While marijuana legalization and consumption have skyrocketed, scientific research about cannabis is running far behind. Many consumers extol the physical and mental benefits of marijuana’s cannabinoid compounds—such as tetrahydrocannabinol (THC) and cannabidiol (CBD)—but how these compounds affect the body and mind are still being researched.
Although generally considered not harmful, cannabis is a drug. And like prescription medicines, it can cause drug-drug interactions, some of which can be harmful. Here, we look at some of these interactions.
How drugs interact
Drugs are metabolized and eliminated by enzymes in the liver—specifically, the cytochrome P450 (CYP) family of enzymes. Of these, CYP3A4 is the most prevalent CYP enzyme in the liver, and is the one responsible for metabolizing an estimated 50% of prescription medications used in clinical practice.
But, the CYP enzymes are also known to cause many clinically relevant drug-drug interactions. Some drugs induce the enzymes’ metabolic activity while others inhibit drug metabolism, which changes the concentrations of drugs present in the body as well as their pharmacokinetic profiles. For example, a drug that inhibits CYP3A4 will slow the metabolic process, resulting in an accumulation of drug concentrations and leading to an increased risk for side effects and possible drug toxicity.
Both THC and CBD are metabolized by CYP3A4. THC is also metabolized by CYP2C9, and CBD by CYP2C19. When cannabis or CBD is taken along with certain prescription drugs, THC and CBD can inhibit or induce the metabolic process. For example, CBD is a potent inhibitor of CYP3A4 and CYP2D6 enzymes, while THC is an inducer of CYP1A2.
Here’s a breakdown of medications known to have drug-drug interactions with THC and/or CBD.
Use of cannabinoids increases the risk of bleeding in patients taking warfarin.
Warfarin has a narrow therapeutic window, so even minor changes to the anticoagulant’s effect can increase the risk of bleeding and thrombosis. Because THC and CBD can inhibit the metabolic activity of the CYP2C9 enzyme, they can increase warfarin levels and thereby increase the risk of bleeding.
In one case report, a man on warfarin presented twice with international normalized ratio (INR) values above 10, as well as bleeding. (An expected INR value for a patient on warfarin is 2 or 3, and an INR value over 4.5 raises the risk of major bleeding.) On both occasions, he had increased his marijuana use beforehand.
Theophylline is a bronchodilator used for treating symptoms of asthma, bronchitis, emphysema, and other lung diseases. Marijuana smoking (but not other types of marijuana use) may hasten the metabolic clearance of theophylline, potentially lowering the drug’s effect.
But it’s not clear whether this interaction comes from the cannabis or is due to the act of smoking, since tobacco smoking produces a similar effect. Another reason to question this connection is that no other form of cannabinoid induces the clearance of theophylline.
CBD increases the effects and the side effects of clobazam, a benzodiazepine indicated for treating seizures associated with Lennox-Gastaut syndrome in children and adults. Instead of being contraindicated, CBD was also FDA-approved for treating seizures associated with Lennox-Gastaut syndrome, as well as Dravet syndrome. Marketed as Epidolex, this prescription CBD was the first-ever marijuana-derived drug approved by the FDA.
However, CBD is a potent CYP2C19 inhibitor. So, when these two drugs are used together, the CBD interaction contributes to clobazam’s efficacy, resulting in a three-fold increase in the plasma concentration of clobazam’s active metabolite. The downside is that this interaction also increases clobazam’s side effect of sedation. As a result, clinicians are advised to lower the dose of clobazam when used in conjunction with CBD.
Valproate is another drug prescribed to treat epileptic seizures, and it’s also indicated for treating manic episodes of bipolar disorder and for preventing migraine headaches.
Taking CBD with valproate can raise liver enzyme levels and may cause liver injury. In clinical trials, 21% of patients with epilepsy taking both valproate and prescription CBD (Epidolex) had elevated transaminase levels that were more than three times the upper limit of normal. (The incidence rate was 30% in patients with epilepsy taking concomitant CBD, valproate, and clobazam.)
The prescribing information for Epidolex recommends discontinuing or adjusting the dose of Epidolex and/or valproate if liver enzyme elevations occur.
Although not a prescription drug, alcohol is still a drug. As such, researchers have found that alcohol may increase THC levels immediately after smoking, although the effect appears to diminish soon afterward.
More research is needed to further understand the interactions of cannabis with these drugs, as well as to discover its as-yet-unknown drug-drug interactions.