NAMA

Mushrooms as Medicinals:
a literature review

Lawrence M. Leonard, MD

 

Shortly after the 1998 McIlvainea publication of Ethnomycology of Tlaxcala, Mexico by Adriana Montoya Esquivel, my wife and I had the privilege of getting to know her and accompanying her on some of her trips to interview indigenous Mexicans about their knowledge of mushrooms. It was very impressive to sit in a one-room tiny "casita" and listen while mother, father, and children watched pictures of fungi being projected on a wall while they opined that a particular fungus was edible or not.

My interest in traditional use of mushrooms as food and medicinals was piqued. However, on a mushroom collecting trip on the Amazon some doubts about medicinals were raised when our guide cut a plant with his machete noting that the sap from the south side of this plant was good for preventing and treating cancer and the sap from the north side was good for tuberculosis. Nodding in agreement, most of the folks in our small group drank the two aliquots of sap. I have since thought a good deal about herbals and mushroom medicinal, i.e., mushrooms and/or their metabolites that are supposed to be either good for your health or prevent disease.

I propose one can inquire into the use of mushrooms as medicinals in a few ways:

  1. From the ethnological approach, inquiring about the historical use of mushrooms by many peoples, in many lands over the ages.
  2. From in vitro experiments with mushroom extracts in laboratory test tubes and Petri dishes and in vivo experiments with laboratory mice or other animals.
  3. From well designed controlled double blind trials in people.

I have no argument with someone who wants to use mushrooms as medicinals because many peoples in many lands over the ages have used mushrooms as medicinals, i.e., the ethnological approach. However, I do not agree that we should be using mushrooms as medicinals from the results of in vitro experiments with mushroom extracts in laboratory test tubes and Petri dishes and in vivo experiments with laboratory mice or other animals. Some people believe that experimental in vitro and in vivo experiments carry over directly to humans. I do not agree. How a cell reacts to a mushroom extract in a test tube or Petri dish is not necessarily the same as how it will react in a person. How mice or other laboratory animals react is not necessarily the same as how people react. Humans are not mice and not even all strains of mice react to the same way. Accordingly, I was hoping to find some good literature involving people in well designed double blind trials to support the use of mushrooms and/or their metabolites as medicinals. Our hunt in the woods would then not only yield some good eats but perhaps be good for our health.

There are a number of members of our mushroom club who are interested in and knowledgeable about the use of mushrooms as medicinals. I asked about them and even bought some Maine Chaga (Inonotus obliquus) to try to improve my immune system and beat my annual severe Maine cold. I asked about medicinal mushroom literature and references. Christopher Hobbs’ book Medicinal Mushrooms was highly recommended. I noted later that it is very frequently cited as an authority.

Hobbs clearly notes the difference between in vitro (experiments carried out in test tubes, Petri dishes, etc.) and in vivo studies (experiments carried out in living animals or people) and writes in his introduction, "If an in vitro study shows a plant extract to have activity, for instance a cancer-inhibiting effect, there is no certainty that the extract will be useful in treating or preventing human cancers." He continues with further significant caveats. However, I think many people who study this book will feel many of the mushrooms noted will be helpful in preventing and treating a disease without considering the caveats. The 38 pages of references from scientific journals intend to give "scientific" credence to the value of mushrooms as medicinals. But the vast majority of these references are in vitro or in vivo mouse experiments, and as Hobbs notes in his introduction, there is no certainty that the extract will be useful. I agree. A substance has to show a benefit in human trials before one can accept its benefit for people.

Rather than reviewing Hobbs’ references here, I'll summarize his chapter on "Medicinal Fungi Monographs" pp 62-199, in which he states there are no (my emphasis) "Human Clinical Studies" for: Amanita muscaria, Armillaria mellea, Auricularia polytricha, A. auricula, Boletus edulis, Claviceps purpurea, Fomes fomentarius, F. pinicola, F. officinalis, Ganoderma applanatum, Geastrum triplex, Lenzites betulina, Lepista nuda, Peziza vesiculosa, Phellinus igniarius, Pleurotus ostreatus, Polyporus tuberaster. He does state there are references to human studies for other mushrooms. I will discuss as many of these I can find later.

I asked about additional books. Paul Stamets’ Mycelium Running was suggested as an authoritive and more up to date book. The author has done some marvelous work in the field of Mycology and the book was highly recommended for the further understanding of this complex field of medicinal mushrooms. He recommends some mushrooms and/or their extracts as medicinal noting many mushrooms are good for diverse clinical problems. The majority of the references are to in vitro or in vivo mouse experiments.

In 2008, to find more recent writings, I reviewed Stamets' website, FungiPerfecti® and his book, MycoMedicinals®. There was then an extensive list of 114 papers in "Selected Supporting Research Papers", ibid p 6-15. I looked at all of the references trying to find ones that did or might involve humans. References which obviously used mice, were in vitro or were reported in only 1 or 2 pages were not reviewed as I felt there would not be enough data to evaluate them. There were 7 articles with humans; most reported non-blinded trials or with no controls; 1 double blind human study was only a 2 page report and so could not be evaluated; Sugimachi (1997) showed no difference in 2 gastric cancer groups; Taguchi (1982) was not reviewed. Xiong (1993) did evaluate 30 chronic hepatitis patients comparing an herb with and without a Polyprorus umbellatus polysaccharide and stated the Polyporus group was "more potent".

Clinical Trials

In order to claim scientific evidence that a substance is good for humans we need to conduct, complete, report and repeat human clinical trials with enough participants so that the conclusions are statistically significant. These should be randomized and double blinded (where neither the patient nor the investigator knows if the patient is receiving the test substance). Possible investigator bias and/or conflict should be reported.

ClinicalTrials.gov

ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. It is a Web-based resource that provides the public with easy access to information on studies of a wide range of diseases and conditions. The website is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH).

As of February 2014 there are 162,059 ongoing trials in 185 countries (43% in the U.S.). Until September 2009 the results of the trials were not mandated to be published so often negative results were not published. The results of trials begun since September 2009 now must be published.

Trials are conducted in a series of steps, called Phases. Each phase is designed to answer a separate research question. Many or most past and present on-going trials can be tracked at ClinicalTrials.gov with its identifying “NCT” number.

  • Phase I: Researchers test a new drug or treatment in a small group of people, generally 20-80, for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
  • Phase II: The drug or treatment is given to a larger group of people, up to approximately 300, to see if it is effective and to further evaluate its safety.
  • Phase III: The drug or treatment is given to large groups of 300-3000 people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
  • Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.

The following are results of a search of ClinicalTrials.gov for various mushrooms and/or their metabolites. The majority of these trials have "no results", the reasons for which are not clear. Some may take a year or two before the results are published, or in some the results may have been "negative" and so not published. Some are "discontinued" because of early complications or poor results. An additional search was entered into many other data bases searching under mushroom names and/or their common metabolites indicated by some as being beneficial to health. A summary follows:

Of these trials, 132 possibly involving people were found. Of these there were 45 that appeared to be possibly Phase I, II or III trials. Of the 45 there were 23 Phase I-II trials which are interesting. These trials involve small numbers of people and accordingly although of interest, no conclusions can be drawn from them. There were 6 other trials, also reviewed in appendix 2 but the number of people involved was unclear. There were 8 probable and 2 possible Phase III trials. There were no Phase IV trials.

Review of the Phase III trials

Taguchi, T et al, 1985. This is a follow-up of a Phase III study of lentinan (a polysaccharide from Shitake (Lentinula edodes) and other chemotherapy agents in patients with recurrent or advanced gastrointestinal cancer. They used life span table analysis to note a prolongation of life with lentinan and tegafur (a chemotherapy drug).

Ichihashi et al, 1987, reported a “randomized cooperatively controlled study” on resected gastric cancer patients (number unknown) treated with PSK (Krestin, a polysaccharide from Coriolus versicolor) and chemotherapy. They stated there was no statistical difference in survival between and treated and non-treated group; they continued however that one subgroup was better (p = 0.089 (but not generally considered significant).

Mitomi, T. et al, 1992, reported on randomized trials with controls using PSK in 448 patients with resected colorectal cancer. Follow-up was 3-5 years and the survival curve was reported as statistically better with the PSK group.

Toi, M. et al, 1992. This was a randomized trial with PSK as an adjuvant with chemotherapy in 914 breast cancer patients. In the estrogen negative receptor patients there was no advantage with PSK but there was a "survival advantage" in the estrogen positive receptor cohort.

Morimoto, T. et al, 1996, reported on 525 patients with breast cancer in a complex study dividing them into estrogen positive and negative groups; the estrogen positive group was then divided into two groups treated with different anticancer drugs and another one with the drugs and PSK; in this arm one anticancer drug was statistically better than a drug and PSK. In the estrogen negative group there were no differences.

Toge T. and Y. Yamaguchi, 2000, reviewed a multicenter trial of 751 patients treated with gastric resection and postoperatively with chemotherapy with and without PSK. Non-stratified results were a little better (p=0.053) with PSK. They broke the results down with granulocyte/lymphocyte ratios and found no difference in survival if G/L ratios were less than 2.0. If the ratio was greater than or equal to 2.0 survival was "extended" (p values not given).

Ito K. et al, 2004, reported on 446 patients in two groups with colon cancer treated with chemotherapy alone and chemo and PSK. Their conclusions were a little confusing: "Survival for cancer death was significantly higher (in PSK-chemo group) but there was no difference in 7 year disease free survival or overall survival… (but) PSK followed by 5-FU (chemotherapy) can improve survival for cancer death."

Owada et al, 2004, reported a randomized study, possibly a Phase III (numbers not known) of cancer patients treated with chemotherapy with and without PSK. They concluded it reduced recurrence and increased survival time. (Note: Alliot, 2004, responded to the report and stated “…this study is not definitively convincing”.)

Ueda, Y. et al, 2006, described a multicenter randomized Phase III trial to begin in 2006 of post-operative adjuvant therapy with PSK + S-1 (a chemotherapy drug) vs S-1 alone in group of "curatively resected Stage II/IIIA gastric cancer". Primary end-points of each arm of 133 patients were time to relapse and survival. I e-mailed him 3-10-09 asking for follow-up results but he did not answer. (Update 2-5-14: no results reported for this clinical trial NCT002160347.)

Yoshino, S. et al, 2008, did a beginning Phase III clinical trial starting Feb 2007 to evaluate the effectiveness of S-1 (a chemotherapy drug) and S-1 with lentinan in patients with advanced or recurrent gastric cancer. The primary end-point would be to compare overall survival between the 2 groups, with 150 patients per arm. Registration was to be or two years and then a two year follow-up. They noted "This study has a chance to prove the efficacy of the non-specific biological modifier." (Update 2-5-14: no results reported.)

Conclusions of above Phase III trials

All the studies were to test PSK or lentinan as an adjunct (i.e.as an additive treatment) to standard chemotherapy in cancer patients. Taguchi et al, 1985, stated there was a “prolongation of life” with lentinan and a chemotherapy drug. Toi, 1992, said there was a “survival advantage” in one subgroup and not in another; Mitomi, 1996, said the “survival curve” was statistically better but further details are not available. Morimoto et al, 1996, said one arm was statistically better and one negative. Toge et al, 2000 said “results were a little better, p=0.053, with one subset with “extended survival” (p values not given) and one subgroup negative. Ito’s, 2004, conclusions were confusing with no difference in survival but then stating PSK and chemotherapy can improve survival for cancer death. Ueda et al started a study in 2006. No results are available as of February 2014. Yoshino started a 2 year study in 2008. No results are available as of February 2014.

Other Trials

There are many other trials and research papers involving mushrooms and/or their metabolites though few involving humans. E.g. in searching for “mushrooms” 11 human studies were found but only four had been completed; one was suspended and the others were active and/or recruiting. Of the four completed 1 was negative and 3 never reported results. Many other in vitro or mouse references were found under the specific name of different mushrooms or their metabolites.

Results

The vast majority of ClinicalTrials.gov Phase I-III trials reviewed here were never reported in follow-up viz. Of the 35 Phase I-II trials, 32 were never reported years after trial completion. I would assume the results were negative; 2 trials were reported as negative; 1 trial reported that glucan “might be a contributing factor in beneficial effects of fiber intake.”

Of the Phase III trials, 1 reported an increase in survival time but another reviewer reported that the results definitely were not convincing; 1 trial was confusing; 2 trials reported no results; 3 other trials each had 2 subgoups broken out and in each 1 subgoup was positive and 1 negative; 2 trials were positive with increase in survival time. Three Phase III trials are on-going, with completion dates after 2/5/14. One Phase III trial was suspended. In all of these trials the metabolite used was as an adjunct to standard chemotherapy in cancer patients.

There were a few Phase III clinical trials (not listed at ClinicalTrials.gov) which showed some promise as an adjunct medicine in conjunction with standard medicines and chemotherapy in patients with metastatic disease but none apparently have gone on to a Phase IV trial.

Many databases were reviewed to find research papers or a clinical trial to support the thesis that a mushroom and/or its extract could prevent a disease in an otherwise healthy person. None were found.

Discussion

There are many reviews of the antioxidant, the antitumor properties and other possible benefits of fungi but the vast majority are based on the experimental findings in the laboratory. This large body of experimental data is from in vitro experiments and in vivo experiments with mice or rats. I have reviewed hundreds of them and they are both interesting and provocative. However, even if a cell reacts in a certain way in a Petri dish in the laboratory it does not mean that it is necessarily significant for humans. Humans are different than mice and even different strains of mice will react differently.

Fisher, M. and Li-Xi Yang, 2002, published a long excellent review of PSK and in summary noted "…PSK and other protein-bound polysaccharides are potent BRMs (biological response modifiers) with diverse biological effects. Further clarification…as well as further elucidation…may provide an innovative modality to be used in conjunction with other conventional therapies in the treatment of cancer. Further studies should be conducted…."

Chang, S-T. 2006, summed up the status of medicinal mushrooms noting "At the present time, many of the medicinal properties attributed to mushroom products are based on data obtained from in vitro and animal-based experiments. Much more advanced science is required to demonstrate that claims of enhanced function and reduced disease risks are also applicable in the human context." and "…mushroom products (nutriceuticals) are likely to prove extremely useful in both alleviating and preventing human disease conditions."

Most trials end with a statement that more work needs to be done as Ajith, 2007, "…intensive and extensive investigations are needed to exploit their (fungi) valuable therapeutic use." Additionally most (but not all) trials couch their conclusions tentatively with possibly, maybe, perhaps etc.

Ulbricht, C. et al, 2009, reviewed many databases for Maitake mushroom (Grifola frondosa) for the Natural Standard Research Collaboration. They stated “There was a lack of systematic study on the safety and effectiveness of maitake in humans…Future randomized controlled trials are warranted.”

There is not much discussion in the literature about the safety or possible side effects of medicinal mushrooms. I do wonder about possible bad side effects. We are appropriately concerned about the possible ill effects of food injected with antibiotics. Some of the perfect (sexual) macro-fungi recommended as medicinals make antibiotics. Why are these possibly good for us and not chicken or beef given antibiotics? Some medicinals are supposed to be good for your immune system; however, some studies show negative as well as positive effects. E.g. Deng, G. et al, 2009, published a study of the immunological effects of Grifola frondosa in breast cancer patients in a Phase I/II trial noting both stimulatory (IL-2) and suppressive (IL-10) cytokines. He stated "Cancer patients should be made aware of the fact that botanical agents produce more complex effects than assumed, and may depress as well as enhance immune function. It is therefore more accurate to view this medicinal mushroom extract (Grifola frondosa) as an immunomodulator, rather than as an immune enhancer." Some fungal metabolites have been reported as having lowered blood sugars in patients (Konno, S. et al, 2008; Pruess, HG et al, 2007 and others). If clinically significant would these possibly be bad for those of us walking around with already low blood sugars? Rao, J & Feng KY, 1990, and others have noted some platelet inhibition; would not these be bad for pre-operative patients to ingest or folks with a bleeding tendency? Hepatic dysfunction has been noted by Mukai, H., 2006, and others taking Agaricus blazei extract. This possibly would be bad for folks with already compromised liver function or taking other medication which might impair liver function. Other possible problems have been noted but this will suffice to raise the question as to whether we really know enough about this subject to recommend that people either eat mushrooms as a medicine or take their extracts.

I did a quick search for recent trials and believe the following probably sums up current thinking with a comprehensive article "Immunomodulating compounds in Basidiomycetes" by Masashi Mizuno and Yosuke Nishitani in J Clin Biochem Nutr. 2013 May; 52(3): 202-207. This is a thorough long review with 55 references. Only one reference (#40) was to a human trial. Although 31 humans were in the trial, only 8 were in a double blinded arm. Their conclusions were (in part) “A number of studies have proposed several antitumor mechanisms. However, it is expected that a more scientific approach is required to build up theories.”

There are a few Phase III ongoing trials and a few completed trials (not listed with ClinicalTrials.gov) but the results of most are not available.

Some of the previously noted sources stated that a substance is good for a person because there is an ongoing trial. To cite this as proof that the substance is good is misleading. It does not mean good; it just means it is being studied. The majority of trials started prior to 2009 have not been and probably will not be reported as they had negative or inconclusive results.

Additionally, even after a trial has been reported as being positive new data may arise showing it to be false. E.g., there had been a good deal of internet touting of selenium as an anti-prostate cancer agent when in 1996 a very large Phase III trial of 35,533 men was begun. Gann PH, 2009, wrote of this wave of hope. However, Lippman SM, 2009, noted the recent announcement that the Selenium and vitamin E Cancer Prevention Trial (SELECT) to show the reduction of prostate cancer was cancelled. It was not preventing the cancer and there was a small, statistically not significant, increase in risk of prostate cancer in the vitamin E group and type 2 diabetes in the selenium group. Even here there are some who disagree with the above findings because of the complexities of epidemiological and immunological research with its “complex positive and negative feedback loops”.

Assuming a Phase III trial were successful, then that substance might be approved for a Phase IV trial. At this point it would probably only be as an adjunct treatment together with an anti-AIDS or cancer chemotherapeutic agent in people with a recurrent and/or metastatic disease.

I believe it is wrong to quote or otherwise advertise the above noted scientific experimental trials as the basis of promoting or selling a mushroom and/or its metabolite to maintain health and/or prevent disease. They certainly may be cited as “being studied” but to imply that the substance is good for you is misleading. It also increases “confirmation bias” to confirm that which one might already believe.

I can not argue if one wants to eat mushrooms and/or their extracts because of a belief system or because there is a long history of peoples doing it. However, don't quote in vitro or in vivo mouse or rat scientific studies to try to support the belief system.

Conclusions

I find no basis from human Phase I-III trials and other trials to suggest the use of mushrooms as medicinals in an otherwise healthy person. Accordingly I believe to suggest the use of mushrooms and or their metabolites as medicinals for healthy people at this time is unjustified on a scientific basis and is misleading.

There are, however, some provocative studies of the use of mushrooms as adjuvant therapy combined with standard chemotherapy and/or surgery in metastatic cancer and as an adjunct treatment in HIV immunocompromised patients. Hopefully, these studies will be confirmed by others in larger well controlled series.

Citation: Lawrence Leonard, MD (2014) Mushrooms as Medicinals: a literature review, McIlvainea 23 (25-30): http://www.namyco.org/publications/mcilvainea/v23/mushrooms_as_medicinals.html

Editor: Michael W. Beug
Publisher: North American Mycological Association
Published: May 1, 2014
Copyright: © 2014 Lawrence Leonard, MD

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