Why is it important to use biologically standardizaed goldenseal?

This work was supported by Grant # 2R44AT003365-02 from the National Institutes of Health/National Center for Complementary and Alternative Medicine to Botanipharm, LLC.  The opinions expressed herein are the Author’s and do not necessarily represent those of the NIH.

Goldenseal, yellow root, Indian puccoon, whatever you call it Hydrastis canadensis is well recognized as one of the most important botanical options available to the natural health care practioner yet many have been have been reluctant to recommend its use due to its endangered status.  Botanipharm, LLC is a 100% grower owned cooperative formed with the purpose of sustainably cultivating goldenseal and producing the highest quality goldenseal products possible thereby relieving pressure on native populations and providing a “guilt-free” alternative to wild collected goldenseal.

This discussion seeks to present information developed through our NCCAM funded research which indicates the currently accepted method of measuring  goldenseal potency proportional to alkaloid content is not reliable. 

IF berberine/hydrastine were the only active compounds in the plant AND there were no inactive compounds that synergized with the actives then this method might be valid.  However, the reality is goldenseal contains hundreds of compounds and to attempt to predict its activity based on the concentration of a few of those compounds just doesn’t make sense.   While chemical markers are necessary for species identification, from a biological activity perspective, goldenseal should be viewed as a single very complex compound and its activity measured and standardized according to the intended use.  The data below illustrates the reasoning behind this assertion.

(Data produced by Dr. Jeremy Tzeng and staff, Clemson University)

Liquid extracts of goldenseal root and leaf were individually assayed as well as three combinations of root and leaf.  The results were compared with a berberine sulfate reference standard and a known antibiotic, ciprofloxacin. The Minimum Inhibitory Concentration (MIC) of each against various digestive tract microflora is shown as well as the amount of berberine contained in each of the goldenseal samples.

Clearly the activity of goldenseal against the selected organisms could not have been accurately predicted based solely on the berberine content or, total alkaloid content for that matter.  Note that in the H. pylori assay, the MIC of goldenseal root and leaf were equal yet the leaf contained only about ¼ as much berberine as the root and roughly 1/5 as much as the berberine standard.

In the case of Shigella, the MIC of the 2:2 ratio was equal to the MIC of the berberine standard even though the 2:2 ratio only contained about 1/10th as much berberine.  The root only sample (4:0) required 345% more berberine to produce the same level of activity as the 2:2 ratio.

Also, please note the Staph. aureus assays.  Strain 1199 is wild type Staph. and 1199B is a selected multi-drug resistant (MDR) strain that overexpresses the Nor A efflux pump.  The MDR strain requires 32 times more Cipro to inhibit its growth compared to the wild strain while the MIC of goldenseal leaf is equal for both strains.  Even more surprising was the observation that when crude goldenseal leaf extract was added to the Cipro MDR assay, the MIC returned to the same level as the wild type (data not shown).

Clearly, something in goldenseal leaf was having a profound effect on Staph. drug resistance.    Our collaborators at UIC and OSU identified at least two new compounds in goldenseal leaf/stem (Colburn, 2007) which had no inhibitory activity when used alone but synergized with other active compounds such as berberine and cipro to increase the active’s effectiveness.  This discovery was later confirmed by others (Junio, 2009, Ettefagh, 2010).  Similar synergy was observed in anti-proliferative assays against stomach and colon cancer cell types.

Another example, in 2006, researchers from the Veteran’s Administration published a ground breaking article in the Journal of Lipid Research titled The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms (Abidi, 2006).  The team reported that goldenseal had an upregulation and stabilizing effect on Low Density Lipoprotein Receptor messenger RNA (LDLR mRNA) similar to that of statin drugs but worked through a different mechanism potentially avoiding undesirable side effects of statins.  They also identified canadine and two other compounds as being more potent than berberine and contributing to the observation that goldenseal root extract was more potent than an equivalent quantity of berberine.

When this article was published, I immediately contacted the Principal Investigator on the project, Dr. Jingwen Liu, and ask her to collaborate with our NIH studies.  She agreed and I sent samples to her lab where they were compared with the activity of the material used to produce data for the article.    Expecting to see similar synergies between the root and leaf as we had seen in the anti-microbial assays, the resulting data was both a surprise and very enlightening.

Note the chart above.  The first data bar to the left was a control with no activity.  The next three bars (HC1, HC2. and HC3) are goldenseal leaf extract at doses of 1 µl.5 µl, and 5 µl, none of which had significant effect at berberine concentrations of up to 3.35 µg.  HC4, HC5, and HC6 are goldenseal root extracts at the same doses as listed for the leaf.  Root sample HC5 had a berberine concentration (3.83 µg) similar to leaf sample HC3 (3.35 µg) yet leaf sample HC3 was inactive while root sample HC5 exhibited activity equal to almost four times as much berberine (15 µg).  HC6 had twice as much berberine as HC5 but its activity was essentially the same as both HC5 and 15 µg berberine. 

The most surprising result was HC7.  HC7 was a 50/50 combination of goldenseal root and leaf.  Not only was the synergy not evident, the addition of leaf to the formulation completely negated the beneficial effect of the root. 

So, what does all this mean?? 

Just because goldenseal product A has twice as much alkaloid content as goldenseal product B, it doesn’t mean product A is more potent.  The idea that, if X is good, 2X is better, is not applicable to goldenseal.  There is limit to the amount of berberine required to produce activity and anything over that is superfluous.

It is also evident that no single goldenseal formulation is appropriate for every indication.  A product that is optimal from an antimicrobial perspective would likely have little effect in maintaining healthy cholesterol levels. 

Bottom Line, the current industry method of evaluating the potential beneficial effects and/or potency of a goldenseal product based solely on the alkaloid content is not reliable.  

There has to be a better way. 

Albert Einstein once commented “things should be made as simple as possible, but no simpler”.  It seems industry has oversimplified goldenseal by attempting to characterize its potency based on a single compound or even a group of compounds.  It kind of like trying to evaluate an orchestra’s performance of Beethoven’s Fifth Symphony based on just the brass section.  You get the gist of the music but you have the feeling something is missing!!

Just as a full orchestra is best heard as a single entity, so should goldenseal be viewed as a single, very complex chemical compound and evaluated in assays relevant to the intended use.  Without question, individual chemical markers are necessary for identity verification however, as the above data suggests, quantifying those compounds does not necessarily reflect product potency due to the presence of other known/unknown active compounds which are not quantified as well as inactive compounds that synergize with the actives.

It is not possible, using current technology, to determine an exact combination of chemical markers in goldenseal to account for its observed activity.  The number of assays required to test all possible combinations would be astronomical.  One outcome of our NIH work has been the development of a method of standardizing goldenseal bioactivity based on the hypothesis that berberine is in its least effective, most toxic form when isolated from the whole plant matrix.  If this hypothesis were true then it would be possible to assay the activity of the whole plant and compare that activity with a known standard.

The process developed evaluates a goldenseal product through a series of 12 bioassays relevant to digestive tract function (or other assays appropriate to the intended application).  These assays look at both beneficial and potentially toxic effects and include anti-microbial effects against both pathogenic and beneficial  microorganisms, anti-proliferative effect against abnormal and normal intestinal lining cells, anti/pro-inflammatory responses, and mutigenicity. 

The activity of isolated berberine is well documented therefore it serves as standard of activity across a broad range of assays.  By comparing the activity of a goldenseal product with that of the berberine standard (or any other relevant standard) across these assays then standardizing the product so that its activity is indexed to that of berberine, i.e., 0.5, 1.0, or 1.5 times the standard, a meaningful statement can be developed and product potency accurately predicted.    Instead of a product label stating each serving contains X amount of berberine, a better way of expressing product potency would be each serving delivers bioactivity equivalent to X amount of berberine.

Up till this point, the conversation has focused on the potential beneficial functions of goldenseal but what about potential toxicity compared to berberine?  Please go back to the MIC data chart above and note the Lactobacillus acidophilus assay.  Both berberine sulfate and ciprofloxacin inhibited L. acidophilus at about the same concentration as that required to inhibit wild Staph.  However, no goldenseal formulation exhibited inhibitory activity on L. acidophilus even at eight times the concentration required to inhibit Staph.   More importantly, goldenseal exhibited a protective effect to friendly bacteria in that berberine concentrations in the goldenseal formulations were as much as 50% greater than the L. acidophilus MIC of isolated berberine sulfate and there was still no inhibition.

In fact, by comparing the overall result of the potentially toxic assays of goldenseal with those of the berberine standard it becomes possible to calculate the efficiency of goldenseal in delivering bioactivity.  In other words, if the increase in activity is accompanied by a corresponding or greater increase in potentially toxic effects then nothing was gained.  Without presenting another round of data here suffice it to say our results indicated that a properly formulated goldenseal product can deliver activity equal to a similar amount of berberine with as much as a 93% reduction in potential toxic effects.

The NIH review panel commented that this method of evaluating goldenseal product performance “may become an industry standard for future standardization protocols”.  The future is here now. Botanipharm’s Goldenseal Advanced™ Organic Liquid Dietary Supplements are the first goldenseal products to be standardized to biological activity and represent the ultimate in goldenseal product performance and reliability.  Best of all, they are the result of more than 10 years research and development by a group of small family operated farms in GA, AL, TN, and NC.

We invite you to partner with us in spreading the word that exceptionally high quality, sustainably produced goldenseal products are now available.   In doing so, you will support our efforts to increase goldenseal cultivation on small farms as well as providing your clients with the healing qualities only Pure, Organic, Goldenseal can provide!!

Randy and Cindi Beavers own/operate Sleepy Hollow Herb Farm (www.sleepyhollowherbfarm.com) in Dalton, GA where they have organically produced goldenseal and other forest medicinal plants since 1996. Randy was Author and Principal Investigator of a series of six Small Business Innovation Research Awards from the USDA focused on the sustainable development of goldenseal as a viable crop option for small family operated farms and two from the National Institutes of Health/National Center for Complementary and Alternative Medicine for development of research grade goldenseal products suitable for use in human clinical studies.  Randy and 10 other growers formed Botanipharm, LLC in 2007 as a vehicle for pooled grower production, cooperative processing, and marketing under a common brand name.

Citations

Abidi P, Chen W, Kraemer FB, Li H, Liu J, 2006. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms J Lipid Res. Oct;47(10):2134-47.

Coulburn J., Y-W. Chin, H. Parekh, S. Yildiz, R. Beavers, A.D. Kinghorn, and C.D. Wu, 2007.  Oral Antimicrobial Compounds from Hydrastis canadensis L. (Goldenseal) Leaves Proceedings of the  International Association of Dental Researchers, Miami, FL July, 2007

Junio, H.A., A. Sy-Cordero, N.H. Oberlies, T.N. Graf, and N.B. Cech, 2009. Non-alkaloidal compounds from goldenseal (Hydrastis canadensis) synergize the antibacterial activity of known alkaloidal constituents. in Proceedings of the 50th Meeting of the American Society of Pharmacognosy. Honoulu, HI, July 2009.

Ettefagh, K.A., J.T. Burnes, H.A. Junio, and N.B. Cech, 2010. Complex goldenseal (Hydrastis canadensis) leaf extracts exhibit synergistic antibacterial activity via efflux pump inhbition. in Proceedings of the 2010 Joint Annual Meeting of the American Society of Pharmacognosy & the Phytochemical Society of North America. Saint Petersburg, Florida, July 2010