Cannabidiol (CBD) and RX Drug Interactions

June 19, 2018

 

Cannabidiol (CBD) can be helpful for a wide range of ailments, offering many benefits, including anti-anxiety, anti-psychotic, anti-nausea, anti-inflammatory, sedation (dose-dependent), and general endocannabinoid support. Studies have shown CBD to be non-toxic. It does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans.

 

Like anything else that helps us, there are factors that need to be considered for safe and effective use. One big consideration is the effect CBD may have on more than 60% of prescription (Rx) medications.  Most Rx medications are broken down by cytochrome CYP450 enzymes (CYP), produced mainly in the liver. This enzymatic system is responsible for the metabolization of many medications. Without this class of enzymes, medications would build up in the body, sometimes to toxic levels. Some common Rx medications affected by these enzymes include antidepressants, anti-seizure drugs, blood thinners (such as warfarin), statins,and hormones. Some of these drugs are of particular concern because they have a narrow therapeutic window, with toxicity at high blood levels.

 

CBD is a strong inhibitor of cytochrome P450, specifically CYP3A enzymes (especially CYP3A4, CYP2C19, and CYP3A5), at least in the short term, according to studies. Cannabis is biphasic and some studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short term but can induce enzyme activity after repeated administration. How CBD affects these enzymes is very important to those patients taking Rx medications, such as those listed above. If CBD induces enzyme activity, then Rx medications are broken down and excreted too quickly, making them less effective. If CBD inhibits enzyme activity then the opposite happens; the drug accumulates in the blood leading, in some cases, to toxicity. This effect is so important medications have been withdrawn from the market due to their strong P450 enzyme inhibitor effect. In 1998, the calcium channel blocker mibefradil (Posicor) was withdrawn from the U.S. market because it was a potent enzyme inhibitor that resulted in toxic levels of other cardiovascular drugs. Substances that cause an inhibition of these enzymes can have adverse outcomes, such as the case when combining a P450 enzyme inhibitor with an anti-depressant which can result in a potentially life-threatening condition known as serotonin syndrome. Buspirone, a common anti-depressant, metabolized by CYP enzymes has been shown to cause serotonin syndrome, a potentially fatal condition, when taken along with a known CYP enzyme inhibitor.

 

Can CBD be safely administered while taking Rx medications at the same time? It appears so. A study was done at the Massachusetts General Hospital, Boston, Massachusetts on 13 children, ages 4-19 with a type of refractory epilepsy to see the effects of CBD on their anti-seizure drug blood levels. The anti-seizure medication used in the study was clobazam. CBD dosing was started at 5 mg/kg body weight and titrated to 20mg/kg of body weight. The study found that CBD does inhibit the enzyme that breaks down the anti-seizure drug, which caused high blood levels of this medication. They also found when taking CBD, while decreasing the anti-seizure dosing, that drug levels came back down to normal, while decreasing seizure activity. The authors of the study found that the concurrent use of CBD and clobazam is safe (under the supervision of a doctor, of course!). 

 

There are variations among people in how they metabolize medications, depending upon the efficiency of their CYP enzyme system, with some people better able to metabolize medications via the CYP system than others. The effect CBD has on one person may be different from the effect it has on the next. Caffeine is metabolized by P450 enzymes. This may account for the variation in how individuals tolerate caffeine, with some clearing it more quickly than others. There are ways to increase CYP activity. For example, there are some herbs, such as St John’s wort, that will induce the action of these enzymes.  It has also been demonstrated that vegetables, particularly cruciferous ones (e.g., cabbage, brussel sprouts and cauliflower), induce CYP enzymes; namely CYP1A1 and CYP1A2.

 

Caution is advised in the elderly population as enzyme activity can be decreased in this population, resulting in higher than normal drug levels. This population requires extra careful monitoring by their doctor if Rx medications and CBD are used together. At what dose does CBD modulate these enzymes? At this point there is no agreement on the cut-off dose below which CBD does not interact with other drugs. A 2013 report on a clinical trial using GW Pharmaceutical’s Sativex, a whole plant CBD-rich sublingual spray, found no interactions with CYP enzymes when approximately 40mg of CBD was administered. A subsequent clinical trial, however, found that 25mg of orally administered CBD significantly blocked the metabolism of an anti-epileptic drug. 25 mg is considered a low dose as many drug trials using CBD are hundreds or thousands of milligrams. If the customer is not taking any Rx medication and using CBD for recreational purposes in doses less than 25 mg, it is probably safe to do so, otherwise, it's recommended that customers seek advice from their medical team before consuming CBD.

 

In conclusion, CBD-Rx drug interactions are dependent on a variety of factors, such as characteristics of co-administered drugs, the involved CYP enzymes, the dose, and the health status of the patient. We recommend the cannabis customer who is taking Rx medications talk with their doctor before adding cannabis to their daily regime. 

 

References

 

CYP2C9, C., & CYP2D6, C. (2007). The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician, 76, 391-6.

 

Geffrey, A. L., Pollack, S. F., Bruno, P. L., & Thiele, E. A. (2015). Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia, 56(8), 1246-1251.

Iffland, K., & Grotenhermen, F. (2017). An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis and cannabinoid research, 2(1), 139-154.

 

Jiang, R., Yamaori, S., Takeda, S., Yamamoto, I., & Watanabe, K. (2011). Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life sciences, 89(5-6), 165-170.

Machado Bergamaschi, M., Helena Costa Queiroz, R., Waldo Zuardi, A., &Crippa, A. S. (2011). Safety and side effects of cannabidiol, a Cannabis sativa constituent. Current drug safety, 6(4), 237-249.

 

Wanwimolruk, S., &Prachayasittikul, V. (2014). Cytochrome P450 enzyme mediated herbal drug interactions (Part 1). EXCLI journal, 13, 347.

Wanwimolruk, S., Phopin, K., &Prachayasittikul, V. (2014). Cytochrome P450 enzyme mediated herbal drug interactions (Part 2). EXCLI journal, 13, 869.

Yamaori, S., Okushima, Y., Masuda, K., Kushihara, M., Katsu, T., Narimatsu, S., & ... Watanabe, K. (2013). Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety. Biological & Pharmaceutical Bulletin, 36(7), 1197-1203.

 

Yamaori, S., Ebisawa, J., Okushima, Y., Yamamoto, I., & Watanabe, K. (2011). Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life sciences, 88(15-16), 730-736.

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