Ginseng for cancer-related fatigue

Scientific name/commonly used name

Scientific names: 1. Panax ginseng C.A. Meyer and 2. Panax quinquefolius L.
Common names: 1. Asian ginseng and 2. American ginseng

The genus Panax

The genus Panax (C. Linnaeus) belongs to the family Araliaceae or ivy plants. From a medical point of view the most important species are Panax ginseng C.A. Meyer and P. quinquefolius L. Additionally, numerous other Panax species exist. In colloquial terms plants of other genera such as, for instance, Eleutherococcus senticosus and Pfaffia paniculata are labelled as “Siberian ginseng” and “Brazilian ginseng” respectively. As a result of a farm bill passed by the US Congress, the FDA ruled that the term "ginseng" could only be associated with the genus Panax - with an appendage instigated by the American Ginseng Growers Association, directed mainly against marketing of so-called "Siberian ginseng".1 P. ginseng and P. quinquefolius are practically the only cultivated species. Especially crème-colored roots are being used for medical purposes. Ginseng roots consist of the primary root, lateral roots and rootlets (hair roots) usually harvested at 4-7 years old.1 In countries such as Canada and South Korea ginseng is sometimes harvested earlier to obviate extensive fungal deterioration.

Main substances

Ginseng roots contain a complex multi-component mixture. The putative main active compounds are ginsenosides, triterpene glycosides, which are saponins, a class of secondary metabolites prevalently found in the plant kingdom.2 Ginsenosides are bitter-tasting, surface active, glycosidic compounds. Through sour or enzymatic hydrolysis they are converted to a triterpene part, the so-called aglycone, and a sugar part. The sugar proportion consists of chains of multiple monosaccharides variously linked to the aglycone.3,4 In chromatography, ginsenosides are labeled with letters and index numbers according to their rate of elution (e.g. Ra1, Rb1, Rg1). So far 38 different types of ginsenosides have been described from P. ginseng and 19 from P. quinquefolius.3 Quantitatively, Rg1 and Rb1 have the greatest significance and are thus labeled as the main ginsenosides. P. ginseng contains more Rg1 than does P. quinquefolius.3,5 Depending on the section of the root, the age of the plant and the manufacturing process (e.g. red or white ginseng), the content and composition of the ginsenosides can vary considerably.4,6,7 The content of ginsenosides is considered to be the quality measurement of a ginseng root: the more variability in content of various types of ginsenosides and the larger quantities of the individual ginsenosides there are, the higher the quality (and the cost) of the root.8 Apart from the ginsenosides, the ginseng root also contains a number of additional substances, including polysaccharides, fatty acids, vitamins, essential oils, trace elements, amino acids.4,8 Ginsan, which is a polysaccharide, has shown to have immunomodulatory effects.9

History / providers

For thousands of years P. ginseng has been regarded in Asia as a panacea, promoting health and longevity.1 At the beginning of the 18th century the Jesuit father Lafitau discovered P. quinquefolius just outside present day Montreal. The plant has been used for hundreds of years by native Americans as a medicinal plant.10 Both ginseng species are still quite extensively used.

Nowadays P. quinquefolius is mainly cultivated in some parts of Canada, in a number of states in the U.S., predominantly Wisconsin and New York, and now also in China. P. ginseng is mainly produced in South Korea, with an annual production of more than 11 thousand tons.8 Apart from being cultivated in their countries of origin, P. ginseng and P. quinquefolius are also grown in many other countries (notably Australia and Germany) and are currently some of the most popular herbal products. Ginseng products which are advertised for healing purposes can be purchased almost anywhere, for instance, at chemists’, in health food stores, drug stores and over the Internet. Ginseng preparations differ in their composition, preservative agents and binding agents.8 This makes it particularly difficult to compare products with one another. Additionally, ginseng can also be found in other products, such as cosmetics, food supplements, teas and soft drinks.

Claims of efficacy / mechanisms of action / claimed indications

Ginseng is used as a tonic for strengthening and invigoration in cases of fatigue and weakness as well as in reduced performance and concentration,11 which also is in accordance with its traditional use in Asian medicine.12,13 From a phytopharmacological point of view, the ginsenosides, particularly Rg1 and Rb1, as well as their metabolites which are produced in the gastrointestinal tract, are thought to be the active agents.3,13,14 Some of the effects possibly result from a modulation of the hypothalamus-pituitary axis or of the central monoamine neurotransmitter system.15 However, ginsenosides have also shown differential effects: Rg1 might work as a stimulant, whereas Rb1 might have more inhibitory effects on functions of the central nervous system.4,16,17 It is, as for other multicomponent herbal extracts, unclear as to what extent the different ginsenosides play a part in ginseng’s overall mechanism of action.8 In Traditional Chinese Medicine, ginseng has been used for thousands of years for balancing what is referred to as the so-called yin-yang equilibrium. P. ginseng is supposed to act as a “warming” substance and thereby strengthen what in Chinese Medicine is called “Yang”; whereas P. quinquefolius is claimed to have a “cooling” effect and strengthens “Yin”.12,18 This could possibly be explained by P. quinquefolius having higher concentrations of ginsenosides. P. ginseng however, possesses a greater variety of ginsenosides.10

Pharmacological aspects

Ginsenosides are deglycosylated in stages in the digestive tract and their metabolites seem to be more active than the ginsonosides themselves.19 Depending on the individual intestinal flora this biotransformation process takes its course to varying degrees.20 Generally, fractions of ginsenosides, which are partly still glycosylated, are resorbed and are bound to serum albumin in the blood.6,7 As a whole, resorption and bioavailability of the ginsenosides after oral consumption are low.10,19 For instance, the latter amounts to 0.1-4% for Rb1 and 2-18% for Rg.19 The elimination of the ginsenosides occurs after attachment to glucuron acid via urine and stool.

Application

Ginseng is one of the most consumed plant products worldwide.8 For healing purposes, the roots are primarily used (primary root, lateral roots and rootlets hair roots) – and mostly as dried powders or extracts. Recommendations for dosage vary from country to country, also within Europe. In Germany a daily dosage of 1-2 g of dried root with a minimum content of 1.5% ginsenosides is recommended (= 1.5g per 100g dried root, calculated for ginsenoside Rg1), which equals 15–30 mg ginsenosides per day.7 In Asian countries, dosage recommendations are much higher than in Europe, the Chinese pharmacopeia for instance recommends 3-9 g root and thus a daily dosage of 45-136 mg ginsenosides. Ginseng is supposed to be consumed 1-2 times daily with plenty of liquid. It is recommended that its application is interrupted after 3 months for a certain period of time.

For therapeutic use of P. quinquefolius for cancer-related fatigue, dosage recommendations are available from clinical studies. These range from 750 mg to 2.000 mg per day.21,22

Shelf life / storage

Ginseng root needs to be kept away from light and humidity and must be stored in air-tight containers. Its shelf life is at least one year. For ginseng products such as capsules and tablets, specified expiry dates apply.

Aspects of pharmaceutical drug and law regulations

The content of ginsenosides according to the European Pharmacopoeia has to be 6.0–12.0% of the sum of ginsenosides (Rb1, Rb2, Rc, Rd, Re Rf, Rg1 and Rg2) expressed as ginsenosides Rb1 (dried extract).23 In Germany for instance, P. ginseng has been licensed as an over-the-counter (OTC) drug by the Federal Institute for Pharmaceuticals (Bundesinstitut für Arzneimittel, BfArm). For those OTC drugs licensed in Germany a minimum content of 1.5% ginsenosides is required.

Costs and expenditures

Costs vary depending on the quality of the ginseng. Daily costs for drugs licensed in Germany amount to approximately 1-3 Euros.

Clinical studies

For the assessment of its clinical efficacy for cancer-related fatigue, results from two RCTs are currently available.21,22

Younus et al. published the results of a small, placebo-controlled pilot study of 20 patients (11 on P.ginseng and 9 on placebo), which so far is only available in abstract form.22 The total fatigue level and the average fatigue value over the last 24 hours (assessed with the Brief Fatigue Inventory), significantly improved in the Ginseng arm. Improvement has also been shown in the QLQ-C 30. According to these results P. ginseng seems to improve cancer-related fatigue during chemotherapy and the researchers also note that it was well tolerated.

In another pilot study of 282 patients with a variety of cancer types the efficacy of P.quinquefolius was tested for cancer-related fatigue in three different dosages and compared with a placebo arm.21 The authors reported a noticeable improvement of fatigue and quality of life in patients treated with 1000 mg and 2000 mg of the powdered root. On the “Brief Fatigue Inventory” scores improved after 8 weeks for activity interference and usual fatigue, and on the vitality scale of the quality of life questionnaire (SF-36) patients in the placebo group had a mean score of 7.3 compared to 14.6 in the 1000 mg ginseng group and 10.5 in the 2000 mg group. However, it must be noted that this study was designed as a pilot trial and was not powered to detect differences between the groups. The observed adverse effects caused by P.quinquefolius were altogether of minor nature. A study aimed at confirming these results is currently recruiting patients (NCCTG Trial N07C2, National Cancer Institute). A third RCT was stopped prematurely for methodological reasons.24

Pre-clinical studies

There are suggestions from animal experiments that the ginsenosides Rg1 and Rb1 can lead to an increase of the oxygen-dependent stamina performance.25

Toxicity

After in vitro and intravenous application ginsenosides have a hemolytic effect, as in fact do all saponins. This is why for a long time saponins were generally labeled to be toxic. However, due to the low bioavailability of these agents there is only a small risk for haemolysis in humans after consumption of food rich in saponins.4 In mice the LD50 (median lethal dose) for individual ginsenosides is between 300 and 1300 mg/kg, which clearly lies above the dosages which are suggested for application in humans (~15-30 mg ginsenosides).4 Long-term studies in animals (up to 6 months) did not indicate any chronic toxicity.35 Findings from animal studies suggest antimutagenic effects of ginsan, a polysaccharide extracted from P. ginseng. There is evidence of teratogenicity with exposure to ginsenosides, but data are derived from animal studies and are based on exposure to isolated ginsenosides at much higher levels than achievable through normal consumption in humans.26,27

Contraindications/precautions / warnings

There are no strict contraindications for the use of ginseng. Ginseng might induce hypoglycemia and therefore caution is usually warranted in diabetes patients. In schizophrenia, hypertension, arrhythmia, cardiovascular and cerebrovascular disease, and insomnia, ginseng might worsen the conditions, especially when used over a longer period of time.12,28 Ginsenosides are suggested to have estrogenic activity, however, the relevance of these in-vitro finding for e.g. women with hormone sensitive conditions remains to be determined.29,30 Data from a pilot trial suggested no safety issues in children and adolescents.31 Little reliable data is available for the consumption of P. ginseng and P. quinquefolius during pregnancy and lactation, especially during the first trimester.26

Adverse effects

Preparations from P. ginseng and P. quinquefolius are universally described as causing only minor if any adverse effects.12 Minor and easily reversible, undesirable effects include headaches, sleep disturbances and gastrointestinal intolerance.32 The FDA has added P. quinquefolius on the GRAS (generally recognised as safe) list. Serious adverse effects are rare and have only been reported from countries where ginseng is being used as an unregulated food supplement and where it is consumed in high dosage. Additionally, combined preparations with P. ginseng seem to produce more adverse effects than monopreparations.6 Recently, a case was reported of a female patient who developed prolonged QT with subsequent torsades de pointes during periods in which she had ingested large amounts of ginseng.33

Interactions

The literature indicates possible interactions between ginseng preparations and MAO inhibitors, Warfarin and antidiabetics.32,34-36 Gurley et al. showed an inhibitory effect of P. ginseng on CYP2D6 but they estimate the extent of the inhibition as clinically irrelevant.37 Inhibitory effects on the cytochrome-isoenzymes 1A2, 2B1, 2E1, 3A4 and 3A23 do not occur.37-39 The effects of ginsenosides on ABC-transporter proteins lets one assume that the former can counteract a multidrug resistency.40,41

Quality problems

The content of ginsenosides is seen as a measurement of the quality of a ginseng root. Preferably, the plant is harvested once at 4-7 years old and all parts of the root (primary root, lateral roots and rootlets including their peel) are processed. Quality varies among these factors affecting ginsenoside content and deficiency is to be expected when this is being deviated from due to time and cost constraints.7 Unlike earlier reviews, a current test of 21 commonly sold ginseng products found that none of them was contaminated with pesticides but one product had lead contamination and three products failed to contain their claimed or minimum expected amounts of ginsenosides.42