Thursday, August 17, 2017

9/15 Berberine Supps (Names Included) on the US Market Contain More/Less Berberine Than the Label Says - Fraud?

Berberine is a yellow-colored alkaloid compound found in several different plants, including European barberry, goldenseal, goldthread, Oregon grape, Phellodendron, and tree turmeric.
Eventually, neither of the two insights from a recent paper in the Journal of Dietary Supplements can really surprise you: the majority of berberine supplements doesn't contain the amount of active ingredient that's on the label - 60% fail to land within the allowable margin of +/-10% and the more expensive "quality brands" are not better than the cheap ones, even if they had label claims of manufacturing under Good Manufacturing Practice (GMP) conditions in Food and Drug Administration inspected facilities, and guarantees purity and potency! In the real world, theory and practice, or, rather, labelled and real berberine content seem to diverge...
When timing matters, for berberine it's not well-researched, but...

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I am honestly (and positively) surprised that the study from the University of Kansas Medical Center does what only a small percentage of the already few studies that investigate the quality of dietary supplements do: it includes the actual product names.
Table 1: Fifteen commercial preparations of berberine available in the United States tested for product potency (Falk 2017).
All products are "berberine only"-products dosed at 400-500mg (according to the label ;-). As you can see in Table 1, the calculated average (± SD) monthly cost based on a dose of 800 to 1,000 mg/day for the preparations is $21.97 ± $9.18 and ranges from $8.48 to $47.40.
This is not the first study showing that berberine products, or goldenseal, one of its natural sources, don't live up to or significantly exceed their promises. In 2003 Edwards and Draper analyzed the hydrastine and berberine concentration in products labeled as containing goldenseal root and found that the former ranged from 0 to 2.93%, whereas the latter, i.e. the berberine concentration, varied from 0.82% to 5.86%. Furthermore, five products contained little or no hydrastine, unusual berberine:hydrastine ratios, and additional peaks not observed with other products. A similar range of concentrations was found by Brown et al. in 2008 who analyzed powdered botanical raw materials, whole root material, and 4 finished product dietary supplements containing either goldenseal powdered root material or extract and found values ranging from 0.2% (w/w) to about 4% (w/w) for each alkaloid. That's not surprising, though, we are, after all, dealing with a natural product. Apples don't have the same fructose content, either, and the fatty acid makeup of eggs will vary significantly; and you should be aware that this will be the case for non-batch-tested supplements, as well.
The actual analysis of the contents of three randomly chosen caps per supplement was conducted using a previously developed and evaluated UHPLC-MS/MS assay.
Figure 1: Percentage of berberine content based on the label claim in commercial preparations of berberine - data is presented as the average (± SD) of percentage of berberine based on the label claim (Funk 2017)
As the data in Figure 1 tells you, the average berberine content of the products was 75% ± 25% of the label claim. That doesn't make the product useless or dangerous per se, but as I will explain in the bottom line. This can be a serious problem.
Why would you even want to use berberine and how much do you need? Berberine is a proven AMPK promoter with multiple proven health benefits ranging from an anti-cancer effect (Sun 2009), and the ability to control type II diabetes just like metformin (Dong 2012), to its ability to keep your blood lipids in check without a statin (Dong 2013) and improving/maintaining your brain health - including potential anti-Alzheimer's effects (Ye 2009). With a bioavailability of ~33.6% with peak values being achieved after 2h and almost complete clearance from the bloodstream, effective dosages range from 0.2-1.5g per day - best taken with meals (which also reduces the risk of hypoglycemia) equally distributed over 24h. 
Furthermore, several products contain significantly less than the 90% of ingredient amounts on the label the FDA requires for pharmacological products - and that, as previously pointed out, even for products where the label informs you that they were produced under Good Manufacturing Practice (GMP) conditions in Food and Drug Administration inspected facilities. Going for the allegedly reputable and often most expensive producers is thus not necessarily a good idea; after all, the scientists' "[a]nalysis of product quality based on the average monthly cost failed to yield a significant relationship between quality and cost" (Funk 2017). In fact,
"[t]he average (± SD) cost of products containing at least 90% of the labeled berberine content was not significantly diļ¬€erent from products failing to meet the 90% potency standard ($27.21± $12.49 vs. $20.28± 5.34, respectively, p= .25). Similarly, Pearson’s pairwise analysis of potency, based on the label claim, and product monthly cost failed to yield a significant relationship between cost and quality (r = .17, p = .53)" (Funk 2017).
This "marked variability in the content of berberine among products avail able from U.S. manufacturers" is, in the authors' eyes, a problem: not because it violates the potency standards set forth by a supplement version of the USP Convention - a supplement equivalent of these requirements for pharmacological drugs does not exist, the variations in potency, Gershwin et al. (2010) and Sarma et al. (2016) observed for other supplements as well are thus not a legal problem, so that, from a legal perspective, the question from the headline, i.e. whether not matching the label claims 100% was fraud, must be answered with no - but because it may, according to Funk et al., pose a health threat.
Berberine works via AMPK, just like lipoic acid - accordingly, both share potentially relevant similar timing issues and could limit anabolism.
Health threat? Isn't that an exaggeration? Well, it depends. For the average consumer, it probably ain't a problem. With the ever-increasing number of studies that show that berberine could be used instead of metformin and/or on top of medical treatments for high blood glucose and/or lipids, some consumers may end with lower/higher levels of glucose or lipids in the blood when they (a) switch from one 500mg product to the other or (b) simply start a new bottle that was produced by the same manufacturer, but contains more/less of the active ingredient (note: I personally was afraid that the deviations from the label may be much larger and am relatively happy with the results, but I guess that's my personal disillusionment).

The last-mentioned possibility that the potency varies not just between products, but also from batch to batch, is also why I wouldn't rely too much on the data from the study at hand.  The next batch of supplement #9, the "best" supplement in this study, of which the authors rightly point out that it was limited "[p]rimarily" by the fact that they "analyzed the berberine content of one individual bottle from each manufacturer" (Funk 2017), may well contain significantly lower amounts of berberine than the one that was tested by Funk et al. for the study at hand. As previously hinted at, this is a general problem with dietary supplements. It's a problem you should know about, and one that disqualifies them as 1:1 replacement for medications, but not one that should make you shy away from supplements altogether, in my humble opinion | Comment!
  • Brown, Paula N., and Mark C. Roman. "Determination of hydrastine and berberine in goldenseal raw materials, extracts, and dietary supplements by high-performance liquid chromatography with UV: Collaborative study." Journal of AOAC International 91.4 (2008): 694-701.
  • Dong, Hui, et al. "Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis." Evidence-Based Complementary and Alternative Medicine 2012 (2012).
  • Dong, Hui, et al. "The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials." Planta medica 79.06 (2013): 437-446.
  • Edwards, David J., and Emily J. Draper. "Variations in alkaloid content of herbal products containing goldenseal." Journal of the American Pharmacists Association 43.3 (2003): 419-423.
  • Funk, R.S. et al. "Variability in Potency Among Commercial Preparations of Berberine." J Diet Suppl. 2017 Aug 9:1-9. doi: 10.1080/19390211.2017.1347227. [Epub ahead of print]
  • Gershwin, M. Eric, et al. "Public safety and dietary supplementation." Annals of the New York Academy of Sciences 1190.1 (2010): 104-117.
  • Sarma, Nandakumara, Gabriel Giancaspro, and Jaap Venema. "Dietary supplements quality analysis tools from the United States Pharmacopeia." Drug testing and analysis 8.3-4 (2016): 418-423.
  • Sun, Yiyi, et al. "A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs." Anti-cancer drugs 20.9 (2009): 757-769.
  • Ye, Minzhong, et al. "Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research." Journal of Pharmacy and Pharmacology 61.7 (2009): 831-837.