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 what the evidence shows about treating cancer with Rick Simpson Oil (RSO), an oil made from the flowers of the cannabis (marijuana) plant. Cannabis has been used medicinally for millennia, but has not been approved by the U.S. Food and Drug Administration to treat any medical condition. Cannabinoids are the components in cannabis; some are commercially available to treat symptoms. Get detailed information in this clinician summary.

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].

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].

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 .

Rick Simpson Oil (RSO) for Cancer: Does It Work?

Rick Simpson Oil (RSO), an oil made from the flowers of the cannabis (marijuana) plant, gets attention online from people who claim it treats cancer. There’s no solid evidence for it. But some early research suggests that some chemicals in marijuana have future potential as a cancer treatment.

Cannabis oil comes in many types and formulations. These include cannabidiol (CBD) oil, which is often part of medical marijuana.

Unlike many other cannabis oils, Rick Simpson Oil is high in tetrahydrocannabinol (THC), which is the main psychoactive chemical in marijuana. THC is the chemical in marijuana that provides the “high.”

Online reports say Simpson is a Canadian engineer and cannabis activist. After a bad fall, he found that marijuana helped lessen his dizziness and other symptoms. Later, when he developed basal cell skin cancers on his arm, Simpson used cannabis oil as a treatment. As the reports go, his skin cancers went away.

What Is Rick Simpson Oil?

RSO is an oil made by washing cannabis buds with a solvent, such as pure light naphtha, and then boiling off the solvent leaving behind the oil.

See also  CBD Oil Pittsburgh

RSO is not a branded product. That means there’s no one “Rick Simpson Oil” for sale. On his website, Simpson explains how to make his namesake oil. But he does not sell a version of the oil for profit.

Because RSO contains high levels of THC, it’s illegal to buy in many places. But in states that have legalized marijuana — either for personal use or for medical use — you can find RSO at cannabis dispensaries.

Can RSO Treat Cancer?

Cannabis oils that contain THC may help control nausea and vomiting for people who are going through chemotherapy. There’s also evidence that they can treat pain and improve appetite.

But research has not shown that RSO or other forms of cannabis oil can treat cancer. Some very early studies on using THC to treat cancer have been encouraging, though.

In animals and in the lab, studies have found that THC and other cannabis chemicals can stop the growth of tumors. These lab studies have looked at cells related to lung, skin, breast, prostate, and other cancers. They’ve found that cannabis can in some cases stop the cancer cells from spreading.

Other research on THC and other cannabis compounds shows that they may kill off cancer cells while sparing healthy cells.

Cannabis is generally safe. Common side effects include dizziness or memory problems.

Other Medical Uses of Cannabis

Many U.S. states and the District of Columbia have legalized marijuana for medical use. There’s evidence that it can treat pain, nausea, and other symptoms.

When it comes to cannabis oil, there are also medical benefits. Research has shown that some CBD oils, including those that contain THC, can help control certain types of seizures among people with epilepsy. The FDA has approved some drugs that contain CBD for seizure treatment.

Show Sources

Karger Open Access: “The Trouble With CBD Oil.”

Iranian Journal of Psychiatry: “Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications.”

Leafly.com: “Who is Rick Simpson and what is Rick Simpson Oil (RSO)?”

Cannabinoids: “Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine.”

Clinical pharmacology and therapeutics: “Cannabis in Cancer Care.”

Journal of the American Medical Association: “Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review.”

Annals of Clinical and Translational Neurology: “A prospective open‐label trial of a CBD/THC cannabis oil in dravet syndrome.”

FDA: “FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy.”

PhoenixTears.ca: “Producing the Oil.”

Current Oncology: “Integrating cannabis into clinical cancer care.”

Pharmacotherapy: “The pharmacologic and clinical effects of medical cannabis.”

Harvard Health Publishing: “Cannabidiol (CBD) — what we know and what we don’t.”

Cannabis and Cannabinoids (PDQ®)–Health Professional Version

This cancer information summary provides an overview of the use of Cannabis and its components as a treatment for people with cancer-related symptoms caused by the disease itself or its treatment.

This summary contains the following key information:

  • Cannabis has been used for medicinal purposes for thousands of years.
  • By federal law, the possession of Cannabis is illegal in the United States, except within approved research settings; however, a growing number of states, territories, and the District of Columbia have enacted laws to legalize its medical and/or recreational use.
  • The U.S. Food and Drug Administration has not approved Cannabis as a treatment for cancer or any other medical condition. components of Cannabis, called cannabinoids, activate specific receptors throughout the body to produce pharmacological effects, particularly in the central nervous system and the immune system.
  • Commercially available cannabinoids, such as dronabinol and nabilone, are approved drugs for the treatment of cancer-related side effects.
  • Cannabinoids may have benefits in the treatment of cancer-related side effects.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

Cannabis, also known as marijuana, originated in Central Asia but is grown worldwide today. In the United States, it is a controlled substance and is classified as a Schedule I agent (a drug with a high potential for abuse, and no currently accepted medical use). The Cannabis plant produces a resin containing 21-carbon terpenophenolic compounds called cannabinoids, in addition to other compounds found in plants, such as terpenes and flavonoids. The highest concentration of cannabinoids is found in the female flowers of the plant.[1] Delta-9-tetrahydrocannabinol (THC) is the main psychoactive cannabinoid, but over 100 other cannabinoids have been reported to be present in the plant. Cannabidiol (CBD) does not produce the characteristic altered consciousness associated with Cannabis but is felt to have potential therapeutic effectiveness and has recently been approved in the form of the pharmaceutical Epidiolex for the treatment of refractory seizure disorders in children. Other cannabinoids that are being investigated for potential medical benefits include cannabinol (CBN), cannabigerol (CBG), and tetrahydrocannabivarin (THCV).

Clinical trials conducted on medicinal Cannabis are limited. The U.S. Food and Drug Administration (FDA) has not approved the use of Cannabis as a treatment for any medical condition, although both isolated THC and CBD pharmaceuticals are licensed and approved. To conduct clinical drug research with botanical Cannabis in the United States, researchers must file an Investigational New Drug (IND) application with the FDA, obtain a Schedule I license from the U.S. Drug Enforcement Administration, and obtain approval from the National Institute on Drug Abuse.

In the 2018 United States Farm Bill, the term hemp is used to describe cultivars of the Cannabis species that contain less than 0.3% THC. Hemp oil or CBD oil are products manufactured from extracts of industrial hemp (i.e., low-THC cannabis cultivars), whereas hemp seed oil is an edible fatty oil that is essentially cannabinoid-free (see Table 1). Some products contain other botanical extracts and/or over-the-counter analgesics, and are readily available as oral and topical tinctures or other formulations often advertised for pain management and other purposes. Hemp products containing less than 0.3% of delta-9-THC are not scheduled drugs and could be considered as Farm Bill compliant. Hemp is not a controlled substance; however, CBD is a controlled substance.

Table 1. Medicinal Cannabis Products—Guide to Terminology

Name/Material Constituents/Composition
CBD = cannabidiol; THC = tetrahydrocannabinol.
Cannabis species, including C. sativa Cannabinoids; also terpenoids and flavonoids
• Hemp (aka industrial hemp) Low Δ 9 -THC (<0.3%); high CBD
• Marijuana/marihuana High Δ 9 -THC (>0.3%); low CBD
Nabiximols (trade name: Sativex) Mixture of ethanol extracts of Cannabis species; contains Δ 9 -THC and CBD in a 1:1 ratio
Hemp oil/CBD oil Solution of a solvent extract from Cannabis flowers and/or leaves dissolved in an edible oil; typically contains 1%–5% CBD
Hemp seed oil Edible, fatty oil produced from Cannabis seeds; contains no or only traces of cannabinoids
Dronabinol (trade names: Marinol and Syndros) Synthetic Δ 9 -THC
Nabilone (trade names: Cesamet and Canemes) Synthetic THC analog
Cannabidiol (trade name: Epidiolex) Highly purified (>98%), plant-derived CBD

The potential benefits of medicinal Cannabis for people living with cancer include the following:[2]

    effects. stimulation.
  • Pain relief.
  • Improved sleep.

Although few relevant surveys of practice patterns exist, it appears that physicians caring for cancer patients in the United States who recommend medicinal Cannabis do so predominantly for symptom management.[3] A growing number of pediatric patients are seeking symptom relief with Cannabis or cannabinoid treatment, although studies are limited.[4] The American Academy of Pediatrics has not endorsed Cannabis and cannabinoid use because of concerns about brain development.

This summary will review the role of Cannabis and the cannabinoids in the treatment of people with cancer and disease-related or treatment-related side effects. The National Cancer Institute (NCI) hosted a virtual meeting, the NCI Cannabis, Cannabinoids, and Cancer Research Symposium, on December 15–18, 2020. The seven sessions are summarized in the Journal of the National Cancer Institute Monographs and contain basic science and clinical information as well as a summary of the barriers to conducting Cannabis research.[5-11]

References
  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]
  2. Abrams DI: Integrating cannabis into clinical cancer care. Curr Oncol 23 (2): S8-S14, 2016. [PUBMED Abstract]
  3. Doblin RE, Kleiman MA: Marijuana as antiemetic medicine: a survey of oncologists’ experiences and attitudes. J Clin Oncol 9 (7): 1314-9, 1991. [PUBMED Abstract]
  4. Sallan SE, Cronin C, Zelen M, et al.: Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 302 (3): 135-8, 1980. [PUBMED Abstract]
  5. Ellison GL, Alejandro Salicrup L, Freedman AN, et al.: The National Cancer Institute and Cannabis and Cannabinoids Research. J Natl Cancer Inst Monogr 2021 (58): 35-38, 2021. [PUBMED Abstract]
  6. Sexton M, Garcia JM, Jatoi A, et al.: The Management of Cancer Symptoms and Treatment-Induced Side Effects With Cannabis or Cannabinoids. J Natl Cancer Inst Monogr 2021 (58): 86-98, 2021. [PUBMED Abstract]
  7. Cooper ZD, Abrams DI, Gust S, et al.: Challenges for Clinical Cannabis and Cannabinoid Research in the United States. J Natl Cancer Inst Monogr 2021 (58): 114-122, 2021. [PUBMED Abstract]
  8. Braun IM, Abrams DI, Blansky SE, et al.: Cannabis and the Cancer Patient. J Natl Cancer Inst Monogr 2021 (58): 68-77, 2021. [PUBMED Abstract]
  9. Ward SJ, Lichtman AH, Piomelli D, et al.: Cannabinoids and Cancer Chemotherapy-Associated Adverse Effects. J Natl Cancer Inst Monogr 2021 (58): 78-85, 2021. [PUBMED Abstract]
  10. McAllister SD, Abood ME, Califano J, et al.: Cannabinoid Cancer Biology and Prevention. J Natl Cancer Inst Monogr 2021 (58): 99-106, 2021. [PUBMED Abstract]
  11. Abrams DI, Velasco G, Twelves C, et al.: Cancer Treatment: Preclinical & Clinical. J Natl Cancer Inst Monogr 2021 (58): 107-113, 2021. [PUBMED Abstract]

History

Cannabis use for medicinal purposes dates back at least 3,000 years.[1-5] It was introduced into Western medicine in 1839 by W.B. O’Shaughnessy, a surgeon who learned of its medicinal properties while working in India for the British East India Company. Its use was promoted for reported analgesic, sedative, anti-inflammatory, antispasmodic, and anticonvulsant effects.

In 1937, the U.S. Treasury Department introduced the Marihuana Tax Act. This Act imposed a levy of $1 per ounce for medicinal use of Cannabis and $100 per ounce for nonmedical use. Physicians in the United States were the principal opponents of the Act. The American Medical Association (AMA) opposed the Act because physicians were required to pay a special tax for prescribing Cannabis, use special order forms to procure it, and keep special records concerning its professional use. In addition, the AMA believed that objective evidence that Cannabis was harmful was lacking and that passage of the Act would impede further research into its medicinal worth.[6] In 1942, Cannabis was removed from the U.S. Pharmacopoeia because of persistent concerns about its potential to cause harm.[2,3] Recently, there has been renewed interest in Cannabis by the U.S. Pharmacopeia.[7]

In 1951, Congress passed the Boggs Act, which for the first time included Cannabis with narcotic drugs. In 1970, with the passage of the Controlled Substances Act, marijuana was classified by Congress as a Schedule I drug. Drugs in Schedule I are distinguished as having no currently accepted medicinal use in the United States. Other Schedule I substances include heroin, LSD, mescaline, and methaqualone.

Despite its designation as having no medicinal use, Cannabis was distributed by the U.S. government to patients on a case-by-case basis under the Compassionate Use Investigational New Drug program established in 1978. Distribution of Cannabis through this program was closed to new patients in 1992.[1-4] Although federal law prohibits the use of Cannabis, Figure 1 below shows the states and territories that have legalized Cannabis use for medical purposes. Additional states have legalized only one ingredient in Cannabis, such as cannabidiol (CBD), and are not included in the map. Some medical marijuana laws are broader than others, and there is state-to-state variation in the types of medical conditions for which treatment is allowed.[8]

Enlarge Figure 1. A map showing the U.S. states and territories that have approved the medical use of Cannabis. Last updated: 10/14/2021

The main psychoactive constituent of Cannabis was identified as delta-9-tetrahydrocannabinol (THC). In 1986, an isomer of synthetic delta-9-THC in sesame oil was licensed and approved for the treatment of chemotherapy-associated nausea and vomiting under the generic name dronabinol. Clinical trials determined that dronabinol was as effective as or better than other antiemetic agents available at the time.[9] Dronabinol was also studied for its ability to stimulate weight gain in patients with AIDS in the late 1980s. Thus, the indications were expanded to include treatment of anorexia associated with human immunodeficiency virus infection in 1992. Clinical trial results showed no statistically significant weight gain, although patients reported an improvement in appetite.[10,11] Another important cannabinoid found in Cannabis is CBD.[12] This is a nonpsychoactive cannabinoid, which is an analog of THC.

In recent decades, the neurobiology of cannabinoids has been analyzed.[13-16] The first cannabinoid receptor, CB1, was identified in the brain in 1988. A second cannabinoid receptor, CB2, was identified in 1993. The highest expression of CB2 receptors is located on B lymphocytes and natural killer cells, suggesting a possible role in immunity. Endogenous cannabinoids (endocannabinoids) have been identified and appear to have a role in pain modulation, control of movement, feeding behavior, mood, bone growth, inflammation, neuroprotection, and memory.[17]

Nabiximols (Sativex), a Cannabis extract with a 1:1 ratio of THC:CBD, is approved in Canada (under the Notice of Compliance with Conditions) for symptomatic relief of pain in advanced cancer and multiple sclerosis.[18] Nabiximols is an herbal preparation containing a defined quantity of specific cannabinoids formulated for oromucosal spray administration with potential analgesic activity. Nabiximols contains extracts from two Cannabis plant varieties. The extracts mixture is standardized to the concentrations of the psychoactive delta-9-THC and the nonpsychoactive CBD. The preparation also contains other, more minor cannabinoids, flavonoids, and terpenoids.[19] Canada, New Zealand, and most countries in western Europe also approve nabiximols for spasticity of multiple sclerosis, a common symptom that may include muscle stiffness, reduced mobility, and pain, and for which existing therapy is unsatisfactory.

References
  1. Abel EL: Marihuana, The First Twelve Thousand Years. Plenum Press, 1980. Also available online. Last accessed June 2, 2021.
  2. Joy JE, Watson SJ, Benson JA, eds.: Marijuana and Medicine: Assessing the Science Base. National Academy Press, 1999. Also available online. Last accessed June 2, 2021.
  3. Mack A, Joy J: Marijuana As Medicine? The Science Beyond the Controversy. National Academy Press, 2001. Also available online. Last accessed June 2, 2021.
  4. Booth M: Cannabis: A History. St Martin’s Press, 2003.
  5. Russo EB, Jiang HE, Li X, et al.: Phytochemical and genetic analyses of ancient cannabis from Central Asia. J Exp Bot 59 (15): 4171-82, 2008. [PUBMED Abstract]
  6. Schaffer Library of Drug Policy: The Marihuana Tax Act of 1937: Taxation of Marihuana. Washington, DC: House of Representatives, Committee on Ways and Means, 1937. Available online. Last accessed June 2, 2021.
  7. Sarma ND, Waye A, ElSohly MA, et al.: Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes. J Nat Prod 83 (4): 1334-1351, 2020. [PUBMED Abstract]
  8. National Academies of Sciences, Engineering, and Medicine: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. The National Academies Press, 2017.
  9. Sallan SE, Zinberg NE, Frei E: Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293 (16): 795-7, 1975. [PUBMED Abstract]
  10. Gorter R, Seefried M, Volberding P: Dronabinol effects on weight in patients with HIV infection. AIDS 6 (1): 127, 1992. [PUBMED Abstract]
  11. Beal JE, Olson R, Laubenstein L, et al.: Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10 (2): 89-97, 1995. [PUBMED Abstract]
  12. Adams R, Hunt M, Clark JH: Structure of cannabidiol: a product isolated from the marihuana extract of Minnesota wild hemp. J Am Chem Soc 62 (1): 196-200, 1940. Also available online. Last accessed June 2, 2021.
  13. Devane WA, Dysarz FA, Johnson MR, et al.: Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34 (5): 605-13, 1988. [PUBMED Abstract]
  14. Devane WA, Hanus L, Breuer A, et al.: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258 (5090): 1946-9, 1992. [PUBMED Abstract]
  15. Pertwee RG, Howlett AC, Abood ME, et al.: International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev 62 (4): 588-631, 2010. [PUBMED Abstract]
  16. Felder CC, Glass M: Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol 38: 179-200, 1998. [PUBMED Abstract]
  17. Pacher P, Bátkai S, Kunos G: The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58 (3): 389-462, 2006. [PUBMED Abstract]
  18. Howard P, Twycross R, Shuster J, et al.: Cannabinoids. J Pain Symptom Manage 46 (1): 142-9, 2013. [PUBMED Abstract]
  19. Nabiximols. Bethesda, MD: National Center for Biotechnology Information, 2009. Available online. Last accessed June 2, 2021.

Laboratory/Animal/Preclinical Studies

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis species (e.g., Cannabis sativa L.).[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biological activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic, anti-inflammatory, and anxiolytic activity without the psychoactive effect (high) of delta-9-THC.

Antitumor Effects

One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo.[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] Two reviews summarize the molecular mechanisms of action of cannabinoids as antitumor agents.[13,14] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. For example, these compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats, while they protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[9]

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in HCC.[15] Both agents reduced the viability of HCC cells in vitro and demonstrated antitumor effects in HCC subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]

An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic mammary cells.[18] Other studies have also shown the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer.[19,20]

CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[21] In this experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In a subsequent study, the investigators found that the antiproliferative effect of CBD was counteracted by selective CB1 but not CB2 receptor antagonists, suggesting an involvement of CB1 receptors.[22]

Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression in tumor cells has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[23] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[24,25]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[26] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[27-30]

CBD may also enhance uptake of cytotoxic drugs into malignant cells. Activation of transient receptor potential vanilloid type 2 (TRPV2) has been shown to inhibit proliferation of human glioblastoma multiforme cells and overcome resistance to the chemotherapy agent carmustine. [31] One study showed that coadministration of THC and CBD over single-agent usage had greater antiproliferative activity in an in vitro study with multiple human glioblastoma multiforme cell lines.[32] In an in vitro model, CBD increased TRPV2 activation and increased uptake of cytotoxic drugs, leading to apoptosis of glioma cells without affecting normal human astrocytes. This suggests that coadministration of CBD with cytotoxic agents may increase drug uptake and potentiate cell death in human glioma cells. Also, CBD together with THC may enhance the antitumor activity of classic chemotherapeutic drugs such as temozolomide in some mouse models of cancer.[13,33] A meta-analysis of 34 in vitro and in vivo studies of cannabinoids in glioma reported that all but one study confirmed that cannabinoids selectively kill tumor cells.[34]

Antiemetic Effects

Preclinical research suggests that emetic circuitry is tonically controlled by endocannabinoids. The antiemetic action of cannabinoids is believed to be mediated via interaction with the 5-hydroxytryptamine 3 (5-HT3) receptor. CB1 receptors and 5-HT3 receptors are colocalized on gamma-aminobutyric acid (GABA)-ergic neurons, where they have opposite effects on GABA release.[35] There also may be direct inhibition of 5-HT3 gated ion currents through non–CB1 receptor pathways. CB1 receptor antagonists have been shown to elicit emesis in the least shrew that is reversed by cannabinoid agonists.[36] The involvement of CB1 receptor in emesis prevention has been shown by the ability of CB1 antagonists to reverse the effects of THC and other synthetic cannabinoid CB1 agonists in suppressing vomiting caused by cisplatin in the house musk shrew and lithium chloride in the least shrew. In the latter model, CBD was also shown to be efficacious.[37,38]

Appetite Stimulation

Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[39] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[40]

Analgesia

Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. Cannabinoids produce analgesia through supraspinal, spinal, and peripheral modes of action, acting on both ascending and descending pain pathways.[41] The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[42] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[43,44]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[45-47] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.[48]

Cannabinoids have been shown to prevent chemotherapy-induced neuropathy in animal models exposed to paclitaxel, vincristine, or cisplatin.[49-51]

Anxiety and Sleep

The endocannabinoid system is believed to be centrally involved in the regulation of mood and the extinction of aversive memories. Animal studies have shown CBD to have anxiolytic properties. It was shown in rats that these anxiolytic properties are mediated through unknown mechanisms.[52] Anxiolytic effects of CBD have been shown in several animal models.[53,54]

The endocannabinoid system has also been shown to play a key role in the modulation of the sleep-waking cycle in rats.[55,56]

References
  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]
  2. Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. The Haworth Press, 2002.
  3. National Toxicology Program: NTP toxicology and carcinogenesis studies of 1-trans-delta(9)-tetrahydrocannabinol (CAS No. 1972-08-3) in F344 rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 446: 1-317, 1996. [PUBMED Abstract]
  4. Bifulco M, Laezza C, Pisanti S, et al.: Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 148 (2): 123-35, 2006. [PUBMED Abstract]
  5. Sánchez C, de Ceballos ML, Gomez del Pulgar T, et al.: Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61 (15): 5784-9, 2001. [PUBMED Abstract]
  6. McKallip RJ, Lombard C, Fisher M, et al.: Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100 (2): 627-34, 2002. [PUBMED Abstract]
  7. Casanova ML, Blázquez C, Martínez-Palacio J, et al.: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111 (1): 43-50, 2003. [PUBMED Abstract]
  8. Blázquez C, González-Feria L, Alvarez L, et al.: Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64 (16): 5617-23, 2004. [PUBMED Abstract]
  9. Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PUBMED Abstract]
  10. Blázquez C, Casanova ML, Planas A, et al.: Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17 (3): 529-31, 2003. [PUBMED Abstract]
  11. Vaccani A, Massi P, Colombo A, et al.: Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144 (8): 1032-6, 2005. [PUBMED Abstract]
  12. Ramer R, Bublitz K, Freimuth N, et al.: Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J 26 (4): 1535-48, 2012. [PUBMED Abstract]
  13. Velasco G, Sánchez C, Guzmán M: Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12 (6): 436-44, 2012. [PUBMED Abstract]
  14. Cridge BJ, Rosengren RJ: Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Manag Res 5: 301-13, 2013. [PUBMED Abstract]
  15. Vara D, Salazar M, Olea-Herrero N, et al.: Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18 (7): 1099-111, 2011. [PUBMED Abstract]
  16. Preet A, Qamri Z, Nasser MW, et al.: Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4 (1): 65-75, 2011. [PUBMED Abstract]
  17. Nasser MW, Qamri Z, Deol YS, et al.: Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6 (9): e23901, 2011. [PUBMED Abstract]
  18. Shrivastava A, Kuzontkoski PM, Groopman JE, et al.: Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 10 (7): 1161-72, 2011. [PUBMED Abstract]
  19. Caffarel MM, Andradas C, Mira E, et al.: Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Mol Cancer 9: 196, 2010. [PUBMED Abstract]
  20. McAllister SD, Murase R, Christian RT, et al.: Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129 (1): 37-47, 2011. [PUBMED Abstract]
  21. Aviello G, Romano B, Borrelli F, et al.: Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med (Berl) 90 (8): 925-34, 2012. [PUBMED Abstract]
  22. Romano B, Borrelli F, Pagano E, et al.: Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine 21 (5): 631-9, 2014. [PUBMED Abstract]
  23. Preet A, Ganju RK, Groopman JE: Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 27 (3): 339-46, 2008. [PUBMED Abstract]
  24. Zhu LX, Sharma S, Stolina M, et al.: Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165 (1): 373-80, 2000. [PUBMED Abstract]
  25. McKallip RJ, Nagarkatti M, Nagarkatti PS: Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174 (6): 3281-9, 2005. [PUBMED Abstract]
  26. Massa F, Marsicano G, Hermann H, et al.: The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113 (8): 1202-9, 2004. [PUBMED Abstract]
  27. Patsos HA, Hicks DJ, Greenhough A, et al.: Cannabinoids and cancer: potential for colorectal cancer therapy. Biochem Soc Trans 33 (Pt 4): 712-4, 2005. [PUBMED Abstract]
  28. Liu WM, Fowler DW, Dalgleish AG: Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 5 (4): 281-7, 2010. [PUBMED Abstract]
  29. Malfitano AM, Ciaglia E, Gangemi G, et al.: Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15 (3): 297-308, 2011. [PUBMED Abstract]
  30. Sarfaraz S, Adhami VM, Syed DN, et al.: Cannabinoids for cancer treatment: progress and promise. Cancer Res 68 (2): 339-42, 2008. [PUBMED Abstract]
  31. Nabissi M, Morelli MB, Santoni M, et al.: Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34 (1): 48-57, 2013. [PUBMED Abstract]
  32. Marcu JP, Christian RT, Lau D, et al.: Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther 9 (1): 180-9, 2010. [PUBMED Abstract]
  33. Torres S, Lorente M, Rodríguez-Fornés F, et al.: A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10 (1): 90-103, 2011. [PUBMED Abstract]
  34. Rocha FC, Dos Santos Júnior JG, Stefano SC, et al.: Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J Neurooncol 116 (1): 11-24, 2014. [PUBMED Abstract]
  35. Pacher P, Bátkai S, Kunos G: The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58 (3): 389-462, 2006. [PUBMED Abstract]
  36. Darmani NA: Delta(9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB(1) receptor antagonist/inverse agonist SR 141716A. Neuropsychopharmacology 24 (2): 198-203, 2001. [PUBMED Abstract]
  37. Darmani NA: Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB(1) receptors in the least shrew. Pharmacol Biochem Behav 69 (1-2): 239-49, 2001 May-Jun. [PUBMED Abstract]
  38. Parker LA, Kwiatkowska M, Burton P, et al.: Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berl) 171 (2): 156-61, 2004. [PUBMED Abstract]
  39. Mechoulam R, Berry EM, Avraham Y, et al.: Endocannabinoids, feeding and suckling–from our perspective. Int J Obes (Lond) 30 (Suppl 1): S24-8, 2006. [PUBMED Abstract]
  40. Fride E, Bregman T, Kirkham TC: Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 230 (4): 225-34, 2005. [PUBMED Abstract]
  41. Baker D, Pryce G, Giovannoni G, et al.: The therapeutic potential of cannabis. Lancet Neurol 2 (5): 291-8, 2003. [PUBMED Abstract]
  42. Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PUBMED Abstract]
  43. Meng ID, Manning BH, Martin WJ, et al.: An analgesia circuit activated by cannabinoids. Nature 395 (6700): 381-3, 1998. [PUBMED Abstract]
  44. Walker JM, Huang SM, Strangman NM, et al.: Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 96 (21): 12198-203, 1999. [PUBMED Abstract]
  45. Facci L, Dal Toso R, Romanello S, et al.: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92 (8): 3376-80, 1995. [PUBMED Abstract]
  46. Ibrahim MM, Porreca F, Lai J, et al.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 102 (8): 3093-8, 2005. [PUBMED Abstract]
  47. Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1): 111-9, 1998. [PUBMED Abstract]
  48. Khasabova IA, Gielissen J, Chandiramani A, et al.: CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol 22 (5-6): 607-16, 2011. [PUBMED Abstract]
  49. Ward SJ, McAllister SD, Kawamura R, et al.: Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 171 (3): 636-45, 2014. [PUBMED Abstract]
  50. Rahn EJ, Makriyannis A, Hohmann AG: Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol 152 (5): 765-77, 2007. [PUBMED Abstract]
  51. Khasabova IA, Khasabov S, Paz J, et al.: Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. J Neurosci 32 (20): 7091-101, 2012. [PUBMED Abstract]
  52. Campos AC, Guimarães FS: Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 199 (2): 223-30, 2008. [PUBMED Abstract]
  53. Crippa JA, Zuardi AW, Hallak JE: [Therapeutical use of the cannabinoids in psychiatry]. Rev Bras Psiquiatr 32 (Suppl 1): S56-66, 2010. [PUBMED Abstract]
  54. Guimarães FS, Chiaretti TM, Graeff FG, et al.: Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100 (4): 558-9, 1990. [PUBMED Abstract]
  55. Méndez-Díaz M, Caynas-Rojas S, Arteaga Santacruz V, et al.: Entopeduncular nucleus endocannabinoid system modulates sleep-waking cycle and mood in rats. Pharmacol Biochem Behav 107: 29-35, 2013. [PUBMED Abstract]
  56. Pava MJ, den Hartog CR, Blanco-Centurion C, et al.: Endocannabinoid modulation of cortical up-states and NREM sleep. PLoS One 9 (2): e88672, 2014. [PUBMED Abstract]
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Human/Clinical Studies

Cannabis Pharmacology

When oral Cannabis is ingested, there is a low (6%–20%) and variable oral bioavailability.[1,2] Peak plasma concentrations of delta-9-tetrahydrocannabinol (THC) occur after 1 to 6 hours and remain elevated with a terminal half-life of 20 to 30 hours. Taken by mouth, delta-9-THC is initially metabolized in the liver to 11-OH-THC, a potent psychoactive metabolite. Inhaled cannabinoids are rapidly absorbed into the bloodstream with a peak concentration in 2 to 10 minutes, declining rapidly for a period of 30 minutes and with less generation of the psychoactive 11-OH metabolite.

Cannabinoids are known to interact with the hepatic cytochrome P450 enzyme system.[3,4] In one study, 24 cancer patients were treated with intravenous irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal Cannabis taken in the form of an herbal tea for 15 consecutive days, starting 12 days before the second treatment.[4] The administration of Cannabis did not significantly influence exposure to and clearance of irinotecan or docetaxel, although the herbal tea route of administration may not reproduce the effects of inhalation or oral ingestion of fat-soluble cannabinoids.

Highly concentrated THC or cannabidiol (CBD) oil extracts are being illegally promoted as potential cancer cures.[5] These oils have not been evaluated in any clinical trials for anticancer activity or safety. Because CBD is a potential inhibitor of certain cytochrome P450 enzymes, highly concentrated CBD oils used concurrently with conventional therapies that are metabolized by these enzymes could potentially increase toxicity or decrease the effectiveness of these therapies.[6,7]

Cancer Risk

A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with Cannabis smoking.

A pooled analysis of three case-cohort studies of men in northwestern Africa (430 cases and 778 controls) showed a significantly increased risk of lung cancer among tobacco smokers who also inhaled Cannabis.[8]

A large, retrospective cohort study of 64,855 men aged 15 to 49 years from the United States found that Cannabis use was not associated with tobacco-related cancers and a number of other common malignancies. However, the study did find that, among nonsmokers of tobacco, ever having used Cannabis was associated with an increased risk of prostate cancer.[9]

A population-based case-control study of 611 lung cancer patients revealed that chronic low Cannabis exposure was not associated with an increased risk of lung cancer or other upper aerodigestive tract cancers and found no positive associations with any cancer type (oral, pharyngeal, laryngeal, lung, or esophageal) when adjusting for several confounders, including cigarette smoking.[10]

A systematic review assessing 19 studies that evaluated premalignant or malignant lung lesions in persons 18 years or older who inhaled Cannabis concluded that observational studies failed to demonstrate statistically significant associations between Cannabis inhalation and lung cancer after adjusting for tobacco use.[11] In the review of the published meta-analyses, the National Academies of Sciences, Engineering, and Medicine (NASEM) report concluded that there was moderate evidence of no statistical association between Cannabis smoking and the incidence of lung cancer.[12]

Epidemiologic studies examining one association of Cannabis use with head and neck squamous cell carcinomas have also been inconsistent in their findings. A pooled analysis of nine case-control studies from the U.S./Latin American International Head and Neck Cancer Epidemiology (INHANCE) Consortium included information from 1,921 oropharyngeal cases, 356 tongue cases, and 7,639 controls. Compared with those who never smoked Cannabis, Cannabis smokers had an elevated risk of oropharyngeal cancers and a reduced risk of tongue cancer. These study results both reflect the inconsistent effects of cannabinoids on cancer incidence noted in previous studies and suggest that more work needs to be done to understand the potential role of human papillomavirus infection.[13] A systematic review and meta-analysis of nine case-control studies involving 13,931 participants also concluded that there was insufficient evidence to support or refute a positive or negative association between Cannabis smoking and the incidence of head and neck cancers.[14]

With a hypothesis that chronic marijuana use produces adverse effects on the human endocrine and reproductive systems, the association between Cannabis use and incidence of testicular germ cell tumors (TGCTs) has been examined.[15-17] Three population-based case-control studies reported an association between Cannabis use and elevated risk of TGCTs, especially nonseminoma or mixed-histology tumors.[15-17] However, the sample sizes in these studies were inadequate to address Cannabis dose by addressing associations with respect to recency, frequency, and duration of use. In a study of 49,343 Swedish men aged 19 to 21 years enrolled in the military between 1969 and 1970, participants were asked once at the time of conscription about their use of Cannabis and were followed up for 42 years.[18] This study found no evidence of a significant relation between “ever” Cannabis use and the development of testicular cancer, but did find that “heavy” Cannabis use (more than 50 times in a lifetime) was associated with a 2.5-fold increased risk. Limitations of the study were that it relied on indirect assessment of Cannabis use; and no information was collected on Cannabis use after the conscription-assessment period or on whether the testicular cancers were seminoma or nonseminoma subtypes. These reports established the need for larger, well-powered, prospective studies, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCTs.

An analysis of 84,170 participants in the California Men’s Health Study was performed to investigate the association between Cannabis use and the incidence of bladder cancer. During 16 years of follow-up, 89 Cannabis users (0.3%) developed bladder cancer compared with 190 (0.4%) of the men who did not report Cannabis use (P < .001). After adjusting for age, race, ethnicity, and body mass index, Cannabis use was associated with a 45% reduction in bladder cancer incidence (hazard ratio, 0.55; 95% confidence interval (CI), 0.33–1.00).[19]

A comprehensive Health Canada monograph on marijuana concluded that while there are many cellular and molecular studies that provide strong evidence that inhaled marijuana is carcinogenic, the epidemiologic evidence of a link between marijuana use and cancer is still inconclusive.[20]

Patterns of Cannabis Use Among Cancer Patients

A cross-sectional survey of cancer patients seen at the Seattle Cancer Care Alliance was conducted over a 6-week period between 2015 and 2016.[21] In Washington State, Cannabis was legalized for medicinal use in 1998 and for recreational use in 2012. Of the 2,737 possible participants, 936 (34%) completed the anonymous questionnaire. Twenty-four percent of patients considered themselves active Cannabis users. Similar numbers of patients inhaled (70%) or used edibles (70%), with dual use (40%) being common. Non–mutually exclusive reasons for Cannabis use were physical symptoms (75%), neuropsychiatric symptoms (63%), recreational use/enjoyment (35%), and treatment of cancer (26%). The physical symptoms most commonly cited were pain, nausea, and loss of appetite. The majority of patients (74%) stated that they would prefer to obtain information about Cannabis from their cancer team, but less than 15% reported receiving information from their cancer physician or nurse.

Data from 2,970 Israeli cancer patients who used government-issued Cannabis were collected over a 6-month period to assess for improvement in baseline symptoms.[22] The most improved symptoms from baseline include the following:

  • Nausea and vomiting (91.0%). (87.5%).
  • Restlessness (87.5%). and depression (84.2%). (82.1%).
  • Headaches (81.4%).

Before treatment initiation, 52.9% of patients reported pain scores in the 8 to 10 range, while only 4.6% of patients reported this intensity at the 6-month assessment time point. It is difficult to assess from the observational data if the improvements were caused by the Cannabis or the cancer treatment.[22] Similarly, a study of a subset of cancer patients in the Minnesota medical Cannabis program explored changes in the severity of eight symptoms (i.e., anxiety, appetite loss, depression, disturbed sleep, fatigue, nausea, pain, and vomiting) experienced by these patients.[23]. Significant symptomatic improvements were noted (38.4%–56.2%) in patients with each symptom. Because of the observational and uncontrolled nature of this study, the findings are not generalizable, but as the authors suggested, may be useful in designing more rigorous research studies in the future.

Forty-two percent of women (257 of 612) with a diagnosis of breast cancer within the past 5 years who participated in an anonymous online survey reported using Cannabis for the relief of symptoms, particularly pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea and vomiting (46%).[24] Among Cannabis users, 79% used Cannabis during their cancer treatment, and 75% reported that Cannabis was extremely or very helpful for relieving symptoms. Forty-nine percent of Cannabis users felt that Cannabis could be useful in treating the cancer itself. Only 39% of the participants reported discussing Cannabis use with their physicians.

A retrospective study from Israel of 50 pediatric oncology patients who were prescribed medicinal Cannabis over an 8-year period reported that the most common indications include the following:[25]

  • Nausea and vomiting.
  • Depressed mood.
  • Sleep disturbances.
  • Poor appetite and weight loss.
  • Pain.

Most of the patients (n = 30) received Cannabis in the form of oral oil drops, with some of the older children inhaling vaporized Cannabis or combining inhalation with oral oils. Structured interviews with the parents, and their child when appropriate, revealed that 40 participants (80%) reported a high level of general satisfaction with the use of Cannabis with infrequent short-term side effects.[25] Survey studies revealed that the majority of responding pediatricians in the United States and Canada supported the use of medical Cannabis for symptom management in patients with cancer.[26,27]

Cancer Treatment

No ongoing clinical trials of Cannabis as a treatment for cancer in humans were identified in a PubMed search. The first published trial of any cannabinoid in patients with cancer was a small pilot study of intratumoral injection of delta-9-THC in patients with recurrent glioblastoma multiforme, which demonstrated no significant clinical benefit.[28,29] A small double-blind exploratory phase IB study was conducted in the United Kingdom that used nabiximols, a 1:1 ratio of THC:CBD in a Cannabis-based medicinal extract oromucosal spray, in conjunction with dose-dense temozolomide in treating patients with recurrent glioblastoma multiforme.[30][Level of evidence: 1iA] Of the 27 patients enrolled, 6 were part of an open-label group and 21 were part of a randomized group (12 treated with nabiximols and 9 treated with placebo). Progression-free survival at 6 months was seen in 33% of patients in both arms of the study. However, 83.3% of the patients who received nabiximols were alive at 1 year compared with 44.4% of the patients who received placebo (P = .042). The investigators cautioned that this early-phase study was not powered for a survival endpoint. Overall survival rates at 2 years continued to favor the nabiximols arm (50%) compared with the placebo arm (22%) (these rates included results for the 6 patients in the open-label group who received nabiximols).[30]

In a 2016 consecutive case series study, nine patients with varying stages of brain tumors, including six with glioblastoma multiforme, received CBD 200 mg twice daily in addition to surgical excision and chemoradiation.[31][Level of evidence: 3iiiA] The authors reported that all but one of the cohort remained alive at the time of publication. However, the heterogeneity of the brain tumor patients probably contributed to the findings.

Another Israeli group postulated that the anti-inflammatory and immunosuppressive effects of CBD might make it a valuable adjunct in the treatment of acute graft-versus-host disease (GVHD) in patients who have undergone allogeneic hematopoietic stem cell transplantation. The authors investigated CBD 300 mg/d in addition to standard GVHD prophylaxis in 48 adult patients who had undergone transplantation predominantly for acute leukemia or myelodysplastic syndrome (NCT01385124 and NCT01596075).[32] The combination of CBD with standard GVHD prophylaxis was found to be safe. Compared with 101 historical controls treated with standard prophylaxis, patients who received CBD appeared to have a lower incidence of grade II to grade IV GVHD, suggesting that a randomized controlled trial (RCT) is warranted.

Clinical data regarding Cannabis as an anticancer agent in pediatric use is limited to a few case reports.[33,34]

Antiemetic Effect

Cannabinoids

Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting (N/V) remain distressing side effects for cancer patients and their families. Dronabinol, a synthetically produced delta-9-THC, was approved in the United States in 1986 as an antiemetic to be used in cancer chemotherapy. Nabilone, a synthetic derivative of delta-9-THC, was first approved in Canada in 1982 and is now also available in the United States.[35] Both dronabinol and nabilone have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of N/V associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic therapy. Numerous clinical trials and meta-analyses have shown that dronabinol and nabilone are effective in the treatment of N/V induced by chemotherapy.[36-39] The National Comprehensive Cancer Network Guidelines recommend cannabinoids as breakthrough treatment for chemotherapy-related N/V.[40] The American Society for Clinical Oncology (ASCO) antiemetic guidelines updated in 2017 recommends that the FDA-approved cannabinoids, dronabinol or nabilone, be used to treat N/V that is resistant to standard antiemetic therapies.[41]

One systematic review studied 30 randomized comparisons of delta-9-THC preparations with placebo or other antiemetics from which data on efficacy and harm were available.[42] Oral nabilone, oral dronabinol, and intramuscular levonantradol (a synthetic analog of dronabinol) were tested. Inhaled Cannabis trials were not included. Among all 1,366 patients included in the review, cannabinoids were found to be more effective than the conventional antiemetics prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Cannabinoids, however, were not more effective for patients receiving very low or very high emetogenic chemotherapy. Side effects included a feeling of being high, euphoria, sedation or drowsiness, dizziness, dysphoria or depression, hallucinations, paranoia, and hypotension.[42]

Another analysis of 15 controlled studies compared nabilone with placebo or available antiemetic drugs.[43] Among 600 cancer patients, nabilone was found to be superior to prochlorperazine, domperidone, and alizapride, with nabilone favored for continuous use.

A Cochrane meta-analysis of 23 RCTs reviewed studies conducted between 1975 and 1991 that investigated dronabinol or nabilone, either as monotherapy or as an adjunct to the conventional dopamine antagonists that were the standard antiemetics at that time.[44] The chemotherapy regimens involved drugs with low, moderate, or high emetic potential. The meta-analysis graded the quality of evidence as low for most outcomes. The review concluded that individuals were more likely to report complete absence of N/V when they received cannabinoids compared with placebo, although they were more likely to withdraw from the study because of an adverse event. Individuals reported a higher preference for cannabinoids than placebo or prochlorperazine. There was no difference in the antiemetic effect of cannabinoids when compared with prochlorperazine. The authors concluded that Cannabis-based medications may be useful for treating refractory chemotherapy-induced N/V; however, they cautioned that their assessment may change with the availability of newer antiemetic regimens.

At least 50% of patients who receive moderately emetogenic chemotherapy may experience delayed chemotherapy-induced N/V. Although selective neurokinin 1 antagonists that inhibit substance P have been approved for delayed N/V, a study was conducted before their availability to assess dronabinol, ondansetron, or their combination in preventing delayed-onset chemotherapy-induced N/V.[45] Ondansetron, a serotonin 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, is one of the mainstay agents in the current antiemetic armamentarium. In this trial, the primary objective was to assess the response 2 to 5 days after moderately to severely emetogenic chemotherapy. Sixty-one patients were analyzed for efficacy. The total response—a composite endpoint—including nausea intensity, vomiting/retching, and use of rescue medications, was similar with dronabinol (54%), ondansetron (58%), and combination therapy (47%) when compared with placebo (20%). Nausea absence was greater in the active treatment groups (dronabinol 71%, ondansetron 64%, combination therapy 53%) when compared with placebo (15%; P < .05 vs. placebo for all). Occurrence rates for nausea intensity and vomiting/retching episodes were the lowest in patients treated with dronabinol, suggesting that dronabinol compares favorably with ondansetron in this situation where a substance P inhibitor would currently be the drug of choice.

For more information, see the Cannabis section in Nausea and Vomiting Related to Cancer Treatment.

Cannabis

Three trials have evaluated the efficacy of inhaled Cannabis in chemotherapy-induced N/V.[46-49] In two of the studies, inhaled Cannabis was made available only after dronabinol failure. In the first trial, no antiemetic effect was achieved with marijuana in patients receiving cyclophosphamide or doxorubicin,[46] but in the second trial, a statistically significant superior antiemetic effect of inhaled Cannabis versus placebo was found among patients receiving high-dose methotrexate.[47] The third trial was a randomized, double-blind, placebo-controlled, crossover trial involving 20 adults in which both inhaled marijuana and oral THC were evaluated. One-quarter of the patients reported a favorable antiemetic response to the cannabinoid therapies. This latter study was reported in abstract form in 1984. A full report, detailing the methods and outcomes apparently has not been published, which limits a thorough interpretation of the significance of these findings.[48]

Newer antiemetics (e.g., 5-HT3 receptor antagonists) have not been directly compared with Cannabis or cannabinoids in cancer patients. However, the Cannabis-extract oromucosal spray, nabiximols, formulated with 1:1 THC:CBD was shown in a small pilot randomized, placebo-controlled, double-blinded clinical trial in Spain to treat chemotherapy-related N/V.[50][Level of evidence: 1iC]

ASCO antiemetic guidelines updated in 2017 state that evidence remains insufficient to recommend medical marijuana for either the prevention or treatment of N/V in patients with cancer who receive chemotherapy or radiation therapy.[41]

Appetite Stimulation

Anorexia, early satiety, weight loss, and cachexia are problems experienced by cancer patients. Such patients are faced not only with the disfigurement associated with wasting but also with an inability to engage in the social interaction of meals.

Cannabinoids

Four controlled trials have assessed the effect of oral THC on measures of appetite, food appreciation, calorie intake, and weight loss in patients with advanced malignancies. Three relatively small, placebo-controlled trials (N = 52; N = 46; N = 65) each found that oral THC produced improvements in one or more of these outcomes.[51-53] The one study that used an active control evaluated the efficacy of dronabinol alone or with megestrol acetate compared with that of megestrol acetate alone for managing cancer-associated anorexia.[54] In this randomized, double-blind study of 469 adults with advanced cancer and weight loss, patients received 2.5 mg of oral THC twice daily, 800 mg of oral megestrol daily, or both. Appetite increased by 75% in the megestrol group and weight increased by 11%, compared with a 49% increase in appetite and a 3% increase in weight in the oral THC group after 8 to 11 weeks of treatment. The between-group differences were statistically significant in favor of megestrol acetate. Furthermore, the combined therapy did not offer additional benefits beyond those provided by megestrol acetate alone. The authors concluded that dronabinol did little to promote appetite or weight gain in advanced cancer patients compared with megestrol acetate.

Cannabis

In trials conducted in the 1980s that involved healthy control subjects, inhaling Cannabis led to an increase in caloric intake, mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods.[55,56]

Despite patients’ great interest in oral preparations of Cannabis to improve appetite, there is only one trial of Cannabis extract used for appetite stimulation. In an RCT, researchers compared the safety and effectiveness of orally administered Cannabis extract (2.5 mg THC and 1 mg CBD), THC (2.5 mg), or placebo for the treatment of cancer-related anorexia-cachexia in 243 patients with advanced cancer who received treatment twice daily for 6 weeks. Results demonstrated that although these agents were well tolerated by these patients, no differences were observed in patient appetite or quality of life among the three groups at this dose level and duration of intervention.[57]

No published studies have explored the effect of inhaled Cannabis on appetite in cancer patients.

Analgesia

Cannabinoids

Pain management improves a patient’s quality of life throughout all stages of cancer. Through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists, the mechanisms of cannabinoid-induced analgesia have been analyzed.[58][Level of evidence:1iC] The CB1 receptor is found in the central nervous system (CNS) and in peripheral nerve terminals.[59] CB2 receptors are located mainly in peripheral tissue and are expressed in only low amounts in the CNS. Whereas only CB1 agonists exert analgesic activity in the CNS, both CB1 and CB2 agonists have analgesic activity in peripheral tissue.[60,61]

Cancer pain results from inflammation, invasion of bone or other pain-sensitive structures, or nerve injury. When cancer pain is severe and persistent, it is often resistant to treatment with opioids.

Two studies examined the effects of oral delta-9-THC on cancer pain. The first, a double-blind, placebo-controlled study involving ten patients, measured both pain intensity and pain relief.[62] It was reported that 15 mg and 20 mg doses of the cannabinoid delta-9-THC were associated with substantial analgesic effects, with antiemetic effects and appetite stimulation.

In a follow-up, single-dose study involving 36 patients, it was reported that 10 mg doses of delta-9-THC produced analgesic effects during a 7-hour observation period that were comparable to 60 mg doses of codeine, and 20 mg doses of delta-9-THC induced effects equivalent to 120 mg doses of codeine.[63] Higher doses of THC were found to be more sedating than codeine.

Another study examined the effects of a plant extract with controlled cannabinoid content in an oromucosal spray. In a multicenter, double-blind, placebo-controlled study, the THC:CBD nabiximols extract and THC extract alone were compared in the analgesic management of patients with advanced cancer and with moderate-to-severe cancer-related pain. Patients were assigned to one of three treatment groups: THC:CBD extract, THC extract, or placebo. The researchers concluded that the THC:CBD extract was efficacious for pain relief in advanced cancer patients whose pain was not fully relieved by strong opioids.[64] In a randomized, placebo-controlled, graded-dose trial, opioid-treated cancer patients with poorly controlled chronic pain demonstrated significantly better control of pain and sleep disruption with THC:CBD oromucosal spray at lower doses (1–4 and 6–10 sprays/d), compared with placebo. Adverse events were dose related, with only the high-dose group (11–16 sprays/d) comparing unfavorably with the placebo arm. These studies provide promising evidence of an adjuvant analgesic effect of THC:CBD in this opioid-refractory patient population and may provide an opportunity to address this significant clinical challenge.[65] An open-label extension study of 43 patients who had participated in the randomized trial found that some patients continued to obtain relief of their cancer-related pain with long-term use of the THC:CBD oromucosal spray without increasing their dose of the spray or the dose of their other analgesics.[66]

An observational study assessed the effectiveness of nabilone in advanced cancer patients who were experiencing pain and other symptoms (anorexia, depression, and anxiety). The researchers reported that patients who used nabilone experienced improved management of pain, nausea, anxiety, and distress when compared with untreated patients. Nabilone was also associated with a decreased use of opioids, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, gabapentin, dexamethasone, metoclopramide, and ondansetron.[67]

Cannabis

Animal studies have suggested a synergistic analgesic effect when cannabinoids are combined with opioids. The results from one pharmacokinetic interaction study have been reported. In this study, 21 patients with chronic pain were administered vaporized Cannabis along with sustained-release morphine or oxycodone for 5 days.[68] The patients who received vaporized Cannabis and sustained-release morphine had a statistically significant decrease in their mean pain score over the 5-day period; those who received vaporized Cannabis and oxycodone did not. These findings should be verified by further studies before recommendations favoring such an approach are warranted in general clinical practice.

Neuropathic pain is a symptom cancer patients may experience, especially if treated with platinum-based chemotherapy or taxanes. Two RCTs of inhaled Cannabis in patients with peripheral neuropathy or neuropathic pain of various etiologies found that pain was reduced in patients who received inhaled Cannabis, compared with those who received placebo.[69,70] A retrospective analysis examined the effect of Cannabis on chemotherapy-induced peripheral neuropathy (CIPN) in Israeli cancer patients who received oxaliplatin-based regimens for gastrointestinal malignancies.[71][Level of evidence: 2Diii] Patients were divided into three groups on the basis of their exposure to Cannabis: Cannabis-first group (received Cannabis before starting oxaliplatin), oxaliplatin-first group (received oxaliplatin before starting Cannabis), and controls (no Cannabis use). A significant difference in grade 2 to 3 CIPN was seen between the Cannabis-exposed patients (15.3%) and controls (27.9%) (P < .001). The neuropathy-sparing effect was more pronounced among those treated with Cannabis first (75%) compared with those who received oxaliplatin first (46.2%) (P < .001). Some limitations of this study were its retrospective design and documentation of Cannabis use as qualitative, not quantitative.

A randomized, placebo-controlled, crossover, pilot study of nabiximols in 16 patients with chemotherapy-induced neuropathic pain showed no significant difference between the treatment and placebo groups. A responder analysis, however, demonstrated that five patients reported a reduction in their pain of at least 2 points on an 11-point scale, suggesting that a larger follow-up study may be warranted.[72]

One real-world randomized controlled trial explored Cannabis use in patients with advanced cancer who received care in a community oncology practice setting (148 screened; 30 randomized; 18 analyzed).[73] Once certified by their oncologists, participants were randomized to receive early Cannabis (EC) or delayed start of medical Cannabis (DC) for 3 months as part of a state-sponsored Cannabis program. The EC group had stable opioid usage compared with the DC group who had an increase in opioid usage during the 3-month study period. Overall, there were no significant changes in quality of life or symptom scores between the groups, with no overall Cannabis-related adverse events. Limitations included a variety of cancer types and no consistent use of Cannabis products (108 different Cannabis products were dispensed during the study period).

Anxiety and Sleep

Cannabinoids

In a small pilot study of analgesia involving ten patients with cancer pain, secondary measures showed that 15 mg and 20 mg doses of the cannabinoid delta-9-THC were associated with anxiolytic effects.[62][Level of evidence: 1iC]

A small placebo-controlled study of dronabinol in cancer patients with altered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[52][Level of evidence: 1iC]

Cannabis

Patients often experience mood elevation after exposure to Cannabis, depending on their previous experience. In a five-patient case series of inhaled Cannabis that examined analgesic effects in chronic pain, it was reported that patients who self-administered Cannabis had improved mood, improved sense of well-being, and less anxiety.[74]

Another common effect of Cannabis is sleepiness. A small placebo-controlled study of dronabinol in cancer patients with altered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[52]

Seventy-four patients with newly diagnosed head and neck cancer self-described as current Cannabis users were matched to 74 nonusers in a Canadian study investigating quality of life using the EuroQol-5D and Edmonton Symptom Assessment System instruments.[75] Cannabis users had significantly lower scores in the anxiety/depression (difference, 0.74; 95% CI, 0.557–0.930) and pain/discomfort (difference, 0.29; 95% CI, 0.037–1.541) domains. Cannabis users were also less tired, had more appetite, and better general well-being.

A single center, phase II, double-blind study of two ratios (1:1 [THC:CBD] and 4:1 [THC:CBD]) of an oral medical Cannabis oil enrolled patients with recurrent or inoperable high-grade glioma. Investigators assessed the side effects and Functional Assessment of Cancer Therapy-Brain (FACT-Br) at baseline and 12 weeks as a primary outcome.[76] There was no difference in the primary endpoint; however, some significant differences were noted in the subscores of the FACT-Br (i.e., physical, functional, and sleep favored the 1:1 ratio) and these endpoints would be appropriate for future research.

Clinical Studies of Cannabis and Cannabinoids

Table 2. Clinical Studies of Cannabis a

Reference Trial Design Condition or Cancer Type Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) b Results c Concurrent Therapy Used d Level of Evidence Score e
5-HT3 = 5-hydroxytryptamine 3; CINV = chemotherapy-induced nausea and vomiting; N/V = nausea and vomiting; RCT = randomized controlled trial.
a For additional information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
b Number of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.
c Strongest evidence reported that the treatment under study has activity or otherwise improves the well-being of cancer patients.
d Concurrent therapy for symptoms treated (not cancer).
e For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[76] RCT High-grade gliomas 88; 45 (1:1), 43 (4:1); None No difference in the primary endpoint Dexamethasone, temozolomide, bevacizumab, lomustine 1iC
[46] RCT CINV 8; 8; None No antiemetic effect reported No 1iC
[47] RCT CINV 15; 15; None Decreased N/V No 1iiC
[50] Pilot RCT CINV 16; 7; 9 Decreased delayed N/V 5-HT3 receptor antagonists 1iC
[68] Nonrandomized trial Chronic pain 21;10 (morphine), 11 (oxycodone); None Decreased pain Yes, morphine, oxycodone 2C
[75] Prospective cohort study Anxiety, pain, depression, loss of appetite 148; 74; 74 Decreased pain, anxiety, depression, increased appetite Unknown 2C
See also  CBD Plus Thc Gummies
Table 3. Clinical Studies of Cannabinoids a

Reference Trial Design Condition or Cancer Type Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) b Results c Concurrent Therapy Used d Level of Evidence Score e
CBD = cannabidiol; No. = number; NSAIDs = nonsteroidal anti-inflammatory drugs; QoL = quality of life; RCT = randomized controlled trial; THC = delta-9-tetrahydrocannabinol.
a For additional information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
b Number of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.
c Strongest evidence reported that the treatment under study has activity or otherwise improves the well-being of cancer patients.
d Concurrent therapy for symptoms treated (not cancer).
e For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[54] RCT Cancer-associated anorexia 469; dronabinol 152, megestrol acetate 159, or both 158; None Megestrol acetate provided increased appetite and weight gain, among advanced cancer patients compared with dronabinol alone No 1iC
[52] Pilot RCT Appetite 21; 11; 10 THC, compared with placebo, improved and enhanced taste and smell No 1iC
[57] RCT Cancer-related anorexia-cachexia syndrome 243; Cannabis extract 95, THC 100; 48 No differences in patients’ appetite or QoL were found No 1iC
[77] RCT Appetite 139; 72; 67 Increase in appetite No 1iC
[53] RCT Anorexia 47; 22; 25 Increased calorie intake No 1iC
[62] RCT Pain 10; 10; None Pain relief No 1iC
[64] RCT Pain 177; 60 (THC:CBD), 58 (THC); 59 THC:CBD extract group had reduced pain Yes, opioids 1iC
[65] RCT Pain 360; 269; 91 Decreased pain in low-dose group Yes, opioids 1iC
[66] Open-label extension Pain 43; 39 (THC:CBD), 4 (THC), None Decreased pain Yes, opioids 2C
[67] Observational study Pain 112; 47; 65 Decreased pain Yes, opioids, NSAIDs, gabapentin 2C

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]
  2. Agurell S, Halldin M, Lindgren JE, et al.: Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38 (1): 21-43, 1986. [PUBMED Abstract]
  3. Yamamoto I, Watanabe K, Narimatsu S, et al.: Recent advances in the metabolism of cannabinoids. Int J Biochem Cell Biol 27 (8): 741-6, 1995. [PUBMED Abstract]
  4. Engels FK, de Jong FA, Sparreboom A, et al.: Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist 12 (3): 291-300, 2007. [PUBMED Abstract]
  5. FDA Warns Companies Marketing Unproven Products, Derived From Marijuana, That Claim to Treat or Cure Cancer [News Release]. Silver Spring, Md: Food and Drug Administration, 2017. Available online. Last accessed January 4, 2019.
  6. Yamaori S, Okamoto Y, Yamamoto I, et al.: Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 39 (11): 2049-56, 2011. [PUBMED Abstract]
  7. Jiang R, Yamaori S, Okamoto Y, et al.: Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28 (4): 332-8, 2013. [PUBMED Abstract]
  8. Berthiller J, Straif K, Boniol M, et al.: Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb. J Thorac Oncol 3 (12): 1398-403, 2008. [PUBMED Abstract]
  9. Sidney S, Quesenberry CP, Friedman GD, et al.: Marijuana use and cancer incidence (California, United States). Cancer Causes Control 8 (5): 722-8, 1997. [PUBMED Abstract]
  10. Hashibe M, Morgenstern H, Cui Y, et al.: Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev 15 (10): 1829-34, 2006. [PUBMED Abstract]
  11. Mehra R, Moore BA, Crothers K, et al.: The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med 166 (13): 1359-67, 2006. [PUBMED Abstract]
  12. National Academies of Sciences, Engineering, and Medicine: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. The National Academies Press, 2017.
  13. Marks MA, Chaturvedi AK, Kelsey K, et al.: Association of marijuana smoking with oropharyngeal and oral tongue cancers: pooled analysis from the INHANCE consortium. Cancer Epidemiol Biomarkers Prev 23 (1): 160-71, 2014. [PUBMED Abstract]
  14. de Carvalho MF, Dourado MR, Fernandes IB, et al.: Head and neck cancer among marijuana users: a meta-analysis of matched case-control studies. Arch Oral Biol 60 (12): 1750-5, 2015. [PUBMED Abstract]
  15. Daling JR, Doody DR, Sun X, et al.: Association of marijuana use and the incidence of testicular germ cell tumors. Cancer 115 (6): 1215-23, 2009. [PUBMED Abstract]
  16. Trabert B, Sigurdson AJ, Sweeney AM, et al.: Marijuana use and testicular germ cell tumors. Cancer 117 (4): 848-53, 2011. [PUBMED Abstract]
  17. Lacson JC, Carroll JD, Tuazon E, et al.: Population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Cancer 118 (21): 5374-83, 2012. [PUBMED Abstract]
  18. Callaghan RC, Allebeck P, Akre O, et al.: Cannabis Use and Incidence of Testicular Cancer: A 42-Year Follow-up of Swedish Men between 1970 and 2011. Cancer Epidemiol Biomarkers Prev 26 (11): 1644-1652, 2017. [PUBMED Abstract]
  19. Thomas AA, Wallner LP, Quinn VP, et al.: Association between cannabis use and the risk of bladder cancer: results from the California Men’s Health Study. Urology 85 (2): 388-92, 2015. [PUBMED Abstract]
  20. Health Canada: Marihuana (Marijuana, Cannabis): Dried Plant for Administration by Ingestion or Other Means. Ottawa, Canada: Health Canada, 2010. Available online. Last accessed October 18, 2017.
  21. Pergam SA, Woodfield MC, Lee CM, et al.: Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer 123 (22): 4488-4497, 2017. [PUBMED Abstract]
  22. Bar-Lev Schleider L, Mechoulam R, Lederman V, et al.: Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med 49: 37-43, 2018. [PUBMED Abstract]
  23. Anderson SP, Zylla DM, McGriff DM, et al.: Impact of Medical Cannabis on Patient-Reported Symptoms for Patients With Cancer Enrolled in Minnesota’s Medical Cannabis Program. J Oncol Pract 15 (4): e338-e345, 2019. [PUBMED Abstract]
  24. Weiss MC, Hibbs JE, Buckley ME, et al.: A Coala-T-Cannabis Survey Study of breast cancer patients’ use of cannabis before, during, and after treatment. Cancer 128 (1): 160-168, 2022. [PUBMED Abstract]
  25. Ofir R, Bar-Sela G, Weyl Ben-Arush M, et al.: Medical marijuana use for pediatric oncology patients: single institution experience. Pediatr Hematol Oncol 36 (5): 255-266, 2019. [PUBMED Abstract]
  26. Oberoi S, Protudjer JLP, Rapoport A, et al.: Perspectives of pediatric oncologists and palliative care physicians on the therapeutic use of cannabis in children with cancer. Cancer Rep (Hoboken) : e1551, 2021. [PUBMED Abstract]
  27. Ananth P, Ma C, Al-Sayegh H, et al.: Provider Perspectives on Use of Medical Marijuana in Children With Cancer. Pediatrics 141 (1): , 2018. [PUBMED Abstract]
  28. Guzmán M, Duarte MJ, Blázquez C, et al.: A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95 (2): 197-203, 2006. [PUBMED Abstract]
  29. Velasco G, Sánchez C, Guzmán M: Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12 (6): 436-44, 2012. [PUBMED Abstract]
  30. Twelves C, Sabel M, Checketts D, et al.: A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma. Br J Cancer 124 (8): 1379-1387, 2021. [PUBMED Abstract]
  31. Likar R, Koestenberger M, Stultschnig M, et al.: Concomitant Treatment of Malignant Brain Tumours With CBD – A Case Series and Review of the Literature. Anticancer Res 39 (10): 5797-5801, 2019. [PUBMED Abstract]
  32. Yeshurun M, Shpilberg O, Herscovici C, et al.: Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study. Biol Blood Marrow Transplant 21 (10): 1770-5, 2015. [PUBMED Abstract]
  33. Singh Y, Bali C: Cannabis extract treatment for terminal acute lymphoblastic leukemia with a Philadelphia chromosome mutation. Case Rep Oncol 6 (3): 585-92, 2013. [PUBMED Abstract]
  34. Foroughi M, Hendson G, Sargent MA, et al.: Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas–possible role of Cannabis inhalation. Childs Nerv Syst 27 (4): 671-9, 2011. [PUBMED Abstract]
  35. Sutton IR, Daeninck P: Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006 Nov-Dec. [PUBMED Abstract]
  36. Ahmedzai S, Carlyle DL, Calder IT, et al.: Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer 48 (5): 657-63, 1983. [PUBMED Abstract]
  37. Chan HS, Correia JA, MacLeod SM: Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 79 (6): 946-52, 1987. [PUBMED Abstract]
  38. Johansson R, Kilkku P, Groenroos M: A double-blind, controlled trial of nabilone vs. prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat Rev 9 (Suppl B): 25-33, 1982. [PUBMED Abstract]
  39. Niiranen A, Mattson K: A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. Am J Clin Oncol 8 (4): 336-40, 1985. [PUBMED Abstract]
  40. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 1.2021. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2021. Available online with free registration. Last accessed August 26, 2021..
  41. Hesketh PJ, Kris MG, Basch E, et al.: Antiemetics: ASCO Guideline Update. J Clin Oncol 38 (24): 2782-2797, 2020. [PUBMED Abstract]
  42. Tramèr MR, Carroll D, Campbell FA, et al.: Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323 (7303): 16-21, 2001. [PUBMED Abstract]
  43. Ben Amar M: Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 105 (1-2): 1-25, 2006. [PUBMED Abstract]
  44. Smith LA, Azariah F, Lavender VT, et al.: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev (11): CD009464, 2015. [PUBMED Abstract]
  45. Meiri E, Jhangiani H, Vredenburgh JJ, et al.: Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin 23 (3): 533-43, 2007. [PUBMED Abstract]
  46. Chang AE, Shiling DJ, Stillman RC, et al.: A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer 47 (7): 1746-51, 1981. [PUBMED Abstract]
  47. Chang AE, Shiling DJ, Stillman RC, et al.: Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Ann Intern Med 91 (6): 819-24, 1979. [PUBMED Abstract]
  48. Levitt M, Faiman C, Hawks R, et al.: Randomized double blind comparison of delta-9-tetrahydrocannabinol and marijuana as chemotherapy antiemetics. [Abstract] Proceedings of the American Society of Clinical Oncology 3: A-C354, 91, 1984.
  49. Musty RE, Rossi R: Effects of smoked cannabis and oral delta-9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: a review of state clinical trials. Journal of Cannabis Therapeutics 1 (1): 29-56, 2001. Also available online. Last accessed October 18, 2017.
  50. Duran M, Pérez E, Abanades S, et al.: Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol 70 (5): 656-63, 2010. [PUBMED Abstract]
  51. Regelson W, Butler JR, Schulz J, et al.: Delta-9-tetrahydrocannabinol as an effective antidepressant and appetite-stimulating agent in advanced cancer patients. In: Braude MC, Szara S: The Pharmacology of Marihuana. Raven Press, 1976, pp 763-76.
  52. Brisbois TD, de Kock IH, Watanabe SM, et al.: Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol 22 (9): 2086-93, 2011. [PUBMED Abstract]
  53. Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, et al.: The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Support Care Cancer 26 (9): 3029-3038, 2018. [PUBMED Abstract]
  54. Jatoi A, Windschitl HE, Loprinzi CL, et al.: Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 20 (2): 567-73, 2002. [PUBMED Abstract]
  55. Foltin RW, Brady JV, Fischman MW: Behavioral analysis of marijuana effects on food intake in humans. Pharmacol Biochem Behav 25 (3): 577-82, 1986. [PUBMED Abstract]
  56. Foltin RW, Fischman MW, Byrne MF: Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11 (1): 1-14, 1988. [PUBMED Abstract]
  57. Strasser F, Luftner D, Possinger K, et al.: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol 24 (21): 3394-400, 2006. [PUBMED Abstract]
  58. Aggarwal SK: Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Clin J Pain 29 (2): 162-71, 2013. [PUBMED Abstract]
  59. Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PUBMED Abstract]
  60. Calignano A, La Rana G, Giuffrida A, et al.: Control of pain initiation by endogenous cannabinoids. Nature 394 (6690): 277-81, 1998. [PUBMED Abstract]
  61. Fields HL, Meng ID: Watching the pot boil. Nat Med 4 (9): 1008-9, 1998. [PUBMED Abstract]
  62. Noyes R, Brunk SF, Baram DA, et al.: Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15 (2-3): 139-43, 1975 Feb-Mar. [PUBMED Abstract]
  63. Noyes R, Brunk SF, Avery DA, et al.: The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18 (1): 84-9, 1975. [PUBMED Abstract]
  64. Johnson JR, Burnell-Nugent M, Lossignol D, et al.: Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 39 (2): 167-79, 2010. [PUBMED Abstract]
  65. Portenoy RK, Ganae-Motan ED, Allende S, et al.: Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13 (5): 438-49, 2012. [PUBMED Abstract]
  66. Johnson JR, Lossignol D, Burnell-Nugent M, et al.: An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage 46 (2): 207-18, 2013. [PUBMED Abstract]
  67. Maida V, Ennis M, Irani S, et al.: Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol 6 (3): 119-24, 2008. [PUBMED Abstract]
  68. Abrams DI, Couey P, Shade SB, et al.: Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 90 (6): 844-51, 2011. [PUBMED Abstract]
  69. Wilsey B, Marcotte T, Deutsch R, et al.: Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 14 (2): 136-48, 2013. [PUBMED Abstract]
  70. Wilsey B, Marcotte T, Tsodikov A, et al.: A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 9 (6): 506-21, 2008. [PUBMED Abstract]
  71. Waissengrin B, Mirelman D, Pelles S, et al.: Effect of cannabis on oxaliplatin-induced peripheral neuropathy among oncology patients: a retrospective analysis. Ther Adv Med Oncol 13: 1758835921990203, 2021. [PUBMED Abstract]
  72. Lynch ME, Cesar-Rittenberg P, Hohmann AG: A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47 (1): 166-73, 2014. [PUBMED Abstract]
  73. Zylla DM, Eklund J, Gilmore G, et al.: A randomized trial of medical cannabis in patients with stage IV cancers to assess feasibility, dose requirements, impact on pain and opioid use, safety, and overall patient satisfaction. Support Care Cancer 29 (12): 7471-7478, 2021. [PUBMED Abstract]
  74. Noyes R, Baram DA: Cannabis analgesia. Compr Psychiatry 15 (6): 531-5, 1974 Nov-Dec. [PUBMED Abstract]
  75. Zhang H, Xie M, Archibald SD, et al.: Association of Marijuana Use With Psychosocial and Quality of Life Outcomes Among Patients With Head and Neck Cancer. JAMA Otolaryngol Head Neck Surg 144 (11): 1017-1022, 2018. [PUBMED Abstract]
  76. Schloss J, Lacey J, Sinclair J, et al.: A Phase 2 Randomised Clinical Trial Assessing the Tolerability of Two Different Ratios of Medicinal Cannabis in Patients With High Grade Gliomas. Front Oncol 11: 649555, 2021. [PUBMED Abstract]
  77. Beal JE, Olson R, Laubenstein L, et al.: Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10 (2): 89-97, 1995. [PUBMED Abstract]

Adverse Effects

Cannabis and Cannabinoids

Because cannabinoid receptors, unlike opioid receptors, are not located in the brainstem areas controlling respiration, lethal overdoses from Cannabis and cannabinoids do not occur.[1-4] However, cannabinoid receptors are present in other tissues throughout the body, not just in the central nervous system, and adverse effects include the following:

  • Tachycardia. . injection.
  • Bronchodilation.
  • Muscle relaxation.
  • Decreased gastrointestinal motility.

Although cannabinoids are considered by some to be addictive drugs, their addictive potential is considerably lower than that of other prescribed agents or substances of abuse.[2,4] The brain develops a tolerance to cannabinoids.

Withdrawal symptoms such as irritability, insomnia with sleep electroencephalogram disturbance, restlessness, hot flashes, and, rarely, nausea and cramping have been observed. However, these symptoms appear to be mild compared with withdrawal symptoms associated with opiates or benzodiazepines, and the symptoms usually dissipate after a few days.

Unlike other commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a low rate (half-life 1–3 days), so even abrupt cessation of cannabinoid intake is not associated with rapid declines in plasma concentrations that would precipitate severe or abrupt withdrawal symptoms or drug cravings.

Cannabidiol (CBD) is an inhibitor of cytochrome P450 isoforms in vitro. Because many anticancer therapies are metabolized by these enzymes, highly concentrated CBD oils used concurrently could potentially increase the toxicity or decrease the effectiveness of these therapies.[5,6]

Since Cannabis smoke contains many of the same components as tobacco smoke, there are valid concerns about the adverse pulmonary effects of inhaled Cannabis. A longitudinal study in a noncancer population evaluated repeated measurements of pulmonary function over 20 years in 5,115 men and women whose smoking histories were known.[7] While tobacco exposure was associated with decreased pulmonary function, the investigators concluded that occasional and low-cumulative Cannabis use was not associated with adverse effects on pulmonary function (forced expiratory volume in the first second of expiration [FEV1] and forced vital capacity [FVC]).

Interactions With Conventional Cancer Therapies

The potential for cytochrome P450 interactions with highly concentrated oil preparations of delta-9-tetrahydrocannabinol and/or cannabidiol is a concern.[8] Few pharmacokinetic interaction studies have been conducted with Cannabis or cannabinoids and conventional cancer therapies. A small study investigated the effect of Cannabis tea in 24 patients who received irinotecan or docetaxel.[9] Administration of the Cannabis tea did not significantly influence exposure to and clearance of either intravenous agent.

An Israeli retrospective observational study assessed the impact of Cannabis use during nivolumab immunotherapy.[10] One hundred forty patients with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma received the checkpoint inhibitor nivolumab (89 patients received nivolumab alone and 51 patients received nivolumab plus Cannabis). In a multivariate model, Cannabis was the only significant factor that reduced the response rate to immunotherapy (37.5% in patients who received nivolumab alone compared with 15.9% in patients who received nivolumab plus Cannabis [odds ratio, 3.13; 95% confidence interval, 1.24–8.1; P = .016]). There was no difference in progression-free survival or overall survival. A subsequent prospective observational study from the same investigators followed 102 patients with metastatic cancers initiating immunotherapy.[11][Level of evidence: 2Dii] Sixty-eight patients received immunotherapy alone while 34 patients used Cannabis during immunotherapy. Over half of the patients in each group had stage IV non-small cell lung cancer. Cannabis users were less likely to receive immunotherapy as a first-line intervention (24%) compared with nonusers (46%) (P = .03). Cannabis users showed a significantly lower percentage of clinical benefit (39% of Cannabis users with complete or partial responses or stable disease compared with 59% of nonusers [P = .035]). In this analysis, the median time to tumor progression was 3.4 months in Cannabis users compared with 13.1 months in nonusers and the overall survival was 6.4 months in Cannabis users compared with 28.5 months in nonusers. The investigators also noted that Cannabis users reported a lower rate of overall treatment-related adverse experiences compared with nonusers, with fewer immune-related adverse events (P = .057). The investigators postulated that this finding may be related to the possible immunosuppressive effects of Cannabis and concluded that Cannabis consumption should be carefully considered in patients with advanced malignancies who are treated with immunotherapy. Limitations noted by the authors that may be confounders in this analysis include the observational nature of the study, the relatively small sample size, and the high heterogeneity of the participants.

References
  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]
  2. Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. The Haworth Press, 2002.
  3. Sutton IR, Daeninck P: Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006 Nov-Dec. [PUBMED Abstract]
  4. Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PUBMED Abstract]
  5. Yamaori S, Okamoto Y, Yamamoto I, et al.: Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 39 (11): 2049-56, 2011. [PUBMED Abstract]
  6. Jiang R, Yamaori S, Okamoto Y, et al.: Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28 (4): 332-8, 2013. [PUBMED Abstract]
  7. Pletcher MJ, Vittinghoff E, Kalhan R, et al.: Association between marijuana exposure and pulmonary function over 20 years. JAMA 307 (2): 173-81, 2012. [PUBMED Abstract]
  8. Kocis PT, Vrana KE: Delta-9-tetrahydrocannabinol and cannabidiol drug-drug interactions. Med Cannabis Cannabinoids 3 (1): 61-73, 2020.
  9. Engels FK, de Jong FA, Sparreboom A, et al.: Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist 12 (3): 291-300, 2007. [PUBMED Abstract]
  10. Taha T, Meiri D, Talhamy S, et al.: Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies. Oncologist 24 (4): 549-554, 2019. [PUBMED Abstract]
  11. Bar-Sela G, Cohen I, Campisi-Pinto S, et al.: Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancers (Basel) 12 (9): , 2020. [PUBMED Abstract]

Summary of the Evidence for Cannabis and Cannabinoids

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for people with cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

  • Be published in a peer-reviewed scientific journal.
  • Report on therapeuticoutcome or outcomes, such as tumorresponse, improvement in survival, or measured improvement in quality of life.
  • Describe clinical findings in sufficient detail for a meaningful evaluation to be made.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of possible scores and additional information about levels of evidence analysis of Complementary and Alternative Medicine (CAM) treatments for people with cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

  • Several controlled clinical trials have been performed, and meta-analyses of these support a beneficial effect of cannabinoids (dronabinol and nabilone) on chemotherapy-induced nausea and vomiting (N/V) compared with placebo. Both dronabinol and nabilone are approved by the U.S. Food and Drug Administration for the prevention or treatment of chemotherapy-induced N/V in cancer patients but not for other symptom management.
  • There have been ten clinical trials on the use of inhaledCannabis in cancer patients that can be divided into two groups. In one group, four small studies assessed antiemetic activity, but each explored a different patient population and chemotherapy regimen. One study demonstrated no effect, the second study showed a positive effect versus placebo, and the report of the third study did not provide enough information to characterize the overall outcome as positive or neutral. Consequently, there are insufficient data to provide an overall level of evidence assessment for the use of Cannabis for chemotherapy-induced N/V. Apparently, there are no published controlled clinical trials on the use of inhaled Cannabis for other cancer-related or cancer treatment–related symptoms.
  • An increasing number of trials are evaluating the oromucosal administration of Cannabis plant extract with fixed concentrations of cannabinoid components, with national drug regulatory agencies in Canada and in some European countries that issue approval for cancer pain.
  • At present, there is insufficient evidence to recommend inhaling Cannabis as a treatment for cancer-related symptoms or cancer treatment–related symptoms or cancer treatment-related side effects; however, additional research is needed.

Changes to This Summary (06/07/2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added text to state that the National Cancer Institute (NCI) hosted a virtual meeting, the NCI Cannabis, Cannabinoids, and Cancer Research Symposium, on December 15–18, 2020. The seven sessions are summarized in the Journal of the National Cancer Institute Monographs and contain basic science and clinical information as well as a summary of the barriers to conducting Cannabis research (cited Ellison et al, Sexton et al., Cooper et al., Braun et al., Ward et al., McAllister et al., and Abrams et al., as references 5, 6, 7, 8, 9, 10, and 11, respectively).

Added text to state that 42% of women with a diagnosis of breast cancer within the past 5 years who participated in an anonymous online survey reported using Cannabis for the relief of symptoms, particularly pain, insomnia, anxiety, stress, and nausea and vomiting (cited Weiss et al. as reference 24). Among Cannabis users, 79% used Cannabis during their cancer treatment, and 75% reported that Cannabis was extremely or very helpful for relieving symptoms. Forty-nine percent of Cannabis users felt that Cannabis could be useful in treating the cancer itself. Only 39% of the participants reported discussing Cannabis use with their physicians.

Added text to state that survey studies revealed that the majority of responding pediatricians in the United States and Canada supported the use of medical Cannabis for symptom management in patients with cancer (cited Oberoi et al. and Ananth et al. as references 26 and 27, respectively).

Added text to state that limitations noted by the authors that may be confounders in this analysis include the observational nature of the study, the relatively small sample size, and the high heterogeneity of the participants.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Cannabis and cannabinoids in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cannabis and Cannabinoids. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq. Accessed . [PMID: 26389198]

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