CBD, alone or with other agents, has been shown to successfully induce cell death, inhibit cell migration and invasion in vitro, decrease tumor size, vascularization, growth, and weight, and increase survival and induce tumor regression in vivo [58,59,62,65,68,70,71,74]. Regarding CBD’s anti-proliferative action on GBM, data show that apoptosis occurs independent of CB1, CB2, and TRPV1, but is dependent on TRPV2 [58,65,66,67,69,72]. Specifically, Ivanov et al. found that CBD, γ-irradiation, and ATM inhibitor KU60019 upregulate TNF/ TNFR1 and TRAIL/ TRAIL-R2 signaling along with DR5 within the extrinsic apoptotic pathway [61,64]. CBD also activates the JNK-AP1 and NF-κB pathways to induce cell death. Less emphasis has been placed on the role of autophagy or cell cycle arrest in CBD-mediated effects on glial cells [57,58,64,72,74].
McKallip et al.  found that in both EL-4 and Jurkat cells, CBD’s anti-proliferative effects were mediated through CB2, but independent of CB1 and TRPV1 . However in a separate study Olivas-Aguirre et al. showed CBD’s effects to be independent of the endocannabinoid receptors and plasma membrane Ca 2+ channels in Jurkat cells . These conflicting results need to be resolved by future studies. Despite this, the majority of research on leukemia/lymphomas confirmed apoptosis as the mechanism by which CBD-mediated cell death occurs, either alone or in combination with other treatment modalities, including γ-irradiation, Δ 9 -THC, vincristine, and cytarbine [105,106,107,110]. One study also demonstrated that CBD decreased tumor burden and induced apoptosis in vivo . Kalenderoglou et al. found that CBD can induce cell cycle arrest in Jurkat cells, with increased cells in G1 phase . CBD treatment also resulted in changes to cell morphology, including decreased size of cells, extensive vacuolation, swollen mitochondria, disassembled ER and Golgi, and plasma membrane blebbing [108,110].
ER is an important organelle that plays a critical role in post-translational modification and folding of proteins, calcium homeostasis, and other biological processes [48,49]. Accumulation of unfolded and/or misfolded proteins triggers the unfolded protein response (UPR), which helps to re-balance the ER homeostasis. UPR temporarily halts protein synthesis and attempts to correct and re-fold proteins. In the case that the unfolded and/or misfolded proteins cannot be corrected in time, they will then be targeted for protein degradation.
At this point, only one study testing CBD’s effectiveness on prostate cancer has been conducted in vivo. More quality studies using mouse models are required before moving to the clinical trial phase.
3.4. Colorectal Cancer
Collectively, the activation of NF-κB and STAT3 signaling transduction pathways in cancer cells, as well as in the inflammatory cells in the tumor microenvironment, provide a great advantage for tumor cell proliferation, survival, migration, and immune evasion ( Figure 4 C,D).
CBD, as well as medical marijuana, must be studied in the same way all other FDA-approved drugs are, by conducting randomized trials, its effects on various age groups and populations, and comparisons to already approved drugs, Dr. Markman says. To date, he says, no studies have met the agency’s criteria or standards to win FDA approval, which Dr. Markman calls “the gold standard.” In order to do so, experts must determine that a drug’s benefits “outweigh the known risks for the intended use,” he says.
CBD is thought to work by targeting cannabinoid receptors (CB1 and CB2) found mainly in the brain and other areas of the body. These receptors are part of the endocannabinoid signaling system, which—while its role is not completely understood— is believed to help regulate various mental functions, including cognition, sleep, pain and mood. CBD may also help regulate the production of cortisol, a hormone that helps the body deal with stress.
While some anecdotal evidence has been publicly shared about CBD’s benefits for cancer patients, the scientific research is lacking. The situation causes a conundrum for doctors who treat cancer patients, says Maurie Markman, MD, President of Medicine & Science at Cancer Treatment Centers of America ® (CTCA).
Available only by prescription, Epidiolex contains a highly purified form of CBD, the FDA says. Safety risks include possible liver damage and the potential for adverse reactions when the drug is taken with other medications—potential hazards that the FDA requires be disclosed on its label.
Cancer and CBD
The FDA acknowledges the “significant public interest in cannabis and cannabis-derived compounds,” but maintains there are “many unanswered questions about the science, safety, and quality” of CBD products. The agency is engaged in “ongoing efforts” to answer these questions, according to its website.
Danish researchers conducted a review of 22 clinical trials conducted over a 19-year span on the use of cannabis and CBD in adults. They concluded that, while CBD may have “therapeutic effects” on some social and psychiatric disorders, the studies showed “substantial risks of bias” and had varying “methodological weaknesses.”
Dr. Markman says he doesn’t discount the many doctors and patients who swear by the plant’s medicinal benefits, but he strongly recommends that any cancer patient contemplating using a CBD product, or medical marijuana, have a conversation with his or her oncologist before doing so.
Grammy Award-winning singer Melissa Etheridge says CBD helped her combat the “collateral damage” of chemotherapy during her treatment for breast cancer. Other segments of the cancer community maintain that CBD is an antidote to chronic pain, chemotherapy-induced nausea, vomiting, neuropathy and appetite loss.
Forbes reported in 2019 that CBD sales in the United States will top more than $20 billion by 2024. Still, many consumers may not be aware that the U.S. Food and Drug Administration (FDA) has not approved the use of CBD in any over-the-counter products. And, with one exception, the FDA has not approved CBD to treat any condition or disease, including cancer. The FDA, so far, has approved just one cannabidiol drug—Epidiolex ® —for the treatment of seizures associated with two forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, and for tuberous sclerosis complex, a condition that causes benign tumors to grow throughout the body.