Given the many restrictions and conditions, it can be difficult to set up a fully legal and functional pipeline for the production and sale of CBD oil. Because different countries allow different activities with regards to cultivation, processing, extracting, etc., of hemp, entrepreneurs have often set up production pipelines that span multiple countries, where hemp is cultivated in one country, while extraction takes place in another, lab testing in a third, and sales take place in yet another country. This obviously makes it harder to determine exactly where a CBD product comes from, who is responsible for its final quality, and what standards were followed. For that reason, thorough analytical testing of final products by certified third-party labs is an essential tool to guarantee the safety and composition of CBD oils.
Almost overnight, CBD oils have become an interesting combination of popular holistic medicine, miracle cure, and a natural answer to the synthetic drugs dominating modern medicine. With CBD, patients receive the promise of being in control of their own ailments, and no longer feeling at the mercy of their treating physicians. This has turned out to be a particularly powerful message. Many patients use CBD oils freely for ailments both confirmed and self-diagnosed, and the rapid innovations with CBD products have actually been quite impressive. But while new CBD products keep entering the market virtually unchecked, effective regulatory control of these products has stayed far behind. As a result, unknown risks about long-term effects remain unaddressed, especially in vulnerable groups such as children, the elderly, and the chronically or terminally ill. It should be noted that this discussion goes well beyond CBD only, as new products containing additional cannabinoids like CBG, THCV, and acidic cannabinoids are following closely behind. We know even less about these compounds than about CBD, and very limited human safety data are available.
Oil has become a favorite mode of administration for many medical users of cannabis and cannabinoids for multiple reasons. First of all, concentrated extracts allow the consumption of a large dose of cannabinoids in an easily ingestible form. With CBD oil, there is no risk of intoxication (getting high) , so much larger doses can be consumed than would be possible for THC-rich products. Many users who prefer the holistic approach of using herbal cannabis worry about the stigma associated with the typical smell caused by smoking or vaporizing it. Cannabis oil has no smell that may identify a consumer as a cannabis user, and it can be used discretely even in a social setting, e.g., at work or around family. Moreover, it can be efficiently dosed simply by counting the number of drops consumed. These same benefits of using a concentrated extract were identified in a large survey among medicinal cannabis users published in 2013 , perhaps as an early indicator of the emergence of cannabis oils as a preferred method of ingestion. Currently, the market is developing further towards more sophisticated and patentable products, including oral capsules, liposomal products, skin creams, and chewing gums containing CBD.
Identifying the Real Risks
© 2018 The Author(s) Published by S. Karger AG, Basel
Today, CBD is used for the treatment of a wide range of medical conditions. This started with the somewhat serendipitous discovery (by parents experimenting with self-medication for their children) that CBD had a therapeutic effect on a serious form of epilepsy in children, called Dravet syndrome . This effect is now under clinical investigation with the pharmaceutical CBD product Epidiolex®, which is currently in phase 3 trials with encouraging results [9, 10]. The media attention generated by its effect on severely ill children gave CBD the push needed to become a much desired medicine almost overnight . Other medical indications that may be treated with CBD, and are supported to some extent by clinical proof, include Parkinson’s disease , schizophrenia , and anxiety disorder . However, although research into the therapeutic effects of CBD is rapidly increasing, most current uses of CBD are not (yet) supported by clinical data. The popular use of these products means that physicians may be confronted with the effects of CBD oil even when they do not prescribe it themselves.
The CBD present in oils and other products is usually derived from fiber-type varieties of cannabis (hemp), because these are naturally higher in CBD content than drug-type varieties (marijuana). Although cultivation of hemp is allowed in many countries around the world, this is usually governed by strict regulations. After being banned for decades, hemp cultivation in the USA has only recently been reintroduced, and is still gearing up for full industrial production .
Although CBD seems destined to play an important role as a therapeutic agent for a growing number of medical indications, we should seriously ask ourselves if the current unregulated production and sale of CBD oils is done responsibly. Despite the fact that CBD is mainly sold as “just” a food supplement, it is often used by severely ill people with the intention of improving their body functions in a way that their standard medication could not. This obviously puts CBD uncomfortably close to the realm of medicines. Interestingly, the WHO, based on a review of available scientific data and input from international experts, recently concluded that CBD does not immediately require rescheduling as a drug , although a fuller review on the risks and benefits of CBD is still being planned. Nevertheless, perhaps the use of CBD products should be assessed in a broader perspective, to cover all ingredients used in the preparation, as well as any contaminants that are already known to be common in recreational cannabis.
Evasion of the attack by the immune system is essential during the development of cancers. This is accomplished through dynamic interactions between different cytokines and their receptors in the tumor microenvironment. Tumors actively secrete different cytokines that attract a variety of infiltrating cells, such as TAMs, dendritic cells, MSDCs, and immunosuppressive regulatory T cells, which in turn help tumors to evade the attack by the immune system ( Figure 4 A). Cytokines released from myeloid cells can also induce genomic instability in tumor cells by directly damaging DNA or epigenetically altering the expression of genes ( Figure 4 B).
A few studies also investigated CBD as an adjunctive to chemotherapy for CRC [101,103]. CRC is often treated surgically in conjunction with the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). Seeking to overcome the potential resistance to FOLFOX, Jeong et al. treated oxaliplatin resistant DLD-1 and colo205 cells with oxaliplatin and CBD (4 µM) and found that CBD was able to enhance oxaliplatin-mediated autophagy through decreased phosphorylation of NOS3, which is involved in the production of nitric oxide (NO) and plays a role in oxaliplatin resistance . The combination of oxaliplatin and CBD caused mitochondrial dysfunction (decreased oxygen consumption rate, mitochondrial membrane potential, mitochondrial complex I activity, and the number of mitochondria) through reduced SOD2 expression. These results were confirmed in vivo as well.
There are also a few case studies that described the use of CBD in patients with high-grade gliomas [80,81]. Two patients were treated with procarbazine, lomustine, and vincristine along with CBD (one patient at 100–200 mg/day orally and the other at 300–450 mg/day orally) for about two years . Both patients did not have any disease progression for two years after treatment. Adverse effects of the treatment included rash, moderate nausea, vomiting, and fatigue, without any lymphopenia, thrombocytopenia, hepatic toxicity, or neurotoxicity. In a case series describing nine patients with grade IV GBM, mean survival with the combination of surgery, radio- and chemo-therapy, and CBD (200–400 mg/day) was prolonged to 22.3 months, and two patients had no signs of disease progression for three or more years .
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.
The TRPV channels are of particular interest concerning the anti-tumor functions of cannabidiol (CBD) ( Figure 1 A, iii), which will be discussed in more detail later. Six different TRPV channels have been identified in humans and can be subdivided into two groups: TRPV1, TRPV2, TRPV3, and TRPV4 belong to group I, while TRPV5 and TRPV6 fall into group II . Though the exact functions of the TRPV channels are still under intense investigation, they are likely involved in regulating cellular calcium homeostasis. For example, TRPV1 and TRPV2 can be found in the cytoplasmic membrane as well as the endoplasmic reticulum (ER) membrane. They both play an important role in regulating the cytoplasmic calcium concentration from the extracellular sources as well as the calcium stored within the ER. Disruption of cellular calcium homeostasis can lead to increased production of reactive oxygen species (ROS), ER stress, and cell death.