Pharmacological Toxicological Effects 51 Endocrine Effects

P. ginseng may exert hypoglycemic effects possibly by accelerating hepatic lipogenesis and increasing glycogen storage (16-18). In a study of 36 newly diagnosed patients with type II diabetes, ginseng at a dose of 200 mg daily exerted a statistically significant benefit on glycosylated hemoglobin (HbA1c) compared to 100 mg of ginseng daily or placebo after 8 weeks of therapy, and patients receiving 100 mg of ginseng had smaller mean fasting blood glucose levels than patients taking 200 mg of ginseng or placebo (18). The actual difference among the mean HbA1c in the three groups was small; the 200-mg ginseng group had a mean glycosylated hemoglobin of 6 vs 6.5% for the 100-mg ginseng and placebo groups. Likewise, the actual difference among mean fasting blood glucose in the three groups was small; the mean fasting blood glucose was 7.7 mmol/L for the 100-mg ginseng group, 7.4 mmol/L for the 200-mg ginseng group, and 8.3 mmol/L for the placebo group at the end of the study. The observed differences might be attributed to differences in body weight among the three groups. The small study sample limits the generalizability of these results. Vuksan and colleagues observed that whether given concurrently or prior to glucose challenge in patients with type 2 diabetes, ginseng blunted the glycemic response by approx 20% (19). In nondiabetic individuals, reduction in glycemic response was only noted when ginseng was administered 40 minutes prior to the glucose challenge. In a related study, investigators demonstrated that dose of ginseng but not timing of administration resulted in a statistically significant reduction in postprandial glycemia in patients with type 2 diabetes following a glucose challenge (20). At 120 minutes postchallenge, reductions in incremental glycemica as much as 60% were noted. Again, these same investigators studied 10 nondia-betic individuals who received different doses of ginseng at different times prior to glucose challenge (21). Compared with placebo, all doses of ginseng reduced the glycemic response up to 90 minutes in some cases. However, time of administration had no effect. Ironically, these same investigators later reported that the effect of ginseng on postprandial glycemia in healthy individuals was time of administration-dependent but not dose-dependent (22), conflicting with their previous reports. Vuksan and colleagues reported that a batch of ginseng that was lower in ginsenosides than previous batches had no effect on postprandial glycemia (23). Finally, it has been reported that different types of ginseng can have differing effects on postprandial glycemia (decreasing, null or increasing) and that these divergent effects may be related to the ginsenoside composition in the preparations (24). Thus, at the present time, it is difficult to predict the effects of ginseng administration on glycemia because varying effects may be noted depending on the composition and preparation of the ginseng.

All the ginsenosids (saponins) so tested have shown antifatigue actions in mice (25). This may reflect the purported "adaptogenic" action of ginseng, which can be defined as an increase in resistance to stresses and is thought to be secondary to normalization of body processes through regulation of the production of various hormones (4). In evaluating the administration of Siberian ginseng for treatment of chronic fatigue syndrome, Hartz and colleagues found no measurable positive effect in those individuals receiving ginseng as compared to subjects receiving placebo (26).

With respect to increasing exercise performance, Hsu and colleagues reported that ginseng attenuated the formation of creatine kinase induced by submaximal exercise in subjects undergoing a treadmill test (27). However, no increase in aerobic work capacity was noted. In a related study of exercise performance effects, Siberian ginseng administration had no effect on steady-state substrate utilization or any physiological measure in individuals undergoing prolonged cycling exercise (28). The study was conducted in a randomized, double-blind, placebo-controlled fashion and followed 7 days of treatment with either ginseng or placebo.

Ginseng appears to have a modulating effect on the hypothalamic-pitu-itary-adrenal axis by inducing secretion of adrenocorticotropic hormone from the anterior pituitary to increase plasma cortisol (29,30), perhaps accounting for improvement in 11 quality of life measurements in a large double-blind study using ginseng extract G115 (31).

Although many products containing ginseng are marketed specifically for postmenopausal women, a recent review concluded that there is insufficient evidence that ginseng is effective for treatment of menopausal symptoms (11). In vitro, Siberian ginseng extract, but not P. ginseng extract, binds to estrogen receptors. Both extracts have affinity for progestin, glucocorticoid, and mineralocorticoid receptors (32). A recent study reported that a morning/evening formulation containing ginseng and other constituents relieved menopausal symptoms, but no placebo control was included so it is difficult to tell whether the effect was caused by the formulation or a placebo effect (33).

5.2. Neurological Effects

Commercially available P. ginseng products have been reported to have stimulant effects on the central nervous system (CNS) in humans (34) (see Section 5). In animal models, ginseng extracts have been shown to have CNS-stimulant effects (35). Ginsenoside Rg1 inhibits neuronal apoptosis in vitro (35), and ginsenoside Rb1 reverses short-term memory loss in rats (4).

It has been suggested that ginseng may hold promise for the treatment of dementia in humans (4,36). To this end, a number of studies have been performed to evaluate the effects of ginseng on cognition. Wesnes and colleagues studied the memory-enhancing effects of either P. ginseng or Ginkgo biloba in healthy middle-aged volunteers (37). These investigators found that administration of either agent resulted in a small but statistically significant improvement in the Index of Memory Quality (~7.5%) as compared to placebo. In a similar study, another group studied the effects of either ginseng, G. biloba, or the combination on the modulation of cognition and mood in healthy young adults (38). These investigators found that all three treatments improved secondary memory performance and that ginseng administration elicited some improvement in the speed of performing memory tasks and the accuracy of attentional tasks. Only ginkgo elicited a self-rated improvement in mood. Scholey and Kennedy (39) again studied the effects of P. ginseng and G. biloba on several tests of cognitive demand. Increasing doses of ginseng improved accuracy but slowed responses on the Serial Sevens test and the combination product caused a sustained improvement in the number of Serial Sevens responses. This was accompanied by improved accuracy on this same test, again in a dose-dependent fashion. These same investigators later conducted a study of the effects of P. ginseng as compared to guarana in several cognitive performance tests (37). Again, ginseng administration led to an improvement the speed of attention task performance, but little evidence of increased accuracy was noted.

However, two studies have also suggested that administration of ginseng (or a combination of ginseng and G. biloba) has no effect on cognition (and mood). Hartley and colleagues evaluated the effects of a 6- or 12-week course of a ginkgo/ginseng combination product (Gincosan®) on the mood and cognition of postmenopausal women (41). Subjects were administered a battery of mood, somatic anxiety, sleepiness, and menopausal symptom tests. The Gincosan treatment had no measurable effect on any parameter. In a similar study of ginseng administration, investigators found no effect of ginseng on positive affect, negative affect, or total mood disturbance in a randomized, placebo-controlled, double-blind trial (42). Persson and colleagues studied the memory-enhancing effects of either ginseng or G. biloba taken over a sustained period of time (mean intake time of 5.3 months) in healthy community-dwelling volunteers (43). No improvement in memory performance evaluated by eight separate tests was noted in either the group receiving ginseng or the group receiving G. biloba. Thus, it appears that conflicting results still exist as to the ability of ginseng to improve memory and cognition; however, even in those studies demonstrating a positive effect, the enhancement was generally small in magnitude.

The administration of ginseng has also been studied in the treatment of attention-deficit hyperactivity disorder (ADHD). Lyon et al., conducted a pilot study (n = 36) evaluating the effects of a combination product containing ginseng and ginkgo for the treatment of ADHD (44). The investigators reported improvement in 31-67% of the subjects depending on the outcome measure; however, no placebo control was included, so it is difficult to ascertain if the effect was caused by the treatment or a placebo effect.

5.3. Cardiovascular Effects

In animal studies, ginsenoside Rb1 decreases blood pressure, perhaps owing to relaxation of smooth muscle (25). In humans, small studies suggest ginseng may decrease systolic blood pressure at a dose of 4.5 g/day (45), and enhance the efficacy of digoxin in class IV heart failure (46). In contrast, ginsenoside Rg1 has been purported to have hypertensive effects (4). Finally, it has been reported that ginseng has no effect on blood pressure in individuals with hypertension (47).

An in vitro study using a crude extract of ginseng saponins and rabbit corpus-cavernosal smooth muscle suggests that some component of ginseng may be a nitric oxide donor, capable of causing relaxation of smooth muscle in the corpus carvernosum (48). This finding might provide a scientific basis for claims that ginseng enhances sexual potency, and for the results of a study that showed increased penile rigidity and girth compared to placebo or trazodone in patients with erectile dysfunction (49).

Red ginseng powder may be useful in hyperlipidemia; it was shown to decrease triglycerides as well as increase high-density lipoprotein (HDL) in a pilot study (50). A previous rat study lends validity to ginseng's ability to decrease triglyceride levels (16), but a study in patients with diabetes showed no effect on total cholesterol, low-density lipoprotein (LDL), HDL, or triglyceride levels (18).

5.4. Hematological Effects

P. ginseng may inhibit platelet aggregation by regulating the levels of cGMP and thromboxane A2 (51).

5.5. Immunological Effects

Red ginseng stimulates accumulation of neutrophils in a dose-dependent manner following intraperitoneal injections in mice (52). Data show P. ginseng extracts are also able to stimulate an immune response in humans. Chemotaxis of polymorphonuclear cells was increased compared to placebo. Both the phagocytosis index and fraction were enhanced in the ginseng groups and intracellular killing was increased compared to the placebo group. Total lymphocytes and helper T-cells were increased as well (53). There have been other reports of increases in cell-mediated immunity as well as natural-killer cell activity (54).

Predy and colleagues evaluated the ability of ginseng to prevent upper respiratory infections in a randomized, placebo-controlled trial (55). Administration of ginseng for 4 months resulted in a reduction in both the mean number of colds experienced, the number of individuals experiencing two or more colds, and the total number of days of cold symptoms. Similarly, McElhaney et al. studied the ability of ginseng to prevent acute respiratory illness in institutionalized older adults (56). The incidence of confirmed influenza cases was lower in the ginseng-treated group as compared to placebo treatment.

5.6. Antineoplastic Effects

Data from in vitro studies, animal models, case-control studies, and cohort studies suggest ginseng may prevent or ameliorate various cancers. These studies have been reviewed in detail elsewhere (57-59). Suh and colleagues studied the effects of red ginseng on the recurrence of cancer after curative resection in patients with previous gastric cancer during postoperative chemotherapy (60). Survival rate was approximately twice that of control, but placebo treatment was not used. Prospective, placebo-controlled studies of ginseng's ability to prevent or treat cancer are lacking.

5.7. Case Reports of Toxicity Caused By Commercially Available Products

In 1979 the term "ginseng abuse syndrome" (GAS) was coined as the result of a study (34) of 133 people who had been using a variety of ginseng preparations for at least 1 month. Most study subjects experienced CNS excitation and arousal. A total of 14 patients experienced GAS, defined as hypertension, nervousness, sleeplessness, skin eruptions, and morning diarrhea. Five of these subjects also exhibited edema. The effects of ginseng on mood appeared to be dose-dependent; four patients experienced depersonalization and confusion at doses of 15 g, and depression was reported following doses greater than 15 g. A total of 22 subjects experienced hypertension. All of the patients experiencing GAS or hypertension were also using caffeinated beverages. Six other subjects also experienced GAS but were considered "atypical" because they were either using Siberian ginseng instead of P. ginseng, or were injecting ginseng, and thus were not included in the study results. One subject experienced anaphylaxis followed by confusion and hallucinations after injection of 2 mL of ginseng extract. The average daily dose of the 14 patients experiencing GAS was 3 g of ginseng root, and most users reported titrating the dose to minimize nervousness and tremor. One subject experienced hypotension, weakness, and tremor when ginseng use was abruptly discontinued. The author compared ginseng's effects to those of high doses of corticosteroids. GAS seemed to be found predominantly during the first year of use, possibly because by the 18-month follow-up visit, ginseng use had declined to an average of 1.7 g daily, and by the 24-month visit, one-half of the patients with GAS had discontinued ginseng use, and 21% of the remaining subjects had stopped using it. Eight subjects were still experiencing diarrhea and nervousness at the 2-year follow-up. Because this study was not controlled, the existence of GAS has been questioned (6).

Hypertension, shortness of breath, dizziness, inability to concentrate, a loud palpable fourth heart sound, "thrusting" apical pulse, and hypertensive changes on fundal examination were reported in a 39-year-old man who had taken various ginseng products for 3 years (61). His blood pressure measured 140/100 mmHg on three occasions over 6 weeks, and when referred for management of his hypertension it was 154/106 mmHg. He was advised to discontinue the ginseng products, and 5 days later was normotensive at 140/85 mm Hg. At 3-month follow-up, he remained normotensive and his other symptoms had resolved. No attempt was made to confirm the identity or composition of the ginseng products.

An episode of Stevens-Johnson syndrome was reported in a 27-year-old man following ginseng administration (two pills a day for 3 days). Infiltration of the dermis by mononuclear cells was noted. The patient recovered completely within 30 days (62).

An association between ginseng and mastalgia has been reported. A 70-year-old woman developed swollen, tender breasts with diffuse nodularity after using a P. ginseng powder (Gin Seng) for 3 weeks. Symptoms ceased following discontinuation of the herb and reappeared with two additional rechallenges. Prolactin levels were within normal limits (63).

A 72-year-old woman experienced vaginal bleeding after taking 200 mg daily of a Swiss-Austrian geriatric formulation of ginseng (Geriatric Pharmaton, Bernardgrass, Austria) for an unspecified time (64). In a similar case, a 62-year-old woman had undergone a total hysterectomy 14 years previously and had been taking Rumanian ginseng alternating with Gerovital® every 2 weeks for 1 year (65). The patient derived a marked estrogenic effect from the product based on microscopy of vaginal smears as well as the gross appearance of the vaginal and cervical epithelium. The patient was dechallenged from the products for 5 weeks, rechallenged with Gerovital for 2 weeks, then rechallenged with ginseng for 2 weeks. Estrone, estradiol, and estriol levels were essentially unchanged over this time period, but the estrogenic effects on the vaginal smear coincided with ginseng use. Using gas chromatography, the investigators found no estrogen in the tablets the patient had been taking. They did discover that a crude methanolic extract of the ginseng product competed with estradiol for the estrogen and progesterone binding sites in human myometrial cytosol.

A 44-year-old woman who had experienced menopause at age 42 experienced three episodes of spotting associated with use of Fang Fang ginseng face cream (Shanghai, China). Interestingly, these episodes of bleeding were associated with a decrease in follicle-stimulating hormone levels and a disor dered proliferative pattern on endometrial biopsy. The woman discontinued use of the cream and experienced no further bleeding (66). Whether the products used in these reports of vaginal bleeding and mastalgia contained P. ginseng or Siberian ginseng (E. senticosus) was not investigated. Whether Panax or Siberian ginseng causes estrogenic effects requires further study.

Maternal ingestion of 650 mg of Siberian ginseng (Jamieson Natural Sources, Toronto) twice daily was associated with androgenization in a neonate (67). The product had been taken for the previous 18 months, including the pregnancy. During pregnancy, the mother noted increased and thicker hair growth on her head, face, and pubic area, and had experienced repeated premature uterine contractions during late pregnancy. At birth, the Caucasian child weighed 3.3 kg, had thick black pubic hair, hair over the entire forehead, and swollen red nipples. The woman continued to take the ginseng product for 2 weeks after the baby's birth, during which time she breast-fed the baby. She was advised to discontinue the product when the baby was 2 weeks old, and his pubic and forehead hair began to fall out. By 7.5 weeks of age, hair was scant, but his testes were enlarged. Weight gain was 1.1 kg during the first 3.5 weeks of life, and 1.4 kg during the next 3.5 weeks. At age 7.5 weeks, his weight (5.8 kg), length (60.6 cm), and head circumference (41.5 cm) were at or above the 97th percentile. At that time, testosterone, 17-hydroxyprogesterone, and cortisol levels were normal. Subsequent information did not confirm the product's androgenic effects. A sample of the raw material used in manufacturing the preparation used by this patient was identified as Periploca sepium (Chinese silk vine), not Siberian ginseng. No an-drogenic effects were noted in rats administered the manufacturer's sample (68). P. sepium ("jia-pi") was reported previously to be mislabeled as Siberian ginseng ("wu-jia-pi"), perhaps owing to similarities in the Chinese terms for these herbs (69).

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