It doesn't matter who you are really. Modern life is stressful and causes various forms of anxiety in all of us. There are so many recommended actions we can take to help reduce that stress. Exercise, meditation, eating whole foods to keep our gut biome happy, and working directly to resolve the source of stress are all proven to work. Various pharmaceuticals come and go in popularity and supposedly help, but most are either or eventually debunked as ineffective. And then there's cannabis. Humans have been turning to cannabis for anxiety relief for 1000 of years. And there are several different ways that we can use cannabis to relieve stress and we will discuss several of them today. Today, we're going to focus on a brand new scientific study published just last week looking at the cannabinoid, cannabagirl, known as CBG, to reduce anxiety. And the results are truly remarkable and will absolutely influence the direction of anxiety medicine research going forward and how we as cannabis enthusiasts avoid anxiety too. If you want to learn about cannabis health cultivation and technique efficiently and with good cheer, I encourage you to subscribe to our newsletter. We'll send you new podcast episodes as they come out delivered right to your inbox along with commentary on a couple of the most important news items from the week and videos too. Don't rely on social media to let you know when a new episode is published. Sign up for the updates to make sure you don't miss an episode. Also, we're giving away very cool prizes to folks who are signed up to receive the newsletter. So go to shapingfire.com and sign up for the newsletter and be entered into this month's and all future newsletter prize drawings. You are listening to Shaping Fire, and I am your host, Shango Los. Welcome to episode 116. My guest today is doctor Ethan Russo. Ethan Russo is a board certified neurologist and former senior medical advisor to GW Pharmaceuticals. He has served as study physician to GW Pharmaceuticals for 3 phase three clinical trials of Sativex. He has held faculty appointments in pharmaceutical sciences at the University of Montana, in medicine at the University of Washington, and as visiting professor at the Chinese Academy of Sciences. He has been president of the International Cannabinoid Research Society and is former chairman of the International Association For Cannabinoid Medicines. In 1995, he pursued a 3 month sabbatical doing ethnobotanical research with indigenous people in Peru. He is author of several books of cannabis medicine and has published over 30 articles in neurology, pain management, cannabis and ethnobotany. He is presently founder of Kratoscience, where he works to formulate cannabis therapeutics for the good of all. Doctor Russo has joined us before on shaping fire several times. Episode 22 on treating traumatic brain injury with cannabis and mushrooms, and episodes 11 and 27 about his famous research papers on cannabinoids and terpenoids. Episode number 67 about treating migraines with mushrooms and cannabis. Episode 80 on cannabinoid hyperemesis syndrome. Episode 83 on the cannabinoid CBG, episode 103 regarding the life's work of doctor Rafael Mishulam, episode 110, taking a good look at Delta 8 THC, and of course the Shaping Fire sessions on the Shaping Fire YouTube channel. During the 1st set today, we will review what we know about CBG cannabigerol and look at the results of prior CBG studies. We will also discuss using isolate versus whole plant preparations during scientific research. In the second set, we will review the mechanics of the study and look pretty closely at the various ways participants were made to be anxious and the battery of skills test participants were given while anxious and using CBG. And during the 3rd set, we will look at the groundbreaking and really remarkable results from this study and compare using CBG to other cannabinoids like CBD and THC for reducing anxiety. Welcome back to Shaping Fire, doctor Russo. Well, it's good to be back with you. Excellent. So, Ethan, you know, why don't we do something new and why don't we start with giving some respect to your other co authors on this paper? Sure. Happy to do that. Well, this was led by doctor Kerry Cutler of Washington State University, who's an associate professor professor of psychology there and has done fantastic work on cannabis over the last several years. Also, her graduate student, Amanda Stuber, did a lot of the interviewing, for folks in the study. And, then Ziva Cooper, who's a professor at UCLA and heads the cannabis research program there. Fantastic. Thank you. You know, the more and more I get into the science side, in-depth in cannabis, the more I realize how important every single person on a paper is. And so I think I like this, and I think I'll I think we'll start plugging those other co authors as going forward. So thanks for that. So let's let's get started by creating a little bit of context for cannabagirl for folks who are relatively new to CBG as a cannabinoid. Now clearly, throughout this entire show, we're going to be talking about CBG in significant detail, but for the moment, would you just give us a general understanding of CBG as a cannabinoid? Yes. Happy to do that. So, let's go back to 1964. That was the year that Rafael Meshullam and Yechiel Ghayoni identified finally, THC, tetradrocannabinol, as the main psychoactive ingredient in cannabis. But that same year, they also discovered cannabagiol and were quite prescient in identifying it as a precursor to all the other major cannabinoids. So it it started there. Interestingly, all the attention was focused on THC. Cannabidiol, had been discovered or identified with clear ideas to its structure only the prior year in 1963. But because there was not this, overt psychoactivity to some of these other compounds, they got much less attention, and that was certainly the case with kinaabegirl. So there were some initial studies looking at what it did in animals, but, it really didn't get the attention it deserved for perhaps another 30 years or more. What would have caused the interest in CBG to increase? Well, you know, along the line, people did take a look at, certain things. In the seventies, it was shown that, CBG is an uptake inhibitor for GABA, which is an inhibitory neurotransmitter. Why that is important is that it could account for muscle relaxant activity and certainly for some, activity as an antianxiety agent, which we'll certainly be talking about more. Additionally, in 2006, it was shown that, there was an antidepressant effect in tail suspension models in in rodents. Along the way, it was shown that there is a mild effect of CBG to lower blood pressure and also to lower intraocular pressure the way THC does, in glaucoma. Subsequently, during this interval, in the early 2000, there was a lot more investigation. Some of this was spearheaded, through support of GW Pharmaceuticals where I was working at the time. They had a program of selective breeding for the so called minor cannabinoids, and one of those was cannabageral. The chief breeder there, Atienda Meyer, actually developed a CBG only plant. And, so that there was a good bit of basic research going on. Among other things, it was shown that, CBG stimulates, several TRP channels, especially TRPM8. M is sort of like, is named for menthol. So this is a a temperature sensitive receptor. Trypmate is important because, certain tumors, especially prostate cancer and some, breast cancer lines, would be targets for this. Additionally, there it was shown that there were antibiotic effects, strong effects against methicillin resistant staphylococcus aureus. That was shown by Appendino et al. This is an important result, because at the time, there were all these hospital acquired infections and many deaths related to MRSA. So this remains in the area of great interest. So 2 of the big things were this, effect on certain cancers. And I should point out that CBG, like just about all the other cannabinoids, shows a a great selectivity in its ability to kill cancer cells while being preservative for normal cells. This is an important distinction because standard chemotherapy agents tend to be toxic to cells in general. So it's always an issue of, can you kill the tumor before you kill the patient or at least make them very sick in the process. So anybody who's been through chemotherapy or has a family member or friend that has is familiar with this concept. So with the cannabinoids, we have the prospect of having much more selective ability to kill cancer without producing overt toxicity. The study reminds us a couple of times that there are nearly no CBG studies that involve humans. And yet we know, you know, quite a bit about CBG and have pretty good ideas about other things we want to research in humans. It gives me kind of a vibe that there is a bit of a sea change as far as human research into CBG. You know, as somebody who is doing this research on the front lines, do you feel that as well that we're at a transition point where we're moving out of purely rodent studies and moving more and more into CBG, studies in humans? Yes. Quite true. So why is that? Again, for better or worse, there's been all this attention on THC. And then, starting about 15 years ago, CBD came to the fore mainly because of its utility in epilepsy, which is well deserved. But, I think people would understand that, CBD has sort of peaked in terms of interest. That It it certainly is a very versatile therapeutic molecule, but, perhaps it hasn't quite, panned out, from a business standpoint. That's certainly true for many companies. So it's pretty much everywhere, but, again, lost in the shuffle were other candidates, particularly CBG. Now that has changed recently because certainly, on the West Coast of the US, there has been selective breeding again leading to CBG predominant or CBG only chemo bars of cannabis. This really started in the northwest, particularly with Oregon CBD. And slowly, CBG interest and breeding has diffused to the rest of the United States and around the world. So along the line, along the way, certainly, there've been a lot of people, particularly in the northwest US that have been using CBG for some years now. And so we have their what we'll call what the scientists call anecdotal experience, what patients and consumers report, but it's only recently that there have been the formal clinical studies, and we'd like to think that we've been at the forefront of that, with our survey study that was published in 2021. And now this, which was the first study to examine in a randomized controlled trial the effect of CBG on anxiety. I have to agree with you, Ethan, that it is no small impact that the CBG dominant cultivars from, Seth and Eric Crawford there at Oregon CBD down in Albany, Oregon has really made a difference here in the Pacific Northwest because up until their CBG dominant cultivar, mostly, we were getting CBG in, THC dominant cultivars, and it's really hard to tell anything either in a controlled study or just anecdotally when THC is the primary ingredient. But when you can strip that out and make a CBG dominant hemp cultivar where, you know, it's nearly entirely CBG, This opens up not only the ability for, that plant material to find its way to research scientists like you, but also it really gives a lot of strength to what, you know, some call anecdotal evidence, some call citizen science. The whole idea that it gets its hand, CBG gets itself into the hands of caregivers who are who don't really have the same constraints as legitimate science do. And so a lot of the initial, you know, grunt work about what we should even look for can happen. And I'm really grateful for those, you know, single cannabinoid dominant cultivars and hopefully, we'll continue to be seeing more of them, Doctor. Darrell Bock Yes. Certainly. You know, this is the kind of selective breeding that took place at, GW Pharmaceuticals, unfortunately, because there was a concentration on development of Sativex and Epidiolex, CBG, again, never got into clinical trials, despite the availability of the CBG only chemo Var, clear back, you know, in the early 2000. So it's just one of those things that got lost in the shuffle. You know, you may not be able to speak to this, and and and my my awareness might not even be true, but it seems to me that there's probably a whole bunch of really interesting cultivars at GW that just like you said, kind of got lost in the mix. And it isn't until similar cultivars are rebred in the public that we see a lot of those because most of the pharmaceutical companies defend that cherished IP, I would assume. Right. So, you know, you've been researching CBG for years and you and I have been talking about it for years now. And this particular study, though, it seems like it's a direct follow-up to another one that you did just a couple years back again with Doctor. Kerry Cutler at Washington State University. A bit more of a general study but it absolutely sets this one up. Would you summarize that study and its results so that we can all have a better picture of what we're building on top of? Sure. So at that time, we weren't in in a position yet to do a randomized controlled trial. 1st, I thought that we really needed a survey, a decent survey of what people were reporting with CBG, preparations, to lend some credence to the idea that, number 1, this could be used therapeutically. Number 2, that there weren't any associated problems. So we initiated a survey study and had a 127 folks that, the stipulation was they had to be adults and they had to be using a preparation that was at least 50% CBG. So that was a mixed, sort of sample. Some of the people were using CBG only products, but a a lot of them, were CBG with THC. And as you mentioned, that creates a few complications, but, for the most part, we got some very useful information. So, Yeah. Let's let's talk about what people saw. Mhmm. 1st, what I expected was, something we did see that a lot of people were using it for the big 3, which are treatment of pain, help with sleep, and, mood, particularly, anxiety. So these are the same things for which many people turn to cannabis, of one type or another. But when we started asking about conditions that people were treating, we got a list of 30 different conditions. And what was really surprising was, people reported that the CBG preparations were highly effective and often much more so than conventional medicines that they'd use for the same purposes. And we got, very highly statistical significance with claims of benefit on pain, sleep, anxiety, but also for some hardcore medical conditions like, inflammatory bowel disease, endometriosis. Now some of the numbers weren't big on those specifics, but when 3 quarters of the people are saying that this is the best medicine that they've ever used, for their condition, you know, it is creating a sync signal that deserves attention. Now at the same time, people were really not reporting side effects to speak of. Some people reported dry mouth, sleepiness, increased appetite, but certainly that would suggest that those were preparations that had some THC, in them. And this is borne out subsequently when we looked specifically just a a CBG only preparation. Similarly, in this survey, 84% reported no withdrawal symptoms when they stopped. So, you know, our conclusions were, first, this was the first study that really looked at therapeutic use of of CBG in humans. Again, anxiety, pain, depression, and insomnia were the most commonly reported target symptoms, and people reported a very high efficacy with, no adverse events to speak of. And, you know, the the main thing was we thought that this is a good indicator that CBG would be safe for future randomized controlled trials. Now we were immediately interested in taking this forward, but it it took a good long time, as these things often do. Recruitment for the new study, which was again a randomized controlled trial of a CBG only chemo Var extract, and its effect on anxiety. This took a while to recruit. It it was confined to people in Washington state because, that's what the institutional review board wanted. But it it came together nicely. So why don't I stop there for a second and see if you have an interim question because I could just go on and on. Sure. Sure. Sure. So, I find it interesting that it was challenging to recruit for this study. I mean, not only were you limited to Washington, which has got its own challenges as since you've got a national audience, but even more so after reading the study, I can imagine that it may have been challenging to find people who met your stipulations because in one hand, for somebody to be open to participating in a cannabis study, they need to be open to cannabis. But then the study required for them to not be using cannabis or any other illicit drugs during, I think it was a 2 or 3 month window. And so many people, you know, were they may have had cannabis or they may have been microdosing or may have done a lot of things. So this actually continues to make the pool of people possible much smaller, right? Well, that's a problem in general. In this instance, we ask that people not use cannabis, for 24 hours. Oh, alright. So, you know, in some studies, they're much more stringent about that. We also wanted people that were cannabis familiar, but not necessarily heavy users. So, and That's that's walking a line right there. Well, sure. You know, there are always exclusion criteria. We wanted to exclude people that might have felt that they had used CBG before and had a bad reaction. They couldn't use, harder drugs within 2 months. They couldn't have a serious psychic psychiatric condition like schizophrenia or bipolarity. They couldn't be pregnant or breastfeeding, and they couldn't have any chronic neurologic disorder or history of a a serious head injury. So, I mean, those were the the kinds of things. And, oh, they also, had to be fluent in English. They had to have a smartphone because one of the tests was done on an app, on a smartphone. And as mentioned previously, just in Washington state, so there were no issues about shipping product over state lines, that might have attracted federal interest, let's say. Yeah. Well, there was, I I found it interesting because, you know, when you reached out that that you were going to be working on this study, I was excited to participate. And then I didn't get through the first sifting process because my association with cannabis and other influences were far too high for the study. But I am happy to say that we let Shaping Fire users or not users, Shaping Fire listeners know about the study and you have some of them in your study. So thanks to everybody who chose to participate. So we talked about the baseline study that you did with Doctor. Cutler over there at Washington State University that laid down the base. And so then you worked with Doctor. Cutler to design this new study. What were the objectives for this new study? Doctor. Darrell Bock It was, again, to see if in a sort of manufactured situation creating anxiety that we could show that CPG made a difference in compared to placebo. And I I just wanted to go back, for a second to, the demographics of, people's cannabis use, because this is important. A lot of studies, you know, for instance, in the survey, obviously, wanted people that had used CBG before. In this one, it we hope that we'd get some people that never used CBG and, because this is really important. What's the reaction of it to somebody that's never had it before? So as it turned out, 65% of the people in the study, which was 34, had no prior experience using cannabagiol. Again, all had been cannabis users in the past. The average was about 3 and a half days a week or 18 days a month. Okay. But with that in mind, you know, again, what were the what was the premise of the study? Well, I'll just read from the purpose. To examine the acute effects of hemp derived CBG on anxiety, stress, mood, and memory, as well as positive and negative subjective drug effects in humans. And the design is what's called a double blind, meaning patients and the administers of, this didn't know who was getting what at the time. Placebo controlled, that means that on one occasion, people got the CBG preparation. On another occasion, they got a placebo, and it was called a crossover study because they had to take both, in separate trials. And it's called a field trial because, this is done over Zoom with patients in their home environment. And someone asking the questions on the other end at Washington State University. I can imagine that, asking people their questions at home actually gets rid of an entire layer of anxiety related questions that that you don't have to do anymore since people are often made to feel anxious just by coming into a facility. Right. That's called white coat anxiety. Oh. And we use that to advantage. Wait. Wait. Wait. Did you say white coat anxiety? Yeah. That's so that's aptly named. Okay. Go ahead. Sure. We use that to advantage though because, part of the testing was I mean, some of this is diabolical. How did we make people anxious? Well, one of the things was, they were told that they had 5 minutes to prepare, to say, what their ideal job would be and how they were qualified for it. And, you know, they were expected to talk this whole time. And if they stop talking, they would be prompted to continue. And, the examiner did a thing of starting out in civilian clothing and then coming back in a white coat. And then there was a thing of a calculation. Usually, the usual calculation when you're testing someone cognitively is to track subtract 7 from 100. This is much worse. It started with a very high number subtracting 17, and every time a mistake was made, they were told to go back to the beginning. So these are the diabolical effective they effective they are for being so gentle, right? Because you're not actually putting them under threat, but it sure can feel like it. And we'll be talking more about those in the second set too because this battery of tests that you gave people were something else. For this set, let's finish with this though. You know, most studies that are happening on cannabis nowadays, they default to using isolate. Even though I prefer whole resin, most studies are using isolate because it is just one specific molecule instead of being the cannabis resin which has got lots of components in it. And yet we know that generally speaking, using resin offers better benefits from isolate which has got its own problems. Why did you choose to go with a whole plant, CBG dominant resin solution in the tincture for the study instead of going with isolate, which is probably more easily available and also is you know, what all your peers in pharmaceuticals are doing? Well, we wanted real world experience. Now, again, this the study drug was a CPG extract that has been used by a good number of people, in the Pacific Northwest. So we knew a little bit about what to expect from it. That was a big advantage. We definitely wanted, CBG only preparation to the extent that there'd be no THC, no significant amount of CBD or other cannabinoids. And in fact, each milliliter of the study drug had 10 milligrams of CPG, a little bit of CBGA. There were barely any THC, point 0 1 milligrams of THC, and the only significant was 0.35 milligrams of caryophylline, which we don't expect to be overtly psychoactive. So each person in the study drug, set, got 2 milliliters of this material in a glass of water. So that was 20 milligrams of CBG and not a lot, else. Now it was a real challenge to figure out a placebo. So the placebo would be something that wouldn't be psychoactive to any great extent, but it it should look like the study drug and and have a taste, that might be hard to tell apart. So I wracked my brain. This was part of my contribution to this study. What can we use that would have this effect? So I wondered, how about an herbal preparation, but one that wouldn't have cannabinoids in it? And, we want something that's sort of green, like the the study drug. So I I thought about the liqueur chartreuse. Chartreuse. For people who don't know chartreuse is, from Europe, 100 of years old, originally made by monks, said to be made, with somewhere between 50 a100 different herbs. It has a distinct herbal taste and it is green, so we use that as the placebo. When I read that in the study, Ethan, I just howled sitting in my living room because number 1, it's really humorous to see chartreuse so out of place and in the wild. Like I was a bartender in my 20s 30s, so I was, of course, very familiar with Chartreuse, but I didn't expect to see it in the study while I was reading it. And then it makes so much sense because even though Chartreuse has got a certain sweetness to it, it is so herbal. And when you watered it way down, I totally see how it could become an effective, placebo that looks and and and acts like a tincture without the active components. Did you find that it worked out pretty well? Because I would think that that would be a home run. Sure. You know, I nobody said, that I'm aware of, that we know this is the drug, and we know that this one isn't. So and, you know, again, people were sent vials and the person administering didn't know what was what. You know, this is a way to maintain the blind, and we think it was quite effective in this instance. Right on. And since since the name of the individual is in this study, we might as well go ahead and mention who provided the CBD tincture for this study. They might find that novel. Yes. This came from 1 Shango Los. Oh, me. Yeah. Well, I I was happy to do my bit for science, Ethan. So I am grateful to have participated. So, all right. So let's go ahead and take our 1st break. When we get back, we're gonna talk a lot about the battery of tests that were given to the research participants because since this study is pointing specifically to how CBG helps with anxiety, it's going to be very interesting to look at these different tests and figure out how they tease at anxiety different ways. So you are listening to Shaping Fire and my guest today is neurologist, Doctor. Ethan Russo. And you know, without these advertisers, Shaping Fire would not happen. So please support them and let them know you heard them on Shaping Fire. This message is for folks who grow cannabis. 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So before the break, we were talking about, the study that this new study was based on, the various advantages that we're starting to see teased out of CBG, and specifically this study, how it looked at the anxiety of patients and CBG's ability to decrease that anxiety. And how the study is designed is remarkable because what it has to do is is subtly push people's buttons in different ways and see whether or not they can handle having their anxiety buttons pushed with the study drug versus the placebo, which we now know was just very watered down chartreuse. So the study consisted of 2 interviews between the research assistant and the participant 1 week apart via Zoom. So before the interview, the research subject ingests a vial of either 20 milligrams of whole plant CBG tincture or the watered down chartreuse placebo. Then, when the interviewer starts, some baseline demographic questions are asked just to kind of like get them talking. But then a whole battery of tests take place. And I got to say, Ethan, reading about them in the study, they really seem numerous and varied and designed to stress like any kind of person out in a way that doesn't do any permanent damage. So I know we've got, you know, a handful of them and they all work in slightly different ways. So I think I just want to hand you the mic and let you walk us through these battery as tests and teach us what they are and what their goal was. Sure. So, at the zero point, they had baseline assessments, mood, anxiety, stress, and drug effects. It may seem strange to ask about drug effect questions when nothing's on board, but you you want to establish, comparison, before the drug is administered. So at that time, as you mentioned, they take the CBG tincture or the, chartreuse placebo. Then they take an online survey using, up some time, and the first testing was at the 20 minute mark. And I wanna mention here, we got a criticism, from one reviewer about, you know, why did you start then? Probably wasn't doing anything, but in the interim, there was a pharmacokinetics study done. Pharmacokinetics is what are the effects, how long does it take for certain effects to appear, And we were able to show that when people took CBG orally, that the effects begin and are seemingly well established by the 20 minute mark. So at the 20 minute mark, there were tests of mood, anxiety, stress, and drug effect ratings. Then, they take the thing called a trier social stress test. They beget more, ratings of all those parameters at 45 minutes. And then, between 45 60 minutes, they'd have the California verbal learning test too, which assesses memory impairment, and they'd have the Druid application. Druid is an app that's designed to assess motor and reaction times and whether someone's impaired. And, you know, this is something that's been validated, and it's done on a smartphone. And then, at time 3, it's 60 minutes. Again, the mood, anxiety, stress, and drug effect ratings. So there were different time points and as you mentioned, these different types of of testing, to see, what would happen. So in choosing these studies, did you approach them as, okay, these are the studies that are always used by scientists who study anxiety, like were this is a preset battery? Or did you, as the designer of the study, have to go and choose these yourself off the shelf, because they're the ones that you respect and the ones that were going to tease out the kind of data points that you wanted to look at. I'm just trying to figure out whether or not these are like boilerplate studies or whether or not that this is more of a custom ordeal? Well, you know, there are always differences, but, these are well accepted types of studies to look at these parameters. So basically what I could say if you looked at studies from Johns Hopkins like the limonene and THC study we just did, a lot of overlap in the tests that were done, and that's for a reason. These are time tested measures, that are well accepted, in the scientific community. When you look at these tests, and, they wanna come about this a different way. We know that anxiety comes in a lot of different forms. And and, you know, people on Vashon Island here where I live have been taking CBG tincture for a couple years, and and the results that people speak back anecdotally, they they review different types of anxiety that the tincture helps with. As you were designing the study, what were you looking to pull out of the various the various tests that you're giving folks. And and I'm not asking you to necessarily go through them all, but but so we can understand how to scientifically think through these tests, would you maybe compare 2 or 3 of them and say, well, this one is looking at this type of anxiety versus this one's looking at the different type of anxiety because unfortunately, most people who who have anxiety, they just say, I'm anxious without the ever having had the opportunity to think about what kind of feeling anxious in general. Situ situational anxiety would be I get stressed when I have to go outside. But, again, and I although I was a psych major in college, I'm not an expert on this, but I can assure you that doctor Cutler and doctor Cooper are, but, again, one of the tests is called the stain anxiety, and another is more specific for stress, as as might be precipitated by subtracting 17 from a high number Mhmm. And having to repeat it. So I I don't think I've given you a great answer, but, what I can say is that over time, we saw these statistically significant differences in the these folks tested twice between their, experience on the CBG and their experience on the placebo. And because, you know, it wasn't always one before the other, it was random as to which came first, You can control, so it's not a matter of well, you know, I'm not stressed because they I knew they were gonna subtract have me subtract 17 from a high number, and it wasn't as bad the second time. In general, these are set up in a way that, there shouldn't be these big practice effects. I wanna poke at that a little bit. The the term practice effects is one I'm unfamiliar with, so that might be what I'm asking about. But, okay. So let's assume that the tincture that is was the CBG tincture presented a certain way, and then the chartreuse presented a certain way. And they both seem like they could have been the CBG tincture, which was the goal. So that's great. But we those of us who who do use CBG regularly, it really has a huge effect on anxiety. In my own personal experience, I've experienced this. So do you have a data point that speaks at all to, to what degree the test subjects were able to determine which one was likely the study drug, not based on presentation, but based on based on, oh my God, this works so much better than the one other one I had. The other one must have been the placebo. Well, you know, I we didn't record people's reaction that way. You don't want to probe too deeply at this point when you're trying to get 2 sets of data points. And, again, you might get varying degrees of response in an individual, but you need numbers. In this instance, 34 folks to see what the overall effect is and whether it has statistical significance. So my answer to your very pertinent question is we rate the benefit in terms of statistics, and now I need to give a little primer on statistics. Statistics, the the lower the number is, the more significant it is. Something is considered medically significant if it has a probability or p value under 0.05. What that means is there's less than a chance one chance in 20 that the results occurred due to chance, meaning that when it's 0.05 or less, we consider that likely a real effect, and then as the numbers are smaller, it's more statistically significant. So in this instance, in the subjective anxiety, ratios, there was a moderately large size significant effect of the condition, meaning one versus the other. That p value was 0.034, so under the 0.05, and over time, it was very significant. So, p value of 0.001, that means one chance in a thousand that this could be just a chance occurrence. That's a real effect. Anytime there's one chance in a 1,000, that, you know, this it it it really is highly statistically significant. Similarly, the stress ratings, the effect over time, p value of 0.001, and a large size simple effect of the condition on the change in subjective stress ratings again at 0.032. It's under the 0.05. But at the same time, there were not major changes in in mood. The thing called the state anxiety scores, again, showed us large statistically significant main effect over time, point 001. Now if we were looking at the graphs from the study, you can see that there's a clear demarcation. There's space between the effects on placebo and the effects on CBG, and the bigger the space between those, the more significant it is. In these, you can see that the differences are pretty clear. You know, again, this wasn't a situation where we asked people for a lot of introspection on what they thought was going on. It it really had to be objective, meaning what did the test show. So, you know, it would have been interesting to ask people more about their reactions. So that's one thing. We showed these clear statistical and significant changes looking at anxiety and stress with these standardized measures. But, at what cost? In other words, were the people impaired when this happened? I mean, you can make someone no longer anxious by sedating them. So what would really be important is to have benefit on anxiety without sedation. So we looked at other measures. 1 was a measure of intoxication. So, this is a place where if there were a lot of THC, you'd expect you'd get significant difference between that preparation and placebo. We also had drug effect ratings, and this is asking people about their reactions and, how much they like the drug. So most often, cannabis users in a clinical trial setting will report that they liked a certain amount of THC. So three measures there, but we saw no significant differences between the cannabagiol and the placebo at any time point with respect to intoxication ratings, they were almost straight lines. Same with drug effect and same with drug liking. So no space between the lines at the three time points, 20 minutes, 45 minutes, and 60 minutes. This is really remarkable because if you test any other drug used for anxiety like a Benzodiazepine, Valium, diazepam, almost always, there's gonna be significant sedation or other complaints, and we just didn't see that. And then there's another dimension here. I'm sorry. I wanna talk a little more about, subjective drug effects. So these are rated 0 to, 0, not at all, to 10 extreme. And again, there were no significant differences between CBG and placebo at any of the three time points, 20 minutes, 45 minutes, or 60 minutes. Then, again, if we have a drug that's good for anxiety, we wanna make sure that it's not producing any impairment. So memory tests were part of the trials. Then a very surprising and important thing happened, which was people on the CBG actually did better on memory tests, and this was statistically significant. So there was a moderate size significant effect of the condition, and that's at the the probability of point 0 5 level and a large statistically significant effect over time. It meaning looking at all the time points and that p value was point 001. So that supports the idea that on this verbal memory test that the performance was significantly better on CBG than it was on placebo. This is not what you expect, from most studies of this type. Especially on cannabis. Yeah, exactly. But, again, lacking THC, CBG is a different kettle of fish. It really is distinctly different in what it does. And to me, this might be the the most, surprising finding. Yeah. It was definitely surprising to me reading it. It was actually kind of like a plot twist in a book as I was reading the study. I'm like, oh, I I didn't know that was here and I didn't certainly didn't expect it coming. I I believe that this next question is outside the scope of the study. But as a neurologist and as somebody who has spent their life studying cannabis, I bet you have an opinion, which is do you think that the improved memory was more related to something this something that CBG was doing to actually improve memory function? Or do you think it was because, memory was increased in the absence of the anxiety which the CBG had solved for? Right. Well, it's likely the latter, that the reduction in anxiety in a test situation led to better performance. However, that might not only be it. There could be memory enhancing properties, and that is gonna have to be teased out in subsequent studies. So there's plenty more to do. I did wanna indicate that there was one final thing that we tested that was again very important, and that was the question of impairment of any type. And, in fact, again, CBG showed, lack of impairment. Participants performed significantly better, in the trial times 2 and 3 after, taking CBG than they did on placebo. So, again, something that may not really have been expected, but what I like to say is what the world needs now is an effective drug for anxiety that doesn't produce impairment or sedation or addiction, and we may have it in the form of cannabagiol. Amen. Now that is a big statement that I can get behind. My goodness. Alright. So, unless you have anything else to add regarding the conclusions of the study, I'm about to go to break and we'll after after the set break, we will we will talk about ramifications and next steps. But do you have anything else regarding the conclusions of the study that you want to tuck in here before we move on? Well, I could summarize now or after the break. Alright. Well, since you're going to summarize, let's summarize after the break because we'll be summarizing a couple different points. So, you are listening to Shaping Fire and my guest today is neurologist Doctor. Ethan Russo. 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And, you know, Ethan, the throughout our conversation, the thing that really send tends to glow big in this study is that 78% of the participants said that CBG works better than their pharmaceutical or other traditional medication, and that is a staggeringly successful number in my eyes that nearly 80% of people said that CBG was better than whatever they normally use. Does this stand out to you as a research scientist too being like an oh my god moment? Yeah. It was a surprise to me that it was that high, but perhaps, in retrospect with, 3 years since then, it's less of a surprise to me because in our formulation work, we've been using CBG extensively, and, the results bear this out. It is an extremely versatile medicine that, really contributes greatly to therapeutic effects. And it just feeds into your, your statement right before we went to commercial about how how big the impact of this can be in, you know, reducing human suffering from anxiety. I mean, it's a big deal Even even though you and I are becoming increasingly comfortable with it, right? Yes. Yeah. So one of the attributes or one of the aspects that I think is worthy of looking at is that so many people presently use CBD and or THC for their anxiety now. And and CBD, CBG, and THC have all 3 of them got different modes of operation approaching anxiety. As you mentioned in the last set, one of the magical things that not magical. One of the impressive things that CBG does is decrease anxiety without intoxication, which as most of us know is is exactly the mode of operation for why THC works. It sedates people and for many people that handles, you know, their major type of anxiety and it decreases. So would you please do us the favor of comparing CBG versus THC for anxiety and then CBG versus CBD so we can tease out a little bit more what is unique about CBG compared to these 2 which are very common commonly used in the cannabis world? Sure. So THC is a very strange one in this regard. It's it's well known that, it THC can be helpful or hurt anxiety, and it's really a matter of dose. So very, very small doses have an antianxiety effect, whereas higher doses can certainly induce anxiety or even panic. And this is an effect that's been known for 4000 years because it was in the ancient Assyrian literature on relation to cannabis that was said to be for or against panic, And, again, a matter of dose. Is is that the biphasic nature? Is that the is that the vocabulary? It's called a biphasic dose response with THC. Now if CBG induces anxiety, I don't know what the dose is. We know anecdotally that people have taken very high doses and not, had this problem. So I don't know what the upper limit is. In this instance, CBG probably is a safer bet if the target is anxiety because we know that there's a dose range that seems to be effective and, without the intoxication that can occur if the THC dose gets too high. You know? So how about the 2 together? Well, again, in our formulation work, we're using CBG with low doses of THC, and, seemingly, it's a really useful adjunctive thing to add that improves clinical response. So there seem to be these at least additive or even synergistic benefits on pain, sleep, and mood. And having CBG aboard may increase what's called the therapeutic index of THC, meaning the amount that you can use without producing side effects, and making the overall effect that much greater. So the idea is that adding CBG to your THC may relay may relieve some of the negative outcomes of THC and, therefore, helping THC do its job while CBG is doing its job? Quite. Right on. Right. And we're we're seeing this where we have situations of people rating their effects of different chemoVARS, and we know what the certificates of analysis tell us about the portions of the different components, it's it's easy to see these patterns. One of the things we're hearing consistently is when there's a consistently is when there's a significant amount of CBG in the preparation along with the THC, that it's much better tolerated, that people have a good experience or benefit on symptoms without THC associated side effects. We've seen some of that anecdotally as well here on Vashon Island because, since the CBG dominant cultivar has been grown here on the island for a few years, people who historically had a strong anxious reaction, dysphoric response to smoking cannabis, even if they used, you know, edibles or oils or things like that, some folks, you know, they're just smoking doesn't work for them because it it shoots them up really fast and and some some folks don't like that. People started mixing CBG flour in with their THC flour and and and a lot of those, you know, sharp increases in anxiety were relieved. And, you know, that those are those are very small number of people, but again, shows the potential for use for folks who are also needing THC for some other issue that they're dealing with, but CBG can take the the edge off. Definitely. Do you have, do do you have compare similar comparisons of CBG versus CBD use for anxiety? Okay. So let's look at why people use them. We've we've mentioned that, the survey patients, use CBG to treat pain, anxiety, and aid sleep. We often hear the same claims for CBD, but we have to parse this out. If we're talking about CBD as an isolate, it actually is alerting at low and moderate doses. It's only at extreme doses. Again, this biphasic dose response that CBD actually, produces any kind of sedation. With respect to anxiety, we know now after these studies that there's a distinct difference. CBD was studied in this, an article by Bergamaski et al in Brazil some years ago. They looked at social anxiety, which is akin to what we were doing here. It required 400 milligrams of CBD isolate to produce a significant antianxiety effect. We got the antianxiety effect with 20 milligrams, so that's a 20 fold difference in dose, meaning that it appears that CBG is much more potent as an antianxiety agent. 400 milligrams of CBD is gonna be quite expensive no matter what kind of preparation. Whereas, hopefully, with a CBG only ChemoVAR, 20 milligrams is is just not that much. It should should be much more economical and I suspect, more effective overall. Do we know enough about the mode of operation of CBD versus CBG to know what they may be doing differently. Certainly based on the size of dose, it it suggests we should move in towards CBG, but but having used both independently for my anxiety, I just simply find CBG to be wildly more effective than CBD, which makes me think that it's doing something different than the CBD. Quite likely. And, again, some of this gets into some really heavy effects, in different areas of the brain and and neurotransmitters. What I believe, and we'll need to have subsequent studies like functional MRI or, PET scans to look at this, but, this is likely affecting, the limbic system, emotional areas of the brain. And, yeah, that likely are a lot of distinct differences, but that's gonna require more investigation. Yeah. That sounds like a great Shaping Fire episode too. So as soon as you got that research done, make sure you let me know, Ethan. Yeah, it might be a while. Another thing that I wanna point out, you just compared, the 20 milligrams of whole plant CBD dominant tincture to 400 milligrams of CBD isolate. And we've already talked a little bit, on other times that we have spoken about the difference between isolate and whole plant preparations. One of the ideas that the paper puts forward is that, one way to tweak the study to look for, additional benefits would be to increase the dosage of the CBG from from the 20 milligrams that was delivered up to 25 to 50 milligrams because some of the other science that is being done at this time are is using isolate up to 50 milligrams. But to me, someone who's very much in the whole plant medicine, the efficacy of isolate and whole resin aren't the same. And time and time again, we see, CBD isolate, for example, not showing the same efficacy as whole plant. How do you weigh for yourself, you know, 20 milligrams of whole plant tincture that was used in your study versus 25 to 50 milligrams of isolate being used in a different study? It seems to me like those are they would be very hard to compare those because they're not apples and apples. Yeah. It's a problem, and this is why, certainly when I'm reviewing, acting as a peer reviewer on other studies, I want specification on what's being utilized. In other words, we wanna see studies where there actually is a certificate of analysis as we provided here. In contrast, where you've got studies where, let's say you're looking at pain, and, there are a whole bunch of different preparations. They might be THC predominant, or they might be type twos with THC and CBD, different doses, different modes of administration. It's very hard to parse out what's doing what, and you come up with generalities like cannabis helps with pain. That's nice, but, science really demands more specificity. And that's why I believe that studies of this type where we have a defined, preparation, we can it's it's much easier to to make these claims, particularly since we had so many significant results. I think that a lot of citizen scientists and caregivers like myself, we we find ourselves running into an issue where, the studies that are being done right now are being used are being done with isolate because isolate is just a single molecule of the cannabinoid and, it's very specific and and and it's also those studies transition very easily to to pharmaceutical research. Your research on the other hand, I, Harold, because you have the audacity to use the plant as it's grown and using a whole resin and using it in ways that that actual patients, actual humans have been using it for 1000 of years, but I can see that since you choose to not use isolate, you might get some pushback from either people who wanna use your work for pharmaceutical applications or folks who just think that a a plant resin is too wild, if you will. There's too many variables because there's cannabinoids that don't even show up in the COA. But but those of us who are into whole plant medicine, we we still hold on that that's where the future of cannabis medicine is. So, you know, as somebody, you, who has been a long time proponent of the entourage effect and whole plant medicine, how do you see it personally as as why you choose to use whole plant medicine versus isolate? Well, the number one reason is I believe in the synergy of the different components. However, I've been on the other side of the fence too. Keep in mind, the study we just did with limonene, isolate with THC isolate. Sometimes you require a deconstruction and reconstruction to understand what the differences are. So I see a a place for both in research. When it comes to therapeutics, I'm firmly in the camp that you want an extract and not an isolate. Right on. That sounds good for me, and it seems to work best on, on the things that we're trying to do with with real people. So, Ethan, do you have any, other, summary or or impact that you would like to share before we wrap up? Doctor. Darrell Bock Sure. You know, going back to the study, that we did, I'd like to run through some key points, if I may. Doctor. Darrell Bock Please do. Yes. Doctor. Darrell Bock Okay. So this was the first study of cannabagiol looking at anxiety in humans. So we're very pleased with that, and it's often a race against time to get these things published before somebody else does it. So, we're pleased with that. So can Abigirl reduced anxiety and stress in this sort of manufactured setting. You had asked about the degree. I have another figure that we can utilize here. So there was an average decrease in 0.95 out of 10. That's a 26% reduction in the anxiety and stress scores that were already low to begin with. So, you know, what does this mean to somebody who has a clinical anxiety disorder? We can't say from this, but you know and I know from people that have utilized CBG preparations that they're usually very pleased with the results. Another point, in this study, CBG actually enhanced verbal memory, and it did that with no significant impairments either in memory or motor functioning, that's psychomotor speed and balance. That was what the Druid app looked at. So the CBG drew Druid score was lower and comparable to placebo and baseline. Again, we saw no evidence that CBG was intoxicating. Intoxicating. The intoxication and drug effect ratings were under 1 on a 10 point scale, and drug liking remained neutral throughout the study. And in terms of side effects, negative drug effect ratings like dry eyes, rapid heart rate, dry mouth, those remain low and did not differ from placebo. So all of these really indicate that this seems to be have an extremely benign profile at the same time that it's producing significant effects on stress and anxiety. Well, that's a great summary. And, you know, on a on a real human level, I can only imagine that you and doctor Cutler are pretty stoked with how this survey turned out or how the research turned out. Yes. We're definitely going on from here. We have immediate plans for 2 more studies. One would be similar to this, but done in the lab, which allows for greater objective measures, you know, measuring blood pressure, measuring cortisol, a stress hormone, measuring reactions to pain on a thing called the cold presser test. So that'll be up, coming up. And we also have plans for a clinical study, where, CBG preparation would be looked at, in terms of an actual disorder. You mean like a what would like you'll target 1? Yes. Exactly. I see. Good. Well, doctor Russo, thank you so much for being a guest today again on Shaping Fire. I mean you've been on the show so many times over over the years now I think this is gonna be a 115th episode 115 and every time you do, we learn we learn something new and great and and usually on the cusp of the science, so, we really appreciate you taking your very valuable time and joining us and and letting us know what the latest is and what it means to us. Well, always a pleasure. I really welcome this opportunity. So, dear listener, if you would like to follow along with doctor Russo's research, there are 2 good places to do that. The first one is you can follow along with Doctor. Russo's research organization, Kratoscientific. So that's credo, c r e d o, dashscience.com. Or in even better places to get familiar with doctor Russo's library of online at ethanrusso.org. You can find more episodes of the Shaping Fire podcast and subscribe to the show at shapingfire.com and wherever you get your podcasts. If you enjoyed the show, we'd really appreciate it if you would leave a positive review of the podcast wherever you download. Your review will help others find the show so they can enjoy it too. On the Shaping Fire website, you can also subscribe to the newsletter for insights into the latest cannabis news, exclusive videos, and giveaways. On the Shaping Fire website, you'll also find transcripts of today's podcast as well. Be sure to follow on Instagram for all original content not found on the podcast. That's at shapingfire and at shangolos on Instagram. Be sure to check out the Shapingfire YouTube channel for exclusive interviews, farm tours, and cannabis lectures. Does your company want to reach our national audience of cannabis enthusiasts? Email hotspot@shapingfire.com to find out how. Thanks for listening to Shaping Fire. I've been your host, Shango Los.