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Postgraduate Medical Journal (1988) 64, 841-846
Review Article
Ginseng - is there a use in clinical medicine?
S.K.F. Chong1 and V.G. Oberholzer2
'King's College Hospital, London SE5 8RX and 2Queen Elizabeth Hospital for Children, Hackney Road,
London E2 8PS, UK.
Summary: Panax ginseng occupies an important place among the tonic remedies of Oriental
medicine. Pharmacological investigations show that crude ginsenosides can increase non-specific
resistance of an organism to various untoward influences. The effects of purified derived derivatives
have only recently become better studied in immunological and cell growth studies in animals and in
man. This has now provided some evidence to suggest that ginseng is a drug that contains many
derivatives with different pharmacological properties, which could be useful in clinical medicine.
Introduction
Ginseng, the root of the arialaceous plant, Panax stimulation and hypertension may occur in high
ginseng, has been used for 5000 years in the Orient dosage.3
as a tonic and restorative. Although all parts of the
plant contain pharmacologically active ingredients,
it is the root that is highly prized. In vitro somatic Chemistry
embryogenesis and flowering of embryoids derived
from mature root callus of ginseng can be readily The separation and isolation of ginseng saponins,
induced,' but cultivation of the root is long and called ginsenosides, was first reported by Russian
difficult, taking 6 or 7 years before it is ready for and Japanese workers using column and thin layer
harvesting. Nowadays large scale ginseng cultiva- chromatography. The acccepted nomenclature of
tion is industrially processed in modern factories in the individual saponins named Rx (x=O, a, bl, b2,
Korea, producing millions of pounds worth of the c, d, e, f, gl, g2) is based on the sequence of spots
root in the form of powder, liquid extracts, tablets detected after silica gel thin layer chromatography.4
and capsules, which are sold worldwide. Interest in The chemical structure of these saponins is based
herbal remedies has not only increased ginseng upon the tetracyclic triterpenes, protopanaxadiol
production manyfold in Europe and America, but and protopanaxatriol. The ginsenosides Ra to Rg2
has encouraged Western pharmaceutical firms and differ in the number and arrangement of sugar
pharmacologists to investigate its actions and residue, glucose, rhamnose, xylose and arabinose,
properties. variously combined with one another and attached
The history of its clinical usage in the Orient has to the hydroxyl groups. Modern extraction tech-
been to restore and enhance normal well being and niques followed by high pressure liquid chromato-
not as curative medicine. Brekhman, of the Acad- graphy have enabled the analysis and
emy of Sciences in Vladivostok, described it as an standardization of the saponin content of the gin-
'adaptogen' - a substance that is innocuous, does seng extracts.S More recently, the chemical struc-
not impair physiological functions, but helps to tures of white ginseng (peeled and dried roots) and
increase resistance against noxious or stressful red ginseng (steamed, ginseng roots without peel-
influences of a physical, chemical or biological ing) have been further determined by 13C-NMR,
nature, and in general has a normalizing effect.2 chemical reactions (including methylation analyses)
Although ginseng fulfils some of these criteria, and enzymatic degradations (Figure 1).6 White gin-
recent reports suggest that side effects of behaviour seng is produced by air-drying the root, while red
ginseng is produced by steaming the root followed
Correspondence: S.K.F. Chong, M.Med., M.R.C.P., M.Sc. by drying. Extracts of red and white ginseng con-
Accepted: 5 July 1988 tain different ginsenosides.
)O The Fellowship of Postgraduate Medicine, 1988
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842 S.K.F. CHONG AND V.G. OBERHOLZER
2
R 0
2HO
24 R2
H2O
R30
-~~~~~~~~~~~~O
1 R2 R1 R2
ginsenoside-Ra : -glc(2-1)glc -glc(6-1)arap(4-1)xyl ginsenoside-Re -glc(2-1)rha -glc
ginsenoside-Ra2: -glc(2-1)glc -glc(6-1)araf(2-1)xyl ginsenoside-Rf -glc(2-1)glc -H
ginsenioside-Ra3: -glc(271)glc -glc(6-1)glc(3-1)xyl ginsenoside-Rg: -glc -glc
ginisenioside-Rb: -glc(2-1)glc -glc(6-1)glc ginsenoside-Rg2: -glc(2-l)rha -H
ginsenioside-Rb2: -glc( 2-1 )glc -glc(6-1)arap ginsenoside-Rh1 -glc -H
ginsenoside-Rb : -glc(2-1)glc -glc(6-1)xyl 20-gluco-ginsenoside-Rf -glc(2-1)glc -glc
ginsenoside-Rc -glc(2-1)glc -glc(6-1)araf notoginsenoside-RI -glc(2-1)xyl -glc
ginsenoside-Rd -glc(2-1)glc -glc OH 24
*20(S)-ginsenoside-Rg3: -glc(2-1)glc -H 24
*ginsenoside-Rh2: -glc -H H 20 525
quiniquenoside-RI2 -glc(2-1)glc(6)Ac -glc(6-1)glc 1
* ginsenoside-ls 1: -glc(2-1)glc(6)Ac -glc(6-1)arap R, 2
-glc(2-1 )glc(6)Ac -glc(6-1)glc
giisenoside-Rsb2 -glc(2-1)glc(6)Ma -glc(6-1)araf * 20(R)-ginsenoside-Rg2: -H -0-glc(2-1)rha
* malonyl-ginsenoside-Rb
nsenoside-2
*malony l-gi
1
-glc(2-1 )glc(6)Ma -glc(6-1)arap
* ginsenoside-Rg2:
-glc(2-1)glc -H
-H -0-glc
3 * 20(R)-ginsenoside-lUh
*rnalonyl-ginsenoside-Rc -glc(2-l)glc(6)Ma -glc(6-l)araf R O1 1
*malonyl-ginsenoside- Rd -glc(2-1)glc(6)Ma -glc 1 N.
notoginsenoside-R4 -glc(2-1)glc -g1c(6-1)glc(6-1)xYI R2 * Red-Ginseng Saponins
g1c: 0--glucopyranosyl xyl: -D-xylopyranosyl arap: rb-arabinopyranosyl araf: c-L-arabinofuranosyl White-Ginseng Saponins
rha: c-t--rhanmopyranosyl Ac:acetyl Ma:malonyl
Figure 1 Chemical structure of ginseng.
Pharmacological effects diglycoside of protopanaxatriol, have, respectively,
suppressive and stimulatory effects upon the central
Whilst subjective effects on well-being have been nervous system. 1 2
reproducibly obtained in many reported series, the
pharmacological properties of Panax ginseng In vivo studies (animals)
reported in man have been contradictory. In ani-
mals, hypertensive and hypotensive effects, histamine Neuropharmacological effects
and antihistamine-like actions, and stimulatory or
depressant activity on the central nervous system Animal experiments on the anti-fatigue effects of
have all been described.7 These contrasting effects ginseng were first performed by Brekhman et al. in
may be partially related to the dosage levels a long-term study in which groups of mice were
employed.8 allowed to swim once every 5 days until exhaustion.
Contradictory reports of the actions of ginseng Over a 2-month period the average swimming
may also be explained by differences in quantities period of the animals given ginseng was double that
of the active ginseng components in preparations of the other group.13 Italian workers reported a
tested in the past, as crude extracts were generally consistent anti-fatigue activity in rats and mice
used.9 The most active components of ginseng have following intraperitoneal administration of standar-
been identified as saponin substances which possess dized extracts.14
hormone-like effects and probably account for its In rats and mice small doses of ginseng extracts
anti-fatigue properties. Clinical improvement in (2.5 to 5.0 mg/kg) injected intraperitoneally
diabetic patients given red ginseng powder orally appeared to increase spontaneous motor activity,
over a 3 month period was reported to be related while larger doses (40 mg/kg or above) had an
to the presence of adenosine and an unknown inhibitory effect upon the central nervous system.15
acidic peptide with insulin-like properties.10 /3- The behaviour response of mice to stress following
Sitosterol, a steroid sapogenin which is absorbed a dose of ginseng extract of 8 mg/kg/day was also
from the gastrointestinal tract and lowers blood studied by Fulder in 1981. The animals receiving
cholesterol has also been isolated from ginseng.1" ginseng showed more crouching and less explora-
The individual ginsenosides can exert opposite tory movements, indicating an exaggeration of the
pharmacological effects which may explain some adaptive behaviour responses to stress.'6 In particu-
contradictory results reported. The main two ginse- lar, red ginseng potentiated the performance of
nosides Rb1, a protopanaxadiol derivative with forced exercise in mice, and delayed the extinction
1,2 glycosyl-glucose and 1,6 glycosyl-glucose sugar of learning behaviour in stressed mice in a recent
residues on 3 and 20 positions and Rg, a 6,20 control study. I 7
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GINSENG IN CLINICAL MEDICINE 843
Endocrine effects Anti-inflammatory effects
The hormone-like effect of these substances was Earlier studies indicated that the saponins of Panax
illustrated by changes induced in rats after long- ginseng had anti-inflammatory properties. These
term oral treatment. There was a modest reduction properties were measured by the stabilizing action
in blood glucose, fall in triglycerides, no change in on the heat denaturation of an albumin solution
cholesterol concentration but a striking fall in eosino- and the suppression of oedema induced by injection
phils. Histological examination revealed signs of of carrageenin into the hind paws of rats. One
hyperfunction in the supra-optic and para- specific compound identified as C42 H72 014, after
ventricular nuclei of the hypothalamus and hyper- isolation and purification, was shown to produce
plasia of zona fasciculata of adrenals suggesting an delayed and prolonged anti-inflammatory effects.26
induction of ACTH release from the hypophysis.
Mediation via the adrenal cortex or the pituitary Immunological effects
adrenocortical axis would explain the anti-stress
properties of ginseng. Purified ginseng saponins More recently, the steroid-like properties of the
have been shown to increase the adrenal cyclic ginseng saponins were demonstrated by modulation
AMP in intact rats but not in the hypophy- of the immune response of mice to influenza virus
sectomized animals. Measurements of plasma infection. Total saponins extracted from Panax
ACTH by radio-immunoassay and plasma corticos- ginseng root when injected intravenously at a dose
terone by competitive protein binding in rats were of 0.2mg into mice effectively suppressed delayed-
made following intraperitoneal administration of type hypersensitivity response to virus and to sheep
ginseng saponin mixtures. A marked response in erythrocytes when given prior to sensitization.27
ACTH excretion coupled with a parallel rise and When administered orally in combination with
fall in corticosterone occurred. There was a linear 6-MFA (an interferon-inducing antiviral substance
dose response curve between rise in corticosterone of fungal origin), ginseng extract significantly
from 1 to a maximum 35 pg% and the amount of enhanced the protection of mice against Semliki
saponin mixture given from 0.5 to 4mg/100g body Forest virus compared to 6-MFA alone.28
weight. This response was attenuated by prior
treatment with dexamethasone 35Mg/100g body
weight i.p. The isolated ginsenosides Rb1, Rb2, Rc, In vivo studies (man)
Rd and Re also produced significant rises in plasma
corticosterone at doses of 3.5mg/l00g body weight Anti-fatigue effects
in rats. The responses could not be explained by
induction of epinephrine, insulin or histamine The tonic effects of ginseng administration over
release, and indicate that the ginosenosides stimu- placebo on one hundred young soldiers in Eastern
late the hypothalamic-hypophyseal system.18" 9 Siberia before a 3km race showed that the soldiers
An oestrogen-like effect of ginseng saponins on who had taken ginseng completed the course on
vaginal epithelium was recently reported which in average 53 seconds faster than the others.29 Further
the absence of changes in serum oestrogen levels experiments on wireless operators and telegraphists
may have arisen from interaction with uterine for mental concentration and coordination were
receptor proteins.20 performed. The individuals on ginseng made fewer
Kimura et al. demonstrated a lowering blood mistakes.30
sugar and increase in blood insulin levels in alloxan In a double-blind study, Sandberg tested the
treated diabetic mice. psychomotor and intellectual function of 33 young
students by measuring their ability to trace on
paper a complex spiral maze and select certain
Biochemical effects letters from randomized groups of letters according
to certain rules. He demonstrated that a single dose
Other reports of their in vivo action have, however, of ginseng extract had similar anti-fatigue effects to
not been consistent. Rg, was shown to increase caffeine.31
DNA, protein and lipid synthesis in rat bone Fulder studied British nurses in a London hospi-
marrow cells22 and to increase labelled leucine tal doing regular periods of night-duty. Korean
incorporation into serum protein of mice, whereas white ginseng or an identical placebo in capsule
Rb, was inactive.23 On the other hand, Rb, was form was given under double-blind conditions to 12
reported to promote serum protein and RNA syn- nurses of both sexes on three successive days before
thesis in rats but Rg, could not.24'25 night-duty. The nurses taking ginseng felt more
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844 S.K.F. CHONG AND V.G. OBERHOLZER
alert and tranquil during their work, and performed Immunological effects in vitro (man)
better during a test of speed and coordination.32
Improved physical performance of 20 top athletes Until recently, little was known of the local effects
aged 18-20 years from 3 different sports was of Panax ginseng on the immunological system.
demonstrated following ginseng administration. Chao40 performed studies with human lymphocytes
This was supported by advantageous changes in activated by phytohaemagglutinin or concanavalin
functional capacity as measured by blood lactate A and showed that Rg1 could promote mitosis at
levels, heart rate and oxygen absorption.33 A concentrations between 0.3 to 0.5 4g/ml. The gin-
double-blind study of 120 subjects aged 30-60 years senoside Rbl, however, had the opposite effect
also confirmed the stimulatory effect of ginseng and inhibiting mitosis and DNA synthesis of stimulated
its capacity to increase performance in visual and lymphocytes.
acoustic reaction tests and in pulmonary function. We extended these studies to examine whether
Significant effects were shown in older men and Panax ginseng had any steroid-like activity. The
women (40-60 years) but not in the younger effects of hydrocortisone or Panax ginseng, and a
adults.33 combination of hydrocortisone and Panax ginseng
on phytohaemagglutinin (PHA-P)-induced transfor-
mation of peripheral blood lymphocytes were stu-
Adverse effects died in 4 normal healthy adult volunteers.
Increasing concentrations of Panax ginseng 0.16-
Reports of acute hypertension following a short 1.60,pg/ml caused a dose-related inhibition of PHA-
course of ginseng treatment have been described,3 P transformation of lymphocytes. A combination of
together with side effects of behaviour stimulation, 500 jug/ml hydrocortisone and 0.80 ,ug/ml Panax gin-
sleeplessness, diarrhoea,34 mastalgia35 and skin seng produced a greater suppression of PHA-P
eruption in high doses. As far as is known, there stimulation than either drug used alone. This sug-
are no drug interactions with ginsenosides.36 gests that Panax ginseng has a steroid-like effect in
vitro and may have a potentiating effect with
hydrocortisone on suppression of T-cell PHA
activation.4'
Pharmacological and immunological studies in vitro There has been a preliminary in vitro study on
(animals) human peripheral blood lymphocytes, that ginseng
extract increases natural killer cell activity and
Stimulation of DNA synthesis in bone marrow cells antibody-dependent cell cytotoxicity (ADCC).42
of rats was shown following the addition of a Further studies need to be done to elucidate
Panax ginseng extract direct to the incubation whether the action of Panax ginseng is truly
medium. At 25 jug/ml synthesis was doubled as 'steroid-like'. Our laboratory is currently investi-
measured by the incorporation of 3H thymidine gating if the purified extracts of Panax ginseng have
into DNA. Protein and DNA synthesis were also an effect on blocking immunomodulatory lympho-
significantly increased in minced testes of rats using kine pathways. Our results show that Rhl, Rh2 and
the same ginsenoside fraction at a concentration of Rd ginsenosides have marked inhibitory effects on
50 ig/ml.22 interleukin 1 and interleukin 2 activity.43
The effect of insulin release in a perfusion system
and from isolated pancreatic islets of diabetic mice
was potentiated significantly by an isolated hypo- Quality control and future research
glycaemic fraction of the ginseng root (DPG 2-3).21
Its mode of action was shown to be related to There is now sufficient published evidence to sug-
stimulating calcium ionic uptake.37 gest that ginseng is a drug.44 Quality control and
The natural killer cell activity in mice with lung standardization of products must, therefore, be
adenoma induced by urethane and benzoapyrene made available for further elucidation of the in vivo
was enhanced by the administration of red gin- and in vitro effects described. A positive result in a
seng.38 Similar results of augmentation of natural controlled study is meaningful, but a negative result
killer cell activity in mice receiving ginseng extracts must be reviewed against the context of variability
have been reported.39 This group of workers also of quality of material and does not necessarily
showed enhancement of humoral (haemag- imply absence of effect in a sample of adequate
glutinating antibody titre) and cell-mediated quality.43
immune response based on macrophage migration Very recently, growth inhibitory activities of vari-
inhibition test in mice to sheep red blood cells and ous ginsenosides against some cultured tumour cells
Semliki Forest virus antigens. have been studied by Odashima et al.45 Ginseno-
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GINSENG IN CLINICAL MEDICINE 845
side Rh2 exhibited persistent growth inhibitory intake are to be avoided.46 It is important to
effects on B- 16 melanoma cell lines. The growth distinguish between its effects which are measurable
rate recovered on removal of the ginsenoside sug- without being necessarily symptomatic, such as
gesting a cytostatic effect. blood pressure, blood sugar, hormone levels, and
those which can be experienced but not easily
quantified, such as well-being. Further work should
Conclusion be directed to investigate to what extent in vitro
evidence is reflected and confirmed in vivo.
Animals studies have in many instances confirmed
the effects of ginseng preparations on man in vivo.
The reported effects have been mainly beneficial
and apparently safe in respect to chronic toxicity. Acknowledgements
However ad-libitum recommendations of ginseng We thank Professor P. Turner, Department of Clinical
are common in America as dose recommendations Pharmacology, St. Bartholomew's Hospital, and Professor
are not required. (The US Food and Drug Admini- J.A. Walker-Smith, St. Bartholomew's Hospital, London,
stration regards ginseng as food). It should be for support and encouragement in the study, and Miss
better controlled if serious side effects due to liberal Linda Van Laere for typing this manuscript.
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Ginseng--is there a use in
clinical medicine?
S. K. Chong and V. G. Oberholzer
Postgrad Med J 1988 64: 841-846
doi: 10.1136/pgmj.64.757.841
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