IngredientsLentinan is a polysaccharide isolated from the fruit body of the shiitake mushroom (Lentinula edodes). Its scientific name derives from its source organism, Lentinula edodes (Berk.) Pegler, known by common names including forest mushroom, Hua gu, pasania fungus, and shiitake.
Lentinan is a water-soluble, high molecular weight (400–800 kDa) polysaccharide. It contains glucose molecules with mostly (1→3)-β-D-glucan linkages in a regularly branched main chain, with two β-(1,6)-D-glucopyranoside branchings for every five β-(1,3)-glucopyranoside linear linkages. It has a molecular weight of approximately 500,000 Da and a specific rotation of +14–22° (NaOH).
The repeating unit of lentinan consists of two lateral β-(1→6) glucose branches on five β-(1→3) glucose linkages. Under experimental conditions, lentinan forms a stiff triple helix in a worm-like shape. Its triple-helix structure is considered important in recognizing host cells.
Lentinan is a heterogeneous polysaccharide, and its monosaccharide composition ratio and molecular weight can vary depending on the source (lentinan variety) and extraction method. The lentinan normally has a high molecular weight, ranging from 1.16 × 10³ to 6.84 × 10³ kDa, which includes glucose, galactose, mannose, and arabinose with different molar ratios.
The nutritional components of Lentinula edodes include bioactive polysaccharides such as β-D-glucan, heteroglucan, xylomannan, and lentinan, as well as eritadenine; free sugars including arabinose, arabitol, mannose, mannitol, trehalose, and glycerol; vitamins (B2, B12, D2); and dietary fibre.
Lentinan is available as capsules, tablets, and injections. Capsules and tablets of lentinan are taken orally as a traditional medicine. Intravenous injection of lentinan is clinically approved and used in hospital settings at a dose of 1–1.5 mg/day. Traditionally, it is extracted from the fruiting bodies of the mushroom; however, the cultivation of fruiting bodies is a time-intensive and often inconsistent process, resulting in low lentinan yields and inefficient extraction of active compounds. Extracting and purifying active polysaccharides such as lentinan from mycelium through fermentation represents a highly promising approach to overcome these challenges.
The biological activity of L. edodes-derived polysaccharides depends on the extraction method, which affects monosaccharide composition, molecular weight, branching degree, and helical conformation. Hot-water extraction is the traditional preparation method; ultrasonic-assisted extraction (UAE) has also been studied and may yield polysaccharides with different structural and bioactivity profiles.
In addition to being a culinary delicacy, shiitakes have a history of being used as medicine in Asia for more than 2,000 years. Throughout history, shiitake mushrooms have been valued not only as food but also as traditional medicine in both Chinese and Japanese healing systems. Ancient texts cite their ability to restore energy, boost the immune system, and aid in recovery.
The medicinal properties of L. edodes have been studied since the Ming Dynasty (1369–1644). The elders of the Japanese Empire considered shiitake as the "elixir of life," increasing vigor and energy.
Shiitakes were initially foraged from the wild, but their high demand led to the development of cultivation techniques as early as the Song Dynasty in China (960–1279 AD). Chinese farmers pioneered a technique of drilling holes into logs and inoculating them with mushroom spores, forming the foundation of modern shiitake cultivation methods.
In traditional East Asian medicine, shiitake is regarded as energetically sweet and neutral, making it a gentle, nourishing tonic for the body that lends itself to regular consumption. It has been used in traditional East Asian medicine for thousands of years to strengthen weakness, in particular of the Spleen and Stomach — the digestive center in classical East Asian systems.
Shiitake mushrooms are used in traditional Chinese, Korean, and Japanese medicine, and contain lentinan and lenthionine. While lentinan itself was not isolated or identified until the modern era, the broader mushroom preparation containing it was the vehicle of these traditional uses.
It is important to note that traditional use preceded the scientific isolation and characterization of lentinan. The whole mushroom or aqueous decoctions were the traditional preparations; the specific polysaccharide lentinan as an isolated compound is a product of 20th-century biochemistry.
In 1969, Professor Tetsuro Ikekawa et al. noted that aqueous extracts from shiitakes inhibited the growth of transplanted tumors in mice. In 1970, Professor Goro Chihara et al. isolated an antitumor polysaccharide from shiitakes and named it lentinan. Lentinan was the earliest and most thoroughly studied of all edible fungi polysaccharides and has been used clinically as an anticancer adjuvant therapy in Japan and China since the 1980s.
Lentinan itself is the principal bioactive polysaccharide of interest in Lentinula edodes, but the mushroom contains additional bioactive components:
The exact immunomodulatory mechanism of action of fungal polysaccharides is not fully known, but it has been documented that these compounds have an affinity for numerous receptors located on human immunocompetent cells, including complement receptor type 3 (CR3), Dectin-1, lactosylceramide (LaCer), scavenger receptors, toll-like receptors (TLRs), and CD28 receptors.
Studies have shown that exogenous β-glucans can serve as pathogen-associated molecular patterns (PAMPs) to activate immune responses by binding pattern recognition receptors (PRRs), such as Dectin-1, CR3, and TLR2. Lentinan activates macrophages, T cells, and NK cells through Dectin-1 receptor signal transduction, thereby enhancing their tumor-killing activity and exerting an immune-stimulating effect.
Lentinan's well-defined triple-helix structure, formed by its β-(1→3) backbone and β-(1→6) side chains, ensures high aqueous solubility and stability, and this structure enables precise recognition of Dectin-1's carbohydrate recognition domain (CRD).
As an immunomodulator, lentinan can activate effective immune system responses in the body, including T cells, natural killer cells, and macrophages. Lentinan has been demonstrated to indirectly activate T cells via IL-12 and IFN-γ produced by lentinan-activated macrophages and dendritic cells. Lentinan acts by inducing antitumor effector cells, such as cytotoxic killer T cells, natural killer cells, and activated macrophages in the host.
Lentinan has been demonstrated to play an immunomodulatory role by stimulating the expression of the pro-inflammatory factors IFN-γ and IL-2, which tilts the balance between Th1 and Th2 cytokine activity in favor of Th1. Lentinan enhances virus-specific T-cell functions induced by DNA vaccine, acts as a vaccine adjuvant, and is reported to enhance T-cell functions in cancer patients.
Lentinan is thought to be inactive in humans when given orally and is therefore administered intravenously in most clinical applications. However, more recent mechanistic research has begun to elucidate how oral lentinan may interact with gut immune tissue. Lentinan was mainly taken up by CD11c+ mononuclear phagocytes within Peyer's patches via Dectin-1. Near-infrared imaging confirmed the absorption of LNT in the small intestinal segment and its accumulation within Peyer's patches after oral administration.
In a mouse model of influenza, lentinan treatment considerably inhibited inflammatory cytokine (TNF-α, IL-1β, IL-4, IL-5, IL-6) levels in serum and lung and improved IFN-γ cytokine levels, which reduced cytokine storms caused by influenza virus infection. The underlying mechanism involved lentinan inhibiting the inflammatory response by regulating the TLR4/MyD88 signaling pathway.
Lentinan is shown to be an immunopotentiator and appears to stimulate macrophage and T-cell proliferation with no direct cytotoxic effect against tumor cells. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
Lentinan dose-dependently prevented streptozotocin (STZ)-induced inhibition of insulin synthesis by blocking the activation of nuclear factor kappa-beta and increasing the level of Pdx-1 in INS-1 cells. These findings suggest that LNT could protect against pancreatic β-cell apoptosis and dysfunction caused by STZ and therefore may be a potential pharmacological agent for preventing pancreatic β-cell damage caused by oxidative stress associated with diabetes. This finding is from preclinical/cell-line research only.
Lentinan was approved as an adjuvant for stomach cancer therapy in Japan in 1985. Lentinan has been approved as a biological response modifier for the treatment of gastric cancer in Japan.
Randomized controlled trial (Tohoku Lentinan Study Group, 1986): A randomized study of mitomycin C (MMC) + 5-FU (control group) versus MMC + 5-FU + lentinan (LNT group) was conducted in 166 patients, comprising 115 cases of gastric cancer and 51 cases of colorectal cancer. Significant increases were observed in the survival rates for the LNT group (p < 0.05) for both patients with gastric and colorectal cancer. No significant difference was observed in response rates between the two groups, though the response rate in the LNT group was slightly higher than the control group. These results suggest that LNT in combination with anticancer drugs prolongs survival time.
Phase III study (published results): Using the life-table analysis method, a higher rate of survival was observed in the lentinan-treated group, especially in combination with tegafur for gastric cancer, showing survival rates of 12.97% (p < 0.05) at two years, 9.51% (p < 0.05) at three years, and 3.81% at four years; for colorectal cancer, 9.10% and 4.55% at two and three years, respectively.
Individual patient data (IPD) meta-analysis (2009): In this study, the effect of immunochemotherapy with lentinan compared with chemotherapy alone was evaluated in patients with advanced gastric cancer through individual patient data meta-analysis. Based on a computerized and manual search, all eligible centrally randomized controlled trials which compared chemotherapy regimens with or without lentinan administration for advanced gastric cancer patients were included. In total, 650 IPD from 5 trials were available. Lentinan significantly prolonged overall survival (stratified log-rank p = 0.011). The overall hazard ratio (HR) was 0.80 (95% confidence interval = 0.68–0.95) and there was no heterogeneity between trials. Additionally, lentinan was possibly more effective in patients with lymph-node metastasis than in non-node metastasis patients (p for interaction = 0.077).
Broader meta-analysis (2017): Seventeen clinical studies were identified containing 1,423 patients. Twelve trials included gastrointestinal cancer (GIC), three trials included lung cancer (LC), and two trials included both cancers. There was an increase in survival rate at one year (risk ratio [RR] = 1.46, P = 0.001) and overall response rate including both complete and partial response (RR = 1.28, P = 0.005). There was also a reduction in progressive disease (RR = 0.57, P = 0.0005), nonsevere adverse events (RR = 0.88, P = 0.004), and severe adverse events (RR = 0.73, P = 0.007). Limited trials reported data of median overall survival and time to treatment failure, and data were insufficient for quantitative analysis; no significant difference was found in 2-year survival rate. Adjuvant lentinan used with chemotherapy achieved improvements in 1-year survival rate, response rate, and adverse events in advanced cancer. The effect seemed to be similar irrespective of cancer type. However, its sustained efficacy on survival was still unclear.
Methodological limitations: Many of the included trials were conducted in Japan during the 1980s and 1990s using older chemotherapy regimens. The trials were predominantly Japanese and Chinese, which may limit generalizability. Most trials were not blinded and used older fluoropyrimidine-based chemotherapy backbones that have since been largely superseded. All 5 clinical studies included in the 2009 meta-analysis were performed in the 1980s and S-1 was not prescribed at that time.
Lentinan has been approved as an adjuvant therapeutic drug in both China and Japan for treating cancers since the 1980s. A systematic review of clinical studies evaluated over 9,474 reported lentinan-associated cancer treatment cases from 135 independent studies in China during 2004–2016. These cases included lung cancer (3,469 cases), gastric cancer (3,039 cases), colorectal cancer (1,646 cases), ovarian cancer (183 cases), cervical cancer (130 cases), Non-Hodgkin lymphoma (70 cases), and pancreatic cancer (15 cases), among others.
One study revealed that lentinan can act as an adjuvant for the treatment of tumors, modulating the balance between Th1 and Th2 cells in patients with non-small cell lung cancer (NSCLC) and providing clinical benefits to patients with cancer. However, large, independent, randomized controlled trials in lung cancer conducted to current methodological standards are lacking.
The antitumor activity of lentinan in colorectal cancer is significantly enhanced when combined with 5-fluorouracil or cisplatin, according to reported clinical data. The Tohoku Lentinan Study Group trial described above also enrolled colorectal cancer patients and showed significant survival benefits in that subgroup.
A meta-analysis including 65 trials involving 4,080 patients examined whether intrathoracic infusion therapy with lentinan and chemical irritants improved clinical efficacy in malignant pleural effusion (MPE). Compared with chemical irritants alone, the meta-analysis demonstrated that lentinan combined with DDP (cisplatin), BLM, or NDP showed a significant improvement in complete response rate, and with DDP, CBP, L-OHP, BLM, or NDP resulted in a significant decrease in treatment failure.
The isolated polysaccharide lentinan from shiitake culture has been used intravenously (IV) at doses of 2 to 10 mg on a weekly schedule as adjunctive therapy for HIV as well as for cancer, primarily in Japan.
Phase I/II placebo-controlled trial: Patients in this study showed a trend toward increases in CD4 cells and in some patients neutrophil activity. Because of the small numbers, these values did not have statistical significance. In the SFGH study arm (infusion over 10 minutes), there were nine side effects severe enough to be reported to the FDA. In the CRI study arm, where infusion was over 30 minutes, there were no side effects reportable to the FDA. Most side effects resolved promptly after discontinuation of medication, and all were relieved within 24 hours.
The overall evidence for lentinan in HIV is preliminary. The Phase I/II trial was underpowered and did not yield statistically significant efficacy findings.
A study aimed to evaluate the safety and efficacy of lentinan nasal drops in patients infected with the Omicron SARS-CoV-2 variant through a dose-escalation study and a placebo-controlled trial. Phase I was a dose escalation trial in which 24 COVID-19 patients were enrolled (12 in the escalation dose group receiving 50, 75, or 100 µg/day, and 12 in the standard treatment group) to evaluate the safety and tolerance of lentinan nasal drops. In the dose-increasing study, lentinan nasal drops showed good safety, and no serious adverse reactions occurred. The virus shedding time of the 100 µg dose group was significantly shorter than that in the control group (7.75 ± 1.71 vs. 13.41 ± 3.8 days, p = 0.01), and 100 µg/day lentinan nasal drops were well tolerated. The results of the placebo-controlled study showed that compared with the placebo group, the time for COVID-19 antigen to turn negative was significantly shorter in the 100 µg lentinan nasal drop group (p = 0.0298), but no significant difference was observed in symptom improvement between the two groups.
This trial was small and exploratory. Evidence for lentinan as an antiviral agent in humans is preliminary.
In an ICR mouse model, the anti-influenza effect and mechanism of lentinan were studied. The results showed that lentinan had a high degree of protection in mice against infection with influenza A virus, delayed the emergence of clinical manifestations, improved the survival rate of mice, significantly prolonged median survival days, attenuated weight loss, and reduced the lung coefficient of mice. It alleviated the pathological damage of mice infected with the influenza virus and improved blood indices. This evidence is animal-model only and has not been validated in human clinical trials.
A wide in vitro spectrum of activity against human pathogens has been described, including activity against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and ciprofloxacin-resistant Pseudomonas strains. Antiviral activity has also been evaluated in vitro against HIV and vesicular stomatitis virus. These in vitro findings have not been replicated in adequately powered human clinical trials.
Despite comprehensive research into its chemical structure and conformation transitions, the exact mechanism of digestion and absorption remains a subject of exploration, especially regarding its potential hypoglycemic effects. The conformation-dependent functionality of lentinan in relation to hypoglycemic effects has yielded inconclusive results and health benefits. With an increasing number of individuals affected by type 2 diabetes mellitus, elucidating the mechanism to unlock its nutraceutical potential is crucial.
In cell-line research (INS-1 cells), lentinan dose-dependently prevented STZ-induced inhibition of insulin synthesis by blocking NF-κB activation and increasing Pdx-1 levels, suggesting it could protect against pancreatic β-cell apoptosis and dysfunction caused by oxidative stress associated with diabetes. This work is preclinical and does not constitute clinical evidence of antidiabetic effect in humans.
Research published in PMC has examined therapeutic effects of lentinan on inflammatory bowel disease (IBD) and colitis-associated cancer in animal models, noting that TLR4 signalling induces the inflammatory response through activation of NF-κB, and that intestinal microbiota plays a critical role in the pathogenesis of IBD. Evidence for lentinan's role in IBD remains at the preclinical stage.
Oral shiitake extract was used in a trial for the treatment of prostate cancer at 8 g/day for 6 months without significant effect on disease progression.
Bioactive polysaccharides obtained from L. edodes have shown an important role as free radical scavengers in the prevention of oxidative damage and can be explored for their potential as natural antioxidants. Current antioxidant evidence is predominantly from in vitro and animal studies.
Several studies have demonstrated that lentinan has favorable properties, including acting as an antiviral, antitumor, antidiabetic, and antioxidant agent and regulating immunity. The body systems and health areas most associated with lentinan research are:
As a result of clinical trials, lentinan was approved as an anticancer agent in Japan in 1985. Currently, lentinan is used in combination with tegafur in order to sustain the treatment of inoperable and recurrent gastric cancer. Lentinan was approved as an adjuvant for stomach cancer therapy in Japan in 1985. It is approved for treating multiple types of cancer, hepatitis, and other diseases in China.
In Japan, two types of β-glucans, krestin and lentinan, are licensed as drugs for gastric cancer treatment. Lentinan is purified β-glucan from shiitake mushrooms and has been used in combination with oral fluoropyrimidines for treating gastric cancer in both adjuvant settings and far advanced tumor stages.
Lentinan does not hold approved drug status in the United States or the European Union as of the current date. In the US, shiitake-derived products containing lentinan are marketed as dietary supplements under DSHEA oversight.
Lentinan is a high molecular weight polysaccharide, and is usually administered by the intraperitoneal route because of poor oral bioavailability and rapid metabolism. This pharmacokinetic property is the primary reason most clinical use has been parenteral rather than oral.
Shiitake dermatitis is a rare and self-limiting condition that is thought to be a toxic cutaneous reaction to lentinan, a polysaccharide derived from shiitake mycelia. It was initially hypothesized that the mechanism of disease related to a toxic reaction to lentinan; however, recent evidence has suggested a potential allergic mechanism.
Flagellate dermatitis is a rare, presumably toxic epidermal damage following consumption of raw or half-cooked shiitake mushrooms. Characteristically, patients develop parallel, whiplash-like infiltrated erythemas with papules or papulovesicles, arranged like scratches and associated with severe itching 1–2 days after eating shiitake mushrooms. The localizations are preferentially the trunk, the extremities, and the nape of the neck.
It affects about 2% of people who consume the mushrooms raw or only lightly cooked. Lentinan activates interleukin-1 secretion, leading to vasodilation, hemorrhage, and the distinctive rash. Notably, this flagellate dermatosis is not observed when mushrooms are thoroughly cooked at temperatures exceeding 145°C. The rash spontaneously resolves within a few weeks.
A severely-itching dermatitis following consumption of the mushroom was first reported by Nakamura in 1977. With an increase in consumption of shiitake mushrooms in Western society, shiitake dermatitis is expected to become more prevalent worldwide.
When exposed to intravenous lentinan during a study on its antitumor properties, only 9 out of 500 patients developed flagellate dermatitis.
The incidence of adverse effects due to lentinan, particularly those requiring withdrawal, is low. Of 98 patients with HIV infection, treatment had to be withdrawn in four because of adverse effects; other adverse effects included one case each of an anaphylactoid reaction, back pain, leg pain, depression, rigors, fever, chills, granulocytopenia, and raised liver enzymes.
In the SFGH study arm, where administration was over a 10-minute period, there were nine side effects severe enough to be reported to the FDA. In the CRI study arm, where infusion was over a 30-minute period, there were no side effects reportable to the FDA. Most side effects resolved promptly after discontinuation of medication, and all were relieved within 24 hours. This suggests that infusion rate is an important safety variable for parenteral administration.
Clinical trials report few adverse events at normal dosages.
Case reports exist of allergic/contact dermatitis, asthma, rhinitis, and hypersensitivity pneumonitis in shiitake workers.
Lentinan may decrease the serum concentration of gabapentin. This interaction was identified in a study examining the effect of mushroom diet on the pharmacokinetics of gabapentin in healthy Chinese subjects, published in the British Journal of Clinical Pharmacology.
Contraindications have not yet been identified. Information regarding safety and efficacy in pregnancy and lactation is lacking.
Shiitake mushroom dermatitis is a rare idiosyncratic skin rash caused by a toxic or hypersensitive reaction to lentinan, a bioactive component of shiitake mushrooms found in the cell wall. Lentinan is a thermolabile polysaccharide which decomposes upon heating; therefore, well-cooked shiitake mushrooms can usually be safely eaten.
The overall strength of the clinical evidence base for lentinan varies considerably by indication:
Health conditions that Lentinan may help support.
A beta-1,3/1,6-D-glucan from Shiitake mushroom (Lentinula edodes), lentinan is approved as an immunological adjuvant in Japan for cancer immune recovery. Multiple clinical studies document NK cell enhancement, T-lymphocyte stimulation, and improved immune markers in post-illness contexts.
Lentinan is the purified beta-1,3-glucan from shiitake mushroom (Lentinula edodes) with established clinical immunomodulatory activity and documented potential for recovery from COVID-19-related lung damage. It is approved as adjunct immunotherapy in Japan. A 2023 PMC review confirmed lentinan showed good potential for post-viral lung and immune recovery.
Lentinan is a beta-1,3-glucan polysaccharide purified from shiitake mushroom (Lentinula edodes) with well-documented immunomodulatory activity. It activates NK cells, macrophages, and T cells, and has been approved as a pharmaceutical immune adjuvant in Japan. Evidence supports its role in enhancing antiviral immune defense.
Body systems that Lentinan may help support.
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