August 04, 2020 Article

Successfully Riding the Wave: Understanding the Risks of CBD Products

An overview of the many contradictions and challenges that manufacturers of hemp-based products are currently facing.

By James Rice and Tom Lewandowski

The 2018 Agriculture Improvement Act, commonly referred to as the 2018 Farm Bill, legalized hemp, defined as cannabis (Cannabis sativa L.) and derivatives of cannabis with less than 0.3 percent tetrahydrocannabinol (THC), by removing it from the Schedule I list of controlled substances. Cannabidiol (CBD) and delta-9-tetrahydrocannabinol are well-known cannabinoids that occur naturally in cannabis, but unlike THC, CBD is non-psychoactive (that is, it does not make users high). Hemp’s new status as a legal agricultural product has resulted in an explosion of hemp-derived CBD consumer products such as oil tinctures, gummies, topically applied products, capsules, dog treats, and more. However, according to the U.S. Food and Drug Administration (FDA), it is currently illegal to market CBD by adding it to a food or by labeling it as a dietary supplement, because the FDA has approved one CBD product, the prescription drug Epidiolex, to treat two severe forms of epilepsy.

While CBD products may not currently be marketed as a food or as a dietary supplement, a vast and growing number of hemp-derived CBD products continue to gain popularity. CBD products are widely available on store shelves and online. Unfortunately, our scientific understanding of their benefits and possible adverse health effects—which will almost certainly play a role in potential product liability claims—has not kept pace with the production and use of these products. To compound this problem, state and federal regulators have yet to enact consistent guidance on how CBD products may be manufactured, how CBD products are marketed, or what, if any, warnings are necessary to provide to consumers.

Making CBD Products

Before being used in consumer products, hemp-derived CBD must first undergo a number of processing steps to separate it from plant matter and other plant-derived chemicals (or phytochemicals). These processing steps have important implications on consumer experience and product quality, and they may even affect a product’s legal status. Yet, state and federal regulators have not enacted specific, consistent guidance on the processes that manufacturers may use to isolate the CBD. Despite this, and the many methods available for isolating CBD from raw hemp, consumers may have the mistaken impression that all CBD products are of the same or similar quality.

Solvent extraction involves the isolation of CBD and other desired (and undesired) phytochemicals from hemp. It produces a crude extract that contains not only CBD but also THC, other minor cannabinoids, lipids, fats, terpenes, pigments, and more. There is a growing demand for these complex phytochemical mixtures, often marketed as “full spectrum” or “whole plant” extracts, which some proponents claim avoid the regulatory issues of pure THC or CBD. However, crude CBD extracts tend to be viscous and opaque, and have a pronounced flavor that may not be universally palatable. Moreover, producers of whole plant extracts may struggle to reproduce composition from batch to batch because of the inherent heterogeneity of plant matter and the possible adulteration by both natural and anthropogenic chemicals, such as THC, pesticides, and heavy metals. Therefore, many crude CBD extracts are then further refined via processes that remove undesired compounds (e.g., winterization) and concentrate CBD (e.g., distillation and crystallization) to produce CBD isolate, the purest form of CBD used in consumer products.

Challenges in Assessing Product Quality and Composition

Robust, transparent, and standardized analytical testing is essential to ensuring that CBD-containing products are marketed correctly and remain safe. Analytical laboratories typically test CBD-containing products for cannabinoid potency to ensure that the CBD is within a specified concentration range and that THC does not exceed 0.3 percent by weight. Analytical laboratories typically also test CBD products for pesticides, heavy metals, and microbes. Moreover, there is increasing attention to chemicals that could be intentionally added to increase yield or potency or both, such as fillers and synthetic cannabinoids. Despite the importance of product testing, analytical method development is in many ways still in its infancy, largely due to a lack of federal guidance, a patchwork of state regulations and proficiency requirements, and the myriad of CBD product types on the market. Analytical laboratories and equipment manufacturers have been left to develop and validate their own, often proprietary, methods, which has resulted in varied results and questions about data quality. Given the high stakes of product testing, this remains a key challenge for hemp growers and CBD product manufacturers.

Health Claims

The range of health claims that have been made for CBD (and, more recently, other cannabinoids) is incredibly wide, from softer claims like reducing anxiety or promoting sleep to definite drug-like claims such as treating opioid addiction, curing acne, or treating diabetes or cancer. More recently, the FDA has warned multiple companies about making claims regarding CBD products protecting against, or treating, COVID-19 infection. To date, the best-supported health claim for CBD is the reduction of anxiety. A number of randomized control trials (the gold standard in drug testing) have indicated such an effect exists (see, e.g., Blessing et al., “Cannabidiol as a Potential Treatment for Anxiety Disorders,” 12 Neurotherapeutics 825–36 (Oct. 2015). Of course, none of these possible claims are FDA-approved. While a tremendous amount of research is currently under way, the validity of these purported health benefits remains far from conclusive. Nevertheless, some manufacturers of CBD products continue to tout their products as a panacea for a myriad of ailments. Of course, not all manufacturers of CBD products make unsubstantiated claims about the health benefits of their products, but those that do create confusion in the marketplace.

Potential Adverse Effects of CBD

What do we know about CBD’s potential adverse health effects? Some data, in both humans and animals, are available from the studies undertaken to obtain regulatory approval for Epidiolex, in which the active ingredient is a highly purified form of CBD. In those studies, which have been reviewed by the FDA and published in peer-reviewed journals, the key adverse findings were liver enzyme changes observed in both animals and humans at the higher tested doses (in humans, these findings were particularly seen in individuals also taking other anti-epileptic drugs). Notably, there were no indications of actual liver injury, and both patients and animals returned to normal readings after the exposure ceased, if not before. These studies were used to establish the maximum allowed dose for Epidiolex of 20 milligrams per kilogram (mg/kg) per day (the starting dose is 5 mg/kg per day). Reproductive and developmental effects, including fetal mortality and neurobehavioral changes, were also seen in animal studies, but only at doses several times higher than the maximum allowed dose of Epidiolex. All told, some high-quality human and animal data on the potential adverse effects of CBD are available, although the studies have been of relatively short duration (e.g., for most patients, less than a year). Longer-term studies would be helpful for educating us about potential effects in chronic consumers of CBD products.

How Much CBD Is Too Much CBD?

A key goal of product stewardship is to ensure that products are not exposing consumers to harmful concentrations of chemical ingredients. So what kinds of exposures are consumers experiencing from CBD products, and could these exposures produce adverse health effects? Based on an informal review of product advertising, most products generally contain fairly modest concentrations of CBD (e.g., recommended doses of 100 mg/day or 1.4 mg/kg for a typical adult). Perhaps a greater concern is the explosion of a huge range of products (such as candy, lotions, milkshakes, and hamburgers), allowing consumers to obtain CBD exposure from multiple sources. Many consumers seem to believe that if a little CBD is good, a lot is even better, so assuming that people have just one source of exposure is probably unrealistic.

Sample calculations using claimed CBD content and use recommendations found for representative products online (see the table below) suggest what the cumulative dose might be for an individual consuming several different types of CBD products compared with the maximum dose of Epidiolex (20 mg/kg per day), a dose established to avoid adverse effects. As shown in the table, an adult consuming a single serving of CBD-containing chocolate would be exposed to well below 20 mg/kg per day. Even if an adult is using several CBD products at the same time, he or she would still likely be exposed to well below the maximum Epidiolex dose, but a child could be exposed to a sizable fraction of that maximum dose. Accidental exposures in children would also be of concern. For example, a child consuming an entire package of CBD-containing gummies would be exposed to the equivalent of the maximum dose of Epidiolex. While this would be an acute rather than a repeated exposure, the fact that it is near the top of the pharmaceutically active dose range would be concerning.

Another important consideration is the continued trend toward CBD products that are more potent or more biologically available (or both). CBD and other cannabinoids have only very limited uptake across the skin and gastrointestinal tract, which is one reason why many of these products appear to have good safety profiles. However, there are multiple reports of delivery systems under development that will enhance uptake (e.g., through nanosphere encapsulation). The introduction of such products into the marketplace could create a safety concern absent appropriate studies and assessments of health risk. Ultimately, most CBD products, if used as intended, do not seem to pose a health risk for consumers, but potential misuse or modification to enhance exposure should be carefully examined for its impact on product safety.

Other Cannabinoids

Though much focus has been directed to CBD (and THC), there is growing interest in other “minor” naturally occurring cannabinoids, some of which are purported to have therapeutic properties or contribute to the “entourage effects” of CBD-containing products or both. These include, for example, tetrahydrocannabivarin (THCV), cannabichromene (CBC), cannabigerol (CBG), and cannabidivarin (CBDV). Improved purification technologies and analytical testing methods to identify and characterize minor cannabinoids is likely to focus a spotlight on them. In other words, as technologies improve, so too will the intended use of minor hemp-derived cannabinoids in consumer products. As is the case with CBD, research on structure, function, therapeutic effects, and health effects should also garner attention, so that these possible future products are introduced into the consumer market safely. In terms of the potential health benefits of these compounds, animal studies have shown CBG, CBC, and THCV to be promising at treating inflammation, and CBG to be promising at treating glaucoma. One human study has shown THCV to have some beneficial effects for diabetes patients.

Overall, however, studies of these chemicals remain largely at the exploratory (or hypothesis-generating) stage, and so product claims about their health benefits are difficult to support. Information on the potential adverse effects of these compounds is also limited. Animal studies of CBG and a 13-week human study of THCV did not suggest adverse effects, but as with CBD, there are no chronic studies in animals, let alone people, at least in the public literature. Overall, we are further behind the curve in our understanding of the risks and benefits of these other cannabinoids than those of CBD, so the increasing interest in putting them in consumer products is yet another example of marketing getting ahead of the science.

THC in CBD Products

On January 3, 2020, the state of California listed THC as being subject to Proposition 65, California’s product labeling law. Cannabis smoke was listed under Proposition 65 in 2009, but the listing of THC itself is novel. The state noted that the decision to list THC was based on reproductive health effects that have been observed in both animal and human studies, in some cases at fairly low concentrations. California will begin enforcing the labeling requirement in January 2021 on products that contain THC above a safe harbor limit. Unfortunately, the state has not identified a safe harbor limit for THC, and there is no indication of when it will propose one. A review of the available THC toxicity literature suggests the state could set a limit in the range of a single microgram of intake per day, or lower.

Given that the allowable federal limit for THC in hemp products is 0.3 percent (3,000 micrograms/gram), it seems likely that federally allowed hemp-based CBD products could require a warning label if sold in California. Given the size of the California market, the cost of state-specific packaging, and the risks of products being inadvertently sold other than where intended, many CBD product companies would likely include Proposition 65 warning labeling on all their products. However, the inclusion of a label warning (e.g., WARNING: Reproductive Harm) may prove confusing for consumers if the product is simultaneously being sold for a perceived health benefit and marketed as being compliant with federal regulations on THC concentrations. This example clearly encapsulates the many contradictions and challenges that manufacturers of hemp-based products are currently facing.

Citations for the studies referred to above can be obtained from the authors upon request.

James Rice, PhD, is a senior project manager in Gradient’s office in Boston, Massachusetts, and Tom Lewandowski, PhD, is a principal in Gradient’s Seattle, Washington, office.


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