From antioxidants to vitamins, many supplements lack official testing

Many pet supplements do not undergo rigorous testing or go through regulatory agencies, potentially putting pets at risk in some cases. Photo: AleksandFinch/Bigstock Dietary supplements are one of the most popular and widely used of the treatments. Surveys find dietary supplement use varies from country to country, but in many developed nations 50-70 percent of adults report using some kind of supplement, and many children are given supplements, as well.1–9 Pet owners also commonly give supplements to their animals, though at somewhat lower rates. About 30 percent of dog owners and 20 percent of cat owners in one survey reported using dietary supplements for their pets.10 The popularity of supplements makes them a very profitable product. The dietary supplement industry is worth hundreds of billions of dollars worldwide, and while the majority of this is the market for humans, veterinary supplements are still a billion-dollar a year business.11,12 Pet owners mostly report giving supplements to prevent or treat specific health problems in their pets.10 They willingly spend a portion of their limited resources for pet healthcare on supplements hoping this investment will pay off in terms of better health for their pets and possible less expense and risk from conventional medical treatments. Is this a sound investment? I have reviewed the evidence concerning many popular supplements used in veterinary medicine elsewhere.13–18 Here, I thought it would be worthwhile to talk more generally about what supplements are and some of the problems that complicate their evaluation and clinical use. What are they? Defining a dietary supplement can be tricky, and there is no single, universally accepted definition. Legal definitions vary from country to country, and these may not always correspond to what ordinary people think of as a dietary supplement. In general, a dietary supplement is some substance, often but not always found in foods, that is taken in concentrated form and is intended to have some beneficial effect on health. Pretty vague, right? Sometimes dietary supplements are legally classified as foods, sometimes they are considered drugs, and sometimes the same substance can be in both categories depending on how it is labeled and used. Herbal remedies are sometimes considered dietary supplements, but they are also given their own regulatory category in some places. Ultimately, there is no hard and fast rule for what a dietary supplement really is. If we are isolating chemicals and concentrating them in pills or liquids, and then taking them to affect our health, how are these not drugs? If these supplements are foods, not drugs, then why are we taking them at high doses in pills rather than just eating more of the foods they come from? Many of the claims made for supplements try to confuse us by suggesting they can have the same effects as drugs, but they are safer because they are foods rather than drugs. This makes little sense from the perspective of biology, or even basic logic! The best we can probably do for now is to consider a dietary supplement to be a nutrient or other chemical typically found in food that is taken in concentrated form to prevent or treat some specific health condition. This should allow us to look at the evidence for the effectiveness and safety of dietary supplements and make some judgements about how much confidence to have in health claims made for them. Importance of testing If a dietary supplement is backed by a scientifically plausible theory for how it could work, if it is rigorously testing in the lab and in animal models to identify any risks and benefits it might have, and if it is then run through the clinical trial process and accumulates solid evidence of safety and efficacy, then it is simply another tool in the toolbox of science-based medicine, just like pharmaceuticals. There are some supplements that have been developed and used in this way. Unfortunately, many supplements are promoted and used without enduring this scientific testing process. Many show some promise in early, pre-clinical studies, and they become popular and profitable treatments without finishing the process and going through the critical and necessary step of clinical studies in real patients. This is a common way for supplement manufacturers to profit without going through the arduous and expensive process of proving their products work and getting an FDA-approved label claim. When efficacy studies are eventually done (usually with supplements intended for humans), these products quite often turn out to be less useful, or less safe, than hoped. Skipping steps in the scientific process wastes time and resources, and it ultimately hurts patients. Those who may choose an insufficiently tested supplement over a proven therapy because they believe it to be safer or more effective based on low-quality evidence can be harmed by the supplement or by delaying truly effective treatment. In veterinary medicine, where resources for research and treatment are scarce and where euthanasia is an option when these resources run out, money and time wasted on ineffective treatments can be very dangerous for our patients. General concepts in dietary supplement use Surveys indicate there are many reasons why people choose supplements for themselves and for their pets, but there are a number of recurring themes; beliefs people have about supplements in general that influence when and how they use them. Looking at some of these concepts may help us take a more critical and scientific perspective regarding supplements. If some is good, more is better The most popular dietary supplements for humans are vitamins and minerals.8,9 These are nutrients that are essential for life and normal health, though they are only needed in very small quantities. Too little of these micronutrients can lead to illness. Some of the most terrible and intractable diseases in human history were the result of vitamin and mineral deficiencies. Children with rickets suffered from soft, deformed bones due to insufficient vitamin D. Sailors and other travelers would lose hair and teeth, bleed from the gums, and suffer from severe infections caused by scurvy, a lack of vitamin C. Identifying and curing nutritional deficiency diseases has been one of the great successes in scientific medicine. Vitamin and mineral supplements, in food and taken directly in pills or other forms, can have miraculous effects at preventing and reversing these conditions. Most of us are at least vaguely familiar with this history, and even today, we can see the impact of nutritional supplements on health in developing nations. Blindness in children due to vitamin A deficiency is still widespread in Africa and Asia, and interventions such as encouraging breastfeeding, supplementing foods, and growing new crop varieties with more of this vitamin have dramatic impact on the health and well-being of these children. Because of personal or cultural familiarity with the dramatic success of nutritional supplements in preventing and treating so many awful diseases, there is a tendency to mythologize these products and to imagine if we can gain such great health benefits by taking enough to prevent a deficiency, we might get even more benefit by taking even more of these supplements. Unfortunately, the idea if some is good more is better, is dangerously mistaken in biology and medicine. Vitamins in particular, and supplements more generally, are often assumed to be benign since they are found naturally in the food we eat. Unfortunately, this is quite clearly not true. The above diagram illustrates how most nutrients work in terms of health. There is an optimum or ideal range for how much of a nutrient we need. This varies with species, the particular nutrient, age, sex, genetics, and many other factors. We typically can’t know exactly what the level of a given nutrient might be for a particular individual, but we know that for a specific population there is a “green zone” in which the level of a nutrient will have the best possible effect on those aspects of health it influences. In the “yellow zone,” we may not have the best possible levels of the nutrient, but we usually don’t have significant diseases associated with it. At the extreme levels, both too little and too much of most nutrients, we can see health problems. Boosting the immune system One of my favorite experiments when I was teaching undergraduate biology was giving the student a Petri dish, a culture medium for growing bacteria and fungal organisms. I would tell the students they could put anything they wanted on the nutrient material in the dish (except body fluids, for obvious safety reasons). Some would put a little water from the classroom water fountain in the dish; others would touch the medium with their favorite pen, the sandwich they had brought for lunch, or other personal items; some would simply set the open Petri dish on their desk for a little while. Invariably, all the dishes grew a variety of colorful bacteria and fungi, and invariably the students were horrified by the presence of so many invisible microorganisms all around them. We swim in a sea of living organisms of which we are mostly unaware. So why aren’t we sick all the time? Well, not all the microorganisms around us are harmful, and some are even beneficial for our health, but the main reason we can live happily and healthily awash in microorganisms is that we have an immune system. Most people realize some things can weaken our immune system and make us vulnerable to diseases we might otherwise resist. Malnutrition,20 poor sleep,21 stress (though that’s a slippery concept),22,23 many diseases, some drugs, even natural aspects of our life cycle, such as being very young or very old,24,25 can make us more vulnerable to infectious disease. This knowledge leads logically to the idea we should look for ways to strengthen or “boost” our immune systems. If we can weaken it, why couldn’t we strengthen it? We can certainly support optimal function of our immune system by avoiding things that weaken it. Not drinking and smoking,26,27 sleeping enough, eating a balanced and nutritionally appropriate diet, and exercising, all support normal immune system function (though some of these, such as exercise, are examples of things with an optimum level, and too much can weaken the immune system, even though the right amount will strengthen it).28 One rationale for taking dietary supplements is they can boost the immune system. As popular as this practice is, there is virtually no evidence this is true. While enough of many nutrients is essential for normal immune function, it has not been convincingly demonstrated that more than enough of any nutrient makes a normal, already healthy immune system any stronger. It is also not clear supplements can compensate for other factors that may weaken the immune system. Taking vitamins, for example, when you are older and have a naturally weaker immune system than you once did, does not appear to be very useful in preventing infections.29,30 And, certainly, supplements aren’t going to get you off the hook for smoking or drinking too much or many of the other behaviors that weaken the immune system. More to the point for our patients, who don’t typically engage in such self-destructive behavior, there is no compelling evidence supplements will compensate for age, pregnancy, illness, or other things that weaken the immune system in pets. The other question people often forget to ask is, “Even if we can boost our immune system, should we?” When your immune system is activated to fight off an infection, for example, you often feel pretty lousy. Boosting your immune system might mean having a fever, a runny nose, and feeling achy and tired all the time, since those are all natural effects of heightened immune system function. Overactive immune systems also cause more serious problems. Allergies are essentially an excessive and improperly targeted activation of our immune systems. When a dog with environmental allergies is chewing on her paws and scratching at her inflamed skin, she doesn’t need her immune system boosted, she needs it turned down! Autoimmune diseases, of course, are serious, often deadly examples of excessive and inappropriate immune system function. Activating or ramping up the function of our pets’ immune system, even if we could do so, isn’t necessarily a good idea for improving their health. If supplements are to be useful in terms of immune function, we have to ensure they are providing an optimum amount of an essential nutrient or that they have some specific, proven effect that reduces the risk of illness in our pets and doesn’t create unpleasant or dangerous symptoms of excessive immune system function. We cannot blithely assume supplements are necessary or are safe and effective in supporting immune system function without appropriate evidence. Antioxidants Antioxidants are widely viewed as good for our health and free radicals are seen as bad, even though most of us have probably forgotten most of what we once knew about redox reactions and the deleterious physiologic effects of oxidation. The antioxidant craze is an example of a legitimate and interesting scientific hypothesis that has been sloppily popularized and turned into a lucrative marketing tool for supplements well before there was good evidence the hypothesis was true or could lead to effective health interventions. Reactive oxygen species (ROS) are a natural product of numerous chemical reactions happening continuously in healthy animals. These ROS are very quick to react with other chemicals, and can lead to damage to important molecules in cells, and ultimately to dysfunction the cells and tissues. The reason we don’t all melt away immediately in an oxidative conflagration is, of course, our bodies have natural antioxidant systems in place to neutralize ROS and both prevent and repair the damage they can do. Some nutrients, such as vitamin C and vitamin E, are utilized as part of these natural antioxidant mechanisms. These systems are not perfect, of course, so damage from ROS does sometimes accumulate, and it has been shown to be one factor in the process of aging and the development of some diseases. Despite the enthusiasm of some early researchers, oxidative damage is not the sole cause of illness or aging, and reducing or eliminating it would not keep us from getting old or developing cancer. However, oxidative damage is a proven risk factor for some diseases and does play a role in the changes that come with age, and there is reason to believe some manipulations of this process might be beneficial in some cases.29 It turns out, though, ROS aren’t just a cause of damage in our bodies, they also perform a variety of vital, beneficial functions. The immune system uses ROS, for example, to kill harmful bacteria and to destroy cancer cells before they can get established and make us sick.31,32 Some laboratory research even suggests reducing the production of ROS may accelerate, rather than retard, aging.33 The research on antioxidant supplements has been extensive and expensive and has gone on for decades. There is no “final word” on the subject, but there is a growing consensus that: oxidative damage is only one of many factors involved in ageing and illness; natural antioxidant systems work pretty well by themselves; and while some antioxidants, such as vitamins, are necessary at normal levels in the diet to help control ROS, excessive consumption of these as supplements not only doesn’t seem to have health benefits, it can actually do harm. Multiple studies in people have shown high doses of antioxidant vitamins do not effectively prevent illness, and they can sometimes increase the risk of cancer and other diseases.34–39 There is little direct research on antioxidant supplementation, in food or as nutritional supplements, for producing health benefits in dogs and cats. A handful of studies show some potentially promising effects on markers of oxidative damage, and a couple seem to show some clinical benefits, but the evidence is scant and weak.40–54 The harmful effects of antioxidant supplementation in humans have only emerged with studies of large numbers of individuals over periods of time far longer than typical veterinary trials, so while few specific safety risks are known for common antioxidants, the assumption of safety is not justified for most. The bottom line is most of the claims concerning the benefits of antioxidants are based on theory or indirect and limited evidence. The specific antioxidant given, the form in which it is given, the other components of the diet, the species, health status, and individual makeup of each animal, and many other factors, all influence the effects of antioxidants. Whether such effects are strong enough to be clinically significant, and whether they are beneficial or harmful if they do have a real effect, is a complicated question, and simplistic, strong claims are not justified. Do supplements work? That question, of course, is too vague to be meaningful or to answer. Every individual supplement, ideally every particular product, should be tested at each level, from theory, to preclinical lab studies, to clinical trials, in the specific species and for the specific problem it is meant to treat or prevent. Frustratingly, this kind of comprehensive scientific evidence is rare in veterinary medicine, so most of the time we have to make decisions about what to give our patients based on lower-quality evidence and extrapolating from studies in humans. This is less than ideal, and since it can easily lead us to the wrong decision, we should also be careful not to have too much confidence in our judgements, and to be open to changing our minds when there is new and better evidence, even if this contradicts our own experiences. For the most part, veterinary supplements are pretty loosely regulated, with even less control than for supplements marketed for humans, and these, in turn, are less tightly monitored than conventional medicines.55–58 Governments tend to focus on monitoring what companies say about their supplements more than on the effects of the products themselves. In the human market, most companies can’t say a supplement prevents, treats, or cures a particular disease unless they have scientific evidence for this, as is required for drugs. Most get around this with vague claims their products “support” or “enhance” or “boost” some normal function. Veterinary supplements are sometimes expected to follow similar rules, and in some jurisdictions are effectively not regulated much at all. In general, the supplement industry is a classic “buyer beware” market in which you can’t trust claims of safety or effectiveness have been proven scientifically or are endorsed by government health authorities. Because a high level of evidence is not required before marketing for most supplements, it doesn’t exist for very many. Lab-animal and in vitro research predominates, and when clinical trials are done, they are often funded and conducted by manufacturers, meaning a significant risk of bias in the results. Are supplements safe? Just as the effectiveness of supplements has to be evaluated on a case-by-case basis, so we have to look closely at the potential risks of each specific supplement individually. However, there are some general concerns with dietary supplements that apply broadly throughout the industry. Because there is inconsistent and often minimal regulation, the ingredients in supplements are frequently misrepresented by manufacturers. This can lead to poor efficacy, even when a supplement should be helpful if the active ingredient is of poor quality, or perhaps not even present at all in a specific product. Probiotics are a stark example of this. Studies of both human and veterinary probiotic products have found a large percentage of them are incorrectly or misleadingly labeled.59–61 Some have minor deficiencies, such as misspelled or incorrect species name for the organisms they are supposed to contain. Many have more serious problems, such as contamination with unintended organisms, lower levels of the intended organisms than promised or, in some cases, no live organisms at all! Even if there is good evidence some probiotics can help a dog recover faster from a case of diarrhea, they aren’t going to get these benefits from a product with little or no probiotic in it. There are similar serious problems with labeling and quality control for many other types of dietary supplements as well. It is often assumed the risk of dietary supplements is negligible. This is often simply an expression of the Appeal to Nature Fallacy, since any substance that has a meaningful effect on the body for good is likely to have some unintended or undesirable effects, as well. It is important to remember, also, safety is frequently related to dose, and even supplements that are safe when used as intended can be dangerous when taken at higher doses, intentionally or accidentally. While joint supplements for dogs, for example, seem to be pretty safe in clinical studies, there have been a number of cases of severe injury and even death from overdoses of these supplements.62,63 Many veterinary dietary supplements are designed to be tasty and appealing to our pets to make it easier to administer them, and this can lead to our animals, especially dogs, eating far too much of such supplements if they get the chance. More worrisome than accidental overdose is the presence of poisonous ingredients in supplements that aren’t supposed to be there. A large and growing number of humans have ended up in the hospital, often with life-threatening disease, such as kidney failure or liver failure, due to undisclosed or illicit ingredients in dietary supplements. Supplement manufacturers have been known to put unidentified herbal ingredients or even illegal prescription drugs into supplement products. Products intended for weight loss, for muscle building, for increasing energy, and for treating sexual dysfunction have turned out to contain amphetamines, anabolic steroids, and prescription medications like Viagra, which are intended to create the effects the manufacturer claims, often without real evidence, consumers will get from the dietary supplement itself. This has led to serious illness and death in people taking such supplements, and the evidence suggests the rates of harm from supplement products is growing.64–78 Finally, there is sometimes real risk even from the intended ingredients in supplements taken at the recommended dose. The fact we often have very little, if any, clinical trial research on most supplement products means we cannot be confident about their effectiveness or their safety. Plenty of supplements have turned out to have unexpected risks, even those we might assume to be the most benign. Vitamin E has been associated with an increased risk of cancer, heart attacks and strokes in several studies.37–39,79–83Men taking high doses of B vitamins have a higher risk of lung cancer than those not taking this supplement.84 Some studies have even shown a higher overall risk of death in people taking vitamin supplements compared with people not taking them.85,86 Non-vitamin supplements have also been associated with a variety of risks, from minor uncomfortable symptoms to severe injury. Tens of thousands of people are admitted to hospital emergency rooms every year for symptoms related to dietary supplement use, and this is for a class of products we often don’t know for sure even have any real benefits.76 In the veterinary world, there is much less research and monitoring of supplement use and adverse effects. There is no particular reason to think supplements marketed to our pets are any safer than those marketed for human use, but we don’t look very hard to monitor the safety of such products, so it is difficult to say how much harm they may be doing. Without real evidence, pet owners and veterinarians are in the uncomfortable position of simply having to hope for the best if they choose to use most of the available products. That may be reasonable if an animal has a serious illness and there are no proven treatments that are likely to help, but it seems a needless risk in healthy pets. Our desire to have control over the fate of our animal friends and to protect them from harm is laudable, but we must also be rational and careful in the choices we make for our pets. Balancing risks and benefits is always necessary in making decisions about any treatment or preventative we use, and this is true of dietary supplements as well. This is made more difficult by the lack of reliable research evidence for most veterinary supplements, but a cautious and skeptical approach can still help us make good decisions for our pets. Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of VPN Plus+. References Kobayashi E, Nishijima C, Sato Y, et al. The Prevalence of Dietary Supplement Use Among Elementary, Junior High, and High School Students: A Nationwide Survey in Japan. Nutrients. 2018;10(9):1176. doi:10.3390/nu10091176 Kobayashi E, Sato Y, Umegaki K, Chiba T. 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