Kevin Spelman, phd, mcpp, will present the topic of medicinal use of Cannabis at the NorthWest Herb Symposium on Whidbey Island, Washington, August 27 through 30, 2015. Dr Spelman is an internationally recognized expert on the molecular biology and clinical therapeutics of botanical medicines. A past National Institutes of Health postdoctoral fellow and Marie Curie research fellow in the European Union, Dr Spelman has published 27 scientific papers and 6 book chapters. He has practiced phytotherapy, informed by the Ayurvedic system, Western herbalism, and modern physiology, since 1989. Past research has included the molecular biology of cannabinoid receptors, brain and ovarian cancer, as well as clinical investigations, immunological studies, and chemical analysis on various medicinal plants. Dr Spelman was also the first researcher to identify cannabinoid-like molecules in the plant genus Zanthoxylum. International research has included the analysis of nutrient levels in teenage women in West Africa, working with children with neurological disorders in Central America, and researching medicinal plants active against malaria in Paris. He is an adjunct assistant professor at Massachusetts College of Pharmacy and Health Sciences, an adjunct professor of botanical medicine at National College of Natural Medicine, and a distinguished lecturer at Maryland University of Integrative Health. Dr Spelman has advised the White House Commission on Complementary and Alternative Medicine and provided expert testimony to the Maryland House of Delegates and the Maryland Senate, as well as advised McCormick & Company on new product development and the Jamaican government’s Scientific Research Council. Most recently, he has joined the scientific advisory board that advises the Oregon Health Authority on Medical Marijuana. Dr Spelman is currently a consultant specializing in laboratory, regulatory, and current Good Manufacturing Practices issues; new product development; and research initiatives.
Integrative Medicine: A Clinician’s Journal (IMCJ): While cannabinoids are not your only area of interest, you have been involved in research in that area. What drew you into that sphere?
Dr Spelman: Initially, what drew me into that sphere, believe it or not, was Echinacea, a medicinal plant that was not Cannabis. While I was at the National Institutes of Health, or NIH, I had the opportunity to study CB2 receptors, cannabinoid 2 receptors, and from there we found alkylamide binding in our model, which had previously been shown, but now we knew our model worked. That made me aware of lots of other medicinal plants that potentially would bind CB2 receptors because alkylamides are not all that uncommon. We were the first ones to show that extracts from the Zanthoxylum genus, which contain alkylamides, could bind to the cannabinoid receptors.
That was pretty fascinating, and that launched it for me because I started seeing the utility immediately in terms of CB2 because this can have a pretty profound effect on immune function and especially be extraordinarily useful in autoimmune diseases—which, by the way, makes me wonder if the contraindications for use of Echinacea for autoimmune diseases are actually accurate.
IMCJ: In what way? Would you expound on that a little bit?
Dr Spelman: CB2 is actually a known target for autoimmune diseases, and CB1 to a lesser extent. Immune cells have predominantly CB2 receptors on them, but they also have some CB1 receptors. We were one of the first groups to show the presence of CB1 receptors on basophils while I was at NIH. In any event, since that is a target for autoimmune disease, and since Echinacea does, in fact, hit that CB2 target, it makes you really wonder about the contraindications for autoimmune conditions with Echinacea.
Moreover, when I first started clinically practicing, there was little of the contraindication information out there—such as the contraindications for Echinacea for autoimmune conditions—until the late 1990s or the early 2000s. When I was practicing in the 1990s, I gave lots of people with autoimmune diseases Echinacea, and I never saw an exacerbation of their condition. Between those 2 pieces—clinical observation and then the immunomolecular biology of it—I really think that we need to rethink Echinacea.
IMCJ: Where did the origins of the contraindication come from?
Dr Spelman: That is a great question. I know it is printed in the Commission E monographs. To be fair, I have heard a few practitioners say that they see Echinacea exacerbating autoimmune diseases. I have just never seen it myself. Echinacea is complex as well; it is not just about hitting a CB2 receptor. The polysaccharides in Echinacea can be immunostimulating. It certainly is possible that in some cases of autoimmune disease that Echinacea could exacerbate the condition. It is also possible that in some cases of autoimmune disease, Echinacea could actually be a therapeutic tool rather than a contraindicated therapy.
IMCJ: It sounds like this could certainly be a target for more research.
Dr Spelman: Very definitely. But unfortunately, as you probably know, given the fact that you are working for this journal, complementary and alternative medicine, or CAM, tends to be underfunded, generally speaking— especially these days when the NIH has been so gutted in terms of finances/funding. It is really sad to see. We are falling behind in the science world, in my opinion, because of the budget cuts that have hit the NIH.
IMCJ: Aside from the Echinacea research, what other aspects of Cannabis research have you been involved in?
Dr Spelman: One of the projects we have going on right now is a retrospective analysis of cancer patients, many of them in stage IV, that used one particular producer’s Cannabis oil. We are in the process of collecting the medical charts so we can look at the outcomes. In some cases, it does look like the Cannabis oil that was used therapeutically has been particularly useful. In other cases, it does not look that way. We would like to be able to differentiate and see what the commonalities are in the cases where it actually worked and why it possibly did not work in other cases.
IMCJ: Is that Cannabis oil a full-spectrum oil or is it a mono extract?
Dr Spelman: No, not a mono extract at all. What we are looking at usually has a 4-to-1 ratio, delta-9-tetrahydrocannabinol, or THC, to cannabidiol, or CBD, as well as all the other cannabinoids and the terpenes. This is one of the interesting things that nobody is talking about much, yet. Everyone is focused on the cannabinoids and secondarily on the terpenes, but there are also some other compounds in there that are known to be particularly important in other plants in terms of constituent families. For example, the flavonoids in Cannabis: The cannflavin A looks pretty interesting. Also, the stilbenes in Cannabis look interesting as well. There has been a paucity of research thus far because everybody has been enamored with the cannabinoids.
IMCJ: What types of benefits may targeted research reveal to be associated with those other components?
Dr Spelman: The cannflavin A—we actually have seen some anti-inflammatory activity already. We may also see some anticancer activity. This is not unusual for particular flavonoids, depending on their structure. For the stilbenes, there really has been such little research done thus far with the Cannabis stilbenes, that I am cautious to say. Let me just give you example of a stilbene that is very well known and has been well studied; that is resveratrol. We may see some similarities there, and we may not. We just need more research at this point to know.
IMCJ: THC is most often referred to in connection to cancer. Are there other areas emerging that look promising for therapeutic THC?
Dr Spelman: Cancer is the main area that I would say that it might be useful. Certainly, in terms of pain, as well, THC looks like it is quite useful there. There is some research to suggest antiseizure activity. Of course, most of that seizure activity is attributed to CBD, which is one of the things that I am really fascinated by.
IMCJ: You were involved with a paper a few years ago that involved the combination of THC and opiates. Correct?
Dr Spelman: Actually, I was not involved in the primary research, but I did write a review on it. That was really fascinating because the United States is 4.2% of the world’s population, and we use well over 80% of the world’s opioids. We have such an addiction issue in the United States with opioids. Any physician will tell you that using them for pain can be problematic. Basically, with vaporized Cannabis, Abrams was able to show that they needed lower doses of opiates, and there seemed to be a synergic effect with the combination of the opioids and the cannabinoids. We could use less opioids and probably decrease the withdrawal potential.
In fact, that is another area that has been shown with THC. It does look like it could be potentially useful for withdrawals from some of the harder drugs like heroin and cocaine—and, by the way, alcoholism. There has been a bit of work done there as well. I think we could do better treating pain and end up with less sequela from long-term opioid use.
IMCJ: You said that CBD was originally what fascinated you about the cannabinoids.
Dr Spelman: Cannabidiol is darn interesting. You always hear people say it is not psychoactive and I think that is a misinterpretation of the definition of psychoactive. It is noneuphoric, but by definition because it is anxiolytic, it is psychotropic—just as much as Valium or any of those drugs tend to be psychotropic. It does have some pretty significant anxiolytic activity and a fair number of people have used it that way. There have also been good studies done on social behavior with people who have generalized anxiety disorder and have a hard time walking into a social setting. There have been some good outcomes observed.
There is also, really fascinatingly, some interesting antipsychotic activity, which appears to be more than just the anxiolytic activity, in the clinical studies that have been done with humans. That, in itself, offers a new tool in the treatment of schizophrenia because there are just so many heinous side effects from the typical pharmacological choices that we end up using for schizophrenia. Then the NIH, interestingly, has a patent on CBD as a neuroprotective agent. It really does offer some very interesting antioxidant activity as well as other neuroprotective activity that I think we need to be aware of as a culture, especially for aging people. Can you imagine if we could delay the onset of neurodegenerative diseases by even a year by using CBD? It would really be a step forward.
Of course, everybody has heard about the antiseizure activity. You have got medical refugees moving to states like Colorado and Washington because of the availability of Cannabis that has high CBD. I should mention, and I think it is very important, that a lot of Cannabis smokers use CBD as an excuse or rationale, saying, “Oh, yeah. I’m gettin’ my CBD!” when, in fact, if you really look at what has been happening in the market, people are basically breeding for higher and higher levels of THC. There are plants now that have upwards of 30% THC concentration in them. Frequently there is now very little CBD contained in these strains
In fact, if you look at what the University of Mississippi grows—the university grows Cannabis for the National Institute on Drug Abuse, or NIDA—their Cannabis is very well chemically characterized and it has about 0.5% CBD. In essence, you are not really getting a dose of CBD by smoking—at least the University of Mississippi’s— Cannabis or using it however people might use it in a vaporizer or even edible. There is really no CBD in it. The same is being shown for all these really high THC strains that are out there at this point. However, what has happened that is interesting is there are some strains now that do have high CBD.
This Cannabis oil I told you about that has a 4-to-1 ratio is unusual. It has got somewhere around 70% THC and then another approximately 20% CBD. It is an interesting step forward, in terms of a product on the market, that offers something positive in terms of its higher CBD content, but I would like to see something with even lower THC. When using Cannabis for pain, if you have an intellectually demanding job, I cannot imagine going to work on THC and trying to do your job. However, if there was nominal or no THC in your remedy, and it was all CBD, I can imagine that such a product would help with pain. CBD can be effective for pain, although people argue that the THC is more efficacious for pain than the CBD. Nonetheless, high CBD has been reported to help people with lower back pain sleep when they get to that point in the night where they just cannot handle the pain anymore. Overall, I think there are some really interesting things happening.
IMCJ: Has CBD also been characterized as an anti-inflammatory?
Dr Spelman: Thanks for mentioning that. There does appear to be an interesting anti-inflammatory activity. Having said that, you start to look at all the issues of aging: often anxiety, often poor sleep, often inflammation, possibly the need of neuroprotection. CBD actually looks like a pretty interesting potential medicinal tool for aging people. I mentioned earlier, in terms of autoimmune diseases, there are also some really interesting immunomodulatory effects by CBD, as well as THC.
I think that many pharmacologists are somewhat amazed by the range of activity by just these 2 molecules, not to mention the whole plant. Being familiar with medicinal plants in general, I think most of your readers will probably understand that this is not the exception. This is the rule: Many phytochemicals are molecular multitaskers. They are often hitting multiple targets— polyvalent is another term that I would use for that— rather than hitting just interfacing with 1 target. It gets really interesting really fast.
IMCJ: Wouldn’t arthritis be a perfect clinical target for CBD then, as a neuroprotectant and as an anti-inflammatory, especially with the level of toxicity that is associated with arthritis drugs?
Dr Spelman: Agreed. There have been studies that suggest that, for example, arthritis; diabetes, both type 1 and type 2; atherosclerosis; Alzheimer’s disease; hypertension; metabolic syndrome; and depression may all be suited to treatment with CBD.
IMCJ: There has been some talk of a connection for Cannabis to metabolism. I know that this research is still in an early stage, but how is that looking?
Dr Spelman: There has been some interesting work done there. For one of the drugs that got pulled off the market, rimonabant, this is one of the issues. They developed this drug that was an antagonist to CB1 receptors because, in fact, as you point out, modulation of metabolism is a really major effect of cannabinoids. Metabolism, your neurological activity, and your immune activity all tend to be fairly profoundly affected by cannabinoids and the endocannabinoid system itself—which also is a whole other topic.
Rimonabant was developed essentially to deal with obesity. It failed miserably because they thought that is all it was going to do. There are so many activities affected by the endocannabinoid system—in this case the CB1—and they had created this antagonist to CB1. It had psychological effects that were not favorable. In fact, I think there were even some suicides from rimonabant. It was pulled from the market.
Nonetheless, I think anybody that has had a history of using Cannabis will tell you that, certainly, there is the “munchies” syndrome that occurs. There really is a pretty strong metabolic connection, and drug companies are still working on trying to figure out how to block the CB1 receptor and thus potentially decrease appetite and deal with obesity without having the side effects—the adverse events of the mood issues—with it. It is not going to be simple and I would be very surprised if they did end up generating a drug that people ended up actually feeling well while they were on a CB1 antagonist, rather than feeling ill while they were on it.
IMCJ: We have been talking primarily about extracts to this point. Would there be tangible benefits from using the whole herb?
Dr Spelman: Sure. One of the things we are starting to see in these supercritical extracts—in other words, CO2 extracts—depending on how they are done, they may be strictly the cannabinoids and not much else. I think this is potentially troublesome for a couple of reasons. Number 1, cannabinoids tend to be extraordinarily lipophilic, so there will be pharmacokinetic issues. Number 2, by removing the terpenes—the smaller, volatile terpenes are well known to have absorptive effects—this may generate another obstacle to absorption. In fact, Pharma uses a monoterpene by the name of cineole on their patches so that a drug can penetrate the skin. The cineole creates a pathway that allows a larger molecule to pass through. With Cannabis, if you remove the terpenes, you are likely going to have decreased absorption.
Getting into concentrates, you are also dealing with substances that I think could lend themselves to addiction, honestly. We have not talked about the dark side of Cannabis yet, but I really do believe there is potentially a dark side as well. A lot of people in the Cannabis industry are waving the flag, saying, “Look how wonderful this is,” but I think every drug has 2 sides to it.
The terpenes are really important. Moreover, if you take medicinal plants in general—let’s take the example of Artemisia annua, known as “Sweet Annie.” The artemisinin that is in there is also very lipophilic, not unlike the cannabinoids in terms of the lipophilicity. What you will find is that trying to get that lipophile, artemisinin, in solution is really problematic. You cannot get much more than about 11 milligrams into a liter of water. What that means is that people are going to have a really hard time absorbing it. The body is fairly aqueous, and so if you do not have a molecule that can move around in an aqueous environment, you are going to have pharmacokinetic issues. You are going to have absorption and metabolism and distribution issues with it. Basically, we are going down the same path with concentrated Cannabis extracts.
To come back to artemisinin: If you make a tea of Artemisia, the whole plant, it has been shown that you can get about 60 milligrams of artemisinin in that same liter of water. You get about 6 times the concentration of artemisinin when you use a whole-plant extract—in essence, a tea.
I would say the exact same thing is very likely to be going on with Cannabis. If we just took cannabinoids and put them in water, we would get very few milligrams into a liter of water. If we did the whole plant—and the flavonoids were in there and the stilbenes were in there and the terpenes were in there—we could probably achieve several times the concentrations that we could get with just the isolated cannabinoids. That would offset a lot of the pharmacokinetic issues we find with a lipophilic molecule. I think that is important.
When it comes to whole plants, Michael Moore said it really nicely: “The advantage of whole plants is that they are broad spectrum and naturally dilute. The disadvantage of whole plants is that they are broad spectrum and naturally dilute.” In other words, there are many different chemicals in a whole plant making it broad spectrum so many different phytochemicals—that can actually do a number of different things. Many of these phytochemicals, as we know, multitask. They modulate more than biochemical pathway. You are really washing a huge number of active molecules over your genome when taking a whole plant extract.
In terms of “naturally dilute,” because you have so many different molecules, not any one of them can be that concentrated, except in the case of people who hybridize their plants to have very high levels of THC. Now you start seeing adverse events. You start seeing people freak out when they use Cannabis that has 25% or 30% THC in it. Generally speaking, however, if you really look at the history of Cannabis, at some of the data on collections of confiscated Cannabis back in the 1960s and 1970s, it was rare for it to be above 6%.
IMCJ: Doesn’t CBD have an antieuphoric effect that mitigates the effects of THC, to a degree? So then wouldn’t the presence of CBD affect the intensity of the resulting effect as THC increases?
Dr Spelman: That is a really good point. If you look at Marinol, which is available in a 2.5-milligram, a 5-milligram, and a 10-milligram tablet, most people cannot handle the 10-milligram tablet because it brings on a lot of anxiety and it does not feel good to them. However, if you add CBD to that, it attenuates the euphoria—which, by the way, a COX-2 inhibitor will do as well. There is a recent study showing this, and I have actually seen it. People trying to treat cancer with high levels of Cannabis oil can ameloriate the euphoric effects by using a COX-2 drug. Nonetheless, back to the CBD. It does attenuate the euphoric effects. When you get to hybrids of 25% or 30% THC, like I said, there is rarely a meaningful dose of CBD in there, so we are back to a drug-like effect rather than a gentle nudge to the system.
IMCJ: Getting back to that “dark side” and what toxicity and/or dependency issues have been shown, there may be some evidence that cannabinoids in some situations can become mitochondrial toxins.
Dr Spelman: Right. In terms of toxicity at very high levels, you are definitely going to get a toxicity. However, in human studies that I am aware of at this point, no toxicity has actually been shown. That does not mean that there have not been side effects. There definitely have been side effects.
Look, water can drown you. Any drug can potentially have adverse events. I would definitely say that for very concentrated Cannabis products with high THC—this is not going to be popular with the Cannabis flag wavers—I really do not get the sense that we truly know enough at this point to be using high doses of THC for long-term issues—unless you are really dealing with cancer. Dealing with chemotherapy, as nasty as it is—and there are all kinds of toxicities shown for the standard chemo drugs—if Cannabis can offer a superior treatment, and in some cases I have seen that it does, then that might be the exception to the fact that we really do need to study this more. Compassionate use, for a plant that has been used since the beginning of the human race, makes sense.
What I have seen in the literature suggests that there are dependency issues that can develop. I have seen people coming off Cannabis oils that would have night sweats and get very irritable. Certainly, there is a dark side to this, and the higher the concentrations of THC, the more likely that we are going to see more and more addiction. Let’s be real. Coffee can be addictive, and people have a hard time getting off coffee.
IMCJ: I previously had an opportunity to interview Dr Abrams on Cannabis, and that is exactly the analogy he drew for the addictive potential—that of caffeine.
Dr Spelman: Caffeine is actually fairly addictive and not easy to get off of. It can be pretty uncomfortable getting off of it. I would say that is a good analogy.
IMCJ: When you speak at the NorthWest Herb Symposium, at the end of the summer, what specific topic will you be addressing there?
Dr Spelman: We will look at the things I just mentioned, as well as the behavioral effects and mood effects of Cannabis and differentiate between THC and CBD, their safety, metabolic effects, immunological effects, and neurological effects. The pendulum is swinging in favor of Cannabis now, and as all pendulums do, they tend to reverse direction, so it will be interesting to see where this goes in another 5 to 10 years.
For more information about the NorthWest Herb Symposium, visit http://www.nwherbsymposium.com/.
Footnotes
Facilitated by the NorthWest Herb Symposium, held on Whidbey Island, Washington, August 27 through 30, 2015.