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Curcumin Under Fire: The Root of The Problem!

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cf456f3f6dfd0ac873ed120e88847beaLast week, a group of researchers from Minnesota, Massachusetts, and Illinois published a review article on curcumin in the reputable Journal of Medicinal Chemistry. The authors argued that curcumin is not the health purveyor it’s made out be. Given that the review so vehemently opposes some of the compelling evidence we have seen, we saw this as an opportunity to re-evaluate and investigate as any good scientist should.

Widely used in both the ayurvedic and Traditional Chinese Medicine (TCM) systems of healing, curcumin derived from the yellow pigment of the turmeric root, is revered and extensively used for religious, cultural and health reasons. Curcumin is probably the most widely studied natural health product on the planet. Thousands of researchers in hundreds of universities worldwide have contributed to an extensive body of published literature on this fascinating molecule. The number of publications has skyrocketed in the last two decades as government and privately sponsored research tries to keep pace with the fervent commercial and health interest surrounding this unique molecule. Curcumin has been linked to a plethora of health benefits, including effects on the skin, liver, gastrointestinal tract, heart, brain, kidneys, pancreas and virtually every other organ.

So, naturally, it was quite a shock to the scientific community, and particularly those studying natural products, when an article published in the Journal of Medicinal Chemistry directly contradicted these claims. Authors describe artemisinin (a natural molecule from the herb Artemisia annua), which is successfully used in the treatment of malaria and for which the discoverer was awarded a Nobel Prize in 2015), as a missile that targets the malaria parasite and destroys in “spectacular fashion”. Conversely curcumin was described as “a missile that continually blows up at the launch pad, and never reaches its intended target”. Authors also stated that curcumin has “never been shown to be conclusively effective in a randomized, placebo-controlled clinical trials for any indication”.

The authors observed the highly unstable nature of the molecule coupled with its interfering nature in many of the assays and detection systems used in conventional research. This lead them to conclude that the curcumin molecule is a perfect contender of the bizarre acronym of the classification system known as PAINS (pan assay interference compound) and IMPS (invalid metabolic panacea) group of compounds, essentially relating it to all smoke and mirrors. Much of this is due to the highly unstable nature of the molecule coupled with its interfering nature in many of the assays and detection systems used in conventional research.  Further, curcumin is poorly bioavailable and eliminated easily by the body. This, the authors claim, limits overambitious claims that position curcumin as a panacea in various disease states.

If this is true then this is a serious blow to the natural product industry, as its main champion. Since curcumin is a hugely popular supplement what is the truth behind such assertions by these authors? Is it a waste of time to consume such a natural product? Let us examine carefully the evidence and assumptions made in the review that lead to such an unfavourable opinion of this molecule.

Types of Studies Reviewed:

First, the authors are correct that the curcumin molecule used in in-vitro studies is different to the ones used in most animal and human studies. In these test tube studies, the curcumin used is a single molecule, but in the animal and human studies, curcumin is generally a mixture of three closely related but different molecules collectively referred to as curcuminoids. As such the mechanistic studies in the test tubes do not accurately reflect the clinical outcomes in animal and human. It is then inaccurate  to link the mechanism found in in vitro studies with the physiological effects observed in animals and humans.

Second, curcumin is indeed a very unstable molecule which quickly breaks down into smaller molecules and binds avidly with various proteins in the body (blood vessels lining, cells, enzymes etc.), and metals. A challenge any natural health product formulator trying to develop an effective “curcumin product” will be very familiar with. Further, curcumin acts as a redox agent, meaning it acts as a reducing and oxidizing agents (giving and taking electrons from other molecules), this duality  complicates the analysis of data.  Finally, curcumin fluoresces (lights up) easily, which complicates imaging and interferes with assay detection systems. This begs the following questions: Is one measuring curcumin or a surrogate marker? Are we seeing a phenomenon or merely observing an epiphenomenon? As the authors astutely point out, these factors combined demonstrate the difficulty in studying curcumin, emphasizing the importance of a well designed study with appropriate measures, as it is easy to provide misleading data with this molecule. However, does this mean that we negate the findings of all  curcumin studies? Or perhaps, the nuance in detecting effects of curcumin, reminds us to scrutinise the study design more closely.

Third, the authors argue that the curcumin molecule undergoes rapid metabolism (breakdown) and has poor cell permeability and thus cannot get across the cell wall. Combined with poor distribution and rapid elimination from the body, they argue that it is unlikely that curcumin can reach its target site and thus be able to produce all the beneficial effects claimed. Again, the author’s claims are true as repeated studies have shown that even when taking large doses up to 12g a day very little is detected in the body.

However, the authors failed to mention a very important point. While curcumin is unstable and easily broken down and eliminated from the body, scientists who understood these difficulties set out to overcome each issue by developing technologies to address each concern and evaluate efficacy using the appropriate markers. Technologies are aimed at stabilizing the curcumin molecule, enhancing uptake, improving absorption into the circulatory system, and improving transportation across the body to the site of action where it is needed.

The authors mention that none of the clinical studies show any evidence of activity, and this may be true because the researchers fail to measure free, un-metabolized curcumin in their assay systems (ie. measuring tools).  As previously mentioned curcumin is quickly broken down into metabolites. The metabolites (glucuronides and sulphates) are bulkier than the original curcumin and have been shown to have significantly less or no biological activity (anti-inflammatory, antioxidant and anti-carcinogenic activity). In addition, these bulky metabolites cannot cross the blood brain barrier and enter the brain. This is particularly important if curcumin is going to have any benefits in cognition, dementia, and Alzheimer’s disease. That being said there is biological activity detected with the free, un-metabolized curcumin while all other forms show little or no activity.  So it is really no wonder so many clinical trials fail to show the expected clinical outcomes.

Another important point not mentioned is that traditionally, turmeric root has been mostly boiled as a tea or cooked in ghee (clarified butter).  These facts highlight that a better strategy for delivery would be to use use water soluble polysaccharides of turmeric combined with the curcuminoids as the ideal formulation. Finally, curcuminoids aren’t the only active molecules present in turmeric. Much is to be said about other components, especially the water soluble polysaccharides known as Turmacins. Recent studies have shown that when Turmacins are combined with a free-form delivering curcuminoid formulation,n there is synergy and significantly greater activity. Currently there are two forms of curcumin that deliver high amount of free and active form of curcumin and these are Longvida and a newer even more potent (3-4 times) form called CurQfen.

Finally, it seems that the researchers somewhat hastily linked curcumin’s relatively poor detectability in cancer studies as evidence against curcumin’s effectiveness. Usually, in human cancer clinical trials, curcumin is used as a last resort (due to ethical reasons) when all other standard treatments have failed. It is unfair to expect curcumin to be magically effective at the later stages of cancer progression, when many potent oncological therapies have failed. In addition, other well designed placebo-controlled human clinical studies have been conducted, where the positive effects of curcumin have been shown, especially with regards to anti-inflammatory and antioxidant effects.

Overall, the authors bring up a number of very good points that highlight the importance of quality scientific design, clear and accurate interpretations of results, and the need to challenge current paradigms. However, some of their conclusions seem to be misdirected by making a blanket statement regarding the ineffective nature of all curcumin, without first excluding those studies that inaccurately measure, falsely report, have poor design, or are not clinically applicable. It would be equally as negligent to ignore findings from strong studies, as it would to assume they are all completely accurate. The scientific and natural health community have a responsibility to the public to appropriately differentiate between “good” and “bad” science, and hopefully bring an innovative approach to solving these difficult matters such as bioavailability.

References:

Nelson, KM et-al “The Essential Medicinal Chemistry of Curcumin” J of Medicinal Chemistry 2017 In-press

Krishnakumar IM “An enhanced bioavailable formulation of curcumin using fenugreek derived dietary soluble fiber” J Functional Foods 2012: 4: 34-357

Krishnakumar IM “Improved blood-brain barrier permeability and tissue distribution following oral administration of food grade curcumin with fenugreek fiber” J Functional Foods 2015: 154: 215-225

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