Even Mandatory FDA Recalls Can’t Make Supplement Manufacturers Stop Lying About What’s in their Products

There is ample evidence that under the current lax regulatory system in the U.S., dietary supplements are frequently mislabeled and adulterated with pharmaceuticals, toxins, and other undesirable substances. Apart from the lack of evidence to support the claims of benefits for most such products, this unreliable labeling represents a real danger to consumers. There are many examples of people injured or killed by such products.

The FDA has made some efforts to control this problem, and one tool used for this purpose is the mandatory recall. A recent short feature in the Journal of the American Medical Association (JAMA) has examined the impact of such recalls and found that, unfortunately, they do not seem to be very effective in encouraging better compliance with the law or quality control on the part of supplement manufacturers.

Cohen PA, Maller G, DeSouza R, Neal-Kababick J.  Presence of banned drugs in dietary supplements following FDA recalls. JAMA. 2014 Oct 22-29;312(16):1691-3. doi: 10.1001/jama.2014.10308.

According to this study, about half of the Class I mandatory recall in the last 10 years have been of adulterated dietary supplements. Over the four-year period from 2009-2012, the FDA recalled 274 dietary supplements. In this study, the authors tested about 10% of these recalled supplement for common banned substances. The results show how unconcerned this industry appears to be about consumer health and safety:

One or more pharmaceutical adulterant was identified in 66.7% of recalled supplements still available for purchase.

Supplements remained adulterated in 85% (11/13) of those for sports enhancement, 67%(6/9) for weight loss, and 20%(1/5) for sexual enhancement. Of the subset of supplements produced by US manufacturers, 65% (13/20) remained adulterated with banned ingredients.

Sixty-three percent of analyzed supplements (17/27) contained the same adulterant identified by the FDA. Six of the 27 (22.2%) supplements contained 1 or more additional banned ingredients not identified by the FDA… Some supplements contained both the previously identified adulterant as well as additional pharmaceutical ingredients.

It is particularly important to note that this was not simply a problem with supplements manufactured outside of the United States, since a majority of domestically produced supplements remained adulterated even after being recalled for representing a serious safety hazard. I completely agree with the authors’ conclusions:

More aggressive enforcement of the law, changes to the law to increase the FDA’s enforcement powers, or both will be required if sales of these products are to be prevented in the future.

Posted in Herbs and Supplements | Leave a comment

EBVM 2014: Building a Community to Advance Evidence-based Veterinary Medicine

I have just returned from one of the most exciting scientific meetings I have ever attended, the EBVM 2014 conference organized by the RCVS Knowledge, the charity arm of the Royal College of Veterinary Surgeons. Over 250 people from around the world attended, full of enthusiasm and ideas for improving veterinary medicine for patients, animal owners, and veterinarians, through the development and promotion of evidence-based veterinary medicine (EBVM). Vets from teaching and research institutions, general and specialty private practice, other sectors of the veterinary profession, and affiliated industries spent two days meeting and talking about EBVM and how it can be developed and implemented to make veterinary care safer and more effective.

The conference grew out of an earlier, smaller meeting in 2012, Sceptical Vet: Evidence or Eminence?, which I also attended. The RCVS first formed an EBVM Network open to everyone interested in EBVM. Members of this network, along with the staff of the RCVS, then put together the goals and agenda for the EBVM 2014 conference. Speakers included pioneering academics involved in EBVM research and teaching, like Dr. Mark Holmes; private practitioners such as myself and Dr. David Ramey; veterinary nurses and other veterinary professionals; and representatives of existing organizations devoted to promoting EBVM, including the Centre for Evidence-based Medicine (CEVM) at the University of Nottingham and the Evidence-Based Veterinary Medicine Association (EBVMA).

The full program is available here, and eventually recordings of all the talks and associated slides will be available on the web. I just wanted to highlight a few key themes and projects addressed at the meeting.

The first of these was the importance of moving EBVM beyond the universities and specialty centers and into general practice. The vast majority of veterinary care is provided by first-opinion veterinarians, and the full impact of EBVM on the welfare of veterinary patients can only be achieved by overcoming resistance and obstacles to widespread practice of EBVM in this setting. Teaching primary care veterinarians what EBVM is, and what it isn’t, and dealing effectively with barriers to adoption of EBVM are all necessary steps that were discussed at this meeting. Examples were also presented of successful implementation of EBVM in general practice, such as a presentation about the adoption of clinical practice guidelines for small animal CPR in my own hospital.

Of course, the lack of high quality and relevant research evidence is one of the greatest barriers to widespread use of EBVM, and much discussion was focused on ways to grow and improve the evidence base. Speakers were not afraid to directly address limitations and weaknesses in the scientific evidence that might reduce the usefulness of EBVM in the clinical setting. If we are to be successful in using EBVM to improve veterinary medicine, we need to be clear-eyed about the limitations in EBVM theory and practice and the pitfalls involved in widespread adoption of it so we can successfully use EBVM methods to improve veterinary care.

Much time was also given to practical strategies for using EBVM, including the best practices for developing and implementing clinical practice guidelines, the uses and misuses of systematic reviews, the teaching of EBVM to veterinarians and veterinary students, and the economic issues of implementing EBVM in different areas of veterinary medicine, from food production and public health to companion animal practice.

Lots of ideas were discussed for future projects. The EBVMA, CEVM and RCVS Knowledge have all endorsed the AllTrials Initiative, a movement in human medicine to encourage the registration of clinical research studies and the open sharing of all data from these trials so that doctors and patients can make the best-informed decisions possible about the use of the treatments studied in these trials. There is currently no way for most veterinary researchers to register their studies, or for others to access their data, and an AllTrials Initiative for veterinary medicine was a popular idea. Projects for generating more and better research evidence, including more research conducted in general private practice, were also discussed, as well as projects to make useful critical synthesis of existing research more widely available to clinicians. RCVS Knowledge also announced their intention to produce a Journal of Evidence-Based Veterinary Practice, and to open a web-based forum for interested veterinary professionals to discuss particular projects and topics in EBVM. I will create a post specifically to provide links to these and other EBVM resources as they become available.

Many of the ideas and projects discussed at EBVM 2014 will take shape in the two years between now and the next major EBVM meeting RCVS plans to sponsor, to be held in Edinburgh in 2016, and I look forward to participating in this process. It was inspiring to spend these two days talking with so many people full of enthusiasm for improving veterinary medicine and the care veterinary patients receive using the tools of science. Evidence-based medicine has changed the landscape of human healthcare dramatically and for the better, and I am confident it will do the same for veterinary medicine. It is truly an exciting time to be in the veterinary profession, and I am proud to be contributing in a small way to this movement.


Posted in Science-Based Veterinary Medicine | 3 Comments

New Systematic Review of Veterinary Homeopathy: Still no Reason to Believe It Works

I have reviewed the overall evidence concerning homeopathy, from basic science through clinical trial research in great detail previously. Despite more than 150 years of effort by advocates for this practice, virtually no reliable evidence has been developed to show it can work or does work.

The same conclusion has been reached by many others, from the systematic reviews of homeopathic trials and systematic reviews of these systematic reviews, to the formal investigations of governmental agencies such as the British House of Commons Science and Technology Committee and the Australian National Health and Medical research Council. While homeopaths have had more than a century to try, they have not been able to produce a body of scientific evidence to convince anyone but themselves that homeopathy works.

In response to criticism of homeopathy based on this lack of believable scientific evidence, veterinary homeopaths have tried presenting their own review of the science, putting as positive a spin on the evidence as they possibly can. However, when I examined this attempt in detail, it was so rife with bias and poor quality research that it amounts to little more than an example of propaganda masquerading as science. Of all the studies presented by the Academy of Veterinary Homeopathy, the overwhelming majority were so clearly biased or poorly conducted that they were meaningless. Many actually found that the homeopathic intervention didn’t work but were cited as positive anyway. Only one paper had reasonably good methodology, but in the face of overwhelming negative evidence, it takes more than one study in 150 years to validate a deeply implausible practice.

There is now a new systematic review which specifically evaluates clinical trials of homeopathy in veterinary medicine and which attempts to employ conventional standards of evidence to control for bias and other study weaknesses.

Mathie RT. Clausen J. Veterinary Homeopathy: systematic review of medical conditions studied by randomized placebo-controlled trials. Vet Rec. 2014;175(15):373-81.

This review was conducted by two advocates for homeopathy, clearly with an interest in supporting the practice: “Each of us is employed by a homeopathy charity to clarify and extend an evidence base in homeopathy.” Yet despite this obvious agenda, the authors attempt to follow the conventional standards for a systematic review, and the result is not very encouraging for homeopaths.

An extensive search found only 18 clinical trials that were eligible to be evaluated. Of these, one had a low risk of bias, six had an uncertain risk of bias, and eleven had a high risk of bias. Of the seven that had a low or uncertain risk of bias, three showed a statistically significant effect, three showed no effect, and one could not be evaluated. Of these seven trials, two were judged to provide “reliable evidence” based on an overall assessment. One showed a significant effect and the other did not. Both, the authors note, had some odd design features that made them different from the standard clinical trial format.

So the best that two committed supporters of homeopathy could find when attempting an objective evaluation of the veterinary homeopathy literature were two studies that were probably pretty reliably conducted, one of which found an effect and one of which didn’t. Once again, in the face of the inherent implausibility of the practice (despite the nonsense about “nanoparticles” which these authors themselves reference as if it solved the plausibility problem), and a century and a half of dedicated effort, such a glaring lack of positive evidence is far more consistent with homeopathy being a placebo than with it being the dramatically effective therapy its proponents claim.

Radical new ideas in medicine just as widely scoffed at as homeopathy have been able to prove themselves and be widely adopted in far less time than this. The notion, for example, that a bacteria could be the major cause of ulcers in humans went from ridicule (when proposed in 1982) to a Nobel prize (in 2005). It is plainly irrational to keep claiming homeopathy has dramatic benefits and that science will one day vindicate it when so much effort has turned up virtually nothing encouraging in the way of clinical research.

Now, undoubtedly proponents of homeopathy will respond to this systematic review by saying “See, there is evidence it works, all we need are more studies!” While the authors did a pretty good job trying to follow the procedures of a good systematic review, these reviews are not infallible. Garbage in can lead to garbage out, and I’ve written before about the danger of uncritically relying on the conclusions of systematic reviews where there is a potential for bias. Even if this review, and my own, did not find obvious reasons to reject the findings of two studies of homeopathy, out of all the many hundreds of those that have been published, this is not a vindication of homeopathy. It is simply a reflection of the limitations of the scientific process to exclude every single source of error when hundreds of attempts are made by committed believers to conduct clinical trials to prove what they already believe is true. Most positive trials in conventional medicine turn out to be false, and there is far more reason to doubt the rare positive study of magical nonsense like homeopathy.

Science never closes a door all the way. Could there possibly be evidence someday that would, consistently and repeatedly and with the best possible controls for error, show homeopathy really can be a miracle cure? The possibility cannot be ruled out 100%, but it must be recognized to be as unlikely as the idea that the next time someone leaps off a twenty-story building they will soar into the sky rather than fall to their death. The odds are so long as to make continued betting a foolish waste of resources. If homeopathy truly were dramatically effective, then like Vitamin C for scurvy and the first antibiotics, the results of clinical trials should be striking and obvious, not incredibly hard to pick out from the mass of negative findings.

This systematic review emphasizes that even with the darkest of rose-colored glasses, it is impossible to see the scientific study of homeopathy as anything other than an utter failure to find real, meaningful benefits, and that the best thing medical researchers could do for patients, human and veterinary, is to give up on this failed idea and move on to more promising research.






Posted in Homeopathy | 5 Comments

More Evidence of the Risk of Infectious Diseases Associated with Raw Pet Foods

I try to keep track of new research on the subject of raw food for pets. So far, the research only allows us to conclude:

  1. There is no evidence to support claims that raw diets are healthier than cooked commercial foods.
  2. There is consistent evidence that raw diets are contaminated with potentially harmful bacteria.
  3. It is not yet clear what the likelihood of infections in people or pets from these bacteria.
  4. Raw bones, often included in raw diets, may reduce calculus and periodontal disease risk, though this isn’t clearly demonstrated. However, they also present a real danger of injury, including broken teeth.
  5. Most homemade raw diets, and some commercial raw diets, may have significant nutritional deficiencies.

The latest study adds to point number 2, that such diets are far more likely than cooked pet foods to be contaminated with bacteria that can cause disease in humans and other animals.

Nemser SM, Doran T, Grabenstein M, et al. Investigation of Listeria, Salmonella, and Toxigenic Escherichia coli in Various Pet Foods. Foodborne Pathog Dis. 2014 Sep;11(9):706-9. doi: 10.1089/fpd.2014.1748. Epub 2014 May 13.

Conducted by the FDA Center for Veterinary Medicine, this study looked at over 1000 food samples over a two-year period. The results clearly show that the risk of contamination with disease-causing organisms is much greater for raw commercial foods than for cooked pet diets.

Of the 480 dry and semimoist samples, only 2 tested positive: 1 for Salmonella and 1 for Listeria greyii. However, of the 576 samples analyzed during Phase 2, 66 samples were positive for Listeria (32 of those were Listeria monocytogenes) and 15 samples positive for Salmonella. These pathogens were isolated from raw foods and jerky-type treats…

This study showed that raw pet foods may harbor food safety pathogens, such as Listeria monocytogenes and Salmonella. Consumers should handle these products carefully, being mindful of the potential risks to human and animal health.

While this doesn’t answer many of the other questions about the risks and benefits of raw diets, it strengthens the position that until some tangible benefits are shown through controlled scientific research, not simply armchair theorizing and anecdotes, there is little reason to take the risk of feeding these diets to our pets. If proponents of these diets want to convince the rest of us the risk of disease is worth taking, they have to do more than say, “It makes sense” or “It worked for me.” They will need to produce genuine scientific data to show the benefits they claim are real and greater than the risks.

Posted in Nutrition | 5 Comments

From the JREF Swift Blog- Alternative Medicine & Placebo Effects: In Pets?

My first contribution to the Swift blog at the James Randi Educational Foundation (JREF) is up today.

Alternative Medicine & Placebo Effects: In Pets?

Placebo effects, of course, operate for all medical therapies, effective or ineffective, conventional or alternative. But when considering alternative therapies, it is especially important to be aware of such effects because these therapies usually lack convincing scientific evidence that they have benefits beyond that of a placebo. As mentioned, uncommon alternative therapies like acupuncture and homeopathy are no better validated scientifically for pets than for people. Even some of the most commonly used therapies, like glucosamine, which is ubiquitous in the treatment of arthritis in old dogs and cats, often lack any reliable evidence they actually help.

Because the false impression of a benefit from an ineffective therapy can truly harm our animal companions, who cannot speak for themselves or tell us directly when we have failed to relieve their symptoms, it is especially important to insist on reliable, controlled scientific evidence for the safety and efficacy of the therapies we use for our pets.

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Acupuncture Works! (Just as Well as Fake Acupuncture Anyway)

The evidence has been accumulating for some time that acupuncture is an elaborate and very potent placebo that can effectively make subjective symptoms better without actually influencing the underlying disease. I have written about a number of studies illustrating this (e.g.  1, 2), and a new one has recently been published.

Rana S. Hinman;  Paul McCrory; Marie Pirotta; et al. Acupuncture for Chronic Knee Pain:  A Randomized Clinical Trial. JAMA. 2014;312(13):1313-1322. doi:10.1001/jama.2014.12660.

This study compared “real” acupuncture using needles and lasers with sham laser acupuncture and a no treatment group. Predictably, all the therapies showed a short-term benefit compared to nothing, but the sham therapy was just as successful (or unsuccessful) as the real therapy:

Analyses showed neither needle nor laser acupuncture significantly improved pain (mean difference; ?0.4 units; 95% CI, ?1.2 to 0.4, and ?0.1; 95% CI, ?0.9 to 0.7, respectively) or function (?1.7; 95% CI, ?6.1 to 2.6, and 0.5; 95% CI, ?3.4 to 4.4, respectively) compared with sham at 12 weeks. Compared with control, needle and laser acupuncture resulted in modest improvements in pain (?1.1; 95% CI, ?1.8 to ?0.4, and ?0.8; 95% CI, ?1.5 to ?0.1, respectively) at 12 weeks, but not at 1 year. Needle acupuncture resulted in modest improvement in function compared with control at 12 weeks (?3.9; 95% CI, ?7.7 to ?0.2) but was not significantly different from sham (?1.7; 95% CI, ?6.1 to 2.6) and was not maintained at 1 year. There were no differences for most secondary outcomes and no serious adverse events.

In patients older than 50 years with moderate or severe chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function.

Such studies clearly show that while acupuncture might make you feel better temporarily, via the placebo effect, it does not produce a real or lasting improvement. This is the definition of a placebo, and while people should be free to seek placebos to feel subjectively better if they want to, they should not be fooled into thinking the effects are real or that truly effective therapies are not needed. And in the case of our pets, it is very likely that the placebo benefits of acupuncture accrue only to us, and that while we feel as if we have helped our pets, we really have not. It is in this misconception, more than the rare physical injuries associated with acupuncture, that the real risk in this treatment methods lies.

Posted in Acupuncture | 2 Comments

The University of Florida’s Integrative Medicine Service: Good Science or a CAM Trojan Horse?

The American Holistic Veterinary Medical Foundation (AHVMF) recently announced the winner of their 2014 education grant. The University of Florida will receive the $10,000 award for demonstrating “their intent and ability to become a force in integrative veterinary medicine.”

I have discussed the term “integrative medicine” before and how it serves as a Trojan horse for smuggling untested or pseudoscientific ideas into academic institutions. Integrative medicine usually means mixing alternative therapies, by definition either unproven or disproven therapies, with conventional science-based medicine as if they were epistemologically or scientifically equivalent. It allows proponents of these therapies to make them more familiar to conventional doctors, which builds a sense of confidence in the methods independent of any research evidence showing they work.

In academia, the push for integration of alternative therapies into the mainstream is also often cloaked in the language or evidence-based medicine. It is claimed that bringing “experts” in these methods into the university will facilitate sound scientific research to determine if they are truly safe and effective. While this is a noble idea, it is often put forward disingenuously by advocates of CAM who are already convinced beyond any doubt that their methods work and who have no willingness to abandon any of them regardless of what the evidence turns out to show. The leaders of the AHVMF have demonstrated repeatedly that their beliefs do not require scientific validation (e.g. 1, 2). It is quite clear that the real purpose of AHVMF grants is not to study CAM and identify both effective and ineffective therapies but to market CAM and develop scientific camouflage for ideas they have no intention of ever truly questioning.

The University of Florida School of Veterinary Medicine is becoming a regular participant in the infiltration of unscientific ideas and practices into ostensibly science-based veterinary medicine. This is the second $10,000 grant the university has accepted from the AHVMF, the first specifically intended to support the school’s acupuncture program. There is a close and reciprocal relationship between alternative medicine advocates and the UF Integrative Medicine service which is much like the potentially problematic relationships often seen between universities and other private industries, such as pet food companies and pharmaceutical companies. In addition to the AHVMF funding, two faculty members in this program are also faculty at the Chi Institute, a leading organization teaching and promoting the pseudoscience of Traditional Chinese Veterinary Medicine (TCVM). And the school has a nutrition residency which is jointly sponsored by the Chi Institute and the pet food company Waltham.

As is typical for integrative medicine departments, the University of Florida group tends to speak both the language of science and the language of alternative medicine freely, even when these contradict one another. The school’s statement on acupuncture cites many conventional mechanisms proposed to explain the possible medical effects of this therapy, including stimulation of nerves, releases of endogenous opioids and endorphins, and so on. These are certainly plausible hypotheses, though despite a great deal of effort they have not been consistently validated by research, so they are still unproven hypotheses. However, the same document employs the mystical, pre-scientific language of TCVM: “There are 361 acupuncture points located throughout the body on meridians. Meridians are the energetic channels that connect all the points to each other.” Unfortunately, acupuncture points probably don’t exist, and the “energy” referred to here is a vitalistic concept that serves no legitimate purpose in scientific medicine.

This document goes on to talk about aspects of acupuncture that clearly depend on an acceptance of traditional, pre-scientific theories of health and disease:

Hemo-acupuncture is performed by inserting a hypodermic needle into a blood vessel that contains an acupoint to draw a few drops of blood. The purpose of this modality is to release heat from the body.

[This is clearly a form of bloodletting, an ancient and completely useless medical therapy found in Europe as well as China and abandoned by science-based medicine long ago. Much of what is described today by acupuncture proponents as ancient acupuncture was likely really bloodletting.]

Moxibustion is a form of stimulation that works by warming the acupoint and causing activation of the point. It uses crushed dried leaves of Artemisia argyi rolled into a cigar-shaped fashion. The herb is burned and then placed over an acupoint without touching the skin. The warming effect of the burned herb causes stimulation of the acupoint….Be cautious when using moxibustion in the summertime because it warms the body and might lead to too much heat.

[Again, this refers to the notion of disease caused by imbalances in theoretical concepts like warm and cold, dry and damp which are distinct from the ordinary meanings of these terms. It is essentially the same as the Western Humoral Medicine which underlay all the ineffective pre-scientific medical practices used in Europe and North America prior to the development of science-based medicine]

In another example of the inconsistencies that arise from the doublethink of trying to practice science-based medicine and pre-scientific ritualistic medicine like TCVM, one of the UF professors admits, unusually for a proponent of acupuncture, that the modern practice is not likely to have much relationship to ancient Chinese medical practices: “There is little argument that canine and feline acupuncture is a modern Western invention… Both detractors and proponents should regard the current practice as a distinctly modern adaptation with unclear lineage to antiquity, even more so when examining small animal treatment systems.” Nevertheless, the UF acupuncture document clearly states, “Veterinary acupuncture has been practiced in China for at least 2,000 years.”

The same professor acknowledges the mystical and religious foundations of modern TCVM and acupuncture, yet he seems untroubled by teaching and employing these methods as if they had meaning, based apparently on personal positive experiences and the dubious and irrelevant tu quoque fallacy that because evidence-based medicine is imperfect anything goes:

The Chinese approach to human disease was historically rooted in changing philosophies, including Daoist, Naturalist, and Confucian traditions. The relative popularity of these philosophies influenced the emphasis on certain Chinese medical concepts, such as the system of opposites (ie, yin-yang theory) and the natural relationships of organs in Five Element theory.

Veterinary medicine has followed the homogenization of Chinese medicine for humans and is now an adapted and standardized mixture of the Five Element, yin-yang, and bian zheng systems.

Modern transpositional meridians, or channels, form the basis for veterinary acupoint nomenclature but remain controversial because of associations with Five Element theory and traditional concepts of Qi (broadly defined as energy).

… detractors should acknowledge the widespread deficits in evidence-based medicine throughout the veterinary profession.

He also says, “Proponents of acupuncture should accept limitations in the technique’s application…” Yet it is puzzling what he means by “accepting limitations in the technique’s application” since his own department’s explanation of acupuncture for clients states, “There are no specific diseases that cannot be treated with acupuncture.”

Most of the academics involved in this sort of integrative medicine appear to honestly believe in the central role of science for evaluating medical therapies, though they often appear not to understand the philosophy or methods of science very well. They often contribute valuable and legitimate scientific knowledge to the profession in other areas. I don’t doubt that their desire to apply science and evidence-based medicine to alternative therapies is genuine.

However, I do doubt their willingness to accept the invalidation of the methods they believe in and champion. It is rare for high quality scientific research to demonstrate an alternative therapy is truly effective unless there is a plausible mechanism consistent with a scientific understanding of nature to begin with. Most of the numerous studies sponsored by organizations like the National Center for Complementary and Alternative Medicine (NCCAM) find no benefit to patients. This would be a perfectly appropriate and legitimate application of science to these therapies if it led to the abandonment of therapies that are ineffective, and an improved awareness of the importance of establishing a plausible hypothesis before spending limited resources on clinical research.

The reality, unfortunately, is that the rare positive studies are trumpeted as vindications, even when they are unreliable, and the many negative studies are ignored or rationalized away. When science is put to the service of advocacy for unscientific beliefs, the result is rarely good science or an improved understanding of nature. Given the obvious anti-science views of the leadership of the AHVMF and the Chi Institute, it seems likely that the work they sponsor will be much like that supported by CAM advocates in human medicine—unlikely to validate many therapies and even more unlikely to lead to anyone giving up on therapies that fail to be validated scientifically.

So while I approve of legitimate scientific inquiry into any therapies that could possibly be beneficial, in which I include many herbal therapies, some manual therapies and even possibly acupuncture (though there, the light of hope is dim and growing dimmer), I fear that UF and other veterinary institutions will be influenced by the financial and ideological support of groups like the AHVMF and the Chi Institute with agenda’s that are incompatible with such legitimate scientific inquiry. Time will tell, but the lesson of such integrative medicine in the human medical field does not encourage hope that veterinary medicine will become more effective or more evidence-based by following this path.

Posted in Acupuncture | 3 Comments

Anxitane (l-theanine) for Anxiety in Dogs

I was recently asked to look into the evidence concerning a potential therapy for anxiety in dogs, a supplement called Anxitane. It is always challenging to evaluate the effects of any therapy for anxiety in any species. Anxiety is a subjective and highly variable state, and how it is triggered, experienced, and manifested is unpredictable. An objective, consistent measure of anxiety is very difficult to find.

In humans, a researcher can ask people to report their level of anxiety, but this can be problematic since many factors besides the treatment being studied can affect the feeling and how the patients report it. In dogs, of course we cannot directly ask them to report their level of anxiety. We can try to correlate specific behaviors or physiological measurements with what we believe to be anxiety or anxiety-inducing experiences, but there is still a great deal of subjectivity and uncertainty to this. And, as is the case for pain and other subjective outcomes, there are many factors besides the treatment being studied which can influence how humans evaluate the effect on the dogs being studied, the so-called caregiver placebo effect.

Nevertheless, it dogs do appear to suffer from states that seem equivalent in many ways to what humans would label anxiety, and since their brains are similar in many important ways to ours, it is reasonable to expect their internal states and the external factors that can affect them will be similar in some ways. So treatments for anxiety in dogs are appropriate to study even if we cannot perfectly delineate the problem we are treating or the outcomes we seek to measure.

What Is It?
Anxitane is a product containing an amino acid, L-theanine, derived from green tea. Amino acids of various kinds have important effects as neurotransmitters in the brain, are supplements with amino acids in them may have important effects of brain chemistry and hence emotional states. L-theanine is structurally very similar to the amino acid neurotransmitter glutamate, and may exert effects in the brain by stimulating glutamate receptors.

Does It Work?
There have been some studies suggesting l-theanine may reduce anxiety in humans. However, the consensus appears to be that there is not yet sufficient evidence to show this amino acid has a meaningful or consistent effect on anxiety in people. A recent systematic review concluded that there were effects seen in some studies but not in others, and no general recommendation could be made based on the existing evidence:

For state anxiety ratings (STAI-S), meta-analysis on the effects of 200 mg of L-theanine at 40–50 minutes post dose did not reveal any significant effects on anxiety.

[Other study] findings provide preliminary evidence to suggest that L-theanine may ameliorate the effects of acute stress, yet may not noticeably reduce baseline levels of anxiety. However, it is important to note that this sample included a certain proportion of high anxiety-prone individuals. While it would not be expected that these participants would respond differentially to placebo and L-theanine, conclusions derived from such a sample should be viewed with caution.

Similarly, the WebMD review of the evidence states that, “Preliminary evidence suggests that taking theanine might make unstressed people feel more tranquil. But theanine doesn’t seem to have this effect on people who are anxious to start with.”

There have been two published studies in dogs evaluating l-theanine for anxiety. The first was a preliminary study in 12 dogs with noise phobia.

V. Bertesell1; M. Michelazzi. Use of L-theanine tablets (Anxitane) and behaviour modification for treatment of phobias in dog: A preliminary study. J Vet Behav. May-June 2007;2(3):101.

The results were not evaluated statistically, because there were too few subjects, and the report does not report if subjects were randomly assigned to groups, if investigators evaluating the response were blinded, or other important indicators of risk of bias and error. The authors indicate there was some apparent effect, but it isn’t clear if it was a true effect or clinically significant:

This is a preliminary study and the number of the subjects is too small to have significant results…Comparison of groups A [Anxitane and behavioral therapy] and B[behavioral therapy alone] showed an improvement in the phobic behavioral manifestations with respect to the dogs’ responses and severity.

The second study compared treatment with Anxitane and a placebo in two groups of 5 laboratory beagles judged subjectively to be afraid of humans.

Joseph A. Araujo; Christina de Rivera; Jennifer L. Ethier; Gary M. Landsberg; Sagi Denenberg; Stephanie Arnold; Norton W. Milgram. ANXITANE® tablets reduce fear of human beings in a laboratory model of anxiety-related behavior. J Vet Behav. September 2010;5(5):268-275.

Dogs were randomly assigned to the two groups, tested before administration of the treatment, and retested after 8 weeks of treatment. The testing consisted of putting the dogs in a field, with and without a human who did not intentionally interact with them, and then measuring the dogs’ behaviors and the extent to which they approached the person when there was a human in the field. The study also evaluated overall level of activity, using activity monitors attached to the dogs, and monitored for any apparent adverse effects.

At baseline, the only difference was that the dogs in the treatment group were more active overall than the dogs in the placebo group. After the 8-week treatment period, there were no differences between the groups in the amount of change in activity level or on the dogs’ behaviors alone in the field. The dogs in the treatment group spent more time near the human and interacted with the human more than the dogs in the placebo group. No obvious adverse effects were seen.

There are a number of limitations to this study. The most obvious are the small number of dogs (5 in each group), and the artificial nature of the study population and the tests. Whether or not this result is applicable to pet dogs with anxiety disorders in the real world is an open question. There were also some other methodological concerns. There were statistically significant differences in three of four measures compared, however the p-value for one of these was barely significant (P=0.0472), and it is not clear if any correction was made for multiple comparisons. And the measures of time spent near the human and interaction with the human actually decreased for both groups after treatment on three out of four measures. It is puzzling why a decrease in fear of humans would lead to less interaction with the human compared to baseline. Finally, it is worth noting that the study was funded by the manufacturer of Anxitane.

Is It Safe?
There is very little evidence concerning the effects of l-theanine in general, however there is no obvious indication of risks in the studies that have been conducted. As an amino acid, the substance is likely to be safe at doses similar to what would be consumed in food, though there could potentially be side effects at much higher doses.

Bottom Line
The theoretical reasoning behind the potential value of l-theanine for treatment of anxiety in dogs is plausible, which means it could work. The research in humans shows some weak evidence for a possible benefit, but the evidence is not sufficient to allow firm conclusions. Likewise, the research evidence in dogs is limited and weak, and it is not possible to say with any confidence whether or not l-theanine has a meaningful benefit for dogs with anxiety. It could work, but at this point we don’t know if it actually does.

Since the product is likely safe, there is little risk in trying it in dogs with anxiety. However, without stronger evidence for a benefit, it should not be viewed as a substitute for therapies with better evidence of efficacy.

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Evidence Update: Azodyl for Chronic Kidney Disease in Dogs

One of the products I have kept track of over the years is Azodyl, a probiotic reported to be useful in treating kidney disease in dogs and cats. Though the company has reported positive results in laboratory studies involving rats, cats, and pigs, the independent studies so far reported in dogs and cats have not found any real-world benefits. Apparently last summer another study was presented at the ACVIM Forum, a conference for veterinary internal medicine specialists.

Kanakubo; S. Ross; H. Finke; J. Kirby; S. Nalor; C. Stafford; L.D. Cowgill. Influence of AzodylTM on Urea and Water Metabolism in Uremic Dogs. ACVIM Forum 2013, June 12-15,. Seattle, WA.28970

The study was not a clinical trial but a laboratory study of a small number of dogs (4) undergoing dialysis for treatment of kidney disease. The investigators evaluated the effects of Azodyl, given at two different doses over 1-2 months of time, by comparing various laboratory tests for measuring kidney function and the processing of nitrogen from protein in the diet in the same dogs before and after giving the probiotic. The study was partially funded by the manufacturer of Azodyl.

The investigators concluded that there were no changes in any of the measured values when these dogs were put on Azodyl. However, the dogs did appear to gain weight from fluid, suggesting that perhaps the product influenced water consumption or absorption.

 The results of this short-term study demonstrated:

  • AzodylTM had no significant or beneficial effect on pre-dialysis BUN in dialysis-dependent dogs.
  • AzodylTM had no significant effect on single treatment or weekly time-average urea, TACurea; urea appearance rate, Ga; or the whole-body urea clearance, Curea.
  • AzodylTM administration produced no demonstrable effect on the intestinal clearance of urea, Cint.
  • AzodylTM administration was associated with a positive increase in total body water requiring increased dialytic removal to maintain dry-weight.
  • Despite manufacturer’s suggestion, AzodylTM did not influence short-term azotemia or nitrogen metabolism in this CKD cohort.
  • AzodyTM was associated with a positive fluid balance in these dogs.
  • These results were unable to support the potential for AzodylTM to facilitate ‘Enteral Dialysis’ in dogs with CKD undergoing hemodialysis


This is a pretty small and unusual population of dogs compared to those who will normally be treated with Azodyl in routine clinical practice, so it does not determine whether or not the product is clinically useful in more typical cases. However, it does undermine some of the theoretical rationale for why Azodyl might be useful in chronic kidney disease in dogs.

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What is “Integrative Oncology” & is it Good for Patients?

I’ve written about so-called “integrative medicine” in the past, and my conclusion was that it is largely a Trojan horse intended to exempt certain alternative therapies from rigorous scientific scrutiny and gain mainstream acceptance without appropriate evidence of safety and efficacy. This is accomplished partly by muddying the waters of what “alternative” and conventional therapies are, claiming certain perfectly ordinary science-based practices such as exercise and a healthy diet are “alternative,” and then using the good data for these to imply that all integrative therapies are equally legitimate. Integrative medicine is largely a marketing concept designed to gradually erode skepticism of unproven and implausible methods without actually demonstrating their value scientifically.

There is an interesting and thoughtful discussion of the specific variety of this phenomenon known as “integrative oncology,” in the current issue of Nature (free with registration). Since the same kinds of language and arguments presented for integrative oncology in humans crop up in veterinary oncology fairly often, this article seems quite pertinent to veterinary medicine.

I encourage anyone interested to read the full article, but here are a few selections:

Integrative oncology is often touted as being useful for relieving symptoms, rather than as a primary treatment for the actual cancer. Unfortunately, a closer examination of many CAM modalities indicates that the vast majority of them rest on principles that, from a strictly basic science standpoint, range from highly implausible to virtually impossible — some rest on principles whose precepts violate well-established laws of physics and chemistry and/or are rooted in pre-scientific vitalism (such as homeopathy and energy medicine…In CAM, as in science-based medicine, prior plausibility is no guarantee of positive results, but prior probabilities that are as close to zero as those of homeopathy are a good guarantee of negative results.

To the extent that conventional medicine might underemphasize non-pharmaceutical health-promoting activities, such as lifestyle interventions and nutrition, integrative oncology could be argued to be useful in its reintroduction of an emphasis on consuming a balanced diet, exercising, and doing things that promote general wellness, some of which could conceivably at least improve the quality of life in cancer patients, if not their overall chances of surviving their disease. However, this reintroduction is not without a price, and it is questionable whether the claimed benefits are worth this price.

Integrative oncology integrates unscientific practices into science-based medicine, and, worse, the non-biologically based subdivisions of CAM is so pervasive, so embedded in the very fabric of integrative oncology, that it opens the door to clinical trials of dubious efficacy and the wasting of time and resources.

…in its current form at least, integrative medicine integrates a great deal of pseudoscience and bad science with science-based oncology.
It does not need to be this way…practicing truly holistic oncology does not require rejecting science and embracing pseudoscience. It is possible to introduce scientifically supportable elements of CAM, such as certain dietary and lifestyle interventions, into oncology as science- and evidence-based supportive modalities There should be no such thing as alternative or integrative medicine. There should only be medicine with strong evidence supporting efficacy and safety. Unfortunately, most of what is being ‘integrated’ with science-based medicine in integrative oncology is either unproven or has been proven not to work. Patients with cancer deserve better.

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