Cannabis sativa or hemp has been widely used by generations of people throughout the world for recreational and psychoactive intentions. It is a bushy annual plant with palmate leaves and tiny green flowers. Three types of biomolecules are present in cannabis: flavonoids, terpenoids and 60+ types of cannabinoids. Due to drug abuse and adverse health effects caused by excessive use of cannabis, the pharmacological properties of this plant have taken a long time to be recognized and exploited. Scientists have now been able to identify that cannabis, when taken in the right amount, can act as a revolutionary medicine and cure several lethal diseases.
Phyto-cannabinoid is a family of natural complex chemicals found in cannabis and their main physiological activity relates to binding and activating several nervous receptors in the body. The most abundantly extracted phyto-cannabinoids from cannabis are tetrahydrocannabinol (THC) and cannabidiol (CBD). (Pertwee, 1999) While THC has a narrow therapeutic window, CBD has been identified for its analgesics, anti-inflammatory, and palliative properties. (Turner, Williams, Iversen, & Whalley, 2017) It is also inferred that the psychoactivity induced by THC is more adverse than its therapeutic effect so unless a correct dosage is identified, THC may become intolerable and ineffective. On the other hand, CBD works as an allosteric modulator that reduces psychoactivity due to THC and follows an alternate pharmacological profile to inhibit cannabinoid receptors.(Manzanares, Julian, & Carrascosa, 2006) It may also be argued that when THC and CBD are inhaled, their bioavailability is higher than when ingested orally – they undergo extensive first-pass metabolism whereby lower doses of CBD are more therapeutic than THC.
To understand the mechanism of action pursued by cannabinoids, it is imperative to explore the Endogeneous cannabinoid system (ECS) in the body that is responsible for neuromodulation, synaptic plasticity and the development of the central nervous system and peripheral system. It consists of enzymes, cannabinoid receptors such as CB1R (CNS-cannabinoid receptor), CB2R (peripheral cannabinoid receptor), TRP (Transient receptor potential), PPAR (peroxisome proliferator-activated receptor) and their ligands known as endogenous cannabinoids such as 2-AG ( 2-arachidonoyl glycerol), anandamide, THC, CBN(Cannabinol), CBD etc. CB1R are mostly found in the cortex, basal ganglia, hippocampus and cerebellum and they have critical roles in inducing muscle spasm, insomnia, chronic pain, and appetite stimulation. Alternatively, CB2R are mostly found in immune system tissues, microglia, and vascular elements and they are responsible for inflammation. These receptors are not only located on the cell membrane but also expressed on intracellular organelles such as mitochondria, Golgi apparatus, and nuclei.(Chakravarti, Ravi, & Ganju, 2014a) Figure 1 illustrates how cannabinoid receptors interact with endocannabinoids to transmit retrograde synaptic messages.
Figure 1: The interaction of endocannabinoids on natural ECS. Adapted from (VICE, 2016)
Cannabidiol is a non-psychotropic plant constituent, it does not interact directly with ECS and has a minimal binding affinity to CB1R or CB2R but influences several endocannabinoid molecular signaling systems, their receptors, and ion channels.(Devinsky et al., 2014) These ECS pathways include 5-hydroxytryptamine (5-HT1a) – a serotonin receptor, transient receptor potential vanilloid receptor 1 (TRPV1), fatty-acid binding protein (FABP), peroxisome proliferator-activated receptors (PPARs) and G protein-coupled receptor 55 (GPR55). (Sultan, Millar, England, & O’Sullivan, 2017) Figure 2 summarizes the functional properties exhibited by CBD at a cellular and molecular level that produce a wide range of physiological effects.
CBD is metabolized in the human body by hydroxylation to form its acidic metabolites. This process is carried out with the help of hepatic P450 enzymes that form covalent bonds with CBD. This interaction between P450 enzymes and CBD conflicts the formation of P450-anandamide complex and may induce pharmacokinetic blockade of psychotropic drugs. (Harvey & Mechoulam, 1990; Machado Bergamaschi, Helena Costa Queiroz, Waldo Zuardi, & Crippa, 2011) It can be administered in high doses, unlike THC that has adverse psychological and euphoric effects. It is also a resorcinol (Mechoulam, Peters, Murillo‐Rodriguez, & Hanuš, 2007) which means that it has anti-oxidative properties and it can be used for oxidative neurological disorders such as cerebral ischemia.
Figure 2: Therapeutic properties of Cannabidiol. Information collected from the following souces. (Bisogno et al., 2001; de Mello Schier et al., 2014; Devinsky et al., 2014; Hernán Pérez de la Ossa et al., 2013; Massi, Solinas, Cinquina, & Parolaro, 2013; Mechoulam, Parker, & Gallily, 2002; Savonenko et al., 2015; Shrivastava, Kuzontkoski, Groopman, & Prasad, 2011; M Solinas et al., 2012; Turner et al., 2017; Zuardi, Crippa, Hallak, Moreira, & Guimaraes, 2006)
The sophisticated and natural neuroprotective effects of CBD have been widely exploited by doctors all over the world to provide palliative care against HIV, chemotherapy, epilepsy etc. Oncologists prescribe CBD to patients for reducing post-chemotherapy side effects such as insomnia, emesis, reduction in appetite, nausea, vomiting, depression and neuropathic pain(McCarberg, 2007). But in the recent years, anticancer properties of CBD have been discovered where researchers have proved anti-proliferative, anti-angiogenic and anti-neoplastic properties against several carcinogenic tumors. (Sarfaraz, Adhami, Syed, Afaq, & Mukhtar, 2008) These oncologic properties are expressed so strongly by CBD due to the direct biological connection between endocannabinoid system and cancer physio-pathology. The expression level of cannabinoid receptors, endocannabinoid, and their enzymes is up-regulated in aggressive tumor cells. Hence CBD is more specific to cancer cells than normal cells. (Velasco, Sánchez, & Guzmán, 2015)
CBD modulates multiple intracellular, molecular and endoplasmic reticulum-mediated signaling pathways in the human cells. (Massi et al., 2013) Therefore, its therapeutic action against malignant tumor cells ranges several actions such as apoptosis, autophagy, cell death, ROS production, metastasis reduction, decreased tumor migration and regression, ECS receptor inhibition(Chakravarti, Ravi, & Ganju, 2014b) These effects are discovered as consistent with lung carcinoma, gliomas, thyroid epithelioma, lymphoma, uterine carcinoma, prostate cancer, skin carcinoma, prostate cancer, pancreatic cancer, and neuroblastoma. (Marta Solinas, Cinquina, & Parolaro, 2015)
Exciting preclinical evidence suggests that CBD shows an acceptable safety profile and it can be used as non-toxic, non-habit forming and novel therapeutic and antitumorigenic agent for the treatment of various cancer types in the future. (Zogopoulos, 2015) As clinical trials progress, CBD anticancer activity is emerging as the most anticipated study with positive preliminary results against advanced stage cancer.
Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., … Di Marzo, V. (2001). Molecular targets for cannabidiol and its synthetic analogs: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British Journal of Pharmacology, 134(4), 845–852. https://doi.org/10.1038/sj.bjp.0704327
Chakravarti, B., Ravi, J., & Ganju, R. K. (2014b). Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget, 5(15), 5852–5872.
de Mello Schier, A. R., de Oliveira Ribeiro, N. P., Coutinho, D. S., Machado, S., Arias-Carrion, O., Crippa, J. A., … Silva, A. C. (2014). Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa. CNS & Neurological Disorders Drug Targets, 13(6), 953–960.
Devinsky, O., Cilio, M. R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., … Friedman, D. (2014). Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6), 791–802. https://doi.org/10.1111/epi.12631
Harvey, D., & Mechoulam, R. (1990). Metabolites of cannabidiol identified in human urine. Xenobiotica, 20(3), 303–320.
Hernán Pérez de la Ossa, D., Lorente, M., Gil-Alegre, M. E., Torres, S., García-Taboada, E., Aberturas, M. del R., … Torres-Suárez, A. I. (2013). Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme. PLoS ONE, 8(1). https://doi.org/10.1371/journal.pone.0054795
Machado Bergamaschi, M., Helena Costa Queiroz, R., Waldo Zuardi, A., & Crippa, A. S. (2011). Safety and side effects of cannabidiol, a Cannabis sativa constituent. Current Drug Safety, 6(4), 237–249.
Manzanares, J., Julian, M. D., & Carrascosa, A. (2006). Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes. Current Neuropharmacology, 4(3), 239–257.
Massi, P., Solinas, M., Cinquina, V., & Parolaro, D. (2013). Cannabidiol as a potential anticancer drug. British Journal of Clinical Pharmacology, 75(2), 303–312. https://doi.org/10.1111/j.1365-2125.2012.04298.x
McCarberg, B. H. (2007). Cannabinoids: their role in pain and palliation. Journal of Pain & Palliative Care Pharmacotherapy, 21(3), 19–28.
Mechoulam, R., Parker, L. A., & Gallily, R. (2002). Cannabidiol: an overview of some pharmacological aspects. The Journal of Clinical Pharmacology, 42(S1), 11S–19S.
Mechoulam, R., Peters, M., Murillo‐Rodriguez, E., & Hanuš, L. O. (2007). Cannabidiol–recent advances. Chemistry & Biodiversity, 4(8), 1678–1692.
Pertwee, R. G. (1999). Cannabis and cannabinoids: pharmacology and rationale for clinical use. Forschende Komplementarmedizin, 6 Suppl 3, 12–15. https://doi.org/57150
Sarfaraz, S., Adhami, V. M., Syed, D. N., Afaq, F., & Mukhtar, H. (2008). Cannabinoids for cancer treatment: progress and promise. Cancer Research, 68(2), 339–342. https://doi.org/10.1158/0008-5472.CAN-07-2785
Savonenko, A. V., Melnikova, T., Wang, Y., Ravert, H., Gao, Y., Koppel, J., … Horti, A. G. (2015). Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation. PLOS ONE, 10(6), e0129618. https://doi.org/10.1371/journal.pone.0129618
Shrivastava, A., Kuzontkoski, P. M., Groopman, J. E., & Prasad, A. (2011). Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Molecular Cancer Therapeutics, 10(7), 1161–1172. https://doi.org/10.1158/1535-7163.MCT-10-1100
Solinas, M, Massi, P., Cantelmo, A., Cattaneo, M., Cammarota, R., Bartolini, D., … Parolaro, D. (2012). Cannabidiol inhibits angiogenesis by multiple mechanisms. British Journal of Pharmacology, 167(6), 1218–1231. https://doi.org/10.1111/j.1476-5381.2012.02050.x
Solinas, Marta, Cinquina, V., & Parolaro, D. (2015). Cannabidiol and Cancer—An Overview of the Preclinical Data. In Molecular Considerations and Evolving Surgical Management Issues in the Treatment of Patients with a Brain Tumor. InTech.
Sultan, S. R., Millar, S. A., England, T. J., & O’Sullivan, S. E. (2017). A systematic review and meta-analysis of the hemodynamic effects of Cannabidiol. Frontiers in Pharmacology, 8.
Turner, S. E., Williams, C. M., Iversen, L., & Whalley, B. J. (2017). Molecular Pharmacology of Phytocannabinoids. Progress in the Chemistry of Organic Natural Products, 103, 61–101. https://doi.org/10.1007/978-3-319-45541-9_3
Velasco, G., Sánchez, C., & Guzmán, M. (2015). Endocannabinoids and cancer. In Endocannabinoids (pp. 449–472). Springer.
VICE, media. (2016). English: The interaction of THC on the natural endocannabinoid system. Retrieved from https://commons.wikimedia.org/wiki/File:Endocannabinoid_system.jpg
Zogopoulos, P. (2015). Cancer therapy-The role of cannabinoids and endocannabinoids. Cancer Cell & Microenvironment, 2(1).
Zuardi, A. W., Crippa, J. A. S., Hallak, J. E. C., Moreira, F. A., & Guimaraes, F. S. (2006). Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas E Biologicas, 39(4), 421–429. https://doi.org//S0100-879X2006000400001