The Health Effects of “Processed Foods” and Why Nutrition is More Important than the Amount of “Processing”

In the endless debates about the health effects of various approach to feeding our canine and feline companions, the subject of “processed foods” or “ultra-processed foods” comes up often. Generally, the argument is made that traditional commercial pet foods, including canned but most especially extruded dry foods (aka kibble), are “ultra-processed” and are functionally equivalent to potato chips and sliced lunch meat. Since the evidence is pretty consistent that convenience foods, packaged snack foods, and most “fast-foods” are associated with increased health risks in humans, the conclusion is that these traditional commercial foods must be unhealthy for our pets.

This is a superficially logical argument, but it is also convenient for proponents of various unscientific approaches to animal health because it fits nicely with the “appeal to nature fallacy” many of them are committed to. That is the idea that something which appears “natural” to them is healthier than something which seems artificial or unnatural.

This is, of course, an arbitrary and nearly meaningless aesthetic judgment, not a rational or scientific categorization. However, since the health risks of ultra-processed foods for humans, and the apparent equivalence of traditional pet diets with such foods, reinforce an existing bias, this is taken as a strong argument for alternative diets that present the appearance of being more “natural: and more like the less processed “whole foods” widely recommended for humans. 

In these discussions, I have tried many times to point out a clear and gaping hole in this reasoning—just because commercial pet foods come in a bag or a can, doesn’t mean they are all the same or that they are equivalent to human snack foods. Potato chips, lunch meats, and fast foods are intentionally designed to be appealing, in terms of appearance, taste, sensory experience (e.g. mouth feel and smell), and low cost. They are not meant to be nutritionally substantive or “healthy” in any way.

This is quite different from pet foods, which are deliberately formulated to be nutritionally appropriate and to support long-term health. The “processing” is not the real problem with “processed foods,” it is the excesses of salt, calories, and harmful fats and the absence of micronutrients, fiber, and other dietary components that make such foods a health risk.

A recent research article and accompanying editorial make this point quite clearly.

Fang Z, Rossato SL, Hang D, Khandpur N, Wang K, Lo CH, Willett WC, Giovannucci EL, Song M. Association of ultra-processed food consumption with all cause and cause specific mortality: population based cohort study. BMJ. 2024 May 8;385:e078476. 

This study evaluated diet and health outcomes in tens of thousands of North American healthcare workers followed for over thirty years. Here are some key findings:

  • People with consumption of ultra-processed foods (UPF) in the highest 25% had an increase in all-cause mortality of 4% compared with people in the lowest 25% of UPF consumption. This is an absolute difference of 64 deaths per 100,000 person years (1472 compared with 1536 deaths per 100,000 person years).The worst diet led to a real, but very small difference in mortality rate compared to the best diet.
  • This difference was a little larger when considering non-cancer and non-cardiovascular causes of death specifically: 9%
  • There was no difference in the risk of death from cancer or cardiovascular disease between the highest and lowest consumption of UPF.

All of this supports the existing evidence that UPF represent a health risk, but it also puts this in perspective. The risk is relatively small, much smaller than other known risk factors such as smoking, drinking excessively, or driving without a seat belt.

Even more telling, “this association was no longer apparent after overall diet quality was taken into account.” This means that there was no detectable difference between those who ate a lot or only a little UPF when the overall quality of the diet was accounted for. Again, the problem with UPF is not the “processing” but the unhealthy nutritional composition, and people who ate a generally healthy diet did not significantly increased their risk of dying if they included some UPF. 

This point is further reinforced by the finding that the mortality risk difference was greater when alcohol was included as a UPF, and it was less when whole-grain bread products were included as a UPF. The health risks were affected by the nutritional quality and the other risk factors associated with a food (such as the toxic nature of ethyl alcohol) regardless of whether both items were equally “highly processed.”

The specific types of food most closely associated with increased mortality risks were meat products and sweetened beverages (though, interestingly, drinks sweetened with sugar had a slightly stronger negative effect that artificially sweetened, again undermining the “natural is better” argument). 

The authors state their conclusion based quite clearly, and it reflects the point I have been making for years now:

Our data together suggest that dietary quality has a predominant influence on long term health, whereas the additional effect of food processing is likely to be limited.

Because the nutritional composition and overall diet quality is what matters, not the level of processing, the implications of this for diet recommendations is clear:

Limiting total ultra-processed food consumption may not have a substantial influence on premature death, whereas reducing consumption of certain ultra-processed food subgroups (for example, processed meat) can be beneficial.

The accompanying editorial expand son this point:

Not all ultra-processed food needs to be universally restricted and…careful deliberation is needed when considering whether to include recommendations about ultra-processed food in dietary guidelines. In countries where affordable, mass produced packaged wholegrain products such as breads are a recommended dietary staple and a major source of fibre, adding a sweeping statement in dietary guidelines about avoiding ultra-processed foods is not helpful.

As veterinary professionals and pet owners, these results reinforce the point that we should not obsess about the “processing” involved in the making of the pet foods we use. While inclusion of some fresh or whole foods may well turn out to have some health benefits, it is far more important that making sure our pets are eating complete and balanced diets that meet their nutritional needs, regardless of the form they take.

Posted in Nutrition | Leave a comment

Evidence Update: A Systematic Review of Studies Evaluating Vegan Diets for Dogs and Cats

Over the years, I have reviewed the general evidence and some specific studies concerning vegetarian and vegan diets for dogs and cats. Despite the aggressive claims of some advocates for such diets (including some egregiously unscrupulous individuals), the actual evidence has not been extensive or definitive. My conclusions in previous posts have been that there is no clear evidence vegetarian or vegan diets have benefits for dogs and cats, and there is some real potential for harm, especially in cats:

Vegetarian Diets for Dogs & Cats, 2019

There is no evidence that vegetarian diets have health benefits for dogs and cats, and no real reason to believe they should be, based on the physiology and nutritional requirements of these species. 

Dogs are omnivores shaped by domestication to be able to eat both plant and animal foods, and in theory they should be able to thrive on vegetarian or vegan diets. However, these diets must be carefully formulated, and many commercial vegetarian dog foods do not appear to be nutritionally adequate. There is also little reliable research evidence showing that dogs can remain healthy fed only a vegan diet.

Cats are clearly obligate carnivores with nutritional requirements that are unlikely to be effectively met by vegan diets. Such diets offer only risks and no benefits for cats and should be avoided.

Plant-based vs Meat-based Diets for Cats: Which is Healthier?, 2021

This study didn’t actually evaluate the effect of plant-based vs. meat-based diets on health or longevity in cats. What the study evaluated was the perceptions of owners about their cats’ diet and health. The difference is crucial. 

All we can say is that owners who choose to feed a plant-based diet believe their cats are a healthier weight than owners who feed meat-based diets. Since plant-based diets are fed to a small minority of cats, the people who feed these diets must choose to do so based on pre-existing beliefs about their health value. Such individuals already believe these diets are healthier, and they are likely to see and report what is consistent with these beliefs, whether or not it is the reality of their cats’ condition.

Prospective, blinded, randomized feeding studies would be needed to allow any strong conclusions about whether or not plant-based diets are safe and healthy for cats.

Are Vegan Diets Healthier for Dogs & Cats?, 2022

The particular population of pet owners surveyed believes that feeding raw and plant-based diets are associated with better health in their pets. They also believe that their veterinarians think their pets are healthier (though whether these vets actually believe this is unknown)…Like previous studies relying on owner surveys and both conducted and funded by folks with strong a priori opinions about diet and health, this is a useful insight into such beliefs. It is not compelling or probative evidence for actual health effects of different feeding strategies. 

Controlled studies with objective measures of outcome and more defined and verified feeding practices are required to draw any meaningful, actionable conclusions about the healthiest feeding strategy for our pets. 

I am neither for nor against vegan diets for dogs, and I am even open to reversing my objection to feeding vegan to cats or raw diets to cats or dogs if strong evidence is generated that these are safe or beneficial practices. 

I recently came across a systematic review of the literature that summarizes and assesses the available evidence concerning vegan diets for dogs and cats.

Domínguez-Oliva A, Mota-Rojas D, Semendric I, Whittaker AL. The Impact of Vegan Diets on Indicators of Health in Dogs and Cats: A Systematic Review. Veterinary Sciences. 2023; 10(1):52. 

The data from review largely support my concerns about the lack of evidence, though the authors draw a somewhat more optimistic conclusion than I would:

In this review, we conducted a formal assessment of the evidence in the form of a systematic review. We found that there has been limited scientific study on the impact of vegan diets on cat and dog health. In addition, the studies that have been conducted tended to employ small sample sizes, with study designs which are considered less reliable in evidence-based practice. Whilst there have been several survey studies with larger sample sizes, these types of studies can be subject to selection bias based on the disposition of the respondents towards alternative diets, or since answers may relate to subjective concepts such as body condition. However, there is little evidence of adverse effects arising in dogs and cats on vegan diets. In addition, some of the evidence on adverse health impacts is contradicted in other studies. Additionally, there is some evidence of benefits, particularly arising from guardians’ perceptions of the diets. Given the lack of large population-based studies, a cautious approach is recommended.

The short version of this is that there aren’t many studies, and most have serious flaws or limitations, so strong conclusions either way aren’t justified.

No obviously horrible risks have shown up, but given that the studies which looked at actual health outcomes were few, short-term, and involved small numbers of animals on several very different diets, it would be a mistake to draw the general conclusion that vegan diets are safe.

Similarly, a few studies claim to show health benefits, but these are all based on owner surveys with groups of owners self-selected to include people already convinced that vegan diets are healthier. This kind of evidence, also frequently cited to support health claims for raw diets, is highly biased and tells us more about what believers in such diets expect to see than about the actual health effects on their pets.

Finally, some nutritionists have pointed out a significant problem with this kind of review– the idea that broad categories of diets (e.g. canned, kibble, raw, fresh, vegan, etc.) can be identified as beneficial or harmful doesn’t really make sense. The health impact of a diet depends on the specific composition, the ratio and availability of nutrients in the diet, and the nutritional needs of each individual. Vague generalizations, such as “vegan diets are healthy” or “kibble is unhealthy” are so broad as to be pretty meaningless, and they don’t help us decide what the best diet is for our specific pets. While some level of generalization is, of course, necessary and useful, these characterizations go too far to be accurate or helpful.

Bottom Line
There is very little research examining the health effects of vegetarian or vegan diets in dogs and cats. The existing evidence has significant limitations, which makes any firm conclusions impossible. 

General theoretical arguments for why such diets should be healthy are not especially plausible nor convincing. It is likely that a properly formulated vegan diet could be adequate for many dogs, and possible for cats as well, but whether there are any benefits to feeding such diets, and whether these might outweigh potential risks, is not yet known. 

Given this uncertainty, and the much better evidence for the appropriateness of cooked, meat-based diets, feeding dogs and cats a specific vegan diet is essentially a haphazard experiment, with as much or more potential for harm as for benefit.  

Posted in Nutrition | Leave a comment

Talks from WVC 2024- Nutrition for Lifespan Extension and Frailty

Here are some low-quality recordings of a couple lectures I gave this year at the Western Veterinary Conference in Las Vegas.

Posted in Presentations, Lectures, Publications & Interviews | Leave a comment

Evidence Update: Is Surgery Necessary for Dogs with Cranial Cruciate Ligament Rupture?

Back in 2011, I first wrote about the issue of concerning whether dogs with cranial cruciate ligament (CCL) ruptures did better with surgery or with non-surgical management. My conclusion at that time was:

For most dogs under 15kg, conservative management (primarily restricted activity for 3-6 weeks, achieving and maintaining and appropriate body weight, and possibly physical therapy and pain medication) can achieve acceptable comfort and function. In larger dogs, significant arthritis is inevitable and dysfunction is extremely likely without surgical treatment. 

In 2013, I write an update looking at an additional study , and concluded:

This study does provide some support for the contention that overweight, large-breed or giant-breed dogs have better long-term outcomes when treated with both surgery and non-surgical therapy rather than with non-surgical therapy alone. However, the limitations in these data are great enough that the case for preferring surgical intervention is not strong

Since that time, there has been some further research, but there has not been one single, definitive clinical study comparing surgery with other approaches for managing CCL disease. This is partly for ethical reasons. Since most vets believe surgery produces a better outcome, it is considered unethical to randomly assign dogs with CCL disease to getting surgery or getting a potentially inferior treatment. 

A new study has attempted to use existing data on a large number of dogs, and some complex analytic techniques, to mimic such a study.

Camilla Pegram, Karla Diaz-Ordaz, Dave C. Brodbelt, Yu-Mei Chang, Anna Frykfors von Hekkel, Chieh-Hsi Wu, David B. Church, Dan G. O’Neill. Target Trial Emulation: Does surgical versus non-surgical management of cranial cruciate ligament rupture in dogs cause different outcomes? Preventive Veterinary Medicine. 2024; 226;106165.

I don’t have the expertise to evaluate the analytic approach in this study. The authors acknowledge many of the usual limitations to large retrospective analyses, but despite these issues, such studies are valuable, especially I the evidence-poor environment of veterinary medicine. 

The results are pretty consistent in showing better outcomes in dogs treated surgically:

The current study shows that on average, surgical management leads to reduced lameness and analgesic prescription outcomes compared with non-surgical management. 

Interestingly, the study did not find any difference between large and small dogs. Both groups seemed to do better with surgery, which is a different finding than some previous research. The authors suggest this may be related to limited numbers of small dogs being treated, since they are less likely to develop CCL disease, so further work is needed to clarify the impact of size on the choice of treatment.

While there are always individual factors to integrate into any decision about the best management for a specific patient, this additional evidence tends to support the existing view that surgery probably produces better outcomes for dogs with CCL disease. While this is not the perfect definitive clinical trial, such a study is unlikely to occur. The evidence that we do have is pretty consistent, and it supports at least a moderate degree of confidence in recommending surgery for those patients in whom it is an option and who have no specific reasons to avoid surgical treatment.

Posted in General, Science-Based Veterinary Medicine | 6 Comments

Fickle Justice: Some Quacks get Punished, Most Get Away with It

One of the goals of this blog has always been to warn pet owners about dangers to their animals: dangerously unreliable ideas and ways of thinking about science and medicine, dangerous therapies (or at least those not yet proven to be safe or effective), and dangerous individuals who promote both unscientific approaches and unproven or unsafe treatments. There is remarkably little effective regulation and oversight of pet healthcare products, apart from prescription medications. Unscrupulous sellers of snake oil, including vets, can often get away with egregiously illegal and dangerous claims and practices.

Despite this, a few of the individuals I have warned pet owners about over the years have faced at least some legal or regulatory sanctions, though the process has been slow and has often not impeded their ability to sell their nonsense. Recently, one particularly bizarre example, Jonathan Nyce, has finally been sentenced to prison for selling fake cancer treatments for dogs, a decade after I started  warning people about him. 

This belated but positive outcome seemed like a good prompt for me to revisit some of the folks I have been writing about for some time who have faced official sanction for their abuse of science and the public’s trust. While the outcome in Mr. Nyce’s case is positive, the balance of these cases have not resulted in effective protection of the public and our pets.

Jonathan Nyce
My first post about Mr. Nyce was in 2014. In it, I looked at his claims for his supposed miracle cancer cure Tumexal (later renamed Naturasone). The product and the marketing had many of the hallmarks of quackery, from secret ingredients to use of testimonials and unpublished, potentially fabricated, test results. Mr. Nyce had a worrisome background, including previously questionable and unsuccessful attempts to market a drug for humans and a criminal conviction for murder, though I made a point of not making my critique of the product or the claims for it a personal critique of Mr. Nyce, since that is not a reliable way to judge such claims. 

In 2020, I briefly reported on the criminal charges filed against Mr. Nyce for his illegal marketing of a fake cancer treatment. Finally, last month, Mr. Nyce was sentenced to 97 months in prison for his activities, which included bilking over 900 dog owners of nearly $1,000,000. Who knows how much harm his deception of well-meaning owners did to the patients themselves? As tempting as it is to rejoice at a well-deserved sentence, the more important question is whether this conviction will do anything to stop others from marketing bogus treatments. I have to admit to not being very optimistic on this point, for reasons which may be clearer as I review some other examples.

Gloria Dodd
Even before covering Jonathan Nyce’s misdeeds, I wrote about veterinarian Gloria Dodd in 2011 (not to be confused with Jean Dodds, about whom more later….). Dr. Dodd was a proponent of a broad array of pseudoscientific nonsense, from auras and homeopathy to crystal healing and dowsing. She was also a seller of many alternative remedies that were either entirely useless (e.g. homeopathic) or untested and based on unscientific principles.

Her practices were determined to cross legal lines more than once. In 2004, the FDA sent her a warning letter for selling a fake “homeopathic vaccine” for West Nile virus. That product was still available when I wrote about her in 2011. 

She was also disciplined by the California Veterinary Medical Board for practices that were blatantly unscientific, “a smoke and mirror power of magic type of practice,” in the words of the VMB. Her license was suspended for prescribing treatments for patients she had never seen in person. However, the courts effectively overturned this ruling, and Dr. Dodds continued to practice her “magic” for years to come. 

Dr. Dodd passed away in 2013, but her company continued to promote her ideas and products for several more years. Regardless of how kind and genuine a person Dr. Dodd may have been, it is tragic that she was able to mislead pet owners about health and veterinary medicine for decades and sell products that could not have been beneficial and may well have harmed patients, either directly or by replacing other, truly effective remedies. The failure of the legal and regulatory system to protect the public from such practices is disappointing, though not unusual.

Al Plechner
Dr. Plechner was another California veterinarian with deeply unscientific ideas about science and medicine. For decades, he treated patients for the mythical entity of “Plechner Syndrome” with high doses of steroids, thyroid hormones, Montmorillonite clay, and a variety of other nonsensical nostrums. While he claimed to have “research” to back his theories, he never published anything, and his descriptions sounded like nothing more than anecdotal case reports. Certainly, he never produced any evidence that convinced actual exerts in veterinary endocrinology that Plechner syndrome existed or had the causes and treatments he championed.

Like most purveyors of pseudoscience, Dr. Plechner did have dedicated supporters, who came out enthusiastically to “correct” me after my first post discussing his methods. His detractors, sadly, were less willing to go public. The private veterinary discussion boards on the Veterinary Information Network (VIN) contain many complaints and laments about Dr. Plechner’s ridiculous ideas, and about patients inappropriately treated with unsafe methods, but these never reached the public. 

In 2015, I was contacted by an individual whose cat had been treated by Dr. Plechner with blatantly inappropriate doses of steroids. The cate suffered skin fragility syndrome (similar to this case) and faced surgery and a prolonged recovery from the effects of the drugs. Though several vets saw this cat and explained that the drugs were the cause of the problem, the owner had difficulty getting someone to support her complaint against Dr. Plechner, due to a combination of personal relationships between him and some of the vets and the general reluctance of veterinarians to call out even grossly inappropriate behavior by their colleagues. 

The owner was able to find an internal medicine specialist to support her complaint to the VMB. Unfortunately, the wheels of justice ground slowly and started turning too late. Dr. Plechner retired and gave up his license in 2016. This did not automatically stop the VMB investigation, but Dr. Plechner then passed away in 2017, and no findings were ever released. However, his website is still active, his books are still for sale, and other vets (themselves with legal troubles) continue to promote his approach.

Jean Dodds
Dr. Dodds pops up often on this blog as she is a prominent voice in the alternative veterinary medicine arena, with lots of dubious ideas and unproven products and practices. I first mentioned her in 2011, in connection with some research on an oral health supplement, and I have provided detailed coverage of her unconvincing work on reduced “doses” of vaccinesfor small dogs (updated here), her unscientific and misleading writing about nutrigenomicsher bogus “allergy test” as well as other dubious tests she promotes, and many other topics. 

Most recently, in 2021 I  briefly discussed the citation against Dr. Dodds from the California Veterinary Medical Boardfor practicing medicine without a license, as she has done for many years. The citations was “satisfied” in August, 2023, presumably meaning she paid the fine and promised not to practice medicine (though I have not been able to find any no public record of how this was resolved). Despite this, Dr. Dodds profile, and the activity of her company, Hemopet (which itself has been fighting with the state over tax obligations) continue to operate openly and freely. The fact that her medical practice has been illegal for years does not seem to have lessened her influence or her business activities in any meaningful way.

Andrew Jones

Dr. Jones did not initially get his own post, but he popped up in passing in another article I wrote in 2010 as an example of the mania for magical “secrets” that alternative medicine proponents often claim to have for treating health problems that science-based medicine can’t cure. Later that year, Dr. Jones chose to give up his veterinary license rather than stop defaming veterinarians who practice mainstream medicine as a way of promoting his own alternative approach. It turned out Dr. Jones’ followers were even more aggressively supportive of their angry saint than those of Dr. Plechner, and when he rallied them, they went on the attack against me in all sorts of corners of the Internet. Several years later, Dr. jones was still perturbed by my criticism, and his supporters continue to leave comments on the blog more than ten years after my first article about him.

Of course, the reason for that is that losing his medical license has done nothing to deter Dr. Jones from selling his bogus “secrets,” and all sorts of products, online. The snake oil business is still booming, and many of his customers see him as a martyr rather than someone who couldn’t keep his medical practice consistent with science and the law. He proudly promotes his book, “From the #1 bestselling author and former practicing veterinarian,Andrew Jones DVM.” Bizarre! And while some do continue to push back against his pseudoscientific claims, Dr. Jones has a thriving career selling nonsense and lies despite no longer being licensed to practice medicine.

Eric Weisman
I first wrote about Mr. Weisman in 2009, the first year of this blog. His ideas about health and nutrition were bizarre and laden with extremist conspiracy theories, and his claims about the diets and practices he recommended were unscientific nonsense. He ultimately lost his chiropractic license and was sanctioned for practicing veterinary medicine without a license long before I started examining his claims. In 2011 he faced criminal charges for practicing human and animal medicine without a license and for animal cruelty. He reached a plea deal and got a slap on the wrist in 2012 despite his ling history of illegal and dangerously delusional behavior. 

In 2018, he signed a stipulation from the Minnesota State Dept. of Public Health admitting to unlicensed practice of alternative medicine and misrepresenting his credentials and promising not to do it again. He also paid a $263 fine. In the most bizarre legal resolution to any of these cases I have yet seen, doing this apparently allows Mr. Weisman to do whatever bizarre voodoo he likes with the permission of the Minnesota state government:

It turns out that the government of Minnesota has entirely given up any pretense of protecting the public from charlatans and witchcraft. Mr. Weisman is doing just as he pleases, offering “consultations:” as well as selling vegan pet food with longevity claims based on a grossly misleading and unscientific interpretation of some published owner survey reports.

Apparently, claiming to be able to treat serious life-threatening illnesses, interpret clinical lab tests and MRI images, and discouraging patients from seeing legitimate, science-based medical practitioners is now A-OK in Minnesota! Yet another quack thriving by deceiving the public. 

Posted in Law, Regulation, and Politics | 3 Comments

Evidence Update: Leap Years Anti-aging Supplement Study

Back in January of 2023 I reviewed claims for a purported anti-aging supplement for dogs called Leap Years. My conclusion at the time was-

Leap Years is similar to most veterinary supplements on the market: It is based on some plausible ideas with limited supporting evidence, and it is marketed with claims that go well beyond anything scientifically proven or reasonable. 

In that review, I pointed out that one piece of evidence the manufacturer cited to support their claims was an unpublished clinical study conducted at the veterinary school at North Carolina State University (NCSU). That study is still has not been published in a peer-reviewed journal, but the company has recently released a report on the preprint service Bioarxiv

This is an increasingly common practice which is supposedly intended to make important information available more quickly, but which in most cases has more public relations value than scientific value. Until a paper is put through peer-review, it has only been critically evaluated by the authors or people they have chosen, which leaves lots of opportunity for bias. Such preprints may change significantly before publication or even never be peer-reviewed and published at all. 

Preprints are clearly a lower level of evidence than full published research reports, but they do at least provide more detail for anyone interested in evaluating the research and claims made using it. As you have probably already guessed, that’s what I intend to do here! 

The Study
The study was a blinded, randomized, placebo-controlled clinical trial conducted in accordance with appropriate methodological guidelines, which is always nice to see. The authors do a good job of describing the methods, including the bias-control practices, progress of subjects through the trial, and the potential limitations. The one critical piece of information missing is the actual chemical compounds used in the supplement. 

As discussed in my previous review, Leap Years supposedly contains an NAD+ booster, which the company states is not NMN but otherwise does not identify. This was given daily for the duration of the 6-month study period. The supplement is also claimed to contain a senolytic, which is also not identified and which was given on two consecutive days each month during the study.

The FDA is pretty clear that veterinary supplements are not covered under the limited regulatory rules for human supplements (the Dietary Supplement Health and Education Act or DSHEA). Anything marketed for animals must either be a food or a drug. Leap Years is clearly not a food, and the claims made for it very much sound like treatment claims for a veterinary drugs: 

[Leap years] significantly improves owner-assessed cognitive function and may have broader effects on frailty, activity and happiness as reported by owners.

That would make it seem like the company is marketing an unlicensed veterinary drug without first demonstrating safety and efficacy, as is required. However, the FDA does not seem to have the resources or political backing to effectively enforce these rules, and the same is true for many other veterinary supplements. Legal or not, it seems to me unethical (if not unusual) to market a supplement with undisclosed ingredients and claim that it prevents or treats serious health problems in dogs. This study does nothing to address that concern.

The trial started with 67 dogs randomized to placebo, low-dose supplement, and high-dose supplement (though the authors refer to these as “low-dose” and “full-dose,” which seems an obvious attempt to avoid the potential negative connotations and anxiety that might come with claiming to provide a “high” dose of whatever the undisclosed ingredients are). Subjects dropped out at various stages of the study for a variety of reasons. The total dropout rate was a bit high (19-26% from baseline to final analysis of the data), as is to be expected with an already old population. However, the dropouts seemed roughly balanced across groups, so while this might have affected the statistical power of the study, it probably didn’t bias the results for or against any of the treatments.

The dogs were included in the study if they were at least 10 years old and had mild or moderate cognitive dysfunction as assessed by a validated tool (CADES). They also had to be cooperative for behavioral testing and not so sick or debilitated that they couldn’t complete the various evaluations of the length of the study. All of these are reasonable inclusion criteria.

There were quite a few outcomes measured, though at least these were appropriately identified as a primary outcome (which is all that is supposed to matter when one critically evaluates a study like this) and secondary outcomes (which are supposed to be viewed as potentially interesting but not probative). 

The primary outcome was the change at 3 months in a validated measure of canine cognitive dysfunction (CCDR, not the same as used to test dogs for inclusion in the study). As the figure below shows, all groups improved, including those taking a placebo, which is a classic finding for non-specific effects of participating in a clinical study. Patients tend to get better due, most likely, to the increased care, attention, and monitoring they get as study subjects, even if the treatment doesn’t do anything (which is part of why having a placebo group is so important). 

At 3 months, the placebo group looks better than the low-dose group, and the high-dose group looks better than both, and the authors report, “There was a significant difference between treatment groups over the three-month period (p=0.02).” However, differences in “successes” and “failures” (improvement or worsening of CCDR scores) between groups were not significant at 3 months.

More importantly, it’s not clear if these differences would be meaningful in terms of function or quality of life even if they were statistically significant. It is not even clear that these differences are real since they are variable across time periods and do not show the expected relationship between dose and response (the placebo group should stay the same or get worse, the low-dose group should get a little better, and the full-dose group should improve more than the low-dose group).

Expanding the chart to include the data from the 6-month timepoints (reported in the supplement to the preprint) shows the lack of these relationships and suggests that there is not clear and meaningful improvement with the supplement. Even though the 3-month timepoints was reported as a prespecified endpoint, it is interesting that it is the only timepoints that seems to show a significant improvement in a treated group and not the placebo group. Despite the statistical difference reported, it is pretty clear that the primary endpoint did not show the treatment to be effective. 

The secondary outcomes also failed to show any clear evidence of a beneficial effect:

  • The CCDR was measured again at 6 months, and there were not changes nor differences within or between the groups
  • There was no change within groups nor differences between them in activity level determined by an objective monitoring device
  • There were no significant differences between the groups in the number of dogs reported to have maintained the same level of activity. The results also don’t show the kind of progressive effect with increasing dose that would be expected if there was actually a real treatment effect:
    placebo 55% unchanged 
    low dose 62% unchanged 
    high dose 44% unchanged 
  • Similarly, no significant differences or dose response was seen in the percentage of dogs reported to have increased their activity level:
    placebo 20% increased
    low dose 10% increased 
    high dose 39% increased
  • There were no statistically significant differences or dose response seen in the proportion of dogs with stable or improved frailty scores:
    placebo 55% stable or improved
    low dose 76.2% stable or improved
    high dose 72.2% stable or improved
  • A variety of cognitive function tests were run on the study dogs. These haven’t been validated to show changes over time or drug treatment effects, though they could potentially be useful for doing so. There were no significant differences and no clear sign of a dose response for these tests.
    • Cylinder test- all groups improved with no differences between them
    • Detour test- there was a slight decline in the full-dose group, a slight improvement in the other groups, and none of these differences were significant
    • Sustained gaze test- all groups improved with no differences between them
  • Gait speed- there were no changes nor differences between groups

    Only a limited subset of the results was reported for owner-reported happiness in the paper, and I have not dug through the full data spreadsheet to find the rest, but the most hopeful subset reported by the authors still does not show a clear effect.
  • At 6 months, there were some differences in the proportion of dogs reported to get better on this measure, but these were not statistically significant, and again they don’t show a logical dose response:
    placebo 24% better
    low dose 47% better
    high dose 35% better
  • At 3 months, there were some differences in the proportion of dogs reported to get worse on this measure, but these were not statistically significant:
    placebo 15% worse
    low dose 10% worse
    high dose 0% worse

The authors also monitored for adverse effects and classified these according to appropriate standards. There were few serious adverse effects observed, and these were evenly distributed between the groups and did not suggest any dramatic safety problems with the product.

Bottom Line
This report does not count as a peer-reviewed publication, and it adds only a little to the evidence already discussed a year ago to support the product claims. However, the report is useful in that it provides more detail about how the study was conducted and what the results were. Generally, the study was designed and reported appropriately, and the level of control, for bias was pretty good. Unfortunately for the company, the results failed to show statistically significant or clearly meaningful benefits for treated dogs. 

The discussion and the company website, of course, try to present the findings in at least a slightly positive light, but the final statement that the product, “can be used safely to mitigate cognitive decline in senior dogs and might have broader effects on dog health manifesting as improved happiness and reduced frailty” is certainly not supported by the actual results reported here. The best we can say is that there were no apparent signs of significant risk and there were a few non-significant findings that might turn out to be mildly beneficial at a low but significant level in a larger study or with different outcome measures.

This level of evidence is never the definitive word for or against a treatment, but that this is the best the company can come up with after over a year on the market is not encouraging. The company makes claims which seem likely to be prohibited for a veterinary supplement, and they rely on anecdote and questionable extrapolation from theoretical science and results in other species to market the product, and the release of this study does nothing to strengthen their case.

March 12, 2024- Addendum
Today Dr. Nir Barzilai announced that Dr. Sinclair was resigning from the presidency of the Academy for Health and Lifespan Research. It is nice to see some consequences for such clear, commercially motivated misuse of science. Hopefully, this will encourage Dr. Sinclair to focus more on research and less on selling unproven supplements, for dogs or humans!

Posted in Aging Science, Herbs and Supplements | 12 Comments

Science, Science Denial, & Drug Development- A response to Dr. Judy Morgan

As I’ve mentioned previously, in the last four years I have continued my clinical practice while also working for Loyal, a biotechnology company pursuing FDA approval of drugs to extend health lifespan in dogs. There is little overlap between my SkeptVet activities and my work at Loyal, and of course my writing here doesn’t represent the official position of the company on anything. But I do like to share here some of the science and publications on aging that I work on at the company. Sadly, that tends to draw the attention of those irritated by my advocacy for science-based veterinary medicine. 

Recently, there was a large amount of publicity surrounding a milestone on the road to potentially getting our first drug approved at Loyal. While this drew mostly positive interest, I was accosted on the SkeptVet Facebook page by a follower of the “holistic veterinarian” Dr. Judy Morgan. Dr. Morgan’s fan asked me to respond to a FB Live video briefly discussing (or “ranting about,” in Dr. Morgan’s own characterization) the press coverage of Loyal’s work. 

I eventually had to block this fan’s account for personal abuse, and I don’t generally bother to respond to trolls since their comments are typically ignorant and disingenuous, and their minds are firmly closed. Dr. Morgan’s fan wanted to set up a “debate” between us, a common tactic among alternative medicine advocates that mistakes theatrical performance for substantive exploration of evidence-based science. As I explained to her on FB, “science isn’t about public debate or performance, its about evidence. [Dr. Morgan] can say what she likes, and support it with whatever evidence she has, and I can do the same, and everyone can evaluate her claims and support for themselves…How we sound or look on video talking to each other isn’t useful or relevant, it’s just theater.”

However, there are some pretty significant misconceptions and misrepresentations of science and the drug approval process generally in Dr. Morgan’s video, and I thought it might be useful to take the opportunity to respond to those and, hopefully, give everyone a clearer picture of how those processes work and how science gives us the best chance at finding therapies that provide meaningful, beneficial impact on the health and wellbeing of our pets.

What Was the Fuss About?
The announcement and associated publicity concerned something called Reasonable Expectation of Efficacy (RXE). This is a standard for supporting evidence that the FDA sets for veterinary drugs as part of the process of pursuing conditional approval. Since the regulatory system is complex and not something vets or pet owners often know much about (I certainly didn’t before becoming involved in this project!), I thought I’d start with a brief outline of how it works. The official explanation and detains can be found on the FDA web site.

Any medicine intended to treat disease in animals must be approved by the FDA. This is to ensure that these medicines are both safe and effective. Of course, as I’ve said many, many times, nothing is ever perfectly safe or always effective, and medicine is about balancing the benefits of a treatment against the potential risks, all in the light of the available scientific evidence and the frustrating, but inevitable, uncertainty about these. Having FDA approval means that a significant degree of scientific evidence at multiple levels is available to support the specific claims of safety and efficacy made for a prescription drug. This is not perfect, but it’s a great deal better than what is available for treatments that don’t go through this process (including supplements and nearly all forms of “alternative” medical treatments).

In the case of the typical FDA approval process, the agency requires several types of supporting evidence for safety and effectiveness. This includes pre-clinical research, that is studies done in test tubes or lab animals showing how a drug works and what biological effects it has. Such studies are an important part of demonstrating what we call “biologic plausibility,” the existence of an explanation for how something works that is consistent with established scientific knowledge. 

Therapies such as homeopathy or “energy medicine” (such as Reiki) lack biologic plausibility because there is no scientific rationale for how they might work; they can only work if much of what we know about basic physical, chemistry, and biology is wrong. While scientific knowledge isn’t always completely correct, the basic knowledge that is the foundation for most of the successful medicine and technology in use today is pretty unlikely to be completely wrong. Clinical studies of these implausible therapies don’t make much sense and are often misleading.

Once there is good evidence for the underlying biology of how a drug might work, then a company seeking approval has to test it directly in the species it is intended for. If the drug is being developed for dogs, then studies must be done in dogs to understand how the drug works and what risks it may have. Sometimes this involves studies in laboratory dogs, often beagles, but it may also involve research in companion dogs. These studies have to comply with rigorous guidelines for methodology and to control various types of bias and error, so they are usually stronger evidence than studies not performed under such guidelines.

Finally, if the evidence to this point shows the drug is likely to be safe and effective for its intended purpose, a clinical trial is performed. This is the “randomized controlled trial” or RCT that people most often associate with medical science, even though it is only one part of a much more comprehensive testing process. In an RCT, ideally some dogs are given the new drug and others are given a placebo (a “fake” drug which does nothing at all), and everyone involved is “blinded” so they don’t know which is which. The details vary with the specific drug being tested, but again the standards for how these RCTs must be conducted to gain FDA approval are very specific and quite high, so the results are pretty good quality evidence. 

This process often takes many years and is very expensive to complete. This is a problem because it makes it harder for veterinarians to get new and properly tested therapies. The system in most countries, and certainly in the U.S., is set up so that private companies are responsible for paying the costs of developing and testing new drugs, and so they aren’t likely to do so unless they think they can make back the money invested in this. Lots of interesting political debates could be had over whether a different system would be better, but that’s beyond the scope of this blog, and frankly nothing about this is likely to change here any time soon.

The FDA recognizes that vets can’t get many treatments that have met the high standards of the typical approval process, and so it allows some compromises to make useful therapies available to vets and their patients. We are, for example, allowed to use drugs approved for humans “off-label,” meaning in ways they were not tested and approved for. Many of the treatments vets use have been tested thoroughly for safety and efficacy in humans but not in dogs or cats. While this increases the potential risks when we use them in these species, often this is still better than the alternative of having no treatment for a given problem, or having treatments that haven’t even been scientifically validated in any species. 

The FDA also doesn’t regulate some treatments much at all. The rules governing dietary supplements are especially lax (and violated all the time with little consequence), so it is much faster and more profitable for companies to make supplements than develop prescription drugs. Sadly, this has led to a booming and lucrative industry (highly favored by alternative medicine advocates like Dr. Morgan) selling products that may be claimed to be safe or effective even when there is little to no real evidence that these claims are true.

A more recent change in the FDA approval system has been the pathway of conditional approval. Under this approach, new drugs must meet all the same requirements for proving safety, manufacturing quality, environmental impacts, and so on as under full approval. However, if a product is targeting a serious health problem with no existing effective treatments (which is clearly the case for aging), and if the RCT needed for full approval is complex and likely to take a long time (again, this is clearly true for drugs intended to extend healthy lifespan), then a drug can be made available to vets for use while that RCT is being conducted. 

In order to do this, the company must provide sufficient evidence that the product is likely to be effective (aka reasonable expectation of efficacy or RXE) along with the usual evidence for safety and other components of approval. Several products have been made available to vets under this pathway, including medications for heart diseasepancreatitis,anemia, and epilepsy.

The big news in the press that prompted Dr. Morgan’s “rant” on FB was that the FDA granted this RXE approval for one of Loyal’s products. The support for this approval included four years of pre-clinical research and 2,300 pages of data and documentation, so it is a pretty robust standard even prior to the completion of the final RCT. The product has not yet been approved, and it is not expected to be available for at least another year even if it eventually achieves this approval. However, the milestone was pretty significant since the FDA has never before granted RXE status (or approval of any kind) for a drug intended to treat the mechanisms and consequences of aging. Ultimately, this has the potential to open up an entire new area of preventative medicine, though there is a long way yet to go towards this goal.

Who is Judy Morgan?
Dr. Morgan is a self-described “holistic” veterinarian. She was in clinical practice for many years, and since retiring she has focused exclusively on selling products, books, and educational courses on her web site as well as a variety of other educational and advocacy activities. She is quite typical of the alternative medicine advocates I have written about many times. She promotes Traditional Chinese Veterinary Medicine (TCVM), homeopathy, raw diets, innumerable untested supplements, and a wide range of dubious or disproven tests and treatments. She is also deeply suspicious of science-based veterinary medicine, condemning conventional diets and ranting about the dangers of conventional drugs, vaccines, parasite preventatives, and other mainstream medical tools. 

Her educational courses often touch on longevity and geriatrics, and she clearly has an interest in these areas. However, her advice is largely unscientific, and she makes numerous false claims about the “proven” benefits of raw diets, TCVM, supplements, and so on. Anyone who suggests vets should choose supplements and foods for maintaining health or treating disease based on supporting “elements” such as Fire, Wood, and Water, or on “balancing” mystical energies like Yin and Yang, cannot be taken very seriously when commenting on science and scientific medicine.

What’s the “Rant” About?
Most of Dr. Morgan’s video has nothing to do with Loyal’s products or the related media coverage. She spends much of her time talking about the work of a Japanese scientist on apoptosis inhibitor of macrophages (AIM), a protein supposedly being developed into a dietary supplement or injectable medicine to prevent or treat kidney disease and extend lifespan in cats (a set of claims that are themselves pretty dubious, and which I will try to find the time to talk about someday). 

Unfortunately, she doesn’t make the transition very clear when she switches from talking about the Loyal RXE coverage and other subjects, and she repeatedly talks about a “vaccine” for aging, although neither Loyal nor the Japanese scientist she discusses are developing a vaccine. This may just be a sloppy shorthand for anything injectable, or a superficial reading of the media coverage (one web site does describe the AIM product as a “vaccine,” though the actual company web site makes it clear that is not what is being developed.) However, since she does spend a fair bit of her time talking about the dangers of vaccines (while still claiming to support them), I think this is part of the obvious effort she is making with this video to cast these products in a suspicious light for her viewers, many of whom are likely as distrustful of vaccines as she is.

Dr. Morgan begins the video by suggesting that she isn’t impressed by the RXE approval and she is “gonna wait ten years and see what the reports are” before even considering using this or any other drug treatment for aging. This is part of a consistent theme throughout the video– suspicion of scientific evidence and a preference for anecdotes to evaluate medical treatments. At one point, she actually says, “one of the great ways to find out what side-effects can be seen is social media.” ???? In her view, “if people are reporting the same side-effect time after time after time” then this is a reliable indicator of the safety of a drug. This ignores the well-established unreliability of anecdotal evidence (as the saying goes, the plural of ‘anecdote’ is not ‘data’). 

She clearly doesn’t understand the role of pre-clinical evidence, not only because she recommends therapies that fail to show basic biologic plausibility, but because she acts as if any use of a drug without a comprehensive RCT is a dangerous experiment. With regard to conditionally approved drugs, she says, “When you go to your vet the day this thing hits the market, your dog is part of that clinical trial, you are saying, Yes, I am going to let my dog be part of that science experiment…it might have some serious side-effects that we don’t know about.”

One could claim that she is simply demanding the highest form of evidence for medical treatments, except that clearly she is comfortable using supplements, diets, and alternative therapies that have never been shown to be safe or effective through clinical trials. What is more, she explicitly admits she would never participate in a clinical trial because she thinks they are too dangerous: “I will not sign my dogs up for clinical trials. I know somebody has to somewhere but it’s not gonna be me.” Instead, she has the bizarre but common belief that scientific evidence is unreliable but if we have enough anecdotes then we can know what therapies are safe or effective. That is the sort of fundamental misunderstanding underlies so much of alternative medicine, and it makes her judgements on specific interventions unreliable.

Consistent with this approach, she often makes false claims about the risks of lack of efficacy of treatments based on anecdotal reports collected online. For example, she claims that isoxzoline parasite preventatives “have killed hundreds of thousands of animals” based on such reports, which is a demonstrably untrue exaggeration (e.g. 123). She also argues that the allergy treatment lokivetmab (a.k.a. Cytopoint) commonly ceases to work because of anti-drug antibody formation (for which there is no substantive evidence) and that there are “tons of side-effects” but the company “[doesn’t] have to report the side-effects that are seen once the drug is used widely,” which is again completely untrue.

Bottom Line
None of the drugs Loyal is developing have been approved for use by the FDA, so of course no one is claiming they have been proven to be safe and effective yet. Having strong scientific evidence at all levels is the whole purpose of going through the prescription drug approval process rather than just launching a longevity supplement, which is a much faster and easier way to get a product to market with minimal scientific evidence. More evidence is needed, and it is being generated.

However, it is clear that better scientific evidence is not really what Dr. Morgan is concerned about. She already believes she can extend lifespan and healthspan with therapies that don’t have any meaningful scientific support, such as raw diets, supplements, and TCVM. And she repeatedly rejects the evidence when it is favorable to treatments she believes are dangerous base don anecdote or just simple prejudice against “injections” and “chemicals” and so on. 

Hopefully, veterinarians and dog owners with a genuine interest in aging and in prolonging healthy lifespan will be interested in any new tools that are developed to achieve this. Hopefully they will critically evaluate the strengths and limitations of the scientific evidence as we all should for all of the therapies we use. However some, and I suspect Dr. Morgan will be one, will automatically reject any pharmaceutical as a safe and effective way of extending healthspan regardless of the evidence because it doesn’t fit their fundamentally unscientific philosophy. That’s fair enough, of course, but those folks shouldn’t try to claim that this rejection is really about holding out for more and better evidence if this is obviously inconsistent with their other claims and practices.

Posted in General | 4 Comments

AVMA Asks for Comments on Draft Code of Conduct

The American Veterinary Medical Association (AVMA) functions mostly as a lobby and PR organization for veterinarians. It is a membership organization and, as such, is beholden to whoever its members are, and the organization is very keen to avoid conflict within the profession or any suggestion of forcing vets to do anything in particular. The wild political drama surrounding a simple resolution in the AVMA House of Delegates to acknowledge the demonstrable uselessness of homeopathy demonstrates this quite starkly.

The AVMA does make some attempts to promote standards “within the family,” generally in the form of non-binding position statements. These are often pretty lukewarm compromises between competing interests, but they have some utility. The AVMA also has a Principles of Veterinary Medical Ethics, and the organization is currently asking for comments from members on a proposed Code of Conduct based on these principles.

This document does offer some acknowledgement of the importance of evidence-based medicine for ethical clinical practice, and it seems possible that this could be strengthened somewhat, though I am not extremely optimistic. Nevertheless, I encourage any readers who are AVMA members to participate in this comment period, and anyone else to consider encouraging any members you know to do so.

Here is the draft code of conduct.

Here is the comment form.

The commenting period will close at 11:59 p.m. Central Time on March 4, 2024.

Here are the comments I made

Section B
subsection 1
paragraph d

“A veterinarian does not have an ethical obligation to deliver care requested by a client that they believe would cause unnecessary pain and suffering for the patient and that is unlikely to be beneficial.”

A veterinarian has an ethical obligation to prioritize offering evidence-based care that is most likely to be beneficial and that maximizes the ratio of likely benefit to potential harms.

Recommendation:
I recommend adding the language in bold to this section.

Rationale:
The purpose of a code of conduct is to articulate “specific types of behaviors that are either expected or required of members of the veterinary profession,” not merely those behaviors that are not expected. This section indirectly indicates that veterinarians should prioritize care that is likely to be beneficial or with likely benefits that outweigh potential harms, yet it does not clearly articulate a positive expectation for the corresponding behavior. The section should indicate that the ethical behavior is to prioritize and offer only care which is expected to have benefits greater than its risks.

Section B
subsection 2
Evidence?based Medicine

“A veterinarian should prioritize the delivery of evidence?based medicine and should inform the client when a therapy does not meet this standard.”

A veterinarian should eschew practices that do not meet a reasonable standard of evidence for safety and efficacy.

Recommendation:
I recommend adding the language in bold to this section.

Rationale:
The guidelines recognize that there is an ethical obligation to “prioritize evidence-based care” because this is the type of car most likely to benefit patients. If this is true, it is not sufficient to simply inform clients when we are offering care that does not meet this standard and then offer care that is not evidence-based or not likely to be safe and effective anyway. Veterinarians should be expected to eschew practices that are unlikely to have benefits greater than their risks based on a reasonable standard of evidence.

Posted in General | 4 Comments

When Should a General Practice Vet Refer Patients to a Specialist?

General practice veterinarians (GPs) are often faced with the question of which services they should provide themselves and which should be left to board-certified specialists. The growing availability of specialty care, the expectations of many pet owners for advanced care resembling that which they receive, the expanding availability of new and more technologically sophisticated interventions, and many other factors all add to the pressure to limit services in general practice and refer more patients to specialists. 

On the other hand, many pet owners struggle to find and afford veterinary care of any kind, much less the most advanced. The concept of a spectrum of care has gained momentum in veterinary medicine largely in acknowledgment of this and in recognition of the fact that intensive, technologically sophisticated, and expensive healthcare may not always be available and may not even the best option for a given patient and client. I was privileged to be invited to contribute to one of the first attempts to characterize the concept of a spectrum of care in the veterinary literature, and it has gained significant momentum since (e.g. 1, 2)

One element to the spectrum-of-care concept is allowing flexibility in what care is provided and by whom while still providing effective, evidence-based treatment. General practice vets are very experienced at the art of providing care within the many constraints of time, money, and expertise available in private practice.

Unfortunately, sometimes both GPs and specialists, especially some in academic settings, mistake the most intensive and advanced specialty care for the best care, or even for the only acceptable kind of care. This makes it harder for GPs to meet the needs of their patients and clients within the inevitable limitations of the “real world,” that is, practice outside of universities or highly affluent communities.

I have been fortunate enough to work for many years at a practice where I was able to learn and provide advanced care options often considered the exclusive province of specialists, such as endoscopy, chemotherapy, and ultrasound. While some specialists have objected to this, many have understood the importance of avoiding rigid distinctions between primary and specialty care in order to effectively meet the needs of all our patients and clients.

Recently, I have developed the impression that newer veterinary school graduates are more reluctant that earlier generations to provide such advanced care tasks. Whether this is a generational change or a result of the messages they are receiving in school, such a trend could potentially further limit the availability of high-quality care and exacerbate both the shortage of veterinary services and the dissatisfaction driving vets from clinical practice.

I recently wrote an editorial for the Journal of the American Veterinary Medical Association (JAVMA) intended to explore the issue of specialty referral, and to hopefully advance discussions within the profession around this subject. This is based solely on my own experiences in practice, and my understanding of evidence-based medicine and the spectrum of care concept, so it is only my thoughts on the subject, not an objective, data-driven analysis. Nevertheless, I hope this will provide useful context and food for thought to GPs and specialists, and perhaps to pet owners as well.

McKenzie, BA. Do it yourself or send for help? Considering specialty referral from a general practitioner perspective. J Amer Vet Med Assoc. 2024; Online early. doi: 10.2460/javma.23.11.0612

Posted in General, Presentations, Lectures, Publications & Interviews | 3 Comments

Evidence Update: What’s New with Cannabis for Pets?

It’s been ten years since my first post on the use of cannabis in dogs and cats. For a while, I regularly covered new research studies, but the number of those has become great enough that keeping up with individual papers is not feasible. Fortunately, the principles of evidence-based have an answer- literature reviews!

There are two main types of review articles of use to clinicians: narrative reviews and systematic reviews. Narrative reviews are far more common in veterinary medicine. These involve individuals or small groups reviewing the research on a given subject and writing a summary from their perspective. These reviews can be very useful, and I have written several myself. But of course they are subject to significant bias. Authors can choose which studies to include and which to ignore, and they can interpret the results through the lens of their existing beliefs on the subject. This doesn’t mean narrative reviews are not useful, but it is a reason for caution in the level of confidence we place in their conclusions.

Systematic reviews are more formal projects, with clear and explicit standards to encourage a comprehensive assessment of the research on a given subject and an objective summary of the strength of the evidence. These are less subject to bias, but they have the weaknesses of often being inconclusive. When there are few studies or most research has significant limitations, no confident conclusion is justified, and most systematic reviews end with the conclusion that more research is needed. This is especially the case in veterinary medicine, where having only a few small studies with significant methodological limitations is the rule.

In the case of veterinary cannabis, there are only a few systematic reviews. One has looked specifically at the literature for cannabidiol (CBD) use in dogs with osteoarthritis (OA).

Patikorn C, Nerapusee O, Soontornvipart K, Lawonyawut K, Musikpodok K, Waleethanaphan K, Anantachoti P. Efficacy and safety of cannabidiol for the treatment of canine osteoarthritis: a systematic review and meta-analysis of animal intervention studies. Front Vet Sci. 2023 Sep 15;10:1248417. doi: 10.3389/fvets.2023.1248417. PMID: 37781283; PMCID: PMC10540436.

As expected, this review had to rely on only a few studies (five), and “All studies were rated as having a high risk of bias.” The conclusion was that CBD “may reduce pain…but the certainty of evidence was very low.” Fortunately, “CBD is generally considered safe and well-tolerated in the short-run, with few mild adverse events observed, such as vomiting and asymptomatic increase in alkaline phosphatase level.” However, as usual the bottom line is that more and better research is needed to allow any confident conclusions about the utility of CBD in arthritis dogs.

A slightly older review looks at all uses of cannabis in dogs.

Lima TM, Santiago NR, Alves ECR, Chaves DSA, Visacri MB. Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials. Anim Health Res Rev. 2022 Jun;23(1):25-38. doi: 10.1017/S1466252321000189. Epub 2022 Jun 15. PMID: 35703023.

Only six studies met the criteria for quality to be included, all in dogs “with osteoarthritis (n = 4), with epilepsy (n = 1), and with behavioral disorders (n = 1)” and all using CBD as the test treatment. All studies showed improvement in the conditions being treated, but “studies were heterogeneous and presented risks of bias that required caution in the interpretation of findings.” As in the more recent study, “CBD was well tolerated with mild adverse effects,” but “More RCTs with high quality of evidence are needed, including greater numbers of animal subjects, additional species, and clear readout measures to confirm these findings.”  

A few narrative reviews have also appeared in the last couple of years that provide a good overview of the uses and evidence for cannabis-based remedies in veterinary medicine. The most comprehensive looks at dogs and cats.

Corsato Alvarenga I, Panickar KS, Hess H, McGrath S. Scientific Validation of Cannabidiol for Management of Dog and Cat Diseases. Annu Rev Anim Biosci. 2023 Feb 15;11:227-246. doi: 10.1146/annurev-animal-081122-070236. PMID: 36790884.

One interesting lesson from this review is that despite severely limited evidence and great uncertainty about what cannabis products might be useful for at what doses with what risks, people are using them all the time for everything. The perception appears to be that cannabis is a safe and effective panacea for companion animals, which of course isn’t substantiated by the actual evidence.

“The cannabidiol (CBD) pet market is expected to increase by $3.05 billion during 2021–2025, with a compound annual growth forecast to reach nearly 30%…A survey conducted online in the United States reported that nearly 60% of pet owners give or were giving CBD to their dogs, and 12% to their cats, most commonly for treating conditions like osteoarthritis (OA), seizures, cancer, or anxiety. From these, 64% found it helps with pain reduction, 50% that it aids with sleep, 49% that it reduces anxiety, and 30% that it reduces convulsions.”

The evidence is generally encouraging for some conditions, particularly pain, but it certainly is nowhere near the level needed to justify this kind of confidence among pet owners. Here are some of the main results reviewed for use of cannabis in various conditions.

  • In canines, recent studies have shown mixed results regarding CBD’s efficacy as an adjunct therapy for managing inflammatory conditions like OA. 
  • Mejia et al. found that CBD administered at 2.5 mg/kg twice daily, either in conjunction with non-steroidal anti-inflammatory drugs or not, did not improve objective measures of pain in client-owned dogs that suffered from OA compared to the placebo. The authors found some improvement in both the placebo and treatment groups, which was attributed to either caregiver’s placebo effect …This was the only study to use objective outcome parameters. 
  • Verrico et al. found a significant reduction in pain (perceived by the owner) combined with increased mobility in large dogs with OA when given CBD for 4 weeks at doses ranging from 0.5 to 1.2 mg/kg. 
  • Similarly, Gamble et al. reported decreased pain and increased activity in client-owned dogs administered 2 mg/kg CBD twice daily for 4 weeks. 
  • Brioschi et al. also found that CBD administered for 12 weeks at 2 mg/kg twice daily significantly reduced the Pain Severity Score in OA dogs when compared to OA dogs not administered CBD. However, all dogs in Brioschi et al.’s study and most dogs in Gamble et al.’s study were administered anti-inflammatory drugs during the clinical trial, indicating a beneficial effect of CBD when combined with anti-inflammatory drugs.
  • Whether CBD is effective in reducing epileptic episodes in dogs with IE [idiopathic epilepsy]  is inconclusive, and to date there are more clinical reports than controlled clinical studies…Two relevant controlled clinical trials explored the effect of CBD in dogs with IE…Additional studies are needed to strengthen the use of CBD or hemp extract in dogs with IE…Despite that, a survey of 297 pet owners with epileptic dogs showed that nearly half of these people were using different supplements to help reduce seizures or control side effects of other medications, and close to 40% of these supplements contained CBD. 
  • A 3-month randomized blinded study found that dogs with IE that received whole hemp extract (THC [tetrahydrocannabinol] < 0.3%) infused hemp oil at 2.5 mg/kg CBD twice daily in conjunction with other epilepsy drugs had a reduction of seizure frequency by 33% compared to the control group. Some study limitations included the small sample size of dogs who completed the trial and the fact that the data could have been analyzed as repeated measures over time to detect individual changes.
  • Garcia et al. conducted a double-blinded placebo controlled cross-over clinical trial in which dogs with IE received a CBD/CBDA-rich hemp extract at an approximate dose of 2 mg/kg twice a day for 3 months, in addition to 3 other antiepileptic drugs.  
  • Similarly, McGrath et al. found a reduction in the total number of seizures (8.0 ± 4.8 placebo versus 5.0 ± 3.6 CBD/CBDA), as well as seizure days (5.8 ± 3.1 placebo versus 4.1 ± 3.4 CBD/CBDA), when dogs were administered the hemp extract. 
  • Animal studies on anxiolytic effects of CBD have shown mixed results. CBD seems to have a bell-shaped curve for managing anxiety, as it seems to be anxiolytic at moderate but not low or high levels…A meta-analysis on human studies concluded that the evidence on cannabis-based products’ effects on anxiolysis is incomplete, because most studies had a small sample size along with some inconsistencies…In dogs, there is no established dose for treating anxiety and fear disorders. The few studies available have focused mainly on the short-term effects of CBD on aggressiveness and fear.
  • A research study on shelter dogs found that CBD (dose calculated to be ?3.75 mg/kg) administered to dogs for 45 days could reduce aggressiveness toward humans but not behaviors related to stress.
  • A second study assessed the effect of CBD supplementation on reducing acute fear triggered by fireworks in dogs supplemented with 1.4 mg/kg/day for 7 days and found no effect of CBD alone on reducing fear-induced stress. 
  • Although there is a need for more scientific evidence that CBD is a therapeutic option to treat behavioral problems in dogs, like fearfulness and anxiety, pet owners perceive the calming and antianxiety effects of CBD favorably. Approximately half of pet owners who have given CBD to their dogs to reduce fear or anxiety think it is effective, even though doses given are inconsistent.
  • No in vivo studies assess the antitumor effects of CBD in either dogs or cats.
  • Several in vitro studies on canine tumor cell lines have demonstrated cytotoxic effects of CBD on cancer cells. [However, you can run a study showing bleach kills cancer cells in vitro, but that doesn’t make it a safe and effective therapy for cancer patients.]

The authors also touch on one of the persistent problems with veterinary cannabis products– since they are sold over-the-counter with no meaningful regulation (and often with illegal claims), there is poor quality control. “Some reports have noted inconsistencies in pet CBD supplements that are available in the market, such as misleading or untested claims, violations of good manufacturing practices, lower amounts of CBD than what was stated on the label, and/or THC above the allowed limit (0.3%). Unfortunately, many cannabis products are marketed in the United States with unsubstantiated claims of efficacy.”

As with most studies and reviews, the general conclusion is that the safety profile of non-THC cannabis products is pretty good, though adverse effects do occur. In dogs, there is great variability in the absorption and blood levels of CBD and other relevant compounds with different products and forms, so we still have little idea how much of any given product is safe or useful to give. In cats, the research is even sparser, and since cats appear to be more sensitive to the effects of cannabis-derived compounds (as with most other drugs), the safety and effectiveness of existing products in cats is largely unknown. 

Both dogs and cats have show gastrointestinal symptoms (e.g. vomiting and diarrhea0 as well as changes in some laboratory values. Lethargy or sedation and behavioral abnormalities can also occur, especially with products containing THC. It is also recognized that CBD and other compound sin cannabis can build up in fat tissues over time, so even when the short-term risks appear to be low, there is no reliable research identifying what risks might occur with long-term use.

Another narrative review from 2023 focuses on the specific use of cannabis-derived chemicals for treatment of pain.

Miranda-Cortés A, Mota-Rojas D, Crosignani-Outeda N, Casas-Alvarado A, Martínez-Burnes J, Olmos-Hernández A, Mora-Medina P, Verduzco-Mendoza A, Hernández-Ávalos I. The role of cannabinoids in pain modulation in companion animals. Front Vet Sci. 2023 Jan 4;9:1050884. doi: 10.3389/fvets.2022.1050884. PMID: 36686189; PMCID: PMC9848446.

This review mostly addresses the underlying biology of cannabinoids and pain. The few clinical studies mentioned are mostly in dogs with arthritis, and the results are mixed, as discussed in more detail in the previous review. The authors conclude there is some evidence to support use of cannabis-derived chemicals for treatment of both acute and chronic pain, but the evidence is largely extrapolation from lab animal studies (especially rodents), and there is little real-world scientific research in dogs and cats to support this.

Bottom Line

Most other reviews have looked at the same limited set of studies and drawn similar conclusions. What we can currently say about the use of CBD (virtually no evidence related to other compounds in cannabis) is this:

  • It is biologically plausible that CBD may be useful in treating pain, inflammation, epilepsy, and possibly some behavioral problems in dogs and cats.
  • The existing evidence is extremely weak. We can have a low degree of confidence in the short-term use of CBD for OA pain in dogs. All other uses rely on extremely limited, low-quality, and often conflicting evidence.
  • The short-term negative effects of CBD, and cannabis generally, appear to be mild. The long-term effects are unknown.

Cannabis is the archetype of a “dirty” drug. It contains hundreds of compounds, most not studied in any depth, and it has effects on many body systems. While this means there is a great potential for cannabis-derived compounds to be useful in many different conditions, it also means the potential for unintended effects and interactions with other drugs is very high unless specific co pounds or subsets of compounds are studied and used individually.

Proponents often talk about the “entourage effect.” This is an idea common in herbal medicine that having multiple compounds in a plant-based remedy is a good thing because they will work in harmony to increase beneficial effects and cancel out each other’s adverse effects. There is no reliable evidence that this phenomenon actually occurs, and it is not very biologically plausible. 

The idea originated with the belief that such remedies were purposefully provided to humans by God, and as such were designed to have this benign nature.  Only the “unnatural” isolation of individual compounds to use as drugs is responsible for the phenomenon of drug side-effects. This argument is not scientifically credible, and it is far more plausible that mixing multiple compounds leads to more adverse and unintended effects. 

Certainly, this is the case with use of cannabis in dogs and cats when THC and CBD are both present in significant amounts. Isolating the CBD reduces these negative effects, so we cannot just assume that using products with multiple compounds and only the THC removed is inherently better than using purified CBD or other cannabis chemicals. Such an entourage effect could occur, but there is not yet compelling evidence for it.

The other important lesson to draw from these recent reviews is that the popularity of cannabis products for dogs and cats is not based on real scientific evidence showing these are safe and effective. This is a fad derived from the popularity of cannabis use in humans, which has origins in ideologies around “natural” medicine, reactions against excessive and largely irrational government prohibitions of cannabis, and factors that have little to do with the actual merits of cannabis as a medicine. 

Hopefully, the high level of interest will drive more research, and we will find out what uses it has. I am concerned, however, that the great confidence pet owners already have in cannabis will mean it continues to be profitable to make and sell unregulated and untested products without any motivation for companies doing so to produce meaningful scientific research evidence. Like glucosamine, which has generated billions of dollars for decades despite being almost certainly useless, the cannabis-based supplement market may be just another example of companies seeking profit and consumers seeking panaceas with neither bothering to put in the effort needed to determine what is actually safe and effective treatment for our pets. 

The evidence has certainly grown in the ten years since I began discussing the issue. Unfortunately, it is still weak and limited, and the enthusiasm for cannabis has grown much faster than the scientific evidence.

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