Cbd oil for gliomas mri images

CBD shows promise for fighting aggressive brain cancer

The researchers believe that CBD’s anti-cancer actions target mitochondria — the cell’s energy producing structures — by causing the mitochondria to dysfunction and release harmful reactive oxygen species. The mitochondria (teal color) in a canine cancer cell line are shown after 48 hours of treatment with a nonlethal dose of CBD isolate (40x objective lens). Credit: Chase Gross, Mando Ramirez, Jade Kurihara, Colorado State University

Findings from a new study examining human and canine brain cancer cells suggest that cannabidiol could be a useful therapy for a difficult-to-treat brain cancer. Cannabidiol, or CBD, is a non-psychoactive chemical compound derived from marijuana.

The study looked at glioblastoma, an often-deadly form of brain cancer that grows and spreads very quickly. Even with major advancements in treatment, survival rates for this cancer have not improved significantly.

“Further research and treatment options are urgently needed for patients afflicted by brain cancer,” said Chase Gross, a student in the Doctor of Veterinary Medicine/Master of Science program at Colorado State University. “Our work shows that CBD has the potential to provide an effective, synergistic glioblastoma therapy option and that it should continue to be vigorously studied.”

Mr. Gross was scheduled to present this research at the American Society for Pharmacology and Experimental Therapeutics annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team’s abstract was published in this month’s issue of The FASEB Journal.

Mr. Gross and colleagues examined human and canine glioblastoma cells because the cancer shows striking similarities between the two species. They tested the effects of CBD isolate, which contains 100 percent CBD, and CBD extract, which contains small amounts of other natural occurring compounds such as cannabigerol and tetrahydrocannabinol, or THC.

A bright field microscopy image (10x) illustrating the swollen intracellular vesicles observed after 48 hours of treatment with a lethal dose of CBD (10x objective lens). Swollen vesicles were a hallmark of CBD-induced cell death in all the cell lines studied. Credit: Chase Gross, Mando Ramirez, Colorado State University

“Our experiments showed that CBD slows cancer cell growth and is toxic to both canine and human glioblastoma cell lines,” said Mr. Gross. “Importantly, the differences in anti-cancer affects between CBD isolate and extract appear to be negligible.”

The new work revealed that the toxic effects of CBD are mediated through the cell’s natural pathway for apoptosis, a form of programmed cell death. The researchers also observed that CBD-induced cell death was characterized by large, swollen intracellular vesicles before the membrane begins to bulge and breakdown. This was true for all the cell lines studied.

The researchers believe that CBD’s anti-cancer actions target mitochondria—the cell’s energy producing structures—by causing the mitochondria to dysfunction and release harmful reactive oxygen species. Their experiments showed that cells treated with CBD exhibited significant decreases in mitochondrial activity.

“CBD has been zealously studied in cells for its anticancer properties over the last decade,” said Mr. Gross. “Our study helps complete the in vitro puzzle, allowing us to move forward in studying CBD’s effects on glioblastoma in a clinical setting using live animal models. This could lead to new treatments that would help both people and dogs that have this very serious cancer.”

Next, the researchers plan to transition from cell cultures to animal models to test CBD’s effects on glioblastoma. If the animal studies go well, the work could progress to clinical trials on dogs that are being treated for naturally occurring glioblastoma at the Colorado State University Veterinary Teaching Hospital.

Citation: CBD shows promise for fighting aggressive brain cancer (2020, April 27) retrieved 9 May 2022 from https://medicalxpress.com/news/2020-04-cbd-aggressive-brain-cancer.html

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Case Report: Clinical Outcome and Image Response of Two Patients With Secondary High-Grade Glioma Treated With Chemoradiation, PCV, and Cannabidiol

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Abstract

We describe two patients with a confirmed diagnosis of high-grade gliomas (grades III/IV), both presenting with O6-methylguanine-DNA methyltransferase (MGMT) methylated and isocitrate dehydrogenase (IDH-1) mutated who, after subtotal resection, were submitted to chemoradiation and followed by PCV, a multiple drug regimen (procarbazine, lomustine, and vincristine) associated with cannabidiol (CBD). Both patients presented with satisfactory clinical and imaging responses at periodic evaluations. Immediately after chemoradiation therapy, one of the patients presented with an exacerbated and precocious pseudoprogression (PSD) assessed by magnetic resonance imaging (MRI), which was resolved in a short period. The other patient presented with a marked remission of altered areas compared with the post-operative scans as assessed by MRI. Such aspects are not commonly observed in patients only treated with conventional modalities. This observation might highlight the potential effect of CBD to increase PSD or improve chemoradiation responses that impact survival. Further investigation with more patients and critical molecular analyses should be performed.

Keywords: high-grade glioma, cannabidiol, pseudoprogression, PCV, chemoradiation, cancer, cannabis, THC-tetrahydrocannabinol

Background

Gliomas, the most common primary brain tumors, account for more than 40% of all CNS neoplasms and are highly resistant to available therapeutic approaches (1, 2). These tumors often have a poor prognosis with a median survival time of ~1 year for patients with high-grade gliomas (grades III/IV) (3, 4). The Stupp protocol has become the standard of care treatment for primary glioblastoma (GBM), and has led to significantly improved survival (5). It consists of chemoradiation (combining chemotherapy and radiation therapy simultaneously) followed by adjuvant temozolomide (TMZ), an alkylating agent, and is associated with a medium survival rate of 15 months.

It was reported that 10% of GBM are secondary (progressing from a low-grade tumor, IDH mutated) (6) and that these patients often previously received prior chemotherapeutic treatment, there being no stand-by treatment for this condition. After progression from a low-grade tumor to a high-grade tumor, combination radiotherapy with TMZ is a good therapeutic option (5). However, patients who failed with TMZ started PCV, a multiple drug regimen (procarbazine, lomustine, and vincristine) adjuvant. Because of the adverse events (nausea and seizures) related to this treatment, we decided to use cannabidiol (CBD) from the irradiation phase onwards. A significant inflammatory response to the therapy was observed in one patient, which we considered pseudoprogression (PSD), and in the other patient, it presented with a marked remission of altered areas compared with the post-operative scans as assessed by MRI.

Tumor pseudoprogression (PSD) can occur in up to 30% of patients after chemoradiation, especially O6-methylguanine-DNA methyltransferase (MGTM) methylated cases. This corresponds to a treatment-related increase in lesion size related to inflammatory responses that simulate the progression of the disease. In almost 60% of cases, PSD occurs within the first 3–6 months after completing chemoradiation (5, 7, 8). PSD does not represent a progression of the disease, and is often a marker of longer survival, presumably because it represents a robust response to treatment (9).

Cannabidiol (CBD) is a prevalent natural cannabinoid. It is a non-intoxicating compound, instead of which may have, antipsychotic effects (10–12), and promote a wide spectrum of pharmacological effects including anti-inflammatory, anti-oxidant, anti-proliferative, anti-invasive, anti-metastatic, and pro-apoptotic activity (13–15). Recent studies have suggested CBD has immunomodulatory effects (15–18).

Cannabinoids are becoming promising anti-tumor drugs and increasing preclinical evidence reported that these compounds, including Δ 9 -tetrahydrocannabinol (THC), inhibited tumor growth in animal models of cancer by targeting specific cancer-cell signaling pathways. Furthermore THC act as broad-spectrum antiemetic against different emetic stimuli. And interestingly displayed as an active agent against immediate and delayed phases of chemotherapy-induced nausea and vomiting (19–23). Unfortunately, there are very few reports of the potential anti-tumor activity of cannabinoids in cancer patients.

Here, we describe two patients with a confirmed diagnosis of high-grade gliomas (grades III/IV), both presenting with MGMT methylated and IDH-1 mutated who, after subtotal resection, were submitted for chemoradiation followed by PCV associated with CBD. Despite the impressive inflammatory imaging immediately after chemoradiation, both patients presented with satisfactory clinical and imaging responses in the following periodic evaluations.

Case Presentation

Patient 1 was a 38 years-old male. In May 2010, this patient was diagnosed with glioma soon after an episode of seizures. MRI showed intra-axial expansive and infiltrative lesions that were cortical and subcortical, and which affected the anterior half of the right temporal lobe and extending from the pole to the Sylvian fissure superiorly and to the right parahippocampal gyrus, posteriorly, and medially. Partial surgical resection was performed in August 2010 and the first pathologic diagnosis was astrocytoma grade II. He underwent chemotherapy with TMZ at a dose of 2,000 mg with cycles every 28 days for 5 days in the years 2011–2013, with no tumor regrowth until the beginning of 2015. At this time, he underwent MRI, which was used to compare the discrete extension of the signal alteration areas, especially the subinsular regions. In March 2015, he resumed chemotherapy with TMZ at a dose of 100 mg/day and the patient then lost 12 kg of body weight, which was associated with anorexia, insomnia, and depression. In May 2015, he suffered a seizure requiring hospitalization. In June 2015, the patient resumed the old chemotherapy regimen with TMZ (2,000 mg every 28 days for 5 days), and a follow-up with MRI; however, the tumor size continued to increase. In January 2016, the neuro-oncology team decided to discontinue treatment with TMZ considering the risk/benefit and planned a surgical re-approach. This was followed by chemoradiation and lasting 6 cycles of PCV associated with CBD. The CBD dosage was ranging from 300 to 450 mg/day.

During chemoradiation, the patient had an excellent clinical performance, practiced sports and had few symptoms of fatigue and/or nausea.

At 1 month after the end of chemoradiation, control MRI (Figure ​ (Figure1) 1 ) was characterized by exacerbation and the ultra-precocious phenomenon of PSD with increased edema and inflammatory disease characterized by extensive areas of contrast enhancement associated with tissue hypoperfusion (not shown). MRI controls demonstrated the progressive reduction of these findings.

(A,B) Pre and post-operative MRI. Red arrow: chemoradiation associated with cannabidiol in a dosage ranging from 300 to 450 mg/day. (C) Control MRI after 1 month of the end of the chemoradiation was characterized an exacerbated and ultra-precocious phenomenon of pseudoprogression with increased edema and inflammatory disease. (D,E) MRI controls demonstrated progressive reduction of these findings.

The result of a pathological study after the first surgery was astrocytoma grade II with Ki67 staining of 5%. After the second surgery, he progressed to GBM grade IV (Figure ​ (Figure2), 2 ), related to increased cellularity, frequent mitosis, presence of micronecrosis, microvascular proliferation/endothelial, Ki67 staining of 30%, and loss of ATRX expression. Biomolecular marker analysis indicated IDH-1 mutated and MGMT methylated.

(A) First surgery: June/2010−1A.HE; 2A. GFAP; 3A. ATRX; 4A. IDH-1 ; 5A.Ki67:4,5%. (B) Second surgery: May/2016−1 B and 2 B (micronecrosis). HE; 3B. GFAP; 4B. EGFR; 5B. IDH-1 ; 6B. Ki67: 30%; 7B: MGMT methylated.

Patient 2 was a 38 years-old male diagnosed as left temporal glial neoplasia in May 2014 after a seizure. MRI showed an expansive infiltrative lesion predominantly in the subcortical region, with poorly defined contours located in the left temporal lobe, involvement of the upper, middle, and lower temporal gyrus, and an increase in the left temporal gyrus cortex. The lesion compromised a large part of the temporal lobe and extended to the temporal isthmus, the posterior aspect of the insula, and was deep in the trigeminal effigy of the left lateral ventricle. There was diffuse erasure of the regional cortical sulci and the Sylvian fissure, as well as a slight compression over the atrium of the left lateral ventricle. Stereotactic biopsy on April 2014 indicated a diagnosis of oligodendroglioma grade II. He received TMZ 1,875 mg with cycles every 23 days (during the 5 days of use he received a dose of 375 mg/day) from September 2014 to July 2015, with no tumor growth until the beginning of 2016. After checking the evolution of the tumor by MRI in February 2016, there was an increase in the dimensions of the remaining lesion, notably in the temporal isthmus, which had a similar expansive effect on the adjacent encephalic structures. The patient was submitted to a partial surgical resection followed by chemoradiation and lasting 6 cycles of PCV associated with CBD. The CBD dosage was ranging from 100 to 200 mg/day.

During the chemoradiation he had an excellent clinical performance, practiced sports, and had few symptoms of fatigue and/or nausea.

MRI control immediately after chemoradiation (Figure ​ (Figure3) 3 ) was used to characterize post-operative changes and showed a significant reduction of the infiltrative components of the tumor. The result of the pathological study after the first surgery (Figure ​ (Figure4) 4 ) was oligodendroglioma grade II. After the second surgery, he was diagnosed as oligodendroglioma grade III characterized by an increase in Ki67 staining of 9% and increased cellularity. Biomolecular marker analysis indicated IDH-1 mutated and MGMT methylated.

(A) MRI showed expansive infiltrative lesion predominantly subcortical of poorly defined contours, located in the left temporal lobe, involving the upper, middle and lower temporal gyrus, with increase of the left temporal gyrus cortex. The lesion compromises a large part of the temporal lobe and extends to the temporal isthmus, posterior aspect of the insula, and deeply to the trigeminal effigy of the left lateral ventricle. There is diffuse erasure of the regional cortical sulci and the Sylvian fissure, as well as slight compression over the atrium of the left lateral ventricle. (B) Intraoperative MRI. Red arrow: chemoradiation associated with cannabidiol in a dosage ranging from 100 to 200 mg/day. (C) MRI control right after chemoradiation was characterized post-operative changes associated with a significant reduction of the infiltrative components of the tumor. (D) Magnetic resonance control after 1 year characterized no evidence of disease progression.

1 C. HE; 2C. GFAP; 3C. P53; 4C. Retained ATRX expression; 5C. IDH-mutated; 6C. Ki67: 9%; 7C. 1 p19q I Co-deleted.

Discussion

Despite multimodal treatment, it is not possible to cure high-grade glioma patients. Therefore, the aim of treatment is not only to prolong life, but also to prevent deterioration of health-related quality of life as much as possible. In these two cases, we observed a significant improvement of clinical evolution. Both had a positive response to the treatment, with no evidence of disease progression for at least for 2 years and they are both alive. Unfortunately, the patient 1 presented tumor recurrence in the brainstem after approximately two and a half years of starting the treatment with chemoradiation followed by PCV.

Even with the prolonged use of CBD, the two patients did not develop any significant alterations in blood counts/plasma biochemistry, which is in accord with other studies showing that the prolonged use of CBD did not significantly affect hepatic or cardiac functions (24, 25). In contrast, a study evaluating the effectiveness and safety of CBD as an adjunctive treatment for seizures in patients with Lennox-Gastaut syndrome using meta-analytical techniques, observed increased alanine or aspartate aminotransferases more than three times the upper normal limit (14.5% vs. 0.6%, respectively) (26). It is important to note that the patients were using high doses of CBD (20 mg/kg/day) associated with anti-convulsive drugs.

The most common side effects associated with chemoradiation are chronic fatigue, loss of appetite, and nausea (27). In addition, the use of steroids causes side effects including increased appetite, agitation, insomnia, moon facies, fatigue, and myopathy (28). Both patients in the current study did not present with any of these side effects, nor did the usual continuous use of steroids during this phase of treatment. In addition, they could maintain their usual work and sports activities.

One of the patients presented with an exacerbated inflammatory response in the first MRI control soon after chemoradiation. The anti-inflammatory and neuroprotective actions of CBD may be related to the absence of side effects associated with PSD, such as headache, or changes relevant to tumor location (29, 30).

The high toxicity associated with PCV has an important impact on the course of treatment (31). A study stated that 28.5% of patients had to stop chemotherapy because of the severe side effects (32). Another study reported a delay in the treatment in 31.3% of patients to permit the toxicity to resolve (33). PCV chemotherapy is associated with major adverse events that need to be taken into consideration. Procarbazine, lomustine, and vincristine-induced hematological toxicity is severe as previous studies reported grade 3 lymphopenia and thrombocytopenia in 75 and 64% of patients, respectively (34). Another study reported that procarbazine induced major hepatotoxicity because it is metabolized by hepatic enzymes (35). Vincristine, as well as anticonvulsants, can also induce hepatic toxicity (33). Nausea and emesis were reported in 70–80% of patients receiving PCV without anti-nausea drugs (34, 36). Neurotoxicity, mostly attributable to vincristine, was also reported (37). Finally, rash was reported as a side effect of PCV (34, 36, 38).

The most common side effects of prolonged used of CBD are somnolence, decreased appetite, gastrointestinal disorders (diarrhea and nausea) (10–13) and increased transaminases levels (39, 40). In our two case studies, treatment with PCV associated with CBD did not cause lymphopenia, thrombocytopenia, hepatic toxicity, or neurotoxicity; however, a rash was observed in one patient and despite the fact that THC was often inhaled in the course of the PCV treatment, moderate nausea, emesis and fatigue were observed in both patients. No negative side effects were reported of the use of THC, but instead an increase in appetite and a reduction of fatigue were observed. The psychoactive effect of THC was considered positive as well as mood improving.

Studies of CBD in animal models of glioma reported its anti-tumor activity (41, 42). Preclinical studies support the idea that the combined administration of TMZ and cannabinoids might be therapeutically exploited for the management of GBM (43, 44). Results showed that the oral administration of THC and CBD in combination with TMZ produced a strong antitumoral effect in both subcutaneous and intracranial glioma cell-derived tumor xenografts (44). Another study investigated the effect of THC and CBD alone and in combination with radiotherapy in a number of glioma cell lines and in an orthotopic murine model for glioma. They showed dramatic reductions in tumor volumes when both cannabinoids were used with irradiation (45).

Two clinical studies (46, 47) of cannabinoid-based therapies in gliomas have been reported. Both clearly showed that cannabinoids did not facilitate tumor growth or decrease patient survival. A phase II clinical trial of 21 patients showed that those treated with a combination of THC and CBD in addition to TMZ had an 83% 1 year survival rate compared with 44% for those who did not receive the study drug. The median survival of the treated group was >662 days compared with 369 days in the group who did not receive the study drug (47). These first results of clinical investigations are promising and indicate the importance of cannabinoid translational research leading to clinically relevant studies.

Histologically, the presence of the 2 mutations, 1p19q and IDH1, have been identified as factors with a favorable prognosis (48, 49), and their impact on the clinical course of glioma patients led to a change in the World Health Organization (WHO) classification in 2007 (6). Both of our patients had IDH-1 mutated and one patient had a 1p19q co-deletion, suggesting they are more likely to respond to the treatment and have a longer life expectancy.

The study had several limitations. Previous preclinical and clinical studies evaluated the combination of THC and CBD associated with TMZ. In this case report it was not possible to use TMZ because the patients had already failed this therapy. We could not find any study that described an association between treatment with PCV and cannabinoids. Furthermore, previous studies reported that combined THC and CBD treatment had a greater anti-tumor effect and impact on survival compared with THC or CBD alone. In this report, it was not possible to make such an association for legal reasons and the absence of a medication containing high doses of THC. Both patients were under 40 years old and had molecular markers that favored a better prognosis. Of note, they remained without disease progression during the time of the study, and they did not develop major side effects between the clinical course of chemoradiation to the follow-up of 6 cycles with PCV drugs, which often prevent the completion of treatment.

Although this study only had two cases, it is interesting to note the good clinical and radiological evolution that might be related to this therapeutic association. Future randomized placebo-controlled trials with a larger number of patients are needed to confirm the study findings.

The wide use of CBD in the neuro-oncology field should be undertaken with caution. Preclinical and clinical studies are essential to demonstrate interactions with standard of care treatments, and its effects on the symptoms, quality of life, and possible immunomodulation should be determined.

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.

Ethics Statement

Patients submitted for treatment with cannabinoids had to complete an extensive form. This form was then sent to Anvisa, Brazil’s highest health regulatory agency for approval. Therefore, permission by the local ethics committee was not required. The patients signed consent forms, which are attached to the medical records.

Author Contributions

PD contributed to the design and implementation of the cannabidiol in the study and to the writing of the manuscript. MM and OF were involved in planning and supervised the study. MD brilliantly interpreted the radiological images and the follow-up and with CL and PD designed the figures. CL performed the pathology’s diagnostic and the complete analysis of the surgery material. Also CL encourage PD to investigate the use of cannabidiol in neuro-oncology tumours and supervised the findings of this work.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. We would also like to show our gratitute to Manuel Guzman, Ph.D., Complutense University Madrid, Spain for sharing their pearls of wisdom with us during the course of this study.

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Concomitant Treatment of Malignant Brain Tumours With CBD – A Case Series and Review of the Literature

Grade IV glioblastoma multiforme is a deadly disease, with a median survival of around 14 to 16 months. Maximal resection followed by adjuvant radiochemotherapy has been the mainstay of treatment since many years, although survival is only extended by a few months. In recent years, an increasing number of data from in vitro and in vivo research with cannabinoids, particularly with the non-intoxicating cannabidiol (CBD), point to their potential role as tumour-inhibiting agents. Herein, a total of nine consecutive patients with brain tumours are described as case series; all patients received CBD in a daily dose of 400 mg concomitantly to the standard therapeutic procedure of maximal resection followed by radiochemotherapy. By the time of the submission of this article, all but one patient are still alive with a mean survival time of 22.3 months (range=7-47 months). This is longer than what would have been expected.

Although relatively rare in absolute terms with an incidence of 3% of total cancer cases, brain tumours, in particular glioblastoma multiforme (GBM), rank among the deadliest diagnoses. GBM accounts for 12-15% of all intracranial tumours and 50 to 60% of astrocytic tumours. GBMs may manifest at any age, but mostly affect adults with a peak incidence between 45 and 75 years of age.

Brain tumours are on the rise. A recent random-effects model that analysed data from 1985 onwards found the overall incidence rate on all primary brain tumours to be 10.82 (95%CI=8.63-13.56) per 100,000 person-years (1). According to a prognostic estimation by the Austrian Ministry of Health, the incidence of brain tumours will increase by 84% for men and 26% for women between 2010 and 2030; death rates will nearly double (2). Similar results come from the UK where brain tumour incidence rates increased by 36% since the early 1990s (3).

Depending on the location and possibility for surgical removal, each type of tumour has its own biology and risks. Survival rates for malignant brain tumours vary widely, depending on the type of tumour, its grade and the location in the brain, with glioblastoma multiforme grade IV having the worst prognosis with a median survival of around 14 to 16 months (4). Only about 8 to 12% of patients survive two years.

Among the most important prognostic factors are age (with younger patients having a better prognosis), molecular factors (IDH1, IDH2, MGMT, and a 1p/19q co-deletion), and tumour location/extent of surgical resection (possibility for complete resection). A major focus of epigenetic research is DNA-methylation, which involves addition or removal of methyl groups on cytosines in cytosine-phosphate-guanine (CpG) dinucleotides and is involved in the regulation of gene expression. Although morphologically identical, different GBM tumours may translate into different clinical outcomes.

The primary aim of interventions is to increase survival and to maintain an acceptable quality of life. The standard treatment of GBM is maximal safe resection followed by adjuvant radiotherapy with concurrent chemotherapy. Temozolomide (TMZ) in combination with radiation therapy has been shown to increase the median survival of patients with newly diagnosed GBM by 2 to 3 months, from 12.1 (radiotherapy alone) to 14.6 months (5, 6). Following TMZ treatment after GBM recurrence, only 21% of patients obtain a progression-free survival (PFS) of six months and a six-month overall survival (OS) of 60% (7).

A number of preclinical studies suggest that phytocanna-binoids might be effective in glioma therapy (8). Although cannabis including extracts containing phytocannabinoids have been reported to reduce the growth of brain tumours in adults (9, 10) as well as in children (11, 12), a major lacuna in the use of herbal cannabis and “CBD-oils” is their poor standardisation, the lack of information on the exact composition, lack of comparability, lack of reproducibility and poor quality control (13). Nabiximols, a standardised, ~1:1 combination of two pharmaceutical grade extracts, one enriched with delta-9-tetrahydrocannabinol (THC), and the other with CBD, was shown recently to increase median survival of patients with recurrent glioblastoma multiforme by about 6 months, from 369 days (placebo group) to over 550 days when added to a dose-intensive temozolomide therapy (14).

In contrast, pure THC as well as CBD, are available as defined active pharmaceutical ingredients. Nonetheless, and despite of the promising preclinical data, reports on treatment of brain tumours with pure cannabinoids are very rare. In a pioneering study, THC was instilled into the resection cavity of patients with recurrent glioblastoma multiforme that had failed previous standard therapy (15). In this study, which did not aim to prolong survival, 5 of 9 patients received more than 1 cycle, and in 3 of these 5 patients, a temporary reduction in tumour proliferation was observed. However, the psychotomimetic properties of THC and down-regulation of CB1 receptors limit dosage and treatment duration. The recent report on the beneficial effects of non-psychotropic CBD in cancer patients is the most actual and the only demonstration of a possible anti-tumour effect of pure CBD in man (16).

Crystalline CBD, isolated from hemp or as a synthetic substance, is available with a purity of at least 98% (Deutscher Arzneimittel Codex DAC/NRF 2016/2, C-052, Avoxa-Mediengruppe Deutscher Apotheker GmbH, Eschborn, Germany) for magisterial prescription in some European countries such as Austria, Germany, Switzerland and the UK. A few companies provide CBD with a purity of 99.8% or higher. CBD is therefore a well-defined alternative to extracts or dronabinol (THC) for anti-tumour therapy. Furthermore, CBD has been reported to be well-tolerated and to reduce epileptic seizures (for which CBD received marketing authorisation by the FDA in June 2018), pain, nausea and to improve quality of life.

Herein, we report experiences with magisterial preparations containing pure (>99.8%) phyto-CBD (source: Trigal Pharma GmbH, Wien, Austria) prepared by a local pharmacy as adjuvant treatment of brain cancer patients. All patients consented to receive magisterial CBD capsules, and the local ethics committee has approved the treatment with CBD.

Case Presentations

Case 1, DI, female patient diagnosed at 38 years of age. In January 2018, an astrocytoma grade II located in the right post-central area was removed. Her medical history showed that her father as well as her grand mother died of a grade IV glioblastoma. Post-surgery, she specifically asked for no other treatment than CBD which was started 6 months after craniotomy, beginning on July 2018 (2×100 mg CBD/day for the first 2 weeks, then 2×200 mg/day). With CBD, her pain (numerical rating scale/NRS) was reduced from 4 to 0-1 within 2 months. Disease is stable at present.

Case 2, EJ, male patient, firstly diagnosed at 13 years of age. In June 1991 an oligoastrocytoma grade III, left occipital, was removed, followed by radio-chemotherapy until November 1992. In May 2015 a new, intraventricular tumour, an atypical grade II meningioma, was diagnosed and removed. The intervention was followed by a transient reduction in his vision on both sites. Because of a possible re-formation of tumour masses, CBD (2×200 mg/day) was started in August 2018. The patient is well, without new problems noted until now.

Case 3, GJ, male patient. In October 2015, at the age of 40 years, a left temporal glioblastoma multiforme grade IV, was diagnosed following epileptic seizures and removed. Thereafter, treatment with bevacizumab, lomustine (CCNU) and radiotherapy (Tumour Treating Fields) was started. Epilepsy is treated with levetiracetam. CBD (2×200 mg/day) was started in the end of May 2017. Since then, no further epileptic seizures have occurred. According to the latest magnetic resonance imaging (MRI) the tumorous formation is marginally decreasing.

Case 4, HB, female patient diagnosed at 44 years of age. In March 2016 an incomplete resection of a right temporo-basal grade II oligodendroglioma was performed. CBD was started in February 2017 and increased stepwise up to 2×300 mg one month later. The patient received levetiracetam as an antiepileptic therapy and intermittently also dronabinol, but no radio- or other therapy were received except analgesics on demand. The MRI in April 2019 showed stable disease.

Case 5, HW, male patient diagnosed at 60 years of age. Following an epileptic seizure, computed tomography and MRI revealed a tumour mass located at the right side of the temporo-occipital lobe. A craniotomy in February 2019 demonstrated the presence of a grade IV glioblastoma multiforme with 50% necrotic tissue (ATRX preserved, IDH1 not mutated, p53 strongly positive, MIB-1 (Ki-67), highly proliferating and positive for GFAP, EGFR). Five weeks later, the patient was re-operated in order to remove residual, progressive tumour tissue. In the end of February, two weeks before the 2nd craniotomy, CBD was started (2×100 mg/day). From April 2019 onwards, the patient also received radio-chemotherapy with temozolomide. At present, there is no sign of tumour recurrence. The patient also receives lacosamid/vimpat to prevent epileptic seizures.

Case 6, KE, male patient, age at diagnosis 61 years. He presented with epileptic seizures in 2016. MRI showed a left mesial-temporal lesion. Craniotomy was preformed under ALA-control and a grade IV glioblastoma (MGMT hypermethylated, 1p19q-deletion) was partially removed in November 2016. Radio-chemotherapy was applied including temozolomide. Beginning in May 2017, comedication with CBD (2×200 mg/day) was started together with dronabinol (7.5 mg/day). The latest MRI in February 2019 demonstrated stable disease.

Case 7, OB, male patient; at the age of five years the child had epileptic seizures. Further examinations revealed an fronto-basal astrocytoma grade II, which was partially removed, followed by radiotherapy. Follow-up examinations in 1993 showed no progression of the lesion. At the age of 41 years, in the end of 2017, the patient complained of reduced sensibility and slight paresis in the left arm and leg. In February 2018, a new mass (measuring 5×5×4 cm) in the right fronto-parietal lobe, straddling close to the pyramidal tract, was detected by MRI and partially removed two days later. Histology demonstrated a grade IV glioblastoma multiforme. Further molecular-pathologic examinations revealed a methylated MGMT gene promoter. At this time the old remaining fronto-basal tumour did not show any progression. Postoperatively, the patient received radiotherapy and temozolomide. A control MRI one month after craniotomy in March 2018 showed progression of the fronto-basal tumour, and CBD (2×200 mg/day) was started as comedication. An MRI in July 2018 demonstrated a possible progression of the old, fronto-basal lesion which had not been irradiated after the intervention in February 2018, as well as changes on the recently operated lesion located in the right fronto-parietal lobe. Therefore, the patient was operated on again in August 2018. Following resection, this mass was diagnosed as necrotic/fibrotic. All MRI scans thereafter, in November 2018, February 2019 and June 2019 demonstrated stable conditions.

Case 8, TG, female patient diagnosed at 49 years of age. In October 2018, a grade IV glioblastoma multiforme (IDH1 negative, no loss of ATRX, expression of EGFR 10%), located at the right parieto-occipital lobe was partially removed, and radio-chemotherapy with temozolomide was started. In November 2018 CBD (2×200 mg/day) was added to the therapy. In February 2019 the patient was re-operated in order to remove the remained, mainly necrotic tumour tissue. At present, there is no sign of progression of the tumour.

Case 9, WC, female patient diagnosed at 35 years of age. In December 2017, a right fronto-parietal grade IV glioblastoma multiforme was partially removed. Radio-chemotherapy with temozolomide was started thereafter. As the tumour was progressive, CBD (2x 100 mg/day) was added to the treatment in March 2018. Over a period of 10 months a slight regression was observed. However, 11 months after diagnosis, the tumour resumed growth and the patient died two months later.

Discussion

Since 2016, nine consecutive patients with brain tumours have received pure CBD in addition to standard treatment (maximal surgical removal of cancer tissue and radio-chemotherapy). Treatment with CBD started with 100 mg twice daily and was increased usually to 200 mg twice daily after 2 to 4 weeks. Six of the nine patients were diagnosed with grade IV glioblastoma multiforme. Since diagnosis, all but one patients are still alive (mean survival time 22.3 months, range=7-47 months); one of them for almost four years, another for almost three years with no signs of progression or new lesions. The mean duration of treatment with CBD for these six patients was actually 17.5 months (range=7-28 months). Patient’s quality of life and survival of this cohort is encouraging and seems to exceed the usual survival in comparable populations.

Dose of CBD and treatment schedule in our patients differed from the low-dose (average 2×10 mg/day, up to 60 mg/day), three days on/three days off schedule applied to cancer patients, as previously reported (16). Up to now, no systematic dose-effect study has been published; the optimal dose and treatment schedule for CBD remains to be elucidated. It may be dependent on the indication. Effects of CBD are very complex (13). Among other targets, CBD influences the levels of endocannabinoids such as of anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Doses of 800 mg CBD/day have been found to increase the AEA levels to approximately 1 pmol/ml after 28 days (17); steady state blood levels around 838-852 ng CBD/ml have been observed after a dose of 800 mg daily (18). Lower doses of CBD result in much lower blood levels (Cmax of 257-314 ng/ml after 250 mg, and ~1 ng CBD/ml after 5.4 mg CBD respectively; 18, 19). This is in the order where cannabinoids have been found, in vitro, to stimulate the growth of various cancer cells (20). Concerning AEA, an anticarcinogenic, concentration-dependent effect on glioblastoma cells was observed in micromolar concentrations (1 to 10 mcM) in vitro, and in picomolar doses per kg in vivo (21); AEA inhibited proliferation as well as cellular migration, and induced apoptosis in micromolar concentrations.

In animal cancer models, doses (administered mainly by intraperitoneal route) differed widely between 1 and 100 mg CBD/kg. To note, in animals, dosing is most often “rhythmic”, with a 5-day on and a 2-day off treatment. At present, its synergistic effects with concomitant chemotherapeutic agents remains elusive. It was therefore prudent in our eyes to administer CBD doses known to be effective for other indications.

Many biological processes are subject of circadian (24 h) and/or circaseptan (weekly) rhythmicity, dosing at the most appropriate (but unknown) time of the day and/or rhythmic dosing with days off may produce different outcomes than the “canonical” continuous dosing. In healthy adults, endocannabinoid blood levels demonstrate marked circadian rhythmicity with more than three times higher 2-AG levels around 12.00 to 13.00 in the afternoon than at 03.30 to 04.30 in the morning (22).

In diseased subjects, the endocannabinoid system is dysregulated. Although results were somewhat conflicting, AEA levels seemed to be lower and 2-AG levels were upregulated in glioblastomas (20). Glioma invasiveness has been linked to the tumour suppressor p38 MAPK; the anti-invasive effect of CBD interferes with this pathway (23). Increased expression and activity of p38 MAPK correlates with poor prognosis in glioblastoma multiforme. Intriguingly, the levels of phosphorylated p38 MAPK are significantly reduced in clock-deficient glioma cells, indicating that the circadian clock plays an important role in activation of this pathway (24).

In summary, preliminary observations suggest a potential role of CBD in the treatment of glioma whereby the optimal dose and dosing schedule remains to be elucidated.

Footnotes

Authors’ Contributions

RL, MK, MS performed the clinical patient work. GN consulted physicians on cannabinoids and wrote the manuscript.

Conflicts of Interest

There are no conflicts of interest to disclose regarding this study. The Authors received no financial support for this case series.