Volume 4, Number 3, 1998, pp. 289–303 Mary Ann Liebert, Inc.

The Scientific Rediscovery of an Ancient Chinese Herbal Medicine: Cordyceps sinensis

Part I JIA-SHI ZHU, M.D., Ph.D.,(1,2) GEORGES M. HALPERN, M.D., Ph.D.,(3) and KENNETH JONES (4)

(1) Department of Pediatrics, Stanford University School of Medicine, Stanford, California. (2) Zhi Dao Tower, 12th floor, Shanghai Medical University, Shanghai, China. (3) Emeritus, University of California, Davis, California. (4) Armana Research, Inc., Gibsons, British Columbia, Canada.

Abstract

This review presents Cordyceps sinensis (Berk.) Sacc., a fungus highly valued in China as a tonic food and herbal medicine. The extant records show the continued use of C. sinensis is now centuries old. The major chemical, pharmacological, and toxicological studies on C. sinensis and the various derived, cultured, fermented mycelial products currently in use are reviewed from the English and Chinese literature. Preclinical in vitro and in vivo studies and clinical blinded or open-label trials in to date over 2000 patients are reviewed. These studies show the main activities of the fungus in oxygen-free radical scavenging, antisenescence, endocrine, hypolipidemic, antiatherosclerotic, and sexual function-restorative activities. The safety of the fungus and its effectswill be reviewed in the second part of this article to be published in the winter issue of this journal.

Introduction

Cordyceps (Cordyceps sinensis [Berk.] Sacc.), also known as Chinese caterpillar fungus or “DongChongXiaCao” (summer-plant, winter-worm), is one of the most valued Chinese medicinal herbs (Figs. 1 and 2). It was initially recorded in Ben-Cao-Cong-Xin (New Compilation of Materia Medica) by Wu-Yiluo during the Qing Dynasty (1757 ao). According to traditional Chinese medicine (TCM), Cordyceps goes to the “Lung” meridian and the “Kidney” meridian (see below) and provides “lung protection,’ “kidney improvement,” and “Yin Yang double invigoration.”

The “Kidney” and “Lung” in TCM

Although we are not practitioners of TCM, we have included brief explanations of some of the organ concepts mentioned in this review that, however, archaic to those of us trained in Western physiology and pathology, were and continue to be applied in traditional prescriptions of Cordyceps. The kidneys are known as “the root of life” in TCM, for they store ‘Jing,’ a substance described as an undifferentiated, prime organic material that is neither yin nor yang and is “the source of reproduction, development, and maturation” (Kaptchuk, 1983). Author and practitioner Ted J. Kaptchuk, O.M.D., in his now classic Western book on TCM, The Web that has no Weaver: Understanding Chinese Medicine, explains the role of the kidneys and the jing as follows:

Conception is made possible by the power of Jing; growth to maturity is the blossoming of Jing; and the decline into old age reflects the weakening of Jing. As time passes, the Jing decreases in both vitality and quantity. Because the Kidneys store Jing, all these processes are governed by the Kidneys. Therefore, reproductive problems such as sterility or impotence and developmental disorders like retarded growth or lack of sexual maturation are seen as dysfunction of the Kidney’s storing of Jing (Kaptchuk, 1983).

Further to the kidneys, Kaptchuk relates that in TCM the understanding is that they have rulership over the bones and produce the bone marrow. And although the lungs are the administrators of respiration, “normal breathing also requires assistance from the Kidneys.” Here, Kaptchuk enters the subject of Qi or chi, the fundamental “energy of life” that the ancients differentiated into different forms, Kaptchuk writes,

The Kidneys enable the Natural Air Qi to penetrate deeply, completing the inhalation process by what is called “grasping the Qi.” The Kidneys are thus the root of Qi,’ while the Lungs are the “foundation of Qi.” Proper breathing thus depends on the Kidneys; and Kidney disharmonies may result in respiratory problems, especially chronic asthma” (Kaptchuk, 1983).

The other meridian that Cordyceps is said to “go to” in TCM is that of the “Lung.” The lungs are said to regulate “the Qi of the entire body” and to rule the Qi (Kaptchuk, 1983)

Kaptchuk explains: The Lungs take in the Natural Air Qi, propelling it downward by their descending property. This is inhalation. The disseminating property, which “makes things go ’round,'” allows for exhalation, the expulsion of “impure” air. When the lungs are healthy, the Qi enters and leaves smoothly, and respiration is even and regular. When an imbalance or obstruction interferes with the Lungs, impairing either the descending or the disseminating func- tions, symptoms such as cough, dyspnea, asthma, or chest distention may result (Kaptchuk, 1983).

When there is a “disharmony of the Lungs,” it is said that stagnant Qi or deficient Qi can result in any area of the body. And if the Qi of the lungs is found to be weak, sweat may be found either insufficient or too profuse and the power of resistance of the “Protective Qi will be poor.” Kaptchuk (1983) writes that the “throat is said to be the ‘door’ of the Lungs and the ‘home’ of the vocal chords, so both the throat and vocal chords are also related to the Lungs. Many common nose and throat disor- ders are therefore treated through the Lungs.” For centuries, the fruit body and attached mycelium of Cordyceps have been the herb of choice in China to treat “lung” and “kidney” asthenia syndromes (TCM terms describing groups of symptoms associated with respiratory and renal diseases and other disease con- ditions) (Table 1). They have been included as a dietary supplement to maintain health and prevent disease (Table 2) (Jiang, 1993; 1994). In the West, Cordyceps only recently received attention after Chinese female runners established several world long-distance records (1500 to 10,000 meters) within a short period of time in 1993. The athletes’ coach attributed their success in part to a special Cordyceps-containing diet that enhanced their physical performance and endurance (Ma, 1997).

Table 1. Medicinal Uses of Cordyceps

• Fatigue
• Night Sweating
• Male and Female Hyposexualities, including Impotence
• Hyperglycemia
• Hyperlipidemia
• Asthenia after Severe Illness
• Respiratory Diseases
• Renal Disfunction and Renal Failure
• Arrhythmias and other Heart Disease
• Liver Disease

NOTE: See references in corresponding sections of review, parts 1 and 2.

Description

Cordyceps is a unique black, blade- shaped fungus found primarily at high altitude on the Qinghai-Tibetan plateau. The fungus is parasitic, growing on and deriving nutrients from several species of caterpillar, although primarily that of the moth Hepialus armoricanus Oberthur, which lives 6 inches underground (Chen and Jin, 1992; Yin and Tang, 1995). In late autumn, chemicals on the skin of the caterpillars interact with the fungal spores and release the fungal mycelia, which then infect the caterpillar. By early summer of the following year, the fungal infestation has killed the caterpillar and the fruiting body can be seen protruding from the caterpillar’s head. This wild form, Cordyceps sinensis, is harvested, whereas the principal fungal mycelium of Cordyceps sinensis, known as Paecilomyces hepiali Chen, is cultivated aseptically (Yue et al., 1995). Because natural Cordyceps (wild Cordyceps sinensis) is rare, Chinese scientists have extsively examined its lite cycle with the aim of developing a technique for isolating fermentable stratus of Cordyceps sinensis. At the Institute of Materia Medica, Chinese Academy of Medical Sciences, one result of this research has been the isolation of the strain Cs-4 from wild Cordyceps sinensis (Berk.) Sacc. Cs-4 has been used to produce a fermented product of the mycelia of Paecilomyces hepiali Chen and contains pharmacologically active components similar to those of the natural Cordyceps. Since its successful isolation in 1982, the Cs4 fermentation product has been studied intensively in China. Industrial fermentation methodology (resulting m a commercial product, JinShuiBao capsule). Chemical composition, therapeutic functions, and toxicity have been thoroughly investigated, and basic research in animals has carried out. JinShuiBao capsule, the Cs-4 fermentation product, has received approval by the National New Drug Review and Approval committee of the Chinese Ministry. of Public Health, and has been used in clinics throughout China for the indications listed in Table 1.

Table 2. Dietary Uses of Cordyceps in Medicinal Dishes

Cooked with an old duck

For patients with Cancer, Asthenia, or after severe illness

Cooked with hen

For hyposexuality (especially emission)

Cooked with black-bone hen

For Asthenia (especially Qi-Yin asthenia)

Cooked with lean pork

For Fatigue, Male Impotence, and Kidney Asthenia

Cooked with sparrow

For antiaging/senescence

Cooked with quail

For Fatigue, Poor Appetite, “Kidney” Asthenia, and Tuberculosis

Cooked with steamed turtle

For Male/Female Hyposexuality

Cooked with baked abalone

For Chronis Bronchitis, COPD, Tuberculosis, Arteriosclerosis, Ataracts, and for Healthy individuals in any season

Data adapted from Jiang (1984)

In total, more than 2000 patients with various medical disorders have been revolved in clinical trials of Cs-4 in China. The results of these clinical studies (blinded or open- labeled) indicate that Cs-4 is very effective and safe, and very similar to the parental, natural Cordyceps in the amelioration of conditions, with only few and mild side effects. Besides Cs-4, several mycelial strains have been isolated from natural Cordyceps and some of them are manufactured with fermentation technology (Yin and Tang, 1995). For instance, sinensis (or Cephalosporium donqchongxiacao), a nonsexual phase strain of Cordyceps known as NingXinBao, XinGanBao, and other names, was isolated by the QingHai Institute of Livestock and Veterinary Sciences. Cn80-2 (Paecilomyces sinensis), another nonsexual phase strain, was isolated by FuJian QingLiu County Hospital and Institute of Microbiology, Chinese Academy of Sciences. SMIH8819 is a product of Sanming Mycological Institute, Fujian, China. 832 (Scydalilum sp.) was isolated by the Navy Institute of Medicine. Hirsutella sinensis, Mortierella hepiali Chen lu sp. nov., Scytalidium hepiali G. L. Lisp. nov., Tolypocladimn sinensis C.I. sp. nov., and others have been isolated natural Cordyceps (Yin and Tang, 1995). The Latin binomials given for the derivative fungi describe imperfect fruit bodies generated when the various mycelia were allowed to grow out. Although derived from the fruit body of Cordyceps sinensis, they are characteristically enough from the parent fungus, to be taxonomically separate; hence the term fungi imperfecti (Alexopoulos, 1962)

Table 3. Seven Classes of Chemical Constituants of Natural Cordyceps

1. Proteins, peptides, all essential amino acids, and polyamines. In addition to ail the essential amino acids,Cordyceps contains uncommon cyclic dipeptides including cyclo-(Gly-Pro), cyclo-(Leu-Pro), cyclo-(Val-Pro), cyclo-(Ala-Leu), cyclo-(Ala-Val), and cyclo-(Thr-Leu). Small amounts of polyamines, including 1,3-diamino propane, cadaverine, spermidine, spermine, and putrescine, have been identified.
2. Saccharides and sugar derivatives (eg, d-mannitol) were identified and their pharmacological activity has been reported. A group of interesting oligosaccharides and polysaccharides (Cs-l) isolated from natural Cordyceps stimulate macrophage function, and promote lymphocyte transformation. A bioactive 23-kd-protein-bound polysaccharide was shown to consist mainly of mannose and galactose in a ratio of 3 to 5, and protein.
3. Sterols, including ergosterol, Delta-3 ergosterol, ergosterol peroxide,/3-sitosterol, daucosterol, and campasterol.
4. Eleven nucleoside compounds have been found in natural Cordyceps. The major nucleosides in C. sinensis include adenine, uracil, uridine, guanosine, thymidine, and deoxyuridine.
5. Fatty, acids and other organic acids. Twenty-eight saturated and unsaturated fatty acids and their derivatives have been isolated from C. sinensis. Polar compounds of natural Cordyceps extracts and Cs-4 include many compounds of hydrocarbons, alcohol, and aldehyde.
6. Vitamins, including vitamins Bi, B2, B12, E, and K.
7. Inorganics, including K, Na, Ca, Mg, Fe, Cu, Mn, Zn, Pi, Se, Al, Si, Ni, Sr, Ti, Cr, Ga, V, and Zr.

Data from Guo, 1986; Huang et al., 1991; Tao, 1995; Xia et al., 1985; Xu, 1992; Yue et al., 1995; Zhu and Xinjingsheng, 1993.

Table 3 lists seven classes of chemical constituents found in natural Cordyceps sinensis and its mycelial fermentation products (Guo, 1986; Huang et al., 1991; Tao, lt295; Xia et al., 1985; Xu, 1992; Yue et al., 1995: Zhu, 1993). Pharmacologically active components of Cordyceps sinensis are still incompletely understood. Cordycepin and cordycepic acid were identified initially in Cordyceps militaris by Cunning- ham et al. (1951) and considered as the active components Later, scientists confirmed that cordycepic acid was in fact d-mannitol. As for cordycepin (3′-deoxyadenosine), its existence in C. sinensis has long been controversial. Although many laboratories failed to confirm its presence in this species, a recent study reported characterization of cordycepin and 2′-deoxyadenosine in an extract preparation of C. sinensis by use of nuclear magnetic resonance (NMR) and infrared spectroscopy (IR) techniques (Chen and Chu, 1996). In addition, other components, such as adenosine, saccharides, and minor elements, were for many years believed to probably play certain roles in the pharmacology of C. sinensis. In TCM, Cordyceps has been used to treat a wide range of conditions, including respira-ton’, renal, liver, and cardiovascular diseases, hyposexuality, and hyperlipidemia (Table 1). Cordyceps has also been used to modulate the immune system and as an adjuvant in cancer therapy. Yet only in comparatively recent times have the medicinal effects of Cordyceps been tested in controlled clinical trials, predominantly in China. In reviewing the results of these studies, where appropriate, we have included animal studies that assist in elucidating the mechanisms of activity involved.

Improvement of Physical Performance and Quality of Life

The preparation and use of Cordyceps as a tonic beverage, although centuries old, was only given greater attention during the last 20 years in China. The recent success of Chinese runners on a special Cordyceps-containing diet brought greater scientific attention to bear on the potential of the mycelia from Cs-4 to improve physical performance and quality of life. The question researchers are now attempting to answer is whether the putatively enhanced physical endurance attributed to Cordyceps can be supported on a strictly scientific basis.

Preclinical animal studies. The effects of Cordyceps extracts on the energy state of mouse liver were examined using in vivo serial 3]p NMR spectroscopy. After mice were given water extracts of Cs-4 (0.2 or 0.4 g/kg) orally for 7 days, the ratio of adenosine triphosphate (ATP): inorganic phosphate (Pi) in the liver was significantly increased by an average of 45% to 55%, as compared with the placebo control group (both p < 0.001 ) (Xu CF, Bao TI’, He CH, Zhu JS, Chang J, manuscript in preparation). The elevated ATP:Pi ratios returned to the baseline levels 7 days after Cs-4 treatment was discontinued. Similarly, during a 3-week intra- gastric treatment of mice with water extracts of another mycelial fermentation product, SMIH8819 (0.2 g/kg per day), there was a consistent increase in the ratio of ATP:Pi in the liver (Manabe et al., 1996). This increase, observed after 1 week of treatment, was maintained throughout the study and was significantly greater than that of control groups. In addition to the promotion of higher bioenergy levels by Cordyceps, researchers examined oxygen consumption by mice and their ability to survive after Cs-4 therapy in a hypoxic environment, to elucidate the effects of Cs-4 on oxygen utilization efficiency (Lou et al.,1986). Under conditions of stimulation of oxygen consumption by a subcutaneous injection of isoprenaline (300 ,ug/kg), Cs-4 extract (equivalent to crude Cs- 4, 5 g/kg, J.p., or 10g/kg, i.g.) significantly reduced oxygen consumption by the mice by 41% to 49% within 10 minutes and by 30% to 36% in the second 10 minutes, as compared with controls (all p <0.001) (Lou et al., 1986). In a low-oxygen environment, the mice lived 2 to 3 times longer after the Cs-4 treatment (all p < 0.001). The Cs-4- induced reduction of oxygen consumption and the prolonged survival of treated animals in a hypoxic environment indicated a more efficient use of oxygen to support essential physiological activities of organs/tissues and greater tolerance to hypoxia-induced acidosis than that of the controls.

A more vigorous study was conducted using an in vivo mouse model of epinephrine- inducedacute pulmonary edema, which causes systemic anoxia, acidosis, and death (Wan and Zhang, 1985). It was noted that mice treated with Cs-4 (6 g/kg, J.g.) had a significantly greater survival rate: 20% mortality at 30 min- utes after epinephrine treatment compared with 80% mortality in the control group (p =0.011); 60% mortality at 60 and 90 minutes after epinephrine treatment compared with 100% mortality in the control group (p = 0.043).

These results suggest that natural Cordyceps and its mycelial fermentation products may improve bioenergetic status by improving an internal balance mechanism by which test animals are able to make more efficient utilization of oxygen under economy of energy consumption. This effect may allow animals to manage efficiently inadequate oxygen supply and a basic energy requirement for essential physiological activities, and to promote greater tolerance to hypoxia-induced acidosis than controls. Whether these properties may to some extent account for the apparent overall enhancement of physical capability and endurance and antifatigue effects found in humans using natural Cordyceps, or its fermentation products as a dietary supplement, is currently the focus of onability to survive after Cs-4 therapy in a hypoxic environment, to elucidate the effects of Cs-4 on oxygen utilization efficiency (Lou et al., 1986). Under conditions of stimulation of oxygen consumption by a subcutaneous injection of isoprenaline (300 ,ug/kg), Cs-4 extract (equivalent to crude Cs-4, 5 g/kg, J.p., or 10g/kg, i.g.) significantly reduced oxygen consumption by the mice by 41% to 49% within 10 minutes and by 30% to 36% in the second 10 minutes, as compared with controls (all p <0.001) (Lou et al., 1986). In a low-oxygen environment, the mice lived 2 to 3 times longer after the Cs-4 treatment (all p < 0.001). The Cs-4-induced reduction of oxygen consumption and the prolonged survival of treated animals in a hypoxic environment indicated a more efficient use of oxygen to support essential physiological activities of organs/tissues and greater tolerance to hypoxia-induced acidosis than that of the controls. Whether these properties may to some extent account for the apparent overall enhancement of physical capability and endurance and antifatigue effects found in humans using natural Cordyceps, or its fermentation products as a dietary supplement, is currently the focus of ongoing multidisciplinary research at various centers in China.

Clinical studies: Placebo-controlled clinical studies examined the effects of Cs-4 therapy in elderly patients with fatigue and other senescence-related symptoms (Cao and Wen, 1993; Zhang et al., 1995). Compared with no improvement in symptoms in the placebo-treated patients, most of the Cs-4-treated patients reported overall clinical improvement (Zhang et al., 1995). The subjective improvements included alleviation of fatigue, cold intolerance, dizziness, frequent nocturia, tinnitus, hyposexuality, and amnesia (Table 4).

TABLE 4. Clinical Effects of Cs-4 on Senescence

Elderly people with symptoms of senescence were enrolled in a double-blind trial and treated with either Cs-4 or placebo (3 g/day) for 3 months. Note: n = number of patients with the symptom prior to the treatment. Results are expressed as percentage of patients who experienced clinical improvement. Data are adapted from Zhang et al. (1995).