Cannabis, also known as marijuana, is a flowering plant recognized for its medicinal and recreational uses. The earliest evidence of the medicinal use of cannabis dates to back 2,700 BC, where the Chinese Emperor Shen Nung described it as a remedy for gout, malaria, rheumatism, and constipation. In the centuries that followed, many more medicinal benefits of marijuana were postulated, but objective scientific research in the field has been limited and restricted due to the illicit nature of the drug (Liu, Lett Drug Disc Des, 2006). However, recent legislative changes in the European Union, United States, and Canada allowing for medicinal and/or recreational use of cannabis have helped to spur new scientific research and raise public awareness on the benefits of medical cannabis.
Accumulating evidence now supports the therapeutic benefits of cannabis for a wide range of conditions, including neurologic and psychiatric diseases, autoimmune conditions, and even cancer (Mechoulam, Chem Biodivers, 2007).
Cannabis exerts is effects through the endocannabinoid system, which influences a broad range of endogenous functions, including nerve cell health, inflammation, nausea, pain, appetite and sleep (Zanettini, Front Behav Neurosci, 2011; Liu, Curr Clin Pharm, 2010; Liu, Lett Drug Disc Des, 2006). Of the many receptors in the endocannabinoid system, two have been identified, namely the CB1 and CB2 receptors, which are primarily expressed in the central nervous system and the immune system (Liu, Lett Drug Disc Des, 2006). The actions of cannabis are mediated through the binding of its individual chemical constituents, known as cannabinoids, to these receptors.
The two most common cannabinoids present in cannabis are Δ9‐tetrahydrocannabinol (THC) and cannabidiol (CBD), which have different chemical properties and effects throughout the body (Marzo, Neurotherapeutics, 2015). THC has high affinity for both cannabinoid receptors and is known for its potent psychoactive properties. This undesirable side effect has largely limited its use in the clinical setting. Meanwhile, CBD has low affinity for these receptors and has limited psychoactive effects. As a result, CBD is a more attractive option for therapeutic applications (Sledzinski, Cancer Med, 2018).
The use of cannabis in cancer management has traditionally been relegated to symptomatic management, including as an analgesic, anti-emetic, and appetite stimulant. However, more recently, mounting evidence has suggested a therapeutic, anti-tumor effect of certain naturally occurring cannabinoids. Specifically, CBD has been shown to reduce tumor size, potential for invasion and metastasis, and development of new tumor-associated blood vessels in multiple in vitro and in vivo models of solid tumors and blood cancers (Ladin, Front Pharmacol, 2016; Massi, Br J Pharmacol, 2013).
There is also evidence to suggest that CBD used in combination with traditional chemotherapies and a certain class of compounds, the cholesterol epoxide hydrolase (ChEH) / antiestrogen binding site (AEBS) inhibitors, may be even more efficacious than CBD alone (Scott, Int J Oncol, 2017). AEBS regulates cholesterol metabolism and, consequently, cell growth (Payre, Mol Cancer Ther, 2008). Two AEBS inhibitors that have proven especially promising are clomiphene citrate and DPPE. Clomiphene is an estrogen modulator typically used to treat infertility. However, in combination with CBD, clomiphene was recently shown to synergistically reduce cell viability and increase rates of programmed cell death in certain cancer cell lines, while also inhibiting tumor growth in vivo (WO2017072773A1). DPPE, on the other hand, is a tamoxifen derivative that is thought to sensitize cancer cells to the activities of chemotherapies. As a tumor grows and mutates, cancer cells can become resistant to therapies in several ways – tumors can overexpress efflux pumps that remove certain agents from the cell or can upregulate enzymes that metabolize and inactivate chemotherapies. DPPE was shown to potentiate the toxicity of multiple chemotherapeutic drugs by both mechanisms (Georges, Biochemical Pharm, 2014; Brandes, Cancer Chemother Pharmacol, 2000).
Taken together, these findings have significant and exciting implications for the future of cancer management.