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Marijuana, Cognition, Psychosis, Addiction, Cannabinoids, THC, CBD, THCV | Amir Englund | #93

Updated: Oct 25, 2022

Full auto-generated transcript below. Beware of typos & mistranslations!

Amir Englund 4:35

name is Amir England, and I'm currently in London and I live here since 2006. And for about 10 years I've been working at Institute of psychology, psychiatry, psychology and neuroscience belongs to King's College London. And my basic scientific background is I've got a degree in psychology and then

PhD in psychopharmacology, specifically cannabinoid psychopharmacology

Nick Jikomes 5:05

and what what actually originally drew you to cannabinoid psychopharmacology.

Amir Englund 5:12

So I think is a bit of a funny story because

I am Swedish, I grew up in Sweden, and I don't think many people know that Sweden has some of the most restrictive drug laws around. So basically what you learned about drugs in sort of middle school was that if you tried an illegal drug, you would potentially die the first time you tried it, or you became a heroin addict. And then that kind of mindset and poor education kept going throughout adulthood, with newspaper articles being very poorly nuanced, and you learning very few facts about drugs, illegal drugs, specifically.

And I think I've always had a bit of a scientific inclination, I was always drawn to TV shows, like an Intel was bullshit, and Mythbusters. Love those shows. So when I studied psychology at the University of Westminster in London, the the scientific method really drew me in, and I got really hooked on that and reading articles, when no one really did like that. I really loved it. But then, particularly when we started learning about the topic, being psycho biology, so you know, the brain neurotransmitters receptors, but also how drugs and medicines influence these. I started reading about different illegal drugs, particularly cannabis, and was quite shocked at how different that was to what I was taught back home in Sweden. So that made it so much more interesting to, you know, dive into this literature, when I had this sense of betrayal in my home country that I've been kind of let down that I've not been taught, you know, the truth really. So we always were given a poorly nuanced view of, of illegal drugs and cannabis. And then I think particularly why cannabis drew me in was because of the endocannabinoid system. So that we have this endogenous system of neurotransmitters, enzymes, receptors, and you know that we have the endocannabinoid system body's produces its own cannabis compounds, I found to be really fascinating reading about potential therapeutic targets within this system. I was really well got me.

Nick Jikomes 8:07

And so what you know, when you think about everything that you know, today from being a professional scientist who studies this stuff, compared to what you were taught, when you were growing up in Sweden, what are the facts and myths when it comes to something like addiction and cannabis, how addictive is THC? Is it addictive at all you hear? You know, you can go on the internet and find the full spectrum of opinions out there. And there's a lot of motivated reasoning. So what's your understanding of the addictive potential of cannabinoids?

Amir Englund 8:42

So cannabis is definitely addictive. And you know, what, what do we mean by that? We have something cool. Cannabis use disorder according to the latest DSM criteria, so if you fill at least two of these in the last 12 months, some of the symptoms might be, you know, very strong craving. That you're giving up chores and duties that you have in your everyday life because of cannabis. You engage in risky behaviors because of cannabis. You neglect family and friends because of cannabis. And you feel the cannabis is taking a bigger and bigger part of your life more than you wanted to. So you failed attempts at controlling or cutting down but also some physical signs of addiction we have which is tolerance, meaning that the more you use of it, the stronger varieties, the higher the dose that you'll subsequently need to feel the same effects. So that's a physiological sign of dependence. And the other physiological ones is that people Who stopped using cannabis experience withdrawal symptoms, problems sleeping, agitation, upset stomach, headache, sweating. Some of these are, you know, physical signs of addiction. So some some of the myths that I've heard about cannabis addiction, I guess relates to Oh, it's just psychologically addictive, not physically addictive. So that's not quite true. And also, that has very little relevance. I think whether or not it's psychological or physical dependence, because compared to other drugs, let's say alcohol, heroin, tobacco, cannabis is less addictive, or fewer people who try that cannabis will develop what's called cannabis use disorder compared to the other drugs. However. Canada cannabis is one of the most difficult drugs to stop using once ones become addicted. And that's a complicated story in and of itself. So it's, it's less addictive than the most other drugs, it's definitely still addictive. I think, on average, it's about nine or 10% become addicted. And there was a recent,

Nick Jikomes 11:20

how would that compare to another drug? So it's nine or 10%? For cannabis? What do we see for something like cocaine or alcohol or another addictive substance?

Amir Englund 11:29

So I think cocaine and heroin would be in the 30s, and upper 30s, tobacco nicotine would be in the 60s, I think alcohol is between 15 to 20. So that's kind of life lifetime risk, more recent studies have found that the risk can be up to 30% for people who use cannabis, but that that's after one has used up to 20 years. So methodology is slightly different. And some of the risk factors for addiction is starting young, having, you know, family history of addiction, and using stronger varieties of cannabis more often.

Nick Jikomes 12:18

I see. And so, you know, when it comes to, when it comes to thinking about how addiction starts, you said, you know, the age that you started out, you know where at where you're at in development matters earlier means more likely to develop a habit. The dose also presumably matters, is that a factor with with drugs in general but THC in particular?

Amir Englund 12:44

Yeah, I was, I would say so. And mentioning the early onset aspect. Now that's obviously in association we can't draw on the causal inference. It might be that you know, if you have a troubled childhood, if you're hanging out with the wrong type of brands, and they're more risk taking and and sensation seeking, that that might lead you to start using cannabis earlier and therefore also be a higher likelihood of becoming addicted.

Nick Jikomes 13:21

And I want to discuss where people teach these psychoactive effects. So can you start discussing for us what is the constellation or what are the different components of psycho activity, the psychoactive effects that THC in particular has, and I want to start to tie that to the CB one receptor for people. So how much of this comes back to CB one receptor and which parts of the psychoactive effects the THC can have are tied to that receptor versus something else?

Amir Englund 13:55

Oh, I would say that the CB one receptor is crucial for the intoxicating effects of THC. There have been studies where you administer THC alongside a CB one receptor antagonist, and you reduce the psychoactive effects of the intoxicating effects. And I mean, there's a there's a plethora of effects that we attribute to CB one activation through you know, THC but also other agonists that bind to the receptor. So, I mean, it's so broad, it's a changes people's perception, you know, in most aspects touch, hearing, smelling seeing and it can it can change it to various degrees as well. So you have obviously the enhancement of the stimuli or Have people who use cannabis often report enjoying music more enjoying food more, smells more enjoying being out in nature more. But then. And this is something that we see sometimes in the lab when we run experiments giving healthy volunteers THC is that you can keep pushing that change of perception to the point where you start perceiving things that actually aren't there. And we start veering into the area of hallucinations, actually. THC can make you change the way your mind works in terms of how you organize your thoughts, and how your cognition works, you know how well you remember things and organize thoughts in your head. Another aspect that we see is similar to thought disorder that we have in people who have schizophrenia. So your your thoughts become muddled. And you sort of thoughts go in tangent, so you start thinking about your bicycle, and then you need to pump it on the tire is full of air, air comes from the outside, outside, there are birds, you know, birds flying the sky, in the sky, there are planes and these thoughts can bounce off each other. What feels like 100 miles an hour, it can be quite distressing people. But similarly, you can also have the creativeness of of THC. So THC can maybe take you outside of the bubble, which is your mind and make you think of things and different perspectives. So the these things happen on a spectrum where on one end, they can be quite pleasant, neutral, or neutral. Be you know positives the person they feel they gain a benefit from our while. On the other hand, it might become overpowering, overwhelming, anxiety and paranoia provoking.

Nick Jikomes 17:06

So one of the things I want to discuss also is when it comes to changes in memory, when you have memory impairment or just altered cognition as it relates to recalling and remembering things, there's the acute effects, so the way THC is affecting you while you're intoxicated with it. And then there are potential chronic effects. So if you are consuming THC over long periods of time, can you have changes or impairments to memory that persist, even in the absence of being intoxicated with THC in the moment? So can you kind of compare and contrast the effects of memory of acute acute intoxication versus any lasting effects that might come from long term chronic use?

Amir Englund 17:51

Yeah. So acutely, while intoxicated, you impair most domains of cognition, the few domains are less affected, one that's less effective is kind of executive function. So like problem solving. So, and I'll obviously motor coordination and things relating to driving. So that's always one good thing to remember is that, you know, don't drive up to using cannabis. There was actually a very interesting study that studied participants after they've used cannabis. And they they said they felt fine two hours later, but Jack diddly it actually took them five hours to feel fine, objectively in terms of their driving performance. In terms of long term impairments, we see sort of a similar pattern. When we compare non users to regular cannabis users, cannabis users do worse, comparatively, as a group, obviously, we don't know if it's because they're, you know, have some underlying susceptibility towards poor cognition that also makes them susceptible to try and cannabis. So we don't know the causal Association, we just know that as a group, they perform worse. But there's been a meta analysis that looked at frequency of use and level of impairment. And what that found is that people who use four times or less a month, on average once a week, they do not show any difference to non using counterparts. There seems to be a cut off somewhere there. So if you go above that threshold, I think it was between five and 21 times a month, then you start showing significant difference to compare to non using counterparts. So and then there's been some studies looking at how Whether or not these cognitive impairments persist or not, and for how long, and it's quite old now, meta analysis, I think from 2012 found that once people stopped using cannabis, after about four weeks, you could not distinguish cannabis users and non users anymore, obviously, you know, depends on the quality of data and the amount of data but at the moment, that's kind of where we're where we're at. So we think that most likely people regain cognitive abilities, if they stopped using cannabis or significantly reduced to about one to once a week or less.

Nick Jikomes 20:46

So, you know, studying this stuff in humans can be difficult because it's hard to tease apart cause and effect when you're when you're talking about observational studies. But you're saying, as a group, people who consume cannabis, especially those that consume it frequently tend to perform more poorly on memory and cognitive tasks than non users. But there does seem to be some kind of frequency or dose dependency or the amount you're consuming really matter. So roughly speaking, when you look at people consuming once a week or less, you don't really see any differences in cognitive or memory performance compared to non users. That's right. Yes. Okay.

Amir Englund 21:24

And then there's another aspect and this is kind of the the jury's still out comes from iconic study in New Zealand called the Dunedin study, where they followed up, study volunteers from birth, and I think they're up to above 45 years of age now. So the same people have been followed up. And this created a bit of controversy when the the first paper came out, I think it was 2012, which suggested that cannabis use was related to, or IQ, you know, the, connected to the old adage of cannabis making you done, really, so that this really affirmed a lot of people's pre existing beliefs. And therefore it was very popular. But what the study actually found is that over a 20 year period, so from the age of 18, to 38, cannabis use, or specifically cannabis addiction was measured five times. And if you tested to be, you know, cannabis addicted, or three out of those five times at least, then you were in the group that had a six point drop in IQ compared to what you were as a as a teenager. So they further divided that group into those who use cannabis before the age of 18. And after a 18, those who started after the age of 18, they had no different IQ performance, while those started before the age of 18, and an eight point drop compared to their teenage performance.

Nick Jikomes 23:15

And is that difference? Big? Would an eight point difference be considered a large difference? I mean,

Amir Englund 23:21

yeah, it would be noticeable. And I think there were also questionnaires answered where they would say that, you know, they would struggle in everyday life due to slight impaired cognition. I mean, it's not to the level of what we call learning disability. But it's slightly below average. So we would take you from average to below average. But the the study was somewhat criticized for not taking other aspects into account. And there were a couple of more studies that followed up looking at genetic liability and other risk factors like drug use, and, or, you know, poor upbringing, and found that when you control for those factors, the association disappeared. So at the moment, the jury's still out whether or not long term cannabis use affects IQ. And if it does, you You most likely need to be addicted to cannabis for up to 20 years. And specifically in that study, that subset of people had stopped using cannabis one year before the final testing points and found that in spite of stopping a year earlier, their their IQ had not improved. So but that's still that's a single study and to actually know whether or not that holds true, we still need more studies to confirm those findings.

Nick Jikomes 24:58

I mean, is there anything in terms of of animal research that might get at that have people tried, you know, giving THC to mice or rodents chronically at earlier versus later ages and seen something akin to what you were just describing?

Amir Englund 25:14

I must confess that I'm not so first on the animal literature. But I think what we do see generally in the animal literature is kind of confirming what we've seen in humans, really. But I can't really point any specific studies now.

Nick Jikomes 25:31

I mean, one thing that definitely seems true is that there's going to be age dependent effects. The one thing that I know from the animal literature is, you know, there's been some studies done in the last few years where they basically show that you can get different, or even the opposite effects and old versus young mice, basically, in young mice, juvenile mice, teaching is going to impair cognition, but actually an older mice, it seemed to improve in some ways. So there are, there does appear to be something interesting going on developmentally. But, you know, one of the issues I think you were getting at in terms of how difficult it is to tease apart all of these different variables that can correlate with things like cannabis use, is that, you know, it's hard to pull those things apart in human studies. Another area where that difficulty, makes it hard to interpret some of the data that's out there is psychosis. So can you talk a little bit about THCs psychotomimetic effects acutely? And what exactly does that mean? Let's describe that for people to start off with, and then we'll maybe discuss what we know or what the controversy has been around, you know, whether or not psychosis becomes more likely in response to chronic THC consumption?

Amir Englund 26:44

Yeah, sure. And I mean, this is this is really, where my main focus of research lies, you know, it's experimental psychopharmacology. And what we do see is an A varies by dose, between 25 to 50%, of healthy volunteers that get a big enough dose of THC will start showing signs of quite mild and brief psychotic, like experiences. So psychotic, like experiences can be things like hearing voices, delusions, believing things that that aren't true. being paranoid, so thinking that someone's out to get you to harm you that there's some uncontrolled force out to get you, grandiosity, you know, believing, having an inflated sense of self, and belief about your abilities that doesn't match up to reality. And what we mentioned before thought disorder, so we call it conceptual disorganization, as well as hostility. So in the lab, we've we see this quite frequently in healthy volunteers, so we test them before THC and after. And the symptoms that we observe are very mild, and they're often very fleeting. So one participant, for instance, he was sat at the laptop and was doing some cognitive tasks, and the hospital fan was going, you know, above his head. But during the intoxication, the sound of the fan had morphed into a group of women that were talking about him, for instance, and that lasted for for a few seconds, but for those few seconds, he truly felt and believed it. He was convinced of that. And then that slowly faded and he started hearing the fan again, he stopped believing it. But for that short moment, what he experienced was psychotic like, so in a patient with schizophrenia, they would likely hear voices on enough like frequently, very, some some people experience voices Occasionally, some hear voices non stop, though, something like that that's an auditory hallucination. Then we had another participant similarly, they were doing cognitive tasks, but this time, one of my researchers was, you know, just texting while someone while the participant was doing the laptop task. And the participant became convinced that she had been filmed by his phone and stopped the task and said, Did you fill me? And he said, No, and this belief persisted. until he actually showed her his phone and showed that there were no videos of her doing the task. So short period of time, convinced that she was being, you know, filmed during the comment with us. And that sort of had a malicious intent as well. There was another participant that for a brief moment, saw our faces morph into doglike faces, lasted for about three or four minutes, and then that was gone. So that would be an example of a visual hallucination. So we get all sorts. And I think that the most frequent one, and the most common one is thought disorder, you really can't keep track of your thoughts and your thoughts are going all over the place, it makes it sometimes quite distressing. Because you feel that you you lack control over your mind, a have difficulty organizing your thoughts. So those are the some of the acute psychotic light effects. And they're nowhere near what people with schizophrenia experience. But it's the same kind of type and quality we call an immunology of symptoms.

Nick Jikomes 31:19

I see so so in scientific speak in a paper or study where you read this about this stuff. When you talk about the acute psychotomimetic effects of THC. It's what you just described, it's certain symptoms that some people display at a particular dose of THC intoxication, that are similar to some of the symptoms that say someone with schizophrenia would experience. But they're typically more mild, they're less intense in their expression. And they are more fleeting they don't last as long as someone with with true psychosis.

Amir Englund 31:55

Yeah. So the the intensity of those symptoms obviously varies from person to person. Some people are really sensitive towards THC, and can have really distressing experiences. But what tends to hold true, at least in these experimental studies is that all of the symptoms subside once the drug stops having an effect. So with three, four hours, all the symptoms gone.

Nick Jikomes 32:24

And what was can you repeat this statistic that you started out with? I think you said something like 25 to 50% of people will have some kind of psychotomimetic symptoms at a high enough dose. So what was that STAT again? And what kind of doses are we talking about?

Amir Englund 32:39

Yeah, so this is this is looking mainly at similar studies where healthy volunteers have been given doses of THC in a research setting. So the rate of psychosis, when given a high enough dose is about 25 to 50%. So I think the dose of inhaled THC would be about 10 milligrams. And then the highest dose I think, that has been given intravenously, has been about five to seven milligrams.

Nick Jikomes 33:17

Okay. So these are these are what we might call normal dose ranges. These are not astronomical doses. There's some they're in the range of what someone would experience if they're consuming illegal cannabis product. They might buy somewhere.

Amir Englund 33:30

Yeah, definitely. But I think what what puts our participants aside to the, you know, recreational cannabis users is that we, we tend to select users that have very low baseline of cannabis use. very infrequent, because we kind of want to maximize the effect that THC has on them to now study these effects more closely. But also, you know, for practical reasons, because when you do these studies, you always ask participants to provide a urine sample on the day of the experiment, to show that there's nothing else on board, so that the thing that we're actually measuring is the compounds that we give the participant on that day. So just bear that in mind that these are very novice users, I would say. infrequent.

Nick Jikomes 34:27

Yeah. So their tolerance is going to be low. So if you're, you know, if you're citing a study, like what you just described, where you've got novice consumers, who have very low tolerance, if you're giving them say 10 milligrams of THC, the results you're seeing then would be expected to be more akin to what a more frequent consumer would get at a higher dose.

Amir Englund 34:48

Correct? Yeah. And studies have looked at this specifically. So they've compared the same doses of let's say, intravenous THC in infrequent users and frequent users, and they see much less pronounced psychotomimetic effects in those frequent users. And similarly, when you look at their cognitive performance during the intoxication, you see that as Previous research has also found common cognitive impairments there at baseline of the cannabis users, but then when you give them a bit of cannabis, it balances out. So it improves their performance slightly. That might be because they're, you know, at early stages of withdrawal, or they've not had THC for a while, because the researchers asked them to stay away from it ahead of the experiment. But they tend to show very little cognitive impairment when when being administered THC in these studies.

Nick Jikomes 35:56

And so when someone is frequently consuming THC, they are going to develop some level of tolerance to it. So they will need a higher dose to achieve the same effects. But how uniform is that adaptation? Is that tolerance? Are there some things that that the person will adapt to, but other things that they won't? In other words, you know, if someone is consuming frequently over an extended period of time, do some of the effects tend to go down in magnitude and others remain elevated? Or remain there? How much you know how much? How much is tolerance being tuned to different subcomponents of the experience that you get to THC?

Amir Englund 36:38

I think it's a really difficult question to answer. And this is a really good one, I think, I think it's probably an area where we need more research to understand, you know, how, over time, the, the intoxication effect changes with increased development and tolerance. I think most aspects of the intoxication will, you know, follow the trajectory of tolerance. So, you know, the pleasurable effects, you know, the effects on on food and on sleep. And I think, and this is now anecdotal, but I've heard the positive effects can just stop all of a sudden as well. So there was a musician that I met at an ad an event, he been using cannabis to help him write music. And he said, it worked for years, but then all of a sudden stopped. Obviously, it's impossible to say whether or not cannabis was related to any of that, or some other aspects of his life changed. So made it so that he didn't benefit from cannabis anymore. But yeah, I think that's an area where we, where we know very little still, but overall, generally, most effects of cannabis are going to be blunted by frequent regular use, and the stronger the product, the more quicker you'll develop tolerance.

Nick Jikomes 38:16

And another way that some of the effects of THC can be blunted, are co administration or pre administration of CBD. Can you start to talk about CBD a little bit? How does it how is it distinguished from THC pharmacologically? And how does that start to tie into the way it modulates the effects of THC.

Amir Englund 38:38

So what we know about CBD is that it's what we call a promiscuous drug. So it binds to many, many different receptors and has many physiological functions on the cell and receptor level. Importantly, it doesn't bind to the CB one CB two receptor directly at any relevant concentration. And that's why even at really high doses, you don't really tend to see any intoxicating effects. So that's the least one thing that a CBD doesn't intoxicate you and impair your cognition is what generally is found in terms of its pharmacology and how we think it might combat or kind of compete with THC is that it has a whole host of indirect CB one effects. So it's what we call an L negative allosteric modulator of the CB one receptor so it binds somewhere else, but then has a sort of an antagonistic effect on the CB one receptor and towards other agonists, who might bind to it might inhibit the breakdown of endogenous canal Benoit's by preventing the the enzyme that breaks it down known as fall and also prevent the reuptake of endocannabinoids. So you've got more endocannabinoids out in the synaptic cleft competing for the receptor when THC is trying to bind to it, and then there are a whole host of other pharmacological targets that are still quite poorly understood, that might also moderate the effects of THC. So, I mean, I can give you a couple of examples. So we, the kind of cannabis studies that started at Kings are about 15 years ago, the first study we gave healthy volunteers, intravenous THC, two and a half milligrams, which I don't know what you would call an average joint, but I would probably say that it's one and a half of those. There's a fair amount. And participants experienced cognitive impairment and psychotic like symptoms in that study. And then we did a subsequent study, very small one pilot study with pre administration of five milligrams of intravenous tea, sorry, CBD, the five milligram CBD, and then one and a quarter milligrams of THC. And in that small study of six people, we saw that the the psychotic, like effects were reduced. So that kind of gave us some, some preliminary data to go look at this properly. So we we managed to get funding for a study where we gave 48 healthy volunteers either 600 milligrams of oral CBD, or a placebo, before they had one and a half milligrams of THC. Now, in this study, we saw similar effects on cognition. So there was an impairment to what we call delayed verbal recall. So participants learned the list of 12 words and 20 minutes later, they were asked to remember as many words as they could. And they were also asked specific questions about paranoid thoughts. And we did the standard psychosis interview, the scale that we always use. Now, THC had predictable effects, so increased psychotic like effects, increased paranoia, and cognitive impairment, but we saw the people who also had CBD, that there was significant reduction specifically in paranoia. So there was no paranoia in the CBD group compared to their baseline in terms of psychotic like effects that happened to 14% in the CBD group and 41% in the THC only group and lastly, the delayed verbal recall. So people tend to perform perform tend to remember one word less on average on this list.

But if you also have the CBD, THC did not reduce your performance. So in that study, we we found the CBD potentially could protect against some of these acute negative effects of THC.

Nick Jikomes 43:43

And I think you said you used 600 milligrams of oral CBD so so people are swallowing hundreds of milligrams of CBD, and then they are getting the THC in the original pilot study used five milligrams of intravenously delivered CBD. How do you what what's, what's the reason for the difference in dosing there?

Amir Englund 44:07

So I mean, funnily enough, the, the difference why we went for oral CBD was a practical one, we just couldn't find a supplier for intravenous CBD anymore. And, you know, we have the choice of, alright, we'll go with capsules, because that's more readily available, easy to find, and or we just delayed the study and potentially run out of funding. So that's really the reason why we went for oral CBD. But at least you know, we found the significant effect in that study, and that kind of led us on to our most recent study, which still not published but you know, is well on its way to be In this study, we wanted to see if there's a particular THC and CBD ratio that's associated with, you know, less of these negative effects. So we were hoping to kind of replicate the finding and find a ratio of CBD to THC. That would be the best. So we had this time 46 healthy volunteers. But this time every volunteer came for four experiments each. So in a way, it was almost four times the size of the study, though, the power is much improved. And we gave healthy volunteers 10 milligrams of inhaled THC delivered through volcano vaporizer. Then your 10 milligrams of THC on each visit alongside of no CBD 10 milligrams of CBD 20 Min milligrams and 30 milligrams. So it's zero to one, one to one to 213 to one,

Nick Jikomes 46:09

and it was all that inhaled through the volcano all inhaled

Amir Englund 46:13

all at once, because that's that's some of the criticism of the previous studies that it's not really naturalistic that someone would swallow a huge dose of CBD, or hours before having a joint. Right, right. So if there were a safer variety of cannabis than, you know, be consumed at the same time, really. But what's to notice that we kept the THC level the same, which is not really lifelike, because if you have a cannabis variety with three times the CBD amount that you know, the plants cannot produce the same amount of THC so have to sacrifice THC levels. So I guess this is a study where if you were to match the THC amount with different CBD THC varieties, are there any benefits of choosing a high CBD variety? So it was double blind. It was randomized, so participants didn't know what ratio they had on which day, there was a minimum of one week in between experiments. And everyone who showed up for an experiment gave a negative urine drug screen beforehand, everyone was fairly infrequent cannabis users, less than once a week on average, they use cannabis, I think the average was actually about eight or nine times a year among the whole group. So very low level use. And again, we saw the same kinds of THC effects. We saw impaired cognition, you know, both immediate and delayed recall. We saw psychotic like effects, we had a couple of extra kind of self rated psychotic scales. And those also increased. In the study, we also measured pleasure bility, because we were interested in, you know, if if we find the CBD THC ratio that's less harmful, is that then going to be less pleasurable, or start going to do to the positive effects. So we, we had participants listened to song that they've pre selected on each experiment, you know, a song that they enjoy. We gave them a piece of chocolate to taste while they were intoxicated, that they'd also tried when they were sober. And we have them rates, you know, all sorts of intoxication related questions. So like, How high do you feel? Do you feel stoned? Drunk? Are the drug effects pleasurable? Do you feel anxious? Do you feel paranoid? So we were quite hopeful because running the experiments were also blind. And for each participant, every time there's different effects. And when you see a different effects in the participants in the lab, you think that oh, you know, they must be the CBD that's driving the difference within this participant. So they have a unpleasant experience on their first experiment. And now even they have a great experience on the second one. We as researchers, we think that's down to CVD. So that's kind of what we thought when we finished the study. But then we unblind when we analyze the data, and there's no difference anywhere whatsoever to be. All all the CBD THC ratios are the same In terms of what they do to cognition, what they do to the subjective effects, the intoxication of measurability of chocolate, measurability of music, psychotic, like effects, all these effects are the same, or even the highest ratio three to one.

Nick Jikomes 50:19

I see. So you tried to 121221321. And you saw no difference. So increasing the CBD to THC ratio didn't lead to fewer bouts of paranoia. It didn't, it didn't get rid of any cognitive impairment they were getting from the THC, it seemed to have no effect.

Amir Englund 50:39

No. So the only effect that we actually managed to see was that the more CBD there wasn't the cannabis, the longer the participant needed, inhale all of it. And the more that they cough was, that was the only effect that we saw a CBD. And we did have the THC only as a comparison to this. So what we take with from this is the, you know, to modify the negative effects, it's not going to be feasible to keep putting in more CBD. I think because the the level of coughing that we got from the three to one ratio. So, you know, I think to reach the CBD levels that we got from giving people 600 milligrams orally, you would probably need to go to, you know, 12 or 20 to one. And I think that would be way too abrasive. Participant to be able to nail

Nick Jikomes 51:49

Yeah, and so I mean, when you think about those ratios, in the context of the different cannabis products that are out there, and you're talking about flower actual plant material, there are no plants that naturally produce that high of a ratio of CBD THC. You know, you can get up to the two to one and maybe even three to one range, but you don't have any plants that are doing 10 to one or 20 to one or 30 to one you could make constant. Go ahead.

Amir Englund 52:12

There are some I think that have I've seen 18 20% CBD with you know, naught point five so that would be

Nick Jikomes 52:22

Yeah, that'd be great. But at that point, the THC is so low

Amir Englund 52:25

that they're not gonna reach. Yeah,

Nick Jikomes 52:29

yeah. So but you're saying basically, the one effect you did see is that as you added more CBD, the vapor got more harsh, it took longer to inhale all of it and people cough more.

Amir Englund 52:40

That's fine. And also we we measured both compounds of CBD and THC and blood and we saw a perfect dose response. So we saw you know, one to one had significantly more CBD in the blood compared to THC alone, two to one had more than one to one and three to one had more than two to one. So it was like a perfect dose response curve and blood but there was no difference in how much THC was absorbed. So there was no we call pharmacokinetic effect where you know, the CBD is pushing out THC from the blood. So all participants got the same amount of well the all the four groups have the same amount of THC.

Nick Jikomes 53:33

So okay, so that's interesting. So, you know, in the realm of, you know what ratios of CBD THC you need for CBD to modulate some of THC has effects to decrease some of the negative side effects that one might experience you know, we know that 600 milligrams of oral given before a regular ish dose of THC does something you just described experiments were you know one to one two to one three to one ratios of inhaled CBD and THC don't seem to do anything. In terms of products that are actually out there. The the only one I've seen that gets anywhere close to this ratio is some gummies that just came out recently and they've got 200 milligrams of CBD and four milligrams of THC in each gummy. Do we have any data on that kind of ratio? Would you expect that to have some kind of effect or do we do we just not know right now?

Amir Englund 54:26

I don't think we can say that we know yet. I'm afraid so we need to firstly we need to replicate the findings of our previous study the woman had 600 milligrams oral CBD. It could just be you know, serendipity that we haven't powered the study enough because, you know, random chance put more tolerant people in our CBD group maybe that's why we saw a CBD effect. And and I think we trust the result Also the latest study a bit more because it was every participant did all four ratios and it was was four times the power study. But this still might be something to high dose oral CBD. We're currently running a study in patients with schizophrenia who use cannabis regularly. And they're getting THC on two occasions once with 1000 milligrams of oral CBD before THC and the other one placebo. So we're still looking into it. And there might also be some metabolic effects that you get from oral route of administration that you wouldn't get from inhaled. So if you take a drug orally, often you get what's called first pass metabolism. So much of the compounds broken down in the liver, and some metabolites are produced. Now we think that one of CBDs metabolites, seven hydroxy, CBD has been found in some preclinical studies to have some some pharmacological activity, whether or not it be the mechanism that blocks THC effects, we still don't know yet. We studied seven hydroxy in the ratio study, but we found only very small levels from inhaled which is kind of what you would expect. So it might just be that either because you're getting a higher dose orally, or because the oral route of administration means that you've got more of this potentially active metabolite that's helping to protect against THC effect

Nick Jikomes 56:58

is a similar idea related to why people say that edibles that orally consumed THC is more psychoactive, more potent and intoxicating than inhaled THC.

Amir Englund 57:10

I mean, I think there's a potential for that, because we know that 11 hydroxy THC, which is one of the two main metabolites of THC is strongly intoxicating, binds well to the CB one receptor. I don't think any recent studies have really looked at how comparable they are. There were some studies from I think, the 70s and 80s, where they gave these metabolites alongside THC. And back then they said that they were slightly stronger, but I think we need more controlled and better powered studies to really confirm that 11 hydroxy is stronger, but it's at least as strong, I would say, based on what we know from previous study to THC. So you're getting THC and you're getting higher levels of 11 hydroxy. So that could be partially What explains why people experience different effects from orally consumed THC. But it could also be that obviously, people are not as good at dosing when something's consumed orally when it takes one to two hours some time for the the effects to come on. And obviously I'm sure you know the, the old mistake of you know, taking a cannabis products orally and not feeling any effects for the first hour and then taking more and then all of it comes at once. That's a very bad experience.

Nick Jikomes 58:57

What about some of the other cannabinoids that are out there there are the so called minor cannabinoids, which are usually present at very low levels in the cannabis plant. Have you looked at all at how some of these other minor cannabinoids are affecting the body physiologically, whether or not they have psychoactive effects or whether or not they might also modulate the effects of THC.

Amir Englund 59:19

So we've only done a small pilot study with n volunteers with Delta nine tetrahydrocannabivarin THCV. At the time, I think we were the first researchers to study it for 40 years. And the previous study had given it to seven people, I think intravenously quite a high dose and found some minor intoxicating effects. We didn't really see anything and it was in a study where we gave participants daily doses for five days. And then on the fifth day They also had THC. THC V didn't produce any effects that the participants could notice, compared to placebo. And it really didn't do that much to any of the THC related effects either. However, in that study, we reduced the dose of THC to one milligrams, and we didn't really see any psychotic like effects and they were only mild cognitive impairments. THCV seemed to block the negative effect on delayed verbal recall. So the list of 12 words that you remember 1220 minutes later. But again, because it was such a small study and only 10 people, we can't really be sure if that's a real effect or not. I've heard from colleagues in America that they've run a study higher doses of thc v that it can produce some mild intoxicating effects. But this field of research is really really new. And there's very little we can say at this point.

Nick Jikomes 1:01:10

I see and so what do we know about its pharmacology so you mentioned you know, what we've mentioned so far as THC obviously activates the CB one receptor, that's where many of its psychoactive effects come from. CBD is this thing called a negative allosteric modulator of the CB one receptor and it's also promiscuous so it binds to other receptors. What do we know about something like thc v what what receptors in the brain? Is it touching?

Amir Englund 1:01:36

So there's still up for debate. But I think the before some of these studies and I think a lot of people are still saying that thc v is New neutral antagonist, so something that binds to the CB one receptor but without really activating it, so just sits there and kind of occupies that space potentially blocking THC effects but not like other compounds like inverse agonists, like the antagonist Ramallah bound, for instance, that bind to the receptor and reduce as baseline activity. Now, I don't know how much you know about rimonabant was an anti obesity drug was trialed, quite effective in reducing body weight but produced psychiatric side effects. So it was pulled from the market. So it doubled the risk of anxiety, depression and suicidality. So that's why the kind of interest for thc v grew, because you thought it was did a similar thing, but not as severely it didn't reduce the baseline activity of the receptor. And I think maybe the truth is somewhere in between that it's a negative, sorry, a neutral antagonist or a very weak partial agonist. So yeah, but again, we've had so few studies of these, you know, minor cannabinoids, that we really, that's, that's somewhere where I think there's going to be much more research done in the next coming years.

Nick Jikomes 1:03:25

I think it's actually worth explaining the amount about example for people. So the idea was, well, if THC gives you the munchies, and it makes animals eat more, and it's it's doing that by activating the CB one receptor, if we maybe find a drug that runs that receptor in the reverse direction, and decreases what's going on through that receptor. We can treat something like obesity. And what you're saying is, it did in fact have the effect on feeding that we would expect, but it had all of these other side effects that led to it being pulled from the market.

Amir Englund 1:03:57

Yeah, exactly. And I think what we what we gain from the whole rimonabant experience was how important the endocannabinoid system is to us. So you can't just like block off the endocannabinoid system as as you would with these drugs. Although, you know, people in these studies, they lost about five kilograms a year. And they showed improvements in their lipids and blood sugar. So it was it was good in that sense. But then it was bad in the psychiatric sense. And that kind of gives us a clue of the importance of the endocannabinoids to functioning mental state. And similarly, what's important to consider is that once someone starts using cannabis really frequently, what you get is a down regulation of the endocannabinoid system. So The body the brain will respond to all of this extra THC, all of this extra activity on the CB one receptor and adapt. So people use frequently they'll get fewer and fewer available CB one receptors. And heavy users compared to non users tend to have lower levels of circulating endocannabinoids. So because the body is noticing all of this extra cannabinoid activity, it's pulling back on its own. And that might be why we see a slight increased risk of depression and anxiety and psychotic, like disorders in really heavy long term cannabis use. So yeah, I think it gives us another angle, the whole Romana bounce experience.

Nick Jikomes 1:05:55

And, you know, when you think about cannabinoid based therapies, you know, obviously the big one that's out there is CBD, a high very high CBD formulation is what's now used for epilepsy. So that's the drug Epidiolex. And that's FDA approved and everything. Are you optimistic that we will see other cannabinoid based therapeutics make it to the level of FDA approval for other disease conditions? And if so, what do you think some of the top candidates are?

Amir Englund 1:06:26

Um, yeah, I do think that will will most likely get new cannabinoid therapeutics I think some candidates might be far inhibitors. So the these are compounds the block the enzyme that breaks down the Endocannabinoid anandamide. So taking these drugs means that you have less of this enzyme and then the body still retains more than no cannabinoids. Now, there might be some therapeutic potential there in terms of cannabis addiction, and cannabis addiction. I didn't mention that before. I think one of the reasons where we've got such poor outcomes in terms of people, you know, getting rid of their addiction is that we don't have any pharmacotherapies for it yet, unlike we have for some other drugs like opioids and tobacco like nicotine replacement. Those so far, I think that the best studies show that low dose THC can help with acute withdrawal, while people are trying to quit. Other areas of interest, again is within evictions. There's been one clinical trial from the UK that found that CBD seems to work in reducing how much cannabis people use while they're trying to quit. So that's, that's an area of interest. And then potentially one of the most hopeful areas is in the area of schizophrenia. So there's been three published trials to and kind of acute or let's say non chronic schizophrenia, though both of those studies showed positive results compared to either an existing anti psychotic or a placebo, where patients were taking the regular antipsychotics and then taking CBD or placebo on top. And both of those studies showed benefit and CBD on psychotic symptoms.

Nick Jikomes 1:08:34

And how much CBD are we talking in those days, so,

Amir Englund 1:08:37

so those studies gave one 800 milligrams and other 1000 milligrams a day. And one study was six weeks long, I was 1000 milligrams, and the other one was four weeks. Third study was in treatment resistant schizophrenia, so that's more chronic. And patients have tried many medications without significant symptom reduction. 600 milligrams for four weeks did not differentiate from placebo in that study. So that might be an area where CBD doesn't really work. So I think there are big trials planned. Here in the UK. I know big clinical trials are going to take place in the next coming years. So within five years, I think we'll know whether or not CBD could potentially be a treatment for schizophrenia.

Nick Jikomes 1:09:35

And what about these other minor cannabinoids, we talked a little bit about thc v. Is there much of anything going on in terms of studying them? Do you think we'll see more research happen there or is the focus going to be mostly on CBD and THC stuff?

Amir Englund 1:09:50

I think probably most research will be on THC and CBD. There has been some trials done that I've read On thc v, there was one where they compared thc v and CBD. And the combination of the two, and people with diabetes looking at various, you know, markers of diabetes of blood sugars and lipids and so on thc v seem to have some significant improvement, but CBD did not. And the interesting thing is that when you put the two together, CBD negated the positive effects of thc v. And that's something that, you know, you would have heard the entourage effect and, you know, whole plant versus single compound and of debates. Which, you know, fair enough, that could be something to, you know, the entourage effect. But we need to remember that these compounds can also compete with each other. So they don't always add benefit. They can also, you know, knock out the benefit of the other compound potentially, is pharmacologically, you always know, potential potentiation of effects by adding one compound to another. But there's also antagonists, you know, similar to remonter, balance and THC.

Nick Jikomes 1:11:26

Yeah, I think that's an important point. You don't hear that mentioned a lot that, yeah, there's always the possibility of some kind of synergy between two compounds, but they can also kind of block or subtract that what the other one's doing.

Amir Englund 1:11:37

Yeah, well, those two mechanisms are most likely equally plausible. Hmm.

Nick Jikomes 1:11:45

And so like you said, you were doing the, I think you said you were doing one of the schizophrenic schizophrenia studies with CBD. What else is on the horizon for you? What are you working on right now.

Amir Englund 1:11:57

So we're hoping to do a similar study in patients with cannabis addiction without any other psychiatric history. So again, trying to, you know, see if a big oral dose of CBD can be protective against the acute effects of THC or memory and, you know, psychopathology. We're quite interested in quite a new phenomenon that's recently been discussed looking at THC units, or standardized THC units. So similar to what we have with alcohol. So we have, well, different countries have different standard units or standard drinks. That's something that we've really been lacking in the cannabis field. So what I'm kind of interested in now and on the back of the last study where we saw the added, see, CBD did not make it less harmful. I want to kind of turn it around and go back on THC dose. But I want to scale back the dose of THC to see at what threshold, do we start seeing the psychotic effects? Or what threshold? Do we see the cognitive impairment? And what threshold? Do we see the positive effects and the intoxication? And then what dose? Can you tell no difference between placebo? So I want to find out, you know, where the sweet spot might lie, or someone who's a very infrequent cannabis user. And I think that will partly inform users, you know, that might not have any experience of cannabis, of if they want to start where they should start. So if I take this amount of THC, I know that most likely I won't have these scary psychotic like effects if I'm a sensitive person. So it'll give me a bit of an intoxication a bit of a pleasurable effects, but at least I won't get that negative effect. So that's something I don't think we fully yet understand, like a what dose of THC do we receive and start seeing these negative effects, then that will then also inform this debate about what a standard THC unit should be? So currently, it's been proposed to be five milligrams of THC, regardless of it being inhaled or taken orally. And I think we just want to provide more data for that discussion. Because that kind of approach I think, is really beneficial in the long term, because I think for public health perspective, being able to tell people Paul, but, you know, this many units of THC per year is related to this much risk of negative outcome and so on. So at least you're able to inform users how harmful their use is because the harms of most drugs do not appear all of a sudden, you know, alcohol is related typing eight or nine different types of cancers. And it does so at a very low level of exposure. But people don't really know that. So I think the cannabis it'd be really useful if we push more towards the standardized THC units.

Nick Jikomes 1:15:44

Well, Amir, you've shared a lot of interesting stuff with us. Is there anything you want to reiterate or any final thoughts you want to leave people with about the effects of THC or other cannabinoids? Generally?

Amir Englund 1:15:56

Um, yeah, so I think one thing, and I've heard from from colleagues that it's more of a controversy in the States than it is in Europe is the link between cannabis use and schizophrenia, like developing a psychotic disorder. And speaking about psychosis is sometimes tricky with the terminology because you can have an acute drug induced psychosis, you can get that for most drugs, having over consumed it over a period of time, where you have a brief psychotic episode, so you become psychotic. And it's not the type of psychotic experiences that we get in our lab, it's more of the ones where it persists for quite some time, usually for a couple of days, until the drug is left the system. And that's quite, that's quite an important risk factor as well. So if you've ever experienced the psychosis, while being intoxicated on cannabis, and that's been quite a bad psychosis that required treatment, studies have found that about a quarter of those people relate to develop a diagnosis of a psychotic illness. That's, that's, you know, very informative for those people, because then at least they know that, alright, I'm particularly vulnerable. So if I carry on using those, there's a risk that I might develop something more chronic. And then there's the the association between cannabis use and later development of schizophrenia. So this is based on epidemiology studies, where people have been followed up through health registries or in follow up studies and cross sectional studies, and found that cannabis users have a higher likelihood of developing a psychotic illness at some point in their lives. I think meta analyses have found that it's about a two to four fold increase risk. Now, to put this into context, if you have a sibling that has schizophrenia, your risk increases tenfold. If your mum has diabetes, when she's giving birth to you, you have an eight fold increase risk. If you live in a metropolitan area, your risk is doubled. If you are a migrant, and you have negative life experiences and trauma, the risk is tripled. Sometimes, even having a cat increases your risk of schizophrenia, because they think cats parry Toxoplasma gondii, which can lead to toxoplasmosis. And that's a risk factor for schizophrenia as well. So the way to think about cannabis and its relationship to schizophrenia is that it's one of a of many risk factors that interacts with the other risk factors to cause schizophrenia. So we don't, we don't have an explanation of why people develop schizophrenia, there's no cause that we causal mechanism that we can point to, we only have these risk factors. But we know that cannabis is one because it's been consistently found in study after study, that the relationship is there in spite of controlling for various other compounds. But that that's not to mean that it's, it's always in schizophrenia, it can just interact with the other risk factor. So I think the the pervasive state statement that's still circulating in the scientific literature is that cannabis use is a component cause that is neither sufficient nor necessary for the risk of schizophrenia. So if you have no other risk factor, then cannabis use is unlikely to ever lead to schizophrenia. And you don't have to ever have used cannabis to develop schizophrenia. So a lot of people who develop schizophrenia have never touched cannabis. So I think these aspects,

these nuances are important to think about when when we think about the relationship and the misuse in schizophrenia, like we'll probably never know if it's causing it or not. Or if it's an epi phenomenon that just happens to happen among people who develop schizophrenia and would have always develop schizophrenia. Um, one way that I like to think about it is similar to heart disease. So we don't know who's going to, you know, experience a heart attack, but we know risk factors, we know that if our parents had a heart attack, it's greater likelihood that we'll have it. We have poor diet, if you know, we don't do enough exercise, we drink a lot of alcohol and smoke tobacco increases our risk. So I guess the same thing applies for cannabis. You know, if, if you have a family history, if you've had a tough, you know, childhood, if you've experienced these negative psychotic, like experiences from using cannabis, it might be good to have an extra thing before engaging in cannabis use.

Nick Jikomes 1:21:39

Yeah, because, you know, this has been controversial for a long time, people often point to all the different studies out there that show the correlation between cannabis use, and the development of psychosis or schizophrenia. But then other people will say, Yeah, but there's all these other variables that correlate with both, there could be genetic factors that predispose you to schizophrenia and to, you know, enjoying cannabis consumption. I talked to one guy named Jonathan Shaffer, and he did this twin study where they looked at a bunch of twins identical and fraternal twins, so they had, you know, the, the genetic component to that data set. And they had enough of these twins that, you know, they had some reasonably high number of them where, you know, one would develop a psychotic, some form psychosis, one wouldn't one would have consumed cannabis, and one would not have. And they did not find that that association between cannabis and psychosis persisted after they controlled for all the other factors they looked at. Other studies have looked at these things, but I think in general, you're probably right. And it's not always the answer people want to hear, which is no cannabis is definitely not necessary to develop schizophrenia, because there's many examples of people who have it, despite never having consumed cannabis. It probably does have some relationship to the development of psychosis, probably in some individuals, at least with certain predispositions interacts with other variables. And it's just extremely difficult to tease apart and understand precisely what's going on there.

Amir Englund 1:23:09

Yeah, and there's some other findings is that the kind of nuanced this picture further, we know that people with schizophrenia who have used cannabis have an earlier onset of the illness compared to those who have not used it. So the illness kicks in sooner. We know that patients who have schizophrenia that use cannabis, they tend to have better cognition. We don't fully understand why it could be that there are a group of people that were already better cognitively. And because they're cognitively more adept that they can, you know, engage in purchasing cannabis, which, you know, for patients with schizophrenia might be tricky otherwise. We also know that patients who use cannabis have particularly bad outcomes of their illness. So they tend to have more frequent relapses and a worse prognosis of their illness. And they're also less compliance with their anti psychotic medication. And other risk factors like age of onset of cannabis use increases the psychosis risk. So if you started using cannabis earlier, the risk of developing psychotic illness is higher. So I think all of these different bits of information kind of help us to understand that, okay. Maybe it's only a risk for some people. But, you know, we know that the frequency the age that you begin to use, the strength of cannabis is also related the risk of, of psychosis so we could be cautious at least and say that me Maybe it's causing it. And if it is causing, well maybe we don't start using cannabis as early, we don't use it as frequently. We don't use as strong a product. And if you're particularly vulnerable because you're you have, you know, mental ill health and your family history, be a bit extra cautious if you've had psychotic experiences while taking cannabis be extra cautious. So we can use all of these little bits of information to making a bit healthier choices relating to cannabis.

Nick Jikomes 1:25:37

Yeah, one thing that's like a little bit unfortunate is how, you know, in the US, at least, where you've got many states now with legal cannabis, you know, the basic pattern that you see everywhere, is that the fixation in this comes from just looking at purchasing patterns, and then the potency of products over time and what people are choosing to spend their money on. You know, people are just sort of fixated on getting as much THC as they can for the dollars that they're spending. And it basically drives the producers to try and get more and more potent products, you know, whether it's getting plant material flour products with as high THC as possible, whether it's creating new concentrates, the general sort of vector that the industry has pointed on is creating higher and higher potency products in terms of THC content. And, you know, I think that's sort of unfortunate, because you do get some of these more negative side effects at the higher potency levels and the higher doses. And you know, I think many people would say that the experience can be very, very good and very lovely, at a reasonably low dose of THC.

Amir Englund 1:26:42

Yeah, and I think what, what's driving that is the same effect that's driving, you know, sales of other drugs like alcohol, and who that is particularly, you know, marketed to, for alcohol and for cannabis. Something called The Pareto principle applies the 8020. So the most of the cannabis in a given society, about 70 to 80%, I think varies between countries is consumed by a minority of cannabis users, the ones that are really heavy users that developed big tolerance. And because they've got a big tolerance, they need the strong products, the strong products, and they need going to be the most attractive ones to them, because of the tolerance that they've built up. So I think, and also, if, if the market is selling, specifically to those users, because there can, you know, that's, you know, where the most of the profits lie, because they're buying 80% of the product, then you're going to see this effect. Unless there there's some kind of regulation to step in to, you know, potentially tax cannabis by quantity of THC. Because correct me if I'm wrong, I think in the States, the tax on cannabis is by weight. Is that right?

Nick Jikomes 1:28:16

Yeah, it's either just, it's either by weight, or it's just, you know, a standard tax on any any product. But there's no, there's no progressive tax based on the potency or anything like that, as far as I'm aware right now.

Amir Englund 1:28:29

Yeah, I think from from alcohol research, they found that that does have an effect, particularly for the really heavy user. So we have an ongoing project and Scotland that's been going for a few years where they have minimum unit pricing. So for every unit of alcohol, the price goes up, leading to the really strong products, the really, you know, the products that contain a lot of units of alcohol become very expensive, but then that only influence impacts negatively the really heavy alcohol user, because if you're, if you just have a couple of beers at a weekend, that's not going to increase that much in price. But if you're consuming two bottles of whiskey a day, that's really gonna cost you way more. So I think in terms of regulation, that there's a lot to be done there.

Nick Jikomes 1:29:26

All right. Well, Dr. Amir, England, thank you for sharing your knowledge and hope to talk to you again at some point. Thanks for having me.


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