Lentinula edodes mycelia

Lentinula Edodes Mycelia (LEM / AHCC): An Encyclopedic Reference

1. Identity, Nomenclature, and Common Preparations

Taxonomic and Chemical Names

Lentinula edodes, also known as shiitake, is both an edible macromycete of high nutritional value and a medicinal mushroom. Miles Joseph Berkeley first called the fungus Agaricus edodes in 1887, and then in 1976 the mycologist David Pegler placed the mushroom in the genus Lentinula. The full accepted scientific name is Lentinula edodes (Berk.) Pegler. The mycelial-stage extract from this organism is commonly abbreviated LEM (Lentinula Edodes Mycelia extract) in the Japanese research literature. A distinct but related commercially standardized extract is marketed as AHCC® (Active Hexose Correlated Compound).

The Organism and Its Mycelium

Lentinula edodes is a xylotrophic white-rot-forming species that can be found growing on oak, poplar, sugar maple, and birch trees, and for mass production it is most often cultivated on wood chips and sawdust. The growth of Lentinus edodes can be divided into two stages: the vegetative phase (mycelium or mycelial growth) and the reproductive phase (fruiting bodies). After the scattered spores have invaded the substrate, the hyphae, which are only visible under a microscope, continually grow and branch to form mycelia, and the fruiting body grows out of the subterranean mycelium through a process called fructification.

It is the second largest cultivated and the most popular edible mushroom in the world, known as "Xianggu" in China and "Shiitake" in Japan.

Common Forms and Preparations

Lentinula edodes mycelia-derived products exist in several distinct forms, each produced by different extraction or culture processes:

• LEM (hot-water extract of mycelia): LEM is a dried powder of a hot water extract of the mycelia of L. edodes before germination, which is cultured in a medium composed of bagasse and rice bran. LEM contains polysaccharides, proteins, nucleic acids, trace minerals, water-soluble lignin, and other components.
• AHCC® (standardized liquid-culture extract): AHCC® is a standardized extract of cultured shiitake or Lentinula edodes mycelia (ECLM) which contains a mixture of nutrients including oligosaccharides, amino acids, and minerals obtained through liquid culture. AHCC glucans are low molecular weight (~5 kDa) polysaccharides with alpha-1,3 linkages.
• Lentinan (isolated polysaccharide): Lentinan is a polysaccharide extracted from Lentinula edodes. The glucan component, especially lentinan, a purified β-1,3-D-glucan with β-1,6 branches and a triple helical structure, has been proven to have marked antitumor activity. An injectable form of lentinan is used for cancer treatment in some countries, but it has not been evaluated in large studies.
• Mycelial solid culture extract (MSCE): A variant cultivated on solid substrates, as used in several Japanese studies on colon cancer models.

Lentinula edodes mycelia is a whole extract prepared from the mycelial culture of Japanese edible mushroom, Lentinus edodes, grown in a solid medium of sugar-cane bagasse and defatted rice bran. The standardized extract of AHCC® was developed in Japan in 1992 by the company Amino Up Chemical Co. Ltd.

2. Traditional and Historical Use

Origins in China

In China, shiitake has been used in traditional medicine for more than 2,000 years. The earliest records of shiitake mushrooms date back to Song Dynasty China (960–1279 AD), where they were recognized for both their culinary and medicinal properties. Ancient Chinese medical texts praised the mushroom for its ability to boost immunity and support overall wellness. The medicinal properties of L. edodes have been studied since the Ming Dynasty (1369–1644).

Japan

Shiitake (Lentinula edodes) is an edible mushroom native to East Asia that has been cultivated in Japan for over 1,000 years. Cultivation methods spread to Japan, with samurai warriors controlling most of the production for the aristocracy. The elders from the Japanese Empire considered shiitake as the "elixir of life," increasing vigor and energy.

People in China first began cultivating shiitake mushrooms about 1,000 to 1,200 years ago, where they knew the species as dongo or shanku. Here, shiitake gained the name that remains widely accepted today — shii, for Castanopsis cuspidata, the hardwood tree species that the mushrooms commonly grow on, and take, the Japanese word for mushroom.

Transition to Modern Medical Use

Lentinan is used widely in Japan and China as an adjuvant to cancer chemotherapy. However, the number of quality clinical trials and studies published in English language, peer-reviewed journals is limited. LEM (Lentinula Edodes Mycelium) is a specialized extract developed in Japan from the root-like mycelium structure rather than the fruiting body. The pioneering work in LEM extraction was done by Noda Shokukin Kogyo, who discovered the unique "self-digestion" process in 1970 — a serendipitous finding during a power outage that led to a breakthrough in extracting bioactive compounds.

3. Key Constituents and Active Compounds

Overview of Chemical Composition

Bioactive compounds such as polysaccharides, purines, proteins (amino acids), fatty acids, polyphenols, and sterols in shiitake mushrooms have been shown to have high nutritional value and enhance human health by promoting anti-inflammatory, antioxidant, antitumor, antiviral, antibacterial, and immunostimulatory effects. Mycelium produces more functional compounds with better activity than the fruiting body alone, according to comparative investigations.

Polysaccharides

LEM contains polysaccharides, proteins, nucleic acids, trace minerals, water-soluble lignin, and other components. The most active components of LEM are two glycogen-like polysaccharide fractions (molecular weight from 50,000 to 100,000 Da).

β-Glucan is the major bioactive component in lentinan with immunostimulatory effect. The antitumor property of lentinan was reported in the 1960s. Biochemical studies indicate that immunocytes can be activated by lentinan through multiple signaling pathways, such as TLR4/Dectin1-MAPK and Syk-PKC-NFκB pathways.

AHCC® is distinguished from most mushroom extracts by its glucan profile: AHCC is primarily composed of α-glucan components as compared to most mushroom extracts, which are composed of β-glucan components.

Lignin and Phenolic Compounds

The hot-water extracts of Lentinula edodes mycelia (LEM) contain carbohydrates, proteins, phenolic compounds, and lignin digest, which perform various physiological activities. Vanillic acid and syringic acid contained in LEM have shown hepatoprotective activities in mice with acute and chronic liver injury, and low-molecular-weight lignin maintained the viability of primary cultured hepatocytes treated with carbon tetrachloride.

Eritadenine

Eritadenine inhibits an enzyme involved in producing cholesterol. The bioactive compound eritadenine and the flavour component lenthionine are both produced in shiitake mycelium.

Additional Notable Compounds

Other constituents of interest found in the mushroom include the antioxidant phenolic compounds gallic acid, protocatechuic acid, and catechin; as well as eritadenine, selenium (as selenomethionine), ergosterol, vitamin D, and calcium.

Intensive chemical investigations of the fruiting bodies and mycelium of shiitake mushrooms (Lentinus edodes) have identified five new compounds named lentinmacrocycles A–C and lentincoumarins A–B, along with fifteen known compounds. Shiitake mushrooms are renowned as the "King of mountain treasures" in China due to their abundant nutritional and health-enhancing properties. The anti-inflammatory activity test showed that lentincoumarins A, (3S)-7-hydroxymellein, (3R)-6-hydroxymellein, and succinic acid exhibited strong NO inhibitory effects (IC₅₀ < 35 μM), and (3S)-5-hydroxymellein and (3R)-6-hydroxymellein exhibited potent TNF-α inhibitory effects (IC₅₀ < 80 μM).

Composition of AHCC® Specifically

Active hexose correlated compound (AHCC) is a mixture of polysaccharides, amino acids, lipids, and minerals derived from co-cultured mycelia of several species of Basidiomycete mushrooms.

4. Established Mechanisms of Action

Immunomodulation: Innate and Adaptive Immunity

AHCC®, which is an extract from the culture of shiitake (Lentinula edodes) mycelia, has a broad range of effects on the immune system including NK and T cells. Such effects could be executed by directly modulating the numbers and functions of these cells as well as by affecting the function of monocytes, macrophages, and DCs with the capacity to promote T cell function.

AHCC treatment significantly delayed tumor development after inoculation of either melanoma cell line B16F0 or lymphoma cell line EL4. Treatment with AHCC enhanced both antigen-specific activation and proliferation of CD4+ and CD8+ T cells, increased the number of tumor antigen-specific CD8+ T cells, and, more importantly, increased the frequency of tumor antigen-specific IFN-γ-producing CD8+ T cells. AHCC treatment also showed increased cell number of NK and γδ T cells, indicating the role of AHCC in activating these innate-like lymphocytes.

Regulatory T Cell Suppression

Administration of LEM resulted in decreased levels of IL-6 and TGF-β in mice serum. These results strongly suggest that LEM can restore antitumor T cell response and can be used as an adjuvant in colon cancer immunotherapy.

Antiviral Mechanisms

LEM and its purified fractions have been shown to have antiviral activities against hepatitis C virus, herpes simplex virus, and human immunodeficiency virus. LEM directly inhibited the virus growth of influenza virus possibly by preventing the entry and/or uncoating processes of viral infection.

Regarding the mechanism of HPV clearance specifically: Researchers found that AHCC® downregulates interferon-β (IFN-β) expression and upregulates IFN-γ, which is crucial for activating cytotoxic T cells and promoting viral clearance. The duration of AHCC supplementation required beyond the first negative result needs more evaluation to optimize success for durable outcomes. The suppression of the IFN-β level to less than 20 pg/ml correlated with clearance of HPV infections and merits further evaluation as a clinical tool for monitoring patients with HPV infections.

Hepatoprotective Mechanisms

LEM has hepatoprotective activities in animals with acute liver injury induced by concanavalin A or D-galactosamine. Moreover, LEM suppresses liver fibrosis and inflammation in mice with chronic liver injury induced by carbon tetrachloride. Low-molecular-weight lignin-rich fraction in the extract of cultured Lentinula edodes mycelia attenuates carbon tetrachloride-induced toxicity in primary cultures of rat hepatocytes.

Antitumor Mechanisms

Lentinan is shown to be an immunopotentiator and appears to stimulate macrophage and T-cell proliferation with no direct cytotoxic effect against tumor cells. Studies conducted in vitro and in animal models demonstrated that L. edodes bioactive compounds, in particular glucans, have anti-inflammatory and antioxidant effects, induce apoptosis of cancer cells, reduce tumor angiogenesis, restore gut microbiome heterogeneity, and improve gut barrier dysfunction.

5. Scientific Evidence by Area of Use

5.1 Cancer — Adjunct to Chemotherapy (Breast Cancer)

Anthracycline-based chemotherapies for breast cancer are known to adversely affect patients' quality of life (QOL) and immune function. For that reason, adjuvants that improve those impairments are required. A randomized double-blind study was conducted to evaluate the effectiveness of LEM, which is an oral biological response modifier (BRM) medicine for cancer patients, as such an adjuvant.

A total of 47 breast cancer patients who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy — including FEC, FAC, AC, and EC regimens — were entered in the study. LEM appears to be a useful oral adjuvant for patients receiving anthracycline-based chemotherapy.

A separate pilot study examined LEM for breast cancer patients on hormone therapy: Twenty patients were studied in total. They received only hormone therapy in the first 4 weeks followed by hormone therapy and LEM during the next 8 weeks. Laboratory tests, QOL score, and peripheral blood cytokine production levels were evaluated during the study period. No changes in QOL or cytokines were noted after the first 4 weeks. In contrast, during the following combined therapy period, improvements were noted in QOL and cytokine levels. Although a future large-scale investigation is necessary to confirm these results, these data suggest that the concomitant use of LEM with postoperative adjuvant hormone therapy improves the QOL and immune function of patients.

Evidence assessment: These trials are small and preliminary. The breast cancer randomized study involved 47 patients, and the hormone therapy study involved 20 patients without a parallel placebo control. Larger confirmatory trials are needed.

5.2 Cancer — Gastrointestinal Cancers

A study investigated the influence of LEM, an oral immunomodulator, on immune function and adverse events from chemotherapy. Subjects comprised 1 gastric and 7 colorectal cancer patients. The first course of treatment was chemotherapy alone and the second was chemotherapy plus concomitant administration of LEM. Adverse events and interferon (IFN)-γ production by CD4+ T, CD8+ T, and CD56+ NK/NKT cells were evaluated at the end of each course. Grade 1 or 2 adverse events were observed at the end of the first course for 6 of 8 patients. In comparison, no patients displayed any adverse events at the end of the second course. Tendencies toward improved IFN-γ production by CD4+ T, CD8+ T, and CD56+ NK/NKT cells were also seen. These results suggest that concomitant use of LEM with chemotherapy can decrease the incidence of adverse effects from cancer chemotherapy among patients with advanced cancer.

Evidence assessment: This is a very small pilot study (8 patients, non-randomized crossover design). Results are preliminary and must be interpreted with caution.

5.3 Cancer — Hepatocellular Carcinoma (Liver Cancer)

Preliminary findings suggest that AHCC may improve prognosis and prevent recurrence after curative resection of hepatocellular carcinoma, improve nutritional status when given during neoadjuvant therapy, and reduce chemo-associated adverse effects. Some limited evidence suggests that taking AHCC might prolong survival and improve quality of life in people with liver cancer.

Evidence assessment: Evidence here is characterised by Memorial Sloan Kettering and Drugs.com as "preliminary" and "limited." No large randomized trials have been completed and published for this indication. Ongoing trials are registered (e.g., ClinicalTrials.gov NCT07118735).

5.4 Cancer — Prostate Cancer

In an open-label multicenter study of patients with early-stage prostate cancer, AHCC was ineffective in reducing prostate-specific antigen levels by 50% or more. Early research suggests that taking AHCC daily for 6 months does not benefit people with prostate cancer.

Evidence assessment: Currently negative or neutral for prostate cancer based on available studies.

5.5 Antiviral — Human Papillomavirus (HPV)

This is one of the most clinically developed areas of AHCC research. The research program was led by Dr. Judith A. Smith at the University of Texas.

Preclinical work established a rationale: The study first demonstrated in vitro suppression of HPV expression. After a single dose at 24 hours and with repeated dosing every 24 hours for 7 days followed by 7 days of no treatment, HPV eradication was achieved. These findings were confirmed with in vivo animal studies. HPV expression was eradicated with once-daily AHCC dosing for 90 days and sustained after a 30-day observation off treatment. Immune modulation (increase) of IFN-α, IFN-β, IFN-γ, and IgG1 was observed in AHCC-treated mice compared to untreated controls.

Two pilot studies in women then led to a Phase II trial: Two pilot studies were recently conducted on women who had documented persistent HPV positive for greater than 2 years. AHCC supplementation of 3 g by mouth once daily was evaluated to support the host immune system to eliminate persistent high-risk HPV infections.

Early results of the ongoing clinical trial evaluating AHCC® for treatment of HPV were presented by principal investigator Dr. Judith A. Smith. The randomized, double-blind, placebo-controlled study followed 50 women for up to 12 months, with one group taking six capsules each containing 500 mg of AHCC® (n=25), and a second cohort receiving placebo (n=25). The results showed that at six months, 58.8% of the patients taking AHCC® showed no signs of the infection. In the placebo group, one patient showed no signs of the infection at three, six, nine, and 12 months of study. AHCC® was well tolerated in patients who received it.

Evidence assessment: The Phase II data (published in Frontiers in Oncology, 2022) represents the strongest clinical evidence for AHCC and an infectious disease indication. The trial was randomized and double-blind; however, it was a single-centre study with a small sample size (50 women) and preliminary results. The authors themselves noted that the duration of supplementation required for durable outcomes needs further evaluation. These findings are promising but not yet sufficient to establish a standard of care.

5.6 Immune Function in Healthy Subjects

The effects of AHCC® on NK and T cells appear to have biological implications as suggested by the results of clinical studies and in vivo animal studies on infections, inflammations, and tumors. A double-blind, placebo-controlled trial in healthy volunteers (Terakawa et al., Nutrition and Cancer, 2008) specifically examined immunological effects in non-cancer subjects and demonstrated measurable immunological changes; however, the clinical significance of those changes requires further investigation.

5.7 Liver Health and Hepatoprotection

In patients with liver injury due to excessive alcohol ingestion, AHCC supplementation at dosages of 1 g/day (three 167 mg capsules 30 minutes before breakfast and dinner) and 3 g/day (three 500 mg capsules 30 minutes before breakfast and dinner) for 12 weeks improved ALT levels, decreased TNF-alpha and IL-1beta, and elevated adiponectin without any adverse effects.

Early research suggests that taking AHCC daily for 6 months does not benefit people with hepatitis C. However, a separate study reported reductions in HCV RNA levels in genotype-3 patients when given AHCC 2 g three times daily for 24 weeks, and control of ALT levels.

Evidence assessment: Hepatoprotective activity is well supported by animal and in vitro data. Human clinical evidence in alcohol-related liver disease is limited but positive. The hepatitis C data are mixed (one study negative, one showing benefit in a subgroup). All evidence is preliminary; larger controlled trials are needed.

5.8 Immune Checkpoint Blockade and Oncology (Emerging Research)

A recent animal study published in Frontiers in Immunology (2022) investigated AHCC® in combination with immune checkpoint inhibitors. The research demonstrated that AHCC® promoted the anti-tumor effect of dual immune checkpoint blockade in a murine colon cancer model, suggesting potential synergy with modern immunotherapy approaches. This remains preclinical (animal model) data only.

5.9 Cholesterol and Cardiovascular Parameters

Shiitake contains versatile bioactive compounds including eritadenine, conferring it promising hypocholesterolemic properties. Eritadenine inhibits an enzyme involved in producing cholesterol; sterols help block cholesterol absorption in the gut; and beta-glucans, soluble fibers from the cell walls, can lower cholesterol. A study in lab rats fed a high-fat diet revealed that those given shiitake developed less fat in their livers, less plaque in their artery walls, and lower cholesterol levels than the animals that did not eat the mushrooms. Nonetheless, these effects need to be confirmed in human studies.

Evidence assessment: The cholesterol-lowering and cardiovascular evidence for L. edodes mycelia specifically, as distinct from the whole fruiting body, is largely preclinical (animal and in vitro). Human clinical evidence is limited.

6. Body Systems and Health Areas Associated with Lentinula Edodes Mycelia

• Immune System: Modulation of NK cells, CD4+ and CD8+ T cells, macrophages, dendritic cells, and cytokine profiles (IFN-γ, IL-6, TGF-β).
• Oncology / Cancer Adjunct: Used as a biological response modifier alongside chemotherapy for gastric, colorectal, breast, and liver cancers; lentinan is approved as an adjuvant drug in Japan and China.
• Hepatic System: Hepatoprotective activity against chemically-induced liver injury and support for liver enzyme normalization in alcohol-related liver disease.
• Antiviral / Infectious Disease: Evidence for activity against HPV, influenza, herpes simplex, hepatitis C virus, and HIV in preclinical models, with HPV showing the most advanced human clinical data.
• Cardiovascular / Metabolic: Potential cholesterol-lowering effects via eritadenine and beta-glucans, primarily established in animal models.
• Gastrointestinal: Studies demonstrated that L. edodes bioactive compounds can restore gut microbiome heterogeneity and improve gut barrier dysfunction.
• Antioxidant: Extracts from fruiting bodies and mycelium have shown antioxidant activities attributed mostly to their polysaccharide content.

7. Dosage Forms and Dosages Reported in Clinical Studies

The following dosages are those reported in peer-reviewed sources; they describe what was studied and not prescriptive recommendations:

• In patients with alcohol-related liver injury, AHCC at dosages of 1 g/day (three 167 mg capsules 30 minutes before breakfast and dinner) and 3 g/day (three 500 mg capsules 30 minutes before breakfast and dinner) for 12 weeks.
• In the HPV Phase II trial, one group took six capsules each containing 500 mg of AHCC® (total 3 g/day).
• Doses of AHCC ranging from 4.5 to 6 grams daily have been used safely for up to 6 months. A lower dose of 3 grams daily has been used safely for up to 9 years.
• In chronic hepatitis C, AHCC 2 g three times daily (total 6 g/day) for 24 weeks was studied.
• In one study, female patients receiving adjuvant chemotherapy for breast cancer were given 1 g of AHCC orally after each meal.
• A current ongoing randomized controlled trial of AHCC® for liver cancer/immunotherapy uses oral administration of 3 g AHCC® daily.

LEM and AHCC® are available in oral forms including capsules, tablets, and powders. Intravenous forms of lentinan (the isolated polysaccharide) have been used in clinical settings in Japan, though this is distinct from the mycelial extract products.

8. Safety Considerations and Known Interactions

General Safety Profile

Active Hexose Correlated Compound (AHCC) is an extract of Lentinula edodes of the basidiomycete family of fungi rich in alpha glucans. AHCC has been used for many years as a dietary supplement to enhance the immune system and in clinical trials as an adjunctive treatment in hepatocellular cancer. A Phase I trial, using FDA guidelines, directly investigated the clinical safety and tolerability of AHCC in healthy subjects. Clinical trials report few adverse events at normal dosages.

Shiitake Dermatitis

Shiitake mushroom dermatitis is a well-documented phenomenon in the literature seen after consuming raw or undercooked shiitake mushrooms (Lentinus edodes). Shiitake dermatitis has been described as a reaction to the ingestion of raw or partially cooked mushrooms and may be a toxic reaction to lentinan. Owing to the fermentative production of the novel food ingredient from the mycelium and the final application of a heat-induced sterilization step, adverse effects reported after the consumption of the fruiting body of the shiitake mushroom are not considered relevant to processed mycelial extracts, according to the European Food Safety Authority (EFSA).

Occupational and Allergic Reactions

Case reports exist of allergic/contact dermatitis, asthma, rhinitis, and hypersensitivity pneumonitis in shiitake workers. Prolonged consumption of shiitake powder has resulted in dermatitis, photosensitivity, eosinophilia, and gastrointestinal upset.

Intravenous Lentinan (Distinct from Oral Mycelia Extracts)

Anaphylaxis, granulocytopenia, and elevated liver enzymes were reported after rapid (10-minute) IV infusion in an HIV trial. These events are associated with the injectable form of isolated lentinan and are not directly applicable to oral mycelial extracts such as LEM or AHCC®.

Allergenicity in Sensitive Individuals

Although an allergenic risk cannot be excluded for sensitive subjects, this risk is expected not to be higher than that resulting from the normal consumption of the fruiting body of Lentinula edodes. (EFSA, 2010)

Pregnancy and Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. There is not enough reliable information about the safety of taking AHCC if you are pregnant or breast feeding.

Contraindications

Contraindications have not yet been identified in the published literature reviewed for lentinan and mycelial extracts at oral doses.

Immunomodulatory Caution

Because LEM and AHCC® exert measurable effects on both innate and adaptive immune responses — including modulation of NK cells, T cells, regulatory T cells, and cytokine production — there is a theoretical concern about use in individuals receiving immunosuppressive therapy (e.g., post-transplant patients) or those with autoimmune conditions. This concern has not been systematically studied in humans. No specific drug interaction data for LEM/AHCC® with immunosuppressants, anticoagulants, or cytochrome P450-metabolized drugs were identified in the peer-reviewed sources examined.

EFSA Regulatory Opinion

The safety of Lentinex® (a Lentinula edodes mycelium-derived beta-glucan product) as a novel food ingredient has been established at the proposed conditions of use and the proposed levels of intake, according to the EFSA Scientific Opinion (2010).

9. Overall Evidence Characterization

There is evidence suggesting that bioactive substances in Lentinula edodes have immunomodulatory and anticancer properties. This fungus is currently classified as a functional food, considering its beneficial effects on human health and special nutritional value. However, the body of human clinical evidence for LEM/AHCC® specifically — as distinct from the whole mushroom or isolated lentinan — remains limited in scale. Most human studies to date are small pilots, open-label series, or preliminary randomized trials. The most robustly-designed human trial is the Smith et al. HPV Phase II randomized, double-blind, placebo-controlled study. Further research is needed to determine the therapeutic potential of this extract. Studies exploring additional immunologic effects of AHCC® and mechanisms underlying these effects in health and disease are warranted.

References

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