Cannabinoids adaptions in oncology

Summary

Cannabinoids are widely studied and used in oncology. Although the most appropriate method of using cannabinoids has not yet been established.

Cannabinoids have been widely studied and used in oncology. Although the most appropriate method for the use of cannabinoids has not yet been thoroughly substantiated, it has been proven that cannabinoids inhibit the development of the cancer process and accelerate cancer cell death, by activating immune processes and relieving symptoms such as pain, anxiety, depression, exhaustion and lack of appetite.

There is also ample evidence that cannabinoids can be particularly effective in addressing various forms of cancer and that they can also be used in combination with other treatments (eg, chemotherapy, radiotherapy) as they will reduce their side effects as they also increase the effectiveness of the treatments.

In addition, there is ample evidence that cannabinoids provide better results than opiates in suppressing pain in cancer patients and that they are particularly effective as natural analgesics.

Patients may occasionally report certain side effects, although these are relatively mild. These effects may be more pronounced at the beginning of the treatment. Some of these patients who started using cannabis formulations reported dry mouth, dizziness, and slight disorientation, but these phenomena eventually subsided. If these effects were to become too unpleasant or should they increase over time, it is recommended to discontinue the cannabinoid intake.

Ethiology, pathogenesis and symptoms of the disease

Oncological diseases are classified as non-infectious chronic diseases, whose origin is explained by genetic, autoimmune or viral theories; also by exposure to chemical toxins and radiation. Cancer disorders in certain organs are mainly associated with an unhealthy lifestyle. All substances that can induce the development of an oncological illness are said to be carcinogenic; They are divided into four classes. According to scientific research, the first class includes carcinogenic substances that can cause malignant tumors. According to the Health Institute, about 23% of all men and 17% of women with malignant diseases die in Lithuania (Health Institute, 2018). In the nomenclature of causes of death, these diseases have been in second place for many years enow (both in Europe and in many other coountries where the incidence of malignant tumors has been growing rapidly for the past several decades (WHO / Europe, European HFA Database, July 2016).

Mechanism and effects of exposure to cannabinoid in oncology

The focus of scientific research is on adapting phytocannabinoids to oncology: both by inhibiting the oncological process itself and by reducing the symptoms of the disease, such as pain, nausea, vomiting… In fact, most of the anti-angiogenic and antiproliferative effects of cannabinoids have been studied in vitro or in mice (Chakravarti B et al., 2014). They revealed that cannabinoids were involved in cell death, slowing or even stopping the proliferation of tumors and metastases; and furthermore, that they played a key role in angiogenesis (anti-angiogenic effect) and in immunomodulation, two crucial factors in oncology. For example, the cannabinoid anandamide (AEA), a CB1 agonist receptor, has been shown to have antiemetic, analgesic, appetite-stimulating, and tumor-inhibiting effects (Joseph J et al., 2004). However, the delta 9-tetrahydrocannabinol (Δ9THC), which has a psychoactive effect, acts on the contrary, acts as an anti-cancer immune suppressant when acting via CB2 receptors (Zhu LX et al., 2000)

Cancer cell apoptosis and cannabinoids
Cannabinoids also have an apoptotic effect on cancerous cells (apoptosis – programmed cell death, Hanahan D, 2000). Also noted are the potential positive effects of cannabinoids when combined with other therapies (radiotherapy, chemotherapy). Combination therapy is more effective than monotherapy and helps to reduce the side effects of therapy, such as nausea and vomiting (Yasmin-Karim S et al., 2018, Smith LA et al., 2015).

Antimetastatic effects of cannabinoids
Pharmacological mechanisms and clinical effects have also been investigated in separate forms of cancer. Cannabinoids have been shown to have anti-invasive and antimetastatic effects in lung cancer cells and in metastatic lung cancer cells taken from cancer patients (Haustein M et al., 2014). Cannabinoids were shown to activate processes that bind lymphokine-activating cells to specific cells (ICAM-1) on the surface of lung cancer cells, causing cytotoxicity and death of these cancer cells. In the study on the effects of CBD on healthy lung tissues (eg, vascular endothelial cells), cytotoxic effects were shown to to have a significantly weaker cytotoxic effect; thus, it can reasonably be said that CBD action is specific to lung cancer cells.

Breast Cancer And Cannabinoids
It is forecasted that in the near future 12% of the world’s women will develop breast cancer. Although mortality from this disease is declining, it remains the second most common cause of death in the female population, and no new treatment exists to date. Breast cancer by its mechanism is a very heterogeneous disease and in the long run, standard treatment can lead to resistance (Blasco-Benito S et al., 2018). On the other hand, it has been determined that cannabinoids modulate the hormone-dependent breast cancer cells. Expression of CB1 and CB2 receptors was indeed detected in breast cancer tissue. Cannabinoids were involved in the apoptosis (natural death) of tumor cells, and in the inhibition of bone pain caused by breast cancer as well as by the loss of bone mass. The Δ9-THC component inhibited the proliferation of cancer cells / tumors. Various experiments with animals also revealed that a natural preparation derived from the Cannabis sativa plant with all its active components was more effective in treating breast cancer than purified Δ9-THC.

Prostate Cancer And Cannabinoids
The most common oncological disease in men of all races is prostate cancer. In these cancers, cancer-damaged prostate tissues express a higher level of CB1 and CB2 receptors than healthy epithelial cells in this tissue. Delta 9-THC, methanandamide, cannabidiol (CBD), anandamide, JWH-015, HU120, 2-AG and its analogue, Noladine, have antiproliferative, apoptotic and anti-invasive effects on various cancer cells of the prostate, in vitro and in vivo.

Skin Cancer And Cannabinoids
Melanoma is the leading cause of death from skin cancer. CB1 and CB2 receptors are detected in both healthy skin tissues and cancer-damaged tissues in both humans and animals. CB1 / CB2 receptor activation was shown to cause apoptotic death of epidermal cancer cells, but did not affect non-transformed (healthy) skin cells.

Pancreatic Cancer and Cannabinoids
Activation of CB1 and CB2 receptors is also observed in one of the most aggressive and most tissue-damaging pancreatic cancers. Cannabinoid receptors on pancreatic cancer cells have shown to play a role in inhibiting the intensity of patient pain and prognosis. Animal experiments have shown that the administration of cannabinoids causes apoptosis of pancreatic cancer cells through CB2 receptor activation and ceramide regulation in p8, ATF-4 and TRB3 genes (Carracedo A et al., 2006).

Blood Cancer (Leukemia) And Cannabinoids
«Many cannabinoids within the resinous extract have demonstrated targeted, antiproliferative, proapoptotic and antiangiogenic properties…. there is potential that cannabinoids might show selectivity when attacking cancer cells, thereby reducing the widespread cytotoxic effects of conventional chemotherapeutic agents.» «It must be noted that where our most advanced chemotherapeutic agents had failed to control the blast counts and had devastating side effects that ultimately resulted in the death of the patient, the cannabinoid therapy had no toxic side effects and only psychosomatic properties, with an increase in the patient’s vitality. The nontoxic side effects associated with cannabis may be minimized by slowly titrating the dosing regimen upwards, building up the patient’s tolerance. The possibility of bypassing the psychoactive properties also exists, by administering nonpsychoactive cannabinoids such as cannabidiol that have demonstrated antiproliferative properties…. Despite the nonstandardization of the medicines, the dose was readily titrated according to the biological response of the patient and produced a potentially life-saving response, namely, the drop in the leukemic blast cell count…. There has been an abundance of research exhibiting the cytotoxic effects of cannabinoids on leukemic cell lines in the form of in vitro and in vivo studies . An oncology and hematology journal, Blood, has published numerous papers over the years constructing the biochemical pathway to be elicited by the anticancer properties of cannabinoids…. In a nutshell,Cannabidiol has garnered much attention as being a potent anti-inflammatory and possible antileukemic and anticancer agent. {PubMed Article}

References
1. Guzman M. Cannabinoids: potential anti-cancer agent. Nat Rev Cancer. 2003;3:745–755.;
2. Powles T, Poele RT, Shamash J, Chaplin T, Propper D, Joel S, Oliver T, Liu WM. Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway. Blood. 2005;105:1214–1221.
3. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol. 2006;70:897–908.
4. Murison G, Chubb C, Maeda S, Gemmell MA, Huberman E. Cannabinoids induce incomplete maturation of cultured human leukemia cells. Proc Natl Acad Sci. 1987;84:5414–5418.

Bone Cancer And Cannabinoids
The importance of cannabinoids for bone cancer has been identified. Chondrosarcoma and osteosarcoma are the most common malignant forms of bone cancer, and bone metastases are one of the most common cancer complications. This complication is usually accompanied by extreme pain. Cannabinoids effectively relieve these pains. Animal experiments have shown that component WIN55,2122 causes apoptosis of sarcoma tumor cells and slows down bone mass loss. The AM1241 component slows down bone loss and prevents cancer-induced bone fractures. The CB2 agonist JWH-015 helps reduce bone pain and bone loss due to cytokine-chemokine suppression; It also helps to prolong survival time and to reduce the symptoms of allodynia (alodynia – pain caused by an irritant such as heat that does not cause pain in a healthy body )

Brain Cancer And Cannabinoids
Glioma is one of the most aggressive malignant tumor forms, resistant to chemotherapy. 38 percent Glioblastoma endothelial cells are found in CB1 receptors and 54% in CB2. CB2 receptor expression is stronger in glioma tissues compared to CB1. Selective CB2 agonists are believed to have an effect on the treatment of this cancer. It has been shown that cannabinoids cause apoptosis of glioma tumor cells and disrupt tumor angiogenesis. It is also thought that cannabinoids that do not interact directly with either CB1 or CB2 receptors can modify Δ9-THC activity. Combination therapy with Δ9-THC and temozolomide (TMZ, antimicrobial therapy for gliomas) has a potent antitumour effect on glioma cells through activated autophagy processes. Sub-maximal Δ9-THC and CBD doses combined with TMZ have a potent antitumour effect on both TMZ susceptible and resistant forms. However, glioma cancer cells can also be resistant to cannabinoids during treatment. The method of microencapsulation (placement of the active substance in the capsule) can slow down the release of cannabinoids and increase their efficacy (Hernan Perez de la Ossa D et al., 2013).

Lymphoma And Cannabinoids
Significant expression of CB1 and CB2 receptors is also observed in non-Hodgkin’s lymphoma in types B cancer cells. Experiments with mice showed that Δ9-THC reduced the viability of these cells through inhibition of metabolic processes and induced apoptosis. The components of R (+) – methanandamide and WIN-55,212-2 play the most important role in apoptosis processes. Canbinoids are also important in the paraptosis processes of this type of cancerous cells (paraptosis is a programmed cell death that does not have apoptotic mechanisms, such as cell fragmentation).

Thyroid Cancer And Cannabinoids
The IL-12 gene was found to be involved in mechanisms of transforming thyroid tissue epithelial cells into ARO cancers. CB2 agonist JWH-133 and CB1 / CB2 agonist WIN-55,212-2 proved to induce apoptosis of ARO and ARO / IL-12 cells.

Multiple Myeloma And Cannabinoids
Multiple myeloma is the second most commonly reported malignant disease in the haematopoietic system. Until now, the disease was considered to be incurable (Anderson KC et al., 2011). The CB2 receptor is found in abundance in the bloodstream and in the immune system. Although clinical trials have not yet been conclusively studied, the mechanisms of cannabinoids have been studied for the treatment of multiple myeloma. These studies demonstrated that cannabinoids caused selective apoptosis of multiple myeloma cells by both caspase activation and ceramide accumulation The CB-WIN-55,212-2 mesylate agonist receptor was found to reduce myeloma cell viability by 85%, but but not to affect healthy tissue cells; it slightly reduced B lymphocytes, but did not affect the viability of T lymphocytes (Barbado MV et al., 2017). The cannabinoids PGN-6 and 217 had no effect on the viability of either B or T lymphocytes even at high doses.

Angiogenesis And Cannabinoids
Cannabinoids are also important in prometastatin mechanisms associated with oncological processes, such as angiogenesis, migration, and invasion of other tissues. The more invasive the cellular angiogenesis, more probable the oncological propagation (metastasis). It was determined that both natural cannabinoids and their synthetic analogues inhibited the migration of breast and lung cancer cells as well as angiogenesis. In addition, cannabinoids have a positive effect on the control of oncological processes throughimmunomodulatory mechanisms. Anandamide and other cannabinoids were shown to reduce the production of cytokines IL-2, TNF-α and INF-γ in human T lymphocytes by activating CB2 receptors (Cencioni MT et al., 2010).

Therapeutic doses and side effects of cannabinoids.

In Israel, under the guidance of Prof. Raphael Mechoulam, who conducted scientific and clinical studies around the world to reveal the therapeutic effect of cannabinoids (Guzmán M., 2018), in 2007, the Israeli Ministry of Health authorized the use of cannabis in medicine. There are now approximately 30,000 patients being treated with cannabinoids in Israel. Most of these patients suffer from oncological diseases and use cannabinoids to relieve the symptoms of the disease. An epidemiological study of the use of cannabinoids in 3,000 of these oncological patients revealed that half of them had been diagnosed with stage 4 cancer and that more than half had acute pain: 8 out of 10 to be exact (Bar-Lev Schleider L et al., 2018). The patients averaged about 60 years of age and each of tem displayed an average of 11 symptoms (sleep disorders, pain, depression and anxiety, fatigue and weakness, nausea and vomiting, loss of appetite). After six months, of these patients had died and 18.8% had also died after discontinuing all treatments. 60.6% of the remaining patients agreed to fill out the questionnaires once again. 95.9 percent of all respondents indicated an average or a significant improvement in their health status. Before initiating cannabinoid therapy, only 18.8% of the patients had rated their quality of life as being “good”. After 6 months of therapy, approximately 69.5% of patients rated their quality of life as “very good” – CBD was well tolerated and the most common side effects reported were dizziness, drowsiness and dryness of mouth. At the beginning of the study, opioids had been the most commonly used medication for these patients. After 6 months of CBD therapy 36% of the patients refused these opiates and a further 9.9 percent had significantly reduced their doses. It should be noted that the use of CBD is more cost-effective and that CBD does not cause any form of addiction; it also eliminates the risk of death that may occur with an opioid overdose. It should, however, be noted that in order to substantiate the therapeutic use of CBD in oncology, there should be more large-scale, well-documented clinical trials.

Consult your doctor before using this diary supplement on your own responsibility.

The following table shows the effects of each cannabinoid.

Cannabinoids and their role in various onco-physiological and other processes (according to Chakravarti B et al., 2014)

Anandamide (AEA), a CB1 agonist	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
2-arachidonoyl glycerol (2-AG),	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
CB1 / CB2 agonist	Neuromodulatory and immunomodulatory effects
Palmitoyl ethanolamide (PEA),	Neuromodulatory and immunomodulatory effects
CB2 agonist	Neuromodulatory and immunomodulatory effects
Docoxatetraenylethanolamide	Neuromodulatory and immunomodulatory effects
CB1 agonist	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
Homogalaminonelethanolamide	Neuromodulatory and immunomodulatory effects
CB1 agonist	Neuromodulatory and immunomodulatory effects
Oleamide, a CB1 agonist	Neuromodulatory and immunomodulatory effects
Δ9-tetrahydrocannabinol (Δ9-	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
THC), a CB1 / CB2 agonist	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
Δ8-tetrahydrocannabinol	Antitumor agent, antiemetic, appetite stimulating effect
(Δ8-THC), a CB1 / CB2 agonist	Antitumor agent, antiemetic, appetite stimulating effect
Kanabidol (CBD), a CB1 agonist	Anti Tumoral agent, facilitates catalepsy, immunosuppressive effects, inflammatory or anti-inflammatory agent (depends on the concentration of the product), anti-psychotic effects
Kanabigerol (CBG)	Multiple sclerosis treatment, antiemetic, anti-inflammatory, treatment of neurological disorders
Kanabichromene (CBC)	Inflammatory anti-inflammatory agent, treatment of neurological disorders, hypomobilism, catalepsy, hypothermia
Tetrahydrocannabivarin (THCV)	Ignition suppressant, hepatitis ischaemia treatment
Kanabigerovarin (CBGV)	Ignition suppressant
HU-210, CB1 / CB2 non-selective agonist	Analgesic effects, multiple sclerosis, neuroprotective effects
CP-55,940, CB1 / CB2 non-selective agonist	Anti-cancer agent, analgesic, antiemetic, appetite stimulating effect
R – (+) – WIN 55,212-2, CB1 / CB2 non-selective agonist	Analgesic, antiemetic, appetite stimulation, inhibition of tumor growth, multiple sclerosis treatment
JWH-015, CB2 selective agonist	Anti-cancer, anti-inflammatory, antiemetic
JWH-133, a CB2 selective agonist	Treatment of neurological disorders, antitrust effects
JWH-139, a CB2 selective agonist	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
HU-308, CB2 selective agonist	Suppression of tumor growth (in glioma, lymphoma, skin carcinoma)
CP55940 CB / CB2 agonist	Analgesic, antiemetic, appetite stimulation, inhibition of tumor growth, multiple sclerosis treatment
R – (+) – methanandamide, CB1 agonist	Analgesic, antiemetic, stimulation of appetite, suppression of tumor growth
AM251 CB1 antagonist	Metabolic syndrome treatment
AM281 CB1 antagonist	Mice improve cognitive impairment caused by naloxone, discontinuation of morphine, various pharmacological options

There is also considerable evidence of an analgesic effect on the oncological process in individuals suffering from neuropathic pain.

A two-week, rendomised, placebo-controlled study found that the administration of cannabinoids at the last stage of the oncological process helped patients to reduce their pain. At the beginning of the study, all patients evaluated the pain by scoring more than 4 points from 0 to 10 points (Darkovska-Serafimovska M et al., 2018). Patients were divided into 3 groups. The first group received Sativex Oral Spray (nabiximol, 2.7 mg THC and 2.5 mg CBD per serving) (n = 60); the second one received oral THC spray (2.7 mg THC per shot) (n = 58), and the third one, placebo spray (n = 59). Doses were titrated over the first week, depending on the tolerance to the product and the intensity of the pain. The maximum dose prescribed was 8 injections over a period of 3 hours with a minimum of 15 minutes between doses, or 48 injections per 24 hours (130 mg THC and 120 mg CBD). After two weeks of treatment with Sativex, 43% of patients reported that the pain had decreased by more than 30%. Statistically speaking, this proportion proved significant because it was very different from that of the placebo group. In the placebo group, pain reduction was clinically significant at 21%. For patients in the THC group, reduction of 23%, a result substantially identical to that of the placebo group. In the Sativex group, 10 out of 60 patients experienced side effects (THC group => 7 out of 58 and placebo group => 3 out of 59). The most commonly reported adverse reactions were: dry mouth, drowsiness, nausea and vomiting.

In 2013, 39 patients with oncological pain treated with opiates were included in a clinical study, but the results were inadequate (Darkovska-Serafimovska M et al., 2018). All of the patients received Sativex. 15 patients out of 39 were treated for less than two weeks, while the other members of the study group failed: some because of adverse effects (23 out of 39), others because of insufficient efficacy (3 out of 39) and others for other reasons. The study concluded that Sativex was suitable for long-term use. It should be noted that no patient on long-term treatment had to increase the dose during treatment.

A placebo-controlled trial study of patients suffering from neuropathic pain related to their cancers revealed that in the group of cannabinoids, based on a score of 0 to 10 points, pain had decreased by 43% over the course of 10 days in comparison to 21% for the placebo group. (Darkovska-Serafimovska M et al., 2018). All the patients were adults with end-stage cancer who had been treated with opioids for at least one week but who still had pain above 4 points on a scale of 0 to 10. Patients were then treated with different doses of Sativex. The first group was given one injection four times a day (10.8 mg THC, 10 mg CBD) (n = 91), the second one – 10 injections per day (27 mg THC, 25 mg CBD) (n = 88), the third – 16 injections per day (43 mg THC, 40 mg CBD) (n = 90). The group, taking only the THC spray and placebo, also participated in the study (n = 90). Within 7 days, the dose was increased (from 1 to 4, 10 or 16 injections) and adjusted for another two weeks. The effect was seen from day 21 to day 35. In the placebo group, 3 out of 91 patients experienced side effects, while 5 out of 91 patients did in the lowest dose group and 6 out of the 88 that had been given the medium dosage, and 20 out of 90 amoong those in the highest dose group. The daily pain tests revealed that the most effective small to moderate doses compared to placebo.

In conclusion, it was determined that for patients suffering from pain related to oncological illnesses, the recommendation should be to divide 27 to 32 mg of the Δ9-THC and 25 to 30 mg of CBD into 10 to 12 doses per day. The maximum daily dose would be 32.4 mg THC and 30 mg CBD. These were the only placebo-controlled clinical trials in patients with oncological pain. No clinical trials have been conducted with other forms of CBD use.

CBD, in addition to its therapeutic effects, helps to mitigate the psychoactive effects of THC. Balanced THC / CBD preparations are considered to be more therapeutically effective and safer than synthetic one-component preparations, such as dronabinol (nabilone), which has a very limited application. The terpenes in the cannabinoids (mycenes, α-pinene and barycaryphylene) have a synergistic therapeutic effect with phytocannabinoids, but these mechanisms are not yet scientifically recognized.

To sum it all up, cannabinoids specifically target cancer cells (not healthy tissue cells). The administration of single cannabinoids is less effective than the natural extract, which contains a broad range of cannabinoids, terpenes and flavonoids. In addition, combined chemotherapy + cannabinoids treatments can improve clinical effects, reduce toxicity, increase targeting of cancer cells, and prevent drug-related complications.

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