The use of cannabis in supportive care and treatment of brain tumor
1 Abteilung für Anästhesiologie und Intensivmedizin, Klinikum Klagenfurt am Wörthersee, Feschnigstrasse 11, 9020 Klagenfurt am Wörthersee (R.L.); CIS Clinical Investigation Support GmbH, Kaiserstrasse 43, 1070 Wien (G.N.)
1 Abteilung für Anästhesiologie und Intensivmedizin, Klinikum Klagenfurt am Wörthersee, Feschnigstrasse 11, 9020 Klagenfurt am Wörthersee (R.L.); CIS Clinical Investigation Support GmbH, Kaiserstrasse 43, 1070 Wien (G.N.)
1 Abteilung für Anästhesiologie und Intensivmedizin, Klinikum Klagenfurt am Wörthersee, Feschnigstrasse 11, 9020 Klagenfurt am Wörthersee (R.L.); CIS Clinical Investigation Support GmbH, Kaiserstrasse 43, 1070 Wien (G.N.)
Corresponding Author: Rudolf Likar, Abteilung für Anästhesiologie und Intensivmedizin, Klinikum Klagenfurt am Wörthersee, Feschnigstrasse 11, 9020 Klagenfurt am Wörthersee ([email protected]).
Copyright © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected]
Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC. Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive. Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.
Cannabis has been used since ancient times. Plant fibers were already employed for textiles and fiber-based constructs about 25,000 years ago. 1 For medicinal use, evidence goes back 5000 years to the Chinese emperor Chen Nung. Archeological findings suggest that palliative cancer treatment with cannabis was already in use 2500 years ago. 2 Later, its use for a large number of various conditions was familiar to Assyrians (3000–2000 BC), Egyptians (Eber’s papyrus, approx. 1534 BC), Romans (Plinius, the elder, 79 AD), Greeks (Dioscorides, 90 AD, Galen, 131–201 AD), and Persians (Avicenna, 1000 AD 3 ). Today cannabis is undergoing a real renaissance.
Apart from cannabis herb (medicinal cannabis) and botanical extracts, essentially 3 types of cannabinoids exist: the body’s own cannabinoids (endocannabinoids), purified phytocannabinoids, and synthetic cannabinoids. Of the phytocannabinoids, pure delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are available in Germany and Austria as pharmacy (extemporaneous) preparation; a refined extract, nabiximols (THC:CBD = 1.08:1.00), received marketing authorization as specialty treatment (Sativex™) of neuropathic pain in 25 countries including Canada and nations in Europe. Synthetic THC (dronabinol), chemically identical to the phytocannabinoid delta-9-tetrahydrocannabinol, is marketed as Marinol™ in the United States, Canada, and Denmark for specialty treatment of chemotherapy-induced nausea, vomiting, and anorexia. CBD is an investigational new drug (IND) in the United States, and a number of clinical trials are actually planned or underway in the United States and Europe (www.clinicaltrials.gov, FDA; https://www.clinicaltrialsregister.eu/ctr-search/search, EMA). Botanical (“drug-type”) cannabis is still prohibited in most countries (Schedule I, according to the Controlled Substance Act, USA), although more and more authorities have granted access for medical purposes (25 states of the United States, Canada, Israel, Switzerland, Germany, and the Netherlands, among others).
Although there are a number of investigational cannabinoids currently in development, the only non-natural, synthetic cannabinoid commercialized today is nabilone with properties that are essentially similar to THC. It is used for the same indications and marketed in the United States, Canada, and in some European countries. Dosages are about 5 to 10 times lower than with THC. It is assumed to be “THC-like,” but considerably fewer publications are available for nabilone. Only nabilone (Schedule II in the United States), THC (Marinol™, Schedule III), the combination of THC with CBD, and cannabis extracts are scheduled drugs due to their psychotropic properties; CBD is not scheduled. Opposite to purified cannabinoids, extracts contain additional cannabinoids and a range of other bioactive compounds such as flavonoids and terpenoids.
Medicinal cannabis, either smoked as dry herb or prepared and taken by vaporizers, has the problem of widely differing compositions and dosages; it is also not allowed in many countries as mentioned before. Last but not least, a growing number of reports on “home-made” herbal cannabis extracts (eg, Rick Simpson oil, Charlotte’s Web, Milagro oil), largely varying in quality and components and taken orally, claim to have been successfully used for an uncountable number of conditions including treatment-resistant epilepsy, anxiety disorders, pain, and cancer. Generally, reliability of such claims cannot be controlled. For this reason and due to the availability for therapy, only THC, CBD, and their combination will primarily be considered in this article.
Cannabinoids interfere with the endocannabinoid system (ECS), the primary components of which are receptors CB1 and CB2 and the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) as their ligands. However, since its discovery in the 1990s, a number of additional targets and ligands have been identified. These include G-protein coupled receptor GPR55, peroxisome proliferator-activated receptors (PPARs), transient receptor potential Ca++ channels (TRPs), and adenosine receptors, but also enzymes for degradation (eg, fatty acid amid hydrolase [FAAH]) or synthesis (eg, diacylglycerollipase [DAGL]). This makes the ECS extremely complex. Because space limitations, reference is also made to recent overviews on specific subjects, rather than to original papers.
Cannabinoids Can be Used in Palliative Care for a Wide Range of Symptoms
Palliative care is related to symptom management and supportive care for patients facing life-limiting illness. It focuses on the amelioration of the quality and duration of remaining life, particularly on physical, emotional, and psychological suffering. Long-term drug safety is also important. Palliative effects of phytocannabinoids, such as on pain, mood, appetite, and radiation- or chemotherapy-induced nausea and vomiting, have been studied in cancer patients since the early 1970s. The striking benefit of these substances is their multitarget action and compatibility with many eventually needed comedications, as well as their impressive safety margin. Although dosages must be adapted to individual needs, multiple therapeutic effects can be achieved simultaneously with only one product, such as reducing pain, spasticity, depression and anxiety; improving mood and sleep; increasing appetite and weight; etc. Many disease-ameliorating effects of cannabinoids and endocannabinoids are receptor-mediated, but many are not, indicating additional involvement of non-cannabinoid receptor signaling pathways.
Cannabinoids Reduce Nausea and Vomiting
A quantitative systematic review 4 that included 30 randomized comparisons of oral THC, nabilone or nabiximols, or the intramuscular levonantradol preparation (no longer available) with placebo in 1366 patients receiving chemotherapy found that, as antiemetics, cannabinoids were more effective than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride. Only a single trial compared THC with one of the agents now most widely used—the serotonin 5-HT3 antagonists—whereby nausea intensity and vomiting/retching were lower in patients treated with THC (71%) than in those treated with odansetron (64%). The combination of both was not more effective (53% 5 ). THC was more effective than odansetron for mildly to moderately severe nausea produced by chemotherapy, but not for severe emetogenic treatments. No single antiemetic is currently available to completely prevent the acute or delayed phases of chemotherapy-induced nausea and vomiting. The most recent guidelines of the National Comprehensive Cancer Network, published in 2015, 6 cautiously mention cannabinoids as a breakthrough treatment for chemotherapy-induced nausea and vomiting not responsive to other antiemetics. In studies, THC has been given in a surprisingly large dose range, mainly in daily doses between 2 × 10 mg/m 2 and 6 × 15 mg/m 2 , 4 but occasionally also in doses of 5 mg/m 2 or less; a direct relationship of antiemetic efficacy to plasma levels has been demonstrated. 7 A dose of 25 mg is likely to results in a mean plasma concentration around 10 ng/ml (equivalent to 32 nM), which is in an order where THC acts as a partial agonist of CB1 and CB2 receptors.
Preclinical research indicates that CBD (2.5 to 40 mg/kg) also suppresses nausea and vomiting, acting in a biphasic manner. Low doses suppress toxin-induced vomiting but high doses potentiate. 8–11 Studies in humans are still missing. Whereas effects of THC are mediated by CB1 receptors, the antinausea/antiemetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT1A receptors (so called serotonin- or hydroxytryptamine-receptor) in the dorsal raphe nucleus. Activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Nausea- and vomiting-reducing effects have also been reported for nabiximols and nabilone. 12 , 13 Interestingly, there have been no reports on a systematic evaluation of combinations of THC and CBD on emesis or nausea in animal models.
Increase of Appetite and Weight is Only Seen with CB1 Agonists such as THC
Loss of appetite and tumor cachexia is a common problem in oncology. A few clinical trials included the change of body weight with THC, but gave mixed results in cancer patients. Whereas a daily dose of 2 × 2.5 mg before meals had no significant effect on weight gain, 14 an earlier, shorter study using a higher dose of 3 × 2.5 mg, administered 1 hour after meals for 4 weeks, had demonstrated increased appetite in cancer patients with a small gain of weight (1.3 kg; range, 1.0–2.7 15 ); orexigenic effects of THC are corroborated by observations made in HIV patients. An increase in weight was also observed in a crossover, placebo-controlled study with much higher doses (0.10–0.34 mg/kg/q.i.d, 2 hours before meals, for 2 weeks). 16 Alterations of chemosensory perception may contribute to the effect of THC. In Table 1 , results of studies with THC in cancer patients are summarized.
Effects of THC on appetite and/or weight
|Dosage oral THC/Day, Duration||Results, THC||Control Group||Reference|
|2 × 2.5 mg/day (no details on fasting status) over a median of 57 days, vs megestrol acetate (Median 80 days)||49% of 152 patients had increased appetite; 11% of 152 patients had a weight gain of 5% or more (3% had a weight gain of 10 % or more)||75% of 159 patients treated with megestrol acetate had increased appetite; 20% of 159 patients had a weight gain of 5% or more (10% had a weight gain of 10 % or more)||14|
|3 × 2.5 mg/day, 1 hour after meal, 4 weeks||13/18 evaluable patients (~70%) had increased appetite, 3/6 had weight gain (1.3 kg)||None||15|
|5-15-22.5 mg/day (divided in three dosages), 1 hour before meals, 2 × 1 week (cross-over)||All patients gained weight,
mean weight gain 0.69–0.39 lbs (THC- placebo vs. placebo-THC, 8 and 9 patients, respectively)
|All placebo patients lost weight; mean loss 2.10–1.11 lbs (THC-placebo versus placebo-THC)||16|
|2 × 2.5 mg/day, fasting,
vs placebo vs cannabis extract, 6 weeks
|65/100 (65% evaluable)*
58% of 65 patients had increased appetite
|33/48 (69% evaluable)*
69% of 33 placebo patients had increased appetite
|2 × 2.5 mg 1 hour before meals, 4 weeks (mean 6.5 weeks)||5/7 patients had increased appetite; weight gain in 3/7||None||18|
*84 of 243 patients screened with major protocol violations (35%); no details on weight changes given. Abbreviation: THC, delta-9-tetrahydrocannabinol.
A case series with 6 patients who received THC showed, however, a loss of effect in 3 of the subjects after several weeks, 19 which may be related to a desensitization of CB1 receptors. It has been hypothesized that weight gain is due to an increase of fat mass as a result of the lipogenic action of THC via CB1 receptors. 20 In fact, the regulation of food intake by the central ECS has proved to be more complex than initially thought because of emerging evidence of a bimodal orexigenic as well as anorexigenic effect of CB1 receptors, depending on whether they are activated in glutamatergic or GABAergic terminals, respectively. 21 Nabilone has similar effects on appetite and weight. In contrast, CBD has no orexigenic effect; high doses (2.5 and 5 mg/kg/day for 14 consecutive days, intraperitoneal) even decreased appetite in rats dose-proportionally. 22 Studies on the effects of nabiximols in humans could not be found.
Cannabinoids Moderately but Consistently Improve Chronic Pain
Chronic pain is another common symptom and not confined only to tumor patients. A recent review that included THC, nabilone, and nabiximols found moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. 23 The average number of patients who reported a reduction in pain of at least 30% was greater with cannabinoids than with placebo. However, there was no difference in average quality-of-life scores as measured by the EQ-5D health status index between nabiximols and placebo. Analgesic effects of THC are dose-related; THC was given in pain studies usually in daily doses between 15 and 60 mg. In a cancer trial, oral THC 20 mg was thought to be comparable to codeine 120 mg, but with more marked psychological effects. 24 In patients with intractable cancer pain, a combination of CBD and THC (nabiximols) achieved a 30% pain-reduction rate in twice as many patients as THC alone; the latter was not significantly superior to placebo. A decreased use of strong opioids was observed with both treatments, with nabiximols as well as with THC, as further outlined below 25 ; preliminary, unpublished experiences of the reporting author suggests similar opioid-saving effects with CBD (2 × 200 mg/day).
Very few experiences have been reported with CBD as a monosubstance; an animal study suggests that CBD (2.5 to 10mg/kg) is protective against paclitaxel-induced neurotoxicity mediated in part by the 5-HT1A receptor system 26 and is able to suppress inflammatory and neuropathic pain. 27 Differences between cannabinoids are likely to exist. A total of 34 patients who were included in a “N of 1” double-blind, placebo-controlled, crossover trial receiving 3 different extracts, THC, CBD, and a 1:1 mixture of them over a 12-week period, judged THC and a combination with CBD most effective in symptom control (placebo < CBD < THC < THC + CBD). However the dose of CBD—each substance was given as sublingual spray containing 2.5 mg—was certainly much too low. 28 So far, studies of the efficacy of CBD in cancer pain (as well as in neuropathic pain) have used insufficient doses of CBD (alone or in combination with THC) to determine efficacy and more studies are needed. Details of some representative studies are given in Table 2 .
Results of THC and/or CBD in treatment of pain
|Single dose of 10–20 mg THC vs 60–120 mg codein vs placebo||Cancer pain, 34 evaluable patients, single doses||10 and 20 mg THC were equivalent in analgesic potency to 60 and 120 mg codeine, respectively; difference to placebo was significant for 20 mg THC and 120 mg codein; peak effect after 3 hours (codein), 5 hours (THC)||24|
|Up to 8 × 2.7 mg THC + 2.5 mg CBD or 2.7 mg THC or placebo per day, oromucosal spray, 2 weeks||Intractable cancer pain, 177 patients (3 groups of 60-58-59 patients)||Significant reduction of pain only with THC + CBD (Numerical Pain Rating Scale): placebo < THC < THC + CBD; no change from baseline in median dose of opioid background medication||25|
|CBD, 2.5–10mg i.p./kg, on day 1,3,5 and 7||Mice, paclitaxel-induced mechanical sensitivity||CBD is protective against paclitaxel-induced neuropathic pain||26|
|2.5 mg CBD or 2.5 mg THC or CBD + THC or placebo; each patient received each treatment for 2 separate 1-week periods||Series of 34 “N of 1” trials; each treatment given randomly over 4 weeks; 16 of 34 patients with multiple sclerosis||Order of pain reduction and quality of “good night’s” sleep: placebo < CBD < THC < THC + CBD; application frequency: median about 8× sublingual / day for treatment groups and 10× for placebo||28*|
|CBD, morphine and combination||Mouse models: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; (c) hot plate thermal nociception||Morphine alone produced anti-nociceptive effects in all three models; CBD alone produced anti-nociception only in the acetic acid-stimulated stretching assay
Combinations produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate nociceptive test and the acetic acid-decreased operant responding for food
|25–50 mg CBD/kg p.o. or 5 mg/kg i.p. for 10 days||Murine model, collagen-induced arthritis||Bell-shaped curve; the optimal oral dose was 25 mg/kg, equivalent to 5 mg/kg i.p.; 50 mg/kg demonstrated more severe arthritic changes||34|
Other notable findings include the reduction in the dose of opioid pain medications with cannabinoids and the blockade of opiate-dependence in rats. 29 Cannabinoids show synergistic analgesic effects with opioids, prevent the development of tolerance to opioids, and rekindle analgesia after a prior opiate dosage has become ineffective. As morphine induces upregulation of CB2 with inflammatory responses in activated microglia (and potentially abnormal immune function), cannabinoids are also counteracting this unwanted effect. Colocalization and cross-talking between CB1 and µ-opioid peptide receptors has been found. 30 , 31 THC and CBD also potentiate glycine receptors, which are important targets for nociceptive regulation at the spinal level. Mechanisms of CBD seem to be rather complex: Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay; thus, the opioid-saving effect of a combination may depend on the pain type. 32 CBD potentiates the descending antinociceptive pathway via adenosine A1 receptors, 5-HT1A receptors, and TRPA1 channels. 33 In murine collagen-induced arthritis, oral CBD demonstrated a bell-shaped curve; the optimal dose was 25 mg/kg, whereas 50 mg/kg demonstrated more severe arthritic changes. 34 Whether this can be generalized for anti-inflammatory actions and whether an analgesic effect of CBD is linear or not is currently unknown. To note, a dysfunction of TRP channels has been implicated in chronic pain. 35
Of potential interest is also the observation that the concomitant activation of CB2 and glucocorticoid receptor α (GRα) by THC abolishes the neuroprotective effects induced by each receptor on central neurons and on glia cells in animal models of remote cell death. 36 No interaction between CBD and glucocorticoids in vivo has been reported at this time.
Cannabinoids Improve Other Cancer-related Symptoms
During the last decades many studies reported that numerous other cancer-related or treatment-related symptoms were also significantly improved by cannabinoids, such as depression, anxiety, fatigue, constipation, sexual function, sleep disorders, and itching. The only cannabinoid likely having a role in depression is CBD as may be concluded from animal experiments. 37 , 38 THC (and combinations) has antianxiety properties in very low doses but can induce anxiety in higher doses such as needed for preventing nausea and emesis or for treatment of pain.
In contrast, inversion of anxiolytic effects is not known for CBD in usual doses, which are on the order of 300 to 600 mg/day. 39 Therefore, reducing the dose or even replacing the antidepressant or anxiety drugs may be possible in some cases. More generally, cancer patients using cannabis uniformly report better influence from the plant extract than from pure or synthetic products. 40 This may be related partly to the positive psychotropic or mood-improving effects of THC, but also by attenuation of the of the THC-induced impairment by CBD and other phytocomponents.
In a recent review, mixed and somewhat inconsistent results have been reported about effects on sleep with cannabinoids, including nabilone and nabiximols. 41 In general, positive effects have been noted by patients, although definite conclusions are impossible due to differences in study quality and assessment methods. Differences between cannabinoids may exist as well. THC seems to decrease the time to sleep latency and to improve sleep quality over a wide dose range of 2.5 to 30 mg. However, when THC (15 mg/day) was combined with a low dose of CBD (15 mg/day) increased wakefulness was observed. 42 CBD shows clearly a biphasic effect. In rats, very low doses of about 0.04 to 0.08 mg/kg, which would correspond roughly to a dose of about 3 to 6 mg CBD in humans, significantly enhanced the total time of waking in a dose-dependent fashion, 43 whereas higher doses of 160 to 600 mg increased sleep time and sedation in humans 44 , 45 as well as in animals. 46 CBD also positively affects REM sleep behavior disorder (RBD). RBD is a sleep disorder that causes people to act out their dreams. Common symptoms include talking, shouting, and complex movements associated with nightmares. The disorder occurs frequently in patients with Parkinson’s disease, but is challenging to treat. In a small, 6-week case series, 46 CBD was administered to 4 patients with Parkinson’s disease who also showed symptoms of RBD. Three of the patients received 75 mg of CBD per day and 1 received 300 mg per day. All 4 patients experienced a significant reduction in symptoms following treatment.
Anticancer Effects of Cannabinoids may be able to Prolong Life
Probably the most exciting property of cannabis, scientific evidence for anticancer effects, goes back to 1974 at the Medical College of Virginia at the behest of the US government, about 2 decades before the endocannabinoid system and mechanism of its actions had been detected. The surprising results of that study, reported in an August 18, 1974 Washington Post newspaper feature, were that marijuana’s psychoactive component, THC, “slowed the growth of lung cancers, breast cancers and a virus-induced leukemia in laboratory mice, and prolonged their lives by as much as 36 percent.”
Funded by the National Institutes of Health to find evidence that marijuana damages the immune system, the study found instead that THC slowed the growth of 3 kinds of cancer in mice—lung and breast cancer, and a virus-induced leukemia. The US Drug Enforcement Agency quickly shut down the Virginia study and all further cannabis/tumor research even though the researchers demonstrated remarkable antitumor effects. 47
Astrocytomas and in particular glioblastomas are the most frequent brain tumors among approximately 180 different types. Malignant glioma remains one of the most aggressive forms of brain cancer, with a median survival after resection, radiotherapy and chemotherapy of 12 to 15 months. In children, brain tumors constitute the second-most-common malignancy. When cells become malignant, they develop more cannabinoid receptors and become more susceptible to endocannabinoids, thus enabling an efficient intervention. In most brain tumors the endocannabinoid system is upregulated and seems to be under epigenetic control. 48 Tumors express not only CB1 but also CB2 receptors and the expression of the latter usually correlates with tumor grade. When CB1 expression in primary glioma samples from treatment-naïve patients (with grade II, grade III, and grade IV glioma tissues) were compared to normal human astrocytes, a striking upregulation of CB1 receptors, but a generally low expression of CB2 receptors, was found. 49 Expression of both receptors increases gradually as a function of cancerous transformation and malignancy. 50 , 51
Interestingly, some benign pediatric astrocytic tumors, such as subependymal giant cell astrocytoma, which may only occasionally cause mortality owing to progressive growth, also display high CB2 immunoreactivity. 52 As other brain tumors lack a more systematic examination of their modulation by the ECS, this review focuses on glioma only.
Cannabinoids Demonstrate Antitumor Effects on Glioma Cells
Cannabinoids decrease tumor progression by at least 2 mechanisms: apoptotic death (tumor cells) and the inhibition of tumor angiogenesis. 53 It has also been reported that cannabinoids inhibit tumor-cell migration and spreading. 54 Cannabinoid administration was found to inhibit matrix metalloproteinase (MMP) expression (MMP-2) in cultured glioma cells, in mice bearing gliomas, and in 2 patients with glioblastoma multiforme. 54 MMPs have long been linked to tumor invasion owing to their crucial involvement in the breakdown of the extracellular matrix and in the proteolytic activation of various classes of tumor progression factors.
Initial studies showed that THC and other cannabinoids induce the apoptotic death of glioma cells by CB1- and CB2-dependent stimulation of the de novo synthesis of the proapoptotic sphingolipid ceramide. 55 Activation of CB2 elicits direct antiinflammatory effects in target cells, suppresses cancer cell proliferation, and induces apoptosis. 56 Activation of TRPV2, like TRPV1, also exerts a negative control on glioma cell survival and proliferation. 56 , 57 CBD increases TRPV2 expression and shows synergistic activity with cytotoxic agents to induce apoptosis without toxic effects on normal astrocytes. 58 Cannabinoids also block the activation of the vascular endothelial growth factor pathway, an inducer of angiogenesis. 55 Most intriguingly, in contrast to the death-promoting action of cannabinoids on cancer cells, the viability of normal (nontransformed) cells is unaffected or, under certain conditions, even enhanced. Although it is widely assumed that THC promotes cancer cell death in a CB1- and/or CB2-dependent manner, anticancer effects of cannabinoids are observed at concentrations that are at least 1000-times above those where interactions with these receptors occur and independent from receptor affinity; dosages are clearly supraphysiological. Therefore, additional, nonreceptor mechanisms such as induction of reactive oxygen species seem to be plausible.
The first and only published clinical study aimed at assessing antitumoral action of THC in humans was a pilot phase 1 trial in 9 patients with recurrent glioblastoma multiforme. All of them had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumor progression at the time they received THC. Each day, an aliquot of a THC solution (100 mg/ml in ethanol) was dissolved in 30 ml of physiological saline solution supplemented with 0.5% (w/v) human serum albumin and was infused into the resection cavity, at days 3 to 6 after surgery. 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. The median duration of an administration cycle was 10 days; 5 patients received more than 1 cycle. In 3 of these 5 patients, a temporary reduction of tumor proliferation was observed. THC administration was safe without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% CI, 15–33). 59 The tumors from these 9 patients expressed different amounts of CB1 and CB2 receptors, but no correlation was found between receptor-type expression and survival. In 2 patients who received THC for 30 and 26 days, respectively, and in whom CB receptor expression had been determined after THC treatment, a slight decrease in CB1 receptor expression but no change in CB2 receptor expression was observed, which might reflect a predominant binding of THC to the former protein or its higher susceptibility to desensitization.
On February 17, 2016, orphan designation (EU/3/16/1621) was granted by the European Medicines Agency to GW Research Ltd, United Kingdom, for THC and CBD from extracts of the Cannabis sativa L. plant for the treatment of glioma. In the United States, clinical trials in glioma patients combining nabiximols (THC + CBD, up to 32.4 mg and 30 mg per day, respectively) with temozolomide are still under progress ( > NCT01812603, > NCT01812616, www.clinicaltrials.gov). Maximal doses of THC and CBD in these 2 trials are about 5- to 15-times lower than doses that were effective in animal studies (see below). Results of a further pilot study with THC (5 mg BID administered 24 hours prior to, during, and 48 hours after completion of oral/intravenous chemotherapy for a maximum of 2 consecutive cycles, > NCT00314808) that started in May 2006 have not been published.
In contrast to THC, CBD does not interact directly with CB1 and CB2 receptors but produces nonetheless a remarkable antitumor effect in glioma as well in a number of other animal models of cancer, including reduction of invasiveness and metastasis. The mechanisms by which CBD kills glioma cells, independently of cannabinoid receptor stimulation, both in vivo and in vitro, has not as yet been completely clarified. It seems to rely—at least in part—on its ability to inhibit the transcription of tumor-related genes (eg, midkine, MDK) and enhance the production of reactive oxygen species in cancer cells. CBD also decreases the activity and content of 5-lipoxygenase. 60 , 61 Lipoxygenases and cyclooxygenases are families of enzymes that metabolize arachidonic acid but also endocannabinoids, potentially to inflammatory leukotrienes, thus interfering with the ECS. CBD might also promote glioma cell death by acting on TRP-channels, particularly on TRPV2. 55 Tumor cell invasiveness, such as of glioma, depends on the expression of the transcriptional regulator Id-1. It is therefore of particular interest that CBD significantly downregulates Id-1 gene expression and associated glioma-cell invasiveness and self-renewal at concentrations that can be achieved in vivo. 62
A number of reports on treatment of various brain tumors with cannabis exist in the internet but are unfortunately restricted to inconclusive or poorly documented anecdotal testimonials on various cannabis extracts (eg, hemp oil) used by patients or their relatives 63 ; this includes also a report on spontaneous regression of pilocytic astrocytoma after incomplete resection in 2 children. 64 Efficacy studies or at least reliable testimonials from physicians and detailed case reports are still missing.
Cannabinoids are Highly Effective in Animal Glioma Models
A recent review article emphasized that all 16 in vivo studies that evaluated cannabinoid action on glioma so far showed statistically significant reductions of tumor volumes when comparing to controls. 65 Six animal glioma studies investigated CBD, THC, or both; one of them in combination with X-rays or temozolomide, which is the benchmark agent for the management of glioblastoma multiforme. Cannabinoids were administered via subcutaneous or intraperitoneal route, but also intra- or peritumoral in widely varying dosages between approximately 4 and 25 mg/kg/day. Duration of treatment was between 7 and 28 days. Results are summarized in Table 3 and also include publications since the data lock date of AM review, December 2012.
Results of THC and/or CBD in animal models of glioma
|THC peritumoral, 15 mg/kg/day for 14 days||Human U87MG astrocytoma, s.c. xenograft, mice||~50% reduced tumor growth, increased apoptosis;||66 ; 67 ;|
|CBD peritumoral, ~25 mg/kg/day, 5 days per week for 23 days||U87MG astrocytoma s.c. xenograft, mice||~70% regression at day 18, but ~50% regression at day 23/end||68 ; 59 ;|
|CBD intraperitoneal, 15 mg/kg, 5 days per week 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||61 ;|
|THC peritumoral, 15 or 7.5 mg THC or 7.5 mg CBD/ kg/day, or 7.5 THC + 7.5 mg CBD/kg/day over 14 days||Human glioma U87MG or T98G cells, s.c. xenograft, nude mice||15 mg THC much more effective than 7.5 mg; 7.5 mg CBD/kg was slightly more effective than 7.5 mg THC/kg; THC + CBD was most effective and similar to 15 mg THC /kg; tumor volume was stable on day 14 & 15; further enhancement by combination of cannabinoids with 5 mg TMZ/kg; T98G cells were resistant to THC or TMZ but not to their combination (CBD was not included)||70 ;|
|THC intratumoral, total dose 2.5 mg THC or 0.25 mg WIN-55,212-2 / rat over 7 days (~1.5–2 mg THC /kg/day)||Intracerebral C6 glioma model, rats (250-300 g b.w.)||THC was ineffective in 3/15 rats, tumor was completely eradicated in 3/15 rats, survival prolonged in 9 rats; WIN-55,212-2 was similarly effective||71 ;|
|CBD + THC (each ~2 mg/kg), intra-peritoneal, on day 9, 13, and 16 after tumor implantation; X-ray (4 Gy) on day 9; CBD-BDS (main: 63.5% CBD, 3.6% THC, 5.2% CBC) or THC-BDS (main: 65.4% THC, 0.4% CBD, 1.8% CBC)||Mouse glioma GL261 cells, orthotopically implanted||>85% decrease of tumor volume and of vascularization on day 21 (animals sacrificed); CBD + THC reduced progression, further enhanced by irradiation (stagnant tumor sizes throughout the experiment); X-rays alone had no dramatic effects||72 ;|
Abbreviations: BDS, botanical drug substance; CBD, cannabidiol; THC, delta-9-tetrahydrocannabinol.
Although neuroblastomas are solid tumors of the nervous system that occur outside of the brain, it is worth mentioning that a high dose of CBD (20 mg/kg i.p./d for 14 days) reduced tumor size by about 46% compared to a vehicle-treated control group in a mouse tumor xenograft model. 66
All studies reported a mean decrease of tumor size between approximately 50% and 95%. Combinations with temozolomide, X-rays, or cannabinoids enhanced the activity further. One study demonstrated that higher doses of THC were more effective, thus confirming a dose-dependency observed already in vitro; differences in sensitivity of glioma cells to cannabinoids exist.
In short, a number of experiments, in vitro and in vivo, have demonstrated that cannabinoids act synergistically, which is of great importance for the development of future anticancer therapies. The treatment of glioblastoma cells with both compounds, THC and CBD, led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. 73 Most intriguingly, in 2 of the above-mentioned in vivo studies, a few animals were completely tumor-free, suggesting definite tumor eradication. 62 , 71 Noteworthy is also the observation that, in vitro, extracts (“botanical drug substance”) were either more (THC-BDS) or less (CBD-BDS) effective than the respective pure cannabinoids; efffects of both extracts were enhanced by irradiation. 72
Discussion and Conclusion
A steadily increasing number of publications demonstrate the high potential of cannabinoids in palliative care. They can be combined with other therapies and seem to be devoid of any significant toxicity. Effects differ, however, between cannabinoids and change also with increasing doses whereby many aspects remain unsolved.
THC, a partial CB1, CB2 agonist, has the stigma of psychotropic effects that are mediated by CB1 stimulation. However, CB1 stimulation is necessary for improving mood and appetite and many other effects. At present, it is hard to imagine a better approach than adjusting THC doses individually to balance wanted versus unwanted effects. Generally, higher doses are needed to achieve analgesic and antiemetic effects. Even much higher, supraphysiologic oral doses would be needed to combat tumors, based on results from preclinical models where animals received roughly between 2 and 25 mg THC and/or CBD per kg body weight once daily. Such high doses preclude an oral use of THC as single substance in humans due to side effects.
Many questions are also unsolved when it comes to chronic treatment with cannabinoids, a particularly important point in palliative care. The desensitization of receptors (CB1) after repeated/chronic exposure to agonists (THC), although reversible, is a well known phenomenon. 74–76 Because CB1 receptors desensitize upon prolonged occupancy, 77 it is conceivable that this may hamper the efficacy of long-term treatments with THC. Full recovery of CB1 receptors after stopping THC for example may take up to several weeks, with regional differences. 78 Can such a desensitization or development of tolerance be reduced or avoided, and—if yes—how? Is a daily treatment, as commonly practiced, necessary or is a pulse-dosing concept with intermittent dosages given as short cycles a better alternative? How long last effects?
CBD and possibly other non-psychotropic cannabinoids, may be a promising alternative for many indications, likely to include nausea, vomiting and improvement of sleep, although more studies in humans are necessary. CBD acts on the ECS as a negative allosteric modulator of CB1 receptors, stimulates the TRPV1, is an agonist of the 5-HT1A serotoninergic receptor and an antagonist to GPR55, and reduces the hydrolysis of AEA by inhibiting FAAH. Despite that it lacks any orexigenic effect, CBD is anxiolytic, antidepressive, and analgesic, similar to THC. Combinations were synergistic under many circumstances such as in pain and antitumor studies. Cannabinoids differ in their antitumor activities and probably in their mechanisms and targets, which is a rationale for combinations. However, for many pharmacological effects (except against tumors) roughly 10-times higher daily doses are needed for CBD compared to THC. This leaves some doubts as to whether a 1:1 fixed combination would be the optimal ratio in every case.
A further, unsolved question is whether the common intervention strategy of 1 to 3 applications of cannabinoids per day can be optimized. More recent findings demonstrate that the activity of the ECS is profoundly modulated by circadian rhythmicity. As an example, CB1 receptor protein is at its highest concentration when AEA levels are lowest and vice versa, whereas the expression of CB2 did not show striking diurnal differences, at least in the rat cerebral cortex. 79 , 80 In healthy volunteers, AEA levels seem to be lower in the late evening and higher in the early morning. In contrast, levels of 2-AG, a full agonist to CB1 receptors and about 100-times more abundant in brain than AEA, follow an opposite course. Concentrations are lowest around 04.00 AM, increase continually across the morning, and peak after lunch in the early-to-mid afternoon, with a nearly 3-fold increase above nocturnal levels. 81 Other receptors are also likely subject to diurnal rhythmicity. In rats, an AEA injection before experimentally induced traumatic brain injury significantly increased survival when traumatic brain injury was induced at 13:00 but had no effect at 1:00. This suggests that the time of administration of cannabinoids could also modulate effects.
Last but not least, nutrition also plays an important role in palliative care. Endocannabinoids (2-AG, AEA) are arachidonic acid derivatives, thus omega 6-fatty acid derivatives. Some pathways of their degradation produce, among others, proinflammatory compounds. A recent study found that 2-AG plasma levels were significantly reduced by a diet high in omega-3 and low in omega-6 fatty acids (H3-L6 intervention), which in turn significantly decreased severity of headaches. 82
In summary, the endocannabinoid system is likely playing a crucial role in palliative care. The future will show whether an optimized treatment strategy with cannabinoids can also prolong life of brain tumor patients by their virtue to combat cancer cells.
Both authors received no funding.
Conflict of interest statement. Both authors declare no conflict of interest.
Cannabis Oil Use: Growing Phenom Appears Safe, Helpful in Brain Cancer
After tracking the progress of about 20 patients with brain cancer who used cannabis, a neuro-oncologist found that the substance caused them no harm, had few side effects and did not interfere with conventional treatments.
Since some of his patients with brain cancer were likely to use cannabis anyway, Nicholas A. Blondin, M.D., figured he might as well oversee that part of their care. After tracking the progress of about 20 of these patients, he found that the supplement caused no harm in this population, had few side effects and did not interfere with conventional treatments.
While Blondin has not yet been able to draw conclusions about whether cannabis has extended overall survival in the patients, he did hear from some that it has improved their quality of life.
Director of neuro-oncology services at Associated Neurologists of Southern Connecticut, in Fairfield, and medical director of the St. Vincent’s Brain Tumor Center, in Bridgeport, the doctor reported his methods and observations in a poster presented Nov. 17 at the 22 nd Annual Meeting and Education Day of the Society for Neuro-Oncology, in San Francisco.
“The patients mostly feel pretty good,” he said. “It does not make them any worse. Besides fatigue if they take too much, which quickly reverses, there are no side effects. It’s not common amongst neuro-oncologists now, but it’s part of the routine care I provide in my practice.”
Blondin shared his results because cannabis use among brain cancer patients is a scarcely studied but growing phenomenon, with one Facebook group about cannabis oil treatment for people who have glioblastoma boasting 9,000 members. Since cannabis isn’t FDA-approved or regulated and there’s little or no instruction about its use in medical schools, “neuro-oncologists need to know about it and understand the treatment potential, pitfalls and side effects,” he said. “Talk about it with your patients, because patients are doing it.”
Medical marijuana is legal in Connecticut and in the majority of American states, and Blondin works with a state-run dispensary to get prescriptions for his patients.
“I mention the option to patients to use with standard treatment when diagnosed, and see if they’re interested, or if their families want them to try it,” he said. He advises against cannabis if the patient has a history of addiction or psychiatric or cognitive disabilities, but considers most he treats to be eligible.
When patients are interested, Blondin registers them with the state, which allows them to buy cannabis at Connecticut dispensaries.
“They grow it all, and manufacture the cannabis oil, in Connecticut, and the quality control is good,” he said. “I know how many milligrams patients are taking. I’ve developed a relationship with the pharmacist at one dispensary, and they know what I want to do. We’re all learning together.”
Working Through Challenges
One challenge is that no particular dose has been established as effective for patients with brain cancer, Blondin said.
Patients who take the drug palliatively are typically looking to ease symptoms ¾ including headaches, nausea, vomiting, gastrointestinal issues, anxiety, lack of appetite and insomnia. These patients usually find it most effective to smoke cannabis oil, often using vaporizer pens, Blondin said. Others use cannabis oil in the hopes that it will kill cancer cells, because there is some evidence in mouse models that cannabinoids, taken in combination with the standard treatment Temodar (temozolomide), can increase the effectiveness of the chemotherapy, he said. The oil comes in foil packets with syringes that are used to inject the substance into capsules, which are then swallowed. Another alternative is a sublingual spray.
In studies, mice were given 10 mg/kg of the oil, so that’s the highest dose Blondin recommends. He suggests that, if patients are experiencing fatigue, they are taking too much. The best way for these patients to find their ideal dose, he said, is to cut back on the amount of oil they’re taking and increase it every two days until they begin to experience fatigue.
Another complicating factor is that it isn’t entirely clear which ingredients in cannabis might be helpful for patients with brain cancer: THC, CBD or a combination, Blondin said.
Patients who take THC experience a high, which may be acceptable for those looking to ease insomnia or anxiety, he said. On the other hand, he said, CBD, which is non-psychoactive, also seems to work well for anxiety. In addition to consulting with Blondin, patients can choose their treatments and doses by doing research online or on social media, seeking advice from the pharmacist at a local dispensary or checking with a private consulting firm such as Green Health Consultants, the doctor said.
A final additional challenge is that cannabis represents an out-of-pocket cost for patients, Blondin said.
His study tracked three groups of patients: low users, who basically registered for cannabis at the behest of their caregivers, but then never tried it; palliative users; and therapeutic users.
Tracked were five astrocytoma patients, four of whom used palliatively and one therapeutically; three anaplastic astrocytoma patients, one of whom used palliatively and two therapeutically; and 12 glioblastoma patients, including three low-use patients, two who used palliatively and seven who used therapeutically. Some started earlier in the course of their treatment than others. Blondin authorized the first of his patients to use medical marijuana on March 3, 2014, and that was when he initiated his effort to track outcomes. In all, he approved four patients to use cannabis in 2014, six in 2015, four in 2016 and six so far this year. His data cutoff date for the study presented at SNO was June 12, 2017.
All of his patients who are taking cannabis palliatively have reported that it is effective, Blondin said. Among those using cannabis therapeutically, he said, all seven glioblastoma patients were alive at data cutoff; their cannabis use had ranged from two to 30 months.
Blondin intends to keep studying the issue and hopes that cannabis will be investigated in clinical trials as a therapy for this population. He is considering crowdsourcing with patients, especially long-term survivors of brain cancer who use cannabis, to learn more about the doses and methods of delivery they choose for themselves, and what they have found effective. “I would want to have other doctors who are interested pool their data,” he added, “so we can find out what’s going on.”