CBD flies off shelves, fosters uncertainty in tox lab

Knowledge of the metabolites that indicate CBD use has only recently been developed, Janis says. “How these metabolites would behave in many testing paradigms was kind of unknown. It raises concerns. One group did an in vitro test, in which they put CBD in artificial gastric fluid and reported it was converted into THC. THC and CBD are so closely related that it is feasible that would happen. But other evidence and the FDA don’t consider CBD a pro-drug converting into THC.”

Dr. Huestis rejects the idea that THC can be formed from CBD; in vivo studies have not demonstrated this effect. “In studies where we gave up to 800 mg of CBD orally to someone, there was no THC present at all,” she reports.

The challenge, Janis says, is the trace amounts of THC that are in CBD products. “It actually depends on how long you’ve been using a product and in what form you take it. If you use a CBD cream and put it on your skin, there’s very little chance that those levels would ever reach a point where a THC test would show positive. If you smoke or orally take large doses for a very long period, then it becomes a hard question to answer. THC metabolites stick around in the body for a very long time. CBD metabolites would be expected to stick around for not as long. It is an unknown. We don’t know for sure.”

Since unregulated CBD products contain a small percentage of THC, it’s unclear what exposures people are getting, he adds. “Typically people will buy CBD in the form of 10-mg gummies, but they may be taking lots of them to self-medicate for whatever reason they deem it benefits them.” In Washington state, where marijuana for recreational use was legalized in 2012, a single THC dose is 10 mg, he notes. “It would take a lot of CBD to get to that intoxicating level of THC from contamination—maybe a whole bottle of gummies at one time. But the current tests for THC are designed to pick up trace levels of THC metabolites, which could be reached without intoxication, so that’s where we have to be careful.”

With CBD oils the most common of the CBD products sold, and 74 percent of oils not containing what is on the label, the CBD oils could contain THC that could produce positive tests, Dr. Huestis says.

“We don’t have the studies in CBD that we do in THC. I did a study of cannabis users who were dependent and trying to quit use in treatment. They were getting a lot of CBD to see if it would help them not crave THC. When they relapsed and smoked, I could see a difference in the THC-to-CBD ratios. When they smoked cannabis, their THC concentration went way up—but only for an hour. So there was no way you could tell if they were only using CBD or occasionally THC.”

Other studies she has helped conduct have shown that heavy users of marijuana can show a significant buildup of THC in the body. “We published our work on how chronic frequent users build up a large body burden of THC,” Dr. Huestis says. “I sent two of these users home after 30 days residence on a closed unit, where they had no access to any drugs. And they still had low but measurable THC.” It makes sense that the same buildup would occur for CBD, she adds, but as yet there are no data to show that.

Labs will need many more studies of THC and CBD levels, she says. “I think labs should consider that in the future, not today, there will be many reasons to monitor CBD and THC as part of therapeutic drug monitoring when patients are on medications. Right now we don’t know what those levels are. There are no studies yet documenting that different cannabinoid drugs are efficacious. For therapeutic drug monitoring, you would monitor the parent drug and its metabolites. We don’t have a commercial source for the 7-hydroxy or carboxy CBD metabolites. And what will make the big difference is if the 7-hydroxy is found to be active. Then we need to be measuring it.”

The Lambert Center at Thomas Jefferson University is now doing a lot of work with physicians interested in testing the efficacy of THC or CBD. “I’m trying to help them design the studies appropriately so in the end you could have data to take to the FDA for drug approval.” The pharmaceutical companies are also developing CBD metabolite tests. “A number of them have produced synthetic CBD, and if they can synthesize that, they should be able to synthesize metabolites. I know they have the 7-hydroxy and carboxy to use as standards or controls,” Dr. Huestis says.

Typically, mass spectrometry to test urine for THC metabolites is available in laboratories, but CBD is not run in many places. More labs are starting to perform their own laboratory-developed tests commercially. “But the lab, of course, has to have a schedule I license because both THC and CBD are schedule I compounds,” she notes.

The FDA’s decision, when approving Epidiolex, to move it from a schedule I to schedule V drug was surprising, Dr. Huestis says, because the agency did not take CBD itself out of schedule I. “So they are waiting to see if there are more compounds, either cannabis extracts or synthetic drugs, that have proven medical indications, and then they will move the drugs to a different schedule.”

Some hoped-for indications have not been borne out in trials. GW Pharmaceuticals, the manufacturer of Epidiolex, also made Sativex, a cannabis plant extract that is 50 percent THC and 50 percent CBD, for example. “It was tested in the U.S. for chronic pain associated with cancer as an adjunct to opioids and it failed,” Dr. Huestis says. “It was not efficacious at reducing the pain of cancer in an adjunctive situation. But it is a plant extract, and many people believe those natural compounds are essential—that they contribute to the efficacy.”

That may have been true of Epidiolex, but plant extracts also have a significant downside, Dr. Huestis says. “It’s really difficult to control the percentages of not only CBDs and THCs but many other components like flavonoids and terpenes when you are growing plants. So being able to produce something reproducible time after time to get an application through the FDA is probably going to be difficult to achieve.”

The general public seems to believe there are no dangers from ingesting large quantities of CBD, Dr. Huestis says. But that notion is incorrect. In an article she wrote about CBD’s adverse effects, she notes that in children with intractable epilepsy, high doses were necessary to reduce seizures. The dosage of Epidiolex recommended by the FDA for these pediatric patients is a very specific regimen, she says. “You start at 2.5 mg per kilogram of body weight, then after two days you go to 5, then to 10. Twenty mg/kg is the recommended dosage by the FDA. Some may need higher doses to control seizures.” For this use, “CBD is effective and it’s a totally new mechanism of action. However, 20 mg/kg is a lot.”

Some children receiving high doses of CBD in Epidiolex can experience serious effects on the liver, causing inhibition of some enzymes and induction of other enzymes. “If you are taking any other medication,” she says, “it could affect the amount of drug available.” A number of pediatric patients have had serious elevations in their transaminases “and had to be withdrawn from the drug in order to get the liver to return to normal.”

“So CBD is not a benign drug. People’s liver function needs to be carefully monitored,” Dr. Huestis warns. Another effect is somnolence, sedation, or lethargy, which has been noted in controlled trials with Epidiolex. This makes it especially hazardous, she says, to have CBD sold without controls.

These potential risks plus the surge in cannabis legalization, the patchwork of laws governing CBD’s legal status, the lack of product regulation, changing DEA and FDA classifications, still-evolving drug test cutoffs, and the shortage of research on efficacy are showing that laboratories have many CBD issues yet to confront as the “home remedy du jour,” as Janis puts it, shoots to stardom in the wellness products market. 

Anne Paxton is a writer and attorney in Seattle.