Do mushroom species work best when combined?

Anyone who pays attention in the dietary supplement industry recognizes that medicinal mushrooms are trending ingredients, especially in combination formulas. Of course, using mushrooms for medicinal purposes isn’t exactly a new trend. For more than two thousand years, mushrooms have been used as medicine. A good example of this is that in September 1991, a 5,300-year-old mummy was found in the Tyrolean Alps, and its first aid kit contained Piptoporus betulinusa fungus he probably used as a natural wormer and laxative.1

Although the mummy in question only had one mushroom in her medicine bag, it is not uncommon these days 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 it just “marketing science”?

Given that the most common use of medicinal mushrooms is as immune system boosters, this seems like a good lead in finding an answer to this question.

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


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

In human research, 34 patients with advanced cancer 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 improved 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 intestine) and decreased the size of existing colorectal adenomas.5


Shiitake (Lentin edodes)6 is currently used to promote healthy immune functionsevenhealthy liver function8and modulate the unwanted growth of the mutated stomach9 and pancreatic cellstenand has been validated in the 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 appears to promote natural killer (NK) cell activity in patients with unwanted growth of mutated cells. AHCC has demonstrated early clinical promise in promoting a healthy immune response.11 This has been shown in animal research where AHCC has helped restore the immune response that had been negatively affected by trauma, infection, and food deprivation.12

In humans, the effect of AHCC on the immune response has been studied 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 started the study and compared to the control subjects. Other immune cell types were also significantly increased in the AHCC group compared to controls.13


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

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

Other maitake extracts such as Pt78 maitake – an extract of maitake fruiting body mushroom with a high concentration of 1.3-1.6 beta-glucans – have also been shown to promote immune function.18, 19, 20

Combine 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 species of mushrooms – reishi, shiitake and maitake – were analyzed for their beta- and alpha-glucan content. Based on glucan content, researchers selected three extracts to combine into a formula and assessed the ability of individual extracts and the formula to impact expression of the cytokines IL-1α, IL-6, IL-10 and TNF-α in humans. 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 have been shown to be very potent immunostimulators with EC50 values ​​(i.e. the concentration of a drug that induces a response halfway between baseline and maximum) less than 100 μg/ml. Interestingly, the mushroom formula had lower EC50 values ​​in TNF-α expression from LPS-stimulated macrophages compared to individual extracts.

Now you’re probably thinking, “What does that mean?” The answer is that he suggests a potential synergistic effect of the mushroom formula. The results of this study illustrate that indeed the mushroom formula exhibited a synergistic immunostimulatory effect on the expression of the majority of cytokines evaluated in LPS-stimulated and non-stimulated human macrophages. This represents the first report of a synergistic immunomodulatory response in human macrophages elicited by 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?” In the case of reishi, shiitake and maitake, the combination has a synergistic immunostimulating effect. While this does not mean that a combination of mushrooms together will exhibit synergy, it certainly validates the use of these three mushrooms together for the purpose of supporting immune function.

About the Author

Gene Bruno, MS, MHS, RH (AHG), is a Certified Nutritionist and Licensed Herbalist with 42 years of experience in the dietary supplement industry. With a master’s degree in nutrition and a second master’s degree in herbal medicine, he has a proven track record in formulating innovative, evidence-based dietary supplements. Mr. Bruno is currently Vice President of Scientific and Regulatory Affairs at NutraScience Labs and Professor of Nutraceutical Science at Huntington University of Health Sciences.


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