Curcumin: Not all brands are created equal!

turmeric, root and powder

What is Curcumin? Curcumin is the yellow pigment in the spice turmuric. It’s derived from the root of the plant Curcuma longa, the root of which looks like this: Aside from it’s orange color, it looks almost exactly like another spice you are more familiar with; indeed it is from the plant family Zingiberacea: the Ginger family.

Why we love curcumin
It belongs to a family of molecules called polyphenols, which happen to confer some special health benefits. Polyphenols increase the activity of our bodies’ natural detoxification system (specifically something called Phase II detoxification), and decrease inflammation in the body. The reason I first became interested in curcumin is because it seems to help prevent Alzheimer’s disease, which Western Medicine has no useful treatment for (and which my grandfather died from). Take a look at the picture below. On the left is a slice of rat brain with the amyloid plaques from Alzheimer’s disease visible as orange dots. On the right is the brain from a rat treated with curcumin:

As you can see, the amyloid plaques are greatly diminished in the rat treated with curcumin. This is what is so exciting about it’s potential in preventing or even treating Alzheimer’s. Below is another slide, with a view of those same plaques (stained red) along the blood vessels of the brain. Again, as you can see, in the slide on the right, they are greatly diminished after treatment:

And curcumin is a promising treatment for more than just Alzheimer’s. Curcumin fights inflammation, and inflammation is central to many disease processes, cancer among them. In fact, curcumin is able to impact every stage of cancer: the first aberrant cell that starts to multiply out of control, the growing tumor trying to stimulate the growth of new blood vessels to feed itself, and the mass that invades adjacent tissue and metastasizes. Curcumin can impact all of these areas because they are all affected by a transcription factor (something in the cell that binds to DNA) called Nuclear Factor kappa B (or NFkB for short). The picture below shows the various signaling molecules that NFkB impacts which cause the growth and ultimately the metastasis of a tumor:

Curcumin inhibits NFkB, and is thus able to greatly impact cancer progression. Take a look at this CAT scan from a patient with liver cancer who had already failed chemotherapy:

 

Dillon N, Aggarwal BB, Kurzrock R. Phase II Trial of Curcumin in Patients With Advanced Pancreatic Cancer Clin Cancer Res 2008; 14(14) July 15, 2008

Notice in the slide on the left, the lower left corner has a large round tumor in the liver, which is essentially gone in the slide on the right. That is an amazing result—so why aren’t all cancer patients taking curcumin?? The problem with curcumin is that it’s very poorly absorbed. The patient whose CAT scan you see above had to take 8 grams (not milligrams) a day, which is a massive amount. Most people cannot tolerate that. In fact, the researchers who did the cancer study above are currently working on a formulation for intravenous use. For purposes of daily prevention, though, we need something you can take by mouth. All ‘standard’ curcumin supplements — even by reputable manufacturers– are so poorly absorbed that they aren’t worth taking at all. In a 2004 paper, Garcea et al gave 3.6 grams per day to patients with liver cancer, and concluded:

“The results suggest that doses of curcumin required to furnish levels [in the liver] sufficient to exert pharmacological activity are probably not feasible in humans.”1

The reason is, curcumin’s structure is such that it doesn’t cross the intestinal wall intact… it gets broken down into metabolites first. And yet, it has been noted that in India, curcumin is eaten in greater quantities than in any other population—sometimes more than two grams a day—and people in India have almost negligible rates of Alzheimer’s disease! Is curcumin the reason? And if so, how is it that they are able to absorb it?

One theory is that the way that Indians prepare curcumin– heating with butter or oil– creates “liposomes” of a sort: little capsules of fat that carry the curcumin, which are then able to get across the intestinal wall. There have therefore been a number of attempts to emulate this mechanism (via barber). A few have had some success. In my opinion, Longvida (sold by Verdure Sciences) is the best choice for Alzheimer’s prevention (in addition to all of curcumin’s other benefits), and that is the brand that we are used in the PhysioAge NeuroPack.

Trying to understand whether a particular brand of supplement provides blood levels that are clinically relevant is where things become interesting for me (and generally indecipherable for the typical consumer). Remarkably, in a few instances this process reveals that out of dozens of companies selling a supplement, only one brand may be worth using! In the case of curcumin, at present only one or two have shown evidence of clinical relevance. (Lipoic Acid is another example of a supplement that has many vendors but only one that I am willing to use at present.) Those who would like to know the (somewhat painstaking) details about how we separate hype from reality and decide which brand of a supplement should be used, click on the following questions:
[dropdown_box expand_text=”” show_more=”Give me all the details! How do you know which brand to use?” show_less=”Just the basics, please.” start=”hide”] How do you decide which brand to use? Many manufacturers claim various ‘tricks’ to increase absorption of their supplements. One common technique used with curcumin is to add piperine, a black pepper extract that does appear to improve absorption somewhat, but unfortunately not nearly enough to matter clinically. The crucial issue is, can a company provide proof that enough of their supplement is actually absorbed– in humans– to be clinically relevant?
This information can be provided in two ways:

  1. human pharmacokinetic (pK) studies, which actually measure serum levels of a supplement after humans ingest it, and show that it reaches levels that were shown to be clinically relevant in animals, or
  2. clinical trials, in which people ingested their supplement and had a positive outcome.

Clinical trials tend to be prohibitively expensive, which is why drug companies that conduct them hope to gain FDA approval and a patent with which to recoup their investment. Small clinical trials do sometimes take place, but pharmacokinetic studies are usually the best we can hope for in the supplement world.

With regard to curcumin: though there are dozens of brands sold, there are only three brands of curcumin for which I have seen human pK studies. One of them uses curcumin complexed with phosphatidylcholine to get across the intestinal wall, sold as Meriva (by Thorne), and another uses a different formulation of phospholipid with a similar mechanism, sold as Longvida (by Verdure Sciences). The third kind with pharmacokinetic studies is BCM-95, made by Arjuna Natural Extracts in India and sold by many vendors here. (I have bought it from Life Extension Foundation as “super-biocurcumin 400mg”; it’s also sold as Curcu-Gel Ultra 500mg). BCM-95s “trick” is they increase the curcumin oils in the formula, and seem to thereby achieve higher absorption.

Why do I suggest Longvida over the others? The short answer is: the UCLA docs researching Longvida have done the most reliable pharmacokinetic studies, and are doing work showing how much is needed to lower amyloid deposits in the brain: they did a study in mice showing that a level of 0.5uM in the blood was enough to reduce the size of pre-existing Alzheimer’s plaques in just 7 days—exciting stuff. Since curcumin is lipophilic, it is thought to accumulate in brain and fatty tissue. The concentration needed to inhibit inflammatory factors and amyloid deposits is probably somewhere between 1-2uM in tissue/cells. Their current thinking is that, with chronic dosing, tissue concentrations may be 10x that in plasma; therefore you only need a plasma level of 0.1-0.2 uM. So: if the goal is 0.2uM plasma concentration, what level do you achieve with BCM-95 vs. with Longvida?

The BCM-95 pK studies seem exciting in that they show roughly 700% better absorption than “regular” curcumin. They did two very small pK studies: In the “Curcugel” study, they state that 2g taken by mouth yields a serum level of about 0.44uM/L, and in the other study they found that 4g yield a peak as high as 1.9uM/L! 2

(Calculations based on a peak of 1400ng/g: MW curcumin is 368.4 g/M = 368.4ug/uM BCM95 1400ng/g= 1.4ug/g= 1.4ug/2mL = 700ug/L= 1.9 uM/L)

This is MUCH higher than what is needed to be effective, so it sounded promising! Now here is the Longvida data for comparison:3

Based on their human pK study,

  • 650mg Longvida yields 22ng/mL plasma = 22000ng/L = 22ug/L; 22ug/L/ 368.4 ug/uM = 0.06 uM/L
  • 2g Longvida=> CMax =32ng/mL= 0.09uM/L 3g => CMax= 0.14uM/L
  • 4g Longvida (8 capsules)=> CMax of 0.22uM/L

So 4g of Longvida orally only gives you 0.22uM/L, BARELY enough for clinical effectiveness, whereas BCM-95 seems to give much more: 1.9uM/L So, why aren’t I recommending BCM-95??

The reason is, I don’t have faith in the BCM-95 studies. Here’s why: Typically, clinical trials of “regular” curcumin show negligible plasma levels with oral dosing: at doses less than 8 to 10 grams per day, the plasma levels obtained should be very low, lower than 5ng/mL or ~0.02uM. 4,5 But this is not the case for the BCM-95 studies. Their studies show 4g of their control, the “regular” curcumin, peaking at about 250ng/g = 125ng/mL = 0.34uM/L. The Curcugel study shows 2g of “regular” curcumin peaking as high as 0.17uM/L (in Volunteer D); in other words even when they used their “regular” curcumin controls, they somehow got more than ten times the concentration usually found in other studies for “regular” curcumin. So it raises doubts about their results, both for regular curcumin and for BCM-95. Perhaps they are accidentally measuring metabolites or… perhaps something else was off. I emailed them about this and they feel certain their HPLC is calibrated well and they know what they’re doing. I don’t think they are trying to scam anyone, but the data just doesn’t make sense to me. [/dropdown_box]   [dropdown_box expand_text=”” show_more=”What about Longvida vs Meriva?” show_less=”Hide this question, please.” start=”hide”]What about Longvida vs Meriva? Both of those brands use some form of phospholipid, but the two formulas do not have identical absorption. Meriva (sold by Thorne) has a small human study showing benefit using two capsules twice a day for osteoarthritis, but that is only based on subjective data (pain and functionality scales rather than serum inflammatory markers). Usana (a large supplement company) analyzed Meriva bioavailability and here is what they said:

Free curcumin could not be detected in any plasma samples, in accordance with previous studies that have mostly failed to detect unconjugated curcumin in human plasma even after the administration of megadoses of curcumin.

However, Usana did find some metabolites of curcumin (referred to as ‘curcuminoids’): The peak plasma total curcuminoid concentration (Cmax) reached with the high dosage of Meriva was 206.9 ng/mL…. [However] Within the context of curcumin human absorption, the >200 ng/mL concentration of conjugated curcuminoids is still lower than the low micromolar concentration of free curcumin required for direct activity against its various targets. 6 In addition, some studies suggest that although some of the curcuminoid metabolites have anti-inflammatory effects (and thus may be helpful against arthritis, which is what Meriva is marketed for), only curcumin, not its metabolites, will work against Alzheimer’s:

Despite dramatically higher drug plasma levels after administering [the curcuminoid metabolite] tetrahydro-curcumin… only curcumin was effective in reducing amyloid plaque burden. Tetrahydro-curcumin had no impact on [Alzheimer’s] plaques or insoluble Amyloid-β… Curcumin, but not tetrahydro-curcumin, prevented Amyloid β aggregation. 7

Therefore, for prevention of Alzheimer’s, Longvida is the better choice. [/dropdown_box]   [dropdown_box expand_text=”” show_more=”What about Curcumall, the brand Ray and Terry sell?” show_less=”Hide this question please.” start=”hide”]What about Curcumall, the brand Ray and Terry sell? I don’t have any evidence that Curcumall is “bad”… I just don’t have any evidence that it works, either. I emailed Tumeron Health Products, the makers of Curcumall, and here is their reply: “The pharmaceutically active ingredients of Curcumall are mainly curcuminoides and volatile oils. The curcuminoides are a mixture of curcumin, desmethoxycurcumin, and bis-desmethoxycurcumin. “ That already tells me it is less likely to be effective in Alzheimer’s, since curcumin itself is likely what is needed for Alzheimer’s prevention. Nevertheless, Curcumall might still confer significant benefit in the prevention of other inflammatory processes, including cancer. So I asked if they have any pK data to show that it is absorbed in clinically relevant amounts. What they sent me was this:

Curcumall was prescribed by doctors and health providers to many patients. Some of the cases treated are very significant cases that demonstrate the absorption of Curcumall from the intestine to the blood stream and the passage through the blood-brain barrier. We list here the most significant cases/patients who were taking Curcumall and reported on its effect on their condition. The anecdotal cases listed below may serve as evidence to the efficacy of Curcumall’s absorption.

…followed by a number of anecdotes of patients that ingested Curcumall and seemed to improve. The problem is, anecdotes are not adequate clinical evidence. If people want to take Curcumall for prevention of cancer or inflammation, I don’t think that’s unreasonable… I just think the evidence in favor of Longvida is stronger. [/dropdown_box]

 

To be clear: Evolved Science has no stake in Longvida or any other supplement company, and neither do I. If Meriva or Curcumall comes out with data showing their superiority, we will happily switch brands for our Supplement Packs. This is precisely why I don’t want to be tied to any one company: we are free to mix and match brands to get the best possible end product!

[dropdown_box expand_text=”” show_more=”Show me the references.” show_less=”Hide references.” start=”hide”] 1. Garcea et al. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer. 2004 Mar 8;90(5):1011-5.

2. Internal study performed by M. Benny and B. Antony, Arjuna Natural Extracts, “Bioavailability of BioCurcumaxTM: http://bcm95.com/pdf/Spice_Board.pdf

3. Gota et al. Safety and Pharmacokinetics of a Solid Lipid Curcumin Particle Formulation in Osteosarcoma Patients and Healthy Volunteers J. Agric. Food Chem., 2010, 58 (4), pp 2095–2099 http://pubs.acs.org/doi/abs/10.1021/jf9024807

4. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 2008;28:110–113. [PubMed: 18204357]

5. Lao CD, Ruffin MT 4th, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 2006;6:10. [PubMed: 16545122]

6. Anand, P.; Aggarwal, B. B. et al. Biochem. Pharmacol. 2008, 76, 1590–1661.

7. Begum, et al. Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer’s Disease. J Pharmacol Exp Ther. 2008 July ; 326(1): 196–208.[/dropdown_box]

 

10/28/13 CURCUMIN UPDATE: PLEASE SEE THIS POST FOR AN UPDATE ON LONGVIDA, AND THIS ONE FOR A DISCUSSION OF THERACURMIN.

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