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Sud Patwardhan: Welcome all to the final day of the 10th GFN in Warsaw here in person for the plenary session to start and kick off the day. It's an honor for me to have two very distinguished doctors who have worked in the nicotine space for decades and have done some phenomenal research in the area. It's an honor for me to introduce the session on the role of Nicotinic Receptors and Brain Disorders. And Professor Paul Newhouse is here to talk about it. If I was to be asked one single line about Dr. Newhouse, it would be that he is the expert on nicotine and brain. And I would like all of us to sit through the next 45 minutes, 50 minutes, where Dr. Newhouse will be able to talk about exceptional work he's done over the decades in figuring out how and what happens with the nicotine receptors in the brain and what does that mean in terms of the role of nicotine separated from tobacco as it stands. And this perhaps is even more important as we have heard for the last three, four days, depending on when you arrived, tobacco harm reduction, how nicotine's misunderstood, and how over the decades, nicotine and tobacco have been conflated. But I think nicotine itself has its own identity. And it's important to understand that identity in a purely scientific, clinical context. So, Dr. Newhouse, please.

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Dr. Paul Newhouse: Thank you very much. It's a pleasure to be here. And I want to thank the organizers of the meeting for inviting me to review with you the potential for nicotine as a therapeutic for brain disorders. So I'm going to tell you a story about nicotine in the brain and nicotinic receptors and what does nicotine do and how do we understand how nicotine acts in the brain, what work we've done over the past several decades to try to unpack that, and to think about whether stimulating nicotine receptors in the brain could be used as a therapeutic strategy for different brain disorders. So the story really starts with these two gentlemen. This is the Nobel Prize for Physiology or Medicine was awarded in 1936 to Otto Levy. and to his friend Henry Dale. And Otto Levy established the chemical basis of neurotransmission using the famous experiment where he stimulated the vagus nerve of a frog heart, took the bath, and then poured it onto a second frog heart and saw the second heart slow down. And he concluded that there was something in the fluid that was released, and he didn't know what it was. He called it Vagashtoff. And it was his friend Henry Dale who identified this as the molecule acetylcholine, illustrated here. And this was the first chemical neurotransmitter identified. And they received the 1936 Nobel Prize for this. And this really launched our understanding of how nerve cells communicate with each other. So acetylcholine was the first neurotransmitter identified. Of course, it's not the last. But the brain cholinergic system is something that we have concentrated our efforts on understanding over the last several decades. We understand that the brain cholinergic system has numerous parts to it. Some of those are illustrated here on the left side of the slide with the green, red, and blue nuclei of the brain stem and prefrontal and basal forebrain areas. The ones that I'm most interested in today are going to be the green and red areas. And those supply most of the cholinergic innervation to the cortex of the brain in this sagittal section sort of halfway through the brain. You can see that those green fibers or projections go all through the cortex. And so almost all neurotransmission in the brain is influenced by cholinergic signaling. With high resolution MRI scanning, we can now see these nuclei actually on an MRI scan, which is illustrated in the upper right section of the brain in these coronal sections, which show you those colored, small colored nuclei, which represent the very tiny structures in the brain that supply all of these acetylcholine. And down here in the lower right-hand side, part of the slide, we can actually image those projections now using PET radio tracers. This is one of our scans from using a compound which is picked up by the cholinergic cells, and because we have an F18 tracer linked to it, we can now image those projections into the brain. And you can see in the red and green and yellow areas where the cholinergic innervation is the most intense. And that's where we're going to find nicotinic receptors, among others. So let's just drill down a little bit. After Henry Dale and Levy identified this transmitter system, it was quickly realized that there were two types of cholinergic receptors. One of them is a so-called muscarinic receptor, and we're not going to talk much about that today. But that's an equally important, maybe even more important, cholinergic signaling system in the brain. And it involves what are called G proteins, which is what is broadly termed metabotropic receptors. Nicotinic receptors, by contrast, are fast signaling ion channel receptors. They are more phylogenetically older than muscarinic receptors and they can transduce ions like sodium and calcium. These nicotinic receptors are found throughout the body, not just in the brain. They're found, of course, they're found in the ear, they're found in skeletal muscles, they're found in the spinal cord, and in many other places, and they seem to be involved in a variety of neuronal and physiological processes, most of which I'm not gonna have time to go over today. But nicotinic receptors exist in our skeletal muscles as well. Luckily, nicotine does not work very well at skeletal muscles. Otherwise, we would have seized up and died the first time we tried smoking tobacco. But luckily, nicotinic receptors don't work very well, or nicotine doesn't work very well at those nicotinic receptors. There's a variety of neurologic and psychiatric disorders that may be associated with abnormalities in nicotinic receptor structure, number, or function. I'm only going to touch on a few of those today. For example, there's a rare form of epilepsy, which has been genetically linked to a mutation in a nicotinic receptor. We'll touch a little bit on depression. We'll touch a little bit on Alzheimer's disease and Parkinson's disease and schizophrenia. So let's talk, let's drill down even further onto this nicotinic receptor. What does it look like? If you think of the receptor as barrel staves around an open pore, so you have these five subunits. If you're looking top down, you would see the five subunits with an open pore in the middle, and those barrel staves are comprised of a variety of different subunits. We call them alphas and betas. There are nine alpha subunits that have been described genetically. And there are at least three beta subunits that have been described. And those can form relatively customized assemblies. And each of those receptors has different properties. The most common ones that are in the brain are the alpha-4, beta-2. It has two alpha-4s and three beta-2s. And then the so-called alpha-7 receptor, which can form basically from a collection of only alpha units. Nicotine or acetylcholine binds in the joint between those barrel staves, as illustrated in these yellow markers. So you can see that nicotine or acetylcholine can bind in numerous places on this receptor and activate it. So the alpha-7 receptor is considered low affinity for nicotine. Nicotine doesn't bind as efficiently to it. It's predominantly presynaptic, in other words, before the synapse of the nerve cell. And it generates fast calcium currents. The alpha-4 or beta-2 subtype is a high affinity. It is pre- and post-synaptic, and it is considered the major excitatory nicotinic acetylcholine receptor in the mammalian brain. Interestingly, we won't have time to talk a lot about this, but it appears that nicotine can actually get into the cell and actually act as a kind of molecular chaperone to help bring nicotinic receptor complexes to the cell surface. Now, what do these nicotinic receptors do in the brain? Well, they don't necessarily transmit information per se. That's really the role of glutamatergic or glutamate receptors. But they act like amplifiers or modulators. They sit in various positions. You can see where the word nicotine is on this slide and pointing. with arrows pointing at the nicotinic receptors, and those act to modulate the actions of other receptor systems in the brain. So dopamine, glutamate, GABA, both excitatory and inhibitory systems are modulated by these nicotinic cholinergic receptors. And so you can see that what nicotine receptors do is they function as a sort of broad modulatory system on a variety of brain activities. Where do these sit? Well, they sit pretty much everywhere there are cholinergic fibers. In this illustration, you can see that the different subtypes of nicotinic receptors are listed here in the left side of the slide. on different pathways, neurochemical pathways, glutamate, GABA, dopamine, and acetylcholine itself. So actually, nicotinic receptors can modulate other cholinergic receptors onto muscarinic receptors. And you can now localize these receptors using various pet radio tracers. Here is an illustration from a group in Germany that's done some really exciting work with a new pet radio tracer, Flubitin. And you can see where those nicotinic receptors reside in the human cortex. So what do these cholinergic systems and nicotinic systems do for cognition? We know broadly speaking that cholinergic systems are involved in the top-down and bottom-up regulation of attentional processing. So your ability to listen to me is basically improved by frontal cortex frontal cortex systems which allow you to direct your attention to me or to the screen. And then if somebody calls your name out in the hallway, you will then turn your attention to that, and that's what we call bottom-up signaling. And so these cholinergic systems are very important for our regulation of attention and secondarily memory. If there's damage to those systems, then we see robust decline in those systems, in those abilities. So a number of years ago, my colleague Julie Dumas and I proposed a role for the cholinergic system in cognitive and brain aging and dementia. And we argued that as time goes on, we tend to have impairments in our ability to regulate attention. We lose resources. And the cholinergic system essentially attempts to compensate for that, which allows us to maintain normal cognitive performance as we age. But if that system becomes dysfunctional, such as in Alzheimer's disease, that cholinergic system can no longer compensate, and we now see obvious memory and attention problems. And without taking you through this story in its entirety, that has been the motivator for our attempt to understand the role of nicotinic systems in this process. Now, we started to do a series of studies beginning to try to understand what role cholinergic systems play in this. And this is a slide where we looked at individuals who have early memory complaints. and then compared those to individuals who did not complain about memory problems. And what we noticed is that the brain activity of people who notice a memory decline, even though they're performing normally, their brains are working harder. And so these orange blobs show you the areas of cortical activity that are increased compared to people who don't notice any memory problems. And this was one of the original motivators for us to say that the cholinergic system essentially attempts to compensate by essentially allowing greater activity in the brain than you would normally have to have. Now, in Alzheimer's disease, we see a failure of this system. The cholinergic system is one of the first things that's attacked by Alzheimer's disease. We're not entirely sure of the reason for that, but it is a very prominent finding. We believe that it's due to the invasion of the basal forebrain by the abnormal proteins that are present in Alzheimer's disease, amyloid and tau. And we notice that there is a decline in the volume of this cholinergic basal forebrain, as shown in the upper right. And that cholinergic denervation of the brain really tracks quite well with cognitive impairment, as shown by Nicholas Bonin. And then you can drill down on the neurochemistry of this and find that what happens to these cholinergic cells is they lose their trophic support. They lose the molecules that are necessary to maintain themselves. We even think that the Alzheimer's pathology may directly lead to nicotinic receptor dysfunction. and impairment. So as illustrated here by Dinley and colleagues, the beta amyloid, one of the two abnormal proteins in Alzheimer's disease can actually directly interact with nicotinic receptors, particularly the alpha 7. subtype and the alpha-4 beta-2 subtype and initially may overstimulate those receptors but then later actually block them and impair cholinergic function even further. Now, we identified many, many years ago that nicotinic systems might be important for human cognitive functioning. And the way we did this was to use drugs that actually block nicotinic receptors. And it turns out there's a drug that was available to do this. It's an old antihypertensive, but it actually acts to block the ion channel itself. And we use that drug to sort of create a temporary chemical lesion in the human brain. And this is from some of our studies in the early 1990s where we were able to show that the drug, which is called mecamylamine, impairs cognitive function to a degree even in normals, but can really impair it in Alzheimer's disease patients. So Alzheimer's disease patients are more sensitive to this drug than a match group of normals, suggesting that their nicotinic receptor function is impaired. And this was one of the first studies, maybe the first study, to actually show that blocking nicotinic receptor function in humans actually produces cognitive impairment. We later showed by using brain imaging, MRI functional brain imaging, that we could reproduce essentially an aging phenotype in normal individuals by using mecamylamine. And so when we block nicotinic receptor function in normals, What we do is, again, make the brain work harder. And we show something called the PASA effect, which has been described in normal aging, where the brain essentially moves processing forward to compensate for impairments in the more parietal and occipital areas of the brain. So as you and I age, we use more and more of our frontal cortex to process information, and essentially blocking nicotinic receptors reproduces that phenotype. We found that this works in different cognitive domains. It's not specific to one cognitive task. Here was the same effect seen in a working memory task. Working memory is what you do when you hold information online for a few seconds to a few minutes. And with nicotinic blockade with mecamylamine increases and shifts the cortical activity during this working memory task. And then we found that the same thing occurs with episodic memory. So mecamylamine increases activity in memory relevant areas for retrieved words. And so, again, this is reproducing that posterior-anterior shift in aging. Episodic memory is remembering what you had for breakfast this morning, what you did yesterday. It's remembering, essentially, biographical or historical information from the recent past. So blocking nicotinic receptors really does seem to impact brain activity, brain systems, and the actual performance. My colleague, Britta Hahn, showed in 2020 that blocking nicotinic receptors also impairs something called default mode deactivation. The default mode is what your brain does when you have nothing else to think about. So essentially, it's going into a kind of idle mode. And when you want to respond to something, you have to shift the brain activity out of that idle mode or default mode. And what blocking nicotinic receptors does is it actually impairs the ability to shift the activity from default mode to other modes of cortical activity. So this was the first time that we've seen that nicotine doesn't really change this shift, but Definitely mecamylamine, the nicotinic antagonist, blocks the ability to some extent of the brain to shift from default mode to other modes of thinking. Now, in general, what do we think that nicotine does? We've talked about blocking nicotine, but what about stimulating with nicotine? What we find, generally speaking, is that nicotine reduces brain activity in cortical areas that are important for a task. And what that means is that we believe that the interpretation of that is that nicotine essentially improves the efficiency of the brain. So cortical activity is energy demanding. It's tiring. And so if the brain is operating efficiently, we want the brain to use as few resources as it can to do a task. And what we find with patients with cognitive impairment, for example, is they're using much more of the brain to do the same task than a person who's not impaired. And what nicotine seems to do is reduce the activity in task-related areas. And that's a general finding across multiple studies. This is one, again, by Britta Hahn, which shows you that in the blue bars, nicotine decreases the signal quite significantly in all of these different regions compared to placebo. We showed that basically we tried to do the reciprocal, looking in the same task-related networks, and my colleague Julie Dumas has recently looked at 69 older adults, 60 older adults with the age of 60, and showed that stimulating nicotinic receptors with nicotine decreases activation, like I described before, and blocking the nicotinic receptors in those same individuals increases activation in the same network. So we have a nice reciprocal relationship between stimulating and blocking nicotinic receptor function. And these effects may differ by age. So, interestingly, this is very preliminary data, but in comparing young people to older adults, we find that nicotine in the older adults decreases activation, like we would expect, but in her hands, she actually found that it increased activation only in the posterior regions of the working memory network. Now, we haven't quite understood exactly the implications of that yet, of whether there's an age difference, but it might be important in understanding the role of nicotine in cognitive function. Now, in Alzheimer's disease, we lose these nicotinic receptors. And this is some of the earliest data on that from the 1980s, actually, from Peter Whitehouse and Ken Keller on the left side of the slide and on the right side of the slide from Elaine Perry and colleagues in Britain. And basically showing that nicotinic receptors are lost with Alzheimer's disease. This was an independent way of confirming this by looking at autopsy data. So this is actual brain autopsy data showing that nicotinic receptors disappear essentially with age and with dementia. And more recently, brain imaging has been able to verify this in living people. Again, this is work by Sabri and colleagues using flubitin pet radio tracers showing that healthy control has much greater signaling in the brain and binding for nicotinic receptors than a patient with Alzheimer's disease. And there's a positive correlation between the Loss of those nicotinic receptors and different cognitive domains like memory or executive function or attention. Then we started to try to experiment with nicotine itself as a therapeutic strategy and going back to the 1980s we didn't have patches or gum or any other nicotine replacement product so we actually made our own nicotine infusion and we gave it by intravenous injection. Not a very easy way to administer it. And we found in a very early study in a few patients with Alzheimer's disease that there was a very, there was a sort of a sweet spot with the dose that we could find that improved error, reduced errors and improved long-term recall with a single dose of nicotine. We then actually studied one of the first novel nicotinic agonists, ABT418, that was an alpha-4 beta-2 selective agonist and found pretty much the same thing, that there was a dose-related improvement with a single dose of this nicotinic-like drug. And we began to think about whether chronic nicotine would have benefits for patients with Alzheimer's disease. The reason for this is shown here by Julie Miwa, who showed that in smokers, they actually upregulate the number of nicotinic receptors in the brain. So smoking actually leads to more nicotinic receptors than a non-smoker has. The reasons for that are complex and I don't have time to go into all of them today. Suffice to say that what we think happens is that nicotine again chaperones those receptor complexes to the cell surface. So we started a pilot trial in the early 2000s to give transdermal nicotine to patients with mild cognitive impairment. This was done in 74 non-smoking patients with early memory loss, or what we call MCI, which is the same as prodromal Alzheimer's disease. And we gave it for six months of treatment, placebo controlled. This is a very simple study design, basically placebo or nicotine for six months. We had a greater number of males than females, but the average age was about 75. And what we found was that it did seem to produce some improvement in cognitive function. So we saw an improvement in attention as shown on the left side of the slide. In this slide, down is good and up is bad. And on the right side of the slide are the effects on memory in paragraph recall and delayed word recall. and showing that the nicotine treated group in the solid line showed a significant and sustained improvement over six months in these parameters. And so this was very promising results. We were quite pleased to see this. It was safe. We had no significant adverse effects. that led to discontinuation. We found that it reduced weight a few pounds. Basically, people lose about two kilograms on transdermal nicotine, and there were no significant cardiovascular effects as well. So it was well tolerated. The adverse event rate was similar. And so we basically then went on to a much larger study, which is called the MIND Study for Memory Improvement with Nicotine Dosing. This study is still running. You can check out our website at mindstudy.org. This is a much larger trial of 300 to 380 individuals who are being treated with transdermal nicotine for up to two years now. And we're going to see if we can reproduce the initial pilot data and also see if we can get sustained long-term benefit with transdermal nicotine. This time, however, we're trying to drill down on Alzheimer's disease biomarkers in these individuals. We will have MRI scanning of a subset of these individuals, spinal fluid, measurement of Alzheimer's disease biomarkers. And we should be able to actually answer questions related to metabolism, metabolic genes, and nicotinic genes as well. So I'll skip over this just in the interest of time, but these measurements of treatment effects are much broader in this study than in the pilot study. So we have 42 sites around the United States that are enrolling patients in this study, and so it's a very broad-based, nationwide study. So let me then turn, so we should have answers in the next year or two about whether transdermal nicotine in a sustained method is helpful for patient's memory and cognitive difficulties. And that can be combined with other Alzheimer's disease treatments that are now coming. to fruition as well, and we can talk about those in the discussion. But let me touch on a few other conditions that we're also looking into nicotinic treatment for, and one of these is late-life depression. My colleague Warren Taylor has really focused on this and is now running a very exciting trial in late-life depression. Nicotinic receptors have long been thought to be involved in mood regulation, and we wanted to test whether stimulating nicotinic function could actually augment the benefits of antidepressants in individuals, especially in late life, who may have cognitive impairment as well. And so Warren hypothesized that improvements in what's called the cognitive control network in the brain may be responsible for beneficial effects of nicotine. In a pilot study we published about four years ago, an open label pilot study, this was not placebo controlled, we saw a dramatic and significant reduction in depression scores in patients for whom nicotine was added to their antidepressant regimen. So these are individuals that were not well treated by their current antidepressants. Nicotine was added and there was a dramatic reduction in their depression scores. There was a reduced bias for negative cognitive information. And so this was very promising and we went back to the NIH to get funding to do a much larger, more mechanistic and confirmatory trial, which is now running called Depressed Mind. And in the preliminary data from the first phase of that trial, we are able to confirm that the antidepressant effect is there. We see it again with a reduction in depression scores. And this time we've been able to look at brain circuit changes and we've shown that there is a relationship between nicotine blood level, nicotine metabolites, and the change in activity in cortical circuits. And so Warren and colleagues were able to see this change. And this is one of the first pharmacodynamic studies that's ever been done with nicotine. So we're very excited about this process. This is being confirmed now in a double blind phase of this trial. And we hope to have information actually tying the effect of nicotine on mood to the change in these cortical control systems. So stay tuned for that. Very exciting work. There's some interesting other work that my colleague Alan Lewis has done looking at the effects of nicotine as a serenic, essentially using it to modulate aggressive behavior. He started this in looking at a rodent model in mice showing that nicotine and nicotinic agonists actually reduce aggression in mice and showing that if you block nicotinic receptors, you lose that ability. And he then did a pilot study in autism patients who were particularly aggressive and showed that there was improvements in irritability and aggression behavior in patients with autism spectrum disorder. And so this is now hopefully being looked at further as another avenue that nicotine may actually act in individuals who have hyper aggressive behavior to reduce that aggression. Some colleagues of mine at the University of California at Irvine and in Berkeley are actually looking now at the ability of nicotine to improve hearing. So it turns out that nicotinic receptors are very active in primary auditory cortex in the brain. And they are involved in modulating our ability to hear different frequencies, different amplitudes, et cetera. And so these folks at UC Irvine and UC Berkeley are now actively looking at changes in hearing physiology in aged individuals. And so what they're finding is that nicotine in older people only improves the ability to distinguish frequencies and frequency modulation. And this is some of their pilot data that they produced back in 2021 showing that nicotine essentially only improves performance in those who are impaired, which is a theme that I'm going to come back to at the end, and they are now testing this to again show in the brain where does this effect occur, where in primary auditory cortex is this effect seen. So that's exciting as well. We've done a pilot study looking at nicotine's ability to improve cognitive function in older adults with Down syndrome. Down syndrome individuals are very at risk of developing Alzheimer's disease because they overexpress the amyloid beta peptide due to the extra chromosome that they have. And so we've begun to explore in these individuals what what the integrity of the cholinergic system looks like, and whether nicotine or nicotinic stimulation would improve their cognitive ability. And in this pilot study, just a small N of five individuals, we were able to show that nicotine essentially improves the ability of the brain to recognize that it's seen something before. And we used electrophysiology. These are cortical evoked potentials to show that nicotine essentially reverses the aging effect in Down syndrome. So that's exciting as well. And we will be continuing that work. And then Alex Conley in my lab and Alan Lewis also looked at acute effects of nicotine in schizophrenia, looking at the ability to improve attention in an emotional go-no-go task, where essentially there's a conflict between the emotion and the signal that you're asked to respond to, and showed, interestingly, that that the patients improve, but not the normals. So, again, this is a recurring theme here, that if you're functioning normally, nicotine doesn't do much for your cognitive function. But if you're not functioning normally, nicotine may be helpful. Now Parkinson's disease has been talked about. We did a study in Parkinson's disease about 30 years ago and found some acute benefits of nicotine. There's been a lot of controversy on this over the years. Some recent data has shown that there is a reduced risk of Parkinson's disease by smoking status. This was a study of 30,000 British physicians, followed for up to 65 years, showing that smoking is protective, although the reasons for this are somewhat obscure. There have been some negative studies of nicotine in Parkinson's disease, but this one study that was done in 2019 did show improvements in freezing of gait and falls, which are two major problems in Parkinson's disease. And the last slide I have then about data is, could nicotine be actually helpful in long COVID? And so a number of us have begun to think about ways we could improve cognitive function in patients who have brain fog or cognitive difficulties following COVID infection. And although this work hasn't started yet, we've proposed to the NIH to essentially combine brain training, computerized brain training with nicotine as essentially an augmentation strategy to improve cognitive function in patients with long COVID. And so whether that work gets, we hope to get that work started in the next six months or so, but there's good reason to think that nicotine may also augment brain plasticity, which can then be taken advantage of by cognitive training or cognitive rehabilitation strategies as well. All right. So in the interest of time, I'm just going to then leave you with a couple of points, which is this. That nicotine effects on cognitive performance depend on your baseline. So and it depends on the difficulty of what you're being asked to do. If your performance is high at the top of this upside down U shaped curve, and stimulating nicotine, nicotinic receptors will not improve it further because you're functioning near the top of the curve. It will only impair performance actually. But if you're doing a difficult task and you're not functioning at the top, then stimulating with nicotinic receptor stimulation with nicotine will actually improve performance. And so the relationship of task difficulty and baseline is very important to understand nicotine effects. So in other words, individuals who are functioning very well are not likely to benefit further by nicotine. But people who are not functioning to their optimum will see a performance enhancement with nicotinic stimulation. And the question that we're always asked to deal with is what's the effect size? Is the effect big enough to warrant treatment with a nicotinic drug? And that remains uncertain for many conditions. And then what is the adverse side effect risk? In these two hypothetical curves on the right side of the slide, you can see that the red line would be adverse side effects and the green line would be this improvement curve. And what you don't want to do is get past the intersection of those two lines. Essentially, you want to always look at the tradeoff between the risks or the adverse effects and the benefits of any cognitive enhancing drug. So in summary then, nicotinic receptor modulation or stimulation appears to be important for maintaining attentional function and memory efficiency. We're investigating a number of different disorders including mild cognitive impairment, early Alzheimer's disease, late life depression and others. There's a potential to explore synergism of nicotine with other approaches to treating cognitive consequences of different disorders like SARS-CoV-2 infection or other disorders that involve attention executive function and memory. The degree to which nicotine is beneficial, which is that effect size conundrum, and the appropriate dosing still remain to be established. And so with that, I will turn this back over to our chair.

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Sud Patwardhan: Thank you so much, Paul. That's a breathtaking presentation in terms of the anatomy and physiology and the pharmacology of nicotine even, and the studies you mentioned that you've been doing over decades. It'll be great for us to have some discussion about that later in the session, but I would like to hear from Dr. Konstantinos Vassilinos, given his work in the area of tobacco harm reduction, but also what struck me was one of the last slides you presented regarding COVID and some of the connections that were being drawn then regarding nicotine and the role of nicotine in a sort of post-COVID world. Maybe, Konstantinos, in your response to Dr. Newhouse's presentation, you can start with that and also anything else you want to comment on, please.

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Konstantinos Farsalinos: Well, first of all, I want to thank Professor Newhouse. It was an excellent presentation that didn't cover the whole story of nicotinic receptors. He mainly talked about the functional part of the brain, but there is also an immunomodulatory effect of alpha-7, mostly, nicotinic receptors, not only in the brain, but throughout the body, through the nicotinic, the whole energetic anti-inflammatory pathway, but also in the brain. Many of the brain diseases are basically inflammatory diseases. So there is a whole different chapter with nicotinic receptors. It's exciting. Nicotinic receptors are present throughout our body. They are also present in the lung. And that's why we did the studies looking at what's happening with smoking and COVID. I saw you presented one of my hypotheses there about the interaction between the alpha-7 nicotinic receptors and COVID. Now, when you talked about late-life depression, That reminded me of a joke that I was hearing several years ago that people shouldn't smoke until the age of 75. And after the age of 75, it wouldn't be a really bad idea to start smoking. Of course, we're not suggesting anyone to smoke. But that was a reference to the late life depression and how probably nicotine may affect it. Now, you know, what is... What is interesting is that the mode of nicotine intake from smoking is very different. from the mode of nicotine intake when we try a pharmacological intervention. So what happens with smoking, and everyone I suppose knows that, is that we have peaks and troughs, we have spikes of very high nicotine and very rapid increase in nicotine concentration that acts on the brain. Then over time, nicotine levels go down. Then it goes up again whenever you smoke. This is something that cannot be replicated when you deliver nicotine either intravenously, of course, that can be done only acutely, but mainly through transdermal patches because that's the main mode of delivering nicotine in interventional studies. And we know that there is the issue of desensitization of receptors everywhere concerning nicotine. So when you give a lot of nicotine, nicotine is present in a steady state, then the receptors get desensitized. There is some form of a tolerance. Now, interestingly in medicine, we always try to maintain a steady state concentration for all medications we give to patients, but that probably is not the case with nicotine. And that's why it's been quite tough to reproduce the effects of smoking on Parkinson's disease that you mentioned. And the British doctor study was a huge study of 65 years of follow-up with 30% reduced risk of developing Parkinson's disease among smokers. and the benefit was winning off with more years of quitting smoking. Of course, as you understand, we cannot suggest smoking as a therapeutic or a prophylactic intervention, but it gives new insights. Now, I'm not sure if the way of delivering the nicotine through patches, which result in steady-state concentrations over time, is the ideal way of doing that. In some cases, I remember my friend who did a study in late 90s in Parkinson's disease. They had to administer very high doses of nicotine in order to see an effect in Parkinson's disease patients. If I remember well, up to 72 milligrams per day. which was quite well tolerated if you gradually increase the dose, but still it's quite high, much higher than what we suggest for smokers. Anyway, it's a really exciting field, which is still at the beginning, I must say, in terms of the potential therapeutic applications. But imagine what's going to happen if an effect is observed, for example, in Alzheimer's disease, and what the effect is going to be in society, because, you know, people are terrified of Alzheimer's disease and dementia, because, of course, it's a disease that largely affects human dignity, and it's really torturing for the patients. So imagine how the perception about nicotine is going to change if an effect on Alzheimer's disease would be found, especially for primary prevention, which is much more important than secondary prevention. Now concerning COVID, we started with the observations In smokers, we were seeing a very small proportion of patients hospitalized with COVID in China being smokers. And knowing that China has a large smoking rate, a very high smoking rate, 50% of men still smoke there. That was unexpected and that is what started our work. I had to look quite hard into the literature to try to create a link between the whole energetic anti-inflammatory pathway and COVID, the graph that you showed in one of your slides. We didn't have the funding to proceed forward. I'm really glad that you're looking to perform a study for post-COVID because it might work and it's mainly brain disorder that is affecting a lot of people with brain fog. The prospects are there, but there are problems. The main problems are that people don't like doing research with nicotine. There have been a lot of hurdles in scientists who have been working with nicotine for mainly neurological problems. There is a lot of prejudice against nicotine. And I'd like to ask Professor Neuhaus if he has seen such prejudice from his colleagues or when he has applied for funding for studies involving nicotine.

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Dr. Paul Newhouse: Well, I guess the short answer is yes, but, right? So we try to make a very evidence-based argument for stimulating with nicotine. And as you may know, I'm sure you know, Constantine, that there was a lot of pharmaceutical interest in nicotinic receptors beginning in the 1990s into the 2000s. And there was an attempt to develop a whole series of subtype selective receptor agonists, all of which failed. And they failed in a way probably because they were too selective. In fact, and nicotine may be a better drug because it activates a multiple subtypes of receptors. And so I think I've been able to make the argument with data that this is worth looking into. You know, I think we do run into challenges when we recruit patients for these studies. But after we explain it carefully, we usually can get around that.

00:52:10 --> 00:54:25

Konstantinos Farsalinos: I'm really glad because when we try to publish our data on smoking and COVID and we only discussed about nicotine replacement therapies, we never mentioned the word tobacco harm reduction. And of course, we never replied that smoking should be used for COVID. we had a lot of disagreement from journal editors who had nothing to do with tobacco and smoking research. There was a lot of resistance in just our words suggesting that nicotine might have a chance and should be tested clinically. I remind you that there were several anti-inflammatory agents that were tested that were supposed to be a contraindication in the case of infections, like interleukin receptor blockers and antibodies. But there was a lot of reluctance, you know, when we suggested that nicotine in the form of replacement therapies, that was the only thing we mentioned, we never, I mean, mentioned harm reduction products or anything commercial. We only discussed about pharmaceutical nicotine. At least at the beginning, there was a lot of reluctance. But then after that, I mean, in the last, in 2021, there are more than 15 studies from throughout the world, from Korea to the US, to the UK, everywhere, showing that there is something happening with smoking. We don't know if it's nicotine or not, but there is something happening with smoking and COVID. A large UK study with more than eight million participants, they found that heavy smokers have an 88% lower chance of being admitted to an ICU for COVID. The same in a study in California, I think two million participants. Studies in Israel, studies in France have found the same. We don't know if it's nicotine. We hope it's nicotine because if it's not nicotine, then you can't do anything because you cannot suggest smoking as a therapeutic intervention for COVID or for anything else.

00:54:25 --> 00:55:51

Sud Patwardhan: Yeah, I think that's a great one to kind of maybe perhaps zoom back into. I think COVID and the findings from the COVID times, and I'm so glad, Paul, that you are looking into that as a potential, the long COVID aspect of your research may hopefully shed some light on this. And I'm hoping that gives us clarity on the potential role of nicotine in any of these things. I wanted to pick on something that Konstantinos said earlier, and then I want to open this up for the audience to ask questions. I'm sure there will be a lot of things that they want to ask about your studies in this area and so on. But taking the advantage of being a chair, I have a chance to ask you one question. And that is the point you mentioned, Konstantinos, about How in your studies, the mind study or the depressed mind study, transdermal patches are being used and that's a steady dosage of nicotine, 7 to 21 milligrams you've said there. Of course, consumers who use, so in the British study, for example, they were smokers, and they're using it as per need, I guess. Would there be any difference, as per your understanding of how nicotine works in the dosage and the peaks and troughs of nicotine in the blood, and hence the brain, that may have a role to play in terms of not just the nicotine's role on the receptors, but also potentially the reward aspect of smoking and the lack of nicotine and hence the dopaminergic system taking over. So is there anything there that may be causing that to be a bit more effective than just plain transdermal delivery? Does that make sense?

00:55:51 --> 00:58:19

Dr. Paul Newhouse: Well, I can address part of that question, right? So one of the major issues in any type of CNS drug development is how much time does the drug need to be on the target? Do you need to have a drug on a target all the time? Some of the time? Exactly what do we need? Because we're always trying to reproduce normal physiology, right? And normal physiology does not necessarily represent constant stimulation or what we call flogging receptors, right? So, we really still don't know very well, with nicotine, how to do this. How much time do we need on the target? Now, I didn't get into the details of this, but in the MIND study, we actually have the patient take the patch off when they go to bed. And so they are not wearing a patch at night because, and this is actually for a very practical reason, which is that we think that nicotine can disrupt sleep a little bit in elderly patients. And so we actually have them remove the patch after 18 hours. Because we don't want, we just anecdotally have noticed that patients will complain of sleep difficulty if they have the patch on through the night. This is a 24-hour patch that we have to use. The other difference is that we really don't know what the right dose is yet. Still, it's odd to say this. The data that Warren Taylor in my center is developing suggests that we actually may need to give less nicotine actually than we have been, that actually less may be more in this situation, that actually there does seem to be this upside down U-shaped function And if we push the dose to 21 milligrams, we actually get worse improvement, not as good improvement, as if we back off. And so it may well be that, as Henry Lester suggested to me 10 years ago, he said, Paul, you're giving way too much nicotine. And I said, Henry, you might be right, but I need to know how to decide that. I need data. And so I think we're beginning to see that now. that in this case, less may be more. So we're still trying to work out time on target and appropriate dosing.

00:58:19 --> 00:58:37

Sud Patwardhan: Thank you so much for that. I think that's the reason I was asking that was, of course, there are products now which deliver nicotine not with the accompanying smoke and hence wondering if the transdermal patch and just wondering in terms of compliance, of course, these are part of a study. So they are pretty good at compliance, you reckon?

00:58:38 --> 00:59:16

Dr. Paul Newhouse: Well, so yeah, when I was I was talking about this with I think with Helen the other day, which is that, you know, you use a patch because it's easy. Right. It's compliance is easy to monitor. Dosing is easy. You don't have to fuss with a administration system like a vaping device where it has to be used repeatedly or something oral in the gum or in the mouth. So patch is very appealing. especially for cognitively impaired patients. That makes sense.

00:59:16 --> 00:59:27

Sud Patwardhan: I'm going to just look at the audience, and I'm hoping that there are quite a lot of questions. So, gosh, who started first? May I start with Caroline, then Clive, then Andy, and then the gentleman, please?

00:59:27 --> 01:00:02

Carolyn Beaumont: Thank you. Thank you, Carolyn Beaumont, General Practitioner, Australia. Just regarding the PASA-type normal age-related cognitive decline, So we hear of other things, non-nicotine things that can help, such as doing crosswords, learning a new language, an instrument, an exercise. Do you have any thoughts on what sort of activities specifically will help improve nicotine receptor upregulation? So activities which could be really beneficial in helping then maybe with lower dose nicotine for cognitive decline.

01:00:03 --> 01:00:13

Dr. Paul Newhouse: So let me be clear here, are you asking how we could show that other activities. interact with nicotinic receptor systems.

01:00:13 --> 01:00:17

Carolyn Beaumont: Yes, that's right. To help maybe augment nicotine therapy.

01:00:17 --> 01:01:09

Dr. Paul Newhouse: Wow. If we can get funding to do that, Carolyn, I'll do that study with you, because that would be a challenge. I mean, I think it's an interesting question, is can we augment cholinergic functioning through non-cholinergic means? I think that's a very interesting question. The most practical way to do that would be to use PET radio tracers, either more general PET radio tracers like FeOBV that we're doing. We are in the early stages of trying to draw relationships between the anatomy of the basal forebrain and these cholinergic projections. and other factors that influence cognitive aging. So stay tuned.

01:01:09 --> 01:01:28

Carolyn Beaumont: Can I sneak in one extra question? Are there other transdermal ways of administering nicotine except for patches? And I'm thinking specifically of gels similar to maybe testosterone gel therapy, because the rashes associated with patches could be quite a deterrent for people.

01:01:28 --> 01:01:32

Dr. Paul Newhouse: I'm not familiar with that, I'm afraid, Carolyn.

01:01:32 --> 01:01:33

Carolyn Beaumont: We have some studies to do.

01:01:34 --> 01:01:43

Sud Patwardhan: Thank you so much, Caroline. Clive? Thanks, Sid.

01:01:43 --> 01:03:13

Clive Bates: Hi, Clive Bates. Two questions, really. First, is there, like, a review article of all of this stuff? And if there isn't, it would be brilliant if there was. And then secondly, because we're lazy, secondly, though, there's people already using nicotine, smokers, vapors, snus users, and what have you. And this knowledge that's amassing here can't be unknown and can't be forgotten or ignored. What should people be told about this stuff? What should they be advised? I mean, I'm just remembering back to the early stages of the COVID epidemic and the first results were coming in that smoking appeared to be protective in some ways. And it always seemed to be that whatever's the question, the answer is quit smoking. I remember saying to people in the UK smoking cessation community, hang on a minute here. You may be advising people to remove something that's protective. And it seems to me that, you know, in the sort of late life depression here, if there's people smoking or using nicotine, even if they've never been told to do that or advised to do it, it may just be working for them in some way, or people who are medicating themselves who have Parkinson's disease and just find that this works. Now we can't unknow those findings, so what should we say to people about these?

01:03:15 --> 01:05:24

Dr. Paul Newhouse: So my thought was, the first part of your question, is there a review on this? Not exactly, but maybe I can get my post-doc to start working on one. But what should we tell people? Well, I think one has to be a little bit cautious here, because the action of a drug or a substance as a preventative strategy is different from that as a therapeutic strategy. So we know, for example, that women who take estradiol right after menopause have a reduced risk of developing dementia later. But when you now turn around and use estradiol as a preventative treatment in those older women, it doesn't work. One has to be cautious about saying, well, because something's associated with reduced risk of X, that means that using it therapeutically will help. Those are two separate questions. The physiology is different. And you have to test those independently. And so I think what we tell people is that we're still trying to unpack what the role of nicotine is therapeutically, which may be quite different from its ability to prevent something. So, for example, the Parkinson's disease is a good example. Smoking seems to be, I mean, there's very rigorous studies now that show that smoking is associated with a lower risk of Parkinson's disease. But most of the therapeutic studies have not succeeded for one reason or another. Now, you know, you and I can look at those studies and say, well, they didn't look at the right thing or they didn't look at the right dose, but it's not a simple metric. And so I think, and I was talking to Helen about this yesterday, we have to be comfortable with complexity.

01:05:24 --> 01:06:02

Clive Bates: A quick follow-up, because we do give people very unequivocal advice about quitting smoking and often quitting nicotine. You know, it's not like there's any doubt in the message that comes about smoking cessation, vaping cessation, nicotine's all bad. So, whilst there is complexity on this sort of therapeutic side, there's no complexity or nuance in the messages about what behavior to follow, even if that behavior, without you ever intending it, or even knowing it, is therapeutic and beneficial, as with the depression case.

01:06:03 --> 01:06:13

Sud Patwardhan: Andy, can we get the mic there to Andy? Before it goes to Andy, just, if there are any online questions, I can't see them on this iPad, so can somebody come and just help out with the iPad if it's?

01:06:13 --> 01:06:58

Andrew Manson: Hi, Andrew Manson. Looking back in the days when indoor smoking was allowed, those sports that required high mental focus, such as poker players, darts players, snooker players, they pretty much all smoked. And in the modern world, the use of snooze amongst sporting athletes, footballers, hockey players, is reportedly on the increase. Is there evidence that in healthy brains, nicotine can help people doing very complex tasks to focus on the task and to perform better?

01:06:58 --> 01:08:15

Dr. Paul Newhouse: This is not my area of focus, but I believe the clearest answer would be that in relation to task difficulty, that nicotinic stimulation will be beneficial. So the more performance is lower at baseline, nicotine can bring it up. And that was that slide, right, the second or third from the end, which says that as a task is difficult, you will see beneficial effects of nicotine. If a task is easy, you will see actual impairment. So it depends on the task. I suspect that your observation is a good one, right, that sports, that things that require significant concentration or sustained attention, right, do benefit from nicotinic stimulation. And that was shown even, you know, 30 years ago by Keith, by the late Keith Wesness when he did his PhD with David Warburton. He showed that nicotine seemed to improve the performance of high attentionally demanding boring tasks that required maintaining intentional focus. So yes, I think there is evidence for that.

01:08:15 --> 01:09:40

Konstantinos Farsalinos: Yeah, but I think that you need to be a bit cautious because if someone is a smoker and then he engages into a complex activity or an activity that needs a lot of attention, then smoking abstinence during this activity is going to deteriorate his function. So they were smoking during playing poker or doing any other activities that required attention because they have been smokers and getting deprived of smoking when you are dependent on that. and you perform a complex activity, this will result in a decline in your performance. And something about what Clive said before, I just wanted to make a very short comment. There's a big difference between primary prevention studies using nicotine usually to show benefits, for example, in Parkinson's disease, and interventional studies administering nicotine through patches. And the big difference is the way that nicotine is delivered and absorbed by the subject. In one stage, we have steady state concentrations in secondary prevention trials when we do it therapeutically. In primary prevention, when we look at smokers, smokers obtain nicotine through a very, very different way. And we're not sure if this plays a role or not in any different effects.

01:09:41 --> 01:09:57

Sud Patwardhan: I think that seems to be the recurrent theme here, that what is done in terms of delivery in a medical, clinical setting versus consumer behavior. John, there's a question here from John, please. And then there's one from Eliza later.

01:09:57 --> 01:11:22

John Summers: Hi, John Summers from the UK. Firstly, I wanted to say thank you. Thank you for your bravery in taking this subject on. The reason I say bravery is my father developed very rapid onset Parkinson's, very rapid degradation Parkinson's in 2015. In February 2015, I took a number of studies to his medics and said, look, you know, he's developing symptoms which I believe may correlate with the studies that were published in the Japanese Journal of Internal Medicine. I had no reply from them. I went and actually visited them physically. And I was threatened with being banned from the hospital and seeing my father. Six weeks later, he died. So how, this is now leading to my question, how do you see us overcoming the militaristic, I mean, in these cases, they hadn't even read the studies. They just saw the fact that I mentioned the word nicotine. and I was threatened with being physically banned from the hospital. How do we overcome this militaristic, you know, absolute bias against any form of nicotine intervention in illness?

01:11:22 --> 01:11:27

Sud Patwardhan: Quick answers, maybe?

01:11:27 --> 01:12:25

Dr. Paul Newhouse: I think the best answer is data, right? So if you have data, that shows a beneficial effect with reasonable tolerance and safety, then I think physicians will listen. I do agree there's a lot of bias out there, but my impression is that you can overcome skepticism and bias with data. And once that data is real enough, I think people will start to listen. There will always be people, physicians, medical professionals, who say nicotine is an addictive substance. Well, as somebody said yesterday, so is morphine, but we still use it, right? And actually, nicotine probably isn't, by itself, very addictive at all. But I think you overcome it with data.

01:12:26 --> 01:13:42

Konstantinos Farsalinos: Thank you so much. It's not only just one sentence. The misinformation is not only related to limited evidence on the efficacy of nicotine in such conditions. The even bigger problem is that most of physicians consider that giving nicotine to an elderly person is a very risky thing to do. Although all studies especially for neurological disorders, which involved delivering nicotine even at high doses in people who have never smoked. They were elderly with cardiovascular disease, with other risk factors. Nicotine was very well tolerated, if given, of course, in a careful way, not with a maximum dose from day one. But... Most physicians think that it's very risky to provide nicotine to an elderly person with other conditions, particularly with cardiovascular disease. Although all the studies are showing that it's very well tolerated. If there are any side effects, it's usually sometimes of arrhythmias, which are not even causing any real issues. So there are a lot of hurdles and a lot of misperceptions that need to be removed from the mind of physicians throughout the world.

01:13:43 --> 01:13:57

Sud Patwardhan: Thank you so much, Konstantinos. Now, I'm conscious there are two questions that have come online, which I can now see. There's a question from Eliza. So may I request Eliza, keep it very short, brief, if you don't mind. And let's not answer it before I've had a chance to ask both questions from here as well, Paul and Konstantinos. Please.

01:13:58 --> 01:14:22

Eliza Hunt: Certainly. Hi, I'm Eliza. So my question is for all the doctors on stage. In terms of the evidence based on post-intervention effects of nicotinic receptor stimulation, or are those effects really limited to the continuous stimuli that are being introduced? And I guess specifically to Dr. Newhouse, how will you be registering that following the medical tapering in your own mind study?

01:14:22 --> 01:14:52

Sud Patwardhan: Thanks for that. The question on Len I have here, which is, rather interesting is Dr. Newhouse, in your research on the therapeutic potential of nicotine, have you explored the possibility that the administration of nicotine in conjunction with the harmful chemicals present in tobacco smoke via combustion mechanism may have unique or synergistic effects on cognitive function or neuroprotection? It's rather edgy, I think, but it's worth potentially answering or not, it's your call.

01:14:54 --> 01:15:10

Dr. Paul Newhouse: So I'm not sure I fully really understand your question. So what you're asking is do I am I looking at prolonged effects of nicotine after the we've stopped the administration. Is that what you're asking. I'm a little bit unclear what you're asking. Can you try that again.

01:15:10 --> 01:15:44

Eliza Hunt: Yes, sorry. Yes, so if the positive effects either in your past studies and in your current study, I guess looking forward, are registered or if you're noticing or observing anything following the introduction of the external stimulus being nicotine, Is that dependent on that, or are there any lingering positive effects, such as, for example, if it would be introduced as a COVID therapy, or post-COVID therapy, would these patients be looking at having a nicotine ingestion for the rest of... I see what you're saying. Wanting to experience it, or could it be temporary?

01:15:45 --> 01:16:27

Dr. Paul Newhouse: So, I mean, that's a great question. Do you need to have nicotinic stimulation for a long period of time, and if so, how long? And these are, we really have no answers for this. I'm sad to say. The reality is that we are attempting to see if the effects are sustained after cessation of treatment, but those attempts to study that have not been well thought out yet, and so we actually just don't have data. And then with regard to the online question about other constituents of tobacco, we have not investigated that.

01:16:27 --> 01:16:55

Sud Patwardhan: Fair point. And look, I'm conscious that there is another session right in ten minutes, and to be fair to the next session, I don't want to take this any more further. But look, It's been great to get such deep, insightful presentation from you, Dr. Paul Newhouse, and great response by Dr. Konstantinos Fasanoulos. A round of applause for the two doctors here, please. I do hope to see that review article anytime soon. Thank you so much. Thank you.