Journal of the American Society of Hypertension 8(8) (2014) 537–541

Research Article

Effect of Rg3-enriched Korean red ginseng (Panax
ginseng) on arterial stiffness and blood pressure in
healthy individuals: a randomized controlled trial
Elena Jovanovski, MSca, Emma A. Bateman, BSca, Jyoti Bhardwaj, MSca,b,Chris Fairgrieve, MDa, Iva Mucalo, PhDc, Alexandra L. Jenkins, RD, PhDa, andVladimir Vuksan, PhDa,b,d,e,*a

Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada;
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;cCentre for Applied Pharmacy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia;d
Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; andeDivision of Endocrinology & Metabolism, St. Michael’s Hospital, Toronto, Ontario, Canada
Manuscript received February 13, 2014 and accepted April 9, 2014b

Abstract
Ginsenoside Rg3, present in steamed ginseng (Panax Ginseng C.A. Meyer), is thought to be a potent modulator of vascularfunction. Our objective was to clinically evaluate acute effects of ginsenoside Rg3–enriched Korean red ginseng (Rg3-KRG)
on measures of arterial stiffness and peripheral and central blood pressure (BP) parameters in healthy volunteers. Using adouble-blind, randomized, crossover design, 23 individuals (9 males:14 females; age, 25  2 years; body mass index,
22  0.6 kg/m2; systolic BP/diastolic BP, 113  3/70  2 mm Hg) were administered 400-mg Rg3-KRG extract or 400mg wheat bran control on two separate visits with a 7-day washout period. Aortic augmentation index and central BP
were measured using applanation tonometry by radial pulse wave analysis, and peripheral BP was evaluated oscillometrically.
Measurements were taken at baseline and at 1, 2, and 3 hours after intervention. Compared with control, there were significant reductions in augmentation index (4.3  8.9%, P ¼ .03), central (4.8  6.8 mm Hg, P ¼ .01) and brachial meanarterial pressure (4.4  6.6 mm Hg, P ¼ .01), central systolic (5.0  7.9 mm Hg, P ¼ .01) and diastolic BP(3.9  6.6 mm Hg, P ¼ .01), and brachial systolic (4.4  10.0 mm Hg, P ¼ .048) and diastolic BP (3.6  6.4 mm
Hg, P ¼ .01) at 3 hours after intervention compared with control. This study is the first to demonstrate Rg3-KRG extract
acutely lowers central and peripheral arterial pressures in healthy adults. Further clinical evaluation is desired to quantify
efficacy in higher risk individuals and in long-term settings. J Am Soc Hypertens 2014;8(8):537–541. Ó 2014 American
Society of Hypertension. All rights reserved.
Keywords: Augmentation index; clinical; ginsenosides; vascular; ginseng.

Financial Support: This study was financially supported by theHeart & Stroke Foundation of Ontario, Canada and by BTGin Co,
Yuseong-gu, Daejeon, Republic of Korea. The study material,
Rg3-KRG, was manufactured and donated by BTGin Co,
Yuseong-gu, Daejeon, Republic of Korea.
Conflict of Interest: Vladimir Vuksan is a holder of an American(No. 7,326,404 B2) and Canadian (No. 2,410,556) patent for use ofviscous fiber blend in diabetes, metabolic syndrome and cholesterol lowering; currently holds grant support for ginseng researchfrom the Canadian Diabetes Association (G-2-09-2920-VV),
Canada and the National Institute of Horticultural & Herbal

Science, RDA, Korea. Vladimir Vuksan received a travel
grant from BTGin Co, Yuseong-gu, Daejeon, Republic of Korea.
Vladimir Vuksan and Alexandra L. Jenkins are part owners of
Glycemic Index Laboratories, Inc. a contract research organization.
For the remaining authors, no conflicts of interest were declared.
*Corresponding author: Vladimir Vuksan, PhD, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital,
30 Bond Street, 10th Floor–Donnelly Wing, Toronto, Ontario,
M5B1W8, Canada. Tel.: (416) 864-5525; fax: (416) 864-5538.
E-mail: v.vuksan@utoronto.ca

1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved.
http://dx.doi.org/10.1016/j.jash.2014.04.004

538

E. Jovanovski et al. / Journal of the American Society of Hypertension 8(8) (2014) 537–541

Introduction
Less than half of individuals with hypertension reach targets for managing blood pressure (BP) using conventional
medical therapies alone.1 In addition to office BP, central
BP and measures of arterial stiffness are validated independent predictors of cardiovascular disease (CVD) mortality
and are among the risk factors conventional practice often
fails to address.2,3 Korean red ginseng (KRG) has been
implicated in improving CVD risk factors including insulin
sensitivity in type 2 diabetes mellitus and endothelial function in healthy individuals, but to date has generated neutral
or moderate effects on arterial stiffness and brachial BP.4–8
Although clinical application of KRG may show promise in
the management of vascular health, the equivocal data warrant further delineation of its structure–function relationships before standardization is applied and a reliable
clinical response can be established.
Evidence to date suggests that the steroidal saponin fraction of ginseng, known as ginsenosides, is a pharmacologically active component.9 We have previously demonstrated
that a ginsenoside fraction of ginseng, rather than the polysaccharide fraction, was responsible for improving augmentation index (AIx), a marker of wave reflection and arterial
stiffness, in healthy individuals.5 Within the ginsenoside
fraction of KRG, particular attention was focused on ginsenoside Rg3, as it had been ascribed potent vasodilator properties in animal models and is thought to be a significant
contributor to ginseng-mediated vasoactivity.10–12 Whether
these findings translate to a clinical setting and could
possibly enter the therapeutic domain, is unknown. Clinicalutility of a standardized ginseng extract that is enriched withginsenoside Rg3 should therefore be considered as a novel
lead for its potential application in vascular health.
The objective of the present study was, therefore, to evaluate the acute efficacy of single dose oral administration ofa standardized ginsenoside Rg3-enriched KRG (Rg3-KRG)
extract on measures of arterial hemodynamics including amarker of arterial stiffness, brachial BP, and central BP in
healthy adult participants.

Methods
Participants
Twenty-four healthy participants were recruited using thefollowing inclusion criteria: age 18–70 years, body massindex <30 kg/m2, brachial BP defined as seated systolic/diastolic BP < 140/90 mm Hg at screening and exclusion
criteria: presence of hypertension as defined by the Joint
National Committee VII criteria,1 diabetes, kidney or liverdisease, bleeding disorder, pregnancy or breastfeeding, useof prescription medication, use of herbal supplements
within 3 weeks of the first study visit, self-reported presence of any major diseases, and alcohol use of >2 drinks

per day. Participants were instructed to follow a nitratecontrolled diet for 3 days before the visits. The study was
conducted in accordance with the guidelines presented in
the Declaration of Helsinki. All participants gave informed
written consent prior to study commencement. Regulatory
approvals were obtained from St. Michael’s Hospital
Research Ethics Board and the Health Canada Natural
Health Product Directorate (ClinicalTrial.gov Identifier:
NCT01951443).

Study Intervention
Within a double-blind, randomized, crossover, placebocontrolled design, study interventions included either a
400-mg dose of ginsenoside Rg3-KRG extract or 400 mg
of wheat bran control. The dose of 400 mg was selected
as a starting dose based on the dose previously found toaffect erectile dysfunction.13 Randomization for treatments
was conducted using a random number table generated by astatistician where treatment allocation sequences occurredin approximately equal numbers (12 participants assigned
to treatment then control and 12 participants assigned to
the reverse sequence). The Rg3-KRG material was manufactured to contain 10% ginsenoside Rg3 and 30% totalsaponins, by BTGin Co Ltd (Daejeon, Republic of Korea).
Briefly, KRG rootlets underwent 50% and 85% ethanol andwater extraction in consecutive steps (70 C, 3 hours). The
extract was treated by enzyme and acid hydrolysis toamplify ginsenoside Rg3 content, followed by substrate
removal and evaporation to powder form. The final productcontained the following concentrations of major ginsenosides: Rb1 (3.77 mg/g), Rg1 (0.57 mg/g), Re (1.86 mg/g),
Rf (12.3 mg/g), Rb2 (1.24 mg/g), Rh1 (4.15 mg/g), Rc(0.99 mg/g), and Rg3 (100 mg/g). The extract and control
interventions were administered in encapsulated form using
an identical size #000 opaque capsule and were indistinguishable from each other.

ProtocolScreened and eligible participants attended the Risk Factor Modification Centre, St. Michael’s Hospital in a fasted
state on two separate mornings, separated by a minimumof 1 week washout period. Individuals first underwent
anthropometric measures and completed a questionnaire.
Baseline measures of aortic AIx, a marker of arterial stiffness, and aortic BP were performed noninvasively in triplicate via applanation tonometry of the radial artery using
the SphygmoCor Vx Pulse Wave Analysis system (AtCor
Medical, Sydney, Australia) by two trained investigators.
Brachial BP was also evaluated in triplicate oscillometrically 1 minute apart (HEM907-XL; Omron Healthcare,
Kyoto, Japan). Following baseline measures, treatment
was administered orally with 200 mL of water. Additional
measures were obtained at 1-hour intervals for a study

E. Jovanovski et al. / Journal of the American Society of Hypertension 8(8) (2014) 537–541

session duration of 3 hours after intervention. Symptom
adverse events were evaluated subjectively through a symptoms questionnaire at 1-hour intervals during study session
and within 24 hours following acute dosing.

Statistical Analysis
The primary outcome measure was aortic AIx, where allvalues are adjusted for a heart rate of 75 beats per minute.
Secondary outcome measures included brachial and central
BP and mean arterial pressure. Changes in each outcome
measure relative to baseline were computed and plotted.
Repeated measures analysis of variance assessed independent and interactive effects of intervention relative tocontrol on incremental hemodynamic indices. Statisticalanalyses were performed using the NCSS statisticalsoftware (Kaysville, Utah). All results are expressed asmean  standard deviation (SD). To detect differences in
AIx adjusted for heart rate of 75 beats per minute of 4%
at a SD of 4.5% unit change with 80% power at a levelof P < .05 (a ¼ 0.05 and 1b ¼ 0.8) and accounting fora 10% attrition rate, a total of 24 participants were to be
recruited.

Results
Twenty three individuals with the following baseline characteristics completed the study: 9 males:14 females; age,25  2 years; body mass index, 22  0.6 kg/m2; systolic
BP, 113  3 mm Hg, diastolic BP, 70  2 mm Hg; andAIx: 9.5  11.6%. One participant withdrew from the study
because of time commitments unrelated to the study. The
design was uniform within sequences and periods. There
was no significant carryover effect of study interventions.
Repeated measures analysis of variance demonstrated asignificant effect of Rg3-KRG on reduction of aortic AIx

539

posttreatment relative to control (4.3  8.9%, P ¼ .03;
Figure 1). Additionally, measured hemodynamic indicesincluding central systolic (5.0  7.9 mm Hg, P ¼ .01;
Figure 1) and diastolic BP (3.9  6.6 mm Hg, P ¼ .01;
Figure 1), brachial systolic (4.4  10.0 mm Hg,
P ¼ .048; Figure 1) and diastolic BP (3.6  6.4 mm Hg,
P ¼ .01), central mean arterial pressure (4.8  6.8 mm
Hg, P ¼ .01), and brachial mean arterial pressure(4.4  6.6 mm Hg, P ¼ .01) were significantly reduced
at the end of posttreatment period relative to control(Table 1). There were no differences between treatments
for self-reported adverse effects. One participant experienced mild headaches posttreatment in both interventions
and another participant experienced transient anxiety posttreatment in the control group. Data in the text are presented
as mean  SD.

Discussion
This study is the first to demonstrate that ginseng
enriched with ginsenoside Rg3 acutely improved indicesof vascular function in healthy young adults with BP in
the low–normal range. The magnitude of pulse wave reflection observed at the end of study session is in line with
angiotensin converting enzyme inhibitor, an antihypertensive agent, reported in a recent meta-analysis.14 These
results are noteworthy in the context of mounting evidence
relating increased arterial stiffness to adverse effects onventricular afterload and the strong independent association between indices of wave reflection, including aortic
AIx, and CVD risk.15 The observations here corroborate
cumulating evidence on vasoactive agents, which lower
brachial BP yet may have an additional favorable impact
on aortic AIx.12,16,17
While this study cannot attribute the significant shift inhemodynamics to a specific bioactive compound, our study

Figure 1. Acute effects of administration of 400-mg Rg3-enriched Korean
red ginseng (-:-) vs. control (-C-)
on (A) augmentation index (AIx)adjusted for 75 beats per minute, (B)brachial systolic BP, (C) central systolic BP, and (D) central diastolic BP
in 23 young, healthy individuals.
Values are presented as mean change
from baseline over 3 h postingestion.
BP, Blood pressure; @75, adjusted for
75 beats per minute. Data are presented
as mean  standard error of themean; *, Significant effect of intervention, P < .05 (repeated measures analysis of variance).

E. Jovanovski et al. / Journal of the American Society of Hypertension 8(8) (2014) 537–541

BPM, beats per minute; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure; SD, standard deviation.
All values expressed as mean  SD. Measured values at 60 min, 120 min, and 180 min are expressed as change from baseline (0 min).
* Effect of treatment  time interaction of interventions, two-way repeated measures analysis of variance.
yDifferent from control, repeated measures analysis of variance (P < .05).

3.28  7.9y
5.04  5.5y
4.84  6.9y
5.71  7.9y
5.06  5.9y
5.53  6.2y
1.13  7.7
1.50  8.7
1.09  7.4
1.48  5.6
0.42  5.4
0.75  6.9
1.13  6.0
0.74  6.4
0.72  5.8
4.49  7.0
1.87  7.4
1.74  3.6
2.16  4.0y
2.45  6.9
2.83  4.5
2.77  4.4
1.71  7.8
7.47  6.4
0.52  7.5
0.26  5.5
0.07  5.7
0.64  7.6
0.75  5.1
0.98  5.4
0.50  5.5
7.70  5.0
3.04  8.9
0.93  3.6
1.87  4.6
2.78  7.5
1.74  3.7
2.10  4.6y
1.16  5.9
6.20  6.4
2.04  6.6
0.78  3.7
0.86  4.1
1.34  6.5
0.41  4.0
0.82  6.6
0.37  4.9
6.21  3.5
113.30  15.0
68.96  9.2
83.54  10.2
99.9  11.7
70.6  10.1
79.8  9.8
29.90  6.3
66.47  11.7
Outcome Measure
Brachial SBP (mm Hg)
Brachial DBP (mm Hg)
Brachial MAP (mm Hg)
Central SBP (mm Hg)
Central DBP (mm Hg)
Central MAP (mm Hg)
Central PP (mm Hg)
Heart Rate (BPM)

112.59  16.6
69.67  10.3
84.12  11.6
100.2  14.5
71.1  10.5
80.8  11.5
28.86  7.6
65.06  13.4

Control
Treatment

Ginseng

Control

Ginseng

Control

Ginseng

Control

Ginseng

.14
.02
.01
.04
.04
.01
.44
.05

P Value*
180 min
120 min60 min0 min
TimeTable 1
Mean hemodynamic values (SD) at baseline and change from baseline in 23 healthy participants administered in a random sequence, 400 mg of Rg3-enriched Korean red ginseng
or 400 mg wheat bran control, in a crossover design

540

supports preclinical literature that orally ingested Rg3 ginsenosides may, in part, be the vasoactive components
responsible for acute benefits. Among the major ginsenosides, ginsenoside Rg3 demonstrated the greatest potency
in inducing an endothelium dependent relaxation in the
rat aorta.11,12 Pharmacokinetic study of 20 (R) ginsenoside
Rg3 time–concentration curves in a two-compartment openmodel suggested a half-life a of 0.46 hours and half-lifeb of 4.9 hours, therefore a rapid absorption and eliminationof Rg3.18 This is the first trial in humans to study hemodynamics of the concentrations of ginsenoside Rg3 at w30
times those present in the natural root. In our preceding trial
with unenriched KRG, a similar effect on AIx was observed
although the magnitude of hemodynamic effect was to alesser extent.5 Such acute improvements in vascular indiceshave not been observed to date in clinical trials examining
unenriched Panax ginseng roots, which demonstrated variable vascular effects.4,5,19
The effects on pulse wave morphology, and AIx inparticular, observed after Rg3-KRG administration may
be attributed not only to modification of viscoelastic properties of the aorta and large arteries, but also to improvement in reflective properties of the peripheral arteries.
Given the acute nature of this trial, it is plausible to inferthat the effect of our interventions was related to the alteration of vascular resistance features rather than changes inaortic wall properties.
The efficacy of the Rg3-KRG contributes to a growing
field of clinical evidence targeted toward stepwise screening
and fractionation of potentially bioactive components inginseng. This is contrary to the uncontrolled, observational
study of high public impact, conducted by Siegel20 in 1979
that contraindicated ginseng in hypertension. The study bySiegel20 and other studies in which the ginseng species andproduct composition are not reported highlight the need foradequate characterization of study material and methods,
so that findings may be reproduced and corroborated or challenged. The use of efficacy-based standardized preparations
in ginseng research, exemplified here, is a prerequisite stepin the formulation of guidelines controlling its consumption
and component-based recommendations for its use.
The strength of this study includes a crossover design
and the stringent inclusion criteria of healthy individuals
with no concomitant medications, both of which reduced
potential variability in treatment effect. We opted to usean acute phase I-like type, rather than chronic trial design
given the uncertainty of the effect of Rg3-KRG on hemodynamics in humans and in the duration that allowed us toabstain from potential confounding effects of meal administration. However, this clinical trial of acute design should
be used to provide experimental basis for further investigations. A dose–response relationship, corroborated by functional arterial markers including circulating biomarkers of
the nitric oxide synthesis pathway, should be establishedin the background of a longer scale trial using Rg3-KRG.

E. Jovanovski et al. / Journal of the American Society of Hypertension 8(8) (2014) 537–541

Conclusion
This study contributes to the growing body of evidence
from clinical trials on the hemodynamic effects of ginseng
and its isolates. Although other studies are required to see if
this effect can be reliably repeated, in addition to longer
term trials, this study provides evidence that in healthy individuals, an Rg3-KRG supplement may be considered a
viable possibility in the armamentarium of proactive
CVD risk management strategies.

References
1. Chobanian AV, Bakris GL, Black HR, Cushman WC,
Green LA, Izzo J, et al. Seventh report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–52.
2. Eliasson B, Cederholm J, Nilsson P, Gudbj€
ornsd
ottir S.
The gap between guidelines and reality: type 2 diabetes
in a national diabetes register 1996-2003. Diabet Med
2005;22(10):1420–6.
3. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality
with arterial stiffness. A systematic review andmeta-analysis. J Am Coll Cardiol 2010;55(13):1318–27.
4. Mark Stavro P, Woo M, Vuksan V. Korean red ginseng
lowers blood pressure in individuals with hypertension.
Am J Hypertens 2004 May;17(5, Supplement):S33.
5. Jovanovski E, Jenkins A, Dias AG, Peeva V,
Sievenpiper J, Arnason JT, et al. Effects of Korean
red ginseng (Panax ginseng C.A. Mayer) and its isolated ginsenosides and polysaccharides on arterial stiffness in healthy individuals. Am J Hypertens 2010;23(5):469–72.
6. Vuksan V, Sung MK, Sievenpiper JL, Stavro PM,
Jenkins AL, Di Buono M, et al. Korean red ginseng(Panax ginseng) improves glucose and insulin regulation in well-controlled, type 2 diabetes: results of a randomized, double-blind, placebo-controlled study ofefficacy and safety. Nutr Metab Cardiovasc Dis 2008;
18(1):46–56.
7. Rhee MY, Kim YS, Bae JH, Nah DY, Kim YK,
Lee MM, et al. Effect of Korean red ginseng on arterial
stiffness in subjects with hypertension. J Altern Complement Med 2011;17(1):45–9.
8. Park BJ, Lee YJ, Lee HR, Jung DH, Na HY, Kim HB, et al.
Effects of Korean red ginseng on cardiovascular risks
in subjects with metabolic syndrome: a double-blind541

randomized controlled study. Korean J Fam Med 2012;
33(4):190–6.
9. Christensen LP. Chapter 1 Ginsenosides chemistry,biosynthesis, analysis, and potential health effects. Taylor SL, editor. 55, 1–99. 2008.
10. Kim ND, Kang SY, Schini VB. Ginsenosides evoke
endothelium-dependent vascular relaxation in rat aorta.
GEN PHARMACOL 1994;25(6):1071–7.
11. Kim ND, Kang SY, Park JH, Schini-Kerth VB. Ginsenoside Rg3 mediates endothelium-dependent relaxationin response to ginsenosides in rat aorta: role of Kþ
channels. Eur J Pharmacol 1999;367(1):41–9.
12. Kim ND, Kim EM, Kang KW, Cho MK, Choi SY,
Kim SG. Ginsenoside Rg3 inhibits phenylephrineinduced vascular contraction through induction of nitricoxide synthase. Br J Pharmacol 2003;140(4):661–70.
13. Ham WS, Kim WT, Lee JS, Ju HJ, Kang SJ, Oh JH,
et al. Efficacy and safety of red ginseng extract powderin patients with erectile dysfunction: multicenter, randomized, double-blind, placebo-controlled study.
Korean J Urol 2009;50(2):159–64.
14. Shahin Y, Khan JA, Chetter I. Angiotensin converting
enzyme inhibitors effect on arterial stiffness and wave
reflections: a meta-analysis and meta-regression of
randomised controlled trials. Atherosclerosis 2012;
221(1):18–33.
15. Wang KL, Cheng HM, Sung SH, Chuang SY, Li CH,
Spurgeon HA, et al. Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study.
Hypertension 2010;55(3):799–805.
16. Weber T, Auer J, O’Rourke MF, Kvas E, Lassnig E,
Berent R, et al. Arterial stiffness, wave reflections,and the risk of coronary artery disease. Circulation
2004;109(2):184–9.
17. Williams B, Lacy PS, Thom SM, Cruickshank K,
Stanton A, Collier D, et al. Differential impact of bloodpressure-lowering drugs on central aortic pressure andclinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation
2006;113(9):1213–25.
18. Pang H, Wang HL, Fu L, Su CY. Pharmacokinetic
studies of 20(R)-ginsenoside RG3 in human volunteers.
Yao Xue Xue Bao 2001;36(3):170–3.
19. Stavro PM, Woo M, Heim TF, Leiter LA, Vuksan V.
North American ginseng exerts a neutral effect onblood pressure in individuals with hypertension. Hypertension 2005;46(2):406–11.
20. Siegel RK. Ginseng abuse syndrome. Problems withthe panacea. JAMA 1979;241(15):1614–5.