Clinical Investigation Support GmbH, Kaiserstrasse, Austria
Anti-cancer effects of cannabinoids have long been argued. Scientific evidence goes back to 1974 at the Medical College of Virginia at the behest of the US government. In an attempt to provide data proving a link between cannabis and cancer risk in order to provide evidence justifying international prohibition, the contrary was observed . With the detection of the endocannabinoid system in the early 90-ies, much insight was gained into the mechanisms of cannabinoids; a number of preclinical studies, in vitro as well as in vivo, confirmed the antineoplastic properties of both, phyto- and synthetic cannabinoids. Out of the phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best studied substances. These two cannabinoids differ in their effective doses: Common oral doses of THC are in the order of two to three times 2.5 mg to 10 mg/day, whereas CBD is currently administered in a dose of 100 to 300mg twice daily; doses up to 1,500mg CBD have been well tolerated. THC has some inherent clinical drawbacks due to its psychotropic properties, in addition to increased anxiety and withdrawal symptoms after high doses and down-regulation of CB1 receptors [3,4]. In contrast, CBD is free from such constraints. Furthermore, THC is unsuited for children and adolescents. Although rare when compared with adults, brain tumors are the most common solid tumors in children.
What are the perspectives of cannabidiol (CBD) for the treatment of glioblastoma?
Glioblastoma (GBM) or WHO grade IV astrocytoma is the most aggressive form of brain tumors and ranks among the deadliest types of cancer. It is also the most common malignant primary brain tumor. Its high proliferation rate and invasiveness, together with a considerable cellular and molecular heterogeneity, is a challenge for treatment. Current therapeutic strategies include surgery, chemotherapy, radiotherapy and combinations thereof. Temozolomid (TMZ) is considered as the benchmark for treatment but resistance to TMZ antitumoral action is frequent and contributes to the overall poor prognosis. After second line treatment with TMZ, median survival is around 5.1 to 13 months, depending on the study .
cannabidiol, CBD, cannabinoids, delta-9-tetrahydrocannabinol, THC, glioblastoma
Cannabinoids demonstrate tumor-specific cytostatic/cytotoxic effects modulating the growth of glioblastoma by multiple, often overlapping mechanisms that repeatedly showed synergism when combined with other treatments. In particular CBD has been reported to activate apoptosis via oxidative stress (increase in ROS production in tumor cells ), and to inhibit tumor cell proliferation by inducing cell cycle arrest. Furthermore, CBD inhibits tumor angiogenesis and infiltration/ invasion even at low concentrations and abrogates resistance of glioma stem-like cells to BCNU (carmustine) therapy . Cannabinoids are synergistic with chemotherapy and also with gamma-irradiation [7-9]. So far, experiments suggest that high doses of cannabinoids are necessary in order to achieve anti-tumor effects. In the inverse, low concentrations or doses respectively, may even enhance the growth of glioma, lung and breast cancer cells in vitro  and in vivo [11,12]. In addition to the tissue concentration and experimental conditions, effects depend very much upon the nature of the tumor cells. Although preclinical results cannot be transferred one-to-one to the situation in man, dose-dependency has been observed not only in vitro but also in animal experiments. A condensed overview on available in vivo results with CBD is presented in table 1.
The findings come as The Brain Tumour Charity has launched an exceptional grant round with a view to funding a phase II/III multi-centre placebo-controlled clinical trial of cannabinoids in the treatment of high-grade gliomas later this year.
“We know there is significant interest among our community about the potential activity of cannabinoids in helping relieve symptoms and as a treatment, and we need to do all we can to accelerate these answers and to drive progress.
“These are really promising findings and we now urgently need to see a larger clinical trial to understand whether adding cannabinoids to chemotherapy could offer precious extra time to live for people living with a glioblastoma.
Sativex – also known as nabiximols – is a complex botanical formulation containing cannabinoids THC and CBD, alongside other components. It is currently licensed and used in treating muscle stiffness and spasms in certain people with multiple sclerosis.
In the first part of the study, 6 patients received a personalised regime of Sativex of up to 12 sprays per day, alongside their temozolomide therapy – and the side-effects were recorded and reviewed.