Questions from the Clinic:
Does marijuana have any value as a therapy for patients with cancer? If so, what compounds are responsible for its anti-cancer properties? Are there any notable drug interactions or side effects that could limit its use?
Figure 1: Marijuana is cultivated from the dried flowers, leaves, stems, and seeds of the cannabis plant. Some active compounds, like cannabidiol, is not impairing, whereas others like tetrahydrocannabinol (THC) induce a high when consumed. Picture courtesy of Unsplash.com.
I. Historical Context
Botanical records indicate that humanity has cultivated Cannabis sativa (C. sativa) for nearly 10,000 years (Figure 1). In antiquity, the Han Chinese regarded C. sativa as a “first-class herb” and used it to treat rheumatic pain, constipation, malaria, and other conditions attributed to loss of yin.(1) Later, during the 19th century, Irish physician William O’Shaughnessy and French psychiatrist Jacques-Joseph Moreau corroborated these use cases and noted that cannabis could help people with muscle spasms, vomiting, convulsions, rheumatism, tetanus, and rabies.(2) Although political prejudices caused interest in C. sativa to decline during the 20th century, the plant has since enjoyed a resurgence in modern times. According to a United Nations report published in 2020, approximately 4.7% of Americans use marijuana on a daily basis.(3) As of October 2021, 36 U.S. states, Puerto Rico, and Guam have also legalized medicinal marijuana despite its prohibition at the federal level (Figure 2)(4). Increasing use of marijuana will very likely fuel inquiries from patients, who may wonder about the plant’s therapeutic potential in cancer settings. As laws surrounding cannabis continue to loosen, it is increasingly imperative for oncologists, clinicians, and patients to become more familiar with the benefits and treatment-related adverse events associated with marijuana consumption.(5)
II. Mechanism of Action
C. sativa is replete with terpene phenolic compounds known as phytocannabinoids. Over time, researchers have isolated and characterized more than 100 plant-based cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabinol, and cannabidiol (CBD).(6) These plant-derived cannabinoids when ingested will interact with two classes of differentially expressed cannabinoid receptors. Cannabinoid receptor type 1 (CB1) is found in the basal ganglia, limbic system, and various non-neural tissues, whereas cannabinoid receptor type 2 (CB2) is predominantly expressed by cells of the immune system and spleen.(7) Activation of CB1 and CB2 by phytocannabinoids or endocannabinoids secreted by neurons and immune cells results in the inhibition of adenylyl cyclase. This inhibition, in turn, results in reduced production of the secondary messenger molecule cyclic adenosine monophosphate (cAMP) and downstream activation of many signaling pathways mediated by mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), or cyclooxygenase 2 (COX2).(8) Additionally, cannabinoids appear to downregulate angiogenesis through modulation of the vascular endothelial growth factor (VEGF) signaling pathway and suppresses metastasis through inhibition of enzymes implicated in cell adhesion and migration.(9)
Cannabinoids also appear to act synergistically, and investigators have noted that use of the whole plant extract has a superior therapeutic effect in comparison to individual isolated cannabinoids. Terpenes and secondary metabolites enhance the activity of isolated cannabinoids. More research is needed to better understand the interactions among the various compounds that occur in cannabis.(7)
III. Completed Studies
Results from completed studies most strongly support the use of cannabinoids to treat patients with chemotherapy-induced nausea and vomiting (CINV). In a Cochrane meta-analysis of 23 randomized clinical trials, investigators noted that patients taking dronabinol or nabilone (cannabinoids) had a higher likelihood of reporting the complete absence of CINV than those assigned placebo.(10) Improvements in CINV are offset by a higher rate of treatment-related adverse events like sedation, dizziness, and disorientation. Despite these side effects, patients across studies have reported a preference for THC:CBD and synthetic cannabinoids over alternative antiemetics like prochlorperazine.(10,11) Because of their efficacy, both the National Comprehensive Cancer Network guidelines and American Society of Clinical Oncology recommend FDA-approved cannabinoids to treat CINV in the event of failure of standard antiemetic therapies.(12,13) Findings from one analysis suggest that 40% of patients receiving chemotherapy still experience nausea and vomiting in spite of treatment with serotonin/5-HT3 and neurokinin 1 antagonists.(14)
Although the “munchies” – a strong, sudden desire to eat – is among the most well-known effects of marijuana, surprisingly less evidence supports its use to counteract cachexia.(15) In a study comparing dronabinol, dronabinol with megestrol acetate, and megestrol acetate monotherapy, researchers concluded that combination therapy offered no statistically significant benefits in terms of promoting appetite or weight gain when compared with megestrol acetate.(16) Some contrasting evidence suggests that patients with advanced cancers taking THC:CBD capsules over a 6 month period can achieve >10% weight gain. That said, the number of participants in the pilot study deriving this benefit was relatively small (n=3), and many patients with advanced cancer had to discontinue the study because of disease progression.(17) Because of the conflicting results in the existing literature, adequately powered studies are warranted to clarify if formulations of cannabinoids can promote weight gain and stimulate appetite. (18)
IV. Current Clinical Trials
Currently, no clinical trials are currently underway to assess the effects of cannabinoids in patients diagnosed with cancer. That said, findings from a double-blind, exploratory phase IB study conducted in the United Kingdom may justify renewed research on this topic. For the trial, investigators administered an oromucosal spray containing a 1:1 ratio of THC and CBD in conjunction with temozolomide in patients with recurrent glioblastoma multiforme. In the open label group (n=6) and randomized group (n=21), progression-free survival at 6 months was 33%. Additionally, 83.3% of patients receiving the THC:CBD mixture with temozolomide were alive at 1 year versus 44.4% of patients who received placebo (P = 0.042). Although the study was not powered for a survival endpoint, overall survival rates at 2 years continued to favor the cannabinoid combination treatment group.(19) These findings require corroboration, as they challenge previous conclusions drawn from earlier studies whose results suggest that intratumoral injection of THC has no meaningful, clinical benefit in glioblastoma multiforme.(20)
A high potency extract formulation of cannabis, Rick Simpson Oil (RSO), has anecdotal evidence supporting its use in patients with cancer. Its creator, Rick Simpson, claims applying the oil to cancer on his skin cleared the spots within days. Many have resorted to using RSO orally and once again the results are only anecdotal and no formal studies in the cancer population are available. RSO’s ability to address high blood pressure, infections, chronic inflammation, arthritis, asthma, and other non-cancerous conditions remains unclear, as less evidence exists to support these claims.(21)
V. Cost & Availability of Cannabis Therapy
The price per ounce of cannabis has progressively fallen since its legalization in many jurisdictions across the United States. According to the Cannabis Control Commission, the monthly average cost for an ounce of adult-use cannabis topped $400 in early 2019. Since then, the average has fallen nearly 10% to $362 in September 2021. Less mature markets situated around states where cannabis sales remain prohibited (e.g., Massachusetts) tend to have higher prices for marijuana than Western states like Colorado, California, Oregon, and Nevada. Increasing supply and competition from legal vendors may drive prices downward in the future, but these forces are counteracted and delayed by licensure requirements.(22) As such, marijuana purchased on the street is generally cheaper and retails between $250 and $300 per ounce. In states where personal and medical use of marijuana is prohibited, street prices are generally higher to account for the risks associated with its illicit cultivation and distribution.(23)
Extensive, high-quality research on cannabis remains relatively scant because of marijuana’s status as a Schedule 1 drug at the federal level in the United States.(24) Indeed, opposition to medicinal marijuana has proven prevalent at the highest levels of government, with former Health and Human Services Secretary Alex Azar quipping that there is “no such thing as medical marijuana” as recently as March 2018.(25) Without sweeping legislation lifting this longstanding ban, researchers will continue to face time-consuming, costly procedural hurdles to obtain authorization to use marijuana in long-term, clinical trials. Acquiring the requisite supply for such studies also represents a challenge, as only one government contractor grows marijuana for federally funded research as of 2018. Varying statewide access policies continue to divide the opinions of doctors, who sometimes take a “don’t ask, don’t tell” approach to marijuana self-medication. Others explicitly advise against its use and substitute opioids or other prescriptions to manage pain.(23)
Demonized as the cause of “reefer madness” as recently as the early 20th century, marijuana has since emerged as an intriguing natural therapy in the context of cancer.(26) Although more research is required to validate its potential anticancer properties, cannabinoids have already demonstrated significant promise as an antiemetic and anxiolytic – a treatment useful for alleviating anxiety.(4) Future research must clarify key questions that remain unresolved surrounding the optimal dose, best route of administration, and specific indications. Additionally, because cannabidiol inhibits cytochrome P450 – an enzyme that metabolizes existing anticancer therapies – researchers need to better understand if there are drug-to-drug interactions that could multiply drug toxicity or decrease the efficacy of existing medications.(27) Additionally, the immunosuppressive impact on CBD2 receptors could potentially blunt some of the immune activation by the newer class of drugs PDL1 and PD1 inhibitors. Obtaining timely answers to these questions is critical to advancing medicine and offering patients with cancer alternatives to pain management drugs (e.g., opioids) and antiemetics forming the standard of care.
Stay strong and curious,
Charles J. Meakin MD, MHA, MS
Chief Medical Executive Care Oncology
Facebook Page: https://www.facebook.com/CareOncology/
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2 Mangal N, Erridge S, Habib N, et al. Cannabinoids in the landscape of cancer. J Cancer Res Clin Oncol. 2021;147(9):2507-2534.
3 United Nations Office on Drugs Crime. World Drug Report 2020, 2020. https://wdr.unodc.org/wdr2020/.
4 PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. Cannabis and Cannabinoids (PDQ): Health Professional Version. Updated October 14, 2021. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US).
5 Bodine M, Kemp AK. Medical cannabis use in oncology. Updated May 28, 2021. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2021.
6 Braile M, Marcella S, Marone G, et al. The interplay between the immune and the endocannabinoid systems in cancer. Cells. 2021;10(6):1282.
7 Singh K, Nassar N, Bachari A, et al. The pathophysiology and the therapeutic potential of cannabinoids in prostate cancer. Cancers (Basel). 2021;13(16):4107.
8 Javid EA, Phillips RM, Afshinjavid S, et al. Cannabinoid pharmacology in cancer research: a new hope for cancer patients? Eur J Pharmacol. 2016;775:1-14.
9 Velasco G, Sanchez C, Guzman M. Anticancer mechanisms of cannabinoids. Curr Oncol. 2016;23:23-32.
10 Smith LA, Azariah F, Lavender VT, et al. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev. 2015;11:CD009464.
11 Grimison P, Mersiades A, Kirby A, et al. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomized, placebo-controlled, phase II crossover trial. Ann Oncol. 2020;31(11):1553-1560
12 National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 1.2021. Plymouth Meeting, PA. Accessed November 30, 2021.
13 Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020;38(24):2782-2797.
14 Aapro M. CINV: still troubling patients after all these years. Support Care Cancer. 2018;26(Suppl 1):5-9.
15 Stromberg J. A scientific explanation of how marijuana causes the munchies. Smithsonian Magazine. https://www.smithsonianmag.com/science-nature/scientific-explanation-how-marijuana-causes-munchies-180949660/. Published February 9, 2014. Accessed November 30, 2021.
16 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. 2002;20(2):567-573.
17 Bar-Sela G, Zalman D, Semenysty V, et al. The effects of dosage-controlled cannabis capsules on cancer-related cachexia and anorexia syndrome in advanced cancer patients: pilot study. Integr Cancer Ther. 2019;18:1534735419881498.
18 Bodine M, Kemp AK. Medical cannabis use in oncology. In: StatPearls [Internet]. Treasure Island, FL. https://www.ncbi.nlm.nih.gov/books/NBK572067/. Updated May 28, 2021. Accessed November 30, 2021.
19 Twelves C, Sabel M, Checketts D, et al. A phase 1b randomized, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma. Br J Cancer. 2021;8:1379-1387.
20 Guzmán M, Duarte MJ, Blázquez C, et al. A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer. 2006;95(2):197-203.
21 Johnson J. Can Rick Simpson oil help treat cancer? Medical News Today. https://www.medicalnewstoday.com/articles/325612/. Published June 29, 2019. Accessed January 20, 2022.
22 Schoenberg S. Marijuana prices show signs of leveling out. Commonwealth Magazine. https://commonwealthmagazine.org/marijuana/marijuana-prices-show-signs-of-leveling-out/. Published October 22, 2021. Accessed November 30, 2021.
23 Smith J. How much does marijuana cost on the street? AddictionResource.net. https://www.addictionresource.net/cost-of-drugs/illicit/marijuana/. Updated June 21, 2021. Accessed November 30, 2021.
24 Taylor M, Bailey M. Medical marijuana’s ‘catch-22’: limits on research hinder patient relief. NPR. https://www.npr.org/sections/health-shots/2018/04/07/600209754/medical-marijuanas-catch-22-limits-on-research-hinders-patient-relief/. Published April 7, 2018. Accessed November 30, 2021.
25 Wedell K. ‘No such thing as medical marijuana,’ Health Secretary says. The Atlanta Journal-Constitution. https://www.ajc.com/news/national/such-thing-medical-marijuana-health-secretary-says/eZkOYR0zXTghh1seUvQPAI/. Published March 3, 2018. Accessed November 30, 2021.
26 Hunt K. Marijuana panic won’t die, but Reefer Madness will live forever. JSTOR Daily. https://daily.jstor.org/marijuana-panic-wont-die-but-reefer-madness-will-live-forever/. Published April 23, 2020. Accessed November 30, 2021.
27 Jiang R, Yamaori S, Okamoto Y, et al. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332-338.