Maitake Mushroom (Grifola frondosa): A Comprehensive Reference
1. Identity, Taxonomy, and Natural Source
Grifola frondosa is a Basidiomycetes fungus that belongs to the family Grifolaceae and the order Polyporales. In Japan its edible fruiting body is known as maitake; mai means dance and take means mushroom. G. frondosa is known as "hui-shu-hua" (grey tree flower) in Chinese, possibly due to its appearance. In the United States and Canada it is commonly called sheep's head, king of mushrooms, hen-of-the-woods, and cloud mushroom.
G. frondosa grows around the stumps of broadleaf trees or trunks and is edible when young. The environment of the northeastern part of Japan is suitable for the growth of G. frondosa. The temperate forests in eastern North America, Europe, and Asia are also ideal for its growth.
It is characterized by forming grayish-brown fan-shaped mushrooms 2 to 7 cm in diameter arising from a tuberous underground structure. The foot is milky white and hardens as it matures. Mushrooms gather together, overlapping one another, forming groups that can acquire monstrous dimensions and weigh more than 45 kg. Growth occurs during the summer or fall on the floor beside the base of trees or stumps.
Carbohydrates and protein are the major constituents contributing to the dry weight of G. frondosa, taking up around 70–80% and 13–21%, respectively, with emerging research linking these constituents to various health benefits.
Commercial Cultivation
Grifola frondosa has only been artificially cultivated since the mid-1980s in Japan. Mass production followed about five years later. By 1999, Japanese cultivators produced nearly 40,000 metric tons, and in 2001, China produced 14,600 metric tons. Annual production in China and Japan has steadily increased due to the popularity of this mushroom. Part of the reason for the relative delay in the onset of human cultivation stems from its biology. Grifola frondosa grows at the base of large oak trees, emanating from the center of the trunk or from large rotting roots, rather than from logs like wood ear, shiitake, and enoki. So it was not easily cultivated by the log method, resulting in the delay in its domestication.
There are three main methods for its cultivation: bottle culture, bag culture, and outdoor bed culture. Bag culture is the most popular in Japan due to its low cost, small space requirements, and easy indoor environment control.
2. Traditional and Historical Use
In Japan and China, maitake has been highly valued not only as a culinary delicacy but also for its medicinal properties for more than 3,000 years. Traditionally, it was used in Eastern medicine to enhance the immune system, lower blood pressure, and support overall health.
Maitake gained fame for its delicious taste and wellness uses during Japan's Edo Period (1603–1868). The feudal lord of the Tohoku region even gifted many maitake to the Edo Shogun. Legend has it that Buddhist nuns and woodcutters discovered maitake mushrooms on a mountain trail and celebrated their find by dancing.
During Japan's feudal era, maitake was used as currency; the daimyo, or provincial nobles, would exchange maitake for its weight in silver from the shogun, the military ruler of Japan.
While it is true that maitake has been plucked and eaten by populations in what is today's China for millennia, the extremely diverse regional names suggest limited scholarly documentation of it in classical Chinese texts. The current Mandarin Chinese name "Huishuhua" (灰樹花), meaning "Grey Treeflower," refers to its multi-petaled appearance. This name is first used in written form in The Fungi of China (中国的真菌) by Deng Shuqün only in 1963.
Traditional Chinese Medicine used maitake similarly to Reishi mushroom, and it was also used in traditional Japanese herbalism. In 1936, Dr. Kisaku Mori, MD, founded the Institute of Mushroom Research to compile and study the use of mushrooms in Kampo (traditional Japanese medicine). After lifelong research on traditional use of medicinal mushrooms in Japan, he published a classic work, Mushrooms as Health Foods, in 1974.
It was only in the 1980s that scientists in Japan took serious scientific notice of the mushroom. A Grifola frondosa polysaccharide-based drug was developed in China and approved as an adjunctive therapeutic drug for cancer treatment by the State Food and Drug Administration (SFDA) in 2010. There are eight fungal glycan-based drugs; some must be injected in order to be effective in vivo, but the Grifola frondosa polysaccharide-based drug can be taken either orally or by injection.
3. Key Constituents and Active Compounds
Since the discovery of the D-fraction more than three decades ago, many other polysaccharides, including β-glucans and heteroglycans, have been extracted from the G. frondosa fruiting body and fungal mycelium, which have shown significant antitumor and immunomodulatory activities. Another class of bioactive macromolecules in G. frondosa is composed of proteins and glycoproteins, which have shown antitumor, immunomodulation, antioxidant, and other activities. A number of small organic molecules such as sterols and phenolic compounds have also been isolated from the fungus and have shown various bioactivities.
3.1 The D-Fraction and MD-Fraction (Beta-Glucan Complexes)
Maitake D-fraction (also called PDF) is the bioactive extract of maitake mushroom and its active constituent is the protein-bound polysaccharide (proteoglucan), more specifically known as β-glucan. PDF has been extensively studied and a number of its medicinal potentials have been unveiled and demonstrated.
The D-fraction or PDF is a protein-bound polysaccharide or proteoglucan, consisting of β-glucan (either β-1,6-linked glucan with β-1,3 branches, or β-1,3-linked glucan branched with β-1,6 glucosides) as a main polysaccharide backbone to which a few uncharacterized protein units are attached. PDF is not a pure form of β-glucan but is a "proteoglucan" having both β-glucan (major) and protein (minor) portions.
This particular extract came to be known as the "D-fraction" and was patented in Japan. The MD-fraction, a more purified and biologically active version of the D-fraction, was later developed and patented. An X-fraction has also been isolated.
Rich in bioactive compounds such as β-glucans and protein units including D-fraction, X-fractions, grilofan, and SX-fraction, this mushroom exhibits potent anti-proliferative and immunomodulatory effects.
3.2 The SX-Fraction
A novel bioactive extract known as "SX-fraction" (MSX), which is a water-soluble glycoprotein with an average molecular weight of 20,000 Da, was discovered to be an extract that can improve insulin resistance. SX-Fraction is a maitake compound (a glycoprotein) that was awarded a US patent in 2007 for anti-diabetic, anti-hypertensive, anti-obesity, and anti-hyperlipidemic effects.
3.3 Proteins, Glycoproteins, and Other Small Molecules
Apart from polysaccharides, other molecular fractions isolated from G. frondosa fruiting bodies or mycelial biomass have shown promising medicinal values. The protein components of G. frondosa, including glycoprotein, have shown anti-tumor, immune-enhancing, anti-diabetic, anti-hypertensive, anti-hyperlipidemic, and anti-viral effects. Moreover, other small biomolecules in G. frondosa have been found to possess health benefits such as anti-inflammation, hypoglycemia, antitumor, and antioxidation.
Studies confirm that Grifola frondosa extract (GE) represents an important source of polysaccharides and phenolic compounds with in vitro antioxidant activity.
4. Established and Proposed Mechanisms of Action
4.1 Immunomodulation
Numerous studies highlight maitake's ability to activate key immune cells, notably macrophages, natural killer cells (NK), and cytotoxic T cells, which are pivotal in immune defence and direct tumour cell destruction. Moreover, its glucans stimulate the production of cytokines such as interleukin-1 and interleukin-2, crucial mediators of immune responses.
The high molecular weight of β-glucans from maitake extract suggests the great difficulty of these molecules in crossing biological membranes by simple diffusion, requiring a specific receptor after entering the systemic circulation in order to trigger their molecular action mediated by second intracellular messengers. Research has reported that the Dectin-1 membrane receptor recognizes glucans with β-1,3 and/or β-1,6 links present on fungal walls, proposing that receptor as a new receptor and as a therapeutic target for the immunomodulatory effects of glucan compounds.
4.2 Antitumor Mechanisms
Besides increasing the ability of macrophages to engulf and destroy cancer cells, microbes, and other foreign cells, the β-glucans stimulate the production of signaling proteins of the immune system, such as interleukin-1, interleukin-2, and cytokines. The β-glucans have been shown to possess anticarcinogenic activity and prevention of oncogenesis and metastasis in certain cancer types. However, the exact mechanisms by which the β-glucans prevent carcinogenesis are unclear.
Research reported that the β-glucan component of maitake's D-fraction can influence the switching on and off of genes expressed in human breast cancer Michigan Cancer Foundation (MCF)-7 cells, leading to apoptosis induction.
4.3 Hematopoietic Effects
Maitake mushroom beta-glucan stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. Maitake appears to enhance differentiation and migration of hematopoietic cells including progenitors and thereby enhances peripheral myeloid cell reactive oxygen species (ROS) function.
4.4 Glycemic and Metabolic Mechanisms
Preclinical studies suggest antidiabetic effects with alpha-glucan via increased insulin sensitivity on insulin receptors and decreased insulin resistance in peripheral target tissues. All treatments compared with control generally decreased circulating glucose levels, but only maitake SX consistently enhanced measured insulin sensitivity. Maitake SX could significantly lower systolic blood pressure in diabetic rats. Only rats receiving maitake SX showed decreased activity of the renin-angiotensin system and increased nitric oxide system activity compared with control.
4.5 Antioxidant and Longevity Pathways
In vivo evaluation demonstrated that treatment with G. frondosa extract significantly reduced the lipid content in C. elegans, decreased the intracellular ROS accumulation and the aging-related lipofuscin pigment, and increased the nematode lifespan. Mutant and gene expression analyses revealed that the activation of the DAF-16/FOXO and SKN-1/NRF-2 signalling pathways was necessary for the anti-obesity and antioxidant activities of the extract, respectively.
5. Scientific Evidence by Area of Use
The following sections describe the state of scientific evidence for each major area of investigation. Where evidence derives solely from animal or in vitro studies, this is explicitly stated. Where human clinical data exist, study design, population, dosage, and outcomes are reported.
5.1 Immunomodulation
Human/Clinical Evidence (Moderate Preliminary Quality): A polysaccharide extract from Grifola frondosa showed immunomodulatory effects in preclinical studies, supporting the potential for clinical use. Whether oral administration in humans produces measurable immunologic effects, however, was initially unknown. In a Phase I/II dose-escalation trial, 34 postmenopausal breast cancer patients who were free of disease after initial treatment were enrolled sequentially in five cohorts. Maitake liquid extract was taken orally at 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for 3 weeks.
No dose-limiting toxicity was encountered. Two patients withdrew prior to completion of the study due to grade I possibly related side effects: nausea and joint swelling in one patient; rash and pruritus in another. There was a statistically significant association between maitake and immunologic function (p < 0.0005). Increasing doses of maitake increased some immunologic parameters and depressed others; the dose-response curves for many endpoints were non-monotonic, with intermediate doses having either immune-enhancing or immune-suppressant effects compared with both high and low doses. The conclusions noted that botanical agents produce more complex effects than assumed, and may depress as well as enhance immune function.
MDS Phase II Study: Based on dose effects from the prior breast cancer trial, a follow-up study was launched using maitake extract at 6 mg/kg (i.e., 3 mg/kg twice daily) in a Phase II, open-label, non-randomized, safety, and efficacy trial enrolling MDS patients with IPSS low- or intermediate-1-risk disease. Of 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil function (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with healthy controls (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrates that maitake has beneficial immunomodulatory potential in MDS. Further study is warranted.
Overall Evidence Assessment: There is a lack of systematic study on the safety and effectiveness of maitake in humans. The available evidence is preliminary and based on small, non-randomized, or phase I/II trials. Large, randomized controlled trials are absent.
5.2 Cancer — Antitumor Activity
Preclinical Evidence: In preclinical studies, various formulations suggest protective effects against high insulin and lipid levels, and inflammation. Antitumor potential, enhanced bone marrow colony formation, reduced doxorubicin toxicity, and enhanced interferon activity have also been shown.
Previous studies indicated that the MD-fraction (MDF), in which the active component is beta 1,6-glucan with beta 1,3-branches, has anti-tumor activity as an oral agent and acts as an immune adjuvant. Using the Colony Forming Unit (CFU) assay to detect formation of granulocyte-macrophage (CFU-GM) colonies, the data showed that the addition of MDF significantly enhanced the development of CFU-GM in a dose range of 50–100 μg/ml (p < 0.004).
Human/Clinical Evidence: Data in humans are limited. In a small case series, tumor regression or significant improvements in symptoms were observed in some subjects who took maitake extract. In small trials, oral maitake extract appeared to have immunomodulatory effects in postmenopausal breast cancer patients, and enhanced neutrophil and monocyte function in patients with myelodysplastic syndrome.
Various physiological benefits of D-fraction have been postulated or demonstrated, ranging from immunomodulatory and antitumor activities. Two major biological activities of PDF — immunomodulatory and antitumor — have been the main targets for scientific and clinical research. To demonstrate and confirm such biological activities, numerous studies have been performed in vitro and in vivo or in clinical settings.
Maitake has been studied to a limited extent for treating cancer; however, the information available is not sufficient to recommend it for this use.
Overall Evidence Assessment: Antitumor evidence remains largely preclinical (animal and in vitro). Available human data are based on small case series and early-phase trials without randomized controls. No large, well-controlled clinical trials have established maitake as an effective cancer treatment in humans.
5.3 Diabetes and Glycemic Control
Preclinical Evidence: SX-fraction of Grifola frondosa significantly increased glucose uptake in rat skeletal muscle L6 cells and resulted in around a 30–63% decline in fasting blood glucose levels after treatment in diabetic patients. Additionally, 8 weeks of treatment with Grifola frondosa inhibited the rise in blood glucose levels in spontaneously diabetic mice.
Human/Clinical Evidence: A clinical study found that Type 2 diabetics taking SX-Fraction for two months were able to significantly reduce their fasting blood glucose, triglycerides, insulin, and body weight. However, the size and methodological details of this study are limited in published literature.
G. frondosa polysaccharides have also been suggested to contribute to the treatment of metabolic disorders such as non-alcoholic fatty liver disease (NAFLD) and diabetes, indicating their potential for preventing or treating hyperglycemia and hyperlipidemia.
Overall Evidence Assessment: Glycemic effects are well-documented in preclinical models. Human data are suggestive but methodologically limited, with small sample sizes and lack of blinding or placebo control. The evidence is preliminary.
5.4 Polycystic Ovary Syndrome (PCOS) and Ovulation
A randomized, open-label comparator trial (N = 57) investigated the ability of a maitake extract formulation standardized to at least 18% SX-fraction as monotherapy and in combination with clomiphene citrate to induce ovulation in women with polycystic ovary syndrome. Nonresponders in either monotherapy group were subsequently switched to combination therapy. Although ovulation cycle rates were higher with clomiphene monotherapy than maitake extract monotherapy (69.9% vs 41.7%, respectively), 87% of monotherapy nonresponders ovulated once switched to the combination therapy.
Maitake SX-Fraction was evaluated in women with polycystic ovaries, a condition in which the ovaries do not produce eggs. SX-Fraction was chosen because insulin resistance is believed to be the underlying cause of the disorder. A glycoprotein extract from maitake mushroom (SX-fraction) is considered as one alternative method for improving insulin sensitivity and also promoting aromatization of testosterone to estradiol in granulosa cells.
Overall Evidence Assessment: Limited to a single open-label randomized comparator trial and a small pilot study. Promising but far from conclusive; larger, blinded, placebo-controlled trials are needed.
5.5 Blood Pressure and Cardiovascular Effects
Studies have shown that maitake mushrooms can lower blood pressure and blood glucose, and modify serum lipid levels. This evidence is predominantly derived from animal studies. Maitake SX could significantly lower systolic blood pressure in diabetic rats. Only rats receiving maitake SX showed decreased activity of the renin-angiotensin system and increased NO system activity compared with control under the conditions examined.
Overall Evidence Assessment: Evidence for blood pressure effects is based primarily on animal (rodent) studies. No controlled human trials specifically evaluating blood pressure reduction by maitake have been identified.
5.6 Antioxidant and Anti-Aging Effects
Treatment with G. frondosa extract significantly reduced the fat content of C. elegans, decreased the production of intracellular ROS and aging-lipofuscin pigment, and increased the lifespan of nematodes. These findings are from an invertebrate model organism and cannot be directly extrapolated to humans.
Overall Evidence Assessment: Antioxidant and anti-aging evidence is confined to in vitro and invertebrate model studies. Human data are absent.
5.7 Antiviral Activity
Antiviral activity of maitake against human immunodeficiency virus (HIV)/AIDS was confirmed by the US National Cancer Institute in 1992. Physiological benefits of D-fraction ranging from treatment for viral infections such as hepatitis B and HIV have been postulated or demonstrated. Robust human clinical trial data for these applications remain limited or absent in the peer-reviewed literature.
6. Body Systems and Health Areas of Association
- Immune system: Activation of macrophages, NK cells, cytotoxic T cells, and dendritic cells; stimulation of cytokine production (IL-1, IL-2); modulation of innate and adaptive immunity via Dectin-1/CR3 receptor engagement.
- Hematopoietic system: Stimulation of hematopoietic progenitor cell differentiation and granulocyte colony-stimulating factor (G-CSF) production; mitigation of bone marrow suppression associated with chemotherapy.
- Endocrine/metabolic system: Improvement of insulin sensitivity; reduction of fasting blood glucose; reduction in triglycerides; potential benefit in PCOS via effects on insulin resistance and ovarian hormone metabolism.
- Cardiovascular system: Reduction in systolic blood pressure in animal models; modulation of the renin-angiotensin system and nitric oxide pathways (preclinical only).
- Oncology-adjacent: Immunological support investigated as an adjunct in cancer and myelodysplastic syndrome; induction of apoptosis in breast cancer cell lines; anti-metastatic activity in animal models.
- Antioxidant/anti-aging: Reduction of intracellular ROS; activation of FOXO and NRF-2 stress-response pathways (demonstrated in C. elegans).
7. Dosage Forms and Reported Dosages
Capsules of the whole powder are generally supplied in 100 to 500 mg capsules; standardized liquid extracts contain 1 mg of D-fraction per drop. Manufacturer-recommended disease-preventive daily doses range from 12 to 25 mg of the extract and up to 2,500 mg of the whole powder. One clinical study evaluating effects of maitake in HIV-positive patients used daily doses of 6 g of the whole powder or 20 mg of a purified extract with 4 g of whole maitake powder for 12 months. An oral maitake extract at a dosage of 3 mg/kg twice daily for 12 weeks has been used to evaluate immunological response in patients with myelodysplastic syndromes.
Extracts standardized to the D-fraction of maitake are commonly recommended. Commercial preparations commonly provide 3 to 25 mg of standardized D- or MD-fraction plus 75 to 250 mg whole powder per capsule.
Maitake is available in various supplement forms. Dry extracts (capsules, bulk powders) and liquid extracts (tinctures) are the most common, and some of them are standardized to 30% of D-fraction. Mixtures of powdered whole mushrooms (500–1,500 mg) and D-fraction (60 mg) can also be found. Some manufacturers add vitamin C to prevent the oxidation of active components.
In the Phase I/II breast cancer immunological study, maitake liquid extract was taken orally at 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for 3 weeks.
In the preceding dose-escalation trial, breast cancer patients received maitake extract orally at 5–7 mg/kg daily over 3 weeks, showing significant dose-related changes in immune function with no serious adverse events or dose-limiting toxicity. Based on these dose effects, the subsequent MDS study was launched using maitake extract at 6 mg/kg (i.e., 3 mg/kg twice daily).
Powders of maitake mushroom may be obtained by air drying, freeze drying, drum drying, spray drying, heat drying, and/or partial vacuum drying maitake mushrooms.
8. Safety Considerations and Drug Interactions
8.1 General Tolerability
In the Phase I/II breast cancer trial, no dose-limiting toxicity was encountered. Two patients withdrew prior to completion of the study due to grade I possibly related side effects: nausea and joint swelling in one patient; rash and pruritus in another. In the MDS Phase II study, maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment was observed.
When taken by mouth, maitake mushroom is possibly safe for most people. There is not much information about potential side effects. Some people have reported nausea after taking maitake mushroom.
8.2 Hypoglycemia Risk
Maitake mushroom might lower blood sugar levels. Taking maitake mushroom along with diabetes medications might cause blood sugar to drop too low. Blood sugar should be monitored closely. Medscape's drug interaction database notes that maitake increases the effects of glimepiride by pharmacodynamic synergism (minor/significance unknown), with an increased risk of hypoglycemia identified in animal research. Analogous pharmacodynamic interactions are listed for glipizide and glyburide.
8.3 Blood Pressure
Maitake mushroom might lower blood pressure. Because it may lower blood sugar levels, maitake should not be taken with other herbs or supplements that may also lower blood sugar, including diabetes medications. Maitake may increase the blood-thinning effects of warfarin (Coumadin).
8.4 Anticoagulants and Perioperative Concerns
Maitake may increase the blood-thinning effects of warfarin (Coumadin) and should only be taken under physician supervision when on blood-thinning medication. People preparing for surgery should not take maitake for at least two weeks prior to avoid issues with blood sugar or blood clotting.
8.5 Pregnancy and Lactation
There is not enough reliable information to know if maitake mushroom is safe to use when pregnant or breast-feeding.
8.6 Immunomodulatory Complexity
Increasing doses of maitake increased some immunologic parameters and depressed others; the dose-response curves for many endpoints were non-monotonic, with intermediate doses having either immune-enhancing or immune-suppressant effects compared with both high and low doses. Cancer patients should be made aware of the fact that botanical agents produce more complex effects than assumed, and may depress as well as enhance immune function.
8.7 Evidence Gaps and Research Limitations
There is a lack of systematic study on the safety and effectiveness of maitake in humans. Based on popular use and supportive scientific data, three indications are discussed in the literature: cancer, diabetes, and immunostimulation. Despite the lack of scientific evidence, maitake mushroom remains a popular agent in commercial products. Future randomized controlled trials are warranted.
Future research efforts must prioritize the complete understanding of the physiological mechanisms responsible for maitake mushrooms' therapeutic properties. Moreover, conducting robust clinical trials to assess potential side effects and drug interactions in human subjects is imperative.
References
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