Although generally considered not harmful, CBD is still a drug, and just like prescription medicines, it may cause drug-drug interactions. Some of these interactions can be harmful based on how drugs interact in the human body. Drugs are metabolized and eliminated by enzymes in the liver called the cytochrome P450 (CYP) family of enzymes. CYP3A4 is the most prevalent CYP enzyme found in the liver and is responsible for metabolizing approximately 50% of prescription medications that are used in clinical practice.
Nevertheless, the CYP enzymes are also known to cause numerous clinically relevant drug-drug interactions. Some of these drugs induce the enzymes’ metabolic activity, whereas others inhibit drug metabolism. This changes the concentrations of drugs existing in the body as well as their pharmacokinetic profiles. Case in point, a drug that inhibits CYP3A4 slows the metabolic process, which results in a buildup of drug concentrations and leads to an increased risk of side effects and possible drug toxicity. CBD and THC are both metabolized by CYP3A4, yet THC is also metabolized by CYP2C9, and CBD is also metabolized by CYP2C19. When cannabis is taken with certain prescription drugs, it can prevent or induce the metabolic process.
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Research shows medications known to have drug-drug interactions with CBD:
It is a bronchodilator used to treat symptoms of bronchitis, asthma, emphysema, and other lung diseases. Marijuana smoking (no other types of marijuana use) may speed the metabolic clearance of theophylline, which potentially lowers the drug’s effect. However, it is still unclear whether this interaction comes from the cannabis or from the act of smoking because smoking tobacco produces a similar effect. Also, no other form of cannabinoid induces the clearance of theophylline, which raises questions about this connection.
Warfarin does not have a wide therapeutic window, and the use of cannabinoids increases the risk of bleeding in patients taking warfarin. Hence, even minor changes to the anticoagulant’s effect could increase the risk of thrombosis and bleeding. Since THC and CBD can impede the metabolic activity of the CYP2C9 enzyme, they can thereby increase warfarin levels and increase the risk of bleeding. In a number of case reports, those on warfarin presented with international normalized ratio (INR) values above 10, as well as bleeding, where the expected INR value for a patient on warfarin is 2 or 3. In such cases, there was an increased marijuana use beforehand.
Clobazam is a benzodiazepine indicated for treating seizures related to Lennox-Gastaut syndrome in both children and adults. CBD increases the effects and side effects of clobazam. CBD was approved by the FDA- for treating seizures associated with Lennox-Gastaut syndrome and Dravet syndrome instead of being contraindicated. This prescription CBD was marketed as Epidolex and was the first-ever marijuana-derived drug to be approved by the FDA.
However, CBD is a strong CYP2C19 inhibitor. So, when these two drugs are used together, the CBD interaction adds to clobazam’s efficacy. This results in a three-fold increase in the plasma concentration of clobazam’s active metabolite. This interaction also increases clobazam’s side effect of sedation, and as a result, it is advised to lower the dose of clobazam with CBD.
Another drug prescribed to treat epileptic seizures is valproate, which is also indicated for treating manic episodes of bipolar disorder as well as for preventing migraine headaches. Taking CBD with valproate can raise liver enzyme levels and may lead to liver injury. In clinical trials, 21% of patients with epilepsy taking both valproate and prescription CBD (Epidolex) had elevated transaminase levels, which were more than three times the higher limit of normal. It is recommended to discontinue or adjust the dose of Epidolex and/or valproate if liver enzyme elevations occur.
Although it is not a prescription drug, it is still a drug. Therefore, researchers have found that alcohol may increase THC levels immediately after smoking. That being said, the effects do appear to diminish soon afterward.
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