PLATYCODON

and Other Chinese Herbs with Triterpene Glycosides

by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine (ITM), Portland, Oregon

INTRODUCTION

Platycodon is an essential herb of the Chinese tradition.  It is used in a very large number of Chinese prescriptions, illustrated by the fact that it is found in 6% of the formulas in the book Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine.  Platycodon has several indications that make it a favored ingredient, including treatment of abscesses, respiratory disorders, intestinal disorders, and injuries. 

Platycodon has single group of several active constituents, called platycodin (the individual components are labeled platycodin A, B, C, etc., to distinguish slight variations).  Platycodin yields pharmacological activities in laboratory experiments that parallel many of the clinical functions of the whole herb.  There are a number of other important Chinese herbs—including ginseng and bupleurum—that have active constituents very similar to those of platycodon. These constituents are classified as triterpene glycosides, a type of saponin; their broad spectrum of valuable actions makes them worthy of further study.

A comparison of the therapeutic actions, dosages, pharmacology, and toxicology of these triterpene glycoside-containing herbs helps clarify both the traditional and modern applications of the herbs.  Decisions to use certain prescriptions—or to write new ones for individual patients—may be influenced by a deeper understanding of the various herbs that have triterpene compounds as their common active constituents.  The analysis can also provide a basis for determining their safety for short- and long-term treatment regimens.  The safety of these herbs is an important issue because of their wide-spread use.  Recently, it was suggested that one of the herb formulas that contains a high dosage of the triterpene glycosides, Minor Bupleurum Combination, may cause adverse reactions in patients with advanced liver disease (see: Update on hepatitis C treatments).  Ginseng was reported, twenty years ago, to produce adverse reactions when used in excessive dosage (Ginseng Abuse Syndrome) and some people have reported sensitivity to the herb at modest doses; many patients and practitioners worry about ginseng in formulas for this reason.  Therefore, it is helpful to determine the nature of the possible reactions to herbs containing these ingredients, and then decide how to best minimize their incidence while getting the maximum benefits from these essential herbs.

Following a description of platycodon, the main herb of interest for this article, an extensive analysis of the triterpene glycosides and herbs that contain them is presented.  Several tables reveal the results of chemical and pharmacological studies and relate this to the actions of traditional herbs and formulas.

PLATYCODON

Platycodon (jiegeng) was first referenced in the ancient Chinese book Shennong Bencao Jing, ca. 100 A.D. (1).  It was described briefly, as follows (2):

Jiegeng. Bitter, non-toxic, treating mainly chest and rib side pain as if stabbed by a knife, abdominal fullness, continual intestinal rumbling, and fright and fear palpitation qi [the physical and mental disturbance caused by fear and fright].  It grows in mountains and valleys.

Platycodon root (see Figure 1) has been used frequently in the practice of Chinese medicine ever since this early description and was included in the early formula guides (3, 4) Shanghan Lun and Jingui Yaolue (ca. 220 A.D.), mainly for treatment of abscesses.  For example, it is an ingredient in Jiegeng Tang (with licorice), Painong Tang (with ginger, licorice, and jujube), and in Painong San (with peony and chih-shih) for skin ailments marked by swelling and pus (5). The apparently different use of platycodon in these formulas (for abscess) versus that reported in the Shennong Bencao Jing (for pain, fullness, intestinal rumbling, fright) occurs also with other herbs used at that time and indicates that the author of the formula books did not rely on the materia medica descriptions (he makes no reference to this work and may not have been aware of it).

Later in Chinese medical history, platycodon became better known for its application to lung disorders and inflammatory conditions of the head and neck.  In fact, platycodon might now be described as the principal herb in Chinese medicine for diseases of the lungs and throat, and an herb commonly used for diseases of the eyes, ears, and sinuses.  In the modern Chinese Materia Medica guides, platycodon is always listed with the “phlegm-resolving” herbs.  Traditional prescriptions for respiratory tract disorders, especially those of the Ming Dynasty and Qing Dynasty periods and up to the present, usually include a combination of platycodon with two or more other herbs from this phlegm-resolving section of the Materia Medica. 

One can also view platycodon as one of the premier herbs for the metal element.  Its color is white (slightly yellowed), its taste is acrid (and bitter), and it is primarily used to treat diseases of the organs and tissues associated with metal: lungs, large intestine, skin, and sinuses.

There is a Chinese theory that platycodon, when used in a formula, helps guide the action of the herbs to the chest area, where they can then affect the entire upper body, including the head.  Hence, for example, it is used in a well-known formula Xuefu Zhuyu Tang (Persica and Achyranthes Combination) that was designed during the 19th century by Wang Qingren to treat injuries to the chest area.  The inclusion of platycodon in the formula is not because of its phlegm-resolving action, but because it focuses the herbs used for treating injuries to the chest area (if the injury to be treated were in the lower abdomen, this herb would be removed, while the others could be retained). This application of platycodon is consistent, also, with its indicated use for injuries to the chest, mentioned in the Shennong Bencao Jing.  Xuefu Zhuyu Tang is one of the most intensively studied and widely-used remedies of modern Chinese medicine and it is currently employed for treatment of cerebrovascular diseases, head injuries, schizophrenia, headaches, and numerous other disorders in which the upper body is affected.

Platycodon is still used in formulas to treat skin swellings, such as abscesses, and is also used for treatment of intestinal abscesses (used orally or by enema) and lung abscesses.  In the treatment of intestinal disorders, it is commonly employed in the prescription called Shenling Baizhu San (Ginseng and Atractylodes Formula), developed during the Song Dynasty (about 1000 A.D.) to treat diarrhea; the formula has been adopted for relieving many inflammatory disorders of the intestines.  Finally, platycodon is said to soothe a sore throat or relieve hoarseness.  These applications describe its main medicinal uses in China (6, 7, 8).  The use of platycodon to treat “fear and fright palpitation qi,” that is, as a sedative has not been pursued.  However, as will be revealed below, other herbs with similar active components are used for such sedative effects.

Platycodon is used as a food in China and Korea, though it is an uncommon constituent in meals.  As described by Smith and Stuart (9) at the end of the 19th century, platycodon root was “eaten as a pot-herb.”  This is done with the young herb, which, according to recent analysis, has a low level of the medicinal ingredients that confer a bitter taste.  Platycodon is a source of dietary starch, serving much the same role as potatoes and other foods obtained from storage roots.  Its taste is rather bland when young roots are collected; the roots are blanched before being used as food in China and this removes some of the bitter saponin.  When preparing the medicinal herb, the roots are only washed briefly, to avoid loss of active constituents.

TRITERPENE (SAPONIN) GLYCOSIDES

Triterpene refers to a particular type of molecular structure that has a four- or five-ring, planar-base molecule containing 30 carbon atoms.  It is synthesized from very simple compounds (acetate units) that are found in all plants, but is mainly synthesized in higher plants (flowering plants) by linking the acetate units “head to tail.”  The triterpenes have an acidic quality, an acrid-bitter taste, and their function in plants remains unknown.  Glycoside refers to the attachment of various sugar molecules to the triterpene unit, which is known as the aglycone or genin when the sugar component is removed. When glycosides are consumed, the sugar molecule is usually cleaved off by enzymatic action either in the gut or in the blood stream. 

In the animal world, cholesterol—and the steroid hormones that are synthesized by the body from cholesterol—are examples of triterpene-like structures. Cholesterol, in animals and humans, enters into the fatty membranes and adjusts their fluidity, which is a possible effect of the triterpene saponins at high dosage. There is another type of saponins, called steroidal saponins, found in some plants that are even closer in structure to cholesterol and steroid hormones, though their actions (when consumed) are not hormonal in nature.  

The triterpenes and the plant steroids are broadly described as saponins; the term refers to their ability to form a soapy material when concentrated.  Saponins can enter into fatty materials and, in large enough quantity, break them up (just as soap can dissolve fat).  Indeed, a well-known toxic effect of these plant compounds, when given in high doses, is to break up red blood cells by disrupting their membranes (hemolytic effect).

The triterpenes are subdivided into about 20 groups, depending on their particular structures.  The base structure that is found in the largest variety of medicinal plants is the oleanane triterpene.  This type of compound may be represented by four of the most frequently occurring forms (see Figures 2, 3, 4): oleanolic acid, ursolic acid, and alpha- and beta-amyrin (the latter three are sometimes put in the subdivision of ursane triterpenes).  Platycodin belongs to the very large class of oleanane triterpenes.

Following are two tables that illustrate what is known about the chemistry and pharmacology of the triterpenes in commonly used Chinese herbs.

Table 1: Triterpenes by Class and the Herbs that Contain Them

Triterpene Class	Sample Herbs	Comments on Pharmacology and Clinical Use
Lanostane	hoelen, schizandra, melia, cimicifuga, ganoderma	These herbs are used to treat liver inflammation;  hoelen, schizandra, and ganoderma are sedatives.
Eburicane	hoelen, cucumis seed, corn silk, citrullus	These are diuretics.
Euphane	euphorbia, frankincense, melia, cucumis	These herbs treat pain.
Dammarane	ginseng (all types, including Chinese, American, san-chi, etc.), jujube, ganoderma, gynostemma, hovenia	These herbs are tonics; ginseng mainly contains dammarane glycosides. Ginseng and hovenia are reputed to lower blood sugar in diabetes.
Protostane	alisma	Alisma is used as an antiinflammatory and diuretic.
Cucurbitacin	citrullus, momordica	These are used for diabetes.
Oleanane	platycodon, forsythia, swertia, jujube, albizzia, licorice, ligustrum, loranthus, ginseng (P. japonicum; san-chi, Chinese ginseng), akebia, clematis, pulsatilla, dianthus, styrax, polygala, frankincense, spilanthus, soja, bupleurum, centipeda, cucumis, gleditsia, daemonorops	Many of these herbs are antiinflammatory; akebia and clematis are used interchangeably as sources of mutong, which, like dianthus, is used for urinary tract inflammation and infection; ginseng, jujube, and licorice are used as qi tonics; ligustrum, forsythia, swertia, and bupleurum are used for hepatitis; styrax and polygala are used for opening orifices; platycodon, centipeda, cucumis, and polygala are used for resolving phlegm; platycodon, cucumis, forsythia, and gleditsia are used for treating abscesses; frankincense and daemonorops (dragons’ blood) vitalize blood circulation.
Lupane	mardensia, pterocarpus, jujube, platycodon, forsythia	Mardensia has properties similar to platycodon, but treats hot phlegm; pterocarpus is a neat clearing herb used for wounds and chest or abdominal pain; butlinic acid, one of the important lupane triterpenes has been investigated as a possible anticancer remedy.
Hopane	pyrrosia, dryopteris	Both of these herbs are used in treatment of urinary tract inflammation with bleeding.
Friedelin	cimicifuga, millettia	Friedelin glycosides may help promote blood circulation.
Taraxerane	taraxacum	Centipeda (see oleanane triterpenoids) is a related plant.
Fernane	dryopteris, imperata	These herbs both treat bleeding.
Arborene	imperata	Imperata is used for bleeding and for hepatitis.
Adianane	imperata
Serratane	lycopodium (huperzia)	This is used in the treatment of pain due to injuries.
Meliacane	melia	Melia is used for treatment of abdominal pain.
Miscellaneous	evodia, dictamnus, lycopodium, aster, cymbopogon, cucumis	Dictamnus is used for skin and joint inflammation.

Table 2: Triterpene-containing Herbs Grouped by Therapeutic Actions

Action	Herbs	Comments
Hepato-protective; treats hepatitis	forsythia, ligustrum, schizandra, imperata, bupleurum, melia, ginseng, swertia, licorice	Most of these herbs clear heat; in laboratory studies, they protect the liver from damage due to chemicals.
Resolves phlegm, relieves cough, treats bronchitis	platycodon, centipeda, polygala, aster, schizandra, ginseng, licorice, bupleurum	These herbs are used in traditional formulas for lung diseases; most are warming in nature.
Treats urinary tract inflammation; diuretic	alisma, hoelen, akebia (and substitute herb clematis), dianthus, dryopteris	These herbs are used in traditional formulas for urinary tract infections; most are cooling in nature.
Treats pain due to inflammation or injury	melia, frankincense, platycodon, san-chi	These herbs are usually not combined together, but are used in a variety of formulas.
Sedative	ginseng, jujube, hoelen, licorice, schizandra, ganoderma	These herbs are used in tonic sedative formulas.
Tonifies qi, raises qi, directs herbs upward	ginseng, bupleurum, platycodon, cimicifuga, jujube, licorice	These herbs are frequently combined in formulas; bupleurum and cimicifuga “raise qi;” cimicifuga and platycodon direct herb actions to the upper body.

The last category (tonifies qi, raises qi) may be of interest for the lack of modern pharmacology information: the traditional action does not easily translate into something that can be studied in the laboratory.  Consider the primary formula for tonifying qi and treating sinking of qi: Ginseng and Astragalus Combination (Buzhong Yiqi Tang).  The formula includes the following triterpene-containing herbs: ginseng, jujube, bupleurum, cimicifuga, and licorice.  These botanically-unrelated herbs fall into two different Materia Medica categories (regulate surface; tonify qi) and have been combined into a single prescription based on traditional indications.  The fact that the herbs (selected and combined on the basis of ancient principles) contain similar active constituents, thus reinforcing their actions by increasing the dosage of triterpene glycosides, is remarkable. 

Another confluence of triterpene-containing herbs is found in the most famous qi-tonifying sedative formula: Ginseng and Longan Combination (Guipi Tang).  It contains ginseng, hoelen, licorice, jujube, and polygala with the triterpenes; further, one of the traditional modifications of the formula (Jiawei Guipi Tang) adds bupleurum (with more triterpenes) and gardenia.

OLEANANE TRITERPENES

Isolated oleanolic acid, the basic oleanane triterpene, is a substance of current therapeutic interest (18).  It has antiinflammatory effects, and is used in treatment of hepatitis in China.  Several of the medicinal herbs that contain oleanolic acid, such as ligustrum, forsythia, and swertia, are remedies employed in China and Japan for the treatment of hepatitis. Oleanolic acid, in the form of methyl oleanate, is one of the important constituents of olive oil (the genus name for the olive tree is Olea, and the family to which it and several oleanolic acid containing herbs belong is the Oleaceae).  Olive oil and olive leaf are both recommended today as health products for various uses.  Oleanolic acid has been approved in Japan as a food additive. 

Oleanolic acid is the base molecule for some of the ginsenosides that have been identified from ginseng and particularly from Panax japonicum, one of the species of Panax used in Oriental medicine.  Numerous beneficial effects of these ginsenosides and similar compounds (called araliasides, from plants of the ginseng family, the Araliaceae) have been claimed, including hepatoprotective, hypoglycemic and hypolipemic effects.

Table 3: Widely-used Chinese Herbs with Oleanolic Acid Saponins as Main Active Constituents.

Common Name	Constituent Group	Content of Saponins and Herb Dosage in Decoction
Bupleurum	saikosaponins (contained in root bark)	1.2–4.7%; dosage: 6–9 grams
Ginseng	ginsenosides (contained in roots; figures given for tap root)	2.2–5.2%; dosage: 3–6 grams American ginseng: 6.2–7.4%; 3–6 grams
Platycodon	platycodins (contained in all plant parts; figures given for root)	>6% official level; dosage: 3–9 grams
Polygala	onjisaponins (figures given for root).	~2%; dosage: 3–9 grams

The four herbs listed in Table 3 are all mentioned in an extensive review article on the pharmacology of saponins (20).  The general activity of this group of herbal constituents are listed in Table 4, based on this article.

Table 4: Pharmacological Activities of Saponins with Reference to Triterpene-containing Herbs.

Activity	Explanation	Sample Saponins
Cytotoxicity	In vitro application of saponins to tumor cells causes cell death.	ginsenosides, saikosaponins, astragalus triterpene glycoside, achyranthes oleanolic acid glycoside
Anti-tumor activity	In vivo application of saponins to animals with transplanted tumor cells.	ginsenosides, anemarrhena steroid saponins
Anti-mutagenic activity	In vitro application of saponins to bacterial cells treated with known mutagens.	glycyrrhizin (from licorice)
Anti-tumor promoting activity	In vitro application of saponins to animal or human cell lines treated with tumor promoters.	gleditsia triterpene saponins, soyasaponin
Antiinflammatory effects and anti-allergy activity	In vivo application of saponins to animals with induced inflammation and/or allergy-type reaction.	saikosaponins, ginsenosides, glycyrrhizin
Immunomodulatory action	In vitro and in vivo applications of saponins to determine immune responses.	saikosaponins, ginsenosides, cycloartane saponins from curculigo
Antiviral activity	In vitro and in vivo applications of saponins to inhibit added viruses.	oleanane triterpenes, glycyrrhizin, soybean saponins
Hepatoprotective effects	In vivo applications of saponins to protect against liver inflammation induced by hepato-toxic chemicals.	ginsenosides, araliosides, glycyrrhizin, saikosaponins, lonicera saponins
Cardiac activities	In vitro applications of saponins to cardiac tissue to detect normalizing action.	ginsenosides
Antithrombotic activity	In vitro applications of saponins to platelets to affect aggregation activity.	ginsenosides
Hypolipemic activity	In vivo application of saponins to inhibit absorption of cholesterol.	“several saponins”
Central nervous system activity	In vitro and in vivo application of saponins to detect changes in neurologic responses	ginsenosides, bacopa saponins
Endocrine activity	In vivo application of saponins to detect changes in hormone levels	saikosaponins

The pharmacological activities based on in vitro and laboratory animal studies (in vivo) listed in Table 4 may not apply to human applications, because the dosage used for the studies is sometimes too high to be replicated clinically.  However, these actions illustrate the fact that the saponins, especially the triterpenes, have a wide range of potentially desirable activities.  Among the triterpene saponins from Chinese herbs, platycodin showed the strongest action on secretion of cortical steroids from the adrenal gland (24), which is a hormonal action that yields antiinflammatory effects.  The article on saponins did not include a description of antidiabetic effects that are elsewhere attributed to some oleanane saponins.  Hypoglycemic actions have been reported for the triterpenes of platycodon, bupleurum, polygala, and ginseng (14, 23).  However, these herbs are not prominently mentioned in review literature on hypoglycemic herbs (21, 22), for which literally hundreds of herbs have been described as potentially useful.  This suggests that their action is not deemed by the reviewers as sufficiently interesting at this time.

PLATYCODON TRITERPENES

Chemical analysis of platycodon active constituents was first carried out during the 1930’s (in Korea) and in more detail during the 1970’s (in Japan), revealing that the root contains a large group of oleanane-type (triterpene) saponins.  In the 1988 Pharmacopoeia of China (10) it is stated that the official material should contain not less than 6% saponins.  An evaluation of platycodon saponin content from several samples reported in 1989 (11) showed that the wild roots of platycodon contained 7.3–11.8% saponins; cultivated roots had 1.7–14% saponins (the very low figure of 1.7% was from an immature plant, which is the food-grade material).  Evidently, obtaining a minimum yield of 6% in the Chinese plants is not difficult, and is usually accomplished by using the wild stock, and can easily be accomplished with cultivated material of appropriate age.  In one Korean report (12), the level of crude saponins in platycodon was said to be 2% in a medicinal grade material (as opposed to the food grade material which is younger and has less); it is possible that the growing conditions in Korea differ from those in China, yielding the lower figure.  Similarly, in a report from Japan on the effect of different cultivation techniques for platycodon, the saponin content of the collected root was only 1.3–1.7%; the roots were collected after less than one year of growth (25).  In Korea, platycodon is used as a food and as a folk remedy for hyperlipidemia, hypertension, and diabetes (12).

Platycodin is the general term for the platycodon saponins, for which there are several minor variants labeled platycodin A, B, C, D, etc., and further divided, such as platycodin D₁, D₂, D₃, etc. (13).  When a saponin extract is made from the root, it is called “platycodin” or “crude platycodin.”

While a number of other non-saponin chemical constituents have been isolated from platycodon, including common plant sterols and starches (e.g., inulin), none of these appear to be responsible for the known activities of the herb, though the starches may help to soothe sore throat due to their mucilaginous quality.

DOSAGE OF PLATYCODON AND ITS TRITERPENES

In traditional Chinese practice, the root slices are boiled along with other herbs to make a decoction.  In some cases, the herbal combination is powdered and then the powder is boiled for a short time to make a tea.  The usual dosage of platycodon is about 3–9 grams for a one day dose, which may be taken in divided doses.  This amount of herb could theoretically yield about 180–540 mg of saponins (assuming 100% extraction and 6% content; the actual extraction would likely be slightly less, but the saponin content would likely be somewhat higher than this minimum figure, yielding a range that is similar to the calculation made here). 

Pharmacology analysis (based on laboratory animal experiments) of platycodon indicates that it has expectorant and antitussive action, hypoglycemic and hypolipemic effects, inhibits excess secretion of stomach acid and inhibits peptic ulcers, reduces inflammation, and has sedative, analgesic, and antipyretic action (14, 15, 16).  Dosages of isolated crude platycodin (mixture of saponins) given orally in laboratory animal experiments to show medicinal effects ranged from 25 mg/kg to 100 mg/kg (rough correspondence in humans by body weight: about 1750 mg to 7000 mg per day).  Crude extracts of platycodon, using water or an ethanol extract (similar to a tincture), were administered orally in doses equivalent to 100 mg/kg to 1,000 mg/kg of the crude herb material (rough correspondence to humans: about 7–70 g/day), though the most common range was 100–500 mg/kg (correspondence: 7–35 g/day).  Thus, the laboratory studies generally involved higher doses of the herb and its saponins than one would encounter using platycodon as the sole saponin source in clinical practice.

PLATYCODON FORMULAS AND TRITERPENES

Many of the formulas that include platycodon are quite large, having more than 15 ingredients, making it difficult to interpret the actual role of platycodon or other individual ingredients in the formula.  However, there are a number of commonly-used formulas, several of which have 15 or fewer ingredients, for which it is possible to assess the role of platycodon and other herbs that contain similar triterpenes.  The following table presents some sample formulas found in Commonly Used Chinese Herb Formulas Companion Guide, which help reveal how platycodon is used and how it is combined with other herbs that have triterpenes.

Table 5: Commonly-used Platycodon Formulas

Disorder Category	Sample Commonly-used Formulas	Other Herbs with Similar Terpene Components in the Formulas
Cold/flu with cough	Morus and Chrysanthemum Combination (Sangju Yin) Lonicera and Forsythia Formula (Yin Qiao San) Bupleurum and Pueraria Combination (Chai Ge Jieji Tang) Ginseng and Perilla Formula (Shen Su Yin)	forsythia, licorice   forsythia, licorice, soja   bupleurum, licorice   ginseng, hoelen, licorice
Bronchitis	Lily Combination (Baihe Gujin Tang) Aster Combination (Ziwan Tang) Platycodon and Schizonepeta Formula (Zhi Sou San) Platycodon and Fritillaria Combination (Qingfei Tang) Morus and Platycodon Formula (Dun Sou San)	licorice aster, licorice, ginseng, hoelen aster, licorice   licorice, schizandra, hoelen, jujube   licorice, bupleurum
Formulas for enteritis, diarrhea	Ginseng and Atractylodes Combination (Shen Ling Baizhu San) Agastache Formula (Huoxiang Zhengqi San)	ginseng, licorice   hoelen, licorice
Formula for injuries to the chest	Persica and Achyranthes Combination (Xuefu Zhuyu Tang)	bupleurum, licorice
Formulas for abscesses (skin diseases)	Astragalus and Platycodon Formula (Qianjin Neituo San) Gleditsia Combination (Tuoli Xiaodu Yin) Schizonepeta and Siler Formula (Jingfang Baidu San) Platycodon Combination (Jiegeng Tang) Platycodon and Jujube Combination (Painong Tang) Siler Combination (Qingsheng Fangfeng Tang)	licorice   ginseng, hoelen, licorice, gleditsia bupleurum, forsythia, licorice   licorice licorice, jujube   forsythia, licorice

Virtually every formula listed above includes the combination of platycodon with licorice.  One or more of the commonly-used herbs, bupleurum, ginseng, and hoelen, are also combined with platycodon in a number of the formulas. 

SAFETY AND DOSAGE

The safety profile of the platycodon main active constituents, triterpenes, should be comparable to the safety profile for ginseng, for which there is far more data than for any of the other herbs.  Ginseng is widely available as an over-the-counter health product and is generally considered safe to use.  There have been some suspicions of harm from excessive dosing or from unusual administration, described as the Ginseng Abuse Syndrome, but when supplied in a reasonable dosing form, the herb appears to be safe.  Persons who consider themselves sensitive to ginseng report an agitational effect that does not appear to be physically harmful and which does not show up as a significant response in placebo-controlled trials (that is, the claimed reaction may be a placebo effect).

The dosage range of triterpene saponins from individual herbs as used in traditional practice may be calculated from the information in Table 3.  Daily dosing of the triterpene saponins range from a minimum of 60 mg (Chinese ginseng or polygala, minimum content, minimum dose) to about 600 mg (platycodon, minimum official content, maximum dose).  These values provide an indication of dosages that would be considered both safe and effective on the basis of traditional practice, as these considerations are ultimately the basis of the recommended dosage ranges. 

In the practice of Chinese medicine it is common to combine many herbs together, and there may be several herbs containing these triterpene saponins in a single formula, making the total daily intake higher.  As an example, one of the most commonly-used formulas in the Orient is Minor Bupleurum Combination (Chinese: Xiao Chaihu Tang; Japanese: Sho Saiko To), which includes not only bupleurum (in doses even higher than 9 g/day) and ginseng, but also two other herbs that contain similar saponins: jujube and licorice.  Thus, the figures given here (range of about 60–600 mg) are conservative. 

Presumably, there is a dose-response relationship in the triterpene clinical effects over the range of 60–600 mg and beyond to a maximum favorable response level, though studies have not been done to reveal the specific nature of the dose-response relationship.

There are two well-known adverse effects of saponins when the dosage is high enough: hemolytic action (causes red blood cells to break) and nauseant effect (causes loss of appetite and vomiting).  The hemolytic activity is thought to be related to the interaction of saponins with cholesterol; in this case, the saponins may combine with cholesterol in the red blood cell membrane, producing pores that lead to cellular destruction.  The nauseant effect has not been studied in detail, but may involve interaction between saponins and the mucous membrane lining of the stomach.  The same saponins are suggested to be useful for treating gastric ulcer (27); the nauseant effect may occur when the dosage is higher than the level that provides a therapeutic effect for the stomach disorder. Indeed, such nauseant reactions are reported for overdosage of many triterpene saponin herbs, but not for normal doses.

Both of these adverse effects of saponins have been observed in laboratory experiments with platycodin (14, 28), but have not been reported from human use of platycodon.  The hemolytic action of the platycodon saponins has prevented their use by injection, which is one of the routes of administration used for herbs in China.  The hemolytic effect is reduced by degradation in the alimentary tract, so that platycodon is safe at normal doses.  The nauseant effect can be observed at very high doses, but these are doses beyond those normally prescribed in clinical practice. 

There are contraindications listed in Chinese medical texts for ginseng, bupleurum, and polygala.  For example, in Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine (8), these are given:

·       Bupleurum: contraindicated in patients with preponderance of liver yang due to exhaustion of kidney yin.

·       Ginseng: contraindicated in excess syndrome, heat syndromes, and lack of deficient qi.

·       Polygala: to be used cautiously for ulcer diseases and gastritis.

In the case of bupleurum, a concern that has been raised in relation to the traditional caution is that its use may cause nosebleeds in some individuals; for ginseng, the excess and heat syndromes might also lead to spontaneous bleeding; the caution about polygala corresponds to the stomach irritation that occurs with saponins.

None of the Materia Medica guides indicated any toxicity or contraindications for platycodon, except for a caution about use when there is hemoptysis in Chinese Herbal Medicine Materia Medica (6); the concern is that this will be exacerbated by the hemolytic action of the saponins.  Therefore, it is clear that in some persons, the saponin-containing herbs, when used at dosages recommended for clinical practice, can cause adverse reactions in persons with certain predisposing conditions.  Liver-yang excess, general excess syndrome, heat syndromes, and gastric irritation may ultimately relate to the basic liver-agitational pattern, where there is pathological liver qi.  What this means, in relation to biochemical effects of triterpenes, still needs to be worked out. At high enough doses, as sometimes prescribed to get a more dramatic therapeutic effect, the herbs might cause the undesired reactions in a more diverse group of people.

The possibility that the saponin-rich Minor Bupleurum Combination causes interstitial pneumonia has been raised.  According to analysis of the situation (see: Update on hepatitis C treatments), the reaction does not appear to reflect any herbal toxicity; instead, it involves an immunological stimulus from the formula that has effects in persons with unusual physiological conditions brought on by a combination of liver cirrhosis and autoimmune processes.  Whether the saponins are responsible for the immunological effects remains unknown.

Saponins are found in some foods, such as legumes. For example, soy saponins (different than soy isoflavones that have been the concern of numerous studies and development of health products) are thought to be one of the beneficial constituents of soy beans.  Food use of platycodon and jujube, and the frequent use of ginseng as a beverage tea (and health food product) indicates that the herbs with oleanolane and dammarane triterpenes are likely to be safe to use when the dosage is moderate.  Generally, the materials used for foods and beverages have a relatively mild flavor, and this is often due to limited amount of the bitter saponins, so the total daily ingestion of saponins remains low.

SAFETY STUDIES OF THE CRUDE HERBS

There are three kinds of safety studies that are conducted:

1.     In vitro studies, usually looking for signs of mutagenic potential.  This could indicate a cancer risk with long-term administration or a risk for use during pregnancy.  However, in vitro studies may seem to imply harm when none exists, due to a number of factors; therefore, they should be interpreted cautiously.

2.     Animal studies, usually aimed at detecting harm from very high doses administered over a short period of time.  For example, an LD₅₀ study will determine what dosage is necessary to cause death to 50% of animals given that dose.  Conversion of dosage to human dosage is quite difficult, and there are often species differences in susceptibility to toxins.  Therefore, such studies are used for a rough estimate of toxicity which must be interpreted with some caution.

3.     Clinical reports, usually involving reports of side effects observed during treatment.  The standards for describing side effects have changed over the years.  At present, drug studies involving a placebo or other control group are reported with all incidents of adverse events, regardless of their apparent cause.  Therefore, incidents that are coincidental are included along with direct responses to the drug (the rate of incidental responses should be about the same with the placebo as with the drug).  Small studies often fail to detect rare side effects that can have a serious nature.  Most herbal clinical studies are small in this sense.  The dosage of test substance, duration of the study, and care taken in monitoring responses are all important in evaluating the reports of side effects or other adverse events.

These three types will be reviewed here.

In Vitro Studies

Platycodon was reported to be inactive in tests for mutagenic activity in reports available in Natural Products Alert (Napralert), but in a MedLine search, one article (30) indicated a mutagenic activity of platycodon.  However, this article, published in 1991, has not been followed up and does not seem consistent with the other literature available on mutagenicity of the tested herbs.

Animal Studies

Numerous animal studies have been conducted with platycodon.  Toxicity studies such as LD₅₀ evaluations show that the toxic dose in animal models is very high, consistent with (though not proving) a non-toxic status for normal human dosage.  For example, the LD₅₀ in mice of platycodon (as decoction) was reported to be 24 g/kg (14).  The decoction was used in a trial of expectorant activity in mice at a dosage of 20 g/kg (19).  In rabbits given 20 g/kg, all survived (at 40 g/kg, all died).  Therefore, the LD₅₀ is rated in excess of 20 g/kg.  Although a direct comparison is not possible, a 50 kg human being would need to consume 1 kg of platycodon as decoction in order to get this dosage per unit body weight.  Human dosing of platycodon (in decoction) is never recommended at greater than about 12–15 g/day for short term use by practitioners of traditional Chinese Medicine.  This corresponds to a platycodin level of about 750–1000 mg/day.

It is reported that platycodin has a pronounced hemolytic action in laboratory animals when administered by injection (as expected), but this action is reduced as the result of decomposition in the alimentary tract when given orally.  The LD₅₀ of purified platycodin was greater than 400 mg/kg: in one report, the LD₅₀ for mice was listed as 420 mg/kg and in rats was listed as being greater than 800 mg/kg (26).  These figures 4–32 times the levels used in pharmacology experiments, as described above.  It was reported that at large oral doses (amount not stated), platycodin stimulated the vomiting center in animals (14).

Crude platycodin was shown to have an inhibitory action on the central nervous system in laboratory animals (29) in the oral dosage range 50–200 mg/kg, which is similar to the range used in the study of other pharmacological actions (25–100 mg/kg).  This sedative effect has been noted in humans with bupleurum (14); polygala is classified in the Chinese Materia Medica guides as a sedative.  Although ginseng is described by Westerners as an “energy booster,” the traditional Chinese description is that it calms the agitated spirit.  Platycodon does not have the reputation of being a sedative, but this action could clearly be expected when the dosage is high, based on the laboratory animal experiments and the effects of the other triterpene-containing herbs.

Table 6: Comparison of LD₅₀ Values for Herbs and their Triterpene Saponins. 
The data indicate very low acute toxicity for both herbs and saponins.

Herbs	LD50
Platycodon	24 g/kg
Polygala	17 g/kg (roots); 10 g/kg (root bark)
Ginseng	>5 g/kg
Active Constituents	LD50
Platycodin	400–800 mg/kg
Ginsenosides	0.2–1.3 g/kg
Saikosaponins	4.7 g/kg

Clinical Studies

Clinical studies of platycodon have been limited.  In the practice of Chinese medicine, platycodon is almost always prescribed in complex formulas.  Platycodon by itself, therefore, has not been the subject of clinical trials.

THEORETICAL CONCERNS

Herbal active constituents may interact with drugs.  Several drugs are affected by fatty substances, which will either enhance or inhibit their absorption.  Saponins may interact with fatty substances or their transporters.  Therefore, to avoid possible interactions, drugs and saponins should not be consumed together.

RECOMMENDED DOSING FOR SAFE AND EFFECTIVE USE OF TRITERPENES

A reasonable adult dosage for each of the crude saponin containing herbs individually would be about 3–6 grams per day for long-term use and about twice that amount for short-term use (see below). The saponin content of the herbs may be highly variable (in the case of platycodon, where the levels have been measured, they can range from below 2% to 14%).  Modern extraction and purification techniques make it possible to produce extracts that are about 85% saponin glycoside content (this has been done, for example, with ginseng).  Such extracts permit more precise dosing of the active constituents.

As a guideline, the following dosage of the saponin glycosides based on intended duration of use, corresponds to clinical experience with apparent safety:

·       Brief use for acute ailment (up to one week): up to 900 mg/day

·       Intermediate use for resolving a disorder (up to one month): up to 600 mg/day

·       Long-term use for managing a disorder (up to one year): up to 300 mg/day

·       Extended use for managing a disorder (more than one year): up to 300 mg/day with monitoring for safety

·       Subclincial dosage (ineffective levels): less than 60 mg/day.

It is evident from the literature on saponins that there is a level at which they can produce adverse effects and that there may be some individuals more sensitive to such effects. These dosage recommendations are intended to provide a reasonable margin of safety while maximizing intended health benefits.  Some individuals may complain of mild nauseant effect or mild sedation.  While there is no reason to expect adverse effects of long-term administration, there is also insufficient data to rely upon to assure safety with prolonged use, especially as the dosage increases to the higher recommended levels.

REFERENCES

1. Hsu HY, et al., Oriental Materia Medica, 1982 Oriental Healing Arts Institute, Long Beach, CA.
2. Yang SZ (translator), The Divine Farmer's Materia Medica, 1998 Blue Poppy Press, Boulder, CO.
3. Hsu HY, et al. (translators, editors), Shang Han Lun, 1981 Oriental Healing Arts Institute, Long Beach, CA.
4. Hong-Yen Hsu and Su-Yen Wang (translators), Chin Kuei You Lueh, 1983 Oriental Healing Arts Institute, Long Beach, CA.
5. Hong-Yen Hsu and Chau-Shin Hsu, Commonly Used Chinese Herb Formulas with Illustrations, 1980 rev. ed., Oriental Healing Arts Institute, Long Beach, CA.
6. Bensky D and Gamble A, Chinese Herbal Medicine: Materia Medica, 1993 rev. ed., Eastland Press, Seattle, WA.
7. Dong ZL and Yu SF, Modern Study and Application of Materia Medica, 1990 China Ocean Press, Beijing.
8. Haung BS and Wang YX (compilers), Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine, 1993 Heilongjiang Education Press, Harbin.
9. Smith FP and Stuart GA (translators), Chinese Medicinal Herbs, 1973 (reprint of 1910 edition) Georgetown Press, San Francisco, CA.
10. Pharmacopoeia Commission of PRC, Pharmacopoeia of the People's Republic of China (1988 English Edition), 1988 People's Medical Publishing House, Beijing.
11. Long QQ, Total saponin contents of the root of wild and cultivated Platycodon grandiflorum, Journal of Chinese Medicinal Materials 1989; 12(3): 37-38.
12. Kim KS, et al., Effects of Platycodon grandiflorum feeding on serum and liver lipid concentrations in rats with diet-induced hyperlipidemia, Journal of Nutritional Science and Vitaminology 1995; 41: 485-491.
13. Hsu HY, Chen YP, and Hong M, The Chemical Constituents of Oriental Herbs, 1982 Oriental Healing Arts Institute, Long Beach, CA.
14. Chang HM and But PPH, Pharmacology and Applications of Chinese Materia Medica, 1986 World Scientific Publishing, Singapore.
15. Zhu YP, Chinese Materia Medica: Chemistry, Pharmacology, and Applications, 1998 Harwood Academic Publishers, Amsterdam.
16. Shoji J, Chemistry and biochemistry of platycodon root, International Journal of Oriental Medicine 1989; 14(3): 124-134.
17. Tyler VE, Brady LR, and Robbers JE, Pharmacognosy 7th Edition, 1976 Lea and Febiger, Philadelphia, PA.
18. Liu J, Pharmacology of oleanolic acid and ursolic acid, Journal of Ethnopharmacology 1995; 49: 57-68.
19. Zhang XY, et al., A preliminary study on the expectorant action of Rheum plamatum and its mechanism of action, Liaoning Journal of Traditional Chinese Medicine 1987; 11(9): 44-46.
20. Lacaille-Dubois MA, and Wagner H, A review of the biological and pharmacological activities of saponins, Phytomedicine 1996; 2(4): 363-386.
21. Ernst E, Plants with hypoglycemic activity in humans, Phytomedicine 1997; 4(1): 73-78.
22. Marles RJ and Farnsworth NR, Antidiabetic plants and their active constituents: an update, Protocol Journal of Botanical Medicine 1996; 1(3); 85-137 (reprinted from Phytomedicine 1996; 2(1)).
23. Suttisri R, Lee IS, and Kinghorn D, Plant-derived triterpenoid sweetness inhibitors, Journal of Ethnopharmacology 1995; 47: 9-26.
24. Hiai S, Chinese medicinal material and the secretion of ACTH and corticosteroids, in Chang, et al. (editors), Advances in Chinese Medicinal Materials Research 1984 World Scientific Publishing, Singapore (pp. 49-59).
25. Katsuko H, et al., Studies on the cultivation and preparation of platycodon root III, Chemical and Pharmaceutical Bulletin 1992; 40(7): 1946-1947.
26. Lee EB, Pharmacological studies on Platycodon grandiflorum IV, Yakagaku Zasshi 1973; 93(9): 1188-1194.
27. Kawahima K, et al., Effects of crude platycodin on gastric secretion and experimental ulcerations in rats, Chemical and Pharmaceutical Bulletin 1972; 20(4): 755-758.
28. Perry L, Medicinal Plants of East and Southeast Asia, 1980 MIT Press, Cambridge, MA.
29. Takagi K and Lee EB, Pharmacological studies on Platycodin grandiflorum I, Yakagaku Zasshi 1972; 92(8): 951-960.
30. Yin XJ, et al., A study on the mutagenicity of 102 raw pharmaceuticals used in Chinese traditional medicine, Mutation Research 1991; 260(1): 73-82.

Figure 1: Platycodon grandiflorum.

Figure 2: Molecular structure of saikosaponins from bupleurum.

Figure 3: Ginsenoside of the Oleanane class.

Figure 4: Molecular structure of polygala triterpene showing
attached sugar molecule (lower left).

May 2000