The use of cannabis in supportive care and treatment of brain tumor.

Abstract

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 AD³). 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 review⁴ 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/m² and 6 × 15 mg/m²,⁴ but occasionally also in doses of 5 mg/m² 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, 1.0–2.7¹⁵); 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.

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 below²⁵; 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 system²⁶ 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.

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 relatives⁶³; 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.

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.

Funding

Both authors received no funding.

Conflict of interest statement. Both authors declare no conflict of interest.

References