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NCCAM is a victim of its own history

Let me begin with a story. An assistant professor submits a reasonable application to NCCAM to investigate the potential metabolic and pharmacodynamic interactions of St. Johns wort with conventional chemotherapy. This was the year or year-and-a-half before SJW was known to have significant CYP3A4 inductive activity due primarily to its component, hyperforin. Said investigator used this preliminary data, not explicitly required for theNIH funding mechanism (called an R21), to question whether St. John’s wort used by depressed cancer patients might interfere with chemotherapy. The original proposal earned a priority score of 228 (as with golf, the lower the better: the best is 100, the worst is 500.)

The major reviewer critique was that the assistant professor, Your Humble Pharmacologist, lacked, at the time, significant natural products chemistry expertise. YHP was then doing his sabbatical in the NC Research Triangle area and wisely sought the support and expertise of the now-late Dr. Monroe Wall and surviving Dr. Manuskh Wani. These gentlemen discovered and solved the structures of taxol from Taxus brevifolia and camptothecin from Camptotheca acuminata. Taxol itself became a blockbuster drug for Bristol-Myers Squibb while camptothecin required water-soluble modifications to foster topotecan (Hycamptin) and irinotecan (Camptosar) that collectively saved or prolonged the lives of thousands of men and women subjected to breast, ovarian, lung, and gastrointestinal tumors. In 2003, they received the designation of an American Chemical Society National Historic Chemical Landmark for their three decades of work in this area. (Sadly, they received none of the profits from these drugs as their discoveries pre-dated the Bayh-Dole Act that allowed NIH funded researchers to share in the revenues of intellectual property emerging from their work.).

Being a savvy young investigator, I sought and enlisted the assistance and support of Dr. Wall and colleagues to provide my team with world-class, natural products expertise. Stunningly, the subsequent application was awared a score of 345 (*much worse than the original) with the criticism from reviewers that all Dr. Wall did was to lend a drug development aspect to an otherwise “herbal” applicaton.

To this day, I cannot fathom who better I could have sought for natural products expertise on this grant application.

Since then, three of my colleagues and I have submitted 13 applications to NCCAM, including an application for a comprehensive Botanical Research Center grant. All 13 received unfundable scores. Among these was a 279-page application for a NCCAM Botanical Research Center – reviewed but not discussed by the evaluation panel.

Nonetheless, I have taken the approach that if NCCAM were to continue its existence, I would try to be part of the solution.  I have accepted several invitations to review research and training grants for NCCAM and I am pleased to say that one or two projects that I ranked highly ended up being very productive, specifically in the area of natural products and traditional herbal medicines.  I also have some friends and valued colleagues who contribute to the scientific integrity of NCCAM. However, my collective experiences lead me to believe that they are voices quenched by the vast wilderness of the promotion and advocacy of “integrative medicine” and CAM.

Chris Mooney recently asked the question as to why sci/med bloggers are up in arms about Sen Tom Harkin’s recent complaints about the National Center for Complementary and Alternative Medicine (NCCAM), the arm of NIH charged with funding studies to investigate the mechanisms and efficacy of modalities not currently considered mainstream medicine. I left a comment for Chris that ended up being a blog post so I’ll share it with readers here and expound a bit for good measure.The problem is that Harkin has stated that the establishment is discriminating against alternative medicine and that it seems to him that NCCAM has been doing too much to disprove the efficacy of alternative therapies. [see excellent post by Dr David Gorski and others here at Science-Based Medicine].The story of Harkin’s amazing statements were first popularized last week by Majikthise journalist, Lindsay Beyerstein, daughter of the famous Simon Fraser Univ Prof Barry L Beyerstein whose article, Why Bogus Therapies Often Seem to Work, I have used often in my lectures. Lindsay notes:

Harkin used his clout on the Appropriations Committee in 1992 to create the National Office of Alternative Medicine. In 1998 he co-sponsored legislation with Republican Bill Frist to upgrade the national office to a national center.

Over a decade later, Harkin’s disappointed that the NCCAM’s research is failing to confirm his biases.

Harkin doesn’t seem to realize that by publicly pressuring an ostensibly independent research center to produce positive results, he’s undermining the credibility of the center he worked so hard to create. If even if NCCAM does come up with positive results, Harkin’s giving the scientific community an excuse to discount that research as tainted.

In reality, many things have been tested, especially herbal remedies in my field, but the majority of the results have been negative. To the contrary of Harkin’s view of NCCAM and the researchers they supported, I would submit that the PIs of these grants were primarily advocates of alternative therapies who were sorely disappointed their ideas didn’t flesh out.

Harkin seems to be espousing an advocacy role rather than a scientific role. Moreover, the foursome that he brought to testify to the Senate primarily spoke of preventive medicine approaches that are not considered “alternative” but are rather being co-opted by so-called “integrative medicine” as their own since the more unscientific modalities have not proven effective. Saying that nutrition and cardiovascular preventive approaches are CAM or integrative medicine is utterly ridiculous.

Hence, I submit that integrative medicine is not “transformational.” Instead, it is the thinly veiled adoption of real medicine that works to provide an air of legitimacy around the highly-questionable approaches often offered, packaging it into a new-agey vibe where “patients” can go to spa-like clinics on academic medical center campuses, and have the luxury of paying out-of-pocket for “services.”

Yes, the key to the integrative business model is avoiding that nasty insurance business and capturing those willing and able to pay. I am waiting for a medical economics study to confirm my informal observations but integrative medicine, IMHO, is medicine for the rich and famous.

Believe me, as a natural products pharmacologist I would love to see some of these remedies have therapeutic efficacy. They may ultimately do so if proper basic science is done first that informs the dosing schedules used for clinical trials. However, NCCAM was under political pressure to show some benefit of anything and therefore supported expensive clinical trials in premature, Hail Mary attempts to get quick and early payoffs.

Instead, NCCAM is left with a trash heap of negative data (ginkgo, glucosamine/chondroitin, echinacea, St. John’s wort, shark cartilage) – not because the approaches are being discriminated again but rather because the science did not support their efficacy.

Hence, I argue that NCCAM is a victim of itself and its own establishment as an advocacy arm, not a scientific arm, of NIH.

Posted in: Basic Science, Herbs & Supplements, Politics and Regulation, Science and Medicine

Leave a Comment (19) ↓

19 thoughts on “NCCAM is a victim of its own history

  1. Joe says:

    To impress the folks at NCCAM, perhaps you should have partnered with Sean Connery’s character from “Medicine Man.”

  2. marilynmann says:

    I have a question, and forgive me if you have already answered it on your blog. Given that in the U.S. herbal remedies are not required to prove safety and efficacy before going on the market, and not even required (so far as I know) to contain the active ingredients that they disclose on the label, which studies have shown to vary widely from one company or even batch to another, isn’t that a fundamental problem with researching herbal remedies? Suppose SJW were found to work (from what I hear the positive trials were all done in Germany for some reason). Even then, how could a physician recommend use of SJW to his or her patient without knowing the specific dosages for any particular SJW supplement?

  3. Marilyn, you are absolutely correct on the variability issue. That is why any herbal formulation used in a clinical trial should be exhaustively characterized chemically. The best example of this was of an Echinacea angustifolia product from a 2005 NEJM paper to test rhinovirus prevention – the trial failed but the 22 pages of analytical chemistry in the supplementary material was superb and should be a model for future studies.

    The primary reason I think that German antidepressant trials of SJW were positive is that European manufacturers generally produce pharmaceutical grade, highly-characterized botanical products. Some are available in the US but are very expensive (as compared with store brands). My only caveat is that some US antidepressant trials with the German products (Lichtwer Pharma’s LI160, for example) did not prove better than placebo. I don’t have a good explanation for that.

    In our laboratory together with my chemistry collaborators, we analyze the content of any extracts we use – here is a 2005 Cancer Research paper from our group illustrating such an analysis of commercial milk thistle products. However, we are also trying to study the isolated single constituents and determine if there is any synergy among the individual compounds in prostate cancer models.

  4. marilynmann says:

    Interesting, thanks.

  5. Joe says:

    David wrote “The primary reason I think that German antidepressant trials of SJW were positive is that European manufacturers generally produce pharmaceutical grade, highly-characterized botanical products.”

    Yet, I dare say, if there was an active ingredient- they did not identify it. Otherwise, every other researcher would focus on it and know how to standardize the herb. Thus, no matter how meticulous the analysis is, it is futile. Although, if reliable activity is detected in an herb, knowing the (characterized) components helps find the active ingredient through fractionation.

    David wrote “My only caveat is that some US antidepressant trials with the German products (Lichtwer Pharma’s LI160, for example) did not prove better than placebo. I don’t have a good explanation for that.”

    I subscribe to the notion that one does not impute to malice that which can be explained by incompetence. It seems to me that homeopathy is big in Germany, and that taints all their dubious (AM) research. That is, when it comes to AM, their standards are low.

  6. Dr Benway says:

    …with the criticism from reviewers that all Dr. Wall did was to lend a drug development aspect to an otherwise “herbal” applicaton.

    LOL. As telling as Harken’s little gaff about NCCAM not doing enough to “prove” CAM therapies.

    The distinction between a “drug” and an “herb” is political, not scientific. For an herb by any other name –including “drug”– would smell as sweet to a suffering patient, provided it had been proven safe and effective.

    I hope you saved the hard evidence of this communication.

  7. happyhumanist says:

    Joe,

    I did some research on securing a NCCAM grant. It seems that you can’t test one chemical component (or active ingredient). You have to test the herb (whichever part is considered active–the leaves, the root, whatever). If a chemist were to isolate one compound and test it, that would disqualify him/her for the grant.

    David, that may be why adding the prestigious researchers to your study doomed you. They isolate chemicals from plants. That’s a big NCCAM no-no!

  8. Joe says:

    @happyhumanist on 07 Mar 2009 at 3:37 pm

    Dang! Just that.

    A long time ago, I worked in a machine shop and picked-up a certain, salty, vocabulary; but “Dang” conveys the point here.

  9. Dr Benway says:

    It seems that you can’t test one chemical component (or active ingredient).

    *scratches head*

    Any reason why? It seems an arbitrary limitation.

  10. Charon says:

    Dr Benway: Because a single chemical is a drug (shudder), instead of a “natural” herbal cure? Herbal remedies that work simply must be different from drugs that work (*stamps feet*).

    Just a guess. I’m an astrophysicist by trade, but fighting against quack naturopathic medicine is a hobby.

  11. Again, what we have here is discordance between pharmacology and federal regulations. Because of the 1994 DSHEA legislation, botanical products (whole herb or crude extracts) can be sold without FDA approval as long as label claims 1) do express the intention for disease treatment or prevention and 2) also include the meaningless “has not been assessed by FDA” disclaimer in microprint.

    However.

    If a botanical medicine is to be used for a drug indication, as has been done by my Colorado colleagues in a Phase I trial of milk thistle in prostate cancer pts, one must file a Botanical Investigative New Drug Application (FAQ here). This abbreviated version of a single-entity IND allows one to use historical data on an herb’s safety and years of traditional use as a substitute for preclinical toxicology studies, thereby allowing administration to humans for a disease treatment or prevention study.

    But, yes, if one were to purify an active compound from an extract, you could not qualify for a botanical IND since there is not a traditional history of use of that single compound (yes, I know, even if it has been used for years in the context of an extract).

    I should note that a handful of companies with excellent scientists are working on gaining FDA approval for highly-characterized botanical extracts where the science supports the mixture may have efficacy and/or a superior side effect profile than the individual constituents.

    A good example is Sativex, an oromucosal spray containing extracts of two strains of Cannabis sativa, used for muscle spasticity in multiple sclerosis and nausea and appetite in cancer patients. Marinol (dronabinol) is a single prescription cannabinoid (delta-9-THC) approved for the cancer indication as well as the anorexia and weight loss in AIDS. However, the single agent has been reported by patients to cause dysphoria and has failed to gain market share – while I’ve not seen a head-to-head comparison, marijuana users who have previously been given dronabinol report that marijuana provides better efficacy and few disturbing experiences.

    Geoffrey Guy, a British physician and founder of GW Pharmaceuticals, acknowledges that smoking is not an acceptable drug delivery method. Moreover, he, together with botanical expert Ethan Russo, recognized that 60+ other cannabinoids in marijuana have both beneficial effects and may minimize the dysphoric effects of pure THC. They developed and patented two strains of the marijuana plant, one optimized for THC content and the other for cannabidiol (CBD). CBD has no intoxicating effects of itself but the combination appears to be more effective and better tolerated than THC alone. Each of the two extracts in the spray are optimized for THC and CBD, respectively, but they also contain all of the other cannabinoids present in each plant. It’s actually pretty remarkable and complex, but the spray has been approved in the UK, Canada and is in clinical trials in the US and Catalonia (I’m sure I missed something but their FAQ is here)

  12. Dr Benway says:

    I imagine a general research pattern like this:

    1. botanical in use somewhere as a folk remedy long enough to appear relatively safe.
    2. controlled trial for efficacy is performed using crude botanical
    3. chemical components of botanical are characterized, along with their relative variability from plant to plant.
    4. suspected active ingredient(s) are identified
    5. trials with active ingredient(s)

    If a researcher applies for an NCCAM grant for #2 and/or #3, I don’t see why the application would be rejected on the basis of that researcher having prior experience with #4 and #5 studies. The grant in question doesn’t fund #4 or #5.

    Looks like anti-chemistry pharmacology, which I can’t get my head around.

    “You may ask questions about which parts of the plant are most useful, so long as you’re not talking about itty bitty molecular parts.”

    The doublethink is an outrage.

  13. Khym Chanur says:

    I wonder if your proposal would have gotten a better score if it had been worded to say that it was studying if giving SJW to chemo patients was a good thing.

  14. mandydax says:

    I still haven’t heard back from Senator Harkin. Nothing at all. Bad woo-politician! No vote for you!

    *sigh*

  15. A-L-E-X says:

    Ive seen some doctors (such as Ray Sahelian, MD, Ph.D) actually recommend St John’s Wort for mild to moderate depression, Saw Palmetto for BPH and Huperzine for memory loss… and Ive seen some studies which seem to verify some level of efficacy. Are you saying that all natural supplements are ineffective or are there some exceptions (such as these)? The chemical actions of the following seem to be well-documented:

    http://en.wikipedia.org/wiki/Hyperforin

    Pharmacology

    Hyperforin is a prenylated phloroglucinol believed to be the main active constituent responsible for the antidepressant effects of extracts of St John’s wort.[3] Hyperforin has been shown to inhibit the uptake of the neurotransmitters serotonin, dopamine, noradrenaline, GABA and glutamate.[4] It was identified as a specific activator of the ion channel TRPC6 which is involved in neuronal axonal sprouting. The activation of TRPC6 causes entry of sodium and calcium ions in neuronal cells which can explain the inhibition of neurotransmitter uptake.[5]
    Hyperforin is also thought to be responsible for the induction of the cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to the Pregnane X Receptor (PXR).[6]

    http://en.wikipedia.org/wiki/Huperzine

    Huperzine A has also attracted the attention of Western medical science. It is currently being investigated as a possible treatment for diseases characterized by neurodegeneration – particularly Alzheimer’s disease.[2][3] It has been found to be an inhibitor of the enzyme acetylcholinesterase.[4] This is the same mechanism of action of pharmaceutical drugs such as galantamine and donepezil used to treat Alzheimer’s disease. Huperzine A is also a NMDA receptor antagonist[citation needed] which protects the brain against glutamate induced damage, and it increases nerve growth factor levels.[citation needed]

    Clinical trials in China have shown that huperzine A is comparably effective to the drugs currently on the market, and may even be a bit safer in terms of side effects.[citation needed] Currently, the National Institute on Aging is conducting a Phase II clinical trial to evaluate the safety and efficiency of huperzine A in the treatment of Alzheimer’s disease in a randomized controlled trial of its effect on cognitive function.[citation needed] Recently, it has been investigated for its effectiveness against epilepsy in an initial 20-person clinical study by Harvard University neuroscientists examining its worth and side effects in those who are not satisfactorily treated by existing pharmaceuticals.[citation needed]

  16. A-L-E-X says:

    Some other substances that Ive found to be of some benefit:

    Co-Enzyme Q10:

    http://en.wikipedia.org/wiki/Coenzyme_Q

    Supplementation

    Because of its ability to transfer electrons and therefore act as an antioxidant, Coenzyme Q is used as a dietary supplement.

    According to the Mayo Clinic[9] “CoQ10 has been used, recommended, or studied for numerous conditions, but remains controversial as a treatment in many areas.” Further clinical results are needed to determine whether the supplementation with Coenzyme Q10 is beneficial for healthy people.

    [edit] Mitochondrial disorders

    Supplementation of Coenzyme Q10 is a treatment for some of the very rare and serious mitochondrial disorders and other metabolic disorders, where patients are not capable of producing enough coenzyme Q10 because of their disorder. Coenzyme Q10 is then prescribed by a physician.[10]

    [edit] Heart failure

    There is some clinical evidence[11] that supplementation with Coenzyme Q10 is beneficial treatment of patients with congestive heart failure. However, The American College of Cardiology recently published an expert consensus document concluding that the value of coenzyme Q10 in cardiovascular disease has not been clearly established.[12] The Mayo clinic says that there is not enough scientific evidence to recommend for or against the use of CoQ10 in patients with coronary heart disease.[9]

    [edit] Migraine headaches

    Supplementation of Coenzyme Q10 has been found to have a beneficial effect on the condition of some sufferers of migraine headaches. So far, three studies have been done, of which two were small, did not have a placebo group, were not randomized, and were open-label,[13] and one was a double-blind, randomized, placebo-controlled trial, which found statistically significant results despite its small sample size of 42 patients.[14] Dosages were 150 to 300 mg/day.

    [edit] Cancer

    It is also being investigated as a treatment for cancer, and as relief from cancer treatment side-effects.[15]

    [edit] Cardiac arrest

    Another recent study shows a survival benefit after cardiac arrest if coenzyme Q10 is administered in addition to commencing active cooling (to 32–34 degrees Celsius).[16]

    [edit] Blood pressure

    There are several reports concerning the effect of CoQ10 on blood pressure in human studies.[17] In a recent meta-analysis of the clinical trials of CoQ10 for hypertension, a research group led by Professor Frank Rosenfeldt (Director, Cardiac Surgical Research Unit, Alfred Hospital, Melbourne, Australia) reviewed all published trials of Coenzyme Q10 for hypertension, and assessed overall efficacy, consistency of therapeutic action, and side-effect incidence. Meta-analysis was performed in 12 clinical trials (362 patients) comprising three randomized controlled trials, one crossover study, and eight open-label studies. The research group concluded that coenzyme Q10 has the potential in hypertensive patients to lower systolic blood pressure by up to 17 mm Hg and diastolic blood pressure by up to 10 mm Hg without significant side-effects.[18]

    [edit] Biosynthesis

    The benzoquinone portion of Coenzyme Q10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is also used for the first steps of cholesterol biosynthesis.

    [edit] Inhibition by statins and beta blockers

    Coenzyme Q10 shares a common biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of Coenzyme Q10, mevalonate, is inhibited by some beta blockers, blood pressure-lowering medication,[19] and statins, a class of cholesterol-lowering drugs.[20] Statins can reduce serum levels of coenzyme Q10 by up to 40%.[21] Some research suggests the logical option of supplementation with coenzyme Q10 as a routine adjunct to any treatment that may reduce endogenous production of coenzyme Q10, based on a balance of likely benefit against very small risk.[22][23]

    [edit] Absorption and metabolism

    CoQ10 is a crystalline powder that is insoluble in water due to its low polarity. It has a relatively high molecular weight (863 g/mol) and its solubility in lipids is also limited so it is very poorly absorbed in the gastrointestinal tract.[24],[25] Absorption follows the same process as that of lipids and the uptake mechanism appears to be similar to that of vitamin E, another lipid-soluble nutrient. Emulsification and micelle formation is required for the absorption of fats. For CoQ10, this process is chiefly facilitated by secretions from the pancreas and bile salts in the small intestine.[26] A general rule is that the higher the dose orally administered, the lower the percent of the dose absorbed.[26]

    Data on the metabolism of CoQ10 in animals and humans are limited.[24] A study with 14C-labeled CoQ10 in rats showed most of the radioactivity in the liver 2 hours after oral administration when the peak plasma radioactivity was observed, but it should be noted that CoQ9 is the predominant form of coenzyme Q in rats.[27] It appears that CoQ10 is metabolised in all tissues, while a major route for its elimination is biliary and fecal excretion. After the withdrawal of CoQ10 supplementation, the levels return to their normal levels within a few days, irrespective of the type of formulation used.[28]

    [edit] Pharmacokinetics and bioavailability

    Some reports have been published on the pharmacokinetics of CoQ10. The plasma peak can be observed 2-6 hours after oral administration, mainly depending on the design of the study. In some studies, a second plasma peak was also observed at about 24 hours after administration, probably due to both enterohepatic recycling and redistribution from the liver to circulation.[29] Tomono et al. used deuterium-labelled crystalline CoQ10 to investigate pharmacokinetics in human and determined an elimination half-time of 33 hours.[30]

  17. A-L-E-X says:

    Phosphatidyl Serine:

    http://en.wikipedia.org/wiki/Phosphatidyl_serine

    Memory and cognition

    Early studies of phosphatidylserine distilled the chemical from bovine brain. Because of concerns about Bovine Spongiform Encephalopathy, however, modern studies and commercially available products are made from soybeans. The fatty acids attached to the serine in the soy product are not identical to those in the bovine product, which is also impure. However, preliminary studies indicate that the soy product is at least as effective as that of bovine origin. [1][2]

    On May 13, 2003, the U.S. Food and Drug Administration stated “based on its evaluation of the totality of the publicly available scientific evidence, the agency concludes that there is not significant scientific agreement among qualified experts that a relationship exists between phosphatidylserine and reduced risk of dementia or cognitive dysfunction.” FDA did, however give “qualified health claim” status to phosphatidylserine, stating that “Consumption of phosphatidylserine may reduce the risk of dementia in the elderly” and “Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly”.

    [edit] Sports nutrition

    Phosphatidylserine has been demonstrated to speed up recovery, prevent muscle soreness, improve well-being, and might possess ergogenic properties in athletes involved in cycling, weight training and endurance running. Soy-PS, in a dose defendant manner (400mg), has been reported to be an effective supplement for combating exercise-induced stress by blunting the exercise-induced increase in cortisol levels.[3] PS supplementation promotes a desirable hormonal balance for athletes and might attenuate the physiological deterioration that accompanies overtraining and/or overstretching.[4] In recent studies, PS has been shown to enhance mood in a cohort of young people during mental stress and to improve accuracy during tee-off by increasing the stress resistance of golfers.[5]

    [edit] Attention-deficit hyperactivity disorder

    First pilot studies indicate that PS supplementation might be beneficial for children with attention-deficit hyperactivity disorder.[6][7]

    [edit] Safety

    Traditionally, PS supplements were derived from bovine cortex (BC-PS); however, due to the potential transfer of infectious diseases, soy-derived PS (S-PS) has been established as a safe alternative. Soy-derived PS is Generally Recognized As Safe (GRAS) and is a safe nutritional supplement for older persons if taken up to a dosage of 200 mg three times daily. [8] Phosphatidylserine has been shown to reduce specific immune response in mice. [9][10]

    [edit] Dietary sources

    PS can be found in meat, but is most abundant in the brain and in innards such as liver and kidney. Only small amounts of PS can be found in dairy products or in vegetables, with the exception of white beans.

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