Chronic immune, allergic, inflammatory and auto-immune disease, such as rheumatoid arthritis, lupus, and asthma.
Mechanism of Action
Approximately 20 nucleosides and their related compounds have been found in Cordyceps spp., including rare derivatives with specific functions such as 2′,3′-dideoxyadenosine, hydroxyethyladenosine, cordycepin, cordycepin triphosphate, deoxyguanosine.1 Cordycepin, an analog of adenosine (3′-deoxyadenosine) is largely credited with immune modulating actions. Research has shown various examples of this constituent altering/improving subpopulations of T lymphocytes, and it may suppress T helper 1 and 2 overproduction and stabilize the ratios of CD 4 through CD 8 T cells.2 Overall, cordycepin affects the synergistic actions of immune cells and the cytokine network, rather than affecting T cells and immune mediators in absolute or static ways.3
Polysaccharides in Cordyceps markedly increase macrophage phagocytosis, the proliferation of splenic cells, and the level of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in immune tissue, including the thymus and spleen.4 Cordysinocan, an immune polysaccharide found in Cordyceps, is able to induce T cell proliferation and the secretion of interleukin (IL)-2, IL-6, and IL-8, and support signal transduction via the phosphorylation of extracellular kinases, and increased macrophage phagocytosis.5
Ergosterol is a ubiquitous steroid-like molecule and vitamin D precursor found in fungi including Cordyceps. It is found to have many immune modulating actions, including effects on IFN, T-cell ratios, IL, signal transduction, and cell maturation and cycles.6
Wild Cordyceps sinensis comes from a caterpillar and fungus combination, and is rare, extremely expensive and not available as a dietary supplement. Research demonstrates that Cordyceps militaris has similar actions to the rare version and can be substituted for clinical applications. C. militaris is cultivated on substrates free from insects in a sustainable manner. The fruiting bodies are believed to contain the most active compounds.
Much of the research regarding Cordyceps relates to its immunomodulatory actions, which may up- or down-regulate T lymphocytes, B lymphocytes, natural killer cells, macrophages, and their release of cytokines and inflammatory mediators in various ways, depending on the situation and pathology. For example, Cordyceps may prevent immune activation produced by the concanavalin alkaloid and other powerful inducers of immune activity,7,8 yet increase T cell counts and activities when suppressed by cyclophosphamide9 or prednisolone.10
Cordyceps and isolated cordycepin, the most researched compound, affect both cellular and humoral immunity, increasing IL release threefold in one mouse study,11 and decreasing IL and IFN release from macrophages and T lymphocytes in an over-stimulated situation.12
Cordyceps also differentially regulates dendritic cell activities according to the presence or absence of the inflammatory signs, favoring Th1-dominant immunity in a resting immune state, but controlling over-reactivity of elicited Th1 immunity in states of immune hyper-reactivity, favoring other T cell types.13 Due to the many animal and molecular studies of this nature, showing an ability to optimize T cell, cytokine, and inflammatory mediator levels and activities, herbalists classify Cordyceps as an “immune modulator.” The ratio of Th1 to Th2 has implications for numerous immune, allergic, and inflammatory disorders, and impacts immunoglobulin levels.14 Due to immune and inflammation modulating actions, Cordyceps has been shown to optimize T cells, immunoglobulin and cytokines in the following conditions:
- Cancer: The induction of IL-2, Th1-type cytokine in T lymphocytes may benefit cancer and immune-suppressed patients.15 Cordyceps militaris also has anti-angiogenic effects, and remarkably suppresses tumor growth via induction of apoptotic cell death, with mechanisms including suppression of vascular endothelial growth factor receptors (VEGF).16 Cordyceps also suppresses tumor growth and enhances survival in animal cancer studies, through balancing immune cells and modifying cytokines.17
- Diabetes: One animal study investigated the immune and inflammation modulating effects of Cordyceps in diabetic mice and reported Cordyceps to slow the inflammatory progression in organs via increased T reg cells and IFN-γ-producing T helper 1 cells in peripheral lymph nodes.18 Optimizing T cell ratios and IL production can also mitigate the long-term inflammatory consequences of diabetes.19
- Rheumatoid arthritis: Cordycepin modulates inflammatory activities in synovial fibroblasts in a manner that may help regulate connective tissue damage in rheumatoid arthritis and related auto-immune disorders via inhibition of IL-1β-induced chemokine production.20
- Lupus: Cordyceps increased survival, decreased proteinuria, and reduced titers of anti-double-stranded DNA antibodies in animal models of lupus. These actions are credited to the ability of Cordyceps to reduce CD4 while increasing CD8 cells, and reduce splenocyte proliferation.21
- Myocarditis: Cordyceps optimizes IFN and T-cell responses in animals with viral myocarditis,22 enhances the maturation of bone-marrow derived dendritic cells in immune deficiency states.23
- Asthma: One human randomized controlled trial (RCT) investigated the additive effects of Cordyceps on blood indices of immune hypersensitivity in asthmatic patients who were being managed on corticosteroid and beta adrenergic–agonist inhalers, found the fungus to lower immunoglobulin E and IL-4 levels significantly as compared with placebo. The study suggested anti-inflammatory effects occurred through regulating the balance of Th1/Th2 and reducing IgE production, and may have the effect of reversing airway remodeling, pending further research.24 Studies in asthmatic children in momentary remission also showed Cordyceps to inhibit the proliferation and differentiation of Th2 cells, and reduce the expression of related cytokines by down-regulating the expression of GATA-3 mRNA, and up-regulating the expression of Foxp3 mRNA in polymorphonuclear blood monocytes, while alleviating the chronic allergic inflammation by increasing the content of IL-10.25
- Condyloma virus and warts: One human RCT evaluated the effects of Cordyceps compared with placebo in patients with condyloma and associated warts, and reported that IL-2 increased and IL-10 decreased only in the treated group; there was also decreased wart recurrence following electrocautery treatment compared with placebo.26
- Organ transplant rejection: Lifelong use of immunosuppressive agents is necessary for patients having undergone an organ transplant, and Cordyceps is being explored as a possible adjuvant therapy that may prevent excessive immunosuppression seen with long-term steroids and associated infection risk, as well as reducing excessive immune activation in the body that can lead to organ rejection.27
- Liver fibrosis in hepatitis B: Cordyceps was investigated for effects on fibrotic degeneration in the livers of patients with hepatitis B, as assessed by laboratory markers. Cordyceps was found to significantly decrease hyaluronic acid and pro-collagen type II, suggesting improvements in fibrotic processes compared with control.28
- Renal failure: Cordyceps was found to improve renal function and optimize cellular immunity compared with control in patients with chronic renal failure.29
Safety in Pregnancy and Breastfeeding
There are no published studies on the use of Cordyceps in pregnancy or lactation, but no genotoxic effects have been reported.
Cordyceps consumption is generally considered safe.30,31 32 C. militaris has shown no in vitro cytotoxicity in animal studies and is considered safe for brain and cognitive health.33
Traditional usage of Cordyceps powder or encapsulated Cordyceps has been several grams per day minimum of the crude herb powder. Dosages of 3–9 g/day have been used as athletic and energy tonics and for acute inflammatory and immune disorders, such as renal failure. Smaller doses are taken if the preparation is a concentrated extract and if taken over the long term for chronic conditions.
Cordyceps has been revered as an energy, immune and longevity tonic and was established as an important medicine with numerous uses in China, Korea, and Japan.
It has long been used to support reproductive and sexual function, enhance libido, and maintain sexual and cognitive health, especially in older decades of life as a remedy for fatigue, asthenia, or following a long illness.
Traditional uses also include the treatment and prevention of cancer and infections (e.g., leukemia), chronic allergic and inflammatory diseases of the lung, liver, kidney, pancreas, and heart, and protection against their long-term sequelae through balancing blood sugar (e.g., diabetes), lipids, and inflammatory processes (e.g. vasculitis).
For all of these traditional indications, Cordyceps is often classified as an adaptogen, an agent capable of improving resistance to physical, chemical, and nervous stressors in numerous non-specific and tonifying ways, and has become popular in the last several decades for improving stamina and athletic performance after Chinese track and field athletes broke several world records reportedly using the fungi as non-steroidal supplement.
Recent Pat Biotechnol. 2013;7(2):153–66. Nucleosides, a valuable chemical marker for quality control in traditional Chinese medicine Cordyceps. Xiao JH, Qi Y, Xiong Q.
2 J Surg Res. 2013;185(2):912–22. Suppression of T-cell activation in vitro and in vivo by cordycepin from Cordyceps militaris. Xiong Y, Zhang S, Xu L, Song B, Huang G, Lu J, Guan S.
3 Am J Chin Med. 2008;36(5):967–80. Cordycepin is an immunoregulatory active ingredient of Cordyceps sinensis. Zhou X, Luo L, Dressel W, Shadier G, Krumbiegel D, Schmidtke P, Zepp F, Meyer CU.
4 Pharm Biol. 2012;50(9):1103–10. Immunomodulatory effect of polysaccharides from submerged cultured Cordyceps gunnii. Zhu ZY, Chen J, Si CL, Liu N, Lian HY, Ding LN, Liu Y, Zhang YM.
5 J Ethnopharmacol. 2009;124(1):61–8. Cordysinocan, a polysaccharide isolated from cultured Cordyceps, activates immune responses in cultured T-lymphocytes and macrophages: signaling cascade and induction of cytokines. Cheung JK, Li J, Cheung AW, Zhu Y, Zheng KY, Bi CW, Duan R, Choi RC, Lau DT, Dong TT, Lau BW, Tsim KW.
6 Br J Pharmacol. 2003;140(5):895–906. Activation and proliferation signals in primary human T lymphocytes inhibited by ergosterol peroxide isolated from Cordyceps cicadae. Kuo YC, Weng SC, Chou CJ, Chang TT, Tsai WJ.
7 J Surg Res. 2013;185(2):912–22. Suppression of T-cell activation in vitro and in vivo by cordycepin from Cordyceps militaris. Xiong Y, Zhang S, Xu L, Song B, Huang G, Lu J, Guan S.
8 Am J Chin Med. 2010;38(5):961–72. Immunosuppressive effect of Cordyceps CS-4 on human monocyte-derived dendritic cells in vitro. Tang J, Tian D, Liu G.
9 J Ethnopharmacol. 2013;149(3):713–9. Comparisons on enhancing the immunity of fresh and dry Cordyceps militaris in vivo and in vitro. Zhu SJ, Pan J, Zhao B, Liang J, Ze-Yu W, Yang JJ.
10 Chin Med J (Engl). 1991;104(1):4–8. Effects of Cordyceps sinensis on murine T lymphocyte subsets. Chen GZ, Chen GL, Sun T, Hsieh GC, Henshall JM.
11 J Microbiol Biotechnol. 2012;22(8):1161–4. Effect of cordycepin purified from Cordyceps militaris on Th1 and Th2 cytokines in mouse splenocytes. Jeong MH, Seo MJ, Park JU, Kang BW, Kim KS, Lee JY, Kim GY, Kim JI, Choi YH, Kim KH, Jeong YK.
12 Pharmazie. 2011;66(1):58–62. Inhibition of cytokine expression by a butanol extract from Cordyceps bassiana. Byeon SE, Lee SY, Kim AR, Lee J, Sung GH, Jang HJ, Kim TW, Park HJ, Lee SJ, Hong S, Cho JY.
13 J Leukoc Biol. 2009;85(6):987–95. Two-sided effect of Cordyceps sinensis on dendritic cells in different physiological stages. Li CY, Chiang CS, Tsai ML, Hseu RS, Shu WY, Chuang CY, Sun YC, Chang YS, Lin JG, Chen CS, Huang CL, Hsu IC.
14 J Med Food. 2008;11(4):784–8. Immunoglobulin and cytokine production from mesenteric lymph node lymphocytes is regulated by extracts of Cordyceps sinensis in C57Bl/6N mice. Park DK, Choi WS, Park PJ, Kim EK, Jeong YJ, Choi SY, Yamada K, Kim JD, Lim BO.
15 Immunobiology. 2010;215(7):516–20. Effects of two basidiomycete species on interleukin 1 and interleukin 2 production by macrophage and T cell lines. Kawanishi T, Ikeda-Dantsuji Y, Nagayama A.
16 Int J Oncol. 2014;45(1):209–18. 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.
17 Molecules. 2017;22(4);pii: E629. Metronomic cordycepin therapy prolongs survival of oral cancer-bearing mice and inhibits epithelial-mesenchymal transition. Su NW, Wu SH, Chi CW, Liu CJ, Tsai TH, Chen YJ.
18 Pharmazie. 2013;68(9):768–71. Treatment with Cordyceps sinensis enriches Treg population in peripheral lymph nodes and delays type I diabetes development in NOD mice. Wang MF, Zhu QH, He YG.
19 Int Immunopharmacol. 2009;9(5):582–6. Immunoregulatory Cordyceps sinensis increases regulatory T cells to Th17 cell ratio and delays diabetes in NOD mice. Shi B, Wang Z, Jin H, Chen YW, Wang Q, Qian Y.
20 Rheumatology (Oxford). 2009;48(1):45–8. Cordycepin inhibits IL-1beta-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts. Noh EM, Kim JS, Hur H, Park BH, Song EK, Han MK, Kwon KB, Yoo WH, Shim IK, Lee SJ, Youn HJ, Lee YR.
21 Clin Exp Med. 2009;9(4):277–84. Immunological alterations in lupus-prone autoimmune (NZB/NZW) F1 mice by mycelia Chinese medicinal fungus Cordyceps sinensis-induced redistributions of peripheral mononuclear T lymphocytes. Chen JL, Chen YC, Yang SH, Ko YF, Chen SY.
22 Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2006;22(3):321–3. Effects of cordyceps sinensis alcohol extractive on serum interferon-gamma level and splenic T lymphocyte subset in mice with viral myocarditis. Li F, Gao XY, Rao BF, Liu L, Dong B, Cui LQ.
23 Biol Pharm Bull. 2006;29(2):354–60. Water extract of Cordyceps militaris enhances maturation of murine bone marrow-derived dendritic cells in vitro. Kim GY, Ko WS, Lee JY, Lee JO, Ryu CH, Choi BT, Park YM, Jeong YK, Lee KJ, Choi KS, Heo MS, Choi YH.
24 Zhongguo Zhong Yao Za Zhi. 2007;32(15):1566-8. Effect of dongchong xiacao capsule on airway inflammation of asthmatic patients. Wang NQ, Jiang LD, Zhang XM, Li ZX.
25 Zhong Xi Yi Jie He Xue Bao. 2010;8(4):341–6. Effects of Cordyceps extract on cytokines and transcription factors in peripheral blood mononuclear cells of asthmatic children during remission stage.
Sun W, Yu J, Shi YM, Zhang H, Wang Y, Wu BB.
26 Zhong Yao Cai. 2000;23(7):402–4. Effect of Cordyceps sinensis on the Th1/Th2 cytokines in patients with Condyloma Acuminatum. Gao Q, Wu G, He D.
27 Transpl Immunol. 2008 Jul;19(3-4):159–66. C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A. Jordan JL, Hirsch GM, Lee TD.
28 Hunan Yi Ke Da Xue Xue Bao. 2000 Jun 28;25(3):248–50. Effects of cordyceps sinensis on T lymphocyte subsets and hepatofibrosis in patients with chronic hepatitis B. Gong HY, Wang KQ, Tang SG.
29 Zhongguo Zhong Xi Yi Jie He Za Zhi. 1992 Jun;12(6):338–9, 323. Effect of Cordyceps sinesis on T-lymphocyte subsets in chronic renal failure. Guan YJ, Hu Z, Hou M.
30 Fitoterapia. 2010 Dec;81(8):961–8. Medicinal uses of the mushroom Cordyceps militaris: current state and prospects. Das SK, Masuda M, Sakurai A, Sakakibara M.
31 J Pharm Pharmacol. 2009 Mar;61(3):279–91. Cordyceps fungi: natural products, pharmacological functions and developmental products. Zhou X, Gong Z, Su Y, Lin J, Tang K.
32 Food Chem Toxicol. 2010 Nov;48(11):3080–4. Safety assessment of Cordyceps guangdongensis.
Yan WJ, Li TH, Lin QY, Song B, Jiang ZD.
33 BMC Complement Altern Med. 2013 Oct 11;13:261. Neurite outgrowth stimulatory effects of culinary-medicinal mushrooms and their toxicity assessment using differentiating Neuro-2a and embryonic fibroblast BALB/3T3. Phan CW, David P, Naidu M, Wong KH, Sabaratnam V.