Cannabis Use May Result in Negative Drug Interactions

According to new research from Washington State University, using cannabis alongside other drugs may pose a significant risk of harmful drug-drug interactions. While more research is needed, the authors stated that one early takeaway from these studies is that cannabis should be used with caution when combined with other prescription drugs.

Cannabinoids, a class of substances found in the cannabis plant, and their major metabolites found in cannabis users’ blood were studied, and the researchers discovered that they interfere with two families of enzymes that help metabolize a wide range of drugs prescribed for a variety of conditions. As a result, either the drugs’ positive effects may diminish or their negative effects may increase due to excessive accumulation in the body, resulting in unintended side effects such as toxicity or accidental overdose.

“Physicians must be aware of the possibility of toxicity or a lack of response when patients use cannabinoids,” said Philip Lazarus, senior author on the papers and a Boeing distinguished professor of pharmaceutical sciences. “It’s one thing if you’re young and healthy and occasionally smoke cannabis, but for older people who use medications, taking CBD or medicinal marijuana may have a negative impact on their treatment.”

Cannabinoids only stay in your body for about 30 minutes before they are rapidly broken down. 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, so we thought we should focus on them as well.

Shamema Nasrin

The findings were published in the journal Drug Metabolism and Disposition in a pair of studies. One study looked at cytochrome P450s (CYPs), a family of enzymes, while the other looked at UDP-glucuronosyltransferases (UGTs), another enzyme family. These two enzyme families work together to metabolize and eliminate more than 70% of the most commonly used drugs from the body.

While previous research on potential drug interactions caused by cannabinoids has been limited, this new study provides the first comprehensive look at the interaction between three of the most abundant cannabinoids, tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), and their metabolites, as well as all of the major CYP enzymes. This is also the first study to look specifically for interactions between cannabinoids and UGT enzymes.

“Cannabinoids only stay in your body for about 30 minutes before they are rapidly broken down,” said Shamema Nasrin, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences and the study’s first author. “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, so we thought we should focus on them as well.”

Cannabis use could cause harmful drug interactions

The researchers used manipulated human kidney cells that allowed them to examine a single enzyme at a time, and they validated their findings in human liver and kidney specimens that contained many of these enzymes. They discovered that cannabinoids and the major THC metabolites inhibited several CYP enzymes strongly. One important finding was that one of the most abundant THC metabolites, THC-COO-Gluc, which had not previously been studied in this context, appears to play a significant role in inhibiting several key enzymes in the liver. When the researchers looked at the UGT enzyme family, they discovered that all three cannabinoids, but especially CBD, inhibited two of the primary UGT enzymes found in the liver. CBD was also discovered to block three enzymes that account for approximately 95 percent of kidney UGT metabolism, which aids in the removal of toxins and certain drugs from the body.

“If you have a kidney disease or are taking one or more drugs that are primarily metabolized through the kidney and you’re also smoking marijuana, you could be inhibiting normal kidney function, which could have long-term consequences for you,” Lazarus said.

According to Nasrin, these interactions between CBD and UGT enzymes may be inhibiting kidney function in patients with acute kidney disease or kidney cancer who are using CBD to treat pain or to try to reduce the side effects of anti-cancer drugs.

“Taking CBD or marijuana may relieve your pain, but it may make the other drug you’re taking more toxic, and that increase in toxicity may mean you can’t continue taking that drug,” Nasrin explained. “There could be serious consequences for anti-cancer drugs, and that’s just one of many drugs that could potentially be affected by the cannabinoid-enzyme interactions we’re seeing.”

Christy Watson, Yadira Perez-Paramo, Keti Bardhi, Gabriela Fort, and Gang Chen, all of whom are or were previously affiliated with the WSU College of Pharmacy and Pharmaceutical Sciences, collaborated with Nasrin and Lazarus on this study.