Behind the Science: Terpenes and Terpenoids

Video Description

When it comes to cannabis and hemp, you may have heard of 'terpenes' before...but what are they? CV Sciences Medical Advisor and founder of the Center for Medical Cannabis Education Dr. Jamie Corroon, ND, MPH explains what terpenes and terpenoids are, what the entourage effect is, and what role terpenes play in hemp-derived CBD products. [FOR EDUCATIONAL PURPOSES ONLY] Connect with us! https://facebook.com/pluscbdoil/​ https://twitter.com/youpluscbd?lang=en​ https://instagram.com/youpluscbd/​ CV Sciences™ fuses nature with science to create practical solutions for boosting health and improving quality of life. We take bold steps every day to provide products you can trust. Formulated using botanical ingredients proven effective when taken together, CV Sciences™ products are designed to keep your life on course. Learn more about CV Sciences: https://cvsciences.com/

 

Video Transcription

Stuart Tomc:
hello and welcome to Terpenes and terpenoids in cannabis. This is Stewart Tomc with the science, regulatory, and education department here at CV Sciences, and many of you have requested a deep dive into terpenes and terpenoids. And today our presenter is Dr. Jamie Corroon, he's an MD and an MPH, and Dr. Jamie Corroon is a consultant and a medical adviser for CV Sciences. However, he is a clinician and a cannabis specialist, and somebody who is not on our sales or marketing team at all. We have hired Dr. Jamie to be a key opinion leader, to punch holes through any of the marketing arguments in the marketplace as they pertain to cannabis and CBD. So today, we're sort of bringing in a paid referee, I'm just saying that for transparency, a paid referee to bring some logic to the terpenoid terpene conversation. He will be joined by our very own Miles Sarill, national educator. We all know that he works for our company, however Miles always shares exciting new scientific evidence to help make our case. So I will turn it over to dr. Carroon to get us started.

Dr. Jamie Carroon
Thank You Stuart thanks for the introduction, and I guess I don't need to really go through my conflicts of interest because you just provided that information to the audience. This is me, I live in San Diego California, I have a medical cannabis specific clinical practice, I also do some clinical research there. I'm the founder and medical director of the Center for Medical Cannabis Education, so with that I'll get into it. 
So most conversations about cannabis, you often hear the term terpenes or terpenoids, quickly followed by the term synergy, which is then quickly followed by the phrase the entourage effect. But what is the entourage effect, and what does it have to do with terpenes and terpenoids, and how important are these compounds in products derived from cannabis, for particularly hemp derived or CBD products. So I'll do my best to answer these questions. 
So, the entourage effect has become the preferred term for describing the physiological synergies that occur when constituents in a cannabis plant interact with one another. And, the basic idea is at the fuller the spectrum, meaning the more phyto cannabinoids there are, the more terpenes and terpenoids there are, the greater the possibility that these compounds will interact in some way to create a synergy. And synergy is often simply described as 1 plus 1 equals 3. And so, there's this idea that if you have enough of these compounds and you have the right ratios of them, and the right compounds, that you can get an effect using a product that is full of them that would be different, and perhaps therapeutically superior than if you were using a product that was highly purified, and has only isolated cannabinoids like THC or CBD. And this phenomenon may explain the differences that individuals report when using different products. But to be fair, the science isn't really in on this, our cultural fascination with the entourage is not yet really supported by the scientific evidence. There's some evidence that supports it, and there's some evidence that refutes it, and so it's really an open question going forward. And especially as a relates to hemp-derived CBD products, it's not clear how important these compounds are and what role they're playing in creating effects, because we don't really have the studies that compare an isolated CBD product with a full-spectrum CBD product in a human population. There's some of those studies in mice, but we don't really have the comparative clinical trials that we need to really draw firm conclusions.
 
In addition to being considered important mediators of the entourage effect, terpenes and terpenoids are also considered to be the class of chemicals that differentiates sativa varieties of cannabis from indica varieties. And as the stories go in popular culture, sativas are energetic and uplifting and good to use during the day, and conversely indicas are sedatives and analgesic, meaning that they reduce pain and they're good to use at night. Unfortunately, these cultural narratives are not yet supported by scientific evidence. And as a result, it's difficult to rely on these labels of indica and sativa when trying to predict the results of these products, because there's really no consistent terpenes and terpenoids profiles of products labeled sativa or flower labeled sativa for that matter. Or products and flower labelled as indica, and since it's really kind of messy, it's really difficult to claim this specific effect would be achieved by a specific formula because there's really no consistency between them. Having said that, there are very knowledgeable researchers, more knowledgeable than I, including Dr. Ethan Rousseau who's a neurologist, and probably one of the most widely renowned experts on cannabis in the world. In this 2016 interview, he is quoted as saying, “the differences in observed effects in cannabis are due to their terpenoid content, which is rarely assayed let alone reported to potential consumers.” And so this idea that these compounds are rarely assayed is very important, because if we want to understand what contributions they make to the effects that individuals experience, we certainly need to know what's in there and how much of them is in there. And very often, that's expensive to do and companies don't provide that information. 
In this interview, Dr. Russo mentions a few other things that I'd like to highlight. So he said that the sedation of the so-called indica strains is falsely attributed to CBD content when, in fact, CBD is stimulating in low and moderate doses. He says that that sedated couch-lock experience that people report is probably due to the myrcene content, and myrcene is a monoterpene. In contrast,  strains or chemovars, that are high in limonene may have an uplifting effect on mood, and that varieties that are high in alpha-pinene may effectively reduce or eliminate the short term memory impairment that is classically associate with THC. Now it's important to note that these statements are largely based on animal studies. I'm not aware of a single human clinical trial where a group of research participants took a product that was high in alpha-pinene, and reported fewer or less intense short-term memory deficits, than the group that received a product that was low pinene. So, this is a really exciting area of research in an exciting area to generate hypotheses, but again we don't have great science on human beings to really substantiate a lot of claims, but keep your eyes open because more studies are being conducted and published every day.
So the aroma the fragrance and the flavor of any plant, but cannabis in particular, is largely mediated by  the essential oil components. And essential oils are primarily composed of terpenes and terpenoids, and some other compounds as well. But these are the family of compounds that give cannabis its piney, diesely odor, or tropical fruity odor, that skunk odor. All of these smells that you're used to smelling when you smell the plant, and the products derived from it, are the results of these compounds. And it's though that initially they serve to protect the plants from microorganisms, from insects, and other animals that might be trying to eat the plant, as well as attract pollinators. And studies have found that Pinene is the most widely distributed terpenoids in nature, followed by Limonene. 
Almost all of these terpenes or terpenoids, at least to my knowledge has been recognized as being safe, many of them generally recognized as or GRAS, by a regulatory body like the FDA, or some other regulatory bodies or by independent panels of toxicologists. So, generally speaking, I think we can conclude that they're safe, even though these compounds may come from different sources. The terpenes and terpenoids in cannabis are chemically not different than the same terpenes and terpenoids that may come from the food. But it's important to know that these compounds are deemed safe by virtue of their intended use, which is to be ingested as a food additive, and then also by definition as a dietary supplement. And so that doesn't necessarily mean that they're equally safe to heat up and inhale, so a lot of times, at least in the cannabis industry, you'll have vape cartridges where the manufacturers will extract THC and CBD, and then they will add high concentrations of terpenes to give flavor and perhaps try to engineer specific effects in these bait cartridges, but the concentrations are much higher than what we see in cannabis flower, and it's not clear that they're heating up these chemicals and inhaling them is safe. We certainly can't extrapolate data from ingesting them to inhaling them. 
So we'll do a quick dive into the chemistry, I won't quiz you, and hopefully this will be fairly painless, but it's important to understand these concepts from a chemical standpoint. So terpenes and terpenoids are comprised of individual subunits, and these subunits are called isoprenes. And isoprenes have five carbons and eight hydrogen, and they are basically the building blocks of terpenes and terpenoids, as the amino acids are the building blocks of protein. And so, you can classify these compounds based on the number of carbons and the number of isoprene units, so for example a monoterpene is comprised of 10 carbons, which is two isoprene units, and a sesquiterpene is composed of 15 carbons, which is 3 isoprene units. And these two types of terpenes or terpenoids are the predominant terpenes and terpenoids found in essential oils and found in the hemp plant. And they have a very low molecular weight, and that means that they have a very low boiling point. And the boiling point is the temperature that a compound is converted from a liquid to a gas. And that's why when you open a bottle of essential oils, you immediately start to smell these monoterpenes because since there are smaller than sesquiterpenes, they have a lower boiling point, which means they're escaping the liquid of the essential oil and becoming a gas at a very low temperature, including room temperature. And so, they interact with receptors on our olfactory nerve and our nasal passages, they can send signals directly to the brain, they can also be inhaled through our lungs and absorbed into our bloodstream.
So terpenes and terpenoids can be acyclic, monocyclic, or polycyclic. What does that mean? On the left here, we have myrcene is acyclic, you can see the chemical structure there's no ring in the chemical structure. You can also see that there are 10 carbons, which tells us that it has two isoprene units, and it's therefore a monoterpene. On the right, we have a limonene, which is a cyclic monoterpene, its mono cyclic, and you can it has one ring in the chemical structure. It also has 10 carbons therefore, it is also a monoterpene. And the difference between terpenes and terpenoids is really the addition of an element other than carbon and hydrogen. So terpenoids have typically oxygen, whereas terpenes only have hydrogen's and carbons. Most people use these terms interchangeably, some people prefer terpenoids to terpene, I try to say them both because the plant and the products contain both, even though mouthful.
 So over 200 different terpenes and terpenoids have been identified in the cannabis plant so far. Most cultivars or varieties contain between 20 and 40, and typically they're in very low concentrations, less than 1% in the plant material by dry weight that is. There are studies that look at this most of the compounds or most of the terpenes and terpenoids in cannabis are monoterpenes. Here is a study that looked at an extract from fresh cannabis flower, and it found that over 90% of the terpenes and terpenoids were monoterpene, and then two-thirds of them were myrcene. This other study looked at 33 different chemotypes, and found that the most common monoterpenes were limonene, beta-myrcene, and alpha-pinene, and the two most common sets of terpenes were caryophyllene and humulene. Now this study looked at dry cannabis flower, the previous study looked at an extract or the oil from fresh cannabis flower, and it's important to understand what is being tested in these studies because these compounds can evaporate during the processing of the flower, or the product. So for example, if you measure terpenes and terpenoids in fresh cannabis flower, there are going to be more than if you measure them than dried cannabis flower, because just during the drying and curing process of the flower you're going to lose monoterpenes, they say around 5%. And so this is kind of a moving target, the more processed the plant material becomes, the different terpenes and terpenoid profile you will see, and sometimes that difference is meaningful and sometimes it's not.
You probably also know that the different extraction techniques lead to different extracts. It's often said that ethanol extraction and steam distillation are the best methods to use to preserve the terpenes and terpenoids, and that co2 extraction is not as good if you want to preserve those compounds. But the truth is that it really depends on how you do it, if you want to capture terpenes and terpenoids you can certainly do it using co2 extraction, so it really depends on what you want in your extract. If you want terpenes and terpenoids and you’re using co2, you will just do the extractions differently so that you can capture those compounds. 
So here we have two certificates of analyses from CV Sciences oil, so this is not a finished product, this is their oil. On the left, we have a certificate analysis for the raw oil, and on the right we have the decarboxylated oil. Now you may know that the plant biosynthesized is acid forms of phyto cannabinoids, so it doesn't actually synthesize CBD or THC, it synthesizes CBD-A and THC-A. In the process of decarboxylation, which is basically adding heat, removes the acid, so THC-A, the A stands for acid, which is a carboxylic acid hence decarboxylation. And so that process as I mentioned requires heat, and therefore you can see that some of the terpene and terpenoids are just lost, just during decarboxylation. So on the left, the concentration terpenes is 0.2%, on the right is 0.12 percent, so again this just underlies the point that processing can alter the terpene and terpenoid profile.
 And these levels, they vary batch to batch. Scientists say that the terpene profile is predominantly tied to the genetics of plant, however seasonality and other environmental factors can certainly influence the terpene terpenoid profile, As cannabis processing as I mentioned earlier. Here is a certificate of analysis of an oil, you see the picture there, and so now we're looking at an extract. And we can look at the percent THC, you're all probably familiar that the farm bill put forth a threshold for THC that could delineate hemp varieties of cannabis from marijuana varieties of cannabis. And so, if there is more than 0.3 percent THC, is deemed marijuana, and if there is equal or less than that amount deemed hemp. 
So we look at this particular extract we can see it's just slightly exceeds that point .3 percent threshold, so this extract legally would be being marijuana. But we know that an extract by definition is a concentrate, and so the starting plant material from which the extract was originated was probably below point 3 percent, and so it was probably hemp. And then if this was going to end up in a finished product, it would probably be diluted with a carrier oil, and then it would drop below that point 0 3 percent again. And so we have something that goes from being hemp, to being marijuana, to being hemp again, which is kind of wacky and confusing, so welcome to the world of cannabis. 
Here are the terpenes and terpenoids profiles of that same concentration, you can see that it's very low, less than 1 tenth of 1%, and the CBD concentration is pretty low too, 1.5. So switching to a finished product now, we're looking at a certificate of analysis from CV Sciences PlusCBD oil gold formula soft gel. And you can see that the total terpene terpenoid concentration is 0.149%, which is basically double what we saw in that extract, and this is a finished product. There are basically five terpenes or terpenoids that exceed a level of detection they are beta-caryophyllene, trans-nerolidol, alpha-humulene, linalool, caryophyllene oxide. So we can see these amounts, but we have to wonder how much of these compounds are enough, what is the concentration, what is the dose that is necessary to produce a terpene specific effect? 
And so if we go back to Ethan Russo, he's been quoted as saying, “concentrations above 0.05% of a specific terpenoid can have a specific effect.” that's 500 parts per billion, that's a very, very low concentration. So, if we use that threshold, and we look at the certificate of analysis from both formulas, soft gels we can see one of these five exceed that threshold, the beat-caryophyllene. However, it really depends on the method of administration. I think that Ethan Russo, when he is talking about these very low concentrations, is really referring to inhalation as a route of administration, and I will explain that in a couple slides. So as far as I can tell, a lot of there a lot of the basis for this idea, that very low concentrations can have terpene terpenoid specific effects, comes from studies looking at forest bathing, which in Japan is called shinrin-yoku. And this is basically a type of nature therapy, where people walk in a forest and inhale all of the wonderful fragrances from the plants and the trees there, that as we mentioned are primarily terpenes and terpenoids, and yes this is actually a thing and it has been scientifically studied. This is a review that was published in 2017 that looked at 127 different papers, and reports that many of them found that this practice led to positive health outcomes, including changes or improvements in objective measures, including biomarkers like cortisol levels. 
However, as I mentioned earlier, inhaling is different than ingesting. So typically, when we inhale something we absorb a lot more of it because the capillaries in our lungs are much more able to absorb these compounds, and also as I mentioned in the beginning of the presentation, we have receptors in our olfactory nerve in our nasal passages, and so signals can be sent directly to the brain just from our nose, let alone having these compounds be inhaled through the lungs and circulated up to the brain in our blood. But with ingestion, some of these compounds and in terms of phyto cannabinoids, a very high percentage of them aren't absorbed at all, and many of them are extensively metabolized to deliver two metabolites that are either inactive, or we don't really know what they do. So I think if we're talking about ingesting a product, and we're talking about concentration or dose of terpenes and terpenoids, I think it has to be a lot higher than 500 parts per billion. 
And if we look to the world of dietary supplements to get a little bit of guidance, here are two natural products that are sold as dietary supplements that are primarily composed of essential oils. On the left, we have a product that is primarily linalool, which is a monoterpene, and it's often used to treat anxiety, and the dose is 80 milligrams, and it's primarily linalool acetate.  So the product on the left is basically lavender essential oil, and on the right this product is basically peppermint essential oil. And the primary component in peppermint essential oil is menthol, which is a monoterpene. And this product is used to treat a lot of the symptoms of IBS, like gastrointestinal symptoms, like bloating, and abdominal discomfort and pain. And the dose here is 0.2 ml.  I don't have the milligram dose, but I am highly confident it is much higher than 500 parts per billion.
Now what some companies are doing in the hemp derived CBD space is they're adding high concentrations of terpenes and terpenoids to their products, oftentimes from non-cannabis sources, and then marketing specific effects. And it's not clear to me, at least today, that this is a good practice. and that this leads to certain effect. I like to think of these products as Frankenstein products, because they don't reflect anything that was created in nature, the ratios of these terpenes and terpenoids for one another and the cannabinoids far exceed anything natural. And this is also true of marijuana products, especially vape products as I mentioned earlier, where they're just putting terpenes and terpenoids in there, and we don't really know it's safe or effective.

Stuart Tomc:
So we're really quick just for a little interaction here. Just to be clear, because from a commercial standpoint, many of our brokers and the people that are listening to the call, and retailers have been told from giant companies, and I'm not going to mention their names, it's inappropriate and it's just tasteless, but a lot of retailers have been told by giant companies the exact opposite of what you just said. People listening are trusting giant companies, they've been told that as long as you mix the cannabinoids together and the terpenes and terpenoids together, that you're basically re-creating the product. Are you insinuating that it's more like a Frankenstein product, and less of a natural product? So who's to believe who?

Dr. Jamie Corroon:
Well, I don't think anyone really knows the answer to this question, and if someone tells you that they do know the answer, I would ask them for the science. I don't think that science exists. And so, when people are talking about scientific concepts and clinical concepts, I always get nervous when there's a tremendous amount of conviction, because there's so much uncertainty here. The best approach is always a conservative approach that acknowledges the uncertainty there, so maybe, maybe not. I'm not convinced that I've never seen any science that that has convinced me, and I've never really seen it studied, so I don't know how anyone could really know. You know, so marketing claims are to be listened to with a degree of skepticism for my perspective.

Stuart Tomc
 thank you very much 

Dr. Jamie Carroon
Ok, so we'll spend the remaining slides looking at these two particular compounds. We heard about myrcene earlier, it's high in in mangoes, and I mentioned earlier that Ethan Rousseau says that this may be the compound that leads to that sedative couch-lock effect that people associate with indica cultivars. And beta-caryophyllene is assessed with terpenoids, you can see there are 15 carbons there, and it obviously has something other than hydrogen and carbon in it, therefore that's why we're calling it a terpenoid. And it is in large concentrations in black pepper. 
And beta caryophyllene may be the compound that gives these products and cannabis flowers of peppery taste. so myrcene, as I stated, has been shown to be a sedative, an antispasmodic, which means reducing muscle spasms, and a hypnotic, which also is another way of saying that it is a sedative based. In animal models, it has also been shown to reduce pain by interacting with one or more opioid receptors, and reduce inflammation by inhibiting the production of an inflammatory chemical, called prostaglandin e2. And one preclinical study, and preclinical study is a study conducted in animals, and this was a rodent study, found that a dose of ten milligrams per kilogram orally, reduced pain behavior longer than morphine. And just a point to Stewart's previous comment and question, if someone is marketing that it their product has myrcene therefore it will reduce pain and inflammation. You know maybe that's true, but look at the dose here, that is used in animal model, ten milligrams per kilogram is almost a thousand milligrams for a 150 pound individual. So, no matter what, there's not that much myrcene in product. I'm not saying it may not do that, it may, but we don't have the data to suggest that the dosage in that product will do that. 
This is another study that also shows that five and ten milligrams per kilogram of myrcene reduce pain and animal, and this was experimentally induced. As far as beta-caryophyllene is concerned, we have to talk a little bit about the endocannabinoid system, because beta-caryophyllene is a cannabinoid, and what does that mean? It means it is a molecule that interacts with a cannabinoid receptor. And so we talked about beta-myrcene, we talked about interacting with opioid receptors, we talked about blocking the production and secretion of an inflammatory chemical like prostaglandins. But here, we're talking about a molecule that's going to interact with a cannabinoid receptor.
So very quickly, I think of three basic components of the endocannabinoid system: the receptors, the endocannabinoids themselves, and then the enzymes that both biosynthesize endocannabinoids and then also hydrolyze or degrade them. There are two cannabinoid receptors that have been identified to date: cb1 and cb2.  It's often said that their distribution is different in that the cb1 receptor is primarily located in the central nervous system, and that the cb2 receptor is primarily located in the periphery of the body, in organs, and on cells of the immune cells immune system, like white blood cells. Now that's an oversimplified description that at least helps us to get the basic model the endocannabinoid system. It's very often described as a neuroregulatory system, so here we have two nerves or neurons that are talking to each other, and nerves talk to each other through neurotransmitters. So this neuron is the presynaptic neuron, and let's say this neurotransmitter is glutamate, it releases glutamate, it diffuses across the synapse and binds to receptor on the postsynaptic neuron. This causes this cell, this neuron to produce anandamide, which is one of the two endocannabinoids that has been identified to date. And I should have said that in the previous slide. Anandamide is also known as arachidonoyl ethanolamine, or AEA, and the other end of cannabinoids that has been identified as two AG, or two arachidonic glycerol, we then see them abbreviated. So when these compounds are produced, they're produced on demand, and arachidonic acid is pulled from the cell membrane by an enzyme. It's converted to an AEA or 2 AG, and it travels up to the presynaptic neuron and binds to a CB1 receptor, and it shuts off the production and secretion of glutamate. And so, it basically is acting as a regulatory trigger, and shutting off this to prevent cytotoxicity. That's neuro regulation the same thing happens in the immune system. Here is a cross-section of the gut. Up here is where food and water would stick. And these white blood cells, a mass cell, and a macrophage, have infiltrated the wall of the gut. And here they are, right here in enlarged form. So these cells are producing anandamide, because there's been a disruption here. Because there is inflammation, they are producing TNF-alpha and other inflammatory chemicals as well. But the anandamide binds to CB1 and primarily CB2 receptors on these white blood cells, and turns off the production and secretion of inflammatory chemicals. So we have neural regulation, where cannabinoids are turning off neurotransmitters, and we have immune regulation where they are turning off inflammatory chemicals.
Beta-caryophyllene does this. It's not a phyto cannabinoid, its a terpenoid, but it acts as a cannabinoid. And so studies have shown that it exerted anti-inflammatory effects, using the CB1 to CB2 receptor and again here's a dose of around five or maybe less than five milligrams per kilogram orally, and scientists have found that that effect does not occur in life without CB2 receptors, so it's mediated by CB2 receptors. The same research group showed in another study that the degree of anti-inflammation is correlated with the concentration of CB2 receptors, so the more cb2 receptors is the more anti-inflammation. So that was a very quick dive into the endocannabinoid system, hope you're still with me.

Stuart Tomc
 I one question for you before we hand it over to miles, this is important on this issue here. Another competitor, we won't mention who they are again that's inappropriate, they're adding beta caryophyllene to their hemp extract. Now we have it naturally occurring in ours as we've all seen in small amounts. Let me get clear on this, if someone's adding a little bit of beta-caryophyllene for their hemp extract, and they're promoting it for pain or inflammation, are you insinuating here that the amount that would be necessary orally may be far more than is the small amount that's in a commercial capsule?

Dr. Jamie Corroon
Yes. We don't really know what the amount is. If we go from preclinical studies to clinical studies, which is the road that we travel, then we have to look at the data that we have, which is preclinical that suggests that the dose would have to be much higher in a human being, and eventually we'll get there. Listeners know the farm bill passed in December 2018, it opened the gates for some of this research to be done on these hemp derived products, so hopefully these companies that are so passionately making these claims will invest money in research to be able to substantiate them. But right now, my conclusion is that we need much higher doses than what is in these products 

Stuart Tomc:
 from anything commercially available, including cannabis extract

Dr. Jamie Corroon
 Yes

Stuart Tomc:
 which we you showed us was surprising that the amount of terpene terpenoid in the cannabis extract technically was even lower than what we had in our hemp extract.

Dr. Jamie Corroon
 Correct, and we don't know what they were trying to achieve with their extract. Maybe they didn't care about loss in the product, or maybe they did a method you know, so we don't really know but yes that was true about that particular case.

Stuart Tomc
So we're going to hand it over to Miles Sarill, our national educator who's going to drive this conversation home a little bit more with some specificity about what we've been doing here in our plants. Miles?

Miles Sarill
Hi everyone. I just wanted to share this one paper with you all in particular just to further add to the discussion that we're having today. This article came out in 2018, it is still fairly recent than in the realm of science. And some of the authors of this study came out of the original laboratory from Raphael Missoula. So if you actually look at the last author, Lumir Hanus over here, was one of the people that discovered anandamide itself. Ruth Gallily is one of the authors of the paper that Stuart and Dr. Corroon and I often like to talk about overcoming the bell-shaped dose-response curve, with full-spectrum extracts. So, this sort of lends a little bit of credibility to what we're going to be talking about with this article over here. And in this article, they are looking at essential oils of cannabis extracts, specifically hemp extracts, so if we could go the next slide please. So they are comparing the essential oils of different varietals, different strains of food, fiber, agricultural, industrial, hemp types. So rather than orangutan Kush or whatever, these are European Union certified seeds, kind of like what we are using in our production, okay. And they're going to be comparing this to just CBD, they're trying to tease apart essentially what is it in the full spectrum extract that might be underlying some of the most efficacy in the areas of inflammation in an animal model. So I wanted to highlight that, in terms of their materials and methods, they're using three different varietals of hemp: Tisza, Felina, and Ferimon. Now Tisza and Felina, the dominant terpene in these is Myrcene, right, some of that mango-y more sedative couch-lock . At least and according to Rousseau, that Dr. Corroon was talking about. And then Feremon is dominant in the terpenoid Beta-caryophyllene. So, perhaps it is possible that Feremon is a little bit similar to the Futura and Fedora that we are using, that also appears to have higher levels of Caryophyllene. So if you can advance the slide, I think I have an arrow over here, or a box rather. Take a look at this. I just thought that it was fascinating, while we're talking about dosages, and how much you need or not, that the lowest dose tested in each one of these essential oils it trends towards the fact that the Feremon plant has a higher anti-inflammatory potential, that the plant dominant in caryophyllene might promote beneficial effects at a lower dose. Now, this is a cell culture study in this slide here, so we can't take away everything from that, but you know I'm always looking for patterns in between the lines here. And again, when we're talking about the study, they're not isolating single terpenes, okay. This is not just looking at beta-caryophyllene, or myrcene, this is taking the whole essential oil of the plant. So it's kind of like a terpene terpenoid soup, and that sounds to me a little bit different than a lot of the studies that Dr. Corroon was just citing previously. 
So now they're looking at various models of measuring pain and inflammation in a rodent, and I know this sounds a little bit barbaric, but this is the type of science that needs to be done. They're looking at paw thickness and paw withdrawal to a hot plate, in order to determine whether or not the animal is in pain, or their pain sensitivity overall. And what we're actually looking at here is that when they test isolated CBD, it is actually more effective in the areas of helping pain and inflammation in the rodents than either one of any of the doses of essential oils of the terpenoids. So, the arrows are just pointing you see the greatest significant effect with cannabidiol alone. And also if you look at inflammatory cytokines, such as TNF alpha in the rodent, that again, the terpenoids don't show any type of effects in terms of reducing TNF alpha at the doses used. Instead, CBD cannabidiol by itself seem to have the most impact on inflammatory cytokines. So what we can kind of take away from this is that the terpenes do exert some types of effects, but by themselves they might not be all that potent at the doses that were tested in these rodents over here. That in fact CBD in isolation by itself had the most profound effects. One thing that the authors did write, that for me stuck out, was that the terpenoids did show some anti-inflammatory properties, but that no dose response was observed, suggesting that a maximum effect was already observed with the lower dose. So I know right now, we're talking about how many terpenes are enough, do you need to add extra amounts, do you need to have just a little bit, and I think that in this industry as a whole we have a tendency to want to fall into just talking about one thing being important, just CBD, just this terpene, just this molecule, right. And I think what I take away from this article suggests that we really need to be again thinking about the synergy. And this is where we can start to open it up for discussion, with Stuart and Dr. Corroon, that maybe some of the terpenoids might modify the effects of the cannabinoids, and that together the soup, the full spectrum of all of them is where we're going to see the most potential benefit, rather than just one type of compound or another.

Stuart Tomc
 thank you Miles 

Dr. Jamie Corroon
Thank you Miles. So just to conclude the: terpenes and terpenoids are everywhere in nature, over 200 have been found in the cannabis plant, but really only between 20 and 40 show up in any particular chemovar. Monoterpenes pre-dominate, but processing and manufacturing can alter the terpenes and terpenoid profile of finished products. Its really not clear yet what dose is needed to achieve a terpene specific effect, and it looks like it depends on the route of administration. These compounds obviously participated in an entourage effect, but we need more science to really quantify the importance of that entourage effect. Myrcene can act like a sedative, and may reduce pain and inflammation. And Beta-caryophyllene acts like a cannabinoid, and may also reduce pain and inflammation. So with that I’d like to thank you for your time, and toss it back to Stuart

Stuart Tomc
thank you. We have questions, but right away before anybody signs off, I have some here before anyone signs off, look at Dr. Jamie currents contact information right there, so please feel free to email him and ask him questions. Again, he is a paid medical consultant, however if you can hear from the way he presents this information, we are very excited to have sort of a very non-biased referee come in from the cannabis world, who is also looking at Public Health. So from our own personal perspective, we can't get clear cleaner, less propaganda information out there than this. And so we want to open it up to a couple of questions. And this is kind of a unique one, that came in, and I'd like your thoughts on this. Sativex, which is approved in many countries around the world but not here, for those of you that don't know what Sativex is, it combines CBD and THC in a little spray, and it's used for multiple sclerosis spasticity and treatment-resistant pain. It's two and a half milligrams of CBD, and two and a half milligrams of THC, with a very small terpene terpenoid profile in there. And I have the question, was there were people that have read some reports, that it's actually being used for cannabis abuse or a overuse disorder in Europe. So the idea that they're using Sativex spray for people that are overusing cannabis, in addition to the work that Scott Shannon did when he gave our product to a young person that was overusing, and felt that they were in the grips of cannabis, how are we making sense here of using cannabis or cannabinoids and terpenoids for potential cannabis overuse, it doesn't really make any sense does it.

Dr. Jamie Corroon
 Well I should say before I try to answer your question I probably don't know that much about this area of research, but the initial thought that I have here is using low doses of the substance that would otherwise induce withdrawal symptoms, if you abstain from using it right. So this is the idea of dependence, and then if you just stop cold turkey you experience a lot of adverse effects, including cravings. And so I do know, kind of anecdotally, that some people are using low doses of THC in order to titrate down from higher doses of THC, so that the body is still getting some THC, and enough to avoid some of those withdrawal symptoms, and to avoid the cravings.

Stuart Tomc 
Okay, thank you and maybe we can follow up on that. But that leads to the next question, can we overdo CBD and cannabidiol, there have been some suggestions that we may be able to overdo THC, what do you think as a clinician with cannabinoids can we overdo CBD? 

Dr. Jamie Corroon
I mean I'm sure you can overdo just about anything, you know. I think the doses that are available, or the amounts of CBD that are available in these hemp derived products, are very low compared to the toxic doses that we've seen in preclinical studies. I mean, when you compare them, there's like more CBD in an entire bottle of CV Sciences Extra Strength Formula of the Soft gel then there is in the amount that is being given to rats in showing toxicity is less , excuse me so I think I mean I'm sure there's there is doses that are toxic to humans, but they're much higher than what we're seeing is this that are available.

Stuart Tomc
 So that leads into the next question, what does Dr. Jamie candidly, think I know people are listening about your product line, in comparison to things like Jesse's jungle juice. How do you answer that?

Dr. Jamie Corroon
 Listen, what I say to everybody is if you were going to experiment with a CBD product, choose a product from a company that is willing to be transparent, who's willing to show you their certificates of analysis, who's willing to invest in research. And I am getting paid by CV Sciences, but CV Sciences has invested in toxicology study on their products, tell me other companies that have done that, you know, so being as one of two - the other one the one got published yesterday. So these companies, they need to be willing to put their money where their mouth is, and need to invest in not only safety research but efficacy research, which is something that CV Sciences has also done, that study is not yet been published, and they need to be willing to show you the certificates of analysis. And small companies may produce good products, but we don't know if they're not willing to do those things. So why take the risk when you can choose a product, company, that is willing to really invest in the data that can substantiate safety nets

Stuart Tomc
And then our last question, when we wrap it up. Do you have an anecdote, or a  person you've consulted with or a patient or someone who actually used the CV Sciences PlusCBD Oil that you think was noteworthy in your practice as a clinician? 

Dr. Jamie Corroon
A lot of them. I mean in my practice, almost everyday people are coming in, wanting to try CBD, everybody is so curious about this molecule. But they don't know where to start, they don't know what is a good quality product, they don't know if there's going to be interactions with their medications, people want to use this to help them sleep, they want to help reduce their joint pain, and their back pain. And so I would say, for both of those indications, people are getting a lot of a lot of relief, not everyone, and it's tricky to figure out what the right dose is, but those the two areas were really seeing the most clinical impact. And then obviously, I put seizure disorders off to the side because that's a little bit more severe and we have an FDA-approved drug  that has been shown to be effective in that case, and so certainly seizure disorders as well, but that in my clinical practice is not the most common use.

Stuart Tomc
I'm sorry we got one more that slipped in here at the last second. When you say tricky, we've heard CV Sciences say start low and slow, and that you should find your sweet spot, and that doesn't sound like science to us. As a clinician of cannabinoids, is it true that it's up to the patient to sort of determine what works best, what do you think about that approach?

Dr. Jamie Corroon
Well I would say its up to the healthcare professional and the patient themselves to figure that out. I think as a consumer, trying to figure that out on your own can be a little tricky, that's what I was saying. But if your healthcare professional is looking at scientific literature, and trying to use that to inform their dosing decisions, and if they're using their own clinical observations and experience based on 50 other patients that were using it to help with their sleep, I think you're going to arrive at an effect that goes a lot more quickly than starting very low and teaching your way up.  I talk to patients all the time that have already purchased the product, and they're already using it, and I  say, “How much you're using?” they say, “three drops”, and it's like, “okay well how much CBD is in three drops?” and its like, “nothing” or they say, “I'm using half a dropper” “okay, well how much CBD is about half a dropper? Yeah, so no one knows how much CBD is if you ask them, no one knows that. A lot of that is because most companies don't want to put that on their label, and again I will highlight CV Sciences as a company from the beginning put it on the label. As a health care professional, how can I recommend a dose of CBD if I don't see it on the label, you know? I'm not going to say two drops or two milliliters, I think in terms of milligrams because that how science works. And so, that's another thing that makes it difficult for patients, because they don't have the information they need on the label to make an informed decision, even if they wanted to start low don't really know what low is. 

Stuart Tomc
They're giving us the flashing light, the last second. So we end exactly on time, are you still able to see patients if people email you?

Dr. Jamie Corroon
 yes of course

Stuart Tomc
Okay so that would be separate, you'd be making an appointment directly with the doctor. Remember, our products at CV Sciences are intended for healthy people, to keep healthy people healthy. Thank you very much for your time today, and we look forward you joining us on the next webinar.