Introduction

Close to 30% of pet owners have used or considered the use of novel ingredients (e.g., nutraceuticals and herbs/botanicals) in their animals. In the USA, approximately 90% of veterinarians sell some type of novel ingredient and the current market of veterinary novel ingredients is between $20 and $50 million per year. The American Veterinary Medical Association recognizes the importance of these medicaments through its guidelines regarding complementary or alternative medicine, which includes veterinary nutraceutical therapy. In Europe and other nations, the use of herbs/botanicals in particular enjoys a long historical use of general acceptance. However, despite the economic and medical impact of novel ingredients, their use is and should be controversial. Much more than drugs, the use of novel ingredients is complicated by issues regarding their safety, efficacy, and manufacturing. The term novel ingredients might be more appropriate and include herbals and botanicals (which are not natural to animals) and nutraceuticals, which, for the purposes of this discussion, might include compounds which are endogenous, or natural to animals (e.g., glucosamines, chondroitin sulfates). Novel ingredients often are used without doctor supervision. Up to 70% of humans do not report herbal use to physicians, in part because of their failure to recognize the products as drugs. Likewise, pet owners do the same. The availability through medically recognized and trusted sources often leads the consumer to assume both their accuracy in labeling, efficacy, and safety.

Labeling

No mandated review holds manufacturers accountable for the labeling of a novel ingredient. Strong consideration should be given to purchasing those products for which assurance in manufacturing can be obtained. Manufacturers should be queried about the accuracy of their label and all aspects of their manufacturing program and queried regarding its participation in any of the programs that offer evidence of quality assurance, such as exists in the USA: ConsumerLab's (www.consumerlab.com) certification seal; trade associations (e.g., NASC when available) or the United States Pharmacopeia whose standards regarding ingredient quality should be met. Currently, 02/10 SAMe are mislabeled; 10/14 silymarin failed due to either inaccuracies in labeling (mg content) or presence of contaminants (e.g., heavy metals, pesticides, cleaning materials, etc.). Labels should contain a list of ingredients and the intended use of the product. Ingredients should be listed by their common name in decreasing order of magnitude based on weight. Note that for selected herbs, the total constituents may not be known. The number of constituents in herbs can be overwhelming: garlic alone contains over 200 active ingredients. Ingredient content can vary with the portion of the plant (leaf, flower, root, stem). Labeling techniques may contribute to the advent of adverse effects. An herbal name may be used in lieu of the more easily recognized chemical name (e.g., guarana for ephedrine or mahuang for caffeine). Adequate directions for use also should be provided. Products whose labeling is accompanied by scare tactics, exaggerated claims and testimonials should be avoided as should products whose label includes medical claims, such as "for use in the prevention or treatment of," or intended to "changes in body structure or function." Consumer Laboratories (www.consumerlab.com) and others have reviewed probiotics. Of 24 products (21 human, 3 pet) reviewed by Consumer Laboratories (October 2007), 5 (4 human, 1 pet) failed to contain the labeled amount of microbes, 6 (4 human, 2 pet) failed to provide at least 10⁹ CFU per serving and 1 (pet) failed with mold contamination.

Safety

"Above all else, do no harm" should be the primary directive regarding the use of novel ingredients. Harm to the patient from the use of novel ingredients can reflect adverse reactions to the active ingredient, excipients, or contaminants; or therapeutic failure, particularly if traditional therapy is overlooked or not pursued in the belief that the novel ingredient will be sufficient. Of these, adverse reactions are the most likely to contribute to harm. Lack of adverse event reports in the literature for a novel ingredient should not be interpreted as evidence of safety, particularly in light of the absence of an effective adverse event reporting system. Outcome measures of adversity, or more ominously, toxicity (i.e., clinical signs, clinical laboratory changes, evidence of histopathology in organs of excretion, teratogenicity, etc.) are more discreet and easily defined than are criteria of efficacy. Despite their endogenous origin, nutraceuticals may be associated with adverse events. Of the novel ingredients, herbal/botanical products may present a greater risk. Often described in advertisements as "mild" because they are "natural," animals have developed sophisticated mechanisms (e.g., efflux pumps, drug-metabolizing enzymes) to prevent the absorption and accumulation of plant chemical products in the body. Herbal products may be unsafe for several reasons. Active ingredients, whether the intended ingredient or another chemical within the plant, may not be safe, particularly when used in excess. The risk of adverse effects to herbs is increased by the presence of many active ingredients in the same plant. Indeed, herbalists often used unpurified plant extracts because different chemicals will interact synergistically. The portion of the plant (i.e., leaf, flower, stem, root, seed) may impact safety. Herbalists often administer the whole plant because toxicity will be reduced by a buffering effect of the whole herb. During growth of the plant, environmental contaminants may become unintended residues during the manufacturing process. Microorganisms, including bacteria, fungi or molds, can either directly contaminate the product or produce contaminating toxins. Bacterial contamination is more likely with root - as opposed to flower or leaf - products. Heavy metals, such as lead, cadmium or mercury, increasingly are contaminating plants exposed to environmental pollutants. Further, unless organically grown, insecticides and pesticides can contaminate herbal products. Factors during production and storage, such as storage length and conditions can alter herbal potency and quality. Finally, herbal products might be supplemented with active ingredients (often referred to as an herb) such as benzodiazepines, ephedrine, caffeine, or fenfluramine (the latter ingredient being one of the two ingredients in the notorius Phen-Fen dietary supplements). Finally, many herbs interact with drugs; examples involving the CNS include enhanced stimulation by caffeine, ephedra, yohimbine, guarana, and ginseng; enhanced sedation by valerian, kava, and St. John's wort. Drug-induced hemostasis defects may be potentiated by garlic, ginger, gingko, ginseng, chamomile, feverfew, and bromelain; whereas the effects of hypoglycemics may be exacerbated by bilberry, bitter melon, dandelion, and garlic. Echinacea and Astragalus may offset the immunomodulatory effects of corticosteroids or other immunosuppressants. In 1975, the FDA reported over 30 herbs prepared as teas to be unsafe. Excessive consumption of herbal teas containing senna, aloe, buckthorn, and other laxatives has been associated with the death of four women The FDA also is currently investigating the potential association of hepatotoxicity and the administration of kava (kava kava, Piper methysticum), an herbal product used for a variety of disorders, including stress and anxiety. Recent regulatory actions offer evidence of the risks that can be associated with the use of these unapproved products. Adverse events have also occurred in veterinary patients. The Animal Poison Control Center (APCC) published a report of adverse reactions in 47 dogs that ingested weight-loss dietary supplement containing guarana (caffeine) and mahuang (ephedrine). Seventeen percent of dogs died following CNS and cardioactive clinical signs.

Efficacy

Dosing of novel ingredients is often empirical and rarely, if ever, based on scientific studies. Establishing the pharmacokinetics of these products is difficult because of the multiplicity of ingredients, and/or nutraceuticals, inability to distinguish the endogenous from supplemented chemical. Criteria which apply to clinical trials for drugs should apply to clinical trials for novel ingredients. The report must include a description of the study design and methods such as random assignment of treatments, placebo controls and blinding techniques that reduce the risk of scientific bias. The need for placebos in veterinary medicine cannot be overemphasized. In humans, the placebo effect in studies evaluating pain can be profound, ranging from 30 to 40% or more. A similar, if not higher, placebo effect should be expected in veterinary medicine. Care should be taken to not interpret the lack of a significant difference as an indication that the groups are the same unless the study investigators demonstrate that the study design provided sufficient power. Credence might be given to the results of a study that demonstrates or fails to demonstrate a clinical difference despite the lack of statistical difference. Negative clinical trials also should be reported; manufacturers should be queried about their inclusion in distributed information. As with drugs, care should be taken when extrapolating information from studies in a species other than the one in which the compound is to be used.