EP104 Pharmaceutical and Cannabis Interaction with guest Jahan Marcu PhD

Patients always want exact answers. I know when I go to the doctor, I too want specific answers to specific questions and I rarely get them. Similarly, when cannabis patients ask me detailed questions, often the answers are also elusive. The best medicine is individualized medicine, and by definition, individualized medicine is going to be somewhat unique to every person.

That said, when it comes to cannabis, if you identify the proper blend of cannabinoids and start slow and low in the dosage, a path to resolving the issue usually presents itself. Cannabis is safe for nearly everyone and humans have had thousands of years to get into relationship with the plant and learn it to be reliable and with few side effects. However, when you add complex chemical pharmaceuticals to the mix, sometimes things don't go as planned.

And most pharmaceuticals have only been around for a mere fraction of the time that cannabis has been used by humans. And also, while a layperson can easily understand the dosing dynamics for cannabis, that is entirely untrue for most pharmaceuticals whose contents are intentionally obscured and instructions for use are shrouded in legally defendable double talk, it is enough to frustrate anyone just trying to get well.

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So go to shaping fire.com to sign up for the newsletter this week and be entered into this month's and all future newsletter prize drawings. And be sure to check out the multiverse Beans Instagram, you are listening to Shaping Fire. And I am your host, Chango Los. My guest today is Jhan Markou. Dr. Markou is a molecular pharmacologist with over 15 years of experience in cannabinoid research and a PhD focusing on the pharmacology of cannabinoids.

Not only has Johanna committed scientist, but he goes way back too. As a cannabis activist and policy influencer, Dr. Markou is a founding partner at the consulting firm of Markku and Aurora, which provides life science consulting to the cannabis and psychedelic fields. He's also chief scientific officer at Physicians Research Center. Plus Jahan also co-developed a biotech application to predict drug drug interactions between cannabis and commonly prescribed pharmaceutical drugs.

And co-authored one of of the first product safety studies on C B D Dr. Marco co-authored American Herbal Pharmacopia Cannabis Quality Control and Therapeutic Monographs, and serves on multiple expert government advisory and trade association committees. He is the founding editor-in-chief of the American Journal of Endo Cannabinoid Medicine and is adjunct faculty at the University of the Sciences in Philadelphia, teaching the pharmacology of cannabis.

He has many research and media publications and has appeared in Rolling Stone Science, nature Jamma, the Washington Post, CNN n and many others. He is host and producer of the How to Launch An Industry podcast and is often called upon as a cannabis and synthetic drug expert witness. Dr. Markou has received numerous awards, including the Mahmud El Soli Award for Excellence in Cannabis Chemistry, and the Billy Martin Research Achievement Award from the International

Cannabinoid Research Society. On today's episode of Shaping Fire, we will talk about how to think through the dynamic challenges presented by cannabis and pharmaceutical interaction and give you a roadmap for doing this research for yourself or the cannabis patients you care for. During the second set, we'll review red flag pharmaceuticals and drug families that present especially high risk and how the availability of new cannabinoids and concentrates has

exacerbated these issues. And in the third set, we look at the differences between endocannabinoid and phyto cannabinoid drug interaction, discuss the state of drug drug interaction research, and we encourage everyone who uses cannabis to visit buds info.com and complete a short questionnaire to help in the research into this topic. Welcome back to Shaping Fire Jahan. Thank you Shago. It's great to be here.

You know, like what, even though you and I have interacted over the years, this is episode 104, and your last visit to appear on shaping fire was all the way back on episode 29. And that seems like such a long time ago. In fact, it was the week of Christmas in 2017. . Wow. Yeah, it was like, like back, back in the before times, you know. so much as it seems like that seems like a lifetime ago for so many things and projects. Um, that's amazing. Yeah, for.

Sure. So, um, and that was in the early days of shaping fire when we focused a bit more on business. So, um, episode 29 is a great one about cannabis product manufacturing, uh, standards. And we don't cover the license market as much anymore, but, um, folks, if you're, if you are in licensed cannabis or in, in, you know, in medical cannabis and in production, that's a really excellent show that has remained evergreen over the years. So,

so I encourage you to go back and, and check out episode 29. If you haven't. I would say, uh, you know, the big update to that though is I've gone from, you know, voluntary certification assessments for regulatory compliance on all types of cannabis operations around the world. And since then, I actually got to visit hemp facilities in China, uh, Europe.

And I've started to work with, um, state governments on, you know, determining compliance assessment criteria and updating regulations, you know, driven by science from that experience. So, you know, I feel like you're, uh, you're like the paleontologist chango. You got to walk with a, you know, a dinosaur like me in the early days. . That's, that's, I guess that's one way to put it. Except you're, you're still so young though, so I hope so.

Cause I think you're younger than me, so, um, so, so, but, but today we're here to talk, to talk and focus on the interplay between cannabis and the pharmaceuticals that cannabis patients may be taking. And we both wanna be clear right off the bat that we are not giving you medical advice today. Uh, we have no way of knowing your actual whole situation.

And our goal today is to flesh out some of the intricacies of this topic and, and help you gain some perspective so that you can figure out effective individualized medicine for yourself or the people that you care for. So, so, alright, let's get right into it. So, Jahan, the idea that any one of so many phyto cannabinoids interacting with any one of thousands of prescription drugs, that they could have an unintended side effect seems like a pretty realistic

thing nowadays. But for years in the medical cannabis community, no one wanted to admit that it was possible, including me. And, and maybe it was simply because there were so little research into it, or, and we just hadn't seen it. Um, but also it could also just be that we're all really protective of our favorite plant cannabis.

But now we know that these interactions actually do exist as, as more and more people use cannabis and we're able to collect more data, are we actually seeing more reports of interactions nowadays? Yeah. Um, the potential for drug drug interactions, regardless of the substance, you know, cannabis has compounds that interact with receptors and are metabolized by our body, um, ELs that wouldn't have all these, you know,

wonderful therapeutic benefits that we hear about. Um, but, but drug drug interactions or DDIs are, are increasing generally across the board, not just for cannabinoids or cannabis, but it is the primary cause of adverse drug reactions. And it's, it's something that creates over half a billion dollars of estimated burden on our healthcare system annually. And there's a lot of efforts to avoid these drug drug

interactions. Um, you know, drug regulatory agencies like the FDA usually mandate this sort of thing. And we know a lot about them for some stuff. Uh, for like Marinol, which was approved, you know, a decade or so before we even knew they were cannabinoid receptors as well as as for Epidiolex or C B D. So these have been explored. Um, but what we're dealing with now is, you know, we live in a really lucky time and in a really lucky place if you're listening to this in the United States,

we have the fda and I know that people like to criticize the fda. Well that's, that's great. That's, that's, that's one of the great things about being alive. You get to criticize things, but it's also the best drug regulatory agency. In fact, it's so good that most of us simply throw away the insert on any medication we get. It's like, as a long fold out map of potential issues. And we're like, oh,

just throw that away. This is FDA approved. Um, so we do live in a time where we buy a loaf for bread, we buy a bottle of aspirin, we get our prescription medications, and we just assume that if it's on a shelf, it's safe and, and the risks, um, you know, are known or they wouldn't or wouldn't be on a shelf. Um, however, you know, there's interesting things are happening with cannabis compounds, you know, due to a strong patient and consumer demand.

Cannabis based products don't follow the traditional standard drug development pipeline that we hold pharmaceutical drugs like, you know, antidepressants or other drugs too. They just, you know, you package and label them at the state level. And so there is a lack of understanding or

appreciation of the potential drug drug interactions. Um, and again, a lot of these occur from, you know, oral administration of multiple substances, sort of the more drugs that you use, the more pharmaceutical drugs, the more medicines you take, the higher your chances of interactions. Um, and you know, this is not, you know, we have to kind of like, you know, I've been a passionate advocate of product safety, particularly for medical cannabis patients for for almost two decades.

And you know, I remember a time when the plant products weren't even tested before giving to people who had compromised immune systems. Um, I remember arguing with, uh, operators to put voluntarily put expiration dates and people saying thing like, well, cookies don't go bad. Um, and, and, but again, we, we see drug drug interactions all the time. We talk about them all the time, but we don't know that we're talking about them. Some of them are for our benefit and some of 'em can increase risk.

Um, let me give you an example of a conversation I had 15 years ago, maybe 20 years ago. Uh, I was just a, just a little researcher at the time, a undergraduate, and I approached a cannabis operation, started talking them up about cbd, you should carry CBD products. This is like gonna be a great thing. And people had started small circles to talk about, and they asked me what it did and I said, oh, well it, it actually blocks the intoxicating effects of thc mm-hmm. .

And they're like, oh my god, that sounds terrible. Nobody will ever want that. But CBD and THC is a form of a drug drug interaction. It's not quite what we're talking about, but it can be, um, one that may not be ideal, um, for some people. Uh, you know, so I think that when we talk about drug drug interactions, we talk about them, we talk about, oh, this variety of cannabis has this mixture of compounds. It's good for this, it helps with this, it, it's has these indications. Um,

there's an array that can be present. Um, so I think we always have to keep in mind that we are familiar with this. We talk about it, you know, it's like saying, I like to talk about, you know, baseball statistics, but I don't like math. Well, clearly you do like math cuz you're analyzing averages and percentages. So we, we do have the fundamentals of this, I think, in the industry.

So we're not really talking about, I think anything new today that you, that you've probably haven't, you know, discussed before. How do drugs interact together to produce an effect?

And let's talk about that how a little bit, um, because the different mechanisms, um, I think it's important for people to wrap their heads around the, the, the first interaction that I was aware of was years ago learning that, uh, C B D can increase the potency of some seizure medications, meaning that the seizure patients taking C B D could sometimes take less of that seizure medication and get the same um, effect in some cases.

Let's dissect that idea because the C B D could be causing the seizure medication to be more potent for many reasons. One being perhaps that the C B D and the seizure medication are doing the same thing and working side by side instead of actually on each other. Or secondly, CBD could be acting in a way that the seizure medication has get, gets more resources or something. There's a lot of different mechanisms for why that could be happening.

And, um, you know, I, I know that you have studied in detail these different mechanisms of drug drug interaction. I'd really appreciate if you would tease them apart and explain a few of them and like, take your time. Give us, give us like three or four so that we can really grok the different mechanisms. , you know, a absolutely. And when we talk about mechanisms, um, you know, we can, I like to think about 'em in three ways. One is cannabinoids as victim, right?

Where the mechanism is that the levels of the cannabinoid is changed. You take a drug and it makes the, you take, you take it with thc, let's call it drug X, right? And you take it with a THC product and suddenly you're feeling way more sedated or have way higher munchies side effect or whatever, pick your side effect for your conceptual example. And it's just, it's increased because the cannabinoid levels are changed by another drug.

So cannabinoid is a victim where its levels in your body are changed. Well, cannabinoids can also be perpetrators. They can cause changes in the levels, uh, of another drug. Um, and so in this case, you know, they might be increasing or decreasing the amount of, like you said, like an anti-epileptic medication or a pain medication. And if this information is well understood, you're absolutely right, it can be leveraged to improve, uh,

healthcare outcomes. You know, if you're like, oh, there's a drug drug interaction between cannabinoids and opioids, you can take less opioids and get the same effect. Wow. We thank goodness we knew about those interactions so that we could take steps to make that a benefit instead of an increased risk. Now, there also are, so we've talked about cannabinoids as victims, cannabinoids as perpetrators, and there are also pharmacodynamic effects. I think that's the first, uh,

five syllable word we've used so far. But there are pharmacodynamic effects. And what this means is that both drugs have overlapping effects and our concepts

of victim and perpetrator don't apply here. But, you know, one thing is like if we take, uh, research on THC and baclofen individually at doses given to people and studies is a little bit of sedation, not too much to write home about, but you put them together, there's like sedation coming from that drug, sedation coming from the other drug and put it together. Sedation plus sedation equals a lot of sedation. Um, and that could be an unwanted side effect and adverse effect.

Um, and so as we continue with this victim and perpetrator analogy, you know, you mentioned cannabidiol. C B D I, I think this is a great example because, you know, here we have a drug that is given to pediatric patients in large amounts who are also taking other medications. And in the, you know, I think even several years ago starting, I think Divinsky published the paper in 2018, and those of you listening can email me, uh, message me on social media.

If anything I mentioned you're like, I want that study, send me that link. Uh, feel free to reach out. But, you know, they should have high doses of cbd, significantly increased levels of nar clobazam, um, which is an active metabolite of Clobazam. So basically what you're saying is you have a baseline amount,

let's call the baseline zero. It's just or normal, right? Um, and so you, when you take it with um, C B D, um, you can start to see that, uh, the amounts of Clobazam and the ratio of Clobazam to nor Clobazam, the metabolite and the, the, the, the parent compound just go a little haywire.

You start to see those levels change if almost completely different than without cbd We're talking, um, you know, the, the, we're seeing, you know, a hundred and fifty, two hundred, three hundred 50% above baseline. Those, uh, you know, those bars on the graph look like skyscrapers of New York City, which is a signal that we need to pay more attention to. And that would be an example of a cannabinoid as a perpetrator of a drug drugg interaction. Um, and so how is this happening?

You might be saying, well, we have a lot of things in our bodies that like to handle drugs. Um, you know, we're, we're hardwired to, uh, consume things, have them hit little proteins, also known as receptors throughout our body and send along little messages. Well, however, we have to have a system that gets rid of the drugs after they've sort of sent their message to the brain, to the body and had their effect. And we have these drug metabolizing enzymes. What do they do?

Well, they are the garbage trucks of drugs. They just like, they like chewing up drugs and helping us pee them out. Um, so the enzymes of responsible for this, so when I say enzymes, I say proteins, I say receptors. These are all things that our body makes from our dna, right? We have, we have dna, it codes, amino acids that form these proteins. And proteins can do a lot of different things.

And these sip p uh, c y p four 50, we call them sipps, uh, for short, for short, for cytochrome P four 50. Um, there are many different forms and um, you know, there are, um, you know, we inherit different ones from our family. And I think this next point is important because with the advent of gene testing, you can find out some information about how you might, uh, metabolize drugs. So, um, there are people who are slow metabolizers, like really poor. That means the drug stick around longer.

There are people that are intermediate metabolizers. There's people who are extensive, and then there are people who are ultra rapid. And that means that if you're an ultra rapid metabolizer, you can take a drug and you may not even feel, or you may feel just the faintest of effects for it before it's metabolized and excreted from your body. There are some really wild examples of this.

Um, uh, you know, for example, um, there is an association with, um, cuz people who, who suffer from, uh, genetically from sickle cell disease, uh, they have some genes, uh, in majority of the population that are conserved. And many of them are ultra rapid metabolizers of opioids. And frequently people with sickle cell disease get prescribed the maximal allowed amount of opioids, which has been steadily decreasing over time, but they tend to be ultra rapid metabolizers.

So whereas most average people would probably fall in the intermediate, in the mid-range of drug metabolizing. Um, and, and a a little opioid goes a long way. There are populations that would rapidly just and wouldn't feel an effect. So it would look really weird on someone's chart at a doctor like, wow, you're taking a lot of opioids, but unless you knew the genetic component and the other drugs they were taking, it may not make a lot of sense. So one is, uh, to know thy self, right?

And so using kind of all available tools to understand, first of all from a baseline, how do I, what, how do I even metabolize drugs? Am I the type of person who can drink coffee all day long and go to sleep because I'm a rapid metabolizer or will just smelling a cup of coffee keep me up for three days? Mm-hmm. like these might be things you can playfully tease out.

And so the reason I wanna mention that, cuz that is a factor, um, with this, um, stuff, cuz there are people who have mutations, uh, polymorphisms, uh, a single little change, um, can cause people to be, you know, much more, uh, say, you know, it can change the amount of THC that's even in their body. So if you are a slow metabolizer of thc, you'll have more THC floating around. Um, and much like someone floating around with nothing to do,

they might get into trouble. And so that it increases the, the chances of a drug drug interaction. So you could, you could have be a slow metabolizer and realize that, you know, I have to be careful about the timing and method of ingestion because, um, this is gonna stick around for longer than the average person. So you could get, you know, depending on how well you metabolize things,

you could have threefold higher levels floating around. Um, which I have to say, uh, if you do a rapid or ultra rapid metabolizer, you'll probably have a better chance of passing, uh, a blood test. If you were ever pulled over for a cannabis related dui, you just better hope and pray you're a rapid metabolizer if it's based on thresholds for the amount in your system. Uh, just to give you an example of some real world implications for this

information, powerful information is available for you to navigate. This, I think is, is the point I'm making. And so we talked about cbd, uh, clobazam, and how that's an interaction where CBD is inhibiting a sip that prevents the metabolism of this class of benzodiazepine, not, not a fun time. Um, and so, uh, you know, we have these sipps, these enzymes, and there's a whole bunch of 'em, and they do different things. Um, I mean, they metabolize different drugs.

And when we think about, you know, cannabinoids as victims, um, there's uh, different sipps and they have fun little names like sip three A four or C two C nine. And, and you're probably wondering, those are so beautiful, I'm so glad scientists named them that way cuz it's totally easy to understand what they do. It's not like, you know, . Um, so C P three A four, um, can be inhibited. They can be activated, uh,

by different drugs. And so ch clarithromycin ketoconazole, there's other protease inhibitors that people take. And when you take those drugs, you're, you're inhibiting some sipps. They, they like to block those proteins for some reason. And if you take a cannabinoid, you could have two to four times the amount of THC or CBD in your bloodstream, in your plasma, uh, relative to just, you know,

taking the cannabinoid alone. And that's, again, these could be drugs that have nothing to do with each other, like clarithromycin or again, keto cazal. Um, and that's a paper I think published in 2013, you know, 10 years ago they identified this reaction. And so what we see is that you have these drug metabolizing enzymes that can be either inhi, can be largely inhibited by a drug that then affects another drug. So t h c needs CYP three A four to be metabolized and processed by the body.

You inhibit that it stays around longer, um, which could have unintended consequences. But again, it all comes down to how we use the information, um, as well. And so I think that there's again, um, you know, a lot of this information is extrapolated from drug metabolism studies. Like, there's not, there's not a lot of clinical work where people are like, we wanna study drug drug interactions. There's, it's all sort of teased out from studies.

And so a lot of this stuff has been put together from almost like detective, like work. Um, and, and again, you know, there are some clinically significant ones and, you know, cbd, um, you know, with Clobazam, warfarin, uh, taro, Myas and methadone have all been, um, implicated in having a potential significant drug drug interaction. But I'll say that there, the, the nuance there is that it also depends a little bit on your genetic

makeup and, and a couple of other factors. But again, on paper, these things have a clinically significant, uh, interaction potentially. Um, and THC does share some of those similar concerns with, uh, you know, tb, CBD and TC both represent, um, an issue with warfare. And potentially as well.

I, I, um, think that we're seeing now exactly how complex this has become, because I think for most of us, we're just kind of thinking in this singular way that the cannabinoids are interacting with pharmaceuticals. And generally we think of it's having a, a, a bad effect. However, you know, we're getting a better idea now that we can have cannabis acting on the pharmaceutical, and then we can have the pharmaceutical perhaps acting on the cannabis and they

could also be going in the, uh, different directions. They can be inhibit, one could be inhibiting the other, or they could also have additive effects. So now that's going in two directions and then, and then, and then there's another two directions because the additive or inhibited effects could actually end up being desirous or they could be something that we

don't want. And so suddenly now we see this like multi-dimensional, um, uh, you know, interplay between these drug drug interactions and like our definitions kind of start to float away because, because some of the interactions for one patient are gonna be negative and, but for a different patient, they're gonna be desirous.

And I think that you've done a really good job at illustrating how, how we, we need to look at, you know, individual patients and not make big, grandiose rules that we're gonna try to apply to everybody, all drugs or all types of patients. And, uh, and I like this encouragement for us to, you know, dig into our genetics as well. You know, especially if we're trying to tease out some kind of drug drug interaction

problem we think we have. Um, uh, and, and we want to get, uh, specific, um, with that, I also like this idea of this perpetrator and victim idea where, where, you know, you've got, you've got one compound that is receiving the action, and the other one that is, is placing the action. Um, let's talk a little bit about the cannabinoids that are already in our body, right? So like up till now we've been talking about adding phyto cannabinoids, so cannabinoids from plants, um, to the mix.

But we know that we already have endogenous cannabinoids in our body. They already exist. And, and usually when we are taking additional phyto cannabinoids from the cannabis plant to supplement the endocannabinoids that our body creates, um, you know, that's, that's our goal. I'm curious, um, do we see any, uh, or or significant interactions between these endocannabinoids that somebody who doesn't even use cannabis will have in them and these pharmaceuticals?

Sure. Um, you know, we certainly can talk about some of the things that will make you realize you have an endo cannabinoid system. So when we talk about the endo cannabinoid system, it's, it's, again, it's not just anandamide and two, a g and p a and oea and all the amino acid conjugated

endo cannabinoids. And, you know, the, we, we could definitely delve into the molecular psychiatry of all those compounds, but we have to remember that a lot of these endocannabinoids are made on demand and they are metabolized quickly. And reason that's important is because, you know, we ha we, we want to focus on anandamide two G, but we also have to focus on them being made. We, we can't just look at the bullet, we have to look at the gun that's firing the bullet.

And in this sense, um, the analogy isn't perfect, but when we think about fa, which is the, as in, you know, I like to think far out research fa out research, but, uh, fa is an enzyme that, you know, chews up the endo cannabinoid. So, uh, it's, it's the, you know, the endo cannabinoid dump truck. It, they're made quickly by our body on demand. Again, most signaling molecules are made and stored and released. Uh, endocannabinoids are made on demand.

And so one interaction with the endocannabinoid system that I think most people have experienced, um, I will describe in a moment, there's actually an over-the-counter medication that anyone can buy that will interact with your endo cannabinoid system. And I'm not, I'm gonna let you think about it for a minute, listener and chango, but I just wanna tell you about this case report real quick.

And so imagine you, uh, had a history of painless injuries in your life, you accidentally cut your finger and everyone's like, oh my gosh, did that hurt? And you're like, ah, it's all right. Stub your toe, don't feel it. Morphine, opioids don't really relieve your pain. You get some minor surgery, uh, from experiencing life. And, you know, you're like, I don't need pain medication. And, and you know, you, people around you and even use like, wow, I have this high threshold for pain.

So how could the endocannabinoid system explain, well, I'm not really getting an effect from opioids, I actually don't even need them. Um, and that's, um, this is from a story that was laid out in a case report about a, a micro deletion in the dna. And it was in a fa gene, the gene that tells our bodies how to make this enzyme that breaks down the endo cannabinoids and that without the dump truck,

the trash just piles up. And so you get a lot of anandamide and, um, you know, decreases in pain sensitivity. And so this actually really happened. The mutant walks among us, it was a 66 year old female, had history of not requiring any pain medication, a history of painless injuries. Wow. And, and why, why do I, why does this relate to an over-the-counter endo-cannabinoid drug?

Well, it's a little tongue in cheek, but peritol or as some of us call it Tylenol, right, uh, requires fo to exert its pain relieving properties. Um, and so a, uh, basically Alex Mock Creos, who's at Northeastern University was an advisor on my thesis, and, um, was also, you know, many of my colleagues like Dr. Josh Hartsel and others, um, worked with him as well. And he discovered, um, a,

a drug. And it turns out that it's, um, it's related to this, but basically, um, without, when, when you take Tylenol, it is metabolized into a FO inhibitor, which temporarily increases the amount of endocannabinoids in your system. And so if you, uh, created, uh, what they did in an experimental model, a permanent FA inhibitor drug, which irreversibly binds fa, you know, perol or Tylenol had no effect. So no endocannabinoid system,

no Tylenol. Um, and this is, again, this is a fun example, an extreme example for us to play with these concepts like, wow, um, I'm taking Tylenol, how does it work? One of the ways it works is by inhibiting this enzyme that allows my endocannabinoids to flourish and be produced in higher than normal concentrations. It does other things as well. And, um, and so I think like there's one example of endocannabinoid interaction.

And, and so the next time you go to a grocery store, you know, look, there's, there's an endo cannabinoid medicine right there on the shelf. Um, but obviously, you know, endo cannabinoids are slightly different in their activity than THC and cbd. They share a lot of interactions. Um, and I think there are other things we can think about. You know, cannabinoids obviously interact with the endocannabinoid system.

And I think one of the ways that we can think about it, um, is that, um, you know, cannabinoids can, you know, inhibit or enhance certain activities of each other. And so, you know, if we have, you know, uh, CBD in there and it's modulating cannabinoid receptors to make them more difficult to be activated, it's actually an, um, a negative allosteric modulator of CB one. You know, what does that do to your natural anandamide signaling, right?

So CBD can definitely influence that. Um, and I think we can think about other aspects, um, there as well. It's, you know, I wish I had like a virtual whiteboard to start drawing out circles and charts, but let me try to sum it up real quickly. So, you know, CBD is a great one to talk about cause it does a lot of, lot of things. It's a very promiscuous, uh, molecule, but it, it increases anandamide levels cuz CBD does have a little bit of fa inhibitor

activity. So it increases anandamide levels that stimulates a bunch of other channels. Um, and, and receptors like Trip V one, um, if you're heard of vlo receptors trip V one something you, you stimulate every day. If you eat spicy food, um, it's,

it's a capsaicin from chili peppers stimulates it. And so, you know, you could take, uh, you know, CBD increases in anandamide levels or you're an, or if you just have naturally high in anite levels, this will counteract or antagonize, uh, the effect of potentially of, um, of CB one receptors on, on glu liturgic neurons. And so you can, um, you know, one thing that THC does is it slows brain activity a little bit.

And what I mean by brain activity doesn't like make your brain dead, but it's one of the reasons it has a benefit, right? Is that people talk about cytotoxicity excessively active neurons. You, if you have seizure or traumatic injury, your neurons might be firing like crazy and firing until they kill themselves. Just like release, release, release, stimulate, stimulate, stimulate, you know, red alert, red alert. Um. And. Uh, you can decrease that signaling.

That's why one of the reasons it makes it hard to remember stuff. Um, but it also makes it, you know, makes it harder to receive a pain signal. So, so what happens is, uh, just simply put THC hits a receptor decreases in glutamate release. Um, however, uh, you can also enhance glutamate release by stimulating trip receptors. And so you could have this sort of give and take these forces going in different directions, um, to impact it. So I know that was a,

a little bit of a heady response. Um, you know, but I mean, there's lots of examples, um, like this, like, um. That's probably the one we need for now though , um, uh, uh, because you're right, it is, it is incredibly complex and we're certainly not going to be able to explain them all. But, um, in, in one episode.

But you made the point very clearly that we need to not go into this with assumptions that a, we know what's going to happen based on science that might be outmoded, and that individuals and the, you know, really show the importance of individualized medicine and that cannabis can do

that. And then also in a way, we're kind of like already swimming in all of these drug compounds that, that, you know, we're taking from over the, or over the counter drugs plus any pharmaceuticals that were being offered. Plus, you know, you add to it maybe some cannabinoids and, and you know,

maybe somebody is also microdosing mushrooms. And, and suddenly now there's this like the, this soup of, of different drug drug interactions going on, and, and there's no surprise that, that there would be some, some sometimes unexpected effects. And before you jump on that, cause I can almost feel you going for it. , we need to take our first short break. We'll be right back.

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Welcome back. You are listening to Shaping Fire. I'm your host, Chango Lo semi guest, today's molecular pharmacologist, jhan Markku PhD. So now Jhan, during the first set, you know, you were very clear that, um, we are seeing more of these pharmaceutical and cannabis so cannabinoid interactions, um, you know, for two big reasons. One being there's more people using cannabis and, and then two, there's more people researching it and, and collecting the data on this stuff,

which is really great. Um, I would have to think that like, not only is there just like more people though using cannabis, um, cannabis itself is expanded. We're suddenly accessing all these like, new new cannabinoids that we are experiencing in, in higher amounts than they would've in land races. And we're also got like new ways to use cannabis like dabbing, where you're suddenly getting all these terpenes and cannabinoids at one time.

And, you know, it's not uncommon for for people to like keel over after like a fat dab. And um, you know, there's just, there's just like so much, there's so much more than we as humans ever interacted with when we were, you know, you know, walking the planes and, and, and mountains and, and pulling cannabis plants out and, and getting, you know, the kind of land races they had, you know, 10,000 years ago or whatever. Um,

will you speak to that? Like, to what effect these new methods, uh, and new ranges of cannabinoids are having on, um, the interaction with pharmaceuticals. ? You know, absolutely. You know, I think, you know, our ancestors, you know, used to just eat cannabis and, you know, clear some land and there'd be more cannabis growing and fresh cut land. You know, they, they didn't have, um, you know, access to chemicals like butane and shoved it in a tube and

extracted. I mean, they would do manual extractions. And, and so I think it's always important to remember that concentrating cannabis has been, been around for a long time. Um, you know, hashish, uh, you know, Arab merchants, uh, used to trade it up and down the coast of Africa. Some of the earliest reports about cannabis use are these black Hashish bars, um, with guys riding basically naked in horseback into villages to trade, um, these products. Um, but the composition of the matter has,

has changed greatly. And I, you know, the, you know, this always reminds me of, uh, a mantra, a phrase or principle for my colleague Teresa Simon, who's epidemiologist. And we've done a lot of database mining, FDA database, adverse events, databases, um, collection tools, unlike the buds info.com thing where we collect experiential data and adverse

events from campus products. So it's a part of a student project, but she says this thing seems like every week at every meeting, she says, um, uh, efficacy gets it on the market, safety keeps it on the market. Hmm. And I think if we've all been in the cannabis industry more than two years, three years, we can all probably think of one or two products that hit the market cuz they were effective. Where are they now?

And we have to really pause and think about that. Um, we have to think about a little bit about our commitments here when we put these products out there. And, you know, I'm trying to get back to your question as I've meandered off the path a little bit. But it just made me think about, you know, a lot of these products are concentrating things beyond what, um, our ancestors would've, you know, encountered in, in the wild. Um, you know, uh, CBL and all these other cannabinoids. I mean,

they've never been consumed in large amounts. It's unprecedented in our, you know, in our, in our timeframe. I mean, people even 20 years ago weren't really consuming huge amounts of purified cannabinoids. Even the, the distribution of cannabinoids and products in concentrated products from Morocco over the century says not nearly compare to the purity and refinement of these dabs waxes, shatters, what, whatever you want to call it, uh, the stuff that looks like earwax that,

uh, and things like that. And, you know, we're this the, there's no, there's no question. Those are very efficient products to deliver cannabinoids into your body. What is unclear is what is the trade off? What are the, what's the risk benefits to using that? And do you need to use as much as you're using or could you use less? Um, and I think that those are questions we have. Um, you know, when we think about, um, you know, there's this old question, uh, the dose, you know,

makes the poison, you know, nothing is poisonous. Everything is poisonous. It's all a matter of dose. And, you know, we think about terpenes, you know, at ambient air levels, terpenes have, are wonderful. Um, you walk into a grocery store and if they've got that produce section, it smells great to be there, cool breeze, light, smell of chlorophyll, and maybe they have some flowers going. But if you concentrate some of those products, um, you know,

you'll find them in as cleaning agents. Uh, laine is a good one. It's delicious and refreshing and uplifting and lemonade and even on a cannabis product has been reported. But if you concentrate it, it makes a great cleaning agent. It can strip a sticker off a metal wall. Um, not necessarily something you want to inhale into your lungs is a pure concentrated terpenes. And, and it, it also depends again, like there are terpenes that you shouldn't even use in a

diffuser if you have a small pet like a cat. Um, and so again, I think we always have to think about, um, that some of these compounds do carry risks. Uh, it's not like they're safe at any level. yeah. Mm-hmm. , you know, without risk at any level. And, and what I'm really talking about here is, you know, uh, there are moments where we should pause and think. There are, there are red lights, there are yellow lights, there's proceed with normal precautions.

There's proceed with extra precautions and there's considered alternatives. And I think, you know, we're really lucky that thc, cbd, low toxicity, great therapeutic index, I mean, they're both FDA approved in one form. Um, you know, we're the, the THC appears in three scheduling categories. Um, if it's below a certain amount, um, you know, it's been legalized in the form of hemp. I mean, hemp chocolates can have more THC in them than a THC product you buy at a

dispensary. I mean, it's so clearly they've, you know, through regulation and stuff like that, and even this public health experiment we have going on, we found that, hey, you know, there are certain, you know, levels that are lower risk than others. And, and thc, C B D, again, just because they're relatively safe doesn't mean that every single thing on the plant is relatively safe. Um, you know, so I think we have to be, it's good to be optimistic,

but also to have skepticism. Skepticism is our friend, like, you know, okay, thc, cbd, we know about them, we know about their acidic components a little bit, but what do we know about the, you know, other a hundred or so compounds that can be found on it in small amounts? You know, I think of, uh, you know, things in nature, the most potent things in nature are often there in the smallest amounts.

Um, you know, if you look at marine biology like nematodes and, and other stuff like that for documentaries, they have, you know, really potent compounds for defense in them. And they're usually, you know, small amounts. Um, and, you know, we think about things like, I think it's T H C P and these other things that are like, ooh, a hundred times more potent. And it's like, what does that really mean? You know, what does that mean? Does it mean it's just gonna be more pleasurable?

Or does it mean you're gonna be catatonic for three or four days if you consume a large amount of it? And then, and these stories, um, are not often popularized for, for a number of reasons. But there are stories, you know, back in the, you know, back in the decades ago, uh, it was very common for pharmacologists, uh, who developed drugs. This is something they phased out when I was a graduate student,

so no fun for me. But the most, one of the most common things was the pharmacologist to take it to see if it actually worked. Um, and it usually ended with a student being doubled over a sink, vomiting. But, um, you know, that was what people would do. And I think we have to, there are lots of stories. If you go to conferences and you ask around, oh, has anyone ever taken this compound that's a hundred to a thousand times more

potent than thc? Someone way tell you a story. Yeah, that guy was catatonic for five days and on his floor of his kitchen, you know, , stuff like that. But, but again, that's not to say there are, I'm not, and I'm not saying that any compounds like that exist on the market that we know of, but again, I'm just wanting to get the idea that, you know, small changes to a molecule, small differences can have dramatic effects. You know, ethanol, we like to drink it.

Methanol can make us go blind. Uh, there, there's a very subtle difference in their chemical structure.

Right on. I want to tie a couple, uh, things that you said together for the caregivers who are listening because, you know, as, as you know, everybody who listens to the show knows that, like, I'm, I'm, I'm very patient centric, and while I myself have not a, a healthcare professional, um, because of the role I play in the community, I talk to a lot of patients and have, have heard, you know, anecdotal stories and like, you know, over a thousand patients.

And so if you're a caregiver based on what, uh, jhan just said, these are the couple of the takeaways that, that I would offer, which would be, um, number one, um, just because you've had a can, uh, a just because you're working with a patient or you are a patient who has always used cannabis and, and has used a particular pharmaceutical for a long time, don't take out a possibility that the cannabis and the pharmaceutical could be

interacting in a new way now because the cannabis that is available to you as a patient has now changed. Maybe you're no longer just, you know, you know, smoking your home grow and, and, and rolling up joints and, and using that for your pain. Maybe now you are dabbing and maybe you are taking edibles with, you know, 200 milligrams of thc or maybe you are, um, you're dabbing and you are supplementing with straight terpenes,

which I see people do, which is like, is so dangerous. Um, because there's, there's no scientific history, uh, of us, of us dabbing straight terpenes like that. And so, so, you know, I'm not saying don't dab. I'm not saying, um, you know,

don't amend with terpenes in your edibles. Other things. What I'm saying is, is you as a patient or as a caregiver, um, uh, it is, it is a helpful perspective to realize that as cannabis changes and in as it's not the same cannabis that we had 30 years ago, that the patient's relationship with cannabinoids and the

pharmaceuticals might change as well. Um, so moving on from, from that to, to the next area, uh, Jahan, you know, I wanted to talk just briefly about isolate versus whole plant, um, uh, medicines because, you know, uh, I, I've warmed up to isolates a little bit. Uh, I, I, I, I've, I've never really had all that much good to say about isolates.

I'm a big fan of, of whole plant, um, cannabis preparations. Um, but I've had to be more open to isolate as, as the breeding for, uh, specific, uh, you know, blends of cannabinoids and plants is, you know, going slower than we want it to go,

to be able to relieve the suffering of, of so many patients. And so, you know, before, before CBD was available everywhere, um, you know, we eventually figured out that, okay, if, if you've got a THC type one plant, but you don't have access to cbd, alright, spiking it with some CBD isolate in the presence of the rest of the cannabinoids in the, in the whole plant resin, that's probably a good thing.

And, and you know, you know, uh, Dr. Agarwal and, and Dr. Russo have all been on the show and, and have said, you know, that's, that sounds like a really good idea. Um, and so more of us are using isolate, um, here and there to, to spike our different preparations. On the other side, you've got pharmaceutical companies that are using, you know, isolate and hand chosen terpenes to make, um, you know, uh, you know, the early endocannabinoid drugs like, uh,

like Epidiolex, right? Which, you know, you know, when I read the, when I read the descriptions, you know, it, it, it, it smacks of like kind of Frankenstein's monster to me a bit. Uh, I would much rather have a plant that as a two to one CBD to THC with a proper terpene profile and, and have it in the resin from the plant and then just use the plant, right? Because there's, there's thousands of years of good relationship between us and the plant that I think is less effective when we,

when we tear it all down and, and put it into a pharmaceutical. But, you know, um, we have, we're going into this direction and it's certainly helping people and that's

good. So I've, I've had to soften my opinionated on this, you know, so, so this is all circling around to this question, is that when we're talking about interactions with other pharmaceuticals, are there any things that we should, um, as cannabis patients or as caregivers, be aware of how isolates might interact with pharmaceuticals differently than how whole plant preparations, like rosins and stuff might interact with pharmaceuticals?

You know, that it's a question that, um, you, the answer is yes and no, you know, to give a truly academic response. So, you know, spiking adulterating or, or, you know, can be one in the same term. Um, so I might, I might use them interchangeably as I just kind of speak off the cuff. Mm-hmm. , but, you know, mixing, let's start with ancient times, right? Uh, so, so ch changing the composition of something you're consuming for the purposes

of, uh, psychoactive effect is, is not a new practice. Um, I would, uh, I, I I would give you very poor odds against the idea that our ancestors mixed lots of plant products together and smoke them. Uh, I'm willing to bet that things like lavender or camomile and, um, callous root, I think even some of these have been documented, were smoked and probably mixed with cannabis. Not all too different in concept from spiking with terpenes, adding a foreign compound to the mix, um, indeed likes ofx.

That's like what you're describing sounds like hows OFX is made. Uh, the, the, the oral mucosal, the tinture that's sprayed under the tongue, that's licensed in over 30 countries, but not in the United States. Um, that is two cannabis varieties extracted by CO2 extraction, turned in an oil and mix together to get this nice ratio of a one-to-one THC to C B D. So it's a proven strategy or tactic, um, in preparing medicine and making consumer products.

Um, anytime you are increasing the dose or your exposure, you're introducing new complications. Um, cannabinoids are waxy and sticky compounds. Um, and, you know, if you're really consuming a lot of the stuff, um, it can stick to everything. It can stick to your teeth. It can start to stick to your lungs. There's been some people who, um, have way, and I'm talking extreme, like a lasagna tray of , you know, uh, dab sort of thing just to be, you know, um, a little silly there. But they're,

they're, they're consuming a lot. And it can coat airways, it can collect on material and things like that. And that, that, that, that may be a bad time for, for some folks. Um, so again, but that's not gonna happen with moderate or, or low use of these products. I mean, um, typically you can't, you know, um, what's sold in a lot of adult use stores, um, regulated adult use dispensaries is, is really not enough, um,

to induce some of these things. But again, you know, chronic consumption of concentrated products can introduce, you know, new things. And I guess, um, let's, let's use an analogy. Um, let's talk like beer, right? Versus, um, you know, vodka, right? Beer, few percent alcohol, maybe 8%. That's a pretty potent beer, right? You know, vodka, they don't even use percents. They use proofs. Uh, you know, it could be quite, uh, , it could be quite a lot more potent by an order of magnitude. Even wine.

Wine can be, you know, upwards of 20% alcohol. That's, you know, twice as much that's, uh, than a beer. You know, if you're talking 40 to 60% by weight, alcohol, I mean, you could be adding a zero onto the percentage of a beer, or beer is 5%, and you have a alcoholic beverage that's above 50% alcohol, that's an order of magnitude more ethanol. So if you're drinking a beer,

you know, you have all these other things in there. Uh, you know, you got some, some flavor compounds, you know, a nice big double hopped ipa. You know, they just, they smell amazing. If you're into plants, um, you can, you can smell the terpenes from the hops plant. You can, there are other compounds in there that give it flavor and body and color. It's, it's a bit dilute though, the alcohol in that mixture. You're,

you're drinking like liquid bread in a sense. You know, if you look at like a Guinness, for example, um, or some of those more heavier beers, unfiltered beers, there, there's other components. Now, what is the difference between a beer and vodka? Well, I just, you know, we can describe it in terms of smell and taste, but you can also describe it in terms of calories and,

and what else is in there. And is it better to drink the, the ethanol in a liquid bread preparation, or is it better to drink it in a pure form? And I wanted to use something that perhaps people who don't use dabs or extracts or are considering it to give them, you know,

an analogy to think about when it comes to these products. Uh, I think the idea of adding a compound to mitigate the side effects, like putting CBD in a product to decrease the potential adverse effects of someone who's sensitive to thc, I think that's a wonderful idea. Um, and, and I'd love to see, I think more, more of that available to people.

It's this form of compound pharmacy, I think . Um, and so I think, uh, you know, it seems like, you know, these extracts have a utility, I think especially in people with severe conditions, cancer, chemotherapy, um, extremely difficult to treat neurodegenerative disorders. You know, when we look at C B D, even, um, you know, the average person, you know, buys a boutique CBD product, might have five milligrams in it,

maybe 20, and they're like, I feel so relaxed. Uh, but, uh, if you look at what's being used in the clinic, we're talking hundreds of milligrams of CBD foreign effect. So, um, we can't really say, oh, it's bad and this is good. It's, it's all a bit of a spectrum in terms of the context of use and, and why you're using it. Um, but again, the more you take of something, the more you have in your body. Again, I use the analogy of the guy walking around town with nothing to do might just

get into trouble if they walk down the wrong alley. So, um, I think about that a little bit too. Um, you know, if you're hanging out playing in the street, cuz you got nothing to do, it's all fine till the wrong car comes along, you know, . So, um, there are things like that I, i, I think about too. So if you're using a lot of cannabinoids and suddenly you get a new prescription medication, um, you know, that might present some, some complications,

that's why, you know that, that they have that advice. You know, go low, start low and go slow. Take it at night when you're using new products, it's to sort of give you like, I'm gonna use it in a safe place. I'm gonna use a small amount and I'm gonna write down what happened and how I felt just so I can start to track things. Because no one's really, you know, sh uh, shanga. I don't think either one of us are saying, um, you know, we're not telling people not to use it.

We think we're just giving 'em pause to think about it, you know, and. E exactly, exactly know, know what you're doing. And just because other people are doing it doesn't mean that it's necessarily right for you. You know, uh, uh, ma make, make informed choices. A absolutely, and I, and I think about, you know, I, uh, I don't golf that often, um, and when I do, it's, it's pretty terrible. But, um, you know, I think the same thing for cannabis is, uh,

same thing. Uh, the things I like in golf are putting the slow putts, the short distance things, you know, hitting, whacking the ball as hard as you can with as much force as you can to go as far as you can, you know, taking heroic doses of things. You know, it's, uh, you might spend a lot of time wondering just where that ball is, . . Versus, you know, putting, you got a green, there's a lot, there's still a, a lot of fun there and a, and a challenge there as well. Um,

but again, it's, it's different strokes for different folks. But again, I, I would really just give people pause about that because you wanna take a holistic approach with this and, and you know, you, when it comes to patients, you know, especially avoiding drug drug interactions, there might be a real strategy here. Maybe you prefer edibles, but the edibles stick around so long because they're, they're swallowed. They go through GI tract, then they go to the liver just like a pill.

However, inhalation avoids that first round, eventually does get metabolized, but it avoids that first round pass metabolism. So if you're consuming, uh, let's call it healthy normal cannabis, not, not special cannabis, not, um, you know, cannabis dipped in hash oil, not dabs, not cannabis with spiked with other cannabinoids, but just good old fashioned,

uh, plant material, you know? And you're inhaling that, you know, you might be able to decrease your chances as a strategy just conceptually, you know, the amount of administration matters, swallowing things makes everything complicated. Um, there's a reason why savix, and if you haven't looked into nabiximols or tinctures, I think this is an area worthy of further development. Um, taking a product that can be applied under the tongue or in the cheek and absorb

buly, don't swallow it. Don't, don't, don't even visualize yourself swallowing it. Um, I don't want any placebo effects on this podcast, but , you, you, uh, you absorb it buly, it goes into your mouth and it goes right into your brain. Like, why send the, the cannabinoids on a wild goose chase through your digestive track and through the body? Oh, they gotta go all travel through the whole body before they get to the brain. It's little, little crazy trip they have to take.

So why not just load the magic school bus and send it right, right to the brain and avoiding, um, some complications potentially. So you have option. You know, the point of this is, is you only option isn't inhalation. Your only option isn't oral. Um, there are potentially other strategies that you could use, and I think these are great conversations to have with the, your PCP or your primary care physician.

not talking about another drug there. Um, but, uh, the, or, or any medical health professional, um, doctors are trained to talk about drug drug interactions. They can look up any of this information quickly, or you can, you know, reach out to me or, or check out, you know, rewind the show and pull some of the, the, the references we talk about, um, and bring those to your clinician. I used to advise medical cannabis patients and I did a lot of advocacy. I'd give them, you know, papers.

I'm sure there's like a couple clinicians at like Kaiser or some medical place in California are being like, who the hell was giving my patients all those peer reviewed studies and having them bring 'em to my office, , you know, so I was sometimes arming, uh, medical canvas patients with peer reviewed studies, studies to share with their clinician to have these types of discussion. How should I consume it?

What are the benefits and risks of consuming these products, uh, topically, orally, sub mucosally, um, by inhalation, um, and these are all, and, and, and in what amounts and, and, and things like that. So these are all great conversations to continue to have. And as you said, it's gonna continue to change cuz products change, varieties of cannabis change. Um, and I think it's always good to just check in about that.

Right on. So, um, when we come back from our commercial break in set three, we're gonna talk about some, uh, uh, red flag drugs and, uh, ca categories of drugs, um, that we wanna be, uh, especially aware of, um, if you are a cannabis patient or you are doing, um, uh, you know, caregiving for somebody else. And, uh, we'll go through those, um, with, uh, jhan. So, uh, we're gonna take a short break and be right back.

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You are listening to Shaping Fire. I am your host Shose, and my guest, today's Molecular pharmacologist, jhan, Markku, PhD. So Jhan, you know, we, we, we've talked a lot about, um, like the, the mindset and the perspectives and the complexity, and we've teased these things apart mostly just so people can see like all these different avenues that we could say are avenues of, of, of concern,

but the really avenues of solutions, right? Because usually by the time, um, a cannabis patient is either A, US and sick, or b, we are a caregiver and we've been called in to help out. Um, usually there is, um, a problem to be, you know,

resolved and and healing to be applied. And, and so what I want to ask you is that, uh, there have gotta be some, some categories of pharmaceuticals that are just red flag because they are, you know, like up, up at the top of the list of drugs that are likely to interact with cannabis.

And, and while, while our goal today has been to like, hopefully arm cannabis patients and caregivers with lots of different ways to, you know, dive into what they're trying to suss, suss out, um, there's probably a, a few that we should just put a big red flag on. And so, so, uh, why, why don't we go through two or three of these? So, so what's at the top of your list of red flag drugs, um, that are going to interact in cannabis in, uh, potentially sketchy ways?

So, um, things to be concerned about. First I'm gonna start with alphabet soup real quick, and then we'll go into more specifics. But if you're taking, um, potential drug drug interactions have to do with drugs that are looking at sip c y P two, C nine, healthcare professionals will know exactly what you're talking about. So if you are listening, pulling out a little piece of paper and writing these down and,

and then throwing them into an air search browser will reveal all. But, uh, sip two C nine, SIP 180, 82 C two B six, and C two C 19. Um, and even some of the acidic cannabinoids, um, like T hc, T H C V A, uh, C B D C B D V A, um, C B G A, these all interact, for example, a CYP two C nine. So if you have taking a medication, which is probably, you know, it's very, these are very common targets of medications, um, you could have a victim perpetrator effect going on.

So a couple of red flag potentials, you know, , um, you know, I, I used to think like I want, um, you know, I already, uh, you know, I have my own podcast as well, and I thought about starting another one just called What the Hell Happened, where people would call in with, um, drug experiences and be like, I was doing fine. I was having fun at this party, and I just got lightheaded and passed out, and like, what the hell happened?

And you know, these stories, um, you know, j joke a little bit there to cut the tension because this is about hypertension and hypotension and, and the hypotensive effects of cannabis. Most people probably don't even notice, or it's transient. You've been sitting down for a while playing a board game or whatever, you know, FIFA on your Xbox, and you, you step up, oh, I feel a little lightheaded, and then you like, oh, oh, I'm better now. But some people that is,

is really severe. And so if you're taking cardiovascular medication, I think, and you have a cardiovascular condition, it's a great idea to really pause and think about things and maybe have a discussion because, um, cannabis does cause hypotension. The blood vessels, uh, you know, will dilate. Um, and, and, and the heart, heart will work a little harder to pump blood around because, you know,

things are a little more relaxed. Um, but that hypotension could result in being so lightheaded that, that you have to sit down or, you know, you really feel, feel the pull of the gravity of the earth and just bam. And that that could be, that could be bad, especially if you hit something on the way down. So I'd say red flag interaction, cardiovascular medications that treat hypertension. Um, you know, I I would say, look, look into that if you're on, um,

anything having to do with cardiovascular medications. All right. What's an, what's another area? Yeah, um, I'd say, um, uh, warfare in, um, and I, I pronounce drugs a little weirdly cuz I had, uh, my mentor was from Lebanon. Um, one of our collaborators that I listened to a lot, uh, was born in Scotland and spent 30 years in Australia. So I'm used to hearing drugs, , pronounced , really weird ways. And so, I don't know the quick way to say apoptosis or apoptosis or ap.

You know, there's all these ways. So, uh, bear with me here. Um, but, uh, warfarin is one, and this is, uh, most people probably clot enjoyed, right? Right. Blood thinning. So yeah, so you, if you take, if that you could potentially, you know, this is where cannabinoids are perpetrators, warfarin will stick around longer. Um, increased risk of excessive bleeding there. Um,

so that would be potential red flag. Something to think about. Consider, again, that's where this mantra we hear or start low and go slow comes in. Uh, we mentioned Clobazam, and this really is again, a risk of, um, benzodiazepine toxicity. So, uh, and, and most notably with C B D. Um, so again, thinking about benzodiazepines and cannabinoids, uh, you may want to proceed slowly there. Um, central nervous depressants could have additive effects.

We already talked about that. Um, um, the, the, a lot of the pens, the clozapine and olanzapine, um, will have reduced efficacy. And I think that that, um, you know, and again, I'll just tie it in the C three, A four and CYP two C nine, um, you know, you should think about, um, those and, and drug drug interactions.

If you have drugs that are metabolized or interact with those, I I would say discuss alternatives, um, that might be appropriate in, in that instance, just based on the literature and, and what's available. It may not be clinically feasible, so you might have to consider, you know, different routes of administration or something, you know.

So you mentioned the, uh, the CLO baan, which is a, a benzo diazepam. So, so while that one, most of us don't come across in our regular life, but I believe another benzo diazepam is Valium, which is like all through, you know, our scene and, you know, you know, your aunt gives one to you or whatever, you know, these are very common to come across. Would we, should we be careful similarly mixing Valium with cannabinoids? Um, yeah, absolutely.

And I would say probably true for any anti-anxiety medication. Like, so. Xxx. Librium, uh, even anti-depressant, Zoloft Proac, uh, Prozac, Lexapro, um, just like naming things off the top of my head, you know, these things even like carry over to the psychedelic space too, you know, people, you're not supposed to, you know,

go on a psilocybin therapeutic session while on these things either. And so, um, you know, mostly what we're concerned about with a cannabis or hemp product is that these increased side effects, dizziness, drowsiness, confusion, um, and, and other difficulties when you're using a diazepam together with something like cannabis. Now again, everyone's gonna be different. Um, some people are probably listening to be like, I do that all the time,

and it's fine. And other people are gonna be like, I'm never doing that again. And, and what we're really talking about here, I think is, you know, cannabis can be a beneficial thing in people's life. And we don't want it to be a, a bad thing. We want it to be a good thing in, in people's life, or at least have no net effect, , no net effect and a good thing. That'd be, that'd be great. And so we're really trying to figure out how do we prevent people from,

you know, having to outta the phrase, I'm never doing that again. Mm-hmm. Or that was terrible. Um, you know, I think of how hard the cannabis industry has worked to get where it is. And, you know, you don't want a, a first time patient who could benefit from cannabis to get the wrong product, have a drug drug interaction, or a side effect and say, you know what, I'm,

I'm never touching that stuff again. And it might have just been a, a simple issue as timing, route of administration, or again, dosing. I wanna focus on one thing that you said. It, it makes a lot of sense that if you would take a, uh, a benzo diazepam like Valer xxx and add, um, thc, uh, blend to it, that you are going, you know, you're, you are more likely to, you know, have, have decreased d dexterity and increase drowsiness and, you know, won't be able to drive your car as well.

And these things that like slow your human down. Right?

That all makes sense. , but you caught me off guard when you, when you mentioned those SSRIs, because so many people who are taking, you know, uh, you know, some of these, these, um, you know, long-term anxiety and depression medications like Wellbutrin and, and you know, that whole basket that you mentioned, many of them also supplement with cannabis either for quality of life or just, you know, because they still have residual anxiety even on those drugs.

Um, what is the mechanism of cannabis interacting with this, this basket of drugs? And is there anything that patients who are blending those themselves at home should watch out for? Great. Um, great question there. Um, hm, hm, let me think about that for a second. , um, the MEUs of action, I mean the, the antidepressants are, is a very broad feel. Um, so we could think about maybe, um, like flexine or, or Prozac. Um, and, and you know, some of these have like that one I like to talk about.

Cuz again, it has no known drug interactions according to, to information available, but it can have overlapping, um, side effects. So that would be more in the pharmaco dynamic area, um, with some of these antidepressants. Um, I'd have to dig in a little bit deeper on some of the mechanisms of actions, um, with those pharmaceuticals. Um, fair.

Enough. Let, let, let's talk about in use then. All right. So may, so maybe, maybe I caught you off guard with the actual, uh, pharmacodynamics, but w if you are taking, um, you know, one of these SSRIs, would these, would the side effects that you would want to be cautious of when taking cannabis, the same ones as the benzo diazepam, are we, are we with the SSRIs? Are we still talking about, um, um, uh, uh, like loss of dexterity and, and, you know,

sedation and difficulty driving cars? Yeah. Or, or are we talking about something, you know, potentially more serious like, um, you know, serotonin poisoning or something? I don't know, I'm just, I'm just guessing. Right? So you might, I think you might experience, um, like, you know, so some of the SSRIs specifically, right? Um,

citalopram I think is a pretty popular one. It's extensively me, uh, metabolized by, um, CYP two C 19, one of the alphabet soup things I mentioned in the beginning of this thing, which is one of the major enzymes that metabolize cannabinoids. And so you could run the risk of having cannabinoids be a victim of an interaction, which could make them more or less effective,

make them more likely to have an unwanted effect. Um, again, just going back to that analogy of the guy strutting around town with nothing to do might walk down the down street or just, you know, it's okay to sit in the middle of the street when it's not busy and do your work that you need to do, but it can get more dangerous the longer you sit there. So, uh, again,

just to try and cobble together an analogy. Um, so I think with the, some of those SSRIs, you might be, think it could be go either way, victim or perpetrator. And this is, you know, kind of at the limit.

I think of a lot of information out there. Um, if even if you go, you know, I worked with, uh, uh, with Penn State, they have a cannabis research center there and, and been advising and participating with their center, and they put up, um, uh, like a, like a little database where you can put in cannabinoids and look up, uh,

potential drug drug interactions. And, you know, it's, it's like, I think of it like this, like they've made the beach and a little bit of shoreline and you can wade into the water and explore what's there. But if you want to go any deeper and like see dolphins and, you know, the shipwrecks and things that we're not there yet with being able to go to that level of exploration. But we do know that SSRIs and cannabinoids do share common routes of metabolism. And that could be,

um, something to think about. Um, you know, cuz not every SSRI goes through the, the same, um, sip, but a lot of them do. All right. The, the, the last, um, medicine category I want to, I want to touch on, um, it may be a specialty that you may or may not like, you know, overlap with, but, but what about, um, uh,

children children's medicines, right? Because, um, you know, the fact that, uh, children who have got, you know, a range of issues, you know, very, very easily pointing at like immunocompromised type kids, like they have, uh, literally been the poster children for cannabis medicine and helping to expand it, you know, over the last 20 years because, um, you know, the way that cannabis medicine helps kids, uh, it, it, it, it, it pulls at your heartstrings and people are like, yes,

these kids should be able to be using cannabis oil for their seizures and, and let's get this law passed, right? And so, um, uh, would you have anything to add about interaction between, um, cannabinoids, which might be be coming from a parent who is feeling desperate and other pharmaceuticals that they might already be on? And just to be reiterate, we are not giving medical advice. All we're doing is pointing out things for, um, caregivers to stay aware of.

I am so glad that we're talking about this because so often when we talk about healthy, normal adult volunteers in a research study, we extrapolate that to the entire population. And in the absence of pediatric drug, drug information, adult information is used. Um, however, there are subtle differences in development and all sorts of things between children and adults. I mean, just look at the differences between a two year old and an eight year old and a

15 year old right there. Mm-hmm. , there's a huge, the, you know, and so the magnitude of a drug drug interaction in a pediatric patient population may differ from adults because of age dependent changes. You know, puberty and prepubescent, for example, can change the drug disposition or response. Um, you know, in some of the early studies with, uh, THC C compounds in pediatric populations, like by the late Raphael Ulum, you know, they didn't really see what they thought,

what they would see in adults given that compound. Um, and, you know, the brains are still in a high state of development. And so, you know, there may not be the same response to th h c or other cannabinoids, and there could be other factors, dose formulation, the dis disease state, body mass, things like that. And I'll say again, that the, the, it needs to be assessed in children separately from adults. And, and this is a challenging thing, but careful consideration,

you need to account for age dependent changes. Um, and you have to build a little more confidence, um, about that. But it is absolutely a concern. Um, and it may, you know, these, these, again, these DDIs are re routinely performed in healthy adult volunteers in early clinical studies. But, you know, it's, there's a lot of ethical, logistical and method challenges to, you know,

doing these types of study in pediatric patients. I mean, you know, uh, I don't know if you've ever tried to get like a four year old to fill out a, a form or a survey might be a little tricky. Um, adults can can do that thing just fine. So I think there's a whole range of it, but, you know, po pediatric patients in the hospital often receive multiple drugs. And so there are efforts to characterize, um, those things.

Um, I, I like this phrase that you've got age dependent changes, and I know that you were talking about kids, but that definitely applies to adults too, because I know that, um, the effects that, um, you know, uh, my, my plant-based drugs and fungus based drugs and my pharmaceutical based drugs,

they have all changed as I've gotten older. And my reaction to it, you know, I was kind of impervious in my twenties and now, you know, I'm a little more aware cuz it's a, you know, it's easier to knock me out of balance. But I like that phrase age dependent changes. Yeah. Um, so that could. Give one solid example. All right. Can more, and this is across the board example, cannabis is not special.

I'm just gonna say across the board, anytime there's a, I think morphine and opioids, fentanyl, um, combined with anything in a clinical setting, um, can have effects on respiratory depression. And so that is something I think, especially when we talk about chronic diseases, hospitalization, outpatient stuff, you know, just because in adult populations we're observing this phenomenon of, um, decreased opioid, um,

overdoses and deaths and adult populations. Again, this is a thing, like we talk about age dependence, right? It may not be quite as clear cut in pediatric population. So I just want to throw that out there as like, um, you know, you can, you can look this up, uh, don't take my word for it, do some of your own research, but again, you can find a lot of information about while these are the potential most difficult areas.

Right on. So I've got two more questions before we wrap up here. Um, I know that, uh, you know, it was our goal today to not answer every potential question that could be asked, asked about this, because there's, it's just too complex. We. Would need 20 more minutes. . Yeah. . Oh. But, but our goal was to help give, give patients and caregivers a, um, a a perspective of how to suss out their solutions in

their unique situation. And so I, I want to, uh, I want to kind of like, uh, you know, kind of like throw you this,

this kind of of umbrella question for you to, to answer here. Um, in what manner would you recommend patients and caregivers go about their own research to discover if they may be having, you know, interactions between their pharma and their cannabis, very specifically, let's say that either you know, you're the patient or you're the caregiver and you're like, you know what, I thi I think that might be what we're seeing.

What would you say is their first and their second step to try to suss that out? Keep, uh, meticulous records? Um, you know, and that doesn't have to mean you're journaling all day. It just means that you are a bit vigilant about that. You're controlling your inputs. Um, so, you know, if you're like, oh, I went to brunch and, and drank four mimosas, and then I took my medicine, and then later that night I smoked cannabis,

and boy did I feel funny. I must have had a drug drug interaction with cannabis. And those, um, you know, my, my prescription meds well, could be the alcohol, could be other things. So, and then could be diet also plays a role. So I think first thing to do, get a journal, find the criteria, find some baseline things. Um, there's no shortage. I think of like questionnaires. You could even draw a smiley faces like, do I feel frowny face today? Do I feel flat line smile today? Um, that's a,

you know, people use those types of charts, um, and things like that. Um, different scales. So find your scales, find your measurements. Um, but again, I think, um, uh, keeping track of what you, you know, I have talked to patients and caregivers in the past, and sometimes I say, Hey, if you have a label on a product, take a picture. Keep a digital journal if you want to do it. It looks almost like a scrapbook.

You have a journal. You, you can peel off the product label, put it in your journal, or write down the information from it and keep track of what you're taking when you're taking it. Um, and, and when you're taking other things, and this is even a strategy that's used for pharmaceutical drugs.

So doctors will be like, okay, well you're taking drug x, I'm gonna prescribe you drug y. If you take 'em both in the morning and you feel X or Y, then then then take this drug two hours later, take it four hours later, take it six hours later. And so start by taking, if you're new to this, everything, you know, this is based on literature that's out there, Russo and, and MacCallum have a great paper on, on dosing strategies and, you know, taking things at night and low amounts, if that's okay,

feels all right. You don't feel the DDIs, you can, you know, start to play with the timing and the dosing and finding that range where you're not getting adverse effects. But again, if you don't feel good, um, you know, it's, it's not great if you get, if you get like all the side effects of cannabis, like, oh man, I feel sedated, I feel hungry, my mouth is dry. Uh, I feel dizzy and I can't remember anything. You know, that's like a lot of boxes to check. And, and you,

and that may not be what you're looking for from a product. And so again, I think it has to do with, um, keeping track of the inputs, control as many variables as you can. Um, and I think you, you'll start to, you'll find that there's a lot of things you'd be like, wow, I've been drinking caffeine all day, and, uh, or I, or I haven't been drinking it all day. And so I think finding those baselines, um, will help you. Is, is. There a database that you recommend more than Google?

Because after the patient journals and they've got some suspicions, they're probably gonna search these drugs and cannabis and see what they get. And Google may be our best option. And I'm always a big fan of the project cbd.org at conditions section , because that, that's always great too. But, um, is, is Google still our best bet? Um, I mean, until AI takes over. Um, you know, you know, the internet can be helpful and I would look for multiple resources that corroborate your evidence.

Don't just take the computer's word for it. Find a couple references online from different types of sources. Maybe the Mayo Clinic, maybe pubmed.gov, uh, maybe from, uh, a webinar where there's a doctor talking about stuff like, use, use a, you know, you have to take on this challenge using all available resources to do that. Cuz things often, just because the same study is cited over and over and over again, doesn't mean the study itself is reproducible and the results are

translatable to you. Mm-hmm. . And so finding, um, you know, the information from diverse sources, finding the same thing, the same results from different people running the studies and, and different reputable organizations come to the same conclusions, you know, that will help. Um, you know, as they say, try and find something written, something you can watch something, someone you can talk to,

to corroborate the evidence. Um, and so I think, you know, that, that is, um, just kind of where we're at because AI and the internet love to lie to you, , you know, there's, that's the ongoing thing. Like, wow, AI will just make stuff up to make you happy. It knows what you want to hear or want to read or want to see. Um, and we have to always be suspicious if we're getting, you know, exactly hearing exactly what we want to hear. Um, you know, you're probably about to buy a used car,

so just be be careful out there. Um, and, and I think that what I would say is try and test things, you know, if we feel okay, if I believe X, let me try and stretch out X as far as it can go, this line of thinking until it breaks. Where is it, where is the weakness in this, this, uh, rationale, whatever it is you're looking at. Drug drug interactions or significance, they're, they're not significance.

So the last question, um, I want to hit on with the, our last two minutes here is, uh, I, I want to, uh, go back to and plug the buds info.com project. You and I have talked about that, um, you know, uh, be before we started and, and, uh, you know, the, the listeners of Shaping Fire knows that we support, um, cannabis research and we are always trying to plug, um, uh, research that we know is going on. We participated in, you know, Ethan Russo's,

you know, CBD and CBG projects before sending people their way. And, um, you know, you've told me about the the good folks behind, uh, buds info.com and, and I looked it up and it, and it looks like something legitimate. So, so my question for you is, is, is what does the research look like to unearth these interactions that you and I have been discussing today? And, you know, um, what kind of research is happening, what does that look like?

And then give me a, a brief plug for buds info.com and then we'll wrap up. Sure. So, you know, my exploration and research has been, you know, a lot of frustration with getting funding Yeah. And grants. And, you know, in some ways, you know, you're always waiting on grants and, and maybe private funding from the industry or stuff. And, and as time's gone on, I found more and more ways, Robert said, you know what, this summer I'm just gonna do the dang research,

and I'm not gonna wait for funding. I'm gonna bootstrap this, you know, I believe in it. I'm gonna invest in it. And there's so many databases out there, there's so much you can find at the tips of your fingers if you're just willing to spend time doing it. And, and, and so unearthing the research for me, you know, um, doing case reports, contacting clinicians, and starting to unearth these things where they have these patient files.

No one, they're busy clinicians, they don't have time to go through 'em. Some of, most of it's like, you know, not, it's like, I can't read this. This is not like the best of it. You find nuggets, you find signals, you know, it's like, it's like searching for extraterrestrial life and suddenly you hear an alien TV show and you're like, what is going on here? And you're like,

I picked up a signal. You know? Um, and I have to say, digging through, we had a paper come out recently about Delta eight THC derived from hemp. And we combed through, um, you know, the lead epidemiologist, um, on the paper, you know, brought this to our attention. Hey, there's this database. We can access it. We can run these queries. We got a whole team together to go through the data.

And it's really exciting because, you know, this is data that's, people are reporting to the FDA to poison control centers, and it's just floating around. Nobody wants to comb through it. And, and I, I, we requested more and more information. They sent us case reports, hospital files, you know, the products, uh, scanned and pictures of the products along with the reports from the patients and why they showed up to the er, what they were feeling.

And we came to realize that one, the classification system for how these things are entering the databases not useful. I'll give you an example. Uh, psilocybin has a, an e at the end of it in the FDA database. So if you search psilocybin, you will find nothing. But if you search psilocybe, you will. Oh, geez. So if you, if you look up, uh, cannabinoid, you may not find anything. If you look up, you know, you, if you know, so think about Delta nine thc.

Is it plus minus version or the minus minus version? Like what, what version is it? Um, so there, there are some issues around there. So it takes a bit of knowing what you're looking for, but that led us to create Buds info. We're like, you know, there's an explosion of product diversity here. And, you know, as a colleague told me, where are the guardrails? And, um, and so we, we decided to bootstrap this. So buds info.com, please check it out, please scan it.

We are trying to use this to centralize the collection of data, standardize the data. Right Now, if there is an issue with a Cana cannabis product, hemp product, and a vulnerable population, it goes to local, state, or city centers and eventually makes it or not at all to a central database. So we may not, we may never, some of this stuff, we may be quite late to the game to uncover. So it's been very, I have to say, it's been very exciting to be sort of on this forefront of public health

where we're finding signals and very specific ones. Um, you know, you know, as, as you would expect, there are not a lot of adverse events for whole plant cannabis compared to other products. Oddly enough, there's not a lot of adverse events being reported yet for psychedelics. But it might be, again, cuz people can't,

finds Sabin in the database to report it mm-hmm. . Um, so there, there are a lot of interesting issues where we've been comparing and trying to figure out are we using the right metrics to detect these signals? And again, it's not about saying cannabis is good or bad, it's about we want everyone's ship to reach a safe harbor, and we wanna know where that big rock is in the harbor so you don't run a ground. And, and right on. Yeah.

Let, let's bring this on home there. Uh, Jahan. So, so what you wanna do, dear listener, is go to buds info.com. There is a short form there for you. Um, it is very easy to fill out. And the questions are about, um, if you've ever had adverse experiences with cannabis and for you to describe that, um, I went ahead and filled one out. It took me like, like four minutes tops. And, uh, and Jay hun, they're, they're, they're all, uh, anonymous, right?

So they're not going into like some tagged database or anything, right? A absolutely not, it is completely anonymous. We're doing this in full compliance so that we don't need an I R B board. So now the great thing about research is learning how to be like when you need certain things and when you don't. So it's totally a anonymized, this was started by students. It's largely run by students. Um, and we are trying to perfect this.

And we think that versus trying to find the Med Formm watch, um, or, uh, a poison control center form. I think we have figured out the as you, as you just said, it, it takes four minutes to fill out and it's easy. And again, what will help federally regulate and federally legalized cannabis is knowing

the risks. And, and I, I strongly believe that, that if we can clearly communicate that we know what the risks are, and we're continuing to a commitment to track what those might be, that I don't think anything will stand in the way of complete legalization and regulation of cannabis. Fantastic. Well, uh, Jan,

thank you so much for joining us today on Shaping Fire. Again, after all of this time, uh, you know, um, this is an incredibly complex area of work, and I am grateful that you are, you know, dedicating your expertise to it amongst some of your, your other areas you love because, uh, we really do need to get to the bottom of this not only for, you know, patient care, uh, but also so that we can get, you know, normalization to have, be more grounded and have its feet under itself better.

Because, you know, we, we are, we are still a long way from that. And, um, and, and so thank you for coming and sharing your, your expertise and your stories and, uh, and you know, your, your goodly nature, uh, with us today, uh, so that we could enjoy it. Uh, thank you. And, uh, thank you very much. I guess I'll see you in 80 episodes, . Yeah. There you go. Well, hopefully sooner than that. Right on. So if, if you want to, um, uh, hear more from Han Markku and you know, you do,

um, uh, uh, he's got a couple of great places for you to go. Well, first of all, let's go ahead and plug, uh, episode 29 of Shaping Fire about the cannabis product manufacturing standards. Um, but, uh, Han's, uh, uh, Instagram is great. Uh, you'll be able to hear about what he is into from week to week and also where he'll be speaking. And, uh, that's just simply at his name, uh, jhan Markou at J A H A n M A R C U. So that's his Instagram. And also he's also, uh,

pretty active on, uh, Twitter. And, uh, that is also his name at Jhan Markku. Um, also, if you're interested in any of the aspects that I, uh, talked about either at the top of the show or came up along the way about, uh, about his consulting, uh, for, for companies or, uh, legal folks, or if you've gotten busted for dui, um, uh, you wanna go to, uh, their, his consulting website, which is markku aurora.com. And so that's Markku, M a r C u dash aurora a r o r

a.com. And then, um, if, if you want to, uh, hear him wax brilliant, um, about the, uh, cannabis industry, um, uh, he has launched a, uh, a relatively new podcast called How to Launch an Industry. And it's all about the, the, the, the birthing and stabilization of, of the cannabis industry and, and, and what our best practice is going forward. And that is at How to launch an industry.com. You can listen to the episodes there, um, as well as, uh, anywhere that you download your podcasts.

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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 chango los on Instagram, be sure to check out Shaping Fire YouTube channel for exclusive interviews, farm tours, and cannabis lectures. Does your company wanna reach our national audience of cannabis enthusiasts? Email hotspot@shapingfire.com to find out how. Thanks for listening to Shaping Fire. I've been your host, Chango Los.