Medicinal Mushrooms: Current Use in Clinical Practice

Abstract

Introduction

With the earliest recorded use of medicinal mushrooms dating to 450 BC, human knowledge and use of these intriguing fungi go back for millennia.¹ The fungi kingdom has many distinct differences from the plant kingdom, as fungi are not capable of photosynthesis and are, therefore, heterotrophic, absorbing nutrients from organic material in their surroundings (unlike plants, which obtain glucose through photosynthesis). In addition, although plant cell walls are composed mainly of cellulose, the cell walls of fungi are composed of chitin and glucans. In most fungi, the predominant polysaccharide found in the cell wall is β-glucan. Mushrooms, the fruiting bodies of macrofungi, also contain numerous other bioactive constituents, such as unsaturated fatty acids, triterpenes, phenolic compounds, glycoproteins, and peptides.²

β-1,3-Glucan is the most abundant β-glucan polysaccharide found in fungal cell walls, comprising 65%–95% of total β-glucan content.³ Although many components of mushrooms may have medicinal properties, much of the research on mushrooms' medicinal activities has focused on β-glucan content, as we will discuss below. In fact, innate immune system function may have close ties to these compounds. Monocytes, neutrophils, macrophages, and dendritic cells all express β-glucan receptors on their surfaces.

These receptors (including dectin-1 receptors, complement receptor type 3 [CR3], and CD5) play a role in recognizing β-glucan as a fungal cell wall component. This recognition, in turn, activates phagocytosis, increases production of reactive oxygen species, and enhances the inflammatory response by activating numerous cytokines, helping the body to respond to fungal pathogens.^4,5

β-Glucans are structurally diverse, and this diversity may have implications for the way the body responds to these compounds both in the case of defense from fungal pathogens and infection, and in the case of therapeutic immune stimulation.⁶ β-Glucans also bind CR3. CR3 may be the primary β-glucan receptor on natural killer (NK) cells and neutrophils, and serves to upregulate cytokine production, and also controls fungal killing and phagocytosis in a complement-dependent manner.⁷ β-Glucans may also be fermented by intestinal bacteria, possibly leading to beneficial changes in the composition of the host microbiome.⁸

In addition to featuring prominently in traditional cuisines around the world, mushrooms are extracted to create a variety of supplements, with medicinal mushrooms representing a burgeoning billion dollar industry globally. Mushroom extracts may be created by a variety of methods, with extraction methods playing an important role in the final chemical composition and constituents of a supplement.

For example, ethanol extraction may lead to a mushroom supplement higher in total phenolic content, creating a supplement with good antioxidant potential. Hot water extraction, in contrast, yields a mushroom extract with much higher β-glucan content (since polysaccharides are water soluble).⁹ Combined extraction produces a mushroom extract with both water-soluble and ethanol-soluble constituents. Clinicians should keep these extraction methods in mind when choosing a mushroom supplement, as different extracts may be better indicated in specific situations.

Medicinal mushrooms have been the subject of extensive research in many areas, and clinically are frequently selected to help support immune function or to help patients with viral infections, cancer, cognitive concerns, and other health conditions. Each of these areas provides fascinating insights into how these mushrooms work, and how they might be our allies in helping our patients achieve better health. Table 1 lists the scientific name and common name for each of the medicinal mushrooms discussed in this article.

Table 1.

Medicinal Mushrooms Discussed in This Article

Scientific name	Common name	Additional notes
Lentinula edodes	Shiitake mushroom	Source of AHCC
Cordyceps sinensis	Cordyceps mushroom, caterpillar fungus
Pleurotus ostreatus	Oyster mushroom
Laetiporus sulphureus	Chicken-of-the-woods
Coriolus versicolor	Turkey tail, yunzhi	Also called Trametes versicolor
Ganoderma lucidum	Reishi mushroom, lingzhi
Grifola frondosa	Maitake, hen-of-the-woods
Agaricus sylvaticus	Blushing wood mushroom
Agaricus bisporus	White button mushroom
Hericium erinaceus	Lion's mane
Agaricus blazei	Royal sun agaricus

AHCC, active hexose correlated compound.

Immune Enhancement

Several different mushrooms have been shown to be effective stimulators of immune function, and may impact a variety of immune targets. In a clinical trial of 52 healthy young adults ages 21 to 41, consuming whole dried shiitake mushrooms as part of the diet at 5 or 10 g daily for four weeks led to significant immune effects. NK cells increased, as did a subset of T cells (P < 0.0001 and P < 0.0001), and both cell types showed an increased ability to express activation receptors. Levels of C-reactive protein decreased, and serum levels of several cytokines and chemokines shifted after four weeks of mushroom consumption. This included a decrease in macrophage inflammatory protein-1α/chemokine C-C ligand 3, and an increase in interleukin (IL)-4, IL-10, IL-1α, and tumor necrosis factor (TNF)-α. In addition, levels of secretory immunoglobulin A in saliva increased, suggesting enhanced gut immunity.¹⁰

An additional clinical trial in healthy elderly subjects (N = 42) looked at supplementation of a proprietary shiitake extract at 2.5 mg daily. Participants were randomized into two groups, receiving either the shiitake extract or a placebo daily for six weeks, followed by a four-week washout period, then a crossover to treatment or placebo for an additional six weeks. Supplementation with the shiitake extract did not result in changes to cytokine or complement levels, but did result in an increase in circulating levels of B cells (even at this very modest dose).¹¹

Cordyceps fungus has also been shown to impact cell-mediated immunity (note that although Cordyceps is technically classified as a parasitic fungus and not as a mushroom taxonomically, Traditional Chinese Medicine describes it as a medicinal mushroom, and Cordyceps is rich in β-glucans^12,13). Seventy-nine healthy adult men were given an ethanol extract of Cordyceps 1500 mg, or a placebo, daily for four weeks. Cordyceps extract was safe and well tolerated, with no significant adverse events reported. Cordyceps supplementation led to a significant increase in levels of NK cells, lymphocytes, IL-2, and interferon-γ compared with placebo (P = 0.001, P ≤ 0.0001, P = 0.0096, P = 0.0126, respectively).¹⁴

A study in healthy athletes has also found that three months of supplementation with a proprietary β-glucan supplement from Pleurotus ostreatus, the oyster mushroom, leads to a significant increase in circulating number of NK cells, and additionally reduces the incidence of upper respiratory tract infection.¹⁵

The immune supportive properties of these and other medicinal mushrooms may have important therapeutic potential for people with acute or chronic viral infections. For example, use of a proprietary β-glucan supplement extract (dosed at 1 mL per 5 kg body weight once daily for six months, with 5 mL of the supplement containing 50 mg β-glucan) from P. ostreatus for a three-month period has been shown to reduce the incidence of respiratory tract infections in children, and to significantly decrease the incidence of either flu or flu-like illnesses.¹⁶

Regarding chronic viral infection, in a study of 61 people who tested positive for high-risk serotypes of oral human papillomavirus (HPV 16 and 18), medicinal mushroom supplementation was found to exert specific benefits. Twenty-one subjects in this trial took chicken-of-the-woods (Laetiporus sulphureus), whereas 41 took a combination of turkey tail (also called Trametes versicolor or Coriolus versicolor) and Ganoderma lucidum. After two months of supplementation, 5% of subjects in the chicken-of-the-woods group experienced clearance of their HPV. In the combination mushroom supplement group, 88% of subjects experienced clearance of HPV (P < 0.001).¹⁷

In adults with HIV who were not on antiretroviral medication, a proprietary supplement containing a mixture of medicinal mushrooms (including Cordyceps sinensis, Cordyceps militaris, Agaricus blazei, T. versicolor, G. lucidum, Grifola frondosa, and Lentinula edodes, with specific amounts of each not provided due to the proprietary nature of the formulation) was found to significantly increase CD4+ T-lymphocyte counts.¹⁸ And in children with HIV (N = 24) receiving antiretroviral therapy, Agaricus sylvaticus administered as a syrup at a dose of 30 mg mushroom extract per kilogram per day (containing 127 mg β-glucan per 100 g), administered once daily for three months, improved antioxidant capacity.¹⁹

Cancer

Several fascinating studies have been conducted on the effects of medicinal mushrooms in people with cancer. Many of the benefits seen in an oncology setting may be attributed to modulation of cellular and humoral immunity, related to factors discussed above, while others may be related to a direct antitumor effect. Clinical trials of mushrooms have been performed in people with breast, colorectal, hepatocellular, prostate, and lung cancers, among others.

Breast Cancer

Human trials of medicinal mushrooms for people with breast cancer have included studies on G. lucidum, G. frondosa (maitake mushroom), L. edodes, and A. sylvaticus. Valadares et al.²⁰ evaluated the effects of A. sylvaticus in 46 participants with stage II or stage III breast cancer receiving chemotherapy. The chemotherapy regimen administered was either cyclophosphamide, methotrexate, fluorouracil, or fluorouracil, doxorubicin, and cyclophosphamide. Patients received either placebo or a hot water extract of A. sylvaticus at a dose of 2100 mg daily divided into two daily doses, for six months.

At the completion of the trial, 46 women had completed the study, 23 each in the placebo and mushroom groups. Subjects who received A. sylvaticus were less likely to experience gastrointestinal (GI) side effects, such as anorexia, constipation, or diarrhea. Also, women who received A. sylvaticus were less likely to experience nausea compared with women in the placebo group (15.3% versus 84.62%). In addition, no patients in the A. sylvaticus group reported fever, whereas 70% of patients in the placebo group reported fever.P-values were not provided for these differences.²⁰

Deng et al.²¹ examined the immunologic effects of maitake extract in postmenopausal women with stage I, stage II, or stage II breast cancers. Women were free of cancer at the time of enrollment, and had completed radiation or chemotherapy at least three months prior, and hormonal therapy at least two months prior. Thirty-four women were enrolled sequentially in five cohorts and received a liquid maitake extract (combined hot aqueous and alcohol extraction) at a dose of 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for three weeks. Two patients withdrew during the trial period due to possible side effects.

Maitake extract induced a number of phenotypic as well as functional immunologic changes, and these were modulatory in nature, with some factors being increased while others decreased. The greatest functional alterations, with a 50% or greater increase from baseline, were in granulocyte response and in production of cytokines IL-10, IL-2, and TNF-α. The greatest differences in these functional increases were seen with intermediate doses of maitake, ranging from 5 to 7 mg/kg daily. The greatest phenotypic changes were observed in CD3+ CD56+ NK T cells and CD4+ CD25+ T cells, with increases of >50% from baseline. These alterations were seen with higher dose maitake, 10 mg/kg daily. In addition, at the higher dose of maitake, 10 mg/kg daily, a decrease in IFN-γ was seen.²¹

These results help highlight the modulatory nature of mushroom supplements; rather than being strictly stimulatory or inhibitory to immune function, mushroom supplements may exert differential effects depending on the cellular or tissue context, and these effects may also vary based on dosage.

Turning to G. lucidum (reishi mushroom), Zhao et al.²² performed a pilot study of reishi supplementation in women with breast cancer receiving hormonal therapy. Women with estrogen receptor positive (ER+) stages I to IIIa breast cancer were randomized to receive either a spore powder of reishi at a dose of 1000 mg 3 times daily, or a placebo, for four weeks. Forty-eight patients were enrolled, 25 in the reishi group and 23 in the placebo group. Compared with those receiving placebo, women who received reishi had significant improvements in levels of fatigue (P < 0.01) and depression (P < 0.01). Reishi group subjects also had improved scores in emotional and cognitive functioning (P < 0.05) compared with placebo group subjects. Reishi supplementation also led to decreases in TNF-α and IL-6.²²

Shiitake extracts may also benefit women receiving endocrine therapy. Suzuki et al.²³ studied the effects of shiitake mushroom (L. edodes) in stage 0, stage I, or stage II breast cancer patients receiving hormonal therapy. All participants had completed surgery, radiation, and chemotherapy at least nine weeks before enrollment. Twenty subjects were enrolled and received 600 mg of a hot water extract of shitake three times daily in an open-label manner. After enrollment, subjects were observed for four weeks, then took the shiitake extract for eight weeks. The majority of subjects (N = 14) were receiving tamoxifen, whereas additional subjects were taking either an aromatase inhibitor or toremifene, a selective ER modulator. A total of 18 subjects completed the trial.

Supplementation with shiitake extract was found to improve quality of life (QOL) utilizing the Short Form 36 instrument. In a subset of patients who were determined to have decreased immunity at baseline (defined as having an IFN-γ/IL-10 ratio of 0.2 or less), shiitake was also found to significantly increase IFN-γ production (P < 0.05) as well as the IFN-γ/IL-10 ratio (P < 0.01). There were no serious side effects reported.²³ Nagashima et al. also found that shiitake supplementation (hot water extract in tablet form at a dose of 900 mg twice daily) compared with placebo preserved QOL and immune function in women with stage I, stage II, or stage III breast cancer receiving adjuvant anthracycline-based chemotherapy.²⁴

Also worth mentioning is that mushroom consumption as part of the diet is associated with a reduced risk of developing breast cancer in both premenopausal and postmenopausal women, in a dose-dependent manner.²⁵ Compounds in white button mushrooms have even been shown to have aromatase-inhibiting properties.^26,27

Colorectal Cancer

A number of studies of medicinal mushrooms have been conducted in people with colorectal cancer, with most focusing on polysaccharide-K (PSK), a β-glucan–rich polysaccharide compound extracted from C. versicolor. Sakai et al.²⁸ compared outcomes for patients with Dukes' B or Dukes' C (corresponding to stage II or stage III) colon cancer (N = 101) who received either oral adjuvant chemotherapy alone or oral adjuvant chemotherapy plus PSK 3000 mg daily for 24 months. Ten-year survival for subjects who received PSK was 81.9%, compared with 50.6% for subjects who received chemotherapy alone (P ≤ 0.007). In subjects with more aggressive disease as evidenced by lymphovascular invasion, 10-year survival was 80.6% for people who received PSK compared with 25.9% in those who did not (P ≤ 0.0050).²⁸

Yoshitani and Takashima²⁹ had similar findings in a trial (N = 63) comparing adjuvant chemotherapy alone with adjuvant chemotherapy plus PSK (dosed at 3000 mg daily for one year) in elderly people of age 70 years or greater with early stage colon cancer. In the PSK group, three-year relapse-free survival was 76.2%, whereas for subjects in the chemotherapy-only group, it was 47.8% (P = 0.041). Overall survival at three years was 80.8% for those who received PSK and 52.8% for those who received chemotherapy alone (P = 0.0498).²⁹

Data from randomized controlled trials (RCTs) on PSK in people with GI cancers have also been reviewed as part of a meta-analysis, conducted by Ma et al.³⁰ A total of 23 RCTs were included, with 10,684 subjects (including not only people with colorectal cancer, but also gastric and esophageal cancers). PSK supplementation was associated with a significant increase in one- to five-year overall survival, and was also found to decrease the incidence of nausea and vomiting (odds ratio [OR]: 0.53, 95% confidence interval [CI]: 0.31–0.91) and leukopenia (OR: 0.60, 95% CI: 0.43–0.83). Doses of PSK for included trials ranged from 300 to 3000 mg daily, with the majority of studies utilizing 3000 mg daily.³⁰

Not only may medicinal mushrooms offer benefits for people being actively treated for colon cancer, but they may also provide benefits to those interested in primary prevention of the disease. Oka et al.³¹ enrolled subjects with colorectal adenomas detected on colonoscopy who received either no treatment or a water-soluble extract of G. lucidum at a dose of 1500 mg daily for 12 months. A total of 96 subjects took the mushroom extract, whereas 102 people served as no-treatment controls. A follow-up colonoscopy was performed at the 12-month time point. In the control group, change in the number of adenomas increased to 0.66 ± 0.10 (mean ± standard error), whereas in the mushroom group, it decreased to −0.42 ± 0.10 (P < 0.01). In the control group, total size of adenomas increased to 1.73 ± 0.28 mm, whereas in the mushroom group it decreased to −1.40 ± 0.64 mm (P < 0.01).³¹

Hepatocellular Carcinoma

One of the more common cancers worldwide, hepatocellular carcinoma (HCC), remains relatively rare in the United States. HCC is an aggressive cancer, and because it is frequently diagnosed at advanced stages, treatment options may often be limited.

Two trials have examined the effects of active hexose correlated compound (AHCC) in people with HCC. AHCC is an extract prepared from shiitake mushrooms containing a mixture of polysaccharides including α-glucans. Matsui et al.³² enrolled 269 patients who underwent surgical resection of HCC. After surgery, 113 patients received AHCC at a dose of 3000 mg daily either until the last follow-up date or until death. The remaining 156 patients were simply monitored after surgery consistent with standard of care, and did not receive AHCC. The follow-up period ranged from 2 to 117 months, and the median follow-up period was 28 months for subjects receiving AHCC, and 30 months for control group subjects.

By the end of the follow-up period, 34.5% of subjects in the AHCC group had a recurrence of HCC, compared with 66.1% in the control group (P = 0.0335). In addition, by the end of the follow-up period, 20.4% of patients in the AHCC group had died, compared with 46.8% in the control group (P = 0.0032). Three subjects in the AHCC group elected to withdraw from the study due to mild nausea. AHCC was well tolerated, with no significant side effects.³²

Cowawintaweewa et al.³³ performed a small trial (N = 44) of AHCC in patients with advanced unresectable HCC. Patients were on no conventional treatment and were receiving supportive care only. Thirty-four patients were randomized to receive AHCC at a dose of 6 g daily, and 10 to receive a placebo. Follow-up ranged from 0.5 to 3.5 months in the placebo group, and 1.5 to >24 months in the AHCC group. At 1.5 months, 50% of subjects in the placebo group had died, whereas no patients in the AHCC group had died. At 3.5 months, no subjects (0%) in the placebo group were alive, whereas eight subjects (61.5%) in the AHCC group were still alive. Survival in the AHCC group was significantly greater at 3.5 months, compared with 1.5 months in the control group (P = 0.000). Six of the patients (18%) who received AHCC lived >7 months, and one patient survived >24 months with magnetic resonance imaging indicating stable disease.³³

C. versicolor has also been studied for patients with unresectable HCC. Chay et al.³⁴ randomized 15 people with HCC that was unresectable, or who were unfit to receive standard treatment, to receive either a Coriolus extract at 2400 mg daily, or a placebo. The authors did not specify which type of turkey tail extract was utilized, except to mention that it was a commercially available extract. Nine patients had hepatitis B and 3 patients had hepatitis C, whereas 5 patients had undergone previous resection and 11 had previously received chemotherapy. The mushroom group contained a larger number of subjects with poorer liver function as well as with prior treatment history. The intervention was continued until disease progression or unacceptable toxicity occurred. The median duration of treatment was 5.9 weeks in placebo patients and 12.1 weeks in Coriolus patients.

There was no significant difference in time to progression or overall response rate (ORR) between the two groups; however, subjects who received the mushroom extract reported improved physical, emotional, cognitive, and social function compared with the placebo group. In addition, subjects who supplemented with the mushroom extract experienced significantly less pain (P = 0.011) and appetite loss (P = 0.006).³⁴

Prostate Cancer

A recent 2019 study conducted in Japan found that mushroom consumption as part of the diet appears to confer specific benefits for prostate health. This pooled analysis included 36,499 men of ages 40–79 years who were followed for a median of 13.2 years. Subjects reported mushroom consumption as part of the diet using a food frequency questionnaire, categorized as <1 time weekly, 1–2 times weekly, or ≥3 times weekly. The authors did not record the specific types of mushrooms eaten, but do note that shiitake, maitake, oyster, and white button mushrooms are all commonly eaten in the region of study. A total of 1204 cases of prostate cancer occurred (a 3.3% incidence rate) during 574,397 person-years of follow-up.

Participants who reported higher levels of mushroom consumption had a decreased risk of prostate cancer compared with those who ate mushrooms <1 time weekly. Subjects who had mushrooms 1–2 times weekly had an 8% lower risk of prostate cancer, and those who ate mushrooms ≥3 times weekly had a 17% lower risk, compared with the men who had mushrooms once weekly or less (1–2 times weekly: hazard ratios [HRs] [95% CIs] = 0.92 [0.81–1.05]; ≥3 times weekly: HRs [95% CIs] = 0.83 [0.70–0.98]; P-trend = 0.023). This effect was strongest in men of age 50 years or older. The authors note that a limitation of this study was that information on the specific species of mushrooms consumed was not collected, making it difficult to determine which specific mushroom or mushrooms may have contributed to their findings.³⁵

Mushrooms may also provide a benefit in men who have already been diagnosed with prostate cancer. Twardowski et al.³⁶ conducted a phase I trial (N = 36) of white button mushroom powder in men with recurrent prostate cancer as evidenced by rising prostate specific antigen (PSA) levels. Participants had adenocarcinoma of the prostate with no evidence of metastatic disease. For men who had surgery as the primary treatment, a rise in PSA of ≥0.2 ng/mL that increased above nadir was required for participation, and for those in whom radiation or other local therapy was used as the primary treatment, a rise in PSA of 2.0 ng/mL above post-therapy nadir was required. Patients had to have completed androgen deprivation therapy or chemotherapy at least six months before enrollment.

The supplement consisted of white button mushrooms that had been freeze dried and powdered, with the powder compressed into 500 mg tablets. Subjects received the mushroom tablets twice daily with dose escalation conducted in six dose levels, 4, 6, 8, 10, 12, and 14 g daily. The median PSA level at the beginning of the trial was 1.9 ng/mL. The overall PSA response rate in this trial was 11% (4 out of 36 subjects, 95% CI: 4%–26%). Two subjects, one receiving 8 g daily and the other 14 g daily, had prolonged PSA complete response, defined as a reduction of PSA to ≤0.04 ng/mL, which continued until the time the study was published. The lengths of these complete responses were 49 and 30 months. In two additional subjects, a partial response was observed, defined as a reduction of PSA of 50% from baseline. Overall, the mushroom supplement was associated with decreased PSA levels in 36% of participants. Eight grams daily was the minimum dose at which a PSA response was seen. There were no dose-limiting toxicities in this trial.³⁶

Lung Cancer

Several interesting studies have been conducted on medicinal mushrooms for people with lung cancer. These include an open-label study of Ganoderma, as well as several trials on both lentinan (a shiitake β-glucan polysaccharide) and PSK. A meta-analysis of lentinan studies is available, as is a systematic review of studies on PSK.

Starting with Ganoderma, Gao et al.³⁷ conducted an open-label trial of a water-soluble polysaccharide supplement derived from G. lucidum. Thirty-six subjects with advanced lung cancer received 5.4 g daily of the mushroom extract for 12 weeks.

Although overall there were no significant differences in mean cytokine levels, NK cell activity, or T cell counts before and after the intervention, there was a great deal of variability, with some of the subjects demonstrating notable changes in immune function. As an example, 20 subjects experienced decreased TNF-α concentration, and this seemed tied to decreased weight loss, nausea, fatigue, and insomnia. In 66.7% of subjects, a stimulation of NK cells also occurred. In addition, plasma cytokine concentrations increased in some participants: IL-2 increased in 17 subjects (56.7%), IL-6 increased in 18 subjects (60%), and IFN-γ increased in 18 subjects (60%). The authors suggest that the small sample size, reduced immune status due to advanced disease stage, or interindividual variability in immune response may have contributed to these results.³⁷

Turning to lentinan, Yin et al.³⁸ conducted a meta-analysis of trials involving lentinan injection for people with nonsmall cell lung cancer. They included only prospective clinical trials in which chemotherapy alone was compared with chemotherapy plus lentinan injection. A total of 12 clinical trials were included in their analysis, with 950 subjects, 458 of whom received chemotherapy only and 492 of whom received mushroom extract plus chemotherapy. Duration of trials ranged from two to eight weeks. Doses of lentinan utilized in the included trials were not reported.

All 12 included studies reported ORR, and pooled results determined that the ORR was significantly improved in the lentinan plus chemotherapy group subjects compared with those who received chemotherapy only (relative risk [RR] = 1.31, 95% CI: 1.14–1.52). Moreover, grades III and IV GI side effects were significantly reduced in subjects who received lentinan plus chemotherapy (RR = 0.54, 95% CI: 0.43–0.68). Grades III and IV granulocytopenia were also significantly reduced in the subjects who received the combination treatment compared with chemotherapy alone (RR = 0.65, 95% CI: 0.51–0.70).³⁸

Lastly, Fritz et al.³⁹ completed a systematic review of PSK and C. versicolor extracts for lung cancer. They included both clinical and preclinical trials. They included 28 studies in their analysis, with 11 being clinical studies and 17 preclinical studies. Of the 11 clinical studies, 6 were RCTs, and all of the included RCTs involved supplementation of 3 g daily of either PSK or polysaccharide P (PSP) from Coriolus. Five trials examined the effects of the mushroom extract given with chemotherapy, and one trial examined the effects of the mushroom extract given for 28 days after completion of chemotherapy.

All six of these RCTs found a benefit on at least one end point, which included measures of immune function, performance status, body weight, cancer-associated symptoms (such as anorexia, fatigue, nausea and vomiting, xerostomia, night sweats, pain, dyspnea, insomnia, and anxiety), or survival. Two trials examined survival, and although neither of these found a significant difference in overall median survival, one found that PSK plus chemotherapy significantly improved one-year survival rates compared with chemotherapy only (88.9% in the mushroom group compared with 61.8% in the chemotherapy-only group, P < 0.05). PSK was also found to be well tolerated and safe, and in one trial it was administered continuously for more than five years.³⁹

Mushroom Supplements in Oncology: Additional Considerations

As already noted, a variety of mushroom supplements have been found to be safe and well tolerated alongside conventional oncology treatments, including radiation, endocrine therapies, and chemotherapies. Evidence of drug interactions is limited, making mushroom supplements a clinically attractive option for oncology patients, many of whom may be on multiple medications. An area where safety data are not established is the use of medicinal mushrooms alongside oncologic immunotherapy. Immune-modulating mechanisms of medicinal mushrooms may in some cases overlap with those of immunotherapeutic drugs, a potential safety consideration.⁴⁰

In addition, as with other nutritional supplements, quality concerns related to mushroom supplements are an important consideration. Some mushroom supplements may fail to meet stated label claims (e.g., one assay of commercially available reishi supplements in the United States found that only 26.3% had ingredients consistent with their labels⁴¹), whereas others may include species substitutions.⁴² These concerns, of course, are important not just for oncology patients, but also for all patients, and clinicians play an important role in helping patients select a mushroom supplement that is of good quality and efficacious. Consider asking the manufacturer of a mushroom supplement how they validate their raw material, whether their supplements are organic, and whether they can provide test results both for contaminants such as heavy metals or pesticides and for potency.

Cognitive Function

Out of the many known medicinal mushrooms, lion's mane mushroom, Hericium erinaceus, is the one most extensively studied for support of cognitive and neuronal health. Numerous preclinical studies have been performed, with Sabaratnam et al.'s 2013 review providing a good overview of the cell line and animal data.⁴³

In addition to preclinical studies, a small double-blind placebo-controlled trial in people of ages 50–80 years with mild cognitive impairment has been conducted. Mori et al.⁴⁴ randomized 30 male and female subjects to receive either lion's mane tablets (250 mg 3 times daily), or a placebo, for 16 weeks. After completion of 16 weeks of supplementation, the participants were then observed for a 4-week period.

The mushroom group experienced significantly increased cognitive function scores based on the Revised Hasegawa Dementia Scale compared with the placebo group at the 8-, 12-, and 16-week time points. Cognitive function scores of people who received lion's mane also increased along with the duration of supplementation, and decreased significantly four weeks after discontinuing the supplement, suggesting that the mushroom would need to continue to be taken for the effects to persist.⁴⁴ Nagano et al.⁴⁵ also performed a small study of 30 women with anxiety and depression and found that lion's mane significantly reduced anxiety and depression after four weeks of use (P = 0.067 for anxiety and P = 0.033 for depression). In this study, lion's mane was dosed as 2 g per day in a specially prepared cookie, whereas the placebo was a regular cookie without added mushroom powder.⁴⁵

Additional Clinical Trials

A number of additional clinical trials have been conducted on medicinal mushrooms, highlighting their ability to effect multiple targets and components of health. The studies mentioned hereunder give a sense of the variety of studies conducted, and of the potential of medicinal mushrooms to be helpful in multiple clinical settings.

Chen et al.⁴⁶ conducted an open trial comparing clomiphene citrate with a Maitake SX-fraction (a patented glycoprotein extract thought to impact insulin resistance) in women with polycystic ovarian syndrome. They included 80 subjects, who were treated as follows: 72 subjects were randomized to receive either clomiphene or Maitake SX-fraction only for 12 weeks and 8 patients who had documented insensitivity to clomiphene at the time of enrollment received both clomiphene and Maitake together.

After 12 weeks, 18 of the 72 subjects who had been assigned to monotherapy were found to be nonresponding, so were then given clomiphene and Maitake together until the 16-week time point. Ovulation was evaluated by ultrasound. Ovulation occurred in 76.9% of patients who received Maitake SX-fraction only, and in 93.5% of patients who received clomiphene only. Of the participants who did not respond to monotherapy, 100% of patients who did not respond to Maitake alone and 75% of patients who did not respond to clomiphene alone achieved ovulation with the combination.⁴⁶

The effects of mushroom supplements on insulin resistance may also extend to people with diabetes. Hsu et al.⁴⁷ performed a small randomized double-blind placebo-controlled trial assessing the effects of A. blazei extract in people with type 2 diabetes mellitus. Participants received the mushroom extract at a dose of 1500 mg, or a placebo, daily for 12 weeks. A total of 60 participants completed the trial, 29 receiving the mushroom supplement and 31 the placebo. Both groups took standard sulfonylurea medication as well as metformin throughout the trial and for at least six months prior.

After 12 weeks, subjects in the mushroom group had a significantly lower homeostasis model of assessment for insulin resistance index compared with placebo group subjects (P = 0.04). In addition, plasma adiponectin (a protein hormone secreted by adipocytes, which helps regulate glucose and lipid metabolism and enhance insulin sensitivity) significantly increased by 20% in the mushroom group, whereas it decreased in the placebo group by 12% (P < 0.001).⁴⁷

Mushroom supplements may also benefit people with cardiovascular disease (CVD). In a small 2018 clinical trial (N = 71), people with either high risk or stable angina were given a freeze-dried PSP extract of G. lucidum containing 180 mg β-d-glucan. Subjects took this extract three times daily for 90 days (providing a total dose of 750 mg daily of PSP, with 540 mg daily of β-d-glucan).

This resulted in decreased blood pressure (BP), with systolic BP decreasing by 9.72 mmHg and diastolic BP decreasing by 5.43 mmHg on average in the participants with stable angina. In people with high-risk angina, systolic BP declined on average by 11.89 mmHg and diastolic by 6.76 mmHg. Superoxide dismutase (SOD) levels also significantly increased among people with stable angina (P = 0.001). SOD did not change significantly in participants with high-risk angina. Malondialdehyde (an oxidative marker and product of lipid peroxidation) levels decreased significantly among people with stable angina as well as those with high-risk angina (P = 0.000 and P = 0.000, respectively). These results demonstrate the ability of the mushroom extract to help support antioxidant status in these individuals with CVD.⁴⁸

Mushroom supplements may also help support antioxidant levels in people undertaking prolonged exercise. Zembron-Lacny et al.⁴⁹ gave 14 healthy men a shiitake extract at 700 mg twice daily, or placebo, for 10 days before two exercise sessions, in a crossover manner. The exercise sessions included a 90-minute run, and 15 minutes eccentric exercise, both completed at 65% VO2max. Although shiitake extract had no impact on markers of muscle regeneration after exercise, it did result in significant increases in nitric oxide concentration both before and after exercise (P = 0.001 and P = 0.001). Shiitake extract was also found to increase thiol redox status (P < 0.001).⁴⁹

Interestingly, mushroom supplementation has also been found to increase physical fitness in women with fibromyalgia. Sixty-four women were randomized to receive either G. lucidum at a dose of 3 g twice daily, dissolved in warm water, or carob (Ceratonia siliqua) powder, also at a dose of 3 g twice daily dissolved in warm water. A total of 25 women in the mushroom group completed the trial, and 23 women in the carob group completed the trial, taking their respective treatment for six weeks.

At the completion of the study period, women who took Ganoderma experienced a statistically significant improvement in aerobic endurance compared with those in the carob group (P < 0.05). In addition, women who took the mushroom supplement had improved lower body flexibility and mean walking velocity compared with women who took carob (P < 0.05 for each).⁵⁰

These studies provide perspective on the great variety of health conditions medicinal mushrooms may help with, as well as the many medicinal properties these supplements possess, whether anti-inflammatory, antioxidative, or insulin sensitizing.

Conclusions

Medicinal mushrooms have numerous applications in clinical practice, and can be considered for people seeking enhanced immune function, defense against viral infection, protection from cancer or from the side effects associated with oncologic treatment, or even improved cognitive function. This review, although not exhaustive, gives the reader a sense of the breadth and variety of clinical studies supporting the use of medicinal mushrooms for people with many conditions. Future research will undoubtedly continue to help us develop our understanding of the antioxidant, immunomodulating, antimicrobial, anti-inflammatory, and other medicinal properties of these powerful fungi. ■

References

Stamets

, Zwickey

. Medicinal mushrooms: Ancient remedies meet modern science. Integr Med (Encinitas), 2014; 13:46–47.

Chaturvedi

, Agarwal

, Gupta

, et al. Medicinal mushroom: Boon for therapeutic applications. 3 Biotech, 2018; 8:334.

Fesel

, Zuccaro

. β-glucan: Crucial component of the fungal cell wall and elusive MAMP in plants. Fungal Genet Biol, 2016; 90:53–60.

Schwartz

, Hadar

. Possible mechanisms of action of mushroom-derived glucans on inflammatory bowel disease and associated cancer. Ann Transl Med, 2014; 2:19.

Goodridge

, Wolf

, Underhill

. β-glucan recognition by the innate immune system. Immunol Rev, 2009; 230:38–50.

Camilli

, Tabouret

, Quintin

. The complexity of fungal β-Glucan in health and disease: Effects on the mononuclear phagocyte system. Front Immunol, 2018; 9:673.

Salazar

, Brown

. Antifungal innate immunity: A perspective from the last 10 years. J Innate Immun, 2018; 10:373–397.

Fehlbaum

, Prudence

, Kieboom

, et al. In vitro fermentation of selected prebiotics and their effects on the composition and activity of the adult gut microbiota. Int J Mol Sci, 2018; 19:3097.

Veljović

, Veljović

, Nikićević

, et al. Chemical composition, antiproliferative and antioxidant activity of differently processed Ganoderma lucidum ethanol extracts. J Food Sci Technol, 2017; 54:1312–1320.

10.

Dai

, Stanilka

, Rowe

, et al. Consuming Lentinula edodes (shiitake) mushrooms daily improves human immunity: A randomized dietary intervention in healthy young adults. J Am Coll Nutr, 2015; 34:478–487.

11.

Gaullier

, Sleboda

, Øfjord

, et al. Supplementation with a soluble beta-glucan exported from shiitake medicinal mushroom, Lentinus edodes (Berk.) Singer mycelium: A crossover, placebo-controlled study in healthy elderly. Int J Med Mushrooms, 2011; 13:319–326.

12.

Panda

, Swain

. Traditional uses and medicinal potential of Cordyceps sinensis of Sikkim. J Ayurveda Integr Med, 2011; 2:9–13.

13.

Smiderle

, Baggio

, Borato

, et al. Anti-inflammatory properties of the medicinal mushroom Cordyceps militaris might be related to its linear (1 → 3)-β-D-glucan. PLoS One, 2014; 9:e110266.

14.

Kang

, Baik

, Kim

, et al. Cordyceps militaris enhances cell-mediated immunity in healthy Korean men. J Med Food, 2015; 18:1164–1172.

15.

Bergendiova

, Tibenska

, Majtan

. Pleuran (β-glucan from Pleurotus ostreatus) supplementation, cellular immune response and respiratory tract infections in athletes. Eur J Appl Physiol, 2011; 111:2033–2040.

16.

Jesenak

, Majtan

, Rennerova

, et al. Immunomodulatory effect of pleuran (β-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections. Int Immunopharmacol, 2013; 15:395–399.

17.

Donatini

. Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: A preliminary clinical trial. Int J Med Mushrooms, 2014; 16:497–498.

18.

Adotey

, Quarcoo

, Holliday

, et al. Effect of immunomodulating and antiviral agent of medicinal mushrooms (Immune Assist 24/7^TM) on CD4+ T-lymphocyte counts of HIV-infected patients. Int J Med Mushrooms, 2011; 13:109–113.

19.

Figueira

, Sá

, Vasconcelos

, et al. Nutritional supplementation with the mushroom Agaricus sylvaticus reduces oxidative stress in children with HIV. Can J Infect Dis Med Microbiol, 2014; 25:257–264.

20.

Valadares

, Novaes

MRCG

, Cañete

. Effect of Agaricus sylvaticus supplementation on nutritional status and adverse events of chemotherapy of breast cancer: A randomized, placebo-controlled, double-blind clinical trial. Indian J Pharmacol, 2013; 45:217–222.

21.

Deng

, Lin

, Seidman

, et al. A phase I/II trial of a polysaccharide extract from Grifola frondosa (maitake mushroom) in breast cancer patients: Immunological effects. J Cancer Res Clin Oncol, 2009; 135:1215–1221.

22.

Zhao

, Zhang

, Zhao

, et al. Spore powder of Ganoderma lucidum improves cancer-related fatigue in breast cancer patients undergoing endocrine therapy: A pilot clinical trial. Evid Based Complement Alternat Med, 2012; 2012:809614.

23.

Suzuki

, Takimoto

, Suzuki

, et al. Efficacy of oral administration of Lentinula eododes mycelia extract for breast cancer patients undergoing postoperative hormone therapy. Asian Pac J Cancer Prev, 2013; 14:3469–3472.

24.

Nagashima

, Yoshino

, Yamamoto

, et al. Lentinula edodes mycelia extract plus adjuvant chemotherapy for breast cancer patients: Results of a randomized study on host quality of life and immune function improvement. Mol Clin Oncol, 2017; 7:359–366.

25.

, Zou

, Chen

, et al. Dietary mushroom intake may reduce the risk of breast cancer: Evidence from a meta-analysis of observational studies. PLoS One, 2014; 9:e93437.

26.

Grube

, Eng

, Kao

Y-C

, et al. White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation. J Nutr, 2001; 131:3288–3293.

27.

Chen

, Oh

S-R

, Phung

, et al. Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus). Cancer Res, 2006; 66:12026–12034.

28.

Sakai

, Yamashita

, Maekawa

, et al. Immunochemotherapy with PSK and fluoropyrimidines improves long-term prognosis for curatively resected colorectal cancer. Cancer Biother Radiopharm, 2008; 23:461–468.

29.

Yoshitani

, Takashima

. Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer. Cancer Biother Radiopharm, 2009; 24:35–39.

30.

, Wu

, Yu

, et al. Can polysaccharide K improve therapeutic efficacy and safety in gastrointestinal cancer? A systematic review and network metaanalysis. Oncotarget, 2017; 8:89108–89118.

31.

Oka

, Tanaka

, Yoshida

, et al. A water-soluble extract from culture medium of Ganoderma lucidum mycelia suppresses the development of colorectal adenomas. Hiroshima J Med Sci, 2010; 59:1–6.

32.

Matsui

, Uhara

, Satoi

, et al. Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: A prospective cohort study. J Hepatol, 2002; 37:78–86.

33.

Cowawintaweewat

, Manoromana

, Sriplung

, et al. Prognostic improvement of patients with advanced liver cancer after active hexose correlated compound (AHCC) treatment. Asian Pacific J Allergy Immunol, 2006; 24:33–45.

34.

Chay

, Tham

, Toh

, et al. Coriolus versicolor (Yunzhi) use as therapy in advanced hepatocellular carcinoma patients with poor liver function or who are unfit for standard therapy. J Altern Complement Med, 2017; 23:648–652.

35.

Zhang

, Sugawara

, Chen

, et al. Mushroom consumption and incident risk of prostate cancer in Japan: A pooled analysis of the Miyagi Cohort Study and the Ohsaki Cohort Study. Int J Cancer, 2020; 146:2712–2720.

36.

Twardowski

, Kanaya

, Frankel

, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer, 2015; 121:2942–2950.

37.

Gao

, Tang

, Dai

, et al. Effects of water-soluble Ganoderma lucidum polysaccharides on the immune functions of patients with advanced lung cancer. J Med Food, 2005; 8:159–168.

38.

Yin

, Ying

, Li

, et al. A meta-analysis of lentinan injection combined with chemotherapy in the treatment of nonsmall cell lung cancer. Indian J Cancer, 2015; 52:e29–e31.

39.

Fritz

, Kennedy

, Ishii

, et al. Polysaccharide K and Coriolus versicolor extracts for lung cancer: A systematic review. Integr Cancer Ther, 2015; 14:201–211.

40.

Lucius

, Hill

. Combining immunotherapy and natural immune stimulants: Mechanisms and clinical implications. J Cancer Res Clin Oncol, 2019; 145:2633–2635.

41.

, Deng

, Chen

, et al. Evaluation on quality consistency of Ganoderma lucidum dietary supplements collected in the United States. Sci Rep, 2017; 7:7792.

42.

Loyd

, Richter

, Jusino

, et al. Identifying the “mushroom of immortality”: Assessing the Ganoderma species composition in commercial reishi products. Front Microbiol, 2018; 9:1557.

43.

Sabaratnam

, Kah-Hui

, Naidu

, et al. Neuronal health—Can culinary and medicinal mushrooms help?. J Tradit Complement Med, 2013; 3:62–68.

44.

Mori

, Inatomi

, Ouchi

, et al. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebo-controlled clinical trial. Phyther Res, 2009; 23:367–372.

45.

Nagano

, Shimizu

, Kondo

, et al. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res, 2010; 31:231–237.

46.

Chen

J-T

, Tominaga

, Sato

, et al. Maitake mushroom (Grifola frondosa) extract induces ovulation in patients with polycystic ovary syndrome: A possible monotherapy and a combination therapy after failure with first-line clomiphene citrate. J Altern Complement Med, 2010; 16:1295–1299.

47.

Hsu

, Liao

, Lin

, et al. The mushroom Agaricus blazei Murill in combination with metformin and gliclazide improves insulin resistance in type 2 diabetes: A randomized, double-blinded, and placebo-controlled clinical trial. J Altern Complement Med, 2007; 13:97–102.

48.

Sargowo

, Ovianti

, Susilowati

, et al. The role of polysaccharide peptide of Ganoderma lucidum as a potent antioxidant against atherosclerosis in high risk and stable angina patients. Indian Heart J, 2018; 70:608–614.

49.

Zembron-Lacny

, Gajewski

, Naczk

, et al. Effect of shiitake (Lentinus edodes) extract on antioxidant and inflammatory response to prolonged eccentric exercise. J Physiol Pharmacol, 2013; 64:249–254.

50.

Collado Mateo

, Pazzi

, Domínguez Muñoz

, et al. Ganoderma lucidum improves physical fitness in women with fibromyalgia. Nutr Hosp, 2015; 32:2126–2135.