The results of two acute placebo-controlled, double-blind cross-over studies assessing the effect of Panax ginseng (G115) on blood glucose levels are reported. In study 1, thirty participants received three treatments: placebo; 200 mg G115; 400 mg G115. In study 2, twenty-seven participants received four treatments: placebo (0 mg ginseng and 30 mg saccharin); ginseng (200 mg ginseng and 30 mg saccharin); placebo–glucose (0 mg ginseng and 25 g oral glucose); ginseng–glucose (200 mg ginseng and 25 g oral glucose). Blood glucose levels were measured at baseline (at 09.00 hours after an overnight fast) and then 60, 90 (study 1 only) and 120 min post-dose. Both studies demonstrated that G115 alone significantly lowers fasting blood glucose levels. Conversely, in study 2 there was a significant drink × ginseng interaction suggesting opposing glycaemic effects of ginseng under fasting and raised blood glucose conditions. These data have implications for the use of ginseng in individuals with poor gluco-regulation

Kennedy, David

Reay, Jonathon

Scholey, Andrew

English

Reay, J. L.

Kennedy, D. O.

Scholey, A. B.

Teesside University Research

The glycaemic effects of single doses of Panax ginseng in young healthy volunteers

The results of two acute placebo-controlled, double-blind cross-over studies assessing the effect of Panax ginseng (G115) on blood glucose levels are reported. In study 1, thirty participants received three treatments: placebo; 200 mg G115; 400 mg G115. In study 2, twenty-seven participants received four treatments: placebo (0 mg ginseng and 30 mg saccharin); ginseng (200 mg ginseng and 30 mg saccharin); placebo-glucose (0 mg ginseng and 25 g oral glucose); ginseng-glucose (200 mg ginseng and 25 g oral glucose). Blood glucose levels were measured at baseline (at 09.00 hours after an overnight fast) and then 60, 90 (study 1 only) and 120 min post-dose. Both studies demonstrated that G115 alone significantly lowers fasting blood glucose levels. Conversely, in study 2 there was a significant drink × ginseng interaction suggesting opposing glycaemic effects of ginseng under fasting and raised blood glucose conditions. These data have implications for the use of ginseng in individuals with poor gluco-regulation.</p

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Short CommunicationThe glycaemic effects of single doses of Panax ginseng in young healthyvolunteersJ. L. Reay, D. O. Kennedy and A. B. Scholey*Human Cognitive Neuroscience Unit, Division of Psychology, Northumbria University, Newcastle upon Tyne NE1 8ST, UK(Received 8 November 2005 – Revised 6 June 2006 – Accepted 6 June 2006)The results of two acute placebo-controlled, double-blind cross-over studies assessing the effect of Panax ginseng (G115) on blood glucose levelsare reported. In study 1, thirty participants received three treatments: placebo; 200 mg G115; 400 mg G115. In study 2, twenty-seven participantsreceived four treatments: placebo (0 mg ginseng and 30 mg saccharin); ginseng (200 mg ginseng and 30 mg saccharin); placebo–glucose (0 mgginseng and 25 g oral glucose); ginseng–glucose (200 mg ginseng and 25 g oral glucose). Blood glucose levels were measured at baseline (at09.00 hours after an overnight fast) and then 60, 90 (study 1 only) and 120 min post-dose. Both studies demonstrated that G115 alone significantlylowers fasting blood glucose levels. Conversely, in study 2 there was a significant drink £ ginseng interaction suggesting opposing glycaemiceffects of ginseng under fasting and raised blood glucose conditions. These data have implications for the use of ginseng in individuals withpoor gluco-regulation.Panax: Ginseng: Acute: Placebo: Blood glucose: Hypoglycaemia: Healthy adultsThe number of diagnosed diabetes sufferers continues to riseexponentially (Mokdad et al. 2003) and the currently availablearmamentarium is insufficient to halt the disease progression.The majority of type 2 diabetes patients eventually requireinsulin therapy (Turner et al. 2000), and it is estimated thatdiabetes is likely to be the fifth leading cause of death globally(Roglic et al. 2005). While the use of mainstream drugs isadvocated by some physicians, many patients are moreinclined toward the use of alternative therapies includingfood supplements and herbal medicines (Shane-McWorter,2005). Despite a lack of evidence for their safety and efficacy,the use of herbal products increased substantially through the1990s, with over 60 % failing to report the use of these pro-ducts to their physician (Eisenberg et al. 1998).‘Ginseng’ usually refers to the dried root of several speciesin the plant genus Panax (Araliaceae family). The most widelyused is Panax ginseng (G115), which is indigenous to the FarEast. Other members of the genus include Panax quinquefo-lius (American ginseng), Panax notoginseng and Panax japo-nicus. Ginseng is known to have gluco-regulatory properties.For example, a decrease in fasting blood glucose andHbA1c was reported in type 2 diabetic patients following 8weeks administration of a proprietary extract of Panax quin-quefolius, taken 40 min before each meal (Vuksan et al.2000b). Additionally, reductions in blood glucose levelswere reported during a standard oral glucose tolerance testin diabetic patients following 3, 6 and 9 g Panax quinquefoliusand in healthy participants administered 1, 2 and 3 g (Vuksanet al. 2000a,b, 2001). With regard to G115, reduced fastingblood glucose levels and glycated Hb (HbA1c) were foundfollowing 8 weeks administration to type 2 diabetic patients(Sotaniemi et al. 1995). Similarly, 24 months of treatmentwith G115 decreased HbA1c in type 2 diabetics (Tetsutaniet al. 2000). We report here the glycaemic results of twostudies that assessed the effects of single doses of G115 onblood glucose levels in healthy volunteers.MethodTwo separate placebo-controlled, double-blind, crossoverstudies were undertaken in healthy young adults. All partici-pants were recruited through university advertisement. Priorto participation each participant gave informed consent andcompleted a medical health questionnaire. All participantsreported that they were in good health, and that they werefree from heart disorders, high blood pressure, respiratory dis-orders, epilepsy, panic attacks and diabetes. Additionally, theyreported being free from ‘over the-counter’ treatments, illicitsocial drugs and prescribed medications, with the exception,for some female volunteers, of the contraceptive pill. All par-ticipants self-reported they were in an overnight fasting stateand were alcohol-free for at least 12 h prior to the 09.00*Corresponding author: Professor Andrew Scholey, fax þ44 (0)191 227 3190, email a.scholey@unn.ac.ukAbbreviation: G115, Panax ginseng.British Journal of Nutrition (2006), 96, 639–642 DOI: 10.1079/BJN20061904q The Authors 2006hours baseline blood glucose measurements (which were allconsistent with expected overnight fasting blood glucoselevels in healthy volunteers). Both studies were approved bythe Northumbria University Division of Psychology EthicsCommittee and conducted in accordance with the Declarationof Helsinki.In study 1, sixteen female and fourteen male participants(mean age 22·6 (SD 5·46) years) received 200 mg ginseng,400 mg ginseng and placebo on separate days. In study 2,ten female and seventeen male participants (mean age21·89 (SD 4·64) years) received four treatments: placebo(0 mg G115 and 30 mg saccharin), ginseng (200 mg G115and 30 mg saccharin), placebo–glucose (0 mg G115 and25 g oral glucose) and ginseng–glucose (200 mg G115 and25 g oral glucose) on separate days. Participants in thesecond study received their capsule treatment (200 mgG115 or 0 mg G115) at time-point zero and then 30 minlater, a 200 ml drink (20 ml sugar-free fruit cordial and180 ml tap water) containing 25 g glucose or 30 mg saccharin.The timing of administration of each treatment was selectedon the basis that ginseng’s gluco-regulatory effects are evi-dent within 1 h of administration while glucose levels peakat around 30 min post-ingestion. In both studies, treatmentswere separated by a 7 d washout period and were counterba-lanced across participants and days. Capillary blood glucoselevels were measured at baseline then 60 min, 90 min(study 1 only) and 120 min post-dose (in study 2 the timingswere calculated from the ingestion of the ginseng or placebocapsule treatment) utilising a Reflotron Plus diagnosticmachine and test sticks (Roche Diagnostics, Mannheim,Germany). The reliability of the test has previously been con-firmed (Price & Koller, 1988).ResultsStatisticsPrior to analysis of ‘change from baseline’ data, raw baselinescores for the three treatment conditions (placebo, 200 mg,400 mg) in study 1 and for all four treatment conditions in study2 (placebo, ginseng, placebo–glucose, ginseng–glucose)were subject to one-way repeated measures ANOVA usingthe Minitab statistical package version 13.1 (Minitab Ltd,Coventry, UK).‘Change from baseline’ post-dose blood glucose levelswere analysed using the Minitab statistical package version13.1. Following an initial repeated measures ANOVA(study 1, treatment £ time of blood sample; study 2,ginseng £ drink £ time of blood sample) a priori plannedcomparisons were made between placebo and each of theactive treatments (200 and 400 mg G115) at each time-pointutilising t tests with MSError as an error term (Keppel,1991). To ensure the overall protection level against Type Ierror, comparisons were strictly planned prior to commence-ment of the study, only probabilities associated with plannedcomparisons were calculated, all planned comparisons weretwo-tailed.BaselineThere were no significant differences in baseline blood glu-cose levels revealed in study 1 (F(2,58) 2·66, P¼0·08) norstudy 2 (F(3,78) 2·25, P¼0·09) (see Table 1).Study 1The initial repeated measure ANOVA (treatment £ time ofblood sample) revealed a significant main effect of treatmenton blood glucose level (F(2,116) 3·59, P¼0·034), but therewas no significant treatment £ time-point interaction (F(4,116)1·49, P¼0·210). Planned comparisons comparing each treat-ment to placebo at each time-point revealed that there weresignificant reductions in blood glucose levels for both ginsengtreatments at all post-dose time-points relative to placebo(Table 1): 200 mg led to reductions at 1 h post-dose (t1163·31, P¼0·001), after 90 min (t116 3·65, P¼0·0003) and120 min post-dose (t116 2·58, P¼0·01). The 400 mg treatmentalso led to reductions at 1 h post dose (t116 3·42, P¼0·0007),after 90 min (t116 3·57, P¼0·0004) and 120 min post-dose(t116 5·50, P¼0·0000001).Table 1. The effects of Panax ginseng (G115) on capillary blood glucose levels in healthy human volunteers‡(Mean values with their standard errors)Pre-dose baselineblood glucose level(mmol/l)Post-dose change from baseline blood glucose level (mmol/l)60 min 90 min 120 minMean SEM Mean SEM Mean SEM Mean SEMStudy 1 (n 30)Placebo 5·336 0·211 20·076 0·248 0·034 0·258 0·013 0·216200 mg G115 5·681 0·159 20·646*** 0·176 20·594*** 0·198 20·432* 0·182400 mg G115 5·939 0·996 20·664*** 0·214 20·580*** 0·212 20·933*** 0·213Study 2 (n 27)Placebo 5·229 0·125 20·198 0·126 20·721 0·114200 mg G115 5·462 0·112 20·630††† 0·096 20·708 0·121Glucose (25 g drink) 5·338 0·153 1·739††† 0·206 20·923 0·156G115–glucose 5·077 0·122 1·980††† 0·268 20·603 0·151Mean values were significantly different from those of the study 1 placebo group: *P,0·05; ***P,0·001.Mean values were significantly different from those of the study 2 placebo group: †††P,0·001.‡ For details of procedures, see p. 639.J. L. Reay et al.640Study 2A repeated measure ANOVA (ginseng £ drink £ time ofblood sample) revealed a significant ginseng £ drink interactionon capillary blood glucose levels (F(1,26) 5·26,P¼0·03). The pat-tern of results, taken across the two post-dose measurements,suggests that the co-administration of ginseng with glucoseserved to further increase blood glucose levels (mean of bothtime-points 0·688 mmol/l) as compared with glucose alone(mean 0·407 mmol/l). Conversely, in the absence of a glucosedrink ginseng serves to further reduce blood glucose levels(mean 20·669 mmol/l) as compared with the saccharin con-dition (mean 20·458 mmol/l).Planned comparisons, comparing each treatment with pla-cebo at each time-point, revealed that the ingestion of oral glu-cose alone (placebo–glucose condition; t26 9·40, P,0·001)and in combination with 200 mg ginseng (ginseng–glucosecondition; t26 10·570, P,0·001) led to significantly increasedblood glucose levels at the 1 h post-dose measurement pointcompared with placebo (Table 1). There were no significantdifferences between the placebo–glucose and ginseng–glu-cose conditions on blood glucose levels. However, followingthe ingestion of ginseng alone (ginseng–placebo condition),blood glucose levels were significantly reduced 1 h post-dose(t26 2·096, P¼0·046).DiscussionBoth study 1 and study 2 demonstrated that a single acute doseof G115 can significantly lower blood glucose levels inhealthy, overnight fasted volunteers. Additionally, study 2revealed a significant interaction between the administrationof 25 g oral glucose drink and 200 mg ginseng. This significantpattern of results suggests that in the absence of a glucose load(i.e. in overnight fasting participants) a single dose of G115(200 mg) resulted in a post-dose fall in circulating blood glu-cose levels, relative to placebo. However, in the presence ofelevated glucose levels following an oral glucose drink, theco-administration of ginseng was associated with furtherraised blood glucose levels, relative to the glucose condition,although no significant increase was revealed at any individualtime-point on the planned comparisons, relative to theglucose condition. Both study 1 and study 2 are indicativeof G115’s gluco-modulating properties in young non-diabeticparticipants.It should be noted that in both studies baseline differenceswere not significant; however, there was a trend for significantdifferences (0·05 , P,0·1) in both studies. While it is feas-ible that this may have contributed to the magnitude of thetreatment effects observed in study 1, where treatment effectstended to be in the opposite direction to initial conditioneffects, this was not the case for study 2. Therefore, it appearsthat the present data represent real physiological effects ofG115 rather than a reflection of chance baseline differencesbetween the conditions. Clearly further replication of the pre-sent findings are needed, as is more research directed at deli-neating the glycaemic properties of G115 in healthy andpatient populations.The present results are dissimilar to the recently reportedhypoglycaemic effects of a different ginseng species, Panaxquinquefolius, during standard oral glucose tolerance tests inboth diabetic and healthy participants (Vuksan et al.2000a,b, 2001) and are inconsistent with two reports ofG115 being associated with significantly increased blood glu-cose levels and insulin responses following a 75 g glucose load(Sievenpiper et al. 2003, 2004) suggesting that differentPanax species produce differing glycaemic responses. Withregard to American ginseng (Panax quinquefolius), Vuksanet al. (2000a) have suggested three possible mechanisms:modulation of glucose disposal, glucose transport or insulinsecretion. The three are not mutually exclusive and the lattertwo may both be mediated by increased NO production(Roy et al. 1998; Spinas et al. 1998). The mechanisms respon-sible for the glycaemic effects of Korean ginseng reportedhere may reflect similar processes possibly with differentlevels of insulin receptor binding reversibility (although thebiological plausibility of this speculative idea remains to beinvestigated). The exact processes affected by this herbalextract remain unknown and may reflect complex additive orsynergistic effects on several physiological systems involvedin gluco-regulation (see Scholey et al. 2005). Until furtherresearch has delineated the mechanisms underlying ginseng’sgluco-regulatory effects, generalisations should not be madebetween the effects of different ginseng species. Sufferersfrom diabetes and similar conditions should exercise cautionin the use of ginseng products.ReferencesEisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, VanRompay M & Kessles RC (1998) Trends in alternative medicineuse in the United States, 1990–1997: result of follow-up nationalsurvey. JAMA 280, 1569–1575.Keppel G (1991) Design and Analysis. Upper Saddle River, NJ:Prentice Hall.Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS& Marks JS (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors. JAMA 289, 76–79.Price CP & Koller PU (1988) A multicentre study of the new Reflo-tron system for the measurement of urea, glucose, triacylglycerols,cholesterol, gamma glutamyltransferase and haemoglobin. J ClinChem Clin Biochem 26, 233–250.Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S,Connolly V & King H (2005) The burden of mortality attributableto diabetes. Diabetes Care 28, 2130–2135.Roy D, Perrault M & Marette A (1998) Insulin stimulation of glucoseuptake in skeletal muscle and adipose tissue in vivo is NO depen-dent. Am J Physiol 274, E692–E699.Scholey A, Kennedy D & Wesnes K (2005) The psychopharmacologyof herbal extracts: issues and challenges. Psychopharmacology179, 705–707.Shane-McWorter L (2005) Botanical dietary supplements and thetreatments of diabetes; what is the evidence? Curr Diabet Rep 5,391–398.Sievenpiper J, Arnason JT, Leiter LA & Vuksan V (2003) Null andopposing effects of Asian ginseng (Panax ginseng C.A. Meyer)on acute glycemia: results of two acute dose escalation studies. JAm Coll Nutr 22, 524–532.Sievenpiper J, Arnason JT, Leiter LA & Vuksan V (2004) Decreasingnull and increasing effects of eight popular types of ginseng onacute postprandial glycemic indices in healthy humans: the roleof ginsenosides. J Am Coll Nutr 23, 248–258.Sotaniemi EA, Haapakoski E & Rautio A (1995) Ginseng therapy innoninsulin diabetic patients. Diabetes Care 18, 1373–1375.Glycaemic effect of Panax ginseng 641Spinas GA, Laffranchi R, Francoys I, David I, Richter C &Reinecke M (1998) The early phase of glucose-stimulated insulinsecretion requires nitric oxide. Diabetologia 41, 292–299.Tetsutani T, Yamamura M, Yamaguchi T, Onoyama O & Kono M(2000) Can red ginseng control blood glucose in diabetic patients?Ginseng Rev 28, 44–47.Turner RC, Cull CA, Frighi V & Holman RR (2000) Glycemic con-trol with diet, sulfonylurea, metformin, or insulin in patients withtype 2 diabetes mellitus: progressive requirement for multipletherapies (UKPDS 49), UK Prospective Diabetes Study (UKPDS)group. JAMA 281, 2005–2012.Vuksan V, Sievenpiper JL, Koo VYY, Francis T, Beljan-Zdravkovic U,Xu Z & Vidgen E (2000) American ginseng (Panax quinquefolius L)reduces postprandial glycemia in nondiabetic subjects and subjectswith type 2 Diabetes Mellitus. Arch Intern Med 160, 1009–1013.Vuksan V, Sievenpiper JL, Wong J, Xu Z, Beljan-Zdravkovic U,Arnason JT, Assinewe V, Stavro MP, Jenkins AL, Leiter LA &Francis T (2001) American ginseng (Panax quinquefolius L.)attenuates postprandial glycemia in a time-dependent but notdose-dependent manner in healthy individuals. Am J Clin Nutr73, 753–758.Vuksan V, Xu Z, Jenkins AL, Beljan-Zdravkovic U, Sievenpiper JL,Leiter LA, Josse RG & Strvro MP (2000) American ginsengimproves long term glycaemic control in type two diabetes:double blind placebo controlled crossover trial. Diabetes 49,Suppl. 1, A95 (abstract).J. L. Reay et al.642

A multicentre study of the new Reﬂotron system for the measurement of urea, glucose, triacylglycerols, cholesterol, gamma glutamyltransferase and haemoglobin.

American ginseng (Panax quinquefolius L.) attenuates postprandial glycemia in a time-dependent but not dose-dependent manner in healthy individuals.

American ginseng improves long term glycaemic control in type two diabetes: double blind placebo controlled crossover trial.

Botanical dietary supplements and the treatments of diabetes; what is the evidence?

Can red ginseng control blood glucose in diabetic patients?

Decreasing null and increasing effects of eight popular types of ginseng on acute postprandial glycemic indices in healthy humans: the role of ginsenosides.

Design and Analysis. Upper Saddle River,

Glycaemic effect of Panax ginseng 641Spinas

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies

Haapakoski E & Rautio A

Marette A

Null and opposing effects of Asian ginseng (Panax ginseng C.A. Meyer) on acute glycemia: results of two acute dose escalation studies.

Prevalence of obesity, diabetes, and obesityrelated health risk factors.

The burden of mortality attributable to diabetes.

The psychopharmacology of herbal extracts: issues and challenges.

Trends in alternative medicine use in the United States, 1990–1997: result of follow-up national survey.

The glycaemic effects of single doses of Panax ginseng in young healthy volunteers

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