At high doses, Epidiolex—the CBD medicine approved by FDA to treat seizures associated with severe and rare forms of epilepsy—has been known to cause an increase in liver enzymes.
Do non-FDA-approved CBD brands also have the potential to cause injury to the human liver? That question is the subject of a recently announced observational study that CBD brands maintained could prove valuable to U.S. regulators.
The CBD study is analogous to what FDA would describe as “post-marketing surveillance for safety,” and it would not answer all of the safety questions raised by FDA about specific products, according to one prominent researcher in the health and nutrition space, Douglas Kalman.
“Unless each company has the same identical CBD that they sell just with their own label, this study is not evaluating the same CBD,” noted Kalman, Ph.D., vice president of scientific affairs with Nutrasource, a contract research organization based in Ontario, Canada.
What’s more, FDA is looking for the kind of safety data akin to that obtained during phase 1 pharmaceutical research, which aims to minimize “extraneous variables” that may or may not affect the organ studied, Kalman said in an interview. Such factors, he said, could include things such as a person’s lifestyle habits of being a heavy alcohol drinker or tobacco user, or using a prescription medication.
Based on the news release announcing the study, Kalman described the information to be collected as “observational consumer behavior data.”
“Maybe there will be some safety elements captured, but for sure, this is not what the FDA is looking for in terms of its request for the CBD community to submit safety data about their products,” he concluded.
Kalman referenced a March 5 statement from FDA’s commissioner, Stephen Hahn, M.D., in which he raised questions about potential harm from CBD products, including liver injury, interactions with other drugs, male reproductive toxicity, and such side effects as drowsiness.
“In addition, there is still much we do not know about other potential risks,” Hahn said. “For example, other than the approved prescription drug, we know little about the potential effects of sustained and/or cumulative use of CBD, co-administration with other medicines, or the risks to vulnerable populations like children, pregnant and lactating women, the elderly, unborn children and certain animal populations.”
Added Hahn: “This does not mean that we know CBD is unsafe to these populations or under these circumstances, but given the gaps in our current knowledge, and the known risks that have been identified, we also are not at a point where we can conclude that unapproved CBD products are safe for use.”
An FDA spokesman, Nathan Arnold, didn’t comment on the observational study in particular, but he noted the importance of developing high-quality data.
“The marketplace for CBD-containing products is quickly evolving and it is critical to develop high-quality data to close the knowledge gaps about the science, safety and quality of many of these products, as well as further evaluate any potential benefits outside of the one FDA-approved drug product to treat two rare, severe pediatric epilepsy disorders,” Arnold said in an email. “We welcome reliable and high-quality data and will continue to engage with stakeholders who want to work toward this goal.”
Patrick McCarthy is co-founder and CEO of ValidCare, a Colorado-based provider of clinical research outsourcing and consumer intelligence spearheading the CBD study. He said he anticipates close to 1,000 consumers participating in the study. Through the collection of individuals’ medical history, a requirement for participants, the study will account for such variables as “health conditions, lifestyle and medication/supplement uses,” McCarthy said via email.
“These variables have potential to inform the regulatory path and instruct further research,” he added.
Focus on liver enzymes
McCarthy said researchers will analyze three other liver function tests if they identify elevations in the primary endpoint known as ALT—alanine transaminase, an enzyme found in the liver. In controlled studies for Lennox-Gastaut syndrome and Dravet syndrome, the developer of Epidiolex, GW Pharmaceuticals plc, reported “the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% in Epidiolex-treated patients compared with 1% in patients on placebo.”
Kalman “is correct that the design is akin to post-market surveillance and that multiple products are incorporated into the study,” McCarthy said. “This is purposeful, as the goal is to determine whether a safety issue exists with oral CBD products currently available in this unregulated market.”
In the observational study, variables, such as age, comorbidities, consumption amount, extraction method, lifestyle and sex, will be “observed for statistical significance,” McCarthy said. He acknowledged “no study is perfect,” but he said FDA has noted its “primary concern is liver safety.”
The study’s findings are “expected to provide clarity for FDA, brands and the American consumer,” he said. “It will undoubtedly raise questions and the opportunity for more targeted product-specific research, which is good for industry and the consumer.”
After reviewing McCarthy’s comments about the study, Kalman said „many covariates and factors [are] in play here.”
„Statistical controls cannot always properly account for these covariates, especially in a meaningful informed way (my perspective),” he wrote in an email. But he said the data that will be generated in the observational study „may be viewed more as a part of the overall bigger picture regarding hemp-derived CBD products in the marketplace.”
The observational “study focuses directly on the FDA’s concern” about elevated liver enzymes in patients taking high doses of Epidiolex—10 milligrams (mg) per kilogram (kg) of CBD daily in an oral solution, or greater than 700 mg for an average-sized adult, said Rosemary Mazanet, M.D., Ph.D., chief scientific officer of Columbia Care, a cultivator, manufacturer and provider of medical and adult use cannabis products.
“The goal of this study is to deliver ‘real world evidence’ about liver function that is associated with current consumer use of doses of 20-60 mg daily of commercially available high-quality products,” Mazanet said in an email. “The resulting data using these products will help the FDA and brands understand whether a consumer safety issue exists. As the FDA has provided feedback to the design of the study, we believe that the findings will be credible to the regulators.”
Columbia Care is one of the seven companies that have committed to participating in the study. Other participants include Boulder Botanical & Bioscience Labs, CBDistillery, Charlotte’s Web, CBD American Shaman, HempFusion and Kannaway.
“Observational human toxicology” has “value,” said Jason Mitchell, co-founder and president of HempFusion, though he acknowledged its limitations.
“Is it a double-blind, placebo-controlled crossover randomized study?” he asked. “No, it is not.”
He added later, “There’s always better research that can be done, but here’s the problem: We don’t have a lot of people lining up to fund it.”
Case in point: Although ValidCare divulged screening more than 100 brands to participate in the research, the reasons other brands didn’t participate in the study, McCarthy noted, were related to one or more factors, including a dearth of funds (over 50%), a belief FDA won’t “act on the data” and concerns that asking customers to participate could “scare” them.
Companies also reported plans to conduct their own studies as part of an investigational new drug (IND) application to obtain FDA approval for products, and the “brand or processor doesn’t think it was their job to do research (about 20%) or that FDA should treat CBD from hemp as a supplement and allow GRAS,” McCarthy explained via email.
Mitchell questioned the integrity of companies that don’t think it’s their “job” to conduct safety research.
“[It’s] always your job and your responsibility to prove, or do everything that you can, to show that what you’re selling is a safe product for human consumption,” he said.
The businessman, however, was sympathetic to financial constraints facing the industry. “To be quite frank, you see companies that are declaring bankruptcy or going into receivership or flat-out just going out of business,” he remarked.
The kind of research Nutrasource’s Kalman described, Mitchell noted after a reporter summed up his remarks, would come at a considerably “higher price tag” than the observational study. McCarthy confirmed each of the seven companies participating in the research has contributed more than $100,000 to the endeavor.
“I have nothing but respect for what the gentleman [Kalman] is saying should be done, but I think this [observational study] is a great step in the right direction,” Mitchell said.
Some marketers of CBD, Kalman said, are investing in animal and human safety studies that are “more akin to pharmaceutical safety drug development” and would form part of a package for new dietary ingredient notifications (NDINs) to FDA. Such notifications are a key safety mechanism required by the Dietary Supplement Health and Education Act of 1994 (DSHEA).
But as Natural Products Insider reported in February, the CBD industry faces a catch-22: FDA isn’t willing to review safety information through a traditional regulatory pathway to market—the NDIN route— because it has determined CBD is excluded from the definition of a dietary supplement.
Some marketers have moved to establish the safety of their hemp ingredients through another regulatory mechanism. For example, over the last 24 months, in partnership with its raw material supplier, HempFusion has been working through the self-affirmed GRAS (generally recognized as safe) process, according to Mitchell. He said animal safety studies have been completed, and he anticipated data would be published in a peer-reviewed journal by July.
Commenting on the observational study, a representative of CV Sciences Inc., Duffy MacKay, said he was “encouraged to see other CBD brands accepting their obligation to consumers’ safety by making an investment into scientific research.” In 2018, CV Sciences announced receiving self-affirmed GRAS status for its hemp-derived CBD gold extract.
“We hope ValidCare plans to publish the data in a peer-reviewed journal to raise the level of legitimacy of the data,” added MacKay, senior vice president of scientific and regulatory affairs, in an email.
The availability and publication of the ValidCare research, along with current published safety data, “will support FDA’s efforts to promulgate regulations,” MacKay said.
Also commenting on the observational study, Mazanet of Columbia Care offered similar remarks. “With this evidence in hand, we hope the FDA will feel confident to begin to regulate the CBD industry, with the aim of providing quality regulations that products must meet in order to be sold,” she said.