Research into efficacy and safety is promising, but lack of standards clouds the market
Auburn University photo
Dr. Dawn Boothe is a specialist in veterinary internal medicine and clinical pharmacology.
The marketing of cannabidiol (CBD) dietary supplements is lucrative and growing, with little evidence of slowing down. However, the U.S. Food and Drug Administration recently sent letters to four dietary supplement manufacturers warning that their products violate the Federal Food, Drug and Cosmetic Act (FD&C Act). The products contain CBD and are being marketed for use in food animals.
This warning is a reminder to veterinarians and their caregiving partners to review the complex rules surrounding the prescribing, purchase and use of oral therapeutic interventions, including those containing phytocannabinoids. They may find the facts surprising.
Some background to start:
Phytocannabinoids are compounds derived from Cannabis plants, most commonly C. sativa. The two most recognized phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and CBD. As the substance in marijuana that produces euphoria, THC generally is recognized as the more psychoactive phytocannabinoid, but both are used to treat a variety of disorders. Although legalized in many states for recreational or medicinal use, marijuana continues to be federally regulated under the Controlled Substances Act (CSA) as a Schedule I substance, the most restrictive drug classification.
In recent years, Congress has loosened the rules on cannabis, first by distinguishing hemp from marijuana (in 2014), and then legalizing hemp throughout the United States (in 2018). Now hemp is federally defined as any part of the Cannabis sativa plant that contains no more than 0.3% THC on a dry-weight basis. Hemp contains CBD as the primary phytocannabinoid. As hemp no longer is subject to the CSA, that would seem to pave the way for its legal inclusion in foods or supplements. However, even if derived from hemp, CBD is not considered by the FDA as an allowable ingredient in either food or supplements.
Understanding the reason requires revisiting the rules governing all oral medicaments.
First, oral therapeutics marketed for human use are regulated by the FDA as either foods, dietary supplements or drugs.
Any ingredient added to foods must be determined by the FDA to be "generally recognized as safe," or GRAS. CBD has not been recognized as GRAS, and thus is not allowed in food.
Dietary supplements are governed by the 1994 Dietary Supplement Health Education Act, an amendment to the FD&C Act advocated by the dietary supplement industry.
DSHEA defines dietary supplements for humans and allows for "structure/function" claims (such as "used to support") on products. The law markedly limits FDA oversight of dietary supplements as compared with drugs, particularly of products sold before 1994. For example, dietary supplements do not undergo a federally mandated premarket assessment of product quality, safety or efficacy.
The law does mandate selected actions that might decrease the risk to human consumers but, disconcertingly, adherence to these rules by supplement manufacturers is lacking.
For example, despite a requirement that FDA be notified of new ingredients in dietary supplements, the agency was notified of only 170 out of more than 75,000 new ingredients that were added between 1994 and 2020.
When it comes to adverse events, DSHEA provides FDA oversight, but reporting is voluntary. Fewer than 1% of adverse events from dietary supplements are likely reported, according to the government's own assessment.
Further, adulteration (meaning the substance has been mixed or packed in a manner that reduces its quality or strength, including by making substitutions) and misbranding (meaning the labeling is false or misleading) appear to be common occurrences. An investigation by the New York State Attorney General's Office found that 80% of samples from herbal products sold by major retailers contained none of the herbal ingredients listed on the labels.
At the same time, supplements may contain active ingredients that aren't on the label. California Department of Public Health researchers found that nearly 800 products tested by the FDA between 2009 and 2016 were adulterated through the addition of active pharmaceutical ingredients — that is, drugs. The added drugs included phosphodiesterase inhibitors (which are used to treat erectile dysfunction), behavior modifiers and anti-inflammatories, including glucocorticoids.
Unsurprisingly, dietary supplements containing CBD likewise have been adulterated and misbranded.
The Associated Press reported in 2019 that CBD-containing vapes and edibles such as gummies have been found to be spiked with psychoactive street drugs.
A plethora of studies have shown contaminants incidentally acquired during plant growth and product processing. The contaminants include potentially harmful microbes, pesticides, heavy metals such as lead, and polycyclic aromatic hydrocarbons (which are presumed carcinogens).
If that sounds bad, consider this: The limited regulatory safeguards on human dietary supplements don't protect animals.
Soon after DSHEA passed, the FDA Center for Veterinary Medicine determined that its provisions do not apply to animals. Therefore, the law does not recognize any product as an “animal dietary supplement.” That means any therapeutic intervention administered orally to animals is considered by regulatory agencies to be a drug or a food. To reiterate: Under the law, there is no such thing as an animal dietary supplement.
Why not? One of the rationales is that humans could be exposed to ingredients contained in supplements consumed by animals that humans eat.
This is a reasonable concern. In the absence of effective oversight of the quality, safety and efficacy of human dietary supplements, the risk of human or animal exposure to unsafe ingredients is real.
Based upon society's tendency to value animals less than people, the risks of products sold as supplements for animals are likely to be greater even than those sold for people. In fact, problems with CBD products sold for animals already have been demonstrated, according to published data.
That brings us to the May 26 FDA letters warning that marketing of dietary supplements containing CBD to food animals is illegal. The fact that the agency had to send the letters suggests that the manufacturers may be unaware of the differences in rules for human versus animal CBD products, or are confused by the nuances.
Therefore, it is incumbent on veterinarians to understand the risks associated with the use of these products. Of course, effectively transmitting these concerns to an unreceptive public or client may be difficult.
Compounding the risks is a lack of standardization in product presentation. The phytochemical content, concentration, formulation and vehicle are so variable from product to product that it's hard, if not impossible, to know what to give and how much.
Returning to how oral therapeutics are regulated by the FDA, we've talked about foods and we've talked about dietary supplements. The third classification is drugs.
There are two FDA-approved oral drugs for humans containing phytocannabinoids. They are Marinol, which is synthetic THC; and Epidiolex, which is plant-derived CBD. Marinol is labeled for the prevention of anorexia, nausea and vomiting. Epidiolex is for the treatment of drug-resistant epilepsy in children.
Here's the final kicker: By law, active ingredients of approved drugs cannot be used in foods or dietary supplements. Therefore, technically, foods and supplements may not contain either THC or CBD.
How is it, then, that products with these ingredients are sold widely with apparent impunity? This fact speaks to the lack of clarity in the FDA's regulatory approach. But what is clear is that agency resources will be used to regulate these products if they present a threat to public health. Hence, the warning letters to manufacturers of products marketed for use in food animals.
CBD is not intrinsically unsafe. Evidence-based guidance on the safety and efficacy of CBD for a variety of disorders in animals is emerging. However, risks posed by dietary supplements may complicate even the most well-designed clinical trial if product quality cannot be assured in the absence of regulatory oversight.
During this period of more questions than answers, and as the FDA (and state veterinary medical boards) finalize their regulatory approach to the cannabis industry, and until the industry itself understands the need for standardizing how they present their products such that consumers can understand their appropriate use, common sense dictates that veterinary clients be directed to those CBD products that have been well-researched in the target species, as is evidenced by multiple reports in peer-reviewed journals.
Another avenue is extralabel use of the approved drug Epidiolex. This is the only way currently that CBD can be used legally under federal law. Veterinarians are empowered to prescribe, dispense and administer any FDA-approved drug as long as the criteria for extralabel drug use are met.
About the author: Dawn Merton Boothe, DVM, MS, PhD, is a specialist in veterinary internal medicine and clinical pharmacology. A 1980 graduate of the veterinary school at Texas A&M University, she was on the faculty there from 1990-2003, after which she joined the faculty at Auburn University in Alabama, where she teaches, does research, and is director of the Clinical Pharmacology Laboratory. Boothe also serves as a clinical pharmacology consultant at the Veterinary Information Network, an online community for the profession. She lives with her husband, two pugs, an Australian shepherd and four cats.
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