ArticlePDF AvailableLiterature Review

Panax ginseng: A Role in Cancer Therapy?

Authors:
  • Block Center for Integrative Cancer Treatment , Skokie, Illinois, USA

Abstract and Figures

Panax ginseng is a plant that has been used in traditional medicine in China for thousands of years. It is used as a general tonic or adaptogen with chronically ill patients and is frequently featured in traditional medicine prescriptions from China, Japan, and Korea used by cancer patients. The putative active compounds are the ginsenosides, of which there are more than two dozen. These compounds are found in both Panax ginseng and in other Panax species that are used in herbal medicine. Analysis of ginsenosides is being used in developing quality control assessments for ginseng, which has frequently been adulterated due to its high cost; many currently available standardized extracts do appear to contain the amounts of ginsenosides listed on package labeling. The toxicity of ginseng appears to be low: some of the reports of toxic episodes of ginseng may actually pertain to other components of multicomponent preparations. Very low incidence of toxicity has been observed in ginseng clinical trials using well-characterized preparations. Numerous pharmacological activities of ginseng and the ginsenosides have been explored: the authors review here the activities relating to cancer. Immune system modulation, antistress activities, and antihyperglycemic activities are among the most notable features of ginseng noted in laboratory and clinical analyses. Much testing has been done in humans to explore ginseng's purported antifatigue properties, but this area remains controversial. A number of investigations point to antitumor properties and other pharmacological activities related to cancer, but no trials have yet confirmed a clinically significant anticancer activity. Cancer patients may empirically find ginseng to be useful when they are fatigued, although clinical trials should be conducted to confirm its benefits.
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Integrative Cancer Therapies
DOI: 10.1177/1534735403251167
2003; 2; 13 Integr Cancer Ther
Yuan S. Chang, Eun-Kyoung Seo, Charlotte Gyllenhaal and Keith I. Block
Panax ginseng: Panax ginseng: A Role in Cancer Therapy?
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10.1177/1534735403251167 ARTICLEChang et al
Panax ginseng
Panax ginseng
: A Role in Cancer Therapy?
Yuan S. Chang, PhD, Eun-Kyoung Seo, PhD, Charlotte Gyllenhaal, PhD, and Keith I. Block, MD
Panax ginseng is a plant that has been used in traditional med-
icine in China for thousands of years. It is used as a general
tonic or adaptogen with chronically ill patients and is fre-
quently featured in traditional medicine prescriptions from
China, Japan, and Korea used by cancer patients. The puta-
tive active compounds are the ginsenosides, of which there
are more than two dozen. These compounds are found in
both Panax ginseng and in other Panax species that are used
in herbal medicine. Analysis of ginsenosides is being used in
developing quality control assessments for ginseng, which
has frequently been adulterated due to its high cost; many
currently available standardized extracts do appear to con-
tain the amounts of ginsenosides listed on package labeling.
The toxicity of ginseng appears to be low: some of the re-
ports of toxic episodes of ginseng may actually pertain to
other components of multicomponent preparations. Very
low incidence of toxicity has been observed in ginseng clini-
cal trials using well-characterized preparations. Numerous
pharmacological activities of ginseng and the ginsenosides
have been explored: the authors review here the activities re-
lating to cancer. Immune system modulation, antistress ac-
tivities, and antihyperglycemic activities are among the most
notable features of ginseng noted in laboratory and clinical
analyses. Much testing has been done in humans to explore
ginseng’s purported antifatigue properties, but this area re-
mains controversial. A number of investigations point to
antitumor properties and other pharmacological activities
related to cancer, but no trials have yet confirmed a clinically
significant anticancer activity. Cancer patients may empiri-
cally find ginseng to be useful when they are fatigued, al-
though clinical trials should be conducted to confirm its
benefits.
Keywords: ginseng; Panax; review fatigue; cancer
Introduction
The root of Panax ginseng C.A. Meyer (Araliaceae),
commonly known as ginseng, has been used in Asia,
especially China and Korea, for more than 5000 years,
owing to the belief that it is a tonic and panacea that
can promote longevity. Its efficacy was first docu-
mented in “Sheng-Nung-Pen-Tsao-Ching,” an herbal
compendium published in the fifth century
AD, which
states,
Ginseng tastes sweet, and its property is slightly cool-
ing. It grows in the gorges of the mountains. It is used
for repairing the five viscera, quieting the spirit, curb-
ing the emotion, stopping agitation, removing nox-
ious influence, brightening the eyes, enlightening the
mind, and increasing the wisdom. Continuous use
leads one to longevity with light weight.
1,2
The plant is indigenous to Korea, northeastern China,
and far eastern Siberia. The wild plant is nearly extinct
due both to excessive collection from the wild for
medicinal purposes and to destruction of its native
habitat,
3
mixed coniferous broad-leafed forests of the
Manchurian type. Ginseng grows normally exclusively
under shade. Relict populations are now found in the
Primorsky area of the Russian Federation and the Chi-
nese provinces of Tsilin and Heyludsian. Ginseng is
now cultivated in Korea and China. The roots of other
species of Panax, as well as quite unrelated plant spe-
cies, have also come to be known as ginseng. Ginseng
is of interest to, and used by, cancer patients world-
wide. In this article, we concentrate mainly on P. gin-
seng, reviewing its taxonomy, traditional medicine
background, phytochemistry, and pharmacology, par-
ticularly as they relate to use by cancer patients; we
comment on some other types of ginseng as well.
Most research to date has concentrated on Korean
or Asian ginseng (P. ginseng); in the present review, the
term ginseng with no other modifier will refer to this
species. Early pharmacological studies of ginseng
extracts were reported by Brekhman
4
and Petkov.
5
The
volume of reports since has become so great that
numerous books have been published on the tradi-
tional uses, chemical constituents, and biological,
pharmacological, and clinical effects of ginseng and
its constituents.
6-25
Abstracts and bibliographies on gin-
seng have also been published.
26
American ginseng,
the root of Panax quinquefolius L., which grows in
Panax ginseng
INTEGRATIVE CANCER THERAPIES 2(1); 2003 pp. 13-33 13
YSC is at the School of Pharmacy, China Medical College,
Taichung, Taiwan, Republic of China. EKS is at the College of Phar-
macy, Ewha Womans University, Seoul, Korea. CG and KB are at
the Program for Collaborative Research in the Pharmaceutical Sci
-
ences, College of Pharmacy, University of Illinois at Chicago, and
Block Medical Center, Evanston, Illinois.
Correspondence: Charlotte Gyllenhaal, Block Medical Center,
1800 Sherman Ave, Suite 515, Evanston, IL 60201. E-mail:
cgyllenhaal@blockmedical.com.
DOI: 10.1177/1534735403251167
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North America and has also been the subject of some
scientific study, has been an important export com-
modity to Asian markets since in the 18th century. Ori-
ginally, American ginseng was collected from its wild
habitat in the forests, but due to market demand from
the Far East, the cultivation of this plant was started
early in the 20th century. It is now grown both in the
United States (in Wisconsin) and in Canada (in
Ontario and British Columbia).
27
Botanical Aspects of
Panax
Panax, the genus to which ginseng belongs, is
formed from two Greek words, pan (all) and akos
(cure), based on the reputed use of the plant in China
as a panacea.
28
Currently, 11 species are recognized in
the genus Panax (see Table 1).
29
Commercially, there are 3 major types of P. ginseng
preparations. The first is the “fresh ginseng,” plants less
than 4 years old, which can be consumed fresh. In the
production of “white ginseng,” derived from plants 4
to 6 years old, the peripheral skin is peeled off the dried
root. In the production of “red ginseng,” derived from
plants at least 6 years old, the root is steamed and
dried, resulting in a caramel-like color and resistance
to deterioration due to fungi and worms. The latter is
particularly valued in China, where it is believed that
red ginseng is superior to white ginseng.
30
In addition to the Panax species, other plant spe-
cies have been given the name of ginseng. The most
widely known of these is Siberian ginseng or Russian
ginseng. This plant, consisting of the root of
Eleutherococcus senticosus (Rupr. & Maxim) Maxim.
(Araliaceae) has also been used in traditional Chinese
medicine for more than 2000 years. It was found to
have effects similar to those of P. ginseng when
Brekhman and his coworkers were looking for a substi-
tute for P. ginseng.
31,32
The chemical and pharmacologi-
cal effects of E. senticosus have been reviewed.
33
Other
non-Panax ginseng species have generally received
less research than E. senticosus. These are shown in
Table 2.
34
These plants do not resemble Panax species
chemically and should not be considered as members
of the ginseng group.
Ethnomedical Aspects
The use of Panax species in Chinese medicine and
related medical systems as general tonics, which
increase vitality in debilitated patients, is the basis of
widespread interest in their application in cancer. A
full discussion of the traditional medicine uses of gin-
seng in cancer is beyond the scope of this review.
Examples of its use in the treatment of cancer are
shown in a compendium of herbal formulas used in
cancer by Hsu
35
as well as by other authors. Ginseng,
along with Astragalus membranaceus Bge.
(Leguminosae), is one of the major tonic herbs given
in the treatment of cancer in traditional Chinese med-
icine and is seen as being important in the mainte-
nance of the individual’s constitution, often weakened
in cancer patients. Formulas containing these herbs
may be given as adjuvants to orthodox medical treat-
ment such as surgery, radiation, and chemotherapy or
may be used without conventional medical interven-
tion. Panax species appear in numerous prescriptions
in Hsu’s work,
35
including 11 of the most frequently
mentioned herbal combinations. These include Gin-
seng and Ginger Combination, Ginseng and Borax
Combination, Ginseng and Ziziphus Combination,
and Ginseng Ten Combination.
Formulas that contain Panax species are usually
composed of multiple herbs and typically include sev-
eral herbs with tonic effects. For instance, Ginseng
and Tang-kuei Ten Combination, a combination con-
sisting of 10 tonic herbs, may be given in cases in which
surgery is contraindicated and the patient has severe
anemia and a weak constitution. Ginseng and Longan
Combination is reported as suitable for those with
continuous hemorrhaging and severe anemia who
cannot tolerate the former prescription. Many indica-
tions for formulas that include ginseng mention such
symptoms as weak constitution, low vitality, lassitude,
and fatigue. A case study of an elderly lung cancer
patient treated in Japan with a formula of 12 Chinese
herbs including ginseng and other tonic herbs (the
Ninjin Yoei To formula; the Chinese name of the same
formula is Ren Shen Yang Rong Tang) was recently
reported.
36
After 7 weeks of receiving the formula, the
patient’s cough disappeared, her appetite recovered,
and tumor marker levels (CEA and CA 19-9) were
reduced. Traditional medicine assessments also
improved.
Chang et al
14 INTEGRATIVE CANCER THERAPIES 2(1); 2003
Table 1. Generally Recognized Species of
Panax
29
Panax bipinnatifidus
Seem
Panax ginseng
C.A. Meyer
Panax japonicus
C.A. Meyer
Panax notoginseng
(Burkill) F.H. Chen ex C.Y. Wu & K.M. Feng
Panax pseudoginseng
Wallich
Panax quinquefolius
L.
Panax stipuleanatus
H.T. Tsai & K.M. Feng
Panax trifolius
L.
Panax vietnamensis
Ha & Grushv.
Panax wangianus
S.C. Sun
Panax zingiberensis
C.Y. Wu & K.M. Feng
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Phytochemical Constituents
of
Panax
Species
Phytochemical studies on Panax species com-
menced in 1854 when panaquinone was isolated
from Panax quinquefolius.
37
Since the beginning of this
century, a number of Japanese, European, and
Korean chemists have been engaged in chemical
studies of saponins from Panax.
38-42
The most promi-
nent of the phytochemicals isolated from the various
species of Panax are the saponin glycosides. Many
other classes of compounds have been found as well.
Saponins of
Panax ginseng
The first 6 saponin glycosides isolated from P. gin-
seng were given the names of panaxoside A, B, C, D, E,
and F.
43
More than 60 ginsenosides have subsequently
been isolated from various Panax species. Based on
the triterpene aglycones, the ginsenosides have been
classified into 3 major categories, namely, the
panaxidiols, panaxatriols, and the oleanolic acid
derivatives. A basic summary of the ginsenosides in
each category for P. ginseng, and the plant parts from
which they were isolated, is shown in Table 3.
Although this table does not attempt to present a
comprehensive or quantitative analysis of all
ginsenosides, it does indicate the diverse and com-
plex nature of the array of saponin glycosides in this
species, many of which are biologically active.
The relative abundance of each ginsenoside in var-
ious Panax species has been summarized.
54,55
An early
attempt was made to evaluate ginseng quality by mea-
suring panaxadiol and panaxatriol ratios.
8
It was
reported that the main root of P. ginseng has equal
amounts of panaxadiol and panaxatriol saponins,
while the panaxadiol/panaxatriol ratio is about 1.5 in
the rootlets (smaller roots that branch off the main
root). Red ginseng was found to have major
ginsenosides similar to those found in white ginseng.
However, the less stable malonyl-ginsenoside esters
are absent from red ginseng due to decomposition
during the steaming process. On the other hand,
minor ginsenosides such as 20(R)-ginsenoside Rg
2
,
20(S)-ginsenoside Rg
3
, 20(R)-ginsenoside Rh
1
, and
ginsenoside Rh
2
are characteristically found only in red
ginseng and are considered degradation products
formed during steaming.
56,57
Later efforts in quality
control, discussed below, emphasize quantitative mea-
sures of ginsenosides, individually or in classes.
Other Constituents Isolated From
P. ginseng
Other chemical constituents isolated from P. ginseng
include alkanes, alkynynes, sterols, fatty acids, fatty acid
esters (lipids), monoterpenes, sesquiterpenes,
phenylpropanoids, chromones, carbohydrates (sugars
and polysaccharides), amines, flavonoids, organic
acids, and vitamins. Amino acids, nucleic acids, various
enzymes, and inorganic compounds (including germa-
nium) have also been isolated from ginseng.
Quality Control
P. ginseng is a popular herb throughout Asia, in
Europe, and in North America.
58
However, its high
prices make adulteration with less expensive plant
material tempting. Numerous attempts to characterize
the quality of commercial ginseng preparations have
been published. Cui, in 1995, assayed 14 pure P. ginseng
root preparations purchased in Europe, Argentina,
Canada, China, and the United States, as well as 20 P.
ginseng extracts.
59
Both the total saponin concentra-
tions and the ratios of panaxatriol, panaxadiol, and
oleanoic acid saponins were analyzed by high-
performance liquid chromatography (HPLC). The
total percentage of ginsenosides (weight/weight) var-
ied from 1.9% to 8.1% in the ginseng root preparations
and from 4.9% to 13.3% in the extracts. Ratios of
panaxatriol/panaxadiol saponins also varied among
samples. Among the root preparations, the ratio
ranged from 0.30 to 0.62, while in 7 extracts for which
individual data were shown, the ratios ranged from
0.30 to 0.40. Thus, not only did the concentrations of
saponins in different samples vary, but the ginsenoside
composition was also inconsistent among products.
Such differences might lead to differences in both clin-
ical and experimental results.
Panax ginseng
INTEGRATIVE CANCER THERAPIES 2(1); 2003 15
Table 2. “Ginseng” Species in Commerce That Are Not in the Genus
Panax
34
Latin Binomial and Plant Family Common Name
Adenophora polymorpha
Ledeb. (Campanulaceae) False ginseng
Angelica sinensis
Diels (Apiaceae) Women’s ginseng
Codonopsis pilosula
Nannf. (Campanulaceae) Poor man’s ginseng, false ginseng
Caulophyllum thalictroides
Michx. (Berberidaceae) Blue ginseng
Eleutherococcus senticosus
Maxim. (Araliaceae) Russian or Siberian ginseng
Lepidium meyenii
Walp. (Polygonaceae) Andean ginseng
Pfaffia paniculata
Kuntze (Amaranthaceae) Brazilian ginseng
Pseudostellaria heterophylla
Pax (Caryophyllaceae) Prince’s ginseng
Rumex hymenosepalus
Torr. (Polygonaceae) Wild red American ginseng
Withania somnifera
Dunal (Solanaceae) Indian ginseng
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Ma and colleagues developed an HPLC method for
detection of 8 major ginsenosides as a standard for
evaluation of the quality of ginseng products, includ
-
ing P. ginseng, P. quinquefolius, and P. notoginseng.
60
They
tested samples grown in Asia and North America. The
major data reported in the study were the ratios of
amounts of different ginsenosides, using ginsenoside
Rb
1
(considered to have tranquilizing effects) as the
denominator in comparisons. Ratios differed among
species, as might be expected. P. quinquefolius had a
low ratio of the stimulant ginsenoside Rg
1
to Rb
1
(ratio
0.07 to 1.40 among 35 samples) in comparison to P.
ginseng (ratio 0.51 to 2.08 in 25 samples). This is consis-
tent with the traditional medicinal attribution of
“cool” or calming properties to P. quinquefolius and
“hot” or stimulating properties to P. ginseng. The over-
lap between the 2 species, however, is obvious and
could be responsible for overlap in the clinical effects
of herbal preparations from the 2 species.
Among 8 P. ginseng samples purchased in the
United States, the total ginsenoside concentrations
ranged from 0.288% to 3.286% in a study that used
HPLC-tandem mass spectrometry as an analytical
method.
61
Four of the samples declared ginsenoside
contents on package labeling: the analyzed
ginsenoside levels ranged from 30.6% of the declared
level to 136.8% of the declared level. American gin-
seng was also analyzed in this study, and Rg
1
to Rb
1
ratios were reported. In the 3 P. quinquefolius samples
in the study, the ratios were all substantially below
those of the P. ginseng samples, consistent with the pre-
vious work by Ma and colleagues.
Continuing concerns about quality control in prod-
ucts in the United States led the American Botanical
Council of Austin, Texas, to begin a Ginseng Evalua-
tion Program (GEP) in 1993. The GEP analyzed
ginsenosides Rb
1
,Rb
2
, Rc, Rd, Re, and Rg
1
, which
together make up 90% of the saponin content of gin-
seng root and are the putative active compounds of
the species. Ginsenoside Rf was also analyzed: this
compound is present in P. ginseng but not P.
quinquefolius and was used as a species recognition
marker.
The initial report of the GEP presented data on P.
ginseng products sold in the North American market
that claim to be standardized, a term that implies to con-
sumers that definite amounts of active compound are
contained in the herbal extract.
62
The GEP found sub-
stantial variation in the terminology of standardiza-
tion. For instance, a product could be standardized to
deliver 100 mg of ginseng extract per unit (eg, cap
-
sule, tablet, softgel) with no claim as to the
ginsenoside content of the extract. A product could
deliver 100 mg of standardized ginseng extract per
unit, again with no claim as to the ginsenoside content
Chang et al
16 INTEGRATIVE CANCER THERAPIES 2(1); 2003
Table 3.
Panax ginseng
Saponins
Compound Class/Name Plant Part Reference
Panaxadiol saponins
Ginsenoside Ra
1
Root
a
44
Ginsenoside Ra
2
Root
a
44
Ginsenoside Ra
3
Root
a
45
Ginsenoside Rb
1
Root 46
Root
a
47
Flower buds 48
Leaves 48
Ginsenoside Rb
2
Root 46
Root
a
47
Fruits 48
Flower buds 48
Leaves 48
Ginsenoside Rb
3
Root 49
Root
a
47
Ginsenoside Rc Root 46
Root
a
47
Fruits 48
Flower buds 48
Leaves 48
Ginsenoside Rd Root 46
Root
a
47
Fruits 48
Flower buds 50
Leaves 48
Ginsenoside Rg
3
20(R) Root
a
47
Ginsenoside F
2
Leaves 51
Ginsenoside Rs
1
Root
a
47
Ginsenoside Rs
2
Root
a
47
Quinquenoside R
1
Root 47
Malonyl-ginsenoside Rb
1
Root 56
Malonyl-ginsenoside Rb
2
Root 56
Malonyl-ginsenoside Rc Root 56
Malonyl-ginsenoside Rd Root 56
Ginsenoside Rh
2
Root
a
56
Panaxatriol saponins
Ginsenoside Re Root 52
Fruits 48
Root
a
47
Flower buds 51
Leaves 48
Ginsenoside Rf Root 52
Root
a
47
Ginsenoside glc-Rf Root 49
Root
a
47
Ginsenoside Rg
1
Root 53
Root
a
47
Fruits 48
Leaves 48
Ginsenoside Rg
2
Root 52
Ginsenoside Rh
1
Root 48
Ginsenoside F
1
Leaves 48
Ginsenoside F
3
Flower buds 48
Leaves 51
Notoginsenoside R
1
Root
a
47
Oleanolic acid saponins
Ginsenoside R
0
Root 46
Chikusetsusaponin V Root
a
47
a. Red ginseng was analyzed.
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of the extract. The product could, finally, be standard
-
ized to contain a minimum of a certain percentage of
ginsenosides, usually 4% to 7%. The last terminology
is the clearest in specifying the amounts of active com-
pounds to be expected, but products with other terms
are found in the market.
The GEP analyzed multiple lots of 13 standardized
ginseng products to determine the extent to which
they met label claims of standardization as to percent
ginsenosides, or the standard of 4% ginsenosides if no
claim of ginsenoside content was made on the product
label (ie, the first 2 types of standardized products
listed above).
62
Of the 8 products that made specific
claims, 4 contained the claimed levels of ginsenosides
in 80% to 100% of the lots analyzed. In 1 product,
fewer than 40% of the lots contained the claimed lev-
els of ginsenosides. For those products that did not
make specific claims of ginsenoside contents, 4 of 5
met the standard of 4% total ginsenoside content in all
lots tested. The majority of standardized ginseng prod-
ucts did thus meet minimal standards of quality con-
trol. However, the GEP recommended revisions of
product labeling to clarify the ginsenoside dose that
could be expected per unit so that consumers have a
clearer idea of ginsenoside dosages they may expect
from the products they purchase (recommended
ginsenoside daily dosages range from 6 to 180 mg,
depending on the source).
Toxicity Assessment
The root of P. ginseng was nontoxic to rats,
63
dogs,
64
and humans
65,66
on oral ingestion. A 95% ethanol
extract was nontoxic by either the oral or the
intraperitoneal (ip) routes in rats.
67
The aqueous
extract produced generalized toxicity in mice at the ip
dose of 0.5 g/kg/day/7 days
68
but was orally nontoxic
in the same animal species at various doses.
69,70
The
LD
50
values of the total saponin fraction in mice were
0.695 and 1.49 g/kg, respectively, for the ip
71
and sub-
cutaneous (sc)
72
routes. Oral administration of the
saponin fraction to beagle dogs showed it to be non-
toxic at 15 mg/kg
73
; it was nonembryotoxic at doses of
1.5, 5.0, and 15 mg/kg.
74
The fraction potentiated
insulin shock in mice.
75
The relatively nontoxic nature of the root extracts
was further supported by the antitoxic actions of both
the aqueous extract and saponin fractions. Aqueous
extracts reduce the toxic effects of 5-fluorouracil and
mitomycin C in rabbits
76
and protected the fibroblast–
fetal lung degeneration by adverse environmental
conditions.
77
In addition, the water and methanol
extracts were nonmutagenic when tested in the B.
subtilis H-17, Salmonella typhimurium TA 100, and TA 98
systems,
78
and the saponin fraction was nonmutagenic
in the S. typhimurium TA 100 and TA 98 systems.
79
Polyacetylenes, which have been reported as
anticancer components of ginseng, were tested for
toxicity in Wistar rats. They induced suppression of
body weight growth; however, 4 days after stopping
administration of polyacetylenes, the growth rate
recovered.
80
Several reports have suggested possible toxicities of
ginseng in humans or possibilities of adverse effects
due to misuse or overdose. Some of the reports of
adverse events attributed to ginseng, however, are con-
sidered to be unreliable due to lack of sound experi-
mental design or proper botanical identification of
the substances in question; we therefore mention
these issues where appropriate. Siegel
81
coined the
term ginseng abuse syndrome after studying 133 users of
ginseng in an open trial in Los Angeles, Calif. The
reported average daily intake was 3 g, but actual con-
sumption varied widely, with some users taking up to
18 g daily. Twenty-two of the subjects experienced
symptoms such as hypertension, nervousness, sleep-
lessness, skin rash or diarrhea, confusion, depression,
or depersonalization. Some subjects reduced their
dosage. A later study by the same author
82
examined
use of American ginseng products and reported simi-
lar symptoms among a group of 10 drug addicts. The
study was not restricted to a single dosage form; rather,
a wide variety of ginseng products were used, includ-
ing root, capsules, extracts, cosmetic creams, tablet,
and teas, and no effort to estimate appropriate dosage
was made. In neither study were the chemical contents
of the products characterized or controlled. It is now
widely recognized that this syndrome is not grounded
in clinical, phytochemical, or pharmacological
evidence.
Nevertheless, reports of the syndrome continue to
surface, with similar methodological deficiencies.
Overuse and excessive use of ginseng are claimed to
lead to headaches, insomnia, hypertension, and palpi-
tations.
83
A case study described as ginseng abuse
recorded a 40-year-old man complaining of heaviness
and congestion in the chest, palpitations, and a heart-
beat of 90 beats per minute under conditions of no
exertion. He had recently attended a convention
where he took 5 to 6 cups of coffee (more than his nor-
mal amount), vitamins, and a “normal” dose of a com-
bination product including P. quinquefolius and E.
senticosus. Blood pressure was normal, as were heart
sounds and electrocardiogram. Symptoms disap-
peared with discontinuance of the ginseng product.
84
The exact composition of this product has never been
validated, however, and the proportion of symptoms
attributable to the Panax component is in doubt.
There are indications from traditional herbal practice
that adverse symptoms may be attributable to
Panax ginseng
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improper use of ginseng, although these are naturally
not documented scientifically. Ginseng is described by
one herbalist as causing feelings of heaviness, aggres
-
siveness, chronic spasmodic pains, and congestion
when used inappropriately for long periods. Ginseng
would usually be prescribed only in cases in which
there is a deficiency of energy or other conditions of
depletion (eg, shock, prostration, diarrhea, loss of
appetite, dehydration, diabetes, forgetfulness,
fatigue, and weakness) and would not be taken during
conditions of acute diseases, inflammatory condi-
tions, colds, and infections in traditional practice.
85
Other reports of untoward effects from ginseng
products are also found in the literature. Sonneborn
and Hansel
86
summarize several. Reports of reproduc-
tive effects from Europe and the United States include
evidence of estrogenic effect in a vaginal smear from a
62-year-old woman who took “Rumanian ginseng.”
This product may actually have been E. senticosus
(Siberian ginseng) since there is no botanical species
known under the common name Rumanian ginseng.
Extracts of E. senticosus have been reported to have an
affinity for estrogen receptors. A 72-year-old woman
reported vaginal bleeding after taking a European
product containing P. ginseng, vitamins, and minerals;
controlled trials of this product in Switzerland, how-
ever, did not show any effect on testosterone,
luteinizing hormone, follicle-stimulating hormone,
or estradiol in men or women. A 44-year-old woman
reported abnormal uterine bleeding while using a
Chinese ginseng cream. A 70-year-old woman devel-
oped mastalgia, and 5 women aged 25 to 40 years
developed breast symptoms, all while taking ginseng
products.
Other case reports of adverse effects attributed to
ginseng include manic episodes and hypertension. A
recent report describes a manic episode in a woman
with an affective disorder who was taking ginseng.
Symptoms disappeared with low doses of neuroleptics
and benzodiazepines.
87
A case report of a 35-year-old
woman with a history of depression noted a manic epi-
sode a few days after ginseng ingestion.
88
Hyperten-
sion, along with dizziness and inability to concentrate,
was reported in a 39-year-old man who had taken
unspecified ginseng products for 3 years; the condi-
tion disappeared when he stopped taking the prod-
ucts. A report of acute hypertension and pressure
headaches in a writer who took ginseng tea for 8 days is
also in the literature.
86
However, a slight reduction in
diastolic blood pressure was observed in a trial in
which 30 subjects were given P. ginseng extract for 28
days. A slight increase in the QTc interval was also
observed, but neither effect was felt to be of clinical
significance. No other changes in electrocardio-
graphic or hemodynamic variables were observed.
89
Reports of adverse events in ginseng clinical trials
include diarrhea observed in 2 of 25 participants in a
trial in Australia, although controlled trials with
higher doses of ginseng did not observe such effects.
86
A systematic global review by Coon and Ernst
90
of
adverse effects of P. ginseng in clinical trials reported
that the incidence of adverse events in experimental
groups taking ginseng was similar to that for placebo
groups. The most frequently reported adverse events
were headaches, sleep disturbances, and gastrointesti-
nal effects.
90
Gastrointestinal side effects are fre-
quently observed in clinical drug trials under both pla-
cebo and experimental conditions, and this report
may represent a nonspecific reaction. Coon and
Ernst
90
point out that causality of adverse events based
on isolated case reports submitted to national drug
safety agencies is difficult to determine. They con-
cluded that their review of clinical trial data of ginseng
monopreparations indicates that these are rarely asso-
ciated with adverse effects beyond mild and transient
disturbances; multicomponent preparations may be
associated with some adverse effects, but the degree to
which these are attributable to ginseng is not clear.
Possible herb-drug interactions between ginseng
and conventional drugs have been reported. A 27-
year-old man developed Stevens-Johnson syndrome
after taking larger than usual doses of ginseng; he was
also taking aspirin and an unspecified antibiotic.
91
Two
women taking phenelzine, an antidepressant, were
reported to have reactions that included headaches,
insomnia, tremulousness, irritability, and vague hallu-
cinations when they took ginseng products in addition
to the phenelzine.
86
A man with membranous
glomerulonephritis being treated with furosemide
and cyclosporin was hospitalized with edema and
hypertension 2 days after taking large doses of a
germanium-containing ginseng preparation.
92
Finally,
a drug interaction between ginseng and warfarin was
reported in a 47-year-old man with a mechanical aortic
valve. After 2 weeks of ginseng ingestion, his interna-
tional normalized ration (INR) was lowered from 3.5
to 1.5. When ginseng was stopped, the INR returned
to 3.3 in 2 weeks.
93
A systematic review by Izzo and
Ernst
94
noted the interactions with warfarin and
phenelzine, as well as a lowering of blood alcohol
level. Vaes and Chyka
95
pointed out that the warfarin
interaction is based on a single case, making it difficult
to evaluate the true risk for interactions. A more scien-
tific assessment of the potential for drug interactions
comes from observation of ginseng effects on
cytochrome P450 drug-metabolizing enzymes. Stan-
dardized P. ginseng extract was found to decrease
CYP1A1, CYP1A2, and CYP1B1 activity in an in vitro
study; high levels (50 µg/ml) of ginsenosides Rb, Rb2,
Rc, Rd, and Rf also inhibited the activities of CYP1
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enzymes.
96
A human study of ginseng effects on
CYP1A2, CYP2E1, CYP2D6, and CYP3A4, however,
found no significant effect on these enzymes, which
are the predominant enzymes responsible for the
metabolism of drugs used in cancer care, such as che-
motherapy agents.
97,98
Ginseng is thus not without potentials for toxicity;
however, for most individuals, the risk of adverse reac-
tions is quite low. One of the more commonly
reported side effects in clinical practice is insomnia;
this can be overcome if ginseng doses are taken in the
morning rather than in the evening. Patients taking
drugs for which interactions with ginseng have been
reported should also be counseled against its use,
based on a precautionary principle.
Biological and Pharmacological
Actions of
P. ginseng
Modern biological studies of P. ginseng were initi-
ated in the late 1950s with the pioneering work of
Brekhman in the USSR and of Petkov in Bulgaria.
Interestingly, Brekhman and Dardymov
31,99
started
their study using human subjects, with animal experi-
ments being carried out subsequently as confirmatory
assays. They found that Soviet soldiers receiving P. gin-
seng ran faster in a 3-km race than did those receiving a
placebo and that radio operators taking this drug were
found to transmit text faster and with fewer mistakes
than did the controls. Brekhman confirmed his results
reported in humans with experiments on mice, which
were put into water where they swam until they were
completely exhausted, taken out of the tank, allowed
to rest, and then repeated the swim. The second swim
of the mice is usually much shorter. The group receiv-
ing the extract of P. ginseng, however, swam longer dur-
ing the second swimming test than did the controls. In
other early work, Petkov
4,100
reported that P. ginseng has
central nervous system–stimulating, hypotensive,
respiratory stimulation, blood-sugar-lowering, insulin
potentiation, erythrocyte count, and hemoglobin con-
tent elevation effects.
Following these reports and the ethnomedical pan-
acea reputation of this plant drug, pharmacological
studies on every conceivable activity have been carried
out. One of the most significant series of studies were
carried out by Takagi and his coworkers,
101
in which
Panax ginseng root was subjected to a series of blind
screening tests to evaluate its pharmacological effects.
Their findings and the early findings of others are
summarized in Table 4. There appear in Table 4 some
apparently contradictory results, which would call into
question the validity of these experiments. However,
systematic pharmacological studies carried out during
each step of the chemical fractionation of P. ginseng
102
and on some of the resulting pure isolates
(ginsenosides)
103-106
showed that the plant material
(root) contains constituents that have opposite phar-
macological actions. Thus, depending on the concen-
tration of a specific saponin at the time of harvest,
opposite pharmacological actions could be observed.
The term adaptogen is frequently applied to the
therapeutic activity spectrum attributed to ginseng in
traditional practice. This term was originally used to
describe a substance that increases the nonspecific
resistance of an organism to adverse influences.
107
Brekhman and Dardymov
31,98
defined adaptogen as a
substance that (1) must be innocuous and cause mini-
mal disorders in the physiological functions of an
organism, (2) must have a nonspecific action, and (3)
usually has a normalizing action irrespective of the
direction of the pathological state. This purported
adaptogenic effect of P. ginseng appears to be rooted
in its immunomodulatory, antioxidant, antistress,
antifatigue, and endocrine actions, which may con-
tribute to the “wellness” of the patient. Other poten-
tial activities that are of relevance to cancer manage-
ment include antitumor/cytotoxic, antihyper-
glycemic, anticoagulant, and hormonal activities. We
review here some of the basic pharmacology of P. gin-
seng in these areas. Recent systematic review articles
discuss the efficacy of ginseng in improving physical
and psychomotor performance in basically healthy
subjects. We will not discuss these areas in detail,
although we will discuss the findings of the reviews.
Immunomodulatory Effects
In this section, we will concentrate on immuno-
stimulatory effects of ginseng relevant to cancer. Im-
munostimulation effects, as manifested by positive
tests for interferon induction, phagocytosis, natural
killer (NK) cells, and B and T cell stimulation in vari-
ous animal species including the mouse, guinea pig,
and human, have been reported for the aqueous,
117
Panax ginseng
INTEGRATIVE CANCER THERAPIES 2(1); 2003 19
Table 4. Pharmacological Effects of
P. ginseng
Extracts:
Early Assessments
Effect Reference
Central nervous system (CNS) stimulation 31, 98, 108
CNS depressant 108
Cholinergic effect 109
Histamine-like action 110
Hypotensive 111, 114
Hypertensive 112
Papaverine-like action 4
Serotonin-like action 113
Non-antihistamine-like action 4
Antihistamine-like action 111
Hypoglycemic action 114, 115
Antiplatelet action 116
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methanol,
118
ethanol, butanol, and petroleum ether
extracts
119
; the saponin fraction
120
; and the
polysaccharide fraction.
121
The following immune
effects of the saponin fraction have been reported: an
increase in NK cytotoxic activity
122
and an increase in
the tumoricidal activity against K562 tumor cells by
macrophages.
73
Ginseng extract enhanced cell-
mediated immune response,
123
and red ginseng
extract augmented NK activity in mice.
73
A ginseng
polysaccharide extract enhanced the lytic death of
L929 cells by murine macrophage, as well as
tumoricidal activity against YAC-1 cells. TNFα activa-
tion, expression of nitric oxide sythase, and nitric
oxide production were all elevated.
124
The extract also
increased cytotoxicity of macrophages against B16
melanoma and induced phagocytosis.
125
Administra-
tion of 20(S)protopanaxatriol, the main bacterial
metabolite of the panaxatriol ginsenosides, reduced
growth of implanted B16 melanoma in mice. In vitro
studies revealed no effect on tumor cell growth;
rather, cytotoxicity of splenic NK cells against the
tumor cells was stimulated.
126
Studies of immunomodulatory effects in humans
have also been reported. A double-blind, placebo-
controlled multicenter trial in 227 patients given 200
mg standardized ginseng extract daily reported an
immune stimulant effect after vaccination against the
common cold or influenza. After 12 weeks of treat-
ment, antibody and NK titers were twice as high in the
treatment group as in the placebo group, and the fre-
quency of colds and flu decreased further in the treat-
ment group. There were 9 reports of adverse reactions
such as insomnia, abdominal discomfort, and anxiety
in the treatment group.
127
NK cell activity toward K562
cells and antibody-dependent cellular toxicity toward
herpes-infected H-9 cells were improved in blood sam-
ples from patients with chronic fatigue or AIDS given
ginseng.
128
In a study of 60 healthy volunteers, groups
given ginseng aqueous or standardized extract had an
increased chemotaxis of polymorphonuclear leuko-
cytes, phagocytic index, and number of T
3
and T
4
lym-
phocytes. The group given standardized extract also
had an increase in activity of NK cells and increased
T
4
/T
8
ratio.
129
Antioxidant Effects
Several studies have indicated antioxidant effects
for ginseng extracts or compounds. Ginsenosides
decreased formation of lipid peroxides after trauma
in mice.
130
The saponin fraction showed an anti-
ischemic effect in rats,
131
while the root decoction
inhibited thio-barbituric acid production in vitro.
132
The ginsenoside fraction and the saponin fraction
have shown free radical scavenging activity in endo-
thelial aortic cells and in an in situ lung model.
133,134
Antioxidant effects have also been shown in animal
models involving carbon tetrachloride–induced
hepatotoxicity
135
and free radical injury to pulmonary
epithelium.
136
Smokers (at least 20 cigarettes per day)
were given red ginseng or other antioxidants (vitamin
E, beta-carotene, vitamin C). Plasma antioxidant
nutrients rose, while levels of 8-hydroxydeoxyguano-
sine (an indicator of oxidatively damaged DNA) and
carbonyl content declined in a time-dependent man-
ner in comparison with those given placebo.
137
Malondialdehyde concentration also decreased grad-
ually after 4 weeks of supplementation with the same
antioxidants.
138
Antioxidant effects of various
ginsenosides were evaluated against the hemolysis of
human erythrocytes induced by a water-soluble free
radical compound. Different ginsenosides had differ-
ent levels of antioxidant activity, while some, when
tested in combination with other ginsenosides, had
pro-oxidant activity.
139
Antistress Effects
Stress refers to phenomena that expose the body to
adverse external influences; these influences may be
physical, chemical, or biological. P. ginseng extracts
have been reported to protect, or help animals and
human to recover, from various types of stress.
7,140,141
Some specific effects on various type of stress are as
described below.
Physical Stress
High and low temperature. Animal studies are the
standard pharmacological assays for temperature
stress. A dose of P. ginseng extract that did not have any
effect on the adrenal ascorbic acid content in normal
rats accelerated the restoration of normal adrenal
ascorbic acid concentrations after their initial deple-
tion during heat or cold stress.
142
Treatment with root
saponins partially prevented the rectal temperature
decline in normal rats exposed to cold stress without
affecting plasma levels of glucose, lipids, or
corticosterone.
143
However, such an effect was not
observed in adrenalectomized rats. Ginsenosides Rb
1
and Re were also reported to inhibit the decrease of
adrenal ascorbic acid levels during heat stress.
144
Pure
ginsenosides, Rb
1
,Rb
2
, Rc, Re, Rg
1
, and 20S and 20R
prosapogenins were also found to exhibit antistress
effects.
145
Ginsenoside Rb
1
was observed by Wang and
Lee
143
to improve thermogenesis and cold tolerance in
rats.
Radiation protection. Extracts of P. ginseng had
radioprotective effects or prolonged the survival time
of irradiated mice.
146,147
Radioprotective effects of P.
ginseng in rats and guinea pigs have also been
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reported.
148
An extract of P. ginseng accelerated the
hematological recovery of mice after x-ray irradia-
tion.
149
Kim et al have reported radioprotective effects
of ginseng proteins on γ-ray irradiated ICR mice. Gin-
seng protein fractions enhanced the recovery of body
and splenic weights and increased the amount of DNA
in liver significantly, accelerated the normalization of
erythrocyte counts,
150
and reduced DNA damage to
normal cells (effects of ginseng on tumor cells
exposed to radiation are discussed below).
151
Chemical Stress
Studies of chemical stress in animals may be appli-
cable to the use of ginseng to moderate stress in
patients undergoing cancer chemotherapy. Effects of
ginseng on chemically induced hepatitis and on pro-
tection from effects of cancer chemotherapy drugs
have been reported. For instance, an extract of P. gin-
seng decreased damage to rat liver from carbon tetra-
chloride intoxication
152
and inhibited the elevation of
serum glutamic pyruvic transaminase in carbon
tetrachloride– or thioacetamide-intoxicated mice.
153,154
Among the studies of ginseng and chemotherapeutic
agents, a water extract of ginseng and Angelica sinensis,
another traditional tonic medicine of China, was found
to reverse cisplatin-induced leukopenia in mice.
155
Ginseng saponin fraction reduced cyclophosphamide-
induced immune suppression in mice.
156
Anti-
clastogenic activity was observed in mice treated with
ginseng extract and exposed to mitomycin or to
cyclophosphamide.
157
Ginseng and Tang-kuei Ten
Combination is a commonly used Chinese combina-
tion herbal preparation including ginseng, Astragalus
membranaceus, Atractylodes macrocephala, Polyporus
hoelen, Angelica sinensis, Paeonia lactiflora, Cnidium
monnieri, Cinnamomum zeylanicum, Rehmannia
glutinosa, and Glycyrrhiza uralensis. A dosage of 50 mg/
kg was observed to reduce the lethality and renal toxic-
ity of cisplatin administered at toxic doses to ICR mice,
without reducing the antitumor effect of the cisplatin
in animals inoculated with Ehrlich ascites tumor. The
dosage used was reportedly proportional to that used
in clinical treatment of adult patients.
158
Biological Stress
After being administered P. ginseng saponins at a
dose of 50 mg/kg iv for 4 days, mice were found to be
more resistant to infections by Staphylococcus aureus,
Escherichia coli, and Salmonella typhi.
159
Oral adminis-
tration of P. ginseng at 0.1 g/kg/day for 3 weeks, fol-
lowed by an injection of trypanosomes, reportedly
attenuated the process of trypanosomiasis; the life
span of the treated mice was prolonged, and the
appearance of trypanosomes in their blood was
delayed.
160
P. ginseng also prevented the development
of fever induced by typhoid and paratyphoid vaccines.
Endocrine Effects
Ginseng extract was reported to increase adrenal
cAMP in intact rats but not in hypophysectomized
rats.
161
The results suggest that it acts on the hypothala-
mus or pituitary so that the latter secretes adreno-
corticotrophic hormone (ACTH), which then stimu-
lates the adrenal cortex.
162
After the ip administration
of ginsenosides Rb
1
,Rb
2
, Rc, Rd, and Re, both ACTH
and corticosterone levels are increased in the plasma.
Their increase is suppressed by pretreatment with
dexamethasone, which acts on the pituitary and hypo-
thalamus.
163
Ginseng components may stimulate or
inhibit cAMP production: both the diol saponin and
triol saponin may have reciprocal effects on pep-
sinogen secretion regulatory agents.
164
Gincosan, a
combination of P. ginseng and Ginkgo biloba L.
(Ginkgoaceae), increased the serotonin level in all
brain structures except for the pons and decreased the
noradrenaline level in Wistar rats. It decreased the
serum level of prolactin and greatly increased the
serum level of ACTH.
165
Ginsenoside Rg
1
was found to
bind to the glucocorticoid receptor.
166
Antifatigue Activities
Following the initial studies of the antifatigue activ-
ity of P. ginseng on Russian soldiers and on radio opera-
tors, antifatigue studies were carried out on laboratory
animals. Various parameters have been used to mea-
sure this activity, including swimming, running against
an endless rope, activity wheels (treadmill exercise),
recovery from exhaustion, and oscillation move-
ments. Numerous studies have reported positive
results. For instance, the antifatigue effect of a ginseng
root preparation has been reported by Rüeckert,
167
and the same effect for red ginseng was reported by
Saito and Bao.
168
Ginsenosides Rg
1
and Rb
1
169,170
have been reported
to possess antifatigue activity. The saponin fraction of
red ginseng was shown to have an antidepressant
effect in mice against desmethylimipramine-induced
immobility and was synergistic with various antide-
pressant drugs; however, the fraction had no effect on
immobility induced by forced swimming, another test
used to assay antidepressant activity that could also
reflect antifatigue activity.
171
However, the entire plant
extract did display antidepressant activity in a forced
swimming model.
172
Ginseng extract was found to have
a behavioral effect that was similar to that of
imipramine, but longer lasting, in another experi
-
ment using the forced swimming model.
173
The
antifatigue activity of P. ginseng in mice has also been
Panax ginseng
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compared with that of piracetam, a clinical antistress
drug.
174
Ginseng increased endurance in both male
and female mice, while piracetam showed an
antifatigue effect only on the male mice. Antifatigue
activities for the 1-butanol (saponin) fractions of P.
ginseng, P. quinquefolius, and E. senticosus (all root prep-
arations) have been reported.
175
Forty-eight hours
before and again 1 hour before the swimming test,
drugs were administered by stomach intubation. No
significant prolongation of swimming time was
observed, nor was the plasma lactic acid level affected.
The effects of P. ginseng extract on tissue glycogen
and adrenal cholesterol depletion during prolonged
exercise have been studied.
144
Ginseng extract inhib-
ited by 21% the decrease of adrenal cholesterol found
in untreated rats after 3 hours of swimming. It had no
effect on hepatic glycogen but did have pronounced
inhibitory effects on endogenous glycogen utilization
in white skeletal muscle during exercise, indicating
that ginseng has carbohydrate-sparing actions during
prolonged exercise. In a similar test,
176
the lactic acid,
total lipid, and glucose levels in the serum and pro-
tein, DNA, RNA, total lipid, and glycogen levels in liver
and muscle were measured before and after the
forced swimming test. It was found that the glycogen
levels in both muscle and liver were higher in rats
treated with saponins of stems and leaves of P. ginseng
(SSLG) than in control rats after the forced exercise.
Only when the rats were fatigued did the group receiv-
ing SSLG consume fat as an energy source and so
spare carbohydrates. The blood total lipid level of the
mice receiving SSLG was increased after forced exer-
cise, while the content of total lipid in muscle tissue
was lowered. It was inferred that the raising of blood
lipid level by SSLG could be one aspect of its
antifatigue mechanism. A standardized P. ginseng
extract (G115, Pharmaton) stimulated D-glucose
transport; this can be related to the suggestion that
ginseng can alter the mechanism of fuel homeostasis
during prolonged exercise.
177
During the 1980s and 1990s, numerous human tri-
als of ginseng and multicomponent preparations con-
taining ginseng were conducted to determine the
effects of ginseng on fatigue and various other aspects
of human performance. In the past 10 years, double-
blind, placebo-controlled trials became more com-
mon as investigators attempted to incorporate princi-
ples of good experimental design into their studies.
Two recent systematic reviews, by Vogler et al
178
and
Bahrke and Morgan,
179
have evaluated these studies.
Both reviews located many randomized studies. Both
negative and positive findings were reported from
these studies in various aspects of human perfor
-
mance: reports of improvements in ability to perform
physical or mental work of various types contrast with
studies in which no such improvements were found.
Further examination of the designs of these studies,
however, revealed that important principles of clinical
research were skirted in almost all of them. Only half
the studies in the review by Vogler et al
178
had a Jadad
score of more than 3 on a scale of 5 (the Jadad score
rates the quality of research design), indicating a very
low quality of research for the entire group of studies.
Bahrke and Morgan
179
emphasized the numerous
studies performed in the sports context that found no
effects of ginseng on performance, pointing out that
most of them had sample sizes too small (8 to 10 sub-
jects per group) to provide adequate statistical power
to detect reasonable differences.
Recent publications on ginseng have concentrated
on quality of life, well-being, and memory enhance-
ment. A randomized trial of ginseng in 83 young
adults (mean age = 26 years) used the G115 standard-
ized ginseng extract and measured positive affect, neg-
ative affect, and total mood disturbance. No differ-
ence in any of these measures of psychological well-
being was found.
180
A small, randomized study of 30
adults, using the SF-36 Health Survey, a validated gen-
eral health questionnaire, found that after 4 weeks of
ginseng dosing, the group that received ginseng had
higher scores on the social functioning, mental
health, and mental component summary subscales of
the survey instrument, although overall scores were
not significantly different. The subscale differences
disappeared after 8 weeks of ginseng intake.
181
Gin-
seng extract G115 was given to healthy young adults at
3 dosages in a double-blind crossover study of its effect
on cognitive performance in acute administration.
Improvements in scales of “quality of memory” and
“secondary memory” were reported with the 400-mg
dosage of ginseng extract. The 200- and 600-mg doses
were associated with decrements in “speed of atten-
tion.” Subjective rates of alertness were lowered after
the 2 lower doses.
182
Three studies of the effects of a
combination of a standardized extract of ginseng
(G115) and a standardized extract of Ginkgo biloba L.
(Ginkgoaceae) have found positive effects on memory
variables. Acute administration of the combination in
a double-blind crossover study in 20 young adults
resulted in improvement in “quality of memory,”
owing to an improvement in secondary memory
rather than working memory. A decrease in “speed of
attention” was also found; both effects are similar to
those noted above for the ginseng-only study by the
same authors.
183
A trial of similar design with the same
combination reported improvements in serial sub-
traction tests.
184
A 14-week randomized trial in 256
middle-aged volunteers using the combination was
found to increase an Index of Memory Quality by an
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average of 7.5%, which reflected improvements to
both working memory and long-term memory.
185
Studies on ginseng in elderly patients have also
been published. A meta-analysis of 21 studies on P. gin-
seng in the treatment of elderly patients with low vital-
ity was published in 1988.
186
Approximately1gofgin-
seng root daily at breakfast and lunch was the usual
dosage in the studies. Studies reported increased con-
centration, better memory, and faster reaction times
after ginseng dosing for 1 month or more; the meta-
analysis attributed a major effect to the ginseng sup-
plements and a less effect to placebo. An uncontrolled
study of 15 elderly patients with chronic respiratory
disease reported improved pulmonary function, oxy-
genation, and 6-minute walking distance after 3
months of ginseng supplements.
187
While recent studies of the effects of ginseng or a
ginseng/ginkgo combination on memory appear
promising, the evaluation of the antifatigue proper-
ties of ginseng is still incomplete and clouded by diffi-
culties in experimental design. What were the specific
difficulties in studies of ginseng and human perfor-
mance? Differences in preparations used, a variety of
dosing schedules, short periods of ginseng
supplementation, no monitoring of compliance with
planned dosing schedules, and an almost complete
lack of any chemical analyses of products used have
complicated the evaluation of human research on gin-
seng and performance. In addition, investigators used
a variety of different measures for performance, not
all of which have been validated for the populations
they used. Most well-designed published studies used
ginseng in combination with other herbal or nutri-
tional substances: while this may be representative of
how much of the population takes ginseng, it does not
allow evaluation of its effects on human performance.
Bahrke and Morgan
179
pointed out that even the best-
designed of the trials that they evaluated, which used
power calculation to determine adequate sample size
and monitored compliance, had many other flaws in
design and analysis. The study of fatigue in human
subjects is complicated by the varied etiology of feel-
ings of fatigue in humans: depression, subclinical ill-
ness of several types, and lack of sleep are among the
more common causes, and this is not taken into
account in the design of studies. Finally, many of the
more recent performance studies on ginseng have
used healthy young adults as subjects. In traditional
Chinese medicine, ginseng is not prescribed for this
population: ginseng is normally used by older adults
or convalescents. No studies of the effects of ginseng
in fatigued cancer patients were found. Because of the
complex etiology of fatigue in cancer patients and the
lack of agreement about proper instruments for
measurement of fatigue in this population, future
studies in this area should be designed with great care.
Antitumor/Cytotoxicity Activities
The antitumor/cytotoxicity profiles of the various
extracts and saponins of the P. ginseng root are unclear
based on conflicting literature reports available.
Numerous studies have examined cytotoxicity of gin-
seng and its fractions and compounds in vitro and in
vivo against a wide variety of cancer cell lines or in vivo
neoplasms. Different studies have reported no
cytotoxic or growth inhibitory activity, or definite
activity, as well as weak or questionable activity. The fol-
lowing selection of results is organized by degree of
activity and cell line or model system and notes the
extract or fraction type, or compound, and reference
for each result.
Inactive results for extracts/fractions were
reported as follows: Ehrlich ascites cells in vitro or in
mice: ether, methanol, water extracts
188
; JTC-26 cells:
water
189
; HRT-18 rectal carcinoma: water
190
; Widr colon
cancer: ethanol, water, methanol,
191
protein
192
; Hep-2
carcinoma: ethanol, methanol
193
; HS-578-T: ethanol
193
;
astrocytes (MTT assay): saponin fraction.
194
Negative
and weak results were reported for other extracts on
the same cell lines by some of these authors. Results
indicating stimulation of cancer growth have also
been noted: a ginseng extract induced growth of MCF-
7 breast cancer cells, although it did not show activa-
tion of estrogen receptors and had no effect on uter-
ine weight when administered to mice.
195
Active results for extracts/fractions were reported
as follows: Ehrlich ascites tumor in mice: ethanol-
water
196
; L1210 cells: ether, hexane, ethyl acetate,
197
petroleum ether,
198
saponin fraction
199
; sarcoma-180
cells or in mice: ethyl acetate, hexane,
200
saponin frac-
tion
201
; hepatocarcinoma G-2: petroleum ether
202
;L-
929 cells: petroleum ether
203
; leukemia P-388: water
194
;
A-549 cells: ethyl acetate
203
; Leuk SNU-717 cells:
saponin fraction
203
; DMBA-induced lung carcinoma:
saponin fraction
205,206
; benzo(a)pyrene-induced lung
carcinoma: saponin fraction.
207
A ginsenoside fraction
induced differentiation of leukemia cells derived
from clinical samples.
208
The petroleum ether extract
inhibited the growth of 3 human renal cell carcinoma
lines and was found to block cell cycle progression at
the G1-S phase transition.
209
American ginseng extract
inhibited growth of MCF-7 (estrogen-sensitive) and
MDA-MB-231 (estrogen-insensitive) cell lines; activity
was attributed to transcriptional activation of the p21
gene.
210
Active results for pure compounds were reported as
follows: cytotoxicity against ovarian cancer in mice:
ginsenoside Rh
2
211
; L-1210 cells: panaxydol,
panaxynol, panaxytriol
212,213
; MCF-7 breast cancer cells:
Panax ginseng
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ginsenoside Rh
2
.
214
Ginsenoside Rs
4
induced apoptosis
in SK-HEP-1 cells; it significantly elevated levels of p53
and p21WAF1 and downregulated cyclin E- and A-
dependent kinase activities.
215
Ginsenoside Rh
2
was
found to induce apoptosis in C6Bu-1 cells; however,
the expression of proapoptotic Bcl-2, Bcl-xl, and Bax
was not altered by the compound, suggesting that
there was another mechanism of apoptosis.
216
Panaxydol was reported to decrease proliferation of
the human melanoma cell line, SK-MEL-1. It was
found that the compound inhibited cell cycle progres-
sion at the G1-S transition; it also increased protein
expression of p27 and decreased cyclin-dependent
kinase 2 activity.
217
Panaxytriol was reported to inhibit
DNA synthesis in and was cytotoxic against P388D1
mouse lymphoma cells, and it induced cell cycle arrest
at the G2/M phase.
218
Ginsenoside Rg
3
inhibited the
growth of the LNCaP prostate cancer cell line. The
cells lost their adherent property; expression of PSA,
androgen receptor, and 5-alpha-reductase genes was
suppressed; apoptosis was induced; and Bcl-2 and
caspase 3 expression were suppressed.
219
In a cancer
chemoprevention assay, ginsenoside Rb
2
prevented
the inhibition of gap junctional intercellular com-
munication in WB-F344 rat liver epithelial cells by
the tumor promoter 12-0-tetradecanoylphorbol-13-
acetate.
220
Ginsenoside Rb
2
dose-dependently inhib-
ited angiogenesis in B15-BL6 melanoma in syngeneic
mice, although it did not directly affect the growth of
melanoma or other tumor cells in vitro.
Inhibition of invasion and metastasis has been
reported for various ginsenosides. Ginsenoside Rb
1
was found to be metabolized to a related compound by
intestinal bacteria; this compound had an anti-
metastatic effect in Lewis lung carcinoma in mice.
221
The invasion of epithelial cells into basement mem-
brane was reportedly inhibited by ginsenoside Rb
2
.
222
Ginsenoside Rb
2
also inhibited invasiveness of
endometrial cancer cell lines Ishikawa, HHUA, and
HEC-1-A; these lines expressed matrix metallo-
proteinase MMP-2, which was suppressed by the
ginsenoside. No effect was seen on the expression of
tissue inhibitors of metalloproteinase.
223
Ginsenoside
Rh
2
, however, augmented metastatic potential of
BALB/c 3T3 cells, while also suppressing carcinogen-
induced initiation. The compound was without effect
in the promotional stage of carcinogenesis.
224
Combining Panax or its compounds with other
agents has also been studied. A combination of gin-
seng extract with vitamin C synergistically inhibited
mouse leukemic cell growth.
225
The saponin extract of
P. ginseng increased proliferation of leukemic cells;
however, in conjunction with homoharringtonine,
cytarabine, adriamycin, or etoposide, the saponin
extract significantly increased inhibition by cytotoxic
drugs and sensitivity to the drugs.
226
Panax notoginseng
increased tumor radiosensitivity in mouse KHT sar-
coma. At lower doses of extract, normal bone marrow
did not experience increases in radiosensitivity,
although at higher doses, increased bone marrow tox-
icity was observed. Ginsenoside Rb
1
, extracted from P.
notoginseng, also increased tumor radiosensitivity, but
increased bone marrow toxicity was not seen with the
pure compound.
227
Mixtures of P. ginseng with other
plant materials have also been studied. An aqueous
preparation of a multicomponent traditional Chinese
medicine tonic prescription containing a mixture of
Astragalus mongholicus, Cinnamomum cassia, Rehmannia
glutinosa, Paeonia albiflora, Cnidium officinale,
Atractylodes lancea, Angelica acutiloba, P. ginseng,
Pachyma hoelen, and Glycyrrhiza species was reported to
have antileukopenic and anti-P-388 leukemia activities
in mice.
228
The contribution of each of the component
plant materials was not determined. The water decoc-
tion of a similar mixture of plant materials was
reported to be active against the L-1210 leukemia in
mouse.
229
Injury to mouse testis by doxorubicin was
attenuated by an intestinal metabolite of ginseng
through an antioxidant mechanism.
230
American gin-
seng, when used alone or concurrently with breast
cancer therapeutic agents, was reported to inhibit the
growth of MCF-7 breast cancer cells.
231
The combina-
tion of panaxytriol with mitomycin C (MMC), which is
a reductive alkylating chemotherapeutic agent,
showed synergistic effects in vitro.
232
Ginsenoside Rh
2
was found to potentiate the inhibitory effect of
cisplatin on the growth of human ovarian cancer cells
in mice when given on a daily basis; mice also survived
longer when given the ginsenoside preparation.
233
Ginsenoside Rh
2
and other Panax compounds
enhanced the cytotoxicity of daunomycin and
vinblastine in multidrug-resistant P388 leukemia
cells.
234
Studies on ginseng and cancer therapy in humans
are rare. A German patent was obtained for the
reported clinical effectiveness of the ginsenoside Rg
1
in the treatment of human stomach cancer.
235
Clinical
research on ginseng revealed positive effects on the
immune function of advanced stomach cancer
patients, a possible explanation for a proposed
anticancer effect.
236
In an open study, 126 cachectic
cancer patients received a commercial combination
product that contained ginseng
237
; improvements in
fatigue, pain tolerance, mental concentration, physi-
cal activity, and appetite were reported.
More reports of human studies on ginseng and can
-
cer focus on cancer prevention. Yun and colleagues
238
conducted 2 case-control studies of ginseng and can
-
cer incidence in Korea. They found reduced relative
risks of various cancers among ginseng users, ranging
Chang et al
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from 0.57 to 0.20 for different forms of ginseng (fresh,
white, and red). Smokers who took ginseng had lower
risks of smoking-related cancers than those who did
not.
238
Yun and Choi
239
conducted a prospective study
in Korea of 4634 people older than the age of 40, from
whom they obtained data on frequency and duration
of ginseng intake in interviews. Ginseng consumers
had a decreased risk of cancer (relative risk = 0.40);
the risk of cancer rose with increasing levels of ginseng
intake. For lung cancer and gastric cancer, the relative
risks were 0.30 and 0.33, respectively. Preliminary clin-
ical trials were carried out in Russia on tissue culture–
derived ginseng extracts. Patients with chronic erosive
esophagitis, a precancerous condition associated with
esophageal cancer, were given ginseng extract in an
open trial. Of 64 patients receiving ginseng, 73%
experienced complete regression of erosion and
inflammatory lesions, while only 16% of 19 control
patients experienced complete regression. A small
open trial of ginseng extract in patients with
endometrial hyperplasia found that 3 patients with
adenomatous-cystic hyperplasia experienced com-
plete regression after 5 to 6 months of ginseng admin-
istration, while 8 patients with atypical hyperplasia
experienced no regression. Of 9 control patients
(both types of hyperplasia), none had a complete
regression.
240
A double-blind randomized trial of red
ginseng (1 g/day) in patients with chronic hepatitis C,
who are at high risk for development of hepatocellular
carcinoma, has been initiated; accrual is planned to be
complete by January 2003.
241
This study was based on a
previous intervention study using a Japanese Kampo
formula, Sho-saiko-to, which showed some potential
for prevention of hepatocellular carcinoma in hepati-
tis patients.
242
Use of the formula was associated with
adverse effects (interstitial pneumonia); however, gin-
seng was not suspected of causing this effect based on
a long history of safe use, and the randomized trial was
thus planned for ginseng alone.
Antihyperglycemic Effect
Another important biological effect reported for P.
ginseng or its saponins is hypoglycemic and
antihyperglycemic activity.
114,115
The significance of ele-
vated blood sugar and insulin levels in cancer is begin-
ning to be recognized. Hyperinsulinemia and non-
insulin-dependent diabetes mellitus (NIDDM) were
observed to be related to incidence of colon cancer in
Japanese men,
243
and a review article suggested that
individuals with NIDDM are susceptible to a variety of
malignancies, including those of the breast,
endometrium, pancreas, and liver.
244
A synergistic
effect of insulin and estradiol on the cell cycle of MCF-
7 breast cancer cells has been observed.
245
In an Italian
study, premenopausal women with higher levels of
fasting glucose were at higher risk for breast cancer;
the effect was also seen with postmenopausal women
with body mass index greater than 26.
246
Normaliza
-
tion of insulin levels is thus of potential significance in
the management of cancer risk and perhaps of cancer
treatment. Research support for the hypoglycemic
activity of ginseng and its components is increasing.
Ginsenoside Rg
1
was reported to increase the number
of insulin receptors rather than to change the recep-
tor affinity.
247
Panaxan A was also reported as a main
component for hypoglycemic activity of P. ginseng.
248
Research on the mechanisms of hypoglycemic activity
suggested that panaxan B increased the plasma insu-
lin level and enhancement of insulin sensitivity, while
panaxan A worked by other mechanisms.
114
In a
double-blind human trial, NIDDM patients were
treated with ginseng or placebo; in the ginseng
groups, blood glucose and body weight were reduced,
while mood and psycho-physical performance were
improved; a higher-dose ginseng group also showed
improvements in glycated hemoglobin. The authors
suggest that ginseng may be a useful adjunct in the
treatment of NIDDM.
249
Lowered blood sugar after
meals was observed in both normal and NIDDM sub-
jects who took P. quinquefolius in a double-blind trial.
250
In subjects with normal glucose tolerance, P.
quinquefolius was observed to reduce postprandial rises
in blood glucose and reduce area under the glucose
curve when compared with placebo in a randomized
trial.
251
Time of administration of the ginseng prepara-
tion (120 minutes to 40 minutes prior to the test meal)
did not affect the reduction in blood glucose levels.
Blood Coagulation Effects
A case of drug interaction between P. ginseng and
warfarin was noted above
93
: ginseng was found to
decrease effectiveness of warfarin. However, the effect
of the plant extract itself, and its chemical constitu-
ents, is generally observed to be anticoagulant. Gin-
seng was observed to have antiplatelet activity related
to inhibition of blood coagulation and enhancement
of fibrinolysis. Panaxynol and ginsenosides R
0
,Rg
1
,
and Rg
2
were reported as main components.
252
A
ginsenoside fraction had an antithrombotic effect and
decreased blood viscosity in rats subjected to thrombo-
sis induced by adrenaline and cold stress.
253
Further-
more, the ginsenoside fraction had an inhibitory
effect in rats on platelet aggregation induced by colla-
gen or thrombin.
254
Hormonal Effects
The reports of side effects such as vaginal bleeding
or breast symptoms noted above under toxicity raise
the possibility that ginseng might have estrogenic
effects. Varied results on this question have been
Panax ginseng
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obtained in laboratory and human studies: as with any
herb or food, laboratory studies and studies of isolated
components give only a restricted picture of function
-
ing in the human body, so that studies of the whole
herb are generally more credible than laboratory
observations. The pleiotrophic effects of herbs and
the variability of herbal constituents among different
preparations must also be borne in mind in evaluating
these and other studies of ginseng. Ginseng fed in the
ration produced an estrogenic effect (increasing
ceruloplasmin levels) in ovariectomized rats,
255
although the concentration in the diet may be higher
than normal doses in humans. No in vitro binding to
estrogen receptors was observed. A more recent study
also observed no binding to the estrogen receptor in
S30 breast cancer cells and no stimulation of alkaline
phosphatase activity or progesterone receptor up-
regulation in Ishikawa endometrial cancer cells. It did
demonstrate, however, induction of pS2, an estrogen-
inducible gene, in the S30 cells.
256
Ginseng extract,
observed to increase growth of estrogen-sensitive
MCF-7 breast cancer cells by some investigators, never-
theless did not show activation of estrogen receptor-α
or estrogen receptor-β or increase uterine weight in
mice.
195
Ginsenoside Rg
1
increased H(3)-thymidine
incorporation in MCF-7 breast cancer cells, although
not in an estrogen receptor–negative cell line; it also
stimulated an estrogen response element-luciferase
reporter gene in HeLa cells. These 2 studies thus indi-
cate phytoestrogenic activities for ginseng or ginseng
compounds. Two clinical studies of ginseng extracts in
postmenopausal women have been reported. A study
in Japan examined 12 women who were not reporting
menopausal symptoms and 8 women with symp-
toms.
257
They were treated with ginseng or placebo for
30 days. Women reporting menopausal symptoms
(fatigue, insomnia, depression) who were treated with
ginseng had improvements in the Cornell Medical
Index and the State-Trait Anxiety Inventory. The ratio
of cortisol to DHEA-S was also improved. A study from
Norway randomized 384 postmenopausal women to
ginseng or placebo treatment. Total scores on the Psy-
chological General Well-Being Index (PGWB), the
Women’s Health Questionnaire, and visual analog
scales did not differ between groups, although scores
on the PGWB subscales for depression, well-being,
and health were significantly higher in the ginseng
group. Hot flashes were not reduced in the ginseng
group. No differences were found for hormonally
related physical variables such as FSH and estradiol
levels, endometrial thickness, maturity index, or vagi-
nal pH, indicating that for this preparation and dos-
age in the studied population, no hormonal effects
were exerted on these tissues. No data were recorded
on breast tissues.
258
These results raise questions about
the estrogenic effect of ginseng, although the mixed
results regarding the stimulation of MCF-7 cell growth
still leave its effects on breast cancer unresolved.
American ginseng and some ginseng constituents
have been observed to suppress MCF-7 growth,
214,231
making it potentially of greater interest to breast can-
cer patients. The results of the Norwegian study, how-
ever, indicate an overall lack of estrogenic effect in the
human body, implying a higher level of safety than the
observations and laboratory reports.
Discussion: Clinical Potential of Ginseng
P. ginseng is used in some traditional Chinese medi-
cine treatments for cancers and is of interest to cancer
patients in other countries chiefly for its reputed
antifatigue properties. Ginseng preparations are
widely available from both traditional practitioners
and commercial outlets such as health food stores.
Ginseng is chemically complex; the ginsenosides are
the most likely candidates for active compounds.
While adulteration of this costly botanical medicine
has long been suspected, recent analyses of commer-
cial standardized extracts available in the US market
indicate that such extracts have ginsenoside contents
that generally correspond to the information shown
on package labels.
The pharmacology of ginseng as it has been tested
in animals and in humans has potential relevance for
cancer patients. Concerns about toxicity do exist:
excessive doses of ginseng may produce over-
stimulation or disturb sleep. Users who experience
disturbed sleep have typically found that the problem
resolves when ginseng is taken early in the day rather
than in the evening. While the concerns about gin-
seng and hypertension seem grounded mainly in case
reports rather than effects noted in clinical trials,
patients with hypertension are usually counseled to
avoid ginseng. There appears to be some evidence for
estrogenic effects from case reports, which would indi-
cate caution in use by patients with estrogen-dependent
breast cancers. Laboratory studies of estrogenic
effects have produced some conflicting results. Sys-
tematic studies of estrogenic effects in humans are too
small to confirm or refute the possibility of estrogenic
effects or effects on breast cells. Drug interactions
have been reported and should be kept in mind when
counseling patients about ginseng use. Many reports
of ginseng toxicity are based on single case reports,
often unsubstantiated with chemical analysis.
The immune, antistress, anticancer, and anti
-
fatigue properties of ginseng are of potential interest
in its adjunctive use in cancer therapy. Stimulation of
various immune system components, including the
cytotoxic activity of NK cells, has been observed in
Chang et al
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animal and human studies, although only one study
demonstrating immunomodulatory effects in cancer
patients has been located. Antioxidant activity has
been confirmed in animals and humans: one animal
study demonstrated protection of normal tissue
against effects of doxorubicin based on antioxidant
effects. Other preclinical studies have demonstrated
increases in sensitivity to cytotoxic drugs with some
ginseng extracts or compounds. A number of animal
models of physical, chemical, and biological stress
have been used to demonstrate protective effects for
ginseng. Protection against adverse effects of radia-
tion has been reported, as has increased tumor
radiosensitivity in an animal model. Potential
cytotoxicity of ginseng has been assayed in many can-
cer cell lines, with mixed results. Several of the
ginsenosides have demonstrated interesting
anticancer activities in vivo and in vitro, including
induction of apoptosis, inhibition of cell cycle pro-
gression, and antiangiogenic activity. None, however,
have yet been studied preclinically as new leads for
drug development. Ginseng users in Korea had a
lower incidence of cancer than did nonusers in a pro-
spective study, indicating a potential cancer preven-
tive activity; however, the correlation of ginseng use
with other dietary patterns that might affect cancer
incidence cannot be ruled out in such a study. Open
trials of ginseng in precancerous conditions in Russia
have indicated interesting preliminary results, and the
use of ginseng for chemoprevention of hepatocellular
carcinoma in hepatitis C patients is being studied in a
randomized trial. The antihyperglycemic effect of gin-
seng may be of potential relevance in cancer manage-
ment, as NIDDM has been observed to be correlated
with increased cancer incidence and elevated insulin
levels may stimulate growth of tumors. Research on
use of ginseng in managing fluctuations in blood
sugar and insulin in cancer patients could be
explored.
Although the above pharmacological properties
suggest that ginseng may contribute, in ways that are
not yet completely clear, to cancer control, the more
typical goal of ginseng use in cancer treatment is to
counteract fatigue and debility. An open study of a
compound preparation containing ginseng in cancer
patients did report improvements in fatigue, mental
concentration, and other variables. Some recent ran-
domized trials of ginseng alone or in combination
with ginkgo indicate potential for improvement of
memory. The antifatigue properties of ginseng in
humans who are weak, ill, or convalescent has not yet,
however, been validated in randomized studies. Many
randomized studies have been conducted on ginseng
or compound preparations containing ginseng in
basically healthy populations, with inconclusive
results. Design of many of the studies has been poor. It
is thus not possible to either rule out or confirm the
usefulness of ginseng on the fatigue and debilitation
experienced by cancer patients at this time. Patients
may thus wish to try ginseng empirically as an adjunct
to other cancer treatments. In this case, the health
care professional should ensure that no contraindica-
tions are present, that the patient is using a reliable
standardized product that actually contains P. ginseng,
and that ginseng dosing does not interfere with sleep
patterns. The patient may then be helped to self-
monitor in a systematic way, such as daily recording of
perceived fatigue levels with and without ginseng use,
to determine whether this ancient remedy, employed
for centuries by a population experienced in the use of
many herbal remedies, has a role in his or her present-
day integrative cancer treatment protocol.
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