Evid Based Integrative Med 2005; 2 (4): 195-206

REVIEW ARTICLE 1176-2330/05/0004-0195/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

The Standardised G115® Panax ginseng C.A.

Meyer Extract
A Review of its Properties and Usage
Francesco Scaglione,1 Marilou Pannacci1 and Orlando Petrini2
1 Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Milan, Italy
2 Medical Department, Pharmaton SA, Lugano, Switzerland

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
1. Physical, Chemical and Pharmaceutical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
2. Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
2.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
2.2 Pharmacokinetics and Drug Metabolism in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2.3 Mechanism of Action of G115® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2.3.1 Immunomodulatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2.3.2 Effects on the Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
3. Human Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.2 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.2.1 Endurance and Vitality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.2.2 Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.3 Cognitive Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3.4 Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
4. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Abstract Ginseng (Panax ginseng C.A. Meyer, ginseng) has been the most precious and renowned tonic drug in
traditional Chinese medicine. Although the original discovery of its therapeutic efficacy has been lost in
antiquity, believers in ginseng as a panacea have sought, cultivated, preserved and extracted its essences for the
treatment of a wide range of ailments. Many patients have used aqueous and alcoholic extracts of ginseng during
convalescence, particularly where previous health problem(s) resulted in some degree of debilitation, and a
corresponding deficit in mental, physical or other functional capacities. An impressive body of information has
been accumulated and scientific research has documented and reviewed the useful effects of P. ginseng C.A.
Meyer. The high variability in composition of the marketed products clearly affects the results of clinical studies.
The availability of the standardised ginseng extract G115® has made it possible to generate reproducible results
in animal studies and human clinical research.
Active constituents found in most ginseng species include ginsenosides, polysaccharides, peptides, poly-
acetylenic alcohols, fatty acids and trace elements. It is generally believed that ginsenosides and their metabolites
are the most important components determining the pharmacological effects of ginseng. Ginsenosides are
triterpene saponins of the dammaran series. They are divided into three groups, classified according to their
chemical structures: 20(S)-protopanaxadiols, 20(S)-protopanaxatriols and the RO ginsenosides. The variability
in the pharmacological activities of the various ginseng species may be related to the different composition of
proportions of ginsenosides.
196 Scaglione et al.

One of the most common standardised extracts, used in many studies, is G115®, which contains 4%
ginsenosides. In view of the wide variations, both qualitative and quantitative, standardisation must control the
total amount of ginsenosides.
Several clinical studies have been conducted with the standardised P. ginseng extract G115®. Here we
briefly review only double-blind, placebo-controlled trials that are judged to be of scientific relevance for the
clinical profile of the product. The efficacy of G115® on physical performance still needs to be confirmed in
Good Clinical Practice (GCP) settings. Several clinical studies with ginseng have not shown any significant
effect on the enhancement of physical performance. The ability of G115® to increase endurance and vitality, on
the other hand, has been demonstrated in a number of non-GCP studies. The efficacy of G115® in relieving
menopausal symptoms is supported by two studies, one of GCP quality. Efficacy in improving cognitive
function has been extensively reviewed. Intake of G115® in acute and multiple doses is associated with
improvements in cognitive function. A series of studies has assessed the effects of G115® in various volunteer
populations using a widely validated and highly sensitive computerised cognitive test system, the Cognitive
Drug Research (CDR) assessment system. Several preclinical studies have indicated that G115® may have
immunomodulatory properties. These findings have been confirmed in two clinical studies. The efficacy and
safety of G115® for potentiating vaccination against the common cold and/or influenza syndrome in a
randomised, double-blind, placebo-controlled, parallel-group, multicentre study were determined. Moreover, the
effects of G115® in reducing the bacterial count in the bronchial system of patients undergoing an acute attack of
chronic bronchitis has been investigated in an open pilot study.
The safety profile of G115® has been well established both from clinical studies in healthy volunteers and
patients and from its use for over 30 years as a marketed medicinal product in many countries worldwide. Few
clinical studies on G115® report adverse effects. In general, the lack of reported adverse effects suggests that
they are few, and those present are very minor. On the other hand, a baseline level of adverse effects should be
expected and is always present, even for placebo groups in clinical trials. A total of 1075 subjects have been
treated with G115® to date in clinical trials. Seventy-one subjects experienced minor adverse effects but no
serious events were reported. The most commonly reported adverse events were headache, itching, sore throat,
skin rash, dry mouth, acne and diarrhoea, with no difference between placebo and G115®. In all trials, no
changes in safety laboratory parameters were seen.

Phytomedicine is slowly evolving from an empirical discipline
to an evidence-based science that relies upon preclinical and
clinical evidence to demonstrate efficacy and safety of herbal
medicinal products. Accordingly, critical reviews and meta-analy-
ses are increasingly devoted to the interpretation of clinical data
used to support the use of herbal remedies in different indica-
tions.[1-3] Results of clinical studies with herbal remedies are
greatly dependent on the variability in composition of herbal
extracts. Unless an extract undergoes strict standardisation, a high
variability in its composition cannot be avoided[4] and correspond-
ingly large variations in clinical activity may be expected.[5]
Ginseng (Panax ginseng C.A. Meyer, ginseng) has been the
most precious and renowned tonic drug in traditional Chinese
medicine. The use of ginseng was first recorded in the Chinese
Materia Medica over 2000 years ago. Ginseng was introduced into
Europe at the end of the 13th Century BC. Increasing medical
recognition beyond Asia was followed by greater commercial
importance for ginseng. Because of great difficulties in its cultiva-
tion, and therefore its high market value, substitution with less
effective or non-effective botanicals has been attempted.[6-9]
Although the original discovery of its therapeutic efficacy has
been lost in antiquity, believers in ginseng as a panacea have
sought, cultivated, preserved and extracted its essences for the
treatment of a wide range of ailments. Many patients have used
aqueous and alcohol extracts of ginseng during convalescence,
particularly where previous health problem(s) resulted in some
degree of debilitation, and a corresponding deficit in mental,
physical or other functional capacities. The high esteem held by so
many over such a long period has been well documented. An
impressive body of information has been accumulated, and scien-
tific research has documented and reviewed the useful effects of
P. ginseng C.A. Meyer.[6-11]
Occasionally, lack of knowledge of inherent properties of gin-
seng, variations in extraction techniques or use of ineffective
substitutes and counterfeits may raise some doubts about the
efficacy of ginseng. For instance, the West German Government’s
State Product Test Institution reported that up to 25% of all
ginseng products contain little or no active ingredients. More
recently, a study carried out by the American Botanical Council
has revealed that marketed ginseng extracts vary greatly in their
ginsenoside content.[12]

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)
Standardised Panax ginseng Extract G115® 197

R1 R2 Ginsenoside

Protopanaxadiol D-Glc(1-2)D-Glc D-Glc(1-6)D-Glc Rb1

R2O
HO
D-Glc(1-2)D-Glc L-Ara(p)(1-6)D-Glc Rb2

D-Glc(1-2)D-Glc L-Ara(f)(1-6)D-Glc Rc

R1O D-Glc(1-2)D-Glc D-Glc Rd

Protopanaxatriol L-Rha(1-2)D-Glc D-Glc Re

R2O
HO
D-Glc(1-2)D-Glc H Rf

D-Glc D-Glc Rg1

HO L-Rha(1-2)D-Glc H Rg2
OR1

Fig. 1. Main ginsenosides so far identified in the Panax ginseng extract G115®. Ara(f) = arabinofuranoside; Ara(p) = arabinopyranoside; Glc = glucose;
Rha = rhamnose.

The high variability in composition of the marketed products
clearly affects the results of clinical studies, as recently pointed out
by Vuksan and Sievenpiper.[5]
The availability of the standardised P. ginseng extract G115
(G115®)1 has made it possible to generate reproducible results in
animal studies and human clinical research.[11,13-15]
This review aims to provide a critical appraisal of the scientific
evidence collected so far on G115®.
1. Physical, Chemical and
Pharmaceutical Properties
Active constituents found in most ginseng species include
ginsenosides, polysaccharides, peptides, polyacetylenic alcohols,
fatty acids and trace elements.[16,17]
It is generally believed that ginsenosides and their metabolites
are the most important components that determine the pharmaco-
logical effects of ginseng;[18] although other chemical constituents
such as the essential oils, various mono- and sesquiterpenes,
double and triple unsaturated alcohols and epoxides of heptade-
cane (e.g. panaxadiol and panaxatriol), mono- and trisaccharides
and peptidoglycans (panaxan A-E) may also have important bio-
logical properties.[17]
Ginsenosides are triterpene saponins of the dammaran series.
They are divided into three groups, classified according to their
chemical structures: 20(S)-protopanaxadiols, 20(S)-protopanaxa-
triols and the RO ginsenosides (figure 1). More than 30 ginseno-
sides have been isolated and characterised and are commonly used
as chromatographic markers in the quality control of ginseng roots
by conventional high-performance liquid chromatography
(HPLC), electrospray HPLC or mass spectrometry.[17] The varia-
bility in the pharmacological activities of the various ginseng
species may be related to the different composition of proportions
of ginsenosides.[18] Appropriate standardisation of the preparation
is extremely important with known ginsenoside content. Only in
the last few decades has standardisation of the ginseng extract to
specifications established by HPLC assays made it possible to
generate reproducible results in animal studies and human clinical
trials. HPLC methods developed for the quantification of ginseno-
side[16] content are included in the US and European pharmaco-
poeias. One of most common standardised extracts, used in many
studies, is G115®, which contains 4% ginsenosides. In view of the
wide variations, both qualitative and quantitative, standardisation
must control the total amount of ginsenosides and the spectrum of
six major ginsenosides, Rb1, Rb2, Rc, Rd, Re and Rg1, and two
secondary ginsenosides.
2. Preclinical Studies
2.1 Toxicology
Several toxicological investigations have been carried out with
G115®. Acute toxicity studies with G115® were carried out in the
mouse, rat and mini-pig. The data collected in the three models
confirm that G115® is devoid of acute toxicity effects.[19,20] Chron-
ic and subchronic toxicity tests in mice, rats, rabbits and dogs

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)
198
showed that G115®, in doses up to 4000 mg/kg/day, did not reveal
any treatment-related toxic effects when administered for periods
up to 25 weeks.[21-24] G115® at a concentration of 0.1–10 mg/mL
did not adversely affect the hepatocyte DNA repair test.[25] It also
did not induce point mutations by base pair changes or frame-
shifts in the Salmonella typhimurium reverse mutation assay.[26]
G115® had no influence on reproduction and lactation parame-
ters of rats.[24] No treatment effects were seen on bodyweight, food
consumption, haematology and chemistry, as well as ophthalmic,
gross anatomical and histological evaluations. Gross autopsies of
the F0 and F2 animals showed no significant treatment effects.
G115® administered to pregnant Wistar rats and pregnant New
Zealand rabbits caused no abnormality in fetal development.[27]
The effects of G115® and its ginsenosides Rg1, Rb1, Re and Rc on
blood pressure were studied by Jenny et al.[28] Rg1 at low doses
(<10 mg/kg intravenously) initially induced a slight drop in blood
pressure accompanied by a decrease in heart rate. At high doses
(100 mg/kg intravenously) Rg1 led to a nonsignificant rise in blood
pressure.
2.2 Pharmacokinetics and Drug Metabolism in Animals
Only one pharmacokinetic study has been performed with
G115® to study the fate of the ginsenosides Rg1 and Rb1 in mini-
pigs. Rg1 showed an extremely short half-life (27 minutes), the
volume of distribution was 360 mL/kg, and the distribution was
best described by a one-compartment model. No other studies of
pharmacokinetic or drug metabolic parameters were carried out
with G115®.
2.3 Mechanism of Action of G115®
The mechanism of action of ginseng has not yet been fully
elucidated. The ginseng literature contains a large number of
studies examining mechanisms supposedly underlying the effica-
cy of ginseng. There is a fair amount of evidence that ginseng
exerts several physiological effects, both at a cellular and a macro-
scopic level. Preclinical studies indicate that G115® acts on the
endocrine system,[6] enhances the immune response,[29-37] im-
proves performance under physical stress,[38] and improves learn-
ing and memory.[38,39] Analysis of two effects of G115® that have
been confirmed in clinical settings follows.
2.3.1 Immunomodulatory Effects
In general, P. ginseng has been reported to have immunomodu-
latory properties, triggering the immune system to elicit a specific
immune response. G115® seems to have a stimulating effect on
phagocytosis and it could induce an increase in host resistance
through stimulation of the immune system.[31] Macrophages treat-
ed with ginseng produce pro-inflammatory cytokines, such as
tumour necrosis factor-α, interleukin (IL)-1β, IL-6 and interfer-
ons.[32] A systematic evaluation of immune system components
© 2005 Adis Data Information BV. All rights reserved.
Scaglione et al.
revealed stimulation of basal natural killer (NK) cell activity
following subchronic exposure to ginseng, which helped stimulate
recovery of NK function in cyclophosphamide-immunosup-
pressed mice.[34] A recent study demonstrated enhanced in vitro
IL-12 production in ginseng-modulated human peripheral blood
mononuclear cells which could induce a stronger helper T cell
(Th)1 response, resulting in better protection against infection with
a variety of pathogens.[36] Studies have suggested that the immu-
nomodulating activities of ginseng may be linked to enhanced
nitric oxide (NO) synthesis in murine macrophages. P. ginseng
activates mouse peritoneal macrophages to produce reactive nitro-
gen intermediates.[35] A recent study demonstrated a clear effect of
ginseng on stimulation of inducible NO synthase (iNOS) expres-
sion via nuclear factor-κB, thus providing a valuable contribution
toward an unveiling of the molecular basis of action of P. gin-
seng.[40] The results of another study in a mouse model of
Pseudomonas aeruginosa pneumonia indicate a Th1-like immune
response.[33] Ginseng has been successfully used in guinea-pigs as
a potent adjuvant of vaccine against porcine parvovirus.[41,42] This
work has demonstrated for the first time that ginseng can amplify a
specific antibody response; thus, treatment of low responders prior
to vaccination may help to trigger a better immunisation.
There is some evidence that stress induces stimulation of innate
immunity. Stress could thus suppress acquired immunity because
of the relatively nonspecific nature of the innate immune response.
The immunomodulatory effects of ginseng in physical stress have
recently been shown to be related to the Toll-like receptors, (TLR;
receptors of innate immunity[43]). P. ginseng G115® apparently
modulates the expression of TLR4 messenger RNA compared
with that of controls and gradually stimulates the immune re-
sponse, making it more specific, thus facilitating host defence and
potentiating the immune response to bacterial or pathogenic chal-
lenge.[37]
2.3.2 Effects on the Endocrine System
Nonclinical data indicate that ginseng acts on the endocrine
system.[6] Some authors postulated some effects on the endocrine
system, on the basis of preclinical studies. In the 1970s the term
‘adaptogen’ was first applied to ginseng to describe its possible
mechanism of action.[44] An adaptogen is defined as a mild-acting,
non-toxic drug that, through unspecific stimulation, improves the
resistance of the organism to the most varied forms of stress and by
its regulating actions restores, revitalises or enhances homeosta-
sis.[45]
It has been postulated that ginseng induces the hypothalamus to
produce adrenocorticotropic hormone (ACTH) and related com-
pounds. Effects of ginseng extracts on the endocrine system may
account for its adaptogenic properties. For instance, the anti-stress
activity of ginseng is markedly reduced by adrenalectomy. After
removal of the pituitary gland, ACTH must be administered for
ginseng to exert its anti-stress activity. Specifically, ginsenosides
Evid Based Integrative Med 2005; 2 (4)
Standardised Panax ginseng Extract G115®
Rb1 and Rg1 have been reported to have a glucocorticosteroid
activity, being a potential functional ligand for glucocorticoid
receptors.[46]
3. Human Pharmacology
3.1 Pharmacokinetics
Cui et al.[47] developed gas chromatographic and gas chromato-
graphic-mass spectrometric methods to detect 20(S)-protopanaxa-
triol (S-ppt) and 20(S)-protopanaxadiol (S-ppd) in human urine.
Using these methods they could detect S-ppt in about 90% of the
urine samples tested, at concentrations between 2.0 and 35 ng/mL
urine. S-ppd-containing compounds could not be traced in the
urine.
In a second experiment,[48] four healthy volunteers were treated
with single or repeated doses of ginseng preparations. After intake
of a single dose of ginseng (1.5–8.8mg S-ppt ginsenosides and
3.5–28.7mg S-ppd ginsenosides) a linear relationship between the
amounts consumed and the glycosides excreted could be identi-
fied. The amount of non-glycosylated S-ppd and S-ppt was ap-
proximately 5% of the total glycosylated sapogenin amount found.
S-ppt was detectable until the 7th day after administration of a
single dose of 8mg S-ppt ginsenosides (detection level 1.5 ng/mL
urine). Steady-state excretion was observed after 5–7 days of
constant ginseng consumption (1.5–8.8mg S-ppt ginsenosides and
3.5–18.9mg S-ppd ginsenosides once daily). During this period,
the daily recovery of S-ppt glycosides was approximately 1.5% of
the daily dose, and that of S-ppd was up to 0.2% of the daily dose,
depending on the preparations used and on the consumed amount.
Both study results demonstrate that ginsenosides are absorbed,
even if only to a low extent.
Tawab et al.[49] performed a pilot study on the metabolism of
ginsenosides, using a mass spectrometric method. Two hydrolysis
products of the protopanaxatriol ginsenosides G-Rh1 and G-F1
were detected in plasma and the compound K in plasma and urine.
3.2 Efficacy
Several clinical studies have been conducted with the standard-
ised P. ginseng extract G115®. We briefly review only double-
blind, placebo-controlled trials that are judged to be of scientific
relevance for the clinical profile of the product. The studies are
summarised in table I.
3.2.1 Endurance and Vitality
The efficacy of G115® on physical performance still needs to
be confirmed in Good Clinical Practice (GCP) settings. Several
clinical studies with ginseng have not shown any significant effect
on the enhancement of physical performance.[62] The ability of
G115® to increase endurance and vitality, on the other hand, has
been demonstrated in a number of non-GCP studies.[50,55,63] The
© 2005 Adis Data Information BV. All rights reserved.
199
same applies to work carried out on psychoasthenia, an ill-defined
indication,[56-58] and on psychomotor functions.[59,60,64-67] While
each individual study mentioned here cannot on its own be taken
as a proof of efficacy, these investigations provide overall, albeit
weak, support for a beneficial effect of G115® in these indications.
Further research is clearly needed to confirm the efficacy of
G115® in these fields.
3.2.2 Menopause
The efficacy of G115® in relieving menopausal symptoms is
supported by two studies, one of GCP quality. An open trial
included 33 women who had undergone hysterectomy and 16
women with climacteric complaints.[68] The authors reported posi-
tive effects of G115® treatment on general health and climacteric
psychosomatic complaints.
In a double-blind, placebo-controlled study 384 symptomatic
postmenopausal women were treated with either 100mg G1105®
twice daily (n = 193) or placebo (n = 191) for 16 weeks to assess
the effect of G115® on quality of life and hormonal levels. No
significant changes were found for follicle-stimulating hormone,
estradiol levels, ultrasound and vaginal cytology values in either
group. The total Psychological General Well-Being (PGWB)
score did not show any significant difference between verum and
placebo, although a significantly better effect was seen for G115®
regarding depressed mood (p < 0.04), general health (p < 0.03) and
well-being (p < 0.05). G115® had no effect on vasomotor symp-
toms but was superior to placebo in enhancing well-being and
relieving somatic symptoms.[53]
3.3 Cognitive Functions
The efficacy of ginseng in improving cognitive function has
been extensively reviewed by Kennedy and Scholey.[11] Intake of
G115® in acute and multiple doses is associated with improve-
ments in cognitive function. A series of studies has assessed the
effects of G115® in various volunteer populations using a widely
validated and highly sensitive computerised cognitive test system,
the Cognitive Drug Research (CDR) assessment system. Two
studies demonstrated that acute single doses of the standardised
G115® could modulate cognitive performance.[13,69] These studies
shared the same randomised, double-blind, placebo-controlled,
balanced-crossover design, with 20 participants receiving three
different single doses of the relevant extract and an identical-
looking placebo on separate occasions 7 days apart. In the first
study,[13] the higher doses (400 and 600mg) were associated with
improvements on ‘Quality of memory’. In contrast to these im-
provements, both of the less active doses (200 and 600mg) were
associated at the later testing sessions with disruptions to the
‘Power of attention’. This improvement to ‘Quality of memory’
performance following 400mg of G115® was replicated in the
second, methodologically similar study which compared the ef-
Evid Based Integrative Med 2005; 2 (4)
© 2005 Adis Data Information BV. All rights reserved.

200
Table I. Tabulated summary of placebo-controlled (pc) trials carried out with ginseng extract G115®

Study Design Subjects Regimen Criteria for evaluation Results

Dörling et al.[50] db 60 healthy volunteers, M G115® 500mg bid, PO × 12wk Response time to light and Beneficial effects of several wks of
and F sound; flicker-fusion threshold; G115® treatment, especially on the
Age 22–80y two-hand coordination; recovery reaction time, two-hand coordination,
quotient recovery period, and recovery
Questioning of subjects: quotient. Questioning showed the
general subjective physical results in the G115® group to be
condition; physical fitness; markedly superior to those in the
mental alertness; attitude to life/ placebo group, especially for the
mood; concentration/memory; parameters of subjective physical
sleep behaviour condition, physical fitness and sleep
behaviour
Scaglione et db, pc, r Healthy volunteers of both Group A: 100mg aqueous Chemotaxis PMN; PHI; PHF; Parameters improved: chemotaxis in
al.[51] sexes ginseng extract PKC 167/79 intracellular killing both active groups after wk 4 and 8,
bid, PO Total lymphocytes (T3); T PHI, PHF and killing in both active
Group B: placebo × 8wk helper cells (T4); suppressor groups after 8wk
Group C: G115® 100mg bid, cells (T8); NK cell activity;
PO blastogenesis of circulating
lymphocytes
Scaglione et db, pc, mc, Healthy M and F volunteers, G115® 100mg bid, PO × 12wk Numerical frequency of Significantly less influenza in the
al.[52] two parallel to be vaccinated against Vaccination with Agrippal® anti- influenza or common cold, G115® group. NK activity and
groups influenza influenza polyvalent vaccine antibody titres, NK activity, antibody titre significantly higher in
G115®: 114 (66 M, 48 F) after 4wk safety parameters, adverse G115® group after 8 and 12wk
Placebo: 113 (66 M, 47 F) events
Mean age 48y
Wiklund et db, pc, r, Symptomatic G115® 100mg bid, PO × 16wk Quality-of-life questionnaire G115® had no effect on vasomotor
al.[53] parallel study postmenopausal women including the Women’s Health symptoms but was superior to
45–65y without HRT for the Questionnaire (WHQ), placebo by enhancing well-being
last 2mo and with no Psychological General Well- and relieving somatic symptoms
bleeding during the last 6mo Being (PGWB) index and visual
G115®: 193 analogue scales; symptom
Placebo: 191 relief, bleeding, tolerability;
hormones (follicle-stimulating
hormone, estradiol levels in
serum); vaginal cytology,
ultrasound
Scaglione et sb, pc, r 20 patients with chronic G115® 100mg bid, PO × 8wk PHI, PHF, intracellular killing PHI, PHF and intracellular killing of
Evid Based Integrative Med 2005; 2 (4)

al.[14] bronchitis, smokers (<20 alveolar macrophages showed

cigarettes per day) statistically significant increase in
the G115® group as compared with
placebo control after 8wk

Scaglione et al.
Continued next page
© 2005 Adis Data Information BV. All rights reserved.

Standardised Panax ginseng Extract G115®

Table I. Contd

Study Design Subjects Regimen Criteria for evaluation Results

Kennedy et db, pc, 20 healthy young adult On each study day participants Baseline cognitive assessment, Significant improvement in ‘Quality
al.[13] balanced, co volunteers received six capsules of test sessions at 1, 2.5, 4 and of memory’ and the associated
Age 20–27y identical appearance, each 6h after the day’s treatment; ‘Secondary memory’ factor at all
5d, with 7d washout period containing either an inert each study day comprised five timepoints following 400mg of
placebo or G115® 100mg. identical testing sessions G115®. Both the 200 and 600mg
Depending on the condition to (completion of the Bond-Lader doses were associated with a
which they were allocated on Visual Analogue Scales, significant decrement of the ‘Speed
that particular day the followed by the Cognitive Drug of attention’ factor at later testing
combinations correspond to a Research test battery) times only. Subjective ratings of
dose of either G115® 0, 200, alertness were also reduced 6h after
400 or 600mg and a matching the two lowest doses
placebo in counterbalanced
order with a 7d washout period
between treatments
Cheah[54] db, pc, Patients with type 2 G115® 100mg bid, PO × 8wk Serum glucose levels, serum No statistically significant differences
prospective diabetes mellitus cholesterol levels and serum between G115® and placebo on any
study with sb G115®: 57 triglyceride levels of the measured parameters
run-in period Placebo: 60
Forgo et al.[55] db, pc, r Healthy volunteers, M and F G115® 100mg bid, PO × 12wk Reaction test, pulmonary Improved pulmonary and physical
G115®: 60 function, hormone functions and reaction times in the
Placebo: 60 determination, self-assessment G115® group
Age 30–60y
Mulz et al.[56] 2 db, pc Patients with psychoasthenic Study I: G115® 40mg + Psychoasthenic symptoms such After 2y treatment with G115® 80%
studies symptoms vitamins + minerals + trace as trouble in falling asleep, of the complaints were cured. In
Study I: 28 (16 M, 12 F) for elements for 2y sleeping and through-sleeping, many cases difficulties falling asleep
verum; 32 (18 M, 14 F) for Study II: G115® 100mg bid, PO psychological and physical were resistant to therapy. With
placebo for 2y restlessness, agitation, bouts of placebo treatment and
Study II: 31 (14 M, 17 F) for depression, indecision, feelings psychotherapy 64% of the
verum; 29 (12 M, 17 F) for of incompetence, diffused complaints showed an improvement.
placebo disturbances of well-being, loss After 2y period of G115® + vitamins
of libido, and, among women, + mineral + trace elements
typical pre- and treatment 78% of the complaints
postmenopausal symptoms disappeared. With placebo and good
psychiatric treatment 72% of the
complaints could be removed
Rosenfeld et db Patients with neurological G115® 100mg bid, PO; Toulouse test (attention and Wechsler-Bellevue test and SCAG
al.[57] disorders; patients with concomitant medication concentration), Wechsler- test improved significantly
Evid Based Integrative Med 2005; 2 (4)

Guillain-Barré syndrome levodopa/benserazide/ Bellevue test (intelligence,

(psychophysical asthenia)
G115®: 50 (24 M, 26 F)
diclofenac/adrenocorticotropic
hormone for 56d
attention, concentration, past
memory, recent memory,
abstract and practical
reasoning, general information
and verbal comprehension)

Continued next page

201
© 2005 Adis Data Information BV. All rights reserved.

202
Table I. Contd

Study Design Subjects Regimen Criteria for evaluation Results

Gianoli and db, pc Patients with asthenia, M 100mg G115®, bid, PO for 4mo Resistance to viral infection, G115® appears to improve
Riebenfeld[58] and F during winter season appetite, weight, performance, resistance to infection, appetite,
G115®: 46 (18 M, 28 F). well-being, sleep, systolic and sleep, well-being and performance,
Mean age 40.1y diastolic blood pressure and to decrease systolic blood
Placebo: 37 (6 M, 31 F). pressure
Mean age 34.6y

Forgo[59] db, pc, r, 2 Healthy M top-class athletes PO G115®S 100mg bid, with Measurement of the aerobic Improvement of O2 absorption and
parallel G115® (4%): 10 7% ginsenosides and PO capacity by means of a bicycle performance in both treatment
groups G115®S (7%): 10 G115®S 100mg bid, with 4% ergometer; determination of groups
Placebo: 10 volunteers ginsenosides + vitamin E serum lactate by repeated
Age 18–31y 200mg for 9wk blood sampling during
increasing intensity of effort;
heart rate recording; hormone
determination in the blood
(testosterone, luteinising
hormone) and in urine (cortisol)

Van db, pc, co 43 healthy M volunteers G115® 100mg bid, PO for two Blood pressure, ECG, No significant conclusions could be
Schepdael[60] Age 24–36y periods spirometer, measurements of drawn from the data collected during
10wk for both periods, no oxygen utilisation; oxygen the first 10wk period. However,
washout period consumption; heart rate, lactic during the second period (wks
acid levels 11–20), V̇O2max dropped
significantly in group 1 (G115®-
placebo), whereas it increased in
group 2 (placebo-G115®). A
deterioration in the second period
was also seen for group 1 but not
for group 2 in exercise test, heart
rate, O2 pulse and lactic acid levels.
Therefore, G115® seemed to
prevent loss of physical performance
characteristic of end-of-season
tiredness

D’Angelo et db, pc, 16 healthy M volunteers G115® 100mg bid, PO for 12wk Tapping test, simple reaction Mental arithmetic statistically
al.[61] parallel study Age 20–24y test, choice reaction, significantly better in the G115®
cancellation test, digit symbol group vs placebo; statistically
substitution test, mental significant increase of performance
Evid Based Integrative Med 2005; 2 (4)

arithmetic, logical deduction of cancellation test, mental

arithmetic, auditory reaction time,
choice of reaction time and logical
deduction when compared with
baseline

Scaglione et al.
bid = twice daily; co = crossover; db = double-blind; F = female; HRT = hormone replacement therapy; M = male; mc = multicentre; NK = natural killer; PHF = phagocytosis fraction;
PHI = phagocyte index; PMN = polymorphonuclear neutrophils; PO = orally; r = randomised; sb = single-blind; SCAG = Sandoz Clinical Assessment-Geriatric; V̇O2max = maximum
oxygen uptake.
Standardised Panax ginseng Extract G115®
fects of single doses of a standardised extract of Ginkgo biloba,
G115®, and their combination against a placebo.[69] Sunram-Lea et
al.[70] used a two-way crossover design and assessed cognitive
function in 30 healthy volunteers using the CDR test battery at one
post-dosing timepoint (90 minutes) and found no enhancement to
‘Quality of memory’, but an improvement to ‘Power of attention’.
Another study with multiple doses of G115®[71] used a double-
blind, parallel-group design. In this study, 18 healthy volunteers
ranging in age from 12 to 53 years were enrolled in the study and
took either G115® 200mg (n = 8) or placebo (n = 10) daily for 21
days. Cognitive assessments using the CDR system were conduct-
ed at pre-dose and at 1, 3 and 6 hours post-dose on days 1, 7, 14
and 21. Analyses of variance showed clear benefits, with the active
group performing significantly better than the placebo group for
‘Power of attention’ and ‘Quality of memory’. These improve-
ments did not start on day 1, but they were clear by day 7 and
sustained thereafter.
Taken together, this research suggests that G115® has positive
acute effects on the quality of memory (two of three trials) and
positive effects on memory and attention in a trial with repeated
administration over 3 weeks.
Wesnes et al.[72,73] have performed two randomised, placebo-
controlled, parallel-group studies on the effects of a combination
of G115® with the standardised G. biloba extract GK501 on
cognitive function in 256 healthy volunteers. In both studies, after
administration of the combination, improvements to ‘Quality of
memory’ were seen throughout the 12-week dosing period. Using
a double-blind, randomised, placebo-controlled, parallel-group
design, Wesnes et al.[74] administered either a low dose of G115®
(40mg) in combination with vitamins and minerals or placebo over
a 3-month period to healthy nursing staff working during night
shifts. The shift work-induced cognitive deficit on ‘Quality of
memory’ was almost completely reversed by the treatment.
This is among the most consistent series of findings ever seen
with a natural product. The improvements in cognitive function
observed with G115®, either alone or in combination with the
standardised G. biloba extract GK501, allow us to conclude that
G115® improves the ability of healthy individuals to hold, learn,
retain and retrieve information in memory, thus proving that
G115® is a cognition enhancer.
3.4 Immunology
Several preclinical studies have indicated that G115® may have
immunomodulatory properties.[31,32,34,37,51] These finding have
been confirmed in two clinical studies.
Scaglione et al.[52] determined the efficacy and safety of G115®
for potentiating vaccination against the common cold and/or influ-
enza syndrome in a randomised, double-blind, placebo-controlled,
parallel-group multicentre study. A total of 227 volunteers were
treated for 12 weeks with either G115® 100mg (n = 114) or
© 2005 Adis Data Information BV. All rights reserved.
203
placebo (n = 113) twice daily. After 4 weeks of treatment they
were vaccinated with an anti-influenza vaccine (Agrippal®). The
frequency of influenza or common cold between weeks 4 and 12
consisted of 42 cases in the placebo group and only 15 cases in the
G115® group, the difference being statistically highly significant
(p < 0.001). Antibody titres rose by week 8 to an average of 171
units in the placebo group and to 272 units in the G115® group
(p < 0.0001). NK activity levels at weeks 8 and 12 were nearly
twice as high in the G115® group as in the placebo group (p <
0.0001). The results showed that G115® is able to improve the
immune response in vivo in humans and can protect against
influenza and common cold.
An open pilot study carried out by Scaglione and co-workers[15]
investigated the effects of ginseng in reducing the bacterial count
in the bronchial system of patients undergoing an acute attack of
chronic bronchitis. Seventy-five subjects experiencing acute at-
tacks of chronic bronchitis were included in the trial. All were
treated with amoxicillin 875mg and clavulanic acid 125mg twice
daily. They were then further randomly divided into two groups,
one (n = 37) receiving only the antibiotic treatment, the other (n =
38) also G115® 100mg twice daily. The duration of treatment was
9 days on average. Of the 75 patients included in the trial, 44 were
evaluable. Significant group and day effects were found after
analysis of the evolution of bacterial count. Significant differences
between treatment groups were found on days 4, 5, 6 and 7 with a
borderline trend on day 8. The log rank test showed a significant
difference between the treatment groups after analysis of time to
clearance (χ2 = 6.2127; p = 0.0127). The median day for reaching
the level of no detection was lower in the antibacterials plus
ginseng group (median 6, mean 5.9, SD 0.3) than in the antibacter-
ials only group (median 7, mean 6.7, SD 0.3). In the group
receiving G115® the bacterial clearance was significantly faster
than in the group receiving the antibacterials alone. This trial
suggests that patients for whom the elimination of bacteria from
the bronchial system may be particularly difficult could benefit
from the use of ginseng.
4. Safety
The safety profile of G115® has been well established both
from clinical studies in healthy volunteers and patients and from
its use for over 30 years as a marketed medicinal product in many
countries worldwide. A comprehensive review of the safety of
ginseng has been compiled by Coon and Ernst.[10] Therefore, here
we limit ourselves to analysis of the most relevant safety data
available for G115®.
Few clinical studies on G115® report adverse effects. In gener-
al, the lack of reported adverse effects suggests that there are few
of them and those present are very minor. Conversely, a baseline
level of adverse effects should be expected and is always present,
even for placebo groups in clinical trials. A total of 1075 subjects
Evid Based Integrative Med 2005; 2 (4)
204
have been treated with G115® to date in clinical trials. Seventy-
one subjects experienced minor side effects but no serious adverse
events were reported.[7,52,53,56,74] Most clinical studies did not dis-
close any adverse events or showed a similar rate for placebo and
G115®, such as itching, sore throat, skin rash, dry mouth, acne and
diarrhoea. Wiklund et al.[53] reported headache (6%), gastrointesti-
nal complaints (16%) and cold or influenza (31%) with no differ-
ence between placebo and G115®. Scaglione et al.[52] reported that
8 of 114 volunteers receiving G115® had adverse events such as
nausea, anxiety, epigastralgia and insomnia.
In all trials, no changes in safety laboratory parameters were
seen.
Some recurring mentions of adverse events and interactions
putatively related to ginseng are worth mentioning. Siegel[75]
observed ginseng users over a period of 2 years and described the
‘ginseng abuse syndrome’ in humans, which he defined as hyper-
tension, nervousness, sleeplessness, skin eruptions and morning
diarrhoea. Both adverse and beneficial effects of ginseng were
reported in his evaluation of 133 ginseng users. Adverse effects
included morning diarrhoea (47 subjects, 3-week onset), skin
eruptions (33 subjects, 3-week onset), sleeplessness (26 subjects,
3-week onset), nervousness (25 subjects, 1-week onset), hyperten-
sion (22 subjects, 13-week onset), oedema (14 subjects, 4-week
onset), decreased appetite (7 subjects, 1-week onset), depression
(6 subjects, 24-week onset), hypotension (5 subjects, 3-week
onset) and amenorrhoea (4 subjects, 16-week onset). Siegel, how-
ever, did not include in his report any subjects taking G115®. In
addition, the so-called ginseng abuse syndrome cannot be consid-
ered to be caused by P. ginseng C.A. Meyer, because the subjects
investigated by Siegel used a wide variety of commercial ginseng
preparations, including Ginseng f.a. rumex. Such preparations are
known to contain anthraquinones, agents that may be responsible
for the high number of diarrhoea cases observed.[76] In addition,
concomitant use of caffeine may have resulted in nervousness and
insomnia. There should be substantiated correlation of adverse
effects exhibited to the actual taking of P. ginseng before Siegel’s
observations can be described as a ginseng abuse syndrome.
Six cases of mastalgia and metrorrhagia have been reported
following ginseng administration,[77-82] but there is no convincing
evidence that ginseng contains estrogen compounds or that endog-
enous estrogen levels are increased.
Four reports of possible interactions were identified in our
search: two reports of a possible interaction with phenelzine,[83,84]
one with warfarin[85] and one with alcohol.[86] With the exception
of the interaction with warfarin, all other reports are based on
ginseng products other than G115®.
Both reports of a possible interaction between ginseng and
phenelzine were described with products other than G115®.[83,84]
In the first, trembling, headache and insomnia were experienced
by a patient when taking phenelzine and ‘Natrol High’ (a fad
© 2005 Adis Data Information BV. All rights reserved.
Scaglione et al.
product containing ginseng); she experienced the same symptoms
when taking phenelzine with ‘ginseng tea’. The second patient,
who was being treated for depression, became hypomanic while
taking phenelzine, triazolam, lorazepam, ginseng and bee pollen.
The phenelzine was stopped and the depression relapsed. Medica-
tion with phenelzine, triazolam and lorazepam was restarted with-
out ginseng and bee pollen but the depression on this second
occasion was not improved. Neither report defines the type or dose
of the ginseng that was taken, nor does either constitute tenable
evidence of an interaction between ginseng and phenelzine, partic-
ularly as no other reports suggesting an interaction have been
located.
A 47-year-old man with a St Jude-type mechanical heart valve
in the aortic position receiving warfarin to prevent embolic events
started taking three capsules a day of G115®. His international
normalised ratio (target range 2.5–3.5), which had been stable for
the previous 9 months, declined 2 weeks after starting ginseng
supplementation to 1.5 and returned to within the target range on
cessation of the ginseng capsules. No other similar reports, either
with warfarin or other anticoagulants, have since been published
or reported.[85]
Finally, an open, nonrandomised clinical trial in 14 healthy
volunteers suggests that P. ginseng can enhance the blood alcohol
clearance rate. Forty minutes after the administration of alcohol
and ginseng the blood alcohol level was 30% lower than following
alcohol ingestion alone.[86]
5. Conclusions
Double-blind, randomised, controlled clinical trials are the gold
standard in clinical research and as such are the only tools useful to
establish the efficacy of herbal remedies. So far, however, clinical
research with herbal medicinal products has yielded contrasting
and often contradictory results.[87-89] While flaws in the design of
the clinical trials, including low statistical power, potentially poor
compliance and uncontrolled open research designs, may account
for some variation in results, the quality of the product used is
crucial to obtain reproducible results. For instance, the extraction
method used to produce the extract greatly influences the compo-
sition of the extract, and different compounds may be enriched in
extracts produced with different extraction methods. Thus, the
pharmacological activity of a given extract will mostly depend on
the extraction method used. Standardisation of extracts is crucial
to guarantee product quality. The standardisation of the method of
extraction ensures that the same amount of active ingredients is
present in all batches, thus balancing naturally occurring fluctua-
tions of the level of active ingredients. We believe that the use of
non-standardised ginseng products has led to negative and non-
reproducible results in several clinical trials.
On the other hand, different methods of standardisation may
yield extracts with distinct properties and make the transferability
Evid Based Integrative Med 2005; 2 (4)
Standardised Panax ginseng Extract G115®
of clinical data from one extract to another almost impossible,
unless bioequivalence and bioavailability trials are used to prove
essential similarity.
Ginseng extracts have been used for several centuries in many
countries. Despite this wide usage, the mechanism of action is only
partly known. An effect on both physical and mental performance
has been demonstrated in vitro and in preclinical settings, but the
efficacy of ginseng in humans has so far been clinically proven
only in few indications, of which the improvement of mental
performance and the immunomodulatory properties are the most
relevant; in most other indications it remains contradictory at best.
Recent placebo-controlled, double-blind studies have shown
that G115® may positively modify parameters related to cognitive
and psychological function as well as immunological function in
humans. The development and use in clinical settings of
standardised extracts such as G115® and sound clinical trial
design will eventually prove whether ginseng has additional clini-
cally meaningful effects.
The results obtained from all clinical studies carried out with
G115® show that this extract is well tolerated. No severe adverse
events have so far been reported. All reported adverse events were
of mild nature and resolved quickly during treatment. They includ-
ed mild and transient gastrointestinal reactions and insomnia. The
standardised P. ginseng extract G115® is a prime example of a
herbal medicinal product that has been developed according to
standards close to those used for new chemical entities. The result
of such a development is a product with constant quality, reliable
efficacy and proven safety.
Acknowledgements
No sources of funding were used in the preparation of this review. The
authors have no potential conflicts of interest directly related to this review.
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Correspondence and offprints: Dr Francesco Scaglione, Department of Phar-
macology, Chemotherapy and Toxicology, Faculty of Medicine, University
of Milan, Via Vanvitelli 32, 20129 – Milan, Italy.
E-mail: francesco.scaglione@unimi.it
Evid Based Integrative Med 2005; 2 (4)