraction task (2 min); a Rapid Visual Information Processing task (5 min); and a “mental fatigue” visual analogue scale. Blood glucose levels were measured prior to the day's treatment, and before and after the post-dose completions of the battery. The results showed that both Panax ginseng and glucose enhanced performance of a mental arithmetic task and ameliorated the increase in subjective feelings of mental fatigue experienced by participants during the later stages of the sustained, cognitively demanding task performance. Accuracy of performing the Rapid Visual Information Processing task (RVIP) was also improved following the glucose load. There was no evidence of a synergistic relationship between Panax ginseng and exogenous glucose ingestion on any cognitive outcome measure. Panax ginseng caused a reduction in blood glucose levels 1 hour following consumption when ingested without glucose. These results confirm that Panax ginseng may possess glucoregulatory properties and can enhance cognitive performance.
Effects of
Panax ginseng
, consumed
with and without glucose, on blood
glucose levels and cognitive
performance during sustained
‘mentally demanding’ tasks
Jonathon L. Reay Human Cognitive Neuroscience Unit, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK.
David O. Kennedy Human Cognitive Neuroscience Unit, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK.
Andrew B. Scholey Human Cognitive Neuroscience Unit, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK.
Abstract
Original Papers J
Psychopharm
Journal of Psychopharmacology
20(6) (2006) 771–781
©2006 British Association
for Psychopharmacology
ISSN 0269-8811
SAGE Publications Ltd,
London, Thousand Oaks,
CA and New Delhi
10.1177/0269881106061516
Single doses of the traditional herbal treatment Panax ginseng have
recently been shown to lower blood glucose levels and elicit cognitive
improvements in healthy, overnight-fasted volunteers. The specific
mechanisms responsible for these effects are not known. However,
cognitive improvements may be related to the glycaemic properties of
Panax ginseng.
Using a double-blind, placebo-controlled, balanced-crossover design,
27 healthy young adults completed a 10 minute ‘cognitive demand’ test
battery at baseline. They then consumed capsules containing either
ginseng (extract G115) or a placebo and 30 minutes later a drink
containing glucose or placebo. A further 30 minutes later (i.e. 60
minutes post-baseline/capsules) they completed the ‘cognitive demand’
battery six times in immediate succession. Depending on the condition
to which the participant was allocated on that particular day, the
combination of capsules/drink treatments corresponded to a dose of:
0 mg G115/0 mg glucose (placebo); 200 mg G115/0 mg glucose (ginseng);
0 mg G115/25 g glucose (glucose) or 200 mg G115/25 g glucose
(ginseng/glucose combination). The 10 minute ‘cognitive demand’
battery comprised a Serial Threes subtraction task (2 min); a Serial
Sevens subtraction task (2 min); a Rapid Visual Information Processing
task (5 min); and a ‘mental fatigue’ visual analogue scale. Blood glucose
levels were measured prior to the day’s treatment, and before and after
the post-dose completions of the battery.
The results showed that both Panax ginseng and glucose enhanced
performance of a mental arithmetic task and ameliorated the increase in
subjective feelings of mental fatigue experienced by participants during
the later stages of the sustained, cognitively demanding task
performance. Accuracy of performing the Rapid Visual Information
Processing task (RVIP) was also improved following the glucose load.
There was no evidence of a synergistic relationship between Panax
ginseng and exogenous glucose ingestion on any cognitive outcome
measure. Panax ginseng caused a reduction in blood glucose levels 1 hour
following consumption when ingested without glucose.
These results confirm that Panax ginseng may possess gluco-
regulatory properties and can enhance cognitive performance.
Keywords
Panax, ginseng, cognitive performance, acute, placebo, blood glucose,
hypoglycaemia, healthy adults.
Introduction
The use of extracts of cultivated members of the Panax genus
(ginseng) is documented as early as the first century (Hu, 1997) in
the Pen-ts’ao-ching of Shên-nung (the divine plowman). Wild
ginseng is also thought to have been in medicinal use for several
thousand years before this time (Yun, 2001). Ginseng’s traditional
use is as a ‘panacea’ or whole body treatment. However, in the US
it has previously been reported to be the most popular self-
administered psychoactive herbal product (Barnes et al., 2004)
with many consumers taking it to aid ‘memory loss’ and ‘absent-
mindedness’ (see: Kennedy and Scholey, 2003). Despite an exten-
sive literature documenting the effects of ginseng on potentially
relevant physiological parameters, chronic administration of
ginseng in humans has produced little evidence of behavioural
effect. This lack of evidence of efficacy may be accounted for by
Corresponding author: David O. Kennedy, Human Cognitive Neuroscience Unit, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK.
Email: david.kennedy@northumbria.ac.uk
the methodological shortcomings in the research. For instance,
few human studies have used adequately standardized ginseng
extracts, and many fail to adopt double blind or placebo controls
(for reviews see: Vogler et al., 1999; Bahrke and Morgan, 1994,
2000; Kennedy and Scholey, 2003).
A recent series of placebo-controlled, double-blind, balanced-
crossover studies has demonstrated modulation of cognitive per-
formance following single doses of Panax ginseng (standardized
extract G115) in young healthy humans. The most consistent
finding is of improved memory performance following G115
alone (Kennedy et al., 2001a, 2002, 2004) and in combination
with both Ginkgo biloba (Kennedy et al., 2001b, 2002) and
guarana (Paullinia cupana) (Kennedy et al., 2004). Whilst these
mnemonic effects appear to be robust, particularly following a
single dose of 400mg in one instance, both lower (200 mg) and
higher (600mg) doses led to significantly slower performance of
attentional tasks (Kennedy et al., 2001b). Similarly, in the same
cohort, whilst 400mg improved accuracy of performing a serial
subtraction task, 200mg led to modest, but significant, reductions
in the speed of performing the same task (Scholey and Kennedy,
2002). These decrements in the speed of task performance contrast
with recent findings for the same 200mg dose of improved speed
of information retrieval, attention and arithmetical performance
(Kennedy et al., 2004; Reay et al., 2005), and significantly short-
ened latency of the P300 component of auditory evoked potentials
(Kennedy et al., 2003), and faster responses on an attentional task
90 minutes following 400mg of G115 (Sünram-Lea et al., 2004).
The mechanisms by which ginseng might modulate human
cognitive performance are not yet well understood, but they may
involve several central and peripheral physiological effects that
are potentially relevant to human cognitive performance. These
include effects on the cardiovascular system, platelet aggregation,
the Hypothalamic-Pituitary-Adrenal system, neurotransmission
and nitric oxide synthesis (see: Kennedy and Scholey, 2003).
Ginseng extracts have also been shown to have gluco-
regulatory properties. For instance, the long-term and acute hypo-
glycaemic effects of ginseng have been demonstrated both in
rodents (Ohnishi et al., 1996; Xie et al., 2002) and humans
(Sotaniemi et al., 1995; Tetsutani et al., 2000; Vuksan et al.,
2000a, b, 2001). With regards to Panax ginseng, a reduction in
fasted blood glucose levels and glycated haemoglobin were
reported following 8 weeks’ administration of 100mg and 200
mg/day of an unspecified extract in 18 participants with type 2
Diabetes Mellitus (Sotaniemi et al., 1995). Similarly, Tetsutani et
al. (2000) reported that 24 months of treatment with 3–4.5g/day
of Korean red Panax ginseng decreased HbA1c (an index of
average blood glucose levels over approximately the previous
month) in 34 type 2 diabetics compared with controls. In the case
of Panax quinquefolius (American ginseng), a decrease in fasted
blood glucose and HbA1c, has been reported in 24 type 2 diabetic
patients following 8 weeks’ administration of 1g of a proprietary
ginseng extract, taken 40 minutes before each meal (Vuksan et al.,
2000b). The hypoglycaemic effects of single doses of P. quinque-
folius have also been demonstrated, with reductions in blood
glucose levels following a 25g glucose challenge, during a 120
minute oral glucose tolerance test in both diabetic patients who
had ingested 3g, 6 g and 9 g (Vuksan et al., 2000a, b), and healthy
participants administered 1g, 2 g and 3 g of P. quinquefolius
(Vuksan et al., 2000a, 2001).
It has previously been established that fluctuations in levels of
circulating blood glucose can modulate cognitive performance.
Cognitive impairment has been demonstrated as a result of both
hypoglycaemia (Holmes et al., 1984; Gold et al., 1985) and
lowered but supra-hypoglycaemic glucose levels (De Feo et al.,
1988; Taylor and Rachman, 1988). Conversely, cognitive
enhancement has been demonstrated across a wide variety of tasks
following a glucose drink (Benton, 1990; Martin and Benton,
1999; Donohoe and Benton, 2000; Kennedy and Scholey, 2000;
Scholey et al., 2001; Sünram-Lea et al., 2002). Other studies have
reported a positive association between the rate at which a
person’s blood glucose levels fall, following an initial peak, and
the level of cognitive performance, particularly during periods of
cognitive demand (Scholey et al., 2001). It follows that any inter-
vention which modulates glucose transport may also affect cogni-
tive performance. There is some support for this notion from the
finding that insulin administration can improve memory in suffer-
ers from Alzheimer’s disease (Watson and Craft, 2004).
Additionally, and of particular relevance to the present study,
Reay et al. (2005) previously reported a placebo-controlled,
double-blind, balanced-crossover study, that demonstrated that the
administration of either 200mg or 400 mg of Panax ginseng
(G115) led to significant reductions in blood glucose levels, with
concomitant speeded performance on a serial subtraction task and
amelioration of mental fatigue following the 200mg dose.
Although this relationship between lowered blood glucose and
raised cognitive performance was not expected, one explanation
for such findings is that increased cellular uptake of blood glucose
resulted in better performance and a concurrent fall in blood
glucose levels. However, it should be noted that there was no cor-
relation between change in cognitive performance and change in
blood glucose following the treatments.
Given the above, it seems expedient to investigate the relation-
ship between the administration of both glucose and ginseng on
cognitive performance and blood glucose levels. Given that cogni-
tively demanding tasks may be the most sensitive to glucose-
related effects, the present placebo-controlled, double-blind,
balanced-crossover study investigated the effects of single doses
of: Panax ginseng (200 mg G115); glucose (25 g); and a combina-
tion of Panax ginseng and glucose (200mg G115 + 25 g glucose)
on blood glucose levels and cognitive performance during sus-
tained ‘mentally demanding’ tasks.
Subjects and methods
Participants
Seventeen male and ten female undergraduate volunteers (mean
age 21.89 years, S.D. 4.64) participated in the study, which was
approved by the Northumbria University Division of Psychology
Ethics committee and conducted in accordance with the Declara-
tion of Helsinki. Prior to participation each participant gave
772 Panax ginseng: effects on blood glucose and cognitive performance
informed consent and completed a medical health questionnaire.
All participants reported that they were in good health, and that
they were free from heart disorders, high blood pressure, respira-
tory disorders, epilepsy, panic attacks and diabetes. Additionally,
they reported being free from ‘over-the-counter’ treatments, illicit
social drugs and prescribed medications, with the exception, for
some female volunteers, of the contraceptive pill. Heavy smokers
(>10 cigarettes/day) and pregnant females were excluded from the
study. Of the 27 participants one was a light smoker (two per day),
and this participant agreed to abstain from smoking on the days of
testing. All participants were overnight fasted, were alcohol free
for 12 hours prior to baseline measure, and abstained from prod-
ucts containing caffeine on the days of testing. Volunteers were
paid £80 for their participation. Participants were randomly alloc-
ated a position on a Latin Square counterbalancing the treatment
order by the computerised generation of random numbers.
The sample size employed was as per a previous study utilizing
the same methodology (Reay et al., 2005), which in turn was
arrived at via a power calculation.
Blood glucose measurement
Blood glucose levels were monitored using a Reflotron Plus diag-
nostic machine and test sticks (Roche Diagnostics, Germany). The
reliability of the test has previously been confirmed (Price and
Koller, 1988).
On each of the four study days, blood glucose levels were
measured via capillary finger prick at baseline, 1 hour post-treat-
ment (before commencement of the first post-dose battery comple-
tion), and after the sixth (i.e. end of testing) completion of the
demand battery.
Cognitive demand battery
A 10 minute, computerized ‘cognitive demand battery’ compriz-
ing the Serial Threes subtraction task (2 mins), Serial Sevens sub-
traction task (2 mins), a Rapid Visual Information Processing task
(RVIP – 5 mins), and a ‘mental fatigue’ visual analogue scale, was
utilized. Tasks within this battery have been shown to be sensitive
to the effects of Ginkgo biloba and Panax ginseng (Scholey and
Kennedy, 2002), and a glucose drink (Scholey et al., 2001). The
overall experimental paradigm has been used to demonstrate posit-
ive effects of a caffeine/glucose energy drink (Kennedy and
Scholey, 2004) and Panax ginseng (Reay et al., 2005). The indi-
vidual tasks are described below.
Serial Sevens A modified computerized version of the Serial
Sevens test was utilized. The original verbal Serial Sevens test
(Hayman, 1942) has appeared in a number of forms, including as
part of the Mini-Mental State Examination for dementia screening
(Folstein et al., 1975). It has been used to assess cognitive impair-
ment during hypoglycaemia (Hale et al., 1982; Taylor and
Rachman 1988), and has also been used to investigate the relation-
ship between blood glucose levels and cognitive performance
(Kennedy and Scholey, 2000; Scholey et al., 2001; Scholey, 2001)
and the acute effects of ginkgo and ginseng (Scholey and
Kennedy, 2002). In the current study, computerized versions of
serial subtraction tasks were implemented (see Scholey et al.,
2001 for details), using tests of 2 mins duration. For the Serial
Sevens task a standard instruction screen informed the participant
to count backwards in sevens from the given number, as quickly
and accurately as possible, using the keyboard’s linear number pad
to enter each response. Participants were also instructed verbally
that if they were to make a mistake they should carry on subtract-
ing from the new incorrect number. A random starting number
between 800 and 999 was presented on the computer screen,
which was cleared by the entry of the first response. Each three-
digit response was entered via the numeric keypad with each digit
being represented on screen by an asterisk. Pressing the enter key
signalled the end of each response and cleared the three asterisks
from the screen. The task was scored for total number of subtrac-
tions and number of errors. In the case of incorrect responses, sub-
sequent responses were scored as positive if they were correct in
relation to the new number.
Serial Threes The Serial Threes task was identical to Serial
Sevens, except that it involved serial subtraction of threes.
Rapid Visual Information Processing task (RVIP) This task
has been widely used to study the cognitive effects of psy-
chotropic drugs, and has been shown to be sensitive to aug-
mented blood glucose levels (Donohoe and Benton, 1999). The
participant monitors a continuous series of digits for targets of
three consecutive odd or three consecutive even digits. The
digits are presented on the computer screen at the rate of 100 per
minute in pseudo-random order and the participant responds to
the detection of a target string by pressing the space bar as
quickly as possible. The task is continuous and lasts for 5
minutes, with eight correct target strings being presented in each
minute. The task is scored for number of target strings correctly
detected, average reaction time for correct detections and
number of false alarms.
‘Mental fatigue’ visual analogue scale Participants rated their
subjective feelings of mental fatigue on a 100mm visual analogue
scale with the left and right end-points labelled ‘not at all’ and
‘very much so’ respectively.
Treatments
Ginseng capsule treatment Active treatments and placebo cap-
sules, matched for size, colour, opacity and odour were provided
by the manufacturer. The individual capsules contained either an
inert placebo, or 100mg of Panax ginseng extract (G115, Pharma-
ton SA, Lugano, Switzerland).
Glucose drink treatment Active treatments and placebo drinks,
matched for sweetness, volume (180ml of tap water and 20 ml of a
sugar-free fruit cordial drink), odour and colour were mixed in the
laboratory on each day of testing. The individual drinks contained
either 25g of glucose or 30 mg of saccharin.
Panax ginseng: effects on blood glucose and cognitive performance 773
Treatment preparation and administration Prior to the com-
mencement of the study, a disinterested third party, who had no
other involvement in the study, prepared the capsule treatments for
each of the individual participants (in accordance with the study’s
Latin Square) and sealed them in containers marked only with the
participant code and study day number. The same third party pre-
pared the glucose and placebo drinks for each participant (in
accordance with the study’s Latin Square) on the morning of each
study day. Depending on the condition to which the participant
was allocated on that particular day, the combination of capsules
and drink corresponded to a dose of: 0mg G115/0 mg glucose
(placebo); 200mg G115/0 mg glucose (ginseng); 0 mg G115/25 g
glucose (glucose) or 200mg G115/25 g glucose (ginseng/glucose
combination).
Procedure
Each participant was required to attend a practice day and 4 active
study days that were conducted not less than 7 days apart to ensure
a sufficient washout period between conditions. Testing took place
in a suite of research-dedicated laboratories with participants visu-
ally isolated from each other.
On arrival on the practice day, participants were randomly
allocated to a treatment regimen according to a Latin Square that
counterbalanced the order of treatments across the 4 active days of
the study.
The practice day was identical to the 4 study days with the
exception that no treatment was offered, nor analysis of the result-
ing data undertaken.
On the 4 remaining study days (testing commencing at 9.00
AM after an overnight fast), after an initial practice run through
the 10-minute ‘cognitive demand battery’ (Serial Threes – 2 mins,
Serial Sevens – 2 mins, RVIP – 5 mins, Mental fatigue rating
scale) on arriving at the laboratory (data not analysed), each par-
ticipant completed the 10-minute cognitive demand battery pre-
dose, followed immediately by ingestion of either 200mg G115 or
placebo capsules. This in turn was followed 30 minutes later by
the ingestion of a 200ml drink which had dissolved within it either
25g of glucose or a saccharine placebo. Thus, the participants
received one of the following treatments: 0mg G115/0 mg glucose
(placebo); 200mg G115/0 mg glucose (ginseng); 0 mg G115/25 g
glucose (glucose) or 200mg G115/25 g glucose (ginseng/glucose
combination). Commencing 30 minutes after consuming the day’s
drink treatment the participants completed the demand battery six
times in succession (i.e. a total of 60 minutes of continuous task
performance). Participant’s blood glucose levels were measured
pre-dose, 1 hour post-dose (i.e. before commencing the cognitive
tasks), and after the six completions of the ‘cognitive demand
battery’.
Statistics
‘Change from baseline’ scores on the serial subtractions, RVIP,
subjective mental fatigue and blood glucose levels were analysed
using the Minitab statistical package version 13.1. Following an
initial repeated measures ANOVA (ginseng glucose demand
battery completion [or time of blood sample]) conducted to deter-
mine main and interaction effects, planned comparisons were
made at each time point utilizing t tests with MSError as an error
term (Keppel, 1991). In the case of blood glucose measurements,
individual a priori comparisons were made between administration
of glucose plus and minus ginseng, and administration of the
glucose placebo plus and minus ginseng. For the cognitive and
mood measures comparisons were made between placebo (0mg
G115/0g glucose) and each of the active treatments. To ensure the
overall protection level, comparisons were strictly planned prior to
commencement of the study, only probabilities associated with
planned comparisons were calculated, and all testing was two-
tailed.
Post hoc correlation analysis Pearson’s Product-Moment Cor-
relation Coefficients were carried out to investigate any relation-
ship between cognitive performance and blood glucose levels.
‘Change from baseline’ blood glucose levels at pre-test and the
end of testing were correlated with ‘change from baseline’ task
performance at the nearest post-dose completion of the demand
battery (i.e. the first and sixth completions respectively). Correla-
tions were conducted separately for each condition.
Results
Baseline scores
Prior to analysis of change from baseline data, raw baseline scores
for all four conditions (placebo, ginseng, glucose and
ginseng/glucose combination) for each of the primary outcome
measures (blood glucose levels, mental fatigue, RVIP, Serial
Threes and Serial Sevens) were subject to one way repeated meas-
ures ANOVAs (participant treatment). There were no signific-
ant differences in baseline performance on any measures. Mean
pre-dose baseline raw scores and change from baseline scores, for
each condition at each post-dose time point on blood glucose
levels and the individual cognitive tasks, are presented in Table 1.
Blood glucose levels
The initial repeated measure ANOVA (ginseng glucose time
of blood sample) revealed a significant interaction between admin-
istration of glucose and time of blood sample [F(1,26)= 104.52, P
< 0.001]. Planned comparisons, comparing each treatment to
placebo at each time point, revealed that the ingestion of a 25g
glucose load alone [t(26)= 9.40, P < 0.001] or in combination with
200mg ginseng [t(26) = 10.570, P < 0.001] led to significantly
increased blood glucose levels at the 1 hour post-dose measure-
ment point. However, following the ingestion of ginseng alone,
blood glucose levels were significantly reduced at the 1 hour post-
dose measurement point [t(26)= 2.096, P = 0.046] (Fig. 1).
The ANOVA also revealed a significant interaction between
administration of glucose and ginseng [F(1,26)= 5.26, P = 0.03] on
blood glucose levels (Fig. 2). Taken across the two post-dose ses-
sions the pattern of blood glucose modulation following the
774 Panax ginseng: effects on blood glucose and cognitive performance
Panax ginseng: effects on blood glucose and cognitive performance 775
Table 1 Effects of 200 mg G115, 25 g glucose, 200 mg/25 g ginseng/glucose combination, and placebo, on task performance and blood glucose levels. Mean baseline performance
score/glucose level and mean change from baseline performance score/glucose level at each post-dose battery completion point/glucose measurement point, with standard errors in
italics. Significance (planned comparisons) is indicated in bold type (Ap < 0.05; Bp < 0.01; Cp < 0.005; Dp < 0.001; Ep < 0.0005)
Post-dose change from baseline score
Measure Pre-dose 1 2 3 4 5 6
baseline
score
Mental fatigue (mm)
Placebo 26.296 3.380 0.296 1.671 7.296 2.663 13.481 3.233 18.481 4.134 27.444 4.683 33.889 5.531
200 mg 25.889 3.687 0.222 1.825 6.296 2.179 13.889 2.883 18.333 3.512 22.519B3.270 26.926D3.737
Glucose (25 g) 27.778 3.794 1.333 1.974 7.000 2.473 14.481 3.413 18.630 3.842 23.148A3.921 28.259C4.372
Combination 25.778 3.237 2.778 3.021 9.593 2.833 16.111 3.099 21.000 3.267 27.852 4.130 33.148 4.099
RVIP reaction time (sec)
Placebo 0.533 0.014 0.008 0.008 0.012 0.009 0.006 0.014 0.016 0.018 0.009 0.014 0.006 0.011
200 mg 0.530 0.020 0.008 0.015 0.025 0.013 0.019 0.010 0.021B0.014 0.005 0.014 0.018 0.015
Glucose (25 g) 0.519 0.018 0.014 0.012 0.023A0.010 0.009 0.010 0.018 0.009 0.009 0.012 0.007 0.012
Combination 0.535 0.016 0.012 0.013 0.017A0.014 0.016 0.017 0.011 0.013 0.001 0.009 0.009 0.013
RVIP (false alarms)
Placebo 2.407 0.920 0.000 0.358 1.852 0.860 0.926 0.792 0.704 0.762 0.519 0.684 3.556 2.878
200 mg 2.889 1.023 0.148 0.395 0.407 0.382 1.519 0.543 1.148 0.533 0.926 0.503 0.963C0.801
Glucose (25 g) 4.593 1.753 1.111 0.783 0.667A0.669 1.185A0.618 0.704 0.449 0.741 0.584 1.259E1.209
Combination 3.407 1.386 0.222 0.390 0.667A0.381 0.074 0.783 0.444 0.892 0.259 0.780 0.222E0.715
Serial 3s (total responses)
Placebo 41.037 2.070 0.222 1.040 1.704 1.083 0.000 1.345 0.704 1.294 0.148 1.313 0.481 0.992
200 mg 40.074 2.362 1.963 1.205 3.259 1.273 2.704A1.223 2.185A1.402 2.000 1.314 3.407C2.255
Glucose (25 g) 40.222 2.629 0.778 1.951 1.000 1.578 3.481B1.502 3.667D1.273 2.259 2.143 2.333A1.844
Combination 40.259 2.645 1.000 0.887 0.630 1.378 0.889 1.181 0.037 1.825 0.111 1.889 1.556 1.803
Serial 3s (errors)
Placebo 1.500 0.255 0.111 0.454 0.222 0.566 0.111 0.308 0.259 0.380 0.741 0.485 0.556 0.408
200 mg 1.241 0.210 0.778 0.435 0.148 0.260 0.630 0.457 0.519 0.274 0.037 0.340 0.185 0.311
Glucose (25 g) 2.304 0.255 0.444 0.351 0.296 0.413 0.259 0.511 0.037 0.513 0.593A0.553 0.185 0.490
Combination 1.714 0.337 0.148 0.426 0.037 0.442 0.296 0.440 1.481A1.436 0.111 0.516 0.926 0.487
Serial 7s (total responses)
Placebo 25.704 1.630 1.778 0.790 0.000 0.801 0.185 0.967 1.852 0.910 1.630 0.744 1.815 0.974
200 mg 25.963 2.182 0.444 0.752 1.148 0.938 1.519 0.881 2.037 0.914 1.370 0.994 2.259 0.919
Glucose (25 g) 26.222 2.091 0.370A0.911 0.074 0.811 1.889 0.725 0.556 0.930 1.407 1.246 1.963 0.944
Combination 25.444 2.021 0.926B0.792 0.074 0.808 2.000 0.887 2.185 1.041 2.481 0.902 2.778 0.959
Serial 7s (errors)
Placebo 1.704 0.301 0.444 0.431 0.222 0.375 0.296 0.406 0.370 0.404 0.407 0.411 1.000 0.406
200 mg 1.852 0.412 0.222 0.535 0.185 0.437 0.148 0.503 0.111 0.466 0.296 0.562 0.074A0.456
Glucose (25 g) 1.593 0.240 0.444 0.411 0.370 0.431 0.667 0.406 0.148 0.409 0.556 0.289 0.000A0.406
Combination 1.667 0.250 0.000 0.325 0.111 0.355 0.185 0.346 0.593 0.478 0.185 0.396 0.000A0.405
Blood glucose levels Pre-dose 60 mins 120 mins
(mmol/litre) baseline post post
score
Placebo 5.229 0.125 0.198 0.126 0.721 0.114
200 mg 5.462 0.112 0.630A0.096 0.708 0.121
Glucose (25 g) 5.338 0.153 1.739E0.206 0.923 0.156
Combination 5.077 0.122 1.980E0.268 0.603 0.151
776 Panax ginseng: effects on blood glucose and cognitive performance
baseline pre-test final
1.5
1.0
0.5
0.0
0.5
1.0
1.5
2.0
2.5 Placebo
200 mg (G115)
Glucose (25g)
Combination
*
*****
*****
Change from baseline
(blood glucose level – mmol/litre)
Change from baseline
(blood glucose level – mmol/litre)
Figure 1 Effects of 200 mg G115, 25 g glucose,
200 mg/25 g ginseng/glucose combination, and
placebo, on blood glucose levels. Figure depicts
mean change from baseline glucose level at 1
hour post-treatment (pre-test) and after six
(final) post-dose completions of the battery
(* p < 0.05; ***** p < 0.0005)
Placebo G115
1.5
1.0
0.5
0.0
0.5
1.0
1.5
Saccharin
Glucose
Figure 2 Post-dose interaction between
ginseng and glucose on blood glucose levels
(mean change from baseline values across
both post-dose measurements)
administration of ginseng was for an increase in circulating blood
glucose levels in the presence of the 25g glucose load but a reduc-
tion in blood glucose levels in the absence of the glucose load
(although it should be noted that post hoc comparisons of the
effects of ginseng within the glucose/placebo conditions were non-
significant in themselves).
Serial Threes subtractions
The repeated measures ANOVA (ginseng glucose demand
battery completion) revealed a significant interaction between the
administration of glucose and ginseng on the total number of
Serial Threes subtractions made [F(1,130)= 4.52, P = 0.043].
Planned comparisons comparing each treatment to placebo at each
demand battery completion revealed significantly more Serial
Threes subtractions were performed following 200mg G115 alone
(ginseng condition) at the third [t(130)= 2.088, P = 0.039], fourth
[t(130)= 2.231, P = 0.027] and sixth [t(130) = 3.004, P= 0.003]
demand battery completions. Similarly, following a 25g glucose
load alone (glucose condition) participants produced significantly
more Serial Threes subtractions on the third [t(130)= 2.689,
P= 0.008], fourth [t(130) = 3.376, P = 0.001] and sixth
[t(130)= 2.174, P = 0.032] demand battery completions (Fig. 3).
Serial Sevens subtractions
No significant results were revealed.
Rapid Visual Information Processing task (RVIP)
The initial ANOVA (ginseng glucose demand battery com-
pletion) revealed a significant main effect of glucose administra-
tion [F(1,130)= 7.72, P = 0.01] on the number of false alarms
participants committed during the RVIP task. There were signifi-
cantly fewer false alarms committed following a glucose load,
irrespective of ginseng administration. Planned comparisons com-
paring each treatment to placebo at each demand battery comple-
tion revealed a significant reduction in the number of false alarms
following a 25g glucose load alone (glucose condition) on the
second [t(130)= 2.804, P = 0.006] third [t(130) = 2.35, P= 0.020]
and sixth [t(130)= 5.361, P = 0.0000004] demand battery comple-
tions. Additionally, a reduction in the number of false alarms was
revealed following a glucose load combined with 200mg G115 on
the second [t(130)= 2.804, P = 0.006] and sixth [t(130) = 3.711, P=
0.0003] demand battery completion. A single significant reduction
in the number of false alarms was also revealed following 200mg
G115 alone (ginseng condition) on the sixth [t(130)= 2.887, P =
0.005] completion of the demand battery only (Fig. 4).
Mental fatigue
Planned comparisons comparing each treatment to placebo at each
demand battery completion revealed a significant amelioration in
subjective ratings of mental fatigue following a 25g glucose load
alone (glucose condition) on the fifth [t(130)= 2.179, P = 0.031]
and sixth [t(130)= 2.855, P = 0.005] completions of the demand
battery. Similarly, a significant amelioration in subjective ratings
of mental fatigue were revealed following 200mg G115 alone
(ginseng condition) on the fifth [t(130)= 2.498, P = 0.014] and
sixth [t(130)= 3.531, P = 0.001] completions of the demand battery
(Fig. 5). There was no effect of the combined treatments.
Post hoc correlation analysis
The post hoc correlations revealed no interpretable significant
relationships between cognitive performance and blood glucose
levels.
Discussion
The present study was designed to investigate the effects of Panax
ginseng on cognitive performance, mood and blood glucose levels,
both in the presence and absence of exogenously raised blood
glucose levels (via administration of a 25g glucose load 30
minutes post-dose). More specifically, it was intended to address
the suggestion that ginseng’s acute positive effects on human cog-
nition may be explained, at least in part, through its potential
promotion of the cellular uptake of glucose. The methodology
employed also allowed an examination of the effect of each indi-
vidual treatment (200mg G115 and a 25 g glucose load) in isola-
tion, in comparison to placebo, on each of the primary outcome
measures.
The results revealed no synergistic relationship between Panax
ginseng (200mg G115) and a 25g glucose load on any of the
primary cognitive outcome measures. The results, however, did
reveal that single doses of either Panax ginseng (200mg G115) or
a 25g glucose load can modulate circulating blood glucose levels,
enhance cognitive performance of a mental arithmetic task (Serial
Panax ginseng: effects on blood glucose and cognitive performance 777
baseline 123456
6
4
2
0
2
4
6
**
***
** ****
*
Placebo
200 mg (G115)
Glucose (25g)
Combination
Change from baseline
(number of responses)
Figure 3 Effects of 200 mg G115, 25 g glucose,
200 mg/25 g ginseng/glucose combination, and
placebo, on the number of Serial Threes
subtractions performed. Figure depicts mean change
from baseline scores at each post-dose completion
(one to six) of the battery (* p < 0.05; *** p < 0.005;
**** p < 0.001)
Threes) and ameliorate the increase in subjective feelings of
mental fatigue experienced by participants during sustained
intense cognitive processing. Accuracy of performing the Rapid
Visual Information Processing task (RVIP) was also improved
following the 25g glucose load.
In relation to blood glucose levels, the results confirmed the
absorption of glucose into the blood stream following a 25g
glucose load, and also revealed a significant interaction between
the administration of ginseng and glucose (Fig. 2) indicative of
Panax ginseng’s glucose modulating properties. The pattern of
results showed that, in the absence of a glucose load (i.e. in
overnight-fasted participants) a single dose of Panax ginseng (200
mg G115) resulted in a significant post-dose fall in circulating
blood glucose levels at the assessment 1 hour following the inges-
tion of ginseng. There was also a significant interaction between
the consumption of ginseng and glucose levels assessed across
both post-dose assessments (Fig. 2). This interaction reflected a
pattern of increased glucose levels when ginseng was taken with
778 Panax ginseng: effects on blood glucose and cognitive performance
baseline 1 2 3 4 5 6
6
4
2
0
2
4
6
*****
**
***
*****
*
**
Placebo
200 mg (G115)
Glucose (25g)
Combination
Change from baseline
(number of false alarms)
40
baseline123456
10
0
10
20
30
****
***
*
**
Placebo
200 mg (G115)
Glucose (25g)
Combination
Change from baseline
(millimetres)
Figure 4 Effects of 200 mg G115, 25 g glucose,
200 mg/25 g ginseng/glucose combination, and
placebo, on the number of False alarms
committed for the RVIP task. Figure depicts
mean change from baseline scores at each post-
dose completion (one to six) of the battery
(* p < 0.05; ** p < 0.01; *** p < 0.005; *****
p < 0.0005)
Figure 5 Effects of 200 mg G115, 25 g glucose,
200 mg/25 g ginseng/glucose combination, and
placebo, on the participants’ subjective ratings
of mental fatigue. Figure depicts mean change
from baseline scores at each post-dose
completion (lower scores indicate reduced
mental fatigue) (* p < 0.05; ** p < 0.01;
*** p < 0.005; **** p < 0.001)
glucose, and reduced glucose levels when ginseng was taken with
placebo (i.e. in a fasted state). It should be noted, however, that
the individual post hoc comparison of means for the ginseng and
placebo groups while in the glucose drink condition did not show
a specific significant increase associated with ginseng per se.
Research has previously addressed the chronic effects of both
Panax ginseng (Sotaniemi et al., 1995; Vuksan et al., 2000) and
Panax quinquefolius (Tetsutani et al., 2000) and the acute effects
of the latter on the glycaemic response to a glucose challenge
(Vuksan et al., 2000b, 2001; Sievenpiper et al., 2003a). Most per-
tinently the results of the present study are consistent with those of
Reay et al. (2005) who demonstrated that the ingestion of either a
single dose of 200mg or 400 mg of Panax ginseng (G115) led to a
significant reduction in circulating blood glucose levels in a cohort
of young, healthy, overnight-fasted volunteers. In the case of the
current study, planned comparisons confirmed Reay et al.’s (2005)
finding that Panax ginseng lead to a reduction in blood glucose
levels 1 hour post-dose in the absence of a glucose load.
The pattern of differential modulation of blood glucose levels
following Panax ginseng with and without a glucose load is not
out of line with previous research that demonstrated an increase in
blood glucose levels during a 120 minute oral glucose tolerance
test (75 g), using data pooled from five different doses of pow-
dered Panax ginseng root (Sievenpiper et al., 2003b). Interest-
ingly, Sievenpiper et al. (2004) reported that an extract of Panax
ginseng, but not eight other ginseng extracts (Sanchi, Siberian,
American, Asian, Korean red, Japanese, wild American, and Viet-
namese) was associated with an increase in blood glucose levels
and a greater insulin response following a glucose load. Taken
with the evidence of opposite effects for Panax quinquefolius
following a glucose load in diabetic and healthy participants
(Vuksan et al., 2000a, 2000b, 2001), these results suggest that the
differential effects of these extracts and members of the Panax
genus require further investigation.
With regards cognitive performance on the serial subtraction
tasks, whilst the initial ANOVA of the Serial Sevens data revealed
a trend (P= 0.07) towards a treatment effect on the total number of
subtractions performed, the only significant results on the
ANOVA were obtained for the Serial Threes task. This initial
analysis revealed a significant interaction between ginseng and
glucose administration for the total number of Serial Threes sub-
tractions performed. Planned comparisons revealed that 200mg
G115 led to a significantly greater number of Serial Threes sub-
tractions being performed at the third, fourth and fifth completions
of the demand battery. Similarly a greater number of Serial Threes
subtractions were performed at the third, fourth and sixth comple-
tions of the demand battery following a 25g glucose load. There
was no effect of combining 200mg with a 25 g glucose load at any
time point (Fig. 3). This improved speed of performance, for both
ginseng and glucose conditions, was not associated with greater
production of errors, precluding the possibility of any treatment
specific ‘speed/accuracy trade-off’.
The improved Serial Threes performance following both single
treatments is generally in line with previous demonstrations of
working memory task enhancement by glucose (e.g. Martin and
Benton, 1999; Sünram-Lea et al., 2002) and recent findings of
faster memory, attention (Kennedy et al., 2004) and Serial sub-
traction task performance (Kennedy et al., 2004; Reay et al.,
2005) and decreased latency of the P300 component of auditory
evoked potentials (Kennedy et al., 2003) following Panax
ginseng. However, they are somewhat at odds with previous
reports of the enhancement of serial subtraction performance
being restricted to the more ‘mentally demanding’ Serial Sevens
task following both 200mg G115 (Reay et al., 2005) and a 25 g
glucose load (Kennedy and Scholey, 2000; Scholey et al., 2001).
Reference to the planned comparisons for the Serial Sevens task
(which are not reported due to a lack of significance on the initial
ANOVA) does, however, show that both glucose alone and
glucose combined with ginseng led to a significant increase in
speed of performance that was restricted to the first completion of
the Serial Sevens. This is entirely in keeping with the previous
studies (Kennedy and Scholey, 2000; Scholey et al., 2001), both
of which involved a single completion of these tasks. This also
tends to suggest that the pattern of results evinced here might be
related to the different demand characteristics of the multiple com-
pletions of these tasks, with the benefits of both glucose and
ginseng only becoming apparent as fatigue (or another unidenti-
fied factor) increased with repeated performance of the Serial
Threes task. With regards ginseng the discrepancy in results here
in comparison to Reay et al. (2005) may well also be due to minor
differences in the levels of single ginsenosides, or groups of gin-
senosides (e.g. the ratio of panaxadiols to panaxatriols) contained
in an extract that is standardized to total per cent content of gin-
senosides.
For the RVIP task the initial ANOVA revealed a significant
main effect of glucose administration on the number of false
alarms committed. There were significantly fewer false alarms
committed following the 25g glucose drink, irrespective of
ginseng administration. Planned comparisons revealed that signifi-
cantly fewer false alarms were committed on the second, third and
sixth demand battery completions for the glucose condition. Sim-
ilarly, significantly fewer false alarms were committed on the
second and sixth demand battery completions for the ginseng and
glucose combination condition (Fig. 4). Accuracy in performing
the RVIP task has previously been shown to be improved follow-
ing a glucose-caffeine energy drink using the same experimental
protocol and demand battery as used in the present study
(Kennedy and Scholey, 2004).
In relation to the reported subjective feelings of mental fatigue
it was found that both 200mg G115 and a 25 g glucose load
administered in isolation led to a significant amelioration in the
participants’ subjective feelings of mental fatigue towards the end
of testings. The result (Fig. 5) of the present study are consistent
with that of Reay et al. (2005) who reported that both 200mg and
400mg of Panax ginseng led to a significant amelioration of
participants’ subjective ratings of the mental fatigue associated
with an extended period of intense cognitive processing.
The mechanisms responsible either for ginseng’s glycaemic
effect or its cognitive effects are not clear at present. With regards
the former, Vuksan et al. (2000a) suggested three possible
mechanisms that could account for modulation in blood glucose
levels. These include the modulation of glucose disposal, glucose
Panax ginseng: effects on blood glucose and cognitive performance 779
transport or insulin secretion. The latter two may well be mediated
by increased nitric oxide (NO) production (Roy et al., 1998;
Spinas et al., 1998). The involvement of ginsenosides in this pro-
posed mechanism is supported by the results of a number of
studies. For example, 8 weeks’ administration of American
ginseng in type 2 diabetics led to an increase in NO concentration
which correlated with improvements observed in HbA1c (Xu et al.,
2000; see also: Reay et al. 2005).
In a previous paper we speculatively suggested that Panax
ginseng may promote the transport of glucose, by an unknown
mechanism, into active cells (i.e. leading to a reduction in circulat-
ing blood glucose levels) and thus facilitating metabolism in task-
sensitive structures (i.e. leading to improved behavioural
performance) (see: Reay et al., 2005). The present study provides
no support for such a hypothesis; for example, there were no
behavioural improvements or reductions in blood glucose levels
revealed following the combination treatment. However, for the
second time, Panax ginseng did lead to improved behavioural per-
formance and concomitant reductions in blood glucose levels
when ingested by participants in a fasted state. Therefore, it still
remains possible that ginseng exerts its beneficial cognition
enhancing effects via some unknown gluco-regulatory mechan-
ism. It should be noted that there was no direct correlation
between the fall in blood glucose levels and performance.
Whilst the current study utilized participants in an overnight-
fasted state, and provided increased glucose levels by administer-
ing a glucose drink in order to provide adequate experimental
control of their gluco-regulatory state, it has to be conceded that
this is not necessarily the normal dietary state of the majority of
consumers at the time that they consume ginseng. Future research
might well be directed towards the effects of ginseng in cohorts in
their normal dietary state. This having been said, the current
research study does reinforce the potential importance of this line
of research with regards treatments for diabetes. Vuksan et al.
(2001) has suggested that Panax quinquefolius may be an effect-
ive alternative therapy for patients suffering from type 2 diabetes.
However, it should be noted that Panax quinquefolius is one of the
less commonly used members of the Panax genus, whereas Panax
ginseng is notable for its global ubiquity.
Whilst its potential utility in the treatment of conditions that
feature disturbed gluco-regulation is of great interest, the present
findings suggest that Panax ginseng (G115) may have opposite
effects when administered in the absence or presence of glucose.
Further research is required to delineate the mechanisms under-
lying the demonstrated gluco-regulatory effects and whether these
effects represent a net benefit or cost to consumers.
In conclusion, 1 hour following administration of Panax
ginseng blood glucose levels were reduced in fasted individuals,
with an overall pattern of blood glucose modulation that suggested
an opposite effect when administered before exogenous glucose.
Both Panax ginseng and glucose, when administered in isolation
of each other, led to improved task performance, and reduced
mental fatigue as a consequence of extended task performance.
These latter effects were not directly related to the modulation of
blood glucose levels. Given the potential utility of a treatment that
beneficially modulates blood glucose levels whilst concomitantly
enhancing cognitive performance, the mechanisms underlying
these effects require further investigation.
Acknowledgements
The study described herein was undertaken as part of a PhD programme (J.
L. Reay) sponsored by Pharmaton SA, Lugano, Switzerland. Materials
were supplied by the sponsor.
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... All 33 included studies, of which ten are between-subject and 23 within-subject design studies, were screened for risk of bias (see Figs. 2,3). This assessment determined that 25 studies [12,14,20,26,27,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] had a high risk of bias, three studies [57][58][59] had some concerns of bias and five studies [11,13,[60][61][62] had a low risk of bias. ...
... All studies except Watanabe et al. [14] used subjective markers of MF. Of these 21 studies, 14 [11,12,41,42,44,48,50,51,53,57,58,[60][61][62] showed a significant difference following the physiological countermeasure (see Table 4 for further details on this matter). Also (neuro)physiological markers were monitored in ten studies investigating physiological MF countermeasures, half of which provided positive results [12,14,39,42,48] (see Table 4). ...
... Nine studies explored the effect of physiological countermeasures minutes to hours before the MF task [11,44,50,51,53,57,[60][61][62]; full details on the moment of application can be found in Tables 4 and 5. Six of the studies used countermeasures, such as caffeine and cocoa flavanols, that have short-term impacts and were administered within an hour of the MF protocol [11,44,50,51,60,61]. In the three other studies, countermeasures were given 90 min before the MF task [53,62] or, in the case of Kennedy et al. [57], the MF task was employed 1, 3 and 6 h after the intake of the countermeasure. ...
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Introduction Mental fatigue (MF) is a psychobiological state that impairs cognitive as well as physical performance in different settings. Recently, numerous studies have sought ways to counteract these negative effects of MF. An overview of the explored countermeasures for MF is, however, lacking. Objectives The objective of this review is to provide an overview of the different MF countermeasures currently explored in literature. Countermeasures were classified by the timing of application (before, during or after the moment of MF) and type of intervention (behavioural, physiological and psychological). Methods The databases of PubMed (MEDLINE), Web of Science and PsycINFO were searched until March 7, 2022. Studies were eligible when MF was induced using a task with a duration of at least 30 min, when they assessed MF markers in at least two out of the three areas wherein MF markers have been defined (i.e., behavioural, subjective and/or [neuro]physiological) and used a placebo or control group for the countermeasure. Results A total of 33 studies investigated one or more countermeasures against MF. Of these, eight studies assessed a behavioural countermeasure, 22 a physiological one, one a psychological countermeasure and two a combination of a behavioural and psychological countermeasure. The general finding was that a vast majority of the countermeasures induced a positive effect on behavioural (e.g., task or sport performance) and/or subjective MF markers (e.g., visual analogue scale for MF or alertness). No definitive conclusion could be drawn regarding the effect of the employed countermeasures on (neuro)physiological markers of MF as only 19 of the included studies investigated these measures, and within these a large heterogeneity in the evaluated (neuro)physiological markers was present. Discussion Within the physiological countermeasures it seems that the use of odours during a MF task or caffeine before the MF task are the most promising interventions in combating MF. Promising behavioural (e.g., listening to music) and psychological (e.g., extrinsic motivation) countermeasures of MF have also been reported. The most assumed mechanism through which these countermeasures operate is the dopaminergic system. However, this mechanism remains speculative as (neuro)physiological markers of MF have been scarcely evaluated to date. Conclusion The present systematic review reveals that a wide range of countermeasures have been found to successfully counteract MF on a subjective, (neuro)physiological and/or behavioural level. Of these, caffeine, odours, music and extrinsic motivation are the most evidenced for countering MF. To provide in-detail practical guidelines for the real-life application of MF countermeasures, more research must be performed into the underlying mechanisms and into the optimal dosage and time of application/intake.
... In a more recent review, 6 the authors found clinical trial data suggesting that ginseng modestly improved thinking and working memory in healthy volunteers. 14,15 Two open-label trials showed that 12-week treatment with ginseng improved AD Assessment Scale-Cognitive Subscale (ADAS-cog) scores in participants with AD. 16,17 Two small open-label trials demonstrated the potential therapeutic benefits of Panax ginseng for AD. 17,18 In the former study, which showed significant effects on ADAS-cog and Clinical Dementia Rating (CDR) following 24-week treatment of low or high dose (4.5 g or 9 g/day) Panax ginseng compared with controls, 16 subjects were followed up for a further 2 years during which time cognitive function was evaluated every 12 weeks using the ADAS and the Korean version of the Mini-Mental State Examination (K-MMSE). ...
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... Ginsenosides can be a useful adjuvant treatment against neurodegeneration-caused cognitive decline. Even among healthy adult individuals, ginsenosides are reported to enhance working memory and cognitive performance in their daily work (Table 2) [50,51]. The anti-aging effect of ginsenoside Rg1 was tested in an aging rodent model induced by D-galactose or D-galactose and AlCl3 [72,73]. ...
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... The results of many clinical trials suggesting the beneficial effects of ginseng on stress and cognitive functions were critically reviewed in several comprehensive and systematic review articles [3,[8][9][10][11][12][13][14]. Overall, ginseng is a promising treatment for mental, industrial, and chronic fatigue [15][16][17][18][19], and for the cognitive enhancement performance of healthy subjects [6,[19][20][21][22][23][24], and patients with mild cognitive impairments [25][26][27][28][29][30][31] and/or neurological disorders [7,[26][27][28]. ...
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... The results of many clinical trials suggesting the beneficial effects of ginseng on stress and cognitive functions were critically reviewed in several comprehensive and systematic review articles [3,[8][9][10][11][12][13][14]. Overall, ginseng is a promising treatment for mental, industrial, and chronic fatigue [15][16][17][18][19], and for the cognitive enhancement performance of healthy subjects [6,[19][20][21][22][23][24], and patients with mild cognitive impairments [25][26][27][28][29][30][31] and/or neurological disorders [7,[26][27][28]. ...
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Numerous in vitro studies on isolated cells have been conducted to uncover the molecular mechanisms of action of Panax ginseng Meyer root extracts and purified ginsenosides. However, the concentrations of ginsenosides and the extracts used in these studies were much higher than detected in pharmacokinetic studies in humans and animals orally administered with ginseng preparations at therapeutic doses. Our study aimed to assess: (a) the effects of ginsenoside Rg5, the major "rare" ginsenoside of Red Ginseng, on gene expression in the murine neuronal cell line HT22 in a wide range of concentrations, from 10-4 to 10-18 M, and (b) the effects of differentially expressed genes on cellular and physiological functions in organismal disorders and diseases. Gene expression profiling was performed by transcriptome-wide mRNA microarray analyses in HT22 cells after treatment with ginsenoside Rg5. Ginsenoside Rg5 exhibits soft-acting effects on gene expression of neuronal cells in a wide range of physiological concentrations and strong reversal impact at high (toxic) concentration: significant up- or downregulation of expression of about 300 genes at concentrations from 10-6 M to 10-18 M, and dramatically increased both the number of differentially expressed target genes (up to 1670) and the extent of their expression (fold changes compared to unexposed cells) at a toxic concentration of 10-4 M. Network pharmacology analyses of genes expression profiles using Ingenuity pathway analysis (IPA) software showed that at low physiological concentrations, ginsenoside Rg5 has the potential to activate the biosynthesis of cholesterol and to exhibit predictable effects in senescence, neuroinflammation, apoptosis, and immune response, suggesting soft-acting, beneficial effects on organismal death, movement disorders, and cancer.
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