Antifatigue Effects of Panax ginseng C.A. Meyer: A Randomised, Double-Blind, Placebo-Controlled Trial

Abstract

Introduction

The medically unexplained chronic fatigues, including idiopathic chronic fatigue (ICF) and chronic fatigue syndrome (CFS) are debilitating illnesses due to severe impairment of the quality of life, due to their unknown aetiology and the lack of effective therapeutics [1]. Therefore, many patients with chronic fatigue use alternative and complementary therapies. One study reported that approximately 80% of subjects with chronic fatiguing illness, including ICF and CFS, used alternative and complementary therapies such as massage or herbal supplements in the United States [2].

Panax ginseng C.A. Meyer is one of the best known medicinal plants worldwide, and has traditionally been used in Asian countries to maintain homeostasis of the body and to enhance vital energy [3]. About 13.6% of subjects with chronic fatigue ingested ginseng supplements in one Korean study [4]. To date, numerous active compounds (including approximately 40 ginsenosides) have been identified in P. ginseng [5]. Also, various pharmacological activities have been identified, such as effects on chemical stress [6] and immune modulation [7] in animal studies, and antitumour activity [8], and effects on glucose metabolism [9] and enhancement of cognitive performance [10] in clinical studies [11].

One group reported anti-mental fatigue effects of P. ginseng (G115) by showing improvements in the cognitive performance of healthy volunteers in serial clinical studies [12], [13]. Another group also demonstrated a positive effect of P. ginseng (G115) on memory in healthy volunteers [14], [15]. Difficulty in concentration and memory or altered mood is a major symptom of chronic fatigue-associated disorders [16], [17]. The aforementioned studies were conducted in healthy subjects, but these positive results suggest an antifatigue effect of P. ginseng in patients with ICF and CFS.

Antifatigue effects of P. ginseng have been strongly anticipated from clinical experience and animal-based experiments [18], [19]. Oxidative stress is considered as a main contributor to the pathology of chronic fatigue [20]. Much experimental and clinical evidence supports the antioxidant properties of P. ginseng [21], [22]. A randomised controlled trial (RCT) showed an improvement in cancer-related fatigue using another species of ginseng, Panax quinquefolius [23]. However, no scientific investigations to date have investigated the antifatigue effects of P. ginseng.

Thus, to evaluate the antifatigue effects of P. ginseng and its antioxidant activities, we conducted a RCT in 90 subjects with ICF.

Discussion

P. ginseng is a popular herbal remedy that has been used in eastern Asian cultures for thousands of years and has been gaining popularity for the treatment of various health-related complaints worldwide [38]. Although ginseng has long been used in clinical settings, the increasing consumption of ginseng products requires more rigorous scientific evaluation to establish appropriate clinical use with regard to efficacy, safety and drug interactions [39]. The present study evaluated the antifatigue effects of P. ginseng and its antioxidant activity to explain the mechanism underlying its effects in patients with ICF. Of the two major unexplained chronic fatigue types, ICF generally shows a prevalence 10 times higher than that of CFS, as 4.2% of subjects have ICF and 0.42% of subjects suffer from CFS in the general US population [40].

In order to reduce the fatigue severity of subjects at baseline, the only patients with ICF were involved and patients with CFS were excluded. The primary endpoint of this study was change in fatigue symptoms as measured by total NRS. The fatigue severity in all three groups was comparable, with total NRS scores ranging from 58.0 to 60.8 and VAS scores from 7.0 to 7.3. These scores represent about 60% and 70% of the maximum possible NRS (99 points from 11 questions) and VAS scores, respectively. During the 4-week administration of P. ginseng extract or placebo, the total NRS and VAS scores showed a decreasing pattern in all three groups. Although the decreasing tendency of the total NRS score was prominent after administration of 1 g and 2 g P. ginseng [95% CI 6.4∼18.6 and 6.4∼14.5, respectively] compared with placebo [95% CI 12.9∼25.1], statistical significance was not reached at the cut off for multiple comparisons (P = 0.068). However, the improvement in VAS score was statistically significant after administration of 2 g, but not 1 g, of P. ginseng (P<0.05).

When we analysed the antifatigue effects of P. ginseng, focusing on the two aspects of physical and mental symptoms, P. ginseng administration was associated with significant improvement only in the NRS mental score, but not in the NRS physical score. This result is in accordance with results from other clinical studies. Although seven high-quality studies using P. ginseng yielded no positive findings with respect to physical outcomes, they did report positive effects on cognitive performance and mood [12], [14], [41]. These results indicate that P. ginseng may exert its antifatigue effects through mental improvements. Besides physical fatigue, mental problems, such as difficulties with learning, memory or concentration, are characteristic symptoms of ICF and CFS [42]. In our results, control group also showed the general improvement of fatigue severity. This would result from placebo effects because placebo group speculated that the drug administered was P. ginseng. Psychological distress has been regarded as both the main cause and symptom of chronic fatigue [43]; therefore, we excluded subjects with severe depression or anxiety symptoms in their past histories when evaluating the antifatigue effects of P. ginseng in patients with ICF in this study.

Although the aetiology of unexplained chronic fatigue is unclear, several recent studies have shown that oxidative stress may be an important contributor to its pathogenesis [40], [44]. Two clinical studies reported increased levels of plasma peroxides and methemoglobin (MetHb) as oxidative stress markers in patients with CFS [20], [45].Therefore, we examined the serum levels of biomakers associated with oxidative stress and antioxidant-associated biomarker profiles before and after 4 weeks of P. ginseng administration. ROS are the main oxidative stressors, and MDA is a quantitative marker of lipid peroxidation by ROS [46]. The subjects with ICF in this study had approximately 1.3-fold higher total serum ROS, and fourfold higher serum MDA, levels comparable with healthy subjects in our previous study [21]. Both 1 g and 2 g P. ginseng administration for 4 weeks significantly lowered the serum total ROS and MDA concentrations compared with the placebo (Table 4).

Oxidative stressors are normally eliminated by protective mechanisms such as free-radical scavengers, SOD, catalase and the GSH oxidation/reduction system. SOD and catalase catalyse the decomposition of superoxide into H₂O₂ and subsequently into water and oxygen [47]. The GSH system plays a central role in multiple defences, particularly via antioxidant-dependent mechanisms, not only against ROS but also against their toxic products [48]. Contrary to our expectations, P. ginseng had no effect on serum TAC, SOD or catalase levels, but administration of 1 g P. ginseng significantly elevated the total GSH content and GSH-Rd activity compared with the placebo (Table 4). In addition to the GSH system, P. ginseng may activate many pathways to exert antioxidant activity related to antifatigue effects because fatigue severity was improved in the 2 g P. ginseng group without a corresponding change in total GSH content or GSH-Rd activity.

We previously reported antioxidant effects of P. ginseng (same dose and period) in healthy subjects [21]. One clinical study reported an extended activity duration and significant attenuation of serum MDA elevation and altered catalase and SOD activity by administration of P. ginseng extract (6 g daily for 8 weeks) to male subjects [49]. Pretreatment with P. ginseng polysaccharides reduced the immobility of mice in the forced swimming test and inhibited the alteration of serum MDA level and GSH-Rd activity [19]. Additionally, ginsenoside-enriched American ginseng extract, the second most popular species of ginseng, suppressed the levels of two oxidative stress markers (F2-isoprostane and 8-hydroxy-deoxyguanosine ratios) in healthy volunteers [50]. Notably, the active compounds of Siberian ginseng (Eleutherococcus senticosus), which is from the same family but not the same genus as P. ginseng, are eleutherosides (not ginsenosides), and no antifatigue effect was observed in a RCT of Siberian ginseng [51]. These results support our findings that the antioxidant properties of P. ginseng may be responsible for its antifatigue effects. However, we are unable to determine whether this antioxidant action plays a key role in staving off fatigue, or which active components are responsible for the antifatigue effects of P. ginseng. Pretreatment with 20(R)-Rg3, a major active compound of P. ginseng, prolonged weight-loaded swimming time without a significant influence on oxidative stress makers [52].

Adverse effects of P. ginseng have been reported only rarely, but include headache and sleep and gastrointestinal disorders [39]. One subject in the 2 g P. ginseng group complained of body rash and pruritus, and recovered quickly after withdrawing from the trial. This likely resulted from an allergic response to P. ginseng and represents an adverse effect. Another subject in the 1 g P. ginseng group discontinued intervention for nonmedical reasons. We estimated the compliance to be over 90% because of the preference of Koreans for P. ginseng; despite this, two subjects withdrew. Above two subjects were dropped before the first time point of measurement at 2-week. For this reason, we analysed the results per protocol (PP), instead of intention to treat (ITT).

To our knowledge, this study is the first RCT to provide systematic evidence of the antifatigue properties of P. ginseng in subjects with ICF. Taken together, these data lead us to conclude that P. ginseng can be used to combat chronic fatigue and that the mechanism underlying this effect may be related to its antioxidant properties.

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