An ABA Products Liability Litigation Committee Invited Article © Gradient, 2020
Successfully Riding the Wave: Understanding the Risks of CBD Products James W. Rice and Tom Lewandowski
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 may even affect a product's legal status. Yet, state and federal regulators have not enacted specific, consistent guidance on the processes 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 refinedvia processes that remove The 2018 US Agriculture and Improvement Act, commonly referred undesired compounds (e.g., winterization) and concentrate CBD to as the 2018 Farm Bill, legalized hemp, defined as cannabis (e.g., distillation and crystallization) to produce CBD-isolate, the (Cannabis sativa L) and derivatives of cannabis with less than 0.3% THC, by removing it from the Schedule I list of controlled substances. purest form of CBD used in consumer products. Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are well-known cannabinoids that occur naturally in cannabis, but Challenges in Assessing Product Quality and unlike THC, CBD is non-psychoactive (that is, it does not make Composition users high). Hemp's new status as a legal agricultural product has resulted in an explosion of hemp-derived CBD consumer products Robust, transparent, and standardized analytical testing is essential such as oil tinctures, gummies, topically applied products, capsules, to ensuring that CBD-containing products are marketed correctly dog treats, and more. However, according to the US FDA, it is and remain safe. Analytical laboratories typically test CBD- currently illegal to market CBD by adding it to a food or labeling it containing products for cannabinoid potency to ensure that the as a dietary supplement, because US FDA has approved one CBD CBD is within a specified concentration range and that THC does product, the prescription drug Epidiolex®, to treat two severe forms not exceed 0.3% by weight. Analytical laboratories typically also of epilepsy. test CBD products for pesticides, heavy metals, and microbes. Moreover, there is increasing attention to chemicals that could be While CBD products may not currently be marketed as a food or as intentionally added to increase yield and/or potency, such as fillers a dietary supplement, a vast and growing number of hemp-derived and synthetic cannabinoids. Despite the importance of product CBD products continue to gain popularity. CBD products are widely testing, analytical method development is in many ways still in its available on store shelves and online. Unfortunately, our scientific infancy, largely due to a lack of federal guidance, a patchwork of understanding of their benefits and possible adverse health effects state regulations and proficiency requirements, and the myriad – which will almost certainly play a role in potential product liability of CBD product types on the market. Analytical laboratories and claims – has not kept pace with the production and use of these equipment manufacturers have been left to develop and validate products. To compound this problem, state and federal regulators their own, often proprietary, methods, which has resulted in varied have yet to enact consistent guidance on how CBD products may results and questions about data quality. Given the high stakes of be manufactured, how CBD products are marketed, or what, if any, product testing, this remains a key challenge for hemp growers warnings are necessary to provide to consumers. and CBD product manufacturers. Successfully Riding the Wave: Understanding the Risks of CBD Products
Health Claims How Much CBD Is Too Much CBD? The range of health claims that have been made for CBD (and more A key goal of product stewardship is to ensure that products are recently, other cannabinoids) is incredibly wide, ranging from not exposing consumers to harmful concentrations of chemical softer claims like reducing anxiety or promoting sleep to definite ingredients. So what kinds of exposures are consumers experiencing drug-like claims such as treating opioid addiction, curing acne, or from CBD products, and could these exposures produce adverse treating diabetes or cancer. More recently, the US FDA has warned health effects? Based on an informal review of product advertising, multiple companies about making claims regarding CBD products most products generally contain fairly modest concentrations of protecting against, or treating, COVID-19 infection. To date, the CBD (e.g., recommended doses of 100 mg/day or 1.4 mg/kg for a best-supported health claim for CBD is the reduction of anxiety. typical adult). Perhaps a greater concern is the explosion of a huge A number of randomized control trials (the gold standard in drug range of products (e.g., candy, lotions, milkshakes, hamburgers), testing) have indicated such an effect exists e.g.( , see Blessing allowing consumers to obtain CBD exposure from multiple et al., 2015). Of course, none of these possible claims are US FDA- sources. Many consumers seem to believe that if a little CBD is approved. While a tremendous amount of research is currently good, a lot is even better, so assuming that people have just one underway, the validity of these purported health benefits remains source of exposure is probably unrealistic. Sample calculations far from conclusive. Nevertheless, some manufacturers of CBD using claimed CBD content and use recommendations found for products continue to tout their products as a panacea for a myriad representative products online (see the table below) suggest what of ailments. Of course, not all manufacturers of CBD products make the cumulative dose might be for an individual consuming several unsubstantiated claims of the health benefits of their products, but different types of CBD products compared to the maximum dose of those that do create confusion in the marketplace. Epidiolex (20 mg/kg per day), a dose established to avoid adverse effects. As shown in the table, an adult consuming a single serving Potential Adverse Effects of CBD of CBD-containing chocolate would be exposed to well below 20 mg/kg per day. Even if an adult is using several CBD products What do we know about CBD's potential adverse health effects? at the same time, they would still likely be exposed to well below Some data, in both humans and animals, are available from the the maximum Epidiolex dose, but a child could be exposed to a studies undertaken to obtain regulatory approval for Epidiolex, sizeable fraction of that maximum dose. Accidental exposures in in which the active ingredient is a highly purified form of CBD. children would also be of concern. For example, a child consuming In those studies, which have been reviewed by US FDA and an entire package of CBD-containing gummies would be exposed published in peer-reviewed journals, the key adverse findings were to the equivalent of the maximum dose of Epidiolex. While this liver enzyme changes observed in both animals and humans at the would be an acute rather than a repeated exposure, the fact that higher tested doses (in humans, these findings were particularly it is near the top of the pharmaceutically active dose range would seen in individuals also taking other anti-epileptic drugs). Notably, be concerning. there were no indications of actual liver injury, and both patients and animals returned to normal readings after the exposure Another important consideration is the continued trend towards ceased, if not before. These studies were used to establish the more potent and/or more biologically available CBD products. maximum allowed dose for Epidiolex of 20 mg/kg per day (the CBD and other cannabinoids have only very limited uptake across starting dose is 5 mg/kg per day). Reproductive and developmental the skin and gastrointestinal tract, which is one reason why many effects, including fetal mortality and neurobehavioral changes, of these products appear to have good safety profiles. However, were also seen in animal studies, but only at doses several times there are multiple reports of delivery systems under development higher than the maximum allowed dose of Epidiolex. All told, that will enhance uptake (e.g., through nanosphere encapsulation). some high-quality human and animal data on the potential The introduction of such products to the marketplace could create adverse effects of CBD are available, although the studies have a safety concern absent appropriate studies and assessments of been of relatively short duration (e.g., for most patients, less than health risk. Ultimately, most CBD products, if used as intended, do a year). Longer-term studies would be helpful for educating us not seem to pose a health risk for consumers, but potential misuse about potential effects in chronic consumers of CBD products. or modification to enhance exposure should be carefully examined for its impact on product safety.
Potential CBD Product-derived Doses Relative to Approved Pharmaceutical Doses
Total Systemic Dosea Fraction Epidiolex Oral Doseb Product CBD Content Use Amount (mg/day) Adult Child Chocolate 50 mg/serving 1 serving 50 0.03 0.17 Chocolate 50 mg/serving 1 serving Lotion 250 mg/oz 1 oz 108 0.07 0.36 Oil 33 mg/mL 1 ml
10 mg/piece, 1 piece 10 0.007 0.03 Gummy Sours 30 pieces total 30 pieces 300 0.2 1.0
Notes: For illustration only, actual uptake will vary with product formulation. (a) Assuming the same extent of systemic absorption for orally consumed products as Epidiolex and a 10-fold lower systemic absorption from lotions, consistent with values reported for other large molecules in dermally applied products (e.g., sunscreens). (b) Epidiolex maximum dose: 1,500 mg/day for a typical adult, 300 mg/day for a typical 5-year-old child. Successfully Riding the Wave: Understanding the Risks of CBD Products
THC in CBD Products Other Cannabinoids On January 3, 2020, the State of California listed THC as being Though much focus has been directed to CBD (and THC), there is subject to Proposition 65, California's product labeling law. growing interest in other "minor" naturally occurring cannabinoids, Cannabis smoke was listed under Proposition 65 in 2009, but the some of which are purported to have therapeutic properties and/or listing of THC itself is novel. The State noted that the decision to contribute to the "entourage effects" of CBD-containing products. list THC was based on reproductive health effects that have been These include, for example, tetrahydrocannabivarin (THCV), observed in both animal and human studies, in some cases at fairly cannabichromene (CBC), cannabigerol (CBG), and cannabidivarin low concentrations. California will begin enforcing the labeling (CBDV). Improved purification technologies and analytical testing requirement in January 2021 on products that contain THC above methods to identify and characterize minor cannabinoids is likely to a Safe Harbor Limit. Unfortunately, the State has not identified a focus a spotlight on them. In other words, as technologies improve, Safe Harbor Limit for THC, and there is no indication of when they so too will the intended use of minor hemp-derived cannabinoids will propose one. A review of the available THC toxicity literature in consumer products. As is the case with CBD, research on suggests the State could set a limit in the single microgram of intake structure, function, therapeutic effects, and health effects should per day range, or lower. Given that the allowable federal limit for also garner attention, so that these possible future products are THC in hemp products is 0.3% (3,000 micrograms/gram), it seems introduced to the consumer market safely. In terms of the potential likely that federally allowed hemp-based CBD products could health benefits of these compounds, animal studies have shown require a warning label if sold in California. Given the size of the CBG, CBC, and THCV to be promising at treating inflammation, and California market, the cost of state-specific packaging, and the risks CBG to be promising at treating glaucoma. One human study has of products being inadvertently sold other than where intended, shown THCV to have some beneficial effects for diabetes patients. many CBD product companies would likely include Proposition 65 Overall however, studies of these chemicals remain largely at the warning labeling on all their products. However, the inclusion of a exploratory (or hypothesis-generating) stage, and so product claims label warning (e.g., WARNING: Reproductive Harm) may prove about their health benefits are difficult to support. Information on confusing for consumers if the product is simultaneously being sold the potential adverse effects of these compounds is also limited. for a perceived health benefit and marketed as being compliant Animal studies of CBG and a 13-week human study of THCV did with federal regulations on THC concentrations. This example not suggest adverse effects, but as with CBD, there are no chronic clearly encapsulates the many contradictions and challenges that studies in animals, let alone people, at least in the public literature. manufacturers of hemp-based products are currently facing. 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.
Citations for the studies referred to above can be obtained from the authors upon request.
James W. Rice, Ph.D. Senior Environmental Scientist [email protected]
Dr. Rice is a Senior Project Manager in Gradient’s Boston, MA office. Tom Lewandowski, Ph.D., DABT, ERT, ATS Principal [email protected]
Dr. Lewandowski is a Principal in Gradient’s Seattle, WA office.