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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.[Level of evidence: 1iC]
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. A growing number of pediatric patients are seeking symptom relief with Cannabis or cannabinoid treatment, although studies are limited. The American Academy of Pediatrics has not endorsed Cannabis and cannabinoid use because of concerns about brain development.
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.
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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. 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.
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.
Revised Table 2 to include the Schloss et al. study in the summary of clinical studies of Cannabis.
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.[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.
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. Other studies have also shown the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer.[19,20]
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 . 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 .
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.
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 . 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 . 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.  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 . 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 .
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 . 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].
INTERNATIONAL AND NATIONAL LEGAL BASIS FOR THE USE OF CANNABINOIDS
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.
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 . 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 . 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 . 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 .
Most synthetic cannabinoids, including dronabinol, nabilone, and synthetic CBD are CB1 and CB2 receptor ligands . 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 .
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.
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 . The plant was also cultivated in other countries in Asia as well as in Europe, especially for making ropes, clothes/fibres, food and paper . 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 . 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 . 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].