As cannabis use becomes more widely accepted and gains international legalization, concerns surrounding interactions with common medications (contraindications) have surfaced. In previous studies, cannabis derivatives have been shown to inhibit P450 enzymes (a necessary enzyme for detoxification), but the extent of this interference has been unstudied. Researchers at Washington State University are the first to demonstrate cannabis has the potential to significantly interfere with prescription drugs.1
Cannabis metabolites affect the body differently
The study, published in Drug Metabolism and Disposition, analyzed the interactions between cannabinoid metabolites and hepatic (liver) P450 enzymes. These enzymes play a key role in metabolizing drugs and other chemicals in the body to avoid toxic build-up.
Cannabinoids found in cannabis mainly include (-)-trans-∆9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD). When consumed, these cannabinoids are converted into metabolites during the breakdown process.
Compared to other cannabinoids, THC metabolites remain in the blood at higher concentrations and significantly longer.1 Thus, they have a greater potential to interfere with other drugs taken even days after consuming cannabis.
Cannabinoids inhibit P450 enzymes
The researchers used enzyme kinetic methods to analyze the effect of metabolites on P450 enzyme activity, how the body affects the drug (pharmacokinetics), and how the drug affects the body (pharmacodynamics). THC, CBN, and CBD all showed competitive inhibition patterns on select P450 enzymes.
Competitive inhibition involves blockage of the active site in enzymes, directly preventing them from attaching to other drugs to break them down. Competitive inhibition of P450 enzymes can lead to a build-up of drugs to a toxic level, especially anti-cancer drugs that are metabolized by P450 enzymes. This competitive inhibition may even lead to an unintentional overdose of prescription drugs or a decrease in the positive effects of drugs if they’re not metabolized efficiently.
THC was found to competitively inhibit the enzymes CYP1A2, CYP2B6, CYP2C9, and CYP2D6, reducing their activity by approximately 50% when 10 micromolar of THC was added. CBN competitively inhibited CYP2B6, CYP2C9, and CYP2E1. The activity of each enzyme was reduced to 75%, 55%, and 80%, respectively, when 10 micromolar CBN was added. Competitive inhibition was found with a decrease of enzyme activity of CYP3A4, CYP2B6, CYP2C9, CYP2D6, and CYP2E1 by more than 50% with 10 micromolar of CBD.1
Greater risks with kidney disease
CBD was found to block three enzymes that perform 95% of kidney UGT metabolism.1 According to Philip Lazarus, senior author of the study, “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.”2
“Physicians need to be aware of the possibility of toxicity or lack of response when patients are using cannabinoids,” commented Philip Lazarus. “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.”2
Beware of cannabis drug-drug interactions
More research needs to be completed to analyze the full mechanism of drug-drug interactions of cannabis on other agents in the body.
References
- Nasrin, S. et al. Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions. Drug Metabolism and Disposition; 49(12): 1070-1080. Doi: 10.1124/dmd.121.000442.
- Van Dongen, J. (2021). Cannabis use could cause harmful drug interactions. EurekAlert! Accessed 16 Dec. 2021. Retrieved from https://www.eurekalert.org/news-releases/937642.
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