| Ganoderma has been use since the 4th century A.D. and is well known in China as "the herb of longevity"6. There are several species of Ganoderma fungi (some of which can be seen below). However the vast majority of the research done on Ganoderma’s medicinal qualities has performed using G. lucidum. Investigating the properties of Ganoderma is fraught with difficulties. One problem is that the fungus contains varying amounts of its biologically active components during its life cycle7. There is further evidence of this variation – six colours of Ganoderma can be grown from the same species notice the difference between the adjacent G. lucidum and that below. In TCM these are considered to have varying degrees of healing power, in fact the price can vary quite considerably. Therefore it could be argued that this might produce inconsistencies in some of the research: two identical methods might yield different results due to variation in the Ganoderma used. |
Ganoderma lucidum |
|||||
 |
 |
 |
||||
| Ganoderma applanatum | Ganoderma lucidum | Ganoderma resiniceum | ||||
|
|
Among cultivated mushrooms Ganoderma is unique in being consumed for its pharmaceutical value rather than as a food. Dietary supplement sale in the United States was worth over 6.5 billion dollars in 1996. Several species of Ganoderma are used in the increasingly important commercial nutraceutical business9. In fact, another source claims that pharmaceutical and nutraceutical products from mushrooms may be worth more than $1.2 billion worldwide8. Moreover, of the 4500 tonnes of Ganoderma produced in 1997, 3000 tonnes were produced in China. Therefore it can be argued that China has economic as well as cultural reasons to propagate the supposed medicinal qualities of Ganoderma. Large-scale scientific investigation of the effects of Ganoderma became possible during the eighties when Prof. Pan Zihang developed a technique to mass-produce this mushroom and to harvest its therapeutically valuable spore6. However the provenance of some of these studies leaves a lot to be desired. |
|||||
USE OF SOURCESGanoderma is one of the most highly regarded herbal remedies in TCM. Therefore a lot of literature investigating its properties is published in Asian journals. As was pointed out earlier the Chinese have both economic and cultural motives to promote Ganoderma’s healing properties. In fact one could also argue that the Japanese also have an economic interest in the production of the mushroom since 500 tonnes was produced7. That is not to say that all the studies done in these countries in unreliable – far from it. However one has to be selective since the provenance of the studies is varied:
However one such study was published in the International Journal of Cancer (a leading periodical on cancer research) despite being financially supported by the Chinese government12. Therefore it would not be fair to distrust a study simply because it is financially supported such bodies. Another method of measuring the reliability of Ganoderma research was needed. It was decided to rate the reliability of each paper according to the "Impact factor" (IF) of the journal from which it was taken [Impact Factor values were obtained from the Institute for Scientific Information’s website40]. Impact factors effectively estimate how widely read a particular journal is among the scientific community. This is worked out by using the number of times a journal is cited in other papers and setting this against the number of papers that journal publishes. World-renowned journals such as Nature are widely read and are therefore frequently cited - thus they have high IFs. Nature published 885 papers in 1997, was cited in 27999 other papers published that year and consequently scored an impact factor of 28.833. It was decided to treat journals with IFs greater than 1 as "reliable". An IF of 1 means that on average there is one citation for every paper published by that journal. This "yardstick of reliability" is limited itself. One could argue that Ganoderma "enthusiasts" reads "pro-TCM" journals. When such journals publish a paper on the topic that article will be subsequently be widely quoted by the "pro-Ganoderma" scientists in their own work. This might improve the impact factor of that journal even if the work is flawed. Another limitation of this way of measuring the reliability of an article was noted while carrying out this investigation. Advances in Applied Microbiology seemed reliable (IF = 1.654). However as it was a general article it had used information from other studies, some of which was published in relatively obscure journals – Yao Hsueh Hsueh Pao, for instance. Due to these limitations IFs were used as a guide to reliability rather than proof of it. |
||||||
 |
||||||
ANTITUMOUR ACTIVITYPerhaps the most significant claim made of Ganoderma is its value as an antitumour agent. The idea of anticancer drugs being derived from mushrooms seems a little surprising at first. However in Japan the Health and Welfare Ministry have approved three different anti-cancer drugs extracted from mushrooms. These three are lentinan, derived from Shiitake; schizophyllan, derived from Suehirotake; and PSK, derived from Kawaratake. PSK, sold in Europe and Japan, is the best-selling cancer drug in the world 13. It seems plausible therefore that Ganoderma could have similar effects. In fact Ganoderma’s effect as an antitumour agent is the mushroom’s most researched quality. |
||||||
| Some encouraging
results have been obtained through in vitro studies. The best example of
these is the work done by Wang et al (1997) which was published in the International
Journal of Cancer (IF = 3.283, indicating that the paper12 is
reliable). They found that polysaccharides from Ganoderma alone (PS-G)
had little effect on the proliferation of cancer cells. The same was true of T
cells and macrophages. However when these were combined (PS-G, T cells and
macrophages) an antitumour effect was noted. They concluded that this was the
result of cytokines released by T cells and macrophages and that this release
was stimulated by the presence of the PS-G. The graph opposite shows this
combined effect (MNC-CM = mononuclear cell-conditioned media). They also
demonstrate that treatment with PSG-MNC-CM markedly induced leukemic-cell
apoptosis. However they also claim that "experimental studies have
repeatedly shown that PS-G has the ability to suppress tumour growth in vivo"
while this is true it is also arguably a little misleading.
|
Graph adapted from Wang et al (1997) |
|||||
| Several studies have demonstrated that Ganoderma has
antitumour effects in vivo. These mostly show antitumour activity against
sarcoma 180 in mice. However a lot of these studies are only too be found in
relatively obscure journals – Han’guk Kyunhakhoechi (!) for instance.
Only one paper has reproduced these encouraging results and been published in a
relatively well-known journal - Bioscience Biotechnology and Biochemistry
(IF = 0.949: although IF<1 it is very close). Zhang et al (1994)14
tested sixteen polysaccharides of which they found three had antitumour effects
on sarcoma 180 in mice – one produced a survival ratio 194% of that of the
control group.
It has also been claimed that Ganoderma not only has antitumour effects but also has radioprotective properties in vivo15. However this has only been successfully demonstrated in one study that was published in the American Journal of Chinese Medicine (IF = 0.293) – showing that this finding is of dubious reliability. Furthermore a recent study by Chiu et al (2000) found no evidence at all for the extract having any value in protecting against the radiomimetic mutagen used (ethyl methanesulfonate - EMS)9. Extensive research has been published on the structure of the supposed antitumour polysaccharides of Ganoderma. This seems somewhat surprising given the almost complete lack of in vivo evidence of the mushroom’s antitumour effects in reliable journals. While there is some encouraging in vitro data it is not enough to substantiate the miraculous antitumour claims that are made of Ganoderma. CARDIOVASCULAR EFFECTS1. Hypotensive Action of Ganoderma lucidum Another medicinal property of G. lucidum that has been proposed and researched is its hypotensive action. Lee et al (1990)16 did work that suggested that the mycelium extract from G. lucidum inhibited sympathetic outflow and concluded that this was responsible for the hypotensive effect. They used anaesthetised rabbits and rats, cannulated the left femoral artery and vein for measurement of arterial pressure and delivery of drugs. The left kidney was then exposed retroperitoneally and a branch of the renal nerve was used to measure renal afferent or efferent activity. They found that the mycelium extract decreased diastolic and systolic blood pressure and this was accompanied by an inhibition of renal efferent sympathetic nerve activity. Moreover they found that the hypotension occurred in an extract dose dependent manner. This in vivo study seems to have yielded conclusive results. The fact that the paper was published in Chemical and Pharmaceutical Bulletin (IF = 1.135) and that the work was done in the USA further adds to its credibility. However a different study17 performed in vitro seems to suggest another way in which G. lucidum may have hypotensive effects. Morigiwa et al (1986) demonstrated that a 70% methyl alcohol extract of G. lucidum inhibited angiotensin-converting enzyme. This would limit blood pressure by blocking the renin-angiotensin system. They also isolated and characterised eight lanostane triterpenes that had ACE inhibitory effects. Of which they found that ganoderic acid F had the greatest effect. Again this study was published in Chemical and Pharmaceutical Bulletin suggesting that the study is reliable. Both the studies discussed so far have used carefully prepared extracts of G. lucidum that was given intravenously (not a satisfactory solution for chronic hypertension); furthermore the effects have only been demonstrated in vitro. However another investigation by Kabir et al (1988)18 demonstrates hypotensive effects in a much less sophisticated and more practical way.
Lanostane triterpenoid skeleton (adapted from Lin et al. 1988) Kabir et al studied the effect of a powder prepared from the cultured fruit body of G. lucidum on the blood pressure of spontaneously hypertensive rats. After a 4-week feeding period, the systolic blood pressure of the rats was significantly lower than the control, indicating that the powder contained a substance that suppresses the elevation of blood pressure19. This is especially conclusive since while the studies by Lee et al (1990) and Morigiwa et al (1986) yielded significant results they did not prove that the effects they describe could be achieved by oral consumption of G. lucidum. Hypertension is an important risk factor in several diseases, most notably in the development of atherosclerosis. This is a highly significant disease process since atheroma of the coronary arteries leads to myocardial infarction - the biggest killer in the UK. Although western medicine has already has effective hypotensive drugs and ACE inhibitors, "anything taken in excess is bad for you" it is therefore often preferable to give a pharmaceutical agent by "dietary methods rather than in highly refined forms. This makes it much harder to overdose"20. Oral consumption of G. lucidium, it seems, may provide a safe but effective way of lowering blood pressure. One could argue that this has implications for western medicine that highly significant. 2. Hypocholesterolaemic Activity During his work on Ganoderma’s hypotensive activity, Kabir et al (1988) investigated its effect on the lipid levels of the spontaneously hypertensive rats. After being fed the powdered fruit body for four weeks the plasma total cholesterol levels were of these rats was significantly lower than the controls. Other investigators such as Shiao et al (1987,1988)21, 22 have isolated specific triterpenes that have hypocholesterolaemic effects. These studies were all published in respectable journals (IF>1) thus their findings seem significant. Hypercholesterolaemia is another recognised risk factor for atherosclerosis - a major killer in the UK, as has been discussed. If Ganoderma has both hypocholesterolaemic and hypotensive activities then it should also significantly reduce the incidence of atherosclerosis – the implications of which would be very important. 3. Platelet Aggregation Inhibitory Effects Of Ganoderma lucidum Although three studies23, 24, 25 that study the effects of G. lucidum on platelet aggregation have been performed only one Shimizu et al (1985)25 was published in a journal with IF >1. In Chemical and Pharmaceutical Bulletin they described how the water-soluble fraction of the fruit body of G. lucidum suppressed platelet aggregation. While they did not determine the mechanism, they did find that the chemical that inhibited the platelet aggregation was adenosine. Furthermore they showed that the content of adenosine was 40mg/1000g of the dried fruit body preparation13. This effect would be very significant since inhibition of platelet aggregation reduces the incidence of blood clots and strokes19. Again though, hypercoaguability is a problem that western medicine already has solutions. However these findings are also significant in another way. If G. lucidum does inhibit platelet aggregation patients with clotting disorders such as haemophilia or who are taking anticoagulants should be strongly advised against using Ganoderma as a complementary medicine. IMMUNOMODULATORY ACTION1. LZ-8 Perhaps one of the most fascinating discoveries in work on Ganoderma is the discovery of an immunomodulatory protein known as Ling-Zhi-8 (LZ-8). This protein was first isolated from the mycelial extract from G. lucidum by Kino et al (1989)26 and has been shown to have some surprising biological properties. Kino et al (1989) demonstrated that LZ-8 could prevent the production of a systemic anaphylaxis reaction in mice if administered repeatedly. 40% of the LZ-8 treated mice were Arthus reaction positive compared to 90% in the control group. They concluded that this showed that LZ-8 reduces antibody production but does not block it completely, although they were unsure of the mechanism for this. They also describe how LZ-8 is a "pseudo-lectin": it shows mitogenic capacity towards mouse spleen cells and human peripheral lymphocytes but is not inhibited by mono- or dimeric sugars. Perhaps even more significantly they claim to have demonstrated that LZ-8 can prevent the onset of autoimmune type I diabetes. Tanaka et al (1989)27 determined the complete amino acid sequence of LZ-8. The sequence showed great similarity to the variable region of immunoglobulin heavy chain both in its primary and predicted secondary structure. Although they do not attempt to use this discovery to help explain LZ-8’s biological properties it would be fair to suggest this is not mere coincidence. It should be noted that these studies appeared in the Journal of Biological Chemistry (IF = 7.199 – even larger than the BMJ’s 5.325!). Using the IF scale this means that they should be the two most reliable papers that have been written on Ganoderma. Furthermore they have demonstrated that LZ-8 shows in vivo effects – most other studies on the biological properties of Ganoderma tend to be based on in vitro data. Their findings should therefore be considered seriously. LZ-8 seems a remarkable discovery, but many questions remain unanswered. For instance why does G. lucidum posses such a protein. The similarity between LZ-8 and Ig VH is even more striking when one considers the "immense genetic distance between vertebrates and basidiomycetes"27. It seems plausible that a better knowledge of how LZ-8 works could prove invaluable in explaining G. lucidum biological properties. 2. Histamine-Release Inhibition Activity Kohda et al (1985)28 has demonstrated that a methanol extract of G. lucidum has an inhibitory action on the release of histamine by mast cells in vitro. He isolated four triterpenes – ganodermic acids A, B, C and D that were suspected for this effect.This study appeared in Chemical and Pharmaceutical Bulletin (IF = 1.135) and was conducted using a sound method – the test used was a simple in vitro assay for anti-inflammatory or antiallergic drugs19, thus their results seem reliable. Other studies by Tasaka et al (1988)29,30 concluded that this inhibition of histamine release was the result of membrane stabilisation. Theoretically this means that G. lucidum may have antiallergic properties in vivo. This could be used to explain the claim that the mushroom can relieve asthma – which is sometimes treated with mast cell stabilisers. However this only demonstrates in vitro histamine-release inhibition. None of the studies on the effects of Ganoderma on histamine release to date have reproduced these effects in vivo. Ironically a handful of studies have shown that, far from being antiallergic, Ganoderma can provoke a hypersensitive response in humans. 3. Sensitization While most papers on Ganoderma focus on the mushroom’s healing quantities a few have shown that it can have unhelpful effects on some people.Human sensitization to Ganoderma antigen was first reported in the Journal of Allergy and Clinical Immunology (IF = 4.509) in 1979 in a study was carried out in Ontario31. They tested patients attending chest/allergy clinics and found that 8.2% reacted positively to the Ganoderma antigen. This allergic reaction occurred in 16% of those tested in a similar study in Auckland32. In 1995 sensitization was reported in India in a paper published in Clinical and Experimental Allergy (IF = 2.939). They found that 28.48% and 17.44% of patients showed marked skin reactivity to spore and whole body extracts, respectively33. A lot of the treatments commonly used in Western medicine are linked with allergies, penicillin its one such example. It does not seem surprising therefore that G. lucidum is too. However it is important to bear this downside in mind when considering the various healing claims made of Ganoderma. ANTI-HIV ACTIVITYSceptics may argue that it is not surprising that Ganoderma has been linked to anti-HIV activity since it already supposedly alleviates or cures all other diseases – why should HIV be any different! However two recent studies have isolated anti-HIV protease substances from the fungus. Moreover both these articles were published in widely read journals – Phytochemistry (IF = 1.179) and Chemical and Pharmaceutical Bulletin (IF = 1.135). This suggests that there may be something in these claims after all. Both studies Min et al (1998)34 and el-Mekkawy et al (1998)35 had similar findings, in fact the two teams also had common group members. Min et al (1998) found five triterpenes that had anti-HIV-1 protease activity. El-Mekkawy et al (1998) isolated anti-HIV-1 protease triterpenes. However they35 also found that ganoderiol F and ganodermanontriol displayed anti-HIV-1 activity. While these effects have only been demonstrated in vitro they do provide enough evidence to give some theoretical basis to the latest claims regarding Ganoderma’s medicinal properties. Only two classes of drugs are currently used to treat HIV infection in western medicine – one class is protease inhibitors, such as Indinavir. These interfere with HIV replication by inhibiting post-translational processing of viral precursor polypeptides36. Hence it could be postulated that since Ganoderma also has anti-HIV-1 protease activity it could therefore be used to treat HIV infection via the same mechanism. CONCLUSIONSDuring the past 50 years, several major advancements in medicine came from lower organisms such as fungi and yeasts37. For instance antibiotics such as penicillin, tetracycline and aureomycin were derived from moulds and caused what can only be described as a revolution in health care treatment. Another example is cyclosporin – a powerful immunosuppressive drug. Therefore it would be by no means unprecedented if Ganoderma also had a positive pharmacological effect. There is a lot of evidence to suggest that Ganoderma does have medicinal potential, there have been several good studies with positive results. Its cardiovascular effects seem particularly significant since cardiovascular disease is the biggest cause of mortality worldwide. Therefore anything that helps lower the risk factors associated with the development of cardiovascular disease, such as hypertension and hypercholesterolaemia, is worthy of a least some consideration. Also worthy of particular note is the discovery of LZ-8. The fact that this celebrated fungus has an immunomodulatory protein seems most unusual. Perhaps it could be used to explain a lot of Ganoderma’s supposed healing qualities. However while there is compelling research that seems to substantiate the claims made of the mushroom there is still no proof. In fact there is some evidence against9. Furthermore the supporting evidence is mostly based on in vitro studies – the research on HIV is one example of this. Even the in vivo experiments have been performed using mice. If Ganoderma really were the "herb of longevity" surely there would be at least some good clinical evidence for it. But the only studies found of this type36, 38 were in relatively obscure journals (IF < 0.3) and used only small sample groups. Die-hard TCM advocates might argue that the clinical evidence for Ganoderma’s success lies in the 4000 years of human observation upon which TCM is based. However there is a complete lack of quality research to show that Ganoderma has any positive effects in Homo sapiens. |
||||||
| The research to date on Ganoderma provides theoretical evidence that the fungus might have medicinal potential. However the lack of solid clinical evidence forces one to be somewhat sceptical. |  |
|||||
References
|
||||||
