Gliomas/Cancer

PrintGliomas (tumors in the brain) are especially aggressive malignant forms of cancer, often resulting in the deaths of affected patients within the 12 to 18 months following diagnosis. There is no cure for gliomas and most available treatments provide only minor symptomatic relief.

A review of the modern scientific literature reveals numerous preclinical studies, as well as a limited number of case reports and human studies, demonstrating cannabinoids’ ability to act as antineoplastic agents, particularly on glioma cell lines.

Writing in the September 1998 issue of the journal FEBS Letters, investigators at Madrid’s Complutense University School of Biology, were the first to report that delta-9-THC-induced apoptosis (programmed cell death) in glioma cells in culture.[1] Investigators followed up their initial findings in 2000, reporting that the administration of both THC and the synthetic cannabinoid agonist WIN 55,212-2 “induced a considerable regression of malignant gliomas” in animals.[2] Researchers again confirmed cannabinoids’ ability to inhibit glioma tumor growth in animals in 2003.[3]

Italian investigators that same year similarly reported that the non-psychoactive cannabinoid, cannabidiol (CBD), inhibited the growth of various human glioma cell lines in vivo and in vitro in a dose dependent manner. Writing in the November 2003 issue of the Journal of Pharmacology and Experimental Therapeutics Fast Forward, researchers concluded, “Non-psychoactive CBD … produce[s] a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.”[4]

In 2004, Guzman and colleagues reported that cannabinoids inhibited glioma tumor growth in animals and in human glioblastoma multiforme (GBM) tumor samples by altering blood vessel morphology (e.g., VEGF pathways). Writing in the August 2004 issue of Cancer Research, investigators concluded, “The present laboratory and clinical findings provide a novel pharmacological target for cannabinoid-based therapies.”[5]

Investigators at the California Pacific Medical Center Research Institute reported that the administration of THC to human glioblastoma multiforme cell lines decreased the proliferation of malignant cells and induced cell death more rapidly than the administration of the synthetic cannabinoid agonist WIN 55,212-2. Researchers also noted that THC selectively targeted malignant cells while ignoring healthy ones in a more profound manner than the synthetic alternative.[6] A separate preclinical trial reported that the combined administration of THC and the pharmaceutical agent temozolomide (TMZ) “enhanced autophagy” (programmed cell death) in brain tumors resistant to conventional anticancer treatments.[7]

A limited number of human studies demonstrate similar results. In 2006, Guzman and colleagues conducted the first ever pilot clinical trial assessing the intracranial use of cannabinoids and GBM. Investigators found that the intratumoral administration of THC was associated with reduced tumor cell proliferation in two of nine subjects. “The fair safety profile of THC, together with its possible anti-proliferative action on tumor cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids,” investigators concluded.[8] Several additional investigators have also called for further exploration of cannabis-based therapies for the treatment of glioma.[9-11]

In 2017, researchers affiliated with the British biotechnology firm, GW Pharmaceuticals, announced that the adjunctive use of plant-derived cannabis extracts was associated with increased survival times in patients with glioma. Trial participants taking medical cannabis lived a median of 550 days while those who did not lived a median of 369 days.[12]

A handful of case reports also provide promising evidence. One report, published in 2011 in the Journal of the International Society for Pediatric Neurosurgery, documents the spontaneous regression of residual brain tumors in two children coinciding with the subjects’ use of cannabis.[13]

Another case report, published in 2018, notes of the reduction of a brain tumor in a five-year-old patient following the use of synthetic CBD. Researchers acknowledged: “A scan carried out in December 2016 showed that tumor volume had decreased by ~60 percent. Further scans, carried out since December 2016, continued to show stable disease. CBD was the only treatment.”[14]

The following year, Brazilian investigators described the use of CBD in two 38-year-old patients with brain cancer. Authors reported that patients’ use of CBD in addition to traditional anticancer treatment was associated with a “significant improvement” in clinical outcomes and a lack of disease progression for two years. Researchers concluded, “These observations are of particular interest because the pharmacology of cannabinoids appears to be distinct from existing oncology medications and may offer a unique and possibly synergistic option for future glioma treatment.”[15]

A case series published that same year also reported on the use of plant-derived CBD in patients with brain cancer. Investigators reported that the concomitant administration of 400 mg of CBD with standard anticancer therapy was associated with longer than expected survival times in eight of nine select patients.[16]

Most recently, a team of Australian researchers assessed the daily administration of cannabis extracts containing either a one to one ratio or a four to one ratio of THC and CBD in 83 patients with glioma. Subjects in the trial consumed the extracts for a period of at least four weeks. Investigators concluded: “This study provides robust evidence that medicinal cannabis administered to this patient population is safe, well tolerated, and can provide symptomatic relief to these patients. … [It] suggests that cannabis, especially a 1:1 CBD/THC mixture, can be helpful for many of the symptoms impacting QoL [quality of life] in this patient population, especially sleep disturbance. As such, MC [medical cannabis] may be a valuable potential therapy for maintaining the best QoL and daily function for this poor prognosis population, whilst also assisting patients during anticancer and potential life extending therapies.”[17]

In addition to cannabinoids’ ability to moderate glioma cells in laboratory models, separate preclinical studies demonstrate that cannabinoids and endocannabinoids can also inhibit the proliferation of other cancer cell lines,[18-19] including breast carcinoma,[20-24] prostate carcinoma,[25-29] colorectal carcinoma,[30-31] gastric adenocarcinoma,[32] skin carcinoma,[33] leukemia cells,[34-38] neuroblastoma,[39-40] lung carcinoma,[41-42] uterus carcinoma,[43] thyroid epithelioma,[44] pancreatic adenocarcinoma,[45-46] cervical carcinoma,[47-49] oral cancer,[50] biliary tract cancer (cholangiocarcinoma)[51] urological cancers,[52] and lymphoma,[53-54] among others. In some instances, improved anticancer activity has been reported when cannabinoids are administered in concert with one another, rather than in isolation.[55-56] A 2013 case report published in the journal Case Reports in Oncology also reports successful treatment with cannabis extracts in a 14-year-old patient diagnosed with an aggressive form of acute lymphoblastic leukemia.[57] Population studies also report an inverse relationship between cannabis use and the prevalence of various types of cancer, including lung cancer,[58] head and neck cancer,[59] and bladder cancer.[60]

Experts acknowledge that there exists “solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer,”[61] and that cannabinoids may one day “represent a new class of anticancer drugs that retard cancer growth, inhibit angiogenesis and the metastatic spreading of cancer cells.”[62-63] Presently, medical cannabis use is prevalent among patients with various types of cancer, though many say that they “desire but are not receiving information about cannabis use during their treatment from oncology providers.”[64] Despite an absence of large-scale clinical trials, “abundant anecdotal reports describe patients having remarkable responses to cannabis as an anticancer agent, especially when taken as a high-potency orally ingested concentrate. … [Further] human studies should be conducted to address critical questions related to the foregoing effects.”[65]

REFERENCES

[1] Guzman et al. 1998. Delta-9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Letters 436: 6-10.

[2] Guzman et al. 2000. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Medicine 6: 313-319.

[3] Guzman et al. 2003. Inhibition of tumor angiogenesis by cannabinoids. The FASEB Journal 17: 529-531.

[4] Massi et al. 2004. Antitumor Effects of Cannabidiol, a Nonpsychotropic Cannabinoid, on Human Glioma Cell Lines. Journal of Pharmacology and Experimental Therapeutics Fast Forward 308: 838-845.

[5] Guzman et al. 2004. Cannabinoids inhibit the vascular endothelial growth factor pathways in gliomas (PDF). Cancer Research 64: 5617-5623.

[6] Allister et al. 2005. Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. Journal of Neurooncology 74: 31-40.

[7] Torres et al. 2011. A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma. Molecular Cannabis Therapeutics 10: 90.

[8] Guzman et al. 2006. A pilot clinical study of delta-9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer 95: 197-203.

[9] Parolaro and Massi. 2008. Cannabinoids as a potential new drug therapy for the treatment of gliomas. Expert Reviews of Neurotherapeutics 8: 37-49.

[10] Galanti et al. 2007. Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncologica 12: 1-9.

[11] Calatozzolo et al. 2007. Expression of cannabinoid receptors and neurotrophins in human gliomas. Neurological Sciences 28: 304-310.

[12] GW Pharmaceuticals, “GW Pharmaceuticals achieves positive results in Phase 2 proof of concept study in glioma,” February 7, 2017.

[13] Foroughi et al. 2011. Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas–possible role of cannabis inhalation. Child’s Nervous System 27: 671-679.

[14] Kenyon et al., 2018. Report of objective clinical responses of cancer patients to pharmaceutical-grade synthetic cannabidiol. Anticancer Research 38: 5831-5835. 

[15] Dall’Stella et al., 2019. Case Report: Clinical Outcome and Image Response of Two Patients With Secondary High-Grade Glioma Treated With Chemoradiation, PCV, and Cannabidiol. Frontiers in Oncology [open access journal].

[16] Likar et al., 2019. Concomitant treatment of malignant brain tumors with CBD: A case series and review of the literature. Anticancer Research 39: 5797-5801. 

[17] Schloss et al., 2021. A phase II randomized clinical trial assessing the tolerability of two different ratios of medicinal cannabis in patients with high grade gliomasFrontiers in Oncology [online access publication]. 

[18] Turgeman and Bar-Sela. 2017. Cannabis use in palliative oncology: A review of the evidence for popular indications. Israel Medical Association Journal 19: 85-88.

[19] Pokrywka et al. 2016. Cannabinoids-–a new weapon against cancer? Postepy Hig Med Dosw 70: 1309-1320.

[20] Cafferal et al. 2006. Delta-9-Tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Research 66: 6615-6621.

[21] Di Marzo et al. 2006. Anti-tumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. Journal of Pharmacology and Experimental Therapeutics Fast Forward 318: 1375-1387.

[22] De Petrocellis et al. 1998. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 95: 8375-8380.

[23] McAllister et al. 2007. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Molecular Cancer Therapeutics 6: 2921-2927.

[24] Cafferal et al. 2010. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Molecular Cancer 9: 196.

[25] Sarfaraz et al. 2005. Cannabinoid receptors as a novel target for the treatment of prostate cancer. Cancer Research 65: 1635-1641.

[26] Mimeault et al. 2003. Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines. Prostate 56: 1-12.

[27] Ruiz et al. 1999. Delta-9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Letters 458: 400-404.

[28] Ramos and Bianco. 2012. The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications. Journal of Urology 28: 9-14.

[29] DePetrocellis et al. 2013. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. British Journal of Pharmacology 168: 79-102.

[30] Pastos et al. 2005. The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase-2. Gut 54: 1741-1750.

[31] Aviello et al. 2012. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. Journal of Molecular Medicine 90: 925-934.

[32] Di Marzo et al. 2006. op. cit.

[33] Casanova et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. 2003. Journal of Clinical Investigation 111: 43-50.

[34] Powles et al. 2005. Cannabis-induced cytotoxicity in leukemic cell lines. Blood 105: 1214-1221.

[35] Jia et al 2006. Delta-9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemic T cells is regulated by translocation of Bad to mitochondria. Molecular Cancer Research 4: 549-562.

[36] Liu et al. 2008. Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach. Leukemia and Lymphoma 49: 1800-1809.

[37] Scott et al. 2013. Enhancing the activity of cannabidiol and other cannabinoids in vitro through modifications to drug combinations and treatment schedules 33: 4373-4380.

[38] Kampa-Schittenhelm et al. 2016. Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns. BMC Cancer.

[39] Manuel Guzman. 2003. Cannabinoids: potential anticancer agents (PDF). Nature Reviews Cancer 3: 745-755.

[40] Marcu et al. 2010. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Molecular Cancer Therapeutics 9: 180-189.

[41] Guzman. 2003 op. cit.

[42] Preet et al. 2008. Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 10: 339-346.

[43] Manuel Guzman. 2003. Cannabinoids: potential anticancer agents. Nature Reviews Cancer 3: 745-755.

[44] Baek et al. 1998. Boron trifluoride etherate on silica-A modified Lewis acid reagent (VII). Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Archives of Pharmacal Research: 21: 353-356.

[45] Carracedo et al. 2006. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Research 66: 6748-6755.

[46] Michalski et al. 2008. Cannabinoids in pancreatic cancer: correlation with survival and pain. International Journal of Cancer 122: 742-750.

[47] Ramer and Hinz. 2008. Inhibition of cancer cell invasion by cannabinoids via increased cell expression of tissue inhibitor of matrix metalloproteinases-1. Journal of the National Cancer Institute 100: 59-69.

[48] Lukhele and Motadi. 2016. Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells. BMC Complementary and Alternative Medicine 16: 336.

[49] Lukhele and Motadi. 2016. Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and cervical cancer cells. BMC Complementary and Alternative Medicine 16: 335.

[50] Whyte et al. 2010. Cannabinoids inhibit cellular respiration of human oral cancer cells. Pharmacology 85: 328-335.

[51] Leelawat et al. 2010. The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration. Cancer Investigation 28: 357-363.

[52] Gandhi et al. Systematic review of the potential role of cannabinoids as antiproliferative agents for urological cancers. Canadian Urological Association Journal 11: 3-4.

[53] Gustafsson et al. 2006. Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Molecular Pharmacology 70: 1612-1620.

[54] Gustafsson et al. 2008. Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation. International Journal of Cancer 123: 1025-1033.

[55] Torres et al. 2011.op. cit.

[56] Scott et al. 2013. op. cit.

[57] Singh and Bali. 2013. Cannabis Extract Treatment for Terminal Acute Lymphoblastic Leukemia with a Philadelphia Chromosome Mutation. Case Reports in Oncology 6: 585-592.

[58] Washington Post. May 26, 2006. “Study finds no cancer-marijuana connection.”

[59] Liang et al. 2009. A population-based case-control study of marijuana use and head and neck squamous cell carcinoma. Cancer Prevention Research 2: 759-768.

[60] Thomas et al. 2015. Association between cannabis use and the risk of bladder cancer: Results from the California Men’s Health Study. Urology 85: 388-393.

[61] Velasco et al. 2015. The use of cannabinoids as anticancer agents. Progress in Neuro-Psychopharmacology and Biological Chemistry. 64: 259-266.

[62] Natalya Kogan. 2005. Cannabinoids and cancer. Mini-Reviews in Medicinal Chemistry 5: 941-952.

[63] Sarafaraz et al. 2008. Cannabinoids for cancer treatment: progress and promise. Cancer Research 68: 339-342.

[64] Pergam et al. 2017. Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer [online ahead of print].

[65] Donald Abrams. 2016. Integrating cannabis into clinical care. Current Oncology 23: S8-S14.