Group 5 Dr. Michael’s discovery of cancer stem cells was deemed to be a “high impact discovery” by the National Cancer Institute (NCI), and he is currently focussing on the development of phytochemicals (plant-based drugs) to treat diseases with significant unmet need. As you can imagine, he is a well of information, and as such is a resource we are only all too keen to tap! Get your pen and paper ready to take notes, as class is in session … Dr. Michael Masterman-Smith. Could you tell us your cannabis story and how you came to see cannabis as medicine? Originally, from a medical science perspective, it came from when I was working as a researcher at UCLA [University of California, Los Angeles]. We were working on these things called “cancer stem cells” in brain tumors. We published the discovery in 2003 identifying cancer stem cells in soft tissue tumors. This quickly grew into a vital area of cancer drug development because additional studies found these cancer stem cells to be in many cancers, they are ‘tumor initiating’ cells and are responsible for malignancy and metastasis. After we knew how to grow and expand these cells in the lab, we were able to develop a library of cancer stem cell lines from patients. Then we did classic pharmacological drug screening with these cells to identify inhibitors of these specific cells. We studied more than 30,000 compounds over the course of about 5 years. We reduced those 30,000 compounds to about 11 compounds that could be therapeutically active in cancer stem cells. About half of those compounds were cannabinoid receptor agonists – called CB1 and CB2 receptor agonists – that told us that cannabinoid compounds could be potentially effective in killing these deadly cells. We published that study in 2011. We were using synthetic compounds common in drug screens as well as FDA-approved drugs. The finding was remarkable. We had shown a potentially useful therapeutic drug class for a particularly lethal cancer. The study was discontinued because further analysis identified effects that could make the drugs problematic in humans. So, we put that study down. About a year-and-a-half ago, I really felt we did not follow what that seminal study was telling us. I thought “There’s something here. This is excellent data – we found a drug class to work with.” I wanted to test phytocannabinoids, plant-based cannabinoids. And I knew this would be a leap from what I had known my entire scientific career but when you’re looking for a cure how you get there takes some unusual routes. I ran into my current partner, Patrick Lang, who’d been working in the cannabis industry and working with formulations providing cancer patients with relatively precise dose formulations. This was mostly in palliative care, where options to the patients were limited. So, from my background in cancer and as a pharmaceutical scientist and his background in the cultivation area, we joined forces, and that was my foyer into cannabinoid medicine. THC to CBN. From https://www.marijuana.com/news/2014/07/biosynthesis-and-degradation-of-cannabinoids-part-2-thcv-%CE%B48-thc-and-cbn/ Could you tell us more about how cannabinoids and terpenoids help against cancer? In order to answer this we have to look at some basic tenets of cancer biology and how cancer cells mutate to stay alive and proliferate as cancer cells. If we look at the classic biological definition of cancer, it is “unregulated cellular proliferation”. The mechanisms that allow unregulated proliferation is a realigning of cellular circuitry to for growth cues. The genetic machinery is essentially altered to overproduce cell surface receptors, called growth factor receptors. These are antennas which amplify and activate chemical signals that run along complex molecular pathways in the cancer cell to drive cancer cell growth and proliferation. Many cancer cancer drugs we use today target these signalling pathways. There is some evidence to show that cannabinoid receptors are expressed on cancer cells. This supports the pharmacological basis for why cannabinoid receptor agonists (i.e. cannabinoids) could be effective for cancer. A cancer cell is trying to figure out ways to grow so it puts its receptors on the cell, one of which happens to be cannabinoid receptors. The pharmacological action of a cannabinoid receptor agonist depends on the cell type. In cancer cells it may be like a trojan horse. Current understanding appears that cannabinoids goes through these receptor and activates the production of a compound called ceramide which regulates the differentiation, proliferation and death of cells. In cancer cells, and perhaps cancer stem cells, this effect is widestream system outage, shutting down cancerous signalling pathways, several of which are major targets in cancer drug development and, often difficult to target pathways, I might add. This is the emerging understanding of the relationship between cancer cells, cannabinoids and cannabinoid receptor agonists that can advance new ways to understand and treat cancer. Do particular cannabinoid and terpenoid profiles need to be used for specific cancers? Do we need specific dosages? We don’t know. If you go from where Rick Simpson came at it, which was taking a crude extract and utilizing what people call the “kitchen sink effect”. A sort of “throw everything in the kitchen sink at it”. Given the diversity of therapeutic chemovariants in crude extract he went with what he had available to him. We know that THC can be a very powerful inhibitor of cancer cells. This is through THC exerting effects through CB1 receptors. CBD goes through other secondary mechanisms to exert effect. And while CBD has shown cytotoxic effect on proliferating, highly dividing cells, the concentration of CBD is higher in order for effective cytotoxicity in cancer cells in vitro (petri dish studies). CBD also exerts its effects through the immune system. There are still many things that need to be studied. I think there is something interesting about ratios because the mechanisms of action of THC and CBD are different, affect different receptor systems but occur together in nature. There may be something more there than meets the eye. A lot of folks in the cannabis industry also want to talk about entourage effects, the synergy of terpenese, flavonoids, chemovariants like CBDV, THCV, CBGV and all the other variants that might exert maximum effect. All of this suggest we still have a lot of research to do. There are 131 potential therapeutic chemovariants, dissecting them all and zero-ing in specific properties in the best interests as a medicine will take patience, ratios of highly expressing THC and CBD chemovariants is the start. The big issue I find in the field of cannabinoid medicine is that we have “pop medicine”, where people have read somewhere on the internet that “this does this, that does that”. It’s anecdotal, somebody heard from somebody else and the next thing you know it’s pop medicine, not medicine. GW Pharma is the only company that has actually gone the way a pharmaceutical company would do it with research and clinical workup on ratios and specific chemovariants. We need more of this type of judiciousness. In the U.S., we have a lot of catch-up to do. And I suspect we will quickly. Getting a MMJ card might still make cannabis more accessible. With all that in mind, how does a cancer patient get the most out of medical cannabis? Cancer patients typically have a lot of things going on. The cancer itself produces an inflammatory response and immune response. There’s pain. I’m going to put it in three ways. The first way a cancer patient could use cannabinoids is just to get some relief from side-effects. They have nausea, pain, feeling miserable because they have cancer. Cannabis can alleviate some of those effects. The second thing that happens is when patients or on chemotherapy. Cannabinoids can work complementary to chemotherapy and can enhance it’s effects. The third step is where we’re getting into the GW Pharma brain tumor study reported I believe in February 2017 and what Rick Simpson had been attempting. This is a high-dose or saturation of the body with cannabinoids, although GW Pharma wasn’t necessarily using high doses. The GW Pharma approach is a very defined dose in a spray formulation, and there is some effect there in extending median survival of recurrent malignant brain tumors. So those are the two different ways we’re moving in concerning the treatment of cancer. “What exactly is the right dose? How much? Is it concentrations, variance, is it a particular pattern of THC to CBD?” There’s a lot of theories, but the definitive studies haven’t been done, and they really should be done if we’re going to be moving towards cannabinoids being used as treatment for cancer, as opposed to just palliative functions. Does cannabis have to be decarboxylated in order to have medical benefits? With decarboxylation, once again, it’s a question I cannot answer “Yes” or “No” definitively. A lot of it goes with the “kitchen sink” approach, where some of the cannabinoids are decarboxylated and some aren’t. Changing the chemical structure of a molecule can change its effects. Decarboxylation, to my understanding, increases the availability of cannabinoids and their ability to get through the blood-brain barrier versus the raw. Let me get back to you on the definitive answer for that question, though. I’ve got to check through my notes and do some research on it in order to give you a better answer. I’m reading and hearing a lot of conflicting information around this issue. Some say cannabinoids need to be decarboxylated for medical effect, yet there are studies out there saying otherwise. I’m in two minds, and trying to figure this out … Yes, we’re all trying to figure it out. It’s sort of a third rail issue – a hot button issue. It can be charged and in a charged environment it can be very difficult to be objective and say, “Show me the data.” I’m a pharmaceutical scientist. If somebody said to me, decarboxylated (or non-decarboxyated) is best, I want to ask first, what is the medical indication and then I’d want to see data, which is not easy to collect, understandably but show me the science, and then you can say “It has to be this.” I don’t want to infuriate anybody, but the cannabis industry is not necessarily overflowing with the dedicated interest, the medical or clinical support or the resources to do the necessary studies. The immaturity of the industry is part of causes that problem. People are trying to sell a product, trying to sell their ideas, trying to sell what they believe in. We didn’t get to showing that cannabinoid receptor agonists could kill cancer stem cells until after 5 years of heavily-funded research. Granted, these are projects that take a long time and we’re trying to figure out a way to do better, less time-intensive, costly studies. But I have a problem with those who don’t even know how to read peer-reviewed papers and what information they should take from it. That’s something that, as this industry and cannabinoid medicine starts to grow, we will start to treat cannabinoid medicine with the same rigor that we treat the pharmaceutical industry with, and have been doing so over the past 100 years. How would you like to see the cannabis industry regulated, and what changes would you like to see in the system? I believe the federal government has a responsibility to give guidance to the cannabis industry on what is acceptable and what is not. There is nothing that we have so far, with the exception of the FDA Botanical Drug Program and Development Guidance for Industry, and this program has not been able to move cannabinoid-based medications through clinical pipelines at any rate comparable to other pharmaceuticals at a time where more and more states are setting up their own medical cannabis programs. If you look at the traditional pharmaceutical approach and biotechnology, you’re looking at a very, very well-organized system that, for better or for worse, has been in operation and has created an economy devoted towards healthcare. There’s none of the support, none of that approach in the cannabis industry. That just doesn’t cut it, considering that there’s more-and-more people using cannabis for medical purposes. I don’t like the idea of people self-experimenting with cannabis medicine, especially when you’re dealing with debilitating or hard to treat conditions. Yet that is the system we have. A system where people go to their doctor and likely do not get the best practice or medical advice on cannabis medicine. Then they go to a dispensary, which are typically not staffed with medical personnel. They get something to consume on their own with no medical guidance and we call it medicine. So, as part of my candidacy for the U.S. House of Representatives I am proposing a five-point plan, part of a broader healthcare push called the “Comprehensive Healthcare Improvement and Economic Accountability Act”. It basically goes through the steps of how to integrate cannabinoid-based medicines into the United States health system. I want to see 5 different things happen. A revision to our federal drug policy. For instance, with regards to CBD alone, which is still listed as a schedule I drug, there is nothing to suggest CBD is as dangerous as it is currently classified. I gave testimony to this effect in the fall to the FDA on this subject. The irony of the testimony was that as we are in the middle of the most deadly opioid epidemic in history and here I was providing testimony on potentially a highly versatile medicinal compound that is low toxic with no evidence of its use as as a drug of abuse. It just does not make sense. The FDA can use some direction on how to integrate cannabinoid medicine. The job of the FDA is to test for safety and efficacy. What the FDA is starting to understand is that cannabis is not as toxic a drug as they used to think it was. Americans consume 75% of the world’s drugs and we pay the most yet we have no guidance whatsoever on the integration of cannabinoids that could potentially offer safer, less toxic and cost-effective ways to improve healthcare.We need to provide a route to insure medical cannabis and medical cannabinoids. The federal government has a responsibility that, if cannabis can be effective at reducing healthcare costs and reduce people’s reliance on other, potentially more dangerous drugs, then its should incentive public, private and military to cover the costs for cannabinoid medicines. We need to support research and development of cannabinoid medicine. Researchers from across the healthcare spectrum need to be free to research and have access to the support and investment we provide through our federal healthcare research institutions. There also needs to be support for our training of physicians in order to integrate cannabis medicine into healthcare practice. “Harmonization”, Medical cannabis programs at the state level need harmonization. This will bring organization and standards to a fragmented cannabinoid medicine system.