Cbd oil dosage for brain tumor

Cbd oil dosage for brain tumor

cannabidiol, CBD, cannabinoids, delta-9-tetrahydrocannabinol, THC, 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 [1].

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 [2]. 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.

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 [5]), 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 [6]. 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 [10] 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.

Table 1. Results of CBD and CBD: THC combinations in animal models of glioma

Treatment

Model

Results

Ref.

~25mg s.c./kg/d, 5d /w for 23 d,

U87MG astro-cytoma s.c. xenograft, 8w old nude mice

~70% regression at day 18, but ~50% regression at day 23/end;

CBD + THC (each ~2 mg i.p./kg) on day 9, 13, 16 after tumor implantation; X-ray (4 Gy) on d9;

CBD-BDS (63.5% CBD, 3.6% THC, 5.2% CBC) or THC-BDS (65.4% THC, 0.4% CBD, 1.8% CBC)

mouse glioma GL261 cells, orthotopically implanted, C57BL/6 mice (~9w old)

85% decrease of tumor volume and of vascularisation on d21 (animals sacrificed); CBD + THC reduced progression, further enhanced by irradiation (stagnant tumor sizes throughout the experiment); X-rays alone had no dramatic effect;

In vitro effects (human glioma cell lines T98G, U87MG, mouse glioma GL261) differed: THC-BDS was more efficacious than THC-P; conversely, CBD-P was more efficacious than CBD-BDS; pretreatment of cells with THC-P + CBD-P together for 4 hours before irradiation increased radiosensitivity (P-pure > 96%)

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CBD 15 mg i.p./kg, 5 days/w

athymic, GSC-bearing nu/nu mice

significant increase in the survival; initial response to CBD (reduction of tumor size at d22), followed by tumor resistance 1w later, d 29)

15 mg i.p./kg, 5 d/w for 28 days

U251 glioblastoma cells, intracranial xenograft, mice

~95% decrease of tumor area; in 1/5 mice treated no tumor cells were observed in any of the brain regions analyzed;

CBD or THC 7.5 mg /kg/d; or CBD + THC 7.5mg each/kg/d; or 15mg THC/kg /d; or CBD+THC each 3.7 mg/kg/d + TMZ 5 mg/kg/d, peritumoral, 15d

human glioma U87MG or T98G cells, s.c. xenograft, nude mice

7.5mg CBD/kg was slightly more effective than 7.5mg THC/kg; THC + CBD (each 7.5 mg/kg) was most effective and similar to 15mg THC/kg; tumor volume was stable on day 14 and 15; further enhancement by combination of THC with 5mg TMZ/kg; the triple combination of THC, CBD, and TMZ strongly reduced the growth of glioma xenografts and overcomed the resistance to TMZ antitumoral action

BDS: Botanical Drug Substance (extract); B.W: Body Weight; CBC – Cannabichromene; d: day; GIC – Glioma Initiating Cells; exchangeable with GSC: Glioma Stem Cells; i.p.: intraperitoneal; nu: nude; s.c.: subcutaneous; TMZ: Temozolomide; w: week

As can be seen, all experiments used relatively high doses of cannabinoids and all reported a significant effect on tumor growth and/or survival; in one experiment, one of five animals were even completely free of cancer after receiving 15 mg CBD/kg [13].

In man, results of glioblastoma treatment with cannabinoids are still limited and restricted to the pioneering study of Guzman et al. [15] with THC, and a recent phase I/II – study that administered nabiximols, a 1:1 combination of two refined extracts, each containing around 65–70% CBD or THC respectively, as add-on treatment to TMZ [16]. In the first study, THC was infused into the resection cavity of nine freshly operated patients with treatment-resistant glioblastoma. Overall, the initial dose of THC administered to the patients was 20 to 40 mg at day 1, increasing progressively for 2 to 5 days up to 80 to 180 mg/day which corresponds to a very high, local dose. Most interesting, in those five patients that received more than one cycle (median duration per cycle: 10 days), three patients demonstrated a temporary reduction of tumor proliferation.

In the second study, patients with recurrent glioblastoma received a combination of CBD/THC up to a maximum tolerated dose (maximum 12 sprays per day, i.e. up to 30mg CBD + 32.4 mg THC per day) or placebo, in combination with dose-intense TMZ. The one-year survival rate was significantly higher (83%) in the group that received nabiximols (12 patients) compared to the placebo-group (9 patients, 53% survived). Median survival was over 550 days compared to 369 (i.e. + 6 months). There is reason to assume that a higher ratio in favor of CBD such as 4/1 to 5/1 (CBD/THC) could achieve similar, may be even better results with a better tolerance as has been suggested by a very recent animal study [17]. With respect to the difference in effective doses between CBD and THC mentioned above, this animal experiment could be particularly relevant for man.

In addition to the antineoplastic action, CBD has been reported to reduce nausea and/or vomiting [18], as well as having anti-depressive and analgesic properties. A very recent case series on glioma patients confirmed these effects [19].

In summary, combination of various anticancer regimens that include cannabinoids seems to be at present the most promising strategy for the treatment of glioblastoma and for improving the survival of patients. The large therapeutic range and excellent tolerance makes CBD an interesting substance for combination with temozolomid, radiation and/or other cannabinoids.

World-first trial tests cannabis-based drug on aggressive brain tumours

A major UK trial of cannabis-based drug Sativex in treating the most aggressive form of brain tumour is to launch at 15 NHS hospitals, following promising results from a phase I study in 27 patients.

The new phase II trial, led by the University of Leeds, will assess whether adding Sativex – an oral spray containing cannabinoids THC and CBD – to chemotherapy, could extend life for thousands diagnosed with a recurrent glioblastoma. Currently, it has an average survival of less than 10 months.

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The drug, already used in treating multiple sclerosis, was found to be tolerable in combination with chemotherapy, with the potential to extend survival, in a phase I trial in glioblastomas earlier this year.

While the phase I study observed that more patients were alive after one year in the Sativex arm compared to the placebo arm, the study was not sufficiently powered to show survival impact.

The new three-year phase II trial (ARISTOCRAT), funded by The Brain Tumour Charity and co-ordinated by the Cancer Research UK Clinical Trials Unit at the University of Birmingham, is due to begin recruiting more than 230 patients across all UK nations in early 2022, subject to sufficient funds being raised.

Having seen its income drop by more than 25% last year due to the pandemic and forced to pause its regular research grant funding programme, The Brain Tumour Charity has today launched an appeal to raise the £450,000 needed to open the trial as soon as possible.

Experts hope that, should the trial prove successful, Sativex could represent one of the first additions to NHS treatment for glioblastoma patients since temozolomide chemotherapy in 2007.

Professor Susan Short (pictured above), is the principal investigator on the new trial and Professor of Clinical Oncology and Neuro-Oncology at Leeds. She said: “The treatment of glioblastomas remains extremely challenging. Even with surgery, radiotherapy and chemotherapy, nearly all of these brain tumours re-grow within a year, and unfortunately there are very few options for patients once this occurs.

“Glioblastoma brain tumours have been shown to have receptors to cannabinoids on their cell surfaces, and laboratory studies on glioblastoma cells have shown these drugs may slow tumour growth and work particularly well when used with temozolomide.

“Having recently shown that a specific cannabinoid combination given by oral spray could be safely added to temozolomide chemotherapy, we’re really excited to build on these findings to assess whether this drug could help glioblastoma patients live longer in a major randomised trial.”

Tackling aggressive brain cancer

Glioblastomas are the most common and most aggressive form of brain cancer, with around 2,200 people diagnosed each year in England alone. They are usually fast-growing and diffuse, with poorly-defined boundaries and thread-like tendrils that extend into other parts of the brain.

Almost all glioblastomas recur even after intensive treatment including surgery, radiotherapy and chemotherapy, and average survival is just 12-18 months from first diagnosis.

Over the last decade there has been significant global interest within both patient and scientific communities about the activity of cannabinoids in brain tumours, with the view that cannabinoid-based products may not only help relieve symptoms but could also have a positive impact on survival.

Several pre-clinical laboratory studies have suggested that cannabinoids THC and CBD may reduce brain tumour cell growth and could disrupt the blood supply to tumours – but to date, clinical evidence that they could treat brain tumours has been limited.

In this new phase II trial, researchers will assess whether adding Sativex to the current standard chemotherapy treatment (temozolomide) could offer extra time to live for adults diagnosed with a recurrence of their glioblastoma after initial treatment.

‘Life beyond a glioblastoma diagnosis’

Stephen Lee, 62 from Leyland in Lancashire, took part in the phase I trial of Sativex in 2015 after his glioblastoma returned following initial treatment. Stephen was first diagnosed in 2010, just a few months after he had very sadly lost his older brother to the same disease. Stephen said: “My diagnosis was very sudden and was one of those days you never forget. Having had to leave work early with a severe headache and a stabbing pain in my right eye, my wife insisted that we go straight to hospital after what my brother had experienced.

“I was admitted that same day, had a scan and that’s when they identified it was a brain tumour. I had the operation the following week, and beforehand my wife and I agreed that we wanted to stay positive, to keep living our lives and to enjoy however much time we had together.

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Stephen Lee with his wife

“I joined the early trial of Sativex in the hope that it could improve my quality of life, but I also thought it was important to do so as the chemotherapy and radiotherapy I was having had all been trialled by other people before it could be used safely. I thought it only right and proper that I followed in their footsteps and joined a trial to help prove a new drug which could benefit so many people in the future with a recurring glioblastoma.

“I took the oral spray 10 times a day, and it was easy as I could take it wherever we were going, even while out for dinner. While I don’t know whether I had Sativex or the placebo, since the trial finished in 2016, all my MRI scans have been clear.

“This new trial is so important as it will give people hope that there could be life beyond a glioblastoma diagnosis and that there are other treatments being trialled to support them to live their lives.”

The trial

The ARISTOCRAT trial plans to recruit 232 participants across a minimum of 15 hospitals: two thirds of the participants will be given temozolomide plus Sativex, while one third will be given temozolomide plus placebo.

Sativex, manufactured by GW Pharma, is an oromucosal spray containing 1:1 THC (Delta-9-tetrahydrocannabinol) and CBD (cannabidiol), with the active ingredients being absorbed in the lining of the mouth, either under the tongue or inside the cheek.

Participants will be asked to administer up to 12 sprays per day (or to the maximum dose they can tolerate if fewer than 12) of Sativex or placebo oral sprays.

Participants will then undergo regular follow-up including clinical assessment (every four weeks), blood tests, MRI scans (every eight weeks), and they will complete quality of life questionnaires. This will also be one of the first trials to integrate with The Brain Tumour Charity’s app BRIAN.

The trial will measure whether adding Sativex to chemotherapy extends the overall length of patients’ lives (overall survival), delays the progression of their disease (progression-free survival) or improves quality of life.

In the initial phase I study, the most common side-effects reported were fatigue, headache, vomiting and nausea, which were mostly classed as being mild-moderate in severity.

Dr David Jenkinson, Interim CEO at The Brain Tumour Charity, which is funding the trial, said: “We hope this trial could pave the way for a long-awaited new lifeline that could help offer glioblastoma patients precious extra months to live and make memories with their loved ones.

“With so few treatments available and average survival still so heartbreakingly short, thousands affected by a glioblastoma in the UK each year are in urgent need of new options and new hope.

“We know there is significant interest among our community about the potential activity of cannabinoids in treating glioblastomas, and we’re really excited that this world-first trial here in the UK could help accelerate these answers. The recent early-stage findings were really promising and we now look forward to understanding whether adding Sativex to chemotherapy could help offer life-extension and improved quality of life, which would be a major step forward in our ability to treat this devastating disease.

“But we also know that for many, this trial won’t come soon enough. In the meantime, while other cannabis-based products may help alleviate symptoms, there is insufficient evidence to recommend their use to help treat brain tumours. For anyone considering using cannabis-based products or other complementary therapies, it’s vital that you discuss these with your medical team first, as they could interact with other treatments such as anti-epileptic medicines or steroids.

“Anyone affected by a glioblastoma can speak to us for support and information on 0808 800 0004 or by emailing [email protected] If you need someone to talk to, we’re here for you.”