ArticlePDF AvailableLiterature Review

Panax ginseng: A Role in Cancer Therapy?

April 2003
Integrative Cancer Therapies 2(1):13-33

DOI:10.1177/1534735403251167

Source
PubMed

Authors:

Eun Kyoung Seo

Ewha Womans University

Charlotte Gyllenhaal

University of Illinois at Chicago

Keith I Block

Block Center for Integrative Cancer Treatment , Skokie, Illinois, USA

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.

Panax ginseng Saponins Compound Class/Name Plant Part Reference

…

Pharmacological Effects of P. ginseng Extracts: Early Assessments Effect Reference

…

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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

: 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,

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

and Petkov.

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.

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

by Yu-Ling Ho on March 29, 2008 http://ict.sagepub.comDownloaded from

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).

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.

Currently, 11 species are recognized in

the genus Panax (see Table 1).

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.

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.

Other

non-Panax ginseng species have generally received

less research than E. senticosus. These are shown in

Table 2.

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

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,

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.

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

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

Panax stipuleanatus

H.T. Tsai & K.M. Feng

Panax trifolius

Panax vietnamensis

Ha & Grushv.

Panax wangianus

S.C. Sun

Panax zingiberensis

C.Y. Wu & K.M. Feng

by Yu-Ling Ho on March 29, 2008 http://ict.sagepub.comDownloaded from

Phytochemical Constituents

Panax

Species

Phytochemical studies on Panax species com-

menced in 1854 when panaquinone was isolated

from Panax quinquefolius.

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.

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.

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

20(S)-ginsenoside Rg

, 20(R)-ginsenoside Rh

, and

ginsenoside Rh

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.

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.

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

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

by Yu-Ling Ho on March 29, 2008 http://ict.sagepub.comDownloaded from

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.

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

(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

to Rb

(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.

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

to Rb

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

,Rb

, Rc, Rd, Re, and Rg

, 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.

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

Root

Ginsenoside Ra

Root

Ginsenoside Ra

Root

Ginsenoside Rb

Root 46

Root

Flower buds 48

Leaves 48

Ginsenoside Rb

Root 46

Root

Fruits 48

Flower buds 48

Leaves 48

Ginsenoside Rb

Root 49

Root

Ginsenoside Rc Root 46

Root

Fruits 48

Flower buds 48

Leaves 48

Ginsenoside Rd Root 46

Root

Fruits 48

Flower buds 50

Leaves 48

Ginsenoside Rg

20(R) Root

Ginsenoside F

Leaves 51

Ginsenoside Rs

Root

Ginsenoside Rs

Root

Quinquenoside R

Root 47

Malonyl-ginsenoside Rb

Root 56

Malonyl-ginsenoside Rb

Root 56

Malonyl-ginsenoside Rc Root 56

Malonyl-ginsenoside Rd Root 56

Ginsenoside Rh

Root

Panaxatriol saponins

Ginsenoside Re Root 52

Fruits 48

Root

Flower buds 51

Leaves 48

Ginsenoside Rf Root 52

Root

Ginsenoside glc-Rf Root 49

Root

Ginsenoside Rg

Root 53

Root

Fruits 48

Leaves 48

Ginsenoside Rg

Root 52

Ginsenoside Rh

Root 48

Ginsenoside F

Leaves 48

Ginsenoside F

Flower buds 48

Leaves 51

Notoginsenoside R

Root

Oleanolic acid saponins

Ginsenoside R

Root 46

Chikusetsusaponin V Root

a. Red ginseng was analyzed.

by Yu-Ling Ho on March 29, 2008 http://ict.sagepub.comDownloaded from

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).

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,

dogs,

and humans

65,66

on oral ingestion. A 95% ethanol

extract was nontoxic by either the oral or the

intraperitoneal (ip) routes in rats.

The aqueous

extract produced generalized toxicity in mice at the ip

dose of 0.5 g/kg/day/7 days

but was orally nontoxic

in the same animal species at various doses.

69,70

The

values of the total saponin fraction in mice were

0.695 and 1.49 g/kg, respectively, for the ip

and sub-

cutaneous (sc)

routes. Oral administration of the

saponin fraction to beagle dogs showed it to be non-

toxic at 15 mg/kg

; it was nonembryotoxic at doses of

1.5, 5.0, and 15 mg/kg.

The fraction potentiated

insulin shock in mice.

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

and protected the fibroblast–

fetal lung degeneration by adverse environmental

conditions.

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,

and the saponin fraction was nonmutagenic

in the S. typhimurium TA 100 and TA 98 systems.

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.

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

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

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.

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.

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

INTEGRATIVE CANCER THERAPIES 2(1); 2003 17

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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.

Other reports of untoward effects from ginseng

products are also found in the literature. Sonneborn

and Hansel

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.

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.

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.

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.

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.

A systematic global review by Coon and Ernst

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.

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

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.

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.

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.

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.

A systematic review by Izzo and

Ernst

noted the interactions with warfarin and

phenelzine, as well as a lowering of blood alcohol

level. Vaes and Chyka

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.

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.

Ginseng extract enhanced cell-

mediated immune response,

123

and red ginseng

extract augmented NK activity in mice.

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

and T

lym-

phocytes. The group given standardized extract also

had an increase in activity of NK cells and increased

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

and Re were also reported to inhibit the decrease of

adrenal ascorbic acid levels during heat stress.

144

Pure

ginsenosides, Rb

,Rb

, Rc, Re, Rg

, and 20S and 20R

prosapogenins were also found to exhibit antistress

effects.

145

Ginsenoside Rb

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

,Rb

, 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

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

and Rb

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

211

; L-1210 cells: panaxydol,

panaxynol, panaxytriol

212,213

; MCF-7 breast cancer cells:

Panax ginseng

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ginsenoside Rh

214

Ginsenoside Rs

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

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

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

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

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

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

222

Ginsenoside Rb

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

, 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

, 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

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

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

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

24 INTEGRATIVE CANCER THERAPIES 2(1); 2003

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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

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

: 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

,Rg

and Rg

were reported as main components.

252

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

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

26 INTEGRATIVE CANCER THERAPIES 2(1); 2003

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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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Panax ginseng: A Role in Cancer Therapy?

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