Cannabidiol Oil for Cancer Patients: Nature’s Best Remedy?
PharmD Candidate (2020)
University of Connecticut School of Pharmacy
Lisa M. Holle, PharmD BCOP FHOPA FISOPP
Associate Clinical Professor
University of Connecticut School of Pharmacy
University of Connecticut Health
Neag Comprehensive Cancer Center
Cannabidiol (CBD) oil is a supplement that has gained tremendous popularity over the past few years. The compound is marketed for numerous indications and sold across the United States by various shops, gas stations, and online retailers. CBD is produced in a variety of formulations, one of the more prevalent being CBD oil.1 One area in which CBD oil is gaining interest is the cancer setting, and because of its wide availability, it is likely that many cancer patients are turning to this alternative medicine to help manage their disease or symptoms. It is therefore important for healthcare professionals to educate themselves regarding the efficacy, safety, and legality of this compound.
CBD is a compound derived from the cannabis plant. Cannabis is the source of one of the oldest plant-based medicines known to man, and for thousands of years it has been cultivated by humans for various purposes.2 Two common strains of the plant are marijuana, cultivated for its medicinal purposes, and hemp, cultivated for its use in food, clothing, and paper.3 The cannabis plant contains various active components, two of which are cannabinoids and terpenes.2 Researchers have identified up to 113 different cannabinoids and 120 different terpenes in cannabis.4 The two cannabinoids delta-9-tetrahydrocannabinol (THC) and CBD are the most prevalent and well-known cannabis components. However, terpenes have also been shown to bind to receptors in animal studies, suggesting that they may play a role in the overall pharmacologic profile of cannabis.2 Many people likely associate cannabis with marijuana and the “high” effect that it elicits. This psychoactive effect is a result of the action of THC on cannabidiol (CB)1 and CB2 receptors.5 CBD does not act in the same way; in fact, it is thought to have antagonistic effects on the CB receptors. As a result, it does not produce the psychoactive effects seen in THC-containing cannabis.5 CBD has a long list of proposed benefits, including potential antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective effects.6 Medicinal marijuana products often contain a combination of THC and CBD but may also be pure THC or CBD alone. CBD oil, however, primarily contains the CBD, with minimal (<0.3%) THC content.
The legal status of cannabis and cannabis-related products in the United States can be difficult to understand. Federally, the Controlled Substances Act (CSA) of 1970 placed cannabis and its components into schedule I, the most restrictive category.7 As of January 1, 2020, 33 individual states, along with Washington, DC, Puerto Rico, and Guam, have implemented laws that allow for medicinal cannabis use. Of these, 11 states plus Washington, DC, and Guam allow for recreational use.8-10 These states can sell all types of cannabis products with varying contents of active ingredients (e.g., THC, CBD) and dosage forms. The 2018 Farm Bill removed hemp, defined as cannabis-derived product with less than 0.3% THC, from the CSA.7 This has allowed for widespread commercial sales of CBD products outside of medical marijuana dispensaries.11 The extracts that are produced from cannabis can range widely in their composition and effects, depending on which part of the plant is used. Hemp seed oil contains no THC and minimal CBD and is extracted from cannabis seeds. CBD oil and cannabis oils, which are extracted from the flower or plant material, contain CBD at variable levels; the difference is that CBD oil can contain only up to 0.3% THC.3 The sale of these products is legal in all states but Idaho, Nebraska, and South Dakota, where no cannabis access laws currently exist. Because these CBD oils do not contain psychoactive levels of THC, they can be purchased and consumed without the recommendation or certification of a provider.3
In 2018, the U.S. Food and Drug Administration (FDA) approved CBD oral solution (Epidiolex) for the treatment of seizures in Lennox-Gastaut and Dravet syndrome.7 Epidiolex, a purified CBD oral solution that contains less than 0.1% THC, was placed into schedule V (low-abuse potential) by the U.S. Drug Enforcement Agency (DEA) in 2018.12,13 This is currently the only FDA-approved CBD product, and it has not been evaluated in cancer patients. According to the DEA, all non-FDA-approved CBD products are still considered schedule I controlled substances.13 The 2018 Farm Bill allows for exceptions to this status under certain conditions. In order for hemp-derived CBD to be considered legal, it must be produced by a licensed grower under specific conditions set forth by the Farm Bill, state regulations, and federal regulations.14 This, along with the implementation of state laws on cannabis access, has made the regulation of CBD products a difficult task.8 A 2016 study investigated the labeling accuracy of online-purchased CBD products. Researchers purchased 84 non-FDA-approved CBD products and tested their CBD and THC content. The alarming findings were that only 31% were accurately labeled within 10% of the reported CBD content, and 21% of the products contained unlabeled THC at a low level.15 The FDA has issued warnings regarding mislabeling to dozens of firms that market CBD products and has warned the public to beware of these products.16
Cannabinoids have been used to treat patients with cancer since 1985, when dronabinol (Marinol), a synthetic THC product, was approved by the FDA to treat chemotherapy-induced nausea and vomiting.17 The specific role of CBD in cancer treatment is still unclear. In vitro and in vivo studies have shown some evidence for CBD’s efficacy as an anticancer agent through mechanisms such as induction of apoptosis or inhibition of tumor growth and metastasis.18,19 In vitro data supports the ability of CBD to induce tumor cell death in patients with glioblastoma.20 Furthermore, case reports have been published showing a potential anticancer effect in lung cancer and ovarian cancer patients.21,22 Regarding supportive care for cancer patients, the role of CBD is again unclear. Evidence exists for the use of cannabis for chemotherapy-induced nausea and vomiting, cancer pain, anorexia and cachexia, and appetite stimulation; however, most studies were poorly designed and evaluated products that also contained THC.2 Until more human trial data become available, the appropriateness of using CBD oil in these indications remains uncertain. Several studies are investigating the use of CBD in patients with cancer for indications such as palliative care in cancer patients to reduce symptom burden; as standard-of-care treatments in patients with multiple myeloma, glioblastoma multiforme, and gastrointestinal malignancies; and for prevention of graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation.23-25 Continuing research is necessary to understand CBD’s usefulness in treating cancer patients.
As noted, CBD lacks the psychoactive effects that are found with other cannabinoids. This does not mean that it can be used without concern. Epidiolex has been associated with hepatocellular injury, sedation, and suicidal behavior and ideation, in addition to more common side effects of decreased appetite (16–22%), diarrhea (9–20%), fatigue (11–12%), and insomnia (5–11%). It is important that patients using CBD be made aware of the possibility that they will test positive in a cannabis drug screen.12 It should be noted that rigorous safety studies have been performed only with prescription Epidiolex, not with over-the-counter or other CBD oil products. Given that the strengths of CBD oil products vary greatly, it is difficult to fully understand the side-effect profile of CBD. Emerging evidence has also indicated the potential carcinogenicity of CBD, with one study finding that CBD can cause chromosomal damage in human-derived cell lines.26 Also of note, CBD interacts with a number of common medications. CBD is a substrate for cytochrome (CYP) p450 enzymes CYP3A4 and CYP2C19; a dose reduction should therefore be considered when a patient is concomitantly using moderate or strong inhibitors of these enzymes, and a dose increase should be considered when a patient is using moderate or strong inducers. In addition, when CBD is used concomitantly with substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, CYP1A2, or CYP2B6, a dose reduction of the substrate should be considered.12 The combination of potential side effects and drug interactions, along with the regulatory issues highlighted above, raises concerns about patient safety. As evidenced by the widespread use and current availability of CBD oil products, patients are likely to consume these products despite a lack of efficacy or safety data. Because of this likelihood, healthcare providers should provide guidance to their patients on selecting the safest product possible. (Table 1 - see PDF) lists considerations for choosing high-quality CBD oil products.3
Overall, very little evidence exists to support the medical use of CBD oil for patients with cancer. Although some case reports have demonstrated benefit, the lack of data from well-designed human trials presents the single largest barrier to acceptance and routine use of CBD by medical professionals. In addition to the lack of evidence, CBD’s questionable legality also presents an obstacle to be overcome before providers can comfortably recommend it to their patients. In the meantime, as the CBD craze sweeps across the nation, providers should focus on educating themselves about the risks and benefits of CBD oil in order to manage expectations and avoid adverse effects and drug interactions in their patients who are curious about CBD.
- Projectcbd.org. What Is CBD? Definition of Cannabidiol and CBD Oil. Available at https://www.projectcbd.org/cbd-101/what-is-cbd. Accessed February 18, 2020.
- Klumpers LE, Thacker DL. A brief background on cannabis: from plant to medical indications. J AOAC Int. 2019;102:412-420.
- VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ guide to cannabidiol and hemp oils. Mayo Clin Proc. 2019;94:1840-1851.
- Aizpurua-Olaizola O, Soydaner U, Öztürk E, et al. Evolution of the cannabinoid and terpene content during the growth of cannabis sativa plants from different chemotypes. J Nat Prod. 2016;79:324-331.
- Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.
- Bridgeman MB, Abazia DT. Medicinal Cannabis: History, Pharmacology, and Implications for the Acute Care Setting. P T. 2017;42(3):180-188. Available at https://www.ptcommunity.com/journal/article/full/2017/3/180/medicinal-cannabis-history-pharmacology-and-implications-acute-care. Accessed February 20, 2020.
- U.S. Food and Drug Administration. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD): Questions and Answers. Available at https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed February 18, 2020.
- ProCon.org. Legal Medical Marijuana States and DC: Laws, Fees, and Possession Limits. Available at https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc/. Accessed February 18, 2020.
- Sifferlin A. Puerto Rico governor signs executive order to legalize medical marijuana. Available at https://time.com/3845638/puerto-rico-medical-marijuana/. Published May 4, 2015. Accessed February 18, 2020.
- Perez J. Marijuana prohibition to end. SaipanTribune.com. Available at https://www.saipantribune.com/index.php/marijuana-prohibition-to-end/. Published February 5, 2019. Accessed February 18, 2020.
- Cohen PA, Sharfstein J. The opportunity of CBD—reforming the law. N Engl J Med. 2019;381:297-299.
- Epidiolex (cannabidiol) [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; 2018.
- U.S. Drug Enforcement Administration. Schedules of controlled substances: placement in schedule V of certain FDA-approved drugs containing cannabidiol; corresponding change to permit requirements. 21 CFR Parts 1308, 1312 [Docket No. DEA-486]. Federal Register 2018;vol 83, no.189. Available at https://www.gpo.gov/fdsys/pkg/FR-2018-09-28/pdf/2018-21121.pdf. Accessed February 11, 2020.
- Hudak J. The Farm Bill, hemp legalization and the status of CBD: an explainer. Brookings. Available at https://www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer/. Published December 14, 2018. Accessed February 20, 2020.
- Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318:1708-1709.
- U.S. Food and Drug Administration. Warning letters and test results for cannabidiol-related products. Available at https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Accessed February 19, 2020.
- Marinol (dronabinol) [package insert]. North Chicago, IL: AbbVie Inc.; 2017.
- Choipark WHD, Baek SH, Chu JP, et al. Cannabidiol induces cytotoxicity and cell death via apoptotic pathway in cancer cell lines. Biomolecules Ther. 2008;16:87-94.
- Yasmin-Karim S, Moreau M, Mueller R, et al. Enhancing the therapeutic efficacy of cancer treatment with cannabinoids. Front Oncol. 2018;8:114.
- Ivanov VN, Wu J, Wang TJC, Hei TK. Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells. Oncotarget. 2019;10:825-46.
- Sulé-Suso J, Watson NA, van Pittius DG, Jegannathen A. Striking lung cancer response to self-administration of cannabidiol: a case report and literature review. SAGE Open Med Case Rep. 2019;7:2050313X19832160.
- Barrie AM, Gushue AC, Eskander RN. Dramatic response to Laetrile and cannabidiol (CBD) oil in a patient with metastatic low grade serous ovarian carcinoma. Gynecol Oncol Rep. 2019;29:10-12.
- Good P, Haywood A, Gogna G, et al. Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD). BMC Palliat Care. 2019;18:110.
- U.S. National Library of Medicine. A Study of the Efficacy of Cannabidiol in Patients With Multiple Myeloma, Glioblastoma Multiforme, and GI Malignancies. Available at https://clinicaltrials.gov/ct2/show/NCT03607643?term=cannabidiol&recrs=abde&cond=Cancer&draw=2&rank=1#wrapper. Accessed February 18, 2020.
- U.S. National Library of Medicine. Safety and Efficacy of Cannabidiol for Grade I/II Acute Graft Versus Host Disease (GVHD) After Allogeneic Stem Cell Transplantation. Available at https://clinicaltrials.gov/ct2/show/NCT01596075?term=cannabidiol+and+cancer&draw=2&rank=7#wrapper. Accessed February 18, 2020.
- Russo C, Ferk F, Mišík M, et al. Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells. Arch Toxicol. 2019;93:179-188.