The demographic of SBM readers are likely to remember the early Miller Lite beer television commercials where sports personalities debated as to whether the beverage “tastes great” or was “less filling.” In one classic version, New York Mets’ Marv Throneberry breaks the shouting match to level his decision: “I feel strongly both ways.”

My colleagues at Science-Based Medicine have generally been opposed completely to the existence of the NIH’s National Center for Complementary and Alternative Medicine (NCCAM). The primary objection is that the Center awards roughly $125 million per year in taxpayer dollars to studies that are generally not based on a strong scientific foundation or, in some cases, absolutely no scientific basis. On the other hand, the best NCCAM-supported studies have provided fruitful results, if not negative with regard to clinical outcomes.

The recent series of articles by Trine Tsouderos at the Chicago Tribune (1, 2, 3, 4) has reignited a national debate as to whether NCCAM is needed at all. After all, NCCAM was not because of science but because of politics, particularly the efforts of Senator Tom Harkin and Representative Dan Burton. And other NIH institutes, such as the National Cancer Institute, seem to do a much more rigorous and science-based job of funding studies of alternative cancer therapies through their unfortunately-named Office of Cancer Complementary and Alternative Medicine, or OCCAM.

In fact, I have long argued that if alternative therapies are to be investigated rigorously, they should be done so under each of the specific NIH institutes and centers (ICs) that have been established to focus on organ systems (National Institute of Diabetes and Digestive and Kidney Diseases; NIDDK) or a class of related disorders (National Institute on Drug Abuse; NIDA).

As it stands now – and take away any objections to the poor scientific foundation of some of the modalities studied – NCCAM is like having a NIH IC assigned to study experimental medicine: all possible modalities against all possible diseases. Even if approaches tested were based on some scientific validity, you’ve got a relatively poorly-funded IC here that is charged with reviewing grants across a huge swath of medicine, basic and clinical.

Co-opting classical pharmacognosy as alternative medicine

Many pixels have been spent here and at other blogs, as well as Trine Tsouderos’ articles, on the least plausible of so-called complementary and alternative medicine. As egregious as that work is, I’m more concerned about the most legitimate, fact-based science that is often considered as “alternative medicine.”

A common tactic of alternative medicine practitioners is to take some approaches of medical validity – such as nutrition, exercise, stress reduction – and combine them with utter nonsense, such as energy healing, to provide some legitimacy to a package that includes some outright deceptive and unethical approaches.

When NCCAM was established, many investigators in the natural products field were encouraged that some of the hardcore chemistry and biology of herbal medicines and other natural medicinal sources would have a home for focused funding. What many of us learned was that NCCAM’s charge was to investigate traditional botanical products as they are used by the public and not to study the individual components.

Around 2000, I wrote a NCCAM grant proposal while at the University of Colorado to study the potential of a component of St. John’s wort in potentially antagonizing the chemotherapeutic effectiveness of drugs such as etoposide (VePesid) and doxorubicin (Adriamycin). The basis for this work was eventually published in Biochemical Pharmacology in 2001 from my cobbling together other funds.

I sought to investigate whether complex St. John’s wort extracts would have a similar effect. Moreover, I hypothesized that different St. John’s wort products would vary in their drug interaction liability based on the content of the products since they are produced in different parts of the world by a spectrum of chemical extraction procedures.

I discussed some of the following story here at SBM in 2009. My initial attempt at getting funding for this new idea returned a priority score of 228. In the old form of NIH grant review scoring, the range was 100 to 500 where, as in golf, the lower score was better. A major criticism was that I as a pharmacologist lacked the chemical expertise to truly interrogate complex botanical extracts.

Fortunately, I was spending the 2000 calendar year doing a sabbatical at Duke University and was fortunate to meet the legendary co-discoverers of taxol and camptothecin, Drs. Monroe Wall and Mansukh Wani, at the nearby Research Triangle Institute. Who better to enlist as collaborators than the team that isolated and solved the structure of these two important drugs using the technology available in the 1960s and early 1970s. (Taxol itself became a prescription drug and has been followed by Taxotere/docetaxel; camptothecin never became a drug itself by gave rise to the semisynthetic FDA-approved drugs Camptosar/irinotecan and Hycamtin/topotecan).

When we resubmitted the grant application, my score became worse: 345. Yes, enlisting true scientific legends to help a little old pharmacologist investigate herbs was viewed as “taking too much of a drug development approach.” I shook my head in disbelief. What had I done wrong? Who better than the RTI group to provide me with chemistry support?

Dr. Wall was livid, to say the least. Without consulting me first – totally fine with me, though – he directly phoned the then-NCCAM director, the late Dr. Stephen Straus. Wall relates that Straus was taken aback by someone other than the application’s principal investigator calling to protest a grant score. Not a wise response. He was Monroe [expletive]ing Wall. Exasperated, he warned me and my colleagues not to waste any more time submitting grant applications to “those crazies.”

Of course, I wouldn’t take no for any answer and continued to craft and fine-tune my proposals. I ultimately joined RTI as an investigator and my colleagues and I submitted 13 proposal versions with not a single one being funded. Dr. Wall passed away in the summer of 2002, exasperated that we were still trying. (I ultimately got the project funded by NCI’s OCCAM but the St. John’s wort extracts did not appear to pose the same problems as the isolated pure compounds.)

These experiences led many of us to question to quality of natural products expertise at NCCAM and in their selection of review panels. For that reason, I offered my services as a grant reviewer almost any time NCCAM called to ask (I had to turn down a recent request because of other review conflicts). My feeling was that I’d rather be part of the solution than shrug off NCCAM as a problem. And, in fact, I’ve learned that NCCAM has recently hired a superb natural products chemist as an internal advisor. Perhaps, as noted in one of Trine’s articles, the NCCAM of today is different from the NCCAM of yesteryear.

But pharmacognosy – the study of natural products – is *not* alternative medicine. It is, in fact, the basis for at least 25% of our prescription drugs and up to 60% of some classes of over-the-counter drugs. (And thank you, Dr. Gorski, for repeatedly being a defender and supporter of pharmacognosy as a non-alternative science!).

Premature clinical trials

What worries me more is how pharmacognosy is approached by NCCAM and how damaging their supported studies can be in leading us to dismiss potentially useful botanical medicines. In attempting to show political supporters the benefits of alternative medicines, NCCAM seems to spend a disproportionate share of their appropriation on expensive clinical trials. My concern has been that clinical trials are warranted when sufficient basic science has been conducted. However, the rush to clinical trials has instead led to multiple clinical trials failures.

The latest example, cited in the Tsouderos articles, was a trial of saw palmetto berry extract for relief of urinary difficulties associated with benign prostatic hypertrophy in men. Published this year in JAMA, the trial revealed that urinary symptoms improved in both the placebo and saw palmetto groups. However, the study was missing one important component: even though increasing doses of saw palmetto extract was used, no one measured blood concentrations of the purported active constituents. Perhaps saw palmetto didn’t “work” better than placebo because the doses used did not contain a high enough concentration of the active compound(s). The supplementary materials for the paper very nicely showed the chemical composition of the extract used but we have no idea if enough of those compounds made it into the blood circulation of the study participants.

Contrast this to pharmaceutical clinical trials. The entire purpose of Phase I drug trials is to examine dosing relative to blood levels of parent drug and metabolites as well as getting a feel for potential adverse reactions. No one in their right mind would attempt – or waste money doing – an expensive, randomized, placebo-controlled drug efficacy trial without first making sure that the drug was being dosed at levels consistent with effects observed in preclinical models (enzyme assays, tissue or organ pharmacology, animal studies, etc.).

Why should we care if saw palmetto wasn’t more effective than placebo in this study? Well, for one, men with BPH might still have an option to prescription drugs if saw palmetto was dosed at a pharmacologically-relevant level. As I approach BPH age, this concern is not irrelevant.

In addition, saw palmetto berries are a cash crop in central Florida, as detailed in this article from investigators at the University of Florida’s Institute of Food and Agricultural Sciences. I’m not sure how negative clinical trials in JAMA might influence crop prices and consumer demand but I’d predict that a trial with a strong positive outcome would be beneficial to Florida farmers.

NCCAM could have great value

I still remain optimistic that NCCAM could be of value to researchers interested in science-based investigations of treatment modalities that are not currently accepted as standard medical practice. While specific ICs could probably do a better job with specific offices – using the OCCAM model at NCI – I believe that NCCAM has accumulated enough political momentum to remain a distinct entity. So, just as I am still willing to review grants for NCCAM, I want it to support the highest quality of science as long as it exists. This means supporting investigators who have strong preliminary data for their approach, that the approach is based in scientific fact that does not violate the basic tenets of chemistry and physics, moderating the rush to support clinical trials until the necessary basic science and human pharmacokinetics are completed (for botanical therapies), and being more open to the kinds of scientific criticism brought forth by journalists like Trine Tsouderos and my co-contributors here at SBM and elsewhere.

My Christmas wish is that we stop wasting money on nonsense.


A personal aside: I’ll be changing my academic affiliation on January 3rd to join the North Carolina State Museum of Natural Sciences as a science communications director in their new Nature Research Center (scheduled for a April 2012 opening). I’ve written more details about this move and a perspective on my research career at my main blog, Terra Sigillata. While I’ll no longer be principal investigator of my own laboratory, I still plan to have a presence in the NRC’s Laboratory of Microbiology and Genomics and conduct citizen science projects on secondary metabolites from microorganisms as potential therapeutics. But the bulk of my work there will actually be even more aligned with the mission of SBM: we’ll be showing the public how research is done rather than just giving facts – “how do we know.” In demonstrating the scientific method and getting people involved in local scientific projects, we hope to improve the level of critical thinking among the general citizenry to make better choices for themselves. I hope you’ll see my expanded professional mission represented in my SBM writings during 2012.





Posted by David J Kroll