Studies Suggest Cannabinoid Metabolites Result in Harmful Drug Interactions

Major metabolites for cannabinoids may interfere with two families of enzymes that help metabolize a wide range of drugs prescribed for a variety of conditions.

The use of cannabis could result in a significant risk of harmful drug-drug interactions, according to a pair of studies published in Drug Metabolism and Disposition. The investigators found that major metabolites for cannabinoids interfere with 2 families of enzymes that help metabolize a wide range of drugs prescribed for a variety of conditions.

This could result in a decrease of the drugs’ positive effects or an increase of their negative effects, as well as potential adverse events, including toxicity or overdose, according to the study.

“Physicians need to be aware of the possibility of toxicity or lack of response when patients are using cannabinoids,” said Philip Lazarus, PhD, Boeing distinguished professor of pharmaceutical sciences at Washington State University (WSU) Spokane, in a press release. “It's one thing if you're young and healthy and smoke cannabis once in a while, but for older people who are using medications, taking CBD or medicinal marijuana may negatively impact their treatment.”

The studies examined 2 enzyme families: cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs). These 2 enzyme families help metabolize and eliminate more than 70% of the most commonly used drugs from the body. The investigators examined how the 3 most abundant cannabinoids—tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN)—and their metabolites interact with all major CYP and UGT enzymes.

"Cannabinoids stay in your body only for about 30 minutes before they are rapidly broken down," said Shamema Nasrin, graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences, in the release. "The metabolites that result from that process stay in your body for much longer—up to 14 days—and at higher concentrations than cannabinoids and have been overlooked in previous studies, which is why we thought we should focus on those as well."

To conduct the study, the investigators used manipulated human kidney cells that allowed them to look at a single enzyme at a time and then validated their results in human liver and kidney specimens. According to the study data, cannabinoids and the major THC metabolites strongly inhibited several CYP enzymes, with one of the most abundant THC metabolites, called THC-COO-Gluc, appearing to play a major role in inhibiting several key enzymes in the liver.

Examining the effect on the UGT enzyme family, the researchers found that all 3 cannabinoids—but especially CBD—inhibited 2 of the primary UGT enzymes present in the liver. CBD was also found to block 3 enzymes that account for approximately 95% of kidney UGT metabolism.

"If you have a kidney disease or you are taking one or more drugs that are metabolized primarily through the kidney and you're also smoking marijuana, you could be inhibiting normal kidney function, and it may have long-term effects for you," Lazarus said in the release.

The investigators said that although more research is required, the early takeaway from these studies should be that caution is required when using cannabis with other prescription drugs.

REFERENCE

Cannabis use could cause harmful drug interactions [news release]. Science Daily; December 13, 2021. Accessed December 14, 2021. https://www.sciencedaily.com/releases/2021/12/211213095020.htm