Eleutherococcus senticosus (Rupr.&Maxim.) Maxim. (Araliaceae) GINSENG KOREAN

HERBAL
MEDICINAL

Ginseng — Korean

Eleutherococcus senticosus (Rupr.&Maxim.) Maxim. (Araliaceae)




BY 

RETTODWIKART THENU

G I N S E N G

Ginseng — Korean

Eleutherococcus senticosus (Rupr.&Maxim.) Maxim. (Araliaceae)

HISTORICAL NOTE (Braun, L and Cohen, M. 2010)

Gin refers to man and seng to essence in Chinese, whereas Panax is derived from the Greek word pan (all) and akos (cure), referring to its use as a cure-all. Ginseng is a perennial herb native to Korea and China and has been used as a herbal remedy in eastern Asia for thousands of years. It is considered to be the most potent Qi or energy tonic in Traditional Chinese Medicine (TCM). Modern indications include low vitality, poor immunity, cancer, cardiovascular disease and enhancement of physical performance and sexual function. However, a recent systematic review of randomised controlled trials (RCTs) found that the efficacy of ginseng root extract could not be established beyond doubt for any of these indications (Coon & Ernst 2002).

SUMMARY AND PHARMACEUTICAL COMMENT (Barnes, J et al., 2007)

Phytochemical studies have revealed that there is no one constituent type that is characteristic of Eleutherococcus ginseng. Studies have shown that components thought to represent the main active constituents (’eleutherosides’) consist of a heterogeneous mixture of common plant constituents, including carbohydrates, coumarins, lignans, phenylpropanoids and triterpenoids. Since the 1950s, many studies (animal and human) have been carried out in Russia, and more recently in Western countries, to investigate the reputed adaptogen properties of Eleutherococcus ginseng. (An adaptogen is a substance that is defined as having three characteristics, namely lack of toxicity, non-specific action, and a normalising action.) Preclinical studies have indicated that preparations of E. senticosus and/or its isolated constituents has a range of pharmacological properties; results of these studies provide some supporting evidence for adaptogenic properties for certain E. senticosus preparations, although pharmacological explanations for the observed actions are less well understood.

Clinical trials of E. senticosus 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 E. senticosus preparations, which vary qualitatively and quantitatively in their phytochemical composition, administered according to different dosage regimens, and to different study populations (e.g. healthy volunteers, older patients with hypertension), making interpretation of the results difficult. At present there is insufficient evidence to support definitely the efficacy of specific E. senticosus preparations in the various indications for which it is used and/or has been tested.

Similarly, there are only limited clinical data on safety aspects of E. senticosus preparations. The clinical trials of E.senticosus root preparations available have typically involved only very small numbers of patients and been of short duration, so have the statistical power only to detect very common, acute adverse effects. Rigorous investigation of safety aspects of well-characterised E. senticosus root preparations administered orally at different dosages, including the effects of long-term treatment, is required. In view of the many pharmacological actions documented for ginseng, and the lack of safety and toxicity data, the use of E. senticosus during both pregnancy and breastfeeding should be avoided.

SPECIES (FAMILY) (Barnes, J et al., 2007)

Eleutherococcus senticosus (Rupr.&Maxim.) Maxim. (Araliaceae)

BOTANICAL NAME/FAMILY (Braun, L and Cohen, M. 2010)

Panax ginseng C.A. Meyer (family Araliaceae) It should be differentiated from P. Aquifolium (American ginseng), P. notoginseng (Tien chi, pseudoginseng), Eleutherococcus senticosis (Siberian ginseng) and other ginsengs.

SYNONYM(S) (Barnes, J et al., 2007)

Acanthopanax senticosus (Rupr. & Maxim.) Maxim., Devil's Shrub, Eleuthero, Hedera senticosa Rupr. & Maxim., Siberian

Ginseng, Touch-Me-Not, Wild Pepper

OTHER NAMES (Braun, L and Cohen, M. 2010)

Ren shen (Mandarin), red ginseng, white ginseng

PLANT PART USED (Braun, L and Cohen, M. 2010)

Main and lateral roots. The smaller root hairs are considered an inferior source. There are two types of preparations produced from ginseng: white ginseng, which is prepared by drying the raw herb, and red ginseng, prepared by steaming before drying. Cultiv ated ginseng differs from wild ginseng, and plants from different countries or regions may also differ greatly. Processing of the crude herb to produce red ginseng appears to increase its potency. Steaming has been shown to alter the composition of the ginsenosides; for example, steaming produces the active 20(S)-ginsenoside-Rg(3) (Matsuda et al 2003) and makes certain ginsenosides more cytotoxic (Park et al 2002a).

The British Herbal Pharmacopoeia (1983) stipulates that ginseng should contain not less than 20% solids (70% ethanol). The German Pharmacopoeia requires not less than 1.5% total ginsenosides, calculated as ginsenoside Rg 1. Chewing gums containing ginseng saponins have also been developed and demonstrate therapeutic effects in some trials (Ding et al 2004).

PHARMACOPOEIAL AND OTHER MONOGRAPHS (Barnes, J et al., 2007)

BHC 1992^(G6)

BHMA 2003^(G66)

BHP 1996^(G9)

BP 2007^(G84)

Complete German Commission E^(G3)

ESCOP 2003^(G76)

Martindale 35th edition^(G85)

Ph Eur 2007^(G81)

WHO volume 2^(G70)

LEGAL CATEGORY (LICENSED PRODUCTS) (Barnes, J et al., 2007)

Eleutherococcus ginseng is not included in the GSL^.(G37)

CONSTITUENTS 

CONSTITUENTS (Barnes, J et al., 2007)

Carbohydrates Polysaccharides (glycans); some have been referred to as eleutherans.(1) Galactose, methyl-a-D-galactose (eleutheroside C), glucose, maltose, sucrose.

Coumarins Isofraxidin-7-glucoside (eleutheroside B1), 7-ethylumbelliferone.(2)

Lignans (_)-Syringaresinol-40,400-di-O-b-D-glucopyranoside (eleutheroside E), episyringaresinol-400-O-b-D-glucopyranoside (eleutheroside E2),(3) 7SR,8RS-dihydrodehydroconiferyl alcohol, dehydrodiconiferyl alcohol, 7,8-trans-diconiferylalcohol-4-O-b-Dglucopyranoside, meso-secoisolariciresinol, (_)-syringaresinol-4-O-b-D-glucopyranoside,(2) sesamin.

Phenylpropanoids Syringin (eleutheroside B), coniferyl alcohol, coniferyl aldehyde, 50-O-caffeoylquinic acid (chlorogenic acid),10,50-O-dicaffeoylquinic acid, 40,50-O-dicaffeoylquinic acid.(4)

Triterpenoids Daucosterol (eleutheroside A), b-hederin (eleutheroside K),(5, 6, G6) 3b-{O-b-D-glucopyranosyl-(1!3)-O-b-D-galactopyranosyl-(1!4)-[O-a-L-rhamnopyranosyl-(1!2)]-Ob- D-glucuronopyranosyl}-16a-hydroxy-13b,28-epoxyoleanane,(1) 3b-{O-a-L-rhamnopyranosyl-(1!4)-O-a-L-rhamnopyranosyl- (1!4)-[O-a-L-rhamnopyranosyl-(1!2)]-O-b-D-glucopyranosyl- (1!x)-O-b-D-glucuronopyranosyl}-16a-hydroxy-13b,28-epoxyoleanane.(6, 7)

Essential oil 0.8%. Individual components not documented.

OTHER PARTS OF THE PLANT (Barnes, J et al., 2007)

Stem (_)-Sesamin, isofraxidin, syringaresinol, eleutheroside B, eleutheroside E, 5-hydroxymethylfurfural, isovanillin.(8)

Leaves Flavonoids, including hyperin (quercetin-3-O-b-galactoside), quercetin, quercitrin, rutin,(9) and four 3,4-seco-lupan-type triterpenoids.(10)

QUALITY OF PLANT MATERIAL AND COMMERCIAL PRODUCTS (Barnes, J et al., 2007)

According to the British and European Pharmacopoeias, Eleutherococcus ginseng consists of the whole or cut, dried, underground organs of E. senticosus (Rupr. Et Maxim.) Maxim.(G81, G84) Eleutherosides A to G are present in roots at concentrations of 0.6–0.9% and in stems at concentrations of 0.6–1.5%.(5) An HPLC method for determining the eleutheroside content of E. senticosus roots, which involves the use of ferulic acid rather than eleutherosides B and E (which are very expensive) as an external standard, has been developed and validated.(11) Methods previously reported for the isolation and quantitative analysis of E. senticosus root material include centrifugal partition chromatography with HPLC,(12) and reversed-phase HPLC.(13) As with other herbal medicinal products, there is variation in the qualitative and quantitative composition of commercial eleutherococcus preparations. Analysis of 25 'ginseng' products available for purchase from a health-food store in the USA included 11 products labelled as containing E. senticosus. All 11 products contained the correct species, as determined by LC-MS/MS (liquid chromatography/mass spectrometry) analysis identifying the presence of eleutherosides B and E and absence of ginsenosides (apart from the two products which were labelled as also containing Panax ginseng). However, there was wide variation between products in the content of these eleutherosides, as determined by HPLC (high-performance liquid chromatography).( 14)

In products containing powdered E. senticosus, eleutheroside B and E content per 100 g of product ranged from 0.009–0.155% and from 0.032–1.122%, respectively, thus total eleutheroside content (B plus E) varied 43-fold between products. With liquid preparations, there was a 200-fold variation in total (B plus E) eleutheroside content between products (0.003–0.551% per 100 g product). For the six products which provided quantitative information on the product label, the actual eleutheroside content varied from 12–328% of that stated on the label. Earlier work involving analysis of commercial products purchased in the USA and Canada found that the eleutheroside B concentrations in E. senticosus capsules, powder and liquid preparations varied from 0.01–0.03% w/w, 0.01–1.00% w/w, and 0.03–0.13 mg/mL, respectively, and that eleutheroside E concentrations varied from 0.04–0.16% w/w, 0.06–0.66% w/w, and 0.01–1.62 mg/mL, respectively.(13)

CHEMICAL COMPONENTS (Braun, L and Cohen, M. 2010)

The most characteristic compounds in the ginseng roots are the ginsenosides, and most biological effects have been ascribed to these compounds. The ginsenosides are dammarane saponins and can be divided into two classes: the protopanaxatriol class consisting primarily of Rg1, Rg2, Rf and Re and the protopanaxadiol class consisting primarily of Rc, Rd, Rb1 and Rb2. Ginseng also contains other saponins, polysaccharides, amino acids (in particular glutamine and arginine) (Kuo et al 2003), essential oils and other compounds. Three new sesquiterpene hydrocarbons have also recently been isolated from the essential oil: panaxene, panaginsene and ginsinsene (Richter et al 2005).

Ginsenosides Rh1, Rh2 and Rg3 are obtained from red ginseng as artifacts produced during steaming. It is likely that ginsenoside is actually a prodrug that is converted in the body by intestinal bacterial deglycosylation and fatty acid esterification into an active metabolite (Hasegawa 2004), and therefore, extrapolation from in-vitro studies or studies in which ginseng or  isolated constituents were given by injection must be made very cautiously. Commercial ginseng preparations are variable in quality. An analysis of 50 products sold in 11 countries shows that there is a large variation in the concentration of ginsenosides (from 1.9 to 9.0%). Some products were even found to be void of any specific ginsenosides. Some ginseng products have also been discovered to be contaminated with ephedrine. Therefore, it is essential that only quality ginseng products be used (Cui et al 1994).

Although the root hairs have a higher level of total ginsenosides than the main root, the main and lateral roots are the preferred medicinal parts. In all probability, it is the ratio of ginsenosides that is important and other important compounds are also active.

FOOD USE (Barnes, J et al.,)

Eleutherococcus ginseng is not used in foods.

HERBAL USE (Barnes, J et al.,)

Eleutherococcus ginseng does not have a traditional herbal use in the UK, although it has been used for many years in the former Soviet Union. Like Panax ginseng, Eleutherococcus ginseng is claimed to be an adaptogen in that it increases the body's resistance to stress and builds up general vitality.(G6, G8, G49)

DOSAGE

DOSAGE (Barnes, J et al., 2007)

Dosages for oral administration (adults) recommended in older standard herbal reference texts are the same for several traditional uses. Dry root 0.6–3 g daily for up to one month has been recommended.(G6, G49) Russian studies in healthy human subjects have involved the administration of an ethanolic extract in doses ranging from 2–16 mL one to three times daily, for up to 60 consecutive days.

Clinical trials of  E. senticosus have assessed the effects of different preparations administered orally according to different dosage regimens. A rigorous trial involving individuals with chronic fatigue investigated the effects of a standardised extract of E. senticosus root providing 2.24 mg eleutherosides (B and E) daily for two months.(15) Studies conducted in Russia and involving healthy human subjects have involved the administration of an ethanolic extract (not further specified) at doses ranging from 2– 16 mL one to three times daily, orally, for up to 60 consecutive days.(5) Doses administered to non-healthy individuals ranged from 0.5–6.0 mL given one to three times daily for up to 35 days. In both groups, multiple dosing regimens were separated by an extract-free period of two to three weeks.(5)

DOSAGE RANGE (Braun, L and Cohen, M. 2010)

·         Extract equivalent to 0.9–3 g crude ginseng root (Bensky & Gamble 1986).

·         Standardised extract: 1.5–4.0% total ginsenosides calculated as ginsenoside Rg1.

·         Liquid extract (1:2): 1–6 mL/day.

·         Cognitive function: Clinical trials using 1.5–3 g three times daily have reported benefits. Lower doses may be associated with ‘cognitive costs’ and slowing performance on attention tasks (Kennedy & Scholey 2003).

·         Cardiovascular use: 1.5–2 g three times daily. Many of the clinical studies published in the scientific literature have used a proprietary extract of ginseng standardised to 4% total ginsenosides (G115 or Ginsana produced by Pharmaton, Lugano,

·         Switzerland). Ginseng is usually given in the earlier part of the day. It should not be given in the evening, unless it is used to promote wakefulness. Ginseng is usually not given to children.

DOSAGE AND DURATION OF USE (Kraft K and Hobbs C. 2004)

– Daily dose: 2–3 g herb.

– Fluid extract (1 : 1): 3 to 5 drops in a glass of water several times a day.

DOSAGES (SIBERIAN GINSENG) (Duke, J. A et al., 2002)

 250–500 mg herb 1–2 ×/day (APA); 0.6–3 g root/day for 1 month (CAN); 4.5–27 g root (FAY); 2–3 g root (KOM; PHR); 1–4 g root/day (MAB); 1–2 tsp fresh root (PED); 0.5–1 g dry root (PED); 1 g dry root:5 ml alcohol/5 ml water (PED); 2–8 ml root extract (1:2) (MAB); 2–16 ml alcoholic root extract 1–3 ×/day up to 60 days (CAN); 0.5–6 ml alcoholic root extract 1–3 ×/day up to 35 days (CAN); 1–2 droppers herb tincture 2–3 ×/day (APA).

PHARMACOLOGICAL ACTIONS

ACTIVITIES (Duke, J. A et al., 2002)

Adaptogen (1; FAY; MAB; SKY; WAM); Adrenal Stimulant (1; AKT; MAB); Anabolic (1; MAB); Antiaging (f; APA; CRC; DAA); Antiaggregant (1; BGB; MAB; PH2); Antidiabetic (1; MAB); Antidote (1; MAB); Antiischemic (1; MAB); Antileukemic (1; BGB); Antistress (2; MAB; SKY); Antitumor (1; APA; MAB); Antiviral (1; PH2; WAM); Aperitif (f; FAY; PH2); Bitter (f; PED); Cardioprotective (1; MAB); Cerebrotonic (f; FAY); Circulostimulant (f; PED); Diuretic (f; APA; PH2); Estrogenic (f; PED); Gonadotropic (1; MAB); Hyperglycemic (1; MAB); Hypoglycemic (1; MAB; PED; PH2); Immunostimulant (1; AKT; FAY; KOM; PH2; SHT; WAM); Insulinogenic (1; MAB); Leukocytotic (1; MAB); Leukopenic (1; MAB); Lymphocytogenic (1; KOM; PH2); Memorigenic (1; APA; BGB; CRC; DAA); Nephrotonic (f; FAY; MAB); Neurotonic (f; FAY); Radioprotective (1; BGB; DAA; MAB); Serotoninergic (1; MAB); Splenotonic (f; FAY; MAB); Stimulant (f; APA); Tonic (2; DAA; KOM; SHT; WAM); Tranquilizer (f; MAB); Vasodilator (f; FAY).

INDICATIONS (Duke, J. A et al., 2002)

ADD (f; SKY); Adrenopathy (1; MAB); Altitude Sickness (f; CRC); Alzheimer’s (f; SKY); Anorexia (f; APA; BGB; CRC; FAY; MAB; PH2); Arrhythmia (1; APA); Arthrosis (f; APA; CRC; MAB; PH2); Atherosclerosis (f; APA); Backache (f; APA; MAB); Bronchosis (1; BGB; CRC; DAA); Cachexia (1; SHT); Cancer (1; APA; MAB); Cancer, stomach (f; CRC; DAA); Cardiopathy (1; APA; BGB; DAA; MAB); CFS (1; APA; MAB; SKY); Cold (f; SKY); Convalescence (2; KOM; SHT); Cramp (f; MAB); Debility (2; APA; KOM; PH2; SHT); Depression (1; APA; MAB); Diabetes (1; APA; MAB; PH2; SKY); Dysuria (f; MAB); Edema (1; MAB); Fatigue (2; AKT; KOM; SHT; PH2; WAM); Fibromyalgia (1; SKY); Flu (f; SKY); Gastrosis (f; DAA); Glaucoma (1; BGB); Heart (f; CRC); Hemiplegia (f; CRC); High Blood Pressure (f; APA; CRC); Hip (f; PH2); HIV (f; APA); Hypercholesterolemia (f; CRC); Hyperglycemia (1; MAB; PED; PH2); Hypoglycemia (1; MAB); Hypotension (f; APA); Impotence (f; CRC; PH2; SHT); Immunodepression (1; AKT; FAY; KOM; PH2; SHT; WAM); Infection (1; PHR; PH2); Inflammation (f; APA); Insomnia (1; APA; CRC; MAB; PH2); Leukemia (1; BGB); Leukocytosis (1; MAB); Leukopenia (1; MAB); Longevity (f; DAA); Lupus (f; SKY); Mental and Physical Dysfunction (1; SHT); Myopia (1; BGB); Nephrosis (f; APA; PH2); Nervousness (f; MAB); Neurasthenia (f; CRC); Pain (f; PH2); Plumosus (f; CRC); Radiation (f; APA); Rheumatism (f; APA; CRC; DAA); Sore Throat (f; SKY); Stress (1; AKT; FAY; KOM; MAB; WAM); Swelling (f; MAB); Thyroid (1; MAB); Trauma (f; MAB); Tumor (1; APA; MAB); Virus (1; PH2; WAM); Water Retention (f; APA; PH2).

PHARMACOLOGICAL ACTIONS (Barnes, J et al., 2007)

The so-called adaptogenic properties of eleutherococcus were first extensively investigated in the countries of the former USSR. Pharmacological studies on extracts of eleutherococcus started in the 1950s. The majority of the early literature on eleutherococcus has been published in Russian and therefore difficulty is encountered in obtaining translations.

A review of the literature up to the early 1980s(5) describes the chemistry and toxicity of eleutherococcus and documents results of in vitro, in vivo and human studies involving the oral administration of an ethanolic extract. More recently, the concept of adaptogens as it relates to eleutherococcus and its chemical constituents has been reviewed.(16) Preparations of eleutherococcus root and/or their isolated constituents have been reported to have several properties in vitro and/or in vivo, including anticancer, antiviral, hypoglycaemic and immunomodulant activities, although robust evidence of these effects from clinical studies is generally lacking.

IN VITRO AND ANIMAL STUDIES (Barnes, J et al., 2007)

The following represents a summary of the results of preclinical studies investigating the effects of eleutherococcus. It draws on data included in a review(5) as well as on more recent papers published in English. Used here, 'ginseng' refers to eleutherococcus unless indicated otherwise.

Antiviral and antibacterial activities In vitro antiviral activity against RNA-type viruses (human rhinovirus, respiratory syncytial virus and influenza A virus) has been demonstrated with an ethanolic extract of ginseng root. No effect was noted in cells infected with DNA-type viruses (adenovirus 5 and herpes simplex type 1 virus).(17)

Hypoglycaemic activity Hypoglycaemic activity has been documented both in normal animals and in those with induced

hyperglycaemia (rabbit, mouse), but with little effect on alloxaninduced hyperglycaemia (rat).(5, 18) Hypoglycaemic activity (mice, intraperitoneal injection) of an aqueous ginseng extract has been attributed to polysaccharide components termed eleutherans A–G.(19)

Central nervous system effects Sedative actions (rat, mouse), CNS-stimulant effects (intravenous/subcutaneous injection, rabbit), and a decrease/increase in barbiturate sleeping time has been reported using an aqueous extract of ginseng root.(5, 20)

Immunostimulant, antitoxic actions Numerous in vitro and in vivo studies have examined the immunomodulatory effects of ginseng. Oral administration of eleutherococcus root prepared as a decoction inhibited mast-cell dependent anaphylaxis in mice.(21) Similar results were obtained using the same animal model for a water extract of ginseng obtained from cell culture.(22) An ethanol extract of E. senticosus root inhibited the release of interleukin (IL)-4, IL-5, and IL-12 from human peripheral blood lymphocytes in in vitro experiments using human whole blood.(23) The release of IL-6 was stimulated by higher concentrations of the ginseng preparation and inhibited with lower concentrations, suggesting that ginseng root has immunomodulatory rather than immunosuppressive or immunostimulant activity.(23) In other in-vitro experiments using human peripheral blood, lower concentrations of an ethanol extract of ginseng root enhanced the proliferation of human lymphocytes, whereas higher concentrations had an antiproliferative effect.(24) In contrast to the findings described above, in-vitro studies using mouse macrophages found that an aqueous extract of ginseng root did not stimulate the expression of a range of cytokines investigated.(25) Increased resistance to induced listeriosis infection (mouse, rabbit) with prophylactic ginseng administration and reduced resistance with simultaneous administration, stimulation of specific antiviral immunity (guinea pig, mouse), regulation of complement titre and lysozyme activity post immunisation have been documented.(5) In vitro, a combination preparation containing E. senticosus extract (11.6 mg, standardised for eleutheroside E 1 mg) and Andrographis paniculata extract (plant parts not specified) enhanced phytohaemagglutin-induced proliferation of human peripheral blood lymphocytes, whereas the preparation inhibited the spontaneous proliferation of human peripheral blood lymphocytes.(26) Immunomodulatory effects have been reported for polysaccharide components isolated from E. senticosus (plant part not stated),(27) and from cell culture of E. senticosus.(28) Polysaccharide administration (100 mg/kg for six days) stimulated phagocytic activity in mice and (following repeated administration of 40 mg/kg) suppressed propogation of human tubercular bacillus in two animal models.(27) Polysaccharide isolated from cell culture increased the proliferation and differentiation of B-cells and increased the cytokine production of macrophages in vitro.(28) Immunostimulant activity in vitro (using granulocyte, carbon clearance and lymphocyte-transformation tests) has been documented for other high molecular weight polysaccharide components.( 29, 30)

Effects on overall performance A beneficial action on parameters indicative of stress or on overall work capacity in mice has been reported for eleutherococcus root bark,(31) although a lack of adaptogenic response has also been shown in mice receiving ginseng infusions.(32, 33) In one study, mice receiving a commercial concentrated extract of ginseng exhibited significantly more aggressive behaviour.(32) Ginseng is claimed to result in a more economical utilisation of glycogen and high-energy phosphorus compounds, and in a more intense metabolism of lactic and pyruvic acids during stress.(5) The adaptogenic effect of ginseng may involve regulation of energy, nucleic acid, and protein metabolism in tissues.(5) It may also be that ginseng limits the binding of stress hormones to their receptors by inhibiting catechol-O-methyltransferase.(34) These hypotheses requires testing in order to elucidate possible mechanisms of action for constituents of ginseng root.

Cardiovascular activity 3,4-Dihydroxybenzoic acid (DBA) has been identified as an anti-aggregatory component in Eleutherococcus ginseng.(1) Compared with aspirin, activity of DBA was comparable to collagen- and ADP-induced platelet aggregation, but less potent versus arachidonic acid-induced platelet aggregation.(1) Ginseng root also showed an endothelium-dependent vasorelaxant effect in vitro. Depending on the vessel size, this was mediated either by nitrous oxide or endothelium-derived hyperpolarising factor.(35)

Effect on reproductive capacity Ginseng has been reported to  improve the reproductive capacity of bulls and cows, and to have no adverse effects on the various blood parameters (haemoglobin, total plasma protein, albumin and globulin, protein coefficient) measured.(5) A preparation of ginseng root increased the motility of human sperm in vitro.(36)

Anticancer and cytotoxic effects An aqueous extract of ginseng root showed additive antiproliferative effects with cytarabine in vitro against leukaemia cells.(37) In in-vitro experiments using human peripheral blood, an ethanol extract of ginseng root displayed cytotoxic activity against human lymphocytes when applied to the system at a high concentration.(24)

Steroidal activity Gonadotrophic activity in immature male mice (intraperitoneal injection), oestrogenic activity in immature female mice, and an anabolic effect in immature rats (intraperitoneal injection) has been reported.(5)

Other activities An aqueous extract of ginseng root administered orally to rats for 30 days (100 or 200 mg/kg body weight daily) before intravenous administration of lipopolysaccharide (LPS) led to reductions in LPS-induced increases in nitric oxide concentrations and lipid peroxidation, and reduced concentrations of indicators of renal dysfunction.(38) An aqueous extract of ginseng cell culture was found to reduce weight gain, serum LDL cholesterol concentrations and triglyceride accumulation in obese mice.(39) Ginseng root stimulated erythropoiesis during paradoxical sleep deprivation in mice by modulation of brain neurotransmitters.(40) Other actions documented for ginseng include an increase in catecholamine concentrations in the brain, adrenal gland and urine,(5) and a variable effect on induced hypothermia (rabbit, rat, mouse).(5)

OTHER PARTS OF THE PLANT (Barnes, J et al., 2007)

Several of the activities described above for eleutherococcus root have also been described for other parts of the plant, such as leaves and stem bark. The antibacterial activity of three compounds isolated by methanolic extraction from the dried leaves of ginseng was tested against various Gram-positive and Gram-negative bacteria. Chiisanogenin, but not hyperin or chiisanoside, demonstrated moderate antibacterial activity against Bacillus subtilis, Staphylococcus epidermidis, S. aureus, Proteus vulgaris and Salmonella typhimurium, with minimum inhibitory concentrations ranging from 50–100 mg/ml.(41) Oral administration of eleutherococcus stem prepared as a decoction inhibited mast-cell dependent anaphylaxis in mice.(42) A beneficial action on parameters indicative of stress or on overall work capacity in rats has been reported for phenolic compounds isolated from eleutherococcus stem bark.(43) Preparations of other parts of the plant and/or their isolated constituents have also been reported to have certain cardiovascular efffects. The triterpenoid chiisanogenin from the leaves of E. senticosus has been shown to be 50 times as potent as aspirin in inhibiting U46619-induced platelet aggregation and 10–20 times as potent in inhibiting adrenaline- and arachidonic acid–induced aggregation.(44) An aqueous extract of ginseng stem bark protected against the effects of transient focal cerebral ischaemia in rats, an effect apparently mediated by microglial activation and inhibition of cyclooxygenase-2.(45) An increase in lipoprotein lipase activity was observed in adipocytes cultured with an aqueous extract of dried ginseng leaves.(46) Aqueous or alcoholic extracts of the stem of ginseng have shown hepatoprotective (47,48) and antioxidant properties(47) in vivo. Anti-inflammatory and antinociceptive effects were noted with an ethyl acetate extract of ginseng stem bark in rats: these were attributed to the in vivo conversion of liriodendrin to syringaresinol.(49) Preparations of other parts of the plant and/or their isolated constituents have been reported to have certain anticancer effects. Fractionated glycoproteins from an aqueous extract of ginseng stem bark inhibited lung metastasis in mice both prophylactically and therapeutically. This effect was mediated by activation of macrophages and natural killer (NK) cells.(50, 51) In studies using a stem bark extract, sesamin was identified as the component with antitumour activity in vitro in human stomach cancer cells.(52) Ethanol-induced apoptosis in a human neuroblastoma cell line (SK-N-MC) was inhibited by an aqueous extract of ginseng (plant part not stated) in vitro.(53) In rats, an ethanolic extract of ginseng stem bark and one of its components, sesamin, showed cytoprotective properties against Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone.(54,55)

CLINICAL STUDIES (Barnes, J et al., 2007)

Clinical trials of E. senticosus 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 E.senticosus preparations, including combination herbal preparations containing E. senticosus, 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, older patients with hypertension), making interpretation of the results difficult.

A large body of clinical research has been published in the Russian literature, making access difficult,(5) although consideration of a review of some of this work indicates that these clinical trials are unlikely to meet contemporary standards in terms of their design, analysis and reporting. Therefore, at present there is insufficient evidence to support definitively the efficacy of specific E. senticosus preparations in the various indications for which it is used and/or has been tested. Details of clinical trials of E. senticosus preparations published in the English literature are summarised below.

In a randomised, double-blind, placebo-controlled, trial, 96 individuals with chronic fatigue (unexplained fatigue of at least six months' duration and a Rand Vitality Index score of 12 or less) recruited using newspaper adverstisements and via chronic fatigue syndrome (CFS) support groups, received capsules containing a standardised extract of E. senticosus root providing 2.24 mg eleutherosides (B and E) daily, or placebo, for two months.(15) At the end of the study, Rand Vitality Index scores had improved in both groups and there were no statistically significant differences between groups (p > 0.05). Sub-group analyses suggested that there was a treatment effect depending on duration and severity of fatigue at baseline, but this requires testing in larger randomised controlled trials. In a two-month, open-label extension to the initial study, all remaining participants received E. senticosus, although they were still unaware of their initial treatment allocation and the likely time to onset of action of E. senticosus. During this phase, participants who received placebo during months one and two showed a statistically significant improvement in mean Rand Vitality Index score when assessed at month four, compared with month two (p = 0.02), whereas participants who had received E. senticosus during months one and two, did not show any statistically significant improvements in Rand Vitality Index scores during the open-label phase of the study.(15) Another randomised, double-blind, controlled trial assessed the effects of an E. senticosus dry extract (Centofiori, Italy; not further specified) 300 mg daily (n = 10), or placebo, for eight weeks on quality of life in 20 participants aged 65 years or more with hypertension and who were undergoing treatment with digitalis (not further specified).(56) After four weeks' treatment, improvements in the social functioning and mental compartment summary scores (p < 0.05 for both) of the SF-36 general health status questionnaire were observed, but at the eight-week endpoint, there were no statistically significant differences between groups. The study, however, has several methodological limitations, including the small sample size and lack of a priori hypotheses for sub-group analyses. Participants in the E. senticosus group were more likely than those in the placebo group to state that they had received verum (70% versus 20%); p< 0.05), so it is possible that unblinding occurred during the study, and this may have biased the results towards a more positive effect for E. senticosus. Also, total SF-36 scores were not reported, and it is possible that there was no statistically significant difference between these at the four-week assessment, thus a placebo response in both groups cannot be ruled out. A report of the study states that no statistically significant differences in blood pressure control and serum digoxin concentrations were observed, although supporting data were not provided.

Several clinical trials have explored the reputed adaptogenic effects of E. senticosus preparations in athletes. A placebocontrolled trial involved ten groups each comprising three male endurance athletes matched for training duration and frequency. Participants (n = 30) were assessed for steroidal hormone indices of stress and lymphocyte subset counts before and after six weeks' treatment with a 35% ethanolic extract of E. senticosus root 8mL daily (equivalent to 4 g dried root), a 60% ethanolic extract of Panax ginseng root 4mL daily (equivalent to 2 g dried root), or placebo.(57) Participants were randomly assigned to treatment within groups of three. Six groups of three completed the study, although data from laboratory tests of blood samples were available for only five groups of three athletes. At the end of the study, E. senticosus recipients had a significantly greater decrease in the testosterone to cortisol ratio, than did placebo recipients (p < 0.05); this appeared to be due to increased cortisol concentrations (which would suggest increased, rather than decreased, stress), rather than decreased testosterone concentrations. There were no significant differences between the three groups in any of the lymphocyte parameters measured, such as lymphocyte count, CD3þ cell, natural killer cell and B-cell CD20þ counts (p > 0.05 for all).(57) It is not clear whether the observed change in testosterone to cortisol ratio in E. senticosus recipients represents a genuine effect, or whether it is a spurious finding, and the effects of E. senticosus on steroid hormone concentrations require further investigation.

In another double-blind, controlled trial, 20 highly trained distance runners received a 30–40% ethanol extract of E. senticosus (not further specified) 60 drops daily, or placebo, for six weeks. Participants were matched by sex, body weight and tenkilometre race pace and then randomly assigned as matched pairs to one of the treatment groups.(58) During the study, participants undertook five 15-minute trials of a submaximal treadmill run (at their ten-kilometre race pace) and one maximal treadmill run (i.e. to exhaustion; Tmax). Data available for eight matched pairs did not show any statistically significant differences between groups in heart rate, oxygen consumption (VO2), expired minute volume (VE), VE/VO2, respiratory exchange rate, Tmax, serum lactate concentrations and participants' rating of perceived exertion. However, because of the small sample size, the study lacked the statistical power to detect any differences between the two groups.(58) Significant improvements in maximal oxygen uptake and oxygen pulse (p < 0.05 for both, compared with a no-treatment control group), and in total work capacity and maximum exhaustion time (p < 0.05, compared with placebo and a notreatment control group) were observed with an ethanolic extract of E. senticosus 2mL twice daily (1 mL contained 0.53 mg syringin (eleutheroside B) and 0.12 mg syringaresinol diglucoside (eleutheroside E)) in a single-blind, placebo-controlled, crossover study involving six healthy male athletes who underwent a series of physical exercises.(59) However, the methodological limitations of the study (small sample size, no apparent random allocation to treatment, single-blind nature of assessments) preclude definitive conclusions.

A small number of other studies has assessed the effects of E. senticosus in healthy, young, non-athlete volunteers. In a randomised, double-blind, controlled trial, 45 volunteers received E. senticosus (Fon Wan Blu Giuliani, Milan, Italy; not further specified) two 'vials' daily for 30 days, and undertook the Stroop Colour-Word test as a challenge stressor before and after treatment.(60) A report of the study describes statistically significant reductions in test-induced increases in systolic blood pressure and heart rate after E. senticosus treatment, compared with baseline values. However, the study is flawed as no statistical comparisons were reported for the E. senticosus group compared with the placebo group. A further study in 50 healthy volunteers compared the effects of a 35% ethanol extract of E. senticosus roots (Taigutan; 1 g extract equivalent to 1 g root, not further specified) 25 drops three times daily for 30 days (n = 35) with those of Echinacin (containing 80 g Echinacea purpurea herb fresh juice in 100 g final product) 40 drops three times daily for 30 days (n = 15).(61) Blood samples taken from participants before and after treatment were subjected to biochemical tests. Statistically significant reductions in concentrations of triglycerides, total cholesterol, LDL cholesterol and free fatty acids, an increase in polymorphonuclear leukocyte phagocytic activity, and increases in other components related to cellular defence were described following E. senticosus treatment, compared with baseline values (p < 0.05 for each), but not following treatment with the echinacea preparation. In a second phase of the study, 20 of the participants were randomly selected to also undertake assessment of physical fitness before and after treatment. Statistically significant increases in oxygen consumption during maximal effort and in exhaled volume were described following E. senticosus treatment, compared with baseline values (p < 0.01 for each), but not in other parameters of physical fitness 320 Ginseng, Eleutherococcus nor for any of these parameters following treatment with the echinacea preparation. However, this study is also flawed as no statistical comparisons were reported for the E. senticosus group compared with the echinacea group, the study did not include a placebo arm, and no corrections were made for multiple statistical tests. In a randomised, double-blind, placebo-controlled trial involving 93 individuals with herpes, a greater proportion of recipients of a standardised extract of E. senticosus root (400 mg daily for six months) experienced improvements in the frequency, severity and duration of episodes of herpes, than did placebo recipients (75% versus 34%; p = 0.0002 for each).(62)

Immunomodulatory activity has been documented for an ethanolic extract of E. senticocus 30–40mL extract (eleutheroside B 0.2% w/v) daily in a double-blind, placebo-controlled trial involving healthy volunteers.(63) A significant increase in the total lymphocyte count, particularly in the T lymphocyte cell count, was observed for ginseng recipients, compared with placebo recipients. Specificity of action on the lymphocytes was confirmed by the fact that neither granulocyte nor monocyte counts were significantly altered.(63) Several other double-blind, placebo-controlled trials, some of which involved random allocation to treatment, have investigated the effects of combination herbal preparations containing E. senticosus as well as Andrographis paniculata with or without other herbal ingredients (Schizandra chinensis and Glycyrrhiza glabra) in the treatment of upper respiratory tract infections(64, 65) and in patients with Familial Mediterranean fever.(66) Another study assessed the effects of a combination preparation containing E. senticosus root extract, Adhatoda vasica leaf extract and Echinacea purpurea extract (plant part not specified).(67) Reports of these studies have claimed beneficial effects for the combination preparations, compared with placebo, on the various outcome measures assessed. However, the lack of randomisation in several of these studies, and the lack of critical analysis of the results by the authors, indicate that further research is required to confirm or refute these findings. A meta-analysis of the trials of a preparation containing standardised extracts of E. senticosus root and A. paniculata herb concluded that there was evidence that the combination was effective in relieving symptoms of acute upper respiratory tract infections, but that further research was required before firm recommendations could be made.(68) In a randomised, double-blind, placebo-controlled, cross-over trial involving 24 healthy volunteers who received a preparation of E. senticosus root 625 mg twice daily, a standardised Ginkgo biloba preparation equivalent to 28.2 mg flavonoid glycosides and 7.2 mg terpene lactones daily, a vitamin preparation, or placebo, for three months, selective memory was significantly improved in E. senticosus recipients compared with placebo recipients at the end of the study (p < 0.02).(69) Several other studies involving small numbers of participants have assessed the effects of a preparation of the leaves of E. senticosus (EnduroxTM) which contain ciwujianosides, a series of triterpenoid glycosides chemically distinct from the eleutherosides. One uncontrolled, open-label study(70) reported beneficial effects on parameters of physical endurance, compared with baseline values, in eight men who had taken a preparation containing 800 mg E. senticosus leaf extract for two weeks, but three other studies with more rigorous designs (randomised, double-blind, placebo-controlled, crossover trials) found no effects for E. senticosus leaf extract at doses of 800 or 1200 mg taken orally for seven to ten days.(71–73) The latter three studies included only ten or fewer participants, so it is possible that they lacked the statistical power to detect any differences between the treatment and placebo groups. The available evidence indicates that E. senticosus leaf extract administered according to the dosage regimens tested has no beneficial effects on perfomance during exercise lasting up to two hours.(74)

MAIN ACTIONS (Braun, L and Cohen, M. 2010)

Adaptogen The pharmacological effects of ginseng are many and varied, contributing to its reputation as a potent adaptogen. The adrenal gland and the pituitary gland are both known to have an effect on the body’s ability to respond to stress and alter work capacity (Filaretov et al 1988), and ginseng is thought to profoundly influence the hypothalamic–pituitary–adrenal axis (Kim et al 2003c). The active metabolites of protopanaxadiol and protopanaxatriol saponins reduce acetylcholine-induced catecholamine secretion in animal models (Tachikawa & Kudo 2004, Tachikawa et al 2003) and this may help to explain the purported antistress effects of ginseng. Ginseng has been shown in numerous animal experiments to increase resistance to a wide variety of chemical, physical and biological stressors. Ginseng extract or its isolated constituents have been shown to prevent immunosuppression induced by cold water swim stress (Luo et al 1993) and to counter stress-induced changes from heat stress (Yuan 1989), food deprivation (Lee et al 1990), electroshock (Banerjee & Izquierdo 1982) and radiation exposure (Takeda et al 1981). As thereare more than 1500 studies on ginseng and its constituents, it is outside the scope of this monograph to include all studies, so we have attempted to include those studies most relevant to the oral use of ginseng. Animal models suggest that ginseng is most usefulfor chronic rather than acute stress, significantly reducing elevated scores on ulcer index, adrenal gland weight, plasma glucose, triglycerides, creatine kinase activity and serum corticosterone during chronic stress (Rai et al 2003). (Refer to the Siberian ginseng monograph for more information about adaptogens and allostasis.)

Cardiovascular Effects

According to in vitro and animal studies, ginseng may benefit the cardiovascular system ‘through diverse mechanisms, including antioxidant, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitter release, improving lipid profiles’ and glycaemic control (Zhou et al 2004).

Antihypertensive Red ginseng has been used as an antihypertensive agent in Korea, but its clinical effect is unclear despite several in-vivo and in-vitro experimental studies. Recent preliminary data suggest that the antihypertensive effects may be partly attributed to an angiotensin-converting enzyme (ACE) inhibitory effect demonstrated by P. ginseng extract in vitro (Persson et al 2006). These effects were additive to the traditional ACE inhibitor enalapril. A study of isolated muscle preparations of animal heart and aorta with an alcohol-based extract of ginseng suggests that the hypotensive effect of ginseng is associated with a direct inhibition of myocardial contractility due to a reduction of calcium ion influx into cardiac cells, as well as the inhibition of catecholamine-induced contractility of vascular smooth muscles (Hah et al 1978). In a prospective, randomised, double-blind, placebo-controlled study of 30 healthy adults, 200 mg ginseng extract given for 28 days was found to increase the QTc interval and decrease diastolic blood pressure 2 h after ingestion on the first day of therapy. These changes, however, were not thought to be clinically significant (Caron et al 2002).

Antiplatelet Although reports from recent in-vitro and in vivo assays claim that P. ginseng is not one of the herbs that contributes to the antiplatelet effects of a Korean combination formula known as Dae-Jo-Hwan (Chang et al 2005), a number of studies have found that several ginsenosides inhibit platelet aggregation. Panaxynol has been shown to inhibit platelet aggregation induced by adenosine disphosphate, collagen and arachidonic acid. Panaxynol and ginsenosides Ro, Rg and Rg2 inhibit rabbit platelets while panaxynol prevented platelet aggregation and thromboxane formation (Kuo et al 1990).

Antihyperlipidaemic Ginsenoside Rb1 has been shown to lower triglyceride and cholesterol levels via cyclic adenosine monophosphate (cAMP) production in the rat liver (Park et al 2002b). P. ginseng extract (6 g/day) for 8 weeks resulted in a reduction in serum total cholesterol, triglyceride, low density lipoprotein (LDL) and plasma malondialdehyde levels and an increase in high density lipoprotein (HDL) (Kim & Park 2003) in eight males. Ginseng has also been reported to decrease hepatic cholesterol and triglyceride levels in rats, indicating a potential use of ginseng in the treatment of fatty liver (Yamamoto et al 1983).

Other cardiovascular effects Ginsenoside Rb2 has been shown to enhance the fibrinolytic activity of bovine aortic endothelial cells (Liu 2003). In animal studies, ginseng inhibits cardiomyocyte apoptosis induced by ischaemia and reperfusion (Zeng et al 2004) and the crude saponins have been shown to reduce body weight, food intake and fat content in rats fed a high-fat diet (Kim et al 2005a). In-vitro studies report that an extract of ginseng fruit can promote vascular endothelial cell proliferation, migration, DNA synthesis and vascular endothelial growth factor mRNA expression, suggesting an effect on the genesis and development of new vessels in the ischaemic myocardium (Lei et al 2008).

Gastrointestinal

Hepatorestorative Oral administration of Korean red ginseng (250 and 500 mg/kg) on liver regeneration has been investigated in 15 dogs with partial hepatectomy. All haematological values except leucocyte counts were within normal ranges for 3 days postoperatively. The levels of aspartate transaminase (AST and alanine aminotransferase (ALT) in the ginseng groups were significantly decreased compared with those in the control group (P < 0.05). The numbers of degenerative cells and areas of connective tissue were significantly decreased in the livers of the dogs treated with ginseng (P < 0.01) (Kwon et al 2003).

Anti-ulcerative Ginseng has been shown in several studies to protect against ulceration. Among the hexane, chloroform, butanol and water fractions, the butanol fraction of a ginseng extract has been shown to be the most potent inhibitor of HCl-induced gastric lesions and ulcers induced by aspirin, acetic acid and Shay (ulcer induced by pylorus ligation). The butanol fraction showed significant increase in mucin secretion, and inhibited malondialdehyde and H+/K+ATPase activity in the stomach. These results indicate that the effectiveness of ginseng on gastric damage might be related to inhibition of acid secretion, increased mucin secretion and antioxidant properties (Jeong 2002). Furthermore, inhibition of Helicobacter pylori stimulated 5-lipoxygenase activity may have a beneficial effect on H. pylori-associated gastric inflammation (Park et al 2007).

Effects on peristalsis Ginseng root extract and its components, ginsenoside Rb1(4) and ginsenoside Rd(7), have been shown to significantly ameliorate chemically induced acceleration of small intestinal transit in vivo. The test results suggest that the protective mechanism involves both an inhibitory effect on the cholinergic nervous system and a direct suppressive effect on intestinal muscles (Hashimoto et al 2003).

Anti-inflammatory Both a crude and a standardised extract (G115) of ginseng varying in saponin concentrations have been found to protect against muscle fibre injury and inflammation after eccentric muscle contractions in rats on a treadmill. The oral ginseng extracts significantly reduced plasma creatine kinase levels by about 25% and lipid peroxidation by 15%. Certain markers of inflammation were also significantly reduced (Cabral de Oliveira et al 2001). In a later study, pretreatment with ginseng extract (3, 10, 100 or 500 mg/kg) administered orally for 3 months to male Wistar rats resulted in a 74% decrease in lipid peroxidation caused by eccentric exercise (Voces et al 2004). The many and varied effects of ginseng may be partly associated with the inhibition of transcription factor nuclear factor (NF)-kappaB, which is pivotal in the regulation of inflammatory genes. Inhibition of NF-kappaB may reduce inflammation and protect cells against damage. Topical application of several ginsenosides (Rb1, Rc, Re, Rg1, Rg3) significantly attenuated chemically induced ear oedema in mice. The ginsenosides also suppressed expression of cyclooxygenase-2 (COX-2) and activation of NF-kappaB in the skin. Of the ginsenosides tested, Rg3 was found to be most effective (Surh et al 2002).

Immunomodulation The immunomodulatory effect of ginseng is based on the production of cytokines, activation of macrophages, stimulation of bone marrow cells and stimulation of inductible nitric oxide synthase (iNOS), which produces high levels of NO in response to activating signals from Th1-associated cytokines and plays an important role in cytotoxicity and cytostasis (growth inhibition) against many pathogenic microorganisms. In addition to its direct effector function, NO serves as a potent immunoregulatory factor. Ginseng enhances interleukin (IL)-12 production and may therefore induce a stronger Th1 response, resulting in improved protection against infection from a variety of pathogens (Larsen et al 2004), including Pseudomonas aeruginosa lung infection in animal models (Song et al 2005), although other studies suggest that it may also assist in the correction of Th1-dominant pathological disorders (Lee et al 2004a). Ginseng polysaccharides have been shown to increase the cytotoxic activity of macrophages against melanoma cells, increase phagocytosis and induce the levels of cytokines, including tissue necrosis factor (TNF)-alpha, IL-1-beta, IL-6 and interferon-gamma in vitro (Shin et al 2002). Ginseng has been shown to be an immunomodulator and to enhance antitumour activity of macrophages in vitro (Song et al 2002). Ginseng has also been shown significantly to enhance natural killer (NK) function in an antibody-dependent cellular cytotoxicity of peripheral blood mononuclear cells in vitro (See et al 1997). Incubation of macrophages with increasing amounts of an aqueous extract of ginseng showed a dose-dependent stimulation of iNOS. Polysaccharides isolated from ginseng showed strong stimulation of iNOS, whereas a triterpene-enriched fraction from an aqueous extract did not show any stimulation. As NO plays an important role in immune function, ginseng could modulate several aspects of host defence mechanisms due to stimulation of the iNOS (Friedl et al 2001). Ginseng promotes the production of granulocytes in the bone marrow (granulocytopoiesis). The ginseng saponins have been shown to directly and/or indirectly promote the stromal cells and lymphocytes to produce human granulocyte–macrophage colony-stimulating factor (GM-CSF) and other cytokines and induce bone marrow haemopoietic cells to express GM-CSF receptors, leading to a proliferation of human colony-forming units for granulocytes and macrophages in vitro (Wang et al 2003). Ginseng polysaccharides have been shown to have potent antisepticaemic activity by stimulating macrophages and helping modulate the reaction against sepsis induced by Staphylococcus aureus. Ginseng polysaccharides have been shown to reduce the intracellular concentration of S. aureus in macrophages in infected animals by 50% compared with  controls. Combination of the ginseng polysaccharides with vancomycin resulted in 100% survival of the animals, whereas only 67 or 50% of the animals survived, respectively, when treated with the ginseng polysaccharides or vancomycin alone (Lim et al 2002a). According to animal studies, long-term oral administration of ginseng extract may potentiate humoral immune response but suppress spleen cell functions (Liou et al 2005).

Anticancer

Oral intake of standardised P. ginseng extract demonstrates a dose-dependent (1, 3 or 10 mg/kg) chemoprotective and antimutagenic effect in animal studies (Panwar et al 2005), and ginsenoside Rg3 has recently been produced as an antiangiogenic anticarcinogenic drug in China (Shibata 2001).

Chemoprotection Oral administration of red ginseng extracts (1% in diet for 40 weeks) significantly (P < 0.05) suppressed spontaneous liver tumour formation in male mice. Oral white ginseng was also shown to suppress tumour promotion in vitro and in vivo (Nishino et al 2001). Dietary administration of red ginseng in combination with 1,2-dimethylhydrazine suppresses colon carcinogenesis in rats (rats were fed 1% ginseng for 5 weeks). It is thought that the inhibition may be partly associated with inhibition of cell proliferation in the colonic mucosa (Fukushima et al 2001). Oral administration of 50 mg/kg/day for 4 weeks of a ginseng intestinal metabolite has been shown to partially protect against doxorubicininduced testicular toxicity in mice. The metabolite significantly (P < 0.01) prevented decreases in body weight, spermatogenic activities, serum levels of lactate dehydrogenase and creatine phosphokinase induced by doxorubicin. It also significantly attenuated germ cell injuries (Kang et al 2002). The methanol extract of red ginseng has been shown to attenuate the lipid peroxidation in rat brain and scavenge superoxides in differentiated human promyelocytic leukaemia (HL-60) cells. Topical application of the same extract, as well as purified ginsenoside Rg3, has been demonstrated to suppress skin tumour promotion in mice. Rg3 also suppresses COX, NF-kappaB and extracellularregulated protein kinase, which are all involved in tumour promotion (Surh et al 2001). Pretreatment with oral red ginseng extract significantly reduced the development of cancer from diethylnitrosamine-induced liver cancer nodules in rats (the developmental rate of liver cancer in the experimental group was 14.3% compared with 100% in the control group). When ginseng was given concomitantly with diethylnitrosamine, the hepatoma nodules were smaller than those of the control group, the structure of hepatic tissue was well preserved and the structure of hepatocytes was normal. Ginseng also prolonged the average life span. These findings suggest benefits of ginseng in the prevention and treatment of liver cancer (Wu et al 2001).

Irradiation protection  Ginsenosides and specifically panaxadiol have been shown to have radioprotective effects in mice irradiated with high-dose and low-dose gamma radiation. Jejunal crypts were protected by pretreatment with extract of whole ginseng (50 mg/kg body weight intraperitoneally at 12 and 36 hours before irradiation, P < 0.005). Extract of whole ginseng (P < 0.005), total saponin (P < 0.01) or panaxadiol (P < 0.05) administration before irradiation (50 mg/kg body weight IP at 12 and 36 hours before irradiation) resulted in an increase in the formation of the endogenous spleen colony. The frequency of radiation-induced apoptosis in the intestinal crypt cells was also reduced by pretreatment with extract of whole ginseng, total saponin and panaxadiol (Kim et al 2003c). These radioprotective effects are partly associated with the immunomodulatory effect of ginseng. Ginsan, a purified polysaccharide isolated from ginseng, has been shown to have a mitogenic activity, induce lymphokine-activated killer cells and increase levels of several cytokines. Ginsan reduced mutagenicity in a dose-dependent manner when applied to rats 30 min before or 15 min after 1.5 Gy of gamma irradiation. The radioprotective effect of ginsan has been partly attributed to a reduction in radiationinduced genotoxicity (Ivanova et al 2006). Ginsan has also been found to increase the number of bone marrow cells, spleen cells, granulocyte–macrophage colony-forming cells and circulating neutrophils, lymphocytes and platelets significantly in irradiated mice (Song et al 2003). One of the causes of radiation damage is lipid peroxidation, which alters lysosomal membrane permeability, leading to the release of hydrolytic enzymes. Ginseng has been shown to markedly inhibit lipid peroxidation and protect against radiation damage in testes of mice (Kumar et al 2003).

Antitumour, antiproliferative, antimetastatic and apoptosis inducing  Stimulation of the phagocytic activity of macrophages may play a role in the anticarcinogenic and antimetastatic activities demonstrated for ginseng in vivo (Shin et al 2004b), and research has continually found tumour-inhibitory effects, especially in the promotion and progression phases (Helms 2004). Ginsenosides Rg3, Rg5, Rk1, Rs5 and Rs4 have been shown to be cytotoxic to Hep-1 hepatoma cancer cells in vitro. Their 50% growth inhibition concentration (GI50) values were 41, 11, 13, 37 and 13 micromol/L, respectively. Cisplatin had a GI50 of 84 micromol/L in the same assay conditions (Park et al 2002a). Several triterpenoids found in the leaves have also demonstrated cytotoxic activity in vitro (Huang et al 2008). Constituents in ginseng have also been shown to inhibit proliferation of cancer cells. Panaxytriol isolated from red ginseng was shown to have a significant dose-dependent cytotoxic activity and inhibit DNA synthesis in various tumour cells tested (Kim et al 2002a). Ginsenoside Rg3 has displayed inhibitory activity against human prostate cancer cells in vitro (Liu et al 2000).   Ginsenosides, especially 20(R)-ginsenoside Rg3, have been shown to specifically inhibit cancer cell invasion and metastasis (Shibata 2001), and ginsenoside Rh2 has been shown to inhibit human ovarian cancer growth in mice (Nakata et al 1998). It is likely that the antitumour-promoting activity of Rg3 is mediated through down-regulation of NfkappaB and other transcription factors (Keum et al2003). Oral administration of 20(S)-protopanaxatriol (M4), the main bacterial metabolite of protopanaxatriol-type ginsenosides, has been shown to inhibit melanoma growth in mice, and pretreatment was shown to reduce metastases to the lungs. This effect is thought to be due to stimulation of NK-mediated tumour lysis (Hasegawa et al 2002). The antimetastatic effects of ginseng are related to inhibition of the adhesion and invasion of tumour cells and also to antiangiogenesis activity. Ginsenosides Rg3 and Rb2 have been shown to significantly inhibit adhesion of melanoma cells to fibronectin and laminin, as well as preventing invasion into the basement membrane in vitro. Other experiments have demonstrated that the saponins exert significant antiapoptotic activity, decreasing the number of blood vessels oriented towards the tumour mass (Mochizuki et al 1995, Sato et al 1994). Ginseng saponins have also been found to promote apoptosis (programmed cell death) in cancer cells in vitro (Hwang et al 2002).

Neurological

Analgesia Intraperitoneal administration of ginsenoside Rf has been shown to potentiate opioid-induced analgesia in mice. Furthermore, ginsenosides prevented tolerance to the opiate that was not associated with opioid or GABA receptors (Nemmani & Ramarao 2003).

Neuroprotection Ginseng saponins have demonstrated dose-dependent neuroprotective activity in vitro and in vivo (Kim et al 2005b). Ginsenosides Rb1 and Rg1 have a partial neurotrophic and neuroprotective role in dopaminergic cell cultures (Radad et al 2004), and Rg3 has been shown to inhibit chemically induced injuries in hippocampal neurons (Kim et al 2002b). Pretreatment with ginsenosides (50 or 100 mg/kg for 7 days) has been shown to be neuroprotective in vivo (Lee et al 2002a). An in-vitro survival assay demonstrated that ginsenosides Rb1 and Rg1 protect spinal cord neurons against damage. The ginsenosides protect spinal neurons from excitotoxicity induced by glutamate and kainic acid, as well as oxidative stress induced by H2O2. The optimal doses are 20–40 micromol/L for ginsenosides Rb1 and Rg1 (Liao et al 2002). The lipophilic fraction of ginseng has been shown to induce differentiation of neurons and promote neuronal survival in the rat cortex. The effect is thought to be mediated via protein kinase-C-dependent pathways (Mizumaki et al 2002). In-vitro studies have also suggested a benefit for ginseng in hypoxia-induced neuronal injury including ischaemia, trauma and degenerative diseases (Park et al 2007). Beneficial effects have yet to be demonstrated in clinical trials. It has been suggested that the neuroprotective effects of ginseng against hypoperfusion/reperfusion-induced brain injury demonstrated in animal models suggest a potential for use in cardiovascular (CVD) (Shah et al 2005).

Cognitive Function  Following oral consumption, the active metabolites of protopanaxadiol saponins may reactivate neuronal function in Alzheimer’s disease according to invivo evidence (Komatsu et al 2005). Ginseng also enhances the survival of newly generated neurons in the hippocampus, which may contribute to the purported benefits of ginseng for improving learning tasks (Qiao et al 2005).

Anticonvulsant Pretreatment (30 min) with 100 mg/kg ginseng significantly protected rats against pentylenetetrazoleinduced seizures (Gupta et al 2001).

Antidiabetic  Hypoglycaemic/antihyperglycaemic effects Human and animal studies have found American ginseng to lower blood glucose level (Vuksan et al 2000a, 2000b, 2000c, 2001a, 2001b). Results for Korean ginseng are less consistent (Sievenpiper et al 2003, 2004). Both ginseng root and berry (150 mg/kg) have been shown to significantly decrease fasting blood glucose levels in hyperglycaemic rats (Dey et al 2003). Intraperitoneal administration of glycans (polysaccharides known as panaxans) and other unidentified compounds has demonstrated hypoglycaemic activity in both normal and alloxaninduced hyperglycaemic mice (Waki et al 1982). Oral administration of P. ginseng root (125.0 mg/ kg) three times daily for 3 days reduced hyperglycaemia and improved insulin sensitivity in rats fed a high-fructose chow, suggesting a possible role in delaying or preventing insulin resistance (Liu et al 2005). However, these doses are very high, and human trials need to be conducted to confirm these results. Diabetic complications Aqueous extract of ginseng was shown to exert no significant effect on weight in normal rats, while it prevented weight loss in rats with streptozotocininduced diabetes. Cell proliferation in the dentate gyrus of diabetic rats was increased by ginseng treatment, but it had no effect on cell proliferation in normal rats. These results suggest that ginseng may help reduce the long-term central nervous system complications of diabetes mellitus (Lim et al 2002b). According to experimental studies, ginseng may also inhibit the formation of glycated haemoglobin due to its antioxidative activity (Bae & Lee 2004).

Steroid receptor activity  Ginseng has been shown to increase the mounting behaviour of male rats and increase sperm counts in rabbit testes. The effect is not by a direct sex hormone-like function, but probably via a gonadotropin- like action. Ginsenoside Rb1 has been shown to increase luteinising hormone (LH) secretion by acting directly on the anterior pituitary gland in male rats (Tsai et al 2003). Ginsenoside Rh1 failed to activate the glucocorticoid and androgen receptors, but did demonstrate an interaction with oestrogen receptors in vitro. The effect was much weaker than 17-beta-oestradiol. Ginseng is therefore considered to contain phyto-oestrogens (Lee et al 2003). However, there are conflicting reports about oestrogen-binding activity, which may in part be explained by the presence or absence of zearalenone, an oestrogenic mycotoxin contaminant (Gray et al 2004).

OTHER ACTIONS (Braun, L and Cohen, M. 2010)

Prevention of damage from toxins  Ginseng extract has been shown to be beneficial in the prevention and treatment of testicular damage induced by environmental pollutants. Dioxin is one of the most potent toxic environmental pollutants. Exposure to dioxin either in adulthood or during late fetal and early postnatal development causes a variety of adverse effects on the male reproductive system. The chemical decreases spermatogenesis and the ability to conceive and carry a pregnancy to full term. Pretreatment with 100 or 200 mg/ kg ginseng aqueous extract intraperitoneally for 28 days prevented toxic effects of dioxin in guinea pigs. There was no loss in body weight, testicular weight or damage to spermatogenesis (Kim 1999). In guinea pigs, P. ginseng also improves the survival and quality of sperm exposed dioxin (Hwang et al 2004).

Promoting haemopoiesis  Ginseng is traditionally used to treat anaemia. The total saponin fraction, and specifically Rg1 and Rb1, has been shown to promote haemopoiesis by stimulating proliferation of human granulocyte– macrophage progenitors (Niu et al 2001). The total saponins at a concentration of 50 microgram/mL most effectively promote CD34+ cells to proliferate and differentiate by cooperating with hematopoietic growth factors (Wang et al 2006).

Antioxidant  In-vitro studies did not find various extracts of ginseng to be particularly potent antioxidants against several different free radicals (Kim et al 2002c). However, animal models have demonstrated effects in type 2 diabetes (Ryu et al 2005), particularly for the leaf, which may suppress lipid peroxidation in diabetic rats (Jung et al 2005). Ginseng extract has also been shown to protect muscle from exerciseinduced oxidative stress in animal studies (Voces et al 2004). Whether these effects are directly due to the antioxidant activity of ginseng components or secondary to other mechanisms, such as blood glucose regulation, is unclear. Additionally, ginseng compounds may require in-vivo conversion to active metabolites in order to exert their full effects.

Hair growth  Red ginseng extract (more so than white ginseng), and especially ginsenoside Rb1 and 20(S)-ginsenoside Rg3, has been shown to promote hair growth in mouse hair follicles in vitro (Matsuda et al 2003).

Anti-allergic activity  Ginsenosides have been demonstrated to have antiallergic activity in vitro. One of the metabolites, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, was found to inhibit beta-hexosaminidase release from rat basophil leukaemia cells and potently reduce passive cutaneous anaphylaxis reaction. The inhibitory activity of protopanaxadiol was more potent than that of disodium cromoglycate, an anti-allergic drug. The compound stabilised membranes but had no effect on hyaluronidase and did not scavenge free radicals. These results suggest that the anti-allergic action of protopanaxadiol originates from its cell membrane-stabilising activity and that the ginsenosides are prodrugs with anti-allergic properties (Choo et al 2003).

Anxiolytic effects  Ginsenosides, and especially ginsenoside Rc, regulate GABA-A receptors in vitro (Choi et al 2003a), and animal models have demonstrated an anxiolytic effect for ginseng saponins (Park et al 2005a).

Wound healing  Ginsenoside Rb2 has been reported to improve wound healing. It is believed that ginsenoside Rb2 enhances epidermal cell proliferation by enhancing the expressions of protein factors related to cell proliferation, such as epidermal growth factor and fibronectin (and their receptors), keratin and collagenase (Choi 2002). Ginsenoside Re may also enhance tissue regeneration by inducing angiogenesis (Huang et al 2005). Topical application of ginseng root extract may also promote collagen production via type I procollagen synthesis, suggesting potential anti-wrinkle effects (Lee 2007).

Improves acne  In an animal model of acne, ginseng extracts reduced the size of comedones by altering keratinisation of the skin and desquamating horny cells in comedones. In a study of experimentally induced hyperkeratosis, ginseng reduced the accumulation of lipids in the epidermis by regulating enzymes associated with epidermal metabolism (Kim et al 1990).

Male fertility  Ginseng-treated rats exhibit a significant increase in sperm count and motility due to activation of cAMP-responsive element modulator in the testes (Park et al 2007).

CLINICAL USE (Braun, L and Cohen, M. 2010)

In the scientific arena, ginseng and the various ginsenosides are used in many forms and administered via various routes. This review will focus primarily on those methods commonly used in clinical practice.

Cancer prevention  The various anticancer actions of P. ginseng, as demonstrated in animal and in-vitro trials, support its use as an agent to prevent the development and progression of cancer. A 5-year prospective study of 4634 patients over 40 years of age found that ginseng reduced the relative risk of cancer by nearly 50% (Yun 1996). A retrospective study of 905 case-controlled pairs taking ginseng showed that ginseng intake reduced the risk of cancer by 44% (odds ratio equal to 0.56). The powdered and extract forms of ginseng were more effective than fresh sliced ginseng, juice or tea. The preventative effect was highly significant (P < 0.001). There was a significant decline in cancer occurrence with increasing ginseng intake (P < 0.05) (Yun & Choi 1990). Epidemiological studies in Korea strongly suggest that cultivated Korean ginseng is a non-organ-specific human cancer preventative agent. In case–control studies, odds ratios of cancer of the lip, oral cavity and pharynx, larynx, lung, oesophagus, stomach, liver, pancreas, ovary and colorectum were significantly reduced by ginseng use. The most active compounds are thought to be ginsenosides Rg3, Rg5 and Rh2 (Yun 2003). Ginseng polysaccharide (18 mg/day) has also been shown to be effective in improving immunological function and quality of life (QOL) in elderly patients with non-small cell lung cancer (Zhang et al 2004). Chemotherapy Overexpression of P-glycoprotein or multidrug resistance-associated protein may lead to multidrug resistance of cancer cells. Protopanaxatriol ginsenosides have been shown to sensitise cancer cells to chemotherapeutic agents in vitro by increasing the intracellular accumulation of the drugs through direct interaction with P-glycoprotein (Choi et al 2003b, Kim et al 2003a). The ginsenoside Rh2 possesses strong tumour inhibiting properties and sensitises multidrug-resistant breast cancer cells to paclitaxel (Jia et al 2004), and animal models demonstrate a synergistic antitumour effect for ginseng acidic polysaccharides and paclitaxel (Shin et al 2004a). Panax ginseng polysaccharide (12 mg IV daily) has also been trialled during treatment for ovarian cancer, and the authors suggest that it is ‘effective, safe and reliable for reducing the toxic effects of chemotherapy’ (Fu et al 2005). In a cohort of 1455 patients with breast cancer recruited to the Shanghai Breast Cancer Study, ginseng use prior to diagnosis was associated with a significantly reduced risk of death (adjusted hazard ratios 0.71; 95% confidence interval: 0.52–0.98). Use of the following diagnosis resulted in a dose-dependent improvement in QOL scores (especially for psychological and social wellbeing) (Cui et al 2006).

Diabetes  The putative effects of Korean ginseng on blood glucose and lipid regulation, oxidative stress and protein glycation suggest a possible role as an adjunctive therapy in the management of diabetes and diabetic complications. A double-blind, placebo-controlled study with 36 subjects found that 200 mg ginseng elevated mood, improved psychophysical performance, and reduced fasting blood glucose and body weight in patients with newly diagnosed type 2 diabetes (Sotaniemi et al 1995). A double-blind, randomised, dose-finding study reported that 2 g of Korean ginseng rootlets is sufficient to achieve reproducible reductions in postprandial glycaemia (Sievenpiper 2006), although studies using 200–400 mg have also demonstrated benefits for lowering fasting blood glucose levels (Reay et al 2006a). In a recent clinical trial, 19 participants with well-controlled type 2 diabetes (sex: 11 M:8 F, age: 64 ± 2 years, body mass index (BMI): 28.9 ± 1.4 kg/m2, HbA1c: 6.5%) received 2 g Korean ginseng 40 minutes prior to meals (total 6 g/day) for 12 weeks in addition to their usual antidiabetic therapy. While HbA1c levels remained unchanged, improvements were noted for plasma glucose (75 g-oral glucose tolerance test-plasma glucose (OGTT-PG) reduced by 8–11%), plasma insulin (PI) (fasting PI and 75 g-OGTT-PI reduced by 33–38%), and insulin sensitivity index (ISI) (75 g-OGTT-ISI increased by 33%) compared with placebo (P < 0.05) (Vuksan et al 2008).

Cardiovascular disease  A 2006 systematic review concluded that there is currently a lack of well-designed, randomised, controlled trials to support the use of ginseng to treat cardiovascular risk factors despite some studies suggesting improvements in blood pressure, blood glucose and lipid profiles (Buettner et al 2006). Although there are reports of ginseng causing hypertension, red ginseng is actually used as an antihypertensive agent in Korea. Acute administration of an aqueous preparation of Korean ginseng (100 mg/kg body weight) to 12 healthy, nonsmoking male volunteers resulted in an increase in NO levels and a concomitant reduction in mean blood pressure and heart rate (Han et al 2005). Ginseng is often used in practice as an adjuvant to both conventional and Complementary and Alternative Medicine (CAM) treatments. Trials have reported that 1.5 g three times daily of Korean red ginseng (4.5 g/day) is useful as an adjuvant to antihypertensive medication (Han et al 1995, 1998). It should be noted however that results in these trials while statistically significant (e.g. systolic pressure−5.7 mmHg) may not be clinically significant. A combination of red ginseng and digoxin was found to be more beneficial than either drug alone in an open study of advanced congestive heart failure. There were no adverse reactions (Ding et al 1995). A combination of ginseng and ginkgo extracts has been found to improve circulation and lower blood pressure in a controlled single-dose study of 10 healthy young volunteers (Kiesewetter et al 1992). Korean red ginseng has also been shown to improve vascular endothelial function in patients with hypertension. The effect is thought to be mediated through increasing the synthesis of nitric oxide (Sung et al 2000).

Hyperlipidaemia  In a small trial of eight males receiving 2 g Panax ginseng extract three times daily (total Panax ginseng extract (PGE) 6 g/day) for 8 weeks, serum total cholesterol, LDL and triglyceride concentrations were decreased by 12, 45 and 24%, respectively, and a 44% increase in HDL was reported (Kim & Park 2003).= Red ginseng, 1.5 g three times daily before meals for 7 days, reduced liver cholesterol, decreased the atherogenic index, and elevated HDL cholesterol in 11 patients (5 normal subjects and 6 with hyperlipidaemia). Serum cholesterol was not significantly altered, but serum triglycerides were significantly decreased (Yamamoto & Kumagai 1982).

Immunomodulation Ginseng has been shown to significantly enhance NK function in healthy subjects and in those suffering from chronic fatigue syndrome or AIDS (P < 0.01) (See et al 1997). Ginseng polysaccharide injection has been shown, in a randomised study, to improve immunity in 130 patients with nasopharyngeal carcinoma and to reduce adverse reactions to radiotherapy compared with controls (Xie et al 2001). Red ginseng powder has been shown to restore immunity after chemotherapy and reduce the recurrence of stage III gastric cancer. The 5-year disease-free survival and overall survival rates were significantly higher in patients taking the red ginseng powder during postoperative chemotherapy versus control (68.2 vs 33.3%, 76.4 vs 38.5%, respectively, P < 0.05). Despite the limitation of a small number of patients (n = 42), these findings suggest that red ginseng powder may help to improve postoperative survival in these patients. Additionally, red ginseng powder may have some immunomodulatory properties associated with CD3 and CD4 activity in patients with advanced gastric cancer during postoperative chemotherapy (Suh et al 2002). Vaccine adjuvant activity Ginseng extract (100 mg ginsan G115/day) improved the response to an influenza vaccine in a multicentre, randomised, double-blind, placebo-controlled, twoarm study of 227 subjects. Compared with vaccine without the ginseng, the addition of ginseng resulted in fewer cases of influenza and common cold. Ginseng increased NK activity and increased antibody production (Scaglione et al 1996). The addition of 2 mg ginseng dry extract per vaccine dose has been shown to potentiate the antibody response of commercial vaccines without altering their safety. The enhancing effect of ginseng was demonstrated during the vaccination of pigs against porcine parvovirus and Erysipelothrix rhusiopathiae infections using commercially available vaccines (Rivera et al 2003).

Cognitive function  There is some contention about the benefits of ginseng for improving memory, concentration and learning (Persson et al 2004). Well-controlled clinical trials are lacking, and variations in dosage and standardisation may affect study results. Some studies have demonstrated that ginseng improves the quality of memory and associated secondary memory (Kennedy et al 2001a). In a randomised, placebo-controlled, double-blind, balanced, crossover study of healthy, young adult volunteers, 400 mg ginseng was shown to improve secondary memory performance on a Cognitive Drug Research computerised assessment battery and two serial subtraction mental arithmetic tasks. Ginseng also improved attention and the speed of performing the memory tasks (Kennedy et al 2002). In a later double-blind, placebo-controlled, balanced, crossover study of 30 healthy young adults, acute administration of ginseng (400 mg) was again shown to improve speed of attention (Sunram-Lea et al 2005). In a double-blind, placebo-controlled study of healthy young subjects, ginseng extract (G115) improved accuracy and slowed responses during one of two computerised serial subtraction tests (Serial Sevens) and it was also shown to improve mood during these tasks (Kennedy et al 2001b). In acute dosing trials, a single dose of ginseng (200 mg G115 extract, with or without 25 g glucose) and glucose has been shown to enhance cognitive performance in healthy young adults. Participants experienced enhanced performance on a mental arithmetic task and a reduction in subjective feelings of mental fatigue during the later stages of the sustained, cognitively demanding task (Reay et al 2006b). In a double-blind, randomised, placebo-controlled 8–9-week trial, standardised ginseng extract 400 mg was found to significantly improve abstract thinking (P < 0.005) and reaction time (not significant) in 112 healthy subjects over 40 years of age. Ginseng was found not to affect concentration or memory (Sorensen & Sonne 1996). In a controlled open-label study, 97 consecutive patients with Alzheimer’s disease were randomly assigned to a treatment (n = 58) or control group (n = 39). The treatment group received Korean ginseng powder (4.5 g/day) for 12 weeks, which resulted in improvements in the cognitive subscale of Alzheimer’s disease assessment scale (ADAS) and the mini-mental state examination (MMSE) (P = 0.029 and P = 0.009 vs baseline, respectively). After discontinuing ginseng, the improved ADAS and MMSE scores declined to the levels of the control group (Lee 2008). In addition, similar trials using 0, 4.5 or 9 g ginseng daily found that patients in the high-dose group showed significant improvement on the ADAS and Clinical Dementia Rating after 12 weeks of ginseng therapy (P = 0.032 and 0.006, respectively). Improvements in MMSE did not reach statistical significance (Heo et al 2008). In clinical practice, Korean ginseng and Ginkgo biloba are frequently used in combination for cognitive benefits. Combining ginseng with ginkgo dramatically improves memory, concentration and speed of completing mental tasks (Kennedy et al 2001a, Scholey & Kennedy 2002). In clinical trials, ginseng directly modulates cerebroelectrical activity  on EEG recordings to a greater extent than Ginkgo biloba (Kennedy et al 2003). In a double-blind, placebo-controlled study, postmenopausal women aged 51–66 years were randomly assigned to 12 weeks’ treatment with a combination formula containing 120 mg Ginkgo biloba and 200 mg Panax ginseng (n = 30) or matched placebo (n = 27). The combination appeared to have no effect on mood or cognition after 6 and 12 weeks; however, these doses may be too low (Hartley et al 2004). According to other trials, it would appear that doses of 400–900 mg of ginseng are required for best results and 200 mg doses have been associated with ‘cognitive costs’, slowing performance on attention tasks (Kennedy & Scholey 2003).

Menopausal symptoms  Korean red ginseng is used to alleviate symptoms associated with menopause; 6 g ginseng for 30 days was shown in a small study of 20 women significantly (P < 0.001) to improve menopausal symptoms, in particular fatigue, insomnia and depression. The women treated had a significant decrease in cortisol and cortisol-to-dehydroepiandrosterone ratio (P < 0.05). No adverse effects were recorded (Tode et al 1999).

Erectile dysfunction  Korean red ginseng has been shown to alleviate erectile dysfunction and improve the ability to achieve and maintain erections even in patients with severe erectile dysfunction (Price & Gazewood 2003). Ginsenosides can facilitate penile erection by directly inducing the vasodilatation and relaxation of the penile corpus cavernosum. Moreover, the effects of ginseng on the corpus cavernosum appear to be mediated by the release and/or modification of release of NO from endothelial cells and perivascular nerves (Murphy & Lee 2002). In men with type 2 diabetes, oxidative stress has been suggested as a contributing factor to erectile dysfunction and animal studies suggest that ginseng can preserve ‘potency’ via its antioxidant effect (Ryu et al 2005). In a double-blind, placebo-controlled study, 60 patients presenting with mild or mild to moderate erectile dysfunction received 1 g (three times daily) of Korean ginseng or placebo. In the five-item International Index of Erectile Function (IIEF)-5,66.6% (20 patients) reported improved erection, rigidity, penetration and maintenance (P < 0.01) after 12 weeks. Serum testosterone, prolactin and cholesterol were not significantly different (de Andrade et al 2007). In a double-blind crossover study, 900 mg Korean red ginseng was found to significantly improve the Mean IIEF scores compared with placebo. Significant subjective improvements in penetration and maintenance were reported by participants, and penile tip rigidity on the RigiScan showed significant improvement for ginseng versus placebo (Hong et al 2002). A significant improvement in erectile function, sexual desire and intercourse satisfaction was demonstrated in 45 subjects following 8 weeks’ oral administration of Korean red ginseng (900 mg three times daily) in a double-blind, placebo-controlled, crossover trial. Subjects demonstrated significant improvement in mean IIEF scores compared with placebo (baseline, 28 ± 16.7; Korean red ginseng, 38.1 ± 16.6; placebo, 30.9 ± 15.7) (Hong et al 2003).

Quality of life  An 8-week, randomised, double-blind study found that 200 mg/day ginseng (n = 15, placebo: n = 15) improved aspects of mental health and social functioning after 4 weeks’ therapy but that these differences disappeared with continued use (Ellis & Reddy 2002). A review of eight clinical studies with ginseng found some improvement in QOL scores. However, the findings were equivocal. Despite some positive results, improvement in overall health-related QOL cannot, given the current research, be attributed to P. ginseng. However, the possibility that various facets of QOL may have improved and the potential of early transient effects cannot be discounted (Coleman et al 2003). A double-blind, placebo-controlled, randomised clinical trial of 83 subjects also did not find ginseng to enhance psychological wellbeing in healthy young adults (Cardinal & Engels 2001). A double-blind, placebo-controlled, crossover study found that 1200 mg ginseng was only slightly more effective than placebo and not as effective as a good night’s sleep in improving bodily feelings, mood and fatigue in 12 fatigued night nurses. Volunteers slept less and experienced less fatigue but rated sleep quality worse after ginseng administration (Hallstrom et al 1982). A recent double-blind, placebo-controlled, balanced, crossover design of 30 healthy young adults taking P. ginseng extract (200 or 400 mg) or placebo demonstrated improvements in performance and subjective feelings of mental fatigue during sustained mental activity. It has been hypothesised that this effect may be due in part to the ability of ginseng to regulate blood glucose levels (Reay et al 2005).

Adaptogenic and tonic effects A randomised double-blind study involving 232 subjects between the ages of 25 and 60 years found that extract equivalent to about 400 mg ginseng root for 4 weeks significantly improved fatigue. Side effects were uncommon, with only two subjects withdrawing from the study (Le Gal & Cathebras 1996). A randomised double-blind study of 83 subjects found that extract equivalent to 1 g ginseng root for 4 months decreased the risk of contracting a common cold or bronchitis and improved appetite, sleep, wellbeing and physical performance (Gianoli & Riebenfeld 1984).

Improved athletic performance  Ginseng is used by many athletes to improve stamina and to facilitate rapid recovery from injuries; however, supporting evidence from welldesigned clinical trials is lacking. To examine the effects of ginseng supplements on hormonal status following acute resistance exercise, eight male college students were randomly given water (control group) or 20 g ginseng root extract treatment immediately after a standardised training exercise. Human growth hormone, testosterone, cortisol and insulin-like growth factor 1 levels were determined by radioimmunoassay. The responses of plasma hormones following ginseng consumption were not significant between the control and the ginseng groups during the 2-hour recovery period (Youl et al 2002). Although ginseng is commonly used to improve endurance, a double-blind study of 19 healthy active women found that 400 mg of a ginseng extract (G115) did not improve supramaximal exercise performance or short-term recovery. Analysis of variance using pretest to posttest change scores revealed no significant difference between the ginseng and placebo study groups for the following variables measured: peak anaerobic power output, mean anaerobic power output, rate of fatigue and immediate postexercise recovery heart rates (Engels et al 2001). A recent study by the same authors also failed to find any benefit from ginseng (400 mg/ day G115; equivalent to 2 g P. ginseng C.A. Meyer root material for 8 weeks) on improving physical performance and heart rate recovery of individuals undergoing repeated bouts of exhausting exercise (Engels et al 2003). When 60 men from the Naval Medical Corps, Royal Thai Navy (aged 17–22 years), given 3 g/day of ginseng or placebo for an 8-week period, were measured for blood lactic acid levels for determination of lactate threshold (LT), no improvements were noted, nor was there any beneficial effect on physical performance (Kulaputana et al 2007). A small study of seven healthy male subjects given 2 g ginseng (three times daily) for 8 weeks reported a significant increase in exercise duration until exhaustion (+1.5 min; P < 0.05), which was related to improvements in lipid peroxidation and scavenger enzymes (Kim et al 2005); however, this study is too small to make generalisations.

OTHER USES (Braun, L and Cohen, M. 2010)

Gastroprotection during heart surgery In a trial of 24 children undergoing heart surgery for congenital heart defects, 12 children received 1.35 mg/kg ginsenoside compound or placebo intravenously before and throughout the course of cardiopulmonary bypass surgery. Ginseng administration resulted in attenuation of gastrointestinal injury and inflammation (Xia et al 2005).

Respiratory Disease  Ginseng extract (G115) has been shown significantly (P < 0.05) to improve pulmonary function test, maximum voluntary ventilation, maximum inspiratory pressure and maximal oxygen consumption (VO2max) in a study of 92 patients suffering moderately severe chronic obstructive pulmonary disease (n = 49, G115 100 mg twice daily for 3 months) (Gross et al 2002).

Helicobacter pylori  Helicobacter pylori can provoke gastric inflammation, ulceration and DNA damage, resulting in an increased risk of carcinogenesis (Park et al 2005b). As preliminary evidence suggests that P. ginseng inhibits the growth of H. pylori (Kim et al 2003b) and can inhibit adhesion (Lee et al 2004b), it may be useful as a gastroprotective agent against H. pylori-associated gastric mucosal cell damage (Park 2005b).

HIV Infection  Long-term intake of Korean ginseng slows the depletion of CD4+ T cells and may delay disease progression in people with HIV type 1 (Sung et al 2005). Ginseng intake in HIV-1-infected patients may also be associated with the occurrence of grossly deleted nef genes (gDeltanef ) (Cho et al 2006) and gross deletions (gDelta) in HIV-1 5’ LTR and gag regions (Cho & Jung 2008). Longterm intake (60 ± 15 months) has also been shown to delay the development of resistance mutation to zidovudine (Cho et al 2001).

SIDE-EFFECTS, TOXICITY, CONTRAINDICATION, WARNING, SIGNIFICANT INTERACTIONS

SIDE-EFFECTS, TOXICITY (Barnes, J et al., 2007)

CLINICAL DATA

There are only limited clinical data on safety aspects of E. senticosus preparations. No post-marketing surveillance-type studies were identified, and there are only a small number of clinical trials of E. senticosus, the majority of which are of poor methodological quality. Trials have assessed the effects of different E. senticosus preparations, including combination herbal preparations containing E. senticosus, 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, older patients with hypertension), making interpretation of the results difficult. The clinical trials of  E. senticosus root preparations available have typically involved only very small numbers of patients and been of short duration, so have the statistical power only to detect very common, acute adverse effects. Rigorous investigation of safety aspects of wellcharacterised E. senticosus root preparations administered orally at different dosages, including the effects of long-term treatment, is required.

In a randomised, double-blind, controlled trial in which 96 individuals with chronic fatigue received capsules containing a standardised extract of E. senticosus root providing 2.24 mg eleutherosides (B and E) daily, or placebo, the proportions of participants experiencing adverse effects were 24% and 28% for the E. senticosus and placebo groups, respectively.(15) After one month's treatment, adverse effects reported by the greatest proportions of E. senticosus and placebo recipients were headache (10% and 8%, respectively), breast tenderness (7% and 3%, respectively) and nervousness (7% and 3%, respectively). There were no statistically significant differences in changes in mean systolic and diastolic blood pressure measurements. The frequency of adverse effects was reported to be lower for both groups during the second month of treatment.

Other studies, which involved only small numbers of participants and which had other methodological flaws, have provided conflicting data on the effects of E. senticosus root preparations on blood pressure measurements. One randomised, double-blind, placebo-controlled trial of an E. senticosus dry extract 300 mg daily for eight weeks study involved 20 participants aged 65 years or more with hypertension and who were undergoing treatment with digitalis (not further specified);(56) it was stated that no statistically significant differences in blood pressure control and serum digoxin concentrations were observed, although supporting data were not provided. Further study of the effects of wellcharacterised preparations of E. senticosus root extracts on blood pressure in different patient groups is required.

Several other clinical trial reports either did not provide any data on frequency and type of adverse effects, or stated that no

adverse effects occurred during the study.

PRECLINICAL DATA (Barnes, J et al., 2007)

Results of various animal toxicity studies have indicated ginseng to be non-toxic.(5) Many species have been exposed to extracts Ginseng, Eleutherococcus including mice, rats, rabbits, dogs, minks, deer, lambs, and piglets.(5) Documented acute oral LD50 values for various preparations include: 23 mL/kg and 14.5 g/kg (mice), and greater than 20 mL/kg (dogs) for a 33% ethanolic extract;(5, 18) 31 g/kg (mice) for the powdered root; greater than 3 g/kg (mice) for an aqueous extract (equivalent to 25 g dried roots/kg).(18) No deaths occurred in mice administered single 3 g/kg doses of a freeze-dried aqueous extract.(59) Symptoms observed in dogs receiving 7.1 mL/ kg doses of an ethanolic extract (sedation, ataxia, loss of righting reflex, hypopnoea, tremors, increased salivation and vomiting) were attributed to the ethanol content of the extract.(5)

A chronic toxicity study reported no toxic manifestations or deaths in rats fed 5 mL/kg of an ethanolic extract for 320 days.(5) Teratogenicity studies in male and female rats, pregnant minks, rabbits and lambs have reported no abnormalities in the offspring and no adverse effects in the animals administered the extracts. Premature death in parent female rabbits fed 13.5 mL/kg ethanolic extract daily was attributed to ethanol intoxication.(5) Mutagenicity studies using Salmonella typhimurium TA100 and TA98, and the micronucleus test in mice have reported no activity for ginseng.(75) Differences in various serum biochemical parameters have been reported between test (ginseng) and control groups.(75) Parameters affected included alkaline phosphatase and gamma-glutamyl transferase enzymes (increased), serum triglycerides (decreased), and creatinine and blood urea nitrogen (increased).(75) No pathological changes were found in rats receiving a ginseng extract.(75)

CONTRA-INDICATIONS, WARNINGS (Barnes, J et al., 2007)

The Russian literature on E. senticosus includes several contraindications and warnings with respect to its use, although the scientific basis and evidence for many of these statements is not clear, and some contradict recent research. These Russian recommendations include the advice that ginseng should be avoided by premenopausal women, healthy individuals aged less than 40 years, and individuals who are highly energetic, nervous, tense, hysteric, manic or schizophrenic,(76) which at least appear to conflict with clinical research on the effects of E. senticosus preparations when taken by athletes (i.e. highly energetic individuals). It is also advised that E. senticosus should not be taken with stimulants, including coffee, antipsychotic drugs or during treatment with hormones, and that individuals considered suitable to use ginseng should abstain from alcoholic beverages, sexual activity, bitter substances and spicy foods during ginseng use.(76) It is also stated that E. senticosus is unsuitable for individuals with high blood pressure (180/90mmHg or greater).(5)

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 ginseng. Some clinical studies involving long-term administration of ginseng have involved ginseng-free periods of 2–3 weeks every 30–60 days.

Drug interactions In view of the constituents of E. senticosus, and the pharmacological actions of E. senticosus preparations and their isolated constituents described following preclinical and, to a lesser extent, clinical studies, the potential for preparations of E. senticosus to interfere with other medicines administered concurrently, particularly those with anticoagulant, hypoglycaemic and/or hypo/hypertensive activity, should be considered. A study involving healthy volunteers (n = 12) who received a preparation containing a standardised extract of E. senticosus root in addition to ground root material (one 485 mg capsule, containing approximately 2mg eleutheroside B and 4mg eleutheroside E, twice daily for 14 days) found that, at the end of the study, there were no statistically significant differences in the pharmacokinetic parameters of the cytochrome P4503A4 probe substrate dextromethorphan and of the CYP2D6 probe substrate alprazolam, when compared with baseline values. These findings suggest that this E. senticosus preparation administered according to this dosage regimen does not affect CYP3A4 and CYP2D6 activity.(77) There is an isolated report of raised serum digoxin concentrations in a 74-year-old man who had been taking digoxin for over ten years to control atrial fibrillation. His serum digoxin concentration had been stable during this time in the range 0.9 to 2.2 nmol/L, but at a routine check-up (day 0) was found to be 5.2 nmol/L and remained high for a further two weeks despite reductions in digoxin dose and, on day 10, cessation of digoxin treatment.(78) On day 26, the patient revealed he had been taking 'Siberian ginseng' capsules since the previous summer (duration of use not specified but was at least two months) and stopped taking the product that day. His serum digoxin concentration returned to within the normal therapeutic range by day 33 (seven days after stopping the ginseng product), and digoxin treatment was restarted. A positive rechallenge was reported during which the patient's serum digoxin concentration rose to 3.2 nmol/L 52 days after re-starting the ginseng product. Positive dechallenge occurred again with the serum digoxin concentration falling to 1.2 nmol/L six days after stopping ginseng treatment. It is not stated in the report whether the patient took the same or a different ginseng product during the second episode of use, and no analysis of the product(s) concerned was carried out. For this reason, the validity of the report has been questioned.(79) Some interference with a serum digoxin immunoassay (the fluorescence polarisation immunoassay) has been reported in vitro and in vivo (mice), leading to artificially raised measurements.(80)

Pregnancy and lactation Teratogenicity studies in various animal species have not reported any teratogenic effects for ginseng. However, in view of the many pharmacological actions documented for ginseng, the use of ginseng during both pregnancy and lactation should be avoided. It is unknown whether the pharmacologically active constituents in ginseng are secreted in the breast milk.

PREPARATIONS (Barnes, J et al., 2007)

Proprietary Single-Ingredient Preparations

Canada: Benylin Energy Boosting. Czech Republic: Eleutherosan. Germany: Eleu-Kokk; Eleu; Eleutheroforce; Eleutherokokk; Konstitutin. UK: Elagen.

Proprietary Multi-Ingredient Preparations

Argentina: Sigmafem. Australia: Astragalus Complex; Bacopa Complex; Bioglan Ginsynergy; Gingo A; Ginkgo Biloba Plus; Medinat Esten; Tyroseng. Spain: Energysor; Natusor Low Blood Pressure; Tonimax. USA: Energy Support; Menopause Support.

ADVERSE REACTIONS (Braun, L and Cohen, M. 2010)

Ginseng abuse syndrome (hypertension, nervousness, insomnia, morning diarrhoea, inability to concentrate and skin reactions) has been reported, and there has been a report of a 28-year-old woman who had a severe headache after ingesting a large quantity of ethanol-extracted ginseng. Cerebral angiograms showed ‘beading’ appearance in the anterior and posterior cerebral and superior cerebellar arteries, consistent with cerebral arteritis (Ryu & Chien 1995). High doses (15 g/day) have been associated with confusion, depression and depersonalisation in four patients (Coon & Ernst 2002).

However, the majority of the scientific data suggest that ginseng is rarely associated with adverse events or drug interactions. A systematic review found that the most commonly experienced adverse events are headache, sleep and gastrointestinal disorders. Data from clinical trials suggest that the incidence of adverse events with ginseng monopreparations is similar to that of placebo. Any documented effects are usually mild and transient. Combined preparations are more often associated with adverse events, but causal attribution is usually not possible (Coon & Ernst 2002).

Allergic reactions to Korean ginseng, including occupation asthma, may occur via an IgE-mediated mechanism (Kim 2008). A case of suspected ginseng allergy has recently been reported in the scientific literature. The case involved a 20-year-old male who developed urticaria, dyspnoea and hypotension after ingesting ginseng syrup. The subject recovered fully and was discharged after 24 h (Wiwanitkit & Taungjararuwinai 2004).

While ginseng use has been associated with the development of hypertension, it has actually been  shown to reduce blood pressure in several studies (Coon & Ernst 2002). Ginseng has very low toxicity. Subacute doses of 1.5–15 mg/kg of a 5:1 ginseng extract did not produce negative effect on body weight, food consumption, haematological or biochemical parameters or histological findings in dogs (Hess et al 1983), and no effects have been observed from the administration of similar doses in two generations of rat offspring (Hess et al 1982).

Traditionally, ginseng is not recommended with other stimulants such as caffeine and nicotine, and a case report exists of a 39-year-old female experiencing menometrorrhagia, arrhythmia and tachycardia after using oral and topical ginseng along with coffee and cigarettes (Kabalak et al 2004).

SIGNIFICANT INTERACTIONS (Braun, L and Cohen, M. 2010)

Albendazole  Panax ginseng significantly accelerated the intestinal clearance of the anthelmintic albendazole sulfoxide, when coadministered to rats (Merino et al 2003).

Alcohol Ginseng may increase the clearance of alcohol from the blood according to an open trial of 14 healthy volunteers (Coon & Ernst 2002) — beneficial interaction possible, but needs confirmation.

Chemotherapy, radiotherapy and general anaesthetics Preliminary evidence suggests that P. ginseng saponins may reduce nausea and vomiting associated with chemotherapy, radiotherapy and general anaesthetics by antagonising serotonin (5-hydroxytryptamine) type 3A receptors (Min et al 2003). Ginseng may also help to sensitise cancer cells to chemotherapeutic agents according to preliminary evidence.

Digoxin  Ginseng contains glycosides with structural similarities to digoxin, which may modestly interfere with digoxin results (Dasgupta et al 2003). These naturally occurring glycosides may cause false elevation of fluorescence polarisation and falsely low microparticle enzyme results, although Tina-quant results appear unaffected (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). There are no confirmed case reports of actual interaction (Chow et al 2003, Dasgupta et al 2003).

Drugs metabolised chiefly by CYP1A, CYP2D6 and CYP3A4 Mixed reports exist as to whether ginseng may act as an inhibitor of cytochrome CYP1A (Gurley et al 2005, Lee et al 2002b, Yu et al 2005) or CYP2D6 (Gurley et al 2005). Ginsenosides F1 and Rh1 (but not ginseng extract) may inhibit CYP3A4 at 10 micromolar (Etheridge et al 2007). Whether these effects are likely to be clinically significant has not been established. Observe for increased drug bioavailability and clinical effects.

Nifedipine  Ginseng increased the mean plasma concentration of the calcium channel blocker nifedipine by 53% at 30 minutes in an open trial of 22 healthy subjects. Effects at other time points were not reported (Smith et al 2001).

Vancomycin  In animal studies, the combination of ginseng polysaccharides with vancomycin resulted in a 100% survival rate for animals treated for Staphylococcus aureus compared to only 67 or 50% survival in animals treated with ginseng polysaccharides or vancomycin alone (Lim et al 2002b). A beneficial additive effect is possible, but clinical use in humans has not yet been established.

Warfarin  No effects on the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin were revealed in an open-label, crossover randomised trial of 12 healthy male subjects who received a single 25-mg dose of warfarin alone or after 7 days’ pretreatment with ginseng (Jiang et al 2004). Whether these effects are consistent in less ‘healthy’ people likely to be taking warfarin or for prolonged concurrent use is unclear. There have been two case reports of ginseng reducing the antithrombotic effects of warfarin (Janetzky & Morreale 1997, Rosado 2003). Additionally, it inhibits platelet aggregation according to both in vitro and animal studies. Avoid using this combination unless under medical supervision to monitor antithrombotic effects.

Zidovudine  Long-term intake (60 ± 15 months) of Korean red ginseng in HIV-1-infected patients has been shown to delay the development of resistance mutation to zidovudine (Cho et al 2001).

CONTRAINDICATIONS AND PRECAUTIONS (Braun, L and Cohen, M. 2010)

Korean ginseng is generally contraindicated in acute infections with fever and in persons who are very hot, tense and overly stimulated. Overuse may result in headache, insomnia and palpitation (Bensky & Gamble 1986). Ginseng should not be taken concurrently with other stimulants including caffeine and should be discontinued 1 week before major surgery. Use in hypertension should be supervised; however, it may prove beneficial for this indication.

PREGNANCY USE (Braun, L and Cohen, M. 2010)

Ginseng is traditionally used in Korea as a tonic during pregnancy. Commission E does not list any restrictions (Blumenthal 2001). There is in-vitro evidence of teratogenicity based on exposure to isolated ginsenosides (especially Rb1) (Chan et al 2003) at much higher levels than achievable through normal consumption in humans and conflicting evidence as to its oestrogenic properties. In light of the lack of good clinical evidence, Korean ginseng should be used cautiously during pregnancy (especially the first trimester) and lactation until more data are available (Seely et al 2008). In a two-generation rat study, a ginseng extract fed at doses as high as 15 mg/kg/day did not produce adverse effects on reproductive performance, including embryo development and lactation (Hess et al 1982).

PATIENTS’ FAQs (Braun, L and Cohen, M. 2010)

What will this herb do for me? Ginseng is a safe herb used to support the body during times of prolonged stress or chronic disease and to restore mental and physical functioning during the rehabilitative process. Numerous studies have identified a range of pharmacological activities that suggest that it may be useful in the treatment of many conditions.

When will it start to work? In practice, it generally appears that ginseng has a quick onset of action with the condition continuing to improve with long-term use; however, this will vary depending on the individual and the indication.

Are there any safety issues? Ginseng may interact with warfarin and other blood-thinning drugs and should not be used with these medications, unless under medical supervision. Avoid use in children or in hypertension, unless under supervision. Use with caution in pregnancy.

PRACTICE POINTS/PATIENT COUNSELLING (Braun, L and Cohen, M. 2010)

Traditional use

Ginseng is traditionally used for deficiency of Qi (energy/life force) manifested by shallow respiration, shortness of breath, cold limbs, profuse sweating and a weak pulse (such as may occur from severe blood loss). Ginseng is also used for wheezing, lethargy, lack of appetite, abdominal distension and chronic diarrhoea. Ginseng may also be used for palpitations, anxiety, insomnia, forgetfulness and restlessness associated with low energy and anaemia (Bensky & Gamble 1986)

Scientific evidence

There is some scientific evidence for the beneficial effects of ginseng for the following conditions. In practice, it is mostly used as a supportive treatment and combined with other herbs to treat a specific condition.

·         Prevention and supportive treatment of cancer

·         Chronic immune deficiency

·         Menopausal symptoms

·         Erectile dysfunction

·         Chronic respiratory disease

·         Enhancement of psychomotor activity, memory and concentration

·         Adaptogenic effects in any chronic condition and for the elderly and infirm

·         Type 1 diabetes

·         Cardiovascular disease (the effects on hypertension remain to be fully investigated)

·         QOL (equivocal scientific support) Commission E recommends ginseng as a tonic for invigoration and fortification in times of fatigue, debility and convalescence or declining capacity for work and concentration. The World Health Organization suggests  that ginseng can be used as a prophylactic and restorative agent for enhancement of mental and physical capacities, in cases of weakness, exhaustion, tiredness and loss of concentration and during convalescence (Blumenthal 2001).

EXTRACTS (SIBERIAN GINSENG) (Duke, J. A et al., 2002)

33% ethanolic extract LD50 = >20 ml/kg orl dog, LD50 = 23 ml/kg orl mus, LD50 = 14,500 mg/kg orl mus. Powdered root LD50 = 31,000 mg/kg orl mus, aqueous extract LD50 = 3000 mg/kg orl mus (CAN). According to Pedersen’s unreferenced book, Siberian ginseng, with aerobic exercise, mobilizes and activates natural killer cells for up to 24 hours, while with exercise alone, they are mobilized for only 2 hours and never activate (PED). Russian studies report amphoteric activity, impeding both hypertrophy and atrophy of the adrenals and thyroid glands; hypoglycemic activity in people with hyperglycemia, and hyperglycemic activity in those with hypoglycemia; it also has a normalizing action in both leukocytosis and leukopenia. Eleutheranes A-G immunostimulant. Liquid extracts increase lymphocyte count, especially T lymphocytes.

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.