cbd oil for glial neoplasm

Cbd oil for glial neoplasm

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

CBD for Brain Cancer

Brain cancer is a disease of the brain in which malignant cancer cells develop in the brain tissue. These malignant cancer cells eventually grow to form a mass of cancer tissue that is referred to as a brain tumor, or also known as an intracranial tumor, that interferes with brain functions such as muscle control, sensation, memory, and other normal body functions.

Tumors composed of cancer cells are called malignant tumors, and those composed of mainly noncancerous cells are called benign tumors. More than 150 different types of brain tumors have been documented, some of which are benign (not harmful) or malignant (harmful cancer cells). Within malignant brain tumors, there are two main groups that are either termed primary, or metastatic.

Primary brain tumors are tumors that originate from the tissues of the brain or the brain’s immediate surroundings. They are categorized as glial (composed of glial cells) or non-glial (developed on or in the structures of the brain, including nerves, blood vessels and glands), and can either be benign or malignant. Metastatic brain tumors include tumors that develop somewhere else in the body (for instance, the breast, stomach or lungs) that then migrates to the brain, usually through the bloodstream. Metastatic tumors are always considered cancerous and malignant in nature.

Statistics show that brain cancer is relatively rare and only makes up 1.4% of all new cancer patients per year (in the United States) with about 16,050 deaths as estimated by the National Cancer Institute (NCI) and the American Cancer Society.

The exact cause of most brain cancer is unknown, but it is thought that various environmental toxins, radiation to the head, HIV, and smoking are all linked to cancers of the brain. Only about 5% of brain tumors may be due to hereditary genetic conditions such as neurofibromatosis, tuberous sclerosis, and a few others.

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Symptoms of Brain Cancer

Symptoms of a brain tumor can be specific (symptoms caused by the tumor itself) or general (symptoms caused by the pressure of the tumor on the brain or spinal cord). Most people are only diagnosed with a brain tumor after experiencing problems such as headaches, issues with motor control, or even personality changes.

  • Headaches, which may be severe and worsen with activity or in the early morning
  • Seizures, including
    • motor seizures / convulsions
    • myoclonic seizures that are single or multiple muscle twitches, jerks, spasms
    • Tonic-clonic (or Grand Mal) seizures that can include a loss of consciousness, loss of body tone, followed by twitching and contraction of the muscles, loss of control of body functions, such as loss of bladder control, a short (30-second or less) period of no breathing that can cause a person’s skin to turn a shade of blue, purple, gray, white, or green. After this type of seizure, a person may be sleepy and experience a headache, confusion, weakness, numbness, and sore muscles.
    • Change in sensation, vision, smell, and/or hearing without losing consciousness
    • May cause a loss of awareness or a partial or total loss of consciousness
    • May be associated with repetitive, unintentional movements, such as twitching
    • Pressure or headache near the tumor
    • Loss of balance and difficulty with fine motor skills (linked with a tumor in the cerebellum)
    • Changes in judgment, including loss of initiative, sluggishness, and muscle weakness or paralysis (linked with a tumor in the frontal lobe of the cerebrum)
    • Partial or complete loss of vision ( linked to a tumor in the occipital lobe or temporal lobe)
    • Changes in speech, hearing, memory, or emotional state, such as aggressiveness and problems understanding or retrieving words (linked with a tumour in the frontal and temporal lobe)
    • Altered perception of touch or pressure, arm or leg weakness on 1 side of the body, or confusion with left and right sides of the body (linked with a tumor in the frontal or parietal lobe)
    • Inability to look upward (linked with a tumor in the pineal gland)
    • Lactation, which is the secretion of breast milk, and altered menstrual periods in women, and growth in hands and feet in adults (linked with a tumor in the pituitary gland)
    • Difficulty swallowing, facial weakness or numbness, or double vision (linked with a tumor in the brain stem)
    • Vision changes, including loss of part of the vision or double vision (linked with a tumor in the temporal lobe, occipital lobe, or brain stem)

    Brain Cancer Types

    Not all brain tumors are malignant with growths such as chordomas, craniopharyngiomas and meningiomas (to name only a few) being benign. Types of malignant brain tumors are gliomas – the most prevalent type of adult brain tumor that accounts for 78 percent of malignant brain tumors. They arise from the supporting cells of the brain, called the glia, that are cells subdivided into astrocytes, ependymal cells and oligodendroglial cells (or oligos). Glial tumors include the following:

    Astrocytomas: The most common type of glioma, accounting for about half of all primary brain and spinal cord tumors and may develop in people of all ages and sexes. They develop from the star-shaped astrocytes that form part of the supportive tissue of the brain. Astrocytomas are most commonly found in the cerebrum, although it can also occur in other parts of the brain.

    Ependymomas: These tumors are derived from a neoplastic transformation of the ependymal cells that line the ventricular system. Ependymomas account for two to three percent of all brain tumors. Most are well-defined, but some are not.

    Glioblastoma multiforme (GBM): GBMs are the most invasive type of glial tumor, and may be composed of several kinds of cells, such as astrocytes and oligodendrocytes. These tumors tend to grow rapidly, spread rapidly to other tissues, and have a poor prognosis. GBMs is more common in people ages 50 to 70 and are more prevalent in men than women.

    Medulloblastomas: Usually occurring in the cerebellum, medulloblastomas are most frequently diagnosed in children. They are high-grade tumors, but they are usually responsive to radiation and chemotherapy.

    Oligodendrogliomas: These tumors are derived from the cells that make myelin, which is the insulation for the wiring of the brain. They are most commonly found in the white matter and the outer layer of the brain, called the cortex, but can form anywhere in the CNS. Oligodendrogliomas can occur at any age but is most often diagnosed in people between the ages of 35 and 44, and is rare in children. Men also seem to be at higher risk compared to women.

    Pediatric Brain Tumors
    • Medulloblastomas
    • Low-grade astrocytomas (pilocytic)
    • Ependymomas
    • Craniopharyngiomas
    • Brainstem gliomas.

    Brain Cancer Medications & Treatments

    If colon cancer develops, many treatments are available to help control it and usually comprises a combination of procedures and medications. Treatment options and recommendations usually depend on several factors, including the type and stage of cancer, treatment side effects, and the patient’s preferences and overall health.

    Pharmaceutical Interventions

    Chemotherapy is the use of powerful medicines to kill tumor cells and brain cancer patients may get a single medicine or a combination, usually given either by mouth or through an IV. In some cases, chemotherapy is given through a shunt put in place to drain excess fluid from the brain.

    Chemotherapy is usually given in two to four cycles with a single cycle being a short period of intensive treatment followed by a period of rest and recovery. The side effects of chemotherapy can be extensive and include nausea and vomiting, mouth sores, a loss of appetite, hair loss, bruising and bleeding as well as an increased risk of infection. Because of this, there is usually a break in the treatment to see how the tumor responded to the therapy.

    Non-Pharmaceutical Interventions
    • Craniotomies are a type of surgery most often used to remove a brain tumor. The surgeon starts by cutting through the scalp and remove a piece of skull to expose your brain. They will then proceed to remove the entire tumor, or as much as possible, after which the surgeon places the piece of skull back into position and sews the scalp together.
    • Neuroendoscopies is when the surgeon makes a small hole in the skull or, depending on the location of the tumor, goes through the nose or mouth. Using small tools and a tiny camera that sends images back to a monitor, the surgeon will remove the tumor.

    Radiation therapy
    Another common therapy for brain cancer is radiation therapy (also called radiotherapy) which uses high-energy rays to kill tumor cells and stopping them from growing and spreading. Unlike chemotherapy, radiation therapy is localized, meaning it usually does not harm cells elsewhere in the body or brain. However, it is not without side effects that can include fatigue, skin redness, nausea, hair loss, weight gain and memory problems.

    • External radiation uses a high-energy beam of radiation that travels through the skin, skull and healthy brain tissue to target the tumor. The treatments take only a few minutes and are usually given every five days.
    • Internal or implant radiation uses a tiny radioactive capsule that is placed inside the tumor from where the radiation destroys it. The radioactivity of the capsule decreases a little each day and is carefully calculated to run out when the optimal dose has been given.
    • Stereotactic radiosurgery is a single large dose of high-energy radiation trained on the tumor from different angles to destroy the tumor without opening the skull. Stereotactic radiosurgery has fewer complications than regular surgery and a shorter recovery time.

    CBD for Brain Cancer

    Research and Scientific Evidence about using CBD for brain cancer

    The clinical evidence for Cannabidiol (CBD) as a viable treatment option for Brain Cancer is promising, especially in relation to human glioblastoma multiforme (GBM) tumors.

    Regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways

    CBD has demonstrated cytotoxic effects on GBM in previous experiments. Publishing their results in the journal Oncotarget in 2017, researchers investigated if there is a way to increase the cytotoxic effect of radiation therapy in GBM by simultaneously administering CBD.

    Using human glioblastoma multiforme (GBM) cell lines, researchers investigated the role of CBD, radiation and small molecule inhibitors of cell signaling pathways in the regulation of GBM cell death. They found that when CBD was combined with small molecule inhibitor treatments of these cell regulation pathways, their activation substantially increased CBD-induced apoptosis in the glioblastoma lines. They also found that a combination of CBD treatment and subsequent high doses of γ-irradiation therapy resulted in the effective induction of apoptosis in the glioblastoma lines. And finally, they demonstrated that CBD sensitizes GBM cells for death via increased surface expression of death receptors such as TNF receptors and TRAIL-R2/DR5.

    Their experiments demonstrated three approaches that confirmed the increased killing efficiency of CBD in GBM, leading the researchers to conclude that radiation-induced death in GBM could be enhanced by CBD-mediated signaling while protecting neurons and neural stem/progenitor cells in the brain.

    Cannabidiol Affects Extracellular Vesicle Release, miR21 and miR126, and Reduces Prohibitin Protein in Glioblastoma Multiforme Cells1,2

    In a 2019 study published in Translational Oncology, investigators looked at the effects of CBD on key-mediators for cellular communication and the reduction of prohibitin proteins in Glioblastoma Multiforme (GBM) cells, since cancers, such as GBM, use extracellular vesicles (EVs) release for drug-efflux, pro-oncogenic signaling, invasion and immunosuppression. The inhibition of EVs have been shown to increase sensitivity of cancer cells to chemotherapy. Previous research shows that CBD is an EV-modulator / inhibitor, leading the researchers to investigate whether CBD affects EV profile in GBM cells in the presence and absence of temozolomide (TMZ).

    Using human GBM cell lines they found that, compared to controls, CBD-treated cells released EVs containing lower levels of pro-oncogenic RNA with increased levels of anti-oncogenic RNA. They also showed that these effects were greater than with TMZ alone. In addition, prohibitin (PHB), an apoptotic signaling protein with mitochondrial protective properties and chemoresistant functions, was reduced in GBM cells following a 1 hour CBD treatment.

    The investigators concluded that this data suggests that CBD may, via modulation of EVs and PHB, act as a complimentary therapy to enhance treatment efficacy of drugs such as TMZ, while also providing supporting evidence for CBD’s apoptotic effects via PHB modulation.

    Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

    Finally, in another study using GBM cell lines and published in the prestigious journal Nature’s Scientific Reports in 2020, researchers address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy, a.k.a. the orderly degradation and recycling of damaged or faulty cellular components.

    They evaluated the effects of CBD and γ-irradiation, alone or in combination with chloroquine (CQ) on the regulation of cell survival in GBM cells. CQ is an inhibitor of the lysosomal function that also causes the suppression of autophagic flux, a mechanism linked to a variety of human pathophysiological processes including brain cancer.

    They found that CBD was a powerful inducer of autophagy, while γ-irradiation alone, or in combination with ATM inhibitor, did not affect or only marginally affect autophagy. These results further showed that CBD-induced GBM cell death more effectively than CQ co-treatment. In addition, a combination of CBD with small molecule inhibitors of cell signaling pathways was more effective for the final killing of GBM cells that using these inhibitors on their own. Lastly, the data indicated substantial protective effects of CBD-induced autophagy.

    Anecdotal Evidence

    Some people opt to treat their colon cancer with cannabis oil, and have done so successfully. However, when it comes to CBD and colon cancer, the anecdotal evidence centers more around CBD being used as a complementary therapy (more on that below).

    CBD as a Complementary Treatment in brain cancer

    Most of the available evidence indicates that CBD may complement cancer treatment, and that CBD may help people with brain cancer by helping reduce pain and inflammation. In addition, many people suffering from brain cancer also report having other side effects from chemotherapy treatment, including sleep problems, feelings of anxiety and depression. In one large case series study investigating the effects of CBD on anxiety and sleep, the results show CBD helps improve sleep and/or anxiety in clinical populations. Similarly, CBD can further support brain cancer patients by reducing stress, anxiety, depression while also helping to promote REM sleep that is thought to help improve overall mood. In addition, CBD is also helpful in managing the seizure activity associated with brain tumor related epilepsy.

    Bottom Line

    Scientific and anecdotal evidence both suggest that CBD can support brain cancer patients, especially by helping to reduce chemotherapy-induced neuropathic pain, inflammation, nausea and vomiting. If you or a loved one are suffering from brain cancer and want to try CBD, talk to your medical practitioner first. He or she can help put together a plan that includes CBD along with other treatment options to help you deal with your symptoms safely and effectively.

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    TN-TC11G (THC+CBD) Combination With Temozolomide and Radiotherapy in Patients With Newly-diagnosed Glioblastoma (GEINOCANN)

    Glioblastoma is the primary brain tumour with the worst prognosis: median survival is only 12 months despite the use of the most advanced treatments. In the past 10 years, survival in the treatment of this disease has not advanced significantly, with the postoperative standard being the administration of chemoradiotherapy with temozolomide, followed by 6 cycles of sequential chemotherapy with temozolomide.

    Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have shown a clear synergistic antitumour effect with temozolomide and radiotherapy in preclinical glioma models. THC and CBD have a wide variety of biological effects by binding with and activating the type 1 and type 2 cannabinoid receptors (CB1 expressed in certain neuronal areas of the brain and CB2 expressed in the immune system and in glial cells). The activation of these receptors initiates a signalling pathway, called the endoplasmic reticulum stress response, which generates tumour cell autophagy by activating TRB3.

    Given these data, the Spanish Group for Neuro-oncology (GEINO) proposes developing a phase Ib, open-label, multicenter, intrapatient dose-escalation clinical trial to assess the safety profile of the THC+CBD combination at a 1:1 ratio, adding temozolomide and radiotherapy in patients with newly-diagnosed glioblastoma.

    The number of patients to be recruited is 30 over 6 months at 8 sites specialising in neuro-oncology.

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