CBD Oil And Cancer

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Cannabidiol (CBD) in Cancer Management Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC Learn how marijuana and drugs derived from the marijuana plant can affect cancer-related symptoms.

Cannabidiol (CBD) in Cancer Management

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Abstract

Simple Summary

Cannabidiol (CBD) is one of the main constituents of the plant Cannabis sativa. Surveys suggest that medicinal cannabis is popular amongst people diagnosed with cancer. CBD is one of the key constituents of cannabis, and does not have the potentially intoxicating effects that tetrahydrocannabinol (THC), the other key phytocannabinoid has. Research indicates the CBD may have potential for the treatment of cancer, including the symptoms and signs associated with cancer and its treatment. Preclinical research suggests CBD may address many of the pathways involved in the pathogenesis of cancers. Preclinical and clinical research also suggests some evidence of efficacy, alone or in some cases in conjunction with tetrahydrocannabinol (THC, the other key phytocannabinoid in cannabis), in treating cancer-associated pain, anxiety and depression, sleep problems, nausea and vomiting, and oral mucositis that are associated with cancer and/or its treatment. Studies also suggest that CBD may enhance orthodox treatments with chemotherapeutic agents and radiation therapy and protect against neural and organ damage. CBD shows promise as part of an integrative approach to the management of cancer.

Abstract

The plant Cannabis sativa has been in use medicinally for several thousand years. It has over 540 metabolites thought to be responsible for its therapeutic effects. Two of the key phytocannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). Unlike THC, CBD does not have potentially intoxicating effects. Preclinical and clinical research indicates that CBD has a wide range of therapeutic effects, and many of them are relevant to the management of cancer. In this article, we explore some of the potential mechanisms of action of CBD in cancer, and evidence of its efficacy in the integrative management of cancer including the side effects associated with its treatment, demonstrating its potential for integration with orthodox cancer care.

1. Introduction

Survey data indicates that cancer sufferers are using cannabis medicinally. A cross-sectional survey in 926 patients at the Fred Hutchinson Cancer Research Centre (Seattle) found that 66% had used cannabis previously, with 24% of respondents having used cannabis in the past year and 21% in the past month. Of the 24% (n = 222) of respondents who were active users, around 75% used cannabis for physical symptoms (pain, nausea, appetite), 63% for neuropsychiatric symptoms (stress, coping with illness, depression/improve mood, sleep), and 26% reported they believed cannabis was helping to treat their cancer. Encouragingly, regardless of symptom, approximately 51% judged cannabis to be of ‘major benefit’ and 39% of ‘moderate benefit’ [1]. An anonymous online survey of 612 US-based members of the Breastcancer.org and Healthline.com communities with a self-reported diagnosis of breast cancer within 5 years found that 42% used cannabis for relief of symptoms (including pain (78%), insomnia (70%), anxiety (57%), stress (51%) and nausea/vomiting (46%)) with 46% of the belief that cannabis can treat the cancer itself. Of those using cannabis, 79% had used it during treatment (systemic therapies, radiation, surgery) [2].

The plant Cannabis sativa L. has several hundred secondary metabolites and cannabidiol (CBD) is one of the key phytocannabinoids. In this paper, I will explore what evidence exists that CBD may be useful in the integrative management of cancer, including some of its relevant mechanisms of action, evidence of efficacy in the treatment of cancer, and symptoms associated with cancer and/or its treatment and evidence that CBD may enhance orthodox cancer treatments. Note that there are several good review papers which I would draw readers’ attention to, including Seltzer and colleagues [3]; Mangal and colleagues [4]; and Moreno and colleagues [5]. In particular, Seltzer and colleagues’ paper [3] provides an excellent and in-depth summary of mechanisms of action of CBD in various forms of cancer, illustrating the extensiveness of the preclinical research that supports the contention that CBD is an efficacious anti-cancer agent.

However, before delving into the scientific evidence on CBD and cancer, it is important to understand a bit of the basics, about the plant Cannabis sativa and our endocannabinoid system.

2. What Is Cannabis and Cannabidiol?

The plant Cannabis sativa has been used medicinally for thousands of years in many cultures including Chinese, Japanese, Indian, and Egyptian, whilst its medicinal use in western countries such as the US, England, and parts of Europe began to occur much later, particularly in the 19th century [6,7,8,9,10,11].

2.1. Constituents of Cannabis

There are over 540 secondary metabolites in the cannabis plant, of which there are over 120 phytocannabinoids, divided into 11 classes [7,12,13]. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most well-researched of the phytocannabinoids. In addition, over 200 terpenes have been isolated from cannabis, along with phenols, steroids, polysaccharides, coumarins, glycosides, flavonoids, alcohols, and other plant nutrients, and these have their own therapeutic actions [13,14]. The so-called ‘entourage effect’ refers to the cooperative effect between the various constituents of the plant, whereby the therapeutic effect of the other constituents may contribute to the overall therapeutic effect of the main phytocannabinoids (i.e., THC, CBD). I like to use the analogy of a rock band, with the rockstars on stage being THC and CBD, the rest of the band members the other phytocannabinoids and terpenes, and the ‘roadies’ being other plant nutrients like polyphenols and so on—there’s no show without the band or the roadies.

2.2. Cultivars of Cannabis

There are several hundred different ‘strains’ or cultivated varieties (‘cultivars’) of cannabis, and their chemical profiles will differ. That is, the relative amounts of key phytocannnabinoids, terpenes, and other plant nutrients will be different in different cultivars of cannabis. And so, the therapeutic actions of different cultivars can also differ.

2.3. Cannabis and Cannabidiol Products

Medicinal cannabis products include dried flower (which can be smoked or vaped) and proprietary forms: (1) cannabis-based liquid extracts, e.g., nabiximols (approximately 1:1 ratio of THC and CBD); (2) phytocannabinoid botanicals: dense cannabis extracts manufactured as oils, oils in capsules, pills, sublingual or intranasal sprays, suppositories, transdermal patches, E-Liquids for vaporization, and topical ointments; and (3) single molecule drugs: synthetic or semi-synthetic prescription drugs (e.g., nabilone, dronabinol, which are FDA-approved) [15].

Note that in the consumer literature, the terms full-spectrum and broad-spectrum are often used in relation to cannabis and CBD products: full-spectrum denotes the presence of all the phytocannabinoids, terpenes, and other plant nutrients naturally found in the plant in the final product, and broad-spectrum denotes the presence of many of the phytocannabinoids and terpenes naturally found in the plant but not all of them. Typically, a broad-spectrum CBD product will have the THC removed [16].

Flower and cannabis oil products differ in terms of their relative amounts of the key phytocannabinoids, THC and CBD, as well as the types and relative amounts of terpenes and minor phytocannabinoids (which have their own therapeutic actions) [14].

If we consider CBD products available on the market, it is clear that they vary considerably. Whole plant (full-spectrum, broad-spectrum) CBD products will differ in terms of amount (concentration, percentage) of CBD and other phytocannabinoids present, as well as the types and relative amounts of terpenes and other plant nutrients present. CBD-predominant products typically have very low amounts of THC. If the CBD oil has been derived from a hemp plant (hemp is simply a cannabis cultivar bred to have a very low amount of THC), then it will contain less than 0.3% THC if produced in the US (the upper legal limit of THC). An important point to note is that whole plant products are likely to work differently to CBD isolate.

2.4. Differences between THC and CBD

THC is responsible for the potentially intoxicating effects associated with cannabis (the potential for causing intoxication, i.e., the euphoria or ‘high’ associated with cannabis, is dose-dependent), but unlike THC, CBD is not potentially intoxicating and not associated with the typical symptoms associated with cannabis intoxication [13,17], making it perhaps more attractive as a treatment option. Both THC and CBD have many therapeutic actions in common, but their mechanisms of action differ [9]. THC is a partial agonist of the CB1 and CB2 receptors, similar to AEA [18]. However, CBD has a low affinity to the cannabinoid receptors, and is believed to exert its actions predominantly via activating the ECS indirectly, as well as interacting with other targets or receptors [19,20,21,22]

2.5. Therapeutic Actions of CBD

CBD has many therapeutic actions, set out in Table 1 . From this table, we see how broad the therapeutic actions of this phytocannabinoid are, and we already start to see the potential relevance of CBD to cancer, its pathomechanisms, and signs/symptoms associated with cancer and its orthodox treatment. I will discuss CBD’s actions in relation to cancer in more detail shortly.

Table 1

Therapeutic Actions of CBD (adapted from [9]).

analgesic
anti-nausea
anti-emetic
anxiolytic
antidepressant
anti-psychotic
anti-convulsant/anti-epileptic
anti-asthmatic
immune-modulatory
antioxidant
anti-inflammatory
antibiotic, anti-bacterial
neuroprotective
anti-cancer and anti-tumoral
[17,18,23,24,25,26,27]

Now that we understand a little about CBD, let’s look at our endocannabinoid system (ECS). As in many respects, the reason that cannabis may be so broad in its therapeutic applications is due to the presence of this ‘ready-made system’ that the constituents of cannabis interact with. I will then look at what happens to our ECS in cancer, and how CBD may be able to assist.

3. Our Endocannabinoid System

3.1. Role of the Endocannabinoid System

The ECS is one of the most important neuroregulatory systems we have, responsible for the homeostasis of most systems in the body. The ECS modulates the following: the immune system (innate, adaptive); inflammation; pain/analgesia; our stress response, emotions/moods, cognitive function, memory and memory extinction; sleep; gastrointestinal (GI) tract homeostasis (including regulation of food intake and satiation, gastroprotection, nausea and emesis, gastric secretion, visceral sensation, GI motility, ion transport, intestinal inflammation and cell proliferation in the gut); energy homeostasis and regulation of lipid and glucose metabolism; embryological development; the cycle of cell life and death, cancer cell control, cyto-protection; neurotransmitters, neuroprotection, neural plasticity, and many others [9,15,20,28,29,30,31,32,33].

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3.2. Components of the Endocannabinoid System

Discovered in the 1990′s, at a simplistic level there are three key components of the endocannabinoid system (ECS): (1) lipid-derived endocannabinoids (the two main ones are N-arachidonylethanolamine or anandamide (abbreviated AEA] and 2-arachidonylglycerol (2-AG)), but there are others), the enzymes that synthesise and degrade them (fatty acid amide hydrolase (FAAH] and mono acyl glycerol lipase (MAGL) being two main ones degrading AEA and 2-AG respectively) plus various transporter systems, and (2) cannabinoid receptors (CB1 and CB2 receptors) [15].

However, it is much more complex and what we have are many more components that make up an ‘extended ECS’ [9]. Firstly, there are other receptors that cannabinoids (endocannabinoids and/or phytocannabinoids) interact with, including G-Protein Receptors (GPR55, GPR18, and GPR119), transient receptor potential vanilloid [TRPV] ion channels (TRPV1 and 2), and peroxisome proliferator activated receptors (PPARα and PPARϒ) [5,10,34]. There are other endocannabinoid-like substances (e.g., N-palmitoylethanolamide [PEA], oleoylethanolamide [OEA] and oleamide). There are also more recently discovered hemopressin-derived peptides (inverse agonists of CB1 receptors), novel lipid compounds (lipoxins and resolvins) that also regulate physiological allostasis, and n-3 endocannabinoid epoxides originating from docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) (de Melo Reis et al., 2021).

Cannabimimetic compounds including omega (n-3 and n-6) fatty acids can signal through the ECS (Frietas et al., 2017); indeed, both AEA and 2-AG are derived from arachidonic acid (from n-6 PUFAs) and levels of the endocannabinoids and their activity are influenced by the ratio of n-6 and n-3 polyunsaturated fatty acids in our diet [35].

The endocannabinoids actually have several biosynthetic and degrading pathways and enzymes which may be shared with endocannabinoid-like mediators; degradation of AEA and 2-AGA leads to arachidonic acid plus several other bioactive signalling molecules [36,37,38,39]. The term ‘endocannabinoidome’ was coined to describe the endocannabinoids, endocannabinoid-like mediators, and the many receptors and metabolic enzymes [36]. See de Melo Reis et al. [35] and Di Marzo and Piscitelli [36] for good descriptions of the ECS and regulation of homeostasis.

3.3. Where Are the CB1 Receptors and CB2 Receptors Located?

CB1 receptors are abundant in the central nervous system (brain, spinal cord) but are also found peripherally in many tissues and organs (though at a lower level of expression than in the brain) [40]. Several isoforms have been found: CB1, CB1A, and CB1B [41,42].

CB1 receptors are found in high concentrations in areas of the brain associated with mood/emotions and cognitive processes as well as movement [10]. Another interesting fact is that CB1 receptors appear ten times more frequently in the brain then mu-opioid receptors, and can co-localise with them to augment the pain-relieving effects of opioids [43,44]. CB1 receptors maintain the delicate balance between neuronal inhibition and excitation, in particular in GABAergic, glutamatergic, and dopaminergic transmission [45]. CB1 receptors are also abundant on the outer membranes of mitochondria [46].

CB2 receptors are particularly abundant in the cells and tissues and organs of the immune system, are also found in many other parts of the body including the brain (where they are highly inducible under conditions of inflammation) [9,47]. CB2 receptors are key mediators of cannabinoid regulation of the immune and inflammatory systems [15], where in general, CB2 receptor activation usually mediates immunosuppressive effects, attenuating the autoimmune inflammatory response, and thereby limiting tissue injury [48]. In addition, a CB2 isoform has been identified, CB2A, in the liver, spleen, neurons, and brain cortex [49]. See Table 2 for locations of CB1 and CB2 receptors in the body.

Table 2

Location of CB1 and CB2 Receptors (adapted from [9]).

Also present in:
Peripheral Nervous System: sympathetic nerve terminals, trigeminal ganglion, dorsal root ganglion, dermic endings of primary sensory neurons; neurons of parasympathetic nervous system

Blood, Tissues, Immune Cells: adipose tissue (white, brown), connective tissue, fascia, fibroblasts, skeletal muscle, bone (osteoclasts, osteoblasts); smooth muscle (vascular and visceral); blood vessels, vascular endothelial cells, blood (leukocytes), vascular smooth muscle cells; immune cells including macrophages, mast cells

Also present in:
CNS (present in lower levels in CNS): cell bodies and dendrites of central neurons; cortex, brainstem, cerebellum, striatum, hippocampus, amygdala, retina, neuronal, glial (astrocytes, microglia) and endothelial cells of brain;

Spinal Cord and Dorsal Root Ganglia

Blood, Tissues, Cells: various human tumours, adipocytes, leucocytes, bone marrow; bone (osteoclasts, osteoblasts, osteocytes), muscle cells, human vascular smooth muscle, endothelial cells

3.4. How Does the Endocannabinoid System Work?

AEA is a partial agonist at CB1 and CB2 receptors, whilst 2-AG is a full agonist [40,45]. CB1 and CB2 receptors are G-protein-coupled receptors, and when activated signal through fast pathways (i.e., Ca 2+ and K + currents) and/or slow pathways (e.g., cyclic AMP-protein kinase A and others) [35]. At a simplistic level, in the nervous system the ECS functions as a retrograde signalling system, decreasing the release and transmission of neurotransmitters.

In the nervous system, endocannabinoids are synthesised on demand from plasma membrane phospholipids in the post-synaptic neuron in response to increased intracellular calcium concentration and/or activated G-coupled receptors [10,83]. When synthesis is triggered, the endocannabinoids move in a retrograde fashion across the synaptic space, from post-synaptic to the presynaptic region, binding with cannabinoid receptors on the presynaptic neuron, and leading to suppression of neuronal excitation and inhibition of depolarisation-induced neurotransmitter release [10]. What happens downstream depends on whether the neurotransmitter is excitatory (e.g., glutamate) or inhibitory (e.g., Υ-aminobutyric acid, GABA) [10,40]. The endocannabinoids are then degraded by their respective enzymatic pathways [39].

CB1 and CB2 receptors can activate many different intracellular signal transduction pathways, including (depending on cell type): protein kinase A, protein kinase C, Raf-1, JNK, mitogen-activated protein kinases (MAPK), p38 MAPKs, extracellular signal-regulated kinase (ERK 1, 2), c-fos, c-jun, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways, mammalian target of rapamycin (mTOR) and more [83,84,85]. Depending on the ligand and subcellular environment, the eventual outcome could be promotion of cell survival or cell death [83].

That is the simple explanation, but of course it is much more complex than that given the existence of other receptors that the endocannabinoids can bind with and the existence of endocannabinoid-like substances. In addition, degradation of 2-AG also produces bioactive signalling molecules, some of which have opposing effects [37,86]. For an in-depth exploration of the ECS, see de Melo Reis and colleagues [35].

Now that we understand something of the ECS, we will now look at the herb Cannabis sativa and how it interacts with the components of our extended ECS.

4. The Endocannabinoid System in Cancer

Cannabinoid receptors are widely expressed on cancer cells as well as normal cells [5]. Research indicates that ECS dysfunction is part of the pathomechanism of many diseases, including cancer (Moreno et al., 2020) and those signs and symptoms associated with cancer and its treatment, such as anxiety, depression, poor sleep [9], and so on.

Cannabinoid receptor stimulation can lead to different outcomes, with protective effects in some tumour subtypes and unfavourable effects in others [5]. Cannabinoid receptors and other receptor members of the extended ECS have been found to be over-expressed or under-expressed in various tumours [4,5]. For example, TRPV1 is under-expressed in glioblastoma multiforme but over-expressed in lung adenocarcinoma; CNR1 (gene coding for CB1 receptors) is under-expressed in lung adenocarcinoma, thyroid carcinoma, breast invasive carcinoma, and uterine corpus endometrial carcinoma and over-expressed in cholangiocarcinoma; CB2 receptors are overexpressed in HR+ breast cancer and gliomas [5,87,88]. Overexpression of CB1 and CB2 receptors was found to be correlated with poor prognosis in stage 4 colorectal cancer [89,90].

Moreno and colleagues [5] explain that changes in expression and activation of cannabinoid receptors and their capacity to form functional heteromers with other receptors alter a cell’s tumorigenic potential and signalling properties. For example, human epidermal growth factor receptor 2 (HER2) forms heteromer complexes with the CB2 receptor in breast cancer cells, and the expression of such complexes correlates with poor prognosis [91]. However, the disruption of these heteromer complexes promotes anti-tumour responses and may represent a new therapeutic target. THC has been found to disrupt HER2–CB2 receptor complexes by selectively binding to CB2 receptors, hampering HER2 activation (by interfering with its homodimerization), and impairing HER+ breast cancer cell viability [91]. Other research has found that CB2 receptors and GPR55, both of which are elevated in most tumours and control cancer cell fate, form heteromers in cancer cells and that targeting these heteromers modulates cancer cell signalling (Moreno et al., 2014). Experiments have shown these heteromers to have unique pharmacological and signalling properties, displaying cross-talk and cross-antagonism at the level of cAMP and p-ERK-1/2 pathways. Further experiments demonstrated an antagonistic effect of THC on GPR55-modulated CB2 receptor signalling via these CB2 receptor-GPR55 heteromers [92].

Some evidence suggests AEA can inhibit proliferation, migration, and invasiveness (in vitro and in vivo studies) and directly inhibit angiogenesis. In an experiment using a proangiogenic phenotype of the highly invasive and metastatic breast cancer cells (MDA-MB-231), an AEA analogue was found to inhibit all the pro-angiogenic factors produced by these cells and consequently these cells lost their ability to stimulate endothelial cell proliferation in vitro [93]. However, some research in gliomas suggests that AEA levels are increased, suggesting pro-cancer activity [94] and in colorectal cancer, depending on the state of the cancer, endocannabinoids can either inhibit or promote CRC growth [3]. In gliomas, the direction of AEA levels has not been consistent: some research has found lower levels of AEA compared with non-tumour tissue, but other studies have found higher levels in gliomas and also in meningiomas, whilst 2-AG has been found to be upregulated in both types of brain cancer [5,95,96,97].

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Mangal and colleagues [4] explain that the role of the ECS is specific to the type of cancer and remind us that cancer is a heterogenous disease. Thus, we cannot assume changes in the ECS are going to be the same in all cancers. Also, given that the ECS is a homeostatic system, it begs the question whether raised levels of endocannabinoids is part of the pathogenesis or a response from the body to bring it back into balance?

5. Anti-Cancer Mechanisms of Action of CBD

Various preclinical studies, from cancel cell line studies to rodent models of cancer, have revealed that various cannabinoids (including endocannabinoids AEA, 2-AG, phytocannabinoids THC, CBD, and synthetic cannabinoid receptor agonists) have anti-cancer activity, addressing many of the ‘hallmarks of cancer’ [98].

Pro-apoptotic, anti-proliferative actions of cannabinoids have been demonstrated in many types of cancers [3,5,99]. Cannabinoid actions include cell cycle arrest, induction of apoptosis, inhibition of chemotaxis, cancer cell migration, adhesion, angiogenesis, invasion, and metastasis [3,100,101,102,103]. Yet, in general, the viability of normal (non-transformed) cells appears to be unaffected or even favoured under certain conditions by cannabinoids (though there are some exceptions); the stimulation of cannabinoid receptors appears to activate different signalling mechanisms in transformed and normal cells [98].

Considering CBD specifically, the literature indicates that in many animal cancer models, CBD’s ability to inhibit the progression of different types of cancer has been demonstrated, including in glioblastoma (GBM), breast, lung, prostate and colon cancer, and melanoma [104,105]. For example, in a mice model of melanoma, CBD treatment was associated with a significant reduction in tumour size compared with placebo, and increased survival [105].

It is apparent that CBD affects many tumoral features and molecular pathways [106] and perhaps this is not surprising, given the fact that CBD has many targets. Much of CBD’s anti-tumour activity is via its regulation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and immune modulation (all important in tumorigenesis) [3]. For example, although CBD has potent antioxidant activity, CBD has been found to be cytotoxic to human glioma cells, triggering caspase activation and oxidative stress [107]. CBD exposure to human glioma cells caused an early production of ROS, depletion of intracellular glutathione, and increased activity of glutathione reductase and glutathione peroxidase, but it did not impair primary normal glia. A different sensitivity to the anti-proliferative effect of CBD in glioma cells and non-transformed cells was demonstrated, believed to be associated with a selective ability of CBD to induce ROS production and activate caspase in tumour cells [107]. Similarly, other research has found that exposure of non-malignant brain cells (including human neural stem/progenitor cells and immortalized human foetal astrocytes) to CBD was not linked with induction of apoptosis [98,108]. Other experiments in glioma [109], leukemia (e.g., [110]), and breast cancer cells [103] have also demonstrated that CBD triggers a signalling mechanism that involves the generation of ROS [103].

Glioma cell research demonstrates CBD alone or in conjunction with other agents can induce cell death, inhibit cell migration and invasion, reduce size of tumours, reduce vascularisation, and induce tumour regression and increased survival [3]. Earlier in-vivo research found that CBD could impair migration of U87 glioma cells, but the mechanism did not appear to be via the classic cannabinoid receptors or receptors coupled to Gi/o proteins [111]. Seltzer and colleagues [3] reported that apoptosis induced by CBD in gliomas appeared independent of cannabinoid receptors but dependent on TRPV2. CBD has been found to activate TRPV2, decreasing proliferation and increasing susceptibility to drug-induced cell death in human cancer cells [112]. In an in-vivo experiment using glioma tumour tissues excised from nude mice, CBD was found to exert antitumoral effects via decreasing the activity and content of 5-lipoxygenase (LOX) and its end-product leukotriene, though no effect was found on COX-2 and end-product prostaglandin E2 (both 5-LOX and COX-2 are isoenzymes very involved in the control of cell growth and death in the CNS) [94]. Other glioma research has shown that CBD inhibits U87-MG and T98G glioma cell proliferation and invasiveness, and can downregulate ERK and Akt pro-survival signalling pathways and decrease hypoxia inducible factor HIF-1α expression in U87-MG cells (HIF-1α is a critical regulator of the hypoxic response, upregulating cell survival associated molecules, promoting invasion and tumour angiogenesis and the switch to glycolytic metabolism) [106].

In very recent research, according to Khodadadi and colleagues [113], the tumour microenvironment and its interaction with tumour cells is critically involved in the development, progression, and resilience of glioblastoma (Khodadadi et al., 2021). They argue that interactions between angiogenic and immune factors are determining factors in tumour vascularisation, immune profile and the lack of responsiveness to the immune system that characterises glioblastoma. In their research using a mice model of glioblastoma (using modified glioblastoma cells from humans), inhalation of CBD for seven days was found to significantly impact the cellular and molecular signalling of the tumour microenvironment [113]. Inhaled CBD limited tumour growth and altered the dynamics of the tumour microenvironment: it repressed P-selectin (which, in cancer, helps tumours metastasise and become treatment resistant), apelin (elevated in glioblastoma, acting to support blood vessel growth and promote cancer stem cells), and interleukin (IL)-8 (typically secreted by glioblastomas to promote cell migration and angiogenesis and found to be elevated in many forms of cancer) [113]. CBD blocked a key immune checkpoint, indoleamine 2,3-dioxygenase (IDO), which functions to block the immune response in tumours. It also enhanced the expression of a complex that aids the immune system to recognise cancer, the cluster of differentiation (CD)103 indicating improved antigen presentation, increased CD8 responses (a protein that aids the immune response), and decreased innate lymphoid cells within the tumour [113].

In breast cancer, CBD exerts anti-proliferative effects through many mechanisms including apoptosis, autophagy, and cell cycle arrest [3,114,115]. CBD has been found to induce programmed cell death in breast cancer cells via coordinating cross-talk between apoptosis and autophagy, in a manner independent of cannabinoid and vanilloid receptors [103]. CBD was also found to downregulate ID1, a regulator of metastasis in breast cancer cell lines [116]. Another experiment in rats which demonstrated anti-tumour properties of five phytocannabinoids (CBD, THC, cannabigerol, cannabichromene, cannabidiol acid) found that CBD most strongly inhibited breast cancer cell growth [114]. CBD and a CBD-enriched extract inhibited breast xenograft tumours in rodents and reduced lung metastases in rodents. From their various experiments, they proposed that CBD does not have a unique mode of action in the cell lines they examined, but found that in MDA-MB-231 breast cancer cells, CBD induced apoptosis via direct and indirect activation of CB2 receptors and TRPV1 receptors and via cannabinoid and vanilloid receptor-independent elevation of intercellular Ca 2+ and ROS [114].

CBD can modulate the tumour microenvironment, reducing secretion of cytokines from cancer cells. Decreased recruitment of macrophages from the tumour microenvironment by cancer cells suppresses angiogenesis within the tumour, limiting the supply of oxygen and nutrients needed for tumour growth [117]. CBD can inhibit exosomes and microvesicles (EMV), mediators of intercellular communication released by cells which affect many physiological and pathological processes including cell migration, differentiation, and angiogenesis. Increased EMV release has been found in cancer, in particular in association with chemotherapy resistance and in the active transfer of pro-oncogenic factors, and chemotherapeutic drug resistance may be partly due to EMV shedding from cancer cells which aids increased active drug efflux [25]. CBD has been found to significantly and dose-dependently inhibit the release of EMVs in three cancer cell lines: prostate cancer (PC3), hepatocellular carcinoma (HEPG2), and breast adenocarcinoma (MDA-MB-231). The mechanism of action may be associated with changes in mitochondrial function (specifically modulation of STAT3 and prohibitin expression) [25].

Other effects of CBD include inhibition of GPR55, known to be elevated in several cancers such as aggressive triple negative breast cancer, where elevated levels are associated with higher chance of developing metastases [118]. GPR55 is related directly or indirectly with changes that promote malignant growth including uncontrolled cancer cell proliferation, angiogenesis, cancer cell adhesion, cancer cell migration, and metastasis [118,119]. CBD was shown to significantly decrease adhesion to endothelial cells and migration of HCT116 cells (metastatic colon cancer cell line), an inhibitory effect that was prevented by GPR55 siRNA knock down in cancer cells [119]. Increased GPR55 has been found in human pancreatic ductal adenocarcinoma (PDAC) specimens [120]. In a mice model of PDAC, pharmacological blockade of GPR55 with CBD, gemcitabine, and CBD plus gemcitabine increased the rodent lifespan compared to vehicle (mean survival 25.4 days, 27.8 days, 52.7 days, and 18.6 days respectively), with many of the signalling pathways involved in reducing PDAC cell cycle progression and cell growth identified [120].

Note that animal research typically uses isolates of CBD (and THC). More research is needed investigating the effects of whole plant (full-spectrum) forms of CBD medicines, including those that compare isolate to whole plant CBD medicines in all forms of cannabis research, as it is likely that isolates will behave differently to full-spectrum CBD medicines. Gallily and colleagues [121] found a very different dose-response curve when investigating the anti-nociceptive and anti-inflammatory effects of CBD in a rodent model: the shape of the dose-response curves changed from bell-shaped (anti-pain effect) or U-shaped (anti-inflammatory effect on paw swelling) for CBD isolate to linear (i.e., an increasing response with increasing dosage, reducing zymosan-induced paw swelling and pain) for the full spectrum CBD extract.

For a more in-depth exploration of mechanisms of action of cannabinoids including CBD in cancer, readers are directed to review papers on the subject (e.g., [3,4,92,99].

6. Evidence of Efficacy of CBD in Management of Cancer and Cancer Treatment-Related Symptoms/Signs

There are many related signs and symptoms endured by people with living with cancer, due to the cancer itself and/or its treatment. These include stress, anxiety and depression, poor sleep, nausea and vomiting (associated in particular with chemotherapy), pain, neuropathy (e.g., associated with chemotherapy and radiation therapy), oral mucositis (e.g., associated with chemotherapy and head/neck radiation therapy), cancer-related fatigue, cachexia, and anorexia. CBD may have a role as part of an integrative approach to the management of many of these, in conjunction with orthodox treatment as well as consideration of diet, exercise/physical activity, promotion of good sleep, adequate vitamin D levels and stress reduction [122]. See Figure 1 .

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Marijuana and Cancer

Marijuana is the name given to the dried buds and leaves of varieties of the Cannabis sativa plant, which can grow wild in warm and tropical climates throughout the world and be cultivated commercially. It goes by many names, including pot, grass, cannabis, weed, hemp, hash, marihuana, ganja, and dozens of others.

Marijuana has been used in herbal remedies for centuries. Scientists have identified many biologically active components in marijuana. These are called cannabinoids. The two best studied components are the chemicals delta-9-tetrahydrocannabinol (often referred to as THC), and cannabidiol (CBD). Other cannabinoids are being studied.

At this time, the US Drug Enforcement Administration (DEA) lists marijuana and its cannabinoids as Schedule I controlled substances. This means that they cannot legally be prescribed, possessed, or sold under federal law. Whole or crude marijuana (including marijuana oil or hemp oil) is not approved by the US Food and Drug Administration (FDA) for any medical use. But the use of marijuana to treat some medical conditions is legal under state laws in many states.

Dronabinol, a pharmaceutical form of THC, and a man-made cannabinoid drug called nabilone are approved by the FDA to treat some conditions.

Types of marijuana compounds

Different compounds in marijuana have different actions in the human body. For example, delta-9-tetrahydrocannabinol (THC) seems to cause the “high” reported by marijuana users, and also can help relieve pain and nausea, reduce inflammation, and can act as an antioxidant. Cannabidiol (CBD) can help treat seizures, can reduce anxiety and paranoia, and can counteract the “high” caused by THC.

Different cultivars (strains or types) and even different crops of marijuana plants can have varying amounts of these and other active compounds. This means that marijuana can have different effects based on the strain used.

The effects of marijuana also vary depending on how marijuana compounds enter the body. The most common ways to use marijuana are in food (edible marijuana) and by smoking or vaping it (inhaled marijuana):

  • Edible marijuana: When taken by mouth, such as when it’s used in cooking oils, drinks (beer, tea, vodka, soda), baked goods (biscuits, brownies, cookies), and candy, the THC is absorbed poorly and can take hours to be absorbed. Once it’s absorbed, it’s processed by the liver, which produces a second psychoactive compound (a substance that acts on the brain and changes mood or consciousness) that affects the brain differently than THC. It’s important to know that the amount of THC in foods that have had marijuana added to them is often unknown and getting too much THC might cause symptoms of overdose.
  • Inhaled marijuana: When marijuana is smoked or vaporized, THC enters the bloodstream and goes to the brain quickly. The second psychoactive compound is produced in small amounts, and so has less effect. The effects of inhaled marijuana fade faster than marijuana taken by mouth.

How can marijuana affect symptoms of cancer?

A number of small studies of smoked marijuana found that it can be helpful in treating nausea and vomiting from cancer chemotherapy.

A few studies have found that inhaled (smoked or vaporized) marijuana can be helpful treatment of neuropathic pain (pain caused by damaged nerves).

Smoked marijuana has also helped improve food intake in HIV patients in studies.

There are no studies in people of the effects of marijuana oil or hemp oil.

Studies have long shown that people who took marijuana extracts in clinical trials tended to need less pain medicine.

More recently, scientists reported that THC and other cannabinoids such as CBD slow growth and/or cause death in certain types of cancer cells growing in lab dishes. Some animal studies also suggest certain cannabinoids may slow growth and reduce spread of some forms of cancer.

There have been some early clinical trials of cannabinoids in treating cancer in humans and more studies are planned. While the studies so far have shown that cannabinoids can be safe in treating cancer, they do not show that they help control or cure the disease.

Relying on marijuana alone as treatment while avoiding or delaying conventional medical care for cancer may have serious health consequences.

Possible harmful effects of marijuana

Marijuana can also pose some harms to users. While the most common effect of marijuana is a feeling of euphoria (“high”), it also can lower the user’s control over movement, cause disorientation, and sometimes cause unpleasant thoughts or feelings of anxiety and paranoia.

Smoked marijuana delivers THC and other cannabinoids to the body, but it also delivers harmful substances to users and those close by, including many of the same substances found in tobacco smoke.

Because marijuana plants come in different strains with different levels of active compounds, it can make each user’s experience very hard to predict. The effects can also differ based on how deeply and for how long the user inhales. Likewise, the effects of ingesting marijuana orally can vary between people. Also, some chronic users can develop an unhealthy dependence on marijuana.

Cannabinoid drugs

There are chemically pure drugs based on marijuana compounds that have been approved in the US for medical use.

  • Dronabinol (Marinol®/Syndros®) is a medicine containing delta-9-tetrahydrocannabinol (THC) and is approved by the US Food and Drug Administration (FDA) to treat nausea and vomiting caused by cancer chemotherapy as well as weight loss and poor appetite in patients with AIDS.
  • Nabilone (Cesamet®) is a synthetic cannabinoid that acts much like THC. It can be taken by mouth to treat nausea and vomiting caused by cancer chemotherapy when other drugs have not worked.

Nabiximols is a cannabinoid drug still under study in the US. It’s a mouth spray made up of a whole-plant extract with THC and cannabidiol (CBD) in an almost one to one mix. It’s available in Canada and parts of Europe to treat pain linked to cancer, as well as muscle spasms and pain from multiple sclerosis (MS). It’s not approved in the US at this time, but it’s being tested in clinical trials to see if it can help a number of conditions.

How can cannabinoid drugs affect symptoms of cancer?

Based on a number of studies, dronabinol can be helpful for reducing nausea and vomiting linked to chemotherapy.

Dronabinol has also been found to help improve food intake and prevent weight loss in patients with HIV. In studies of cancer patients, though, it wasn’t better than placebo or another drug (megestrol acetate).

Nabiximols has shown promise for helping people with cancer pain that’s unrelieved by strong pain medicines, but it hasn’t been found to be helpful in every study done. Research is still being done on this drug.

Side effects of cannabinoid drugs

Like many other drugs, the prescription cannabinoids, dronabinol and nabilone, can cause side effects and complications.

Some people have trouble with increased heart rate, decreased blood pressure (especially when standing up), dizziness or lightheadedness, and fainting. These drugs can cause drowsiness as well as mood changes or a feeling of being “high” that some people find uncomfortable. They can also worsen depression, mania, or other mental illness. Some patients taking nabilone in studies reported hallucinations. The drugs may increase some effects of sedatives, sleeping pills, or alcohol, such as sleepiness and poor coordination. Patients have also reported problems with dry mouth and trouble with recent memory.

Older patients may have more problems with side effects and are usually started on lower doses.

People who have had emotional illnesses, paranoia, or hallucinations may find their symptoms are worse when taking cannabinoid drugs.

Talk to your doctor about what you should expect when taking one of these drugs. It’s a good idea to have someone with you when you first start taking one of these drugs and after any dose changes.

What does the American Cancer Society say about the use of marijuana in people with cancer?

The American Cancer Society supports the need for more scientific research on cannabinoids for cancer patients, and recognizes the need for better and more effective therapies that can overcome the often debilitating side effects of cancer and its treatment. The Society also believes that the classification of marijuana as a Schedule I controlled substance by the US Drug Enforcement Administration imposes numerous conditions on researchers and deters scientific study of cannabinoids. Federal officials should examine options consistent with federal law for enabling more scientific study on marijuana.

Medical decisions about pain and symptom management should be made between the patient and their doctor, balancing evidence of benefit and harm to the patient, the patient’s preferences and values, and any laws and regulations that may apply.

The American Cancer Society Cancer Action Network (ACS CAN), the Society’s advocacy affiliate, has not taken a position on legalization of marijuana for medical purposes because of the need for more scientific research on marijuana’s potential benefits and harms. However, ACS CAN opposes the smoking or vaping of marijuana and other cannabinoids in public places because the carcinogens in marijuana smoke pose numerous health hazards to the patient and others in the patient’s presence.

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