Herbal remedies to treat stress The ginsengs

These consist of the dried root of several species of the genus Panax of the family Araliaceae. Asian or Oriental ginseng, extensively cultivated in China, Korea, Russia, and Japan, is P. ginseng C. A. Meyer, the most

commonly used species. American ginseng is P. quinquefolius L. Another species, less frequently encountered, is sanchi or tienchi ginseng from P

notoginseng F. H. Chen (Burkill), formerly P. pseudoginseng (Burk.) F. H. Chen. 2 Japanese (Chikusetsu) ginseng is P. japonicus C. A. Meyer, syn. P. repens Maxim. There are qualitative and quantitative differences in the constituents of all three species, but in general, their effects are similar. American ginseng is mostly exported to Asia. Asian ginseng, which is the type that has been most completely investigated, is the ginseng mostly consumed in the West. However, research on American ginseng has been escalating over the past two decades.

The principles believed to be responsible for ginseng’s physiological activities are triterpenoid saponin glycosides, generally referred to as ginsenosides but also known, mainly in Japan, as panaxosides. Asian ginseng contains at least thirty ginsenosides, each of which is designated by an uppercase “R” followed by a subscript letter or letter and subscripted numeral or numeral. Its exact composition varies according to the age of the root, the location where grown, the season when harvested, and the method of curing or drying. Because some of the pure ginsenosides produce effects directly opposite to those induced by others and because all are present in the root in relatively small amounts, only the whole root is used in herbal preparations. Asian (Chinese or Korean) ginseng is pro- cessed in two ways to produce “white” (root peeled and dried) and “red” (steamed and dried) ginseng (the latter is actually caramel colored).

Hundreds of experiments carried out in small animals have shown that ginseng extracts can prolong swimming time, prevent stress-induced ulcers, stimulate hepatic ribosome production, increase activity of the immune system, stimulate protein biosynthesis, prevent platelet aggrega- tion, and induce many other effects—all of which might contribute to its general tonic or “adaptogenic” effects. Many of these activities have been compared to corticosteroid-like actions, and results of endocrinological

Chapter eleven: Performance and immune deficiencies 199 studies in animals have suggested that the ginsenosides may augment

adrenal steroidogenesis via an indirect action on the pituitary gland by increasing secretion of ACTH (see Figure 8.1, Chapter 8). 5

In spite of the voluminous literature available on ginseng, the num- ber of reports of reliable human clinical trials is relatively sparse. The results of a total of thirty-seven clinical studies published between 1968 and 1990 have been evaluated. Fifteen of the studies were controlled and eight were double-blind. While taking ginseng preparations, the subjects in thirteen of the studies (1,572 cases) showed improvement in mood; in seventeen studies (846 cases) patients had improved physical performance, and in eleven studies improved intellectual performance was reported. However, the results of the two surveys here summa- rized were statistically evaluated in only about half of the studies, and they were judged unlikely to conform to current scientific standards

regarding study design and conduct. 6 The authors of a more recent review of thirty-five studies (sixteen clinical trials) concluded that their quality was too low to provide convincing evidence of ginseng’s effec-

tiveness in improving human physical performance. 7 All the studies reported the absence or near-absence of adverse effects related to ginseng therapy.

More recently, a double-blind study was conducted to study the influence of ginseng on the quality of life in coping with the stress of living in

a large city. The 501 male and female volunteers were randomized to take either one capsule containing 40 mg ginseng extract plus multivitamin supplement or the multivitamin supplement alone (control) daily for twelve weeks. The quality of life was assessed monthly by a standardized ques-

tionnaire that addressed such issues as perceived well-being, pain, personal satisfaction, depression, energy, sex life, and sleep. The group of subjects taking ginseng extract showed a significant improvement in the quality of life, whereas the control group showed only slight improvement. 8

Subsequently, in a randomized controlled trial (RCT), 200 mg of the proprietary P. ginseng extract Ginsana™ (n = 15) or placebo (n = 15) was daily administered to healthy, young (eighteen years or older) subjects; aspects of mental health and social functioning, assessed by use of general health status questionnaire, were improved after 4 weeks of therapy, compared to placebo, but the differences were attenuated with continued

use. 9 Another study with eighty-three adults (forty women, forty-three men of mean age 25.7 years) with the same extract at two dosages (9,200 and 400 mg) daily found no effect on positive affect, negative affect, or total mood disturbance (all P > 0.016). 10

In the treatment of functional fatigue, a multicenter, comparative, double-blind, clinical study of a total of 232 patients showed that 40 mg of ginseng extract plus multivitamins and minerals taken over forty-two days improved the complaints experienced by patients suffering from

200 Tyler's herbs of choice: The therapeutic use of phytomedicinals fatigue, with tolerability comparable to that of placebo. 11 One should men-

tion, however, that a flaw in the experiment was the lack of vitamins and minerals in the placebo.

Side effects of ginseng consumption attained some notoriety when they were addressed in a 1979 article by Siegel. 12 Because the paper appeared as a “Clinical Note” in the prestigious Journal of the American Medical Association, the results of the study were widely disseminated and have been extensively quoted in the herbal literature. Siegel claimed that ingestion of ginseng could result in hypertension, nervousness, irritability, and similar side effects in 14 of 133 volunteers; these effects were grouped under the generic title “ginseng abuse syndrome” (GAS). In a detailed analysis of Siegel’s work, Castleman pointed out that there was no control or analysis to determine what types of ginseng were being ingested and, further, some of the subjects were taking excessive amounts—as much

as 15 g per day. 13 Also, Blumenthal noted that, apart from serious meth- odological flaws in the study, it failed to assess the potential influence of accompanying medications, notably caffeine. 14

Authorities now tend to discount the existence of GAS, but Siegel’s study continues to be quoted in the literature. On the basis of its long-term usage and the relative infrequency of reports of significant side effects, it is safe to conclude that ginseng is not usually associated with serious adverse reactions. 5

In recent years, concern has been expressed about the potential for ginseng affecting the influence of the anticoagulant warfarin (Coumadin ® ). One case of decreased INR (international normalized ratio) has been

reported in which P. ginseng was combined with warfarin, 15 apparently paradoxical because ginseng has components with anticoagulant activity; a subsequent study in rats found neither pharmacodynamic nor

pharmaco kinetic interactions of P. ginseng with rats. 16 However, a later RCT found a significant reduction of INR AUC (area under the curve), peak plasma warfarin level, and warfarin AUC following administration of powdered root of P. quinquefolius (American ginseng) to twenty young, healthy patients following daily warfarin dosing. 17

Ginseng is certainly the most costly root; choice specimens with humanoid shapes retail for thousands of dollars. Incidentally, it is this similarity to the human figure that, based on the doctrine of signa- tures, provides the herb with its ancient reputation as an aphrodisiac. Commercially, ginseng is available in a variety of forms, including teas, capsules, extracts, tablets, roots, chewing gum, cigarettes, and candies. In some of these forms, it is extremely difficult to determine the quality and quantity of the root present. Experiments carried out in the late 1970s showed that 60 percent of fifty-four ginseng products tested were worth- less and 25 percent contained no ginseng at all. 18,19 These surveys have

been criticized on the basis of inadequate analytical methodology.

Chapter eleven: Performance and immune deficiencies 201 Later studies indicated an improvement in compliance of commercial

products with indicated species identity but also confirmed wide variation in content of ginsenosides, the presumed main active constituents. Cui and others indicated that forty-four of fifty commercial products from eleven countries contained 1.9–9.0 percent (weigh/weight) of ginsenosides, while six of undetermined identity contained no ginsenosides

(one contained ephedrine). 20 Cui found that the ginsenoside content of twenty purported ginseng extract preparations varied from 4.9 to 13.3 percent (w/w). 21

A later analysis of twenty-five products (purportedly, eight P. ginseng, four P. quinquefolius, one P. notoginseng, nine eleuthero, and three mixtures of various ginsengs) indicated correct labeling but wide variability in con- centration of marker compounds. Concentrations of ginsenosides varied by fifteen- to thirty-six-fold in capsules and liquids, respectively, and con- centration of eleutherosides varied by forty-three- and two hundred-fold in capsules and liquids, respectively. 22

The Ginseng Evaluation Program conducted by the American Botanical Council supported the improvement in botanical identification and the continued variation marker content. 23 With a little experience, whole ginseng root is easily recognized organoleptically, so it is recommended that, to ensure quality, the herb be purchased in that form. Alternatively, one must rely on the reputation of the producer or manufacturer.

In summary, ginseng has an ancient reputation as a tonic and aphrodisiac. Some supporting evidence for its effectiveness as an adaptogen has been obtained from small animal and human studies, but additional data from controlled human trials need to be obtained before a definitive evaluation can be made on the therapeutic value of ginseng. The German Commission E has approved ginseng as a tonic to combat fatigue and weakness, as a restorative for declining stamina and impaired concen- tration, and as an aid to convalescence from illness and degenerative conditions. 24

Those who choose to consume ginseng for its purported effects do so in the form of a tea prepared from 1 teaspoonful (3 g) of the finely chopped drug and 1 cup (240 mL) of boiling water, covered, and allowed to steep for five to ten minutes before straining. The infusion is taken one to three

times a day for three to four weeks. 24 Alternatively, capsules containing 250 mg of the root are used. In short-term use for young and healthy indi- viduals, the dosage is 0.5–1 g of powdered root as two divided doses in the morning and evening on a fasting stomach. Therapy should last for two to three weeks followed by a drug-free period of two weeks between con- secutive courses. In long-term use for the elderly and in convalescence, the

dose is 0.4–0.8 g daily and can be taken continuously. 5 Ginseng preparations standardized on the basis of their ginsenoside content are available. Dosage is according to the manufacturers’ instructions.

202 Tyler's herbs of choice: The therapeutic use of phytomedicinals Eleuthero

The root of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. of the family Araliaceae was introduced into modern herbal practice some thirty-five years ago by Soviet scientists who were seeking a cheap and abundant sub- stitute for ginseng. Everything possible seems to have been done to make this common plant mimic the scarcer ginseng. When various compounds were isolated from it, they were designated eleutherosides, a name resem- bling ginsenosides, even though they were not triterpenoid saponins but, rather, were sterols, phenylpropanoid derivatives, lignans, oleanolic acid glycosides, and the like.

When eleuthero was first marketed in the United States in the late 1970s, the name “Siberian ginseng” was utilized, further compounding the confusion. 25 In fact, so many people today confuse eleuthero with ginseng (Panax species) that knowledgeable persons almost universally refuse to use the Siberian ginseng designation and commonly refer to the herb by its abbreviated scientific name, eleuthero. A plethora of non-Panax species have been inappropriately dubbed “ginseng”—usually quali- fied by a national association—such as the widely promoted “Brazilian ginseng” (Pfaffia paniculata), “Indian ginseng”–Ashwagandha (Withania somnifera), and “Peruvian ginseng”–Maca (Lepidium–meyenii meyenii), the reputed aphrodisiac. 26

As noted, eleuthero contains a series of unrelated compounds designated eleutherosides to which the physiologic action—tonic/adaptogenic—has been ascribed. The ginsenosides typical of ginseng are not present.

Eleuthero is often misidentified or adulterated. In 1990, a case in Canada was reported in which a product labeled Siberian ginseng, ini- tially confused with ginseng by the attending physicians, was subsequently determined to be the bark of Chinese silk vine (Periploca sepium

Bunge of the family Asclepiadaceae), an herb used in traditional Chinese medicine. 27 Another sample of so-called Siberian ginseng that did consist of eleuthero was adulterated by the addition of 0.5 percent caffeine, presumably to provide a stimulant effect to the user. 28 A later case report attributed an elevated digoxin assay to consumption of eleuthoro, where the likely substitution of Periploca sepium, which contains cardiac glycosides, probably confounded the digoxin assay. 29,30

Almost all of the studies dealing with the biological effects of eleuthero have appeared in the Russian literature. According to the summary by Farnsworth and colleagues, studies conducted on a total of twenty-one hundred human subjects with no pathology were designed to determine the ability of humans to withstand various adverse conditions and to improve work output and athletic performance. Male and female subjects from nineteen to seventy-two years of age were given a 33 percent alcoholic

Chapter eleven: Performance and immune deficiencies 203 extract of eleuthero one to three times daily for periods up to sixty days. 31

The results were generally positive, and no side effects were reported. Another group of studies involved twenty-two hundred human patients suffering from various pathological conditions, including diabe- tes, hypertension, cancer, heart disease, and the like. Measurable improvement was said to be effected in many cases.

Eleuthero is widely recommended for, and utilized by, athletes in the United States, who are told that it “stabilizes blood sugar levels during exer- cise” and “supports the body in adapting to increased levels of mechanical and biochemical stress (ergogenic) that is induced from training and com-

peting.” 32 However, this recommendation has been brought into question recently by a well-designed clinical trial with elite athletes (twenty highly trained distance runners). The eleuthero and placebo groups consumed the respective products daily for six weeks and were tested every two weeks for various ergogenic parameters. The conclusion was that ergogenic claims made for eleuthero could not be supported based on trial results. 33

Some advocates fail to distinguish between ginseng and so-called Siberian ginseng (eleuthero). From the scientific viewpoint, it is appar- ent that most of the Russian studies of the effects of eleuthero on human beings were not double-blind and also lacked adequate controls. Haas has concluded that the only effect of eleuthero that is adequately documented

is that of an immunomodulator. 34 The adaptogen concept, particularly regarding eleuthero, has been challenged as being too vague, and the plant’s effects are more properly characterized as antioxidant, anticancer, hypocholesteremic, immunostimulatory, anti-inflammatory, antipyretic, or antibacterial. 35

Although capsules of eleuthero are readily available on the market, on the basis of existing evidence, its value after evaluating the results as a tonic/adaptogen remains unproven. However, the German Commission

E, on the basis of older studies conducted prior to 1991, concluded that eleuthero was an effective tonic.

Herbal remedies to treat stress The ginsengs