HERBAL
MEDICINAL
Siberian Ginseng
GINSENG, ORIENTAL GINSENG
(Panax ginseng C.A. Mey.) +++
BY
RETTODWIKART THENU
Siberian Ginseng
GINSENG,
ORIENTAL GINSENG
(Panax
ginseng C.A. Mey.) +++
HISTORICAL NOTE (Braun, L and Cohen, M. 2010)
Siberian ginseng has been used for over 2000 years, according to
Chinese medical records, where it is referred to as Ci Wu Jia. It was used to
prevent colds and flu and to increase vitality and energy. In modern times, it
has been used by Russian cosmonauts for improving alertness and energy and to aid
in adaptation to the stresses of life in space. It also has been used as an
ergogenic aid by Russian athletes before international competitions (Mills
& Bone 2000) and used after the Chernobyl accident to counteract the effects
of radiation (Chevallier 1996).
SUMMARY AND PHARMACEUTICAL
COMMENT (Barnes, J et al., 2007)
The chemistry of Panax ginseng root
is well documented. Research has focused mainly on the saponin components (ginsenosides),
which are generally considered to be the main active constituents, although
pharmacological actions have been documented for certain non-saponin
components, principally polysaccharides. Many of the pharmacological actions
documented for ginseng, at least in preclinical studies, directly oppose one
another and this has been attributed to the actions of the individual
ginsenosides. For example, ginsenoside Rb–1 exhibits CNS-depressant,
hypotensive and tranquillising actions whilst ginsenoside Rg–1 exhibits
CNSstimulant, hypertensive and anti-fatigue actions. These opposing actions are
thought to explain the ’adaptogenic’reputation of ginseng, that is the ability
to increase the overall resistance of the body to stress and to balance bodily functions.
Preclinical studies have indicated that preparations of Panax species and/or their isolated
constituents have a range of pharmacological properties; results of these
studies provide some supporting evidence for the traditional uses and adaptogenic
properties for certain Panax species
preparations, although pharmacological explanations for the observed actions
are less well understood.
Clinical
trials of Panax species
preparations have focused on assessing effects related to the reputed
adaptogenic properties of this herbal medicinal product, although rigorous clinical
investigations are limited. Studies have tested different preparations of
different Panax species
and different commercial products (which vary qualitatively and quantitatively
in their phytochemical composition) administered according to different dosage
regimens, and to different study populations making interpretation of the results
difficult. At present there is insufficient evidence to support definitely the
efficacy of specific Panax species
preparations in the various indications for which they are used and/or have
been tested.
Similarly,
there are only limited clinical data on safety aspects of Panax species preparations. Clinical trials
of Panax species
root preparations typically have involved small numbers of patients and been of
short duration, so have the statistical power only to detect very common, acute
adverse effects. The available evidence suggests that preparations of Panax species root are well-tolerated when
used for limited periods of time at recommended doses. Rigorous investigation
of safety aspects of well-characterised Panax species root preparations administered orally at different dosages,
including the effects of long-term treatment, is required. In view of the many
pharmacological actions documented, the potential for preparations of Panax species to interfere with other medicines
administered concurrently, particularly those with similar or opposing effects,
should be considered. In general, and in view of the lack of safety data, it is
appropriate to advise against the long-term or otherwise excessive use of Panax species. The use of Panax species during both pregnancy and breastfeeding
should be avoided.
SPECIES (FAMILY) (Barnes, J et al., 2007)
Various Panax species (Araliaceae) including:
*Panax ginseng Meyer
†Panax quinquefolius L.
‡Panax notoginseng (Burk.) Chen ex C.Y. Wu
This monograph focuses on P. ginseng, although some information
on other Panax species is also included.
SYNONYM(S) (Barnes, J et al., 2007)
*P. quinquefolius
var. coreensis Sieb., P. schin-seng T. Nees, P. schin-seng var. coraiensis T.
Nees, P. versus Oken, Ren Shen, Asian Ginseng, Chinese Ginseng, Korean Ginseng,
Oriental Ginseng
†P. quinquefolius
var. americanus Raf., P. quinquefolius var. obovatus Raf., P. cuneataus Raf.,
P. americanus var. elatus Raf., American Ginseng
‡Aralia
quinquifolia var. notoginseng (Burk.), P. Pseudoginseng var. notoginseng
(Burk.) Hoo & Tseng, San Qi, Sanchi Ginseng, Tienchi Ginseng
OTHER
COMMON NAMES (Linda, S-R. 2010)
American ginseng, Asiatic ginseng, Chinese ginseng, fi
ve-fi ngers, Japanese ginseng, jintsam, Korean ginseng, ninjin, Oriental
ginseng, schinsent, seng and sang, tartar root, Western ginseng
OTHER NAMES (Braun, L and Cohen, M.
2010)
Ci Wu Jia, devil’s bush, devil’s
shrub, eleuthero, eleutherococcus, eleuthero root, gokahi, ogap’I, russisk rod,
taigawurzel, touch-me-not, Wu Jia Pi
ORIGIN
(Linda, S-R. 2010)
Ginseng is now found throughout the world. Panax
quinquefolius is native to North America; Panax ginseng is native to the Far East.
PART(S) USED
Root. White ginseng
represents the peeled and sun-dried root whilst red ginseng is unpeeled,
steamed and dried.
USES
(Linda, S-R. 2010)
Ginseng has been used for a variety of purposes for
about 5000 years. It has been used to increase physical endurance and lessen
fatigue, to improve the ability to cope with stress, and to improve
concentration. It also may improve overall well-being. Many herbalists consider
it a tonic.
Investigational
Uses
Initial research is exploring the use of ginseng to improve
cognitive functioning and to treat diabetes mellitus, hyperlipidemia, seizure
disorders, cancer, male infertility, male erectile dysfunction, emphysema, and
rheumatoid arthritis and to enhance immunity.
PHARMACOPOEIAL AND OTHER
MONOGRAPHS (Linda,
S-R. 2010)
BHC 1992(G6)
BHP 1996(G9)
BP 2007(G84)
Complete German Commission E(G3)
Martindale 35th edition(G85)
Ph Eur 2007(G81)
USP29/NF24(G86)
LEGAL CATEGORY (LICENSED
PRODUCTS) (Linda,
S-R. 2010)
GSL(G37)
CONSTITUENTS
CONSTITUENTS (Linda, S-R . 2010)
The following is
compiled from several sources, including General References G2 and G6.
Terpenoids
Complex mixture of compounds (ginsenosides or panaxosides) involves three aglycone
structural types – two tetracyclic dammarane-type sapogenins (protopanaxadiol
and protopanaxatriol) and a pentacyclic triterpene oleanolic acidtype. Different
naming conventions have been used for these compounds. In Japan, they are known
as ginsenosides and are represented by Rx where 'x' indicates a particular
saponin. For example, Ra, Rb-1, Rc, Rd, Rg-1. In Russia, the saponins are referred
to as panaxosides and are represented as panaxoside X where 'X' can be A–F. The
suffixes in the two systems are not equivalent and thus panaxoside A does not
equal Ra but Rg-1.(1) The saponin content varies between different Panax
species. For example, in P. ginseng the major ginsenosides are Rb-1, Rc and
Rg-1 whereas in P. quinquefolis Rb-1 is the only major ginsenoside.(1)
OTHER CONSTITUENTS (Linda, S-R.
2010)
Volatile
oil (trace) mainly consisting of sesquiterpenes including panacene, limonene,
terpineol, eucalyptol, a-phellandrene and citral,(2) sesquiterpene alcohols
including the panasinsanols A and B, and ginsenol,(3, 4) polyacetylenes,(5, 6) sterols,
polysaccharides (mainly pectins and glucans),(7) starch (8– 32%), b-amylase,(8)
free sugars, vitamins (B1, B2, B12, panthotenic acid, biotin), choline
(0.1–0.2%), fats, minerals. The sesquiterpene alcohols are stated to be
characteristic components of Panax ginseng in that they are absent from the volatile
oils of other Panax species.(4)
CHEMICAL COMPONENTS (Braun,
L and Cohen, M. 2010)
Glycosides
(eleutherosides A–M, including saponins, coumarins, lignans, phenylpropanoids,
oleanolic acids, triterpenes, betulinic acid and vitamins), steroid glycoside
(eleutheroside A), lignans (syringin, sesamin, chlorigenic acid), glycans
(eleutherans A–G), triterpenoid saponins (friedelin), saponin (protoprimulagenin
A), hydroxycoumarin (isofraxidin), phenolics, polysaccharides, lignans,
coumarins and resin. Nutrients include magnesium 723 microgram/g, aluminium 188
microgram/g and manganese 37 microgram/g and vitamins A and E (Eleutherococcus senticosus
2006, Meacham et al 2002, Nissen 2003,
Skidmore-Roth 2001, Panossian et al 1999).
QUALITY OF PLANT MATERIAL AND COMMERCIAL PRODUCTS
According
to the British and European Pharmacopoeias, Panax ginseng consists of the whole
or cut dried root, designated as white ginseng, treated with steam and then
dried, designated red ginseng, of Panax ginseng C.A.Meyer.(G81, G84) As with
other herbal medicinal products, there is variation in the qualitative and quantitative
composition of crude plant material obtained from Panax species and commercial Panax
ginseng preparations and those derived from other Panax species. Thirty seven
commercial samples of root from P. ginseng (n = 22), P. quinquefolius (n = 10)
and P. notoginseng (n = 5) obtained from herbal outlets in Taiwan were analysed
to determine their respective chemical profiles.(9) The saponin content of P. notoginseng
and P. quinquefolius was higher than that of P. ginseng, although statistical
analyses to support this were not performed. Mean total saponin (Rb–1, Rb–2,
Rc, Rd, Re, Rf, Rg–1) contents for P. notoginseng, P. quinquefolius wild, P.
Quinquefolius cultivated, P. ginseng white, and P. ginseng red were 118.7,
58.0, 43.1, 5.2 and 5.9 mg/g, respectively. Variations in total saponin content
within species and types of ginseng were also found: P. notoginseng 23.8–30.7,
P. quinquefolius wild 8.7–24.0, P. quinquefolius cultivated 8.4–19.5, P. ginseng
white 3.5–9.0, and P. ginseng red
3.9–7.2 mg/g.(9) In another analytical study, the saponin content of 47 samples
of ginseng obtained from 12 Panax taxa was examined using reverse-phase
high-performance liquid chromatography. Material from P. ginseng was found to
have the lowest total saponin content (5.8–15.6 mg/g).(10) Analysis using gas chromatography
(GC) and GC-mass spectrometry of best-selling commercial preparations of Panax species
purchased from pharmacies and health-food stores in European countries, Argentina,
Canada, China and the USA found variations in their saponin content: P.
ginseng, pure root preparations, 1.9–8.1% (n = 14); P. ginseng, extract
preparations, 4.9–13.3% (n = 20); P. quinquefolius, 5.2% (n = 1); P.
notoginseng, 7.5% (n = 1).(11) Analysis of 25 'ginseng' products available for
purchase from a health-food store in the USA included eight products labelled
as containing Panax ginseng, four labelled as containing P. quinquefolius, one
labelled as containing P. notoginseng, and three labelled as containing
mixtures of different species.(12) All of the products labelled as containing
Panax species contained ginsenosides, although total ginsenoside content varied:
monopreparations of powdered P. ginseng,
0.29–3.36 mg/100 g product (n = 6); monopreparations of powdered P.
quinquefolius, 1.24–2.91 mg/100 g product (n = 2); monopreparation of powdered
P. notoginseng, 4.27 mg/100 g product (n = 1); liquid monopreparations of P.
ginseng, 0.44–0.69 mg/100 mL product (n = 2); liquid monopreparations of P. quinquefolius,
0.78–1.30 mg/100 mL product (n = 2). Of the 16 products containing Panax
species, seven were labelled as containing a specific concentration of ginsenosides,
yet the actual content deviated from the labelled amount, containing 18.0–136.8%
of the amount stated on the label.(12) All but one of these products contained
a lower concentration of ginsenosides than the labelled amount. In 2005, the
USA Department of the Interior Fish and Wildlife Service determined that wild
P. quinquefolius root must be at least ten years old and have four 'prongs' or
leaves before it can be legally exported from the USA.(13) This decision extended
the previous five-year minimum age limit determined by the Convention on
International Trade in Endangered Species (CITES).(14)
FOOD USE (Barnes, J et al., 2007)
Ginseng
(P. ginseng) is listed by the Council of Europe as a natural source of food
flavouring (category N2). This category indicates that ginseng can be added to
foodstuffs in small quantities, with a possible limitation of an active
principle (as yet unspecified) in the final product.(G16)
HERBAL USE (Barnes, J et al., 2007)
Ginseng
(P. ginseng) is stated to possess thymoleptic, sedative, demulcent and
stomachic properties, and is reputed to be an aphrodisiac. Traditionally, it
has been used for neurasthenia, neuralgia, insomnia, hypotonia, and
specifically for depressive states associated with sexual inadequacy.(G2, G6,
G8, G64) P. ginseng and other Panax species have been used traditionally in
Chinese medicine for many thousands of years. Uses include as a stimulant,
tonic, diuretic and stomachic,(15) but typically the different species have
different clinical uses. Traditionally, use has been divided into two
categories: short-term – to improve stamina, concentration, healing process,
stress resistance, vigilance and work efficiency in healthy individuals, and
long-term –to improve well-being in debilitated and degenerative conditions
especially those associated with old age.
Figure 1. Panax ginseng –
dried drug substance (root).
DOSAGE
PRODUCT
AVAILABILITY (Linda,S-R. 2010)
Capsules, dried root used for decoction, extract,
powder, standardized extract, tea, tincture; may be found in creams and lotions
used to treat wrinkles
Plant Part Used:
Roots
DOSAGES
(Linda,S-R. 2010)
Standardized extracts contain 5% ginsenosides (an
aglycone chemical component believed to act as a stimulant).
General Use
• Adult PO capsules: 200-500 mg extract daily
(Blumenthal, 1998)
• Adult PO infusion: pour boiling water over 3 g herb,
let stand 10 min, strain; may be taken tid for 3-4 wk
• Adult PO powdered root: 1-4 g daily
• Adult PO standardized extract: 200-500 mg daily (Blumenthal,
1998)
• Adult PO tincture: 1-2 ml extract daily (1:1
dilution) (Blumenthal, 1998)
Male Infertility
• Adult PO crude herb (root, high quality): 1.5-2 g tid
(Murray, Pizzorno, 1998)
• Adult PO extract: 100-200 mg tid standardized to 5%
ginsenosides (Murray, Pizzorno, 1998)
Rheumatoid
Arthritis
• Adult PO crude herb: 4.5-6 g/day in divided doses
• Adult PO extract: 500 mg daily-tid
Attention Defi
cit Hyperactivity Disorder
• Child PO: 200 mg bid in combination with ginkgo biloba _ 4 wk
DOSAGE (Barnes, J et al., 2007)
Traditionally,
dosage recommendations differ for short-term use by healthy individuals and
long-term use by elderly or debilitated persons.
·
Short-term (for younger and healthy individuals) 0.5–1.0 g root
daily, as two divided doses, for a course generally lasting 15–20 days and with
a treatment-free period of approximately two weeks between consecutive courses.
Doses are recommended to be taken in the morning, two hours before a meal, and
in the evening, not less than two hours after a meal.(15)
·
Long-term (for older individuals and those with poor health)
0.4–0.8 g root daily. Doses may be taken continuously.(1) In China, doses used
traditionally and currently are typically 3–9 g root powder daily taken as a
decoction.(16) Dosages used in clinical trials vary depending on the Panax
species, type of preparation and indication under investigation. Several
studies have assessed the effects of a standardised extract of P. ginseng root
(G115) at doses of 100–400 mg daily for 4–12 weeks.
DOSAGE AND DURATION OF USE: (Kraft, K and Hobbs C. 2004)
·
Tea: Boil 3 g of the finely cut dried roots for
at least 30 or 45 minutes and steep for another 15 minutes. Strain and drink or
store in refrigerator for use during the day. If only larger root pieces and
whole roots are available, the patient should crush or cut the roots into
coarse pieces before use; precrushed roots may also be available.
·
Daily dose: Dry extract: 1–2 g. For a usual 5 : 1
extract, the dose would be about 1 g, equivalent to 2 “0” caps or usually 2
tablets/day. Standardized extract (5–10 % ginsenosides, typically 200 mg per
unit); 1–2 capsules or tablets twice daily. Tea: one cup, 3 to 4 times a day.
Treatment should be continued for 3 months followed by a break, after which
treatment can be re-initiated.
DOSAGES (Duke, J. A et al., 2002)
Tea
3–4 ×/day, 3–4 weeks (PH2); 0.33–0.66 g root 3 ×/day; 0.6–3.0 g root 1–3 ×/day,
3 weeks–3 months (AHP); 0.5–1 g root daily, 15–20 days (CAN); 1–2 g root/day
(PH2); 1–9 g root (FAY); 1–10 g root/day (MAB); 0.4–0.8 g root/day, long term
(CAN); 1–2 g Asian root/day (APA); 0.5 tsp dried Asian root/cup water 1–2 ×/day
(APA); 1 tbsp fresh root (PED);
0.5–2
g dry root (WHO); 2 g dry root:10 ml alcohol/10 mg water (PED); 0.5–3 g dry
root/day or 1–6 ml fluid extract (1:2) (KEB); 1–2 g dry root (KOM; PED); 0.5–1
g powdered root (PNC); 3–9 g powdered ginseng/day (AKT); 3 (550 mg) capsules 3
×/day (Korean); 1–4 (250 mg) StX capsules (5–9% ginsenosides) (APA); 100 mg StX
(4–7% ginsenosides) 1–2 ×/day; 1 (535 mg) StX 2 x/day (Korean).
DOSAGE RANGE (Braun, L and
Cohen, M. 2010)
•
1–4 g/day dried root or equivalent preparations.
• Fluid extract (1:2): 2–8 mL/day (15–55
mL/week).
• Tincture (1:5): 10–15 mL/day.
• Acute dosing: 4 mL in a single dose
before activity.
Extracts
with standardised levels of eleutheroside E (syringin) (> 0.5 mg/mL) are
recommended. Russian and Korean sources appear to have higher levels of this constituent. So,
variations in therapeutic activity may be predicted (Wagner
et al 1982). As there can be a significant product variability in the level
of eleutherosides between capsules and liquids, standardisation may be
necessary for quality assurance (Harkey et al 2001). In
practice, Siberian ginseng is often given for 6 weeks with a break of at least
2 weeks before resuming treatment.
ACTIVITIES (Duke, J. A et
al., 2002)
Adaptogen
(1; KEB; MAB; SHT; WHO); Adrenergic (1; AKT); Alterative (f; CRC; DAA; PED);
Analgesic (f; CRC; DAA); Antiaging (f; AKT; MAB); Antiaggregant (1; PH2; PNC);
Antialcoholic (1; KEB; MAB; PH2); Antiarrhythmic (1; KEB; PH2); Anticancer (1;
PH2); Anticatecholamine (1; PH2); Anticholinergic (1; KEB; PH2); Anticonvulsant
(f; FAY); Antidepressant (1; BGB); Antidiuretic (f; KEB); Antifatigue (1; BGB;
PNC; WHO); Antihepatomic (1; KEB); Antiinflammatory (1; KEB); Antiischemic (1;
KEB); Antimitogenic (1; DAA); Antioxidant (1; BGB; PH2); Antiprolactin (1;
WHO); Antiprostatic (1; KEB); Antipsychotic (f; FAY); Antiradiation (1; MAB;
WHO); Antiseptic (f; CRC; DAA); Antithromboxane (1; PH2); Antitumor (1; BGB;
KEB; WHO); Antiulcer (1; APA; FAY); Antiwrinkle (f; MAB); Antiviral (1; WHO);
Anxiolytic (1; BGB; KEB); Aperitif (f; CRC; DAA); Aphrodisiac (1; APA; CRC;
DAA); Apoptotic (1; PH2); Bitter (f; PED); Cardiotonic (1; AKT; APA; DAA; KEB;
PED); Carminative (f; CRC; DAA); Caspase Stimulator (1; PH2); Chemopreventive
(1; MAB); Circulostimulant (1; PED); CNS Sedative (1; FAY; KEB; PNC); CNS
Stimulant (1; KEB; PNC); Corticotrophinogenic (1; PH2); Cytotoxic (1; PH2);
Demulcent (f; CRC; DAA); Diuretic (f; CRC; DAA); Elevates HDL-Cholesterol (1;
MAB); Emetic (f; CRC); Energizer (1; APA); Estrogenic (1; DAA; KEB; PNC);
Ethanolytic (1; KEB); Expectorant (f; CRC; DAA); Fatigue (f; APA); Gonadotropic
(1; CRC; KEB); Hemopoietic (1; KEB); Hepatoprotective (1; KEB; PH2; WHO);
Hepatotonic (1; PED); Hyperglycemic (1; KEB); Hypertensive (1; PNC);
Hypocholesterolemic (1; BGB; PH2); Hypoglycemic (1; DAA; KEB; PNC; WHO);
Hypotriglyceridemic (1; BGB; PH2); Immunostimulant (1; APA; PED; MAB; PH2; WHO);
Interferonigenic (1; KEB; PH2); Memorigenic (1; BGB; KEB); Mineralcorticoid (1;
KEB); Mitogenic (1; DAA); Negative Chronotropic (1; PH2); Negative Inotropic
(1; PH2); Nervine (f; CRC; PH2); Neurotonic (f; CRC; PH2); Nicotinic (1; PH2);
NKC-Genic (1; PH2); NO-genic (1; BGB; PH2); Nootropic (1; KEB); Osteoprotective
(1; MAB); Phagocytotic (1; KEB); Positive Inotropic (1; PH2); Radioprotective (1;
BGB; FAY; HH2); Respirastimulant (f; FAY); Roborant (f; BGB); Secretagogue (1;
APA); Sedative (f; APA; DAA); Serotonilytic (1; KEB); Sialagogue (f; CRC; DAA);
Spermatogenic (1; KEB); Stimulant (f; CRC; PNC); Stomachic (f; CRC);
Testosteronigenic (1; KEB); Thymoleptic (f; MB); Tonic (1; AKT; CRC; DAA; KOM; MAB;
SHT); Tranquilizer (f; CRC; DAA); Ulcerogenic (1; FAY); Vasodilator (1; BGB).
INDICATIONS (Duke, J. A et
al., 2002)
Aging
(1; CRC; DAA); Alcoholism (1; KEB; MAB; PH2); Amnesia (f; APA; CRC; DAA);
Anemia (f; AKT; CRC; FAY); Angina (f; KEB); Anorexia (f; APA; BGB; DAA; PH2);
Anxiety (1; BGB; KEB; MAB; PH2); Arrhythmia (1; DAA; KEB; PH2); Asthma (f; CRC;
DAA; KEB; MAB); Atherosclerosis (f; CRC; DAA); Bleeding (f; CRC); Bite (f;
CRC); Boil (f; CRC); Bruise (f; CRC); Cachexia (2; CRC; KOM; PH2; SHT); Cancer
(1; APA; BGB; CRC; DAA; KEB; JLH; PH2; WHO); Cancer, breast (f; JLH); Cancer,
lung (1; KEB); Cancer, stomach (f; JLH); Carcinoma (f; JLH); Cardiopathy (f;
KEB); Chemotherapy (f; AKT); Cold (f; JAD); Colitis (f; APA); Convalescence (1;
KOM; SHT; WHO); Convulsion (f; CRC; DAA; FAY; MAB); Cough (f; CRC; WHO);
Debility (2; FAY; KOM; PH2; SHT; WHO); Depression (1; BGB; KEB); Diabetes (1;
CRC; KEB; PH2; WHO); Divination (f; CRC); Dysentery (f; CRC; DAA); Dysmenorrhea
(f; CRC; DAA); Dyspepsia (f; CRC; DAA; MAB); Dyspnea (f; DAA; KEB; MAB; WHO);
Enterosis (f; CRC; DAA); Epilepsy (f; CRC; DAA); Epistaxis (f; CRC; DAA);
Fatigue (2; AKT; CRC; DAA; KOM; PH2; SHT; WHO); Fear (f; CRC; DAA); Fever (f;
CRC; DAA; WHO); Flu (f; PH2); Gas (f; CRC; DAA); Gastrosis (1; CRC; PH2; WHO);
Gonadotrophy (f; DAA); Hangover (f; CRC; DAA); Headache (f; APA; DAA); Heart
(f; CRC); Hemoptysis (f; DAA; PH2); Hepatoma (1; KEB; HH2); Hepatosis (2; WHO);
High Blood Pressure (f; CRC; DAA); High Cholesterol (1; BGB; KEB; PH2);
Hyperglycemia (f; CRC; DAA); Hypoglycemia (1; KEB); Hypothermia (f; WHO); IDDM
(1; WHO); Immune Dysfunction (1; JAD); Immunodepression (1; APA; PED; MAB; PH2;
WHO); Impotence (1; BGB; DAA; PH2; SHT; WHO); Infection (f; KEB); Infertility
(1; BGB; KEB; MAB; PH2); Inflammation (1; KEB); Insomnia (1; APA; CRC; DAA;
PH2); Leukopenia (1; KEB); Longevity (1; KEB); Low Blood Pressure (1; CRC; DAA;
PNC); Malaria (f; CRC); Menopause (f; KEB); Menorrhagia (f; CRC); Mental
Derangement (f; KEB); Morning Sickness (f; WHO); Nausea (f; CRC); Nephrosis (f;
CRC); Nervousness (f; APA; CRC; DAA); Neuralgia (f; MAB); Neurasthenia (f; CRC;
DAA); Neurosis (f; KEB; PH2; WHO); NIDDM (1; BGB; MAB; WHO); Obesity (1; PH2);
Pain (f; CRC; DAA); Palpitation (f; CRC; DAA; KEB); Polyuria (f; CRC; DAA);
Post-Menopause (f; BGB); Proctosis (f; CRC); Prolapse (f; KEB; MAB); Radiation Sickness
(1; KEB); Respirosis (f; AKT); Rheumatism (f; APA; CRC; DAA; PH2; WHO); Senile Dementia
(1; APA; KEB); Sheehan’s Syndrome (1; KEB); Shock (1; DAA; MAB); Slow Thinking (1;
SHT); Sore (f; CRC; JLH); Spermatorrhea (f; CRC); Splenosis (f; BGB; CRC; DAA);
Sting (f; CRC); Stress (2; KOM; MAB; PHR); Swelling (1; CRC; DAA; JLH); Thirst
(f; CRC); Tuberculosis (f; WHO); Tumor (1; BGB; KEB; WHO); Ulcer (1; APA; FAY;
WHO); Vertigo (f; CRC; DAA); Virus (1; PH2; WHO); Vomiting (f; PH2); Water
Retention (f; CRC; DAA); Wrinkle (f; FAY; MAB). (Commission E approves as a tonic “for
invigoration and fortification in times of fatigue and debility, for declining
capacity for work and concentration, also during convalescence” (KOM); reading
that reinforces my contention, in my ginseng book, that carrots could do a lot
of the same thing at less than 1% of the price. I still feel that much of the
literature on ginseng and soy comes from selective publications of sponsored
research, making them look undeservedly better than carrot and black beans, for
example.)
PHARMACOLOGICAL ACTIONS
(Barnes, J et al., 2007)
In
the 1950s, early studies on ginseng reported its ability to improve both
physical endurance and mental ability in animals and humans.(17) In addition,
the 'tonic' properties of ginseng were confirmed by the observation that doses
taken for a prolonged period of time increased the overall well-being of an
individual, measured by various parameters such as appetite, sleep and absence
of moodiness, resulting in an increased work efficiency.(10) Since then,
numerous studies have investigated the complex pharmacology of ginseng in both
animals and humans. The saponin glycosides (ginsenosides/panaxosides) are
generally recognised as the main active constituents in ginseng, although pharmacological
activities have also been associated with nonsaponin components. The following
sections on preclinical and clinical studies are intended to give an indication
of the type of research that has been published for ginseng rather than to
provide a comprehensive bibliography of ginseng research papers.
IN VITRO AND ANIMAL
STUDIES
Pharmacokinetics
There are only limited data on the pharmacokinetics of the constituents of P.
ginseng. Ginsenosides Rg–1, Rb–1 and Rb–2 have been detected in the
gastrointestinal tract of rats following oral administration of P. ginseng root,
although absorption rates are low.(18–21) Corticosteroid-like activity Many of
the activities exhibited by Panax ginseng have been compared with
corticosteroid-like actions and results of endocrinological studies have
suggested that the ginsenosides may primarily augment adrenal steroidogenesis via
an indirect action on the pituitary gland.(22) Ginsenosides
have
increased adrenal cAMP in intact but not in hypophysectomised rats and
dexamethasone, a synthetic glucocorticoid that
provides positive feedback at the level of the pituitary gland, has blocked
the effect of ginsenosides on pituitary corticotrophin and adrenal
corticosterone secretion.(22) Hormones produced by the pituitary and adrenal
glands are known to play a significant role in the adaptation capabilities of
the body.(23) Working capacity is one of the indices used to measure adaptation
ability and ginseng has been shown to increase the working capacity of rats following
single (132%) and seven-day (179%) administration (intraperitoneal).
Furthermore,
seven-day administration of ginseng decreased the reduction seen in working
capacity when the pituitary– adrenocortical system is blocked by prior
administration of hydrocortisone.(23) Hypoglycaemic activity Hypoglycaemic
activity has been documented for ginseng and attributed to both saponin and polysaccharide
constituents. In vitro studies using isolated rat pancreatic islets have shown
that ginsenosides promote an insulin release which is independent of extracellular
calcium and which utilises a different mechanism to that of glucose.(24) In
addition, in vivo studies in rats have reported that a P. ginseng extract increases
the number of insulin receptors in bone marrow and reduces the number of glucocorticoid
receptors in rat brain homogenate.(25) Both of these actions are thought to
contribute to the antidiabetic action of P. ginseng, in view of the known diabetogenic
action of adrenal corticoids and the knowledge that the number of insulin receptors
generally decreases with ageing.(25) Hypoglycaemic activity observed in both
normal and alloxaninduced hyperglycaemic mice administered P. ginseng or P. quinquefolium
(intraperitoneal) has also been attributed to nonsaponin but uncharacterised
principles(26–29) or to glycan (polysaccharide) components.(30–34) Glycans
isolated from Korean or
Chinese
P. ginseng (A–E) were found to possess stronger hypoglycaemic activity than those
isolated from Japanese P. ginseng (Q–U).(34) Proposed mechanisms of action have
included elevated plasma insulin concentration due to an increase of insulin secretion
from pancreatic islets, and enhancement of insulin sensitivity.(32) However,
these mechanisms do not explain the total hypoglycaemic activity that has been exhibited
by the polysaccharides and further mechanisms are under investigation.(32) The
effect of panaxans A and B from P. ginseng roots on the activities of key
enzymes participating in carbohydrate metabolism has been studied.(29) DPG-3-2,
a non-saponin component, has been shown to stimulate insulin biosynthesis in
pancreatic preparations from various hyperglycaemic (but not normoglycaemic) animals;
ginsenosides Rb–1 and Rg–1 were found to decrease islet insulin concentrations
to an undetectable level.(27)
Cardiovascular
activity Individual saponins from P. notoginseng have been reported to have
different actions on cardiac haemodynamics.(35) For instance Rg, Rg-1 and total
flower saponins have increased cardiac performance whilst Rb and total leaf
saponins have decreased it; calcium antagonist activity has been reported for
Rb but not for Rg; Rb but not Rg has produced a protective effect on experimental
myocardial infarction in rabbits.(35) Negative chronotropic and inotropic effects
in vitro have been observed for ginseng saponins and a mechanism of action
similar to that of verapamil has been suggested.(36) In vitro studies on the
isolated rabbit heart have reported an increase in coronary blood flow together
with a positive inotropic effect.(37)
Anti-arrhythmic
action on aconitine and barium chloride (rat) and adrenaline (rabbit)-induced arrhythmias,
and prolongation of RR, PR and QTc intervals (rat), have been documented for saponins
Rc-1 and Rd-1 from P. notoginseng. The mode of action was thought to be similar
to that of amiodarone.(38) Ginsenosides (i.p.) have been reported to protect
mice against metabolic disturbances and myocardial damage associated with
conditions of severe anoxia.(39) P. notoginseng has produced a marked hypotensive
response together with bradycardia following intravenous administration to rats.
The dose-related effect was blocked by many antagonists suggesting multi-site
activity.(37) Higher doses were found to cause vasoconstriction rather than
vasodilation in renal, mesenteric and femoral arteries.(37) The total ginseng
saponin fraction (Panax species not specified) has been reported to be devoid of
haemolytic activity. However, individual ginsenosides have been found to
exhibit either haemolytic or protective activities. Protective ginsenosides
include Rc, Rb-2 and Re, whereas haemolytic saponins have included Rg, Rh and
Rf.(40) The number and position of sugars attached to the sapogenin moiety was
thought to determine activity.(40) Haemostatic activity has also been
documented.(41) Oral administration of P. ginseng to rats fed a high
cholesterol diet reduced serum cholesterol and triglycerides, increased
highdensity lipoprotein (HDL) cholesterol, decreased platelet adhesiveness, and
decreased fatty changes to the liver.(42) P. ginseng has also been reported to
reduce blood coagulation and enhance fibrinolysis.(43)
Panaxynol
and the ginsenosides Ro, Rg-1 and Rg-2 have been documented as the main
antiplatelet components in P. ginseng inhibiting aggregation, release reaction
and thromboxane formation in vitro.(43) Anti-inflammatory activity and
inhibition of thromboxane B2 have previously been described for panaxynol.( 43)
Anticomplementary activity in vitro (human serum) has been documented for P.
ginseng polysaccharides with highest activity observed in strongly acidic
polysaccharide fractions.(7) Effects on neurotransmitters Studies in rats have
shown that a standardised P. ginseng extract (G115) inhibits the development of
morphine tolerance and physical dependence, of a decrease in hepatic
glutathione concentrations, and of dopamine receptor sensitivity without
antagonising morphine analgesia, as previously documented for the individual
saponins.(44) The inhibition of tolerance was thought to be associated with a
reduction in morphinone production, a toxic metabolite which irreversibly blocks
the opiate receptor sites, and with the activation of morphinone–glutathione
conjugation, a detoxication process. The mechanism of inhibition of physical
dependence was unclear but thought to be associated with changed ratios of
adrenaline, noradrenaline, dopamine and serotonin in the brain.(44) A total
ginsenoside fraction has been reported to inhibit the uptake of various
neurotransmitters into rat brain synaptosomes in descending order of gamma-aminobutyrate
and noradrenaline, dopamine, glutamate and serotonin.(45–47) The fraction
containing ginsenoside Rd was most effective. Uptake of metabolic substrates 2-deoxy-D-glucose
and leucine was only slightly affected and therefore it was proposed that the P.
ginseng extracts were acting centrally rather than locally as surface active
agents. Studies in rats have indicated that the increase in dopaminergic receptors
in the brain observed under conditions of stress is prevented by pretreatment
with P. ginseng.(48) Hepatoprotective activity Antoxidant and detoxifying
activities have been documented.(49) Protection against carbon tetrachloride- and
galactosamine-induced hepatotoxicity has been observed in cultured rat
hepatocytes for specific ginsenosides (oleanolic acid and dammarane series).(49,
50)
However,
at higher doses certain ginsenosides from both series were found to exhibit simultaneous
cytotoxic activity. Cytotoxic and
antitumour activity Cytotoxic activity (ED50 0.5 mg/mL) versus L1210 has been
documented for polyacetylenes isolated from P. ginseng root.(5, 6, 51) The
antitumour effect of ginseng polysaccharides in tumour-bearing mice has been associated
with an immunological mechanism of action.(52) Ginseng polysaccharides have
been reported to increase the lifespan of tumour-bearing mice and to inhibit
the growth of tumour cells in vivo, although cytocidal action was not seen in vitro.(52)
Antitumour activity in vitro versus several tumour cell lines has been
documented for a polyacetylene, panaxytriol, from P. ginseng.(53) Antiviral
activity Antiviral activity (versus Semliki forest virus; 34–40% protection)
has been documented for P. ginseng extract (G115, Pharmaton) administered orally
to rats.(54) The extract also enhanced the level of protection afforded by
6-MFA, an interferon-inducing agent of fungal origin.(54) P. ginseng has been found
to induce in vitro and in vivo production of interferon and to augment the
natural killer and antibody dependent cytotoxic activities in human peripheral
lymphocytes.(54, 55) In addition, P. ginseng enhances the antibody-forming cell
response to sheep red blood cells in mice and stimulates cell mediated immunity
both in vitro and in vivo.(54, 55) In view of these observations, it has been proposed
that the antiviral activity of P. ginseng may be immunologically mediated.(54,
55)
MAIN ACTIONS (Braun, L and Cohen, M. 2010)
Adaptogenic
(modulates stress response) Siberian ginseng appears to
alter the levels of different neurotransmitters and hormones involved in
the stress response, chiefly at the hypothalamicpituitary- adrenal axis (HPA)
axis. Various mechanisms have been proposed including inhibition of catechol-O-methyltransferase,
which inactivates catecholamines (Gaffney et al 2001a).
As a result, catecholamine levels are not depleted and release of new
catecholamines from nerve synapses is decreased (Panossian et al
1999). In theory, this may reduce the risk of the organisms’ adaptive
responses becoming depleted and moving into the exhaustionphase of the stress
response. In addition, eleutherosides have been shown to improve carbohydrate metabolism
and energy provision and increase the synthesis of protein and nucleic acids,
although the direct molecular targets responsible for this adaptive response
remain unknown (Panossian et al 1999). Eleutherosides have also
been reported to bind to receptor sites for progestin, oestrogen,
mineralocorticoids and glucocorticoids in vitro and therefore may theoretically
exert numerous pharmacological actions important for the body’s stress response
(Pearce et al 1982). Owing to such
actions, herbalists and naturopaths describe the herb’s overall action as
‘adaptogenic’. The term ‘adaptogen’ describes substances that increase the
ability of an organism to adapt to environmental factors and to avoid damage
from such factors (Panossian et al 1999). The term ‘allostasis’ (see
Clinical note) has been adopted in the medical arena to describe ‘the ability
to achieve stability through change’. Although the mechanism of action
responsible is still unclear, several theories have been proposed to explain
the effect of Siberian ginseng on allostatic systems, largely based on the
pharmacological actions observed in test tube and animal studies. Depending on
the stage of the stress response, Siberian ginseng can act in different ways to
support the ‘stress system’. Research suggests that there is a threshold of
stress below which the herb increases the stress response and above which it
decreases the stress response (Gaffney et al 2001b).
Therefore, for example, if allostatic load is such that responses have become
inadequate, then the resulting increase in hormone levels would theoretically induce
a more efficient response. Alternatively, situations of chronic overactivity,
also due to allostaticload, would respond to Siberian ginseng in a different
way, with negative feedback systems being triggered to inactivate the stress
response (Gaffney et al 2001a). As a result, Siberian ginseng could theoretically
induce quite different effects, largely dependent on whether allostatic
responses were underactive or overwhelmed. The dosing regimen may also
be significant. While multi-dose administration in chronic stress engages the
HPA axis balancing the switch-on and switch-off responses, single doses (~ 4
mL) in acute stress trigger a rapid response from the sympathoadrenal system, resulting
in secretion of catecholamines, neuropeptides, adenosine triphosphate (ATP) and
nitric oxide (Panossian & Wagner 2005). Studies have demonstrated
that maximal effects are achieved around 4 weeks but do not persist at the
8-week time point, which may help to explain the practice of giving Siberian
ginseng for 6 weeks with a 2-week break before repeating.
CLINICAL NOTE — ALLOSTASIS (Braun, L and Cohen, M. 2010)
Allostasis
is the body’s adaptation to stress. Allostatic (adaptive) systems are critical
to survival and enable us to respond to changes in our physical (such as
asleep, awake, standing, sitting, eating, exercising and infection) and
psychological states (such as anticipation, fear, isolation, worry and lack of
control). The consumption of tobacco, alcohol and our dietary choices also
induces allostatic responses (McEwan 1998).
These systems are complex and have broad boundaries, in contrast to the body’s
homeostatic systems (e.g. blood pH and body temperature), which are maintained
within a narrow range. Most commonly, allostatic responses involve the sympathetic
nervous system and the HPA axis. Upon activation (e.g. when a challenge is
perceived), catecholamines are released from nerves and the adrenal medulla,
corticotrophin is secreted from the pituitary and cortisol is released from the
adrenal cortex. Once the threat has passed (e.g. the environment is more
comfortable or infection is controlled), the system is inactivated and levels
of cortisol and catecholamine secretion return to baseline. Chronic exposure to
stress can lead to allostatic load, a situation resulting from chronic overactivity
or underactivity of allostatic systems. The situation is characterised by
maladaptive responses whereby systems become inefficient or do not turn off
appropriately. Currently, there is much interest in understanding the
association between numerous diseases such as cardiovascular disease and
overwhelming allostatic load. One measure that is used to gauge an individual’s
allostatic response is the cortisol response to a variety of stressors. As
such, cortisol
Immunomodulation
Siberian ginseng appears to exert an immunomodulatory rather than
just an immunosuppressive or stimulating action; however, evidence for the immune
enhancing effects of Siberian ginseng is contradictory. Clinical studies in
vitro and in vivo have revealed stimulation of general non-specific resistance
and an influence on T-lymphocytes, natural killer (NK) cells and cytokines (Bohn
et al 1987, Schmolz et al 2001), although other studies
suggest that Siberian ginseng does not significantly stimulate the innate macrophage
immune functions that influence cellular immune responses (Wang
et al 2003). Alternatively, another in-vitro study has demonstrated
that activation of macrophages and NK
cells does occur and may be responsible for inhibiting tumour metastasis both
prophylactically and therapeutically (Yoon et al 2004). The
main constituents responsible appear to be lignans (sesamin, syringin) and
polysaccharides, such as glycans, which demonstrate immunostimulant effects in
vitro (Davydov & Krikorian 2000, Wagner et al 1984).
Additionally, effects on the HPA axis will influence immune responses. It has
been suggested that eleutheroside E may be responsible for the improved
recovery from reduced NK activity and the inhibition of corticosterone elevation
induced by forced swimming in mice (Kimura & Sumiyoshi
2004) and may contribute to the antifatigue action.
Antiviral In vitro studies show a
strong antiviral action, inhibiting the replication of ribonucleic acid
(RNA) type viruses such as human rhinovirus, respiratory syncytial virus
and influenza A virus (Glatthaar- Saalmuller et al 2001).
Anabolic
activity Syringin
and other eleutherosides appear to improve carbohydrate metabolism and
energy provision by increasing the formation of glucose-6-phosphate and
activating glucogen transport (Panossian et al 1999),
and Siberian ginseng extracts have been reported to improve the metabolism of
lactic and pyruvic acids (Farnsworth et al 1985).
Additionally, preliminary evidence of possible anabolic effects makes this herb
a popular treatment among athletes in the belief that endurance, performance
and power may improve with its use. While initial animal studies showed promise
for improving weight gain and increasing organ and muscle weight (Farnsworth
et al 1985, Kaemmerer & Fink 1980), clinical studies confirming whether anabolic
effects occur also in humans could not be located.
OTHER ACTIONS (Braun, L and Cohen, M. 2010)
Anticoagulant
and antiplatelet effects Animal studies have demonstrated
prevention against thrombosis induced by immobilisation (Shakhmatov
et al 2007), and the 3,4-dihydroxybenzoic acid constituent of
Siberian ginseng has demonstrated antiplatelet activity in vivo (Yun- Choi
et al 1987). A controlled trial using Siberian ginseng tincture for
20 days in 20 athletes detected a decrease in the blood coagulation
potential and activity of the blood coagulation factors that are normally
induced by intensive training of the athletes (Azizov
1997). Whether the effects also occur in non-athletes is
unknown.
Vascular
relaxant In vitro studies have demonstrated vasorelaxant effects for
Siberian ginseng. The effect is thought to be endothelium dependent and
mediated by NO and/or endothelium-derived hyperpolarising factor, depending on the size of the blood
vessel. Other vasorelaxation pathways may also be involved (Kwan
et al 2004).
Anti-allergic
In-vitro studies demonstrate that Siberian ginseng has anti-allergic
properties in mast cell-mediated allergic reactions (Jeong
et al 2001). The mechanism appears to involve inhibition of histamine, tumour
necrosis factor-alpha (TNF-alpha) and interleukin-6.
Anti-inflammatory
Excess production of nitric oxide (NO) is a characteristic of
inflammation, and Siberian ginseng has been shown to significantly suppress NO
production and inducible nitric oxide synthase (iNOS) gene expression in a
dose-dependent manner (Lin et al 2008). The downregulation of iNOS expression may be the result of
inhibition of intracellular peroxide production (Lin et al 2008) or
through blocking c-Jun NH2-terminal kinase (JNK) and Akt activation (Jung et
al 2007). Contradictory results have been shown for inhibition of
cyclooxygenase (COX)-2 expression (Jung et al 2007, Raman et
al 2008).
Radioprotective
Animal studies have found that administration of Siberian
ginseng prior to a lethal dose of radiation produced an 80% survival
rate in mice (Miyanomae & Frindel 1988). This result suggests that
Siberian ginseng may protect against radiation toxicity.
Cardioprotective
Oral administration of Siberian ginseng (1 mL/kg) to rats for 8
days prevented stress-induced heart damage and chronic administration
increased beta-endorphin levels and improved cardiac tolerance to D, L-isoproterenol
and arrhythmia caused by adrenaline. The cardioprotective and antiarrhythmic
effect may be related to an increase in endogenous opioid peptide levels (Maslov
& Guzarova 2007). Benefits following a 45-min coronary artery occlusion were not
demonstrated in this study (Maslov & Guzarova
2007) but have been in studies using Siberian ginseng in a
polypharmacy combination known as ‘Tonizid’® (Lishmanov et al 2008).
Neuroprotective Preliminary
animal studies have suggested possibleneuroprotective effects in transient
middle cerebral
artery occlusion in Sprague-Dawley rats.
Infarct volume was reduced by 36.6% by inhibiting inflammation and microglial
activation in brain ischaemia after intraperitoneal injection of a water
extract of Siberian ginseng (Bu et al 2005).
Similarly, intraperitoneal injection of Siberian ginseng was found to relieve
damage to neurons following hippocampal ischaemia hypoxia and improve the
learning and memory of rats with experimentally induced vascular dementia (Ge
et al 2004). Siberian ginseng extract appears to protect against neuritic
atrophy and cell death under amyloid beta treatment; the effect is thought to
be due at least in part to eleutheroside B (Tohda et al 2008).
The saponins present in Siberian ginseng have also been shown to protect against
cortical neuron injury induced by anoxia/ reoxygenation by inhibiting the
release of NO and neuron apoptosis in vitro (Chen et al 2004).
Hepatoprotective
Animal studies have demonstrated that an intravenous extract of
Siberian ginseng decreased thioacetamide-induced liver toxicity when
given before and after thioacetamide administration (Shen et
al 1991). More recently, oral administration of aqueous extract and
polysaccharide was found to attenuate fulminant hepatic failure induced by
D-galactosamine/lipopolysaccharide in mice, reducing serum aspartate
aminotransferase (AST), alanineaminotransferase (ALT) and tissue
necrosis factor (TNF)-alpha levels (Park et al 2004). The
protective effect is thought to be due to the water-soluble polysaccharides.
Coadministration of Siberian ginseng may also act to enhance the
antihypoxant action of amtizole, improving the protective effect on hepatic
antitoxic function and lipid metabolism (Kushnerova & Rakhmanin
Iu 2008).
Reduces
obesity Animal studies have demonstrated that the inclusion of
Siberian ginseng attenuated the ‘weight gain, serum low density
lipoprotein (LDL) cholesterol concentration and liver triglyceride accumulation
in mice with obesity induced by high-fat diets’ (Cha et al 2004).
Glycaemic
control and insulin-sensitising effect Animal studies have
indicated a potential for hypoglycaemic effects when used intravenously.
Syringin appears to enhance glucose utilisation (Niu et
al 2008) and lower plasma glucose levels in animal experiments. The
effect may be due to an increase in the release of acetylcholine from
nerve terminals, stimulating muscarinic M (3) receptors in pancreatic
cells to increase insulin release (Liu et al 2008).
Syringin may also enhance the secretion of beta-endorphin from the
adrenal medulla to stimulateperipheral micro-opioid receptors, resulting in a
decrease of plasma glucose in insulin-depleted diabetic rats (Niu
et al 2007). Eleutherans A–G exert marked hypoglycaemic effects in
normal and alloxan-induced hyperglycaemic mice (Hikino et al 1986),
and eleutherosides show an insulin-like action in diabetic rats (Dardymov et
al 1978). However, these effects have not been borne out in human studies
(Farnsworth et al 1985)
and may not relate to oral dosages of Siberian ginseng. A small, double-blind,
randomised, multiple, crossover study using 12 healthy participants actually showed
an increase in postprandial plasma glucose at 90 and 120 min when 3 g Siberian
ginseng was given orally 40 min before a 75-g oral glucose tolerance test (Sievenpiper
et al 2004). More recently, oral administration of an aqueous extract of
Siberian ginseng was shown to improve insulin sensitivity and delay the
development of insulin resistance in rats (Liu et al 2005).
As a result, further trials in people with impaired glucose tolerance and/or
insulin resistance are warranted.
CLINICAL USE (Braun,
L and Cohen, M. 2010)
Stress
Siberian ginseng is widely used to treat individuals with
nervous exhaustion or anxiety due to chronic exposure to stress or what is now
termed ‘allostatic load situations’. The biochemical effects on stress responses
observed in experimental and human studies provide a theoretical basis for this
indication (Abramova et al 1972, Gaffney et al 2001a). One
placebo-controlled study conducted over 6 weeks investigated the effects
of an ethanolic extract of Siberian ginseng (8 mL/day, equivalent to 4 g/day
dried root). In the study, active treatment resulted in increased cortisol
levels, which may be consistent with animal research, suggesting a
threshold of stress below which Siberian ginseng increases the stress response
and above which it decreases the stress response (Gaffney
et al 2001b).
Fatigue
Siberian ginseng is used to improve physical and mental
responses during convalescence or fatigue states. While traditional stimulants
can produce a temporary increase in work capacity followed by a period
of marked decrease, the initial increase in performance from adaptogens is
followed by only a slight dip and performance remains above basal levels (Panossian
et al 1999). The ability of Siberian ginseng to increase levels of
noradrenaline, serotonin, adrenaline and cortisol provides a theoretical basis
for its use in situations of fatigue. However, controlled studies are
limited. A randomised, double-blind, placebo-controlled trial of 300
mg/day (E. senticosus dry extract) for 8 weeks assessed health-related
quality of life scores in 20 elderly people. Improvements were observed did not persist to the 8-week time point. It
would appear that improvements diminish with continued use (Cicero
et al 2004), which may help to explain the practice of giving
Siberian ginseng for 6 weeks with a 2-week break before repeating. A recent
randomised placebo-controlled trial evaluated the effectiveness of Siberian
ginseng in chronic fatigue syndrome (CFS). No significant improvements were
demonstrated overall; however, subgroup analysis showed improvements in fatigue
severity and duration (P < 0.05), in CFS sufferers with less severe
fatigue at 2-month followup (Hartz et al 2004).
Further studies are required to determine whether Siberian ginseng may be a useful
therapeutic option in cases of mild to moderate fatigue. Commission E approves
the use of Siberian ginseng as a tonic in times of fatigue and debility, for declining
capacity for work or concentration and during convalescence (Blumenthal
et al 2000). In practice, it is often used in low doses in cases of fatigue
due to chronic stress (Gaffney et al 2001a).
Ergogenic
aid Siberian ginseng extracts have been reported to provide better
usage of glycogen and high-energy phosphorus compounds and improve the
metabolism of lactic and pyruvic acids (Farnsworth et al
1985). Experimental data suggest that syringin and other eleutherosides
may improve carbohydrate metabolism and energy provision by increasing the
formation of glucose-6-phosphate and activating glucogen transport (Panossian
et al 1999). While initial animal studies showed promise for improving
weight gain and increasing organ and muscle weight (Wagner
et al 1985), recent randomised, controlled clinical trials have produced
inconsistent results in healthy individuals and athletes (Dowling
et al 1996, Eschbach et al 2000, Mahady et al 2000),
and a recent review concluded that only poorer quality trials have demonstrated benefit
while well-designed trials have not shown significant improvement in endurance
performance, cardiorespiratory fitness or fat metabolism during exercise ranging
in duration from 6 to 120 minutes (Goulet & Dionne 2005).
In the mid 1980s, a Japanese controlled study conducted on six male
athletes over 8 days showed that Siberian ginseng extract (2 mL twice daily) improved
work capacity compared with a placebo (23.3 versus 7.5%) in male athletes,
owing to increased oxygen uptake (P < 0.01). Time to exhaustion
(stamina) also increased (16.3 versus 5.4%, P < 0.005) (Asano
et al 1986). Other research however has failed to confirm these effects (Dowling
et al 1996, Eschbach et al 2000). A randomised, double-blind, crossover
trial using a lower dose of 1200 mg/day Siberian ginseng for 7 days reported
that treatment did not alter steady-state substrate use or 10 km cycling
performance time (Eschbach et al 2000). Additionally, an 8-week,
double-blind, placebo-controlled study involving 20 experienced distance
runners failed to detect significant changes to heart rate, oxygen consumption,
expired minute volume, respiratory exchange ratio, perceived exertion or serum
lactate levels compared with placebo. Overall, both submaximal and maximal
exercise performance were unchanged (Dowling et al 1996).
Siberian ginseng may however reduce blood coagulation factors induced by
intensive training in athletes (Azizov 1997)
and has been shown in combination with micronutrients to improve iron metabolism
and immunological responsiveness in 39 high-grade unarmed self-defence
sportsmen (Nasolodin et al 2006). Whether these effects
also occur in other scenarios is yet to be established. Clinical studies investigating
whether ergogenic or anabolic effects observed in experimental studies occur in
humans are lacking, and therefore Siberian ginseng cannot currently be
recommended to improve athletic performance (Palisin & Stacy 2006).
Siberian ginseng does not appear on ‘The 2008 Prohibited List’ of the World
Anti-doping Agency (WADA 2008).
Prevention
of infection Due to the herb’s ability to directly and indirectly modulate
immune responses, it is also used to increase resistance to infection.
One doubleblind study of 1000 Siberian factory workers supports this,
reporting a 50% reduction in general illness and a 40% reduction in absenteeism
over a 12-month period, following 30 days’ administration of Siberian ginseng (Farnsworth
et al 1985). More recently, a 6-month controlled trial in males and females with
recurrent herpes infection found that Siberian ginseng (2 g/day) successfully reduced
the frequency of infection by 50% (Williams 1995). In
practice, Siberian ginseng is generally used as a preventative medicine, as
administration during acute infections is widely thought to increase the
severity of the illness, although this has not been borne out in controlled
studies using Siberian ginseng in combination with other herbs. A small randomised
controlled trial (RCT) demonstrated a significant reduction in the severity of
familial Mediterranean fever in children using a combination of Siberian
ginseng with licorice, andrographis and schisandra (Amaryan
et al 2003), and a combination of Siberian ginseng with schisandra and
rhodiola was found to expedite the recovery of patients with acute non-specific
pneumonia (Narimanian et al 2005).
Cancer
therapy A polypharmacy preparation known as AdMax®, which contains Eleutherococcus
senticosus in combination with Leuzea carthamoides, Rhodiola
rosea and Schizandra chinensis, has been shown to boost the suppressed
immunity in patients with ovarian cancer who are subject to chemotherapy (Kormosh et
al 2006). Which herb or combination of herbs is responsible for the
effect is unclear.
OTHER USES (Braun, L and Cohen, M. 2010)
Given the herb’s ability to increase levels of serotonin and noradrenaline
in animal studies (Abramova et al 1972), a theoretical basis exists for the use
of Siberian ginseng in depression. In traditional Chinese medicine (TCM),
Siberian ginseng is used to encourage the
smooth flow of Qi and blood when obstructed,
particularly in the elderly, and is viewed as a general tonic. It is therefore used for a myriad of indications, usually
in combination with other herbal medicines.
Numerous studies use Siberian ginseng in
combination with other adaptogens, such as Rhodiola
rosea and Schisandra chinensis,
which may potentially act synergistically for
improved effects.
CLINICAL STUDIES (Barnes, J et al., 2007)
Clinical trials of preparations of P. ginseng and other Panax species
have focused on assessing effects related to the reputed adaptogenic
properties of this herbal medicinal product, although rigorous clinical
investigations are limited. Studies have tested different Panax species preparations,
including combination herbal preparations containing P. ginseng, which vary
qualitatively and quantitatively in their phytochemical composition.
Furthermore, different preparations have been administered according to different
dosage regimens, and to different study populations making interpretation of
the results difficult. A large body of clinical research has been published in
the Chinese and other Asian literature, making access difficult, although many
of these studies are unlikely to meet contemporary Western standards in terms
of their design, analysis and reporting.(16) Therefore, at present there is
insufficient evidence to support definitively the efficacy of specific Panax
species preparations in the various indications for which they are used and/or
have been tested. Details of several clinical trials of ginseng (Panax spp.)
preparations published in the English literature are summarised below. Effects
on physical performance Several studies have found that preparations of P.
ginseng do not improve physical performance in healthy adults. In a randomised,
double-blind, placebo-controlled trial, 38 healthy adults received an aqueous
extract of P. Ginseng (G115, Pharmaton SA, Lugano, Switzerland) 200 mg twice
daily for eight weeks.(56) Participants underwent exhaustive exercise testing
before and after the intervention; recovery from exercise was also monitored.
At the end of the study, data from 27 participants were available for analysis.
No statistically significant differences in physical performance and heart rate
recovery were detected between the ginseng and placebo groups.(56) Similar randomised,
double-blind, placebo-controlled studies have found that treatment with P.
ginseng root extract (G115) 200 mg daily for eight weeks had no statistically
significant effects on maximal work performance, oxygen uptake during resting,
exercise and recovery, respiratory exchange ratio, minute ventilation, heart
rate and blood lactic acid concentrations in 19 healthy adult females (p>
0.05 for each),(57) and no effect on oxygen consumption, respiratory exchange
ratio, minute ventilation, heart rate, blood lactic acid concentrations and perceived
exertion in 36 healthy adult males who received P. ginseng root extract (G115)
200 or 400 mg daily for eight weeks.(58)
In a further randomised,
doubleblind, placebo-controlled trial involving 28 healthy adults, administration
of P. ginseng root extract (not further specified) 200 mg daily for three weeks
had no statistically significant effects on maximal exercise capacity, total
exercise time, work load, plasma lactate concentrations, haematocrit, heart
rate and perceived exertion.(59) As all of these studies involved only small numbers
of participants it is possible that they did not have sufficient statistical
power to detect a difference between the treatment and placebo groups if one
exists. Effects on cognitive performance Several studies have examined the
effects of preparations of P. ginseng root, typically the commercial product
G115, alone, or in combination with other herbal ingredients, on cognitive
performance. Generally, these studies have involved healthy volunteers, and
trials evaluating the effects of P. ginseng root preparations on patients with
impaired cognitive function are lacking. Further research examining the effects
of acute and longer-term administration of preparations of P. ginseng and other
Panax species in both healthy individuals and patients with impaired cognitive
function are required.(60) In a double-blind, placebo-controlled, crossover
study involving 15 healthy individuals, P. ginseng root extract (G115) 200 mg
as a single oral dose had significant effects on certain aspects of electroencephalogram
recordings, such as reductions in frontal theta and beta activity, when compared
with placebo.(61) These findings suggest that P. ginseng root extract can
directly modulate cerebroelectrical activity.(61) In a double-blind, placebo-controlled,
crossover study, 30 healthy individuals received capsules containing P. ginseng
extract (G115) 200 or 400 mg as a single dose before undergoing a battery of
tests designed to assess cognitive performance.(62) A statistically significant
improvement in one test of cognitive performance (serial sevens) was observed
with the lower ginseng dose, compared with placebo, but no statistically
significant difference was observed with the higher dose, and there were no
statistically significant differences in other tests of cognitive performance
for either dose.(62) There was a statistically significant improvement in scores
for mental fatigue for both doses when measured after the third battery of
tests, but this finding was not consistent when measured at other timepoints. In
another double-blind, placebo-controlled, crossover study, 28 healthy
individuals received single doses of P. ginseng root extract (G115) 200 mg, an
ethanolic extract of guarana (Paullinia cupana) 75 mg, both herbal preparations,
or placebo, with a one-week wash-out period between each; participants
undertook a battery of cognitive performance tests before and after
treatments.(63)
Administration of P. ginseng root extract, compared with
placebo, led to statistically significant improvements in some (e.g. speed of attention,
speed of memory, secondary memory) but not all (e.g. accuracy of attention,
working memory, Bond-Lader mood scales) tests of cognitive performance,
although improvements were not observed at every timepoint measured after
administration. In some tests,
administration of both ginseng and guarana led to greater improvements than did
ginseng alone.(63) In similar experiments, 20 healthy individuals received
single doses of P. ginseng root extract (G115) 200, 400, 600 mg, or placebo,
and a combination of P. ginseng root extract and Ginkgo biloba leaf extract at doses of 200 and 120, 400 and 240,
600 and 360 mg, respectively, or placebo.(64) Statistically significant
improvements in one cognitive performance test (serial sevens) were observed with
administration of P. ginseng root extract 400 mg, compared with placebo, but
reduced performance in this test was seen following administration of the 200
mg dose. Following administration of the combination preparation, statistically
significant improvements in certain tests at certain timepoints, but these results
were not consistent for all doses tested and across all timepoints measured in
the study. The effects of the same combination preparation of P. Ginseng and G.
biloba on memory were assessed in a randomised, doubleblind, placebo-controlled,
multicentre, parallel group trial involving 256 healthy volunteers aged 38–67
years (mean (SD), 56 (7) years).(65) Participants received a preparation
containing P. Ginseng root extract and G. biloba leaf extract 100 and 60 mg,
respectively, twice daily, 200 and 120 mg, respectively, once daily, or placebo,
for 12 weeks. Assessments were undertaken at weeks 4, 8, 12 and 14 of the
study. At the end of the study, the primary outcome variable the Quality of
Memory Index was significantly improved in the treatment group, compared with
the placebo group (p = 0.026). No statistically significant effects were seen
with respect to the secondary outcome variables power and continuity of attention,
and speed of memory processes.(65)
In
a randomised, double-blind, placebo-controlled, parallel group trial, 64
healthy volunteers with neurasthenic complaints received a combination preparation
containing P. ginseng root extract and G. biloba leaf extract at doses of 50
and 30 mg, respectively, 100 and 60 mg, respectively, 200 and 120 mg, respectively,
or placebo, twice daily, for 12 weeks.(66) At the end of the study,
participants in the higher-dose ginseng–ginkgo group, compared with the placebo
group, achieved significantly higher scores in tests designed to assess cognitive
function (p = 0.008). Hypoglycaemic activity Most studies investigating
hypoglycaemic activity of ginseng preparations have assessed effects in healthy
(non-diabetic) individuals. In a randomised, single-blind (the study may have
been conducted double-blind but this was not specifically stated), placebo-controlled,
crossover trial, nine individuals with type-2 diabetes mellitus (mean (standard
deviation, SD) glycosylated haemoglobin HbA1c 0.08 (0.005); reference range for
well-controlled type-2 diabetes mellitus, 0.065–0.075) received a capsule containing
'American' ginseng (P.quinquefolius, containing protopanaxadiols Rb–1 1.53%,
Rb–20.06%, Rc 0.24%, Rd 0.44%, and protopanaxatriols Rg–1 0.1%, Re 0.83%;(67)
Chai-Na-Ta Corp, British Columbia, Canada) as a single dose both 40 minutes
before a 25 g oral glucose challenge and, on a separate occasion, at the same
time as the oral glucose challenge.(68) Incremental glycaemia at 45 minutes was
significantly lower following ginseng treatment with either regimen (i.e. given
with or before glucose challenge) than it was following placebo administration
(p < 0.05 for both). In similar experiments involving non-diabetic individuals,
a statistically significant reduction in incremental glycaemia was only
observed when ginseng was administered 40 minutes before glucose challenge.(68)
Further
experiments in non-diabetic individuals indicated that the effect on
postprandial glycaemia was not dose-dependent as glucose tolerance was similar
following administration of doses of ginseng ranging from 1–9 g.(69, 70)
However, the effect of P. quinquefolius was time-dependent as reductions in
postprandial glycaemia were observed only with administration of P.
Quinquefolius 40, 80 and 120 minutes,(69, 70) but not 0, 10 and 20 minutes, before
glucose challenge.(70) In another similar randomised, blinded,
placebo-controlled, crossover trial involving non-diabetic individuals, no
effect on post-prandial glycaemia was observed following oral administration 40
minutes before glucose challenge of 6 g of the same commercial P. quinquefolius
preparation, but obtained from a different batch.(67) This conflicting result
may be due to the lower ginsenoside content of the latter product (containing
protopanaxadiols Rb–1 0.65%, Rb–20.02%, Rc 0.11%, Rd 0.12%, and
protopanaxatriols Rg-1 0.08%, Re 0.67%).(67)
Other
similar studies involving non-diabetic individuals have reported different and
less consistent results for preparations of P. ginseng. In two randomised,
single-blind, placebo-controlled, crossover studies, 11 individuals received
capsules containing 500 mg three-year-old powdered whole root of P. Ginseng (containing
protopanaxadiols Rb–1 0.18%, Rb-2 0.09%, Rc0.07%, Rd 0.02%, and
protopanaxatriols Rg-1 0.16%, Re 0.17% and Rf 0.12%) at a single dose of 1, 2,
3, 6 and 9 g 40 minutes before glucose challenge.(71) No statistically
significant differences were observed for the treatment versus placebo groups.
Furthermore, when results for all P. ginseng groups were pooled, the 2- hour
plasma glucose concentration was higher in the P. Ginseng group than in the
placebo group. These findings are in contrast to effects observed for P.
quinquefolius, and could be explained by differences in the ginsenoside content
of preparations derived from the two species.(71) In a double-blind, placebo-controlled,
crossover study in which 30 non-diabetic individuals received capsules
containing P. Ginseng extract (G115) 200 or 400 mg as a single dose before
undergoing a battery of tests designed to assess cognitive performance,(62) statistically
significant reductions in blood glucose concentrations
occurred
for both doses of ginseng at all measured post-treatment timepoints (p <
0.01 for all). Immunomodulatory activity In a randomised, double-blind, placebo-controlled
trial, 38 healthy adults received an aqueous extract of P. ginseng (G115, Pharmaton
SA, Lugano, Switzerland) 200 mg twice daily for eight weeks.(56) Participants
underwent exhaustive exercise testing before and after the intervention in order
to effect immunosuppression. At the end of the study, data from 27 participants
were available for analysis. No statistically significant differences in secretory
immunoglobulin A (IgA; the primary immunoglobulin contained in secretions of
the mucosal immune system) parameters were detected between the P. Ginseng and
placebo groups, indicating that the P. ginseng preparation had no effect on
mucosal immunity.(56)
A
randomised, double-blind, placebo-controlled trial involving 60 healthy
individuals assessed the effects of two different extracts of P. ginseng on
immune parameters.(72) Participants received an aqueous extract of P. ginseng
(not further specified) 100 mg, a standardised extract of P. ginseng (G115) 100
mg, or placebo, twice daily for eight weeks. Analysis of participants' blood samples
taken before and after four and eight weeks of treatment indicated that both
extracts had statistically significant effects on various immune parameters,
compared with baseline values,(72) although from a report of the study, it is
not clear whether or not these changes were statistically significant when
compared with values for the placebo group.
Cancer
prevention A small number of epidemiological studies have explored the effects
of ginseng use on prevention of cancer. A case–control study involving all cases
of newly diagnosed cancer during a one-year time period at a major hospital
cancer centre in Korea included 905 cases and 905 age, sex and date of
admission matched controls.(73) Of the 905 cases, 62% had a history of 'ginseng'
(not further specified) use (determined by face-to-face interviews using a structured questionnaire),
compared with 75% in the control group (p <0.01). The odds ratio (95%
confidence interval) (OR; 95% CI) for cancer in relation to ginseng intake was
0.56 (0.45 to 0.69). This study was subsequently extended to include a total of
1987 case–control pairs.(74) Ginseng users had a lower risk of cancer, compared
with non-users (OR 0.50; 95% CI 0.44 to 0.58); ORs (95% CI) for being diagnosed
with cancer differed for use of different types of ginseng; the lowest being
for fresh ginseng extract 0.37 (0.29 to 0.46), white ginseng powder 0.30 (0.22
to 0.41) and red ginseng extract 0.20 (0.08 to 0.50). No decrease in risk was
seen with use of fresh ginseng slices, fresh ginseng juice and white ginseng
tea: OR (95% CI), 0.79 (0.63– 1.01), 0.71 (0.49–1.03), 0.69 (0.45–1.07),
respectively.(74) ORsvwere lowest for ovarian (0.15), larynx (0.18),
oesophageal (0.20) and panceatic (0.22) cancers.
The
questionnaire used in the case–control studies described above was used to
determine ginseng use in a cohort study involving 4634 people aged over 40 years.(75)
In this study, 54.7% of cancer cases had a history of ginseng use, compared
with 71.2% of individuals without cancer. The relative risk (RR; 95% CI) for cancer
was reduced with ginseng intake (0.40, 0.28–0.56; p <0.05). When evaluted by
intake of type of ginseng, the RR was significantly reduced with ginseng
extract (0.31, 0.13–0.74) and multiple combinations of ginseng preparations
(0.34, 0.20–0.53), but not for other types of ginseng.(75) The available
evidence for the cancer preventive effect of ginseng preparations in humans is inconclusive,
and further methodologically rigorous research is required.(76, 77)
Quality
of life The effects of different preparations of P. Ginseng root on
quality-of-life measures have been asssessed in several randomised, controlled
trials involving different participant groups, including healthy individuals,
post-menopausal women and patients with diabetes. A systematic review of trials
published by the end of the year 2002 included nine studies, of which eight involved
a placebo control group, four involved the administration of monopreparations
of P. ginseng root, and five involved combination preparations of P. ginseng
and vitamins/minerals.(78)
The
review did not provide details of the specific P. Ginseng preparations tested
in the trials, only that doses ranged from 80–400 mg daily and that studies lasted
from two to nine months. These variations in products tested, together with
differences in study design, outcome measures evaluated, and participant groups
involved, make overall interpretation of the results difficult and, to some
extent, invalid. All but one of the included studies reported improvement in at
least one quality-of-life measure, or a subscale, but there were conflicting
findings. In essence, at present, evidence of a beneficial effect for P.
ginseng on quality-of-life measures is inconclusive. Further research is needed
to establish the effects, if any, of preparations of P. ginseng root and other
Panax species on quality of life. Furthermore, results of trials should be
considered in the context of the chemical profile of individual preparations, since
this is likely to differ qualitatively and quantitatively between
products.
One of the studies included in the review described above found that P. ginseng
root extract (G115) 200 or 400 mg daily for eight weeks had no statistically
significant effects on psychological well-being, as assessed using the Positive
Affect Negative Affect Scale, in a randomised, double-blind, placebocontrolled trial
involving 83 healthy younger adults (mean age 26 years).(79)
Other
effects The effects of an aqueous extract of P. ginseng roots on blood alcohol
clearance were assessed in an open study involving 14 healthy men aged 25–35
years; each participant served as his own control.(80) Participants consumed a
single dose of alcohol (25% ethanol 72 g per 65 kg body weight) over 45 minutes
with and without P. ginseng root extract 3 g/kg body weight. Blood samples
taken 40 minutes after the end of the period of alcohol ingestion showed blood
alcohol concentrations of 0.18% and 0.11% for the control and treatment periods,
respectively (p < 0.001). The design of this study does not allow the
observed effects to be attributed to ginseng administration, and the hypothesis
that P. ginseng increases blood alcohol clearance requires testing in
methodologically rigorous randomised, controlled trials.
SIDE-EFFECTS, TOXICITY
(Barnes, J et al., 2007)
CLINICAL DATA
There are only limited clinical data on safety aspects of preparations
of P. ginseng and other Panax species. There is a lack of formal post-marketing
surveillance-type studies, and existing pharmacoepidemiological studies
typically have assessed potential benefits and not risks of harm(s). There is a
substantial number of placebo-controlled clinical trials of preparations of P. ginseng
and other Panax species, although many of these have methodological
limitations, including lack of randomisation and/ or double-blinding. Trials
have assessed the effects of different preparations, including combination
herbal preparations containing different Panax species, which vary qualitatively
and quantitatively in their phytochemical composition. Furthermore, different
preparations have been administered according to different dosage regimens, and
to different study populations (e.g. healthy volunteers, patients with
hypertension), making interpretation of the results difficult. The clinical
trials of Panax species root preparations available typically have involved
small numbers of patients and been of short duration (typically four to 12
weeks), so have the statistical power only to detect very common, acute adverse
effects. Rigorous investigation of safety aspects of correctly identified, well-characterised
Panax species root preparations administered orally at different dosages, including
the effects of long-term treatment, is required. A systematic review of data
available up to May 2001 relating to adverse events of monopreparations of P.
ginseng preparations identified 48 placebo-controlled trials, 14 trials with an
active control group, and 20 uncontrolled studies.(81) Of these, 42 trials involved
healthy individuals and athletes, and the remainder involved older individuals,
postmenopausal women or patients with hypertension, respiratory diseases, hepatitis,
erectile dysfunction. Thirteen placebo-controlled studies provided sufficiently
detailed information on reported adverse events. Six of these studies, mostly
involving healthy individuals, had assessed the effects of a P. ginseng root
extract (G115) typically at a dose of 200 mg daily for three to 16 weeks,
although one study lasted for two years. Five other placebo-controlled studies
assessed the effects of red P. ginseng root taken for around two to 12 weeks (one
study involved administration for one year), and in two other studies, the
species and type of ginseng were not clearly specified. Adverse events reported
generally were similar in type and frequency to those reported for the placebo
groups.(81) Nine placebo-controlled trials, four of which assessed a P. ginseng
root extract (G115), stated that no adverse events occurred during the study
period.
Placebo-controlled trials of P. ginseng published since the systematic
review was conducted, and placebo-controlled trials assessing the effects of
preparations of P. quinquefolius, typically
have not provided detailed information on the occurrence of adverse
events. One study stated that there was no difference in symptoms, mostly
gastrointestinal adverse events, between the P. quinquefolius and placebo
groups reported during the study,(67) whereas another study assessing P. quinquefolius
stated that no adverse effects occurred during the study.(70) The systematic
review also identified publications describing 27 case reports associated with
the use of 'ginseng', although for 22 reports no information was provided on
the type (i.e. red or white P. ginseng), preparation and dosage of P. ginseng
ingested, and it is unlikely that any chemical analysis of the products
ingested was undertaken. Four cases of agranulocytosis initially attributed to use
of P. ginseng-containing products, were later attributed to undeclared
ingredients (aminopyrine and phenylbutazone) detected in the products.(81) For
many of the cases, there were other factors, including concurrent medications
and cessation of treatment effects, that could explain the observed effects.
The cases included six reports of mastalgia, two of post-menopausal vaginal
bleeding and one of metrorrhagia (uterine bleeding at irregular intervals,
usually for prolonged period of time) in women who had ingested or applied (one
case of vaginal bleeding was associated with use of a 'ginseng' face cream(82))
'ginseng' products. Several of the reports describe positive dechallenge and/ or
rechallenge. Most of these reports, however, are from the older literature and
involved the use of unlicensed, poorly described products; a causal association
with Panax species has not been established, and the relevance of these reports
to products marketed currently is not clear. Two cases of mania have also been
described. One involved a 35-year-old woman with depressive illness who was
stabilised on treatment with lithium and amitriptyline and who stopped lithium
treatment and began taking ginseng (not further specified).(83)
The second report described
a 26-year-old-man with no history of psychiatric illness who experienced a
manic episode two months after starting treatment with red P. ginseng root 500
to 750 mg daily on five days per week.(84) Analysis of the product found no
evidence of notable contaminants. The World Health Organization's Uppsala Monitoring
Centre (WHO-UMC; Collaborating Centre for International Drug Monitoring)
receives summary reports of suspected adverse drug reactions from national
pharmacovigilance centres of over 70 countries worldwide. A systematic review
of information available up to May 2001 relating to adverse effects associated
with P. ginseng summarised reports from the WHO-UMC database describing a total
of 168 adverse reactions associated with monopreparations of ginseng.(81) However,
this number of reports relates to unspecified 'ginseng' preparations, not
necessarily preparations of P. ginseng. To the end of the year 2005, the WHO-UMC's
database contained only nine reports, describing a total of 20 adverse
reactions, for monopreparations specified as P. ginseng.(85) In a phase 1 study
involving healthy males aged 18–35 years who received an extract of P. ginseng
root (21.4 mg/mL; standardised for ginsenosides 10.5%) 20 mL twice daily for
ten days, no adverse effects on fertility parameters, including volume of
ejaculate, number of spermatozoids per millilitre, and proportions of active,
inactive, normokinetic, dyskinetic and akinetic spermatozoids, were observed,
compared with baseline values.(86) In 1979, two studies referred to a 'ginseng
abuse syndrome' (GAS) which emphasised that most side-effects documented for 'ginseng'
were associated with the ingestion of large doses together with other
psychomotor stimulants, including tea and coffee. GAS was defined as diarrhoea,
hypertension, nervousness, skin eruptions and sleeplessness; other symptoms
occasionally observed included amenorrhoea, decreased appetite, depression, euphoria,
hypotension and oedema.(87, 88) However, these two studies have been widely
criticised over the variety of ginseng and other preparations used, and over the
lack of authentication of the ginseng species ingested.(1, G19)
A review of the Russian literature describes symptoms of overdose
as those exhibited by individuals allergic to ginseng, namely palpitations,
insomnia and pruritus, together with heart pain, decrease in sexual potency,
vomiting, haemorrhagic diathesis, headache and epistaxis, and that ingestion of
very large doses has been reported to be fatal.(15) The primary publications upon
which these statements are based have not been used here, so the quality of the
reports, including their descriptions of the ginseng preparations implicated,
has not been assessed here.
PRECLINICAL DATA (Barnes, J et al., 2007l)
Results documented for toxicity studies carried out in a number
of animal species using standardised extracts (SE) indicate P. Ginseng to be of
low toxicity.(89–93) Single doses of up to 2 g SE have been administered to
mice and rats with no toxic effects observed.(92) LD50 values (p.o.) in mice and
rats have been estimated at 2 g/kg and greater than 5 g/kg.(89) In addition,
LD50 values (i.p., mice) have been estimated for individual ginsenosides as 305
mg/kg (Rb-2), 324 mg/kg (Rd), 405 mg/kg (Re), 410 mg/kg (Rc), 1110 mg/kg
(Rb-1), 1250 mg/kg (Rg-1), and 1340 mg/kg (Rf); an LD50 (i.v., mice) of 3806
mg/kg has been estimated for the saponins Rc-1 and Rd-1.(89) Doses of
approximately 720 mg of a P. ginseng extract (G115) have been administered orally
to rats for 20 days with no toxicological effects documented.(93) Daily doses
of up to 15 mg G115/kg body weight have been administered orally to dogs for 90
days with no toxic effects documented. An initial increase in excitability
which disappeared after two to three weeks was the only observation reported in
rats fed 200 mg G115/kg body weight for 25 weeks.(92) P. quinquefolius has been
reported to be devoid of mutagenic potential when investigated versus
Salmonella typhimurium strain TM677.(94)
CONTRA-INDICATIONS,
WARNINGS (Barnes, J et al., 2007)
The older literature includes statements that the use of P.
Ginseng is contra-indicated during acute illness, haemorrhage and during the
acute period of coronary thrombosis,(1) and it has been recommended that P.
ginseng should be avoided by individuals who are highly energetic, nervous,
tense, hysteric, manic or schizophrenic, and that P. ginseng should not be
taken with stimulants, including coffee, antipsychotic drugs or during treatment
with hormones.(1, G49) The scientific basis and evidence for many of these
statements is not clear. However, in view of their documented pharmacological
activities, Panax species preparations should be used with caution in patients
with diabetes and cardiovascular disorders. In general, and in view of the lack
of safety data, it is appropriate to advise against the long-term or otherwise
excessive use of Panax species.
Drug interactions In view of the pharmacological actions of Panax
species preparations and their isolated constituents described following
preclinical and, to a lesser extent, clinical studies, the potential for
preparations of Panax species to interfere with other medicines administered concurrently,
particularly those with anticoagulant,
hypoglycaemic and/or cardiovascular activity, should be considered.
Two cases of a suspected interaction between 'ginseng' and phenelzine
have been documented. One report described insomnia, headache and tremulousness
in a 64-year-old woman who began taking a 'ginseng' tea in addition to her
existing phenelzine treatment; the woman previously had used 'ginseng' tea
alone without experiencing any adverse effects,(95) and three years after the
first epidsode of concurrent use of phenelzine and 'ginseng' tea, the woman
ingested 'ginseng' capsules and experienced similar symptoms.(96) A second report described a
42-year-old woman for whom treatment with phenelzine was initiated because of
major depressive illness. The woman was also receiving triazolam and lorazepam
and began self-treatment with unspecified preparations of ginseng and bee
pollen.(97) She experienced headaches, irritability and visual hallucinations.
A causal relationship with use of Panax species in these cases cannot be
established.
There is an isolated case report of a suspected interaction between
P. ginseng and warfarin involving a 47-year-old-man with an aortic heart valve
who was receiving warfarin for thromboprophylaxis. Two weeks after the man
began treatment with a P. ginseng root extract (Ginsana), his international
normalised ratio (INR) fell to 1.5, having previously been stable for nine months.(98)
On stopping use of the P. ginseng preparation, his INR returned to within the
target range. In a randomised, open-label, crossover study, 12 healthy male individuals
received a single dose of warfarin 25 mg alone or after seven days' treatment
with capsules containing P. ginseng root (containing extract equivalent to 500
mg root; standardised for ginsenosides 8.93 mg, as ginsenoside Rg–1) two or
three times daily.(99) There were no statistically significant differences in
area under the plasma-concentration time curve (AUC), elimination half-life
(t1/2), total clearance, volume of distribution, maximal plasma concentration
(Cmax) and time to maximal concentration for either R-warfarin or S-warfarin
when warfarin was taken following P. ginseng treatment, compared with values
for ingestion of warfarin alone. There were also no statistically significant differences
in protein binding of R- and S-warfarin, or in warfarin pharmacodynamics as
assessed using INR values, following P. ginseng administration. By contrast,
another drug interaction study involving healthy volunteers found that a
preparation of P. quinquefolius root reduced the anticoagulant effect of
warfarin. In a randomised, double-blind, placebo-controlled trial, 20 healthy individuals
received powdered root of P. quinquefolius (containing Rb–1 1.93%, Rb–2 0.20%,
Rc 0.61%, Rd 0.42%, Re 1.68% and Rg–10.35%) 1 g twice daily, or placebo, for
three weeks; treatment was taken for a total of three weeks, beginning four
days after oral administration of warfarin 5mg daily for three days,
concurrently with a second three-day period of warfarin administration, and for
four days after the second period of warfarin exposure.(100)
There was a significantly greater reduction in the magnitude of
the INR, the primary outcome measure, in the P. quinquefolius group, compared
with that in the placebo group (p = 0.0012). The contrasting findings for P. ginseng
root and P. Quinquefolius root preparations could be explained by differences
in their chemical composition, particularly ginsenoside content. The effects of
different Panax species preparations on warfarin pharmacokinetics in patients receiving
warfarin treatment or prophylaxis require investigation. In another drug
interaction study involving healthy individuals (n = 20), participants received
a P. ginseng root extract preparation (Ginsana, Pharmaton, Connecticut, USA;
standardised for ginsenosides 4%) 100 mg twice daily for 14 days.(101) Data
collected over a one-week period before P. Ginseng administration provided a
within-subject control group. At the end of the study, there were no statistically
significant changes in the 6-b-hydroxycortisol : cortisol ratio following P.
Ginseng administration, compared with baseline values, suggesting that P.
ginseng did not induce CYP3A enzyme activity.(101) By contrast, in in vitro
experiments, a P. ginseng root extract (G115; standardised for 4% ginsenosides)
and a P. quinquefolius root extract (standardised for 10% total ginsenosides)
both inhibited CYP1A1, CYP1A2 and CYP1B1 activities in a concentrationdependent
manner.(102) P. quinquefolius root extract was 45-fold more potent than P. ginseng
root extract in inhibiting CYP1A2. The ginsenosides Rb–1, Rb–2, Rc, Rd, Re, Rf
and Rg–1, added to the system either individually or as a mixture, at
concentrations reflecting those at which the ginseng extracts caused
inhibition, did not affect CYP1A and B enzyme activities. These findings led to
the suggestion that other ginsenosides could be responsible for the inhibitory
effects on the CYP enzymes investigated, or that the effects could be due to
other compounds, such as tannins, as these were not removed from the
extracts.(102)
Pregnancy and lactation No fetal abnormalities have been observed
in rats and rabbits administered a standardised P. Ginseng extract (40 mg/kg,
p.o.) from day 1 to day 15 of pregnancy.(92) P. ginseng has also been fed to
two successive generations of rats in doses of up to 15 mg G115/kg body
weight/day (equivalent to approximately 2700 mg P. ginseng extract) with no
teratogenic effects observed.(89) However, the safety of P. ginseng during pregnancy
has not been established in humans and therefore its use should be avoided.
Similarly, there are no published data concerning the secretion of pharmacologically
active constituents from P. ginseng into the breast milk and use of P. ginseng during
lactation is therefore best avoided. However, a more recent study which
investigated the effect of ginsenoside Rb–1 on the development of rat embryos
during organogenesis in vitro found that median total morphological scores were
significantly lower for embryos exposed to ginsenoside Rb–1 at concentrations
of 30 mg/mL, compared with those for control embryos (p <0.05).(103) The
clinical relevance of these findings is not known. The effects of ginsenoside
Rb–1 and other ginsenosides, including the possibility of additive effects, on
embryogensis requires further investigation.
The safety of P. ginseng during pregnancy has not been established
in humans. Similarly, there are no published data concerning the secretion of
pharmacologically active constituents from P. ginseng into the breast milk. In
view of the lack of safety data and the findings described above, and until
further information is available, the use of P. ginseng preparations during pregnancy
and breastfeeding should be avoided.
CONTRAINDICATIONS
(Linda, S-R. 2010)
Pregnancy category is 1; breastfeeding category is 2A.
Ginseng should not be given to children. It should not
be used by persons with hypertension, cardiac disorders, or hypersensitivity to
it. If breast cancer or other estrogen-dependent conditions are present,
ginseng should not be used.
SIDE
EFFECTS/ADVERSE REACTIONS (Linda, S-R. 2010)
CNS: Anxiety, insomnia, restlessness (high doses), headache
CV: Hypertension, chest pain, palpitations, decreased
diastolic blood pressure, increased QTc interval.
GI: Nausea, vomiting, anorexia, diarrhea (high doses)
Ginseng Abuse
Syndrome: Edema,
insomnia, hypertonia
INTEG: Hypersensitivity reactions, rash
INTERACTIONS
(Linda, S-R. 2010)
Drug
Anticoagulants (anisindione,
dicumarol, heparin, warfarin),
antiplatelets,
salicylates:
Ginseng may decrease the action
of these products.
Anticonvulsants:
Ginseng may provide an additive
anticonvulsant action (theoretical).
Antidiabetics (acetohexamide,
chlorpropamide, glipizide, metformin, tolazamide, tolbutamide, troglitazone): Because ginseng is known to decrease blood glucose levels, it may increase the
hypoglycemic effect of
antidiabetics; avoid concurrent
use.
Immunosuppressants
(azathioprine,
basiliximab, cyclosporine, daclizumab, muromonab, mycophenolate, tacrolimus): Ginseng may
diminish the effect of immunosuppressants; do not use immediately before, during, or after transplant surgery.
Insulin: Because ginseng is known to decrease blood glucose
levels, it may increase the hypoglycemic effect of insulin; avoid concurrent
use.
MAOIs (isocarboxazid,
phenelzine, tranylcypromine): Concurrent
use of MAOIs with ginseng may result in manic-like syndrome.
Stimulants: Use of stimulants (e.g., xanthines) concurrently with
ginseng is not recommended; overstimulation may occur.
Herb
Caffeine,
guarana, yerba maté, tea: Ginseng
with these agents may lead to added stimulation (Jellin et al, 2008).
Ephedra: Concurrent use of ephedra and ginseng may increase
hypertension and central nervous system stimulation; avoid concurrent use.
Food
Caffeinated
coffee, cola, tea: Overstimulation
may occur when ginseng is used with caffeinated coffee, cola, and tea; avoid
concurrent use.
Lab Test
Blood glucose: Ginseng may decrease blood glucose (decoctions,
infusions).
Plasma partial
thromboplastin time, INR: Ginseng
may increase plasma partial thromboplastin time and INR.
Serum, urine
estrogens: Ginseng may have an additive
effect on serum and 24-hour urine estrogens.
Serum digoxin: Ginseng may falsely increase serum digoxin.
CLIENT
CONSIDERATIONS (Linda, S-R. 2010)
Assess
· Assess the reason the client is using ginseng.
· Assess for hypersensitivity reactions and rash. If these
are present, discontinue the use of this herb and administer an antihistamine
or other appropriate therapy.
· Assess for ginseng abuse syndrome: insomnia, edema, and
hypertonia.
· Assess for the use of stimulants, anticoagulants,
MAOIs, and antidiabetics (see Interactions).
Administer
· Instruct the client to store ginseng products in a cool,
dry place, away from heat and moisture.
· Instruct the client to avoid the continuous use of
ginseng. The recommendation is to use this herb for no more than 3 continuous
months, taking a break between courses (Mills, Bone, 2000).
Teach
Client/Family
· Inform the client that pregnancy category is 1 and
breastfeeding category is 2A.
· Caution the client not to give ginseng to children.
· Advise the client to use other stimulants and antidiabetics
carefully if taking concurrently with ginseng (see Interactions).
· Warn the client of the life-threatening side effects of
ginseng abuse syndrome.
· Instruct the client that Siberian ginseng
and Panax ginseng are not the same.
CLINICAL NOTE — CASE REPORTS OF SIBERIAN GINSENG NEED CAREFUL
CONSIDERATION
(Braun, L and Cohen, M. 2010)
Some adverse reactions attributed to Siberian ginseng have subsequently
been found to be due to poor product quality, herbal substitution and/ or
interference with test results. For example, initial reports linking maternal
ginseng use to neonatal androgenisation are now suspected to be due to
substitution with another herb, Periploca sepium (called Wu jia
or silk vine), as American herb companies importing Siberian ginseng from China
have been known to be supplied with two or three species of Periploca (Awang 1991).
Additionally, rat studies have failed to detect significant androgenic action (Awang 1991,
Waller et al 1992) for Siberian ginseng. Another example is the purported
interaction between digoxin and Siberian ginseng, which was based on a single
case report of a 74-yearold man found to have elevated digoxin levels for many
years (McRae 1996).
It was subsequently purported that the herbal product may have
been adulterated with digitalis. Additionally, Siberian ginseng contains
glycosides with structural similarities to digoxin that may modestly interfere
with digoxin fluorescence polarisation (FPIA), microparticle enzyme (MEIA) results,
falsely elevating digoxin values with FPIA and falsely lowering digoxin values
with MEIA (Dasgupta & Reyes 2005). It should be noted that measuring
free digoxin does not eliminate these modest interferences in serum digoxin
measurement by the Digoxin III assay (Dasgupta et al 2008).
ADVERSE REACTIONS (Braun, L and Cohen, M. 2010)
Clinical trials of a 6 months’ duration have shown no side effects
from treatment (Bohn et al 1987). High doses may cause slight drowsiness,
irritability,anxiety, mastalgia, palpitations or tachycardia, although these side
effects may be more relevant to Panax ginseng. It is suggested that a
spontaneous subarachnoid haemorrhage in a 53-year-old woman who was using an
herbal supplement containing red clover, dong quai and Siberian ginseng was
likely to be due to the dong quai (Friedman et al 2007).
SIGNIFICANT INTERACTIONS (Braun, L and Cohen, M. 2010)
As controlled studies are not available, interactions are
currently speculative and based on evidence of pharmacological activity and
case reports. Studies have reported that normal doses of Siberian ginseng are
unlikely to affect drugs metabolised by CYP2D6 or CYP3A4 (Donovan
et al 2003).
Anticoagulants An in-vivo study demonstrated
that an isolated constituent in Siberian ginseng has anticoagulant activity (Yun-Choi
et al 1987), and a clinical trial found a reduction in blood coagulation
induced by intensive training in athletes (Azizov 1997).
Whether these effects also occur in nonathletes is unknown. Given that a study
looking at the concomitant application of Kan Jang (Siberian ginseng in
combination with andrographis) and warfarin did not produce significant effects
on the pharmacokinetics or pharmacodynamics of the drug (Hovhannisyan et
al 2006), a negative clinical effect is unlikely.
Chemotherapy An increased tolerance for
chemotherapy and improved immune function has been demonstrated in
women with breast (Kupin 1984, Kupin & Polevaia 1986)
and ovarian (Kormosh et al 2006) cancer undergoing
chemotherapy treatment. Caution— as coadministration may theoretically reduce
drug effects. However, beneficial interaction may be possible under
medical supervision.
Diabetic
medications Claims that Siberian ginseng
has hypoglycaemic effects are based on intravenous use in animal studies
and not observed in humans for whom oral intake may actually increase
postprandial glycaemia (Sievenpiper et al 2004). Observe diabetic patients
taking ginseng.
Influenza
virus vaccine Ginseng
may reduce the risk of post-vaccine reactions (Zykov &
Protasova 1984), a possible beneficial interaction.
CONTRAINDICATIONS AND
PRECAUTIONS (Braun, L and Cohen,
M. 2010)
Some authors suggest that high-dose Siberian ginseng should be
avoided by those with cardiovascular disease or hypertension (blood pressure
(BP) > 80/90 mmHg) (Mahady et al 2000). Others merely suggest a
caution, as reports are largely unsubstantiated (Holford & Cass
2001). As such, it is recommended that people with hypertension should
be monitored if using high doses. In a
study of elderly people with hypertension, 8 weeks of Siberian ginseng use did not
affect BP control (Cicero et al 2004). Due to possible effects
on glycaemic control (Sievenpiper et al 2004), care should be taken in people
with diabetes until safety is established. Suspend use 1 week before major
surgery. Traditional contraindications include hormonal changes, excess energy states,
fever, acute infection, concurrent use of other stimulants and prolonged use.
PREGNANCY USE
Insufficient
reliable information is available, but the herb is not traditionally used in
pregnancy.
PATIENTS’ FAQs (Braun, L and Cohen, M. 2010)
What
will this herb do for me? Siberian ginseng affects
many chemicals involved in switching on and off the body’s stress
responses. As such, it is used to improve wellbeing during times of chronic
stress; however, scientific research has yet to fully investigate its use in
this regard. It may also boost immune function and reduce the
frequency of genital herpes outbreaks. Evidence for improved
performance in athletes is unconvincing.
When
will it start to work? Effects on stress levels should develop
within 6 weeks, whereas immune responses develop within 30
days.
Are
there any safety issues? It should not be used in
pregnancy, and high doses should be used with care by those with
hypertension.
PRACTICE POINTS/PATIENT COUNSELLING (Braun, L and Cohen, M. 2010)
·
Siberian
ginseng appears to alter the levels of different neurotransmitters and hormones
involved in the stress response, chiefly at the HPA axis.
·
It
is widely used to treat individuals with nervous exhaustion or anxiety due to
chronic exposure to stress or what are now termed ‘allostatic load situations’.
It is also recommended during convalescence or fatigue to improve mental and
physical responses.
·
Siberian
ginseng may increase resistance to infection and has been shown to reduce frequency
of genital herpes outbreaks with longterm use.
·
The
herb is popular among athletes in the belief that endurance, performance and
power may improve with its use, but clinical studies have produced inconsistent
results.
·
It
is not recommended for use in pregnancy, and people with hypertension should be
monitored if using high doses.
PREPARATIONS (Barnes, J et al., 2007)
Proprietary single-ingredient preparations
Argentina:
Ginsana; Herbaccion Bioenergizante. Australia: Herbal Stress Relief. Austria:
Ginsana. Belgium: Ginsana. Brazil: Ginsana; Ginsex. Canada: Ginsana. Czech
Republic: Ginsana. France: Gerimax Tonique. Germany: Ardey-aktiv; Coriosta
Vitaltonikum N; Ginsana; Hevert-Aktivon Mono; IL HWA; Orgaplasma. Italy:
Ginsana. Malaysia: Ginsana. Mexico: Raigin; Rutying; Sanjin Royal Jelly.
Portugal: Ginsana. Russia: Gerimax Ginseng (Геримакс Женьшень); Ginsana (Гинсана).
Singapore: Ginsana. Spain: Bio Star. Switzerland: Ginsana; KintaVital. Thailand: Ginsana;
Ginsroy. UK: Korseng; Red Kooga.
Proprietary multi-ingredient preparations
Argentina:
Dynamisan; Herbaccion Ginseng Y Magnesio; Optimina Plus; Total Magnesiano con
Ginseng; Total Magnesiano con Vitaminas y Minerales; Vifortol. Australia: Bioglan
Ginsynergy; Extralife Extra-Brite; Ginkgo Biloba Plus; Ginkgo Complex;
Glycyrrhiza Complex; Infant Tonic; Irontona; Nervatona Plus; Panax Complex;
Vig; Vig; Vitatona. Austria: Gerimax Plus; ProAktiv. Brazil: Gerin; Poliseng. Canada:
Damiana-Sarsaparilla Formula; Energy Plus; Ginkoba. Chile: Gincosan; Mentania.
Czech Republic: Gincosan. France: Nostress; Thalgo Tonic; Tonactil. Germany: Ginseng-Complex
"Schuh"; Peking Ginseng Royal Jelly N. Hong Kong: Cervusen. Italy:
Alvear con Ginseng; Apergan; Bioton; Fon Wan Ginsenergy; Forticrin; Fosfarsile
Forte; Fosfarsile Forte; Four-Ton; Ginsana Ton; Neoplus; Ottovis. Malaysia: 30
Plus; Adult Citrex Multivitamin þ Ginseng þ Omega 3; Total Man. Russia:
Doppelherz Ginseng Aktiv (Доппельгерц Женьшень Актив); Doppelherz Vitalotonik
(Доппельгерц Виталотоник). South Africa: Activex 40 Plus. Singapore: Gin-Vita. Spain:
Energysor; Redseng Polivit; Ton Was; Vigortonic. Switzerland: Biovital Ginseng;
Burgerstein TopVital; Geri; Gincosan; Imuvit; Supradyn Vital 50þ; Triallin.
Thailand: Imugins; Imuvit; Multilim RG; Revitan. UK: Actimind; Red Kooga Co-Q-10
and Ginseng; Regina Royal Concorde; Seven Seas Ginseng; Vitegin Capsules;
Wellman. USA: Energy Support; Mental Clarity.
REFERENCE
Barnes, J.,
Anderson, L. A., and Phillipson, J. D. 2007. Herbal Medicines Third
Edition. Pharmaceutical Press. Auckland and London.
Braun,
L and Cohen, M. 2010. Hebs and Natural Supplements An Evidence Based
Guide 3R D Edition. Elsevier Australia. Australia.
Duke, J. A.
with Mary Jo Bogenschutz-Godwin, Judi duCellier, Peggy-Ann K. Duke. 2002. Handbook
of Medicinal Herbs 2nd Ed. CRC Press LLC. USA.
Kraft, K and
Hobbs, C. 2004 . Pocket Guide to Herbal Medicine. Thieme.
Stuttgart New York.
Linda
S-Roth. 2010. Mosby’s Handbook Of Herbs & Natural Supplements, Fourth
Edition. Mosby Elsevier. USA.
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