Cordyceps – Ophiocordyceps sinensis / Cordyceps militaris

Japanese nameTochukas
Chinese nameDong Chong Xia Cao
English nameCaterpillar Fungus

Cordyceps species are unique among the medicinal mushrooms in growing on an insect host rather than a plant host. To date over 700 species of Cordyceps have been identified worldwide, in most cases growing parasitically on their insect hosts. However, it has also been suggested that in some cases a symbiotic relationship exists whereby the insect host derives a selective advantage from the fungal anamorph (the asexual form of the fungus), especially in marginal environments where energy efficiency is at a premium, such as the high Tibetan plateau above 3,000m where the main species used traditionally, Ophiocordyceps sinensis, occurs naturally (although previously part of the Cordyceps genus, molecular phylogenetic analysis has now led to its being placed in a separate genus, the Ophiocordycipitaceae)1,2.
Although traditionally harvested Cordyceps is still available, the vast majority of Cordyceps on the market today is cultivated on non-insect, grain-based substrates leading to improved quality control and affordability. Despite the commercially cultivated Cordyceps being grown on a different substrate from wild collected Cordyceps, HPLC analysis shows identical chemical profiles and the two are seen to be interchangeable clinically3.
As well as polysaccharides and lipids, Cordyceps species contain a large number of nucleoside analogues, prominent among which is cordycepin, 3-deoxyadenosine, which is found in high levels in Cordyceps militaris and which differs from adenosine in the absence of oxygen at the 3 position of its ribose part4-7. Because of its close similarity to adenosine some enzymes cannot distinguish between the two and it is able to participate in certain biochemical reactions, including RNA/DNAsynthesis, where its incorporation leads to the termination of the RNA/DNA molecule, there being no oxygen to bond with the next nucleotide8-11.
This ability to interrupt RNA/DNA synthesis has led to the use of such nucleoside analogues, termed reverse transcriptase inhibitors, in the treatment of viral infections including HIV and hepatitis as well as cancer, under pharmaceutical names including AZT (Retrovir), Videx and Epivir. In normal healthy cells such reverse transcriptase inhibitors are out-competed by the corresponding nucleoside but in rapidly dividing cancer cells and virally infected cells they are able to exert effective inhibition of replication.
Adenosine in the form of adenosine monophosphate (AMP) and adenosine triphosphate (ATP) also plays a central role in energy metabolism and cyclic nucleotides including cAMP play an important role in signal transduction and regulation of hormone production, actions which correlate well with the observed activity of Cordyceps in these areas.
As well as O. sinensis and C. militaris, a large number of trials have been carried out using a fungal strain isolated from wild O. sinensis specimens by China’s Academy of Sciences and selected for ease of cultivation by large-scale liquid fermentation technology. Termed Cs-4, this is currently identified as Paecilomyces hepiali and continues to be one of the main Cordyceps-related species used in China.
One in vitro study, however, showed Cs-4 to have immunosuppressive activity and the immune-suppressant drug Cyclosporin A has been shown to be present in other fungal strains isolated from wild O. sinensis specimens12-14.

ANTI-AGEINGO. sinensis has traditionally been used as a supplement for the elderly and those recovering from long illness. Studies with Cs-4 in healthy elderly subjects showed significant increases in oxygen uptake, aerobic capacity and resistance to fatigue.
Experimental evidence based on polysaccharide extracts indicates that O. sinensis is also able to improve brain function and antioxidative enzyme activity (superoxide dismutase, glutathione peroxidase and catalase), which, together with its beneficial effect on cardiovascular function, makes it an excellent supplement for the elderly15.

ATHLETIC PERFORMANCE – The use of O. sinensis, together with other supplements, by the record breaking Chinese athletes of the early 1990s has attracted considerable interest in its potential to enhance athletic performance.
A 1996 study on long distance runners reported a significant improvement in 71% of participants and O. sinensis and C. militaris as well as the Cordyceps anamorphs Cs-4 and Cs-HK1, have been shown to increase endurance in animal models. Studies on sedentary humans also show a significant increase in energy output and oxygen capacity16-20. However, three studies failed to demonstrate any effect on performance in competitive cyclists or other professional athletes and it has been suggested that this may be because such athletes are already operating at or close to their maximum aerobic capacity21, 22.

SEXUAL FUNCTIONO. sinensis produces clear benefits for male sexual hypofunction when taken over a period of time.Anecdotal evidence and reports from China also indicate possible benefits for female libido.
Based on animal studies O. sinensis and C. militaris have a clear effect on increasing levels of male sex hormones, improving testes morphology, sperm quantity and quality.
In vitro research indicates that Cordyceps affects the signal transduction pathway of steroidogenesis after the formation of cAMP23-27.

FERTILITYO. sinensis is increasingly being used by leading specialists in the field of infertility and clinical evidence suggests that Cordyceps has a beneficial impact on female fertility and the success of IVF. In part this may be due to its ability to stimulate 17β-estradiol (oestrogen) production, through increased StAR (steroidogenic acute regulatory protein) and aromatase expression28. In common with other mushrooms, Cordyceps’ ability to regulate immune function and in particular NK cell activity may also play a part.
The ability of O. sinensis to increase oestrogen production also has potential for the management of postmenopausal osteoporosis29.

DIABETES – Experimental evidence indicates that O. sinensis is able to:
• Trigger release of insulin
• Increase hepatic glucokinase
• Increase sensitivity of cells to insulin
In one randomized trial 95% of patients treated with 3g/day O. sinensis mycelial biomass saw improvements in their blood sugar profile compared with 54% treated by other methods. In addition it has been reported that consumption of 4.5g/day O. sinensis mycelial biomass by patients with alcohol induced diabetes also produced a reduced desire for alcohol3,30-34.
Recent evidence indicates that Cordycepin and related nucleoside derivatives play an active role in the anti-diabetic action of O. sinensis and that C. militaris, which has high levels of cordycepin, also has significant hypoglycaemic activity35, 36.

HEPATOPROTECTIVE -Multiple studies have shown the ability of both O. sinensis and C. militaris to inhibit hepatic fibrosis and help restore liver function37-39. One clinical study using 3g/day O. sinensis mycelial biomass to treat alcohol-induced liver steatosis in 14 patients showed reductions of 70% in AST levels, 63% in ALT levels and 64% in GGT levels over a 90 day period40.

RENAL HEALTHO. sinensis has traditionally been considered to support the kidneys and 3.5g/day has been shown to both improve kidney function in patients with chronic renal failure and speed recovery in patients with gentamycin-induced kidney damage3.

RESPIRATORY DISEASE – Traditionally O. sinensis has been used to treat respiratory ailments and is reported to be beneficial for asthma and COPD3.

ANTI-VIRAL – As mentioned above, the nucleoside analogues present in Cordyceps species are able to inhibit viral replication. At the same time the polysaccharides in Cordyceps modulate the immune response to viral infections. This combination of enhanced immune response and interrupted viral replication makes Cordyceps, especially C. militaris, one of the most effective mushrooms for tackling chronic viral infections9,10.

CANCER – Because of its combination of immune-modulating polysaccharides and nucleoside derivatives, many practitioners consider Cordyceps to be one of the most useful mushrooms for helping improve treatment outcomes in cancer, with cordycepin reported to induce apoptosis (cancer cell death) in multiple cancer cell lines, including: oral, colorectal, bladder, leukaemia, melanoma, multiple myeloma, breast and prostate41-52.

Main Therapeutic Applications – Fertility and sexual function, energy, diabetes, lung function, kidney support, liver disorders.
Key Component – Nucleoside derivatives.
Dose – Cordyceps’ unique properties are principally those of its nucleoside derivatives and as these are largely excreted (research on C. militaris shows that 98% of cordycepin is secreted into the growth medium53) mycelial biomass products offer the natural dosage format for Cordyceps. 2-3g/day mycelial biomass is used in most cases while higher levels have been reported to give good results in a range of cancers2.
Some practitioners prefer to use C. militaris for cancer and viral infections due to its higher cordycepin levels54,55.
Caution – Hormone dependent cancers (prostate and breast) due to increased levels of oestrogen and testosterone.
Although Cs-4 shows benefits for exercise and endurance, possible immune suppression mitigates against its use in immune deficient conditions.

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11. Cordycepin (3′-deoxyadenosine) inhibits human platelet aggregation in a cyclic AMP- and cyclic GMP-dependent manner. Cho HJ, Cho JY, Rhee MH, Park HJ. Eur J Pharmacol. 2007;558(1-3):43–51.
12. Immunosuppressive effect of Cordyceps CS-4 on human monocyte-derived dendritic cells in vitro. Tang J, Tian D, Liu G. Am J Chin Med. 2010;38(5):961–972.
13. Mycelium cultivation, chemical composition and antitumour activity of a Tolypocladium sp. fungus isolated from wild Cordyceps sinensis. Leung PH, Zhang QX, Wu JY. J Appl Microbiol. 2006;101(2):275–283.
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16. Increased aerobic capacity in healthy elderly humans given a fermentation product of Cordyceps CS-4. Xiao Y, Huang XZ, Chen G, Wang MB, Zhu JS. Med Sci Sports Exerc. 1999;31(5):S174.
17. Randomized double-blind placebo-controlled clinical trial and assessment of fermentation product of Cordyceps sinensis (Cs-4) in enhancing aerobic capacity and respiratory function of the healthy elderly volunteers. Xiao Y, Huang XZ, Zhu JS. Chin J Integr Med. 2004;10(3):187–192.
18. Effect of medicinal plant extracts on forced swimming capacity in mice. Jung K, Kim IH, Han D. J Ethnopharmacol. 2004;93(1):75–81.
19. CordyMax enhances aerobic capability, endurance performance, and exercise metabolism in healthy, mid-age to elderly sedentary humans. Zhu JS, Rippe JM. Chin J Gerontology. 2001;20:297–298.
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21. Cordyceps sinensis supplementation does not improve endurance performance in competitive cyclists. Parcell AC, Smith JM, Schulthies SS, Myrer JW, Fellingham G. Med Sci Sports Exerc. 2002;34(5):S231.
22. Does Cordyceps sinensis ingestion aid athletic performance? Walker TB. Strength Cond J, 2006;28(2):21–23.
23. Effect of Cordyceps militaris supplementation on sperm production, sperm motility and hormones in Sprague-Dawley rats. Chang Y, Jeng KC, Huang KF, Lee YC, Hou CW, Chen KH, Cheng FY, Liao JW, Chen YS. Am J Chin Med. 2008;36(5):849–859.
24. In vivo and in vitro stimulatory effects of Cordyceps sinensis on testosterone production in mouse Leydig cells. Hsu CC, Huang YL, Tsai SJ, Sheu CC, Huang BM. Life Sci. 2003;73(16):2127–2136.
25. Influence of Cordyceps sinensis on reproduction and testis morphology in mice. Jin HL, Guo RX. Shenzhen J Integr Tradit Chin West Med. 2006;16(5):289–292.
26. Improvement of sperm production in subfertile boars by Cordyceps militaris supplement. Lin WH, Tsai MT, Chen YS, Hou RC, Hung HF, Li CH, Wang HK, Lai MN, Jeng KC. Am J Chin Med. 2007;35(4):631–641.
27. Estrogenic substances from the mycelia of medicinal fungus Cordyceps ophioglossoides (Ehrh.) Fr. (Ascomycetes). Kawagishi H, Okamura K, Kobayashi F, Kinjo N. Int J Med Mushrooms. 2004;6(3):249–252.
28. Upregulation of steroidogenic enzymes and ovarian 17β-estradiol in human granulosa-lutein cells by Cordyceps sinensis mycelium. Huang BM, Hsiao KY, Chuang PC, Wu MH, Pan HA, Tsai SJ. Biol Reprod. 2004;70(5):1358–1364.
29. The co-effect of Cordyceps sinensis and Strontium on osteoporosis in ovariectomized osteopenic rats. Qi W, Yan YB, Wang PJ, Lei W. Biol Trace Elem Res. 2011;141(1-3):216–223.
30. Polysaccharides in fungi XXXVI. Hypoglycemic activity of a polysaccharide (CS-F30) from the cultural mycelium of Cordyceps sinensis and its effect on glucose metabolism in mouse liver. Kiho T, Yamane A, Hui J, Usui S, Ukai S. Biol Pharm Bull. 1996;19(2):294–296.
31. Structural features and hypoglycemic activity of a polysaccharide (CS-F10) from the cultured mycelium of Cordyceps sinensis. Kiho T, Ookubo K, Usui S, Ukai S, Hirano K. Biol Pharm Bull. 1999;22(9):966–970.
32. Anti-hyperglycemic activity of natural and fermented in rats with diabetes induced by nicotinamide and streptozotocin. Lo HC, Hsu TH, Tu ST, Lin KC. Am J Chin Med. 2006;34(5):819–832.
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34. Cordycepin suppresses expression of diabetes regulating genes by inhibition of lipopolysaccharide-induced inflammation in macrophages. Shin S, Lee S, Kwon J, Moon S, Lee S, Lee CK, Cho K, Ha NJ, Kim K. Immune Netw. 2009;9(3):98–105.
35. Aqueous extracts of Cordyceps militaris (Ascomycetes) lower the levels of plasma glucose by activating the cholinergic nerve in Streptozotocin-induced diabetic rats. Cheng YW, Chen YI, Tzeng CY, Chang CH, Lee YC, Chen HC, Tsai CC, Hsu TH, Lai YK, Chang SL. Int J Med Mushrooms. 2013;15(3):277–286.
36. Studies on the antidiabetic activities of Cordyceps militaris extract in diet-streptozotocin-induced diabetic Sprague-Dawley rats. Dong Y, Jing T, Meng Q, Liu C, Hu S, Ma Y, Liu Y, Lu J, Cheng Y, Wang D, Teng L. Biomed Res Int. 2014:2014:160980.
37. Inhibitive effect of Cordyceps sinensis on experimental hepatic fibrosis and its possible mechanism. Liu YK, Shen W. World J Gastroenterol. 2003;9(3):529–533.
38. Dynamical influence of Cordyceps sinensis on the activity of hepatic insulinase of experimental liver cirrhosis. Zhang X, Liu YK, Shen W, Shen DM. Hepatobiliary Pancreat Dis Int. 2004;3(1):99–101.
39. Cordyceps militaris alleviates non-alcoholic fatty liver disease in ob/ob mice. Choi HN, Jang YH, Kim MJ, Seo MJ, Kang BW, Jeong YK, Kim JI. Nutr Res Pract. 2014;8(2):172–176.
40. Cordyceps sinensis supplementation as immunonutrition in alcohol induced liver steatosis-II. Santos C. Mycology News. 2004;1(9):2–6.
41. RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells. Chen LS, Stellrecht CM, Gandhi V. Br J Haematol. 2008;140(6):682–691.
42. Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction. Wong YY, Moon A, Duffin R, Barthet-Barateig A, Meijer HA, Clemens MJ, de Moor CH. J Biol Chem. 2010;285(4):2610–2621.
43. Effect of cordycepin on interleukin-10 production of human peripheral blood mononuclear cells. Zhou X, Meyer CU, Schmidtke P, Zepp F. Eur J Pharmacol, 2002;453(2-3):309–317.
44. Cordycepin suppresses TNF-alpha-induced invasion, migration and matrix metalloproteinase-9 expression in human bladder cancer cells. Lee EJ, Kim WJ, Moon SK. Phytother Res. 2010;24(12):1755–1761.
45. Role of Cordycepin and Adenosine on the phenotypic switch of macrophages via induced anti-inflammatory cytokines. Shin S, Moon S, ParkY, Kwon J, Lee S, Lee CK, Cho K, Ha NJ, Kim K. Immune Netw. 2009;9(6):255–264.
46. Involvement of autophagy in cordycepin-induced apoptosis in human prostate carcinoma LNCaP cells. Lee HH, Kim SO, Kim GY, Moon SK, Kim WJ, Jeong YK, Yoo YH, Choi YH. Environ Toxicol Pharmacol. 2014;38(1):239–250.
47. Cordycepin: a bioactive metabolite with therapeutic potential. Tuli HS, Sharma AK, Sandhu SS, Kashyap D. Life Sci. 2013;93(23):863–869.
48. Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29. Lee SY, Debnath T, Kim SK, Lim BO. Food Chem Toxicol. 2013;60:439–447.
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50. Advances on Cordyceps militaris constituents and pharmacological effect. Fan HT, Lin HS. Zhongguo Zhongyao Zazhi. 2013;38(15):2549–2552.
51. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells. Ruma IM, Putranto EW, Kondo E, Watanabe R, Saito K, Inoue Y, Yamamoto K, Nakata S, Kaihata M, Murata H, Sakaguchi M. Int J Oncol. 2014;45(1):209–218.
52. Antitumour activity of Cordycepin in mice. Yoshikawa N, Nakamura K, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M. Clin Exp Pharmacol Physiol. 2004;31(S2):S51–S53.
53. Production of cordycepin by surface culture using the medicinal mushroom Cordyceps militaris. Masuda M, Urabe E, Sakurai A, Sakakibara M. Enzyme Microb Technol. 2006;39(4):641–646.
54. Cultivation of medicinal caterpillar fungus, Cordyceps militaris (Ascomycetes), and production of cordycepin using the spent medium from levan fermentation. Wu FC, Chen YL, Chang SM, Shih IL. Int J Med Mushrooms. 2013;15(4):393–405.
55. Determination of nucleosides and nucleobases in different species of Cordyceps by capillary electrophoresis-mass spectrometry. Yang FQ, Ge L, Yong JW, Tan SN, Li SP. J Pharm Biomed Anal. 2009;50(3):307–314.