With a lot left to learn, there’s no easy answer.Three physicians talk about the history and current state of research and treatment, from auspicious anecdotes to federal roadblocks, covering everything from modern experimentation in Colorado to the history of heroin in the United States and World War II. But as states continue the push for legalization, the outlook for medical marijuana appears more optimistic than ever. 

Eugene G. Pereira, M.D., Sarasota Memorial Pain Center: There’s been a lot of effort to bring marijuana into the medical realm and part of it’s successful but most of it not. Piggybacking on it to some extent is an effort to legalize marijuana in the state; 23 or more states in the union and Washington, D.C. territory have legalized marijuana to a certain degree. And right now there are two clinically available marijuana compounds, such as Marinol, that are used for nausea primarily. They are trying to pass certain strains of specially grown marijuana products for children with uncontrolled seizures, but the push is getting a lot of pushback and there’s a lot of legislation involved.


SRQ: What do you see as the benefits of using medical marijuana? Valerie Riddle, M.D., AltMed: There are a number of areas where we have at least anecdotal evidence that people derive benefit and there have been studies that seem to lend some credence to the benefit. I think all of us are familiar with Charlotte’s Web and the potential for use in intractable epilepsy. 


Charlotte’s Web?  Riddle: Sanjay Gupta did a couple of series on CNN and in the first one he looked at a girl out in Colorado. Her name was Charlotte and she had seizures that were unbelievably frequent. It’s hard to imagine, but she was having tens and even hundreds of seizures a day, had tried all the different available anti-epileptic medications and really wasn’t getting any benefit from them. But she had access to a type of cannabis called Charlotte’s Web that has a very high concentration of cannabidiol (CBD) and a very low concentration of THC - THC being the psychoactive component. And she had a remarkable response to that, reducing her seizures dramatically. It was almost unbelievable if you hadn’t seen it. That generated a great deal of interest in the use of CBD or high-CBD cannabis for seizures.


How would this work? Riddle: It’s hypothesized we have what’s called an endocannabinoid system in our bodies, which is the receptor system that binds cannabidiol and THC. Some of those receptors are highly concentrated in the brain and so there’s at least a hypothesis, maybe some actual evidence, that the effect of CBD happens through those receptors, whether it’s direct or indirect binding to the receptors, and that’s how that works for epilepsy. Using cannabis that has a higher concentration of THC in children in particular comes with some controversy and some caution because there have also been reports that use of marijuana that contains THC in children and adolescents can lead to some delayed brain development and other things like that. But cannabis has pros and cons just like anything we choose to use in a therapeutic manner. I’m not aware of any drug on the market that’s devoid of potential downside or side effect, so I see it as another option that we should be paying attention to and should be exploring. I would love to see research opened up. It is extremely difficult to do research in the United States because [marijuana] is federally illegal. 


Especially regarding the epilepsy, has this been able to progress and be studied beyond the anecdotal? Is research happening or is it being held back? Riddle: It is not being held back because there’s a company based in the U.K. called GW Pharmaceuticals that actually does have an open investigational new drug application in the United States for a botanically derived cannabis extract called Epidiolex and they are doing clinical trials in patients with seizures. So it has gone beyond the anecdotal. And there are a number of other reports of people who have had remarkable responses in terms of reducing their epileptic seizures. You like to see it in a controlled manner before you believe all the anecdotes, but often those anecdotes will bear themselves out if you do the research properly.


What are the possible negatives that make this a controversial issue? Beau R. Braden, D.O., Sarasota Memorial Hospital: The first step is to keep in mind that there’s a difference between marijuana, which is a plant, and the chemicals that are derived from it, like delta-9 tetrahydrocannabinol (THC), which is a compound that comes from it and can be synthetically produced as well. Lipitor, for example, came from red rice yeast in China and Aspirin comes from the bark of the willow tree, but we’re not smoking willow trees. It’s important when we talk about pharmaceuticals to first say that we’re getting our stuff from nature. It’s not like we’re inventing weird chemicals that aren’t derived from nature. When we find these molecules it’s important to be able to study them. And because of the mentioned prohibition, it has been very difficult. This new surge in states to push medical marijuana is always very tricky from the regulatory side because we’re used to dealing with molecules that are patented and studied, and to have a whole plant or part of a plant genetically modified and studied is a little bit unscientific in a way. This is not to say that it doesn’t have clear and obvious effects. Before World War I, the most popular drug in the world was heroin, and during the Treaty of Versailles, Germany had to surrender its patent for the Bayer Company for heroin, and that was part of the negotiations. Aspirin was the other patented medication they had. So throughout history there have been cases where people have discovered things, they’ve turned them into drugs, they’ve been refined and have been worked through. But it’s important to keep in mind that when you’re in Colorado or Washington and dealing with marijuana products, these are already genetically modified plants. There are a lot of people who have MBAs from Yale and Harvard coming into those states, setting up a business and using modern science to increase the activity of the plant. The old 1950s-60s marijuana that people were smoking while listening to The Grateful Dead was not genetically modified, so it was around 2-3 percent bioactive. Now you can get concentrations that are 30-40 percent bioactive. These are high-concentration products and we haven’t really studied what is a clinical range or appropriate range, if there is one. Marinol, which is approved and has been found to be helpful and studied and appropriate, obviously has a clinical range that we use. We need to do the science, we need to make sure there’s an indication that it’s safe, what the clinical range is and what the toxic range is and what it could be useful for and what it can’t be used for. It’s surprising though, there was actually an antagonist that was developed for marijuana a long time ago.


An antagonist? Pereira: An opposing chemical. Braden: Right. But what they found is that it made people commit suicide. So it was discontinued in Stage III trials. You have to be very careful when you make presumptions for Stage I or Stage II trials - we need to have the data and the details and know what we’re giving to people. I’m a big fan of clinical research and if you took a hundred college students and asked them if they wanted to participate in a clinical trial with marijuana, you’d probably get a lot of people to sign up, which is nice, as opposed to saying you’re doing a clinical trial for Chemical 648293. It’s usually a hard thing. Pereira: College students are, in the research world, slightly above the level of rats and mice. I say that tongue-in-cheek because they are living hand-to-mouth and part of the way they get through college sometimes is enrolling in trials. Now, the lack of scientific evidence to a degree of certainty in today’s world of evidence-based medicine is appalling here because we don’t have anything to talk about. Literally. Besides anecdotal evidence and just stepping into the water with pushback over trying to detoxify the illicitness of marijuana, which was imposed on the country in the ‘70s by President Nixon and the outcry has been going on since then as to why marijuana is on the same shelf as heroin. Everyone is supposedly doing it or around it. The things we can talk about are observations and models and use similar experiences with other major cultural changes that have happened.


What about the studies that have been done?

Pereira: Going back to the basics – there is the external plant that Dr. Braden so rightly pointed out has been modified to become much more potent and more psychoactive. All the studies that have been done and that have actually been published and peer-reviewed and all the prospective studies which are going on have used very small amounts of the drug molecule to see what effect it has on various parts of the body. As a pain physician, there is no clear-cut evidence for marijuana working in many of the pain conditions that we treat today. There is a glimmer of hope in neuropathic pain where people have had nerve damage. As a way of almost throwing the kitchen sink at it, people have tried marijuana and some have felt it gave them some relief. Again, it’s not quantified, the studies are small and we don’t know how effective it is compared to other products. Now that is clouded by the fact that mainstream pharmaceutical companies that have possession of molecules that have shown some promise in a scientifically-derived manner have not wanted their lion’s share of the market to be disrupted for obvious financial reasons. So getting through that murky environment of trying to bring a new product into the market which does not bear much financial gain for people who have already established a business model is difficult, to say the least.


Some compounds, such as Marinol, are already in use, right? How much is left understood? Pereira: There are 80 active psychoactive compounds in the marijuana plant and only two have been highlighted – the THC and the cannabidiol. Anecdotally, everyone knows about someone who had a bad trip. A bad trip comes from understanding that the THC molecule can unearth or unmask an underlying psychosis. Cannabidiol is supposed to have some mellowing properties and that’s why people have been tinkering with it now in a very scientific and sophisticated manner. Those are the two compounds that the light has been shone on but there’s even less research on even identifying the other psychoactive compounds in the marijuana plant. Internally they have found two main groups of receptors called CBD1 and CBD2 – there are unknown receptors that exist, I’m sure. There are some in the brain, some on the cell wall, some on the spinal cord, and all of these exert certain effects. One of the main receptors is known as anandamide, which is called the bliss molecule, and apparently when that molecule is attached to a receptor the person feels joy or bliss. There are three or four of those type of cannabinoid molecules created in the body. As recently as two months ago, a French company was in the headlines because they took six healthy people and gave them an enzyme that blocks the breakdown of the joy molecule. They wanted to make people who were potentially depressed have more of that euphoria by preventing the breakdown of that short-lived molecule. The shocking part was that six of less than a hundred people enrolled in the study went bonkers. One of them died and some are still in a vegetative state. They still don’t know exactly what happened yet. Riddle: But that was a synthetic molecule and an enzyme and not marijuana and not cannabis. Pereira: Absolutely. I’m just trying to allude to the fact that we are still very ignorant about the final effects. Riddle: There’s still a lot to be learned, I agree. Braden: Just speaking practically, if we’re studying neurotransmitters, you’re talking about the compartment that’s surrounded by cerebral spinal fluid in the brain. I want to highlight the complexity and difficulty. One of the things that you’ve seen a lot of as well is hyperemesis syndrome – repetitive nausea and vomiting that people will develop, which some think is akin to an allergic reaction or a sensitization of serotonin receptors. It’s hard to say because it’s really difficult to biopsy brain cells or intestine or to get a lot of the data. Riddle: It’s very difficult, but I think that’s true of any drug development research, and there are certainly compounds approved for which we don’t understand all of the information we might like to know in terms of its methods of action or concentration in the brain or all of those. Some of those complexities and challenges are not necessarily unique to cannabis. Braden: I would even say most drugs we don’t know the mechanism to. Riddle: That’s true. We struggle, I think, to overcome some of the stigma attached to cannabis. It’s unfortunate that it has a bad rap in many circles, but there is an opportunity to demonstrate medicinal benefit.


To be clear, no doctor is recommending people smoke anything, right? We’re talking pills and sprays and other such methods. Pereira: The studies have used all three modalities – the oils, the vaping and the fumes. Obviously, the smoking route is the one most currently used by the population, and that has all the baggage of smoke attached to it. But the fact is that you’re now taking something that has been shunned by society and saying this is something worth looking into.


In the face of this uncertainty and social stigma, what are those things that keep you optimistic for this line of research? Riddle: It’s related to the fact that there are so many people who seem to derive benefit. I think back to the early days of HIV. There’s a disease that was attached to a stigma, but there were people that really felt strongly that there ought to be some attention paid to figuring out what the infection was about and how to treat it. You got a groundswell of activism and that drove some very important research. We learned more about viruses in that time than we had ever learned before. I see some similarities here, where we have a compound associated with quite a bit of stigma, it has pros and cons associated with it – everything in life does – and you have a groundswell of folks saying there’s something here. We don’t understand it yet, but there’s something here and we need to learn more about it and we need to see if the benefits people think they’re deriving from it are true. That’s why I have optimism. If you can get enough people believing something may work, you actually may get some good research out of it. I’m not aware of any deaths ever reported as being due to an overdose of marijuana. We have a heroin epidemic in this country and people are dying all over the place, and I don’t see those two drugs being the same, even if they’re both Schedule 1. It takes people who are willing to step out of the box and get out of “this is the way we’ve always done it so this is the way we should do it” or “we shouldn’t go down that path because there could be negative effects.” We only relatively recently understood that we had a receptor system for cannabinoids, so to me we’re in a very early stage of research. Braden: My thought is that in a way the cart is before the horse. In Colorado there’s been at least one case that I know of where somebody did in fact die because of an action that he took because of a psychosis that was marijuana-induced. Pereira: That was a case where it was proven beyond a doubt that it was that active compound he ingested that resulted in that psychosis being activated. He was not on any other medication that could be potentially held liable for that action or worked in conjunction with the product. Braden: Right. So if you were to say, “Is it safer for people to be in very carefully controlled clinical trials when trying these molecules or allowed to buy products mixed with peanut butter cups and cookies with high doses?” I would say the trial is a lot safer. Are there going to be side effects? Most everything we use has some sort of side effects, and sometimes the side effect is also beneficial. A great example is Viagra. You don’t want to presume your findings before you do the study. But we don’t really have the study. So I say do the study, get some clear answers and then we can debate. Pereira: Society is rushing to bring forth the marijuana products, either chemically or the whole plant itself, to the mainstream, touting its medicinal value without the evidence. I’m not biased against it — I have no skin in the game and I look forward to having more products to help my patients — but that to me is like the construction worker who in the evening drinks a fifth of Jack Daniels and that’s his pain medicine. As cruel as that sounds, that’s the reality of what we’re dealing with. We know the dark side of alcohol, and there have been clear-cut associations with the dark side of using marijuana as it is being used now in society. So with all the signs on the door saying ‘Do Not Enter,’ we are taking a giant step, which I will laud if we can find something good coming out of it. Everything has been created for good, some people say, but the other line is, “Everything is a poison; it just depends on the dose.” Riddle: There’s a lot we don’t understand, but we won’t get those answers if we don’t make the effort to get those answers.


Final Thoughts? Braden: We have to make sure that the studies conducted are clinically useful. You can select out a certain population and write study criteria to get a drug approved that might not be clinically useful, and it would be nice to have the studies answer specific questions. Pereira: We are all three unanimously bemoaning the fact that there is not enough clinical data to make a positive judgment on the Marinol compound or the drug itself. I, for one, urge caution on rushing to legalize the compound or the plant in the guise of a medicinal virtue we haven’t seen in well-controlled studies. We still have a long way to go before we decide one way or another. I just hope that the research is designed to show realities and not clouded judgments based on the financial benefit to people involved. Riddle: The paradigm for how we conduct clinical research with something like cannabis needs to change. As we select our populations for clinical trials, we often aren’t necessarily capturing the real world and I would love to see some thought to how we harness what’s already happening and derive some data from that, rather than trying to design perfectly controlled clinical trials. SRQ