Donald I. Abrams, MD
A RECENT survey of 400 clinical oncologists found that 80% discuss the use of medical cannabis with their patients, and although nearly 50% recommend it, fewer than 30% consider themselves knowledgeable enough to make such recommendations.1 Oncologists are perhaps among the most evidence-demanding of all medical specialists, as we deal with a serious illness and use medications with significant potential for adverse effects. We prefer to make recommendations supported by published literature. Due to the essential prohibition against conducting clinical trials demonstrating the potential therapeutic effects of botanical cannabis, such data are largely unavailable.2
On the other hand, pharmaceutical preparations of the main psychoactive component of the cannabis plant—delta-9-tetrahydrocannabinol (THC)—have been licensed and approved for the treatment of chemotherapy-induced nausea and vomiting since 1986, suggesting that oncologists have had access to becoming familiar with the use of a cannabis-based medicine longer than any other specialty group.3,4 Numerous studies conducted in the 1970s and 1980s demonstrated that dronabinol and nabilone were superior to placebo and comparable to the antiemetics available at that time.5 A more recent trial found dronabinol to be similar to ondansetron in the prevention of delayed nausea and vomiting, although ondansetron is no longer the standard of care for this indication.6
Dearth of Clinical Trials
THE NATIONAL Academies of Sciences, Engineering, and Medicine (NASEM) 2017 review of The Health Effects of Cannabis and Cannabinoids ranked the evidence that cannabinoids are effective for chemotherapy-induced nausea and vomiting as among the strongest available in the medical literature.2 The parent botanical, however, has been studied in just three clinical trials and was only made available in two of those studies after dronabinol had failed.
The only legal source of cannabis for research in the United States continues to be the National Institute on Drug Abuse, which has a congressional mandate to study substances of abuse as substances of abuse—not as therapeutic agents. Thus, although they can supply the cannabis for such a trial, funding must come from elsewhere.
In this situation, the absence of evidence from randomized clinical trials does not necessarily support a lack of effectiveness. Nearly half (48.4%) of the oncologists in the aforementioned survey believed that cannabis was equally or more effective than standard antiemetic treatments.1 In a study of 2,000 Israeli patients with cancer who had government licenses to use medicinal cannabis, 91% ranked nausea and vomiting as the most common symptom improved.7
“In addition to benefits in managing pain and nausea, cannabis is the only antiemetic agent that also can increase appetite.”— Donald I. Abrams, MD
Tweet this quote
It has been suggested that the main function of our system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) is to help us to modulate pain.8 The NASEM review also ranked pain as one of the best supported indications for cannabis and cannabinoids in the medical literature.2 Their use in neuropathic pain, in particular, has the strongest support from a number of clinical trials in patients with human immunodeficiency virus–related peripheral neuropathy, as well as a small study of vaporized cannabis in diabetic neuropathy.9-11
A 16-patient crossover placebo-controlled trial of nabiximols—a whole plant extract with a 1:1 ratio of THC and the nonpsychoactive cannabidiol used as an oromucosal spray (approved in the United Kingdom but not in the United States)—was conducted in patients with chemotherapy-induced peripheral neuropathy, with results supporting a larger follow-on trial.12 In rodent models, cannabinoids are not only effective in treating neuropathy induced by the vinca alkaloids, platins, and taxanes, but they can also prevent its development.13-15 In addition to neuropathic pain, there is preclinical and some clinical evidence that cannabis may be synergistic with opiates in pain relief.16 Nabiximols has been studied in patients with cancer pain in a number of trials and has demonstrated variable benefit.17,18
Other Potential Benefits
IN ADDITION to benefits in managing pain and nausea, cannabis is the only antiemetic agent that also can increase appetite. Although negative clinical trials have resulted from studies of THC pharmaceuticals in cancer-associated anorexia-cachexia syndrome,19 the plant itself is often associated with the “munchies.” Of the oncologists responding in the survey, 64.5% said that cannabis was equally or more effective than available therapies for poor appetite or cachexia.
Cannabis may also be a useful sleep aid and mood elevator in patients with cancer. Cannabidiol has been studied as an antianxiety agent, and patients also report that cannabidiol-dominant products are often helpful for inducing sleep.20 As physicians, and especially oncologists, have embraced more targeted therapies, the notion of a single botanical therapy that can have so many varied positive effects seems implausible, if not a bit retro. However, for patients with cancer, to be able to impact nausea, anorexia, pain, mood, and sleep with a single agent as opposed to a number of prescription medications is often desirable.
“Although there is a growing body of in vitro evidence and data from animal models suggesting that cannabinoids may have some antitumor effects, evidence from human studies published to date to support such a claim is lacking.”— Donald I. Abrams, MD
Tweet this quote
A growing number of patients with cancer are being convinced by Internet advertising that cannabis may have some role in the treatment of their malignancy. Although there is a growing body of in vitro evidence and data from animal models suggesting that cannabinoids may have some antitumor effects, evidence from human studies published to date to support such a claim is lacking.21,22
The NASEM review veered from the charge to include only meta-analyses, systematic reviews, and high-quality human clinical trials by including a single report summarizing 34 in vitro and animal studies of cannabinoids in gliomas in a paragraph found in the chapter on therapeutic effects.23 As the cannabinoid receptor type 1 is the most densely populated G protein–coupled 7-transmembrane domain receptor in the brain, it is plausible that cannabinoids may have an impact in this setting. In fact, preclinical evidence suggests that cannabinoids selectively kill glioma cells without affecting normal brain cells.
In addition to a direct antitumor effect, cannabinoids appear to inhibit vascular endothelial growth factor and neoangiogenesis as well as matrix metalloproteinase-2, which allows cancer cells to become invasive and metastasize. As yet unpublished data from a small placebo-controlled study of nabiximols in conjunction with temozolomide in recurrent glioblastoma multiforme demonstrated significantly more patients achieving 1-year survival, with a trend toward prolonged overall survival.24 With many human tumor types showing increased or decreased expression of cannabinoid receptors being associated with better or worse outcomes, the possibility of future treatments based on the manipulation of these receptors by cannabis-derived therapies seems likely.25
AS A PRACTICING oncologist in San Francisco for the past 35 years, I have seen countless patients with cancer benefit from the therapeutic effect of this versatile botanical therapy. Polls have suggested that oncologists are the medical subspecialists most likely to appreciate the utility of this misclassified Schedule I substance in our patients.26
Although the plant has value in symptom management, as yet there is no evidence that any cannabis-based product can actually cure cancer (although the preliminary data from the nabiximols in glioblastoma study are certainly provocative). Despite the survey finding that oncologists feel ill-informed to discuss the use of cannabis with their patients due to the lack of published evidence, we can rest assured that it is not an intervention that requires a package insert for most users. ■
Dr. Abrams is Past Chief, Hematology-Oncology, Zuckerberg San Francisco General Hospital, and Professor of Clinical Medicine, University of California, San Francisco.
DISCLOSURE: Dr. Abrams is a scientific advisor for AXIM Biotechnologies, Insys Therapeutics, Intec Pharma, Maui Wellness Group, Scriptyx, Tikun Olam USA, and Vivo Cannabis; and has received speaker honoraria from Spectrum Cannabis.
1. Braun IM, Wright A, Peteet J, et al: Medical oncologists’ beliefs, practices and knowledge regarding marijuana used therapeutically: A nationally representative survey study. J Clin Oncol 36:1957-1962, 2018.
2. National Academies of Sciences, Engineering, and Medicine: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC; National Academies Press; 2017. Available at nationalacademies.org/hmd/Reports/2017/health-effects-of-cannabis-and-cannabinoids.aspx. Accessed November 28, 2018.
3. Abrams DI, Guzman M: Cannabis in cancer care. Clin Pharmacol Ther 97:575-586, 2015.
4. Abrams DI: Integrating cannabis into clinical cancer care. Curr Oncol 23(suppl 2):S8-S14, 2016.
5. Smith LA, Azariah F, Lavender VT, et al: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev Nov 12;(11):CD009464, 2015.
6. Meiri E, Jhangiani H, Vredenburgh JJ, et al: Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin 23:533-543, 2007.
7. Schleider LB, Mechoulam R, Lederman V, et al: Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med 49:37-43, 2018.
8. Donvito G, Nass SR, Wilkerson JL, et al: The endogenous cannabinoid system: A budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmacology 43:52-79, 2018.
9. Abrams DI, Jay CA, Shade SB, et al: Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. Neurology 68:515-521, 2007.
10. Andreae MH, Carter GM, Shaparin N, et al: Inhaled cannabis for chronic neuropathic pain: A meta-analysis of individual patient data. J Pain 16:1221- 1232, 2015.
11. Wallace MS, Marcotte TD, Umlauf A, et al: Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 16:616-627, 2015.
12. Lynch ME, Cesar-Rittenberg P, Hohmann AG: A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47:166-173, 2014.
13. Rahn EJ, Makriyannis A, Hohmann AG: Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol 152:765-777, 2007.
14. Khasabova IA, Khasabov S, Paz J, et al: Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. J Neurosci 32:7091-7101, 2012.
15. Ward SJ, McAllister SD, Kawamura R, et al: Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 171:636- 645, 2014.
16. Abrams DI, Couey P, Shade SB, et al: Cannabinoid–opioid interaction in chronic pain. Clin Pharmacol Ther 90:844-851, 2011.
17. Portenoy RK, Ganae-Motan ED, Allende S, et al: Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. J Pain 13:438-449, 2012.
18. Johnson JR, Lossignol D, Burnell-Nugent M, et al: An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage 46:207-218, 2013.
19. Jatoi A, Windschitl HE, Loprinzi CL, et al: Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: A North Central Cancer Treatment Group study. J Clin Oncol 20:567-573, 2002.
20. Bergamaschi MM, Queiroz RH, Chagas MH, et al: Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 36:1219-1226, 2011.
21. Guzman M: Cannabinoids: Potential anticancer agents. Nat Rev Cancer 3:745-755, 2003.
22. Velasco G, Sánchez C, Guzmán M: Towards the use of cannabinoids as antitumour agents. Nature Rev Cancer 12:436-444, 2012.
23. Rocha FC, dos Santos Júnior JG, et al: Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J Neurooncol 116:11-24, 2014.
24. GW pharmaceuticals achieves positive results in phase 2 proof of concept study in glioma. Press release, February 7, 2017. Available at www.gwpharm.com/about/news/gw-pharmaceuticals-achieves-positive-results-phase-2-proof-concept-study-glioma. Accessed November 28, 2018.
25. Ladin DA, Soliman E, Griffin L, et al: Preclinical and clinical assessment of cannabinoids as anti-cancer agents. Front Pharmacol 7:361, 2016.
26. Rappold RS: Legalize medical marijuana, doctors say in survey. WebMD. April 2, 2014. Available at www.webmd.com/pain-management/news/20140225/ webmd-marijuana-survey-web#1. Accessed November 28, 2018.