Cbd oil ratio for cancer

Cannabinoids in cancer treatment: Therapeutic potential and legislation

The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids. The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes. Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer. In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite. In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types. Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries. In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration. Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients. The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.

INTRODUCTION

The first discovered and most important source of cannabinoids was the plant Cannabis sativa L., which has been used as an herbal remedy for centuries. The earliest archaeological evidence of cannabis medical use dates back to the Han Dynasty in ancient China, where it was recommended for rheumatic pain, constipation, disorders of the female reproductive tract, and malaria among other conditions. In traditional Indian Ayurvedic medicine, cannabis was used to treat neurological, respiratory, gastrointestinal, urogenital, and various infectious diseases [1]. The plant was also cultivated in other countries in Asia as well as in Europe, especially for making ropes, clothes/fibres, food and paper [2]. In Western medicine, the use of cannabis was notably introduced by the work of William B. O’Shaughnessy (an Irish physician) and Jacques-Joseph Moreau (a French psychiatrist) in the mid-19 th century, who described positive effects of cannabis preparations, including hashish (the compressed stalked resin glands), on pain, vomiting, convulsions, rheumatism, tetanus and mental abilities. Cannabis was recognized as a medicine in the United States (US) Pharmacopoeia from 1851, in the form of tinctures, extracts and resins. However, in the beginning of the 20 th century, cannabis use decreased in Western medicine due to several reasons: increased use as a recreational drug, abuse potential, variability in the quality of herbal material, individual (active) compounds were not identified and alternative medications, with known efficacy, were introduced to treat the same symptoms [2,3]. In 1941, as the result of many legal restrictions, cannabis was removed from the American Pharmacopoeia and considered to be in the same group as other illicit drugs [3]. Consequently, the exploration of medical uses of cannabis has been significantly slowed down for more than a half of century. In 2013, a step forward was made with the inclusion of a monograph of Cannabis spp. in the American Herbal Pharmacopoeia [4]. Moreover, the current legislative changes in the European Union (EU), US and Canada that allow cannabis for medical and/or recreational use, the progress in scientific research and public awareness on the benefits of medical cannabis all contributed to the rising interest in the therapeutic potential of cannabinoids [5,6].

In recent years, cannabinoids have been extensively studied for their potential anticancer effects and symptom management in cancer patients [7-9]. One of the first studies describing antineoplastic activity of cannabinoids was published in 1975 [10]. Potential antitumor activity of plant-derived or phytocannabinoids, e.g., (−)-trans-∆9-tetrahydrocannabinol (THC), cannabinol (CBN), ∆8-THC, cannabidiol (CBD) and cannabicyclol (CBL), as well as of synthetic cannabinoids, such as WIN-55,212-2, is the focus of current research [7,8,11].

In the 1990s, the main components of the endocannabinoid system (ECS) were identified as follows: (i) two types of cannabinoid (CB) receptors, CB1 and CB2 receptor; (ii) two main endogenous ligands (endocannabinoids) in mammals, anandamide or N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG); and (iii) endocannabinoid metabolic enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAG lipase). FAAH is the primary catabolic enzyme for fatty acid amides (FAAs), a class of bioactive lipids including AEA, while MAG lipase is a key enzyme in the hydrolysis of 2-AG [12-16]. Subsequent studies demonstrated the important role of the ECS and endocannabinoids in different physiological and pathological processes, such the regulation of excitatory and inhibitory synaptic transmission in the central nervous system (CNS), food intake, nociceptive signaling, analgesia, immunomodulation, inflammation, and cancer cell signaling [17-19].

In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite [8,20]. In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids and suggested new therapeutic opportunities for cancer patients [20]. However, recent research also emphasizes the importance of safety measures when using cannabinoids, since these compounds can potentially impair cognitive functions, especially in adolescents [21].

The aim of this article is to review the relevant literature on anticancer effects of plant-derived and synthetic cannabinoids, to increase our understanding of their potential mechanisms of action and possible role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries.

MOLECULAR BASIS FOR CANNABINOID TREATMENT OF CANCER

The role of the endocannabinoid system in cancer

Endocannabinoids interact with different types of receptors, including the two Gi/o-coupled CB receptors, CB1 and CB2 [18]. While CB1 receptors are mainly located in the CNS and, to a lesser degree, in some peripheral tissues, CB2 receptors are primarily expressed on the surface of immune cells [22]. Due to the low expression of CB2 receptors in the CNS they represent a promising pharmacological target, as selective CB2 ligands potentially would not have psychotropic effects [23]. In addition, other CB receptor types and isoforms or completely different pharmacological targets of cannabinoids have been described, for example transient receptor potential vanilloid receptor 1 (TRPV1), orphan G-protein coupled receptor (GPR)55, peroxisome proliferator-activated receptors (PPARs) [24,25], transient receptor potential melastatin 8 (TRPM8), TRP vanilloid 2 (TRPV2) and TRP ankyrin 1 (TRPA1) channel [26]. It is important to note that cannabinoids may also exert their antitumor effects independent of the CB receptors, for example as demonstrated in human pancreatic cancer cell line MIA PaCa-2 [27].

The biological role of the ECS in cancer pathophysiology is not completely clear [20] but most studies suggest that CB receptors and their endogenous ligands are upregulated in tumor tissue [28,29,31,34-39,41,48] and that the overexpression of ECS components (i.e., receptors, ligands, and enzymes) correlates with tumor aggressiveness [49-51]. However, a tumor-suppressive role of ECS was also indicated by some studies, e.g., the upregulation of endocannabinoid-degrading enzymes was observed in aggressive human cancers and cancer cell lines [51]. Moreover, experimental studies showed that the activation of CB receptors by cannabinoids is antitumorigenic in most cases, i.e., it inhibits tumor cell proliferation, induces apoptosis in vitro, and blocks angiogenesis and tumor invasion/metastasis in vivo [35,46,51,52]. The effects of CB receptor (over)expression in selected human tumor cell lines are described in more detail in Table 1 .

Antitumor effects of cannabinoids

By targeting the ECS, cannabinoids affect many essential cellular processes and signaling pathways which are crucial for tumor development [51,53,54]. For example, they can induce cell cycle arrest, promote apoptosis, and inhibit proliferation, migration and angiogenesis in tumor cells ( Figure 1 ) [53,54]. In addition to CB receptor-mediated (CB1 and CB2 receptors) cannabinoid effects, it appears that these processes can also be CB receptor-independent (e.g., through TRPV1, 5-hydroxytryptamine [5-HT]3, or nicotinic acetylcholine receptor [nAChR] among others) [53], suggesting that molecular mechanisms underlying the antitumor activity of cannabinoids are even more complex than originally thought. Moreover, it is expected that future studies will discover novel molecular targets of cannabinoids [53].

Example of different signaling pathways induced by cannabinoids in cancer cells [46,51,53-55]. By targeting the endocannabinoid system (ECS), cannabinoids affect many essential cellular processes and signaling pathways which are crucial for tumor development. .

The ability of plant-derived and synthetic cannabinoids to control cancer cell growth, invasion, and death has been demonstrated in numerous experimental studies using cancer cell lines and genetically engineered mouse models. Also, different types of cannabinoids may have different modes of action. For example, a phytocannabinoid THC promotes apoptosis in a CB-receptor dependent manner, while CBD exerts this effect independently of CB1/CB2 receptors and possibly includes the activation of TRPV2 receptor, at least in some cancer types. Also, some CB receptor agonists are less efficient in promoting cancer cell death although they demonstrate higher affinity for CB receptors than THC, such as synthetic CB receptor agonist WIN-55,212-2. Better understanding of homo- or hetero-oligomerization of CB receptors, their interactions with lipid rafts for example, and mechanisms of selective G-protein coupling may clarify these differences [54]. Finally, because molecular changes are tumor-specific in most cases (i.e., the presence of intra- and inter-tumor heterogeneity), CB-receptor mediated antitumor effects largely depend on the type of cancer that is being investigated and characteristics of derived tumor cell line, including the donor characteristics, tumor site of origin and hormonal responsiveness [53-55].

PLANT-DERIVED CANNABINOIDS AND THEIR ANTITUMOR ACTIVITY

Phytocannabinoids are a group of C21 terpenophenolic compounds predominately produced by the plants from the genus Cannabis. Different resources indicate that there are more than 90 different cannabinoids together with their breakdown products, although some report that > 60 compounds is a more accurate estimation. Among these, the most abundant are THC, CBD, CBN and cannabichromene (CBC) followed by ∆8-THC, cannabidiolic acid (CBDA), cannabidivarin (CBDV) and cannabigerol (CBG). The highest content of cannabinoids is located in the flowering tops of the plant and small, young leaves around the flowers [56].

Pharmacologically, THC is a partial agonist at CB1 and CB2 receptor with inhibitory constant (Ki) of 40.7 nM for CB1 and 36.4 nM for CB2 [57]. ∆8-THC is a stable isomer of THC with similar Ki [58]. The most studied non-psychotropic phytocannabinoid is CBD which does not have psychotomimetic activity. CBD has a low affinity for CB1 and CB2; it was suggested that it acts as an antagonist of CB1/CB2 agonists but also as a CB2 inverse agonist (an inverse agonist binds to the same receptor-binding site as an agonist and it does not only antagonize the effects of the agonist but exerts the opposite effect). Other mechanisms of action of CBD, that are independent of CB receptors, include FAAH inhibition, inhibition of AEA reuptake, it acts as an agonist at PPARγ, TRPV1, TRPA1 and an antagonist at GPR55 and TRPM8 ( Table 2 ). CBN is a weak partial agonist at CB1 (Ki of 308 nM) and CB2 (Ki of 96.3 nM); CBG is a potent TRPM8 antagonist, TRPV1 and TRPA1 agonist, and CB partial agonist; while CBC is a potent TRPA1 agonist and weak inhibitor of AEA reuptake [59].

Plant-derived cannabinoids are approved only for some indications, but additionally have been used off-label. For example, a standardized alcoholic cannabis extract nabiximols, which has the THC: CBD ratio of 1:1 and is available as an oromucosal spray, was approved in Germany for the treatment of moderate to severe refractory spasticity in multiple sclerosis. Examples of off-label use of this medication are of chronic pain in several medical conditions and symptomatic treatment of selected neuropsychological disorders (e.g., anxiety and sleeping disturbances). Common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), dry mouth, and psychoactive effects among others. Nevertheless, tolerance to these side effects develops within a short time in almost all cases. Withdrawal symptoms are rarely observed in the therapeutic setting [60].

An exciting area of research is the technological improvement of existing pharmaceutical formulations, especially the development of new cannabis-based extracts. Romano et al. [57] found that a CO2 extracted cannabis extract, with a high content (64.8%) in Δ9-tetrahydrocannabivarin (THCV), inhibits nitrite production induced by lipopolysaccharides (LPS) in murine peritoneal macrophages, and thus may have a potential to modulate the inflammatory response in different disease conditions [57]. Another study compared in vitro antioxidant activity and gene expression of antioxidant enzymes between ethanol and supercritical fluid (SF) extracts of dehulled hemp seed. SF extract exhibited higher radical scavenging activities compared to ethanol extract. Both extracts upregulated the expression of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in human hepatoma (HepG2) cells challenged with H2O2, and this effect was greater for SF extracts at the concentration of 500 µg/mL [61].

Different plant-derived cannabinoids and cannabis-based pharmaceutical drugs have been the subject of intensive research for their potential antitumor activity, especially in cancer cells that overexpress CB1 and/or CB2 receptors compared to normal tissues [62]. Many studies were conducted in different cell lines with cannabis extracts or individual isolated compounds and the results are sometimes confounding, because efficient anticancer effects, such as decreased proliferation of cancer cells, activation of apoptosis, inhibition of cell migration and decreased tumor vascularization are mainly recorded in breast, prostate and glioma cancer cell lines. In contrast, protumorigenic activity of natural cannabinoids, i.e., increased cell proliferation, has been reported in lung, breast, and hepatoma cell lines [63]. It appears that the balance between protumorigenic and antitumor effects of cannabinoids critically depends on their concentration, among other factors. For example, Hart et al. [64] showed that the treatment of glioblastoma U373-MG and lung carcinoma NCI-H292 cell line with nanomolar concentrations of THC (instead of commonly used micromoral concentrations) led to increased cell proliferation. The authors also emphasized that nanomolar concentrations of THC are more likely to be detected in the serum of patients after drug treatment [64]. Therefore, in cancer therapy, it is very important to consider the risk of acceleration of tumor growth due to the concentration-dependent proliferative potential of cannabinoids [64].

In addition to THC, CBD is another plant-derived cannabinoid that has been extensively studied for its potential antitumor effects [39,65-68]. In a panel of human prostate cancer cell lines, Sharma et al. [67] showed that CBD is a potent inhibitor of cancer cell growth, while this potency was significantly lower in non-cancer cells. Moreover, CBD downregulated CB1, CB2, vascular endothelial growth factor (VEGF) and prostate-specific antigen (PSA) in prostate cancer cells, as well as pro-inflammatory interleukin (IL)-6 and IL-8 in LPS-stimulated dermal fibroblasts, suggesting its anti-inflammatory properties [67]. Other studies showed that CBD preferentially inhibited the survival of breast cancer cells by inducing apoptosis and autophagy [65] and inhibited proliferation and cell invasion in human glioma cell lines [66].

The expression of CB1 and CB2 receptors on immune cells suggests their important role in the regulation of the immune system. Recently, it was demonstrated that the administration of THC into mice induced apoptosis in T cells and dendritic cells, leading to immunosuppression. Several studies suggested that cannabinoids are able to suppress inflammatory responses by downregulating cytokine and chemokine production and upregulating T-regulatory cells. Similar results were obtained with endocannabinoids, i.e., the administration of these compounds or the use of inhibitors of enzymes that break down endocannabinoids had an immunosuppressive effect and resulted in the recovery from immune-mediated injury to organs, e.g., in the liver [69]. As indicated in previous paragraphs, cannabinoids were able to stimulate cell proliferation in in vitro and/or in vivo models of several types of cancer. For example, a treatment with THC in the mouse mammary carcinoma 4T1 expressing low levels of CB1 and CB2 led to enhanced growth of tumor and metastasis, due to the inhibition of the antitumor immune response, primarily via CB2. Moreover, THC led to an increased production of IL-4 and IL-10 in these mice, indicating that it suppresses the Th1 response by enhancing Th2-associated cytokines as confirmed by their microarray data (Th2-related genes were upregulated and Th1-related genes downregulated). Lastly, the injection of anti-IL-4 and anti-IL-10 monoclonal antibodies partially reversed the THC-induced suppression of the immune response [70]. In another study, THC promoted tumorigenicity in two weakly immunogenic murine lung cancer models by inhibiting their antitumor immunity; namely, the inhibitory cytokines IL-10 and transforming growth factor beta (TGF-β) were upregulated, while interferon gamma (IFN-γ) was downregulated at the tumor site and in the spleens of the mice treated with THC [71]. These findings suggest that THC could decrease tumor immunogenicity and promote tumor growth by inhibiting antitumor immunity, probably via CB2 receptor-mediated, cytokine-dependent pathway. Additional studies on the interactions between cannabinoids and immune cells will provide crucial data to improve the efficacy and safety of cannabinoid therapy in oncology [72].

SYNTHETIC CANNABINOIDS WITH POTENTIAL ANTITUMOR EFFECTS

Most synthetic cannabinoids, including dronabinol, nabilone, and synthetic CBD are CB1 and CB2 receptor ligands [73]. Studies in cells and animals show that they produce similar qualitative physiological, psychoactive, analgesic, anti-inflammatory, and anticancer effects to plant-derived cannabinoids, but they can be up to 100× more potent than THC [73,74]. Similar to naturally occurring cannabinoids, synthetic cannabinoid agonists also demonstrated anticancer effects in certain cancer cell lines in vitro [17,75]. Oil and alcohol-based drops or capsules of dronabinol and nabilone (synthetic THC) as well as synthetic CBD are approved to treat cytostatic-induced nausea/vomiting in cancer patients and to stimulate appetite in patients with acquired immune deficiency syndrome [57].

Recently, a subclass of compounds emerged that act on metabolic enzymes involved in the regulation of ECS activity, such as inhibitors of FAAH which increase the levels of endogenous cannabinoid AEA. They were developed with the purpose to treat a variety of neurological diseases, chronic pain, obesity, and cancer [76]. A study investigating the combination of the synthetic analogue of AEA Met-F-AEA and the selective irreversible carbamate-based FAAH inhibitor URB597 showed that they synergistically inhibited epidermal growth factor (EGF)-induced proliferative and chemotactic activity of non-small cell lung cancer cell lines A549 and H460 [77]. Moreover, the two FAAH inhibitors URB597 and arachidonoyl serotonin (AA-5HT) had antimetastatic effects on A549 lung cancer cell metastasis [78]. However, recently in France, the first-in-human phase I clinical trial of an experimental FAAH inhibitor BIA 10-2474, for neuropathic pain treatment, ended up tragically; one person died and other four had irreversible brain damage [79,80]. The magnetic resonance imaging (MRI) showed evidence of deep cerebral hemorrhage and necrosis in the affected patients [79]. Other clinical trials conducted on FAAH inhibitors are Merck’s MK-4409, Pfizer’s PF-04457845, and Vernalis’ V158866; no adverse effects were reported with these agents and they were considered safe in humans [79,81,82]. Thus, it could be speculated that the negative effects of BIA 10-2474 occurred because the drug may have interacted with a wrong and unexpected molecular target [79]. Nevertheless, no FAAH inhibitor is yet approved for therapeutic use.

To summarize, the antitumor effects of synthetic cannabinoids such as the inhibition of cell growth, viability, proliferation and invasion, enhanced apoptosis, and suppression of specific proinflammatory cytokines are generally similar to the antitumor effects of plant-derived cannabinoids. Moreover, synthetic cannabinoids have the potential to be even more selective and potent than their natural counterparts and, thus, represent a promising therapeutic approach [73,74].

INTERNATIONAL AND NATIONAL LEGAL BASIS FOR THE USE OF CANNABINOIDS

As the number of studies investigating the medical and therapeutic potential of cannabinoids has increased in recent years, it is necessary to change the legislation on the use, cultivation, and marketing of cannabinoids. This should, however, be done with extreme care. In the Republic of Slovenia, the legislator made a significant progress in this area in 2017, which will be elaborated below.

In the EU Member States, the basis for developing and passing the legislation on cannabinoid use is provided by international conventions, including: i) the United Nations Single Convention on Narcotic Drugs, 1961 [83] and the 1972 Protocol amending the Single Convention on Narcotic Drugs, ii) the Convention on Psychotropic Substances 1971 [83], and iii) the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988 [83].

The United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances provides additional legal mechanisms for enforcing the 1961 Single Convention on Narcotic Drugs and the 1971 Convention on Psychotropic Substances. Much of the treaty is devoted to fighting organized crime, but it also prohibits possession of drugs for personal use saying that “Subject to its constitutional principles and the basic concepts of its legal system, each Party shall adopt such measures as may be necessary to establish as a criminal offence under its domestic law, when committed intentionally, the possession, purchase or cultivation of narcotic drugs or psychotropic substances for personal consumption contrary to the provisions of the Conventions”, and this includes the cultivation of opium poppy, coca bush and cannabis plant for the production of narcotic drugs [83].

The United Nations Single Convention on Narcotic Drugs, 1961 sets out four Schedules. Substances controlled by the state are set out in Schedule I and Schedule II, preparations in Schedule III, whereas Schedule IV defines drugs, such as heroin. The Single Convention’s Schedules range from most restrictive to least restrictive, as follows: Schedule IV, Schedule I, Schedule II, Schedule III. Cannabis, cannabis resin, extracts and tinctures are included in the Schedule IV of The Single Convention on Narcotic Drugs. Tetrahydrocannabinol (THC, synonym delta-9-THC) is included in the Schedule I of the Convention on Psychotropic Substances. Delta-9-THC and its stereoisomers, including dronabinol, are listed in the Addendum 2 to the Convention on Psychotropic Substances. Nabilone is not controlled under international law [84].

Under the EU regulatory framework, the subject matter is regulated by Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use [85]. Pursuant to the Article 3 of Directive 2001/83/EC, this Directive shall not apply to medicinal products prepared in a pharmacy in accordance with a medical prescription, medicinal products prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia, and medicinal products intended for research and development trials. This Directive also allowed the use of medicinal products for human use, intended to be placed on the market in the Member States and either prepared industrially or manufactured by a method involving an industrial process. This made cannabinoid-based medicinal products available in all the Member States, provided they are permitted by the national legislation [84].

In the Republic of Slovenia, illicit drugs including cannabis, are governed by the following regulations: i) Production of and Trade in Illicit Drugs Act [86], ii) Act Regulating the Prevention of the Use of Illicit Drugs and the Treatment of Drug Users [87], iii) Criminal Code of the Republic of Slovenia [88], iv) Decree on the classification of illicit drugs [89], v) Rules on method and form of record-keeping and of reports on illicit drugs [90], and vi) the Rules governing the procedures for the issue of licenses for illicit drugs marketing [91].

As previously mentioned, in 2017 the adoption of the Decree amending the Decree on the classification of illicit drugs [92] was made. This Decree removed cannabis from Schedule I and placed it under Schedule II, with the note that the use of cannabis for medicinal purposes is permitted in accordance with the Medicinal Products Act [93] and Pharmacy Services Act [94], and in accordance with the rules and regulations governing the prescribing of cannabinoid-based drugs.

The aforementioned amendment to the Decree on the classification of illicit drugs now allows patients to use medicinal cannabis as a means of treatment, including the cannabis plant and cannabis resin. Medicinal products are thus not limited anymore to products containing nabilone or cannabis extracts, but also extend to tinctures adjusted and harmonized to delta-9-THC, as long as they meet the conditions laid down in the Medicinal Products Act.

Changes in the legislation on the use of cannabinoids for medical purposes and inclusion of these compounds in the list of medicinal products needs to be coordinated with the changes in both labor law and the regulation of workplace drug testing. Naturally, any change should be adopted in strict agreement with work, health, and safety regulations and ensure smooth workflow for the employees.

CONCLUSION

Cannabinoids are a large and important class of complex compounds that have a promising therapeutic potential for the treatment of variety of diseases, including cancer. In this review, we focused on studies that provided evidence for anticancer effects of plant-derived and synthetic cannabinoids and their potential mechanisms of action. Cannabinoids were able to effectively modulate tumor growth in different in vitro and in vivo cancer models, however, these anticancer effects appears to be dependent on cancer type and drug dose. Understanding how cannabinoids are able to modulate essential cellular processes involved in tumorigenesis, such as the progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and immune system are crucial for improving existing medications and developing new therapeutic approaches.

Although still strict, the legislation on the use of cannabis-based medications has been improved, especially following the promising results of related basic research. The Republic of Slovenia established a legal basis for the use of cannabinoids in the years 2016 and 2017. The increasing popularity of cannabis and cannabis-based medication should lead to clear regulatory guidelines on their use, in the near future.

ACKNOWLEDGMENTS

The authors acknowledge Jan Schmidt for his initial help in preparing this manuscript.

Cannabis, cannabinoids and cancer – the evidence so far

Few cancer topics spark as much online debate as cannabis.

The bottom line is that right now there isn’t enough reliable evidence to prove that any form of cannabis can effectively treat cancer in patients. This includes hemp oil, cannabis oil or the active chemicals found within the cannabis plant (cannabinoids) – whether natural or man-made.

Many researchers worldwide are actively investigating cannabinoids, and Cancer Research UK is supporting some of this work. These studies use highly purified chemicals found in the cannabis plant, or lab-made versions of them, and there is genuine interest in these as potential cancer treatments. But this is very different to street-bought cannabis and hemp oil available online or on the high street, for which there is no evidence of any impact on cancer.

Cannabis is still classified as a class B drug in the UK, meaning that it is illegal to possess or supply it. Cancer Research UK can’t comment on the legal status of cannabis, its use as a recreational drug, or its medical use in any other diseases. But we are supportive of properly conducted scientific research into cannabis and its derivatives that could benefit cancer patients.

Unfortunately, there are many unreliable sources of information about cannabis, particularly online. This post contains up-to-date, evidence-based information on cannabis and cancer, so with lots to cover, this is a long article. To help you find what you’re interested in, follow the links below to different sections. Or read on for everything you need to know about cannabis and cancer.

Cannabis and cannabinoids – what are they?

Cannabis is a plant known by many names, including marijuana, pot, grass, weed, hemp, hash or dope.
The plant produces a resin that contains complex chemicals called cannabinoids.

The two main cannabinoids are:

  • Delta-9-tetrahydrocannabinol (THC) – a psychoactive substance that can affect how the brain works, creating a ‘high’ feeling.
  • Cannabidiol (CBD) – may relieve pain, lower inflammation and decrease anxiety without any psychoactive effects.

Cannabinoids lock on to molecules on the surface of cells called cannabinoid receptors. As well as cannaibinoids found in plant resin, our body produces cannabinoid chemicals – called endocannibinoids – which also attached to these receptors. These receptors are involved in many processes throughout the body, from appetite to the sensation of pain.

Through many detailed experiments – summarised in this Nature Reviews Cancer article – scientists have discovered that both natural and synthetic cannabinoids have a wide range of effects on cells, which is why there’s interest in if cannabis can treat diseases like cancer, as well as help relieve side effects.

Can cannabinoids treat cancer?

Many hundreds of scientific papers looking at cannabinoids and cancer have been published so far, but these studies simply haven’t found enough robust scientific evidence to prove that these can safely and effectively treat cancer.

Research is still ongoing though, with hundreds of scientists investigating the potential of cannabinoids in cancer and other diseases as part of The International Cannabinoid Research Society. And in 2015 the scientific journal Nature published a supplement of review articles about various aspects of cannabis. It’s free to access.

Much of the research into cannabinoids and cancer so far has been done in the lab

Claims that there is solid “proof” that cannabis or cannabinoids can cure cancer is highly misleading.

This is because virtually all the scientific research investigating whether cannabinoids can treat cancer has been done using cancer cells grown in the lab or animals. While these studies are a vital part of research, providing early indications of the benefits of particular treatments, they don’t necessarily hold true for people.

So far, the best results from lab studies have come from using a combination of highly purified THC and cannabidiol (CBD), a cannabinoid found in cannabis plants that counteracts the psychoactive effects of THC. But researchers have also found positive results using man-made cannabinoids, such as a molecule called JWH-133.

There have been intriguing results from lab experiments looking at a number of different cancers, including glioblastoma brain tumours, prostate, breast, lung, and pancreatic cancers. But the take-home message is that different cannabinoids seem to have different effects on various cancer types, so they are far from being a ‘universal’ treatment.

There’s also evidence that cannabinoids have unwanted effects. Although high doses of THC can kill cancer cells, they also harm crucial blood vessel cells. And under some circumstances, cannabinoids can encourage cancer cells to grow, or have different effects depending on the dose used and levels of cannabinoid receptors present on the cancer cells.

Cannabis in clinical trials

To robustly test the potential benefits of cannabinoids in cancer, clinical trials in large numbers of people with control groups of patients – who aren’t given the treatment in question – would be needed.

A few small clinical trials have been set up to test the benefits of cannabinoids for people with glioblastoma multiforme. Results published from a pilot clinical trial where 9 people with advanced, incurable glioblastoma multiforme – the most aggressive brain tumour – were given highly purified THC through a tube directly into their brain showed that THC given in this way is safe and doesn’t seem to cause significant side effects. But as this was an early stage trial without a control group, it couldn’t show whether THC helped to extend patients’ lives.

And a second clinical trial, supported through our Experimental Cancer Medicine Centre (ECMC) Network, tested whether Sativex (nabiximols), a highly purified pharmaceutical-grade extract of cannabis containing THC, CBD, and other cannabinoids could treat people with glioblastoma multiforme brain tumours that have come back after treatment.

In 2021, scientists reported the final results of this phase 1 study to treat people with recurrent glioblastoma with Sativex in combination with the chemotherapy drug, temozolomide. Researchers found that adding Sativex (patients were allowed to choose the amount they took) had acceptable levels of side effects, which included vomiting, dizziness, fatigue, nausea and headache. They also observed that more patients were alive after one year using Sativex (83%) compared to those taking the placebo (44%). However, this phase 1 study only involved 27 patients, which was too small to confirm any potential benefits of Sativex, and was intended to find out if it was safe to take by patients.

This trial is being extended into phase 2 (known as ARISTOCRAT) to explore if this treatment is effective and which patients are most likely to respond to this treatment. If the trial is , it is set to launch at 15 NHS hospitals in 2022, with over 230 patients to be recruited. To find out more about this work, you can listen to our podcast – That Cancer Conversation – where we hear from Professor Susan Short, one of the researchers leading this study.

We’ve also supported a trial that’s testing the benefits of a man-made cannabinoid called dexanabinol in patients with different types of advanced cancer. The trial finished recruiting in 2015 and researchers established a safe dose of the drug, but further development of the drug was stopped due to a lack of evidence around the drug’s effectiveness. Full trials results are yet to be published.

Unanswered questions

There are still many unanswered questions around the potential for using cannabinoids to treat cancer. It’s not clear:

  • which type of cannabinoid – either natural or synthetic – might be most effective
  • what kind of doses might be needed
  • which types of cancer might respond best to cannabinoids
  • how to avoid the psychoactive effects of THC
  • how best to get cannabinoids, which don’t dissolve easily in water, into cancer cells
  • whether cannabinoids will help to boost or counteract the effects of chemotherapy

These questions must be answered for cannabinoids to be used as safe and effective treatments for cancer patients. It’s the same situation for the many hundreds of other potential cancer drugs being developed and tested in university, charity and industry labs all over the world.

Without doing rigorous scientific research, we will never sift the ‘hits’ from the ‘misses’. If cannabinoids are to get into the clinic, these hurdles first need to be overcome and their benefits proven over existing cancer treatments.

Can cannabis prevent cancer?

There is no reliable evidence that cannabis can prevent cancer.

There has been some research suggesting that endocannabinoids (mentioned earlier) can suppress tumour growth, and in experiments where mice were given very high doses of purified THC, they seemed to have a lower risk of developing cancer. But this is not enough solid scientific evidence to suggest that cannabinoids or cannabis can cut people’s cancer risk.

Does smoking weed cause cancer?

The evidence is a lot less clear when it comes to whether cannabis can cause cancer.
This is because most people who use cannabis smoke it mixed with tobacco, a substance that we know causes cancer. In the UK, more than three quarters of people who smoke weed reported normally mixing it with tobacco.

This makes it hard to disentangle the potential impact of cannabis on cancer risk from the impact of the tobacco. As of 2021, we can’t be sure whether the increased risk is due to tobacco or whether cannabis also has an independent effect.

We do know from decades of evidence that there is no safe way to use tobacco – it’s addictive and harmful for your health. People who smoke weed mixed with tobacco increase their risk of cancer and other conditions. Tobacco also contains the very addictive substance nicotine. This means people who regularly smoke weed mixed with tobacco may find it harder to stop.

> Read about the free support and quitting tools available to help you to stop smoking for good on our website.

Can cannabis relieve cancer symptoms like pain or sickness?

There’s good evidence that cannabinoids may be beneficial in managing cancer pain and side effects from treatment.

As far back as the 1980s, cannabinoid-based drugs including dronabinol (synthetic THC) and nabilone were used to help reduce nausea and vomiting caused by chemotherapy. But there are now safer and more effective alternatives and cannabinoids tend to only be used where other approaches fail.

In some parts of the world, medical marijuana has been legalised for relieving pain and symptoms (palliative use), including cancer pain. But one of the problems with using herbal cannabis is managing the dose. Smoking cannabis or taking it in the form of tea often provides an inconsistent dose, which may make it difficult for patients to monitor their intake. So, researchers are turning to alternative dosing methods, such as mouth sprays, which deliver a reliable and regulated dose.

Large-scale clinical trials in the UK have been testing whether a mouth spray formulation of Sativex (nabiximols) can help to control severe cancer pain that doesn’t respond to other drugs. Results from these didn’t find any difference in self-reported pain scores between the treatment and the placebo.

Cannabinoids may also have potential in combating the loss of appetite and wasting (cachexia) experienced by some people with cancer, although so far clinical evidence is lacking. One clinical trial comparing appetite in groups of cancer patients given cannabis extract, THC and a placebo didn’t find a difference between the treatments, while another didn’t show any benefit and was closed early.

Is Cancer Research UK investigating cannabinoids?

Cancer Research UK has funded research into cannabinoids, notably the work of Professor Chris Paraskeva in Bristol investigating the properties of cannabinoids as part of his research into the prevention and treatment of bowel cancer. He has published a number of papers detailing lab experiments looking at endocannabinoids as well as THC, and written a review looking at the potential of cannabinoids for treating bowel cancer.

We also support Dr Laureano de la Vega, a Cancer Research UK Fellow at the University of Dundee, who in 2019 started to explore if CBD can limit cancer’s ability to spread, using lung and triple negative breast cancer cells grown in the lab.

We’re also involved in the only 2 UK clinical trials of cannabinoids for treating cancer, mentioned above, through our national network of Experimental Cancer Medicine Centres.

Our funding committees have previously received other applications from researchers who want to investigate cannabinoids but these failed to reach our high standards for funding. If we receive future proposals that meet these stringent requirements, then there is no reason that they wouldn’t be funded, assuming we have the money available.

Unfortunately, some scammers are using the email address [email protected] and claiming to be based at our head office, tricking cancer patients and their families into handing over money for “cannabis oil”, after which they receive nothing in return. This is a scam and has nothing to do with Cancer Research UK or our employees, as we wrote about in 2015. If you believe you have been a victim of this fraud, please contact the police.

“It’s natural so it must be better, right?”

There’s no doubt that the natural world is a treasure trove of biologically useful compounds, and there are countless examples where these have been harnessed as effective treatments.

Numerous potent cancer drugs have also been developed in this way – purifying a natural compound, improving it and testing it to create a beneficial drug – including taxol, vincristine, vinblastine, camptothecin, colchicine, and etoposide. But although these purified drugs in controlled high doses can treat cancer, it doesn’t mean that the original plant (or a simple extract) will have the same effect. So, although cannabis contains certain cannabinoids, it doesn’t automatically follow that cannabis itself can treat cancer.

“But it worked for this patient…”

Doctors sometimes publish case reports about extraordinary or important observations they have seen in their clinic. For example, there is a published case report of a 14-year old girl from Canada who was treated with cannabis extracts (also referred to as “hemp oil”). But very little reliable information can be taken from a single patient treated with what’s an unknown mix of cannabinoids outside of a controlled clinical setting.

There are also many videos and anecdotes online claiming that people have been completely cured of cancer with cannabis, hemp/cannabis oil or other cannabis derivatives.

Despite what these sources may claim, it’s impossible to tell whether these patients have been ‘cured’ by cannabis or not. There is usually no information about their medical diagnosis, stage of disease, what other cancer treatments they had, or the chemical make-up of their treatment. These sources also only publish the “success stories”, and don’t share how many people who used cannabis or its derivatives had no benefit, or worse, were potentially harmed.

Robust scientific studies describe the detail of experiments and share the results – positive or negative. This is vital for working out whether a potential cancer treatment is truly safe and effective, or not. And publishing this data allows doctors around the world to judge the information for themselves and use it for the benefit and safety of their patients.

This is the standard to which all cancer treatments are held, and it’s one that cannabinoids should be held to, too.

Dr Wai Liu at St George’s University is researching cannabis and cannabinoids for treating cancer to build up the evidence. He is happy to collect individual stories from UK patients and can be contacted by email. In the US, the Office of Cancer Complementary and Alternative Medicine gathers similar stories for their Best Case Series.

“What’s the harm? There’s nothing to lose.”

If someone chooses to reject conventional cancer treatment in favour of unproven alternatives, including cannabis, they may miss out on treatment that could save or significantly lengthen their life. They may also miss out on effective symptom relief to control pain or other problems.

Many of these unproven therapies are also expensive, and aren’t covered by the NHS or medical insurance. In the worst cases, an alternative therapy may even hasten death.

Although centuries of human experimentation tell us that naturally-occurring cannabinoids are broadly safe, they are not without risks. They can increase heart rate, which may cause problems for patients with pre-existing or undiagnosed heart conditions. They can also interact with other drugs in the body, including antidepressants and antihistamines. And they may also affect how the body processes certain chemotherapy drugs, which could cause serious side effects.

Cannabis is an illegal (class B) drug in the UK and there are further risks associated with using black market or home-made preparations, particularly cannabis oil, such as toxic chemicals left from the solvents used in the preparation process.

There are also many internet scams by people offering to sell cannabis preparations. As well as the risk of getting something with completely unknown chemical or medicinal properties and unknown effectiveness, scammers are tricking cancer patients and their families into handing over money for “cannabis oil” which they then never receive.

We understand the desire to try every possible avenue when conventional cancer treatment fails. But there is little chance that an unproven alternative treatment bought online will help, and it may well harm. We recommend that cancer patients talk to their doctor about clinical trials that they may be able to join, giving them access to new drugs in a safe and monitored environment.

“Are cancer charities hiding cannabis as a cure?”

We’ve blogged previously about how unjust this is to the thousands of scientists, doctors and nurses working as hard as they can to beat cancer, and to the many thousands of people in the UK and beyond who give up their time and money to fund our work.

History shows that the best way to beat cancer is through rigorous scientific research. This approach has helped to change the face of cancer prevention, diagnosis, treatment, leading to survival doubling over the past 40 years.

As a research-based organisation, we want to see reliable scientific evidence to support claims made about any cancer treatment, be it conventional or alternative. This is vital because lives are at stake. Some people may think that a cancer patient has nothing to lose by trying an alternative treatment, but there are big risks.

“Big Pharma can’t patent it so they’re not interested.”

Some people argue that the potential of cannabinoids is being ignored by pharmaceutical companies, because they can’t patent the chemicals naturally occurring in cannabis plants. But there are many ways that these compounds can be patented – for example, by developing more effective lab-made versions or better ways to deliver them.

Other people argue that patients should be treated with ‘street’ or homegrown cannabis preparations, and that the research being done by companies is solely to make money and prevent patients accessing “the cure”.

But the best chance of ensuring that the potential benefits of cannabinoids – whether natural or man-made – can be brought to patients is through research using quality-controlled, safe, legal, pharmaceutical grade preparations containing known amounts of the drugs.

This requires time, effort and money, which may come from companies or independent organisations such as charities or governments. And, ultimately, this investment needs to be paid back by sales of a safe, effective new drug.

It’s true that there are issues around drug pricing and availability and we’re pushing for companies to make new treatments available at a fair price. We would hope that if cannabinoids were to be shown to be safe and effective enough to make it to the clinic, they would be made available at a fair price for all patients who might benefit from them.

“Why don’t you campaign for cannabis to be legalised?”

Cannabis is classified as a class B drug in the UK, meaning that it is illegal to possess or supply it.

Cancer Research UK does not have an organisational policy on the legal status of cannabis, its use or abuse as a recreational drug, or its medical use in any other diseases. But we are supportive of properly conducted scientific research into cannabis and its derivatives that could benefit cancer patients and we will continue to monitor developments in the fields and evidence as it emerges.

In summary

Right now, there simply isn’t enough evidence to prove that cannabinoids – whether natural or synthetic – can effectively treat cancer in patients, although research is ongoing. And there’s certainly no evidence that ‘street’ cannabis can treat cancer.

We’re supportive of properly conducted scientific research into cannabis and its derivatives that could benefit cancer patients. Many researchers are actively exploring this approach, and Cancer Research UK is supporting, and will continue to support, scientifically robust research into cannabis and cannabinoids that reaches the high-quality standards set by our funding committees.

References and further reading:

  • CancerHelp UK – Does smoking cannabis cause cancer?
  • CancerHelp UK – Is cannabis a treatment for brain tumours?
  • CancerHelp UK – Twotrials of Sativex for cancer-related pain
  • National Cancer Institute (US) – Information about cannabis and cannabinoids for cancer patients
  • National Cancer Institute (US) – Information about cannabis and cannabinoids for health professionals
  • Velasco, G., Sánchez, C. & Guzmán, M. (2012). Towards the use of cannabinoids as antitumour agents, Nature Reviews Cancer, 12 (6) 444. DOI: 10.1038/nrc3247
  • Sarfaraz, S. et al (2008). Cannabinoids for Cancer Treatment: Progress and Promise, Cancer Research, 68 (2) 342. DOI: 10.1158/0008-5472.CAN-07-2785
  • Guindon, J. & Hohmann, A.G. (2011). The endocannabinoid system and cancer: therapeutic implication, British Journal of Pharmacology, 163 (7) 1463. DOI: 10.1111/j.1476-5381.2011.01327.x
  • Engels, F.K. et al (2007). Medicinal cannabis in oncology, European Journal of Cancer, 43 (18) 2644. DOI: 10.1016/j.ejca.2007.09.010
  • Twelves, C., Sabel, M., Checketts, D. et al (2021). A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma. British Journal of Cancer 124, 1379–1387. DOI: 10.1038/s41416-021-01259-3
  • Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting – Todaro (2012) Journal of the National Comprehensive Cancer Network
  • Bowles, D.W. et al (2012). The intersection between cannabis and cancer in the United States, Critical Reviews in Oncology/Hematology, 83 (1) 10. DOI: 10.1016/j.critrevonc.2011.09.008
  • Hall, W., Christie, M. & Currow, D. (2005). Cannabinoids and cancer: causation, remediation, and palliation, The Lancet Oncology, 6 (1) 42. DOI: 10.1016/S1470-2045(04)01711-5 . , Wai Liu, The Conversation

More on this topic

Comments

Until you’re a terminal cancer patient you just wont understand the desperation to live as long as possible, even if it were mere days extra time. I would try anything for extra time with loved ones.
I can’t believe there isn’t more research into cannabis and cancer. And for those that say “well it doesn’t work for everybody” guess what conventional cancer treatment doesn’t either.
Stage 4 cancer = no cure, terminal in most cases.

Why is it that charities raking in millions every year can find the evidence of cannabis for not treating cancer but cant find the overwhelming evidence that it can and does treat cancer ?

Great reading I have lung cancer I’m being treated with chemo now and would be interested in a trail it’s small cell lung cancer

Without full spectrum cannabis oil my life around a year into breast cancer I doubt I would be here now

It has enabled me to come off opioids and live a semi normal life

It sickens me to think drs happily give out meds that are killing people but won’t give out a herb that has O deaths yes Zero

I have even contacted professor Mike barns pleading with him to help me find a trial but guess what not one in the uk

The fact cannabis is illegal in this county is all political and NOTHING to do with our health

It’s about time charity’s like yours start campaigning for us, most of us medical cannabis users are spending far to much on it in order to feel well I echo what another commenter said that all stage 4 should be at least offered cannabis as an alternative

Also why can’t the hospital doctors give medical cannabis too relieve sickness and pain of cancer it’s cruel

I think that medical cannabis should be given too all stage 4 cancer patients that are told it’s aggressive and treatment wont help under medical care it could be done safely then with trial an error they will know if it works legalise cannabis for the sick wake up Boris

Thank you for sharing this amazing blog. It is easy to learn and understand. It’s a truly useful blog.

“Why don’t you campaign for cannabis to be legalised?” Your answer was ridiculous that’s all you said was that it’s illegal to possess or buy or what ever I think the question was why won’t you campaign to have it legal so then it can be tested more . Don’t beat around the bush ( No pun intended) just say it’s not worth the effort for the money you would have to spend .

this blog post is very perfect and has a lot of very vital info, thanks so much for this work

We’ve recently seen stories in the press claiming that the US government has “admitted that cannabis kills cancer” (for example, this one in the Metro), based on the observation that pages on the US National Cancer Institute information website carry details of the current scientific evidence around the effects of cannabis and cannabinoids on cancer cells in the lab and animal models.

The first thing to point out is that the NCI’s cancer information website is an independent resource for doctors and the patients, and is not a statement of NIH, NCI or US government policy.

Furthermore, the information on these pages isn’t new, nor is it an ‘admission’ of any kind: the scientific evidence about cannabis, cannabinoids and cancer, which these media stories are referring to, has been openly published on the NCI’s website for several years – for example, see this page from the same section of the NIH website on cannabis and cannabinoids from 2011, accessed via the internet archive.

We often see websites with long lists of scientific papers claiming that cannabis is a “cure” for various cancers. However, when we look at the detail of the data and the experimental detail of the research, it becomes clear that although they may be interesting and build evidence to show that cannabinoids may one day bring benefits for cancer patients, they are far from being a cure.

The main point to realise is that virtually all these studies have been done in cancer cells grown in the lab or in animals. These are quite artificial systems and are much less complex than a real cancer growing in a patient.

For example, most experiments with cells grown in the lab use cancer cells that were originally taken from a tumour many years ago, but have been grown for a long time in the lab – known as cell lines. One problem with such cells is that they are all very similar on a genetic and molecular level, but we know that in real cancers, the cells can be very different from each other and respond in different ways to treatments. Also the usual way of testing cannabinoids in animals has been done by transplanting cancer cells (either mouse or human) into mice. Usually only a small number (5-20) will be used for each experiment.

There’s growing evidence that these particular kinds of models (known as xenografts) aren’t as good at suggesting a treatment could work, compared to more sophisticated genetically engineered animals, as they don’t accurately represent the situation in real tumours. So although these kinds of experiments can point towards useful approaches, as well as revealing the underlying molecular ‘nuts and bolts’ of what’s going on, they can’t tell us if something will definitely treat cancer effectively and safely in human patients. They do not “prove that cannabis cures cancer”, as the headlines would have us believe.

Put simply, Petri dishes are not people. Most chemicals that show promise in lab or animal experiments turn out not to work as well as hoped when tested in patients. These kinds of human studies, known as clinical trials, are the only way we can really know if a cancer treatment is effective. There’s more about clinical trials on our website: http://www.cancerresearchuk.org/cancer-help/trials/types-of-trials/

It’s also important to think about what’s being claimed when people use the word “cure”. To most people, including us, this means that a cancer is completely treated and does not come back. When we look at the data in the papers listed below, none of them come close to showing these kinds of results. For the experiments involving cells grown in the lab, a proportion of the cells are killed or stop growing, but some of them carry on. Similarly in animal experiments, there is no data that shows a 100 per cent success rate for cannabinoids. For example, most mice treated with cannabinoids will still have tumours, although the cancers may be growing more slowly and spread less in some of them.

This isn’t just true for cannabinoids – it’s true for virtually all cancer drugs used today. Cancer is a very complex biological problem – there are hundreds of different types of cancer, each with important molecular and genetic differences. There’s good evidence to show that every individual’s cancer is as unique as they are, and that tumours can evolve and change within the body to become resistant to treatments.

We know that cancer drugs don’t work for everyone all the time – that’s why there’s so much effort going on to find more effective treatments – but it’s vital that doctors have a solid body of evidence showing how well the treatments they’re using are likely to work. If you or someone you loved were going to take any kind of drug, would you be happy if it had only been tested in very high doses on cancer cell lines grown in the lab, or in mice injected with cancer cells? Or would you want to know that it had been trialled in large numbers of people, and there was good data on how effective it is, whether it’s safe in the dose given, what the side effects are, and the proportion of people that can be expected to get better?

This kind of evidence can only come from a combination of lab studies leading to clinical trials. At the moment, while there are hundreds of interesting lab studies of cannabinoids (just some of which are included in the list below) there is only one clinical trial that has been published. So for now, cannabinoids, whether natural or synthetic, are a very long way from being what we would describe as a “cure” for any type of cancer.

We’ve looked at each of the papers in one of the commonly-seen lists (for example, here), and noted down the kinds of experiments they are. Many of them are available as open access papers, so it’s possible to look at the data for yourself. Hopefully this is a useful explanation of the kind of scientific research that is currently ongoing into cannabinoids and cancer, and the process of gathering evidence to show whether a potential cancer therapy works.

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 (refer to 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]
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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]

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  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]
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  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]
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  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]
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  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]
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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.

(Refer to the Cannabis section in the PDQ summary on Nausea and Vomiting Related to Cancer Treatment for more information.)

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 Refer to text and the NCI Dictionary of Cancer Terms for additional information and definition of 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 an explanation of the level of evidence scores, refer to 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
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 Refer to text and the NCI Dictionary of Cancer Terms for additional information and definition of 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 an explanation of the level of evidence scores, refer to 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.

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  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, refer to the PDQ summary on 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 (03/16/2022)

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:

  • be discussed at a meeting,
  • 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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