Endocannabinoid Mechanics

And so for many, it’s easier for them to give you their best guess. Rather than say they don’t know. And so it goes with so many cannabis educators as well. It’s not hard to get a speaking gig on cannabis medicine at a cannabis convention without any actual scientific or medical training. I’ve seen a multitude of speakers and panelists who are simply parroting what they heard from someone else or something they read in an unsourced internet post. Too many medical cannabis speakers vaguely explain the endocannabinoid system. And when you ask follow up questions, reply with additional vagueness and platitudes but not very much detail or scientific rigor. These are the charlatans and carpetbaggers that degrade our community as a whole. However, there’s a new breed of cannabis educator ready to replace these folks. They are well educated, well spoken enough, confident enough and full of heart and the right intentions. I’m seeing more and more of a new generation who are able to study cannabis medicine, or the cannabis plant in school. They combine the highest ideals of our community with the knowledge that comes from rigorous study. I am exceptionally enthused by this new generation of cannabis leaders and look forward to working with them and someday handing off the baton to them as they take over. I encourage you to do the same. If there is someone that you follow online that has the depth and accuracy of information that you respect. Take a moment and tell somebody about them or make a post to your social media about them intentionally help their message rise above the noise of charlatans so that more of your friends and family have the opportunity to learn from someone offering real science and real actionable information. shining light on good cannabis people is an act of cannabis activism. If you want to learn about cannabis health, business 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 to 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 for sign up to receive the newsletter. There’s nothing else you need to do to win except receive that newsletter so go to shaping fire calm to 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’m your host Shango los. 

Introducing Miyabe Shields

Today my guest is Miyabe Shields PhD. Dr. Shields is co founder of Real isolates, which ironically focuses on the importance of secondary plan components and synergistic cannabis blends. So essentially whole plant medicine Miyabe received their PhD in pharmaceutical sciences focusing on the biochemistry of the endocannabinoid system from Northeastern University in 2018. Miyabe has authored or co authored six peer reviewed publications, and presently has a patent under review for a novel fungus and plant extraction method. Miyabe also has a substantial list of Honors and awards, including a 2016 International cannabinoid Research Society pre doctoral research award, their Tick Tock channel at Miyabe. PhD, has 130,000 followers and is where I first met Miyabe. Today we’re going to focus on the detailed mechanics of the endocannabinoid system and further understand how cannabinoid cannabis medicine works. Welcome to the show Miyabe Thanks for having me. 

Cannabinoids and the Endocannabinoid System

So the cannabinoids interact with cannabinoid receptors in the endocannabinoid system. And they do that by binding with those receptors. That’s how they take action. That’s how they do what they do. But what is actually going on at a chemical level when a cannabinoid pings or receptor, most cannabis educators just kind of generally explain agonist and antagonist and leave it at that, but my audience really wants to understand what’s going on at that granular level. So if you would, please explain what’s going on at that point of the receptor and maybe include why some cannabinoids act upon some receptors and not others.

Cannabinoid Receptor and Molecules  

Miyabe Shields
Alright, so we’re gonna dive into structural biochemistry then but a protein so receptors are proteins, and not protein like nutritional protein that we eat in our diet, but a protein molecularly just means a long string of amino acids. So basically, the receptor is this giant ribbon amino acids, which are it’s a really long molecule, and it forms these different shapes, and receptors, like the gpcrs, which is a type of receptor, which is what the cannabinoid receptors are happened to be these shapes that have like seven like helixes, or cylinders. And they’re, they’re arranged in such a way that they’re floating around in our membranes. And what actually happens when a molecule binds to a receptor is that it changes the shape very, very slightly. And that change in shape, which we call a change in conformation, is what activates or inactivates the receptor. So this is like, it’s it’s this amazing process where when THC binds to the CB, one receptor, when it changes the shape of the receptor by binding it, all of a sudden, this new area of the receptor becomes available, because if you’re imagining these seven cylinders, all kind of floating around, all of a sudden, when THC binds, it arranges the seven cylinders, you know, such that this other patch is available that starts the signaling process, it’s called a signaling cascade that happens afterwards. And in terms of why certain molecules have different actions, or can bind to different receptors, that that comes down to three different things. And the first one is shape. So you know, everyone’s heard square peg, round hole. The same thing with receptors and with molecules, there’s a binding pocket. For most molecules, which is on the receptor, it’s like a piece of the receptor that’s shaped such that it can accept these molecules in the CB one receptor, THC binds, you know, somewhere towards the top, and it binds every single time in the same exact way, because it fits into this shaped like a square peg. And another molecule that doesn’t fit into that pocket will not bind to that receptor. So that’s the first thing. And the second thing is charges like positive and negative charges. So in chemistry, there are partial positive and negative charges. And just like magnets, they attract and repel one another. So inside, in addition to the binding pocket having a very specific shape, there also are very specific charges, almost like a magnet that interact with the charges on THC or CBD, that then help to bind it even closer. And then the third thing is what’s called Vander Waals interactions. But it’s really a metaphor for I just think of it like fatty Velcro. Because molecules that are very Fatty, like the cannabinoids, which are, you know, extremely fatty molecules, they can have these interactions with each other where they kind of stick to other fatty molecules. And that’s the third thing that kind of binds these molecules to the receptors. And you have to have a matchup between the shape the charges and the fatty Velcro, for a molecule to have what’s called affinity to a receptor, which just means that the molecule will bind to the receptor. And then the next step further will be what happens to the receptor when that molecule binds. So what you were mentioning about like the different ways in which a molecule can interact with the receptor, THC is often called a partial agonist for a CB one receptor, that means that it turns it on, but only partially, and this is because when THC binds, it changes the shape to turn the receptor on. There are other molecules that can also bind to the receptor, but they change the shape in a different way that leaves the receptor off. These are called inverse agonists. And then there are molecules that bind and don’t change the shape at all. And these are called neutral antagonists. So there’s and that’s just, you know, those are the three main ones, there’s actually a large array of, of other interactions that the molecules have. And I’ll stop there.

Shango Los
I like that idea that you’ve got these these, these spirals, and and the cannabinoid approaches the receptor, and those excite somehow and then reveal this this lock that the cannabinoid may or may not have the appropriate key for does the does the receptor get sick or excited to add to reveal that lock to every cannabinoid that goes by that seems like that would use a lot of energy or gender? Or does the receptor know when it’s being approached by the cannabinoid if it’s the right one that it should change shape for?

Miyabe Shields
So this is actually what’s the most like what’s the most fascinating thing to me about biochemistry is that nothing is conscious and nothing of these receptors, and enzymes, the proteins all the signaling molecules like the endocannabinoids, Phyto cannabinoids like THC, CBD, serotonin serotonin receptors, all of these none of them are current consciously aware of things approaching OR, or NOT approaching, everything is just happening based on a chemical equilibrium. And everything actually, in our whole entire bodies, pretty much occurs due to forces of enthalpy, which is energy and entropy, which is like a measurement of disorder and chaos. And right, everything in the universe tends towards disorder and chaos. And between those two, you know, factors, it’s, it’s just like whether or not something is statistically likely to occur. So the receptor is sitting there, the receptor is in the as is in the membrane, and it’s empty. And it’s, you could say that it’s waiting for a molecule, but really, it’s just kind of floating around. And then when you have THC molecules floating around, at a certain concentration, there will be enough THC molecules present that it will be, you know, energetically favorable for it to bind to the receptor. And so that what I mentioned earlier about the shape, the charges, and the fatty Velcro, you know, hydrophobic interactions, those three things determine how energetically favorable it is. So the affinity determines how little or how much you need of a certain drug to cause the receptor to what you call to get excited. Because it’s all it’s all based on whether or not it’s it’s favorable. And these things are just kind of floating around, like waiting to interact, and whether or not they interact depends entirely upon how closely they are shaped to one another and, and attract one another.

Shango Los
So so the it’s, it’s a nonconscious thing that is looking to continually bring the energies into balance. And so it sounds like to a certain degree, how the the likelihood of the receptor and the cannabinoid to interact, is a level of subtlety that that might just be based on luck. I mean, not to be, I mean, it sounds like that you need takes a little bit of luck, they’re gonna put them next to each other, but we don’t even necessarily know if that if it’s going to if they’re going to interact until they do,

Miyabe Shields
right. So rather than luck, it’s it’s based on chemical affinity or properties. So it’s not luck, because the receptor has a shape that happens to fit the molecule very well. So if you think about it is like, Okay, if you and if you and I are like boats float, we’re in two boats floating in the ocean. And then there’s like, we’re bumping into each other, whether or not the boats will stick to one another depends on how strong the magnets and Velcro we have on the outside of the boats are to one another. Right? So it’s it is exactly like you’re saying, like luck, in a certain sense, like the the molecules are just kind of floating around. But whether or not it chooses to interact, and it’s not necessarily a choice, it depends upon how strongly they’re attracted to one another by these these chemical forces. So it’s, it’s pre determined, in some sense, where the more of a molecule you add to the solution, the more of them that are present, the higher the statistical chance of a likelihood. And it is exactly as you described, although I wouldn’t say that it’s luck, I would say it’s, it’s chemically and energetically favorable. At that point,

Shango Los
I regretted using luck. As soon as I said it, I’m really I’m talking to a hard scientist,

Miyabe Shields
I get I get what you’re saying, though, it is. It’s not conscious, though, which is, it is something amazing to think about that, you know, if I go to snap my fingers, like, you know, snap it, and I snap my finger is the chemical reactions that occur that allow me to snap those fingers. At a certain point there, there is a conscious thought that goes into beginning that cascade, but all of the molecular interactions that occur are actually just energetically favorable.

Shango Los
So far, I’m glad that when we you know, we go to snap, the probabilities are that it happens, you know, pretty much without fail.

Miyabe Shields
Exactly. And all of those probabilities are pre determined by our signaling systems and receptors. And I mean, that’s just how amazing it’s miraculous to me. I mean, it’s, it’s amazing that we can think about snapping our fingers and that, you know, for most of us, and most of the time, you know, to snap your fingers, it’ll just happen.

Shango Los
So let’s, let’s pull out a levels of magnitude a little bit. So how many of these cannabinoid receptors do we have in our body? Because, you know, it’s, it’s a lot of people. You know, when I, when I was brought into cannabis medicine, I was taught that the number of receptors you have are not related to body weight. It has everything to do with your particular ability, and likelihood to grow more receptors. But more and more within dosing I’m seeing from people giving dosing recommendations based on body weight, which, as far as I’m aware, doesn’t match the science as I learned it five, six years ago. So what is the state of the art now about How many these receptors we have? And if there’s any relationship to body mass,

Miyabe Shields
so I don’t I can’t say this for absolute fact but I do not think that the number of receptors are related to your your body mass like at all, and they change all the time. That’s another thing that we’re not like well aware of that we’re still figuring out is that there are a lot of interactions with our environment and with our diet and yes, using cannabis that change the density, what’s called a receptor density for CB one receptors, and, you know, and also something you pointed out just how many how many receptors do we have? Normally we talk a lot about CB one. Sometimes we’ll talk about the CB two receptor which is generally attributed to the immune system, but we rarely talk about the other receptors beyond that, which you know, there’s there’s multiples and there’s also receptors that we originally classified in different systems that interact with the endocannabinoid system. And, you know, this is gonna get a little bit into the weeds here in terms of like separating out different receptor types for for specific purposes. But I personally don’t believe that the systems are separated at all. The endocannabinoid system is integrally linked to the serotonin system, the dopamine system outputted, the GABA system, there’s actually an Endocannabinoid that is dopamine plus arachidonic acid, it’s there’s a, there’s a serotonin, or accidental amine to ethanolamine, as well, I mean, there’s, those are like rare endocannabinoids. And we don’t research them as much as we’ve researched, or we haven’t yet researched them as much as we’ve researched. The other ones, but it also is fascinating because the CB one receptors, and the CB two receptors have been shown to dimerize, which means they bind to receptors in in other systems, like for the dopamine, it’d be the D two receptor. And it’s been shown that if they dimerize, and if there’s more than one type of receptor, that it will have a different effect. And so we’re still in the even though receptor pharmacology has, there’s been a lot of work and a lot of amazing progress. I still think we’re in the early, you know, in the early stages of understanding these receptors, how they interact with each other. And then to go further into your question about like dosing and, and knowing how much is good for someone, I really don’t think that there’s any way to judge that from the outside. I can’t think of any way that you would know, honestly, other than starting small, and starting with the least amount possible and titrating up slowly until you get your desired effect. Because everybody’s so different, right? Yes, exactly. And especially with the endocannabinoid system, it’s a chicken or an egg. situation where since it’s so connected to the other systems, any change in any of those systems will cause changes in the endocannabinoid system. 

Endocannabinoid Deficiency

There is this theory. It’s a theory although I believe there’s a lot of evidence for it, that many of us have what’s called clinical Endocannabinoid deficiency, which means that we have less circulating endocannabinoids which actually means we have more cannabinoid receptors. Um, and this can cause a slew of problems from like GI issues, mental health, chronic pain. And it’s, you know, it’s still it’s still in the early stages to being we’re still early to being able to understand all of this and how genetics play a role into this.

Shango Los

When we when we had Dr. Russo on a few months back and well, heck, probably even a few years back now we had him on to talk about his clinical Endocannabinoid deficiency paper. And he talked about this, this evolving idea of the endocannabinoid tone, the cannabinoid tone. And and he said at the time that, you know, we weren’t really sure how we were going to measure it. But But people were starting to use this vocabulary to talk about the general I don’t know veracity of the endocannabinoids present in the body, you know, whether you had many or whether or not you had few or or whether or not your system was sluggish. But we haven’t talked to him about that in a long time. And and I know you’re not not de Roos, though, so I’m I’m asking for your opinion, not not his Of course, but what are you seeing as the State of the Science because you know, you are you are a real, you know, a more recent PhD and you are in the trenches, doing, you know, basic cannabinoid science every day. Does this idea of the cannabinoid tone? Is it is it still being played with Or have we moved past that?

Miyabe Shields
I mean, I believe that I have low Endocannabinoid tone. And I know other scientists who feel the same way. I mean, it’s it’s really there is no way of clinically testing it yet. You know, if I went to my doctor and I asked, Hey, can you check the level of my endo ammonoids First of all, they don’t have blank stare. Attempts to do that. But you know, second of all, it’s really really difficult to measure the endocannabinoids because they, they degrade they oxidize really, really easily. They’re it’s it’s difficult. So there are many reasons why the endocannabinoid system has been a little bit sluggish in research behind like other assault systems like serotonin and dopamine or like salt based systems, you know, you’re cooking in the kitchen, it’s easier to clean a glass that had salt water in it than it has to clean a glass that had like butter mixed with maple syrup. And it’s the same when you get to the molecular scale. So if not, if not, maybe even a little bit more difficult when things get sticky. But in going back to that Endocannabinoid tone and the state of it, I think that there is a lot more research coming out like more recently, I’ve seen some more clinical data on, you know, different instances of people with chronic health conditions where they’re finding, hey, this has they have low endocannabinoids, like the ones that come to mind are autism spectrum disorder and PTSD. Both. There have been clinical studies for both of those populations that show that you have a decreased amount of circulating endocannabinoids. And with PTSD, they’ve actually shown that that either it’s a chicken or an egg, there’s an increase in the number of CB one receptors. And so in theory, if you were, you know, to have a clinical Endocannabinoid deficiency and like me, you know, I’ll just talk about myself, I believe I have low endocannabinoids. I don’t I don’t make enough of them. And this is how cannabis helps me because the molecules in cannabis mimic the endocannabinoids. And so I have a sub threat, I have a low level of endocannabinoids. And it causes me a myriad of symptoms, really. And if I use cannabis products, my body is feeling like a restoration of balance. Because even though I’m low in endocannabinoids, I’m giving my body Phyto cannabinoids that restore that that signaling. I don’t know if that. Is that clear? That makes sense.

Shango Los
Yeah, absolutely. As a matter of fact, I would think that just about everybody is experiencing Endocannabinoid deficiency. If you look at what the general causes are, which are, you know, generally, you know, stress, questionable street sleep, questionable nutrition, environmental toxins, and immune suppressing pharmaceuticals. I mean, that’s American life.

Miyabe Shields
And it’s funny, you mentioned nutrition, because that I mean, the endocannabinoids are omega six fatty acids. And, yeah, we often, we often don’t think about how, you know, pushing for certain, you know, high carb, low fat diets would affect your Endocannabinoid tone. I mean, most Yeah, I agree. It’s most people potentially have a deficiency. And the only thing to say, though, is that like you don’t know this, right? I mean, this is the only thing left clinically is to actually go in there and figure it out. And I think it’s it’s in progress to and to go all the way back to answering the question. It is in progress. And I do believe I have spoken to many people who believe that Endocannabinoid deficiency is real. And so far in terms of like a theory, and calling it a theory, there hasn’t been anything to refute it. So that’s important.

Shango Los
Mm hmm. So here around here, we pretty much take it as fact. So it’s interesting actually, to hear, you know, frontline scientists, like you referring to it as a theory because we’re like sold already, you know, so yeah, I mean, yeah, gravity. Gravity is a theory. Well, good point. 

Fluctuation of Receptors Levels Throughout Life

So so let’s talk you really attracted my attention when you said that over the course of our lives, the amount and sorts of receptors that we have come and go, that’s super interesting to me. And then the part that you mentioned that the cannabinoids are fatty acids and last episode, we had Dr. Chris Spooner on and he was encouraging everybody to take fish oil supplements as a way to support your endocannabinoid system. So I’m going to give you kind of like a big big area question and you can take it where you wish. I’m curious to know if our receptors increase and decrease during our lives are they is this increase in decrease more related to Well, I guess I want to know what factors are right Is it is it age is a diet is it everything because most of us want to I would think want to increase the number of receptors in our body so that we can process more cannabinoids for our overall health. And so we would want to build those up. And if there are things that we can do, or awarenesses, we should have times in our life that the the number of receptors would go down, that would probably be good information for us to know.

Miyabe Shields
Absolutely. And I do want to point out that for some people, it would be good to have your receptor levels actually go down, which would be like making more endocannabinoids. It’s all about a balance. So you’re trying to find You’re trying to find the right balance. And some of us have too many receptors and some of us have not not enough. And it’s interesting about the omega three fish oil supplements. My very first research project ever was looking at omega three and omega six dietary fatty acids in in mice. And seeing like what changes that had on on a coaster noids and which are downstream of the endocannabinoids. And I think so in terms of what causes the changes in receptor density. I mean, there’s a number of factors age is certainly a factor. I lean away from just saying everything because that’s just a non answer, right. But unfortunately, it’s, it’s pretty much true. But I mean, age is certainly a fast factor because the endocannabinoid system is really important for a huge number of very important processes, right? Like the basic, the basic ones, our metabolism, immune system, and inflammation, and then overall brain activity, brain hyperactivity. So those are really, really important tasks. And they have different needs, depending on whether or not we’re still growing as we’re children as we, you know, as we age and mature. So age is certainly a factor and it does change. The other factor that you mentioned, stress, stress is a factor. Because cortisol and elevated levels of stress factors in the brain will change it and and this is where we get into the chicken and the egg. Because it’s hard to know whether like whether the endocannabinoid system and the dysregulation of it is the source of the problem or whether it’s a symptom. However, an unbalanced a quote unquote, like unbalanced or dysregulated. endocannabinoid system has been associated with almost every single disorder or pathology, like, I don’t think I can think of a single one that hasn’t been associated with the endocannabinoid system other than like genetic mutations or genetic disorders that have a very clear like molecular mechanism.

Cannabis Panacea

Shango Los
And it’s funny because that’s kind of a challenge, right? Because it’s great to have this one herb that can help us in so many ways, but it also has caused so many people to say, Oh, what is with this cannabis medicine? They talk about it like it’s a panacea. Like it’s like it solves everything and and what I try to tell people is like, no, it doesn’t solve everything. It just solves one thing, but that one thing is the endocannabinoid system and it touches all the systems, it makes it very hard for people to believe

Anti-inflammatory Effect of Cannabinoids

Miyabe Shields
That’s, that’s a great way of putting it the way the way that I usually explain it is that you know, the the cannabinoids are really powerful anti inflammatories, and it’s my personal belief that almost all of these disorders come from like dysregulation and inflammation and not not inflammation in terms of like, Oh, I sprained my ankle, and now my ankle has swollen up and is inflamed. But you know, at the cellular and molecular level, inflammation is just inflammatory signaling molecules. And like you said about about, you know, Endocannabinoid tone being kind of an American having low Endocannabinoid tone being an American feature, there is, there’s a lot of evidence that shows that having high in systemic inflammation is is a problem. And that we don’t really have any way of knowing or understanding where we’re at and our threshold until we remove something, right. So it’s like, a title like speaking from my personal experience, like I have a lot of inflammation all the time, stress causes inflammation, and then also like chronic pain, inflammation, gi inflammation. There’s so many things with which I think inflammation plays a mechanistic factor, because it’s, I mean, in terms of our immune system, like what is inflammation at the molecular level, it really is the most basic way that our body signals to itself, hey, something is wrong here. Like, if you think of it as like, one cell trying to talk to another cell in the body, when it releases inflammatory, like inflammatory factors. It’s trying this is one part of your body, one single cell, trying to tell the other part of your body, hey, something’s wrong here. And so having super high levels of inflammation causes just a large number of problems. And we often get like desensitized to it because we’re just living with systemically high inflammation. And so when Yes, cannabis has, like, you know, people are saying, Oh, it’s a cure all. I do not believe it’s a cure all. But I do believe that it’s a powerful anti inflammatory, and that inflammation plays a crucial role in most disorders and is really, you know, not like under appreciated, but it’s just that it’s not really talked about as inflammation because in the general public, when we think of inflammation, we think of like a swollen lip or or a bruised ankle, not signaling version of it. Exactly. And inflammation is probably the most basic cellular response to stress that any type of of life has and that we develop it’s, it’s part of what’s called the the innate immune system. So like our immune systems have two different two different sides of it. And inflammation is the most basic side. And so cannabis helps by being a powerful anti inflammatory, and there are so many symptoms that are mechanistically related to systemic inflammation.

Shango Los
So if we have so we’ve been talking about how the endocannabinoid system is actually integrated with all the systems and I like what you said early on that, you know, you you actually see it all as one system not really as discrete parts, because they’re all there’s so much interplay. And, and in passing, we all just kind of say, Oh, you know, the endocannabinoid system is the body’s homeostasis devices. You know, if something’s running hot, it cools it down if something sluggish it picks it up. Well, that’s, that’s great as far as like copywriting goes, right? But what happens at a more chemical level, like like we did earlier on, what what happens that? What, what is the method of action that the endocannabinoid system takes to create homeostasis?

Endocannabinoids and Homeostasis

Miyabe Shields
So I would say that it’s different in different parts of the body in different parts of the brain, it could even be different. But the number one, like most generic way of describing it would be that it it can quiet like different cells, and it tells things to be quiet. So sometimes you hear people saying, like, oh, cannabis makes you slow, or cannabis reduces your brain activity. You know, technically, that’s true. But that’s not always a bad thing. Because sometimes there’s too much brain activity, and it’s desirable to quiet parts of the brain that are not supposed to be speaking. So if you think about the way that we’re talking about, I’m talking about signaling now from one brain cell to another brain cell, you can think about it as a one way street, or like, have you ever played the game telephone? Sure, where Yeah, where one person whispers in someone’s ear, and then and so on, and it’s, it’s one direction, that’s how neurotransmitters fire. So they go from the one you have one brain, or they’re like an end to end daisy chain. Yes, that’s exactly the end to end, and you have one neuron, and then you have what’s called a synapse, which is the place or the space between the neuron and then you have the other end. So you have a speaking neuron and a listening. Now, does that make sense, they’re just talking a talking side and then a listening side to the pre synapse before is the talking side. And the post synapse is the listening side. And for all of the classic neurotransmitters, they fire from the pre synapse across the synapse to the post synapse, so they go from speaking side to listening side. And the endocannabinoids are the only molecules that go the opposite direction. And so the endo cannabinoids are created in the post synapse on the listening side. And they transport across the synapse in what’s called a retrograde fashion, like opposite. And they go to the pre synapse. So essentially, if you have a long daisy chain, if let’s let’s say in your telephone line of one way, daisy chains, you have one telephone in there that’s talking way too loud or way too much. The only way for us to quiet it other than finding a way to go all the way around the daisy chain again to quiet it is through the endocannabinoid system, which talks in the opposite direction and says hey, like can you just be quiet?

Shango Los
And what is sent what what is actually sent is that a particular chemical that sent upstream and the endocannabinoid there is the endocannabinoid self. And so then it goes and it will interact with a receptor there and then and then depending on the nature of how it’s talking, it’ll either be agonist or antagonist or would you say reverse agonist,

Miyabe Shields
inverse agonist. So, all the all the endocannabinoids are some not all of them, but the main ones and end amide into a G r agonist, partial agonist at the at the cannabinoid receptors. So if we’re going back to the the presynaptic and postsynaptic, the talking in the listening end, you have the endocannabinoids, they get created on the listening end, and then the receptors are on the talking end. So they are being transported across the synapse, they bind to the receptors and they activate them. And when you activate the cannabinoid receptors, it activates this very specific G protein that is inhibitory. And that G protein follows a signaling cascade that ultimately it changes the voltage. All of all of our cells have a voltage potential, it’s like an it’s an electrical potential to fire. So if you think about it like whether or not a brain cell let’s say this brain cells firing way too often, if you then synthesize the endocannabinoids, and then they activate the cannabinoid receptors, the cannabinoid receptors will change the voltage of that entire cell so that it’s less likely to fire. I follow this so and please ask me a question.

Shango Los
I’m just catching up so so and because it’s less likely to fire that is its response to the up chain saying, like, Don’t talk so much. That’s really great. You know me Not me, I really and there’s actually liberation in this information. I can’t be the only one listening to you going, Oh my God, I’ve wondered this for so long. But most people are, most people don’t have this education. And to have it be so contemporary, that they can speak to us in this level of detail. So this is this is really fantastic. So thank you and we are going to go ahead and take our first break. You are listening to shaping fire and my guest today is cannabis scientist and educator Miyabe Shields. 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Welcome back you are listening to shaping fire. I am your host Shango Los and our guest this week as cannabis scientist and educator Miyabe Shields. So during the first set we were talking about the endocannabinoid system itself the the system of receptors and and how they work to keep our body in homeostasis. Clearly, we could have continued on on that topic and it’s been so fascinating but we’re going to shift a little bit during second set and focus on individual cannabinoids because since most of what we try to learn here on shaping fire are things that we can use either for our own health or, or in the you know, the, for the health of the people that we are We love, you know, we try to keep things very, very usable, very actionable information. So let’s let’s start talking about individual cannabinoids. So Miyabe you know, most of us have seen the chart showing how cannabinoids degrade from starting as CBG or CBN. And then degrading down into other cannabinoids when exposed to time or heat I believe it is. So it’s not really usually explained why though. And, you know, I’ve seen on your Tiktok many times you play with the molecular models, and I know you’ve got an intimate understanding of this. So if you’ve walked us through it, what is happening and why is it happening at the chemical level?

Chemical Equilibrium and Cannabinoid Degradation

Miyabe Shields  

Alright, so we’re gonna basically go all the way back into talking about how that everything in the universe, I mentioned earlier that in in the body, everything comes down to a chemical equilibrium. But actually, this applies to everything in the entire universe pretty much, although I’m not sure about, I’m not sure if you go way out into space that that applies. But um, but pretty much everything comes down to basically, energy and entropy. So the reason why these molecules degrade is because if you leave them open to oxygen, so let’s let me back up. If you were to have the molecules by themselves, like in a complete vacuum, AND and OR you can add what we call like an inert gas, which is like argon or helium, it’s a gas that is nonreactive. If you were to have the molecule, and it were to be kept in the dark, in some either a vacuum or a gas that’s non volatile, and if it were to be kept very, very cold, like as cold as you possibly could keep it, in theory would be stable that way forever. The only reason why things degrade with heat, light and exposure to air and oxygen, is because even though we see air around us, we don’t think anything of it. There’s a lot of things floating Iran in the air, mostly oxygen and nitrogen, and some other forms like carbon dioxide, and other depending on where you are and what’s what’s in your air, right. But you know, have you heard that story where it’s like, Hey, we asked the fish, how’s the water and the fish goes like what’s water? Yeah, we’re, we’re pretty much the same way with air. So we don’t really think too much about it. But there’s plenty of things in air that when you expose them over time, will, will come to have a chemical reaction with these molecules. And the cannabinoids are quite stable. But there are certain areas of it that are prone to oxidation, that’s the main chemical reaction that occurs. And then slowly from there, things will continue to break down because oxygen is pretty reactive. In terms of like the types of, of molecule or the types of atoms that you introduce, it introduces charges, whenever you have charges around, they’re likely to interact with other charges. And that’s, that’s the reason. So the reason why it occurs is just that it’s it’s chemically favorable. So that’s another reason why if you, if you heat things, you’re giving them energy, and it just happens faster. So the reason why he is a factor is just because it adds energy into the systems of the process exactly for this thing to occur that would have occurred regardless. And yeah, there’s, I guess, if you look at a molecule, there are certain areas of certain molecules that are more vulnerable to degradation or to like an attack of an outside molecule. And all of these things depend on how these atoms are linked together, and how stable that link is to one another. Because if you think about it, if you have seen my videos, and you see the molecules are held together by these little plastic, you know, they’re they’re just bonded together by these little plastic strings. In my model, all of those pieces of plastic look the same. But in real life, they’re all different. And they’re they’re different strengths, like some of the atoms are held together by a fishing line, and others are held together by steel poles.

Shango Los  

So so different cannabinoids have got their weak spot where they’re at the most risk.

Miyabe Shields  

Yep. And that that will change when you once you introduce a you oxidize it, then everything changes again. And that’s one of the things I found so fascinating about chemistry. In the beginning, it’s just this crazy, crazy amount of versatility and then small small changes in molecular structure cause giant changes, you know, downstream. So

Cannabinoids THC and CBD – Benefits Now, Benefits Later 

Shango Los  

let’s talk about the time of efficacy for you know, two of our most favorite cannabinoids, THC and CBD. So, excuse me so for for caregivers everywhere. We’re often trying to explain to our patient you know, the timeframe that they’re going to get relief. And you know, most most cannabis patients that especially at the beginning, they don’t have a really good understanding of the endocannabinoid system. And honestly, most caregivers, even the ones with their heart in the right place might not have that great of an understanding of the endocannabinoid system they just know how to apply the medicine in ways that tend to get relief and for that everyone is grateful. However, you know, there are faster acting cannabinoids and there there are there seem to be slower action of the cannabinoids as well. And I’m going to give you an example that’s pretty common for caregivers to talk about which I’m open to the possibility that this is not true, right. So, you don’t have to defend my position of if this is wrong, like call it out. But very often when we talk about CBD people talk about benefits that you get now and benefits you get later for example, if you are having you know an anxious day full of rumination you can take some you know whole plant CBD and you know something with CBD dominant and it will you know, have a tendency to correct the balance of chemicals and or you know, hit the receptors that that that decrease your experience of dysphoria of anxiety so, so, so that would be your benefit potentially today. But over the long term, for example, after somebody has been taking CBD for you know, for six weeks I’ll often hear back from them and they’ll say oh yeah, you know, I I started taking CBD big for my migraines. But then the diarrhea that I’ve had for three years cleared up and and I explained to them, you know, in layman’s terms, that one of the properties of a strong endocannabinoid system is that the system goes through and does housekeeping like cleaning the cilia in the gut of the mucus and so there’s there’s essentially gifts with purchase when you when you take CBD things that you never intended, but which are totally great to have So I’m very open to the possibility that there’s scientific mess in that example. Yeah. So so so feel free to, you know, correct me but but essentially, the point part I’m trying to get at is cannabinoids, same as I have help now and help later.

How does how,

what’s up with that from your viewpoint as a scientist.

Miyabe Shields  

So I would say that, first of all, that it’s not, it’s absolutely not a pseudoscience. And that it’s definitely true that there are different types of effects that are separated. So help now would be what you would call an acute effect. That’s something that’s happening immediately. So we’re gonna use CBD as the example. CBD actually has very low affinity for the CB one and CB two receptors, but it has been shown to be what’s called an allosteric modulator at the CB one receptor, which is just a fancy way for saying it like binds to a different location. But let’s let’s use CBD as an example. So the acute effect of CBD is when you are actually taking the CBD. And like it happens within like, let’s say if you take it if you take it orally like in a tincture or an edible, you know, it takes 45 minutes to an hour, and then like maybe it lasts like two hours, maybe four hours, that those effects that you feel right then are acute effects. So that’s the effect of the molecule binding to the outside of the CB one receptor and it actually decreases the CB one receptors activity. That would be an acute effect. The health later that you described health now being acute affect health later is what’s called a like a longer term effect. This actually comes from how our body restructures itself, our body does housekeeping like you mentioned, the endocannabinoid system does housekeeping. Our body goes through all of its systems, and does housekeeping pretty much you’re in a constant state of managing what is happening now and what’s going to happen in the future. And what your body does, when let’s say you’re taking a little bit of CBD, I take a bit of CBD every day. And what my body has done over time is it’s responded to that happening. So I get the acute effects from taking CBD every day. But then there’s also these secondary long term effects that happen later, which is your body restructuring and changing certain levels of receptors, and changing certain levels of endocannabinoids. And other like highly likely other signaling molecules like serotonin. And actually, this may seem like a little bit like scary that there’s these two types of effects. But that’s pretty much the entire premise of like SSRIs, and anti, like, you know, mood mood stabilizing medications, many of those also function in the same way where they take a few weeks to, to see actually whether or not they’re going to, you know, have have a beneficial effect, because they work on this, what is a secondary mechanism, that’s a longer term thing. So our bodies do these things. So every single receptor, when it’s when it’s activated, will eventually go through a process to inactivate it. Part of this is our body takes it it’s called endocytosis. And our body like recycles the receptors, you can think about it as like a recycling program. And if you think about it as a recycling program, every time our body recycles these receptors, it’s kind of like counting and taking into account how many of each type is being recycled. And then it will adjust the amount that it creates, like in response to that. That’s,

Shango Los  

that’s incredible. It’s It’s, it’s, it’s, I mean, I know we don’t want to put too much consciousness into these processes, but it’s like a thinking machine itself. It’s self calibrating based on what our body needs. And I love that.

Miyabe Shields  

Oh, absolutely. I mean, yeah, it’s between knowing that things are happening completely, like based on just chance or luck as you put it earlier, but as I was putting it chemical like chemical affinity, and energy everything is happening based on that but it’s it’s this magical combination that is quite conscious. I mean, there is the reason why this is happening is to try and keep us well and to try to keep us alive and functioning. And life is miraculous in that way.

THC, Inflammation and Pain

Shango Los  

Before we move on, I want to hit on one more example of this acute versus longer term impacts and let’s talk about THC with inflammation since you sound like you’re very deep on inflammation as well. So we talked about THC being useful both in the moment acutely for inflammation, pain, and then long term for inflammation as well. And for lack of having heard a better explanation how I normally ask the how I normally explained it to patients when they stopped me like after a talk or something I’ll say, Well, you know, if you take THC now, even at sub sub perceptual doses, you are decreasing some inflammation now, but even more, so you’re decreasing your experience of the pain that comes from inflammation now, which makes you feel like you have less inflammation. But then if you keep on taking THC every three or four hours, the natural anti inflammation characteristics of THC keep on for lack of a better term beating down on inflammation, and or shushing, I guess, you know, telling telling those receptors to be quiet. And, and then over time the inflammation goes down, because those cells are not yelling as much that there is a problem. So I don’t know if that’s the correct size. But there does seem to be this dichotomy between th C’s helping an inflammation patient now in the next three hours, versus a month from now, when they’ve been taking THC all that time. And they’re all like, gosh, you know, my, my arthritis is significantly improved.

Miyabe Shields  

Oh, absolutely. One of I guess what I would say this has to do with is that inflammation is like a threshold or an exponential response, where you feel pain above a certain threshold, right? of inflammation, and your body responds to that by firing, like, let’s just call it like a pain signaling, it’s like a, it’s like a chain, depending on where your inflammation is. So actually, rheumatoid arthritis runs in my family, and I wake up with stiff fingers all the time now. And the pain would originate in the nerves in my hand, so the inflammation originates in your hand and the but you actually feel the pain in your brain, right? So it’s true that they have anti inflammatory properties. It’s also true that if you reduce inflammation, and you decrease the amount of pain that you feel, overall, that you’re decreasing the strength of the pathway of pain, which is something that’s, you know, it’s difficult, it’s a difficult topic, and it’s difficult to prove. But there’s this thing that happens that people neuroscientists say all the time you say, I don’t know if you heard it, but it’s neurons that fire together wire together. That’s this is the this is the saying, because when you have brain cells that are in a circuit, and they’re used to firing in this circuit, they become stronger. So actually, if you think about them as like roads, if you imagine, like when you’re, if your brain is totally naive, it’s like a desert or an area, and there’s, there’s no roads, there’s no point from A to B, so everything’s just a dirt path, you start making the dirt path. But then over time, you start using this one path more and more and more, let’s save, that’s the pathway for inflammatory pain, right, your body becomes really sensitized to that path, because you’re using it so much, that it’s not a dirt road anymore, it turns into a street, that then turns into a major highway that then turns it turns into the fastest route of signaling. And our neuro our brain cells are like that. So when they fire together, they wire together more tightly, and it’s easier for them to go down these pathways. And so it’s interesting, specifically with pain, it’s so difficult to piece apart, whether or not it’s inflammation, certainly, but also whether it’s it’s a sensitization to your body, even even feeling pain. And this is I don’t have the answers for this, either. This is just, you know, me talking out loud thinking about inflammation and how people feel inflammation and pain because, like from, from my perspective, I have chronic joint pain, I have a lot of form, I have a lot of injuries, that I’ve been told that these injuries are the cause of my pain. But I’ve also had a lot of scans and things where I didn’t disclose to anyone that I had prior injuries, and no one can see anything structurally wrong with any any part of it. And there’s this, there’s this piece that I guess you cannot prove, which is where is the sensitization like where is the sensitization to pain. Part of it is in the inflammatory factors, which is the acute effect, what you were saying part of it is that that first effect, which is that there are inflammatory factors there and that cannabis can help by reducing that inflammation. And then the second part of it is breaking the cycle of firing your pain cells all the time, or your pain signaling pathway all the time because like, the less than your body uses that pathway, the less likely it will be to sort of follow down that pathway. You know, I’ve been talking a lot about just like entropy and chemical like statistical chance of something happening and and Everything in the body just runs downhill. So, if anything like the easiest path for Yes, and if it’s the easiest path for your body to feel pain because your body has been in pain for years and years and years, it will be difficult to break that cycle without removing the pain. And then there’s obviously the fact that some there are some aspects of pain that are structural that are caused that the cannabinoids can only help so much with right like if you have a nerve impingement or something that’s actually like causing like a physical causes. It’s mechanically wrong. But I think for from my opinion, a big piece of the long term benefits of cannabis for chronic pain is breaking the cycle. And also in what I mentioned earlier in the in the quieting or the shushing of the cells, because some of us are hypersensitive to a lot I mean, I’m, I’m hypersensitive to a lot of stimuli, not just not just pain, but other types of things too, right, like auditory stimuli or, or, like, certain types of like, tactile feelings. And, you know, we, we don’t know, between between person to person, if you can’t tell what someone’s threshold for pain is, because pain is completely subjective. You know, we we can only feel what we feel in, in our bodies, which is why those

Shango Los  

Pain charts are always so unsatisfying, you know, I feel seven today, or six, or sometimes they show, you know, stick drawing faces, it’s like, oh, gosh, this is a fool’s errand from the beginning.

Miyabe Shields  

Right. And as speaking from someone who has pretty much lived like my entire life at like a five or above, like, at a, at a certain point, it just starts becoming like a status quo and your body actually, your body actually can think of it that way is that if that makes sense, like your body gets into these patterns that it will perpetuate. And I think that in some ways, that’s that’s a way that the cannabinoids can help is by decreasing that that sensitivity. And then there’s there’s another follow up piece, which is that the cannabinoids and the metabolites, so we talked about THC, and you mentioned that like, you know, if there’s an onset of action, and then it’s metabolized by the body, and it’s it is sequestered away in our fat, and it gets stored in our fat. And that’s, that’s one of the reasons why you can test positive on a on a drug test for weeks and weeks afterwards, is because our body’s still is processing and releasing these metabolites. So if you’re using over a longer course of time, then you have a buildup of these metabolites. It’s something called like the depot effect, it’s actually something that is harnessed for other medications like birth control is the first one that comes to mind utilizes the depot effect for like a long term release, essentially. So that’s a whole nother mechanism in which like a long term effect of cannabis can can build up and be slowly released. Because even though those metabolites are not psychoactive, it doesn’t mean that they’re not still circulating at low levels causing, like anti inflammatory effects. And that’s something that I think is, is possible. But to my knowledge, I don’t know if either of those things have been like proven

Cannabis Tolerance and Taking Tolerance Breaks

Shango Los  

Right on I follow that. So let’s talk about tolerance brakes for a moment. So we understand that tolerance, brakes are good so that we can increase our sensitivity to cannabinoids. And we also know that anybody who works with patients knows that trying to convince a patient to go on a tolerance break is very difficult. Because if you know for a lot of people, they get to cannabis last. And then when it works, they’re all like, well, none of the pharma works without terrible side effects. And they hold on to cannabis so dearly. And now we’re telling him to, you know, take 237 days off, which seems unreal, and I think every of all of us who work with patients would would be served by having a better understanding of what happens at a chemical level during a tolerance break so that we can make it more you know, more real, more mechanical for the patient that we’re trying to encourage to give up their most effective medication for a few days. So we go through what happens in our body during a tolerance break.

Miyabe Shields  

Yep, absolutely. So when when you are using cannabis regularly and so I use cannabis regularly and I regularly take tolerance breaks. And when you’re using it regularly, what your body does have a compensatory reaction, which is what I was describing earlier as it decreases the level of CB one receptors that are present. And this is kind of an oversimplification simplification because there are other changes that occur too. But for the most part, when you have that decrease in CB one receptors, you notice it because you have to increase the amount of cannabis that you use to Got the same effect, right. And this is, at the this is kind of at the crutch of tolerance is you, your body has less and less CB one receptors. And actually, you know, I personally believe that a certain level of tolerance is beneficial for me, I maintain a low level of tolerance, like I never, I never take a tolerance break to completely re sensitize because if I completely re sensitize, my body goes 100% the opposite direction and it makes way too many CB one receptors. So essentially when you’re talking to, or wait, what would be my opinion, if I was talking to cannabis patients about tolerance brakes and why they’re necessary. It’s because you’re trying to balance the endocannabinoid system. And when you use cannabis every day, you’re constantly lowering not constant, it doesn’t happen like super quickly like not to don’t want to make anyone look paranoid, but you’re lowering your level of CB one receptors, right like that, as you use cannabis, if you use it every day, you use it over time, you’re going to be lowering those CB one receptors. When you go on a tolerance break, it allows your body to make more CB one receptors and increase them again. And you’re kind of always shooting to find a sweet spot. And if you just continuously use cannabis, and you never take a tolerance break, you’re continuously developing tolerance, and you’re going to be continuously lowering your CB one receptor density. And for some people, there’s not a huge downside to that. But for others, there’s big negative side effects. And it all depends on the patient and what their goals are, right? Because one of the biggest problems or tolerance is that when you develop a tolerance, then the cannabis is no longer effective for what you need it to be effective for. And I was just talking to another scientist about this is that, in our opinion, the reason why we take tolerance breaks is because we need the plant to work when we need it. And maybe that would be a way to describe it to people who are maybe hesitant to try even taking a tolerance break. Because that you don’t want the planet to lose efficacy. You don’t want it to stop working. And it’s possible that that happens when you develop tolerance. And it’s also possible that continuing to develop tolerance will lead to other negative side effects like having problems sleeping or having like other like, there’s some people who get withdrawal symptoms of anxiety when they go to take a tolerance break. So essentially, the more tolerance you develop, the more difficult it becomes to take a tolerance break. And it’s always easier just to regularly take, you know, build breaks into your routine. And I again, though this is this is going to be different from from person to person because I feel like I’m hypocritical even saying this because I do maintain a level of tolerance, like I pretty much takes I take very short tolerance breaks, but I don’t take breaks that are longer than a week. And I don’t don’t completely re sensitize my system because my system as it is on a complete tolerance break is not a high quality of life for me. So it I don’t want to be I don’t want to like mislead, or you know, spread spread negative negative suggestions, this is just like my experience is that I do maintain a low a very, very low tolerance. And I find that to be beneficial and i think it’s it’s all about finding that balance and maybe explaining it in that way where you need the balance of having the risk like the relief like having the plant actually provide you with an effective relief balance with having the right level of receptors in your brain

Shango Los  

Right on I follow this and it makes a lot of sense to because there are a lot of patients who they do want to take some amount of tolerance breaks so that the cannabis is more effective for them on a daily basis. They want to get their receptors and you know cannabinoids more in balance but at the same time going down to zero tolerance can be very extreme as well because I know that if I if I have to stop using cannabinoids for a while for some reason, when I come back sometimes I get so high that like it’s dysphoric right? Or people who have got severe pain and they use cannabinoids at work to treat their pain. Well you know if they were to go a significant amount of time for a complete tolerance break. Well they may just be like super stoned at work. You know like there there really is, you know advanced patients with a lot of experience about cannabis. really embrace the whole idea of individualized cannabis Pathak care because we are all different, but not the beginning. We have to give patients general ideas and then you know, it takes them almost no time. You know, once a patient has got cannabinoids, they become you know, scientists of their own body and it’s It’s great to see,

Miyabe Shields  

I think that that’s an amazing piece of you know, I on one side, I know that it’s something that people view is a very negative thing about cannabis and about plant medicine just in general is that everyone’s overall, it works for some people and does nothing for other people. And there’s no, I think that that’s an amazing gift to be able to be empowered, you know, with with the option. And I do think that having like guidelines, though, like, for example, if I was talking to someone new, who is who is just getting into cannabis, I absolutely would tell them to take tolerance breaks. I also think that tolerance breaks are really great, you know, clarity or relativity, where then you can approach your use, again, every time you take a tolerance break. It allows you to rehash exactly what therapeutic benefits you’re getting from the plant, how it’s helping you. And it gives you more perspective, I think, on that. So I absolutely would in the beginning, like advise people to take dollar and sprigs. And then like you said, most of the time, you know, if this when when cannabis works for someone, and like you said, it’s a last resort, I mean, I’d have to admit, like cannabis was not the first thing that I tried. And it was in many ways a last resort, like I was not, I was not well. And when people are when you when you come to that, and you find something that works for you, it drives you to be so interested in it, because especially in this prohibition era, when we’ve been educated, or at least I was educated that there, you know, there’s nothing worse than being an addict and that it’s going to ruin your life, and that it’s this horrible, horrible thing. And then, you know, you experience this relief from it that you don’t get from anything else. I think that instills a passion of understanding of health on a deeper level. And I think that’s one of the greatest things about cannabis. I think personal empowerment and personal responsibility in our in our lives is important. And, and a huge positive thing. So I would encourage like other people, you know, listening and people that like spreading the knowledge and the and the education that there’s a lot of power in personal experience. And I know scientists are always talking about, you know, clinical research and having to have, you know, having trying to have the most experimental hard scientific data. I agree with that. I think that research is necessary. But I also think that there is a huge, huge amount of value in in the personal stories and in the personal narrative. And we’re all a part of that. So

Shango Los  

Right on the the oral history of medicine. So I’ve got one last quick question for you, before we go to commercial, these tolerance breaks that we’re talking about that don’t get rid of all of your tolerance, but bring you down to more usable levels. While we know that they are different for every single person, we have to recommend something to people for their like, first time until so they can start start somewhere. When you take one of these tolerance breaks, you said you you know rarely do it more than a week. Okay. But what’s your regular, like, my regular is 48 hours, I go to full calendar days with the with now anything and and on day three, I seem to be, you know, reset? What it how does it work for you? And what do you recommend?

Miyabe Shields  

Wow, that’s so funny. We are very, very similar. So yeah, it all depends on what your therapeutic minimum is. So the therapeutic minimum is like the smallest dose that you can use to get the benefit that you’re looking for. Right? And, and each of us has a different minimum, some some people have a therapeutic minimum, far, far above mine, mine’s actually pretty low. So let’s say that you have a therapeutic minimum that is like, well above like 50 milligrams of like an edible, an edible dose or something, something relatively large, right? It would probably mean that you would have to take tolerance breaks more often, if you wanted them to be as short as what you and I are talking about. For me, my normal thing is I go usually somewhere between 36 to 48 hours, at least every week and a half or so, that seems to that seems to keep them I don’t have a regular schedule I did. For a while when I proposed my PhD thesis I was I was like, Oh, I’m proposing a PhD thesis. Let me also propose this other thesis in my life. And that’s actually when I first introduced CBD into my regimen and I was keeping a notebook and I was writing everything down. I was very rigid for about three years with it and developed a routine that now I can sort of just sense by feel. But sometimes if I have if it lines up where I’m free and I have a good time on the weekend to take like a macro dose or a larger dose than I normally would, the beneficial effects can last for far longer for And so that’s sometimes I like kick off my tolerance break so to say with like a larger dose I normally would and then I experienced benefits that lasts for a few days after that and it can begin like what would be a tolerance break and then another thing that’s important about tolerance breaks that I just want to hit on before we go to commercial is that it’s it’s a good time when you’re on a time to break also to think about your diet and water intake and other nutritional it’s just it’s just a good time to think about it because you’re already doing something different. So since you’re already doing something different and taking a tolerance break you could think about really trying to you know make change like I you mentioned about like fish oil supplements or like even just in general unsaturated fatty acids right like olive oil or coconut oil or fish or thinking about about your diet and sleep hygiene and other times I use tolerance brakes as times to think about my overall health.

Shango Los  

It’s like a little mental retreat. One more one more thing before we go to break these tolerance breaks this is all cannabinoids right You can’t just stop THC but keep using CBD right you have to you stop all cannabinoids because you’re trying to give the whole system a break right?

Miyabe Shields  

I never stopped taking CBD but that’s just me that’s just me personally and I use like pretty low low doses of it I didn’t I don’t experience I don’t experience any like tolerance with CBD but I use it much lower concentrations I have I definitely have spoken to people like specifically people with seizures or migraines but us that benefit from like larger doses of CBD, it will they will develop tolerance to it. So I do cycle them in terms of like CBG CBD THC but THC is probably the only one that I take mandatory tolerance breaks from

How THC and CBD Receptors Respond to Taking Breaks 

Shango Los  

As far as how the receptors respond as far as like making more or making less which is essentially what we’re trying to do with the tolerance break. Will it if we’re still taking CBD and we’re not taking THC do the THC receptors go down in number as we want them to.

Miyabe Shields  

So in theory, CBD has almost like an opposite effect on the CB one receptor as THC so in theory, it would not although I can’t say like with 100% knowledge that it’s true because so here’s here’s the theory, right? Like THC activates the CB one receptor and it’s that activation that causes the decrease. And CBD actually, like it doesn’t get activated, it binds to the outside and it turns it down. Like it turns down the volume. So it acts in a totally different mechanism. It’s not clear to me whether CBD has changed has caused changes in CB one receptor density, I would need to look into that to see if, if anything has been done before. But I’m not. In theory, it doesn’t interact the same the same exact way. But I’m not. I’m not Yeah,

Shango Los  

what you’re saying makes sense, though. I mean, there’s a lot of the stuff that we talked about that we have to go on, you know, your educated intuition because this research hasn’t been done but you’re certainly got a perspective and a VISTA point of viewpoint of the medicine which is you know, a lot better than most of ours So, so I’d rather go with your opinion then and then not know at all. So

Miyabe Shields  

yeah, well I mean, this is also it’s my opinion and maybe the study has been done and I haven’t read it yet. I mean there’s no there’s there’s um there’s a lot more coming out and I am excited for us to you know, I am excited to see where we go with research and like where the information takes us because I would like to know that is something that’s interesting, like CBD, CBD the largest to me at least benefits I in my opinion are happening through the serotonin receptors for me, but I use it for mental health. And CBD is really promiscuous. It’s a complicated molecule. I mean, it’s promiscuous, like it’s not necessarily a bad thing, but it binds to many things in the body. It’s busy.

Shango Los  

Right on so let’s go ahead and take that break. Finally, you are listening to shaping fire and my guest today is cannabis scientist and educator Miyabe Shields. This message is for folks who grow cannabis. I’m talking to home growers, patients and commercial growers to probably talking to you. When you plan out your next growing cycle. Be sure to check out Humboldt CSI seeds at Humboldt csi.com Caleb inspectah and his family have lived in Humboldt County for over 100 years. For the last 40 years. Three generations of his family have cultivated extraordinary sense of Mia cannabis in humble Mendocino and Trinity counties, because of his lineage and the hard earned experience that comes from growing up, smoking and sifting large populations of cannabis plants in Northern California. The seeds you’ll cop from CSI will be winning genetics based on longtime heavy hitters and updated and receptive to bring out new and exotic traits and better yields. 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THC, CBD and Whole Plant Isolates

So Miyabe we are to the part of the show that I have been the most uncomfortable about. And I didn’t tell you much about this in advance. So, you know, I know your company that you helped found, which you know, is not the point of the show today, but it’s called real isolates, right. And I know that you are a pharmaceutical chemist, and you spend a lot of time looking at cannabinoid isolates. And for people who aren’t familiar, we’re talking about the pure molecule THC, pure molecule, CBD. Whereas normally I’m talking on this show about, you know, taking the whole plant resin from directly from the plant. So instead of pulling out the isolates of the plant, and then mixing and matching them, like a pharmaceutical company would to kind of, you know, build a medicine, I’m more in the family of let’s breed a plant that affects that has the positive effect for the for the patient. And then let’s just do a whole resin extraction of that plant. And then we’ve got a we’ve got a vet, we’ve got a medicine directly from nature. And so that’s what we talk about a lot on this show. But, you know, you are right there on the frontlines of this science. So, so what what is your take on this, like, you know, you, you clearly understand what I’m talking about, about whole plant medicine and the resin. But I also know that from what I understand a lot of your research is into these individual molecules. And for many of us, like, you know, when CBD was really hard to find, I mean, nowadays the prices crashed, but you know, six years ago, CBD was really hard to find. And so we would we would often recommend to patients that they take a whole plant extract from a THC plant, and then add isolate to it to kind of artificially spike it so they could get the CBD that the studies were saying they were needed. And oh my gosh, I felt like I was making or participating in Frankenstein medicine, you know, so so with with that whole kind of set up, what are your thoughts in comparing whole plant medicine versus the more common use of CBD isolate THC isolate, and now God help us do you know, delta eight isolette?

Miyabe Shields  

Well, actually, it’s funny that you mentioned that our company named real isolates is sort of a play on words, because there are there’s no such thing as a real isolate. And we do research and doing research involves isolating these compounds and, and looking at them. But in terms of the efficacy of whole plant extracts versus isolates, I think that there are huge benefits to chemo diversity that are undervalued and under researched. And actually our whole company, which I know is now probably a misnomer at the time, we thought it was funny, real isolates. At the time, we were like this makes perfect sense. We’ll tell everyone about how there’s no real life let’s so it’s like a science joke that no one gets. Well, hopefully people will get it eventually. But actually, our entire our entire researches that we do and everything is based upon you know, this theory that I’ve been working on that has to do with chemo diversity and the potentially essentially, what you were just describing a whole plants making crude extracts with whole plants and the extremely, extremely complex pharmacology that comes with crude extracts. Because if you think about Have you have you heard of the the three body problem in physics? No, I’m not familiar with that. Okay, so basically, it’s just a problem that says, In physics in a vacuum of space, if you have two planets or two bodies, it’s it’s very, very easy to derive a mathematical equation that describes those two bodies, it’s very predictable, and it’s it’s safe. So pharmaceutical chemistry is in many ways, a two body problem because you have the one synthetic molecule, or in this case, if you were looking at isolates of CBD and THC, you have the one molecule and then you have the the human body, right. But in physics, there’s this problem where instead of two bodies, you introduce a third body like a third planet, and they’re all rotating around each other. And all of a sudden, it becomes impossible to generate an equation to describe as it suddenly gets so complex, and that’s with three and the cannabis plant has over 400 unique molecules in depending on the strain depending on the grow. So depending on like the genetics and the cultivar, depending on the grow conditions and how it’s grown, depending on the drying care process, and how it’s dried and cured. Then depending on how it’s extracted, whether Not at distill what are the distillation parameters like fraction distillation versus short path distillation, it is 100 plus body problem, like, easily for sure. But I’m at the point where like, I embrace that problem because that 100 plus body problem has very specific solutions. But I don’t believe that isolates can consult. That’s just a personal opinion of mine. I personally believe that there are huge advantages to chemo diversity, which is just a description of like the number of total molecules that are in an extract. Like, for example, I have huge success making topicals with crude extracts of cannabis and willow bark. And White willow bark has the precursor has salicylic acid in it, which is the scaffold that we use to make aspirin. But in addition to salicylic acid, it has a bunch of other rare, you know, rare derivatives of salicylic acid, similarly to how cannabis has all the rare cannabinoids and terpenes and flavonoids and other fatty acids and bioactive molecules, right? And do we do we understand exactly how all of these things interact? Like, no, we don’t understand that at all. Yet, we’re not there yet where we could say, I will give you a synthetic mixture of all 400 of these things to cause a very specific effect. I mean, that would be the holy grail, or that would be you know, that would be the goal eventually of research. But we’re nowhere close to there. And in my opinion, does the whole planet have unchartered territory and Uncharted opportunities for various specific therapeutic effects and or increased effects? for like a lower like risk potential? Like Yes, I think that isolates not necessarily CBD isolate, but Okay, well, CBD isolate, maybe I’ll, I could talk a little bit about that. Right. So epidiolex is the pharmaceutical CBD formulation. And the dose for epidiolex is extremely high. I mean, it’s in the it’s in, like, from my weight, it would be like more than a gram more than once per day.

Extremely, extremely high dose for it to be efficacious. And obviously, that’s, you know, seizure disorders require higher doses. But it’s my personal opinion that you could potentially eight CBD, meaning you make CBD more effective by giving it with other cannabinoids that act synergistically. So a synergistic interaction means more than additive. And these are things that are difficult to prove in a laboratory setting. And I know that people are working on it, and that it’s, it’s being done. But in In the meantime, in terms in terms of just like what my opinion is of it, I think that the whole plant extracts have a lower risk potential for negative effects and potentially in many ways, have a higher efficacy. Although there are advantages, there are no doubt advantages to distilling and purifying. You can’t You can’t argue that there, there are some advantages to that. I guess just in the in the personal context, I am a big fan and use crude extracts and flower.

Shango Los  

And I got to tell you, I’m very relieved, because I thought I was going into a debate with a scientist who loved isolates. And I’m like, Oh my god, how am I going to hold my own defending whole plant? And then here you are saying, Oh, actually whole plant, you know, is, you know, is probably preferred, which is a huge relief to me.

Miyabe Shields  

Well, the whole plant is really just a combination of Isolates. Right? But, but it’s not I mean, it’s kind of like contrary right, because I by name isolate means you’re isolating one thing and there there are absolutely advantages to isolate, although, but then in my opinion, I’m not for chronic use. Like specifically we’re talking about tolerance and taking tolerance breaks. And I know I didn’t, I didn’t mention it when you’re talking about it. But there’s, there’s a very specific type of withdrawal and acute withdrawal that is coming up more and more called Cannabis Hyperemesis Syndrome or CHS. And it’s my personal opinion that that develops due to a very, very specific type of tolerance and withdrawal to just THC. And I know it’s not nowhere near close to us, we’re nowhere near close to understanding exactly how all of these things work or whether or not this is this is like 100% the mechanism but when you take a whole plant extract that has you know, a large number of different different cannabinoids also you know the perfect example of this section which is you know, 

Smoking Cannabis vs Edibles with Isolates and Distillates

touching on my current research project is smoking right like I I prefer cannabis smoke to the edible experience. I know that that’s true for a majority of people actually, I certainly pulled. I pulled off my social media and got over 13,000 responses and it’s pretty much an overwhelming majority of people prefer smoking and there’s there’s no doubt advantages to edibles. And that’s in a competent way to that there’s no doubt advantages to pharmaceutical formulations but many edibles these days are made with distillate they’re made with very, very concentrated distillate, even though it’s not isolate is practically isolate. I mean, it depends it depends on you know, the the dispensary, the producer, the producer and the lab that’s making it. But there is often I think it’s common practice for people to distill above 85%. Right, which basically means that you’re taking out everything else and you’re hyper selecting for the cannabinoids. And, you know, and kind of going in a circle here, but I prefer smoking and I always had and and majority of people prefer smoking. And one of the reasons why I believe that is because smoking produces the most diverse formulation out of anything that you possibly could intake in terms of like a crude edible extraction like butter, or RSO (Rick Simpson Oil) versus a distillate extraction versus smoking. The distillate edibles are on one side. And so like isolates and distillate are on one side of like the purest form of just THC, or just CBD. And then crude extracts or whole plant extracts are in the middle. And then smoking is on the opposite side in terms of just the total number of the complexity of the formulation of cannabinoids that you’re taking in. And that you know, this has been my big passion and something that I’m passionate about researching for like for a while now is why is that and looking into it. And you know, it would take a supercomputer and a lot of simulation to even be able to to begin to predict the current like the complex interactions like at the receptor level that occurred with with so many different mixtures, right, like, especially especially when you have the fact that you have like flavonoids and terpenes. And other bioactive molecules, like there’s a lot of factors to take into consideration. 

Creation and Transformation of New Cannabinoids by Combustion

Shango Los  

And you blew me away the other day when you when you taught that, that even regardless of what your your analytics say about your flower, when you burn the flower, you are actually bringing additional cannabinoids into existence so that a burnt combusted flower like in a joint or something is even more pharmacologically complex than what you think is in it when you look at your lab tests.

Miyabe Shields  

Absolutely. I mean, there’s, we always talk about the negatives and the downside to smoking. And I there’s it you can’t argue that there are some negatives to smoking as a method. But there are some benefits as well. And there are some very, very unique, you know, things that occur. And yeah, in terms of what I was mentioning about like dependent regardless of what the flower looks like, I mean, a lot of THC will get converted because it is a it’s a reactive molecule, and you heat it to a very, very high temperature. And then the flower has other reactive molecules as well. The terpenes are all extremely volatile. And then there’s just the fact like when we talk about combustion, you know, true combustion means you’re going all the way down to co2 and water. And we do not fully combust the the flour. I mean, when you’re at the very, very end of your bowl, and it’s all white and ashy. Like Yeah, okay, that’s, you know that that’s completely combusted. But when we’re typically smoking, you know, like, when you’re not running totally dry, like you’re not fully combusting. You’re heating and extracting at the same time. And you’re also transforming. And yeah, it’s I think chemo diversity has a huge impact on the overall effect. I mean, I can tell you right now that like no one will be able to convince me that smoking doesn’t give me a different formulation because it feels so different. Sure does like and there’s so many specific effects in terms of strain specificity that I’m and perhaps I just don’t have experience with enough experience with strain specific edibles. Because you know, so many edibles are made with distillate which distills them back down. 

Shango Los  

So it simplifies them and then I just know that the high is not nearly as good smoking, you know, distillate or actually any version of distillate. Let’s let’s let’s finish with this question because I don’t want to keep you longer than we agreed to. 

Real Life is Messy

The when we talk about whole plant medicine with many scientists at conventions, people tell me a whole plant medicine is messy. We can’t control it. We don’t know what’s in it, whereas you’re talking about the benefits of chemical Diversity. And and you know, I come from a place of efficacy that just works so much better. When you’re talking scientists to scientists, what do you tell that other scientists who says that, you know, cannabis resin is messy and uncontrolled. And so we should go in a different direction.

Miyabe Shields  

I tell them that real life is messy, beautiful. Real Life is pretty uncontrolled, and that I absolutely love the scientific rigour of getting in the lab and minimizing variables. But that’s just not life. And I know that this is something that many scientists do and will in future disagree with me over and I was very hesitant about talking about it for for a long time for that reason, because I do agree that there is it is messy. I mean, I, I agree that it’s unknown, right? And it’s, it’s complicated, but then I also can’t help but think about reality. And, you know, reality is messy and uncontrollable and complicated. And to your point, you know, just to close, like, the most important thing to me is helping other people improve their quality of life. And efficacy is where it’s at. And let me just like, this is just like a thought, a little like thing, a seed of thought. But, you know, most drugs that go to clinical trial from like pharmaceutical, synthetic drugs going into clinical trial. First of all, it’s extremely expensive to get them to a clinical trial, but by the time they get there, the most common reason why they fail is not because they’re toxic, but it’s because they are not efficacious. The most common reason why a drug will fail a clinical trial is because it just simply doesn’t work. So I guess my question to another scientist who would say that it’s messy, my question would be like, so it’s messy, but it works.

Reduction of Suffering is the Goal of Cannabis

Shango Los  

And the reduction of suffering is the goal.

Miyabe Shields  

Is it the goal, right, exactly. Is that the goal? And if that is the goal, which I think everyone agrees that that’s the goal, then why shouldn’t we value something that’s messy and try to work with it? Because I, I totally agree and understand it is messy there. There’s tons of questions. I mean, even with, you know, my project is looking at cannabis smoke. I opened Pandora’s box. And there’s a lot of questions and a lot of things to figure it out and a lot of unknown and I think the unknown makes people scared. But you know, there’s the thing about science like where scientists are like searching around in the dark underneath one streetlamp. So like the universe is this dark, mysterious thing. And science just has this, like the little streetlamps of technology. Like if you imagine every new technological advances a new little streetlamp that you can kind of like turn on and look under, and all of us are down on our hands and knees as scientists with a magnifying glass looking under the streetlamp and then everyone else is like, well, what if the answer is in the dark? You know what I mean? And we we don’t have the answer to that. So you know, that would be I guess this is like and I would love to have a discussions with I’m sure I will have many discussions with other scientists on this. But um, you know, I’ve been speaking with a lot of people on chemo, diversity and most people that I talked to, especially people who have used and benefited from plant medicine, most of those people who have that and hear what I’m saying about chemo diversity are just kind of like right that just, it just makes sense.

Conclusion

Shango Los  

That’s fantastic. Miyabe it has been such a joy to interview you your your depth and detail of knowledge is like so liberating. And and and you know, it says in the intro to the show that we do all of this with good cheer, and you’re you’re such a cheerful and enjoyable person to chat with. I really appreciate it and I got to tell you, like I had so many I’ve got a whole you know, half show of questions that we didn’t get to you, would you be so kind to come back again soon so that we can continue our conversation.

Miyabe Shields  

Oh, absolutely. Thanks for having me. This was really enjoyable and I love talking about this stuff. It’s actually my it’s like extremely special and narrow interests of mine.

Shango Los  

Fantastic. Well, thank you so much. We’ll talk to you again soon. If you are interested in following Miyabe Shields on social media there is a lot of fun there. So I’m going to start out by giving you their Instagram which is Miyagi, which is MiyabePhD, because the tick tock channel keeps on getting deleted and and and there isn’t a website yet so so just go to MiyabePhD on Instagram, and from there you will be able to start picking up on the rest of their teaching. You can find more episodes of the shaping fire podcast and subscribe to the show at shaping fire calm and wherever you get your podcasts. If you enjoyed the show, we’d really appreciate it if you’d 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 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 shaping fire and at Shango Los on Instagram. Be sure to check out shaping fire YouTube channel for exclusive interviews, farm tours and cannabis lectures. Does your company want to reach our national audience of cannabis enthusiasts email hotspot at shaping fire calm to find out how. Thanks for listening to shaping fire. I’ve been your host Shango Los.