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Ep #15 Transcript | Ziva Cooper: Medical Marijuana, Clinical Research & Cannabinoid Therapeutics

Full episode transcript below. Beware of typos!

Nick Jikomes

Ziva Cooper, thank you for joining me.

Ziva Cooper 1:50

Thanks so much, Nick. It's wonderful to be here today. Thank you for having

Nick Jikomes 1:53

me. Yeah. How are you doing? And how are you? How are you doing with COVID? And everything? You're in New York, right?

Ziva Cooper 1:59

No, actually, I moved from New York a couple of years ago. So I'm in Los Angeles. So you know, it's it's a big change. For me. I was in New York for about 13 years and haven't I think my last trip was to New York about a year ago. And you know, we've been grounded the whole time. So thank you for asking, and things are going well, thankfully, Los Angeles is looking up now. And you can't complain about the weather here. So there's that.

Nick Jikomes 2:29

Great, can you tell people a little bit about what you're doing at UCLA and what your scientific background is just so people know where you're coming from?

Ziva Cooper 2:36

Yeah, so I'll first start off with my scientific background, and then I'll talk about how I ended up at UCLA. My scientific background, even though most people I think know me for work in humans, I actually received a degree in bio Psychology at University of Michigan and my, my doctoral work was really concentrating in preclinical models of substance use disorders. So, you know, I did studies with rodents and I specifically concentrated on opioids at the time. And I looked both at the analgesic effects of opioids as well as the negative effects. So substance use related negative effects of opioids in animals. What is analgesia? Thank you for asking. So analgesia is pain relief. And, you know, we know that opioids are very good pain relievers, but they're also negative effects. And so I was really looking at both of those animals. And it's interesting, I feel like I haven't really strayed very much from that overall theme. In 2007, I moved to Columbia University, to get training, from my postdoctoral fellowship on how you can administer psychoactive substances, like opioids, to people under a very controlled situation, so that we can actually study the effects of substances in people, rather than looking at changes in population levels, or looking at indirect effects of substance use in people over time. So it's a very unique type of laboratory, where you can actually administer a controlled substance to people and be able to measure very specific effects. So how does this substance affect your heart rate? How does it affect your mood? How is it metabolized in your blood? And how are those effects compared to placebo? So in other words, like a sugar pill. And during that time at Columbia, I became very close with one of my mentors who was studying cannabis. And that kind of led me into the world of cannabis and cannabinoid research. And I think part of the reason why I was drawn to it Human Research of cannabis and cannabinoids was because at the time again, it was 2007. So California had already legalized cannabis for a while for medical purposes, they had legalized in 1996. And other states were coming on board. And there was a lot of talk about the therapeutic effects of cannabis. And I realized that there really wasn't very, there weren't very many placebo controlled studies in the area that looked both at these, you know, the therapeutic effects as well as the adverse effects. And so it seemed like a pretty significant gap in knowledge there. And so many questions to ask, that could be answered in the setting I was in.

I continue doing some opioid research as well. And I'm still doing some of that right now. And so that's kind of my my background as to how I got involved in this field. So you asked me what I'm doing now. So I moved to UCLA about two years ago, UCLA started a initiative when cannabis for adult use became regulated, or legalized, and they became legalized in about 2016. And then they implemented the laws in 2018. And it was clear that with this regulation where we had medical use, and non medical use, that was legal, there is going to be an uptick in availability of cannabis products, and most likely use as well by patients and non patients. And there were going to be a lot of questions that needed to be answered, not just about, like, how the policy changes, impacted, use and, you know, public health parameters, but also a lot of questions that a lot of patients would probably be having, you know, asking their physicians about, you know, can they use this product or that product for this indication, and also about some of the negative effects as well, what does it mean that a diverse array of products would soon be available to people more accessible to people. And so the initiative was founded in late 2017. I came on board as the research director. So at the time, UCLA didn't have very many controlled Drug Administration studies of cannabis. There's actually his deep history of UCLA doing this type of work. But there weren't that many investigators. So you might have heard of like Don taskin, who's a famous pulmonologist and Mike Ross, also a pulmonologist who is doing some of these studies looking at the impact of cannabis use and respiratory health. But apart from that, very, very few people did this work, and it's hard work to do. You know, you got to know all the regulatory hurdles, how to get funding, how to store the drug, where to get the drug. And so I came on board to help kind of Pioneer this type of research. And then about a year later, I became the director of the cannabis Research Initiative. And it's really great, because, um, Los Angeles, you know, it's no secret that the cannabis industry is blooming here, there are billboards on my way to work. There are all types of products that are emerging in the health food stores. And indeed, patients are constantly being bombarded by questions from their patients, and people in public health have their questions as well. And so I entered into a situation where people from all over campus, whether they were a legal scholars, or people interested in public policy, or public health, or physicians, were really excited to do this work and engage in a collaborative research enterprise. And so we have about 100 faculty from across the campus who are engaged in this research now and it's been really, really exciting two years. So and I'm looking forward to see to seeing how it how it grows in the future.

Nick Jikomes 9:05

And is this UCLA research initiative? Is that encompassing all forms of research, or is it focused on human clinical?

Ziva Cooper 9:12

Yes, so my lab, the cannabis and cannabinoid research laboratory is very focused on the control Drug Administration components. And so you know, I have a laboratory that is cleared to help people smoke and vaporize and use cannabinoids orally. And so we can do those nice double blind placebo controlled studies. We also have most of my studies are actually with healthy volunteers, where I'm probing, you know, different variables that impact the effects of cannabis on the body and the brain. And then we also have studies with patients, so patient studies where we're looking at specific diseases and then we also have again, a grants in Public Policy. We have grants doing neuro imaging studies where the products aren't being administered cannabis isn't being ministered, but we're looking at activation in certain brain regions when people are exposed to cues associated with cannabis. And there's so there's really a wide range of research that's happening. And we also have preclinical research as well. So people who are doing rodent studies, so, um, you know, it seems like it, I feel like you know, when you're in graduate school, or, or when you're in a certain situation, you're always told to focus. And make sure that you when you do something, you do something, right, you don't go out all over the place. But I have to say at UCLA, I'm in this unique position, where the faculty from all different areas of expertise, are excited to do this work. And you know, I, of course, have my area that I'm good at. I'm not an epidemiologist, but I have epidemiologists, or we have epidemiologists, as part of the initiative, who are eager to tackle that part of the research. And so it's great, you know, we can do a lot of a lot of work here in Los Angeles that I think is appropriate to be done here, just because, again, the industry, it's really hard to ignore the fact that it's growing here. And that there are a number of people who are using these products for a range of different indications. And I think that might be different in other states, you know, something in the Midwest where the regulation hasn't happened yet, or where the industry isn't as prevalent. So it's an exciting opportunity.

Nick Jikomes 11:39

So one of the things I wanted to ask you towards the beginning, is, there's a lot of different types of people interested in medical cannabis. And each of those different cohorts of people that you could talk about, I think use and imagine something different when they when they use a phrase like medical cannabis or cannabis as medicine, maybe one side of the spectrum, you've got clinical researchers who have a very specific thing in mind when they use the word medicine. And then maybe on a different side of the spectrum, you've got activists who refer to other types of cannabis consumption as medicine. So I just wanted to ask you, what is medicine? How do you define it? And what counts and doesn't count?

Ziva Cooper 12:21

You know, I don't think it's up to me to to make that definition or to say that I am I am not a physician. Um, and I feel like when when we do surveys studies, for instance, we ask people, do you use cannabis for a medical reason? And or do you use for non medical reason? And it's really up to them to self report how they feel like they are using cannabis. I'm not asking them if they have a medical cannabis card, or if they have a physician who's giving them a recommendation. It's their self report about this. Now, how do those surveys that are very meaningful and important to get give us a sense of how people are using these products in the community? And for what reasons? How do those surveys translate to medical practice? is complicated. And so you know, when I have conversations with the physicians, let's say UCLA, or other health care systems, you know, they really struggle. Not all of them. But you know, this is a common theme where cannabis and the endocannabinoid system isn't necessarily taught in medical schools. And so when when patients get questions from when I'm sorry, when physicians get questions from patients, they're really not sure as to how to guide them, and how to inform them. And I think that in places like UCLA and other you know, medical universities, physicians hang their hat on evidence based approaches, right. And so data that depicts how cannabis or how these cannabis based products can be used under rigorous controlled conditions. So in this study where the placebo is being compared to the active cannabis or cannabinoids, I feel like those studies are really helpful and important in informing physicians and and public health as to not just if a certain product or cannabinoid is helpful for a certain indication for a medical use, but also its importantly its safety. Right. And so, you know, to circle back to your question, what is medical cannabis? I think it probably depends on the professional that you talk to and the individual. And it's really I think it's really up to when you're having a conversation with a community member and they say that they're Using medical cannabis, you know, that's they're explaining how they view their their medical cannabis use, or cannabis use. Is that helpful?

Nick Jikomes 15:08

Yeah, that's helpful. So it's really a functional perspective. It's about how someone, the patient, or who would call themselves, the patient is actually using it. They're using cannabis for some reason that they don't view as merely for fun.

Ziva Cooper 15:22

Right. And I will say that I think that there's a variety of reasons why people use cannabis, I think that sometimes we think about the medical versus recreational, but there are other reasons why people use it. So you know, this path to well being where it's not necessarily specifically for a medical indication, but people are using it, because they feel like it enhances their overall well being. People use it for spiritual reasons, right. So there's a number of different reasons why people use cannabis that aren't always explored. That, you know, probably should be explored. And you know, sometimes they overlap. I you know, there was a study that came out showing that 90% of people who report using cannabis for medical reasons, also use it for non medical reasons. So people can have lots of different motives and reasons for us.

Nick Jikomes 16:17

One of the areas that I definitely want to dig into early on is pain. So one of the most common things people report using cannabis for in terms of medical application is pain management. So what do we really know about cannabis for pain? And maybe let's kind of zoom in on THC and CBD? What do we know? What do we really know there? And I'm really interested in the potential interaction or replacement, that might be the potential for cannabis to replace opioids. So can you kind of compare and contrast contrast the cannabinoids in the opioids in the context of pain management?

Ziva Cooper 16:52

Yeah, absolutely. And thank you. This is you know, one of my favorite topics. It's what I spend a lot of my time thinking about. And when we think about cannabis, and cannabinoids, those chemicals in the cannabis plant, as being novel strategies to decrease the need for opioid use for pain relief, you hit the nail on the head where, you know, we can't think of cannabis is just one thing. You know, we have to think about what are the chemicals in the plant that are important in playing this role, with respect to being able to decrease the need for opioid use, or eliminate the need for opioid use completely. And when you look at survey data, or where you look at observational studies, there have been numerous studies demonstrating that people are substituting cannabis for their opioids, and they're able to decrease their opioid use over time. And that's great. The question is, what type of cannabis are they using? And if this was done in a controlled setting, but we see the same effects, what are some of the safety concerns that we just have to think about with respect to at some point mixing cannabis with opioids? And that's where I think these controlled studies come into play, where we're trying to actually understand these different cannabis constituents, and how they might be helpful in reducing or eliminating the need of opioids. Now, to first answer that question, I think that you have to figure out if cannabis and these constituents are pain relieving on their own, so forgetting about the opioid question for a second, can't, are they just able to help reduce pain on their own? And then you can think about, you know, our will they be helpful in eliminating opioid use, and you can look into what studies have been done in this respect. So I mentioned to you earlier that I started off on my professional path in the animal laboratory, and frequently I actually always refer to the animal laboratory studies to help inform how do I design my clinical studies. And if you look in the animal literature, you see a really nice story with THC specifically. So tetrahydrocannabinol THC Delta nine tetrahydrocannabinol is the primary psychoactive component of cannabis. And it's the it's known intoxicating component of cannabis and it's the most widely studied cannabinoid as a cannabis plant. And when you look at animal studies, THC produces these pain relieving effects and a wide range of models and animal studies. And what's nice also is that there's really nice data showing that when you combine a low dose of THC with a low dose of an opioid That isn't usually pain relieving, and you put the two together, you actually get a synergistic effect and pain relief such that, you know if THC equals one and an opioid equals one on pain relief when you put the two together, they'll equal three. So there's some really nice rationale for seeing how this could work and people. Now, even though those studies were elegantly done in animals, they haven't necessarily been fully fleshed out yet in people, which is surprising, given the fact that there have been so many reports of people who are now using cannabis and cannabis based products in lieu of opioids. Now, what do we know in humans right now? Let's talk about THC first. We know that based off of whatever meta analysis you look at, so in other words, a meta analysis where you're combining data from all these different placebo controlled studies, we know that there is strong evidence, substantial evidence based on a report that I was associated with demonstrating that cannabinoids are helpful for chronic pain, which is a that's a very general big statement to make because there's all different types of chronic pain. And THC has only been studied in a couple of these types of chronic pain. So neuropathy is a type of chronic pain that it's been shown to have an effect with

Nick Jikomes 21:34

what's your apathy.

Ziva Cooper 21:36

Um, neuropathy is it is that it's a type of neurological pain that can happen over time. So people with diabetes can have neuropathy, people with HIV. Chemotherapy, people who have certain chemotherapy treatments can develop neuropathy over time, and it could feel like tingling or numbness or hotness burning cold sensation. And it's it can be incapacitating for for certain patient populations. And that this is an area that has been studied with positive results with cannabis with THC, as well as other products with THC in them. So, so there have been a number of studies that have demonstrated that cannabinoids might be helpful for chronic pain. Now, whether or not that can help decrease opioid use, again, is a kind of a black box at this point. We did a study where we looked at in healthy people. We did a study where we looked at how THC can produce pain relieving effects, again in a healthy population, but we use like a painful test. And we saw how people reacted on that painful test when they received cannabis with THC. And then we looked at the effects of THC on a very low dose of an opioid. So dose of an opioid that doesn't usually produce pain relieving effects. And what we saw as we saw significant increases in pain relief when we had when we put the combination together. And so that gave a nice signal of what we see in the animal literature where the one plus one equals three phenomenon that hasn't yet been tested in a patient study where you have patients enrolled, and you're looking to see if the use of cannabis with THC might help to reduce opioid use over time under a placebo controlled condition. And the studies are very difficult to do. And I think that's part of the reason why it hasn't been done yet. I think that there are certain studies that are going to roll out soon that look at this. But again, there's not just regulatory barriers, but also just study design issues that make it a difficult question to ask.

Nick Jikomes 24:00

So we know from animal models, that if you combine THC with an opioid, you get the synergistic effect where one plus one can equal three, we have reason to suspect something like that could be true in humans, because there's so many people who seem to be using cannabis for chronic pain and reporting that they're decreasing their opioid usage. But we haven't yet formally shown with the placebo controlled study in humans that you get this one plus one equals three effect

Ziva Cooper 24:25

in patients correct patients. Yeah. And then you asked about CBD and what do we know about CBD? And so it's interesting because we see that one of the primary reasons why people use CBD is for pain as well. But if you look at the literature, there's very little information about the effects of CBD by itself. For pain and humans. You look at the animal literature and there is some really compelling evidence showing that CBD is helpful for certain types of pain. Animals. And in fact, One study found a synergistic like effect with opioids and CBD. But in humans to date, as far as I know, there have only been two studies that have looked at CBD by itself for pain. And those were done about 15 years ago. Most studies that have used CBD have included THC as well. And we know that THC has promised for pain. And so we it's hard to suss out what CBD is necessarily doing. We have a study right now at Columbia University that's very similar to the study I just described to you where we have healthy participants, they come in, they smoke cannabis with THC, we look at their pain response, we see how that THC can synergize with an opioid. In the study that we're doing right now we're looking at different types of cannabis that have either high amounts of THC, high amounts of CBD, or the two combined. And then we're looking at the synergistic effects with the opioid. So we're pretty much replicating what we did before. But we're probing CBD here to see if we can get a similar effect with CBD. And so that's CBD. So it's interesting because a lot of people think based off of how CBD is, is really popular in the market and the things that you hear about CBD and the things that people are reporting about CBD, that they're using it and it's helpful for condition nothing's ever helped them before. But when you go back to the literature, it's it's shocking to see how little data there has been in this space.

Nick Jikomes 26:47

So going back to the animal models, where we can dig a little bit deeper than we can in humans. I'm interested in this idea of drug synergy where you can combine two drugs and get this one plus one equals three effect. So you said we've shown that in animals for THC and opioids, do we know anything about mechanism and what might be going on at like a cellular or receptor level that actually allows that to happen.

Ziva Cooper 27:12

So there has been some data probing the interaction between THC between just the opioid system where opioids work at and the cannabinoid system where cannabinoids work at. And it's been known for a while, I would say at least, you know, I think that there have been even papers since 1995, that there's this kind of bi directional reciprocity between the opioid and cannabinoid systems for certain endpoints. So for example, for certain endpoints, if you block you can create certain behavioral effects, or block certain behavioral effects. If you give THC but you block the opioid receptor, you're going to block THC effects. And if you give an opioid and block the cannabinoid receptor, you're going to block the opioid effects. And so there is certain degree of reciprocity. And some of that has been worked out in the behavioral field. So looking at pain relief, looking at dependence, so when organisms get exposed to THC, or opioids for many days in a row, and then you stop giving them that THC or an opioid, they'll develop withdrawal. And so there's been studies looking at the reciprocity there as well. But with respect to mechanism, as far as I know, it hasn't really been worked out very well. I know that there have been studies looking at the direct effects of let's say THC on opioid receptors. But the truth is, is that I haven't dug into that literature in a pretty long time, but I do remember that it is pretty scant. And so I don't think that the mechanism has really been worked out yet.

Nick Jikomes 29:04

And one, one of the things I wanted to talk about in this context is abuse potential. So obviously one of the, you know, with opioids, they're truly a double edged sword because they are highly effective for pain management, but they're also among the most addictive substances out there. So can you talk a little bit about abuse potential for opioids, in contrast to THC,

Ziva Cooper 29:28

I'm, I'm very happy to talk about abuse potential. It's one area that I that I study in all of my investigations, I'm always looking at understanding the abuse potential of the cannabinoids that that I test. Now with respect to comparing the opioids to cannabis, it's kind of like comparing apples to oranges. You know, there's a if they're very different drugs and there's a very different consequences of use over time. Time, there are similarities. For instance, when you like I just said before, when you use opioids chronically for a period of time, there is the development of dependence. And when you stop then there's withdrawal. Similarly with cannabinoids, this has been worked out in the preclinical literature and also in human literature where there is a subset of the population when using with high frequency cannabis or THC. And then then there's abstinence, there is a withdrawal. There is a withdrawal a constellation of withdrawal symptoms. Interestingly, that does not happen with CBD at least we haven't seen a signal of that yet with CBD. So looking at abuse liability, one aspect of understanding if cannabinoids or cannabis can substitute to or can substitute for opioids for pain relief. Another interesting aspect of this is can cannabis or cannabinoids also reduce the abuse liability of opioids? Is it possible that we can reduce some of the negative effects of opioids if people still need to take some of opioids, and that's something that we're looking at. in animal models, there was a really nice Rodin paper that demonstrated that the addition of THC decreases opioid, what we call self administration, in the animal literature, and there's been that's been shown in rodents, as well as a one or two studies in non human primates as well. In people right now, when you're just talking about THC and its ability to decrease the abuse liability of opioids, we don't have data on that yet. There's been some interesting data looking at CBD, and its ability to decrease some effects that are associated with abuse liability, or opioid use disorder. But there haven't been good studies yet in humans looking at this effect. But it's one area that we are probing in this study that we have ongoing at Columbia. And another study where we're looking at terpenes, as well, and how terpenes might also be able to help reduce abuse liability of opioids, and increase the pain relieving effects of opioids.

Nick Jikomes 32:22

Which terpenes are you choosing to investigate? And why did you make the choices you made given the very large amount of choice that you had?

Ziva Cooper 32:32

These are good questions. So the terpenes that we chose to look at, for this particular grant are beta caryophyllene, and myrcene. These terpenes are one of the handful of terpenes that are shown to have higher concentrations. Again, still small concentrations in cannabis, but higher concentrations and many, many other terpenes. And there are two terpenes that have nice preclinical data, demonstrating that they do have analgesic effects. But interestingly, different than opioids and different than THC, you have to give the animal 10 times the dose that produces pain relief, to see a psychoactive effect to see a potentially adverse effect. So these two particular terpenes. To me, when I looked at the preclinical literature, there was a pretty strong signal for its pain relieving effects, most signal for psycho activity. And also what's interesting about these terpenes is that there does seem to be just like with THC and opioids, there's this bi directional effect. If you look at the animal literature, there's some really interesting elements there that also suggests that these terpenes act in tandem with opioids to produce pain relief, and in fact, the beta caryophyllene. There's a study that looked at the synergy between beta caryophyllene and opioids. So it was that one plus one equals three phenomenon. And so I thought those terpenes were really interesting to probe given the volume of preclinical compelling preclinical data. You know, I know that there's interest in other terpenes, for other for other effects. But when writing this grant, and really focusing on pain, it seemed like these terpenes would be most interesting and compelling.

Nick Jikomes 34:33

Interesting. So what you're what you're saying, if I'm understanding correctly, is that there is animal literature out there showing a synergistic effect with something like beta carry off lean, a common Canvas terpene and an opioid drug. Correct. So what's kind of what's kind of funny about that is, you know, a really hot idea that people like to talk about in the cannabis world is the entourage effect, where the it DHEA is two or more compounds, say a cannabinoid and terpene or, or an array of those compounds can have synergistic effects. For the most part, I don't think there's any direct evidence for cannabis derived cannabinoids in cannabis derived terpenes definitely having an entourage effect that anyone's proven yet. But there are there is a precedent for this type of thing, is what you're telling us.

Ziva Cooper 35:23

There, there is a precedent and and you're right. And Nick, over the last year, you know, there have been a couple of studies that have come out that have not been in necessarily encouraging about, you know, on a molecular level about the entourage effect. And we're not necessarily saying that we're looking at the entourage effect itself, we're looking at one aspect of this that I didn't mention is that we are combining we're looking at these terpenes by themselves, to see what effect they have by themselves, if any, you know, and given the gambler trophy, we think they might that's what our hypothesis is, or else we want to do the study. And then we are looking at combinations of these terpenes with different doses of THC. So a dose of THC that isn't pain, relieving in our pain model and isn't intoxicating in our pain model. And so we're giving the terpene with this low dose of THC to see if maybe there might be a synergistic effect or an additive effect. And then we're giving it with a higher dose of THC that's known to produce pain relieving effects, and some mild intoxication. One thing I didn't know to say about beta caryophyllene. Another kind of intriguing aspect to it is that it's been shown that it acts at the CB two receptor as a CB two receptor agonist. And just recently, there have been studies looking at its potential in animals to reduce markers of abuse liability in cocaine, there was a nice study that looked at cocaine, it's been looked at for alcohol as well. And so if beta caryophyllene is acting at the CB two receptor and having this effect to maybe potentially decrease abuse, liability of substances, might be able to reduce the abuse liability of THC may be able to reduce the ability abuse liability of opioids. So there are so many questions to ask. And we are just touching the very, very surface. I mean, it's the first study, I think, in humans to actually look at isolated beta caryophyllene. To the extent that we can isolate it in people to look at the pain relieving effects, and how it might interact with THC. And we're doing the same thing with myrcene as well, we're giving myrcene by itself, and then myrcene combined with a couple of different doses of THC. And then in a second study, we're going to look at the combination of these with opioids. So it's a it's a complex study, it's going to take a little while to get through, but hopefully, you know, we'll get some signals.

Nick Jikomes 38:02

Yeah, I'm glad you guys are doing this work. I was unaware of it actually, what for people who don't know, can you talk about the CB two receptor? How would you describe that in contrast to CB one and what do we know about the very basic biology there.

Ziva Cooper 38:15

So the CB one receptor is well known to be first of all, but both receptors are, you know, heavily populated in the brain, cb two leso in the brain unless there is known to be some type of neural insult at least that's what's popular believe but all over the body across organ systems. cb one receptor I believe that it is it's part of a G protein coupled family. So the dopamine receptors are G protein coupled serotonin receptors opioid receptors. And I believe that the CB one receptor is the most prevalent G protein coupled receptor in the brain. So more so than dopamine more so than opioids. More so the serotonin so that just demonstrates how it's really it plays a prominent role in behavior in homeostasis and stress response. Given the sheer number of those receptors in the brain, cb two receptors, I should say that CB one receptors are known to be responsible for th C's intoxicating effects, as well as its their their therapeutic effects as well such as pain relief, and appetite stimulation. For example. cb two receptors are thought to play more a role in immune immunomodulatory functions. And THC actually accept both CB one and CB two we just know more about its effects or I say I know more about its effects on on CB one then CB two. But when we hear about how cannabinoids are anti inflammatory, were usually referring to their effects on the CB two receptor. The CB two receptor has been probed for the potential to help with abuse liability of substances. And so that's kind of how to beta caryophyllene story with the CB two receptor comes into play.

Nick Jikomes 40:22

Interesting. So you've got CB one, cb two, cb one is mostly in the brain, that's the one that helps get you high. Basically, THC binds to CB one. That's the intoxicating one. cb two we're simplifying things a little bit. But CB two is the anti inflammatory.

Ziva Cooper 40:37

Recite totally simplifying some but I mean, you have CB one in the body as well. And people should remember that as well. But when we think about the psychoactive effects and toxic effects, it's that is happening in the brain.

Nick Jikomes 40:49

Interesting. So gpcrs really common receptors, we had a whole episode of Brian Roth, if people want to dig into that more, he he's one of the major gpcr researchers out there. And he talked a lot about that. But one other thing I'm interested for these studies that you're doing Ziva is, how are you giving these compounds to people? What is the method of consumption for them? And can you help us think about the doses they're taking, relative to what someone might be getting? If they are smoking a joint say?

Ziva Cooper 41:18

So Nick, the questions that you're asking right now are really integral with respect to how we can get these studies done in human researchers. I'm sorry, human volunteers. So again, I've told you a little bit a little bit about terpenes, we have some other studies with compound minor cannabinoids that have not given been given to humans yet. And so how do we decide how to give this to people where essentially, we there haven't been controlled studies yet. And what we do is we look at how people are using cannabis in the natural ecology, you know, the common ways that they're using it, and what are the concentrations that they are people are usually exposed to. And so when again, you're you're putting your head, you're administering these compounds for the first time in people by themselves, you don't want to expose people to any, any increased risk, then you know, what they're normally being exposed to. And so what we did for these studies is we looked at the lower levels of these terpenes, commonly found in cannabis, and then the higher concentrations that are commonly found in cannabis. And in fact, in California, those those concentrations are pretty easy to find. And so we modeled our administration in the laboratory to mimic what people are usually exposed to, but we're just taking everything out of the cannabis plant. So we're only looking at the terpenes here, and the mode of administration here, again, because it's the first time that we're looking at these people. The mode of administration, again, reflects how people most commonly use cannabis, which is through inhalation. And so for these studies, we're having participants vaporize the terpenes by themselves or in combination with THC, again, because that's reflecting how people are normally exposed to these chemicals. And then once we have results from the concentrations that we see here and we get signals for safety, you know, tolerability, and maybe even effectiveness for pain, intoxication, cognitive disruption, then you can you know, be able to start looking at higher doses based off of what you find, and also based off of what people are doing. So now we're starting to see you know, people are using terpenes, or minor cannabinoids, you know, orally so they're taking tinctures or they're drinking this stuff, or they're using edibles. And so when you see that are enough, people are exposed to these cannabinoids and terpenes on a on a regular basis. It allows you to safely look at them in the lab as well.

Nick Jikomes 44:07

Interesting, no, I'm glad you're doing it. That way, you're not giving astronomical doses that aren't relevant to what people are exposed to when they're choosing to go out and use some of these products. And I'm gonna be really excited to see what comes out of these. I actually wasn't aware, I know that there's at least one group in Hopkins doing some of these coadministration studies where they're giving two or more compounds at once. And I think there's just a fascinating area to think about this interactive synergistic potential for different compounds.

Ziva Cooper 44:37

Yeah, yeah, we have a similar study that just recently got funded. It's not approved yet. But we're excited to get this study started and it's looking at cannabigerol CBG, which is a minor cannabinoid, that's on people's radar now, you know, you see articles about it every single day on the media, and we're looking at CBG as well by itself and in combination With THC, we're looking at its pain relieving effects, as well as its appetite stimulating effects. Because it seems like an animal models, it is a appetite stimulant, which is useful for certain patient populations.

Nick Jikomes 45:13

So one other area I'm interested in, and I guess just staying with the studies that you're doing, how are you thinking about the kinds of people you're recruiting for these studies, and in particular, I'm interested in two dimensions of variability. One is sex. So how men and women might actually be affected differently by these compounds. And the other one is age, how relatively old versus relatively young individuals might be differently affected.

Ziva Cooper 45:40

So Nick, this is you hit on two important points here, because we're seeing that in the past, men outweighed women with respect to cannabis use two to one. Over the last couple of years, we're starting to see that gender gap narrow quite a bit, especially with respect to medical use, where in many surveys, females and males are equal with respect to their medical cannabis use. And for certain indications. For instance, like fibromyalgia, clearly, there's going to be more females than males, because that's a Fibromyalgia more likely affects women than men. And then with respect to the age aspect, I think the latest statistic or a statistic that was cited a couple of years ago, it demonstrated that there has been a over 400% increase of cannabis use in the population of 55 years and older. And that's not going to be going away anytime soon. We know that older people are turning to cannabis for medical purposes, and also for non medical purposes. And the number of controlled studies where people looked at the safety and the potential effectiveness of cannabis and cannabinoids in older populations, I think might be one at this point. I think there's been one study looking at this. And so that's definitely an area that needs to be assessed. And also thinking about the animal literature for both of these both. How does cannabis and cannabinoids differ between men and women, as well as older populations? If you look at the animal literature, there's a really strong evidence showing that age and sex strongly impact the outcomes or the effects of THC, at least THC if others haven't been studied, I think CBD has been studied as well with respect to age at this point. So we have a grant right now that's looking at differences between men and women. And how sex plays a role both with respect to the negative effects of cannabis. So like you mentioned, abuse, liability, intoxication, cognitive impairment, as well as the therapeutic effects. And what's interesting is when you do look in the animal literature, and you see really nice data showing that female animals are much more sensitive than males, on a host of endpoints for THC effects, including pain relief, as well as the negative effects. So female animals are much more sensitive than males. And so we're going to be testing that in our in our laboratory. Another important point, Nick is not just sex and age, but also chronicity. of use. So how often are people using, we know that people develop tolerance, tolerance, development is true for a number of psychoactive substances. So this is true as well for cannabis. And if you look at sex dependent effects, we see that although females in the animal laboratory, females are much more sensitive to THC effects, when you first give it to them, but after about a week, or two or three of exposure, females about tolerance at a much faster rate than males. So they won't show pain relief after three weeks of administration to that those that you use on day one, whereas the males will still show that pain relief. And this is something that we've shown about a couple years ago in our laboratory, where we created females who are daily cannabis users, people who use cannabis daily, males and females. And we found that in males, when they use cannabis with THC, we saw pain relief in females. We did not see any pain relief in that population. And so we're looking to see if this is indicative of females across the board, or is it because these were people who are using cannabis daily. So we're interested in looking at people who don't use Cannabis daily who may be use it once a week or once a month, and comparing them to these daily cannabis users. And we're looking at a number of variables, we're looking to see if hormones might contribute to these differences. We're looking at Endocannabinoid level, so your body's natural cannabinoids and how that might also alter the effects. And so that's, I think, a really important area of interest that has grown. There's been increasing interest about it just again, because the fact that more women are turning to cannabis and cannabinoid based products for medical indications. And we know very little about differences between men and women in this area.

Nick Jikomes 50:41

And what are what are the signals we're seeing in the animal literature for the effective age.

Ziva Cooper 50:50

And so the effective age, I think, that one impressive study that always comes to mind, when I think about when I first realized how age plays such an important factor in this, there was a study, I think it was might have been three years ago, where the researchers, I think it was like in nature medicine, the researchers had adolescent rats, and then they had like elderly rats. And they expose both groups of rats, to chronic THC administration.

Nick Jikomes 51:23

The same dose in both groups like every single day, they're giving them THC

Ziva Cooper 51:27

every single day. In fact, this was like round the clock, I think they were inserted with pellets that had like a time release one of those time releases. And at the end of, you know, a week or two weeks, they looked at some markers of memory and attention that you can look at an animal's. And what they found is that in the adolescent rats that were given the THC, they showed decrements in the memory and the attention all those markers of like cognition. So the animals that had been, you know, exposed to THC every day had much poor performance and animals that hadn't been in the adolescent group. And when

Nick Jikomes 52:04

they measure them, they're actually there's no THC in the system, right? So they're seeing a decrement after they're given chronic THC. But but they're tested without THC in the system.

Ziva Cooper 52:14

You know what I? That's a good point, Nick, I have to look back at that. But that's a very important point. And maybe you remember this paper as well.

Nick Jikomes 52:23

Yeah, that's okay.

Ziva Cooper 52:26

But then in the older group, and again, you could correct me if you if I miss remembering in the older group of animals, they actually showed that compared to the elderly animals that didn't get the THC, they had improved, you know, measures of cognition. And so when I saw that, I was like, Wow, that is really interesting how you could get such diverse effects, just due to age. And since then, there have been some other studies looking at, you know, ultra low doses of THC administration and older animals, and how that impacts inflammatory responses and cognitive responses. So there have been a couple of really notable findings, I think, in the animal literature that are compelling enough to look at, you know, these effects in, in older human adults. Yeah,

Nick Jikomes 53:19

now that that paper was very striking, just to summarize everything, essentially, you give THC for a month to young and old rodents, and you more or less get the opposite effect. And it was just quite striking, I think they actually are doing or at least planning to do clinical trials in elderly humans, where they're going to be looking to see if low doses of THC, improved cognition, which again, is the opposite of what you tend to see and younger individuals. backway. So what do you have anything else going on in your lab in particular? Or did you or the studies you described, what you're mainly focused on right now?

Ziva Cooper 53:58

Oh, yeah, there's a lot of really exciting studies going on. So we have a bunch of studies looking at these opioid sparing effects of cannabis constituents. We have you sex dependent, sparing effects, I'm sorry, sex dependent effects of THC of cannabis among males and females. We have a study looking at the potential anti inflammatory effects of cannabis use and people with HIV. And so that's also an interesting story that's kind of born out of preclinical research. So, research with non human primates and that is not a placebo controlled study. That's an observational study where we're we're looking at markers of inflammation in people with HIV who are using cannabis and not using cannabis and also trying to figure out if how people are using cannabis might impact inflammatory markers, anti inflammatory markers, so that's exciting. And then I've also branched out and I'm doing some stuff for some public policy people, which is interesting a kind of a different wheelhouse. And then lastly, we have studies in patient populations as well. So we have a double blind placebo controlled study looking at CBD for rheumatoid arthritis. So you know, there's been one interesting study, looking at the combination of THC and CBD and people with rheumatoid arthritis over five weeks, that was somewhat encouraging. And so now we're going to be looking at we did not do that study that was study was done in about 2006. And now we're looking just at CBD, in part because we think that based on animal literature, CBD might be anti inflammatory. And so we're looking at a couple of different doses of CBD compared to placebo over 12 weeks. So it's a good chunk of time to be able to see a signal. And then we have some other patients these that are percolating, where we're working on our approvals for those as well.

Nick Jikomes 56:03

Well, this is perfect, I wanted to ask you a variety of things about CBD. It's an interesting molecule, it's still quite mysterious. And it's obviously, you know, a major part of popular consciousness right now you can go to the corner store, you know, bartles, or Walgreens and, you know, people are essentially putting CBD and everything. So for the study that you mentioned, you mentioned, you're testing two different doses. In general, my understanding of the CBD literature is that when we give CBD to people, and it has a bonafide effect of some kind, we're typically giving them a very large dose. So what do we know about bioavailability? What kind of doses are you using? And how should we ultimately I want you to get to talk talking to people about how likely is it that taking five or 10 milligrams of CBD in a product that you bought, actually doing anything?

Ziva Cooper 56:55

So Nick, thank you for that. And this is another point that I drive home to people is that not only do we have very few studies with CBD by itself for all the indications that people are using it, but the studies that we do have that have shown promise have been using whopping doses compared to what people can get at dispensaries. So typically, on the high end of CBD concentrations that you can get a dispensary is at least in Los Angeles, 50 milligrams, 100 milligrams, the doses that have shown a positive signal in the few clinical sites that have been done have been 400 milligrams, 800 milligrams, 1200 milligrams, those are high doses. And if you were to actually to get those doses from dispensaries, you'd be breaking the bank, right? I mean, they're, they're super high doses per day. And you asked about, you know, how we're figuring out the doses for rheumatoid arthritis study. And essentially, you know, when you write a proposal, and you know, you're trying to look at an effect that hasn't been studied yet. And in the laboratory, under rigorous situations, you have to go to the literature, and you have to determine your doses based off of what's been done in the past, for safety reasons. So you can make sure that the doses that you're giving are actually safe in the population that it's been studied and before, and also just to know that it's shown some positive impact on the endpoints that have been tested in the past. And so we're basing our doses off of the literature that has shown that it under certain circumstances, a dose of cannabidiol might have anti anxiety effects. And so those are high doses, you know, 600 milligrams, 800 milligrams if you're looking at the opioid study, and with respect to safety, as well, and so we're using high doses for those studies. One aspect of you know, one thing you asked about was bioavailability, which I think is an important component to this and why the doses are usually so high. So we know that the bioavailability of CBD can be as low as 6% when given orally. So that means that if you are taking 100 milligrams, only six milligrams of that will be bioavailable, and that can have all types of downstream effects, including the fact that if CBD is working, you need so much of it just to get into your system and to have an effect. And also you have to think about as been shown in the past that when you're taking this much drug, what kind of impact is it going to have on let's say, the liver, the liver that is processing all this stuff, and we know that high doses can have some negative impact on the liver and that's that's also really important to know. With respect to the products that people are getting in the dispensary Like you said, they're five milligrams, 10 milligrams, or at the general health food stores, do these have an effect. So based off of what we've seen in the literature where you need 300 milligrams, 600 800 milligrams, one would think that, you know, 10 milligrams, what kind of an effect with that have, in fact, there have been very few studies looking at these very low doses that people are using. Now, just because we don't have good data on those low doses doesn't necessarily mean that it doesn't work, it doesn't do something, both on the safety side, as well as the potential effectiveness side, if somebody's taking 10 milligrams, 50 milligrams, 100 milligrams every day, for a year. What are the outcomes of that exposure every single day? And the truth is at this point, we don't know. And part of the question also is what type of product is it? Um, you know, they have all these companies now are trying to make CBD products that have increased bioavailability. There have been some studies, one came out recently showing that some of these preparations do enhance bioavailability. So are people taking these types of products that have enhanced by though the bioavailability? And what are the outcomes? And the truth is that we really don't know at this point, the products that are available, there's there isn't really oversight for them. So the FDA isn't testing those products. So we actually don't know the long term or short term impact of taking these products that are like you said, they're available at your corner store, they're available at Bed, Bath and Beyond. So there's there's really a lot of unknowns at this point.

Nick Jikomes 1:01:45

Two areas I wanted to ask you about in terms of where the evidence is, our inflammation and anxiety. I think everyone everyone who's interested in CBD is probably at least heard about what's happened for epilepsy with epidiolex. So if you don't know about that, I'll just encourage people to go to go read about that elsewhere. But what do we know for CBD in terms of anti anxiety effects? and inflammation effects? You've touched on both but but what's been nailed down so far?

Ziva Cooper 1:02:16

I want to touch on the anti inflammatory components first, because I think that it's natural for people to say that CBD is an anti inflammatory. It's like, at this point, it's like a given Yep. Um, but for me, and I do not know the literature through and through. But aside from one study, that was not a controlled Drug Administration study, or maybe I think there might be two studies now that have shown some decrease in markers associated with inflammatory response and people that have used CBD. So I don't think that we actually have a good handle on this yet. And I don't I don't think that people have looked at this and patient population. people haven't really looked at CBD and many patient populations periods. And I haven't seen studies that have rigorously assessed markers of inflammation in these patients studies. I think in animal studies, we have some really nice compelling data, but we haven't yet translated that to humans. So when I hear people say, CBD is anti inflammatory, in my head, I think that they're really pulling from the strong animal literature and, and molecular literature at this point. And this is an area that also we hope to try and fill at UCLA and do the studies to actually determine if that's if that's really an effect. Now anxiety, we talked about how pain is one of the primary reasons why people use CBD. anxiety, I think is the second reason that pain, anxiety sleep, right? So people are using CBD for anxiety Now, does it do? Does it help with anxiety? When you ask people in a survey data, they'll self report to say that? Yes, it's helpful. And what about the rigorous placebo controlled studies? So this is an area that there have actually been a handful of studies looking at CBD compared to placebo for anxiety. And up until about a year ago, these studies were just looking at one dose of CBD and how it might impact certain aspects of anxiety. If you think about somebody who has anxiety, they're not necessarily taking a therapeutic just one time. Right? So people frequently if they have generalized anxiety disorder out of his anxiety disorders, they're usually taking these medications, you know, every day for an extended period of time. So up until a year ago, we didn't really have good data about what happens when people use this regularly or for a week or for a month. And just this past year, there have been some studies that have come out that have looked at the effects of using CBD for a week on some measures of anxiety. There was even one study that had participants use canal for a month. And at the end of the month, they looked at measures of anxiety. And so there have been positive signals. But I will say, we based off of how many people might be using this for anxiety, a whole range of anxiety disorders, or different types of anxiety, different doses, we still know very little about this. And I think that I think that it's a promising area, I know that there is a certain subset of people who do not respond to traditional pharmacotherapies that help with anxiety. So we are in need of another pharmacotherapy to help treat with anxiety, cheap treat anxiety. And if CBD offers a potentially safe way to help with anxiety that doesn't have some of the adverse effects that other pharmacotherapeutic agents have, then that will be great. But we're still I think, pretty far away from saying with certainty, that CBD is helpful for anxiety at this dose or this, those are the steps.

Nick Jikomes 1:06:21

So I wanted to ask you to about some of the research, mechanics and rules involved in doing this type of work. So on the very front end, you mentioned that part of your role at UCLA is just getting all this whole structure up and running, including how to get funding. And so where is the funding coming from to do this kind of work? And how difficult when you're working with THC? Is it to actually get this research going, given the schedule one status of THC.

Ziva Cooper 1:06:58

There are a number of barriers to getting this research up and running and you hit on one very important barrier, and that is the schedule one status of THC. But it certainly isn't the only barrier. You also mentioned funding. Where do we get money to look at the therapeutic effects of cannabis and cannabinoids. This is not an area that traditionally the NIH has supported. Now that has changed to some degree. And in fact nyda the National Institute on Drug Abuse is even funding some of these studies looking at the therapeutic effects of cannabis and cannabinoids. So that's kind of remarkable National Institute on Drug Abuse was the main Institute of the NIH that funds the study to look at the adverse effects of cannabis and cannabinoids, but now they are looking at this plant and the chemicals in the plant as potential therapeutics for a range of indications. So that's encouraging. There are other Institute's in the NIH, they're also involved with this. So I mentioned this grant that I have looking at terpenes, in combination with THC. And that study is, you know, a study probing the therapeutic effects. And it's funded by a part of the Institute called the part of the national, the National Institutes of Health called the National Center for Complementary and Integrative Health and CCI Ah, and so they have a line of funding that is dedicated to this. So we're starting to see that funding is starting to free up a little bit at the NIH. But in general, funding is very competitive at the NIH level, it's about 18% of applications will get funded. And so it's hard, it's hard to get a study funded, you have to know what you're doing. If you are somebody who's just getting into this field, and hasn't been doing this work before. It's very difficult to get a grant funded because there's a question of feasibility Are you going to be able to get through all this red tape, like you said, that is associated with a schedule one status. With respect to funding also, there have been other encouraging, you know, Silver Linings for the world class overlying? I mean, just in general, it's positive, we're starting to see increased support from states. So in the state of California, there is the California state funded center for medicinal cannabis research. And so they specifically find studies to California based researchers. Looking at the therapeutic effects of cannabis and cannabinoids, the those funding dollars are even more competitive than NIH. Okay, so it's even harder to get that grant. And again, it's taxpayer money. Yeah, it's from it's from sales. Yeah. And it was written into the bill back also when my medical cannabis is regulated and then again, when adult Cannabis became regulated or legalized.

But again, if you don't very competitive if you haven't delved into this field before, you have to have a mentor or you have to know somebody who can help you guide guide you through all these processes. Okay, so there's the funding issue. Then there's the schedule one status issue where if you're going to deal with cannabis, or THC, unless there is a type of THC that is not scheduled one, so you can get oral capsules or a oral solution that is synthetic THC that is FDA approved. And so that's schedule two, or schedule three, so you don't have to worry about the schedule one. But anything else cannabis or THC totally by itself, like the way we use it in our lab is schedule one. Now in order to get your schedule one license, you have to first you have to have a protocol, by the way, you have to have a protocol where you need to use cannabis. Okay, so you can't just go to the Drug Enforcement Administration, the DEA and say I want to schedule on license, you have to say you have to show them that you have a reason for it. In order to have a reason for it, think about what you need. In order to have a study proposal, you need a money, you need money, you need funding for that study proposal, right? So you know, you get back to that funding issue, once you have funding or support from your institution. And they say, Okay, here's $100,000, you can do whatever kind of study you want. studies do not cost $100,000 more money than that. But then you need to have a facility, you need to have a space where you can store your schedule on material that also requires funding. Because you need to have all types of security, you need to have the space, you need to have a space where nobody else is going into only the person that has this scheduling license and who's on that schedule and license. So you need a lot of institutional support for this. I'm lucky when I came to UCLA, like I explained to them, like the only way that I can do this work is if I have institutional support if you give me a space where I can put the drug in a very secure setting. And I also need a letter from you saying that you support this work. So you get your DEA license it you need a approved protocol from the IRB with the funding, you need a product that can be studied in humans, okay, safely. And so I'm going to get to that in a minute. But getting the whole schedule on license it takes a very long time to to obtain. And that length of time can vary based off of what state you're in, based off of how communicative your DEA office is. So there's that and we can talk we can we can have a whole two hour segment on that. A third main barrier that people forget about is again, one that I just alluded to, and that the product that I give to people or that we give to people as researchers, it has to meet a certain standard has to meet FDA standard for quality control. Okay, so for example, even if cannabis was a schedule one anymore, even if THC wasn't schedule one, for example, hemp derived CBD, which is no longer classified as a schedule one substance, so I can get CBD anywhere, why can't I just go down to Whole Foods and get whatever CBD supplement they're selling there and then give it to my participants. You can't do that. Because for our studies, to get approval, I have to submit my protocol and a very detailed description about the product, I'm using it to the FDA, and the FDA has to approve it. And they have to see that the study product that you're using is stable over a period of time doesn't have a certain amount of heavy metals or pesticides, that you know the certificate of analysis that comes with it is actually correct that it's 100%, CBD and no THC. And it's really hard to find that product. I mean, I think that that is probably the toughest thing. toughest part of doing this work is actually identifying where I can get my study drug from. And also, wherever I get my study drug from, they also have to be able to give me a placebo. Right if I'm doing a placebo controlled study, I need a placebo as well. So that is a significant limitation that I think often goes overlooked when we talk about limitations and barriers to this work in the United States. Because we automatically think about the schedule one issue as being a huge barrier and it is but the other barriers are also really important.

Nick Jikomes 1:14:42

Where do you get your CPD from?

Ziva Cooper 1:14:45

So um, I have hunted for different companies that can really help me and support me through this FDA process and are welcome MIT to say that they can give me the product for x y&z study and a matching placebo. And that's an integral component to these grants that I write, for example, you know, if you're going to put in a grant for funding and the funding is really competitive, you better show reviewers that you know where you're getting your, your drug product from, because that's a major limitation. So I do have some sources that that can provide me with that information that I need for the FDA. And we work together I mean, it's not it's it's a difficult process. Same thing with the THC, the THC that I get, I have to work with a company and they have to be very generous with their time and their documentation. And so, you know, it's interesting, because you get to know another part of this field of work that isn't necessarily what, what I'm trained to do. So it's been fascinating, and also kind of fun as well.

Nick Jikomes 1:16:00

Interesting. So you mentioned that $100,000 wasn't enough. And for non scientists, I actually think it's, it's helpful to get a sense of what we're talking about here. So assuming all of the infrastructure is in place, assuming you've got all your approvals. Well, how many people are in some of the studies you're running? And what's the order of magnitude for the cost there? How much is it to do a study with X number of people?

Ziva Cooper 1:16:22

So Nick, it really depends on what you're looking at. So a lot of my studies require us to draw blood from people so I can see what are those levels of CBD once they take it, or what are those levels of THC or terpenes in their blood. And when you're drawing blood, you're looking at lots of different time points after the drug is administered. So let's say 10 different time points, eight different time points. And then that blood has to get analyzed by a specialist using specialized equipment. And so those types of analyses are very expensive, they're very, very informative, and they're important, but they're very expensive. Um, I will put this out there, I don't you know, every lab has a different budget scheme. And you have to have personnel to be able to run the study, you have to have a nurse, you have to have research assistants, and all these people have to get paid. And so different labs have different types of needs. I will say that, in general, the NIH budget is usually capped at about $500,000 a year. And so a lot of the studies that we do are about five years, okay, so you can imagine, sometimes that cap is reached sometime it is it isn't reached, for my studies, because they're very intense studies where people come in several times, and they're getting their blood drawn several times, they're not large studies at all, for example, I'll enroll I'll screen 60 people get 30 people in. So they're not large studies, other studies, when you're working with patient populations, and you have to enroll a hundreds of people, you know, 200 people, that can be enormously expensive, you know, 5 million, 10 million. So these aren't cheap, um, it's different, you know, industry also does these types of studies. And they have, I think, different endpoints that they need to reach. And so there's other costs that are entailed with those types of industry studies, our studies are not nearly as expensive because, you know, most of what I'm doing is that I'm doing, you know, scientific investigations, I'm not looking to develop a new drug for a new indication, they're really the understand what do these terpenes do? And people, you know, we know this in animals, what are they doing, people cannot be translated to a patient population. So they can be very expensive. But you know, you just think about the number of people that have to work on a study and you think about what their salaries are. And it gets to be, it's be happy.

Nick Jikomes 1:18:55

Yeah, so it's not just you and a postdoc doing some work. It's it's a network of people doing hundreds or 1000s of

Ziva Cooper 1:19:02

hours of work. Exactly. Yeah.

Nick Jikomes 1:19:05

So what are you most excited about? in Canvas research? Generally? What do you think is on the horizon? That we'll get an answer to in the next year to say,

Ziva Cooper 1:19:15

so Okay, you're too Oh, my goodness, I thought you're gonna say five or 10 years.

Nick Jikomes 1:19:19

I'll give you five. I'll give you five the next few years. Okay,

Ziva Cooper 1:19:22

so I think some exciting things for me are obvious ones that we've already talked about. So this issue about CBD, seven, one out of seven adults are using it for all these different indications. When you talk to a scientist or somebody who's in this area, you know, we'll throw up our hands and be like, we just don't know. You know, we just really don't know at this point. In five years, there are so many studies happening right now across the globe. We are going to have a much better sense about what CBD can do and cannot do. Again, I think based off of preclinical literature, there is potential, huge potential for this for cannabidiol. But we have yet to see this potential borne out in human studies yet. And so I think that we'll be able to see that in human studies, like you said before, it's a really messy drug. It has 10s, if not hundreds of targets. And we don't understand its mechanism. And I think that on the preclinical and molecular side, we're going to see a lot more of that being flushed out if possible. I mean, there's so many different ways and pathways that I can work on. So that will be really interesting. I think that we talked about these drug combinations are or cannabinoid component combinations, and I think we're going to see a lot more of that work being done, which will also be really exciting. And what's interesting is that that work I think is really being pushed by the emerging products that the popularity of some of these emerging products for instance CBG or like you know, delta eight THC, everybody's heard about Delta eight THC. We there are a couple of studies in humans, but they haven't been done in like 20 years, all of a sudden, you know, people are using Delta eight THC, we got to know what it does. And so there is this interesting cycle here where although the emerging products and the industry isn't being pushed by science, it is helping to propel science and scientific questions. So there I think that we have our work cut out for us for decades, and we will definitely be learning more about minor cannabinoids and terpenes and a combination of the two. Um, they're also one one area that we haven't focused on very much Nick, is the endocannabinoid system and therapeutics that are leveraging the endocannabinoid system that are showing promise. Right now in some studies, I think that again, in five years, we're going to see a lot of studies in this area, we're already starting to see some some studies in this area where we're looking at the endocannabinoid system in general, and how we can not delay the endocannabinoid system for some therapeutic endpoints. So moving a little bit away from the plant, right, and thinking about the biology, I think those are some really exciting areas.

Nick Jikomes 1:22:14

Interesting. Well, yeah, this is an exciting area. For me, obviously, I'm really interested in all this stuff. Are there any final thoughts that you want to leave people with? who are following this type of research or just generally interested in the medical potential of cannabis?

Ziva Cooper 1:22:30

Um, I think some final thoughts would be is that or what are that? For me, I have, I have found that this community, talking to other scientists in the field, whether they're in academia, whether or not in academia, as well as hearing from community, about the interest that they have, or learning from their experiences has really been instrumental in shaping my journey over the last 10 years. And I don't think I necessarily had that early on in my professional career or scientific career, maybe it's because I was, you know, in graduate school as a postdoc, but I have to say that I'm learning from the community and being able to have a dialogue. I mean, there's a lot of like, heated debates on several different topics around the cannabis. But in general, it has been really refreshing to be able to have open dialogue about what we know what we don't know where the interests lie, and also from learning from each other about these about these areas. I will say that, you know, in general, I always stress the importance of really relying on the data that's coming out and not going to the media. You know, you see a splashy news headline, and you know, you're quick to say, okay, CBD is going to help the, you know, COVID infection rates. And, you know, you see that, okay, well, what does that study say? Where has it been published, you know, has it been peer reviewed, really, not taking the headlines for face value, and doing a little bit of the work, doing a little bit of the work to kind of dig deeper to try and really understand what is underneath those headlines, both for positive reasons and negative reasons as well. And so, you know, it takes work to do that. But at the same time, it's also really fun. I mean, not a day goes by where I feel like I don't learn something in this field, both from media and the community and with people who are experts in the field. So I think it's, I think it's, you know, it's a wonderful community all around.

Nick Jikomes 1:24:47

Can I sneak one more question? Sure. So one thing that's very difficult, I don't really know what the answer to this is. If you're not a scientist, but you're interested in this stuff, Or some other field that we could think about analogously. And there are all of these media articles coming out with a huge variability in the quality of those articles in terms of their accuracy and how well they're respecting what was actually done in the studies. You know, in some ways, people who aren't scientists have little more to rely on than what they see in the media. So how would you recommend that someone who isn't a scientist, take that extra step to dig deeper? What's what are some potential strategies there?

Ziva Cooper 1:25:29

So we, you know, one thing I always look for when I see a big media headline is, and I'm a scientist, so I'm trying to look for this. But first, what was the species? You know, that was used in this study? Alright, so frequently headlines, like CBD is anti inflammatory. And frequently, the headlines are made from studies that aren't necessarily being translated to humans. Alright, so I think that's really important for people to understand. A cell is not a mouse is not a rat is not a monkey is not a human. Okay, so the translation is critical. I'm not saying that there can't be a lot of promise from studies in in nonhumans. But it's really important to put that in context. So that's the first thing does the media piece address that really important? Second thing does the media piece actually give readers the link to the article. So frequently, I it's mind boggling how often you see that these splashy headlines, and then they don't even have the link to the article. And that is really important. Even if you get the article and you find that it's very difficult to get through, then that's one thing. And sometimes you can even glean just from the part first part of the article, the abstract, where it talks about, you know, some of the results in more common language, at least you can look at the abstract then third is what perspectives are being offered in that article, or they're being or their perspectives from the author, or their, from the of the of the study or their perspectives from people outside of the author's institution. And I think that's also really important to attend to, but I agree with you next, sometimes it's really hard to get through these articles, if the studies if you can find them. But I think an interesting thing that I see happening, unfortunately, I don't have so much time these days, but on Twitter, I do see that there is considerable effort from researchers and academics to explain what the study's findings are, and really what the take home points are. Now, of course, the people who you're looking at on social media, they also have biases that you have to keep that in mind. But if you're if, if a number of people are talking about a similar paper, then hopefully you can cobble together, you know, a sense of what people in the field actually think about that particular study.

Nick Jikomes 1:28:00

So I think I heard three things. There are three tips or three practices for anyone, but but in particular, non-scientist one, if you're reading a headline article, look to see if it was done in humans, or nonhumans. And at least be mindful of that, and pay attention to whether or not the journalist was making that clear. The second thing is to look to see if they're linking to the original study. And if they're not, then that's a highly suspicious thing. And if they are, the last thing would be you can look at the study. And you don't need to read the whole study, because you might not have the time or the inclination to do that. But just that first paragraph, if you can read that one paragraph and just sit down and patiently read that you can probably learn a lot about whether or not the article is actually true to the underlying study. Is that great? Great. Awesome, great tips. Thank you for your time. Ziva. I think your research is really exciting. At some point, I hope I can get down to UCLA after the the COVID situation is over and get out of the cloudy weather up here in Seattle. So I'm a little jealous that you have that. But thank you for your time and I look forward to talking to you again.

Ziva Cooper 1:29:08

Thank you so much neck, it's a lovely Thank you

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