Friday, July 27, 2018

Quality of Curcumin Supplements From US Retailers Better Than You May Have Feared | Plus: High Price ≠ High Quality

Curcumin has become increasingly popular over the past years. No wonder in view of the ever-extending list of potential health benefits - "potential" is, as T. Tsuda highlights, yet a keyword in this context.
No, you don't have to email me asking for the brand names of the 87 products Skiba et al. bought and analyzed (32 of them) for their latest study in Molecular Nutrition and Food Science (Skiba 2018) ... honestly, bros: I would have told you the names if I knew them. Unfortunately, the scientists from the University of Arizona, Tucson, follow the example of so many colleagues before them and tell us only the criteria they used to narrow down the 228 surveyed items to a list of 87, of which they later sent 32 to the HLPC analysis.

After excluding identical products available at multiple retailers (n = 99) or containing different capsule counts (n = 42), Skiba et al. recorded the exact type, amount, and recommended daily dosage of turmeric; whether or not additional bioactives (natural products, vitamins, or minerals) had been added and whether the supplements contained piperine/black pepper extract or proprietary formulations to enhance curcuminoid bioavailability.
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In a second step, the authors tried to find out how much actual curcumin is supposed to be each capsule. That sounds hilariously easy ("just check the label"), but turned out to be quite a problem because some of the products contained proprietary blends the curcumin content of which was not on the label - in those 7 cases, the scientists simply estimated the content based on comparison with similarly composed formulations. Eventually, ...
"[p]roduct-specific daily recommended curcuminoid doses were calculated as the product of the maximum number of daily capsules recommended and calculated capsular curcuminoid content, which was corrected for bioequivalence for enhanced bioavailability proprietary or piperine-containing products (curcuminoid content multiplied by fold-increase in curcuminoid bioavailability, published or claimed)" - Skiba 2018.
In a final step before the samples were sent to two independent labs where they were analyzed using high-performance liquid chromatography (HPLC), the researchers picked N=32 products based on the following criteria: cost per capsule (<5th or >95th percentile, using median priced retailers and 60 count bottles); commercial availability (sold at 3 retailers and/or store-specific generic brands); type of turmeric content (root, proprietary enhanced bioavailability formulations, curcuminoid-enriched extracts); inclusion of other bioactives (piperine and/or 3 additional bioactives).
Figure 1: Assayed turmeric DS curcuminoid content (n = 35). A) Total curcuminoid content (g per capsule), as determined by the commercial or academic laboratories, is expressed as a ratio of measured versus calculated content (based on label information). Scatterplot includes mean ± SD, with dashed lines indicating ratios 20% different than anticipated. Means are not statistically different (p = 0.08). For products with outlying values, sample identification numbers are indicated. B) Composition of curcuminoids, expressed as % curcumin (%CURC), as determined by commercial versus academic laboratories. Dashed box indicates products with >90% CURC, as assayed by both laboratories. Closed box indicates products meeting USP curcuminoid extract specifications (70–80% CURC), as assayed by both laboratories. Open triangles indicate root-only products, which do not contain curcuminoid extracts (Skiba 2018).
All supplements were purchased in April 2017 and stored at room temperature protected from light prior to shipment to laboratories for analyses (of products with outlying values a new bottle was purchased and tested in order to avoid the influence of outliers).
Nelson et al. highlight the complex chemical structure of turmeric and multiple problems related to the use of standardized assays with curcumin, a substance that belongs to the group of PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas - in other words, much of the data from in-vitro studies could be worthless | (Nelson 2018). 
Is curcumin a total fraud? In a recent paper in the Journal of Medical Chemistry, Kathryn M. Nelson and her colleagues point out that the "essential medicinal chemistry of curcumin" and the apparent lack of human studies that would confirm that curcumin alone (not alongside its natural synergists in turmeric) was "effective" would be reason to remain skeptical.

Why do I mention this issue? Well, Nelson's very technical (chemistry) perspective on curcumin supports the idea that "the purer, the better" is - as I will suggest later in this article - not a valid approach to choosing the best curcumin product. In fact, the proven health benefits of the whole spice may, as Tsuda rationalizes in his review, actually be a result of other compounds or the complex mix of the former and their downstream metabolites and degradation products and/or their hitherto largely unknown effects on the microbiome. 
As you can see in Figure 1, the results of the lab analyses confirm that the vast majority (80-83%) of the supplements is within the +/- 20% margin of the labeled curcumin content. In that, the scientists highlight that "[t]he two methods used to analyze relative amounts of CURC, DMC, and BDMC were in close agreement" (Skiba 2018). That's also true for the "sole product whose assayed curcuminoid content was <35% of anticipated," the curcuminoid content of which "remained low upon testing of a second lot (33% of anticipated | Skiba 2018).

As expected: More expensive products were not generally better

The scientists also found that there was no statistically significant relationship between the amount of anticipated total curcuminoids detected and point of sale information related to cost (ranging from 46 cent to $49.37 per gram) or content (turmeric or other bioactives).
Figure 2: Even though the most expensive product has a higher concentration of pure curcumin that's not necessarily a sign of superior quality because DMC and BDMC have antioxidant properties of their own.
The different make-up, on the other hand, may be important as bis-desmethoxycurcumin, for example, has been shown to have lower anti-inflammatory, but similar anti-allergic and unique anti-coagulant activities (Khalandar 2018) compared to curcumin. Since all three of them are potent anti-oxidants, it's yet difficult to tell the real-life consequences of the different composition.
Table 1: Two viable strategy to increase the total and maximal absorption by improving the bioavailability of curcumin are micronization and packaging it into micelles, a study in 23 healthy human volunteers demonstrates.
The bioavailability problem: As you may remember adding your turmeric/curcumin powder to yogurt can increase its low bioavailability (~1%) fifteen-fold (learn more). Alternative ways to enhance the amount of curcumin that will actually end up in circulation are (a) the addition of piperine/black pepper extract (which may be problematic because of piperine effects on the cytochrome cascade and thus the metabolism of endogenous molecules, including hormones like testosterone and estrogen as well as drugs (some scientists estimate 50% of all drugs), (b) the micronization of the powder, and (c) packaging curcumin in micelles (Schiborr 2007). Unlike adding piperine, the latter are yet not exactly simple and pricey processing steps.

Especially in view of these extra-costs it is worth citing Schiborr et al. who wrote in (the corrected version of) their 2014 paper in Molecular Nutrition and Food Science: "To the best of our knowledge, the hitherto highest published curcumin plasma Cmax of 8420 nmol/L and 1770 nmol/L were achieved with a single oral dose of 10 g or 8 g of native curcumin, respectively" - simply using a higher dosage of mixed curcumins may thus be more effective than buying expensive "extra bioavailable" products that use micronization, or micellar or phospholipid versions of highly purified curcumin.
Figure 3: Inhibition of NF-κB by curcuminoids. A comparison of the inhibition of tumor necrosis factor alpha, TNFα, a cell signaling protein (cytokine) with a prominent role systemic inflammation, of a curcumin mix, pure curcumin, demethoxycurcumin, and bisdemethoxycurcumin clearly indicates that the natural mix is the superior anti-inflammatory agent (Sandur 2007).
Studies like Sandur et al. (2007) even suggest the opposite, i.e. that pure curcumin is less efficient than the natural form of mixed curcumins that contain <70% curcumin, when they are derived directly from turmeric, and between 70–80% when they are extracted for high curcumin contents.

Pertinent in studies in form of randomized controlled clinical (=human) trials are yet lacking. It is thus difficult to say if you'd really be better off with the cheap curcumin + piperine combination for 46 cents per gram than with the proprietary blend in a highly purified curcumin product that will cost you half a grant for a single gram.

Moreover, the optimal ratio of 'the curcumins' and the importance of other molecules in turmeric may well depend on what you're trying to achieve by supplementing with curcumin, e.g. blood-thinning effects, an overall reduction in inflammation, reduced histamine, etc... but, that's a topic for another article.
What about residual solvents or lead? If you're concerned about pro-carcinogenic substances in your curcumin products, I have good and bad news. The bad news is that solvents and lead were detected in all products tested. The good news, however, is that the concentrations were below the USP recommended limits for all but two products which contained 116% and 126% of the USP limit for lead in dietary supplements. Both the lead and the solvent content were not generally associated with price or bioactive content, however, there was a trend for higher concentrations of both in plain turmeric root extracts - especially when compared to proprietary formulations.
One thing that should be addressed right away, though, is that products which achieve curcumin concentrations beyond the regular 70-80% that will be achieved by extracting curcumin from turmeric is, as Skiba et al. point out "suggestive of (1) possible substitution of chemically synthesized curcumin for plant-derived curcuminoids, a practice forbidden by US federal regulation," or "(2) the unlabeled use of curcumin-only extracts further purified from turmeric-derived curcuminoid" - whether that was the case for any of the studies products wasn't tested, though.

Now you may be asking yourself: "Wait a minute. Is synthetic curcumin even a problem?" Good question, unfortunately, we don't know the answer to it, yet. What we do know, though is that the inferior stability of synthetic curcumin in biological fluids (Kharat 2017), obviously suggests that it is indeed inferior to its natural twin. Accordingly, future studies should investigate both, the impact of 'tainting' curcumin products with synthetic curcumin and the previously discussed effect of the ratio of pure curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcum (BDMC) on the biological/medicinal effects of curcumin supplements... and, eventually, consider potential health effects of and synergies with other substances in turmeric, which is, after all, the agent that has been used for thousands of years in traditional medicine.
If you want to avoid curcumin, yogurt may be your bioavailable enhancer (x15) of choice | learn more.
So, what do you have to know about that curcumin product from the supermarket? The general quality of curcumin supplements on the local US market is better than you may have thought (much better than fish oil, of which you'll remember that it often goes rancid on the shelves).

Both the lead and solvent levels are within the USP limits for almost all products (esp. for lead this is very different with the whole turmeric root powders that are sold for culinary use as a spice at your local supermarket) and >80% of the products fall within the +/- 20% margin when it comes to deviations from the officially labelled curcumin content.

In this context I cannot repeat often enough that the price of the supplements was not indicative of either the accuracy of the labeled curcumin content or the presence of potential carcinogens in form of class 1 and class 2 solvents and/or lead... and, what's at least as important: some of the cheaper less pure products may actually have a lower curcumin to demethoxycurcumin + bisdemethoxy-curcumin ratio could be more effective than the expensive purified formulations | Comment!
References:
  • Khalandar, S. Dada, et al. "A Current Review On Curcuma Longa Linn. Plant." International Journal of Pharmaceutical, Chemical & Biological Sciences 8.1 (2018).
  • Kharat, Mahesh, et al. "Physical and chemical stability of curcumin in aqueous solutions and emulsions: Impact of pH, temperature, and molecular environment." Journal of agricultural and food chemistry 65.8 (2017): 1525-1532.
  • Sandur, Santosh K., et al. "Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism." Carcinogenesis 28.8 (2007): 1765-1773.
  • Skiba, Meghan B., et al. "Curcuminoid Content and Safety‐Related Markers of Quality of Turmeric Dietary Supplements Sold in an Urban Retail Marketplace in the United States." Molecular nutrition & food research (2018): 1800143.
  • Tsuda, Takanori. "Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives." Food & function 9.2 (2018a): 705-714.
  • Tsuda, Takanori. "Curcumin: An Effective or Deceptive Dietary Factor? Challenges for Functional Food Scientists." (2018b): 1059-1060.