The medicinal use of mushrooms has a very long tradition in the Asian countries, whereas their use in the Western hemisphere has been slightly increasing only since the last decades. The edition of the new scientific journal International Journal of Medicinal Mushrooms (Begell house, Editor-in-Chief S. P. Wasser), several books and reviews about medicinal mushrooms (1–6) and biologically active compounds from mushrooms (7) as well as international conferences about this topic confirm this trend. The market value of medicinal mushrooms and their derivative dietary supplements worldwide was ~US $1.2 billion in 1991 (8) and was estimated to be US $6 billion in 1999 (9).

Mushrooms need antibacterial and antifungal compounds to survive in their natural environment. It is therefore not surprising that antimicrobial compounds with more or less strong activities could be isolated from many mushrooms and that they could be of benefit for human (12). But only compounds from microscopic fungi are on the market as antibiotics till now.

Figure 1 Lentinula edodes; Photo: Prof. Jan Lelley.

In contrast to bacterial infectious diseases, viral diseases cannot be treated by common antibiotics and specific drugs are urgently needed. Antiviral effects are described not only for whole extracts of mushrooms but also for isolated compounds. They could be caused directly by inhibition of viral enzymes, synthesis of viral nucleic acids or adsorption and uptake of viruses into mammalian cells. These direct antiviral effects are exhibited especially by smaller molecules. Indirect antiviral effects are the result of the immunostimulating activity of polysaccharides or other complex molecules (19).

Figure 2 Ganoderma lucidum; Photo: Prof. Jan Lelley.

Table 1 Immunomodulating drugs from mushrooms (selected)

Figure 3 Grifola frondosa; Photo: Prof. Jan Lelley.

In Eastern Europe, the fruiting bodies of I. obliquus have been used as a folk medicine for cancer and stomach diseases since the 16th or 17th century (35). Antitumor effects of several extracts and isolated compounds could be demonstrated in tumor cell systems and in animal assays (36,37). Several triterpenes and ergosterol peroxide contribute to the activity. The melanin complex of I. obliquus has high antioxidant and genoprotective effects on peroxidase-catalyzed oxidation of aminodiphenyls (38).

So called ‘immunomodulators’ (biological response modifier, immunopotentiators and immunostimulants) are the most important medicinal mushroom drugs used especially in Japan, China, Korea and other East Asian countries today. They are summarized in the following sections.

The immunostimulating effect of lentinan was also investigated in patients with AIDS. In a phase II study, 107 HIV positive patients were treated with didanosin (400 mg per day, p.o. 6 weeks). After that time, 88 patients got additionally 2 mg lentinan per week intravenous for 24–80 weeks, the patients of the control group got only didanosin. The combined treatment resulted in a significant increase of the number of CD4+ cells after 38 weeks in comparison to control group (54).

In a non-random case series, a combination of MD-fraction and whole powder of G. frondosa was investigated to determine its effectiveness for 22- to 57-year-old cancer patients in stages II–IV. Cancer regression or significant symptom improvement was observed in 58.3% of liver cancer patients, 68.8% of breast cancer patients and 62.5% of lung cancer patients. The trial found a <10–20% improvement for leukemia, stomach cancer and brain cancer patients (55). MD-fraction appears to repress cancer progression and primarily exerts its effect through stimulation of NK cells activity (47). The MD-fraction has been approved by the Food and Drug Administration (FDA) for an Investigational New Drug application to conduct a phase II pilot study on patients with advanced breast and prostate cancer (56).

In a small clinical trial, powder of S. crispa (Wulfen): Fr. (300 mg per day) was given orally to several cancer patients after one course of lymphocyte transfer immunotherapy. Performance status of 14 cases were monitored after several months, and 9 cases were improved (61,62). In China, several preparations from Hericium caput-medusae (Bull.: Fr.) Pers. [syn. Hericium erinaceus (Bull.: Fr.) Pers.] are on the market for treating chronic stomach diseases and other purposes (63). Agaricus brasiliensis Wasser et al. is a new cultivated medicinal and gourmet mushroom with benzaldehyde and its precursor benzoic acid as major components of the volatile fraction (64). Because the North American endemic species Agaricus blazei Murrill and the widely cultivated medicinal A. blazei ss. Heinem. proved to be different species, A. blazei ss. Heinem. was described as a new species, A. brasiliensis (65). The biggest group of active substances is composed of polysaccharides, obtained from fruit bodies, mycelium and culture filtrate (66,67). Acetone extract of fruit bodies contained six antitumor-active steroids (66). Antimutagenic effects were also found (68).

Recently, more attention is given to the identification of molecular pathogenesis mechanisms of cancer. In this connection more specialized targets for potential antitumor drugs were identified. It could be shown that some compounds from mushrooms act on such targets. Some examples are provided below.

Ganoderic acids A (8c) and C (8d) from G. lucidum are inhibitors of farnesyl protein transferase. Because this enzyme participates in Ras-dependent cell transformation, inhibitors represent a potential therapeutic strategy for the treatment of cancer (89). Phellinus linteus (Berk. & M. A. Curtis) Teng was found to contain antiangiogenic activity in the chick embryo chorioallantoic membrane assay (90) and to inactivate cancer-related kinases (91). Antiangiogenic activity was also reported for polysaccharides from A. brasiliensis (92). The sesquiterpenoid cryptoporic acids A-G (14) from Cryptoporus volvatus (Peck) Murrill inhibit the tumor promotion activity of okadaic acid in two-stage carcinogenesis experiments. The effect is possibly related to their strong radical scavenging activity (93). Antimutagenic effects were found for methanolic extracts of P. ostreatus (94), methanolic extracts of Lactarius vellereus (Fr.) Fr. (95) and for water extracts of A. bisporus and G. lucidum. The genoprotective effect of A. bisporus has been related to the enzyme tyrosinase (96).

A dried oyster mushroom (P. ostreatus) diet (5%) reduced pathological changes in dimethylhydrazine-induced colon cancer in rats but did not influence significantly the incidence of tumors. This effect is explained by the antioxidant properties of this mushroom and by its fiber content (97).

Although extracts of many mushrooms can stimulate the immune system, some suppress immune responses. This could be of interest, e.g. for the treatment of allergic diseases that are increasing worldwide.

p-Terphenyl compounds from Thelephora ganbajun M. Zang, Thelephora aurantiotincta Corner, Boletopsis grisea (Peck) Bondartsev & Singer (115) as well as from Paxillus curtissii Berk. (116) showed strong antioxidative properties. Betulinan A (20) from Lenzites betulinus (L.: Fr.) Pilát is about four times more active as a radical scavenger than vitamin E in inhibition of lipid peroxidation (117). Lipid peroxidation is also inhibited by the sterins A and B from Stereum hirsutum (Willd.: Fr.) Pers. (118).

Ergosta-4-6-8(14),22-tetraen-3-one (21), isolable from many mushrooms, has been shown to possess antialdosteronic diuretic properties (119).

Potentiators of ADP-induced platelet aggregation have been found in Polyporus umbellatus (Pers.): Fr. (Cho-Rei) [5α,8α-epidioxy-ergosta-6,22-dien-3-ol (4)] and others (120).

Diabetes mellitus is a metabolic disorder affecting ~250 million people worldwide. More effective and safer treatment modalities for type 2 diabetes patients need to be investigated, focusing on overcoming peripheral insulin resistance. A polysaccharide fraction of G. frondosa (SX fraction, p.o.) showed hypoglycemic action in five patients with type 2 diabetes (56).

Ganoderan A and B, glucans from G. lucidum fruiting bodies (121), coriolan, a β-glucan–protein complex obtained from submerged grown T. versicolor biomass (122) and an acidic glucuronoxylomannan from the fruiting bodies of Tremella aurantia Schwein. (123) exhibited hypoglycemic effects in several test systems and ameliorated the symptoms of diabetes.

Seventy-one patients with confirmed type 2 diabetes were treated with polysaccharide fractions from G. lucidum (Ganopoly, 1800 mg three times daily for 12 weeks). At week 12, mean post-prandial glucose values had decreased to 11.8 mmol l⁻¹ in the Ganopoly group [significant difference to placebo group, (124)].

Tremellastin, containing 40–45% acidic polysaccharide glucuronoxylomannan and obtained by alcohol precipitation of culture broth, decreased intrinsic blood glucose levels as well as triglyceride levels in rats after 15 treatment days (p.o. 100 mg kh⁻¹; 500 mg kg⁻¹). Hypoglycemic effects in glucose-loading and streptozotocin-induced hyperglycemic rats could not be found (125).

Preparations from the traditional Chinese drug Cordyceps (consisting of fungi parasitic in insects) and from fermented mycelia meliorate diabetes in a diabetic animal model using streptozotocin-induced rats after p.o. application (126). Crude polysaccharides from cultured mycelium of Cordyceps have shown significant activity after intraperitoneal injection (127). Besides, Cordyceps is highly appreciated by Chinese medical practitioners as a treatment for many ailments (128).

Dehydrotrametenolic acid (22), found in several polypores including Wolfiporia cocos (Schwein.) Ryvarden & Gilbn., Laricifomes officinalis (Vill.: Fr.) Kotl. & Pouzar (syn. Fomitopsis officinalis (Vill.: Fr.) Bondartsev & Singer and Laetiporus sulphureus (Bull.: Fr.) Murrill, acts as an insulin sensitizer in glucose tolerance tests and reduces hyperglycemia in mice with noninsulin-dependent diabetes (129).

Ethanolic extracts and a proteoglycan from P. linteus show anti-inflammatory effect in the collagen-induced arthritis and in the croton oil-induced ear edema test in mice and antinociceptive effect in the writhing test (90,130). Other compounds effective in the writhing test are the ganoderic acids A (8c), B (8a), G (8g) and H (8h), isolated from G. lucidum. These substances showed a stronger effect in this animal model than acetylsalicylic acid (131).

Methanolic extract of Pleurotus pulmonarius (Fr.) Quél. fruiting bodies (500 and 1000 mg kg⁻¹) reduced carrageenan-induced and formalin-induced paw edema in mice. The activity was comparable to the reference diclofenac (10 mg kg⁻¹). The effect seemed to be related to the significant antioxidant activity of the extract. The IC 50 value for hydroxyl-radical scavenging was 476 μg ml⁻¹ and for lipid peroxidation inhibition 960 μg ml⁻¹. Besides, the extract showed significant solid tumor-reducing activity in mice (132).

The edible mushroom G. frondosa contains ergosterol, ergosta-4-6-8(14),22-tetraen-3-one (21) and 1-oleoyl-2-linoleoyl-3-palmitoylglycerol, which inhibit cyclooxygenases 1 and 2 activity (133).

Ganoderic acids R (17a) and S (17b) and ganosporeric acid A (8i) from G. lucidum show in vitro antihepatotoxic activity in the galactosamine-induced cytotoxic test with primary cultured rat hepatocytes (134,135). In vivo two fractions of a total triterpenoids extract of G. lucidum (75% ethanol) can protect mice against hepatic necrosis induced by chloroform and d-galactosamine. The hepatoprotective effects were perhaps related to the ability to promote the activity of scavenging enzymes for hepatic free radicals in mice, and thus to raise the ability of antioxidation in mice (136).

Ganopoly, the polysaccharide-containing preparation of G. lucidum, was proven in a double-blind, randomized and multicentered study in patients with chronic hepatitis B (HBV DNA positive; application of Ganopoly for 12 weeks, then 13 weeks followed up, 600 mg three times per day equal to 27 g fruiting body, p.o.). Within the 6 months study period, 33% (17/52) of treated patients had normal aminotransferase values and 13% (7/52) had cleared hepatitis B surface antigen from serum, whereas none of the controls had normal enzyme values or had lost HBsAg. The drug was well tolerated (137).

Apart from well investigated psychoactive mushrooms like Amanita muscaria (L.: Fr.) Pers. or Psilocybe species some further mushroom extracts and compounds have been found with special central effects that could be of pharmacological interest.

Phenol-analogous compounds [hericenons C (23), D, E, F, G, H] from H. erinaceus induce the synthesis of nerve growth factor and might have an ameliorative effect in Alzheimer's dementia (63). Erinacin E (24) from Hericium coralloides (Scop.: Fr.) Gray [syn. Hericium ramosum (Mérat) Letell.] fermentation broth is a highly selective agonist at the kappa opiod receptor (IC 50 of 0.8 μM, binding at the μ opiod receptor with an IC 50 of >200 mM). Such compounds may exhibit antinociceptive activity without side effects observed with μ receptor agonists like morphine (138).

Screening investigations of selected basidiomycetes indicate inhibitory effects of P. betulinus, G. applanatum, H. annosum, Fomitopsis pinicola (Sowerby: Fr.) P. Karst and Daedaleopsis confragosa (Bolton: Fr.) J. Schröt. on neutral endopeptidase (enkephalinase, EC 3.4.24.11) (IC 50 values between 40 and 55 μg ml⁻¹). Selective inhibitors of this metalloendopeptidase could be useful in the treatment of pain with a spectrum of activity similar to that of opioids (139).

Scutigeral (25), isolated from fruiting bodies of Scutiger ovinus (Schaeff.: Fr.) Murrill [syn. Albatrellus ovinus (Schaeff.: Fr.) Kotl. & Pouzar], has affinity to the brain dopamine D1 receptors and may act as an orally active pain killer targeting vanilloid receptors [VR1, (140)]. Albaconol (26) from the fruiting bodies of Scutiger confluens (Alb. & Schwein.: Fr.) Bondartsev & Singer [syn. Albatrellus confluens (Alb. & Schwein.: Fr.) Kotl. & Pouzar is an antagonist at the VR1 receptor with an IC 50 value of 5 μM (141).

In principle, whole mushrooms (mainly fruiting bodies), extracts (from fruiting bodies or mycelium) and isolated compounds are suitable for use. The material could be obtained by collection from the wild, cultivation of mushrooms in farms and harvesting of the fruiting bodies or by cultivation of mycelium in fermenters with liquid or solid substrates. Extracts could be prepared by extraction of mushrooms (dried or fresh) with suitable solvents. Pure compounds could be obtained by isolation from the natural or cultivated material or by chemical synthesis. Very often, the natural compound serves as lead compound for the preparation of a high variety of derivatives. Because most mushrooms can be cultivated in an economic matter, the production of mushroom compounds, especially proteins, by genetically modified organisms seems not to be necessary.

At present, between 80 and 85% of all medicinal mushroom products are derived from the fruiting bodies, which have been either commercially farmed or collected from the wild, for example, lentinan and various products from G. lucidum. Only ~15% of all products are based on extracts from mycelia. Examples are PSK and PSP from T. versicolor and tremellastin from Tremella mesenterica. (Retzius): Fr. A small percentage of mushroom products are obtained from culture filtrates, e.g. schizophyllan from S. commune and protein-bound polysaccharide complex from Macrocybe lobayensis (R. Heim) Pegler & Lodge [syn. Tricholoma lobayense R. Heim (142)].

After production, suitable galenic formulations like capsules, tablets or teas have to be developed, dependent on the material. Mixtures of several mushrooms or of mushroom and substrate become more and more common (9).

The review demonstrates that mushrooms, similar to plants, have a great potential for the production of useful bioactive metabolites and that they are a prolific resource for drugs.

The responsible bioactive compounds belong to several chemical groups, very often they are polysaccharides or triterpenes. One species can possess a high variety of bioactive compounds, and therefore of pharmacological effects. The best example is G. lucidum, which not only contains >120 different triterpenes but also polysaccharides, proteins and other bioactive compounds (43,143).

The spectrum of detected pharmacological activities of mushrooms is very broad. Dependent on increasing knowledge about chemistry, biotechnology and molecular biology of mushrooms as well as an improvement of screening methods (high throughput screening, genomics and proteomics), a rapid increase in the application of mushrooms for medicinal purposes can be expected.

Prerequisition for a use as drug, nutraceutical or other purpose is the continuous production of mushrooms (fruiting bodies or mycelium) in high amounts and in a standardized quality. In the opinion of Chang (142), mycelial products are the ‘wave of the future’ because they ensure standardized quality and year around production. A further necessity is the establishment of suitable quality parameters and of analytical methods to control these parameters. Nevertheless, the legal regulations for authorization as drug or as dietary supplements or as food should get more attention (9). Control of possible side effects (i.e. allergies) during broad use is necessary. Finally, also the nutritional value of mushrooms should be taken into account.

We thank Professor Dr Hanns Kreisel Greifswald, for his excellent help in all mycological problems and for revision of the manuscript and Professor Jan Lelley Krefeld, for giving photos and further information.