It seems nearly everywhere you look these days someone is selling, pitching or endorsing CBD, the acronym for cannabidiol, one of the key ingredients in cannabis. Whoopi Goldberg, Tom Hanks and Olivia Wilde are just a few celebrities to tout CBD as an elixir for conditions such as endometriosis, fibromyalgia, PTSD, anxiety, muscle tension and insomnia.
Cancer and CBD
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).
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.
It’s extremely important to know that cannabis is not a cure or treatment for breast cancer, despite many claims. It’s dangerous to use cannabis instead of proven cancer therapies. It’s also important to talk to your doctor before using cannabis products to make sure it won’t interact or interfere with any of your medicines or treatments.
What conditions is medical cannabis used for?
Many other countries also allow the use of medical marijuana, including Australia, Canada, the United Kingdom, and many others in Europe and South America.
Is medical cannabis legal?
Medical cannabis is not approved by the FDA for use in people with cancer. But three synthetic THC medicines have been approved to treat nausea and vomiting caused by chemotherapy:
CBD has been shown to induce Noxa-mediated apoptosis through the generation of ROS and excessive ER stress . In HCT116 and DLD-1 cells, CBD treatment induced ROS overproduction, especially mitochondrial superoxide anion, and this was linked to Noxa activation. Jeong et al. also found that Noxa-activated apoptosis was dependent on excessive ER stress from ATF3 and ATF4 . These proteins bind the Noxa promoter and stimulate its expression. Similarly, in vivo, CBD-treated CRC tumors also resulted in a significant decrease in tumor size and induction of apoptosis by Noxa.
In contrast to the Δ 9 -THC-related cannabinoids, CBD has no known psychoactive effects, and therefore, has recently been the focus of intense research in many therapeutic areas, including cancer. At present, the Food and Drug Administration (FDA) has only approved Epidiolex, purified CBD, for use in patients with seizures associated with the Lennox-Gastaut syndrome or Dravet syndrome . Globally, more than 40 countries have approved medical marijuana/cannabis programs, whereas this is true of 34 states in the USA, plus the District of Columbia, Guam, Puerto Rico, and US Virgin Islands. While marijuana is considered a Schedule I controlled substance in the US, the Drug Enforcement Administration ruled that CBD is a Schedule V controlled substance . When approved by the FDA, CBD must contain less than 0.1% of Δ 9 -THC.
Endoplasmic reticulum (ER) homeostasis, stress, and the unfolded protein response (UPR). (A) ER homeostasis is mediated by 78-kDa glucose-regulated protein (GRP78). Under stress conditions, GRP78 dissociates from pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzymes 1α (IRE1α), as well as the activating transcription factor 6 (ATF6), leading to activation of their downstream signaling cascades in order to restore ER homeostasis. (B) When ER homeostasis fails to be restored, excessive UPR could lead to apoptosis, primarily via upregulation of C/EBP homologous protein (CHOP). PM: cytoplasmic membrane; eIF2α: eukaryotic initiation factor 2α; ATF4: activating transcription factor 4; GADD34: DNA damage inducible protein 34; XPB1: X-box-binding protein (XBP1s: spliced form); ERO1α: endoplasmic reticulum oxidoreductase 1α; PDI: protein disulfide isomerase; DR5: death receptor 5; TRAIL: TNF related apoptosis-inducing ligand; IP3R: inositol 1,4,5-triphosphate receptor; BAP31: B cell receptor-associated protein 31; Bid: BH3 Interacting Domain Death Agonist; TRAF2: tumor necrosis factor receptor-associated factor 2; RIDD: regulated IRE1-dependent decay; ASK1: apoptosis signal-regulating kinase 1; JNK: JUN N-terminal kinase; E2F7: E2F transcription factor 7; E2F1: E2F transcription factor 1.
Glioma is the most common primary brain malignancy. The grade IV glioma, also called glioblastoma multiforme (GBM) or glioblastoma, is one of the most aggressive types of cancer. The prognosis of GBM is very poor with only 4–5% survival within five years. Current treatment modalities include surgery, followed by radiotherapy and chemotherapy with Temozolomide (TMZ) or Carmustine (BCNU). Unfortunately, most GBM tumors are resistant to these treatments.
3.2. Breast Cancer
In GBMs, CBD inhibits the PI3K/AKT survival pathway by downregulating the phosphorylation of AKT1/2 (pAKT) and p42/44 MAPKs without effecting the total AKT and p42/44 MAPK protein levels [57,59,61,70,72,73]. This pathway may also be responsible for CBD-mediated autophagy in glioma stem-like cells, since in those cells, PTEN is upregulated while AKT is downregulated . PI3K pathway plays an important role in the expression of TRPV2, which is a potential target of CBD. In U251, Δ 9 -THC and CBD together, but not separately, downregulated p42/44 MAPKs . Whereas Scott et al. revealed that alone, CBD treated T98G and U87MG cells, albeit at a higher concentration (20 µM), decreased pAKT and p42/44 MAPKs levels, and more so when combined with γ-irradiation . CBD can also activate the pro-apoptotic MAP kinase pathway. Ivanov et al. found that CBD treatment together with γ-irradiation led to the upregulation of active JNK1/2 and p38 MAPK, especially in U87MG cells . However, using U251 cells, Marcu et al. showed that Δ 9 -THC and CBD did not increase the activity of JNK1/2 or p38 MAPK . The discrepancy could be due to the genetic difference among different GBM cell lines.
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.
Using HCT115 and Caco-2 cells, Aviello et al. found that 10 µM of CBD exerts anti-proliferative effects through multiple mechanisms . CBD may act through indirect activation of the receptors by increasing endocannabinoids, specifically 2-AG, in CRC cell lines. In vivo, CBD at 1 mg/kg significantly reduced azoxymethane-induced aberrant crypt foci, polyps, tumors, and the percentage of mice bearing polyps. CBD’s antitumor mechanism was determined to be through the downregulation of the PI3K/AKT pathway and the upregulation of Caspase-3.
Massi et al. explored how CBD modulates 5-lipoxygenase (5-LOX), COX-2, and the endocannabinoid system in GBMs [68,73,76]. They found that 5-LOX, but not COX-2, was decreased by CBD in vivo. CBD treatment also resulted in increased expression of fatty acid amide hydrolase (FAAH), which reduces the level of AEA, suggesting that CBD may inhibit the production of inflammatory mediators by indirectly attenuating the endocannabinoid system in GBMs.
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.