SPOKANE — Cannabis use appears to have an effect on how certain prescription drugs metabolize in the body — perhaps negatively — leading to toxicity or accidental overdose, local research indicates.
Washington State University researchers looked at cannabinoids — tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) — along with the cannabinoids' major metabolites in users' blood and found that they interfered with two families of enzymes in the body that help metabolize a wide range of prescribed medications.
The findings indicate that using cannabis alongside other drugs is a concern for people who regularly take prescriptions, while a majority of healthy people are likely fine, said Dr. Philip Lazarus, a WSU Spokane senior author.
"What we showed is that the major cannabinoids like CBD or THC, as well as their metabolites in the blood of people smoking or consuming it, they inhibit the major enzymes in our body which metabolize everything we eat, drink and absorb — they're metabolized and then excreted in urine or feces," said Lazarus, a Boeing distinguished professor of pharmaceutical sciences.
"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."
While more research is needed, the authors said an early takeaway is to be cautious using cannabis with other drugs. They think either the prescription drugs' positive effects might decrease, or their negative effects might increase, such as building up in the body to become toxic.
Both pharmacists and physicians would need to be aware of the possible impacts if patients are simultaneously taking prescriptions and using cannabinoids, Lazarus added. He equated it to how pharmacists now caution people on statins for high blood pressure to avoid drinking grapefruit juice because compounds in the juice can inhibit the major enzyme that metabolizes the statin.
The WSU findings were in a pair of studies published in the journal Drug Metabolism and Disposition. One study focused on a family of enzymes called cytochrome P450s (CYPs), while the other looked at UDP-glucuronosyltransferases (UGTs). Together, the two enzyme families help metabolize and eliminate more than 70% of the most commonly used drugs from the body.
The researchers used manipulated human kidney cells that allowed them to look at a single enzyme at a time and to validate their results in human liver and kidney specimens in which many of these enzymes were present. They found that cannabinoids and the major THC metabolites strongly inhibited several CYP enzymes.
Next, the group plans to apply the research to people who use CBD products and participate in a study.
"Cannabinoids stay in your body only for about 30 minutes before they are rapidly broken down," first author Shamema Nasrin said in a news release. Nasrin is a graduate student in Pharmacy and Pharmaceutical Sciences. "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."
One of the most abundant THC metabolites, THC-COO-Gluc, appears to play a major role in inhibiting several key enzymes in the liver. The researchers found that all three cannabinoids, but especially CBD, inhibited two of the primary UGT enzymes present in the liver. CBD also was found to block three enzymes that account for about 95% of kidney UGT metabolism, which helps clear toxins and certain drugs from the body.
"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.
Nasrin said the interactions between CBD and UGT enzymes could be inhibiting kidney function in patients with acute kidney disease or kidney cancer who may be using CBD to ease pain or reduce drug side effects.
In the lab with people who use CBD products, another example of what could be studied is how acetaminophen might be affected, Lazarus said.
"If they consume some CBD a half hour beforehand, does the acetaminophen get metabolized at a different rate than if you didn't take CBD?" he said.
"You can take blood samples over time and see the levels of the metabolites of acetaminophen. You can do that with anything that you think might be interfered by cannabinoids, so you have to know the metabolism pathways for any drug you're thinking of, and you have to look at whether or not that drug is metabolized by the same enzyme that the cannabinoids are interfering with.
"It's not going to interfere with everything, but we think it might be interfering with those drugs that are metabolized by the same pathways cannabinoids are blocking."
Also, acetaminophen taken frequently and long-term can affect kidneys negatively, "so if you're not excreting it well because you're also taking marijuana, you might be hurting your kidneys at a much faster rate," he said.
"It might actually improve your pain relief, but it'll cause more toxicity. Similarly, we're thinking with opioids, like hydrocodone that you take after surgery, if you're also taking CBD, it might be interfering with the metabolism of hydrocodone. It could be toxic, and it might lead to overdosing ... depending on how well or how poorly you're excreting because you're taking cannabinoids."
The researchers' work in the lab indicated a solid parallel for common usages of cannabis, he said.
"The concentrations that we see happening in the lab are approximately the same as the concentrations that a typical marijuana cigarette would basically cause in a person, so they're at the concentration where we think something might be going on.
"Maybe in a normal course of things, it doesn't interfere with your everyday processes that much, even though your enzymes might be inhibited for a little while. But if you're taking another drug at the same time, it might interfere with the metabolism of that drug and cause problems."
Others who worked with Nasrin and Lazarus on this research include Christy Watson, Yadira Perez-Paramo, Keti Bardhi, Gabriela Fort and Gang Chen, all of whom are, or previously were, at the same WSU college.