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Cannabinoid/Drug Interactions

Important information on Cannabinoid/drug interactions from “The Cannabis Scientist.” It’s the same reason some medicines have a “grapefruit warning” sticker on them. Would non-first-pass delivery systems (rectal and vaginal suppositories) avoid it? One reason edibles are so powerful is that the liver processes the THC into even-more stony metabolites.

When drugs collide

Widespread legalization has seen the use of medicinal cannabis increase exponentially and, with it, the risk of clinically significant drug-drug interactions (DDIs). DDIs can result in serious adverse events, specifically those affecting CYP-mediated drug metabolism. But what is the likelihood of clinically significant DDIs between cannabis-based therapies and conventional medications? Researchers used supersomes to screen the inhibitory potential of cannabinoids in vitro, evaluating twelve cannabinoids at the predominant drug-metabolizing isoforms: CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, and CYP2C19. The cannabinoids exhibited varied effects and potencies across the CYP isoforms. While most inhibited CYP2C19, CYP2D6, CYP3A4, and CYP2B6 were either not affected or only partially inhibited by the cannabinoids.

No CBD

We spoke to Lyndsey Anderson, Research Fellow at the Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Australia, to find out more.

What exactly is a supersome and why did you choose it as a model?

“Supersomes are microsomal vesicles that contain a single CYP450 enzyme isoform. Human liver microsomes are rich in CYP450 enzymes and can also be used in drug metabolism and drug interaction studies. However, human liver microsomes contain a mix of drug metabolizing enzymes that can have broad genetic variability. We used Supersomes so that we could investigate the effects of the cannabinoids on drug metabolism by each CYP450 enzyme individually.”

How common are negative interactions between cannabinoids and approved drugs?

“The most well-known drug interaction between cannabinoids and approved medications is the interaction between cannabidiol (CBD) and clobazam – a first line treatment for the severe childhood epilepsy Dravet Syndrome. Significant drug-drug interactions have been reported between either CBD or cannabis and anticonvulsants, anticoagulants, anti-platelet medications, antipsychotics, and immunosuppressants. These interactions have been attributed to interactions at CYP450 enzymes and are associated with an increased incidence of adverse events.”

What problems does it cause for patients and in what indications are they most prevalent?

“Drug-drug interactions at CYP450 enzymes can have significant implications for patients, especially in those treated with drugs that have a narrow therapeutic window. In our study, we found that most of the cannabinoids inhibit CYP2C9 and CYP2C19, which together metabolize nearly 25 percent of approved drugs. Noteworthy drugs metabolized by these isoforms with narrow therapeutic windows include warfarin, clopidogrel, phenytoin, amitriptyline, and sulfonylureas. Drug-drug interactions that alter the metabolism of these drugs can result in plasma concentrations outside the normal therapeutic range and lead to serious adverse events. Therapeutic drug monitoring and subsequent dose alterations may be warranted for CYP2C9 and CYP2C19 substrates.””

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