Acetylcholine

Foreign. I'd like to welcome everybody today's presentation on acetylcholine functions and interactions. I'm your host, Dr. Donnelly Snipes. We're going to review the functions of acetylcholine, identify mood and behavioral disorders associated with acetylcholine imbalance, and explore interactions between acetylcholine and other neurotransmitters and hormones. Acetylcholine often doesn't get talked about. We talk about norepinephrine, serotonin, dopamine, those are the big ones. And gaba, those are the ones we mainly talk about in mental health circles. But acetylcholine is interacts with all of those. So it's important that we don't first forget that there are more seasonings in this soup than just the four main ones. So what does acetylcholine do? It stimulates skeletal muscles, smooth muscles, dilates blood vessels, can slow the heart rate, and increases body secretions. So, you know, that's kind of interesting. We'll find out in a little bit that it also can increase blood pressure. So it slows down, slows your heart rate, but it can increase blood pressure. So it's interesting. Depending on where in the body the receptors are and the type of receptors, acetylcholine may have slightly different functions. Now, acetylcholine has two main types of receptors, muscarinic and nicotinic. And we're not going to get down that deep into it today. But suffice it to say that acetylcholine is a very chameleon like neurotransmitter. Acetylcholine is essential for memory and learning, especially fear based memories. So when we learn something and we're afraid, acetylcholine is more present and will help consolidate that memory to remind us to be afraid in the future. That can work against us. It's also responsible or in part for attention. Now you remember hopefully, as we go through these, dopamine and norepinephrine are also essential for memory, learning, attention, cognition, motivation and arousal. So a lot of our neurotransmitters overlap, which again is why we can't just look at a particular symptom and say, oh, that person's dopamine is low, or that person's serotonin is low. So it's important to pay attention to some of those things. I don't want to get ahead of myself. I'll talk about that more later. Acetylcholine is also essential for prompting rapid eye movement. Sleep. The central nervous system undergoes several dynamic changes during sleep which are mediated by norepinephrine, serotonin and acetylcholine. And we need to have all of those present and in the right balance and at the right times in order to promote healthy, restful sleep. Sleep contributes to memory and brain plasticity and triggers overnight learning. So it is essential that we have that acetylcholine in there so we have that good quality sleep so we can consolidate what we've learned from the day and form those memories and contribute to blain brain plasticity. Interestingly, acetylcholine is also involved in immunity during infection. Immune derived acetylcholine that is actually created from some of your immune cells is necessary for the T cells to migrate to infected tissues. So if your acetylcholine is low, then it's, your body is going to have a harder time getting those T killer T cells to migrate to what, wherever the infection is. So that's a really interesting thing that we want to think about because we need those T cells to be able to fight off infection. And you can think about that in terms of, you know, an illness like a virus or a bacterial infection or even something like hiv, which obviously is also a virus. That and how it might impact the person if their acetylcholine levels are low and impact their body's ability to help them get healthy. In terms of mood and behavioral disorders, Alzheimer's patients have low acetylcholine levels. They have difficulty concentrating with memory, with attention, with um, and even with some movement sort of things. In Parkinson's, a lot of the acetylcholine deficits are seen in the problems with muscles with muscle contraction delirium. Now this is one of those that's more in our, our ballpark. Delirium can be caused by acetylcholine deficiency and dopamine excellence excess relative to each other. And I've made the analogy before about. And you can think soup, you can think, you know, some kind of sauce, anything that has a lot of spices in it. Okay. And if you don't have the spices in the right balance, you're not going to get the right effect. I'll give you the example. When I was young, my grandmother taught me how to, how to bake. And she taught me that salt and, and sugar potentiate each other. It creates a fuller flavor when you've got salt and sugar together. But you obviously want to have them in the right balance, otherwise you're going to have icky taste in Cookies. The same thing for lemon and vanilla. They potentiate each other. And it's important that you don't have too much of one or not enough of another in order to make sure that whatever you're baking tastes right. Same sort of thing for our neurotransmitters. Acetylcholine is also implicated in anxiety disorders when it is excessive compared to other neurotransmitters. So when it is way high, because it suppresses GABA and it tends to suppress serotonin. So when it's way high, then a lot of your excitatory neurotransmitters are way high. Acetylcholine, interestingly enough, is the second most, most abundant excitatory neurotransmitter that we have. Glutamate is the first. And when glutamate is inadequate or not functioning for some reason, acetylcholine will actually step up and become the primary excitatory neurotransmitter. So kind of bear that in mind. When we're thinking about acetylcholine. We need a little bit. Just like with cortisol, we need a little bit to give us energy and focus. Focus and, you know, keep everything functioning like it's supposed to. But too much can contribute to anxiety and irritability. Too little can contribute to apathy and anhedonia. Part of that is because of, you know, too much or too little of what acetylcholine does. But also part of that is because when you have too much or too little, it impacts the levels, the. The percept. Perceived levels of the other neurotransmitters. So your nicotinic acetylcholine receptor agonists. So these are medications that increase acetylcholine and increase the activity of the nicotinic receptors. Nicotine, nicotinic. You know, you see where we're going here, Interestingly, can improve mood and cognitive performance in people who are depressed. So people who are depressed may tend to have. May Tend to feel more flat, and that can contribute to feelings of depression, and that can be caused by not enough acetylcholine. Now, remember, and we'll talk in a little while, that too much acetylcholine can contribute to anxiety, which. Which ultimately can cause HPA, axis disregulation, and depression. So you don't want to assume that, oh, this person is flat. They need more acetylcholine. We just want to recognize that this could be one of the many different things that could be causing these symptoms. Nicotinic, acetylcholine receptor agonists regulate mood, anxiety and aggression related behavioral states. Now think about people that you've worked with before who are smokers or people who are smokers who are trying to quit and how that impacts their mood. When they are smoking. They are activating. Nicotine is a nicotinic acetylcholine receptor agonist. They are activating those receptors that helps improve their mood, improve their focus, improve those things. It helps improve mood to a certain extent. And there was one study that I read, and it's actually in your classroom, so you can go read the whole study that indicated that, that some nicotinic acetylcholine receptor agonists actually can be helpful in certain people with aggression related behavioral states. So if they tend to get, become very aggressive when they get anxious, um, interestingly, even though acetylcholine is excitatory, they have found that because if you stimulate the nicotinic acetylcholine receptors, it actually may help attenuate some of that aggression. So think again about smokers. My mother was a hardcore smoker for many, many years. And when she would get stressed out, one of the first things that she would do would be reach for a cigarette because it helped her feel calmer. So it met the addictive power of nicotine. Kind of makes sense. And they're starting to look at medications that activate those nicotinic receptors in order to help treat depression, anxiety and, and irritability. And you know, a few of them are out on the market right now and they may be an alternative. If you've got people who are depressed, clients you're working with who are depressed, who aren't responding to SSRIs, for example, that's generally what is thrown at them to begin with. Well, you know, maybe something else might be helpful there. There are all kinds of antidepressants out there. And one of them, just to stay on track, one of them is a nicotinic acetylcholine receptor agonist. Symptoms of excess acetylcholine can be increases in hypervigilance. Now this is something we want to pay attention to. When people have high levels of acetylcholine, they tend to notice things that they wouldn't normally notice. And it, so it increases their, increases their scanning, it increases their input, so to speak. And, and that hyper vigilance. So that's not necessarily a good thing. It increases fear learning like we talked about earlier. So if somebody does something and has a bad experience, it is really going to solidify that, unfortunately, because of the power of the solidification of the fear learning. It may also mean that that person will not want to try it again. So people with too much acetylcholine may be risk averse. It increases anxiety when it's in excess, when it's, when you're too stimulated, it increases anxiety. Interestingly, it interacts with your cannabinoid receptors, your CB1 receptors and promotes the munchies. It actually does contribute wanting to eat. It contributes to rumination and reduced psychological flexibility. That goes back to that amygdala and that fear based processing. You know, your brain is saying we need to focus on this fear thing so we, you know, aren't taken unawares. It can cause delirium, confusion, headache or drowsiness, increased body temperature and flushing. Think about what happens when you get anxious or when you have an adrenaline surge. What happens? Body temperature goes up, you start to flush, your blood pressure goes up, you're preparing for that fight or flight process and it increases the release of gastric acid. Gastric acid. And we've talked before about the importance of the gut brain access and how the health of our gut and the ph and the microbiome in our gut is communicates via the vagus nerve with the brain to let the brain know how healthy the organism is. And if there's a stressor or something going on. So as stress increases and gastric acid is released in the stomach, then that message is going to go up to the brain via the vagus nerve and tell the brain hey, there's some anxiety stuff going on here. There was an article that I read that is also in your, in your classroom. And basically it was a meta analysis of a lot of different studies on the impact of acetylcholine on mood. And the three categories that they looked at were, well, four if you want to count the controls. Unipolar depression, bipolar depression and bipolar mania. So when they administered acetylcholine esterase inhibitors to people with depression, now this is acetylcholine esterase and acetylcholine esterase is a chemical that breaks down acetylcholine. So if that is inhibited, then there's more acetylcholine available. So it increases acetylcholine levels. When they increased acetylcholine, it actually worsened depression in people who already had depression and it induced depression in people who weren't depressed to begin with. Interesting. Your muscarinic acetylcholine receptor agonists. So the substances that increase the activation of the muscarinic acetylcholine receptors also worsened depression and induced depression in controls who were under the influence of cannabis and induced depression in people with Alzheimer's disease. So remember we were talking just a minute ago about activating the nicotinic acetylcholine receptors improved mood. But activating the muscarinic acetylcholine receptors actually can worsen depression. This is, you don't need to know all these granular things for the test. I just want you to be fascinated by the flexibility of acetylcholine and how something, a neurochemical that we don't really talk about very often can have such significant impacts on mood and physiological health. When people were provided, given a substance that was an anti muscarinic, so it squashed, it inhibited the muscarinic receptors, it served as an antidepressant. So lo and behold, when you increase nicotinic receptors or reduce muscarinic receptors, you are creating an antidepressant effect in a lot of people. And nicotinic acetylcholine receptor agonists. So again, increasing nicotinic acetylcholine receptors was an antidepressant in non smokers. They didn't look at smokers. But theoretically people who were smoking were already getting the nicotine through their nicotine products. Bipolar depression, your acetylcholine esterase inhibitors increasing acetylcholine worsen depression in bipolar depression as well your acetylcholine receptor agonists. So the, the receptors for acetylcholine, if you want to like rev turbocharge those that also worsen depression. And your anti muscarinic were still antidepressant in nature, whether it was unipolar or bipolar depression. Now when we think about bipolar mania and it makes sense, your acetylcholine esterase inhibitors can reduce mania. Well, they worsen depression. So they tend to have a slowing effect on the person or a dampening effect. So it makes sense that those would also reduce mania. And your acetylcholine receptor agonists also reduced mania. So there are a lot of different ways that acetylcholine can impact mood. Remember, in our brain, your body has to make acetylcholine, it has to make the neurotransmitters. So there can be a breakdown there because the people don't have the building blocks they need. Then the body has to secrete the neurotransmitters. It has to, you know, get the signal and, you know, secrete them. There can be a breakdown in that transmission there. So not enough gets secreted. There can be a breakdown. Once the neurotransmitter is secreted, it may get broken down too quickly before it can be absorbed by the receptors on the other side. So that's a third area where you can have a breakdown in the system. It could get to the other side but not be able to be effectively transmitted down the line. So there are at least four places along the line where acetylcholine and other neurotransmitters can have a breakdown in the system. So we don't necessarily know where a per. Where the breakdown is in a person's system. So with your acetylcholine esterase inhibitors, those are the ones that go into the synapse and say, okay, we're not going to break this down. We're going to keep it just like your SSRI is. Basically, we're going to keep it in the synapse longer so it can function more effectively. We're not producing more, we're just making what's there available for longer. Your muscarinic and nicotinic acetylcholine receptor agonists went to the other side, and whatever was in that synaptic space, it turbocharged those receptors. So instead of just sopping them up like a sponge, it was like having a shop vacation, if you want to think about it that way. So these substances are working on different aspects of the neurotransmitter neurotransmission system. So I thought that was interesting in terms of physical issues and addiction. Cancer cell processes such as proliferation and appetite, topsis. I can never say that word right. Are mediated by overexpression of acetylcholine receptors in different kinds of tumors. So acetylcholine is involved in cancer, and we don't want to have over expression of those acetylcholine receptors because that means there's more receptors and that means it'll suck up even more acetylcholine and potentially can. Can worsen cancer. Fluctuations of acetylcholine might also have a causative role in epilepsy and catalepsy. It impacts people who are diabetic because insulin actually opposes acetylcholine. One interesting little test or side effect, I don't know what you want to call it. When people have diabetes, they tend to have a lot, a lot of thirst. One of the symptoms of diabetes is having excessive thirst. When people have excessive acetylcholine, they aren't thirsty at all. Acetylcholine actually suppresses thirst while insulin increases thirst. So that was kind of interesting addiction. Nicotine particularly acts through stimulating the nicotinic acetylcholine receptors, which increase dopamine concentration. Other drugs of abuse also act with acetylcholine to increase dopamine concentrations. And we know that dopamine somehow is involved in the addictive reinforcement process. Psychomotor deficits accompanying aging. You know, we slow as we get older, and hypoxia are attributed to alterations in the synthesis and release of dopamine and acetylcholine. So when people have extended hypoxia, they're deprived of oxygen, either because of a stroke or sleep, severe sleep apnea or something else horrific. It can contribute to changes psychomotor deficits henceforth. And this is thought to be because hypoxia can contribute to brain changes that may alter the way the body synthesizes and releases dopamine and acetylcholine. We also know that there are changes in brain functioning and behavior following the ingestion of particular foods or nutrients, which I thought to be really kind of cool. Increases in serotonin and acetylcholine synthesis can occur subsequent to nutritional intake of tryptophan, tyrosine and choline. Reductions in acetylcholine and increases in serotonin are seen with the ingestion of carbohydrate foods that can cause a spike in insulin. So if we have clients that are particularly sensitive to chemicals to foods that they ingest, they may be particularly sensitive to even normal foods that may cause a spike in blood sugar or intake of foods, or deficiency of foods that have the amino acids that are used to make the neurotransmitters that, you know, keep the body just humming along just fine. So it's interesting to note, which is why encouraging people to keep a food diary, a nutrition diary, whatever you want to call it, can be helpful because we can take a look and see if there are any commonalities or any trends. What's the word? I'm looking for common themes in what they're eating and their mood in order to get choline and tyrosine, which are needed to make acetylcholine. Animal based products, especially eggs and beef liver, are highest in choline. Now, you know, we have a lot of clients that are vegetarians or vegans, so they don't have animal based products in their diet. Okay, that's fine. You can also get choline through soybeans, red potatoes, kidney, lima and navy beans, broccoli, peanuts, wheat Germ. It's a lot of things. You just need to go online and do a search for foods that are highest in choline, for example. Now, the nice thing about dietary sources, as opposed to supplements or medications or things like that, is your body tends to take what it needs and excretes the rest. So if somebody is, you know, eating, for example, a lot of eggs, they are probably getting way more choline than they need. But generally their body is going to, you know, dispose of the unnecessary vitamins. That's not always true. I've read some articles where some people are particularly sensitive to foods that are high in choline, like egg yolks and beef liver. So they are advised from, against eating those sorts of things. But it's important for clients to just be intuitive in their eating and notice when they eat something, how does it make them feel? If it's neutral, great. If it's positive, fabulous. If it makes them feel antsy, anxious, sluggish, blah, you know, then take note of it and maybe eliminate that diet, that food, that particular food from their diet for a short period of time with the consultation with their physician. You know, obviously it's important that we don't step outside our bounds of confidence and make dietary prescriptions. But, you know, sometimes it can be a guessing game to figure out, you know, what exactly it is that might be contributing to some of their presenting symptoms. In terms of using acetylcholine agonists to treat addictions, I have not found a lot of information out there on it being used to treat addiction per se, with the exception of your nicotine replacement therapy medications and those few antidepressants out there which are also used in nicotine replacement therapy. So there's not a lot of them that are out there right now, but it certainly is an avenue that they are examining for future, for future study because it's addiction like depression and anything that goes on with a human is not a one size fits all. So that's a great question. So let's talk about interactions really quick. Serotonin interacts with acetylcholine 5ht, which is your serotonin, inhibits acetylcholine release from your cholinergic. Cholinergic. Cholinergic, sorry, neurons by acting on a pre synaptor receptor localized in cholinergic terminals, which is a whole lot of scientific speak for serotonin inhibits acetylcholine release, which is interesting to know. So they work, you know, sort of opposing each other. Well, let's think about that. And, and SSRIs have also been found to reduce acetylcholine activity in certain areas of the brain. Serotonin tends to be a neurochemical that's involved in modulation of our emotions. When we don't have enough serotonin, we tend to depressed. When we have too much serotonin, we actually can feel anxious. But it's interesting to note that acetylcholine being excitatory, is inhibited, is dampened by serotonin. So if you have someone who is depressed, then, you know, we want to consider where is that depression coming from. Obviously, acetylcholine doesn't impact itself. GABA is reduced as acetylcholine increases. Well, that totally makes sense. GABA is our main natural volume, our main, main natural calming neurochemical. Acetylcholine is one of our two main excitatory neurochemicals. So of course they're going to work in opposition. Unfortunately, that also helps us understand why acetylcholine can contribute to anxiety levels. As GABA goes down, acetylcholine goes up. Your endocannabinoids, your cannabis receptors, your natural cannabis receptors work with acetylcholine receptors in emotional learning and memory. Think of it like a, like a factory system or a machine. And they work. In order for those memories to be formed effectively, both the endocannabinoids and, and the acetylcholine receptors have to be functioning correctly. So they work as part of a team. Dopamine is increased when acetylcholine receptors are activated. Well, dopamine is our main motivation. Neurochemical. It helps us with attention, with focus, with perseveration, and not, not rumination, but persevering and keeping on doing what we're doing. So it makes sense that acetylcholine, which has a lot of those same characteristics, also increases dopamine. Now, some of the interesting things. Remember I said acetylcholine was involved in muscle contraction and helping us have those normal smooth muscle contractions without the tremors, without weakness, without, you know, tonic clonic anything. So dopamine and acetylcholine are increased together. Interestingly, acetylcholine and dopamine are low in people with restless leg syndrome and Parkinson's. And dopamine is high in people with schizophrenia. And they suspect that acetylcholine may also be high in people with schizophrenia. So as one goes up, we can assume that the other is likely going up as well. But a lot of times the targets for the medications for restless leg syndrome Parkinson's and schizophrenia have been the dopamine receptors almost to the exclusion of your acetylcholine receptors. So that is another avenue that they're looking at right now. Cortisol, our stress hormone, is stimulated by acetylcholine. Well, that makes sense. An excitatory neurotransmitter is going to be stimulated by our stress neurotransmitter. So totally makes sense. Adrenaline and acetylcholine are both excitatory substances and involved in energy creation. So when that HPA axis, our threat response system kicks off, cortisol is released, acetylcholine goes up, adrenaline is released in order to give us the energy. Dopamine's released to give us the energy and focus for that fight orf flight reaction. Acetylcholine increases T4 release. And this kind of happens backwards the way I would expect it to happen. But you know, whatever, it's how the scientists name it, named it. T4 is the thyroid hormone that's released, that is broken down and converted to T3, which is what we need in order to have normal thyroid functioning. But acetylcholine can increase T4 release and T3 inhibits acetylcholine. I didn't write that really clearly on the slide, but when you get enough T3, it's sort of a self regulating system. When there's not enough thyroid, then acetylcholine says, oh, we need more of this in the pipeline. And then when we get enough, when enough of it's broken down into T3, then the acetylcholine receptor says, say, hey, we've got enough T3 here so you can stop producing it. Kind of an interesting self regulatory system, but it's another reason that, or another potential cause for problems in the thyroid system. Now acetylcholine, I know you had probably had no idea. I had no idea either also impacts our gonadal hormones. So as our testosterone, estrogen, progesterone, DHEA are altering, so is our acetylcholine levels. So testosterone actually is antagonistic. As testosterone goes up, acetylcholine actually goes down, which I thought was really interesting because low testosterone is often associated with depression. But that obviously doesn't have anything to do with acetylcholine levels because low testosterone would be associated with. Well, I guess it could be. Low testosterone would be associated with high acetylcholine. And if you remember back here, get back to it. High acetylcholine increases depression. So testosterone, if testosterone is low, acetylcholine is high, which can contribute to depressive symptoms. DHEA does this weird little thing where it increases the release of acetylcholine, but then it dampens the receptors. It's like he wants a bunch of. A bunch of acetylcholine in this synapse, but then it doesn't have anywhere to go. So it doesn't really have a whole lot of impact, at least from the studies that I found. Progesterone does not directly inhibit acetylcholine, but it actually reduces acetylcholine receptor permeability. So it goes over to those receptors and it says, no, you know, you don't want to suck up that much acetylcholine. So it stops them from taking in as much of the acetylcholine from the synaptic space. An interesting little side note is that progesterone is a precursor to cortisol. So acetylcholine. Is increased in the system when, when progesterone is high. Now, estrogen also increases acetylcholine levels. So we know that when estrogen levels fluctuate, we tend to see some potential premenstrual dysphoric disorder. We tend to see some mood changes, especially in people who are especially sensitive to estrogen or people who are taking oral estrogen, either for, for. For whatever reason. And we know that estrogen increases acetylcholine and can be associated with depression, hyper vigilance, irritability. My point with the estrogen and the. One of my points with the, with the gonadal hormones is that, remember, as we age, our gonadal hormones go down generally, and that often contributes to a decline in cognitive functioning as well as a decline in energy levels. And we tend to slow a little bit more. Well, if you look back at some of the stuff we've talked about, part of that could be due to a decrease in acetylcholine caused by the. Or any. I'm sorry, an increase in acetylcholine caused by the reduction of the gonadal hormones. So it's kind of interesting to think about, you know, how is it, what is it that's going on with aging that makes us slow? And, you know, like I said, we do know that gonadal hormones reduce, are reduced as we age. So acetylcholine goes up. So depressive symptoms and slowing may also go up. Now, acetylcholine esterase is a, is the chemical that breaks down acetylcholine. And if you want to increase acetylcholine levels, then there are certain venoms that will do it, like black widow spider venom. Obviously, generally we don't want to do that. And, but glaucoma medications will increase acetylcholine levels. So that is important to know. If you've got a client who has glaucoma, coma and is having mood symptoms, we want to look at the impact that those medications are having and, you know, encourage them to advocate with their doctor to maybe address those issues. They may need to medicate the side effects because, you know, glaucoma. If you need the meds, you need the meds. But it is important to take a look at that in order to reduce choline. I'm sorry, acetylcholine levels. Kava, which is an over the counter supplement, may reduce acetylcholine levels and it helps us feel calmer. Clonidine, which is a common blood pressure medication. Dramamine, you know, we've all the, the motion sickness medication and drum roll, please. Benadryl, Diphenhydramine. Diphenhydramine is used in a lot of our over the counter sleep aids and it's important to recognize why this might be a problem. I said earlier that we need acetylcholine, norepinephrine when we sleep in order to solidify memories and contribute to brain plasticity. We need acetylcholine to contribute to or to promote REM sleep. When you take particularly diphenhydramine, it actually inhibits REM sleep and certain antidepressants also inhibit REM sleep, which can contribute to problems down the road because you're not getting all of those phases of sleep that we need. So that's an important thing. If you've got a client who habitually takes a sleep aid with diphenhydramine in it to sleep every night and they're having mood symptoms, that is something to encourage them to look at and talk with their doctor about alternate ways of helping them get better quality sleep other than the diphenhydramine. They've also found, and this is completely, well, not completely unrelated, that extensive use of diphenhydramine has been related not necessarily causatively, but has been correlated with the development of dementia later in life. Well, my guess would be, or I wouldn't be surprised to learn, that some of that has to do with the inhibition of acetylcholine, which is involved so intimately in our cognition. So if we're constantly altering that system, it may end up making permanent changes that can contribute to dementia later in life. So that's just kind of another one of those interesting little quirky things. This is another reason why it's important during an assessment to ask clients about all the medications they're taking as well as all the supplements they're taking. You can go to drugs.com and yeah, drugs.com and they have two different places on that website that I actually have got them bookmarked because I go to them so often. One place you can put in all the clients medications and over the counter supplements that they're taking and you just list them all in there and you can look for interactions. So it's the interaction checker. That's one great thing to do and to point out to clients because a lot of times they may be taking over the encounter supplements that they're not thinking about or they think are helping them in addition to prescription meds and they haven't told their doctor about it. So you can help them identify any potential interactions that they may need to be talking with their doctor about. You can also go to another place on their website and it's the side effect checker. And you can look at each different medication and over the counter supplement the person is taking and examine side effects that are common to that substance in order to see if something that they're taking may be contributing. For example, kava and valerian are commonly used over the counter as nutraceuticals for anxiety. However, there's a lot of research out there that has linked particularly valerian to increases in depression in people who, you know, have anxiety and depression. And then they take valerian. It tends to be too sedating. You know, obviously again, this is to point out things to clients to educate them so they can talk with their doctor about anything that involves nutrition or medication. But it also educates them about ways to learn more about their own health. Hey, I was right. I'm getting you guys out early. Good for me. Acetylcholine is not often talked about, but is a necessary excitatory neurotransmitter. It interacts with your gonadal hormones, your thyroid hormones and several other neurotransmitters. Acetylcholine itself, you know, most of the medications that are out there don't directly, directly act on it, with the exception of the ones that, like I said earlier, are the nicotine replacement medications. Some of those interact either directly or indirectly on acetylcholine. Choline is necessary to make acetylcholine. Tyrosine is an amino acid and it's necessary to make acetylcholine Too much acetylcholine contributes to anxiety and irritability, and too little can contribute to anhedonia. But we also know that that is not always the case. So with, as with anything with acetylcholine, it's a it depends sort of thing because when, remember when those muscarinic receptors are activated, it can increase depression. And when the nicotinic receptors are activated, it actually tends to improve mood. So it really depends on which receptors that we are monkeying around with. Now I know that was a lot of information and you know, it's probably not something you're going to use necessarily in day to day practice, but it is something that's certainly interesting to note that there are other things out there besides serotonin, for example, that contribute to depression, that contribute to anxiety, that contribute to cognitive dysfunction. There are a couple of articles now for the webinar. You don't have to read them, but there are a couple of articles in your classroom that talk about the impact of acetylcholine specifically on mood and behavior. So I thought those were interesting. They were ones that I referenced in the presentation. So I gave you the long form if you're really interested in doing a deep dive. Is there a relationship between acetylcholine and head injury? Well, my gut would be to say that acetylcholine is found throughout the body, so and it is found in the prefrontal cortex. And a lot of times those head injuries are do involve that prefrontal cortex. So I think the issue would be more about looking at what areas of the brain were injured because the prefrontal cortex has receptors for all of the neurotransmitters in there. And yes, acetylcholine receptors are in there for certain. But I think with head injury a lot of times it's more of a structural problem where areas where those receptors were are no more than an alteration in the acetylcholine signaling system. Does that make sense? I will look while we're while I'm waiting to see if anybody has any other questions. Okay, so obviously I haven't read this article. If you are still here, Mary, I'll send you a link to it. Pharmacological treatment of neurobehavioral Sequel following traumatic brain injury and that came up specifically. When I when I looked for acetylcholine and head injury. The side effects of head injury are driven by the disruption of key neurotransmitter homeostasis, including dopamine, norepinephrine, serotonin, and acetylcholine. So that would be really on point with what you're what with what you're saying. The neurostimulants are centrally acting medications that seek to restore neurotransmitter abnormalities and ameliorate the symptoms post traumatic brain injury. So that's probably a very interesting article. And here's one more I'm probably giving you more than you actually wanted, but. Previous studies have shown that traumatic brain injury reduces cholinergic neurotransmission and decreases the release of acetylcholine. So my earlier statement, my hypothesis would have been wrong. Apparently there is a disruption of the receptors a lot of times after traumatic brain injury. So those two articles should give you somewhere to start. And you can, I'm sure pubmed has a lot more in there if you want to, you know, do a deep dive into it.