Curcumin, Is it Really Bad?
Paul Anderson, NMD
Research review of:
“The Essential Medicinal Chemistry of Curcumin”. Kathryn M. Nelson, Jayme L. Dahlin, Jonathan Bisson, James Graham, Guido F. Pauli, and Michael A. Walters. Journal of Medicinal Chemistry Article ASAP. DOI: 10.1021/acs.jmedchem.6b00975
In the abstract, the authors make the statement: “The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, non-bioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.”
They go on in their conclusions to state: “With respect to curcumin/curcuminoids and in vivo studies and clinical trials, we believe there is rather “much ado about nothing”. Certainly, the low systemic exposure levels reported in clinical trials do not support its further investigation as a therapeutic.”
Very strong assertions which have caused some to claim there is no benefit to the use of curcuminoids in medicine or research at all. I truly think the contentions in the abstract and introduction are placed to garner inflammatory headlines by those unable or unwilling to read the whole paper (which is quite long and technically demanding). In the ‘summary’ section below I will also point out some of the many statements the authors make later in the paper that take a great deal of wind out of the sails of their inflammatory assertions made in the abstract.
Without going into a point by point assessment of this paper, it does bring up some very good considerations in turmeric/curcumin chemistry, pharmacology and potential for human medical use. First (for purposes of ‘voir dire’ or why are you commenting with any authority), I currently have supervised the widest ranging pharmacologic human intervention trials using the most broad forms of intravenously administered curcumin in the world. Additionally, I have authored the only monograph1 regarding such use, which is used in locations both in and outside the US for the purposes of hospital-patient care with intravenous curcumin as well as research basis.
I believe what we have seen (and NOT seen) employing curcuminoids intravenously in some populations where change is obvious (end stage cancer metastasis) underscores what I have been attempting to share with physicians using curcuminoids medically for a number of years. This matches up with some of the arguments made in the Nelson paper as well.
I believe their thesis is correct but the conclusions for practicing physicians and researchers are more nuanced and do not reflect a “needs too much study before being employed” approach. To simplify my research and clinical use findings that I believe make the distinctions between the points made by Nelson et.al. and myself I’ll summarize in four key areas:
- Curcuminoid pharmacology is complex
Turmeric and the constituents known as curcuminoids are complex pharmacologically and have different MOA in some cases. Additionally in vitro and in vivo outcomes are often different due to poor absorption orally (in some cases and not others). This caused the early human trials with intravenous application – to actually see if this was a dose and distribution issue (more on that below). But yes, as Nelson points out and as I and many have said repeatedly in lectures on the topic, one must know the form of curcuminoid, dose and potential absorption / target tissue delivery in order to have clinical success.
- The pharmacologic preparation/form makes a difference
I’ll minimize discussion of the oral forms here as the potential for absorption of one form over another (and that manufacturer assay accuracy for the type of curcuminoid) are available ad nauseam and two are referenced below2,3. But as evidence for the assertion that one ‘version’ may have very different effects over another, I can personally attest that in intravenous application we saw great differences (from oral administration). This turned out to be a combination of stability of preparation (if you think oral curcumin is difficult to stabilize try making a sterile intravenous product for humans…) and the ability of that preparation to deliver the curcuminoid to the tissue. Of the four forms tried only one form (the emulsion) could meet both criteria and actually had positive outcomes (with the same infused dose!).
- The dose makes a difference
Again without belaboring the already published data it is well known that there (as with most all agents) is a dose response curve for curcuminoids. This is also evidenced by the difference in some in vitro data versus in vivo data. One trigger for the human intravenous trials originally was the observation that all the potential beneficial curcuminoids could offer a patient with advanced cancer were often not seen clinically with oral use. The theory we tested was “if we infuse a parenteral solution of curcumin is there a dose at which we see a tumor response?” So we had two variables; one being ability to bypass the gut absorption and the other being the need to establish a dose response.
To shorten a very long story we found that:
- Intravenous administration had an obvious benefit over oral in tissue delivery
- Dose made a significant difference in clinical response.
Much of this is outlined in the monograph below, but the take home is that we saw inflammatory disease modification (autoimmune, neuroinflammatory, pain etc.) at low dose and we saw oncologic effect (regression of metastases, regression of primary tumors, stable or regressed disease) only at high dose / never at low dose. All oncology patients were in Stage-4 disease with multiple failed therapies (standard oncology and integrative) and had progressive treatment resistant disease. Most all had used oral curcumin prior as well. (Again these doses are laid out in the monograph – but as a caution the intravenous administration of curcumin is very complex and requires training and use of only one of the available forms, the emulsion, of parenteral curcumin.) The reason for this specificity is that currently the other forms are either not safe at high dose or are not as bioavailable as the emulsion when used at high dose.
To restate: Our work with intravenous curcumin replicated one significant factor we see with oral preparations which is the form is critical but also the pharmacologic manner in which it is stabilized as well.
- The target location makes a difference
In oral use for GI disorders and other topical uses (vaginal and rectal suppositories etc.), we often clinically see a broader response with regard to the type or form of the curcuminoid. When attempting to reach tissues in the body we often see that the preparation (related to absorption) form and dose be more critical. And in some high dose response uses (oncologic as mentioned) only (currently speaking) were dose responses seen when employing an intravenous preparation.
Yes the form, preparation, location and dose are critical (and if using intravenous application extremely critical). But many agents (in the drug or natural world) that have great potential benefit for disease modification and health have just as complex implementation and pharmacology guidelines.
Nelson et.al. do, later in the paper, make some statements which I believe lessen the force of their inflammatory rhetoric in the abstract and introduction. I believe these statements support my statements above more than their global assertions about curcuminoids. I will restate just a few of these:
- “In addition, there is increasing evidence that TxM agents [“ethnic and traditional medicines”] cannot be adequately described with reductionist pharmacology models but require consideration of polypharmacology and synergy.” COMMENT: Of course. As described above, this is a very true statement which takes some weight from their initial logical structure on which their assertions were made.
- “This orthogonal perspective on the druggability of NPs [“natural products”] is further supported by the metabolic feedback hypothesis164, which states that bioactivity, especially of many food-borne phytochemicals, can act via weak negative biological feedback mechanisms, escaping in vitro detection and blurring our understanding of mechanisms of action.” COMMENT: Again, of course. It is extremely encouraging to see the honesty of the authors in this statement, and their discussion of how we cannot likely treat all natural products as we do drugs in research modeling and procedures. They do list some (more simple molecule) examples where a natural product was able to be treated in research in the drug model and it worked well (artemisinin, Taxol, etc.) but fully admit that in complex molecules this likely will not be the case. Again weakening the logical basis for their initial assertions.
- Their final words in the paper underscore what I and other clinician researchers of natural products have known for some time: “Collectively, recognition of these factors may remove complicatedness from ongoing research while inspiring the development of out-of-the-box approaches to unraveling the complexity and potential health benefits of turmeric and other NPs.”
What are the logical conclusions that we can draw from this discourse? Do we “throw the baby out with the bathwater”? (Curcumin is difficult and we have to be thoughtful and critical of the forms, uses and product choices so let’s just say it’s not worth it…). I believe not.
Even a recent “surprising” case report underscores the potential utility of curcumin in oncology. 
As mentioned, I have seen high dose intravenous curcumin reverse metastasis when no drug or other natural agent had any effect. I have seen it do many other unique things. As I have said not all curcuminoids are the same and not all locations of action respond to the same form, so like any good physician, we need to understand the pharmacologic form, mechanism, target location and dose and apply appropriately. If done in this manner, I can attest that (when form, dose and location are matched appropriately) very remarkable medical outcomes can be achieved.
- Anderson PS. Curcumin Monograph for IV Use. 2017. Available from: https://www.academia.edu/20316553/Curcumin_IV_Use_Monograph
- Prasad S, Tyagi AK, Aggarwal BB. Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice. Cancer Research and Treatment : Official Journal of Korean Cancer Association. 2014;46(1):2-18. doi:10.4143/crt.2014.46.1.2.
- Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutrition Journal. 2014;13:11. doi:10.1186/1475-2891-13-11.
- Zaidi A, Lai M, Cavenagh J. BMJ Case Rep Published online: Feb. 2017. doi:10.1136/bcr-2016-218148