Cannabis Therapeutics and the Future of Neurology

Ethan B. Russo  (October 2018)

To Proceed to the Article Click Here

Strong scientific evidence of cytotoxic benefit of phytocannabinoids has been available since 1975 (Munson et al., 1975) and highlighted three decades later (Ligresti et al., 2006), but the historical record suggests ancient use by Egyptian Copts (THC and/or THCA; Reymond, 1976; Russo, 2007) with similar claims by Renaissance herbalists in Europe (CBD and/or CBDA; Russo, 2007). Brain tumors are the subject of an excellent current review (Dumitru et al., 2018). To summarize available research, specific pro-apoptotic activity of THC in C6 glioma was reported (Sánchez et al., 1998), and shrinkage of in situ human glioma cell line tumors was observed with CBD (Massi et al., 2004). Intra-tumoral THC administration in glioblastoma multiforme (GBM) produced slight life prolongation over expectations in nine human patients (Guzmán et al., 2006). Case reports from Canada documented total regression of residua in two pilocytic astrocytomata in children after smoked cannabis (Foroughi et al., 2011). Careful laboratory analysis has established synergistic benefits of combinations of THC, CBD and standard chemotherapy with temozolomide on glioma (Torres et al., 2011). Clinical application of the concept has been reported online in a Phase II randomized controlled trial (RCT) of 21 patients with recurrent GBM on temozolomide plus nabiximols up to 12 sprays per day (32.4 mg THC plus 30 mg CBD plus terpenoids) vs. placebo with an 83% 1-year survival vs. 53% in controls (p = 0.042) and survival exceeding 550 days vs. 369 for controls, and only two withdrawals in each group due to adverse events (AEs)2.

Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs

Claudia A. Dumitru, I. Erol Sandalcioglu and Meliha Karsak  (May 2018)

To Proceed to the Article Click Here

Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection and radio-chemotherapy, more than 95% of GBM patients die within 5 years after diagnosis. Thus, there is still an urgent need to develop novel therapeutic strategies against this disease. Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM. This review article summarizes the latest findings on the molecular effects of cannabinoids on GBM, both in vitro and in (pre-) clinical studies in animal models and patients. The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors. Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment. Taken together these findings underline the importance of elucidating the full pharmacological effectiveness and the molecular mechanisms of the cannabinoid system in GBM pathophysiology.

Insight on the Impact of Endocannabinoid System in Cancer: A Review

Ana Isabel Fraguas-Sanchez, Cristina Martin-Sabroso, Ana Isabel Torres-Suarez  (2018)

To Proceed to the Article Click Here

In the last decades, the endocannabinoid system has attracted a great interest in medicine and cancer disease is probably one of its most promising therapeutic areas.  On the one hand, endocannabinoid system expression has been found altered in numerous types of tumors compared to healthy tissue, and this aberrant expression has been related to cancer prognosis and outcome, suggesting a role of this system in tumour growth and progression that depends on cancer type.  On the other hand, it has been reported that cannabinoids exert an anticancer activity by inhibiting the proliferation, migration and/or invasion of cancer cells; and also tumour angiogensis.

 A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM).

Chris Twelves, Susan Short, Stephen Wright  (May 2017)

To Proceed to the Article Click Here

Several plant-derived cannabinoids have shown efficacy in animal models of GBM, particularly when co-administered with temozolomide, a commonly-used treatment in both primary and recurrent disease. This randomized study provides preliminary evidence that 1:1 CBD:THC offers some efficacy in patients with recurrent GBM when used as an adjunct to dose-intense temozolomide and confirms the safety and feasibility of individualized dosing.

Letter to the editor re Sredni et al.: spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system

Paul Steinbok  (December 2016)

To Proceed to the Article Click Here

I wish to compliment Sredni et al. [1] for their report “Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system.” They found that incompletely resected pediatric low-grade gliomas which remained stable or involuted spontaneously expressed higher levels of the cannabinoid receptor 1 (CNR1) than those tumors which progressed. They suggested that spontaneous involution of these pediatric low-grade gliomas may have been induced by endocannabinoids. I found this particularly interesting in the light of our previous report of two incompletely resected septum pellucidum pediatric low-grade astrocytomas that involuted spontaneously concurrent with the use of cannabis [2]. I wonder if one might be able to identify a population of low-grade gliomas and perhaps other brain tumors with elevated levels of CNR1 that might be particularly susceptible to involution with the use of cannabis. This “drug” could then be potentially used as a chemotherapeutic agent in such patients.

Anti‑carcinogenic activity of anandamide on human glioma in vitro and in vivo

Chao Ma, Ting‑Ting Wu, Pu‑Cha Jiang, Zhi‑Qiang Li, Xin‑Jun Chen, Kai Fu, Wei Wang, Rui Gong  (December 2015)

To Proceed to the Article Click Here

The poor prognosis of gliomas is to a large extent attributed to the markedly proliferative and invasive nature of the disease. Endocannabinoids have emerged as novel potential anti‑tumor agents. The present study aimed to investigate the anti‑carcinogenic activity of anandamide (AEA), an endocannabinoid, on glioma cells. To assess the functional role of AEA in glioma, the effects of AEA on cell proliferation, migration, invasion, apoptosis and the cell cycle in vitro, and tumor growth in vivo, were investigated. AEA markedly inhibited the proliferation of U251 cells in a dose‑ and time‑dependent manner.

Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients’ cells

Elena Ciaglia, Giovanni Torelli, Simona Pisanti, Paola Picardi, Alba D’Alessandro, Chiara Laezza, Anna Maria Malfitano, Donatella Fiore, Antonio Christian Pagano Zottola, Maria Chiara Proto, Giuseppe Catapano, Patrizia Gazzerro and Maurizio Bifulco  (June 2015)
CB1 is implicated in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in several physio-pathological conditions. We shed light on previously unrecognized molecular mechanism of CB1-mediated modulation of human glioma progression and provide the first and original demonstration of CB1-STAT3 axis as a new target and predictor biomarkers of the benefit from specific therapies. Indeed CB1 antagonism capable of tumoral cell division’ control while making the glioma immunovisible and engaging the immune system to fight it may represent a hopeful alternative to other established chemotherapeutics. Because different aspects of glioma biology have been separately targeted with very limited success, we speculate that CB1 inhibitors which enclose in the same molecule cytotoxic potential and high activity to boost competent immune surveillance mechanisms, at a degree that seems to be correlated to the levels of CB1 immunoreactivity, might have profound implications for exploring new therapeutic anti-glioma actions.

The use of cannabinoids as anticancer agents

Guillermo Velasco, Sonia Hernández-TiedraDavid DávilaMar Lorente  (June 2015) 

To Proceed to the Article Click Here

It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.