Remarkably, Marijuana is legal in the United States, even with its classification as a Schedule I drug. With two-thirds of states passing legislation to allow either medical or recreational marijuana use, the national trend is undeniably towards legalization1. The active compound in marijuana is tetrahydrocannabinol (THC), which is responsible for the plant’s characteristic psychoactive high. But one lesser-known compound has come into the limelight recently: cannabidiol, or CBD.
New and creative uses of CBD seems to pop up every month in the news, usually in commercial products. Canada legalized recreational marijuana in late 2018, and Coca-Cola made headlines when they were reported to be in talks with a Canadian marijuana company to produce CBD-infused beverages2. The United States has seen a rise in restaurants selling coffee, pastries, and smoothies with the compound added, but this is illegal due to FDA classification of CBD as a drug3. If CBD were to be given the same freedom as compounds designated as dietary supplements by the FDA, it is likely there would be an explosion in the production of CBD-infused products.
This marijuana-derived chemical appears to be operating in a similar market niche as probiotics, where the health benefits are dubious but proponents swear by their effects. A quick Google search can validate many benefits of CBD. One website purports that the drug can serve as an analgesic, anxiolytic, anti-cancer, anti-psychotic, anti-emetic that also prevents acne, Alzheimer’s, and cardiovascular disease4. According to these sites, doctors have been under-prescribing this wonder-drug! Many of these individual claims are substantiated by only one or a handful of studies. Higher levels of medical evidence have not shown conclusive positive or negative effects of CBD or other cannabis products5.
The FDA has a history of taking a more conservative approach to cannabis-based therapeutics. Sativex, a 50:50 THC and CBD preparation, was approved for symptoms of multiple sclerosis (MS) a decade ago in Europe. This drug is not approved for the treatment of MS by the FDA. Epidiolex is the first cannabis-based drug to be approved for use in the United States6. Epidiolex is an oral preparation of pure CBD and contains no psychoactive THC. The only approved use is 20 mg/kg/day for Lennox-Gastaut and Dravet syndromes, both forms of treatment-resistant epilepsy. While the DEA classified Epidiolex as a Schedule V drug, making CBD preparations more accessible to healthcare providers and researchers than ever before, it remains to be seen whether CBD use will rise through off-label prescriptions. The cost of Epidiolex will likely be a barrier to widespread use, ringing up at over $30,000 per year.
Cannabinoid compounds in marijuana have been shown to activate two G-protein coupled receptors, CB1 and CB2. Both are coupled to Gi proteins, which inhibit the release of neurotransmitters7. Endocannabinoids and THC are known agonists of CB1 and CB2, but CBD is thought to be an antagonist, meaning that it produces the opposite effects of THC8. This may account for the anti-inflammatory cellular effects of CBD, including increased membrane stability, modified cytokine release, and decreased oxidative stress. As is true with many drugs, it is difficult or impossible to synthesize the plethora of CBD’s cellular actions into one coherent mechanism of action. Further research will be needed to validate the proposed actions of CBD, which fortunately will be easier with a less restrictive DEA classification of Epidiolex.
What is the harm in restaurants selling their CBD-infused frappuccinos if it now has an FDA-approved use? Some well-known side effects include nausea, appetite changes, irritability, and fatigue, which are notable but not necessarily dangerous. However, CBD has been recognized as a potent CYP3A4 inhibitor9. Through this mechanism, CBD could raise the plasma concentrations of drugs with small therapeutic windows such as warfarin to dangerous levels. Thus, if prescribers are unaware of a patient’s CBD intake, they may prescribe dangerous doses of certain medications. As state governments, and possibly the federal government, loosen their grips on marijuana and marijuana-based products, researchers should pay special attention to drugs such as CBD that are ascribed a miraculous set of benefits but may have more adverse consequences than previously known.
- PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. Cannabis and Cannabinoids (PDQ®): Health Professional Version. PDQ Cancer Information Summaries [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK65755/. Updated 2018 Aug 16.
- Skerritt J, Giammona C. Coca-Cola is Eyeing the Cannabis Market. Bloomberg. 2018 Sept 17. Available from: https://www.bloomberg.com/news/articles/2018-09-17/coca-cola-eyes-cannabis-market-in-push-beyond-sluggish-sodas.
- Rabin RC. CBD Is Everywhere, but Scientists Don’t Know Much About It. New York Times. 2019 Feb 25. https://www.nytimes.com/2019/02/25/well/live/cbd-cannabidiol-marijuana-medical-treatment-therapy.html.
- Kubala J. 7 Benefits and Uses of CBD Oil (Plus Side Effects). Healthline. 2018 Feb 26. https://www.healthline.com/nutrition/cbd-oil-benefits.
- Bramness JG, Dom Geert Gual A, Mann K, Wurst FM. A survey on the medical use of Cannabis in Europe: a position paper. European addiction research [Internet]. 2018;24(4): p201-205. https://doi.org/10.1159/000492757.
- Rubin R. The Path to the First FDA-Approved Cannabis-Derived Treatment and What Comes Next. JAMA. 2018;320(12):1227-1229. doi:10.1001/jama.2018.11914.
- Mackie K. Cannabinoid Receptors: Where They are and What They do. Journal of Neuroendocrinology [Internet]. 2008;20:10-14. doi:10.1111/j.1365-2826.2008.01671.x.
- Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2007;153(2):199-215. doi:10.1038/sj.bjp.0707442.
- Grinspoon P. Cannabidiol (CBD) – What We Know and What We Don’t. Harvard Health. 2018 Aug 24. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476.
Luke Wohlford is a medical student in the University of Arizona College of Medicine - Phoenix, Class of 2022. He graduated from the University of Arizona in 2018 with a Bachelor of Science in physiology. Luke plans to go into emergency medicine has special interests in public health and EMS. He spends most of his free time hanging out with his dogs Kanye and Kelso or feeling guilty about not exercising.