Full episode transcript (beware of typos!) below:
Nick Jikomes
Dr. Yasmin Hurd, thank you for joining me. Thanks for having me. Can you tell everyone where you're at where you work? And just a little bit on your background as a scientist?
Yasmin Hurd 2:57
Yes, um, I am the director of the addiction Institute at the Icahn School of Medicine at Mount Sinai in New York. And my I'm a neuroscientist. I study the neurobiology of addiction and with a goal of trying to develop medications based on what we learned about, as I said, the neurobiology of addiction.
Nick Jikomes 3:21
So you do a lot of research on CBD that ties into your work as an addiction scientist, and CBD is very popular right now. In general. You can find it at the corner store. It's sort of this big health and wellness craze. Can we start out by just having you explain what is CBD? And what do we know about its basic biology? Yeah, it's been a real roller coaster for me in context that you said CBD is now everywhere in the water even literally in the water.
Yasmin Hurd 3:55
And so CBD is cannabidiol and cannabidiol is a cannabinoid in the cannabis plant. Or many people now I think even know hemp plants, but it's one of about 140 cannabinoids, the cannabinoid that most people on the street know about, or before CBD became so popular was THC, or is THC and THC is the cannabinoid that leads to the high you know, the rewarding effects. And CBD though does not produce intoxication like THC. So CBD cannabinoid definitely impacts the brain so it does have biological psychological effects, but those effects are not linked to the intoxication aspects of cannabis and a lot of the research now, my group and others is looking at it in regard to aspects of anxiety, craving, etc.
Nick Jikomes 4:56
And so CBD is a plant cannabinoid like the THC as you mentioned, we have an endogenous cannabinoid system and endogenous cannabinoids, can you speak a little bit about how CBD influences the endocannabinoid system in our bodies?
Yasmin Hurd 5:13
So our natural cannabinoid system as you said, the Endo, the endogenous endocannabinoids. We have their lipid chemicals and they bind to cannabinoid receptors. And there are two main cannabinoid receptors in the body CP one and CP two, the exogenous the plant derived cannabinoids like CBD and THC. They interact with our natural endocannabinoid system and primarily out these receptors, but mainly for THC. So THC is an agonist that binds to our cannabinoid receptor. CBD actually does the opposite in part, it's an inverse agonist, meaning it has even antagonistic effects out the cannabinoid receptor. However, it modulates our natural lipid or natural endogenous endocannabinoid ligands that binds to these receptors by enhancing the levels of these receptors, these ligands through his thought inhibiting these transporters that take up these natural cannabinoids. So perhaps I should step back and say, You know what are coming back into the biology of endocannabinoid system. So these endocannabinoids are made when your body needs them. So that would call the made on demand. Many transmitters in the in the brain, especially since I'm a neuroscientist I'll focus most on that. They're synthesized and stored. And when they're needed, they're released. And but the endocannabinoids they're actually synthesized on demand, and then they transport back across the space between cells, the synapse, and are taken up by transporters, these chemicals that take up the endocannabinoids. And it's believed that CBD inhibits these transporters. And so therefore, the natural endocannabinoid levels then are elevated, but they're not elevated dramatically, but they're elevated. So that's one of the mechanisms of few of the mechanisms by which CBD directly and indirectly modulate the endocannabinoid system.
Nick Jikomes 7:34
Interesting. So when you ingest CBD, potentially, at least to some extent, you may actually change the levels of your own dodginess cannabinoids.
Yasmin Hurd 7:43
Correct. But, again, he there, there, there's let's put it this way. There's a lot of research that's needed. So in terms of finding out the true mechanism, by which CBD works, because in addition to the endogenous cannabinoid system, CBD actually interacts with multiple transmitter systems. So for example, it will modulate our opioid system and part even, it will modulate serotonin, a transmitter that's really important for regulating mood. It's will modulate, you know, so a number of transmitter systems. And that broad pharmacological effect of that CBD has is interesting, because it's actually not potent, really, really potent at any one of them. Except a new an orphan receptor, that it now appears to work as an antagonist for this receptor, we're still trying to figure out the actions of this transmitter system. But being able to tweak it, you know, small amounts different transmitter systems, actually is not a bad thing. In pharmacology, we used to call these quote unquote, dirty drugs. But I've started to look at it very differently after studying CBD now because a lot of times when we try to develop these, these medications that are very powerful at one receptor system, it normally leads to side effects because you're either really hammering as an agonist really turning on one receptor or really potently blocking another, and CPD tweaks. It turns up the knobs up and down for a number of transmitter systems but not in a powerful manner, but in a way that modulates that really is more in a way homeostatic, I think.
Nick Jikomes 9:43
So it's it's tweaking many different receptors or systems in the brain. It's not really potently affecting any one of them. Can you speak a little bit more about what we know about CBD drug properties? So you mentioned and people have mentioned previously on the show that it's not a particularly potent drug. But you just mentioned that that could be a benefit. What else do we know about drug like properties? So toxicity and bioavailability. I mean,
Yasmin Hurd 10:12
every every drug, every medicine has positives and negatives. And every it comes back to dose dose is everything. And so yes CBD at especially the doses that our people are taking in their water, or their coffee and so on and, you know, is not at a high dose that is normally going to be toxic. There's been a lot of studies on CBD at doses. So when people buy them normally in you know, the, on the boutiques, and so on, for example, 10 and 20 milligrams, 25 milligrams of CBD is what's normally sold. On a clinical level, most of the studies are studying 100 to like 600 milligrams of CBD. And those studies do not find any adverse effects, really, in terms of, you know, toxicity at a level that you would say this is not a medic, this is not going to be used as a medication. And what I mean in terms of liver toxicity or other things, there's definitely studies that have even gone up to six 6000 milligrams CBD and not found, you know, really bad side effects. The side effects that people have mainly seen are more gastro intestinal, so GI tract diarrhea kind of thing, even sleepiness, but now CBD is being that part of its negative, quote unquote negative could be used for people, you know, for sleep inducing sleep for the negative side effects in terms of liver enzymes, and so of course, toxicity in terms of your liver damage is always an issue with every medication. And for kids that were treated with CBD for epilepsy, the interaction with some of their anti epileptic drugs could lead to changes in elevating liver enzymes, and that's not not good. But in other clinical studies that have gone on so far, and yes, many of them are small, they've not seen, you know, this type of toxicity. So, interaction is really important for the negative things that one are, you know, that many of the studies are showing, and like I said, you know, anti epileptic medications, it interacts with, you know, say anti depressant medication, benzodiazepine anticoagulants so many of most drugs, obviously are metabolized are broken down in by our liver. And the liver enzymes. CBD could also work at those enzymes can also be targets for modulating CBDs metabolism. So that's the thing we try to make sure that, you know, it's important that when you're taking other medications, like I said, anticoagulant or anti depressant, it's really critical that you let your doctor know that you're taking CBD because CBD could in fact influence how that drug is metabolized. And that drug could also metabolite influence how CBD is metabolized. And that's how you could increase a toxicity.
Nick Jikomes 13:35
Interesting. So CBD is fairly benign on its own, but because it can impact metabolism of drugs in the liver, there can be these drug drug interactions that we presumably just don't know a lot about yet.
Yasmin Hurd 13:46
Correct. And we're gonna know more since now, there are a lot more studies being done with CBD. I mean, a lot of animal studies had been done, and shown, obviously a good profile, or else it would never have gotten past the FDA to even go into clinical trials. So most of the animal studies had shown that it did not have these, you know, terrible, or, you know, adverse events that we would not want to develop it for medication.
Nick Jikomes 14:14
And because this is such a big component of the health and wellness industry at this point, you see, you see claims for just about anything you can think of CBD is claimed to help with sleep, pain and inflammation, mood, almost anything you can think of we know that, you know, you've got an FDA approved medication Epidiolex for epilepsy. What are the other areas where there's at least some clear evidence that CBD has a positive impact beyond epilepsy?
Yasmin Hurd 14:46
You know, this is the challenge where you have you have a drug that's actually going before the cart before the horse, so the research is not there. To substantiate all of the claims that's being made about CBD for its clinical properties, so as I said, other than epilepsy, there have been some small studies done in relation to, for example, schizophrenia in terms of psychosis, showing that it has potential for having antipsychotic properties. Similarly for anxiety that it has an anti anxiety properties and delidded properties. In our research, we showed also in again, small studies, that it decreased craving and anxiety in people who had an heroin use disorder. There are studies going on for Crohn's disease, there's studies going on with for pain, but most of those studies are inconclusive. So there, there's still a lot that we don't know, even though it's being touted as basically like a miracle drug for all of these indications. And I never believe in miracle drugs. I believe in miracles once in a while, but I don't believe in miracle drugs. But I do think that a drug can have benefits in different indications, because a compliment back again, to dose and the dosing regimen. So perhaps for certain symptoms, you will need a high dose, you know, having two times a day, while for another indication, you could only need a small dose once a week or something. But these are the things that we need to find out about CBD and the data is not there to really give conclusive, you know, insights to the public. That's now buying up CBD oil, you know, in a lot. Yeah.
Nick Jikomes 16:45
Interesting. So you've done some work that I want to get to eventually related to CBDs effect on as a treatment for addiction. But before we get there, I thought it would be good to have you talk about opioids and the treatment of pain. So how do we how do we normally treat pain today, and how to opioid drugs work on a basic level.
Yasmin Hurd 17:07
Um, so you know, pain is one of the symptoms that most Americans are, you know, can relate to, and that's why you have over 10 million people being medicated with opioid analgesics. And the opiate analgesics. If you have acute pain, trust me, give me an opioid. If I have a nail that just went through my hand, I want, you know, that pain to stop. And they have been quite effective clinically. And so opioids, they modulate our natural opioid system, all of these drugs, they're there, they impact on something in our system, and our bodies obviously, and the endogenous opioid system is really key to regulating or translating a lot of like, you could say, the, you know, signals from the your sensory. So, like I said, you know, I got a nail in my hand, the signals that go through to my spinal cord to then register that, that, that injury, the signal in the spinal cord are mediated by the opioid peptides or natural opiate peptides or natural opioids are and they bind to opioid receptors there, and they also then the signal that goes up into our brain, where opioid system again modulates the perception, so it's the brain that perceives the pain. So that's the nociception of it. But that whole signal from your hand to your spinal cord up to your brain, the opioid are endogenous opioid system is part of that process. So opioid analgesics, they will inhibit, they will activate sorry, those those opioid receptors, and those opiate receptors will then inhibit the natural other transmitters systems that mediate these pain signals. And so, for example, a transmitter even called glutamate, where it will, you know, trigger the release of glutamate and substance B and other peptide that really mediates these pain and opioids will then reduce them. So it's an interaction the opioid system sits at the spinal cord, and brain circuits that are important for sensing the nociception are the signal of pain and the perception of pain. There's a long way to say it's complicated.
Nick Jikomes 19:53
Yeah, so we have an endogenous opioid system and an endogenous cannabinoid system, the endogenous opioid Are peptides. So they're almost like little proteins, as opposed to the endogenous cannabinoids, which are small lipids or fatty molecules. Exactly. And so are the opioids. Are they used on demand like the endocannabinoids? Or are they more like other transmitters that are stored and released.
Yasmin Hurd 20:15
So the opioids are exactly like other transmitters that are stored in release. And so the cell activity will trigger the release of these opioids. And that's the thing so our, again, our natural endogenous whether it's opioids or endogenous cannabinoid system, they are at physiological very low levels. And now you take a very potent opioid, and you will overwhelm that system for pain. That's good, because now you're blocking much, much more strongly the pain signals. And that's what these opioid analgesics do. The problem is that they not only add those, they're not only stimulate opioid receptors in the pain pathways, they can also stimulate opiate receptors in reward pathways that and that's why with repeated use long term, you then get activation of these quote unquote, addiction related neural circuits.
Nick Jikomes 21:21
So opioids are not merely blocking pain or altering pain perception. If you take an opioid even even when you're not in pain, it feels good. So they have these perceptual emotional effects in the absence of what they're doing to block any pain signal. Exactly. Exactly. And is that why they are particularly addictive as a class of drugs?
Yasmin Hurd 21:44
Yes, and they're addictive as a class of drugs. Because those knew a bit receptor, the opiate receptors were these morphine and oxycodone and so on, where they bind. And so I set a particular receptor like this called the new opioid receptor, and this receptor sits in, like I said, neural circuits that immediate reward and these rewarding circuits in the brain. And when stimulation, very profound stimulation of these opiate receptors, it leads to this rapid euphoric, genic, hedonic, nice feeling state. And certain opioids do that much better than others, because it's very rapid into the brain, and out. And so for example, fentanyl, that's bad, it's hits us receptors very hard. And so the brain is like, wow, I just, like got this incredible, you know, rush this, and then it's gone. So this very fast, pounding of our natural, rewarding pathways, that's one of the things also, they elevate, they, they, they indirectly elevate the transmitter dopamine, when many people know, you know, even on the street, if you're even if you're not a neuroscientist, what dopamine and dopamine is a transmitter. That's very much a critical part of addiction, neurobiology. So dopamine goes up, you feel good. And these opioids increase dopamine very much.
Nick Jikomes 23:19
Interesting. So how do you? How do you actually define addiction as a neuroscientist, and in particular, I often hear people talk about substances that are psychologically versus physically addicting. And typically, as far as I can tell, what they mean by that is, if something is psychologically addicting, it's basically less addicting than something that's considered a hard drug, it's very physically addicting. Is that a valid distinction? And how do you think about the spectrum of habit forming potential of drugs as a neuroscientist?
Yasmin Hurd 23:53
So for me, when people think that's psychological addiction, it means that it's not as addictive that's actually false. As a neuroscientist in the addiction field, you know, I go by what the clinical diagnosis relating to addiction so it's a disorder, a chronic disorder that is related strongly to compulsive types, behavior, craving, you will give up so many other things in search of this drug in in the need for this drug. Despite all the negative effects that this drug may induce, you're still taking musing and seeking as I said, this drug, many people can put that as a psychological, however, there is significant I mean that you don't need physical addiction in order to have a substance use disorder as strong addiction. And it's this chronic and relapsing disorder. And for me, you know, Controversy Is it a is it a brain disorder, it's a brain disorder, it, you know, are the neural circuits that mediate the reward the circus that mediate the changes in cognition that the decision making processes, the craving, the emote, the negative emotional state that drives even the drug seeking behavior, that's all in the brain. And it's a whole brain disorder as well, we may know specific circuits that might mediate the reward that might mediate the cognitive that might need mediate, the anxiety might mediate the depression. But there are many circuits that all go together to, you know, undermine the homeostatic state of the normal, quote, unquote, brain that's not seeking and needing and dealing with all the negative aspects of addiction, many people think about addiction that people are just trying to get high. That's not addiction, you know, the initial stage, of course, when someone takes a drug, and they feel really great. And they want to do that, again, perhaps the next time, maybe even few years later, and they do it. And again, and again, that's not addiction, addiction really is about, as I said, you know, the negative aspects people are in, and you use the word psychological, even the psychological psychological pain that drives a lot of the, the, you know, George Kuh, who now heads the naturalist have an AAA of alcohol disorders, this dark side of addiction, he used to call it and, you know, the Dark Side drives a lot of the behaviors to seek the drug, and so on. So, for me, addiction is a complex disorder, it's not as easy as people think, to just, you know, stop, or that it's just driven by reward. It's, it's a very complex disorder.
Nick Jikomes 27:01
So drugs of abuse often feel good. And so they have these these positive effects that people like initially, but with escalating usage, as your body adapts to that drug and gets used to it, more or less, the absence of the drug in your system can actually cause negative issues. And you're saying that relapse is often in part, at least due to people trying to avoid those negative feelings that come with the absence of the drug that they've been, they've been accommodated to.
Yasmin Hurd 27:31
Absolutely. And you know, but also, you know, stress is a huge aspect of drug seeking. And just most of the things that people why people searched the relapse comes back to these negative things that happens in their lives, the stresses that happen, the, you know, the depression, that happens. And so it's not that people are really going to try to get that reward again. Yes, definitely. It's not a, there are people obviously, who seek drug to feel good. And the question is, you know, at different stages of the addiction cycle, that's another thing, it's a cycle, you're not in the same place the whole entire time. And that's why it also makes it complex. Because in early stages of the addiction, even when you know that you're it's driven a lot by this more positive reinforcing effects. And you know, definitely, that it might lead to some negative, you're still Wow, this feels good. And then the slippery slope, and then before you, you start losing that control, and then when you lose that control, you're already lost that control to then go back. So you, the stage of addiction, also, obviously is mediated by different neural circuits. And that's why treating addiction can also be challenging because we're someone is an addiction, you can't treat everybody the same. And often, a lot of the treatments are the same.
Nick Jikomes 29:01
What are some of the typical treatments for severe drug addiction that would be used in the clinic today?
Yasmin Hurd 29:09
Um, that, again, is one of the problems with substance use disorders is that we don't have as many tools in the clinic as we should. So for opiate addiction, at least, for opiate use disorders, we have opioid replacement therapies such as methadone, buprenorphine, for other substances of abuse, for example, the psychostimulants like cocaine and so on, you mainly treat the symptoms. So you will treat the depression, the anxiety, and so those often are the medications that are given. So it's not that there are so such specific except for, especially for opioids. It's as a part of our discussion today, but they're not that many special specific medications, you're you're you're treating instead the symptoms that that person may be showing at that time. And there's a there are a lot of behavioral interventions to try to help people manage their their disorder.
Nick Jikomes 30:15
How is addiction to become addicted to a drug? Does it require repeated use of that drug?
Yasmin Hurd 30:26
Yes. So you know, and I think that this is one of the things that get a lot of people who feel that individuals who have a substance use disorder that they kind of brought it on themselves, and they're weak and all of that, but it really, you know, isn't there a lot of things that we know that increase the risk of someone developing a substance use disorder, even genetics, you know, early life, trauma is a huge issue as well. But even with every, every factor that could contribute to addiction vulnerability, if you never take the drug, you will, of course, not develop a substance use disorder, if you take the drug once, you need to take it again. And again, to change the neural circuits in a way, as I mentioned, in terms of changing, you know, cognition, changing your anxiety, you know, all of these circuits. However, for some people, because of their vulnerability, just that exposure to that to that drug, once they, they they quickly can transcend into addiction versus others. And it depends also on the on the drugs. So for example, opiates are very addictive, while cannabis is not. So you know, you can, if you're you can give you know, 10 people or 100 people or how many people you want in your your study, an opioid and, and cannabis, and you're not, and obviously, a larger percentage of people are going to become addicted to opioids to them well to cannabis, a few people will also become addicted to cannabis, but it's gonna be much fewer. So the type of drug also matters in terms of coming back to our earlier discussion of hitting, you know, hitting those reward circuits. And the endogenous transmitter systems like dopamine, you know, so those transmit those drugs that have a big impact on dopamine, they're going to be much more addictive than those that have a much smaller effect on the dopaminergic system, for example.
Nick Jikomes 32:40
So it sounds to me like there's at least three sort of sets of factors that affect the addictive potential of something. One is the drug itself, and its level of potency, and how rewarding it is to is just intrinsic features of that person, there's just genetic and developmental differences between people in terms of how sensitive they are to any given drug. And then three, we've sort of touched on this indirectly, that would be the context or the environment in which the person is taking the drug. So there's the the famous experiments in rodents that have been described by others where, you know, you give a rat access to a drug of abuse, in a cage, where it has nothing else, there's pretty much just the drug and maybe some water, and then you give another rat, or even the same rat access to the same drug, but it's got access to toys and mates and friends to play with. And the second rat is much less likely to become addicted than the first one.
Yasmin Hurd 33:37
And the same thing happens in humans. So yes, rats in our, in our studies, they're bored. If you're, you know, brought to a cage where you can like hit a drug, and, and you put back in a good where you're by yourself, and you're nothing else. Yeah, even if your mother said, Don't do it, you know what, when you go into that cage, most likely, nine out of 10, people would push that lever. And so that's the whole thing. Environment Matters. Another factor actually. So you, you're great at translating every single thing I would say in a much very loving, clear manner, and development. So the developing brain is also critical. So the earlier exposure to a drug, we know that it increases vulnerability to addiction, while if someone starts when they're, you know, an adult much later, we don't see the same addiction vulnerability doesn't mean that an adult can develop an addiction. Now, they can still develop it, but they're not going to be as sensitive. So all of there's so many factors that go into why an individual what why this one person develops an addiction, another dozen and I call it like the Russian roulette. You know, each person is given a gun with a certain number of bullets, and this person has many more bullets because they have If they're, you know, had some genetic risk, they're in a much tougher environment, they got started earlier, they had huge trauma. So practically, if it's a six gun, you know, six bullet gauge, they have, like, five of those are filled with a bullet why this person perhaps have won. So that's why when people think, oh, that person is just weak, or they are just this, they have no clue until you walk in their shoes, and knows exactly what has happened to them, and the lives and and, and their forefathers lives. You know, it's really challenging to say everybody should be the same in terms of addiction vulnerability.
Nick Jikomes 35:41
That's a great, that's a great metaphor, I've never heard it put quite that way. So in terms of treating addiction, we talked about some of the standard treatments, it sounds like there's basically two kinds of options for addiction treatment. One is to give people drugs that are more or less weaker versions of the drug that's causing the problem. And the other is simply to give them other drugs that treat the symptoms of withdrawal, like anxiety, say,
Yasmin Hurd 36:04
Sir, behavioral, I mean, so I, you know, if we're talking about treatment, I do think that behavioral interventions are really important, even though I am a neurobiologist, trying to develop a pharmacological treatment. I do think that behavioral interventions are important adjuncts for everything that we think about for treating substance use disorders.
Nick Jikomes 36:30
And so do you think that, you know, in the current situation over the last year, people are my understanding is that drug abuse has probably gone up considerably since COVID started? And do you think it's essentially, for the same reason that the rats in the boring cage are more likely to get addicted?
Yasmin Hurd 36:49
Yeah, and it's been stressful with COVID. You know, and so people are isolated, and they don't know what's going to happen, and it was just a stressful time. And it's interesting, you know, um, the alcohol stores are considered essential business during COVID. And in one part, I understood it. But of course, it's you're giving people you're, you're giving them a product that will increase their addiction vulnerability, or validation will increase the risk of, you know, getting into alcoholism, and some people have, and definitely a lot of the research has shown that there's been an increase in all substances. And last year, I mean, the overdose increase, over 82,000 people I think, died of overdoses last year at the highest for a very long time, even though like the opioid epidemic, you know, we had so many people dying, and bumped up again last year. So we forget that there is an epidemic that is still going on, even though we have this pandemic of COVID. And that epidemic of, you know, drug overdose, and opioid overdoses is still real. And it's, it's extremely sad. It's extremely sad, because it kind of gets, you know, lost in all of the stress of COVID. And all of obviously, the horrific numbers of people who have died from COVID.
Nick Jikomes 38:31
Can you start to describe for people some of the work that your lab has done in terms of CBD as a potential treatment for addiction. And I want us to be careful, one of the things that's very interesting about your lab is you do both animal research and you do human research, usually those
Yasmin Hurd 38:47
Yeah. A masochistic lesson was like, Okay, why? Why?
Nick Jikomes 38:54
So can you describe some of that research and we'll just be careful to distinguish between the animal work and and the human work and where each one is at?
Yasmin Hurd 39:03
Yeah, um, so my research program for many years, actually had two lines and they converged, the two minds was looking at the neurobiology of, of, of opioid addiction. And I studied on a molecular level, people, for example, who have died from opioid overdose, and animal models where they self administer heroin, and trying to see if we, if we can figure out what is really changed in the brains of humans who have an opiate use disorder, and we can replicate that in an animal model. We can actually start now coming up with treatments, and that was a strategy for that line. And then the other line of research was that we knew that many of the adults who had an opiate use disorder started out with, you know, other drugs like cannabis. And so we started to look at the neurobiological effects and also even genetics we looked at Different factors of what really, you know, could contribute neurobiologically to some of the things that we saw in Heron users. And when we looked at cannabis, we started looking at our animal models. And we studied, like the prenatal effects of of THC, and the adolescent effects of THC, when they became adults, and we looked at they self administer heroin, and, and so on. And we could see from both prenatal and adolescent THC exposure, that when they were adults, they actually self administered more heroin, especially under stressful conditions. Not every rat, just like humans, there's behavioral traits to certain things, you can talk about another time that we're delving into in terms of trying to understand you're about to do that. But when we were doing our animal work, and we always inferred it to cannabis, but we were actually studying THC. And as I mentioned, in the beginning of the discussion that there are over 140 cannabinoids in the, in the cannabis plant. And so I said to my team, let's at least study one other cannabinoid. So we're not just saying this is cannabis, but it's really THC. And so we decided to look at CBD. And I want to look at CBD because at that time, I mean, it still is technically it's the second most enriched cannabinoid in the cannabis plant. Over the years, CBD has gone down dramatically in the recreational fans on the street, while THC concentrations have gone up really into my too much. So when we gave CBD to our animal model, we were actually surprised we, I thought, actually, if anything would makes them increase to as we saw with THC. And we saw that there was a reduction in their heroin seeking behavior. And what I mean by that is, just like humans, when when animals take a drug, the context the environment, folk with day take the drug start to have meaning. So when the animals self administer drug, a light goes on in their environment. And so we can show them the light later, after they've developed, you know, this chronic drug taking behavior, we can show them the light, and they're not getting the heroin. And but they're still pressing the lever to try to get the heroin. So that light is enough to be that environmental cue. And so that's when we gave them CBD, it actually decrease their heroin seeking behavior. So that lever pressing when they're not getting the drug, but there's environmental context or stress. We call it drug seeking, as an analogy to the human. And so for me, it was fascinating. And it was fascinating because of the animals, even like, a few weeks after their last CBD administration, it still was having an effect on decreasing their drug seeking behavior. So because like I said, I'm masochistic, I wanted to see whether or not it would work in humans, because there are a lot of studies that are done in animal models, we publish, and it drives me crazy practically every week, we've cured a disease and a mouse, or a rat, but it doesn't get translated to a human. And so before I went down the journey of trying to see whether or not CBD was worth that investment, to figure out how it worked, I said, Let's at least look into human. So yes, it's unusual to jump quickly. So we then carried out pilot studies. Sure, a little challenging, we can talk about another time, but
we saw that and it was placebo, double blinded, so neither the the study participants or the investigators knew what they were getting or giving. And we showed them videos just like the animals in terms of having a cue in their environment. And we showed them like a heroine cues versus placebo cues like trees or something, you know what water and those individuals who had been given placebo and shown that heroin cue they craved, and CBD reduce that craving. So it replicated our animal studies. And what we hadn't studied in the rats at that time in our animal models, was the fact that in the humans, they also decreased their anxiety, the CBD. We've now replicated that in our animal models. So that was the pathway into studying CBD and at that time, no one was studying CBD really, there are just a few groups, especially in relation to psychosis that started to study and definitely no one on the street knew what CBD was. So it was challenging to get the studies going and to you know, convince people that there was something here and many people You know, bashed us that, you know, we're trying to well trying to promote cannabis use. So in one sense I had one group who disliked us because we had shown that developmental THC was bad for the developing brain. And then this other group was saying, Oh, you're trying to push cannabis with CBD for showing that it could be a treatment. So, you know, both groups say to us, but we went with like that.
Nick Jikomes 45:26
Yeah, I think the common the common mistake both of those types of people make is to think of cannabis as a singular thing. But the whole point is, it's actually a cocktail of different drugs, then you have to understand each one. Can you talk a little bit more about the human studies with CBD? Were these people in the study already addicted to opioids? And how much CBD were you giving them? Yeah.
Yasmin Hurd 45:49
So the study participants had to have in this first they had to have a heroin use disorder. So they were already heroin addicted.
Nick Jikomes 45:59
But they are currently using the drug. No, so
Yasmin Hurd 46:03
they had to be abstinent, at least, at least one to two weeks. I mean, most people were in like a, I mean, like one to three months of abstinence when we started down. And we didn't want to study them during, you know, withdrawal, acute withdrawal, because that's a completely different thing as well and then becomes very complex. CBD might help with withdrawal, I don't know. But I wanted to look at what we saw in our animal models, which is mainly craving, you know, drug seeking. And so we wanted to look at that and not, like I said, this acute withdrawal, which can be challenging during for people just coming off opioids. We, as I said, at that time, no one knew anything about CBD. So to be honest, I just gave the people the dose that were given to the rats that were just asked, so the dose turned out to be 408 100 milligrams of CBD. And it was given about an hour before they were shown the queue. They were brought back the next day given untested again, and they sort of were given three doses as a very short study, because that's what we saw in our animals. Is this a short exposure to CBD actually had an impact. But it was, as I said, a high dose of 408 100 compared to what people buy in the stores was like 20 milligrams or something.
Nick Jikomes 47:33
And are these pills, were they swallowing pills?
Yasmin Hurd 47:36
So we did. Again, they're very, there was actually I don't, I don't, there was only GW at that time had human CBD for human clinical trials. I tried to get other companies, but and even NIH, but it was going to be too expensive to make with CBD at that time. Now, there are a lot of companies, a lot of you know, unfortunately, we can talk about that as well. And so GW made me capsules to start, by this time, our second pilot, they had now had Epidiolex. So we actually use Epidiolex oral solution for the second trial.
Nick Jikomes 48:19
So is it an oral solution like that you put on your tongue or you drink it? Okay, so it's largely an oral route of administration.
Yasmin Hurd 48:28
Exactly. And we're now working, you know, so for me, you would ask the question, I realized I hadn't really responded by bioavailability. So you know, that's one of the things with cannabinoids, cannabinoids do not get absorbed very well. And so for example, only about four to 6%. If you take it and you know, these oral solutions, not on the tongue, you only get a small percentage that gets into the body. And so for me for medication development, we want to absolutely improve bioavailability which will also improve decrease variability between people, because depending on what you eat, or something, you can decrease, you know, you can have more or less CBD that goes in, because we don't want to people to inhale. So obviously inhalation is you know, going to give you a greater amount of the drug in your body, but inhaling anything is not medicinal. So, we did not want to develop any type of inhalation strategy. So we're looking at different types of formulations and working on that now.
Nick Jikomes 49:40
So when you say inhaling is not medicinal, can you distinguish for us between three classes of inhalation from from like a clinicians perspective? You could talk about smoking something you could talk about vaporizing something, and you could talk about an inhalant like that you might take if you're an asthma patient, how do you think about those three different types of inhalation
Yasmin Hurd 50:00
and and you know, for asthma patients, absolutely, those are great. The problem. And so one, one product that we're looking at has that kind of strategy. And so that's fine. So you're right, I want to make sure it's about smoking, we don't want, you know, smoking is not the best route. vaping is also not a bad route. But because of all the things that have gone on with vaping. And with the, you know, these black market types of vaping devices that led to a lot of the lung problems, we also don't want vaping. So inhalants are absolutely fine. And but we're trying to go with perhaps, the conventional type of things that people consider medicine, and wither under the tongue words, types of capsules that are very, that will be very fast in terms of, you know, their bioavailability, where we're prioritizing those types of strategies.
Nick Jikomes 51:08
What um, so when you swallow versus put something under the tongue versus inhale it, just just for the sake of talking about it, because there are so many people out there inhaling things different ways. How does bioavailability generally compare across those modes of consumption for cannabinoids?
Yasmin Hurd 51:26
Well, inhaling is going to get you the very fast into your into the body, you have a lot of blood vessels under your tongue, so that also the absorption is pretty quick. So that would be a route after inhalation. And then oral would be the lowest for the bioavailability.
Nick Jikomes 51:45
And so on. Do you have any, I assume you have some ongoing studies that are following up on what you've described so far. So what's going on today in your lab for CBT?
Yasmin Hurd 51:55
So um, there are a number of different paths that we're going down right now. So I'm going back. Okay, well, first, we're, you know, the goal is to try to make medicine, so definitely larger clinical trials to really see does this replicate in a larger population, because if it doesn't replicate in a larger population, then you know, it's not going to be effective in the clinic. But if you can carry out large clinical trials, and figuring out even the subgroups of people who might be might benefit from CBD, or even if it's women are better than men, and so on, those are still very helpful. Since as we talked about before, there's still not enough medications for substance use disorders. So I don't expect one medicine to cure everything. And I don't believe also that there will be a cure, but to treat everything. So if we can even help a certain subgroup, to me, that will be amazing. So it's being able to now do larger clinical trials so that we can even see one replicate and see if there are subgroups who are more that benefit more than others. The other thing, I'm coming back to the fact that I'm a neuroscientist, so I want to know what's happening in the brain. Why is CBD being beneficial in decreasing craving and anxiety? And we're doing that in two ways. We're going back to our animal models now where we can go and get more molecular insights. And that's, you know, I think, really critical. And, like I said, we're able to replicate what we saw in humans, even on the anxiety front. So really trying to pin down the neurobiology because we might actually come up with another non cannabinoid medication by understanding how CBD is impacting on these specific neuromodulators and neural circuits. But I'm also Zed masochistic. And so we're also doing in vivo imaging in humans, to see about the neurobiology in the actual human brain, in people being given in people with an opiate use disorder. So very similar to what we did before. So we definitely are recruiting so people, anyone, you know, that can contact us. So people with an opiate use disorder who are abstinent short term apps and just by an hour and looking at CBD and seeing how it's impacting the human brain, because I think that that's also critical if we're going to develop medicine for humans that we understand more about the human neurobiology.
Nick Jikomes 54:43
So in the studies that you described from your lab where you gave people with opioid use disorder, CBD, you're giving them between four and 800 milligrams. We talked earlier about the fact that CBD is not intoxicating, like kids THC, but it is psychoactive I'm curious could even though it was double blinded, could the people getting the CBD dose? Feel it the report any type of psycho activity?
Yasmin Hurd 55:10
No, you know, and I'm we're using lower dose, we're gonna use lower doses now to also see how low can you go to still get an effective outcome? The Finland's interesting is sometimes that zeolitic The reduction of anxiety makes some people think, oh, that could be intoxicated and intoxicating, but feeling calm. Sometimes people are like, Oh, I feel good. And they think feeling good may be in an intoxicant, but it's not. And very few people, even that those doses told us that they were like, oh, you know, like floating on air or so no one, no one said that. And, you know, the side effects that people reported, even people who had gotten the placebo, you know, also reported, you know, so it's sometimes it's psychological. And that's why it is really critical for us to do placebo, double blinded control studies, again, I actually have nothing against placebo, if we couldn't replicate placebo, I'm all for it, everybody gets a saline, you know, sugar tablet is fun, but it's, you know, it's called. But again, in terms of being able to replicate, and to develop medicine, that, you know, is accurate. It's like, you know, when you go into your medicine, chest and cabinet, and you take, you know, aspirin, there's a specific dose, and you know what that aspirin is going to do each time. That's what we're trying to develop. And so we need to make sure you know, that the dose, the route of administration, the particular subgroup that we know all of these things for CBD, and so without doing a double blinded placebo control, people might start to say, Oh, I'm feeling great, but they're really aren't. And then they, they, you know, then they do go and relapse. So we really want to make sure that it's not just people hoping it works, wanting it to work, even on the clinical front, that, you know, everybody wants to help the patients that it really is working, it has to be effective.
Nick Jikomes 57:29
So in your studies you've been using, or at least that for that one study, you're using Epidiolex. So this is presumably 98 99%, very pure CBD? Are you doing anything? Or do you have any interest in understanding the so called entourage effect, the fact that multiple compounds from cannabis, for example, a particular ratios might be more effective for certain things,
Yasmin Hurd 57:52
you know, yes or no. So I do believe that many of the terpenes in cannabis can help to boost some of the effects of CBD or even THC. And so I think that those are important to study. And if we then figure out the ratio, when you think about it, in order to get the right ratio, you have to do a lot of research to figuring that out. I'm already exhausted. So I'm helping other people do that, and I'm happy to work with people. However, I'm going to come keep bringing home this message medicine, aspirin, we're going to go on and taking the bark of the tree, right, that's where it came from. But there are other chemicals in the bark of the tree. But it was you know, taking the specific chemical that we knew then that had this, you know, analgesic, anti inflammatory all of these these effects. We want the same thing for CBD, at least to start. So you know, that you that this is exactly the the amount of CBD the other chemicals Yes, might potentially eight or reduce it, but you know, at least, you know, this amount will will be reproducing to give you this this outcome. So I don't think that it's it, that the other chemicals are necessary to have a positive outcome. But clearly, once you know some of them will allow us to decrease perhaps the amount of CBD that's needed. And then you could increase you know, some other terpene or other chemicals from the plant. But it will take a lot of work to talk about that. So the that ratio so and the entourage quote unquote entourage effects are also complicated by the fact that biology usually works in like an inverted U shaped meaning things work really it's a positive outcome. and it has like this optimal dosing and ratio condition. And then as you increase the dose, it starts to go down. And so you start to have a decrease. So this inverted U, it's works great, then it starts not being effective and doesn't work. That's also a critical thing when you talk about entourage of people like to throw around that term, but it's much more complicated. So you can, even with CBD and THC, there are different amounts of THC and CBD. And depending on the measure that you're having, that you can see that CBD can be beneficial in in potentially eating certain positive aspects of THC and other times it can reduce it, reduce it. So it is not that simple, quote unquote entourage and to make it a medicine. I think that's challenging. But if you have a specific strain of cannabis that has a certain ratio of CBD, and you know, all the other chemicals, and you can you can make that reproducibly absolutely, that could be medicine. Absolutely.
Nick Jikomes 1:01:10
How did you even get into this area? What made you interested in studying cannabinoids in the first place?
Yasmin Hurd 1:01:17
Um, you know, the funny thing is I started, as I mentioned earlier, you know, we're looking at the adult brain, in trying to understand the neurobiology and knowing that people, it's not just a drug that brought them there. There's other things so the genetics and trying to understand early life events, and like I said, cannabis was one of them. And the funny thing I was saying, My friends always tease me when I went into addiction because my friends from college, because they're like, Yasmin, you never did anything. You're Jamaican. You don't even smoke marijuana, you know, so they're like, you're stuffing this, you have to take it if you're gonna study it. Um, so it wasn't an interest in cannabis, the drug as I have an interest in it now, because I think it's a really, it's a complex, really fascinating plant. And being from Jamaica, you know, originally. I never thought about cannabis in that way. And then in terms of looking at the developmental effects of cannabis, but it was THC, and then studying CBD, and now the terpenes. And studying all of these things. It's been fascinating. So it's just, it's, it's, you know, you ask a question. I thought it was a simple question that I asked. And then 10 years later, you know, it's become it's, it has grown to this. So you never know where the path is gonna lead you.
Nick Jikomes 1:02:48
So did you go to college in the US or in Jamaica? Oh, no,
Yasmin Hurd 1:02:51
I moved to the US when I was a teenager. Yeah, yeah. When
Nick Jikomes 1:02:55
did when did you first get interested in science?
Yasmin Hurd 1:02:59
I always tell people, I was a weird kid. Even to make. I was always interested in the brain as a kid, I have no idea why I've always loved science. I was just weird. I, my family, no one is a scientist or doctor in or nurse? Well, actually, that's not true. I have a couple nurses in my family. So my aunt's will, will kill me if I say that, but you know, my parents weren't. I've always been fascinated about why people are the way they are in terms of just their behavior with fascinated by behavior. And just the planet. I mean, it's when I was a kid, and just you know, it's just fascinating of why we're here. It's, it's still something that I think about all the time.
Nick Jikomes 1:03:41
Okay, so you've basically been interested in this. You were sort of always on this path. You were always interested in science and the brain and you just you just stayed on that path throughout your entire life.
Yasmin Hurd 1:03:51
Yeah, yeah. I, as I said, I'm weird. I know. I know. I you know, and I'm looking forward to just laying on a beach and not thinking about what those neurons when talking to each other, and so on, you know, and but I can't stop thinking about how the brain works and whether, you know, the results that we have from this one thing can help to an idea for a treatment. It's It's strange, I can't stop it. I have OCD. So my OCD is there. So yeah.
Nick Jikomes 1:04:28
Any other research going on right now that you think is particularly exciting in terms of addiction biology and CBD? Not necessarily in your lab?
Yasmin Hurd 1:04:37
Yeah. I mean, I think, you know, for Well, one thing that we're doing that I can't really tell but it's really fascinating, but it doesn't have to do with addiction, but CBD, but we'll see if it works and then I can come back. CPD is now you know, touted for so many things that it's worrying But you know, there are developmental disorders that are being studied that it will be fascinating if there are specific developmental disorders that CBD could help with other than those rare forms of childhood epilepsy that Epidiolex was, you know, got the FDA approval for, because that's one of the things that is so challenging in terms of trying to help kids with mental illness. And in our society where we don't have enough treatments. I think that that's, you know, I'm fascinated and optimistic and hope that those studies will work out. But the fact that now, you know, CBD is thrown with so many things, my brain sometimes just like, say, okay, yet another thing oh, you know, for writers cramp, you know, like everything. So there's so many things that CBD is being tested for. But for me, I'm particularly interested in developmental disorders, that I hope that they will show some positive signals.
Nick Jikomes 1:06:03
So earlier, you mentioned towards the beginning, you mentioned that there has been some research with respect to CBDs, anti psychotic effects for things like schizophrenia, this is an area that people I think, are often unaware of that doesn't get quite as much attention as some other areas. What do we actually know there? So what are traditional anti psychotic drugs? And what how do we define psychosis as as a neuroscientist?
Yasmin Hurd 1:06:28
So I mean, I, it's funny that that CBD is not gotten more attention in that, that realm, because actually some of the earliest studies with CBD related to psychosis and psychosis in terms of, you know, classic thing that people think about, you know, the people hallucinating, you know, loss of true cognitive control, you know, paranoid paranoia. So CBD, most anti psychotics, they are, they, they modulate our, again, coming back to even if I talked about like dopamine, and some aspects of serotonin as well, but they, they block the classic anti-psychotics block these dopamine receptors, and a lot of them have negative side effects. And, you know, even more toxic side effects and so on. And so many people who have schizophrenia, were diagnosed with schizophrenia, they even stopped taking their medications due to the bad side effects. They have done studies with CBD, where they have shown that they could use with study CBD in psychosis in people's Korea, with their anti psychotic medication so that it could be an adjunct. So therefore, you could even decrease the amount, hopefully, of these classic anti psychotic medications. But even CBD by itself was reducing psychosis and in and in particular, there are some fascinating studies from England, in terms of prodromal effects of CBD. And what I mean by that is, we know there are certain risk factors for schizophrenia. And these teenagers that show these signs invariably go on to develop it. You go goal for medicine is to try to before someone, you know, develops the disorder to their prodromal that they're in the early stages. They've not yet gotten the full blown disorder, but they're at a point where they may be treatable. And they've now been looking at CBD in such individuals. And from my understanding, the preliminary studies looked really promising that if CBD could be effective in prodromal, psychosis, this is a game changer. So I think that that would be extremely critical for mental illness in general. There are a lot of other disorders that I think that then it could lend itself for. But Schizophrenia has been something that CBD had been studied early on, and it hasn't gotten I don't know why it hasn't gotten the, the attention as other disorders, but you know, we'll see whether or not the prodromal effects the effects of CBD to on on individuals that are prodromal to potentially get the disorder will be effective. Because again, he doesn't have all those negative side effects. And, you know, with with, with teens and children, you want to tried to have medications that are not going to have such a heavy hit on the brain?
Nick Jikomes 1:10:05
Yeah, and I would imagine, you know, especially for something like schizophrenia, where the, you know, the onset or the critical period is not necessarily in your teens, but maybe in your young adult years, with the anti the traditional anti psychotics if they're dopamine receptor antagonists. The side effects that are probably pretty gnarly, like lack of motivation, lack of pleasure, is it that type of stuff?
Yasmin Hurd 1:10:27
Yeah, so you, so it blunts a lot of your, you know, feelings, you know, positive feelings, and so on. So those are some of the negative side effects of those particular medications. And, you know, it's, it's challenging, it's, you know, I don't think that people understand that a lot of the medications that are, that really do help people. I mean, I want to say they do help people, but they do come with a lot of side effects. And so individuals stop taking them because of those side effects. And so that's why it's also critical for us to try to develop medications we tried to, but you know, without, you know, such severe side effects, the goal is not to try to develop medication side effects. But coming back to the, you know, the earlier discussion, why I'm actually fascinated by CBD is that, you know, we were taught in school in pharmacology that you find the purest, the strongest agonist, or the pure, strongest antagonists, but those are the ones that are producing all of these side effects. So for me, something that is, has a softer impact of tweaking the different, you know, on a more modulatory manner, rather than like a hammer, I think that that's the thing that, you know, has opened my eyes, at least I'm thinking differently about perhaps how we should develop medications. And it doesn't mean it has to be for all medications, it has to be the strategy. But for mental illness, especially where the side effects do cause a lot of individuals to stop taking their meds, I think that this is something you know, we should consider.
Nick Jikomes 1:12:08
Do you think that's a change that's happening more generally, in this world, at least on the research side, where people are looking, looking a little bit more closely on drugs that you would otherwise traditionally have called Dirty?
Yasmin Hurd 1:12:20
Yes, I know, it depends. I mean, there's still two schools, two camps of this, and it depends on who you get to review your grants. Some of them say no, you know, this is it or not. But I think one of the things that sighs that we're also doing is repurposing medications. So there have been a lot of medications that have been tried and hasn't worked, as we've talked about earlier. But there are now databases of those. And as we learn about the biology of certain disorders, people are now screening these databases of these medications that didn't work for, say cancer, but actually might work, even in addiction. And because now we see that the mechanism by which they worked, we see similar things that are occurring for a particular addiction or psychosis or something. And that, to me, is also important, because many of these drugs have been tested. And we know the side effects. We know that the you know, all of these things, so repurposing some of these medications are also something that the field is doing, besides saying, stepping back from calling things dirty, and I hate the word dirty, you know, because end of the day, a lot of our transmitter our own modulators in our bodies are, quote unquote, dirty. And it is the symphony that makes for our behavior, our thoughts. It's not one transmitter that does is working at one time, it's all of these transmitters and neuromodulators, and different cells firing and different circuits activated. Why I moved my hand, why I thinking certain things. So that's why for me having a more modulatory type of of a multi scaled approach rather than this one transmitter approach, I think is important.
Nick Jikomes 1:14:17
Interesting. Well, do you have any final final thoughts for people about CBD and cannabinoids or addiction biology generally?
Yasmin Hurd 1:14:25
I mean, for me, I do think that why in terms of you know, we've talked obviously about CBD a lot. And that about THC, you know, I've mentioned briefly the issue of very high concentrations of THC today in cannabis being consumed recreationally and that is a problem for mental illness. That is a problem for addiction. We know that it's THC that leads to the addiction and the higher the concentration of THC vote, the more vulnerable people are to developing a cannabis use disorder. So Many people think that you can develop an addiction to cannabis. And you do. In fact, cannabis use disorder is one of the highest disorders in our country. So, you know, and about like 30% of people develop cannabis use disorders who, you know, play with cannabis. So it's not a benign drug. And we need to really clamp down on that as well and educate people about the health risks of this high THC cannabis that's being consumed. So for all that's being said about CBD, which is great. It's important that we don't forget that. And, I mean, coming back to, you know, even psychosis in our dual diagnosis moored at Sinai, a large percentage of people in the dual diagnosis meeting have addiction and mental health disorder. It's cannabis with psychosis is cannabis with psychosis. So, no one can tell me that cannabis does not have negative effects. So even though I'm trying to also look at the beneficial properties of cannabis, it's, it's a drug and we need to be respectful of it. And I said, especially in certain vulnerable groups, and that's why I you know, I, I want people to also explore and educate themselves about cannabis. Even though we have a natural endocannabinoid system. It's not as powerful and potent as the as the concentrations of THC out on the street today.
Nick Jikomes 1:16:42
Alright, Yasmin Hurd, thank you for your time.
Yasmin Hurd 1:16:44
Thank you so much.
:28
Welcome to the good chemistry podcast. I'm your host, Nick Jacobus and today I'm speaking with Dr. Yasmin Hurd. Yasmin is the director of the addiction Institute Chair of translational neuroscience and Professor of Psychiatry in neuroscience at the Icahn School of Medicine at Mount Sinai in New York City. Her research explores the neurobiology of drug use, including the impact of cannabis, cannabinoids and opioids on the brain and behavior. Dr. Herd conducts both basic research into the mechanisms of drug action using animal models as well as clinical work in humans. Dr. herd and I discussed a variety of topics related to cannabinoids, opioids and the neurobiology of addiction. Much of our talk focused on the research or lab has done on CBD or cannabidiol, including its effects on anxiety and its potential use in the treatment of opioid addiction. As always, if you enjoy the content of this podcast, please like, share or subscribe. I'm also experimenting with a new tool called locals. Locals is an app that allows podcast hosts and other creators to interact and build a community directly with their fans. If you go to good chemistry.local.com You can sign up to become a good chemistry community member. This allows you to do a variety of things, including communicate with me and with other community members. You can make posts, you can ask questions that will be answered either by me or by other community members, you can make suggestions to the show, you can actually ask questions of me directly in a live chat tool. And I'll be posting content here including episode updates and upcoming guest lists. And so if you want to try it out for free, use the promo code great Chem great ch E M, and you can become a part of the community through the end of May 2021. Today's show is brought to you in part by dosed an all natural Canvas company specializing in dose controlled cannabis products made with plant based ingredients. To learn more about dosed their products and where they are available, please visit their website through the link in the episode description. And with that, here's my conversation with Dr. Yasmin Hurd.
Dr. Yasmin Hurd, thank you for joining me. Thanks for having me. Can you tell everyone where you're at where you work? And just a little bit on your background as a scientist?
Yasmin Hurd 2:57
Yes, um, I am the director of the addiction Institute at the Icahn School of Medicine at Mount Sinai in New York. And my I'm a neuroscientist. I study the neurobiology of addiction and with a goal of trying to develop medications based on what we learned about, as I said, the neurobiology of addiction.
Nick Jikomes 3:21
So you do a lot of research on CBD that ties into your work as an addiction scientist, and CBD is very popular right now. In general. You can find it at the corner store. It's sort of this big health and wellness craze. Can we start out by just having you explain what is CBD? And what do we know about its basic biology? Yeah, it's been a real roller coaster for me in context that you said CBD is now everywhere in the water even literally in the water.
Yasmin Hurd 3:55
And so CBD is cannabidiol and cannabidiol is a cannabinoid in the cannabis plant. Or many people now I think even know hemp plants, but it's one of about 140 cannabinoids, the cannabinoid that most people on the street know about, or before CBD became so popular was THC, or is THC and THC is the cannabinoid that leads to the high you know, the rewarding effects. And CBD though does not produce intoxication like THC. So CBD cannabinoid definitely impacts the brain so it does have biological psychological effects, but those effects are not linked to the intoxication aspects of cannabis and a lot of the research now, my group and others is looking at it in regard to aspects of anxiety, craving, etc.
Nick Jikomes 4:56
And so CBD is a plant cannabinoid like the THC as you mentioned, we have an endogenous cannabinoid system and endogenous cannabinoids, can you speak a little bit about how CBD influences the endocannabinoid system in our bodies?
Yasmin Hurd 5:13
So our natural cannabinoid system as you said, the Endo, the endogenous endocannabinoids. We have their lipid chemicals and they bind to cannabinoid receptors. And there are two main cannabinoid receptors in the body CP one and CP two, the exogenous the plant derived cannabinoids like CBD and THC. They interact with our natural endocannabinoid system and primarily out these receptors, but mainly for THC. So THC is an agonist that binds to our cannabinoid receptor. CBD actually does the opposite in part, it's an inverse agonist, meaning it has even antagonistic effects out the cannabinoid receptor. However, it modulates our natural lipid or natural endogenous endocannabinoid ligands that binds to these receptors by enhancing the levels of these receptors, these ligands through his thought inhibiting these transporters that take up these natural cannabinoids. So perhaps I should step back and say, You know what are coming back into the biology of endocannabinoid system. So these endocannabinoids are made when your body needs them. So that would call the made on demand. Many transmitters in the in the brain, especially since I'm a neuroscientist I'll focus most on that. They're synthesized and stored. And when they're needed, they're released. And but the endocannabinoids they're actually synthesized on demand, and then they transport back across the space between cells, the synapse, and are taken up by transporters, these chemicals that take up the endocannabinoids. And it's believed that CBD inhibits these transporters. And so therefore, the natural endocannabinoid levels then are elevated, but they're not elevated dramatically, but they're elevated. So that's one of the mechanisms of few of the mechanisms by which CBD directly and indirectly modulate the endocannabinoid system.
Nick Jikomes 7:34
Interesting. So when you ingest CBD, potentially, at least to some extent, you may actually change the levels of your own dodginess cannabinoids.
Yasmin Hurd 7:43
Correct. But, again, he there, there, there's let's put it this way. There's a lot of research that's needed. So in terms of finding out the true mechanism, by which CBD works, because in addition to the endogenous cannabinoid system, CBD actually interacts with multiple transmitter systems. So for example, it will modulate our opioid system and part even, it will modulate serotonin, a transmitter that's really important for regulating mood. It's will modulate, you know, so a number of transmitter systems. And that broad pharmacological effect of that CBD has is interesting, because it's actually not potent, really, really potent at any one of them. Except a new an orphan receptor, that it now appears to work as an antagonist for this receptor, we're still trying to figure out the actions of this transmitter system. But being able to tweak it, you know, small amounts different transmitter systems, actually is not a bad thing. In pharmacology, we used to call these quote unquote, dirty drugs. But I've started to look at it very differently after studying CBD now because a lot of times when we try to develop these, these medications that are very powerful at one receptor system, it normally leads to side effects because you're either really hammering as an agonist really turning on one receptor or really potently blocking another, and CPD tweaks. It turns up the knobs up and down for a number of transmitter systems but not in a powerful manner, but in a way that modulates that really is more in a way homeostatic, I think.
Nick Jikomes 9:43
So it's it's tweaking many different receptors or systems in the brain. It's not really potently affecting any one of them. Can you speak a little bit more about what we know about CBD drug properties? So you mentioned and people have mentioned previously on the show that it's not a particularly potent drug. But you just mentioned that that could be a benefit. What else do we know about drug like properties? So toxicity and bioavailability. I mean,
Yasmin Hurd 10:12
every every drug, every medicine has positives and negatives. And every it comes back to dose dose is everything. And so yes CBD at especially the doses that our people are taking in their water, or their coffee and so on and, you know, is not at a high dose that is normally going to be toxic. There's been a lot of studies on CBD at doses. So when people buy them normally in you know, the, on the boutiques, and so on, for example, 10 and 20 milligrams, 25 milligrams of CBD is what's normally sold. On a clinical level, most of the studies are studying 100 to like 600 milligrams of CBD. And those studies do not find any adverse effects, really, in terms of, you know, toxicity at a level that you would say this is not a medic, this is not going to be used as a medication. And what I mean in terms of liver toxicity or other things, there's definitely studies that have even gone up to six 6000 milligrams CBD and not found, you know, really bad side effects. The side effects that people have mainly seen are more gastro intestinal, so GI tract diarrhea kind of thing, even sleepiness, but now CBD is being that part of its negative, quote unquote negative could be used for people, you know, for sleep inducing sleep for the negative side effects in terms of liver enzymes, and so of course, toxicity in terms of your liver damage is always an issue with every medication. And for kids that were treated with CBD for epilepsy, the interaction with some of their anti epileptic drugs could lead to changes in elevating liver enzymes, and that's not not good. But in other clinical studies that have gone on so far, and yes, many of them are small, they've not seen, you know, this type of toxicity. So, interaction is really important for the negative things that one are, you know, that many of the studies are showing, and like I said, you know, anti epileptic medications, it interacts with, you know, say anti depressant medication, benzodiazepine anticoagulants so many of most drugs, obviously are metabolized are broken down in by our liver. And the liver enzymes. CBD could also work at those enzymes can also be targets for modulating CBDs metabolism. So that's the thing we try to make sure that, you know, it's important that when you're taking other medications, like I said, anticoagulant or anti depressant, it's really critical that you let your doctor know that you're taking CBD because CBD could in fact influence how that drug is metabolized. And that drug could also metabolite influence how CBD is metabolized. And that's how you could increase a toxicity.
Nick Jikomes 13:35
Interesting. So CBD is fairly benign on its own, but because it can impact metabolism of drugs in the liver, there can be these drug drug interactions that we presumably just don't know a lot about yet.
Yasmin Hurd 13:46
Correct. And we're gonna know more since now, there are a lot more studies being done with CBD. I mean, a lot of animal studies had been done, and shown, obviously a good profile, or else it would never have gotten past the FDA to even go into clinical trials. So most of the animal studies had shown that it did not have these, you know, terrible, or, you know, adverse events that we would not want to develop it for medication.
Nick Jikomes 14:14
And because this is such a big component of the health and wellness industry at this point, you see, you see claims for just about anything you can think of CBD is claimed to help with sleep, pain and inflammation, mood, almost anything you can think of we know that, you know, you've got an FDA approved medication Epidiolex for epilepsy. What are the other areas where there's at least some clear evidence that CBD has a positive impact beyond epilepsy?
Yasmin Hurd 14:46
You know, this is the challenge where you have you have a drug that's actually going before the cart before the horse, so the research is not there. To substantiate all of the claims that's being made about CBD for its clinical properties, so as I said, other than epilepsy, there have been some small studies done in relation to, for example, schizophrenia in terms of psychosis, showing that it has potential for having antipsychotic properties. Similarly for anxiety that it has an anti anxiety properties and delidded properties. In our research, we showed also in again, small studies, that it decreased craving and anxiety in people who had an heroin use disorder. There are studies going on for Crohn's disease, there's studies going on with for pain, but most of those studies are inconclusive. So there, there's still a lot that we don't know, even though it's being touted as basically like a miracle drug for all of these indications. And I never believe in miracle drugs. I believe in miracles once in a while, but I don't believe in miracle drugs. But I do think that a drug can have benefits in different indications, because a compliment back again, to dose and the dosing regimen. So perhaps for certain symptoms, you will need a high dose, you know, having two times a day, while for another indication, you could only need a small dose once a week or something. But these are the things that we need to find out about CBD and the data is not there to really give conclusive, you know, insights to the public. That's now buying up CBD oil, you know, in a lot. Yeah.
Nick Jikomes 16:45
Interesting. So you've done some work that I want to get to eventually related to CBDs effect on as a treatment for addiction. But before we get there, I thought it would be good to have you talk about opioids and the treatment of pain. So how do we how do we normally treat pain today, and how to opioid drugs work on a basic level.
Yasmin Hurd 17:07
Um, so you know, pain is one of the symptoms that most Americans are, you know, can relate to, and that's why you have over 10 million people being medicated with opioid analgesics. And the opiate analgesics. If you have acute pain, trust me, give me an opioid. If I have a nail that just went through my hand, I want, you know, that pain to stop. And they have been quite effective clinically. And so opioids, they modulate our natural opioid system, all of these drugs, they're there, they impact on something in our system, and our bodies obviously, and the endogenous opioid system is really key to regulating or translating a lot of like, you could say, the, you know, signals from the your sensory. So, like I said, you know, I got a nail in my hand, the signals that go through to my spinal cord to then register that, that, that injury, the signal in the spinal cord are mediated by the opioid peptides or natural opiate peptides or natural opioids are and they bind to opioid receptors there, and they also then the signal that goes up into our brain, where opioid system again modulates the perception, so it's the brain that perceives the pain. So that's the nociception of it. But that whole signal from your hand to your spinal cord up to your brain, the opioid are endogenous opioid system is part of that process. So opioid analgesics, they will inhibit, they will activate sorry, those those opioid receptors, and those opiate receptors will then inhibit the natural other transmitters systems that mediate these pain signals. And so, for example, a transmitter even called glutamate, where it will, you know, trigger the release of glutamate and substance B and other peptide that really mediates these pain and opioids will then reduce them. So it's an interaction the opioid system sits at the spinal cord, and brain circuits that are important for sensing the nociception are the signal of pain and the perception of pain. There's a long way to say it's complicated.
Nick Jikomes 19:53
Yeah, so we have an endogenous opioid system and an endogenous cannabinoid system, the endogenous opioid Are peptides. So they're almost like little proteins, as opposed to the endogenous cannabinoids, which are small lipids or fatty molecules. Exactly. And so are the opioids. Are they used on demand like the endocannabinoids? Or are they more like other transmitters that are stored and released.
Yasmin Hurd 20:15
So the opioids are exactly like other transmitters that are stored in release. And so the cell activity will trigger the release of these opioids. And that's the thing so our, again, our natural endogenous whether it's opioids or endogenous cannabinoid system, they are at physiological very low levels. And now you take a very potent opioid, and you will overwhelm that system for pain. That's good, because now you're blocking much, much more strongly the pain signals. And that's what these opioid analgesics do. The problem is that they not only add those, they're not only stimulate opioid receptors in the pain pathways, they can also stimulate opiate receptors in reward pathways that and that's why with repeated use long term, you then get activation of these quote unquote, addiction related neural circuits.
Nick Jikomes 21:21
So opioids are not merely blocking pain or altering pain perception. If you take an opioid even even when you're not in pain, it feels good. So they have these perceptual emotional effects in the absence of what they're doing to block any pain signal. Exactly. Exactly. And is that why they are particularly addictive as a class of drugs?
Yasmin Hurd 21:44
Yes, and they're addictive as a class of drugs. Because those knew a bit receptor, the opiate receptors were these morphine and oxycodone and so on, where they bind. And so I set a particular receptor like this called the new opioid receptor, and this receptor sits in, like I said, neural circuits that immediate reward and these rewarding circuits in the brain. And when stimulation, very profound stimulation of these opiate receptors, it leads to this rapid euphoric, genic, hedonic, nice feeling state. And certain opioids do that much better than others, because it's very rapid into the brain, and out. And so for example, fentanyl, that's bad, it's hits us receptors very hard. And so the brain is like, wow, I just, like got this incredible, you know, rush this, and then it's gone. So this very fast, pounding of our natural, rewarding pathways, that's one of the things also, they elevate, they, they, they indirectly elevate the transmitter dopamine, when many people know, you know, even on the street, if you're even if you're not a neuroscientist, what dopamine and dopamine is a transmitter. That's very much a critical part of addiction, neurobiology. So dopamine goes up, you feel good. And these opioids increase dopamine very much.
Nick Jikomes 23:19
Interesting. So how do you? How do you actually define addiction as a neuroscientist, and in particular, I often hear people talk about substances that are psychologically versus physically addicting. And typically, as far as I can tell, what they mean by that is, if something is psychologically addicting, it's basically less addicting than something that's considered a hard drug, it's very physically addicting. Is that a valid distinction? And how do you think about the spectrum of habit forming potential of drugs as a neuroscientist?
Yasmin Hurd 23:53
So for me, when people think that's psychological addiction, it means that it's not as addictive that's actually false. As a neuroscientist in the addiction field, you know, I go by what the clinical diagnosis relating to addiction so it's a disorder, a chronic disorder that is related strongly to compulsive types, behavior, craving, you will give up so many other things in search of this drug in in the need for this drug. Despite all the negative effects that this drug may induce, you're still taking musing and seeking as I said, this drug, many people can put that as a psychological, however, there is significant I mean that you don't need physical addiction in order to have a substance use disorder as strong addiction. And it's this chronic and relapsing disorder. And for me, you know, Controversy Is it a is it a brain disorder, it's a brain disorder, it, you know, are the neural circuits that mediate the reward the circus that mediate the changes in cognition that the decision making processes, the craving, the emote, the negative emotional state that drives even the drug seeking behavior, that's all in the brain. And it's a whole brain disorder as well, we may know specific circuits that might mediate the reward that might mediate the cognitive that might need mediate, the anxiety might mediate the depression. But there are many circuits that all go together to, you know, undermine the homeostatic state of the normal, quote, unquote, brain that's not seeking and needing and dealing with all the negative aspects of addiction, many people think about addiction that people are just trying to get high. That's not addiction, you know, the initial stage, of course, when someone takes a drug, and they feel really great. And they want to do that, again, perhaps the next time, maybe even few years later, and they do it. And again, and again, that's not addiction, addiction really is about, as I said, you know, the negative aspects people are in, and you use the word psychological, even the psychological psychological pain that drives a lot of the, the, you know, George Kuh, who now heads the naturalist have an AAA of alcohol disorders, this dark side of addiction, he used to call it and, you know, the Dark Side drives a lot of the behaviors to seek the drug, and so on. So, for me, addiction is a complex disorder, it's not as easy as people think, to just, you know, stop, or that it's just driven by reward. It's, it's a very complex disorder.
Nick Jikomes 27:01
So drugs of abuse often feel good. And so they have these these positive effects that people like initially, but with escalating usage, as your body adapts to that drug and gets used to it, more or less, the absence of the drug in your system can actually cause negative issues. And you're saying that relapse is often in part, at least due to people trying to avoid those negative feelings that come with the absence of the drug that they've been, they've been accommodated to.
Yasmin Hurd 27:31
Absolutely. And you know, but also, you know, stress is a huge aspect of drug seeking. And just most of the things that people why people searched the relapse comes back to these negative things that happens in their lives, the stresses that happen, the, you know, the depression, that happens. And so it's not that people are really going to try to get that reward again. Yes, definitely. It's not a, there are people obviously, who seek drug to feel good. And the question is, you know, at different stages of the addiction cycle, that's another thing, it's a cycle, you're not in the same place the whole entire time. And that's why it also makes it complex. Because in early stages of the addiction, even when you know that you're it's driven a lot by this more positive reinforcing effects. And you know, definitely, that it might lead to some negative, you're still Wow, this feels good. And then the slippery slope, and then before you, you start losing that control, and then when you lose that control, you're already lost that control to then go back. So you, the stage of addiction, also, obviously is mediated by different neural circuits. And that's why treating addiction can also be challenging because we're someone is an addiction, you can't treat everybody the same. And often, a lot of the treatments are the same.
Nick Jikomes 29:01
What are some of the typical treatments for severe drug addiction that would be used in the clinic today?
Yasmin Hurd 29:09
Um, that, again, is one of the problems with substance use disorders is that we don't have as many tools in the clinic as we should. So for opiate addiction, at least, for opiate use disorders, we have opioid replacement therapies such as methadone, buprenorphine, for other substances of abuse, for example, the psychostimulants like cocaine and so on, you mainly treat the symptoms. So you will treat the depression, the anxiety, and so those often are the medications that are given. So it's not that there are so such specific except for, especially for opioids. It's as a part of our discussion today, but they're not that many special specific medications, you're you're you're treating instead the symptoms that that person may be showing at that time. And there's a there are a lot of behavioral interventions to try to help people manage their their disorder.
Nick Jikomes 30:15
How is addiction to become addicted to a drug? Does it require repeated use of that drug?
Yasmin Hurd 30:26
Yes. So you know, and I think that this is one of the things that get a lot of people who feel that individuals who have a substance use disorder that they kind of brought it on themselves, and they're weak and all of that, but it really, you know, isn't there a lot of things that we know that increase the risk of someone developing a substance use disorder, even genetics, you know, early life, trauma is a huge issue as well. But even with every, every factor that could contribute to addiction vulnerability, if you never take the drug, you will, of course, not develop a substance use disorder, if you take the drug once, you need to take it again. And again, to change the neural circuits in a way, as I mentioned, in terms of changing, you know, cognition, changing your anxiety, you know, all of these circuits. However, for some people, because of their vulnerability, just that exposure to that to that drug, once they, they they quickly can transcend into addiction versus others. And it depends also on the on the drugs. So for example, opiates are very addictive, while cannabis is not. So you know, you can, if you're you can give you know, 10 people or 100 people or how many people you want in your your study, an opioid and, and cannabis, and you're not, and obviously, a larger percentage of people are going to become addicted to opioids to them well to cannabis, a few people will also become addicted to cannabis, but it's gonna be much fewer. So the type of drug also matters in terms of coming back to our earlier discussion of hitting, you know, hitting those reward circuits. And the endogenous transmitter systems like dopamine, you know, so those transmit those drugs that have a big impact on dopamine, they're going to be much more addictive than those that have a much smaller effect on the dopaminergic system, for example.
Nick Jikomes 32:40
So it sounds to me like there's at least three sort of sets of factors that affect the addictive potential of something. One is the drug itself, and its level of potency, and how rewarding it is to is just intrinsic features of that person, there's just genetic and developmental differences between people in terms of how sensitive they are to any given drug. And then three, we've sort of touched on this indirectly, that would be the context or the environment in which the person is taking the drug. So there's the the famous experiments in rodents that have been described by others where, you know, you give a rat access to a drug of abuse, in a cage, where it has nothing else, there's pretty much just the drug and maybe some water, and then you give another rat, or even the same rat access to the same drug, but it's got access to toys and mates and friends to play with. And the second rat is much less likely to become addicted than the first one.
Yasmin Hurd 33:37
And the same thing happens in humans. So yes, rats in our, in our studies, they're bored. If you're, you know, brought to a cage where you can like hit a drug, and, and you put back in a good where you're by yourself, and you're nothing else. Yeah, even if your mother said, Don't do it, you know what, when you go into that cage, most likely, nine out of 10, people would push that lever. And so that's the whole thing. Environment Matters. Another factor actually. So you, you're great at translating every single thing I would say in a much very loving, clear manner, and development. So the developing brain is also critical. So the earlier exposure to a drug, we know that it increases vulnerability to addiction, while if someone starts when they're, you know, an adult much later, we don't see the same addiction vulnerability doesn't mean that an adult can develop an addiction. Now, they can still develop it, but they're not going to be as sensitive. So all of there's so many factors that go into why an individual what why this one person develops an addiction, another dozen and I call it like the Russian roulette. You know, each person is given a gun with a certain number of bullets, and this person has many more bullets because they have If they're, you know, had some genetic risk, they're in a much tougher environment, they got started earlier, they had huge trauma. So practically, if it's a six gun, you know, six bullet gauge, they have, like, five of those are filled with a bullet why this person perhaps have won. So that's why when people think, oh, that person is just weak, or they are just this, they have no clue until you walk in their shoes, and knows exactly what has happened to them, and the lives and and, and their forefathers lives. You know, it's really challenging to say everybody should be the same in terms of addiction vulnerability.
Nick Jikomes 35:41
That's a great, that's a great metaphor, I've never heard it put quite that way. So in terms of treating addiction, we talked about some of the standard treatments, it sounds like there's basically two kinds of options for addiction treatment. One is to give people drugs that are more or less weaker versions of the drug that's causing the problem. And the other is simply to give them other drugs that treat the symptoms of withdrawal, like anxiety, say,
Yasmin Hurd 36:04
Sir, behavioral, I mean, so I, you know, if we're talking about treatment, I do think that behavioral interventions are really important, even though I am a neurobiologist, trying to develop a pharmacological treatment. I do think that behavioral interventions are important adjuncts for everything that we think about for treating substance use disorders.
Nick Jikomes 36:30
And so do you think that, you know, in the current situation over the last year, people are my understanding is that drug abuse has probably gone up considerably since COVID started? And do you think it's essentially, for the same reason that the rats in the boring cage are more likely to get addicted?
Yasmin Hurd 36:49
Yeah, and it's been stressful with COVID. You know, and so people are isolated, and they don't know what's going to happen, and it was just a stressful time. And it's interesting, you know, um, the alcohol stores are considered essential business during COVID. And in one part, I understood it. But of course, it's you're giving people you're, you're giving them a product that will increase their addiction vulnerability, or validation will increase the risk of, you know, getting into alcoholism, and some people have, and definitely a lot of the research has shown that there's been an increase in all substances. And last year, I mean, the overdose increase, over 82,000 people I think, died of overdoses last year at the highest for a very long time, even though like the opioid epidemic, you know, we had so many people dying, and bumped up again last year. So we forget that there is an epidemic that is still going on, even though we have this pandemic of COVID. And that epidemic of, you know, drug overdose, and opioid overdoses is still real. And it's, it's extremely sad. It's extremely sad, because it kind of gets, you know, lost in all of the stress of COVID. And all of obviously, the horrific numbers of people who have died from COVID.
Nick Jikomes 38:31
Can you start to describe for people some of the work that your lab has done in terms of CBD as a potential treatment for addiction. And I want us to be careful, one of the things that's very interesting about your lab is you do both animal research and you do human research, usually those
Yasmin Hurd 38:47
Yeah. A masochistic lesson was like, Okay, why? Why?
Nick Jikomes 38:54
So can you describe some of that research and we'll just be careful to distinguish between the animal work and and the human work and where each one is at?
Yasmin Hurd 39:03
Yeah, um, so my research program for many years, actually had two lines and they converged, the two minds was looking at the neurobiology of, of, of opioid addiction. And I studied on a molecular level, people, for example, who have died from opioid overdose, and animal models where they self administer heroin, and trying to see if we, if we can figure out what is really changed in the brains of humans who have an opiate use disorder, and we can replicate that in an animal model. We can actually start now coming up with treatments, and that was a strategy for that line. And then the other line of research was that we knew that many of the adults who had an opiate use disorder started out with, you know, other drugs like cannabis. And so we started to look at the neurobiological effects and also even genetics we looked at Different factors of what really, you know, could contribute neurobiologically to some of the things that we saw in Heron users. And when we looked at cannabis, we started looking at our animal models. And we studied, like the prenatal effects of of THC, and the adolescent effects of THC, when they became adults, and we looked at they self administer heroin, and, and so on. And we could see from both prenatal and adolescent THC exposure, that when they were adults, they actually self administered more heroin, especially under stressful conditions. Not every rat, just like humans, there's behavioral traits to certain things, you can talk about another time that we're delving into in terms of trying to understand you're about to do that. But when we were doing our animal work, and we always inferred it to cannabis, but we were actually studying THC. And as I mentioned, in the beginning of the discussion that there are over 140 cannabinoids in the, in the cannabis plant. And so I said to my team, let's at least study one other cannabinoid. So we're not just saying this is cannabis, but it's really THC. And so we decided to look at CBD. And I want to look at CBD because at that time, I mean, it still is technically it's the second most enriched cannabinoid in the cannabis plant. Over the years, CBD has gone down dramatically in the recreational fans on the street, while THC concentrations have gone up really into my too much. So when we gave CBD to our animal model, we were actually surprised we, I thought, actually, if anything would makes them increase to as we saw with THC. And we saw that there was a reduction in their heroin seeking behavior. And what I mean by that is, just like humans, when when animals take a drug, the context the environment, folk with day take the drug start to have meaning. So when the animals self administer drug, a light goes on in their environment. And so we can show them the light later, after they've developed, you know, this chronic drug taking behavior, we can show them the light, and they're not getting the heroin. And but they're still pressing the lever to try to get the heroin. So that light is enough to be that environmental cue. And so that's when we gave them CBD, it actually decrease their heroin seeking behavior. So that lever pressing when they're not getting the drug, but there's environmental context or stress. We call it drug seeking, as an analogy to the human. And so for me, it was fascinating. And it was fascinating because of the animals, even like, a few weeks after their last CBD administration, it still was having an effect on decreasing their drug seeking behavior. So because like I said, I'm masochistic, I wanted to see whether or not it would work in humans, because there are a lot of studies that are done in animal models, we publish, and it drives me crazy practically every week, we've cured a disease and a mouse, or a rat, but it doesn't get translated to a human. And so before I went down the journey of trying to see whether or not CBD was worth that investment, to figure out how it worked, I said, Let's at least look into human. So yes, it's unusual to jump quickly. So we then carried out pilot studies. Sure, a little challenging, we can talk about another time, but
we saw that and it was placebo, double blinded, so neither the the study participants or the investigators knew what they were getting or giving. And we showed them videos just like the animals in terms of having a cue in their environment. And we showed them like a heroine cues versus placebo cues like trees or something, you know what water and those individuals who had been given placebo and shown that heroin cue they craved, and CBD reduce that craving. So it replicated our animal studies. And what we hadn't studied in the rats at that time in our animal models, was the fact that in the humans, they also decreased their anxiety, the CBD. We've now replicated that in our animal models. So that was the pathway into studying CBD and at that time, no one was studying CBD really, there are just a few groups, especially in relation to psychosis that started to study and definitely no one on the street knew what CBD was. So it was challenging to get the studies going and to you know, convince people that there was something here and many people You know, bashed us that, you know, we're trying to well trying to promote cannabis use. So in one sense I had one group who disliked us because we had shown that developmental THC was bad for the developing brain. And then this other group was saying, Oh, you're trying to push cannabis with CBD for showing that it could be a treatment. So, you know, both groups say to us, but we went with like that.
Nick Jikomes 45:26
Yeah, I think the common the common mistake both of those types of people make is to think of cannabis as a singular thing. But the whole point is, it's actually a cocktail of different drugs, then you have to understand each one. Can you talk a little bit more about the human studies with CBD? Were these people in the study already addicted to opioids? And how much CBD were you giving them? Yeah.
Yasmin Hurd 45:49
So the study participants had to have in this first they had to have a heroin use disorder. So they were already heroin addicted.
Nick Jikomes 45:59
But they are currently using the drug. No, so
Yasmin Hurd 46:03
they had to be abstinent, at least, at least one to two weeks. I mean, most people were in like a, I mean, like one to three months of abstinence when we started down. And we didn't want to study them during, you know, withdrawal, acute withdrawal, because that's a completely different thing as well and then becomes very complex. CBD might help with withdrawal, I don't know. But I wanted to look at what we saw in our animal models, which is mainly craving, you know, drug seeking. And so we wanted to look at that and not, like I said, this acute withdrawal, which can be challenging during for people just coming off opioids. We, as I said, at that time, no one knew anything about CBD. So to be honest, I just gave the people the dose that were given to the rats that were just asked, so the dose turned out to be 408 100 milligrams of CBD. And it was given about an hour before they were shown the queue. They were brought back the next day given untested again, and they sort of were given three doses as a very short study, because that's what we saw in our animals. Is this a short exposure to CBD actually had an impact. But it was, as I said, a high dose of 408 100 compared to what people buy in the stores was like 20 milligrams or something.
Nick Jikomes 47:33
And are these pills, were they swallowing pills?
Yasmin Hurd 47:36
So we did. Again, they're very, there was actually I don't, I don't, there was only GW at that time had human CBD for human clinical trials. I tried to get other companies, but and even NIH, but it was going to be too expensive to make with CBD at that time. Now, there are a lot of companies, a lot of you know, unfortunately, we can talk about that as well. And so GW made me capsules to start, by this time, our second pilot, they had now had Epidiolex. So we actually use Epidiolex oral solution for the second trial.
Nick Jikomes 48:19
So is it an oral solution like that you put on your tongue or you drink it? Okay, so it's largely an oral route of administration.
Yasmin Hurd 48:28
Exactly. And we're now working, you know, so for me, you would ask the question, I realized I hadn't really responded by bioavailability. So you know, that's one of the things with cannabinoids, cannabinoids do not get absorbed very well. And so for example, only about four to 6%. If you take it and you know, these oral solutions, not on the tongue, you only get a small percentage that gets into the body. And so for me for medication development, we want to absolutely improve bioavailability which will also improve decrease variability between people, because depending on what you eat, or something, you can decrease, you know, you can have more or less CBD that goes in, because we don't want to people to inhale. So obviously inhalation is you know, going to give you a greater amount of the drug in your body, but inhaling anything is not medicinal. So, we did not want to develop any type of inhalation strategy. So we're looking at different types of formulations and working on that now.
Nick Jikomes 49:40
So when you say inhaling is not medicinal, can you distinguish for us between three classes of inhalation from from like a clinicians perspective? You could talk about smoking something you could talk about vaporizing something, and you could talk about an inhalant like that you might take if you're an asthma patient, how do you think about those three different types of inhalation
Yasmin Hurd 50:00
and and you know, for asthma patients, absolutely, those are great. The problem. And so one, one product that we're looking at has that kind of strategy. And so that's fine. So you're right, I want to make sure it's about smoking, we don't want, you know, smoking is not the best route. vaping is also not a bad route. But because of all the things that have gone on with vaping. And with the, you know, these black market types of vaping devices that led to a lot of the lung problems, we also don't want vaping. So inhalants are absolutely fine. And but we're trying to go with perhaps, the conventional type of things that people consider medicine, and wither under the tongue words, types of capsules that are very, that will be very fast in terms of, you know, their bioavailability, where we're prioritizing those types of strategies.
Nick Jikomes 51:08
What um, so when you swallow versus put something under the tongue versus inhale it, just just for the sake of talking about it, because there are so many people out there inhaling things different ways. How does bioavailability generally compare across those modes of consumption for cannabinoids?
Yasmin Hurd 51:26
Well, inhaling is going to get you the very fast into your into the body, you have a lot of blood vessels under your tongue, so that also the absorption is pretty quick. So that would be a route after inhalation. And then oral would be the lowest for the bioavailability.
Nick Jikomes 51:45
And so on. Do you have any, I assume you have some ongoing studies that are following up on what you've described so far. So what's going on today in your lab for CBT?
Yasmin Hurd 51:55
So um, there are a number of different paths that we're going down right now. So I'm going back. Okay, well, first, we're, you know, the goal is to try to make medicine, so definitely larger clinical trials to really see does this replicate in a larger population, because if it doesn't replicate in a larger population, then you know, it's not going to be effective in the clinic. But if you can carry out large clinical trials, and figuring out even the subgroups of people who might be might benefit from CBD, or even if it's women are better than men, and so on, those are still very helpful. Since as we talked about before, there's still not enough medications for substance use disorders. So I don't expect one medicine to cure everything. And I don't believe also that there will be a cure, but to treat everything. So if we can even help a certain subgroup, to me, that will be amazing. So it's being able to now do larger clinical trials so that we can even see one replicate and see if there are subgroups who are more that benefit more than others. The other thing, I'm coming back to the fact that I'm a neuroscientist, so I want to know what's happening in the brain. Why is CBD being beneficial in decreasing craving and anxiety? And we're doing that in two ways. We're going back to our animal models now where we can go and get more molecular insights. And that's, you know, I think, really critical. And, like I said, we're able to replicate what we saw in humans, even on the anxiety front. So really trying to pin down the neurobiology because we might actually come up with another non cannabinoid medication by understanding how CBD is impacting on these specific neuromodulators and neural circuits. But I'm also Zed masochistic. And so we're also doing in vivo imaging in humans, to see about the neurobiology in the actual human brain, in people being given in people with an opiate use disorder. So very similar to what we did before. So we definitely are recruiting so people, anyone, you know, that can contact us. So people with an opiate use disorder who are abstinent short term apps and just by an hour and looking at CBD and seeing how it's impacting the human brain, because I think that that's also critical if we're going to develop medicine for humans that we understand more about the human neurobiology.
Nick Jikomes 54:43
So in the studies that you described from your lab where you gave people with opioid use disorder, CBD, you're giving them between four and 800 milligrams. We talked earlier about the fact that CBD is not intoxicating, like kids THC, but it is psychoactive I'm curious could even though it was double blinded, could the people getting the CBD dose? Feel it the report any type of psycho activity?
Yasmin Hurd 55:10
No, you know, and I'm we're using lower dose, we're gonna use lower doses now to also see how low can you go to still get an effective outcome? The Finland's interesting is sometimes that zeolitic The reduction of anxiety makes some people think, oh, that could be intoxicated and intoxicating, but feeling calm. Sometimes people are like, Oh, I feel good. And they think feeling good may be in an intoxicant, but it's not. And very few people, even that those doses told us that they were like, oh, you know, like floating on air or so no one, no one said that. And, you know, the side effects that people reported, even people who had gotten the placebo, you know, also reported, you know, so it's sometimes it's psychological. And that's why it is really critical for us to do placebo, double blinded control studies, again, I actually have nothing against placebo, if we couldn't replicate placebo, I'm all for it, everybody gets a saline, you know, sugar tablet is fun, but it's, you know, it's called. But again, in terms of being able to replicate, and to develop medicine, that, you know, is accurate. It's like, you know, when you go into your medicine, chest and cabinet, and you take, you know, aspirin, there's a specific dose, and you know what that aspirin is going to do each time. That's what we're trying to develop. And so we need to make sure you know, that the dose, the route of administration, the particular subgroup that we know all of these things for CBD, and so without doing a double blinded placebo control, people might start to say, Oh, I'm feeling great, but they're really aren't. And then they, they, you know, then they do go and relapse. So we really want to make sure that it's not just people hoping it works, wanting it to work, even on the clinical front, that, you know, everybody wants to help the patients that it really is working, it has to be effective.
Nick Jikomes 57:29
So in your studies you've been using, or at least that for that one study, you're using Epidiolex. So this is presumably 98 99%, very pure CBD? Are you doing anything? Or do you have any interest in understanding the so called entourage effect, the fact that multiple compounds from cannabis, for example, a particular ratios might be more effective for certain things,
Yasmin Hurd 57:52
you know, yes or no. So I do believe that many of the terpenes in cannabis can help to boost some of the effects of CBD or even THC. And so I think that those are important to study. And if we then figure out the ratio, when you think about it, in order to get the right ratio, you have to do a lot of research to figuring that out. I'm already exhausted. So I'm helping other people do that, and I'm happy to work with people. However, I'm going to come keep bringing home this message medicine, aspirin, we're going to go on and taking the bark of the tree, right, that's where it came from. But there are other chemicals in the bark of the tree. But it was you know, taking the specific chemical that we knew then that had this, you know, analgesic, anti inflammatory all of these these effects. We want the same thing for CBD, at least to start. So you know, that you that this is exactly the the amount of CBD the other chemicals Yes, might potentially eight or reduce it, but you know, at least, you know, this amount will will be reproducing to give you this this outcome. So I don't think that it's it, that the other chemicals are necessary to have a positive outcome. But clearly, once you know some of them will allow us to decrease perhaps the amount of CBD that's needed. And then you could increase you know, some other terpene or other chemicals from the plant. But it will take a lot of work to talk about that. So the that ratio so and the entourage quote unquote entourage effects are also complicated by the fact that biology usually works in like an inverted U shaped meaning things work really it's a positive outcome. and it has like this optimal dosing and ratio condition. And then as you increase the dose, it starts to go down. And so you start to have a decrease. So this inverted U, it's works great, then it starts not being effective and doesn't work. That's also a critical thing when you talk about entourage of people like to throw around that term, but it's much more complicated. So you can, even with CBD and THC, there are different amounts of THC and CBD. And depending on the measure that you're having, that you can see that CBD can be beneficial in in potentially eating certain positive aspects of THC and other times it can reduce it, reduce it. So it is not that simple, quote unquote entourage and to make it a medicine. I think that's challenging. But if you have a specific strain of cannabis that has a certain ratio of CBD, and you know, all the other chemicals, and you can you can make that reproducibly absolutely, that could be medicine. Absolutely.
Nick Jikomes 1:01:10
How did you even get into this area? What made you interested in studying cannabinoids in the first place?
Yasmin Hurd 1:01:17
Um, you know, the funny thing is I started, as I mentioned earlier, you know, we're looking at the adult brain, in trying to understand the neurobiology and knowing that people, it's not just a drug that brought them there. There's other things so the genetics and trying to understand early life events, and like I said, cannabis was one of them. And the funny thing I was saying, My friends always tease me when I went into addiction because my friends from college, because they're like, Yasmin, you never did anything. You're Jamaican. You don't even smoke marijuana, you know, so they're like, you're stuffing this, you have to take it if you're gonna study it. Um, so it wasn't an interest in cannabis, the drug as I have an interest in it now, because I think it's a really, it's a complex, really fascinating plant. And being from Jamaica, you know, originally. I never thought about cannabis in that way. And then in terms of looking at the developmental effects of cannabis, but it was THC, and then studying CBD, and now the terpenes. And studying all of these things. It's been fascinating. So it's just, it's, it's, you know, you ask a question. I thought it was a simple question that I asked. And then 10 years later, you know, it's become it's, it has grown to this. So you never know where the path is gonna lead you.
Nick Jikomes 1:02:48
So did you go to college in the US or in Jamaica? Oh, no,
Yasmin Hurd 1:02:51
I moved to the US when I was a teenager. Yeah, yeah. When
Nick Jikomes 1:02:55
did when did you first get interested in science?
Yasmin Hurd 1:02:59
I always tell people, I was a weird kid. Even to make. I was always interested in the brain as a kid, I have no idea why I've always loved science. I was just weird. I, my family, no one is a scientist or doctor in or nurse? Well, actually, that's not true. I have a couple nurses in my family. So my aunt's will, will kill me if I say that, but you know, my parents weren't. I've always been fascinated about why people are the way they are in terms of just their behavior with fascinated by behavior. And just the planet. I mean, it's when I was a kid, and just you know, it's just fascinating of why we're here. It's, it's still something that I think about all the time.
Nick Jikomes 1:03:41
Okay, so you've basically been interested in this. You were sort of always on this path. You were always interested in science and the brain and you just you just stayed on that path throughout your entire life.
Yasmin Hurd 1:03:51
Yeah, yeah. I, as I said, I'm weird. I know. I know. I you know, and I'm looking forward to just laying on a beach and not thinking about what those neurons when talking to each other, and so on, you know, and but I can't stop thinking about how the brain works and whether, you know, the results that we have from this one thing can help to an idea for a treatment. It's It's strange, I can't stop it. I have OCD. So my OCD is there. So yeah.
Nick Jikomes 1:04:28
Any other research going on right now that you think is particularly exciting in terms of addiction biology and CBD? Not necessarily in your lab?
Yasmin Hurd 1:04:37
Yeah. I mean, I think, you know, for Well, one thing that we're doing that I can't really tell but it's really fascinating, but it doesn't have to do with addiction, but CBD, but we'll see if it works and then I can come back. CPD is now you know, touted for so many things that it's worrying But you know, there are developmental disorders that are being studied that it will be fascinating if there are specific developmental disorders that CBD could help with other than those rare forms of childhood epilepsy that Epidiolex was, you know, got the FDA approval for, because that's one of the things that is so challenging in terms of trying to help kids with mental illness. And in our society where we don't have enough treatments. I think that that's, you know, I'm fascinated and optimistic and hope that those studies will work out. But the fact that now, you know, CBD is thrown with so many things, my brain sometimes just like, say, okay, yet another thing oh, you know, for writers cramp, you know, like everything. So there's so many things that CBD is being tested for. But for me, I'm particularly interested in developmental disorders, that I hope that they will show some positive signals.
Nick Jikomes 1:06:03
So earlier, you mentioned towards the beginning, you mentioned that there has been some research with respect to CBDs, anti psychotic effects for things like schizophrenia, this is an area that people I think, are often unaware of that doesn't get quite as much attention as some other areas. What do we actually know there? So what are traditional anti psychotic drugs? And what how do we define psychosis as as a neuroscientist?
Yasmin Hurd 1:06:28
So I mean, I, it's funny that that CBD is not gotten more attention in that, that realm, because actually some of the earliest studies with CBD related to psychosis and psychosis in terms of, you know, classic thing that people think about, you know, the people hallucinating, you know, loss of true cognitive control, you know, paranoid paranoia. So CBD, most anti psychotics, they are, they, they modulate our, again, coming back to even if I talked about like dopamine, and some aspects of serotonin as well, but they, they block the classic anti-psychotics block these dopamine receptors, and a lot of them have negative side effects. And, you know, even more toxic side effects and so on. And so many people who have schizophrenia, were diagnosed with schizophrenia, they even stopped taking their medications due to the bad side effects. They have done studies with CBD, where they have shown that they could use with study CBD in psychosis in people's Korea, with their anti psychotic medication so that it could be an adjunct. So therefore, you could even decrease the amount, hopefully, of these classic anti psychotic medications. But even CBD by itself was reducing psychosis and in and in particular, there are some fascinating studies from England, in terms of prodromal effects of CBD. And what I mean by that is, we know there are certain risk factors for schizophrenia. And these teenagers that show these signs invariably go on to develop it. You go goal for medicine is to try to before someone, you know, develops the disorder to their prodromal that they're in the early stages. They've not yet gotten the full blown disorder, but they're at a point where they may be treatable. And they've now been looking at CBD in such individuals. And from my understanding, the preliminary studies looked really promising that if CBD could be effective in prodromal, psychosis, this is a game changer. So I think that that would be extremely critical for mental illness in general. There are a lot of other disorders that I think that then it could lend itself for. But Schizophrenia has been something that CBD had been studied early on, and it hasn't gotten I don't know why it hasn't gotten the, the attention as other disorders, but you know, we'll see whether or not the prodromal effects the effects of CBD to on on individuals that are prodromal to potentially get the disorder will be effective. Because again, he doesn't have all those negative side effects. And, you know, with with, with teens and children, you want to tried to have medications that are not going to have such a heavy hit on the brain?
Nick Jikomes 1:10:05
Yeah, and I would imagine, you know, especially for something like schizophrenia, where the, you know, the onset or the critical period is not necessarily in your teens, but maybe in your young adult years, with the anti the traditional anti psychotics if they're dopamine receptor antagonists. The side effects that are probably pretty gnarly, like lack of motivation, lack of pleasure, is it that type of stuff?
Yasmin Hurd 1:10:27
Yeah, so you, so it blunts a lot of your, you know, feelings, you know, positive feelings, and so on. So those are some of the negative side effects of those particular medications. And, you know, it's, it's challenging, it's, you know, I don't think that people understand that a lot of the medications that are, that really do help people. I mean, I want to say they do help people, but they do come with a lot of side effects. And so individuals stop taking them because of those side effects. And so that's why it's also critical for us to try to develop medications we tried to, but you know, without, you know, such severe side effects, the goal is not to try to develop medication side effects. But coming back to the, you know, the earlier discussion, why I'm actually fascinated by CBD is that, you know, we were taught in school in pharmacology that you find the purest, the strongest agonist, or the pure, strongest antagonists, but those are the ones that are producing all of these side effects. So for me, something that is, has a softer impact of tweaking the different, you know, on a more modulatory manner, rather than like a hammer, I think that that's the thing that, you know, has opened my eyes, at least I'm thinking differently about perhaps how we should develop medications. And it doesn't mean it has to be for all medications, it has to be the strategy. But for mental illness, especially where the side effects do cause a lot of individuals to stop taking their meds, I think that this is something you know, we should consider.
Nick Jikomes 1:12:08
Do you think that's a change that's happening more generally, in this world, at least on the research side, where people are looking, looking a little bit more closely on drugs that you would otherwise traditionally have called Dirty?
Yasmin Hurd 1:12:20
Yes, I know, it depends. I mean, there's still two schools, two camps of this, and it depends on who you get to review your grants. Some of them say no, you know, this is it or not. But I think one of the things that sighs that we're also doing is repurposing medications. So there have been a lot of medications that have been tried and hasn't worked, as we've talked about earlier. But there are now databases of those. And as we learn about the biology of certain disorders, people are now screening these databases of these medications that didn't work for, say cancer, but actually might work, even in addiction. And because now we see that the mechanism by which they worked, we see similar things that are occurring for a particular addiction or psychosis or something. And that, to me, is also important, because many of these drugs have been tested. And we know the side effects. We know that the you know, all of these things, so repurposing some of these medications are also something that the field is doing, besides saying, stepping back from calling things dirty, and I hate the word dirty, you know, because end of the day, a lot of our transmitter our own modulators in our bodies are, quote unquote, dirty. And it is the symphony that makes for our behavior, our thoughts. It's not one transmitter that does is working at one time, it's all of these transmitters and neuromodulators, and different cells firing and different circuits activated. Why I moved my hand, why I thinking certain things. So that's why for me having a more modulatory type of of a multi scaled approach rather than this one transmitter approach, I think is important.
Nick Jikomes 1:14:17
Interesting. Well, do you have any final final thoughts for people about CBD and cannabinoids or addiction biology generally?
Yasmin Hurd 1:14:25
I mean, for me, I do think that why in terms of you know, we've talked obviously about CBD a lot. And that about THC, you know, I've mentioned briefly the issue of very high concentrations of THC today in cannabis being consumed recreationally and that is a problem for mental illness. That is a problem for addiction. We know that it's THC that leads to the addiction and the higher the concentration of THC vote, the more vulnerable people are to developing a cannabis use disorder. So Many people think that you can develop an addiction to cannabis. And you do. In fact, cannabis use disorder is one of the highest disorders in our country. So, you know, and about like 30% of people develop cannabis use disorders who, you know, play with cannabis. So it's not a benign drug. And we need to really clamp down on that as well and educate people about the health risks of this high THC cannabis that's being consumed. So for all that's being said about CBD, which is great. It's important that we don't forget that. And, I mean, coming back to, you know, even psychosis in our dual diagnosis moored at Sinai, a large percentage of people in the dual diagnosis meeting have addiction and mental health disorder. It's cannabis with psychosis is cannabis with psychosis. So, no one can tell me that cannabis does not have negative effects. So even though I'm trying to also look at the beneficial properties of cannabis, it's, it's a drug and we need to be respectful of it. And I said, especially in certain vulnerable groups, and that's why I you know, I, I want people to also explore and educate themselves about cannabis. Even though we have a natural endocannabinoid system. It's not as powerful and potent as the as the concentrations of THC out on the street today.
Nick Jikomes 1:16:42
Alright, Yasmin Hurd, thank you for your time.
Yasmin Hurd 1:16:44
Thank you so much.
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