Education, communication can reduce risks of cannabidiol use among patients with cancer

Pain and other common adverse effects of cancer treatment — such as nausea and vomiting, mucositis, depression or anxiety — can dramatically decrease quality of life.

Many patients with active disease and cancer survivors use complementary or alternative medicines (CAM) to alleviate these symptoms.

Commonly used CAMs include herbal supplements, yoga or tai chi, massage, acupuncture, special diets and mindfulness meditation.

Some patients opt for cannabis products, the use of which is controversial and heavily regulated in the United States.

Clarity is lacking regarding the legality and effectiveness of both cannabis and cannabidiol (CBD) oils — a cannabinoid found in marijuana plants — and access to these products is inconsistent among states.

However, CBD oils increasingly are being sold online and by retailers. This has contributed to increased popularity among the public, making it essential that members of cancer care teams understand the potential risks these products pose to their patients.

CBD and the FDA

The FDA does not evaluate the safety and efficacy of CBD products prior to their introduction on the market.

These products must undergo new drug approval prior to use only if they are deemed unsafe or the distributor makes claims consistent with an intent to diagnose, cure, mitigate, treat or prevent disease.

There are more than 100 cannabinoid compounds found in the cannabis plant. The two most abundant are CBD and tetrahydrocannabinol (THC).

THC found in the cannabis plant is the cannabinoid compound responsible for its psychoactive effect (eg, hallucinations).

CBD is a cannabinoid compound derived from the oily resin of the Cannabis sativa L plant species.

Because CBD oil is extracted from cannabis plants using pressurized carbon dioxide, it technically is not classified as an essential oil; however, people use it in a manner similar to many essential oils.

The Agricultural Improvement Act of 2018 removed hemp from the federal Controlled Substances Act in cases when cannabis plants and derivatives contain no more than 0.3% THC on a dry weight basis. However, the FDA retains authority over these products, and they must comply with the federal Food, Drug and Cosmetic Act.

The only FDA-approved CBD product is Epidiolex (Greenwich Biosciences), approved in 2018 for treatment of patients aged 2 years or older who experience seizures associated with Lennox-Gastaut syndrome or Dravet syndrome.

Epidiolex — which contains no THC — is classified as a schedule V medication. This is the least restrictive schedule of the Controlled Substances Act, suggesting these agents have the lowest potential for abuse.

Epidiolex is an oral solution for ingestion. However, self-care CBD products have a variety of routes of administration, including oral, transdermal and inhalation via vaporization.

CBD pharmacology

CBD has a multisite, complex mechanism of action.

The endogenous cannabinoid system stimulates inhibition of neurotransmitters of the nervous system through activation of the cannabinoid 1 (CB1) receptor.

CBD is an antagonist of the CB1 receptor, with various effects and affinities for eight other sites of action.

Pharmacokinetics of CBD varies by formulation and route of administration.

In general, CBD is highly lipophilic and, therefore, has poor oral bioavailability (approximately 6%).

Its lipophilic nature supports a wide volume of distribution, and CBD can accumulate in the adipose tissue of chronic users.

CBD is hepatically metabolized by the cytochrome enzymatic system and has extensive first pass metabolism. As such, inhalation and transdermal routes of administration can result in higher peak plasma concentrations. Further, CBD has a long terminal half-life, averaging around 24 hours.

Cancer and CBD use

Because CBD products other than Epidiolex are not regulated by the FDA, the prevalence of their use — including by individuals with cancer — is not well understood.

Martell and colleagues sent anonymous surveys to 3,138 adults with cancer at two comprehensive centers and two community centers to assess their cannabis use. The analysis included 1,987 (63%) sufficiently completed surveys.

Results, published in 2018 in Current Oncology, showed 43% of respondents had used cannabis, a finding independent of age, sex, education level and cancer type. Of those who reported cannabis use, 41% had used oils or edibles.

Eighteen percent of respondents reported having used cannabis in the previous 6 months, with common reported reasons including cancer-related pain (46%), nausea (34%) and other cancer symptoms (31%).

Studies are ongoing regarding the potential anticancer effects of CBD, but current evidence is insufficient to support clinical application.

Use of CBD products by patients with cancer is most likely to be as self-care for symptom management.

Efficacy data to support the use of CBD products for supportive care are extremely limited. Further, clinical trial data is based on a diverse range of products studied, and this lack of standardization is a barrier in application to clinical care.

Adverse effects

Adverse effects associated with CBD use typically are minor and mild.

The most common include somnolence, decreased appetite and diarrhea, although there is a concern for hepatotoxicity. For more detailed information about adverse effects, providers are encouraged to refer to the FDA package insert for Epidiolex.

CBD also creates the potential for interaction with other therapies.

It is an inhibitor of p-glycoprotein; an inhibitor of CYP2C19, CYP2C9 and CYP3A4; and a substrate of CYP3A4 and CYP2C19. This is especially important for patients with cancer who are treated with certain chemotherapies — such as anthracyclines and paclitaxel — as well as those who receive morphine for pain.

Further, concomitant use of CBD with sedative drugs may lead to additive toxicities.

In March 2019, the CDC began reporting on a national outbreak of e-cigarette or vaping product use-associated lung injury (EVALI).

The CDC determined THC-containing e-cigarette or vaping products, particularly from informal sources, are linked to most EVALI cases. One chemical of concern is vitamin E acetate, which may interfere with normal lung functioning when inhaled.

The FDA and CDC recommend that consumers not use THC-containing vaporization products — especially from informal sources like friends, family or online dealers.

Further, because CBD vaporization products have been found to be adulterated with THC, the safest option would be for providers to advise against use of CBD products that are inhaled via vaporization.

Bonn-Miller and colleagues evaluated labeling of CBD products (ie, oils, tinctures and vaporization liquids) relative to laboratory-analyzed concentration of CBD. The results, published in 2017 in JAMA, showed only 30.9% of products were labeled accurately.

Oils were the most accurately labeled and vaporization liquids were least accurately labeled. Further, THC was detected in 21.4% of products analyzed.

CBD oil research efforts

Mücke and colleagues conducted a systematic review to evaluate the use of cannabinoids in palliative medicine. The study population included terminally ill patients with cancer, as well as patients with AIDS.

In the cancer cohort, researchers reported no significant difference between cannabinoids or placebo for improving caloric intake, reducing nausea/vomiting or pain, or improving sleep. However, the trial included multiple cannabinoid products, including THC, CBD and synthetic agents.

Another review by Donvito and colleagues reported preclinical and clinical evidence supporting the use of medical cannabis for pain, but adverse events associated with use may preclude its application to care, making compounds such as CBD more attractive for future study.

Clinical trials are underway. A multicenter, randomized, placebo-controlled study aims to define the role of CBD in the management of cancer symptoms. This study is evaluating the impact of CBD on symptom burden as a whole.

As a result, pending these data, the role of CBD may be for improvement in the general well-being of individuals with cancer.

Balance between art and science

As a pharmacy resident, I was particularly challenged by cancer pain management encounters with patients.

In my early years, I developed a bad habit of viewing situations as black or white. Thankfully — with mentoring, experience and wisdom — I have grown to change “or” into “and.”

I have come to appreciate that cancer pain management is a delicate balance between art and science. It is a complex interplay among multiple bodily systems, social determinants of health and the inner world of a patient.

I have learned to hold my preencounter patient care plans with an open hand. Although I am an oncology pharmacist, not all patients suffering from cancer pain need or want a prescription from me.

This repeated observation piqued my curiosity regarding the practice of integrative health care.

In many ways, cancer care has evolved into an integrative health care approach.

As the Academic Consortium for Integrative Medicine & Health states: “Integrative health care reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic and lifestyle approaches, health care professionals and disciplines to achieve optimal health and healing.”

Integrative health care is not CAM, but it recognizes approaches that fall under this category as potential avenues toward health and healing. Perhaps the mere act of recognition would create openness for patients to disclose important health factors they otherwise would not, such as CBD use.

Provider considerations

A cross-sectional study by Sanford and colleagues showed one-third of patients with cancer and cancer survivors used CAM within the previous 12 months. Disturbingly, 29.3% of those who used CAM did not report it to their physicians, with the most commonly expressed reasons for nondisclosure being that the physician did not ask (57.4%) or the patient’s perception that physicians didn’t need to know (47.4%).

Patients who use cannabis products may fear repercussions from members of their care team if they acknowledge doing so.

Providers should create a “safe space” for patients to share this information.

An integrative health care approach is particularly important.

Providers should consider routinely asking patients with cancer about CBD use as part of the medication reconciliation process, and they should focus discussions on education and safe use where controllable given the lack of data.

When patients report use or interest in CBD oil products, providers should ensure they are fully informed about the risks associated with these products, the lack of demonstrated benefit, and the fact optimal dosing is not known.

The risks include the potential for adulterated CBD products, with some containing THC. Consequently, patients should be informed about the risk for a positive toxicology screen for THC with CBD use.

Safety concerns associated with CBD products for self-care include ambiguity with regard to safe dosing, the potential for mild adverse events, risk for hepatotoxicity, drug interactions and development of EVALI after use of CBD products for inhalation via vaporization.

There is no product proved safe and effective that providers can recommend to patients for self-care. Consequently, risk mitigation should be employed.

Providers should discourage use of CBD via inhalation, as information about EVALI continues to accrue. Considerations for product selection include how much THC is included, availability of a certificate of analysis, and whether products list the amount of CBD by dose. Providers also should encourage patients to avoid products that make health claims.

The FDA package labeling for Epidiolex is a good source of general information about CBD. However, it should be noted that over-the-counter CBD oil products are not FDA approved; therefore, efficacy, safety and dosing are not comparable. Providers who would like more information on CBD should visit the National Center for Complementary and Integrative Health website.

Investing in a relationship with the patient will support safe use of CBD oil products, as providers and patients can freely share information about their use. Shared decision-making informed by evidence then can be employed regarding CBD oil use and whether it is safe in the context of a patient’s cancer care plan.

References:

• Academic Consortium for Integrative Medicine & Health. Introduction. Available at: imconsortium.org/about/introduction. Accessed on Sept. 16, 2020.
• Bonn-Miller MO, et al. JAMA. 2017;doi:10.1001/jama.2017.11909.
• CDC. Outbreak of lung injury associated with the use of e-cigarette, or vaping, products. Available at: www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. Accessed on Aug. 14, 2020.
• Donvito G, et al. Neuropsychopharmacology. 2018;doi:10.1038/npp.2017.204.
• FDA. FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). Available at: www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed on Sept. 16, 2020.
• Good P, et al. BMC Palliat Care. 2019;doi:10.1186/s12904-019-0494-6.
• Kis B, et al. Int J Mol Sci. 2019;doi:10.3390/ijms20235905.
• Manion CR and Widder RM. Am J Health Syst Pharm. 2017;doi:10.2146/ajhp151043.
• Martell K, et al. Curr Oncol. 2018:doi:10.3747/co.25.3983.
• Mücke M, et al. J Cachexia Sarcopenia Muscle. 2018;doi:10.1002/jcsm.12273.
• National Center for Complementary and Integrative Health. Cannabis (marijuana) and cannabinoids: What you need to know. Available at: www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-need-to-know. Accessed on Sept. 16, 2020.
• NCI. Aromatherapy with essential oils (PDQ) — Health Professional Version. Available at: www.cancer.gov/about-cancer/treatment/cam/hp/aromatherapy-pdq. Accessed on Aug. 14, 2020.
• Sanford NN, et al. JAMA Oncol. 2019;doi:10.1001/jamaoncol.2019.0349.
• VanDolah HJ, et al. Mayo Clin Proc. 2019;doi:10.1016/j.mayocp.2019.01.003.

For more information:

Jill S. Bates, PharmD, MS, BCOP, FASHP, can be reached at batesjill@gmail.com.