The U.S. Food & Drug Administration is under growing pressure to finally regulate products that contain cannabidiol (CBD), the cannabinoid that has had a meteoric rise to health-fad status in part because it is non-intoxicating. Hemp-derived CBD was legalized under the 2018 Farm Bill, but food and drug products prepared with it remain technically illegal until the FDA creates regulations.
Legislation that would further push the FDA to move on the CBD matter is even currently pending before Congress.
But there is some hope for imminent action. As Marijuana Moment noted, on July 12, the FDA’s acting chief information officer Amy Abernethy tweeted that the “FDA is expediting its work to address the many questions about cannabidiol (CBD),” describing it as “an important national issue with public health impact and an important topic for American hemp farmers and many other stakeholders.”
“We are enthusiastic about research into the therapeutic benefits of CBD products but also need to balance safety,” Abernethy continued. “To understand the breadth of issues and gather data on safety we have conducted a public hearing, reviewed the medical literature and have an open public docket.”
Market Watch reports that cannabis stocks rose in response to those tweets. But they came on the heels of a more formal FDA statement explaining the agency’s delay in promulgating the regs — and citing some disturbing claims about the potential health impacts of CBD.
Fears of Liver Damage
The statement posted to the FDA website on June 19 is entitled: “What You Need to Know (And What We’re Working to Find Out) About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD.”
The statement says that the FDA “recognizes the significant public interest” in CBD. It makes note of the FDA hearing on the matter held on May 31, and last year’s FDA approval of “one prescription drug product” containing CBD, Epidiolex. But by way of explaining the delay in the regs, the statement lowers the boom: “However, there are many unanswered questions about the science, safety and quality of products containing CBD.”
After citing questions about “cumulative exposure” (e.g. from using multiple CBD products on the same day) and the effects of CBD on special populations (e.g., children and the elderly), the statement cites recent research purporting to link CBD use to liver damage. The wording appears to raise caveats about making CBD products available on an over-the-counter basis.
According to the statement, during its review of the marketing application for Epidiolex, the FDA “identified certain safety risks, including the potential for liver injury. These are serious risks that can be managed when an FDA-approved CBD drug product is taken under medical supervision, but it is less clear how these risks might be managed when CBD is used far more widely, without medical supervision and not in accordance with FDA-approved labeling.”
How Worried Should We Be?
The study was published in the journal Molecules and examined at the effects of CBD on the livers of mice. The mice were given doses that aligned with the human equivalent of the maximum dose of CBD in Epidiolex, according to the report. The researchers found that CBD quickly had a detrimental effect. “CBD exhibited clear signs of hepatotoxicity,” the study authors wrote, raising “serious concerns about potential drug interactions, as well as the safety of CBD.”
Speaking with health and nutrition website Nutra, the study’s lead author, Igor Koturbash of the University of Arkansas at Little Rock, said: “I don’t want to say that CBD is bad and we should ban it. But in my opinion, there is clearly not enough research.”
Not Very, Says Project CBD
Project CBD, the California-based nonprofit dedicated to promoting and monitoring research into CBD, recently wrote up a scathing dismissal of the liver damage claims. It states that this “sensational claim was based on a dubious study.”
For starters, the Little Rock study made no actual testing of humans, which Project CBD calls “a hugely important distinction.” The critique also questions the claim that the mice were tested with doses proportional to those used by humans, asserting that “in the real world CBD consumers are not ingesting 0.25% of their body weight” — the maximal dose used in the study.
Project CBD also questions the wisdom of drawing conclusions about human consumption from “mega-dosing mice.” It states: “The maximum human dosage recommended for the CBD-isolate Epidiolex is 20 mg/kg, which is over 100x less than what the Little Rock researchers force-fed their experimental mice. They also tried smaller doses (ranging between 61.5 to 615 mg/kg) of CBD, which was given daily for 10 consecutive days.” Project CBD calls these dosages “ridiculous,” even when “allometric scaling” is factored in — that is, estimating an equivalent dose for a larger organism. (The formation “mg/kg” refers to milligrams of medication per kilograms of the body weight.)
The Project CBD critique also charges that the Little Rock study is full of “strange statements, problematic publishing and unreasonable experimental design.” For example, the researchers say that “75% of mice gavaged with 615 mg/kg developed a moribund condition,” but only six mice received that dose, and 75% of 6 is 4.5. That means that the Little Rock researchers were claiming that four-and-a-half mice died from CBD but one-and-half mice survived. Obviously, that’s impossible.
Then, there were double standards in the research, Project CBD continues: “The authors disparage the significance of positive medical findings about CBD (such as CBD’s anti-inflammatory and antioxidant properties) by citing only in vitro research. Yet a sentence later, they tout a score of harms allegedly attributable to CBD based on… in vitro and preclinical work.” In vitro refers to research carried out in a test-tube or petri dish rather than an actual organism.
“Only one of the citations is based on human research, and it did not show toxicity,” writes Project CBD. That 2017 human study, led by Saoirse O’Sullivan and published in the Journal of Clinical Investigation, actually showed a decrease in blood pressure after consuming CBD (600 mg or roughly 10 mg/kg). O’Sullivan and her colleagues at the University of Nottingham concluded that CBD may have “a role in the treatment of cardiovascular disorders.” Project CBD charges that the Arkansas team “misrepresents O’Sullivan’s work as proof that CBD is cardiotoxic.”
Project CBD concludes that the Little Rock study is “a hit piece against CBD, not legitimate scientific work.”
The critique notes that there have been efforts before to “search for a lethal dose of cannabinoids.” One early effort to kill an animal with a gigantic dose of THC was described in a 1972 paper by scientists at the Mason Research Institute in Worcester, Mass. “In their quest to prove the dangers of THC, they attempted to kill almost 400 rats, a couple dozen beagle dogs and some rhesus monkeys. The rat dosages ranged from 225-3600 mg/kg of orally administered THC, a higher amount than the CBD dosage used in the Little Rock experiment.”
The researchers were presumably disappointed when the monkeys failed to die — even when they were dosed with nearly 1% of their bodyweight. It turned out that rats could be killed by THC, but it took roughly 1,000 mg/kg. Extrapolating with allometric scaling, this translates to about 10 grams of pure THC for a human — far more than anyone would ever consume.
We welcome further examinations of the Little Rock study. But the most in-depth deconstruction offered so far is that by Project CBD. And its conclusions can be summed up in the pithy dictum of popular wisdom: Don’t believe the hype.