Ginseng

Ginseng is an herb from the genus Panax of the Araliaceae family that is an important part of traditional Chinese medicine (TCM).[1] It is termed an “adaptogen,” as it is believed to have properties that help to restore balance to the body and protect the body from physiologic stress.[1,2] There are two main types of ginseng: Asian (Chinese or Korean) ginseng, called Panax ginseng, and American ginseng, Panaxquinquefolius.[3] Both Asian and American ginseng have a common mixture of active ingredients, called ginsenosides, although the concentrations of each ginsenoside are slightly different.[4]

Ginsenosides are plant saponins, or steroid-like compounds. More than 150 ginsenosides have been identified from ginseng roots, leaves, stems, berries, and flowers.[5] Based on different ginsenoside compositions, in TCM, Asian ginseng has properties ascribed to it as “yang,” or a ”hot herb,“ whereas American ginseng is thought to be a “yin,” or a ”cooling herb.“[1,2] Siberian ginseng, called Eleutherococcus senticosus, is often marketed as a ginseng product with properties similar to Asian and American ginseng, but it is actually from a different plant genus.[1] This article will focus on Asian and American ginseng.

Ginseng is available as an extracted herb or as a dry ground root. The root is considered to be the source of ginsenosides, the active constituents. It is recommended that standardization be achieved through dosing of 0.5–2 grams daily of dry root or equivalent extract, with a 4%–5% ginsenoside content. Extraction can be done with water or alcohol, and the properties of ginseng are affected by the way that it is extracted and processed.[6,7]

American ginseng is native to North America. It was introduced to European settlers by Native Americans in the early 1700s, and harvested in large quantities and exported from the US to Asia beginning in the 1800s. More than 90% of cultivated ginseng grown in the US is grown in Wisconsin, because the state’s climate and mineral-rich soil provide optimal conditions for growing healthy ginseng roots. Wisconsin farmers began cultivating ginseng in the 1900s.[1,8]

A minimum of 3 years, preferably 4 years, is required to grow the roots before they can be harvested. The seed beds must be protected from the sun in the summer and from the cold in the winter. The berries are harvested by hand and de-pulped. The seeds are washed, dried, and buried until the next summer, when they are planted. The roots are also then harvested by hand, refrigerated 10–20 days, and then washed and put on racks for drying. The drying process takes 14 days. How the cooling, washing, and drying are done contribute to the quality of the herb.[8]

Panax (Asian) ginseng is > 5,000 years old, initially from the Manchurian mountains in China.[1] Currently, Asian ginseng can be from Korea or China. White Asian ginseng is dried, unprocessed root, whereas red ginseng is derived from steam processing. The heat is thought to increase the potency of the ginseng. Asian ginseng also has to grow for at least 5 years in order for the roots to mature.

Because of the long growing time required for mature ginseng, the labor-intensive cultivation process, and changes in the plant’s natural growing habitat, the ginsenoside concentrations and quality of this herb can be quite variable.[9,10]

How Is It Currently Used?

The botanical/genus name “Panax” means “all-heal” in Greek.[1] With more than 150 identified ginsenosides and other active components such as polysaccharides, all with biologic properties, it is easy to appreciate ginseng’s reputation for widespread use.[2] Ginseng has been used to improve the immune system, cognition, several aspects of fatigue, appetite, physical performance, anemia, glucose regulation, digestion, and sexual performance, and to decrease stress. Various properties of ginseng are being studied as a cancer treatment, particularly for breast and colorectal cancer.

What Is the Evidence Related to Ginseng and the Needs of Cancer patients and Survivors?

Ginseng may be one of the most widely studied herbs. A recent literature search covering the past 6 years yielded 992 references related to ginseng. Most of the published literature falls into the category of basic science, and Asian and American ginseng appear to be equally studied. However, studies in humans, particularly controlled trials, are lacking.

Various in vitro and animal studies have delineated properties of specific ginsenosides. The ginsenoside Rb1 has demonstrated activities consistent with neural and neurocognitive protective effects, such as modulating sodium channels,[11] protecting striatal neurons from 3-nitropropionic acid–induced damage,[12] stimulating neurosecretory cells (eg, dopamine and glutamate),[13] and modulating gaba-aminobutyric acid (GABA) neurotransmission.[14]

Properties that may indicate ginseng has a role in fatigue include both stimulatory and anti-inflammatory effects. The Rg1 and Rb1 ginsenosides have been linked to exercise performance in rats.[15] In MCF-7 human breast cancer cells, a hot-water extract of American ginseng inhibited growth through inhibition of the mitogen-activated protein kinase (MAPK) pathway,[16] a cell-signaling pathway that is upregulated in response to proinflammatory cytokines. Increases in inflammatory cytokines have been associated with fatigue.[17] With regard to anticancer activity, in cell cultures of ER+ breast cancer tissue, American ginseng inhibited cell growth and was synergistc with tamoxifen, Cytoxan (cyclophosphamide), methotrexate, doxorubicin, and 5-fluorouracil.[18] Cell cultures of human colorectal cancer cells were also impacted by steamed American ginseng, which caused apoptosis, likely through mitochondrial damage.[3]

Human clinical trials published in the mid 1990s evaluating effects of ginseng on physical performance in healthy individuals were mixed and suffered from methodological weaknesses.[19–22] More recently, two pilot trials were completed in people with cancer. One study was done in a population of chemonaive patients receiving chemotherapy: during treatment they were randomized to Asian ginseng at a dosage of 250 mg three times per day, or to a placebo. The group that received ginseng reported significantly less fatigue, as measured by the Brief Fatigue Inventory. However, this study was very small (N = 20) and was only reported in abstract form.[23] Another pilot trial evaluated three doses of American ginseng vs a placebo in a heterogeneous group of 290 cancer survivors. Improvements on the Brief Fatigue Inventory and Vitality subscale of the SF-36 were higher for patients who received the two larger ginseng doses (1,000 or 2,000 mg/day) than those on placebo or 750 mg/day of ginseng.[24] A large phase III trial of more than 360 patients is being conducted by the North Central Cancer Treatment Group and will likely be completed this summer, evaluating 2,000 mg of American ginseng vs placebo for fatigue.

Two studies have been published evaluating effects of ginseng on cognition. One small, randomized, double-blind trial assessed its effects on cognitive function in 32 healthy adults. Three doses of American ginseng (100, 200, and 400 mg) were tested and compared with placebo. A battery of neuropsychiatric tests was performed before treatment and at 1, 3, and 6 hours after the study subjects had consumed the ginseng. The most consistent results were an improvement in working memory with 200- and 400-mg doses.There were no adjustments made for multiple endpoints, and several areas of cognition were evaluated.[25] A larger study that was not placebo-controlled evaluated 4.5 grams per day of Asian ginseng in 58 people diagnosed with Alzheimer’s disease. The investigators included a control group of 39 people who were age- and gender-balanced. The primary endpoint was the mini–mental state examination (MMSE) and Alzheimer disease assessment scales (ADAS). The group receiving ginseng improved slightly on the MMSE over a period of 12 weeks, while MMSE scores in the control group declined slightly. A similar improvement in the ginseng group and loss in the control group was demonstrated with scores on the cognitive subscale of the ADAS.[26] Effects of ginseng related to cancer have not been explored.

Finally, an epidemiologic study done in Shanghai with a cohort of 1,455 women with breast cancer suggested that current use of ginseng was associated with better quality of life scores, particularly those related to psychological and social well being. The investigators also found that regular use of ginseng was associated with a reduced disease-free and overall survival rate, compared with nonusers. This study did not report on the dose of ginseng used, but it did include various types of ginseng. The analysis adjusted for age at diagnosis, hormone receptor status, surgery, and several other treatment variables.[27]

What Are the Potential Risks?

American ginseng is categorized as a class I herb using the American Herbal Products Association Safety Rating, which means that it is considered generally safe if used appropriately.[28]

In a journal article evaluating American ginseng for diabetes, doses of up to 3 grams daily did not yield any side effects.[29] In a dose-finding, placebo-controlled trial evaluating 750–2,000 mg of American ginseng as a possible treatment for cancer-related fatigue, there were no differences between the ginseng and placebo arms in terms of any reported adverse event or self-reports of nausea, insomnia, headaches, anxiety, nervousness, or dizziness over 8 weeks of use.[24] Some articles report the possibility of insomnia, but there are no published trial data to support this.

A Korean study of Panax ginseng performed in men and women with Alzheimer’s disease reported side effects of “heat-sense,” dizziness, nausea, anorexia, headache, and diarrhea in 7 of 58 patients taking 4.5 grams/day of ginseng over a period of 12 weeks.[26]

There have been some reports that ginseng has estrogenic properties and should, therefore, not be used by people who need to avoid estrogen.[1] This property is likely due to two issues. The first relates to an identified fungus on the roots, which in one study did not account for adverse events, but may be associated with possible estrogenic activity.[30] The second relates to the extraction method. Alcohol extraction confers estrogenic properties to the ginseng and should be avoided, especially by those for whom estrogen is contraindicated. Consumers should be aware of the type of ginseng they are purchasing, including whether it is ground root or an extract. Using larger, more established companies and contacting them to obtain this information would be advised.

The Ginseng Board of Wisconsin (www.ginsengboard.com), a nonprofit organization of Wisconsin ginseng growers, lists companies in the US and overseas that sell USDA-graded Wisconsin ginseng, tested for pesticide residues.

With respect to cytochrome P450 activity, American ginseng has not been found to inhibit any CYP450 pathways.[1,31–33] There is limited evidence that Asian ginseng may activate CYP3A4 or inhibit CYP2D6 in vitro, but at this time, it is not believed that the effects have any clinical relevance.[1] Both pathways are important for drug metabolism.

Safety during pregnancy has not been established. One study using a whole rat embryo culture model found evidence of teratogenicity attributable to the ginsenoside Rb1, a component of both Asian and American ginseng.[34]

What’s the Bottom-Line Message?

Established and emerging data demonstrate some mechanisms of action of ginseng that would be consistent with its having positive effects on cancer as a disease, and on some common symptoms experienced by cancer survivors: namely, cognitive deficits, fatigue, and neuropathies. However, clinical trials in survivors are lacking. There are very limited pilot data and epidemiologic data in cancer survivors supporting the benefits of ginseng in fatigue and overall well being. There are also limited pilot data in Alzheimer’s disease and in healthy adults that support its benefits in cognition. More research is needed to clarify the role of ginseng in cancer, and to definitively determine appropriate dosing, side effects, and drug interactions. Standardization and quality of this herb are also potential concerns.

Financial Disclosure: The author has received American ginseng and placebo from the Ginseng Board of Wisconsin, a nonprofit organization, for two studies of ginseng in cancer patients.

References:

References

1. Natural Standard: Natural Standard Ginseng monograph. Available at: www.naturalstandard.com.

2. Attele AS, Wu JA, Yuan CS: Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 58(11):1685–1693, 1999.

3. Li B, Wang CZ, He TC, et al: Antioxidants potentiate American ginseng-induced killing of colorectal cancer cells. Cancer Lett 289(1): 62–70, 2010.

4. Wang X, Sakuma T, Asafu-Adjaye E, et al: Determination of ginsenosides in plant extracts from Panex ginseng and Panex quinquefolius L. by LC/MS/MS. Anal Chem 71(8):1579–1584, 1999.

5. Christensen LP: Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res 55:1–99, 2009.

6. Gafner S, Bergeron C, McCollom MM, et al: Evaluation of the efficiency of three different solvent systems to extract triterpene saponins from roots of Panex quinquefolius using high-performance liquid chromatography. J Agric Food Chem 52(6):1546–1550, 2004.

7. King ML, Adler SR, Murphy LL: Extraction-dependent effects of American ginseng (Panex quinquefolium) on human breast cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther 5(3):236–243, 2006.

8. Ginseng Board of Wisconsin: [information about ginseng, its cultivation, and selected research into possible health benefits]. Available at: www.ginsengboard.com. Accessed on March 20, 2011.

9. Harkey MR, Henderson GL, Gershwin ME, et al: Variability in commercial ginseng products: An analysis of 25 preparations. Am J Clin Nutr 73(6):1101–1106, 2001.

10. Schlag EM, McIntosh MS: Ginsenoside content and variation among and within American ginseng (Panex quinquefolius L.) populations. Phytochemistry 67(14):1510–1519, 2006.

11. Liu D, Li B, Liu Y, et al: Voltage-dependent inhibition of brain Na(+) channels by American ginseng. Eur J Pharmacol 413(1):47–54, 2001.

12. Lian XY, Zhang Z, Stringer JL: Protective effects of ginseng components in a rodent model of neurodegeneration. Ann Neurol 57(5):642–648, 2005.

13. Lee SD, Lo MJ: Ginsenoside Rb1 promotes PC12 cell cycle kinetics through an adenylate cyclase-dependent protein kinase A pathway. Nutr Res 30(9):660–666, 2010.

14. Yuan CS, Attele AS, Wu JA, et al: Modulation of American ginseng on brainstem GABAergic effects in rats. J Ethnopharmacol 62(3):215–222, 1998.

15. Wang LC, Lee TF: Effect of ginseng saponins on exercise performance in non-trained rats. Planta Med 64(2):130–133, 1998.

16. King ML, Murphy LL: American ginseng (Panex quinquefolius L.) extract alters mitogen-activated protein kinase cell signaling and inhibits proliferation of MCF-7 cells. J Exp Ther Oncol 6(2):147–155, 2007.

17. Collado-Hidalgo A, Bower JE, Ganz PA, et al: Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin Cancer Res 12(9):2759–2766, 2006.

18. Duda RB, Zhong Y, Navas V, et al: American ginseng and breast cancer therapeutic agents synergistically inhibit MCF-7 breast cancer cell growth. J Surg Oncol 72(4):230–239, 1999.

19. Allen JD, McLung J, Nelson AG, et al: Ginseng supplementation does not enhance healthy young adults’ peak aerobic exercise performance. J Am Coll Nutr 17(5):462–466, 1998.

20. Engels HJ, Wirth JC: No ergogenic effects of ginseng (Panex ginseng C.A. Meyer) during graded maximal aerobic exercise. J Am Diet Assoc 97(10):1110–1115, 1997.

21. Pieralisi G, Ripari P, Vecchiet L: Effects of a standardized ginseng extract combined with dimethylaminoethanol bitartrate, vitamins, minerals, and trace elements on physical performance during exercise. Clin Ther 13(3):373–382, 1991.

22. Ziemba AW, Chmura J, Kaciuba-Uscilko H, et al: Ginseng treatment improves psychomotor performance at rest and during graded exercise in young athletes. Int J Sport Nutr 9(4):371–377, 1999.

23. Younus J, Collins A, Wang X, et al: A double blind placebo controlled pilot study to evaluate the effects of ginseng on fatigue and quality of life in adult chemo-naive cancer patients (abstract 733). Proc Am Soc Clin Oncol 22:733a, 2003.

24. Barton DL, Soori GS, Bauer BA, et al: Pilot study of Panex quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. Support Care Cancer 18(2):179–187, 2010.

25. Scholey A, Ossoukhova A, Owen L, et al: Effects of American ginseng (Panex quinquefolius) on neurocognitive function: An acute, randomised, double-blind, placebo-controlled, crossover study. Psychopharmacology (Berl) 212(3):345–356, 2010.

26. Lee ST, Chu K, Sim JY, et al: Panex ginseng enhances cognitive performance in Alzheimer disease. Alzheimer Dis Assoc Disord 22(3):222–226, 2008.

27. Cui Y, Shu XO, Gao YT, et al: Association of ginseng use with survival and quality of life among breast cancer patients. Am J Epidemiol 163(7):645–653, 2006.

28. Blumenthal M: The ABC Clinical Guide to Herbs. Austin, TX, American Botanical Council, 2003.

29. Vuksan V, Sievenpiper JL, Koo VY, et al: American ginseng (panax quinquefolius) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Intern Med 160(7):1009–1013, 2000.

30. Gray SL, Lackey BR, Tate PL, et al: Mycotoxins in root extracts of American and Asian ginseng bind estrogen receptors alpha and beta. Exp Biol Med (Maywood) 229(6):560–568, 2004.

31. Budzinski JW, Foster BC, Vandenhoek S, et al: An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 7(4):273–282, 2000.

32. Gurley BJ, Gardner SF, Hubbard MA, et al: Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John’s wort, garlic oil, Panex ginseng and Ginkgo biloba. Drugs Aging 22(6):525–539, 2005.

33. Wanwimolruk S, Wong K, Wanwimolruk P: Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4. Drug Metabol Drug Interact 24(1):17–35, 2009.

34. Chan LY, Chiu PY, Lau TK: An in-vitro study of ginsenoside Rb1-induced teratogenicity using a whole rat embryo culture model. Hum Reprod 18(10):2166–2168, 2003.