The SkeptVet Blog

Some of the most popular forms of alternative medicine are the myriad herbs and “dietary supplements” (a faux category created by the 1994 Dietary Supplement Health and Education [DSHEA] act to allow marketing of unproven drugs without regulatory oversight). These nostrums are potentially more useful than outright quackery like homeopathy or “energy medicine” because they contain actual physiologically active chemicals. Unfortunately, that means these are also the most likely for of CAM to cause direct harm.

There have been numerous examples of this kind of harm in the past. Kidney failure caused aristolochic acid in traditional Chinese medicines, lead poisoning from contaminated Ayurvedic and Chinese preparations, and deaths from ephedra-containing supplements such as ma huang are among the most dramatic and well-publicized examples. Below is an extensive list of references regarding these and other such examples.

Despite this, the perception that such preparations are “safe and natural” still seems widespread, and it seems difficult to disabuse people of this notion. However, I am encouraged by a number of recent indications that the risks associated with untested and unregulated supplement use may be getting more attention. I recently wrote about an article looking at the association of herbal therapy with poorer compliance and quality of life in asthma patients.

Another article on the subject that recently caught my attention was entitled Dietary Supplement Polypharmacy: An Unrecognized Public Health Problem?, published in eCAM. The article is essentially a series of anecdotes, so of course it proves nothing about the overall impact of herbal remedies. However, the theme that emerges from the cases reported strikes me as key to understanding the risks of such treatments. The cases almost all involved people who took herbal preparations for more psychological than medical or rational reasons. They generally took a variety of supplements, often with no systematic dosing or schedule or even any understanding of what they were taking or what the intended effects or possible side effects were. This is only possible because these people accepted the baseless notion that somehow because they were “natural” these preparations could be expected to have beneficial effects without any risk, any dose/response relationship, or any of the usual limitations know to affect pharmaceuticals.

Ironically, the people discussed in the article also commonly reported turning to herbs and supplements because of fears of the side effects of conventional medical therapies. This is similar to the attitude reported in the study of asthma patients. Clearly, any therapy that has measurable effects is going to be tinkering with a complex and massively interconnected system, and this makes it highly likely that unanticipated or undesirable effects will occur as well. In scientific medicine, it is understood that all therapeutic decisions require a cost/benefit analysis, and that while it is appropriate to avoid unnecessary interventions that might do more harm than good, there are clearly many circumstances in which the risks of a treatment are far outweighed by the potential benefit. CAM advocates and users seem to have the notion that these rules only apply to conventional medicine, and they tend to have an exaggerated awareness of risks while taking the benefits for granted. They then fall prey to the irrational and demonstrably false notion that CAM therapies are exempt from the rules of pharmacology and physiology that constrain scientific medicine and that they can somehow get something for nothing–benefits without risk. This is a dangerous notion which must be debunked so that the true potential of herbal medicines can be developed in a rational and scientific way and unnecessary risks be avoided.

Finally, the cases illustrate the sense many CAM users have of not being in control of their medical care when dealing with conventional, scientific medicine. Being able to change their diet, take supplements or herbal remedies guided by their own internal sense of how they are responding, and so on gives them a feeling of having some control over their bodies and their care. This is a challenging psychological issue. Scientific medicine has rightly moved away from the paternalistic model and acknowledges that patients have the ultimate right to make decisions about their own care. However, it is also an undeniable fact that health care have factual knowledge and a overall perspective that make their assessments and decisions about specific interventions generally more reliable than those of lay people with a personal and intense emotional investment in their or their pets health.

Somehow, scientific medical providers need to do a better job of dealing with the psychological aspects of disease in their patients or, in the veterinary domain, their patients’ owners. We must understand and manage the normal psychological factors that lead people into use of unproven or bogus therapies while maintaining a solidly scientific and evidence-based standard for the medicine we employ. And we must do all of this within the limitations of time and resources under which we operate. A significant challenge indeed.

Another article I ran across recently that bears of the dangers of herbal medicine use is A review of the potential forensic significance of traditional herbal medicines in the Journal of Forensic Sciences (Byard RW. 2010:55(1);89-92). This is a nice summary of some of the specific dangers of unregulated and unscientifically used herbal preparations, including direct toxicity, heavy metal poising, adulteration with toxins, interaction effects of multiple active compounds taken together, and interactions with conventional medicines. These risks are exacerbated by the facts that many users of herbal remedies don’t tell their doctors what they are taking (or they may not know themselves), most doctors know little about the possible risks of such remedies, and there is no meaningful regulatory control over the preparation or marketing of these products.

On this last point, a revision to DSHEA has been proposed in the Senate by Tom McCain (R-AZ) and Byron Dorgan (R-ND). While not perfect, this bill would improve the FDA’s ability to monitor dietary supplements and other currently under-regulated supplements and to force removal of these from sale if there is evidence of harm. Given the power of the supplement lobby and their biggest legislative boosters, Tom Harkin (D-IA) and Orin hatch (R-UT), and the general anti-regulation mood of the country, I am not overly optimistic this will become law, but I am encouraged at least that mainstream political figures are at least willing to talk about the inadequacy of consumer protections in the area of herbs and supplements, and this alone may raise awareness of this underappreciated risk.
Coon JT, Ernst E. Panax ginseng: A Systematic Review of Adverse Effects and Drug Interactions. Drug Saf 2002;25(5):323-44 Drug Saf 2002;25(5):323-44

Cupp MJ  Herbal remedies: adverse effects and drug interactions. Am Fam Physician 1999 Mar 1;59(5):1239-45

Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int. 2008 Jul;74(2):158-69. Epub 2008 Apr 16.

Emery DP, Corban JG  Camphor toxicity. J Paediatr Child Health 1999 Feb;35(1):105-6

Ernst E Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000 Nov;143(5):923-

Fugh-Berman A Herb-drug interactions. Lancet 2000 Jan 8;355(9198):134-8

Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol. 1997 Apr;37(4):344-50

Lai MN, Lai JN, Chen PC, Tseng WL, Chen YY, Hwang JS, Wang JD. Increased risks of chronic kidney disease associated with prescribed Chinese herbal products suspected to contain aristolochic acid. Nephrology (Carlton). 2009 Apr;14(2):227-34.

Lawrence JD.  Potentiation of warfarin by dong quai. Page RL 2nd, Pharmacotherapy 1999 Jul;19(7):870-6

Means C.  Selected herbal hazards. Vet Clin North Am Small Anim Pract 2002 Mar;32(2):367-82

Norred CL, Finlayson CA Hemorrhage after the preoperative use of complementary and alternative medicines. AANA J 2000 Jun;68(3):217-20

O’Connor A, Horsley CA. Yates, KM “Herbal Ecstasy”: a case series of adverse reactions.  N Z Med J 2000 Jul 28;113(1114):315-7

Pittler MH. Ernst, E Risks associated with herbal medicinal products. Wien Med Wochenschr 2002;152(7-8):183-9

Poppenga RH. Risks associated with the use of herbs and other dietary supplements. Vet Clin North Am Equine Pract. 2001 Dec;17(3):455-77, vi-vii

Pies R  Adverse neuropsychiatric reactions to herbal and over-the-counter “antidepressants”. J Clin Psychiatry 2000 Nov;61(11):815-20

Prakash S, Hernandez GT, Dujaili I, Bhalla V. Lead poisoning from an Ayurvedic herbal medicine in a patient with chronic kidney disease. Nat Rev Nephrol. 2009 May;5(5):297-300.

Raman P, Patino LC, Nair MG. Evaluation of metal and microbial contamination in botanical supplements. J Agric Food Chem. 2004 Dec 29;52(26):7822-7

Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G  Acute heart transplant rejection due to Saint John’s wort. Lancet 2000 Feb 12;355(9203):548-9

Saper RB, Phillips RS, Sehgal A, Khouri N, Davis RB, Paquin J, Thuppil V, Kales SN. Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet. JAMA. 2008 Aug 27;300(8):915-23.

Shad JA, Chinn CG, Brann OS Acute hepatitis after ingestion of herbs. South Med J 1999 Nov;92(11):1095-7

Smolinske SC J Am Med Womens Assoc 1999 Fall;54(4):191-2 Dietary supplement-drug interactions.

Yang HY, Wang JD, Lo TC, Chen PC. Increased mortality risk for cancers of the kidney and other urinary organs among Chinese herbalists. J Epidemiol. 2009;19(1):17-23. Epub 2009 Jan 22.

Zhang SY, Robertson D. A study of tea tree oil ototoxicity. Audiol Neurootol 2000 Mar-Apr;5(2):64-8

Kidney failure from aristolochia in TCM herbals preparations.

Lead, mercury and arsenic in herbal preparations.

Lead in TCM preparations.

Lead in ayurvedic preparations.

Lead in herbal preparations.

Tea Tree Oil Can be toxic to cats.

Toxic metals in Brazilian herbal preparations.

Contamination of herbal products with undisclosed pharmaceuticals.Widespread contamination of supplements with undisclosed toxins and parmaceuticals

Proponents of CAM often claim that one major advantage to their methods is the absence of side effects seen with conventional medical treatments. This makes little sense since there is no “free lunch” in physiology, and an intervention that affects one part of the system is going to have effects on other parts as well. Those practitioners who claim a “holistic” approach ought to realize this. If the treatment has absolutely no side effects, it’s probably because it isn’t doing anything at all.

And there is plenty of evidence that some CAM treatments can be harmful. While certain therapies, like homeopathy or reiki, may have little direct harm, they can still discourage patients from seeking and complying with more effective, evidence-based therapies. And the very CAM therapies most likely to turn out to have real benefits, herbal preparations, are also the most likely to cause unintended harmful effects, which is why they need to be properly studied before being used in practice.

A recent article in the Annals of Allergy, Asthma and Immunology surveyed primarily low-income inner city patients with chronic asthma to identify use of herbal treatments and any apparent association with how well their disease was controlled. What they found was that a moderate number of patients (25%) used herbal remedies for their asthma. Only about 39% of these people told their doctors about the use or herbal remedies, which raises the concern for unanticipated drug interactions. And about 20% of the herbal medicine users (about 5% of the total number of patients) used herbal treatments in place of their prescribed therapies.

Not surprisingly, the folks who used herbal preparations had a lower quality of life score and were significantly less likely to be complaint with their prescribed treatment regime than those patients who did not use herbal products. The authors also reported a trend towards poorer asthma control scores among herbal users. but this did not achieve statistical significance so it may not be a real finding.

The authors were careful to point out, correctly, that the association cannot identify a causal connection between quality of life and herbal remedy use. The poorer compliance with prescribed therapy can reasonably be suspected to be the causal factor, but it is impossible from this study to rule out a direct harmful effect from the herbal remedies or the possibility that people are seeking these remedies because they are not having an acceptable response to conventional therapy and that their poor compliance came after turning towards the CAM therapy.

However, there was also a correlation between use of herbal treatments and certain beliefs about conventional therapy, including concern about possible side effects and difficulty in following the prescribed treatment regime. This suggests that anxiety about the conventional treatment might be associated with susceptibility to the promises of safe and easy relief often used to market herbal therapies. This paper illustrates the dangers of such marketing strategies, which play into patient concerns which may be perfectly legitimate but which then offer alternatives which do not provide the relief the patient is seeking.

I recently received a tip about a pest control product for pets (and people) that has woo written all over it. Anaglyph over at Tetherd Cow has written about the shooTAG pest repellant device, and has posted a follow-up response to a comment from the company CEO. I have little to add to his comments.

The product promotional materials are entertaining to read if you like science fiction. They freely refer to mysterious “bioenergetic fields,” “resonances,” and, of course, “quantum physics.” They offer testimonials and fanciful pseudoscientific explanations for how the product, which seems from the description to amount to a little strip of magnetic tape like the one on the back of your credit card,  somehow interacts with mysterious energies from the pet and the earth to repel pests. What they don’t offer is anything resembling a plausible scientific rational or actual research evidence to suggest any of their claims are true.

Some examples:

“ shoo!TAG™ represents a paradigm shift in the pest management industry. shoo!TAG™ utilizes Nature’s energetic principles in combination with physics, quantum physics and advanced computer software technology. The key to shoo!TAG™ is the three dimensional electromagnetic field embedded in the magnetic strip.

shoo!TAG™ utilizes the power of the bio-energetic field which surrounds all living things to create a frequency barrier which repels targeted pests for up to four months.

shoo!TAG™’s magnetic strip is encoded with beneficial frequencies and resonances and an electromagnetic charge bearing a polarized energy signature, which when introduced into the bio-energetic field of the wearer produces results. ”

As always, one must be suspicious of “paradigms shift” language, which basically says, “We’ve found something that contradicts all the know laws of established science and we know it works because we think it works.” Likewise, non-physicists claiming to explain unlikely mysteries by referring to quantum physics is a big red flag. Quantum phenomenon are weird, but they seem only to apply at the atomic level, not the macroscopic level of dogs and fleas, and the mathematics required to truly understand them, as opposed to the metaphors of popularized explanations, is beyond most of us. That makes it easy to refer to a mysterious process as due to “quantum physics,” but it’s just a bit of vacuous pseudoscientific gibberish designed to obscure the lack of a real mechanism of action.

The company web site also makes pretty strong claims of efficacy, which I would think would interest the federal government since such claims have to be backed up by actual scientific evidence or they constitute fraudulent advertising. Sadly, the government rarely has time to investigate and control such small-time mountebanks, and they usually just switch labels and IP addresses and continue selling their quackery.

The only part of the company materials that goes beyond entertaining nonsense to outright irresponsible BS is the frequent claims that if the product doesn’t seem to be working, one should blame not the product but the “toxic” medical treatments the pet may have previously received, such as steroid medication, vaccines, and validated pest control products. Apparently these have not only their know side effects but mysteriously perturb the undetectable energy fields of our pest I such a way as to render the quantum mechanical mechanism of the wooTag–uh, I mean shooTAG– ineffective.

” Please keep in mind that if an animal has recently had a surgery, vaccinations, steroid medication, or you have been using heavy poison products on them it will take longer for your animal to detox and strengthen its energy field. It is important to note that, because the tags work with your pet’s energy field, it is important that they are as healthy as possible. We have found that animals that are on or have recently taken steroid drugs, that have recently had surgery, or are old do not respond well to our products.”

Once again we see a company marketing unproven, and unlikely nonsense through fear and misinformation and rationalizing their own failure by trying to shift the blame to the animals, the owners, or the medical therapies previously given. Truly irresponsible, shameless profiteering at the expense of pet owner’s fears. The people who promote such should be, but apparently cannot be, ashamed.

Back in September, I reviewed the evidence (or lack thereof) supporting claims of benefits from nutraceuticals in cognitive dysfunction. One of the more popular ingredients in many of the products sold with such claims is Ginkgo biloba, and at the time of my earlier review I concluded:

“The clinical trial evidence in humans does not support a beneficial effect for cognitive impairment or dementia, as summarized in a Cochrane review…”

This month, a new study of ginkgo biloba for prevention of cognitive decline in humans has been published in the Journal of the American Medical Association. It is a large, multicenter, randomized, double-blinded, placebo-controlled prospective clinical trial, and thus represents a very high level of evidence. It concludes quite clearly.\

“Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.”

Another nail in the coffin for this particular wonder-herb.

At last, the definitive nail in the coffin of chiropractic? Hardly. A recent study in the journal Chiropractic and Osteopathy uses an epidemiological approach to examine the question of whether the founding “lesion” of the chiropractic philosophy, the vertebral subluxation, can be shown to be associated with any disease. Their conclusion reads like a Science-Based Medicine or Quackwatch summary:

“Subluxation was not found to be linked to any one disease complex…There were no studies that offered a biological plausibility that would isolate subluxation as a causal factor in disease. There were no studies linking the subluxation as a coherent construct and supported by generally known facts about the natural history and biology of any disease. There were no studies found that suggested the subluxation as a causal agent similar to other factually demonstrated causal agents…There is significant lack of evidence to fulfill basic criteria of causation. This lack of crucial supportive epidemiologic evidence prohibits the accurate promulgation of the chiropractic subluxation.”

Short and sweet, the basic abnormality chiropractors claim to fix cannot be shown to exist or to cause any disease. One might think this would be a fatal blow to the enterprise of chiropractic, but sadly that is not the case. For one thing, it has been shown before in other studies that the subluxation cannot be reliably identified by chiropractors and that when pushed to demonstrate it in some objective way, most chiropractors and their lobbying organizations engage in some impressive yoga to cover the fact that they cannot. But as chiropractic is fundamentally faith-based medicine, being unable to demonstrate that the disease they are treating exists doesn’t worry chiropractors. Even those who disavow the subluxation theory happily continue the sort of manipulative practices Palmer originally invented to fix the supposed subluxation, and they simply justify it with the time-honored refuge of all woo, “Well, I don’t know how or why it works, but it works!”

Of course, this conclusion cannot be reliably demonstrated by objective evidence either. Though chiropractic does seem to have some benefit on subjective perceptions idiopathic lower back pain, the fact is it has been shown to be at best roughly equivalent to conventional therapy (rest, NSAIDs, physical therapy, and patient education materials) or to a good massage. If it were truly risk free and presented truthfully as offering mild benefits for back pain, I would have no objections. And a few chiropractors have adopted this approach in an attempt to take what benefit their interventions might provide out of the realm of faith and into that of responsible medicine, but these are a minority and often reviled within their own profession. But while I believe evidence is critical and should be the cornerstone of medical practice, I also understand that it is not as compelling as personal experience for many people, and the first step on the road to recovery from addiction to unscientific therapies is to understand we have a problem and need something better than our own experience and intuition to validate or invalidate the safety and efficacy of medicine. So while this should be a critical study undermining the claims of mainstream chiropractic, it has garnered little attention and will probably have little impact on the popularity of the method.

I recently ran across an article in the journal Evidence-Based Complementary and Alternative Medicine (eCAM) titled Evaluating Complementary Therapies for Canine Osteoarthritis–Part II: A homeopathic Combination Preparation (Zeel) (Hielm-Bjorkman, A et al 2009:6(4)465-471).

According to the authors, “a homeopathic combination product (HCP) for canine osteoarthritic pain was evaluated in a randomized, double-controlled and double-blinded clinical trial…[and] that the HCP (Zeel) was beneficial in alleviating chronic orthopedic pain in dogs, although it was not as effective as Carprofen.”

There are many levels on which any clinical research article should be critically evaluated. The potential biases of the authors and the journal, the quality of the methodology, the statistical analysis of the data, and the degree to which the conclusions follow from the data are all common criteria by which such publications can be judged. R. Barker Bausell in his book Snake Oil Science does an outstanding job illustrating some reasons why not everything that makes its way into a scientific journal is reliable science and why such critical evaluation is necessary.

In this case, the journal makes some effort to follow the principles of evidence-based medicine, but it is guilty of some serious Tooth Fairy Science, in which rigorous methodology is applied to some fundamentally irrational premises. Skimming through some archival issues also indicates a pretty strong preference for publishing positive findings for CAM interventions. None of this automatically invalidates anything published, but it is one factor to consider since the effect of personal as well as financial biases on research outcomes is well established.

As for the authors, I am not able to establish much about their biases. Two of the authors are professors at the University of Helsinki School of Veterinary Medicine, and the lead author’s research summary  suggests a strong attachment to CAM. Her doctoral dissertation was a study on gold implantation, green-lipped mussel extract, and Zeel for use in canine osteoarthritis, and it appears she is publishing this thesis research as a series of articles in eCAM.

The methodology is generally sound, with a couple of exceptions. First, while the product studied is identified as homeopathic and an inject able version of it is listed in the US Homeopathic Pharmacopoeia, even the authors insert the caveat that “this is not a classical homeopathic treatment.” The preparation contains 14 listed ingredients, many of which are present after having been diluted 1:10 only 2-8 times, for “molar concentrations of 10^-5 to 10^-12mol/L.” Such concentrations are low, but still higher than the usual case for homeopathic preparations, which cannot conceivable contain any of the original ingredient. It is possible, then, that this substance could contain some pharmacologically active substances. The ingredients listed (same as the injectable product) are:

1. Arnica montana, radix (mountain arnica)
   Dulcamara (bittersweet)
   Rhus toxicodendron (poison oak)
   Sanguinaria canadensis (blood root)
   Symphytum officinale (comfrey)
2. Mineral ingredients:
   Sulphur (sulphur)
   (alpha)-Lipoicum acid (thioctic acid)
   Coenzyme A (coenzyme A)
   Nadidum (nicotinamide adenine dinucleotide)
   Natrum oxalaceticum (sodium oxalacetate)   
3. Animal-derived ingredients
   Cartilago suis (porcine cartilage)
   Embryo totalis suis (porcine embryo)
   Funiculus umbilicalis suis (porcine umbilical cord)
   Placenta suis (porcine placenta)

The subjects were appropriately randomized into treatment, placebo, and positive control groups, with Carprofen as the positive control. The subjects in each group all appear to be comparable at baseline. The placebo group did have higher baseline scores on 5/7 measures of pain, but the authors state that no statistically significant differences were found between groups at this point.

The placebo control was not ideal. The treatment product was visibly different from the Carprofen and the placebo (which were identical to each other). The owners were given extra Carprofen in its original packaging for rescue, so clearly they would be able to identify the treatment product as different. In addition, all subjects also received an inert capsule as part of a separate study, so while the Zeel group received “an ampoule of clear liquid” once daily and “a slightly green (lactose) capsule,” the Carprofen and placebo groups received the green capsule and “a white pill” twice daily. It is not clear what if any affect such a discrepancy might have had on the subjective assessments of owners, or potentially blinded investigators who might have detected group assignment from comments made by owners.

Most of the assessment measures were subjective, such as owner rating scales or visual analog pain scores and investigator clinical exam assessment. Some force plate analysis was done, though this proved problematic. Two subjects had to have their force plate measurements discarded because they were too lame to allow accurate measurement. These subjects, however, were all in the placebo arm and so this would be expected to have the effect of decreasing perceived efficacy of the treatment.

The force plate measurements were “repeated until sufficient valid results were obtained for both left and right limbs.” It was not stated whether the number of trials needed to achieve this differed between groups, which could have affected the results is some subjects had to run back and forth significant more than others to get a valid reading, which might itself affect the reading.

The biggest methodological problem I see in the study is in order to calculate the percent of subjects improved or not improved in each group at the 8-week assessment period, “the results of each variable were converted into dichotomous responses of ‘improved’ or ‘not improved.’” Converting scale variables into dichotomous variables can exaggerate differences between groups. If the measurement was unchanged, the subject would be classified as “not improved,” but if there was even a miniscule change from baseline then the subject would fall into either “improved” or not “improved category.” Thus, subjects with dramatic improvements in scale measurements would be weighted the same as subjects with marginal, and likely clinically insignificant changes in the variable. Without the raw data, of course, it is impossible to tell what if any effect this procedure might have had on the final conclusions. However, the tabulation of the data presented in the article appears to show much greater improvement in terms of the percentage of subjects improved than in terms of the actual median improvement of the variables themselves, suggesting that in fact such an exaggeration occurred.

The authors also stated that “for dogs that had used extra Carprofen more than three times per week at W8 [4 dogs in the placebo arm] we changed all their variable values at evaluation W8 into the most negative value measured at that time.…to counteract the effect of the NSAID…” This seems a clear fudging of the data which made the placebo group appear to have worse outcome measures than it actually did. Certainly, it is possible that these dogs needed more Carprofen than the treatment group because the treatment was having a beneficial effect. But it is just as possible that the placebo group took more Carprofen because of differences in disease severity, in owner attitudes or behavior, or some other factor. And what makes the arbitrary designation of three times a week an appropriate justification for altering the data in this way is unclear. In any case, the effect of this decision is to make the outcomes appear worse for the placebo group, which clearly makes the treatment group outcomes appear relatively better.

Patients given Carprofen clearly showed improvement over baseline at a rate significantly higher than placebo. 67-86% of subjects were categorized as “improved” for the various outcome measures, and the actual values for each measure were improved from 2-5 times more than for the Zeel group. In the treatment group significantly more subjects were classed as “improved” compared to placebo in 3 out of 6 measures. Again, this is likely inflated by the conversion of scale data to dichotomous data. The Zeel group also showed significantly greater improvement than the placebo group in 4 out of 6 specific measures, though for one the P value was 0.049, quite close to the cutoff of 0.05.  

The authors also state that use of supplemental or rescue Carprofen occurred in 14% of the Carprofen group, 28% of the Zeel group, and 8% of the placebo group. Though they claim that the only significant difference was between the Carprofen and placebo groups, this is puzzling, both because the Zeel group had a percent of rescue use dramatically higher than the other groups, and because of the earlier statement about manipulating the data for the placebo group to “counteract” the effect of Carprofen use for that group.

No differences in bloodwork values or clinical side effects were seen between groups.

The authors also make the unsupported statement that “it is generally accepted that seasonal differences influence OA, with patients being worse in cold, damp and unstable weather.” A number of studies have found this traditionally assumed relationship to be difficult to verify and likely a minor and insignificant factor in arthritis pain for most patients (1, 2, 3), so it does not qualify as “generally accepted.” Nevertheless, the authors go on to claim that a trend observed of worsening symptoms for the placebo group during the treatment phase of the study and subsequent improvement during the post-treatment follow-up was due to the weather, and that the opposite trend seen in the Zeel and Carprofen groups was due to the effects of the treatment agents. It seems more likely that the placebo group simply different in significant ways from the other groups, which casts further doubt on the conclusion that the test product was of meaningful benefit.

The authors conclude by putting the usual best possible spin on the weak results, suggesting that combined with in vitro results reported elsewhere they justify further research and pointing out that NSAIDS, which even they acknowledge are clearly superior for treatment of pain, have side effects, despite the fact that none were seen in this study. As I’ve said before, the resource limitations on research in veterinary medicine requires the most efficient use of those resources to maximize benefit, and such studies of implausible interventions are not going to benefit our patients. The authors clearly wish to find something positive in their results, but the study does not justify the commitment of more time and resources and talent to this methodology when better therapies are already available, and when decades of research on homeopathic preparations has failed to validate them. Such papers provide the aura of scientific legitimacy to such methods, but they are tooth fairy science, not evidence-based medicine, and they are a dead end we would do well to stop travelling down.

Bioelectronics corporation has announced its intent to market a new device for treatment of osteoarthritis in pets. The device, the HealFast®Therapy PetPatch™, is a pulsed electromagnetic field (PEMF) device that attaches over a swollen or painful joint ad is intended to “to reduce swelling, relieve pain and enhance the healing of surgical incisions, accidental wounds, sprains, strains and chronic wounds.”

PEMF devices are widely available for human use, and as usual for CAM nostrums they are based on some suggestive in vitro and laboratory studies and weak clinical trial evidence. Electromagnetic fields do have measurable effects on cells in vitro, and there are some recognized medical uses for them. Some evidence suggests an improvement in outcome for non-union fractures, and there may be some benefit in terms of reduced pain and swelling following surgery. However, overall the evidence for clinical benefit is equivocal, as indicated by a number of review studies:

“All trials examined knee OA and one also performed a separate evaluation for cervical OA patients. The results of this analysis show improvements in all measurements for knee OA, but their clinical significance from a patient’s perspective was questionable. Only two outcomes favoured treatment for cervical OA trial and none were considered clinically important. There were no reported side effects. The reviewers conclude that there is an urgent need for further large-scale studies of pulsed electric stimulation with a focus on knee OA to establish the clinical relevance of treatment.” Cochrane Review

“We cannot make any definitive statements on the effects of electrotherapy for people with acute or chronic mechanical neck disorders (MND). Based on this review of 11 trials and 525 people with MND, the current evidence on Galvanic current (direct or pulsed), iontophoresis, TENS, EMS, PEMF and permanent magnets is either lacking, limited, or conflicting.” Cochrane Review

“McCarthy and colleagues (2006) noted that the rehabilitation of knee osteoarthritis often includes electrotherapeutic modalities as well as advice and exercise.  One commonly used modality is PEMF.  Its equivocal benefit over placebo treatment has been previously suggested.  However, recently a number of randomized controlled studies have been published that have allowed a systematic review to be conducted.  The authors concluded that this systematic review provides further evidence that PEMF has little value in the management of knee osteoarthritis.  There appears to be clear evidence for the recommendation that PEMF does not significantly reduce the pain of knee osteoarthritis.”AETNA insurance company literature summary

“In a randomized, placebo-controlled study, Ay and Evcik (2008) examined the effects of PEMF on pain relief and functional capacity of patients with knee osteoarthritis.  A total of 55 patients were included.  At the end of treatment, there was statistically significant improvement in pain scores in both groups (p < 0.05).  On the other hand, no significant difference was observed within the groups (p > 0.05).  These investigators observed statistically significant improvement in some of the subgroups of Lequesne index (e.g., morning stiffness and activities of daily living) compared to the placebo group.  However, these researchers could not observe statistically significant differences in total of the scale between two groups (p > 0.05).  Applying between-group analysis, the authors were unable to demonstrate a beneficial symptomatic effect of PEMF in the treatment of knee osteoarthritis in all patients.  They stated that further studies using different types of magnetic devices, treatment protocols and patient populations are warranted to confirm the general efficacy of PEMF therapy in knee osteoarthritis and other conditions.” AETNA insurance company literature summary

“Furthermore, in a systematic review on wound care management, Cullum, et al. (2001) concluded that there is generally insufficient reliable evidence to draw conclusions about the contribution of laser therapy, therapeutic ultrasound, electro-therapy and electromagnetic therapy to chronic wound healing.  Flemming and Cullum (2001) also concluded that there is currently no reliable evidence of benefit of electromagnetic therapy in the healing of venous leg ulcers.” AETNA insurance company literature summary

This would seem to suggest that a responsible company would make an investment in investigating a promising therapeutic concept in the hopes of eventually finding a beneficial, and presumably profitable, product. Unfortunately, as I’ve discussed before this instead is seen as a perfect opportunity to make a quick buck selling something based on its promised rather than its demonstrated value. What is especially disturbing about the Bioelectronics’ press release is the unabashed trumpeting of the potential profit to be made and the clearly stated intent to market the device directly to consumers, bypassing the veterinarians who presumably might have troubling questions about the evidence behind the company’s claims: “A comprehensive direct to consumer marketing program will support the launch of the new product. The centerpiece of the campaign is a new TV commercial which will begin rolling out next week.”

So for those of you who are veterinarians, be prepared for the clients who will soon be coming to you having seen the new commercial. Hopefully, they’ll be seeking you advice, but unfortunately it’s always dissatisfying for client and vet alike to have to answer the glowing testimonials and marketing hype for one of these products by a sober and bland summary of equivocal research evidence. Still, that’s our job!

There is widespread agreement among veterinary behaviorists, and veterinarians in general, that one consequence of the improved longevity of our patients has been an increase in clinical behavior problems associated with brain aging. Changes in sleep/wake cycles, activity level, housetraining behavior, recognition of familiar humans and other animals, and cognitive abilities are often seen in older pets, and these can severely affect the pets’ quality of life and the relationship between pet and owner. No standardized diagnostic test for these age-related changes exists, and each pet may experience different specific changes in behavior and ability. However, there is enough similarity in the types of changes seen in older pets that it is reasonable to discuss and address them as a syndrome until research allows us to identify more specific categories of age-related dysfunction and to elucidate the specific pathophysiology of each.

Likewise, there are a number of anatomical changes seen in dog and cat brains with age and associated with clinical symptoms or functional deficits. These include reduction in brain mass, cell and axonal degeneration and changes in the relative number of different cell types in the brain, and accumulation of beta amyloid.  In dogs, these changes show some striking similarities with those seen in people with Alzheimer’s and other age-associated cognitive disorders. There are, however, significant differences as well, such as the absence in dogs of the characteristic neurofibrillary tangles seen in humans afflicted with Alzheimer’s disease. Therefore, though the similarities may justify tentatively viewing age-associated cognitive and behavior changes in dogs and humans as sufficiently alike to suggest that research findings in one species may have relevance to the other, we must be careful not to simply assume they are the same disorder with the same pathogenesis or the same response to pharmacological manipulation.

There are no universally or highly effective therapies for age-related cognitive and behavioral dysfunction. Some drugs, such as selegilene, have shown limited ability to improve clinical symptoms, but it is a disorder for which veterinary medicine has little to offer in the way of amelioration. Much more research must be done to understand the causes of the clinical problem and how these may be addressed.

As always, when there is a poorly understood problem with no ready medical solution, potential therapies abound and the standards of evidence required to justify their marketing and use are generally low. A number of nutraceutical products, vitamins or other dietary supplements used with the intent of achieving a beneficial pharmacological effect, are marketed for age-associated behavioral problems. Most of these are supported by reasonable theoretical rationales, suggestive in vitro research, some promising laboratory animal studies, and limited clinical research with few subjects and generally poor methodological quality.

As with probiotics, these remedies fall in an intermediate category between CAM and scientific medicine. There is reason to believe they may eventually prove useful, but the available data is not currently adequate to demonstrate this, and it is certainly not adequate to justify producing and selling such products to the general public. But manufacturers of neutraceuticals consider the time between the proposal of a hypothesis that a supplement might be beneficial and the accumulation of sufficient data to decide the truth as a golden time for marketing. As a recent article from the Los Angeles Times news service put it regarding one of these compounds:

For the purveyors of vitamins, minerals and herbal remedies, that is a five- to seven-year opportunity not to be missed. Consumers’ dreams of forestalling the ravages of age have been engaged, and they will buy and swallow anything that gleams with the luster of science. While they wait for science to flesh out resveratrol’s promise, consumers’ demands for the stuff can be built, tapped and satisfied with products that offer plenty of promise but tread lightly around the preliminary state of the scientific evidence.

“There’s a watershed time for a good nutraceutical,” says Dr. Joseph Maroon, a University of Pittsburgh neurosurgeon, author of a book titled “The Longevity Factor” and co-founder of a company, Xenomis, which rolled out a line of resveratrol-based supplements last May.

Resveratrol, in short, stands at the juncture of hope, profit and scientific promise — a social phenomenon galloping ahead of research that is undeniably intriguing but very incomplete.

Most of the products marketed for cognitive and behavior problems in older pets are combinations of multiple substances, which makes any rigorous scientific evaluation of them difficult. It is also the case that many of the studies available have been sponsored or conducted by companies marketing the product being tested, and while this does not invalidate the results, it is well-documented that such studies are more likely to be positive than independently conducted research.

Hill’s Pet Nutrition has created a veterinary diet fortified with Vitamins C and E, L-carnitine, omega-3 fatty acids, and lots of fruit and vegetable ingredients. The company has published results of several studies which support the contention that the diet has some protective benefits in terms of cognitive decline and age-associated behavior problems. It is impossible to identify which ingredients, singly or in combination, might account for this effect, but the evidence is good that there is some clinically significant benefit. As always, replication by independent investigators would strengthen the case, and further research to identify which components of the diet are of relevance would be useful.

Other products, such as CEVA Animal Health’s Senilife and VetPlus’ Aktivait, contain multiple ingredients each proposed to prevent or treat age-related cognitive dysfunction via plausible mechanisms based on in vitro or laboratory animal studies. Again, which if any of these ingredients might actually be beneficial is impossible to determine from clinical studies using the combination product. And so far the clinical research evidence is weak, consisting mostly of small, inadequately controlled trials often sponsored by the manufacturer. I will try to discuss each ingredient independently and then review the available literature on some combination products.

Phosphatidylserine-

Phosphatidylserine (PS) is a phospholipid that occurs in cell membranes. It is hypothesized, based on laboratory studies, to facilitate normal function of nerve cell membranes and influence levels of various neurotransmitters. A 2003 FDA report reviewed the clinical literature in humans and concluded that the evidence did not support assertions that this compound has preventative or treatment benefit for cognitive dysfunction and dementia in people. The agency did approve a highly qualified claim for the product:

Dementia claim and disclaimer:

“Consumption of phosphatidylserine may reduce the risk of dementia in the elderly.

Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of dementia in the elderly. FDA concludes that there is little scientific evidence supporting this claim.”

Cognitive dysfunction claim and disclaimer:

“Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly.

Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly. FDA concludes that there is little scientific evidence supporting this claim.”

One important caveat to the data the FDA analyzed is that most research has been done on PS derived from bovine brain tissue. Due to the risks of acquiring bovine spongiform encephalopathy (BSE or “Mad Cow Disease”) from this source, the FDA prohibited its use, and the proposed commercial products contain PS derived from soybeans. The plant derivative differs structurally from bovine-derived PS, so there is some question about whether data regarding one is applicable to the other. I was not able to identify the source of the PS in the various veterinary products and research trials.

I was also not able to find any veterinary clinical trials for cognitive dysfunction examining PS alone. It is included in a couple of combination products, including Senilife and Aktivait. As discussed below, the clinical research evidence for these products is weak. No evidence regarding the safety of the substance was found, apart from the theoretical concerns about BSE discussed in the FDA report.

Ginkgo Biloba-

This is a very popular herbal product which is purported to have a wide range of beneficial effects on cognition, memory, depression, anxiety, tinnitus, and headache. It has vasodilatory effects and acts as a scavenger of oxygen free radicals in vitro and in laboratory animal studies. The clinical trial evidence in humans does not support a beneficial effect for cognitive impairment or dementia, as summarized in a Cochrane review below.

Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. Overall, evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable. Of the four most recent trials to report results, three found no difference between Ginkgo biloba and placebo, and one reported very large treatment effects in favour of Ginkgo biloba

The review also concluded that there were no significant safety concerns for it’s use. The NCCAM summary of this product indicates no benefit seen even in a large NCCAM sponsored study of Alzheimer’s patients, and lists a number of possible toxic effects.

Again, I have found no veterinary clinical trials looking at Ginkgo biloba alone as a preventative or treatment for age-associated cognitive and behavior problems. It is included in Senilife, which I discuss below has limited weak evidence to support a beneficial effect.

Resveratrol-

Resveratrol is a chemical extracted from grapes that has been touted as a general anti-aging panacea. There are numerous in vitro and lab animal studies that suggest the compound may act as an antioxidant and have a variety of effects promoting and inhibiting the expression of a number of genes. There is mixed evidence in lab animals that it may prolong life and inhibit, or in some cases promote, cancer. Human clinical trials for a number of possible uses are ongoing, but no data is available to suggest safety or efficacy for any particular use.

Likewise, there are apparently no veterinary clinical trials of resveratrol alone for cognitive and behavior dysfunction. As the newspaper article quoted above suggests, it is a promising but unproven compound which has been marketed well in advance of reliable evidence to its safety and efficacy. Resveratrol is an ingredient in Senilife, which has only weak supporting research evidence for clinical benefit in veterinary patients.

Pyridoxine (Vitamin B6)-

Pyridoxine is believed to have anti-oxidant properties and may be a co-factor in the synthesis of some neurotransmitters. According to a Cochrane review, clinical research in humans has not demonstrated any benefit in terms of mood or cognition in elderly people, and no high-quality studies are available investigating its use for dementia or cognitive impairment.

Two trials of vitamin B6 supplements for healthy elderly people qualified for this review, with no beneficial effects on mood or mental function detectable. Homocysteine levels were not assessed. No ill effects of vitamin B6 were observed. No trials studying effects of vitamin B6 treatment for people with dementia or cognitive impairment were identified.

The NCCAM has also published an evidence review which concludes, “Human studies were generally of poor quality. Weak evidence suggests possible benefits of B1 supplementation and injected B12 in AD. The effects of B6 and folate are unclear. Overall, dietary intake studies do not support an association between B vitamin intake and AD. Studies evaluating B vitamin status were mostly inadequate due to poor study design. Overall, studies do not support an association between B vitamin status and age-related neurocognitive disorders.”

While these reviews did not find evidence of health risks with pyridoxine supplementation, neurologic disorders have been reported with pyridoxine supplementation in humans and in dogs (Study 1, Study 2). No clinical trials were found investigating pyridoxine use for treatment or prevention of age-associated behavior disorders. It is a component of Senilife.

Vitamin E-

Vitamin E is purported to have benefits in a number of conditions due to its anti-oxidant properties. However, a Cochrane review of the research regarding the compound and Alzheimer’s Disease or cognitive impairment in humans found:

To date only one randomized controlled trial has assessed the efficacy of Vitamin E in the treatment of AD patients and only one assessed the role of Vitamin E in patients with mild cognitive impairment (MCI). In the Vitamin E study for moderately severe AD patients a lower number of those taking Vitamin E declined to incapacity over a two year period compared with the placebo group. However, AD patients taking Vitamin E experienced a greater number of falls. In the MCI study, Vitamin E 2000 IU daily produced no significant difference in the rate of progression to AD compared to the placebo group… There is no evidence of efficacy of Vitamin E in the prevention or treatment of people with AD or MCI. More research is needed to identify the role of Vitamin E, if any, in the management of cognitive impairment.

No clinical trials have been done on Vitamin E for cognitive dysfunction in veterinary patients. As I’ve previously discussed, Vitamin E supplementation has been shown to have potential risks, including increasing the risk of heart failure and possibly cancer.

S-Adenosylemethionine (SAMe)-

SAMe is a molecule already present in the body that has anti-oxidant properties and that is involved in the synthesis and regulation of some neurotransmitters. It also appears to play a role in the regulation of nerve cell membrane structure and function. There is some in vitro and laboratory animal evidence suggesting it might be of benefit in cognitive disorders in humans, though the clinical trial evidence is limited and mixed.

A small, short-term study sponsored by Virbac Laboratories investigated the use of SAMe to reduce symptoms of age-related cognitive dysfunction. Despite its limitations, the study was well-designed and showed convincing evidence for an improvement in daytime activity and possibly some improvement in sleep problems. It did not show any benefit for confusion or disorientation. No adverse effects were seen in the study subjects. Further study of this compound is certainly warranted.

Co-Enzyme Q10-

A component of the energy production pathways in mitochondria, CoQ10 has been suggested to be of value in Alzheimer’s disease in humans. The laboratory animal study evidence is mixed, with some trials showing reduction in beta amyloid in mice and others showing no effect or even a worsening of cognitive function in mice. A 2003 review found no reliable evidence of benefit in humans and suggested more study is needed. No trials appear to have been conducted in aged dogs or cats with cognitive dysfunction. The compound is an ingredient in the combination product Aktivait. 

Combination Products-

 The manufacturer of Senilife indicates in its marketing literature that some sort of research demonstrates the efficacy of the product. There are lots of charts and graphs and “percentage improvement” numbers, but no information about study subjects, protocol, blinding, placebo control, or anything else that would allow evaluation of this purported data. However, there have been some clinical studies published looking at the product. An open-label study of eight dogs done in Italy showed some beneficial changes in some clinical parameters. Of course, this is a very weak level of evidence appropriate only for suggesting that further study is warranted.

 Another study looked at Senilife in a group of nine laboratory beagles ranging from 7-13 years of age and evaluated performance on a short-term memory test. The study reported marked improvement in performance of the animals on the supplement. However, the study was small, examined a laboratory cognition task that might or might not have relevance to clinical disease, and was not randomized or blinded. It also utilized a crossover design, which is inappropriate for a progressive disorder such as age-associated cognitive dysfunction. Additionally, during the second phase in which the original treatment group became the control group, there was no difference in the performance of this group between treatment and control. The authors interpret this as a persistent effect of treatment, but they did not clearly eliminate other possible explanations, such as differences between the groups not related to the intervention.

Another combination product, called Aktivait is marketed for age-relative cognitive and behavior problems. It contains the essential fatty acids DHA and EPA, N-acetyl cysteine, Vitamin C, L-carnitine, Vitamin E, Coenzyme Q10, phosphatidylserine, and selenium. A clinical trial of 41 dogs has been published which found a benefit for some measures of dysfunction in naturally occurring disease. The trial was randomized, placebo-controlled, and double-blinded. It reported significant improvements in some measures (daily scores for activity and recognition of owner and global score for housetraining) but not others (daily scores for sleep disturbances, social interaction, incidents, locations, and substrates for inappropriate toileting and global scores for disorientation, sleep patterns, and social interaction). This suggests that the authors conducted multiple comparisons and focused only on those that showed a positive effect while downplaying the majority that did not, but they way the data is presented it is not clear if this is the case. The study also reported that for one of the assessments which improved, housetraining, the treatment group had a significantly higher rate of problems that the placebo group at the beginning of the trial, so the groups were clearly not matched properly for this measure.

So far, the available evidence for Senilife and Aktivait is suggestive of benefit but generally very weak. This is always the case in the early stages of investigating a potential therapy, and does not reliably indicate what the results of larger, better-designed studies will determine to be the real truth. However, there are serious ethical questions associated with marketing and selling such remedies on the basis of such weak evidence given the large proportion of therapeutics that show early promise and later turn out to be useless or even dangerous. I certainly support further study of possible interventions for age-associated cognitive and behavioral problems, but I think such research would be better done on elucidating the underling pathophysiology and on single interventions targeted at understood elements of the syndrome, rather that clinical trials of shotgun-type combinations therapies supported by companies looking to sell these products.

References

Araujo, J., Lansberg, G., Milgram, N., Miolo, A. Improvement of short-term memory performance in aged beagles by a nutraceutical supplement containing phosphatidylserine, Ginkgo biloba, vitamin E, and pyridoxine. Canadian Vet J, 49(4):379-385; 2008.

Dalton, K., Dalton, MJT., Characteristics of pyridoxine overdose neuropathy syndrome, Acta Neurol Scand 76:8-11, 1987.

Dodd, CE., Zicker, SC., Jewell, DE. Can a fortified food affect the behavioral manifestations of age-related cognitive decline in dogs? Vet Med 98:396-4080; 2003.

Heath, S. et al. Nutritional supplementation in cases of canine cognitive dysfunction: Results of a clinical trial, Proceedings 29th World Congress of the Small Animal Veterinary Association, 2004.

Osellaa, M/C, et al. Canine cognitive dysfunction syndrome: Prevalence, clinical signs and
treatment with a neuroprotective nutraceutical. Read online Sept. 20, 2009 at  http://www.crashinggoodtime.com/CDS.html
Reme, C.A., et al. Effect of S-adenosylmethionine tablets on the reduction of age-related mental decline in dogs: a double-blinded, placebo-controlled trial. Vet Ther 9(2):69-82; 2008.

 First, I just wanted to point out that I have added another example to the list of harm done by use of CAM. In this case, it’s a tragic story about a young women suffering needlessly yet unwilling to give up on useless therapy.

On a larger scale, but just as tragic and infuriating, the results are available for the NCCAM-funded study of the Gonzalez cancer therapy.* Dr. Kimball Atwood has written extensively about the therapy and the NCCAM trial (The Ethics of “CAM” Trials: Gonzo Part I, II, III, IV,V, VI, and VII). Despite a host of serious ethical concerns, which Dr. Atwood has detailed extensively, the government funded a study in which people were allowed to elect a CAM therapy with no scientific plausibility or standard chemotherapy for their pancreatic cancer. It should surprise no one that the outcome clearly shows the Gonzalez regime to be ineffective. People on conventional chemotherapy lived 3 times longer than those on CAM treatment (14 months vs 4.3 months), and contrary to the usual CAM propaganda about cancer therapy, those who elected the alternative regime had a significantly poorer quality of life for those 4 short months.

It is true that the conventional therapy for this disease does not offer great hope for people with this disease. And the patients who followed the Gonzalez treatment did so by their own choice (the trial was originally randomized, but most patients refused to accept random allocation to treatment groups). But as I’ve argued before, the understandable desperation of people in this situation does not justify giving them false hope for help from methods unlikely to be of any real benefit. And the irrational pursuit of such hope cost the people in the CAM arm of this study almost a year of life on average and a great deal of suffering. Of course, it is difficult to argue that people should not be permitted to choose irrational hope over bleak reality. but it seems obvious that doctors who encourage such a choice by promoting, or refusing to critique, such therapies are failing in their duty to their patients. And this study illustrates nicely how NCCAM is complicit in this by giving a patina of legitimacy to bogus treatments.

CAM proponents frequently argue that unless their methods have been thoroughly investigated by large, well-designed and well-conducted clinical trials, critics of them are not adhering to their own standards of evidence. Because some ideas which seemed implausible in the past turned out to actually be true, they argue that any attempt to focus our research efforts based on scientific plausibility is mistaken. Such an argument seems very effective in supporting the work of NCCAM and in getting a foothold for unlikely therapies in mainstream medicine, but it is riddled with weaknesses.

Firstly, it ignores the fact that most ideas which seem implausible at first really are wrong, and they fail when tested. The fact that there are exceptions, and that the availability bias makes them seem more representative than they really are, does not support investigating anything and everything regardless of its provenance or consistency with well-established scientific principles. The argument also would require our desperately limited resources for scientific research to be spent indiscriminately, especially on popular or catchy ideas rather than the more mundane concepts that have a solid foundation in basic science and pre-clinical research.

As this study shows, testing anything and everything also exposes test subjects to avoidable risk and suffering. Even in cases where there is little hope in mainstream, scientific therapy there is no reason to think the false hope CAM offers is the better choice. No CAM therapy which is implausible or mysterious in its principles, or outright contrary to what we understand about the universe, has demonstrated under rigorous clinical testing to be the miracle its proponents have claimed for it. Progress comes far more often from laborious and careful work building on what is known than from wild guesses by lone geniuses.

Lastly, the clinical testing of implausible CAM methods seems likely to be futile even when the results are as clear and stark as in this trial. One might hope that this study will dissuade people from pursuing the Gonzalez therapy, and even cause them to question the underlying marketing of CAM methods, which use anecdote and the limitations of scientific medicine to claim far more than they can really provide to sick people or animals. But the past does not suggest this will be true. Faith-based medicine ultimately does not rely on empirical validation, and its followers rarely accept any evidence that they are mistaken. The spinning of these trial results will likely begin shortly, and the proponents of the method will continue to offer it, and it’s false hope, to vulnerable cancer patients without a qualm.

*Pancreatic Proteolytic Enzyme Therapy Compared with Gemcitabbine-based Chemotherapy for the Treatment of Pancreatic Cancer

John A. Chabot, Wei-Yann Tsai, Robert L. Fine, Chunxia Chen, Carolyn K. Kumah, Karen A. Antman, and Victor R. Grann^*

From the Herbert Irving Comprehensive Cancer Center, Department of Medicine and Surgery, College of Physicians and Surgeons; and Departments of Biostatistics, Epidemiology, and Health Policy and Management, Joseph L. Mailman School of Public Health, Columbia University, New York, NY; Boston University Medical Center, Boston, MA; and Department of Statistics, National Cheng-Kung University, Taiwan.

^* To whom correspondence should be addressed. E-mail: vrg2@columbia.edu

Purpose: Conventional medicine has had little to offer patients with inoperable pancreatic adenocarcinoma; thus, many patients seek alternative treatments. The National Cancer Institute, in 1998, sponsored a randomized, phase III, controlled trial of proteolytic enzyme therapy versus chemotherapy. Because most eligible patients refused random assignment, the trial was changed in 2001 to a controlled, observational study.

Methods: All patients were seen by one of the investigators at Columbia University, and patients who received enzyme therapy were seen by the participating alternative practitioner. All met strict clinical criteria for eligibility. Of 55 patients who had inoperable pancreatic cancer, 23 elected gemcitabine-based chemotherapy, and 32 elected enzyme treatment, which included pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. Primary and secondary outcomes were overall survival and quality of life, respectively.

Results: At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. Kaplan-Meier analysis found a 9.7-month difference in median survival between the chemotherapy group (median survival, 14 months) and enzyme treatment groups (median survival, 4.3 months) and found an adjusted-mortality hazard ratio of the enzyme group compared with the chemotherapy group of 6.96 (P < .001). At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P < .01).

Conclusion: Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment.

One of the most impressive-sounding labels for an unproven alternative therapy is Orthomolecular Medicine. And the origin of the term, coined by Nobel laureate Linus Pauling, gives it added gravitas. As it turns out, though, it’s just a fancy way of claiming that there are medical benefits to giving high doses of vitamins above and beyond the ordinary, and quite small amounts necessary for normal health. Proponents of this concept argue that many diseases are due to undetected vitamin or mineral deficiencies, usually attributed to the unspecified evils of modern life or industrial agriculture. They also seem to follow the philosophy that if a little is good, more is better in arguing that extremely high doses of essential micronutrients can treat or prevent illness.

It is culturally difficult to argue against the benefits of vitamins, or to suggest they might cause harm. The memory of a time in which people in Western societies were routinely deficient in micronutrients, and when supplementation provided seemingly miraculous benefits, is still accessible. And there are still places in the world in which the poor not only do not have our nutrient-excess health problems but in which vitamin deficiencies are still common, and supplementation can be beneficial. Recent surveys suggest vitamins are seen as generally benign even by doctors, who commonly use them as placebo therapy.

However, the grand claims made in the 1970s by Pauling and others about the benefits of megadoses of vitamins have had a long time to prove themselves, and they have so far failed to do so. In human medicine, the loosely-organized set of theories called Orthomolecular Medicine has passed through the classic stages of CAM research:

1. An untested idea

2. An idea with support from a few random in vitro and animal model studies

3. An idea with a few supportive findings in small, poorly designed clinical studies

4. An idea clearly debunked in larger and better-designed studies but whose proponents cling to it tenaciously despite the lack of evidentiary support because they see themselves as visionaries ignored or oppressed by the unimaginative and venal mainstream medical establishment.

In veterinary medicine, as usual, not all of the stages are well-represented. The closest I have been able to find to Stage 3 are some case reports and papers from the 1970s that are long on grand theorizing and short on data by Dr. Wendell Belfield. These are balanced by a number of in vitro and animal model studies showing the implausibility or potential dangers megadoses of vitamins, but to my knowledge well-designed, adequately powered clinical trials have not been done to definitively prove or disprove any of the claims orthomolecular practitioners make. In my opinion, this is as it should be since the basic plausibility, the in vitro data, and the data from human medicine all argue against wasting resources on something so unlikely to prove safe and effective, but it is always nice to be able to show with solid data that likely nonsense truly is nonsense.

Since there do not appear to be definitive studies, I have put together some information of a cautionary nature about some commonly advocated vitamin therapies. This is certainly not a comprehensive literature review, nor do I claim it is the final word on megadose vitamin therapy. I have selected cautionary research to illustrate the potential risks of orthomolecular therapies and to remind everyone why the burden of proof is properly on proponents of this approach to justify their extravagant claims. It is also important to emphasize that the use of vitamins in high doses to prevent or treat disease is essentially using these compounds as drugs. They are not “nutritional” therapies when given above the recognized necessary amounts but active pharmaceuticals, and as such any possible benefits will come with associated risks and side effects.

Vitamin A

As a fat-soluble vitamin, Vitamin A can accumulate over time, making reaching dangerous levels more likely. As for most vitamins, there are clear benefits to appropriate amounts, and supplementation sometimes shows benefit for people in impoverished environments with inadequate nutrition, but the evidence does not support benefits for supplementation of healthy people with adequate diets or clear benefits for treating non-deficiency diseases.

Excessive dietary Vitamin A can worsen osteoporosis and raise the risk of hip fractures.

A nice summary of the risks of Vitamin A, including neurologic disease, birth defects, and osteoporosis.

A Cochrane Review that presents mixed evidence for the possible benefit of Vitamin A for reducing mortality in children with measles.  However, another review found no benefit for non-measles pneumonia.

A Chochrane Review showing Vitamin A does not reduce transmission of HIV from mother to offspring.

A Cochrane Review that found no value in Vitamin A for preventing lower respiratory tract infections in children, and even a few studies showing and increase risk with supplementation.

Vitamin C

The original megavitamin Linus Pauling promoted obsessively in his later years. The most extensively studied claims of orthomolecular practitioners are those relating to Vitamin C, and these are the claims that have been most soundly disproven. In addition, recent evidence illustrates the real risks of large doses of Vitamin C.

Vitamin C can interfere with the effectiveness of chemotherapy.

A pair of detailed reviews and refutations of a couple of papers purporting to finally show some value to megadoses of Vitamin C . First Post Second Post 

A paper showing Vitamin C not helpful, and potentially exacerbating for hypertrophic osteodystrophy in dogs.

No evidence oral Vitamin C improves immune system parameters in dogs.

Cochrane Reviews-Evidence does not support Vitamin C for prevention or treatment of the common cold and is generally absent or of unreliable quality for the use of Vitamin C in prevention or treatment of pneumonia, tetanus, and asthma.

Vitamin D

There is a great deal of interest in the potential of this vitamin to reduce cancer risk. However, the evidence so far is mixed, with some studies showing a decreased risk (e.g. colon cancer), little or no change in risk (e.g. breast, prostate, and others), and even some increase in risk (e.g. pancreatic cancer among smokers). Excessive amounts can cause kidney stones, abnormal heart rhythms, and other serious side effects. This is one substance for which I think there is justification to conducting further research.

Vitamin E

In this study, Vitamin E use increased the risk of lung cancer.

A pair of studies that showed Vitamin E had no protective benefit for prostate cancer and increased the risk of heart failure.

Multivitamins and Miscellaneous

A systematic review and meta-analysis published in the Lancet that suggests not only do antioxidants and Vitamin A and E supplements not prevent cancer, they may actually increase mortality risk.

A large study that found no benefit to multivitamin supplements for older women.

Neurologic toxicity with oral supplementation of Vitamin B6 in dogs.

Extensive research into orthomolecular claims in neurologic and psychiatric disease has found no evidence of benefit.