Do mushroom species work better when combined?

Nutritional Outlook, Volume 25, Issue 7

Is there any real value in combining mushrooms in a blended product, or is it just “marketing science”?

Anyone in the dietary supplement industry who is paying attention recognizes that medicinal mushrooms are trending ingredients—especially in combination formulas. Of course, the use of mushrooms for medicinal purposes is not exactly a new trend. For more than two thousand years, mushrooms have been used as medicines. A great example of this is that in September of 1991 a 5,300-year-old mummy was found in the Tyrolean Alps, and his medicine kit contained Piptoporus betulinus, a mushroom he probably used as a natural worm-killer and laxative.1

Although the mummy in question only had a single mushroom in his medicine kit, nowadays it is not unusual to find various combinations of mushrooms used together in dietary supplement formulations. But here’s the question: Is there any real value in combining mushrooms in a formula, or is that just “marketing science”?

Since the most prevalent use of medicinal mushrooms is as immune system booters, this seems like a good avenue for pursuing an answer to this question.

Let’s begin by identifying the fact that medicinal mushrooms are a rich source of naturally occurring polysaccharides, especially beta-glucans. It is these compounds which have been shown to directly stimulate immune reactions. Now, let’s take a look at three well-known and well-researched mushrooms that have demonstrated value for the immune system: reishi, shiitake, and maitake.


The active constituents in reishi (Ganoderma lucidum) are primarily polysaccharides, including beta-glucans and triterpenes.2,3,4 Reishi constituents seem to have a variety of effects, including antioxidant, immune modulating, and cardiovascular benefits.2

In human research, 34 advance-stage cancer patients were treated with 1.8 g of reishi polysaccharide fractions, three times daily orally before meals, for 12 weeks. The results were that reishi polysaccharide fractions enhanced the immune responses in patients.4 In a 12-month study, a water-soluble extract of reishi (1.5 g/day) suppressed the development of colorectal adenomas (precancerous lesions of the large bowel) and decreased the size of existing colorectal adenomas.5


Shiitake (Lentinula edodes)6 is currently used for promoting healthy immune function7, healthy liver function8, and modulating the unwanted growth of mutated stomach9 and pancreas cells10, and has been validated in scientific literature for these purposes.

Active hexose correlated compound (AHCC) is an extract derived from shiitake, and, like its predecessor, has antioxidant effects and is thought to act as a biological response modifier. It seems to promote the activity of natural killer (NK) cells in patients with unwanted growth of mutated cells. AHCC demonstrated early clinical promise in promoting healthy immune response.11 This was shown in animal research where AHCC helped restore immune response that had been negatively affected by trauma, infection, and food deprivation.12

In humans, the effect of AHCC on immune response was investigated by measuring the number and function of circulating dendritic cells (DCs), a type of immune cell, in healthy volunteers. Twenty-one healthy volunteers were randomized to receive placebo or AHCC for four weeks. The results were that the AHCC group had a significantly higher number of total DCs compared to when they first started the study and compared to the control subjects. Other types of immune cells were also significantly increased in the AHCC group compared to controls.13


As with other mushrooms, maitake (Grifola frondosa) contains beta-glucan, the D-fraction of which appears to be the most active and potent form. Maitake’s immunostimulant properties include the activation of natural killer cells, cytotoxic T-cells, and interleukin-1.14

In human research15, there was a statistically significant association between maitake and immunologic function (p < 0.0005) in breast cancer patients. A maitake D-fraction–based drug was developed in China and approved as an adjunctive therapeutic drug for cancer treatment by China’s State Food and Drug Administration (SFDA) in 2010.16 This maitake D-fraction has been studied extensively for about 30 years.17

Other maitake extracts such as maitake Pt78—a maitake fruiting body mushroom extract with a high concentration of 1,3-1,6 beta-glucans—have also been shown to be effective for promoting immune function.18, 19, 20

Combining Reishi, Shiitake, and Maitake

So now that we know that each of these mushrooms and their derivatives have individual value for the immune system, what happens when they are combined?

To examine this, a study21 was conducted in which nine commercially available preparations from three mushroom species—reishi, shiitake, and maitake—were analyzed for beta- and alpha-glucan content. Based on the glucan content, researchers selected three extracts to combine into a formula and evaluated the ability of the individual extracts and formula to impact on the expression of cytokines IL-1α, IL-6, IL-10, and TNF-α in human macrophages with and without lipopolysaccharide (LPS) stimulation. (LPS stimulates immune responses by interacting with the membrane receptor CD14 to induce the generation of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6.)

The majority of mushroom extracts in the formula were found to be highly potent immunostimulators possessing EC50 values (i.e., the concentration of a drug that induces a response halfway between the baseline and maximum) lower than 100 μg/ml. Interestingly, the mushroom formula had lower EC50 values in TNF-α expression from LPS-stimulated macrophages compared to the individual extracts.

Now you’re probably thinking, “What the heck does that mean?” The answer is that it suggests a potential synergistic effect of the mushroom formula. The results of this study illustrate that indeed the mushroom formula exhibited an immunostimulatory synergistic effect on the expression of the majority of cytokines evaluated in both LPS-stimulated and non-stimulated human macrophages. This represents the first report of a synergistic immunomodulatory response in human macrophages elicited from a mushroom formula rationally derived from beta- and alpha-glucan content.


So, the answer is “yes” to the original question: “Is there any real value in combining mushrooms together?” In the case of reishi, shiitake, and maitake, the combination has a synergistic immunostimulatory effect. While this doesn’t mean that a combination of any mushrooms together will exhibit synergism, it certainly validates the use of these three mushrooms together for purposes of supporting immune function.

About the Author

Gene Bruno, MS, MHS, RH (AHG), is a certified nutritionist and registered herbalist with 42 years of dietary supplement industry experience. With a master’s degree in nutrition and a second master’s degree in herbal medicine, he has a proven track record of formulating innovative, evidence-based dietary supplements. Mr. Bruno currently serves as both the vice president of scientific and regulatory affairs at NutraScience Labs and professor of nutraceutical science at Huntington University of Health Sciences.


  1. Halpern GM, Miller AH. Medicinal Mushrooms: Ancient Remedies for Modern Ailments (New York: M. Evans & Company, 2002), 59-74
  2. Wasser SP et al. “Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: A modern perspective.” Critical Reviews in Immunology, vol. 19, no. 1 (1999): 65-96
  3. Yuen JW et al. “Anticancer effects of Ganoderma lucidum: A review of scientific evidence.” Nutrition and Cancer, vol. 53, no. 1 (2005): 11-17
  4. Gao Y et al. “Effects of ganopoly (a Ganoderma lucidum polysaccharide extract) on the immune functions in advanced-stage cancer patients.” Immunological Investigations, vol. 32, no. 3 (August 2003): 201-215
  5. Oka S et al. “A water-soluble extract from culture medium of Ganoderma lucidum mycelia suppresses the development of colorectal adenomas.” Hiroshima Journal of Medical Sciences, vol. 59, no. 1 (March 2010): 1-6
  6. Jones K. Shiitake: The Healing Mushroom. (Rochester, VT: Healing Arts Press, 1994)
  7. Chang R. “Functional properties of edible mushrooms.” Nutrition Reviews, vol. 54, 11 Pt. 2 (November 1996): S91-S93
  8. Jones K. “Shiitake: A major medicinal mushroom.” Alternative and Complementary Therapies, vol. 4, no. 1 (1998): 53–59
  9. Taguchi I. “Clinical efficacy of lentinan on patients with stomach cancer: End point results of a four-year follow-up survey.” Cancer Detection and Prevention, vol. 1 (1987): 333-349
  10. Matsuoka H et al. “Lentinan potentiates immunity and prolongs survival time of some patients.Anticancer Research, vol. 17, no. 4A (July-August 1997): 2751-2755
  11. Kidd PM. “The use of mushroom glucans and proteoglycans in cancer treatment.” Alternative Medicine Review, vol. 5, no. 1 (February 2000): 4-27
  12. Aviles H et al. “Active hexose correlated compound (AHCC) enhances resistance to infection in a mouse model of surgical wound infection.” Surgical Infections, vol. 7, no. 6 (December 2006): 527-535
  13. Terakawa N et al. “Immunological effect of active hexose correlated compound (AHCC) in healthy volunteers: A double-blind, placebo-controlled trial.” Nutrition and Cancer, vol. 60, no. 5 (2008): 643-651
  14. Nanba H et al. “The chemical structure of an antitumor polysaccharide in fruit bodies of Grifola frondosa (maitake).” Chemical & Pharmaceutical Bulletin, vol. 35, no. 3 (March 1987): 1162-1168
  15. Deng G et al. “A phase I/II trial of a polysaccharide extract from Grifola frondosa (maitake mushroom) in breast cancer patients: Immunological effects.Journal of Cancer Research and Clinical Oncology, vol. 135, no. 9 (September 2009): 1215-1221
  16. He Y et al. “The biological activities of the antitumor drug Grifola frondosa polysaccharide.” Progress in Molecular Biology and Translational Science, vol. 163 (2019): 221-261
  17. He Y et al. “Grifola frondosa polysaccharide: A review of antitumor and other biological activity studies in China.” Discovery Medicine, vol. 25, no. 138 (2018): 159-176
  18. Wesa KM et al. “Maitake mushroom extract in myelodysplastic syndromes (MDS): A phase II study.” Cancer Immunology, Immunotherapy, vol. 64, no. 2 (February 2015): 237-247
  19. Vetvicka V et al. “Immune-enhancing effects of maitake (Grifola frondosa) and shiitake (Lentinula edodes) extracts.” Annals of Translational Medicine, vol. 2, no. 2 (February 2014): 14
  20. Vetvicka V et al. “Immunostimulating properties of two different β−glucans isolated from maitake mushrooms (Grifola frondosa).” Journal of the American Nutraceutical Association, vol. 8, no. 3: 33-39
  21. Mallard B et al. “Synergistic immuno-modulatory activity in human macrophages of a medicinal mushroom formulation consisting of reishi, shiitake and maitake.” PLoS One vol. 14, no. 11 (November 7, 2019): e0224740