In the early part of the 20th century, the U.S. government classified cannabis as a Schedule 1 drug: a dangerous substance with no medical value. For many years, that classification prevented systematic research in cannabinoid use in medicine. As a result of societal changes and an intense and growing public debate around the potential therapeutic benefits of marijuana, the role of cannabinoids in medicine, and particularly in oncology, is now under reexamination.
“Whether we like it or not, these drugs are now widely available in many states and countries throughout the world, either for medical or recreational use,” said Declan Walsh, MD, at the 2018 Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) Annual Meeting.1 “So I think we need to be more selective and thoughtful about looking at individual benefits and clinical conditions, rather than thinking about them in a raw and nondiscriminatory way.”
Cannabis and cannabinoids vary tremendously, as do their potential benefits and risks. “Different opiates have different activities and different side effects, and we need to think about cannabinoids in exactly the same way,” said Dr. Walsh, Chair of the Department of Supportive Oncology at Levine Cancer Institute in Charlotte, North Carolina.
Different opiates have different activities and different side effects, and we need to think about cannabinoids in exactly the same way.— Declan Walsh, MD
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The desired therapeutic benefit from a particular cannabinoid should be weighed against its side-effect profile or that of any drug a patient is receiving, particularly when that agent is being used for symptomatic purposes. “So systematic investigations not just of efficacy—but of safety and side effects—are critical in thinking objectively about these drugs,” he said.
According to Dr. Walsh, the widespread recreational use of marijuana has overtaken the scientific literature and scientific discussions, creating significant difficulties in clinical practice. Many patients with cancer are taking cannabinoids without informing their physicians, so obtaining accurate drug histories, not just of prescribed medications, but of all medications the patients are actually taking, is critically important to safe medical practice.
“Public conversation has gone way beyond the evidence base, and now I think it is a significant concern,” noted Dr. Walsh.
Not All Cannabinoids Are Psychoactive
Modern cannabis is stronger than it was several decades ago, because the plants have been bred, manipulated, and altered to increase the potency of the psychoactive component, tetrahydrocannabinol (THC), a cannabinoid receptor agonist.
Tetrahydrocannabinol comes in various forms: hashish, for example, is a resin or paste derived from the stems of the marijuana plants, with a high concentration of THC, whereas marijuana is the dried, cured flowers of the plant and has a lower THC concentration than the resin. The effects of THC from these two delivery systems alone can be excitatory or inhibitory—as well as widely varied depending on the individual and other external factors—underlining the need for provider education on the variety of cannabinoid preparations and routes of administration (ie, smoking, eating, vaping).
THC and cannabidiol are separate and distinct cannabinoids, with different actions and effects on the central nervous system. “The relative proportion of these two chemicals in different cannabinoid preparations can make a huge difference on an individual and on the effects in clinical practice,” he added. Thus, when considering cannabinoid use in the oncology setting, weighing the risk/benefit profile not only for each individual patient, but also for each drug preparation, is vital.
Cannabinoids as Antitumor Agents?
An internal endocannabinoid system (similar to that for endorphins) naturally occurs in the body and regulates various physiologic functions. Manipulating one of two major cannabinoid receptors, CB1 or CB2, will result in differential therapeutic effects. The CB1 receptor is mainly in the central nervous system, whereas the CB2 receptor is mainly peripheral in the immune system and in hematopoietic cells.
Patients are also already using cannabinoids, and the conversation is out there. We need to make sure that we’re equipped to talk about these issues.— Declan Walsh, MD
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Preclinical research has demonstrated that cannabinoids in vitro can induce a series of events that lead to apoptosis, cell-cycle arrest, and cell death. “There [are] no human data at this point to support this, but some laboratory results clearly show that these drugs can inhibit cancer cell growth, angiogenesis, and also metastasis,” said Dr. Walsh. “Interestingly, normal cells appear affected, which raises some intriguing possibilities for research in this area in the future.”
A recent report also identified the presence of CB1 and CB2 in tumor tissues, again raising the prospect that cannabinoids might be used as antitumor agents in some tumors.2
Cannabinoids for Management of Treatment Side Effects
In addition to central nervous system effects, cannabinoids have anti-inflammatory activity, making them potentially useful in the treatment of side effects associated with chemotherapy. The role of cannabinoids in the treatment of nausea and vomiting and as appetite stimulants has been well described. Limited research suggests they can relieve other chemotherapy side effects associated with inflammatory reactions, such as neuropathic pain, cisplatin nephrotoxicity, doxorubicin cardiotoxicity, bleomycin of the lung, ocular toxicity, and hemorrhagic cystitis, said Dr. Walsh. The anti-inflammatory role of cannabinoids warrants further and more detailed investigation, he noted.
Are Cannabinoids a Triple Threat?
For some patients, cannabinoids may provide control of multiple symptoms with a fairly low side-effect profile. In addition, they have antiproliferative and cytotoxic properties and perhaps efficacy in providing relief from treatment toxicities. “Even if there is no proven value in clinical practice, our patients are reading about this every day on the Internet, and the conversation is going to come up,” he said.
The “good news,” he added, is that these drugs are not associated with respiratory depression and have an acceptable side-effect profile as well as few withdrawal symptoms. Additionally, the evidence is conclusive for their lower addiction rate compared with other substances such as alcohol, nicotine, and opioids.
In the four articles addressing cannabinoids in cancer care in this issue of The ASCO Post (see related articles), conclusions may differ on the efficacy of cannabinoids in controlling chemotherapy-related nausea and vomiting and other effects of cancer and its treatment. This may be due in part to differences in the evidence reviewed, differences in individual perspectives, differences in the characteristics of cannabis or cannabinoid exposure (ie, oral cannabinoids, marijuana plant, other formulations), among other differences.
These articles are not intended to accept or reject the associated risks and benefits of cannabinoids in cancer care. Rather, these articles are intended to call attention to the need for more research on the use of medical marijuana in oncology. Marijuana is legal in many states and patients may ask their clinicians about the drug’s role in their care. Oncologists need to be able to provide informed guidance and evidence-based care for their patients with cancer.
The Future of Cannabinoids in Medicine
According to Dr. Walsh, a new research agenda should focus on possibly separating the psychotropic effects of cannabinoids from other potential therapeutic effects. Additionally, he advocates for the revision or modification of the drug’s Schedule 1 drug status.
“The public debate is stimulating political policies that may be wise or unwise, which in turn is creating further public demand,” he said. “But patients are taking these medications, so we need to know how they are taking them and make sure they are taking them safely. I think a change in the [U.S. Food and Drug Administration’s] approach will be enormously helpful.”
Although Dr. Walsh argues that the public debate over marijuana vs opioids has oversimplified the issue, there is no doubt that the United States currently faces an opioid addiction epidemic, largely due to overprescribing and inappropriate prescribing of these agents. “This is a debate that’s going to continue for some time to come,” he surmised.
“Patients are also already using cannabinoids, and the conversation is out there,” he added. “We need to make sure that we’re equipped to talk about these issues.” ■
This article was revised postpublication on 9/12/2018.
DISCLOSURE: Dr. Walsh reported no conflicts of interest.
2. Fraguas-Sánchez AI, Martín-Sabroso C, Torres-Suárez AI: Insights into the effects of the endocannabinoid system in cancer: A review. Br J Pharmacol 175:2566-2580, 2018.
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