Key quality control aspects about cannabinoid-rich hemp products that a veterinarian needs to know: a practitioner’s guide

Jack Henion Diagnostic Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, NY

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 PhD
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Stacey Evans Ellevet Sciences, South Portland, ME

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Joseph J. Wakshlag Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY

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Abstract

There is considerable confusion in the veterinary profession surrounding the rise in hemp cannabidiol-based animal products and what veterinarians should know before discussing these products with clients. There is emerging evidence for the potential use in case management across many veterinary indications; however, the cannabinoid concentrations and whether these are isolated cannabinoids or whole hemp extracts is difficult to elucidate, even from the published papers. Much like any extract from a plant, there are multiple considerations including quality control, pharmacokinetics in the intended species, microbiological and chemical contamination, and product consistency—all aspects that should be considered before a conversation can begin with a client. The aim of this review is to help practitioners make informed decisions and better facilitate discussions with clients for companion animals kept as pets. This review will not address food animal issues, as established withholding times have yet to be fully researched.

Abstract

There is considerable confusion in the veterinary profession surrounding the rise in hemp cannabidiol-based animal products and what veterinarians should know before discussing these products with clients. There is emerging evidence for the potential use in case management across many veterinary indications; however, the cannabinoid concentrations and whether these are isolated cannabinoids or whole hemp extracts is difficult to elucidate, even from the published papers. Much like any extract from a plant, there are multiple considerations including quality control, pharmacokinetics in the intended species, microbiological and chemical contamination, and product consistency—all aspects that should be considered before a conversation can begin with a client. The aim of this review is to help practitioners make informed decisions and better facilitate discussions with clients for companion animals kept as pets. This review will not address food animal issues, as established withholding times have yet to be fully researched.

An Overview of Hemp-derived Cannabis and Cannabinoids

The main cultivars of hemp include Cannabis sativa and Cannabis indica strains, and significant cross breeding across the industry often makes distinguishing Cannabis species difficult. The Cannabis plant can produce over 100 different cannabinoids. All cannabinoids are derived from an initial cannabinoid called cannabigerolic acid (CBGA). In general, depending on the genetics of the plant and various synthase activities, CBGA will be endogenously metabolized into other cannabinoids; however, Cannabis breeding and hybridization of plants has allowed for development of strains that primarily make CBGA through elimination of synthases that form other cannabinoids. The 2 cannabinoids that predominate are tetrahydrocannabinolic acid (THCA) in marijuana and cannabidiolic acid (CBDA) in hemp. There are some plants that make larger quantities of cannabichromenic acid as well (Figure 1).1 During processing and storage, there is decarboxylation of the acidic forms into the neutral forms, particularly if exposed to light, oxygen, and heat.2 This decarboxylation will lead to production of the neutral cannabinoids, Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD). Additionally, any residual THC can be isomerized to Δ8-THC or cannabinol, which are not native to the plant but may have potential pharmacological properties.3 Many of these cannabinoids are routinely tested for by analytic laboratories, the results of which should be available for practitioners to view in a certificate of analysis (COA) before recommending a product to their clients, and this testing laboratory should be certified for cannabinoid analysis (see Current Status of Testing below). Most importantly, most hemp products will have residual THCs consistent with a hemp extract (< 0.3%) rather than marijuana, which will be higher. Δ9-THC is the primary cannabinoid that should be avoided as THCA is nonpsychotropic, yet decarboxylation of THCA can occur over time or with heating, leading to Δ9-THC formation. In addition, processing of hemp may lead to exo-THC or Δ8-THC formation, which, although less psychotropic, can be found in analyses in small amounts; therefore, we recommend that veterinarians ensure that the total THCs (including THCA, THC, exo-THC, and Δ8-THC) is no more than 0.3% (eg, an oil or chew should be < 3 mg/mL or g), which is often the case for veterinary hemp CBD products.4 What is important to understand is that many reports will say that THC derivatives are not detectable, yet if the lower limit of detection is 1 mg/mL or g, it would be deemed free of THC; hence, the lower limit of detection should be set at 0.01 mg/mL or g or lower for a product to be deemed “THC free.”4

Figure 1
Figure 1

Depiction of major cannabinoid production in typical Cannabis cultivars showing the formation of cannabigerolic acid (CBGA) from geranyl diphosphate (GPP) and olivetolic acid (OA). Based on synthase activity, CBGA will become cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), or cannabichromenic acid (CBCA) as native cannabinoids to the plant. When heated, extracted, or exposed to UV light, decarboxylation occurs to form neutral cannabinoids cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), or cannabichromene (CBC).

Citation: Journal of the American Veterinary Medical Association 261, 7; 10.2460/javma.22.10.0470

In concert with this, the hemp plant, like many other plants, will contain small amounts of other molecules including flavonoids, terpenes, carotenoids, and small hydrocarbons.5,6 Flavonoids and carotenoids are found in many plants, fruits, and vegetables, and there is significant literature to support that these are healthful compounds as antioxidants or molecules that influence signaling pathways in companion animals79; yet it is heavily debated as to whether the small amounts found in hemp CBD products have any significant activity. Terpenes are more plentiful in hemp CBD extracts, can be found at concentrations as high as 5 to 10 mg/mL or g in pet products,4 and are what provide the characteristic flavor and smell of extracts made from whole hemp extraction procedures.2,10 Although the medicinal benefits of the terpenes and lesser cannabinoids found in hemp are speculative, they may influence cannabinoid metabolism and absorption from full-spectrum hemp products, and these terpenes are often not listed on a typical COA.1113

In complying with USDA federal hemp laws, responsible companies that sell hemp CBD products for animals have a COA from an independent third-party lab. Such companies also make that COA accessible on the product packaging or company website so veterinarians can easily access the COA that shows the product has no more than 0.3% THCs.14 It is good practice for veterinarians to request that a company send a full COA on the most current lot of their products as well as prior lots to ensure compliance and product consistency.

The USDA requirement for DEA-certified labs to detect THC in hemp became effective on January 1, 2023, and applies to hemp crops, not hemp products.15 COAs for veterinary examination should be on the final products being distributed rather than the plant or extract being used to make a product. The National Animal Supplement Council (NASC), a nongovernmental organization, sets voluntary standards for certain types of animal products in the US. The NASC comprises companies that comply with its requirements for labels, claims about products, adverse event reporting, and good manufacturing practices certification to ensure high-quality animal products through annual audits due to the lack of federal companion pet animal supplement laws.16,17 Veterinarians can look for products that have an NASC seal on the product, providing evidence that the manufacturer is committed to quality and safety.

While the FDA recently stated that it does not plan to propose any rules to allow hemp CBD in human dietary supplements and food for humans and animals, the FDA said that “a new regulatory pathway could provide access and oversight for certain CBD-containing products for animals.”18 The FDA also indicated that it will work with Congress on a strategy to develop regulations for hemp CBD products for humans and animals.

State Regulation of Hemp Products

While many states do not have explicit laws regarding the use of such products, there are states that have laws that explicitly allow hemp CBD products for animals, and veterinarians are advised to seek out state information based on veterinary medical state board and state agricultural legislation. For example, Florida requires hemp CBD animal products to be registered as a type of feed even though such products are not considered feed in other jurisdictions.19 Other states like Utah require that any hemp CBD product register with the Utah Department of Agriculture.20 Vermont has a unique regulation in which any dosage form animal health products (ie, products marked as animal supplements), including hemp CBD dosage form animal health products, must register with the Vermont Agency of Agriculture.21 Finally, Nevada has a law that explicitly allows veterinarians to use and recommend hemp CBD products for animals and prohibits the Nevada State Board of Veterinary Medical Examiners from disciplining such veterinarians.22

Veterinary state boards however do not regulate hemp CBD products. Instead, they regulate the practice of veterinary medicine, which includes the use of treatment options. The American Association of Veterinary State Boards (AAVSB), a nonprofit voluntary membership organization, the members of which are veterinary state boards, has issued guidance for its member boards on how to address questions from licensed veterinarians about CBD products. For example, the AAVSB states that veterinarians who use, sell, or suggest hemp CBD products for companion animals only recommend hemp CBD products that are safe, have a COA by an independent third party, and have the science to support claims about the products.23 These recommendations help a veterinarian confirm in good faith that a product is hemp (not marijuana), is safe, and does what the manufacturer says it does, all of which help a veterinarian comply with the standard of care. The AAVSB guidance also indicates that a veterinarian who prescribes, dispenses, or administers any CBD product not approved by the FDA shall inform the client of such and document appropriately in the medical record.

The AVMA is a professional organization that does not regulate veterinarians. In addition to other activities, the AVMA affords members access to professional and personal insurance programs as well as business resources through the AVMA Trust and its affiliated trusts, the Professional Liability Insurance Trust (AVMA PLIT) and LIFE Trust (AVMA LIFE). The Professional Liability Insurance Trust provides members with access to professional liability insurance and veterinary license defense coverage, which can provide coverage for claims of malpractice or complaints against a veterinarian’s license, including complaints regarding hemp CBD use.

Current Status of Testing—Third-party Analysis and International Organization for Standardization Accrediting

The importance of accuracy and scientific integrity in Cannabis testing laboratories (both hemp and marijuana cultivars) for public and client protection continues to be reported in the news, primarily in cases of human product consumption. As an example, a recent Michigan case involved the recall of Cannabis products due to inaccurate and/or unreliable results from a testing laboratory.24 Since there is a lack of standardized requirements for achieving, documenting, and maintaining quality practices in Cannabis testing laboratories, each state and its participating laboratories “does it their own way.”

The trend toward legalizing medicinal and adult use of Cannabis in many states has led to each state developing and implementing their own methods, so there is little standardization in analytical methods or procedures federally. This has led to considerable variability in the quality of results. There have been reports of a client sending the same sample to 2 or more Cannabis testing laboratories and getting different results from each. Each sample has a composition, and different capable laboratories should get a similar answer for that composition. A recent report25 describes the importance and procedure for improving quality in Cannabis testing laboratories.

Although many states require these laboratories to show compliance with ISO-IEC 17025, General Requirements for the Competence of Calibration and Testing Laboratories (https://www.iso.org/ISO-IEC-17025-testing-and-calibration-laboratories.html), for licensure, the implementation and management must be done in an organized and rigorous manner. The laboratories should have written standard operating procedures and follow them. One way to monitor a laboratory’s capability is to implement a program of proficiency testing. This is done by an independent licensed organization such as A2LA (https://a2la.org/accreditation/cannabis-testing/), which provides samples for testing by the laboratory that are blind to the laboratory. Thus, the submitting organization knows the composition of the sample and expects the laboratory to analyze the sample and get the correct answer. This is regularly done with antidoping facilities, for example, but unfortunately this procedure is not yet generally adopted by the Cannabis testing laboratory industry.

Since there is growing concern regarding the quality of analytical results for Cannabis-derived products determined by Cannabis testing laboratories, these labs need to demonstrate that they are accredited and can derive accurate and precise answers from analyzed samples. ISO-IEC 17025 accreditation can provide a solid foundation for providing a quality laboratory, but each laboratory must implement analytical parameters, designate personnel qualifications, and develop specific procedures that provide the needs of the laboratory and its clients. Thus, the leadership of the facility should be asked to demonstrate that this is the case for their laboratory.

Current Veterinary Products and Testing—Across Human and Pet Products

In humans, CBD and THC have been shown to have the potential to be valuable therapeutic drugs. They may be of value in the treatment of cancer, nausea and vomiting, pain, epilepsy, and inflammatory bowel disease, making them popular products in the human arena.26 There now exists an increasingly large variety of Cannabis products from hemp cultivars ranging from oils and tinctures to foods and drinks for humans. These Cannabis-derived products are typically made from an extract of the hemp plant that may be the basis of products created for pets as well, whereby the extract is blended with a water or oil base for delivery that can be incorporated into many different matrices for delivery (ie, paste, oil, water, lipid emulsion, or chew) with a final concentration of < 0.3% THCs. The growing interest in these Cannabis-derived products for humans has led animal owners to administer Cannabis-derived products to their ailing companion pets.

For animals, there is even less information available on the toxic or therapeutic effects of Cannabis plant constituents than for humans. Recent studies have analyzed a random assortment of oils and found poor correlation between the composition indicated by the label and the actual content in some of the products across both human and veterinary markets.4,2729 When assessing products it was found that nearly half of products contained either 10% over or under the expected amounts based on concentrations on the packaging.27,28 It should be noted that the analytical technology is available to provide accurate identification and quantification of each constituent in the product. Whether this is done depends upon the integrity of the vendor and the quality of its third-party laboratory. More importantly, as veterinarians we look for cost effectiveness of the animal products we recommend, and costs have ranged from $0.05 to $0.58/mg of cannabinoid4; therefore, close scrutiny of milligrams of cannabinoid per milliliter or gram are important in making recommendations to clients in the most cost-effective manner for those choosing to use these products.

Microbiologics and Mycotoxins

Currently there are no specific pathogenic bacteria or fungi federally mandated for testing across hemp CBD products, or even marijuana.30 Two major pathogens associated with farming in general are salmonella and enteropathogenic Escherichia coli. There have been reports of both of these pathogens in marijuana consumption, making it entirely possible for contamination issues, which is why testing is necessary.31,32

Fungal contamination of Cannabis is much more likely to be due to environmental conditions, is commonly observed during the harvesting and drying process, and is different across geographical areas.33,34 The actual fungi are of little concern in hemp CBD products since extraction techniques eliminate live organisms; however, the mycotoxin residues are concerning. Aspergillus spores that contain aflatoxin can accumulate during drying and storage, leading to a variety of systemic issues.3538 Total aflatoxin levels (B1, B2, G1, and G2) should be below the limit of 20 μg/g based on current California Code of Regulations Title 16, which is currently the “gold standard” for testing.37 In a recent analysis38 of 142 seized Cannabis samples, no samples were positive for aflatoxin, and as a protective measure California law also has allowable limits of Aspergillus spore contamination in dry plant material.

Ochratoxin A is also a potential contaminant with strong nephrotoxic effects and immunosuppressive capabilities.3941 A recent examination38 of 142 herbal or resin Cannabis products showed that one-third of samples contained ochratoxin A, yet these levels would not garner any health concerns as they were below the levels established by California regulations according to Title 16, which is < 20 ug/kg.37 In general, though mycotoxins seem to be of minimal concern, good-quality control merits minimal testing of these 2 potential mycotoxins in all pet hemp CBD products for oral consumption, which should be part of a COA.

Heavy Metals and Pesticides

Cannabis is well-known for its ability to phytoremediate soils, meaning that Cannabis plants will extract soil contents, including heavy metals.42 Considering the potential for environmental soil contaminants in outdoor-grown hemp, analysis of heavy metals including nickel, cadmium, arsenic, and mercury are recommended and required by California Title 16 guidelines for Cannabis regulation.37 A recent study4 examining oral hemp CBD products in dogs showed that lead contamination was found in 1 of 29 products at concentrations higher than the USP limits of chronic toxic exposure. If following California regulations, 2 of the products from this study would also fail testing limits of arsenic exposure.4,37

Cannabis extracts are not always the culprit, as many products are made with oils or other edible matrices that could also be the source of this contamination, making final product testing paramount to ensure that these contaminants are not occurring from the hemp CBD extracts or the matrix in which the oral hemp CBD extract is delivered.

Pesticide testing is important in product quality control. The use of pesticides (insecticides, antifungals, and others) does occur in the hemp industry, and residues may be carried over into extracts utilized in the manufacturing of concentrated products for oral consumption. To date, there has not been any comprehensive pesticide analysis of orally consumed products in the veterinary or human market, but there is information on Cannabis plants themselves elevating concerns based on the US Environmental Protection Agency and USP regulations surrounding usable pesticides and allowable limits.4346 Currently, in the US market there are no federal pesticide testing requirements, yet Oregon and California have legislation on testing pesticides that can be used for hemp production testing.37,45 There are over 150 potential pesticides, and most testing facilities are now testing for over 50 pesticides, with California legislation containing the most extensive list for analysis. Adulteration with nonapproved pesticides found in an Oregon study gives pause regarding hemp suppliers44,46; therefore, ideally the product manufacturer should have control over the hemp extract and know which insecticides and fungicides are being used so that testing is thorough and owners and veterinarians can be informed before making choices.

Solvents and Extraction

There are many methods for extraction of cannabinoids and other chemicals from Cannabis. This is done either with solvents (eg, isopropanol, ethanol, and methanol) or high heating procedures, which can alter the biochemical nature of the cannabinoids and result in decarboxylation of acidic cannabinoids and terpene losses in these extracts.47 More complex, low-heat, high-pressure supercritical carbon dioxide or hydrocarbon extraction allows for more consistent extraction of the natural acidic forms of the cannabinoids and terpenes native to Cannabis.48 Regardless, either process will result in concentrating of cannabinoids and terpenes for hemp CBD products. Of course, these concentrates can have residual solvents and these solvents fall into 3 classifications from most toxic such as benzene (class 1 solvents to be avoided entirely) to class 2 molecules, which have toxic potential, or class 3 molecules, which have limited toxic potential, with allowable concentrations in ppm in products according to the USP 2019.49

To our knowledge, there have been no formal studies examining solvents used in pet products, while in human products it has been shown that the most commonly found solvents are isopropanol and ethanol in 29% of products tested above the USP limits.50 Currently, California Code of Regulations Title 16 has more stringent testing than the USP limits. Based on these regulations, third-party testing laboratories typically utilize the California regulations for quality control assurances.

Conclusions for the Veterinarian

There are over 100 hemp CBD products from a variety of distributors on the veterinary market. Differences in cannabinoid concentrations between products have been recognized in the veterinary market, making client interpretation and dosing difficult.4 As we have pointed out, a COA reporting cannabinoid concentrations, heavy metals, pesticides, solvents, mycotoxins, and microbiologics is an essential first step in identifying a safe product that can potentially be discussed with guidance by a veterinarian. Although difficult for a veterinarian to determine through a COA, the company should be producing hemp CBD with good manufacturing practices, which will include a USDA-certified hemp facility audit annually, and a reputable company will be able to provide information regarding this audit and, more importantly, be a member of the NASC. Although beyond the scope of this review, there is concern surrounding pharmacokinetics and efficacy of these products, as there are few published reports to date and the absorption and efficacy can depend on many different factors, including dose, cannabinoid content, extraction techniques, and matrix for delivery.11,51 Considering the complexity, it is ideal for veterinarians to seek out companies with pharmacokinetic data in the intended species and efficacy data around indications.

Acknowledgments

Joseph Wakshlag, Stacey Evans, and Jack Henion are all consultants or paid employees of Ellevet Sciences.

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  • Figure 1

    Depiction of major cannabinoid production in typical Cannabis cultivars showing the formation of cannabigerolic acid (CBGA) from geranyl diphosphate (GPP) and olivetolic acid (OA). Based on synthase activity, CBGA will become cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), or cannabichromenic acid (CBCA) as native cannabinoids to the plant. When heated, extracted, or exposed to UV light, decarboxylation occurs to form neutral cannabinoids cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), or cannabichromene (CBC).

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    • Export Citation

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