Ginseng

Scientific Name(s): Panax ginseng C.A. Meyer or Panax quinquefolius L. Family: Araliaceae (ginseng)

Common Name(s): P. ginseng : radix ginseng , Asian ginseng , Chinese ginseng , Korean ginseng , or Oriental ginseng ; P. quinquefolius : American ginseng or Canadian ginseng

Uses

Ginseng root is widely used for its adaptogenic, immunomodulatory, antineoplastic, cardiovascular, CNS, endocrine, and ergogenic effects, but these uses have not been confirmed by clinical trials.

Dosing

According to the Complete German Commission E Monographs , crude preparations of dried root powder 1 to 2 g can be taken daily for up to 3 months. In numerous clinical trials, the dosage of crude root has ranged from 0.5 to 3 g/day and the dose of extracts has generally ranged from 100 to 400 mg.

Contraindications

Contraindications have not been established aside from known hypersensitivity.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Limited evidence exists for any established interactions, with most data derived from laboratory studies and healthy volunteers. Very few case reports exist; however, exercise caution when using the following medicines: antidiabetic drugs/insulin, antipsychotic drugs, caffeine and other stimulants, furosemide, imatinib, monoamine oxidase inhibitors (MAOIs), and nifedipine. Interactions with warfarin and antiviral drugs are conflicting.

Adverse Reactions

It is estimated that more than 6 million people ingest ginseng regularly in the United States. There have been few reports of severe reactions and a very low incidence of adverse events has been reported in clinical trials. Hypersensitivity and anaphylaxis have been reported. Inappropriate use of P. ginseng or ginseng abuse syndrome includes symptoms such as hypertension, diarrhea, sleeplessness, mastalgia, skin rash, confusion, and depression.

Toxicology

None known.

Botany

Ginseng commonly refers to P. quinquefolius L. or P. ginseng C.A. Meyer, 2 members of the family Araliaceae. Several other species are less commonly used in Asia. The ginsengs were classified as members of the genus Aralia in older texts. In the eastern and central United States and Canada, P. quinquefolius is found in rich, cool woods; a large crop is grown commercially in Wisconsin. The Asian species P. ginseng is cultivated in Korea and China. The short plant grows 3 to 7 compound leaves that drop in the fall and bears a cluster of red or yellowish fruits from June to July. The shape of the root can vary depending on the species and has been used to distinguish types of ginseng. Medicinally, the root is considered the most valuable part of the plant in providing the pharmacologically active ginsenosides. Ginsenoside content varies with the age of the root, season of harvest, and method of preservation. While at least 4 ginsenosides are detectable in most young roots, this number more than doubles after 6 years of growth. High-quality ginseng is generally collected in the fall after 5 to 6 years of growth. 1 , 2

P. ginseng should not be confused with Siberian ginseng ( Eleutherococcus senticosus ), a related species with different chemistry. 1

History

Ginseng is perhaps the most widely recognized plant used in traditional medicine and now plays a major role in the herbal health care market. For more than 2,000 years, various forms have been used medicinally. The name Panax derives from the Greek word for “all healing,” and its properties have been so touted. Ginseng root's man-shaped figure (shen-seng means “man-root”) led proponents of the doctrine of signatures, an ancient European herbalists philosophy, to believe that the root could strengthen any part of the body. Through the ages, the root has been used in the treatment of asthenia, atherosclerosis, blood and bleeding disorders, and colitis, as well as to relieve the effects of aging, cancer, and senility.

Evidence of the root's general strengthening effect has been examined for its ability to raise mental and physical capacity, as well as its protectant effect against diabetes, neurosis, radiation sickness, and some cancers. Today, its popularity is widely due to the adaptogenic or stress-protective effect of the saponins. 3 , 4

Chemistry

Major compounds in ginseng include triterpene saponins, polyacetylenes, sequiterpenes, polysaccharides, peptidoglycans, nitrogen-containing compounds, and other compounds, including fatty acids, carbohydrates, and phenolic compounds. 2 , 5 , 6 The triterpene saponins are considered the most active compounds, and some estimates report up to 150 different ginsenosides, grouped into either dammarane or oleanane groups. 6 Many analytical methods have been described and standards published. The European Pharmacopoeia requires a minimum of 0.4% combined Rg1 and Rb1 ginsenosides, while the Chinese Pharmacopoeia requires ginseng radix (dry root) to have not less than 0.3% Rg1 and Re combined ginsenosides and not less than 0.2% Rb1. 5

Most traditional ginseng herbal preparations contain ginsenosides. However, a commercially available product, known as CVT-E002, a patented aqueous extract of approximately 80% to 90% poly-furanosyl-pyranosyl-saccharides from the roots of North American ginseng ( P. quinquefolius ), does not contain ginsenosides. 7 Adulterants are commonly found in ginseng preparations due to the high cost of authentic ginseng roots, and the presence of natural methylxanthines may also contribute to some reported physiological effects. 6 , 7 , 8

Variances in cultivation and processing methods, as well as the individual genetics of each plant source, result in varying chemical compositions among commercial products. This may contribute to the lack of consensus among studies on the pharmacology and efficacy of ginseng and should be considered when conducting and interpreting research. 2 , 9 A second factor that may have produced erratic results is the discovery that ginsenosides are metabolized extensively by the human gut microflora and that some of the metabolites are pharmacologically active. Colonic bacteria can remove the 3 sugars from ginsenoside Rb1 in stepwise fashion, and the deglycosylated compounds are then esterified in the liver with the fatty acids stearic, palmitic, and oleic acid. These esters persist in the liver for as long as 24 hours. 10 Thus, differences in an individual's gut flora may lead to differing pharmacological responses to ginseng preparations.

Uses and Pharmacology

Reviews of the effects of ginseng have been published. Most studies have used whole-root preparations, with considerable variations due to uncertain species identification, age of the roots, and curing process used. Variations in saponins between the species also may contribute to the lack of consensus among researchers on ginseng's pharmacology. 2 , 6 , 11

Cancer
Animal data

Both ginsenosides and polyacetylenes have demonstrated anticarcinogenic effects in vitro, including direct cytotoxic and growth inhibitory effects, induction of differentiation, and inhibition of metastasis. High concentrations of M1, an active metabolite of Rb1, Rb2, and Rc, induced cell death of mouse melanoma cells by regulating proteins involved in apoptosis. Ginsenosides Rh2 and Rh3 induced differentiation of promyelocytic leukemia cells into granulocytes; Rg3 inhibited adhesion and invasion of melanoma cells and decreased pulmonary metastasis. 6 , 12 , 13

Clinical data

Epidemiological data support a protective effect of ginseng on nonspecific organ cancers. 6 , 14 A long-term study of ginseng 1 g taken weekly for 3 years among adults with long-term atrophic gastritis showed no effect on the overall relative risk of cancer. In the male subgroup analysis, there was a reduction in the risk of non–organ-specific cancers. 14

Trials evaluating the effect of ginseng (both P. quinquefolius and P. ginseng ) on cancer-related fatigue at doses of 1 to 2 g/day over 8 to 12 weeks have shown effects for some, but not all, aspects of mental and physical functioning. 15 , 16 Ginseng may improve some of the adverse effects of chemotherapy-related transcatheter arterial chemoembolization. 17

Cardiovascular effects

Ginseng saponins have been reported to act as selective calcium antagonists and enhance the release of nitric oxide from endothelial and neuronal cells. In vitro studies have shown that total ginseng saponins extracted from Panax notoginseng and P. quinquefolius inhibited calcium entry through receptor-operated calcium channels without affecting calcium entry through voltage channels or intracellular calcium release. 6 , 18

Animal data

In studies involving rabbits and dogs, ginsenosides Ro and Rb from P. ginseng offered a protective effect in myocardial ischemia and reperfusion injuries. This effect may be partly mediated by increased release of prostacyclin and by activation of nitric oxide synthase and subsequent release of nitric oxide. An inhibitory effect on platelet aggregation and on the conversion of fibrinogen to fibrin has been demonstrated, and the prevention of atheroma in rabbits fed a high-cholesterol diet has been observed. 6 , 19

Clinical data

Clinical trials evaluating the effect of ginseng on the cardiovascular system are limited. Hypotensive and hypertensive effects have been postulated. In a short-term study in healthy adults, ginseng 3 g had no effect on blood pressure but lowered the arterial augmentation index, 20 while a 12-week study among hypertensive adults found no effect of ginseng on 24-hour blood pressure or on renal function. 21 Shenfu injection, a mixture of ginseng and monkshood, has been used to prevent reperfusion injury following mitral valve replacement. 22 Sanchi ( P. notoginseng ) is widely used in traditional Chinese medicine in acute ischemic stroke. The saponins in sanchi are similar to those found in P. ginseng and are classified as dammarane saponins (Rb1 and Rg1 primarily). A review of clinical trials found limited evidence of effect of sanchi on short-term effects of ischemic stroke, but noted that the trials were of limited methodological quality. 23

CNS effects

Rb1 and Rg1 appear to play a major role in CNS stimulatory and inhibitory effects and may modulate neurotransmitters. Cholinergic activity, implicated in mediating learning and memory processes, is affected by certain ginsenosides. Antioxidant, anti-inflammatory, antiapoptotic, and immune stimulatory effects are suggested to contribute to a protective effect in neurodegenerative disorders. 24

Animal data

Animal studies show that Rb1, Rg1, and Re prevent scopolamine-induced memory deficits, and that Rb1 and Rg1 appear to increase central choline uptake and facilitate the release of acetylcholine from hippocampal tissues. Results from a study in aged rats suggest that daily oral administration of P. ginseng extract 8 g/kg/day for 12 days improved learning performance. In animal tissues, ginseng extract inhibited gamma-aminobutyric acid (GABA), glutamine, dopamine, noradrenalin, and serotonin uptake in a concentration-dependent manner. 6 , 24 , 25 , 26

Clinical data

Limited high-quality clinical trials have been conducted, and systematic reviews include data from very few studies. 11 , 27 An anxiolytic effect via GABA modulation was suggested to be responsible for an observed improvement in sleep disorders for fermented ginseng. 28 Among healthy adults, short-term effects of P. ginseng and P. quinquefolius include increased mental performance, increased calmness, and decreased mental fatigue. 29 , 30 , 31 A review of the effect of ginseng on cognitive function in Alzheimer disease found an effect in favor of ginseng for the mini-mental status examination and Alzheimer Disease Assessment Scale for the 2 included studies. 27 , 32

Diabetes
Animal data

Widespread usage of ginseng and the availability of limited clinical trial data make animal studies largely redundant.

Evidence appears to support the modulation of insulin sensitization and secretion based on cholinergic, dopaminergic, adrenergic, and nitric oxide actions found with ginsenosides. These have been noted to affect glucose metabolism in animal studies. 24 , 33 , 34

Clinical data

Limited quality clinical trials have been conducted among adults with diabetes, with the majority of studies evaluating ginseng in healthy volunteers. Improvements in blood glucose measures and glycemic control have been reported in some, 33 , 34 , 35 , 36 , 37 but not all, 31 , 38 , 39 studies.

Ergogenic effects
Animal data

Widespread usage of ginseng and the availability of limited clinical trial data make animal studies largely redundant.

Clinical data

Evidence supporting the efficacy of ginseng in improving physical performance is conflicting. Physical performance in young, active volunteers did not improve in 4 studies; however, other studies reported a decrease in heart rate and an increase in maximal oxygen uptake. 11 , 40 One comprehensive literature search evaluated P. ginseng preparations in data from human studies. Properly controlled studies using higher doses (standardized to 2 g/day of dried root) administered for at least 8 weeks and in larger subject numbers more often exhibited improvement in physical or psychomotor performance. Benefit was seen in untrained subjects or in those older than 40 years. 41

Immunomodulatory and adaptogenic effects
Animal data

Animal studies have shown that ginseng extracts can prolong swimming time, prevent stress-induced ulcers, stimulate the proliferation of hepatic ribosomes, increase natural killer-cell activity, and possibly enhance the production of interferons. 42 Increased spleen B lymphocyte proliferation and serum immunoglobulin production have been documented in animal models. Increased peritoneal exudate macrophage production of the cytokines IL-1, tumor necrosis factor–alpha, and IL-6, and the production of nitric oxide has also been reported. 43 , 44

Clinical data

Studies in healthy volunteers measuring T-lymphocyte immunomodulation yield equivocal results. 11 , 26 Studies in healthy sedentary men and healthy physically active men have found no effect of ginseng on immune markers. 40 , 45 Modulation of CD8+ T cells and interleukin production was reported in sedentary men beginning to exercise. 45 A possible effect of ginseng on the CD4+ T cell count in HIV-positive men was reported. 46

Clinical trials supported by the manufacturers of a patented P. quinquefolius preparation suggest a lowered incidence of influenza with the use of ginseng as a prophylactic, especially among elderly patients. 47 , 48 , 49 , 50 , 51 Dosage studies have taken place to evaluate the effect of ginseng in children with upper respiratory tract infections. 52

Other effects

Studies in postmenopausal women suggest ginseng 1 g daily (as Korean red ginseng) may increase sexual arousal possibly via a relaxing effect on the clitoral cavernosal muscle and vaginal smooth muscle. 53

In men, an improvement in erectile function has been shown in a meta-analysis of clinical studies. 54 , 55

Dosage

Ginseng root is standardized according to ginsenosides content, and can be chewed or taken as a powder, liquid extract, decoction, or infusion.

According to the Complete German Commission E Monographs , crude preparations of dried root powder 1 to 2 g can be taken daily for up to 3 months. 8 In numerous clinical trials, the dosage of crude root has ranged from 0.5 to 3 g/day and the dose of extracts has generally ranged from 100 to 400 mg. 2 , 11 , 13 Other trials have used higher dosages. 38

Pregnancy/Lactation

Use during pregnancy and lactation should be avoided due to insufficient evidence of safety. 2 , 56 An association of ginseng with androgenization in a case report is considered doubtful and more likely due to an adulterant in the preparation. 56 , 57 Evidence from a cohort study and a review of clinical trials conducted in Singapore found no association of adverse events among pregnant women consuming ginseng products, and ginseng is widely used in Asian countries in pregnant women. 56 Concerns regarding estrogenic effects of ginseng are unestablished, while in vitro teratogenicity in rats has been reported at artificially high doses of ginsenosides. 2 , 56

Interactions

Limited evidence exists for any established interactions, with most data derived from laboratory studies and healthy volunteers. Very few case reports exist; however, caution should be exercised when using the following medicines with ginseng: antidiabetic drugs/insulin, antipsychotic drugs, caffeine and other stimulants, furosemide, and MAOIs. 2 , 56

A 26-year-old man taking imatinib 400 mg daily for 7 years was diagnosed with imatinib-induced hepatotoxicity 3 months after he started drinking energy drinks containing P. ginseng . After treatment, he was able to restart imatinib without recurrence of elevations in his liver enzymes. 58

In a study in healthy volunteers, administration of a single dose of nifedipine after subjects ingested ginseng for 18 days increased nifedipine plasma concentrations 53% when measured 0.5 hours after nifedipine administration. 59

Reports of an interaction between warfarin and ginseng are conflicting. There are case reports that ginseng may decrease the anticoagulant effect of warfarin. However, open-label studies found no effects of P. ginseng on international normalized ratio or prothrombin times after 2 weeks of coadministration. 60 , 61 , 62

Likewise, in studies conducted among healthy volunteers, ginseng exerted no influence on the pharmacokinetics of zidovudine ( P. ginseng ) 63 or indinavir ( P. quiquefolius ). 64

Adverse Reactions

It is estimated that more than 6 million people regularly ingest ginseng in the United States. There have been few reports of severe reactions, and a very low incidence of adverse events has been reported in clinical trials. 56 Hypersensitivity and anaphylaxis have been reported. 65

Inappropriate use of P. ginseng has been described and caused symptoms such as hypertension, diarrhea, sleeplessness, mastalgia, vaginal bleeding, skin rash, confusion, and depression. A ginseng abuse syndrome was described based on an uncontrolled study in which participants used up to 15 g ginseng daily. When the dosage was reduced to 1.7 g/day, adverse reactions resolved. 2 , 56

Estrogenic effects have been reported in both pre- and postmenopausal women. However, studies with standardized extracts have shown no effect on estrogenic receptors (rats) or progesterone receptors (humans). 2 , 56

Toxicology

Embryotoxicity due to ginsenosides Rb1, Rc, Re, and Rg1 has been demonstrated in rat embryos. 56 In vitro studies found no carcinogenicity, mutagenicity, or teratogenicity for Radix ginseng . 2

A doping-control urinalysis was conducted under International Olympic Committee (IOC) doping control guidelines for CVT-E002 200 and found no IOC-banned substances that might induce a positive doping-control urinalysis. 66

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