Written by: Adam Leitenberger, editorial director
If you decide that you’re interested in trying medical cannabis to treat your breast cancer symptoms or treatment side effects, here are some things to consider before you do:
“It’s important for people to know that anything they ingest that produces a change in their bodies is acting like a drug, and it has the potential for side effects, interactions with other drugs, as well as benefits,” said Virginia F. Borges, M.D., MMSc., professor of medicine and director of the Breast Cancer Research Program at the University of Colorado Cancer Center. “People have to be as diligent about researching medical marijuana as they would be with any other supplement or drug they were taking.”
The effects of cannabinoids also vary depending on how they are consumed. The most common ways to consume medical cannabis are:
Side effects and safety of medical cannabis
It’s not well understood how cannabis products may interact with other medicines, including cancer therapies. That’s why it’s important to talk to your doctor about using medical cannabis both before and during treatment. Working together, you can come up with the best way to relieve your symptoms.
Marijuana (the form of cannabis that contains more than 0.3% THC — enough to cause a high) is illegal nationwide under federal law in the United States. At the same time, most U.S. states have passed their own laws either legalizing the use of marijuana entirely or to treat certain medical conditions. But even in states where marijuana is legal, U.S. federal government employees and people who work for companies that receive federal grant funding cannot legally use marijuana under the Drug-Free Workplace Act.
Inhaling cannabis smoke or vapor takes effect within minutes and fades more rapidly. Inhaling can give you more control over the dose you take, when the effects will start, and how long they will last. But many oncologists prefer that their patients not smoke or vaporize cannabis products, especially during active cancer treatment that can affect the lungs or immune system. That’s one reason why it’s important to talk to your doctor before you start using cannabis.
What to expect when using medical cannabis
Eating edibles or taking oils by mouth can take one to a few hours to take effect and can last up to about 6 hours. It can be difficult to know the dose in some edibles and how long the effects will last. Oils, sprays, and tinctures may give you more control over the dose you take.
Every person’s situation is unique. The best forms and doses of medical cannabis and the reasons for using it will vary from person to person.
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].
Tissue microenvironment often plays an important role in supporting tumor establishment, expansion, and metastasis. The tumor microenvironment is primarily comprised of infiltrated leukocytes, including tumor-associated macrophages (TAMs), dendritic cells, and myeloid-derived suppressor cells (MDSC) . The crosstalk between the infiltrated cells and tumor cells could suppress the immune response and create a pro-survival environment for tumor cells.
The interplays between tumor cells and inflammatory cells during tumorigenesis. (A) The effect of tumor cells on inflammatory cells. Tumor cells secrete many cytokines to alter the microenvironment to promote tumor growth and invasion and to blunt the anti-tumorigenic immune response. (B) Inflammatory cells affect the genomic stability of tumor cells. AID: activation-induced cytidine deaminase; DNMT1: DNA methyltransferase 1. (C) Inflammatory cells enhance tumor cell proliferation and survival through autocrine and paracrine signaling. (D) Inflammatory cells promote tumor cell migration, invasion, and metastasis through cytokine and chemokine production. COX-2: cyclooxygenase 2; MMP: matrix metalloproteinase; E-cad: E-cadherin; EMT: epithelial-mesenchymal transition; sLex: sialyl Lewis X; CXCR: CXC chemokine receptor; BV: blood vessel.
While Ramer et al. discussed plasminogen activator inhibitor-1’s (PAI-1) pro- vs. anti-tumorigenic actions, they provided evidence supporting the former . At 1 µM CBD, there was a decrease in PAI-1 mRNA and protein in A549, H358, and H460. This was confirmed in vivo using the A549 mouse model with 5 mg/kg CBD three times a week. In vitro, CBD’s anti-invasive property was reduced by siRNA knockdown of PAI-1 and was increased with the treatment of a recombinant PAI-1. The CBD-mediated decrease in PAI-1 is due, in part, to the activation of CB1, CB2, and TRPV1, as their antagonists reversed the effect. Therefore, CBD works as an agonist of CB1, CB2, and TRPV1 in lung cancers.
3.4. Colorectal Cancer
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.
Many downstream effects of CBD have been investigated. Multiple papers reported an increased level of oxidative stress in CBD, but not Δ 9 -THC, treated GBM cell lines [58,65,73,76]. Massi et al. found that the level of ROS increases in a time-dependent manner, with significance after only five hours, when U87MG cells were treated with 25 µM CBD . At the same time, glutathione, an antioxidant, was significantly decreased after six hours of CBD treatment. In contrast, there is no pronounced ROS increase in CBD treated normal glial cells. Co-treatment of CBD and antioxidants, including N-acetyl cysteine (NAC) and α-tocopherol (i.e., vitamin E), attenuated CBD’s killing effects . Taken together, studies in GBM cell lines suggest that CBD induces cell death most likely by upregulating ROS. Scott et al. found that CBD also increased the expression of heat shock proteins (HSPs), which was found to be associated with the increased production of ROS because NAC hindered the role of HSPs . Interestingly, the use of HSP inhibitors together with CBD were shown to increase the cytotoxic effect and reduce CBD’s IC50 value significantly, from 11 ± 2.7 µM to 4.8 ± 1.9 µM in T98G cells. This suggests that HSP inhibitors may be used as an adjunctive treatment with CBD. Recently, Aparicio-Blanco et al. administered CBD in lipid nanocapsules (LNCs) to GBM in vitro in an attempt to provide a prolonged-release formula of CBD . LNCs loaded with CBD were more effective at decreasing the IC50 values when they were smaller in size and exposed for longer periods.
Taha et al. studied patients with stage IV non-small cell lung cancer, clear cell renal cell carcinoma, and advanced melanoma treated with nivolumab immunotherapy (anti-PD-1 agents) and patients who had additionally used cannabis, including CBD and Δ 9 -THC . They showed a decreased response rate to treatment in groups using cannabis with nivolumab, whereas patients not using cannabis were 3.17 times more likely to respond to treatment with nivolumab. However, cannabis use resulted in no significant difference in overall survival and progression-free survival. This group suggested that there may be a possible negative interaction between cannabis and immunotherapy.
CHOP induces apoptosis via multiple pathways ( Figure 3 B): (i) It increases the transcription of GADD34 ; (ii) It increases the transcription of ER oxidoreductase 1 alpha (ERO1α), which then re-oxidizes PDI and generates ROS; (iii) It increases the transcription of the inositol 1,4,5-triphosphate receptor (IP3R), which then increases the calcium level in the cytoplasm; (iv) It activates the extrinsic cell death pathway via death receptor 5 (DR5) and caspase-8 mediated activation of truncated Bid (tBid), which then translocates to the mitochondria and promotes the release of cytochrome c; (v) It activates the intrinsic cell death pathway by directly decreasing the expression of pro-survival factors, Bcl-2 and Bcl-xL, and increasing the expression of pro-apoptotic factors, such as Bax, Bak, Bim, Puma, and Noxa; (vi) It activates caspase-8 via TRAIL-DR5 on the cytoplasmic membrane, which cleaves B cell receptor-associated protein 31 (BAP31) and forms p20. p20 then releases calcium from the ER into the cytoplasm, which is taken up by mitochondria and results in the further release of cytochrome c.
CBD exerts its anti-proliferative effects on breast cancer cells through a variety of mechanisms, including apoptosis, autophagy, and cell cycle arrest [67,83,87]. Ligresti et al. reported that CBD-treated MDA-MB-231 cells induced an apoptotic effect involving caspase-3, whereas CBD exerted its effects on MCF-7 through cell cycle arrest at the G1/S checkpoint . That being said, cell cycle arrest at the G1/S checkpoint has been more recently demonstrated in MDA-MB-231 and 4T1 cells after CBD treatment . While the activation of CB2 and TRPV1 receptors were seen in MDA-MB-231 cells, the effect was partial. More recent studies have found the anti-proliferative effects of CBD on breast cancer cells to be independent of the endocannabinoid receptors . CBD has been consistently shown to generate ROS, which in turn inhibit proliferation and induce cell death [63,67,87,88,89]. CBD exerts its pro-apoptotic effects by downregulating mTOR, AKT, 4EBP1, and cyclin D while upregulating the expression of PPARγ and its nuclear localization [83,87]. Shrivastava et al. showed that inhibition of the AKT/mTOR signaling pathway and induction of ER stress also induced autophagy alongside apoptosis . At increased CBD concentrations, or when autophagy was inhibited, the levels of apoptosis increased. They further showed that CBD may coordinate apoptosis and autophagy through the translocation and cleavage of Beclin-1.