Panax ginseng is considered a tonic or adaptogen that enhances physical performance, relieves fatigue, promotes vitality and increases resistance to stress
(Fulder, 1990, Tang et al., 1992). Chinese traditional medicine considers ginseng to have beneficial effects on physical capacity, alertness, and power of concen- tration, especially in the elderly and those recovering from illness (Fulder, 1990, Tang et al., 1992). It is also used by athletes to enhance their ‘energy level’ (Bahrke and Morgan, 2000).
Although the mechanism underlying the alleged ergogenicity of ginseng on physical performance has not been defined, theories include stimulation of the hypothalamic–pituitary–adrenal cortex axis and increased resistance to the stress of exercise, enhanced myocardial metabolism, increased haemo- globin levels, vasodilation, increased oxygen extrac- tion by muscles, reduced oxidative stress, and improved mitochondrial metabolism in the muscle, all of which theoretically could enhance aerobic exercise performance (Kim et al., 2005).
A careful study by Pieralisi et al. (1991), using a double-blind crossover design, indicated that ginseng significantly increased workload and oxygen uptake in normal subjects. At a fixed workload, ginseng decreased oxygen consumption, carbon dioxide production, and plasma lactate. Chinese ginseng improved maximal oxygen uptake (VO2max), post- exercise recovery (heart rate lowered 6 beats/min for the 6 min after exercise), pectoral strength (by 22% as measured by a dynamometer), and quadriceps strength (by 18% as measured by dynamometer) (McNaughton et al., 1989). Administration of ginseng or its components enhanced exercise endurance by altering fuel homeostasis during exercise, increased free fatty acid utilisation in preference over glucose for cellular energy demands in rats and mice (Bahrke and Morgan, 2000; Bucci, 2000). However, based on a review of the ergogenic properties of ginseng, most clinical trials investigating the value of Panax ginseng in enhancing physical performance have shown no clinical effect (Bahrke and Morgan, 2000). For example, two studies found no effects of ginseng on physical performance. The first study showed that 8 weeks of supplementation with a standardised ginseng extract of 200 mg a day failed to affect work performance and energy metabolism in a group of healthy women (Engels et al., 1996). The second study, examined the effects of doses of 200 and 400 mg of standardised ginseng extract compared with a placebo, given to 36 healthy men and found
no effect of ginseng at either dose on physiological or psychological parameters such as oxygen consump- tion, respiratory exchange ratio, minute ventilation, blood lactic acid concentrations, heart rate and perceived exertion (Engels et al., 1997). In another small study 28 healthy, adult subjects were given a standardised ginseng extract for 21 days, but no ergogenic effects were found (Allen et al., 1998).
An examination of available data reveals most of the variation in results arises from a dose–response and duration effect, differences between subjects’ age, and the variability in the quality of the supple- ment and/or different methods of study. Properly controlled studies exhibiting statistically significant improvements in physical or psychomotor perfor- mance almost invariably used higher doses (usually standardised to ginsenoside content equivalent to 2 g dried root daily), longer durations of study (⫾8 week), and larger subject numbers, indicating greater statistical power (Buettner et al., 2006). With lower doses, short durations, and small subject numbers, studies show no significant differences in performance, physiologic, or psychomotor measure- ments (Morris et al., 1996; Engels and Wirth, 1997; Allen et al., 1998).
Forgo et al. (1982) studied 120 subjects aged 30–60 years for 12 weeks in a double-blind study. Subjects were given either placebo or 200 mg/day of a standardised ginseng extract. Supplementation was associated with significantly reduced reaction times for those subjects aged 40–60 years but not for those aged 30–39 years. Men in this youngest group showed no significant effect from ginseng on pulmonary functions (vital capacity, forced expira- tory volume, maximum expiratory flow, and maximum breathing capacity). Women aged 30–39 years and both sexes aged 40–60 years showed significant improvements in all four measurements of pulmonary function after 12 weeks of supplementa- tion. No significant changes by age or sex were found for serum concentrations of luteinising hormone, testosterone or oestradiol. As with pulmonary func- tion, subjective self-assessment showed significant improvements in women of all ages but only in men aged 40–60 years. Importantly, changes became significant after 6 weeks of supplementation and were more significant at 12 weeks, suggesting a slow-acting effect. Thus, studies lasting fewer than
12 weeks (Morris et al., 1996; Engels and Wirth, 1997; Allen et al., 1998) may not have been long enough to show a significant effect. For example, in a study with 31 healthy men who took 200 or 400 mg of extract daily for 8 weeks, no change in physiological or maximal exercise (Engels and Wirth, 1997) was found. In addition, there was no ergogenic effect on peak aerobic exercise performance following a 3-week supplementation period of 200 mg of 7% Panax ginseng in healthy young adults with moderate exercise capacities and unrestricted diets (Allen et al., 1998).
Ginseng exhibits effective antioxidant, free- radical scavenging activity, and inhibits lipid peroxi- dation (Fu and Ji, 2003). Intense exercise may increase the production of free radicals or reactive oxygen species. A free radical prefers to steal elec- trons from the lipid membrane of a cell, initiating a free-radical attack on the cell known as lipid peroxi- dation. Kanter et al. (1988) have demonstrated that post-exercise plasma creatine kinase (CK) elevations may be related to an exercise-induced lipid peroxida- tion. Low physiological levels of NO could act as an antioxidant, protecting the muscle from any delete- rious effect of exhaustive exercise (Perez et al., 2002). NO production after a single bout of exercise may reflect a systemic inflammatory response to heavy exercise. In a recent study on rats, ginseng treatment (11 mg/kg) protected muscles from eccentric exercise injuries and reduced NO concentrations in vastus and rectus (Cabral de Oliveira et al., 2005).
Hsu et al. (2005) reported that oral supplemen- tation with American ginseng (400 mg per capsule, 4 capsules daily) containing 8.7% ginsenosides Rb1 for 4 weeks in 13 male volunteers (aged 23 years) significantly reduced the leakage of plasma CK during exercise, but did not enhance aerobic work capacity. The reduction of plasma CK may be due to the fact that ginseng is effective for decreasing skeletal muscle cell membrane damage, induced by exercise during an exhaustive treadmill run. Thus, under appropriate conditions, ginseng root extracts may increase muscular strength and aerobic work capacity. Requirements are:
• sufficient daily dose (ⱖ2000 mg P. ginseng root powder or an equivalent amount of root extract with standardised ginsenoside content)
• sufficient duration for effects to develop (ⱖ8 wk) • sufficient intensity of physical or mental activity
(especially in untrained or older subjects)(Bucci, 2000).
Ginseng may exert greater benefits for untrained or older (⬎40 years) subjects and does not appear to exert any acute effects on physical performance.
Role of nitric oxide
Studies have shown that ginseng and ginsenosides induce NO release, a primary vasodilator. Specifically in an animal model and in-vitro studies, ginseng causes vasorelaxation and prevents manifes- tations of oxygen free-radical injury by promoting release of NO by endothelial cells. Purified compo- nents of GS, Rb1and especially Rg1, relax pulmonary vessels, and this effect is eliminated by nitro-L- arginine, an inhibitor of nitric oxide (NO) synthase (Chen et al., 1996). In support of this proposal, Kim
et al. (1992) found that conversion of [14C]L-
arginine to [14C]L-citrulline in confluent bovine aortic endothelial cells in culture was enhanced significantly by ginseng and by Rg, but not by Rb. A single injection (intraperitoneal) of ginseng extract (200 mg/kg) increased the levels of nitrites, nitrates and cGMP in rat serum and urine (Han and Kim, 1996). These effects were reversed by inhibition of NO synthase and restored by L-arginine. Similar action was observed in the rat kidney, isolated glomeruli, and cortical tubules and the action was blocked by inhibition of NO synthase. Ginseng extract appears to stimulate NO production in the kidney and thus may protect against ischaemia by increasing renal blood flow (Han and Kim, 1996). Kang et al. (1995) found that addition of ginseng to a high-cholesterol diet fed to rabbits preserved most of the normal dilatation of preconstricted aortic rings in response to acetylcholine. Interestingly, ginseng did not change endothelium-dependent relaxation to acetylcholine in animals receiving a normal diet. The mechanism of this effect is unknown but could reflect enhanced NO production or some enhancement of the guanylate cyclase pathway. Therefore, it would be appropriate to determine whether ginsenoside affects expression of NO synthase and guanylyl cyclase genes.
Several observations suggest that release of NO by ginseng may underlie the antioxidant effect of the extract. Wink et al. (1993) showed that NO-releasing agents protected Chinese hamster lung fibroblasts (V79 cells) from oxy-radical damage caused by hypoxanthine/xanthine oxidase, implying that NO, even at low concentrations, need not be cytotoxic.
The study also assessed whether similar actions would be seen after digestion designed to mimic the pH exposure after oral ingestion. Both digested and undigested ginseng dilated preconstricted perfused lung and preserved acetylcholine dilation following free-radical injury (Rimar et al., 1996). Ginsenosides Rg and Rb were much less effective vasodilators after similar digestion, suggesting that standardised extracts of ginseng may be more effective after oral administration than individual ginsenosides. It has been noted that ginsenosides from the protopanaxa- triol group (e.g. Re and Rg), but not the protopanaxadiol group (e.g. Rb and Rc), enhanced the release of NO from endothelial cells (Kang, 1995). Kim et al. (1999) also showed that Rg3 mediated endothelium-dependent relaxation through eNOs activation in rat arteries.
The relaxing blood vessels may contribute to the antifatigue and blood-pressure-lowering effects of ginseng. In a human study, a single administration of a ginseng water extract (500 mg/kg) increased NO levels in exhaled breath and concomitantly decreased mean blood pressure (Han et al., 2005). Ginseng also improves the vascular endothelial dysfunction in patients with hypertension possibly through increasing synthesis of NO (Sung et al., 2000). In some studies, total root extract was more effective than isolated ginsenosides. However, it appears that direct effects of ginseng on physical performance by enhancing the release of NO from endothelial cells in humans have not been conclusively linked.
Recent studies, therefore, suggest that some cardiovascular protection effects of ginseng may be explained by the enhanced presence of NO. Evidence has been offered that:
• ginseng enhances formation of citrulline from added arginine, implying enhanced synthesis of NO
• known inhibitors of NO synthase, including oxyhaemoglobin and substituted arginine
derivatives, block both the action of ginseng on citrulline formation from arginine and Ach- induced vascular relaxation of preconstricted tissue
• when used, arginine reverses the action of NO synthase inhibitors
• when measured, tissue cGMP has been increased by ginseng
• some of the effects can be potentiated by the presence of arginine in ginseng extracts. It was found that 5mg/mL of a commercial ginseng extract may provide an average of 1 lmol/L arginine in the assays; this is enough to account for all inhibition of NO synthase (Bejar et al., 2003).
Using a pulmonary model in which endothelial injury is caused by a variety of reduced oxygen species, the protective action of ginseng is shown. Ginsenoside (50 or 200 lg/mL) prevented these vascular effects and also reduced the pulmonary oedema that follows free-radical injury (Kim et al., 1992). The latter effect was eliminated by 100 lmol/L nitro-L-arginine, an inhibitor of NO synthase. These data are consistent with the proposal that ginseng causes vasorelaxation and prevents manifestations of oxygen free-radical injury by promoting release of NO.