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E137 - Ethan Russo - Anxiety, Limonene & CBG

Dr. Ethan Russo has made immense contributions to the understanding of cannabis. 2024 was particularly productive as Dr. Russo’s name kept popping up in some very interesting papers. We got him to chat with us about two of them.

First there is the entourage effect paper. The entourage effect is the idea that different cannabinoids, terpenes and other components of the cannabis plant work together synergistically to give a desired effect. Professor Raphael Mechoulam and colleagues first talked about the entourage effect amongst endogenous cannabinoids in the human body. Dr. Ethan Russo and others have expanded the idea to phytocannabinoids and other cannabis plant components. But it is still just an idea. Now there is a trial that looks at if inhaled limonene makes THC cause less anxiety in people. This could be the beginning of the evidence to validate the entourage effect.

Second, we chatted about a CBG paper. We have a lovely sound bite that describes CBG as a “bubble bath for your brain”. This study gives us some early evidence of the clinical effects of CBG, and whether it actually reduces anxiety.

Let’s do some learning!

Episode Transcript

Trevor:  Kirk. We're back.

Kirk: Hey, Trevor. How's it going?

Trevor: Really well. So we may or may not be getting some construction noise in the background. You know, we had this all set up for a Saturday morning and got all set and then Doris said, and the window guys coming. Doris has been trying to get some windows replaced on our house since I think this time last year and parts weren't coming in and he was busy and weather wasn't agreeing and suddenly the window guy is going to be tearing out some of our windows and replacing them now. Well, we'll see how that goes.

Kirk: Perfect.

Trevor: So I got Dr. Ethan Russo to agree to talk to us again. Hurray.

Kirk: Yeah. Nice. Nice interview.

Trevor: Big fan. Big fan. But no, it was. I'm really glad he said yes because I was not making it up at all that it seemed like every time I turned around this summer, a paper came out with his name on it and he agreed to let us squish two of them together, which was nice because, you know, they're both really interesting. I couldn't decide which one I want to talk about more.

Kirk: You know, it's interesting Doctor Russo. He's considered one of the most published MDs out there. Right. And once again, this is timely because he's talking about anxieties, depressions and how cannabis can help. And my Rant to the World is that… fuck do we not live in awful times where everybody is anxious, everyone's depressed and everyone just needs a boot to the head with something to cheer them up. And here's Russo going out there and saying, by the way, cannabis possibly can help. Further research is needed. But yeah, so how does, how is cannabis going to help us according to Russo's two papers you've got here?

Trevor: Well. so let's talk about, honestly and this was my favorite. Terpenes even before we did this. I'll admit I like, I like limonene in my cannabis because I am a go to sleep kind of guy. Yeah, I have cannabis and it's usually the end of the evening kind of thing for me. But if it has lots of limonene in it, I don't. So that's sort of my, my experience is lemon  fresh thing is really nice. But what they. So let's but let's back up a little bit. Entourage Effect. We've mentioned it several times. I even thought that Russo was the coiner of the phrase, but he said, now is Dr. Mechoulam and colleague, the discoverer of THC. Back in the 60s they were talking about Entourage Effect, as in there's a bunch of cannabinoids the body produces – Anandamide, 2 AG -- are the famous one. And there's a bunch of quote unquote minor human cannabinoids, and they work together to have a bigger effect than sort of greater than the sum of their parts kind of effect. And then it got extended outwards into, well, maybe some of these things that a plant's different cannabinoids might sort of add together to make a bigger effect. And now it's been extended out to things like terpenes. So we've been talking about entourage effect. If you go back to Dr. Mechoulam since the 60s, Dr. Russo has a fairly famous paper from 2011, but for a while about other stuff making cannabis or things like THC work or work differently. But there just hasn't been a lot of clinical evidence, lots of anecdotal, but not a lot of clinical. So Dr. Russo, bunch of people from Johns Hopkins actually got some NIH money and are trying to sort of show the entourage effect in real people in in a clinical trial and they did limonene making you be less look at if limonene would make you less anxious from THC.

Kirk: Yeah before we get into this just talk a little bit more about the Entourage Effect. Yeah. I also found that interesting how the definition of Entourage has changed. So now that we talk about the Entourage Effect more with cannabinoids coming from outside our body. So we've talked about the Entourage Effect often in our podcast. And if you go to our Webpage and search Entourage Effect, I'm sure 100 episodes are going to come up because we talk about it often. But my understanding from the perspective of the Green Culture is that the Entourage Effect is everything the Terpenes, the cannabinoids, everything that's within that flower, right? So if I smoke a whole flower, I'm getting the Entourage Effect of the THC, the CBD, the CBG, the CBCs, the Terpenes  from that cultivar. So if you if you make a cookie out of it, then you grind it up decarbonize it you get the you get that Entourage Effect. So what he's done, though, and again, correct me if I'm wrong or if this is another way of interpreting the Entourage Effect. He is taking THC, right?

Trevor: Yeah,.

Kirk: Because he wasn't using flower in these studies. He was using vapes. He vapes and placebos.

Trevor: Yeah.

Kirk: Similar to other studies like, for example, the one driving autobahn, the episode of driving. So. So he took THC in one study with a Terpene, and he took THC with another study with a minor cannabinoid CBG. And then he's saying he's using the word Entourage to say that those two components in each study is causing the effect. Is that is that is that the way to interpret that?

Trevor: Yeah, now the CB, we will talk about CBG.

Kirk: stay on Limonene.

Trevor: That is a different paper.

Kirk: Stay Limonene.

Trevor: This one was specifically THC and limonene and yeah, that we've isolated those two and it's, you know a little bit of THC, a lot of limonene, a lot of THC, a little bit of limonene and sort of went through all those iterations to see what effect it has specifically on anxiety. And there's a bunch of different ways they measure anxiety.

Kirk: Before we get into it stay on defining Entourage Effect. So by blending those two, is he saying in his study that is an Entourage Effect?

Trevor: Yes. So the idea is that the two of those two get what they're looking to see is if you add limonene to THC, you do get less anxiety.

Kirk: Okay.

Trevor: That's sort of what that's what they're for.

Kirk: They're using the term Entourage to define that. And now some people who listen to our podcast will probably say heresy and not the Entourage Effect. But we preface this.

Trevor: And if you if you read the paper, you'll even see it in their Entourage Effect isn't tightly defined. Different people have but you're right there's definitely the argument well people who are on the pharmaceutical end, it just it's so much easier to get something licensed if you pull out a molecule from the plant and turn that into a drug.

Kirk: Yeah,.

Trevor: But, you know, is that a good idea? Or if you take the whole plant or, you know, we've even had the middle ground with people like Dr. Didi Meri who say, well, you know, sometimes 2 or 3 cannabinoids together are good for a particular he was looking at breast cancer at that point. 2 or 3 cannabinoids together are better than the sum of their points. But sometimes just one is fine. So you know where on the spectrum from individual molecule which is easiest to license to entire plant, what's good or not. I think that whole spectrum is Entourage Effect.

Kirk: And I just want to make sure because some of our listeners are going to want that defined, because what we've done is we've broadened the definition of Entourage Effect for the purpose of, of this episode, right? So people need to understand that. And you mentioned it very briefly, This is how the pharmaceutical companies are going to get into cannabis as medicine and make money and how Western doctors will eventually recognize it as a medicine, when we can definitely say that through studies that these things work. So okay, so that was good. That was important. Yeah. So do you want to talk about what a terpene is and, and like limonene I mean, I found it fascinating he talked about Myrcene.

Trevor: Sure.

Kirk: That that's the one that locks you down and pretty much Myrcene is the biggest cannabinoid. Right,.

Trevor: Terpenoid.

Kirk: Terpenoid Sorry. Right. Yeah. So so limonene and there's D and L right. There's D- Limonene.

Trevor: Yeah. So that we won't go into all the chemistry and honestly I am probably not even the person to get into all the chemistry but the Terpenes, so and you'll hear these two words interchangeably. Terpene and terpenoid. For our purposes, the same thing. And the easiest way. Or how about the way I think about it? Terpenes are the things that make cannabis smell. They're the things that give us the aroma. They do other things as well. But, you know, and Terpenes aren't just in cannabis. They are in other things. So like the limonene Terpene or Terpenoid is in citrus fruit. They're for citrus fruit, smell citrusy and, you know, pinene smells like pine needles and is actually in pine needles. So they are I don't think it's terrible. I'm sure some chemists will disagree, but I think for a general idea of what terpene is, it's the stuff that makes cannabis smell the way it does.

Kirk: Yeah. Yeah. okey.

Trevor: And the interesting part from our point of view is not only does it make it smell, it seems to affect how the cannabis affects the person.

Kirk: Yeah, yeah. And that's what we're learning, right? And it's also, as Dr. Russo says, when you walk down an aisle in the supermarket, you can smell the Terpenes coming from some of these washing fluids. Now, I would say go to a natural store and you're probably getting real Terpenes, But that's a different one. Lemon Skunk, super silver haze, Jack Here. These are strains that maybe up on Limonene and limonene is a very fresh, very fresh smelling thing. So we should we should listen Dr. Russo. So when we come out, do you want to talk more about the second study then, or do you have more do you want to say about this study?

Trevor: Sure Well, let's talk about CBG more the other end.

Kirk: People need to know that this interview is discussing two papers, right one about and we said that cannabinoid and one about Terpenes. Okay. So let's listen, Dr. Russo.

Trevor: So, Dr. Russo, it sure seemed like every time I turned around this summer there was a another paper with your name on it. Yeah. You've. You've been busy.

Dr. Ethan Russo: Sure. Well, there are a couple more that might not quite make it in 2024, but we're trying, trying to get the word out.

Trevor: All right. So I want to start with a one on the Entourage Effect. So the title is Vaporized D-Limonene Selectively Mitigates Acute Anxiogenic effects of Delta nine tetrahydrocannabinol and Healthy Adults Who Intermittently Use Cannabis. And that is in Drug Alcohol Dependance. So before we do a whole bunch of you get to into the weeds. Let's start with just the term Entourage Effect. I'm going to start with I thought you coined in 2011, but I see some you saying that you think it was actually Mechoulam a little earlier than that. But just tell people what the Entourage Effect is and sort of what and we'll sort of get into how this paper looks at that.

Dr. Ethan Russo: Sure. So actually, it dates back to 1998. So Professor Mechoulam and Ben-Shabat in his lab came up with the concept of an Entourage Effect. Now, this originally applied to endocannabinoids, the cannabinoids within our body, and the idea being that a couple of the best known Anandamide and 2-arachidonoylglycerol worked better in conjunction with a bunch of related molecules that didn't seem to have a lot of activity on their own. And this was demonstrated experimentally in their 1998 paper. The following year in 1999, they had another paper and implied that this could well apply to herbal cannabis, being that not just THC and CBD, but up to 148 other cannabinoids and additional biochemicals reside within. And they said that sometimes plants are better medicines than the compounds derived from them. Now they also pointed out that this was theoretical at that time in relation to cannabis. However, I had very much subscribed to this concept before they published. And I've spent most of the intervening 25 years trying to demonstrate that they were right about their hypothesis. So that's the background. Additionally, I will state that under legal circumstances, in the early, early years of this century, I did a series of experiments. This was done in the Netherlands primarily, but vaporizing and double blind fashioned THC with or without different terpenoids. And to me the effects were very clear in showing modification of THC effects. For example, one that isn't in the paper yet, but THC on its own when its vaporized produces a dysphoric effect, not the euphoria that people commonly associate with cannabis usage. Additionally, it's very scattering. Hard to maintain a coherent thought. So sort of like the short term memory impairment people can get from cannabis but more accentuated when adding alpha pinene This short term memory impairment can be reduced or eliminated. So the clarity of thought returns, but the intoxication or high, if you will, is still there. But in the course of doing this, I and some other colleagues tested a bunch of substances and one of them was limonene. Now limonene, whether people realize it or not, is going to be very familiar to them as long as their nose is still working because this is the scent of citrus. The main ingredient of any of the citrus fruits. And you'll certainly encounter it walking down the detergent aisle and the supermarket, because psychologically this scent evokes cleanliness to us. Which is interesting because limonene is also an excellent solvent and cleaning agent physically, not just psychologically, but with limonene combined with THC, what I noticed was a brightening effect. Also definitely an uplifting mood. But at the time these were just anecdotal experiments, so it's not something that was meeting scientific proof, which these days requires basically randomized controlled trials, double blind. And it took all this intervening time to do it. Fortunately, with the team at Johns Hopkins University that's always been interested in things like this, we put together a study with NIH funding that resulted in this publication. Now, I better take a breath there and let it follow up.

Trevor: No, no, no that is perfect. So, like, I was going to say, I read in the paper it said this is one of the first, if not the first we'll call clinical or clinical blinded studies on the Entourage Effect. You and others have talked about it for a while, but now this is some you know, we'll call it hard data on the fact that a terpenoid might affect how THC works and specifically you're looking at anxiety. Is that right?

Dr. Ethan Russo: Right. Sure. That's correct. And there were some antecedents too. Back in the 90s there was a study done by Kimora Komori et al, in Japan where they wafted a citrus scent in the air among hospitalized, depressed patients who were on medication and cut their Hamilton Depression scales in half and got most of them off of their standard antidepressants. So there was evidence previously, but, you know, this had never really found its way into clinical practice. So the idea in the study was to utilize people who were customary cannabis users and put them through a whole series of experiments and different concentrations of material that was vaporized and did their best to mask any excess vapor by blowing through a filter after each inhalation. But different amounts of THC with or without different amounts of limonene. So each person, if I remember correctly, went through nine trials with different concentrations. Ultimately, what was seen was a dose response effect so that there was more anxiety with more THC and a decrement in the anxiety with increase in concentrations of limonene. And that was most pronounced, as you might imagine, at the highest doses of each because people were somewhat tolerant to cannabis effects. And some of the people weren't that anxious with the lower doses.

Trevor: That's great. And just we don't have to go through all of them. But yeah, you put two to test, we'll call anxiety. The team put the patients kind of through their paces there as visual analog scales where they 21 different things. Did the drug affect feel positive, did feel negative. I felt sick. I felt paranoid. I felt anxious. My heart was racing. Then you did a subjective scale before and afterwards at STAI-S scale. Then you had them do cognitive tasks. Like shape recognition and typing things on keyboards. Check their vital signs, your heart rate, their blood pressure. So there was lots of things you were looking at to see how anxious they may or may not have been on the various, limonene, not limonene combinations. So what did you find after sort of putting them through all of these anxiety tests?

Dr. Ethan Russo: Well, first ones not a surprise. High enough dose of THC and this was pure THC. It was not, they weren't smoking joints, for example. So clearly, THC, as the dose escalates, it's more anxiogenic. Makes people feel stressed or anxious. And that could be substantially reduced in a statistically significant manner with increasing doses of limonene. Now at the end, we're talking about 30mg of THC, which is way too much. If someone doesn't have some degree of tolerance and 15mg of limonene, which is a lot. Not every type of cannabis has limonene in it at all. For example, a 1% concentration would be really high and that would be, you know, about a milligram or a little bit less. So one of the criticisms was that, sure, you showed an effect. But you don't get cannabis like this. Well, in fact, you could clearly with concentrates and particularly with CBD predominant material, there may be a tiny amount of THC. And we've actually found chemovar that have a greater concentration of limonene than they do THC. So these things can occur. But the idea was to deconstruct and reconstruct and show that there is this ability to modify THC effects with the Terpenoid.

Trevor: And that's really good. I was going to say, so it was mentioned sort of in the preamble of the paper that it has been found that if we use Dronabinol, which is basically THC or nabilone and which is that THC analogs are close enough to THC in cancer chemo patients, sort of a rate limiting or dose limiting step is that some patients really feel pretty anxious and paranoid, for lack of a better word. So it is a real problem when we're using it medically. So I guess we're hoping that maybe limonene might help with some of that down the road.

Dr. Ethan Russo: Yeah, exactly. So the idea in this kind of thing say that we're formulating for an effect. You want to have enough THC to have benefit on pain or spasticity or whatever the presenting problem is. But without producing anxiety, which is one of the primary side effects of cannabis or THC. So with limonene and presumably other ingredients, one can improve the therapeutic index of THC, which is to say the amount that you can give without producing side effects. So again, I think that in this instance it was amply demonstrated in this article.

Trevor: And it really does. And I really want to get to the other one. But my last little bit about this one is I was getting the impression that this might be the first of many sort of Entourage Effect papers that you, that the team was sort of looking at. Is this sort of one of a few?

Dr. Ethan Russo: Yeah, I sure hope so. You know, it depends on budgeting from NIH and the capacity of Johns Hopkins to do the work. But there's another study in process trying to do the same thing with limonene, but orally.

Trevor: Okay.

Dr. Ethan Russo: And it may be that that doesn't work as well. We'll have to see. Clearly Inhalation does. A similar study with Myrcene. Now Myrcene and THC is going to produce what colloquially is called couch-lock. This mobilization. So there's plenty Myrcene in cannabis. Its usually the most abundant Terpene but that's not always a desirable effect. Unless you're trying to sleep. So again, we're trying to demonstrate that these things make a difference and hopefully help the consumer that's trying to figure out what are the effects that I'm looking for and what might be provided by this particular chemical variety. Chemovar that I'm seeing at the dispensary.

Trevor: So that is great. And we could talk forever on that one, but I really want to try and fit one more paper in because, well, we only get we only get you for so long. So another paper here in Nature Scientific Reports, "Acute effects of cannabidiol or CBG on anxiety, stress and mood, double blind, placebo controlled crossover field study." And just for longtime listeners of the show, Dr. Carey Cutler is the lead author on this one. And we've had her on for, I believe it was migraines in the past. So another sort of friend of the show on this one. So CBG or cannabidiol. It's definitely popular. We hear people talking about it. We have a famous little audio clip on some of our shows where a young lady describes a CBG as a bubble bath for her brain, and that just sounds neat. So we play that over and over again. So, what was sort of the idea behind this study? So it sounds like it's sort of another first. There hasn't been a lot of clinical study on CBG.

Dr. Ethan Russo: That's right. So three years ago we did the first survey of people using CBG predominant material, and we're very surprised at the number of claims of medical benefit in 30 different conditions. But background CBG, cannabigerol, was discovered back in the 60s, right along with THC by Professor Mechoulam. They recognized it as a precursor. So I like to call it the mother of all cannabinoids, but normally the plant doesn't stop there and it tends to be a high throughput too towards THC and CBD. However, again, some 20 years ago Eison deMayer, who was at GW Pharmaceuticals, where I worked for 11 years produced CBG only plants. So they lacked the enzyme that would lead on to THC and CBD. However, not much was done with it. Now again, I had the occasion to use CBG in double blind fashion in these legal experiments back then, and I was really struck by, first of all, it was not intoxicating and yet it had a profound effect on anxiety. I would sort of play devil's advocate with myself and think of things that would normally make me nervous and it just didn't happen. CBG seemed to produce a compartmentalization where you could conceptually think, well, that problem is still there, but I'm not going to dwell on it right now. So this is very unusual affect particularly since there was no sedation with it either. Existing drugs that are used for anxiety typically are sedating or addictive or both, you know, particularly benzodiazepines.

Trevor: The benzodiazepines. That's kind of their description.

Dr. Ethan Russo: Yeah, sure. So this is quite different. But again, nothing happened for a long time. A few years ago, CBG material became available, especially in the northwest U.S. and it's gradually getting further afield. But we definitely wanted to examine this. And after the prior study, looking at a survey, we wanted to do a controlled double blind set of experiments with CBG, and there were some similarities with the limonene study in that this was done, in this instinct that's done over Zoom, but with tests that are meant to induce anxiety and some of these are a little bit diabolical.

Trevor:  I wanted to talk to you about one of them because I don't I don't mind public speaking and actually I like math so but even I was going, So you made them do a speech, you know had the research assistants sort of correct them if they took too long and then they had math problems its sounded awful.

Dr. Ethan Russo: You got a few minutes to prepare one to come back and talk about you're doing an interview, describe your ideal job. And he had to fill this this big amount of time. And in the meantime, the person doing this would change it into a white coat just to enhance the anxiogenic effect. The other one was to start at a very high number and ask them to subtract by 13. And every time they made a mistake, they'd have to go back to the beginning. So again, such as science, this is how you make people nervous. But

Trevor: It worked.

Dr. Ethan Russo: Yeah. So we were using a preparation that was derived from herbal cannabis and that was a pretty straight CBG preparation as a tincture. There was a tiny amount of beta-caryophyllene, small amount, and this is not overtly psychoactive by any means. So we had a pretty pure preparation and 20mg, which is actually a little bit higher than people typically use. But we wanted to get a good effect and people were sequentially tested from 20 minutes to 60 minutes with these various tests and cognitive tests. So the headlines were that there was a very pronounced effect on anxiety and stress levels, but no impairment and actual improvement in verbal memory. So that one was a big surprise. And all of these that I've just mentioned were statistically significant. So we're really excited about this. I mean, I've said this before and other fora, but what the world needs now is a non sedating, non-addictive, anti-anxiety agent. There are a lot of things to be nervous about in the world today. We don't need to go into detail there.

Trevor: No, we don't. We won't tell anybody how many days it's post-election when we did this interview. But yeah, the word recall I want because that one struck me, too. And it was said right in the paper, this is surprising, but I thought that was well set up in the paper that one of the problems with THC is short term memory flash - I can't find the word for that-  where not only did you not get that with CBG, it sounded like the word recall actually got better.

Dr. Ethan Russo: It was.

Trevor: The answer to why is we don't know. But do we have any speculation on what's going on?

Dr. Ethan Russo: Okay. I see two possibilities here. One is when you remove anxiety, you improve performance. And maybe that's true in general, even if you don't carry a diagnosis of anxiety disorder. So that's one. Second is maybe it's actually greasing the skids in the hippocampus so that you make connections between neurons, that the synapses are speeded up. We don't know. So, I mean, a follow up to this would obviously be to do like functional MRI testing and see what lights up after CBG or, you know, things like positron emission tomography to look at the metabolic effects and the energy expenditures. So there are all kinds of different things that we could look at subsequently. But we're going on from this with Carey. We're collaborating on a study that I hope will begin soon. We'll be using a higher dose of CBG with people in the lab and again, way to produce anxieties with what's called the cold processor test. This is a refrigerated unit of water and you put your arm in it and you hold it down until you can't handle the pain anymore. So we're going to look at pain threshold and again, induced anxiety and how that's affected. So because the prior study was done over Zoom in lab we have the capability of monitoring blood pressure, cortisol, stress levels and things of this sort. So we're trying to take it proverbially to the next level in terms of scrutiny of the idea and proof thereof.

Trevor: No, it's very fascinating. And I'm not a psychoanalyst, so I'm a little outside my zone, but I'm just when you're talking about the non sedating, non sort of being able to compartmentalize, I'm thinking about like anxiety things like PTSD, where if, you know, I could sort of compartmentalize the really bad thing. Now, maybe it would be easier for me to talk about that with the therapist and sort of work through some stuff that, you know, not being it being a hot element, I don't know, hot stove that I don't even want to touch it. It sounds really promising.

Dr. Ethan Russo: Sure. Yeah, we're very excited about this and we feel that I'm going to make a bold prediction. We've certainly seen a craze attendant to the development of cannabidiol products. I think that CBG has even greater potential.

Trevor: That doesn't sound unreasonable though. Like I said, just anecdotally, Kirk likes to do tours of just cannabis shops and see what people are using it. Last summer when he did the cross-Canada tour, everybody was talking about CBG and how much they loved it, so. So yeah, the Rec market really, really likes it. So doesn't sound like a big surprise to have the medicinal market sort of playing catch up on that. That would be that would be great.

Dr. Ethan Russo: Sure.

Trevor: Anything. And we have now nicely summed up two really big studies. Anything we sort of missed on either of those or anything you think the audience needs to know about CBG and or limonene?

Dr. Ethan Russo: Yeah, I just would go on about CBG to say that it seems to have great versatility in its other effects. It's selective for certain kinds of cancer in it and apparently it can be used in big doses, unlike THC for that kind of treatment and it does have effects on pain. I was talking to a manufacturer last week and she said that they're finding a reason to put it in almost everything, whether it's medicinally oriented or the recreational market, because everything works better with some CBG content. And similarly, in the formulation work that I'm doing at Credo Science, we're finding reason to put it in most preparations.

Trevor: And just on the preparation side, is it all CBG or are you doing things with CBGa as well?

Dr. Ethan Russo: There's even less known about it. There are preparations that combine the two, but you know, I'm going to rest on the usual suggestion that more research is needed. Yeah, I just can't tell you what the effects of that are to any great extent.

Trevor: No. Fair enough. Well, again, we really appreciate your time and going through two complicated things with such eloquence. Thank you very much.

Dr. Ethan Russo: Thanks so much for the opportunity.

Trevor: So we have that wonderful sound byte that we play periodically in our show about CBG is like a bubble bath for my brain. And that's what this second study was, was looking at. I got a big kick out of the fact that it was the lead author is actually Dr. Carey Cutler, and we have interviewed her back on Episode 43 about migraines. And she's actually she's the lead author on this one. Yeah. They found innovative, and I like Dr. Russo's word, diabolical ways to stress people out over Zoom and then give them some CBG and see if they could make them less stressed. Like I just we talked about a little bit in the interview. But just think about this for a second. You're on a Zoom call and okay, you have five minutes to come up with why you are the best person for this job. Go now. And if you after your a little bit of prep time, if you use pause for more than 20s the person in the now wearing a white coat needled you want to keep going. What do you have to say about that? And then they'll start it, you know, 2073 start subtracting by 13. You got that wrong like. Yeah. Yeah. You can see, yeah, they could induce a bunch of stress over Zoom and then check to see if the CBG helps them out.

Kirk: Yeah, it's an interesting paper. Just again going back into episodes. Episode 113 was Road Stories. And we learned from we learned from Peyton about using a bubble bath for my brain.

Trevor: Bubble bath for my brain.

Kirk: And she's a Bud tender. She's a Bud tender. Where was she? A bud tender now She was in Saskatchewan. I met her in Saskatchewan. So that's Episode 113 Meadow Lake, Yes. So she's a quote that we love.  On this paper, again, the Entourage Effect. We discussed that up front. There are some weaknesses with this paper in the sense and they discussed the limitations in this paper.

Trevor: Yeah.

Kirk: The fact that it was very subjective, small amount of people.

Trevor: And done over Zoom so you could actually, you know, check people's heart rate or cortisol levels. But sometimes it's that you got to play with the cards that are giving you. And as far as they know, this is either the first or one of the first to even just try to elucidate what CBG is doing to people. Like, you know, there's been lots of research on THC and lots on CBD, but CBG, Cannabigerol, there's just hasn't been a lot of actual clinical trials with people and you know, and placebo controlled and that kind of thing. So even I think Dr. Russo, I think he mentioned in there, I don't think it was off camera that they would like to use this as a stepping stone to some actual in clinic, in lab trials where they could measure your heart rate and measure your cortisol levels and other, we'll call them, less subjective measures of stress.

Kirk: Yeah, there's a couple of little nuances that I picked out of his conversation. One I found interesting is that THC by itself is dysphoric. Yes.

Trevor: Yeah.

Kirk: And you know, it's interesting because I've often spouted off to people that I don't consider myself cannabis naive, but in the last five years I pretty much have only consumed my own home grown and I have had some commercial stuff and, and I think we've discussed it's that, wow, like 60% give me a break. Infused cannabis and stuff. But what I notice most people like if I go to a concert, most people are a sucking from a vape, right? And a lot of these vape cartridges are straight up THC, right? Some of them have terpenes in them, some of them have offered. But I've often marvel that that and you watch people who are sucking on a high THC vape and you think, gee whiz, have they mixed anything with that, what's the Entourage Effect? Because if you have straight up THC, you're pretty much going to be disrupted. It's not it may not necessarily be a good experience. Whereas if you've blended with some Terpenes, according to the study with Limonene in or blend it with some other cannabinoids such as CBD or CBGs, you'll get a much pleasant experience from it. And that's what I found interesting. It sort of it sort of compliments the concept that the plant the plant offers more than just THC.

Trevor: Yes, Yeah. No, and absolutely. And, you know, score one for that. Sorry. Although you go to some conferences, it sure seems like it's a competition. It's not really a competition between the single ingredient people and the whole flower people. We can all play nicely together and there are going to be times where a single ingredient or 3 or 4 out of the plant is the answer. And there's going to be others where the whole plant. But it's definitely there's definitely something to be said about all the probably thousands of chemicals in the cannabis plant working together.

Kirk: Yeah. yeah. I'm going back to the going back to the concept of growing cannabis and trying to take this academic paper and apply it to the green culture. CBG is called the Mother of Cannabinoids because it is the first primary cannabinoid that the flower produced.

Trevor: and everything else come off of it?

Kirk: yeah, yeah. So CBG is in the flower. So you grow in your plant, it sprouts a little flower. You start getting stamens on. It full of CBG. Now what happens is as those CBG convert to other cannabinoids, THC, of course, and I should be saying THCa, CBDa and all the other cannabinoids. And what happens now as a grower? Because I wanted to talk a little bit about these papers as a grower. A few harvests ago, I planted a crop and I was going off to I was going off to B.C. that actually the last crop I was going off and I was about three weeks, maybe two weeks from when I should have harvested. And many, many of the growers would tell you and Jorge talks about this, there's pretty much a week within the growing period that is the harvest time. Where the where the cannabis plant is at the best, in his opinion as a grower. And I was a week off, so I harvested the plants a week early, which disappointed a few of my cannabis teachers or growers. My sensei disappointed him that I didn't have the respect for the plant that I harvested early. But what I have found from that harvest now I haven't got it, I haven't had it, I haven't had it tested. But I, I believe, from what I understand, is more than likely that plant probably has a higher level of CBGs in it. Those plants than my normal grow does, and probably less CBNs. Because when you start thinking about the other cannabinoids CBN, THCa will convert to CBN's as the pot grows and ages as a plant or ages and cures in your jar in your cellar. So CBG is the very first one and like we know, it's a bubble bath for your brain. So I'm actually kind of interested, like my Cannabis that I'm consuming right now is from that harvest and I do find it more energetic. I do find that when I consume that plant, I want to go for a walk. And I do feel more clarified and I sleep well. So I'm thinking that's probably high in CBG. And if you if so, if you're looking to have bubble bath for your brain and you are a grower and you probably know this already because you'd be growing is to consider the harvest time will affect your CBG levels. So that big diatribe was it would basically that.

Trevor: Yeah no no that that I would find it fascinating. Yeah yeah and you know probably cost prohibitive but it would be really fascinating to take you know Kirk plant X or your four plants or whatever and harvest them at different weeks and send each one off to be tested and see what the different levels the cannabinoids were. I would love to see that.

Kirk: so would if I could afford it, but, but you know what? I had two plants when I got home from Haida Gwaii this spring. I had two plants growing in my backyard because I just threw some shake out there and two plants grew. And again, I do have a license and it's behind. It's all properly, respectfully grown. But we had such a great autumn this year that I didn't harvest one of the plants. I didn't harvest until the middle of probably the early part of October before the first frost hit. The second plant, I harvested in pieces. So I took half of it out and let the other half sit for two weeks. So no, that would be what I'd like to do is take that plant, harvested it here, harvested the rest of the plant two weeks later, get that tested to see what's happened with CBG. Yeah.

Trevor: That'd be really cool. But to circle back actually to paper, one that made me think of something is the limonene and THC, you know, limonene reducing anxiety. The paper mentioned and Dr. Russo brought up that the amount of limonene they used isn't normally found in cannabis plants. Like it's way more.

Kirk: Yeah.

Trevor: So while, you know, it's interesting you found this effect Russo but you know, it's doesn't really exist in nature. But he threw out there kind of as an afterthought, but not something for the growers or maybe the breeders out there to take into account. They do exist though. Plant, you know, strains that produce enough limonene that they would have sort of the amount that they were using in this plant. So because we mentioned again, there's so many things to go through with them. But back to the limonene one, when we are treating cancer patients for like a not enough appetite and nausea and we use the commercial pharmaceutical stuff like Dronabinol, which is basically THC and Nabilone, which is almost THC. One of the limiting things is if we give some people too much of either of those, they get really anxious and paranoid, and they don't want to take anymore. You know, understandably. But if you could have a strain of cannabis that was grown intentionally with a large amount of limonene, you know, this is several steps, but just the way my brain goes is, you know, wouldn't that now be a really good one to use possibly in cancer patients who are using it for their nausea so it could help with their nausea but not make them paranoid? I think just, you know, for all your growers slash breeders out there, high limonene, high limonene plants, I think you should look into that, especially for the medical medicinal.

Kirk: Sure. And I mean, who doesn't like the smell of a lemon, right? You put it under your nose. It just it's lovely. These two studies like to look at these studies are it's they're great to have, Right. But these are the type of studies that Western medicine says this doesn't answer the questions. Right. And he does say it in the study. There are severe limitations to these studies. Low, low participation level. The data, they don't, you know, 30 people. Also very subjective data gathering. But what these well, they're weak papers from the perspective of Western medicine. Right. I mean they're weak papers but.

Trevor: There aren't there are thousands of participants. But for that you need millions of dollars.

Kirk: Sure, sure. Yeah. No, I'm not dissing the papers. What I like about these papers is that, again, the whole cannabis culture and this is pre-Cannabis Act. Okay? This is before we were taught that cannabis is a substance of abuse. The green culture understands cannabis helps people. The green culture believes that there's reasons why different strains work. There's this intuitiveness about the green culture. These papers basically tell me that the intuition of the green culture and the broad brush of those people that use cannabis and understand cannabis, these papers prove those intuitions, correct. Right. That's what these papers.

Trevor: Yep.

Kirk: This is what these papers do for me. But from as a nurse in Western medicine, part of my job is to say, weak paper man. However fantastic paper to support subjective, what people are finding. So it's a timely paper. Papers. They're timely papers I will support the papers. I will advertise the papers. We are doing a podcast of the papers. But man, we need to have a thousand people, and we need to have clinics. We just need more studies to bring the western people up on top of it. Right? Or I don't know what that old adage adjective, medicine used to be bark and leaves. Then it became test tubes. And now we're going bark and leaves. There's this whole parody. Didn't you learn that in pharmacy school someplace?

Trevor: No. No, I slept through that.

Kirk: Sure you did. But medicine used to be barks and leaves, right? Yeah. And then we discovered and this is what big pharma is trying to do with cannabis, and this will help big Pharma. And like you said, to help us fine tune it. But I like it because it just is basically telling me what I think is true. People like to smell limonene, so why wouldn't limonene take anxiety away and look it worked. And CBG it's a young cannabis cannabinoid and it actually is it balances the Entourage Effect and it proves it. So yeah, good papers.

Trevor: Good. So as we never forget to remember too, at the beginning I'm Trevor Shewfelt  I'm the pharmacist.

Kirk: Well, I'm Kirk Nyquist. I'm the registered nurse. I enjoyed. I enjoyed listening to him. I enjoyed reading the papers. So good one. Another Good one.

Trevor: Another Good one.