 Cannabis use has become more prevalent in recent years. With increasing legalization of cannabis, it is crucial for both medical and recreational users to be aware of the possible drug interactions that can occur with the plant. Just like any other drug, cannabis contains compounds, also known as cannabinoids, that are pharmacologically active. Most commonly known of these cannabinoids are Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Cannabinol (CBN). These cannabinoids are metabolized by specific enzymes in the body, but can also alter (e.g., increase or decrease) the activity of various enzymes in the body. Drug levels can be altered with concomitant use of cannabis, and conversely, cannabinoid levels can also be altered with concomitant use of conventional medications. For these reasons, it is important that cannabis users and clinicians understand how cannabis can interact with conventional drugs. As always, talk to your doctor or pharmacist if you have questions or concerns regarding cannabis-drug interactions. Which drugs warrant caution when using cannabis? Potential Increased Cannabinoid Effects with Concomitant CYP3A4 and CYP2C9 Inhibitors: CBD and THC are CYP3A4 substrates. Inhibition of CYP3A4 can lead to increased serum levels of CBD and THC. CYP3A4 inhibitors such as ketoconazole can increase serum concentrations of CBD and THC. Other CYP3A4 inhibitors include macrolide antibiotics, calcium channel blockers such as verapamil, benzodiazepines, PDE inhibitors such as sildenafil, and antiretrovirals. Animal studies have shown that CBD is also a CYP3A4 inhibitor, but this pharmacokinetic characteristic is still being evaluated in humans. Additionally, CBD and THC are both substrates of CYP2C9. CYP2C9 inhibitors such as fluoxetine can also increase serum concentrations of CBD and THC. There have been case reports of concomitant use of fluoxetine and cannabis resulting in mania. Other CYP2C9 inhibitors include amiodarone and cotrimoxazole.  Pharmacokinetic Effects of Cannabis on Other Drugs: Cannabis may alter serum warfarin concentration, resulting in very high INR levels and bleeding. Warfarin is metabolized by CYP2C9, so this is likely due to THC mediated CYP2C9 inhibition. CBD, the major non-psychoactive component in cannabis, is a CYP2C19 inhibitor. Drugs that are metabolized by CYP2C19 will therefore be affected when combined with CBD. Clobazam, an anti seizure medication, is one example. Clobazam is converted to its inactive metabolite by CYP2C19. Studies demonstrated that coadministration of CBD and clobazam caused an eight-fold increase in the active serum concentration of clobazam, and thus an increased risk of benzodiazepine toxicity. Another reported interaction exists with clopidogrel, an antiplatelet pro-drug. Clopidogrel is metabolized into its active form by CYP2C19. Inhibition of CYP2C19 by CBD can result in decreased serum concentrations of clopidogrel, and thus a decrease in drug efficacy. Effects of Smoking Cannabis: Smoking cannabis (as well as tobacco) induces CYP1A2 and can thus decrease serum concentrations of drugs metabolized by CYP1A2, such as theophylline, clozapine, and olanzapine. Additive Effects: Sympathomimetic agents, such as amphetamines and cocaine, when combined with cannabis may lead to additive adverse effects, such as tachycardia and hypertension. Similarly, central nervous system (CNS) depressants such as alcohol, opioids, and benzodiazepines, in combination with cannabis can result in increased drowsiness and impaired coordination. Are you aware of the possible interactions cannabis may have with your medication? To learn how cannabis may have interactions on medication you’re taking, book an appointment with our medical cannabis doctors through our virtual booking link or by giving us a call (617-500-3595). Dr. Caplan and his team at The CED Clinic in Chestnut Hill, MA are available to guide and support you! References:
Sara Gyulakian, CED Intern Sara Gyulakian is a pharmacy student at Massachusetts College of Pharmacy. She recently joined CED Clinic as a graduate research intern. Sara believes that alternative medicine, such as medical cannabis, has infinite potential to help patients across a variety of disease states. Utilizing her robust knowledge in clinical pharmacology and disease state management, as well as her experience in drug safety, she hopes to spread evidence based knowledge and awareness regarding medical cannabis. Sara has worked in both clinical and community based positions within Harvard Medical School teaching hospitals, as well as research and development in the pharmaceutical industry. As a Boston native, she enjoys going on runs by the Charles River, painting, and spending time with family and friends. Sara looks forward to working alongside Dr. Caplan in developing and sharing evidence based information regarding medical cannabis with the world. 
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