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Toxicology Rounds

Toxicology Rounds

Should EPs Worry about CBD Toxicity?

Gussow, Leon MD

doi: 10.1097/01.EEM.0000657672.65371.f2
    CBD, toxicity, cannabidiol. The tweet from Carl's Jr. announcing its burger with CBD-infused sauce.
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    All of a sudden last year, cannabidiol seemed to be everywhere. Stores in my neighborhood selling CBD-infused oils, syrups, and gummies started popping up more frequently than new Starbucks. Restaurants, cafés, and retailers across the country began adding CBD to foods such as lattes, cereal, cupcakes, and pizza. Last April 20, a date considered to be National Weed Day, a Carl's Jr. in Denver even featured a Rocky Mountain High burger made with CBD-infused sauce. (USA Today. Aug. 16, 2019; http://bit.ly/38aXpe9.)

    What this means for emergency physicians is that a significant proportion of the patients we see are probably taking CBD in some form. But is CBD safe? The U.S. Food and Drug Administration issued a consumer update in November warning that “CBD has the potential to harm you, and harm can happen even before you become aware of it.” The FDA argued that CBD can cause liver injury and serious drug-drug interactions, among other effects. (FDA. Nov. 25, 2019; http://bit.ly/30nNCyF.) Because the CBD boom shows no signs of slowing, let's review what we know about the drug's pharmacology and toxicology.

    What is CBD? Cannabidiol is a chemical found in Cannabis plants. It is a cannabinoid, but CBD is not psychoactive and will not produce a euphoric high. CBD appears to have some sedative effects at high doses.

    Is CBD legal? CBD is commonly derived from hemp, which is a type of Cannabis plant containing not more that 0.3 percent tetrahydrocannabinol (THC) by dry weight. The federal government did not differentiate hemp from marijuana until recently; both were considered Schedule I controlled substances. This changed when the 2018 U.S. farm bill exempted CBD derived from hemp from regulation under the Controlled Substances Act. The FDA still considers it illegal, however, to add CBD to food or drink, to market it as a dietary supplement, or to make specific health claims about it. Regulation on the local level varies by state. The FDA also approved CBD in 2018 as the proprietary drug Epidiolex for treating two rare forms of childhood epilepsy.

    How is CBD metabolized? CBD is primarily metabolized by hepatic P450 enzymes, most significantly CYP3A4 and CYP2C19. In vitro studies have shown that CBD also inhibits these enzymes, especially at higher doses.

    Can CBD-induced P450 enzyme inhibition produce clinically significant drug-drug interactions? Possibly. A recent report from the University of Cincinnati described an apparent drug-drug interaction between CBD and tacrolimus, an immunosuppressive agent used to prevent rejection of solid-organ transplants. (Am J Transplant. 2019;19[10]:2944; http://bit.ly/36XnbCu.) A 32-year-old woman with refractory epilepsy being treated with tacrolimus for interstitial nephritis had been stable for more than a year, with consistently therapeutic drug levels and normal serum creatinine. After entering an open-label clinical trial of CBD at a dose of 1000 mg bid (20 mg/kg/day), her seizure activity decreased but her tacrolimus level nearly tripled. This pattern suggests that CBD-induced P450 enzyme suppression was causative; tacrolimus is metabolized by CYP3A4. The authors said they were not able to identify another probable cause.

    To be sure, this case report has problems. The authors did not specify the nature of the patient's interstitial nephritis or why it was being treated with tacrolimus. This is puzzling because tacrolimus can cause interstitial nephritis and renal insufficiency. Unfortunately, not enough clinical information is in the paper to resolve these issues.

    A similar drug-drug interaction was reported between CBD and the antiepileptic agent clobazam, which is metabolized by CYP3A4 and CYP2C19. (Epilepsia. 2015;56[8]:1246; http://bit.ly/3733460.) The CBD doses used in treating seizures are huge compared with the doses listed on over-the-counter products. The patient in the tacrolimus case report received up to 2900 mg/day. Compare that with the amount of CBD contained in a bag of Buddha CBD chamomile tea, a whopping 5 mg. That is surely a homeopathic dose, not even enough to reduce seizure activity in a gnat.

    Does CBD cause hepatotoxicity? Yes, at least if you're a mouse and have been force-fed massive amounts of the drug. An animal study gained considerable attention when University of Arkansas scientists gavaged mice with high doses of CBD, up to 2460 mg/kg as a single acute dose or 615 mg/kg/day for 10 days in a subacute study. Most animals showed chemical or clinical manifestations of hepatotoxicity at the higher doses. (Molecules. 2019;24[9]:1694; http://bit.ly/2Nw8RZT.)

    But this was in mice, and the CBD doses used were truly enormous. Any attempt to apply the results to humans taking much lower doses would be ridiculous. Nevertheless, Forbes claimed that the study proved that people who “use CBD are at an elevated risk for liver toxicity.” (July 11, 2019; http://bit.ly/2svVoKq.) Obviously, the reporter was not familiar with Paracelsus or the concept that the dose makes the poison. I was not able to find any reports in the medical literature of CBD causing hepatotoxicity, but the package insert for Epidiolex states that the drug was associated with reversible transaminase elevations in some patients during premarketing controlled studies.

    Should EPs worry about adverse effects and drug-drug interactions in a patient taking a CBD gummy bear every day? My take is that “worry” is too strong a word. Clinicians should certainly be aware of the potential adverse effects of taking high doses of CBD, but also that a patient is likely ingesting nowhere near a concerning dose unless he is taking Epidiolex.

    The bottom line: All EPs will continue to see increasing numbers of patients taking CBD in some form, but my guess is that such use will virtually never cause clinically significant toxicity except for patients taking Epidiolex.

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    Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog atwww.thepoisonreview.com, follow him on Twitter @poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.

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